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C.J.

Sylvester 212-713-1419 Jeffrey Chaffkin 212-713-2432 Stacy Parker, Dale Shivnarain Associate Analysts

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Industry Outlook

Pharmaceuticals

Health Care Group

Disease Dynamics: The Cancer Market


November 8, 2000

EQUITY RESEARCH

Significant Opportunities Remain

Disease Dynamics: The Cancer Market November 8, 2000

UBS Warburg LLC

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UBS Warburg LLC

Disease Dynamics: The Cancer Market November 8, 2000

Significant Opportunities Remain


There are several reasons for writing this report: Continued limited success with current cancer therapies. Tremendous R&D activity in this specific therapeutic market. Cancer is a clear beneficiary of the knowledge that is being developed out of the analysis of the human genome.

This report provides an in-depth review of current trends in the cancer market from three perspectives: scientific, medical/treatment and investment. The report culminates in an analysis of the various companies and their positions in this growing market. We have attempted to provide a review of the recent scientific advances on such topics as oncogenes, multidrug resistance and biologic therapies. Using a patient database of approximately 10,000 individuals, we have provided an analysis of the utilization trends in the U.S. cancer market, which provides detailed insight into what regimens are being used for the various types of cancer. We have also reviewed the most recent treatment literature and summarized current treatment trends for the major cancers in the United States.

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Disease Dynamics: The Cancer Market November 8, 2000

UBS Warburg LLC

Table of Contents
Introduction .................................................................................................................... 5
Cancer Overview ................................................................................................................. 8 Key Concepts: Cell Biology............................................................................................... 10 Key Concepts: Molecular Biology .................................................................................... 11 Key Concepts: Oncogenes................................................................................................. 15 Treatment .......................................................................................................................... 18 Key Concepts: Immunotherapy ....................................................................................... 27 Key Concepts: Drug Resistance ........................................................................................ 31 The Next Wave of Agents ................................................................................................. 33 How Cancer Is Staged ....................................................................................................... 37

The Individual Cancer Markets .............................................................................39


Introduction ...................................................................................................................... 40 Breast Cancer..................................................................................................................... 43 Lung Cancer ...................................................................................................................... 52 Colorectal Cancer.............................................................................................................. 60 Non-Hodgkins Lymphoma ............................................................................................. 63 Ovarian Cancer ................................................................................................................. 69 Bladder Cancer .................................................................................................................. 73 Pancreatic Cancer.............................................................................................................. 77 Prostate Cancer ................................................................................................................. 80

Company Cancer Portfolios ....................................................................................85


Introduction ...................................................................................................................... 86 Alza .................................................................................................................................... 86 American Home Products ................................................................................................ 88 Amgen................................................................................................................................ 89 AstraZeneca ....................................................................................................................... 90 Aventis ............................................................................................................................... 92 Bayer AG............................................................................................................................ 95 Bristol-Myers Squibb ........................................................................................................ 95 Eli Lilly ............................................................................................................................. 102 Genentech........................................................................................................................ 105 IDEC Pharmaceuticals .................................................................................................... 107 Merck & Co. .................................................................................................................... 108 Novartis ........................................................................................................................... 108 Pfizer ................................................................................................................................ 111 Pharmacia Corp. ............................................................................................................. 112 Roche ............................................................................................................................... 117 Schering-Plough.............................................................................................................. 118 SmithKline Beecham....................................................................................................... 122 Cancer Terms .............................................................................................................. 125
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Disease Dynamics: The Cancer Market November 8, 2000

Introduction
This report is designed to provide a detailed overview of the cancer market, which we believe remains one of the largest untapped disease markets in the world and which consequently presents a large opportunity for the pharmaceutical industry. In 1999, cancer and cancer-related therapies generated approximately $9.5 billion worldwide; this was up 29% over 1998. It is estimated that cancer results in health care expenditures of more than $110 billion annually worldwide.
Exhibit 1: Worldwide Major Oncology Drug Revenues
Dollars in millions

In 1999, cancer and cancer-related therapies generated approximately $9.5 billion worldwide; this was up 29% over 1998.

Oncology Market Revenues


(Worldwide Revenues in Millions)

Product Taxol Lupron Zoladex Paraplatin Aredia Nolvadex Taxotere Gemzar Sandostatin Casodex Intron A** Leuplin Camptosar Rituxan Ellence Herceptin Hycamtin Arimidex Platinol-AQ Furtulon Eulexin Proleukin Ethyol Fludara Campto Eloxatine Nilandron Oncoseed VePesid Ifex Femara Navelbine Leukine Bondronat Adriamycin PFS Leustatin

Class taxane GnRH analog GnRH analog alkylating agent bisphosphonate nonsteroidal antiestrogen taxane nucleoside analog somatostatin nonsteroidal antiestrogen interferon GnRH analog topoisomerase I inhibitor monoclonal antibody anthracycline antibody topoisomerase I inhibitor aromatase inhibitor platinum derivative antineoplastic nonsteroidal antiestrogen recombinant IL-2 cytoprotective antineoplastic topoisomerase I inhibitor platinum derivative antiandrogenic agent radionuclide antineoplastic antineoplastic aromatase inhibitor vinca alkaloid GCSF bisphosphonate anthracycline antineoplastic

Company Bristol-Myers Squibb TAP AstraZeneca Bristol-Myers Squibb Novartis AstraZeneca Aventis Eli Lilly Novartis AstraZeneca Schering-Plough Takeda Pharmacia Genentech/Idec Pharmacia Genentech SmithKline Beecham AstraZeneca Bristol-Myers Squibb Roche Schering-Plough Chiron Roche/ALZA Schering AG Aventis Sanofi Aventis Nycomed Bristol-Myers Squibb Bristol-Myers Squibb Novartis GlaxoWellcome Immunex Roche Pharmacia Johnson&Johnson

1998 1,206.0 750.0 624.8 525.0 390.9 523.7 380.4 306.8 310.9 243.6 620.0 271.0 193.7 162.6 177.3 N/A $ 117.7 $ 103.1 $ 132.0 $ 149.5 $ 171.0 $ 93.0 $ 35.0 N/A N/A N/A $ 45.5 N/A $ 84.0 N/A $ 103.1 $ 63.0 N/A $ 55.2 $ 67.0 $ 53.0 $ $ $ $ $ $ $ $ $ $ $ $ $ $ $

$ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $

1999 1,481.0 730.0 686.0 600.0 588.0 573.0 514.0 455.8 360.7 340.0 650.0 298.0 293.4 279.4 210.0 188.4 151.2 140.0 136.0 131.6 130.0 112.0 101.3 94.0 92.6 83.1 83.0 82.2 80.0 79.0 70.7 70.0 69.1 68.0 61.0 56.0

Growth 22.8% -2.7% 9.8% 14.3% 50.4% 9.4% 35.1% 48.6% 16.0% 39.6% 4.8% 10.0% 51.5% 71.8% 18.4% N/A 28.5% 35.7% 3.0% -11.9% -24.0% 20.4% 189.4% N/A N/A N/A 82.6% N/A -4.8% N/A -31.5% 11.1% N/A 23.3% -9.0% 5.7%

Total Cancer and Cancer-Related Therapies

$ 7,958.7

$ 10,138.5

27.4%

Source: MedAdNews. **Please note: Schering-Ploughs Intron A is used for oncology and hepatitis; approximately 50% of its sales are in cancerrelated indications; full-year revenue is reflective of all indications.

Disease Dynamics: The Cancer Market November 8, 2000

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We believe there are three key reasons why the cancer market could offer tremendous growth opportunities in the future. First, the macro trends clearly indicate growth. Through 2020, the older segments of the population, which are the segments most likely to develop cancer, will continue to expand to unprecedented levels (see Exhibit 2).
Exhibit 2: Worldwide Demographic Trends, 2000-20
120% 100% 80% Percent Change 60% 45-64 40% 20% 0% -20% -40% Age Group Total Europe Japan U.S. Totals 0-44 80+

64-79

Source: United Nations.

Second, we have seen a steady increase in the amount of research and development (R&D) activity associated with developing cancer therapies. Prior to the end of the 20th century, there were only a handful of companies with a presence in the oncology market. Now, it appears as though every major pharmaceutical company is vying for position in this potentially lucrative market. Fortunately, advances in molecular biology have furthered the understanding of the disease and cancer is no longer a black box. This increase in understanding has facilitated the drug development process and lowered the risk profile of cancer therapies. In a PhRMA annual survey from 1999, there were 354 drugs in development for cancer. This number was greater than the number of drugs in development for heart disease, stroke, AIDS, rheumatoid arthritis, diabetes and Alzheimers disease combined. Consequently, a majority of pharmaceutical companies are now looking to this market for future growth. Third, the margin for improvement over current therapies remains large. There continues to be a relative inadequacy of current cancer therapies when compared to other diseases. Current therapies, for the most part, have limited success with no real significant improvements in survival being seen in the past several years. Physicians continue to measure improvement in patient survival in months rather than years when looking at new therapies. Interestingly, it is estimated that the typical cancer drug works in 30-40% of the population. It remains unclear as to why one individual responds to a certain therapy while others with the same diagnosis do not. Additionally, current therapies are difficult to administer with minimal availability of oral agents (most

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Disease Dynamics: The Cancer Market November 8, 2000

current therapies require multi-hour infusion regimens) and the majority of agents having severe side-effect profiles. Additionally, there are some experts who believe that, in the future, cancer could possibly be treated in a similar fashion to HIV. Perhaps in the future patients would initially be treated to stop the spread of the disease and then take a certain therapy chronically in an effort to keep the disease at bay. Currently, patients cycle off and on cancer therapies in monthly shifts (e.g., a three-month chemotherapy cycle). In this new paradigm, once patients go into remission, they remain on therapy indefinitely. In the U.S., cancer is the second-leading cause of death behind cardiovascular disease. But it is likely, in the next few years, that cancer will become the number one cause of death. The reasons behind this appear to be twofold. First, deaths due to cardiovascular disease are decreasing because of more effective therapies resulting from a greater understanding of the molecular components involved in cardiovascular disease. Second, people are living longer; consequently, since cancer tends to be caused by an accumulation of genetic mutations, the longer individuals live, the greater the likelihood that they will develop cancer. However, the underlying molecular mechanisms of cancer are just being unearthed and the relative understanding of them is still developing. Currently, although unfortunate, mortality from cancer remains very high. The only curative therapies for cancer, surgery and radiation, are usually only effective if the disease is found early. For the most part, current chemotherapies are palliative in effect and rarely offer a long-term cure. Recently, most of the popular press has focused on the next wave of new medicines that will result from the entire human genome being known. Although we believe the actual completion of the Human Genome Project is somewhat of an arbitrary landmark with regard to drug discovery, it does highlight the large potential opportunity for the industry. Approximately 20 years ago, the first oncogene defects were discovered. Since that time, the number of drug targets has risen dramatically. But as the scientific understanding of cancer has grown, so, too, has the rate of discovery of drug targets. We believe we are at the early stages of drug development for cancer. For example, it took approximately 40 years to understand hypertension and to develop drugs such as the ACE inhibitors and the ARBs; consequently, the opportunities in cancer remain quite impressive, in our opinion.
In the U.S., cancer is the secondleading cause of death behind cardiovascular disease. But it is likely, in the next few years, that it may become the number one cause of death.

We are at the early stages of drug development for cancer. . . it took approximately 40 years to understand hypertension and to develop drugs to treat it. Consequently, the opportunities in cancer remain quite impressive.

Disease Dynamics: The Cancer Market November 8, 2000

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Cancer Overview
Statistics suggest that approximately 30% of Americans will develop cancer in their lifetime and roughly twothirds will die of the disease.

The term cancer is used to describe a group of diseases that are characterized by uncontrolled cell growth, cell differentiation and the spreading of cells throughout the body. Approximately 1.22 million new cancer cases are expected to be diagnosed in the U.S. this year. It is estimated that in the U.S., over 563,000 deaths can be attributed to cancer annually. That makes cancer the second-leading cause of death, behind heart disease. Current statistics suggest that approximately 30% of Americans will develop cancer in their lifetime and roughly two-thirds of these individuals will die from their disease. The following two charts indicate the historical relative incidence rates of various cancers in women and men, respectively.
Exhibit 3: Age-Adjusted Female Cancer Death Rates by Site
1979-1997
70,000

60,000

50,000

40,000

30,000

20,000

10,000

1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997

LUNG

BREAST

COLORECTAL

UTERINE

OVARIAN

PANCREAS

BLADDER

Source: CDC Mortality Data.

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Disease Dynamics: The Cancer Market November 8, 2000

Exhibit 4: Age-Adjusted Male Cancer Death Rates by Site


1979-1997
100,000 90,000 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997

LUNG PANCREAS

COLORECTAL LIVER

PROSTATE STOMACH

ESOPHAGUS

BLADDER

Source: CDC Mortality Data.

Cancer is caused by both environmental and genetic factors, which can sometimes work in concert to promote the disease. Factors such as inherited traits, hormones, viruses, chemicals or radiation can produce or stimulate cancer cells. In men, the most prevalent sites for cancer are the prostate gland and the lung; the most common sites in women are the breast and the lung. Virtually every tissue in the human body can spawn malignancies, with some tissues being able to produce several different types of cancer. A malignancy occurs after an accumulation of genetic mutations in a particular cell. Researchers are currently aware of a basic set of rules that governs the development of a malignancy. Cells of a tumor descend from a common ancestral cell that, at some point, usually decades before a tumor is detected, began a process of inappropriate cellular reproduction. It is likely that the malignant transformation of the particular cell came about through the accumulation of mutations in specific classes of genes within the cell. Current theories suggest that anywhere between five and 15 cumulative mutations are required to cause a malignancy. Although each cancer has a unique profile, the basic processes that produce tumors tend to be quite similar. Normally, cells divide to produce more cells only when the body needs them. However, if cells continue dividing when new cells are not needed, a mass of tissue forms. This mass of tissue is referred to as a tumor. Tumors can be divided into two categories, benign or malignant. Benign tumors are rarely lifethreatening and, in most cases, can be surgically removed without any future complications. Malignant tumors are cancer. Importantly, malignancies possess an insidious property, the ability to migrate from the site where they originated. Malignancies can invade and damage nearby tissues and organs. Often, cancer cells from a malignant tumor enter the bloodstream and cause tumors to develop in other regions of the body. This process is referred to as metastasis.

Malignancies possess an insidious property, the ability to migrate from the site where they originated. They can invade and damage nearby tissues and organs, through a process known as metastasis.

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Key Concepts: Cell Biology


The cell is the basic unit of all animals and plants. Cells are endowed with the unique ability to replicate and differentiate themselves, two qualities that are central to any discussion of cancer. They have clearly defined morphology (structure) and physiology (function). All cells have the potential to assume any morphology and to have any physiological characteristic through differentiation, a developmental process that results in structural and functional distinction between tissues. Cells differentiate from pluripotential (developmentally plastic) stem cells. Once differentiated into a particular type of cell, for example a liver cell, that cell has the ability to replicate itself through cellular division, producing more differentiated cells. To facilitate further discussion, we are providing a brief review of cell structure. The central core of the cell, the nucleus, houses the cells genome (its complete set of DNA) and is the primary site of cancerous development. Protein synthesis takes place in the endoplasmic reticulum and the Golgi apparatus found in the cytoplasm, while the mitochondria are the fuel-processing centers of the cell. Receptors are located on both the cell membrane and the nuclear membrane and are the site of interaction between the extracellular environment and the cell, as well as the means through which the genome and the cytoplasmic infrastructure communicate. The centrioles play an important role in cell division while the lysomes are acid-filled vesicles that are important to the destruction of cellular debris and the cell itself. Cancerous cells can be distinguished from normal cells through microscopic examination. Changes in the phenotype, or physical appearance and function, of a cell can help to determine its normalcy. In a tumor, for example, the cells will typically have a higher nucleus-to-cytoplasm ratio, prominent nucleoli and few specialized structures, all typical of actively dividing cells. In addition to changes in the degree of cell division, cancerous cells also exhibit alterations in their ability to produce certain types and amounts of proteins, including enzymes and hormones. Protein synthesis is an essential function of all cells. The process begins in the nucleus, where strands of DNA arranged into unique units called genes provide the template for all the proteins a cell produces. The genes themselves are arranged into series known as gene families, which, in turn, are arranged into chromosomes. The DNA strands of a given gene are transcribed into a special type of RNA called messenger RNA (mRNA) through a process known as transcription, signaling the beginning of protein synthesis, which takes place in the cell nucleus. There are several proteins and enzymes that facilitate this process, including RNA polymerase and transcription factors. Once the DNA is transcribed into RNA, the mRNA travels to the cytoplasm and inserts itself into the rough endoplasmic reticulum, where the second step in protein synthesis, a process known as translation, takes place. During translation, the code written in the language of ribonucleic acids is translated into the language of amino acids, which are the basic units of proteins. We discuss deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and amino acids (proteins) in greater detail below.

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Exhibit 5: The Cell

Source: MS Encarta Encyclopedia.

Key Concepts: Molecular Biology


To fully understand how cancer develops and how drugs combat cancer, it is necessary to understand some basic concepts in molecular biology and genetics. In each of our several trillion cells, there is a nucleus. This nucleus houses 23 pairs of chromosomes. Chromosomes are packets of compressed and entwined DNA. DNA is the famous double helix; conceptually, think of a ladder that is twisted. Each rung of the ladder is made up of a base pair. Notably, approximately 3 billion base pairs make up our entire genome (a genome is an organisms complete set of genetic information). The intrinsic elegance of our complexity is the simplicity of our genetic code. Specifically, there are only four types of bases in every piece of DNA. The bases are denoted by A adenine, C cytosine, G guanine and T thymine in every organism. Interestingly, the differences between the human genome and the mouse genome are relatively small. Furthermore, we share about 99.9% of our genome with chimps. Clearly, the variation between our species is due to a very small number of genes. A key to understanding how DNA is our genetic code lies in the simplicity of its design. These bases come in complementary pairs so that A always pairs with T and C always pairs with G.

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Exhibit 6: Gene Microstructure

Source: Primer on Molecular Genetics, DOE.

Therefore, conceptually, one side of the DNA ladder is the exact complement of the other. Consider, if we designate one side A and the other side A, strand A can serve as a template for making a new strand A, whereas A can serve to make a new strand of A. Therefore, genetic information can be copied through a method that separates A from A, and each separated strand then serves as a template for the production of a new complementary partner strand. Therefore, as a direct consequence of the base pairing, it becomes clear that DNA carries information by means of the linear sequence of the bases. Each nucleotide (a base attached to the sugar-phosphate backbone or rail of the ladder)A, C, T or G can each be considered a letter in a four-letter alphabet that is used to write out biological messages.

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Exhibit 7: The Process of DNA Replication

Source: DOE.

Although the principle of gene replication or reproduction is simple and elegant, the actual process is extremely complex and will not be discussed further in this report. Genes are made up of DNA. Importantly, in most cases, a single gene will encode for a specific protein, although in some instances, different genes can synthesize the same proteins. It is important to note that our bodies are composed of roughly 100,000 different types of proteins. Proteins are made up of building blocks called amino acids. There are 20 essential amino acids found in humans and these are linked up to form the various proteins that are in our body. The rules by which the nucleotide sequence of a gene is translated into the amino acid sequence of a protein, the genetic code, has been known for 40 years. The sequence of nucleotides in messenger RNA (mRNA), which acts as the intermediate between DNA and protein, was found to be read in a serial order in groups of three (see Exhibit 8). Each triplet (or codon) specifies one amino acid. Theoretically, there are 64 (43) possible amino acids. The following exhibit illustrates this concept. The unbolded items refer to abbreviations for amino acids. For instance, if your three base pairs are CTT, then the amino acid produced would be leucine. Interestingly, if the three bases are TAA, TAG or TGA, no amino acid is produced; these three codons, known as stop codons, specify the termination of the protein chain that is being produced.

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Exhibit 8: The Genetic Code for Proteins

T T Phe
Phe Leu

SECOND BASE C A G
Ser Ser Ser Ser Pro Pro Pro Pro Thr Thr Thr Thr Ala Ala Ala Ala Tyr Tyr STOP STOP His His Gln Gln Asn Asn Lys Lys Asp Asp Glu Glu Cys Cys STOP Trp Arg Arg Arg Arg Ser Ser Arg Arg Gly Gly Gly Gly

F I R S T B A S E

Leu

C Leu
Leu Leu Leu

A Ile
Ile Ile Met

G Val
Val Val Val

T C A G T C A G T C A G T C A G

T H I R D B A S E

Source: UBS Warburg LLC.

A gene specifies a sequence of amino acids that must be linked to make a particular protein. It is this protein that will carry out the work of the gene. Proteins are responsible for everything your body does.

To review, a gene is the blueprint for an inherited trait. A gene specifies a sequence of amino acids that must be linked together to make a particular protein. It is this protein that will carry out the work of the gene. When a gene is properly stimulated, the cell usually responds by synthesizing the specific protein. Proteins are responsible for everything your body does, and can even regulate when genes are turned on or turned off. Consequently, malfunctioning genes are intrinsically involved in most diseases. When a gene is active or expressed, the sequence of bases in its DNA is used as a blueprint to produce a specific protein. Knowing which genes are expressed in healthy and diseased tissues allows the identification of proteins required for normal functioning of the body and the identification of genes that may cause disease.

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Key Concepts: Oncogenes


Over the past 15 years, a considerable amount of attention has been given to the particular genes that control cell proliferation and cell death. It is thought that a disruption or mutation in these genes could be one of the underlying causes of cancer. Some mutations may occur in cells of the reproductive organs, which may explain the high incidence of cancer in some families. Other mutations may be due to exposure to environmental carcinogens or viruses. However, for cancer to occur, it must be the result of more than one mutation in the DNA that make up a gene. As mentioned previously, it appears that several distinct changes in a gene or gene family are necessary for full expression of a cancer cell. Research involving cancer and DNA has focused on two elements of the human genome: the oncogenes and the tumor suppressor genes. Proto-oncogenes are normally occurring genes that are the progenitors of oncogenes. They become oncogenic through mutations or level of expression. Some oncoproteins are mutant forms of the regular proteins, while others are the same as the normal protein but may be expressed when they should not be or may be expressed at an abnormal level. The protooncogene and oncogene are identified by an italicized, three-letter code, such as src (v-src indicates a viral oncogene while c-src would indicate a cellular oncogene). The oncoprotein is designated by the same three-letter code with the first letter capitalized and without the italics (e.g., Src.) Tumor suppressor genes are also prevalent in every cell and act to control normal cell proliferation. Oncogenes and tumor suppressor genes have five general categories of gene products, including: growth factors; receptors, both cell surface and intracellular; intracellular transducers, including proteintyrosine kinases; nuclear transcription factors; and cell-cycle control proteins, such as p53, which fall into the tumor suppressor category. In general, oncogenes encourage cell growth, whereas tumor suppressor genes inhibit it. It appears as though a disruption between the activity of oncogenes and the inactivity of tumor suppressor genes is a crucial factor in carcinogenesis. Approximately 20 proto-oncogenes have been identified and their protein products are located throughout the cell. Examples of these products include tyrosine kinases and growth factors; in the following tables, we identify genes that are currently associated with various cancers.

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Exhibit 9: Oncogenes
ONCOGENES Genes for growth factors or their receptors v-sis/PDGF erb-B erb-B2 (HER-2 or neu) RET K-ras N-ras c-myc N-myc L-myc Bcl-2 Bcl-1 (PRAD1) MDM2 Codes for platelet-derived growth factor. Involved in brain cancer Codes for the receptor for epidermal growth factor. Involved in brain and breast cancer Codes for a growth factor receptor. Involved in breast, ovarian and salivary gland cancers Codes for a growth factor receptor. Involved in thyroid cancer Genes for stimulatory signals Involved in lung, ovarian, colon and pancreatic cancers Involved in leukemias Genes for transcription factors that activate growth-promoting genes Involved in leukemias and breast, stomach and lung cancers Involved in brain and nerve cell cancers Involved in lung cancer Genes for other kinds of compounds Codes for a protein that normally blocks cell suicide. Involved in follicular B cell lymphoma Codes for cyclin D1, a stimulatory component of the cell's clock. Involved in breast, head and neck cancers Codes for the antagonist of the p53 tumor suppressor protein. Involved in connective tissue cancers

Source: Scientific American.

Exhibit 10: Tumor Suppressor Genes


TUMOR SUPPRESSOR GENES Genes for proteins in the cytoplasm Involved in colon and stomach cancers Codes for a relay molecule in a signaling pathway that inhibits cell division. Involved in pancreatic cancer Codes for a protein that inhibits a stimulatory (Ras) protein. Involved in myeloid leukemia Involved in brain cancer and other cancers of the nervous system Genes for proteins in the cell nucleus Codes for p16 protein, a braking mechanism in the cell cycle clock. Involved in numerous cancers Codes for the pRB protein, a master brake of the cell cycle clock. Involved in retinoblastoma and bone, bladder, small cell lung and breast cancer Codes for the p53 protein which can halt cell division and induce abnormal cells to commit suicide. Involved in a wide range of cancers Genes for proteins whose cellular location is unclear Involved in breast and ovarian cancers Involved in breast cancer Involved in kidney cancer

APC DPC4 NF-1 NF-2 MTS1 RB p53

BRCA1 BRCA2 VHL

Source: Scientific American.

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Possibilities for Gene Therapy?


Abnormalities in the p53 tumor suppressor gene are prevalent in a wide variety of tumors; its restoration could perhaps be used as a cancer therapy. Two companies are involved in the development of p53 gene therapy, Schering-Plough and Aventis. Schering is currently in Phase II and earlier studies with its p53 tumor suppressor gene therapy for treating various solid tumors. Schering has a number of agreements that continue to advance this therapeutic platform. Currently, Schering has a collaboration with Gene Logic, Inc. to help identify patients with a missing or defective p53 gene in their tumors. Aventis, in collaboration with Introgen, is also developing cancer gene therapies. Its lead product, INGN 201, combines the p53 gene with a gene delivery system the company has developed. The gene delivery system uses a modified adenovirus, a common cold virus, to deliver the p53 gene to cancer cells. The two companies have commenced Phase III trials in head and neck cancers. Phase II trials are ongoing in non-small-cell lung cancer. In Phase II trials, 112 patients with either recurrent or refractory head and neck cancer were treated with INGN 201. A preliminary analysis showed that when investigators administered INGN 201 locally, tumors shrank or stopped growing in 25% of patients treated. During the first half of 2000, gene therapy received a great deal of scrutiny due to some adverse events and the death of a young man enrolled in a University of Pennsylvania study. However, now that additional safeguards have been established and implemented, it appears as though gene therapy is beginning to gain momentum. On April 28, reports of the first unequivocal success for gene therapy were issued. Several infants, who likely would otherwise have died of a severe immune disorder known as severe combined immune deficiency (SCID), were treated effectively with gene therapy to repair a genetic flaw in their immune systems. The gene therapy was effective at ten months when the story was reported. This experiment marked a tremendous step forward for the gene therapy community because this was the first real instance where diseased children were effectively cured of disease.

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Treatment
Aggressive initial combinedmodality treatments are increasing the likelihood of a potential cure and increasing survival times.

The evolution of cancer treatment modalities remains very dynamic. The roles of surgery, radiation and chemotherapy tend to be specific for each type of cancer and even more specific for the individual patient. Cancer treatment and therapy often involve two forms of treatment; one form is intended to eliminate the tumor itself and any further spread (i.e., chemotherapy); the second form is intended to make the patient more durable to future therapies (i.e., blood factor stimulants). Aggressive initial combined-modality treatments increase the likelihood of a potential cure and increase survival times. Importantly, it is necessary to consider the aggressiveness of the treatment and its associated toxicity, mortality and the cost/benefit relationship of the treatment. There is a current emphasis on using chemotherapy as an adjuvant to surgery or radiation therapy, but this type of treatment must be properly sequenced because certain toxicities are associated with improper sequencing of agents.

Surgery
Surgery continues to play the key role in oncology. Surgery is needed for biopsies and is usually the definitive treatment for most individuals with cancer. However, since its relative importance to pharmaceutical companies is minimal, we will not go into further detail on cancer surgery in this report.

Radiation
Radiation plays an integral role in both the primary and the palliative treatment of cancer. There are currently two types of radiation therapies: 1) electromagnetic radiation such as X-rays, and 2) subatomic particle radiation, which consists of alpha particles, electrons, protons, etc. X-rays are most commonly used to treat malignant tumors; however, gamma rays, which are similar to X-rays, except that they are emitted by radioactive isotopes of radium or cobalt, are also used. Radiation therapy damages cells by transferring energy to tissues in the form of photons. Photons damage both malignant and healthy tissues by producing ionization within cells. The toxicities associated with radiation therapy can be divided into two groups, early and late radiation effects. Early radiation effects are often referred to as acute toxicity and include erythema (redness of the skin), desquamation (peeling of the skin in scales), nausea, alopecia (baldness) and bone marrow suppression. The late radiation effects usually determine the limiting toxicity of the therapy and include tissue necrosis (death) and tissue fibrosis. Advances in imaging such as CT scanning have improved the radiation oncologists ability to visualize tumors and limit the impact of the radiation on surrounding healthy tissues. Additionally, advances in areas such as photodynamic therapy, which employs a systemically delivered tissue sensitizer, have been used to treat malignancies involving the skin, esophagus, bladder and brain.

Chemotherapy
Chemotherapy is the use of chemical agents to destroy malignant tissue. Over the years, clinical trials have indicated that chemotherapeutic agents used in combination produce higher rates of objective responses and longer survival rates when compared
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to single agents used alone. To understand the impact and efficacy of chemotherapy, it is necessary to understand the cell life cycle. Cells reproduce by duplicating their contents and then dividing into two; this is commonly referred to as the cell division cycle. Many rounds of cellular division are required to create a new individual, but cell division is required in the adult body as well, to replace cells that are lost by wear and tear or through apoptosis (programmed cell death). There are four divisions in the cell cycle, which are depicted in the diagram below (S, G2, M and G1). DNA is replicated during the S phase. The cell cycle usually lasts between 24 and 48 hours in normal human cells; however, in malignant cells, the cell cycle can be as long as 120 hours, but these cycle times are not fixed. They can be increased or decreased depending on a variety of factors. Although it is poorly understood, the growth rate of tumors decreases as the tumor increases in size. Two factors appear to account for this, a decrease in the fraction of tumor cells that are dividing and an increase in the rate of apoptosis (or cell death). As cells accumulate, whether it be in normal or cancerous tissue, there is a decrease in the frequency with which they initiate new rounds of DNA synthesis and thereby produce new cells.
Exhibit 11: Interactions of Chemotherapeutic Agents in the Cell Cycle
Antibiotics Antimetabolites S (2-6h)

G2 (2-32h) M (0.5-2h)

Vinca alkaloids

Mitotic inhibitors Taxoids

Alkylating agents

G1 (2-?h)

G0
Source: UBS Warburg LLC.

Ideally, cancer treatment should be performed on a tumor whose cells are rapidly dividing or cycling. Tumors with a high mitotic rate are thought to be more responsive to chemotherapy than those with a smaller fraction of dividing cells. Therefore, the strategy behind cancer therapy is to get noncycling cells to begin to cycle again. This is achieved by using a combination of initial surgery to reduce the tumors size, followed by chemotherapy. By reducing the tumors size, surgery effectively gets a greater portion of cells cycling again. After the primary tumor is removed, microscopic metastases may remain at distant sites, but because of their small size, they are by definition composed primarily of cycling cells.

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Nearly all chemotherapeutic agents interfere with DNA synthesis, with precursors of DNA or with mitosis. In general, chemotherapeutic agents that induce DNA damage are administered by short-term infusions. Nucleotide analogs (nucleotide analogs resemble the building blocks of DNA) such as antimetabolites are only thought to be effective during S phase and, consequently, are given by continuous infusion to maximize the potential exposure of cycling tumor cells. However, many agents, particularly the alkylating agents (more on the different classes of agents below) can kill cells that are not cycling and are therefore sometimes referred to as non-cell proliferationdependent drugs. Drug classes like the antimetabolites and antibiotics are termed cell proliferation-dependent drugs because they are most active in cells during S phase. Finally, several factors are considered when developing a chemotherapeutic regimen, including combinations of drugs based on pharmacological properties, drug sensitivity of the tumor, and any overlapping toxicities.

Classes of Chemotherapeutic Agents


Alkylating Agents
Alkylating agents were the first anticancer drugs ever used and are descendants of mustard gas. As stated previously, alkylating agents are non-cell-proliferating dependent, and are therefore generally more effective against slow-growing tumors. The alkylating agents are typically divided into six classes: nitrogen mustards, ethylenimines, alkyl alkone sulfonates, nitrosureas, platinum-containing compounds and nonclassical alkylators. The major toxicity common to all of these agents is myelosuppression or bone marrow suppression. Additionally, alkylating agents often cause gastrointestinal upset; however, these effects may be offset by prescribing the appropriate anti-emetic agents. One of the more widely used classes of alkylating agents, and the one that is of the greatest investment significance, is the platinum-based class of agents. Bristol is clearly the dominant player with Platinol (cisplatin) and its second-generation compound Paraplatin (carboplatin). Together, these compounds generated close to $500 million in U.S. sales in 1999, according to IMS. Notably, Eli Lilly and Sanofi attempted to get their platinum-based agent Eloxatine (oxaliplatin) approved in the U.S. for colorectal cancer; however, the Food and Drug Administration (FDA) advisory committee did not believe that the Phase III trial data were sufficient to warrant an approval. In midOctober, Eli Lilly returned its oxaliplatin rights to Sanofi and the companies dissolved their joint venture. Sanofi is currently conducting two Phase III trials for the drug in the second-line treatment of metastatic colorectal cancer. The following table illustrates some of the most common alkylating agents used today.

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Exhibit 12: Commonly Used Alkylating Agents

Alkylating Agents
Brand Name Biscloroethylamines Leukeran Chlorambucil GlaxoWellcome CLL, Hodgkin's lymphoma and NonHodgkin's lymphoma breast, ovarian, CML, ALL, lymphomas testicular Lung, CLL, CML, Hodgkin's lymphoma ovarian, multiple myeloma bladder, breast, Hodgkin's lymphoma, nonHodgkin's lymphoma Oral $8 million Generic Name Company Approved Indication Admin 1999 U.S. Revenues

Cytoxan

Cyclophosphamide Bristol-Myers

Oral, IV

$33 million

Ifex Mustargen

Ifosamide Mechlorethamine

Bristol-Myers Merck

IV IV

$80 million $1 million

Alkeran Aziridines Thioplex

Melphalan

GlaxoWellcome

Oral, IV

$13 million

Thiotepa

Immunex

IV, IM

$32 million

Alkyl alkone sulfonates Myleran BiCNU Busulfan Carmustine GlaxoWellcome Bristol-Myers CML Oral Hodgkin's IV lymphoma, nonHodgkin's lymphoma, multiple myeloma, primary brain Oral Hodgkin's lymphoma, primary and metastatic brain pancreatic IA, IV Hodgkin's lymphoma, metastatic melanoma " " Hodgkin's lymphoma brain ovarian bladder, ovarian, testicular " " colorectal IV $2 million $5 million

CeeNu

Lomustine

Bristol-Myers

$1 million

Zanosar Nonclassic agents DTIC-Dome

Streptozocin Dacarbazine

Pharmacia Bayer

$1 million $5 million

Generics Matulane
Temodar Platinum based agents Paraplatin Platinol

Dacarbazine Procarbazine
Temozolomide Carboplatin Cisplatin

Various Roche
Schering-Plough Bristol-Myers Bristol-Myers

IV IV
Oral IV IV, IA

$4 million $1 million
Launched 2000 $396 million $103 million

Generics Eloxatine

Cisplatin Oxaliplatin

Various Sanofi

IV,IA IV

$1 million N/A

Source: UBS Warburg LLC, IMS America.

Antibiotics
The antibiotics are a large, diverse class of drugs that are grouped together solely based on their origin. They are effective against a variety of tumor types. The major class of drugs in this group is the anthracyclines, which include doxorubicin, daunorubicin, epirubicin, idarubicin and mitoxantrone. The anthracyclines are thought to interfere with the replication of DNA. When DNA replicates, the double helix must be pulled apart into two strands. A specific enzyme helps with this process. That enzyme is known as topoisomerase. Antibiotics interfere with the action of DNA topoisomerase II, resulting in DNA strand breaks. During cell division, the levels of topoisomerase II rise rapidly and the cell becomes more vulnerable to some of these agents. In the following table, we highlight some of the more common antibiotic agents used today.

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Exhibit 13: Commonly Used Antibiotic Agents

Antibiotic Agents
Brand Name Adriamycin Generic Name Doxorubicin Company Pharmacia Approved Indication ALL, AML, Wilm's, neuroblastoma, soft tissue, bone, breast, ovarian, bladder, thyroid, stomach, Hodgkin's " " cervix, head&neck, larynx, penis, skin, testicular, Hodgkin's and non-Hodgkin's testicular, Ewing's, Wilm's, rhabdomyosarcoma ALL, AML, acute monocytic leukemia Kaposi's sarcoma Kaposi's sarcoma AML, ALL Admin IV 1999 U.S. Revenues $15 million

Generics Blenoxane

Doxorubicin Bleomycin

Various Bristol-Myers

IV IM, subQ, IV
IV

$26 million $25 million

Cosmegen

Dactinomycin

Merck

>$1 million

Cerubidine DaunoXome Doxil Idamycin Mutamycin Generics Novantrone

Daunorubicin Daunorubicin (liposomal) Doxorubicin Idarubicin Mitomycin C Mitomycin C Mitoxantrone

Bedford Labs Gilead Alza Pharmacia Bristol-Myers Various Immunex

IV IV IV IV

$10 million $2 million $50 million $27 million $12 million $3 million $55 million

stomach, pancreatic IV " " IV leukemias IV

Source: UBS Warburg LLC, IMS America.

Antimetabolites
The antimetabolites are a large group of drugs that interfere with metabolic processes vital to the physiology and proliferation of cancer cells. The mechanism of action varies between the types of drugs, but in general, they prevent the synthesis of nucleotides or inhibit enzymes by mimicking nucleotides. These drugs have been used since 1948 in the treatment of cancer. For instance, some antimetabolites are purine or pyrimidine analogs (recall the four bases that compose DNA: A and G are purines, T and C are pyrimidines). These analogs are sometimes modified into nucleotides, at which point, they are incorporated into DNA and RNA, where they inhibit enzymes or result in faulty transcription or translation. Due to the suppression of cellular division and proliferation that is caused by antimetabolite therapies, many tissues that are actively dividing (i.e., in the bone marrow or the gastrointestinal tract) will experience toxicity. Consequently, patients taking these types of therapies will experience bone marrow suppression, dry mouth, diarrhea and hair loss. Importantly, the pattern and severity of treatment toxicities vary greatly depending on the drug administered and the schedule of administration, among other factors. Eli Lilly has one of the newest entrants to the market in this class of agents with Gemzar (gemcitabine), which is indicated for the treatment of non-small-cell lung cancer and pancreatic cancer. Gemzar had approximately $450 million in worldwide sales during 1999 and is currently the key product in Lillys oncology franchise. The newest entrant into this market is Roches oral agent Xeloda (capecitabine). Xeloda received FDA approval for the treatment of metastatic breast cancer in August 1998. This is an oral pro-drug of 5-FU. It is converted to 5-FU in three enzymatic steps. Interestingly, prior to 1999, oral anti-cancer agents were not covered by Medicare, but the Health Care Financing Administration (HFCA) has since issued guidelines indicating that oral pro-drugs are to be covered by Medicare.
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Another potential new antimetabolite is Bristol-Myerss Orzel, which is still awaiting FDA approval. This drug is an oral formulation of UFT capsules and leucovorin. UFT, which Bristol in-licensed from Japans Taiho Pharmaceuticals in 1995, combines the 5-FU pro-drug tegafur with uracil. Uracil is an enzyme inhibitor that increases the half-life of 5-FU. On March 17, Bristol withdrew its new drug application (NDA) for the drug after receiving a favorable review from an FDA advisory committee. On April 20, the company resubmitted its NDA, apparently to allow the FDA time to review additional analyses, particularly on the role of uracil in the combination. In the following table, we highlight some of the more common antimetabolic agents used today.
Exhibit 14: Commonly Used Antimetabolic Agents

Antimetabolic Agents
Brand Name Generics Generic Name 5-Fluorouracil Company Various Approved Indication breast, colon, rectum, stomach, pancreas, skin ALL, AML, CLL ALL CLL pancreas, lung head & neck, ovarian, CML, malignant melanoma 1999 U.S. Admin Revenues IV, IA $1 million

Generics
Elspar Fludara Gemzar Hydrea

Cytarabine Asparaginase Fludarabine Gemcitabine Hydroxyurea

Various Merck Berlex Eli Lilly Bristol-Myers

subQ, IV IM, IV IV IV Oral

$6 million $4 million $49 million $230 million $9 million

Generics

Hydroxyurea

Various

Generics

Leucovorin

Various

Leustatin Generics

Cladribine Methotrexate

Johnson & Johnson Various

Nipent Purinethol Orzel Tabloid Xeloda

Pentostatin

SuperGen

Mercaptopurine GlaxoWellcome UFT and leucovorin Bristol-Myers Thiguanine GlaxoWellcome Capecitabine Roche

Oral head & neck, ovarian, CML, malignant melanoma antidote for folic acid Oral, antagonists, IM, IV megaloblastic anemia hairy cell leukemia IV leukemias, breast, Oral, head, neck, lung, IM, IV Burkitt's lyphoma, lymphosarcoma, nonmetastatic osteosarcoma refractory hairy cell IV leukemia AML, ALL Oral colorectal Oral AML Oral metastatic refractory breast Oral

$15 million

$40 million

$12 million $56 million*

$2 million $40 million Filed $2 million $15 million

Source: UBS Warburg LLC, IMS America.

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Plant-Derived Agents
For more than 200 years, compounds derived from plants have been used to treat cancer. The oldest such agent is colchicine, which was capable of stopping cell division. During the 1950s, the vinca alkaloids, vincristine and vinblastine, were discovered and to this day remain relatively widely used. Bristols Taxol (paclitaxel) and Aventiss Taxotere (docetaxel) are two of the newer plant-derived compounds and belong to a new class of agents referred to as taxanes. The epipodophyllotoxins, including Bristols VePesid (etoposide) and Vumon (teniposide), are semisynthetic compounds derived from plants. The final group of plant-derived agents are derivatives of camptothecin (CPT) and consist of Pharmacias Camptosar (irinotecan) and GlaxoSmithKlines Hycamtin (topotecan). The taxanes and vinca alkaloids are relatively unique among anticancer agents, in that they do not target DNA. The vinca alkaloids disrupt cell division by binding to structural cellular proteins called tubulin. Tubulin is the building block of microtubules, which are critical in orchestrating proper cell division. Microtubules are responsible for pulling the chromosomes to either side of the parent cell, ensuring that each daughter cell receives a full set of genes. The taxanes exert their effects by altering the dynamics of the microtubules. Importantly, since these compounds disrupt cellular division, they are cell-cycle dependent and are only effective when cells are dividing. The majority of drugs that are of investment significance are the more recently launched products, such as Bristols Taxol, SBs Hycamtin, Pharmacias Camptosar and Aventiss Taxotere. In the following table, we highlight some of the more common plant-derived agents used today.
Exhibit 15: Commonly Used Plant-Derived Agents

Plant-Derived Agents
Brand Name Camptosar Hycamtin Navelbine Oncovin Generic Name Irinotecan Topotecan Vinorelbine Vincristine Company Pharmacia SmithKline Beecham GlaxoWellcome Eli Lilly Approved Indication colorectal ovarian non-small cell lung ALL, Hodgkin's lymphoma, nonHodgkin's lymphoma, neuroblastoma, Wilm's, rhabdomyosarcoma "" ovarian, breast, nonsmall cell lung, KS breast breast, testicular, non-Hodgkin's lymphoma, Hodgkin's lymphoma, KS "" refractory testicular, small cell lung Admin IV IV IV, oral IV 1999 U.S. Revenues $248 million $90 million $62 million $1 million

Generic Taxol
Taxotere Velban

Vincristine Paclitaxel
Docetaxel Vinblastine

Various Bristol-Myers
Aventis Eli Lilly

IV IV
IV IV

$1 million $830 million


$140 million >$1 million

Generic VePesid Generic


Vumon

Vinblastine Etoposide Etoposide


Teniposide

Various Bristol-Myers Various


Bristol-Myers

IV $1 million Oral, IV $36 million Oral, IV $13 million

"" ALL

IV

$1 million

Source: UBS Warburg LLC, IMS America.

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Biological Agents
Another, more recently developed treatment modality for cancer uses biological agents to elicit tumor regression. The various therapies used include recombinant cytokines, such as IL-2 and interferon-alpha. Additionally, IL-4 and IL-12 are also being evaluated. Furthermore, recently approved monoclonal antibodies, such as Genentechs Herceptin and IDECs Rituxan, have recently gotten recognition as viable and effective therapies. In the following table, we highlight a few of the more common biological agents used in chemotherapy.
Exhibit 16: Common Biological Agents

Biologic Agents
Brand Name Herceptin Generic Name Trastuzumab Company Genentech Approved Indication HER2 overexpressing breast leukemia, Kaposi's sarcoma non-Hodgkin's lymphoma low-grade refractory non-Hodgkin's CD20 positive B-cell lymphoma leukemia, Kaposi's sarcoma 1999 U.S. Admin Revenues IV $123 million

Intron-A Ontak Rituxan

Interferon alpha Denileukin diftitox Rituximab

Schering-Plough Ligand IDEC Pharmaceuticals

IV IV IV

$156 million >$1 million $227 million

Roferon-A

Interferon alpha

Roche

IV

$18 million

Source: UBS Warburg LLC, IMS America.

Hormonal Agents
In many organs and cell types, hormones can stimulate cell division and growth. Consequently, some hormonal agents are effective at reducing or eliminating tumor cell growth in a specific tissue type. Most hormonal agents work as agonists to inhibit tumor growth or as antagonists that compete with endogenous hormones that promote growth. TAPs Leupron (leuprolide) and AstraZenecas Zoladex (goserelin) are effective in the treatment of prostate cancer because both therapies inhibit production of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which promote prostate cancer cell growth. In the following table, we highlight some of the more common hormonal agents used today.

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Exhibit 17: Commonly Used Hormonal Agents

Hormonal Agents
Brand Name Arimidex Generic Name Anastrozole Company AstraZeneca Approved Indication Advanced breast in postmenopausal women with disease progression following tamoxifen Stage D2 metastatic prostate Adrenal carcinoma, ectopic ACTH producing tumors Prostate Metastatic breast in postmenopausal women with estrogen receptor pos. or unknown tumors 1999 U.S. Admin Revenues Oral $44 million

Casodex Cytadren

Bicalutamide Aminoglutethimide

AstraZeneca Novartis

Oral Oral

$146 million >$1 million

Eulexin Fareston

Flutamide Toremifene

Schering-Plough Roberts

Oral Oral

$54 million $5 million

Femara

Letrozole

Novartis

Advanced breast in Oral postmenopausal women with disease progression following antiestrogens Prostate, endometriosis Adrenal cortex carcinoma Breast, uterine and AIDS associated cachexia " " Stage D2 metastatic prostate Breast " " Advanced prostate

$9 million

Lupron

Leuprolide

TAP

Lysodren Megace

Mitotane Megestrol

Bristol-Myers Bristol-Myers

SC or $822 million IM (depot) Oral $3 million Oral $117 million

Generics Nilandron
Nolvadex Generics Zoladex

Megestrol Nilutamide
Tamoxifen Tamoxifen Goserelin

Various Aventis
AstraZeneca Various AstraZeneca

Oral Oral
Oral Oral SC

$14 million $9 million


$66 million $278 million $190 million

Source: UBS Warburg LLC, IMS America.

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Key Concepts: Immunotherapy


As scientists have gained an increasing amount of knowledge about the human immune system, they are rethinking ways to attack disease. Currently, it is clear that molecules can be engineered in such a way that we can convince our own body to use its defenses to attack cancer cells. Human immunity is the result of the production of antibodies that are targeted at specific antigens (substances that are recognized by the immune system and that cause the immune system to create antibodies). Antibodies bind to antigens on foreign cells and inactivate or kill them. Antibody-mediated immunity is regulated by B cells, which reside in the bone marrow and spleen. B cells are responsible for producing antibodies. B cells divide and form plasma cells and B memory cells. After an antigen is recognized, the plasma cells make and release between 2,000 and 20,000 antibody molecules per second for the next few days. B memory cells live for months or years. Antibodies bind to specific antigens in a lock and key fashion, forming an antigen-antibody complex (see Exhibit 18). Antibodies are Y shaped molecules whose functions include recognition and binding to antigens and inactivation of the antigen.
Exhibit 18. Antibody and Antigen Structure

It is clear that molecules can be engineered in such a way that we can convince our own body to use its defenses to attack cancer cells

Source: DOE.

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The concept of immunotherapy is not new; the foundations for this theory originated in the 1800s, when physicians noticed that tumors sometimes regressed in patients who had bacterial infections. Twenty years ago, some researchers had postulated that by stimulating the immune system, one can increase the bodys capacity to rid itself of unwanted cells, including cancer. For instance, superficial bladder cancer (cancer occurring on the inner wall of the bladder) responds well to a vaccine used to combat tuberculosis (Bacillus Calmette-GuerinBCG). Usually, superficial bladder cancer recurs after surgery to remove the malignancy. However, if a physician injects BCG into the bladder after surgery, the risk of recurrence is reduced significantly. The exact mechanism of how the vaccine works is not known. In theory, the vaccine causes a prolonged inflammatory response, which increases the duration for which immune cells can fight foreign compounds locally. It is important to note that this vaccine is relatively nonspecific; it works by causing a generalized immune response. As stated previously, the lethality of cancer is due to its ability to metastasize. Consequently, for an immunotherapy to be truly successful, it must have the ability to target cancer cells that may have a common site of origin but that are currently found in distant regions of the body. Additionally, any therapy must also have the ability to differentiate between healthy and malignant tissue. Over the years, researchers have identified antigens that are specific to tumors. As mentioned previously, antibodies tag antigen-presenting foreign compounds to be destroyed by the rest of the immune system. During the 1970s, researchers began developing antibodies directed specifically against certain antigens. Initially, scientists were injecting mice with certain antigens, allowing the mice to develop immunity and then harvesting the antibodies that the mice produced. The antibody-forming cells are isolated from the mouses spleen. Then they are combined with tumor cells, which is referred to as a hybridoma. Each hybridoma produces relatively large quantities of identical antibody molecules. By allowing the hybridoma to multiply in culture, it is possible to produce a population of cells, each of which produces identical antibody molecules. These antibodies are called monoclonal antibodies because they are produced by the identical offspring of a single, cloned, antibody-producing cell. However, these types of monoclonal antibodies are ineffective as therapeutic agents because the mouse antibodies were recognized as foreign by our immune systems and, consequently, are destroyed rapidly. By the 1980s, researchers developed ways of manipulating the mouse antibodies by incorporating portions of human antibodies. This process, known as humanizing, effectively reduces the degree of immunogenicity that an antibody may have. Additionally, genetic engineers have created mice that produce antibodies that are 100% human. In Exhibit 19, we illustrate the four types of antibodies being generated for therapeutic use. Chimeric antibodies are composed of both mouse and human proteins, but the percentage of mouse protein is much greater than in the humanized antibody.

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Exhibit 19: Schematic of Various Types of Antibodies

MOUSE

CHIMERIC

HUMANIZED
Source: UBS Warburg LLC.

HUMAN

There are two ways in which antibodies can destroy tumors. First, they can invade the tumor and elicit other steps in the immune response and have a persons own body attack the tumor. Second, one can use an antibody to deliver some sort of toxic agent to the tumor. A good example of the first scenario is the monoclonal antibody Rituxan (rituximab) marketed by IDEC Pharmaceuticals for the treatment of B-cell nonHodgkins lymphoma. In this form of lymphoma, greater than 90% of the B-cells express an antigen known as CD20. Rituxan binds to this antigen. It is hypothesized that the binding of Rituxan induces cell-mediated toxicity and perhaps apoptosis (programmed cell death). Ultimately, the cells Rituxan binds to die. An example of the second scenario is Coulter Pharmaceuticals Bexxar (tositumomab plus radiolabeled iodine) for the treatment of non-Hodgkins lymphoma. Like Rituxan, Bexxar is a monoclonal antibody that is targeted against the CD20 antigen that is found on B-cells. However, unlike Rituxan, Bexxar is combined or conjugated with radioactively labeled iodine. Conceivably, Bexxar has two mechanisms of killing cancer cells. The first mechanism would be similar to that of Rituxan, but the radioactive iodine offers the potential to damage DNA within the cells. Bexxar is considered to be a targeted chemotherapeutic agent. Coulter has co-developed Bexxar with SmithKline Beecham. Coulter submitted a biologics license application (BLA) for Bexxar for the second-line treatment of nonHodgkins lymphoma on June 30, 1999. The company was granted a priority review, but received a refusal to file letter from the FDA on August 27, 2000. The FDA requested that Coulter reformat selected data and reorganize certain analyses. On September 18, SmithKline Beecham and Coulter announced that they had resubmitted the BLA to the FDA. On October 5, the companies announced that the FDA had granted the product a priority, or six-month, review. Coulter believes they could possibly launch Bexxar sometime next year.

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Vaccines
Recently, two advances have enabled researchers to design more specific vaccines. First, there have been tremendous improvements in the techniques used in molecular biology. Second, scientists continue to advance their knowledge of the mechanisms involved in the immune system activation, specifically in the case of vaccines, the activation of T cells. As mentioned earlier, bladder cancer responds to the bacillus Calmette-Guerin (BCG). But this vaccine is relatively nonspecific; it works by causing a generalized immune response. Several trials evaluating nonspecific vaccines or their products have proved ineffective. However, several bacterial agents are now being combined with tumor-associated antigens (TAAs) as a means of creating a more specific immune response target at the tumors themselves. TAAs are structures, such as proteins or carbohydrates, which are present on cancer cells and not normal cells. Several TAAs have been identified, and they represent a wide array of molecules. For example, carcinoembryonic antigen (CEA) is produced by colon cancers and other adenocarcinomas such as breast, lung and pancreatic cancer. Many tumor cell vaccines have entered definitive Phase III trials. Those trials that have been completed indicate a prolonged relapse-free survival without an overall survival difference. It remains unclear whether the FDA will accept a superior time to relapse with no survival difference as grounds for approvability. Peptide and other antigenspecific vaccines are slightly earlier in development and may hold more promise for cancer patients.

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Key Concept: Drug Resistance


Multi-drug resistance is one of the principal mechanisms by which many cancers become resistant to chemotherapy and a primary reason behind treatment failure. The cells of a tumor are heterogeneous, in that some will be killed by chemotherapy while others will survive. Consequently, chemotherapy kills drug-sensitive cells, while drugresistant cells survive. When the tumor grows again, a greater proportion of cells in the tumor will be drug resistant. Tumors may become resistant to chemotherapy for one of two reasons. One, the tumor originated in an organ that may be intrinsically resistant (e.g., liver or kidney cancer). These organs have an ability to export large molecules through organic cation transporters. A second means by which the tumor cells become resistant to therapy is due to genetic mutations within a subset of cancer cells whereby the mutation enables these cells to continue to grow and divide even in the presence of a previously toxic chemotherapeutic agent. Interestingly, most cancers appear to gain resistance to many agents and sometimes to therapies to which they have had no prior exposure. This type of resistance profile can be recreated in a cell culture and led to the discovery of the multidrug-resistance (mdr) gene family. These genes appear to encode for transmembrane pumps (see Exhibit 20) involved in the transport of large organic compounds. mdr-1, a member of this gene family, has been the most intensively studied. It encodes for a transmembrane protein pump, referred to as P-glycoprotein, which exports numerous organic compounds including the anthracyclines and alkaloids. Another cellular pump involved in drug resistance is a multi-drug resistance protein, or MRP. The mechanism by which this occurs remains unknown. Notably, drugs like cyclosporine and verapamil can block the export of chemotherapy drugs by mdr-1. There are other mechanisms by which tumors may become resistant to therapy, all of which are highlighted in Exhibit 21. One well-studied mechanism is through mutations in the p53 tumor suppressor gene, which allows the cell to ignore the apoptotic, or cell death, response that occurs after DNA injury mediated by chemotherapy. Another mechanism of resistance may be decreased drug uptake, or increased drug export that is mediated by the aforementioned mdr-1-related proteins. Two other possible mechanisms could be a compensatory amplification in the amounts of the cellular drug target, or a mutation in the target that renders it resistant to the effects of the particular therapy. Several companies are involved with the development of drugs that target these two types of pumps that confer tumor resistance. It is important to note that companies can use these molecular data in two ways. The most readily apparent way is to deplete the cancerous cells of their chemoprotective features that are mediated by the pumps, perhaps designing a compound that doesnt allow the pumps to be synthesized within the cells. Another less readily apparent application would be to confer these chemoprotective traits onto bone marrow cells, to allow them to deal with chemotherapy better. Myelosuppression (bone marrow suppression) continues to be the doselimiting toxicity in a large proportion of chemotherapeutic regimens.
Multi-drug resistance is one of the principal mechanisms by which many cancers become resistant to chemotherapy and is a primary reason behind treatment failure

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Exhibit 20: The Possible Mechanism of Chemotherapy Resistance


DRUG

1
Failure to induce apoptosis

Increased drug export

2 MDR1 5
Reduction in drug uptake

Inactivated p53

3 4
Mutation in drug target

Amplification of drug target

Drug resistance can occur through: 1) failure of the drug to induce apotosisp53 can regulate the sensitivity to drugs by changing the expression of proapoptotic and anti-apoptotic molecules, such as Bcl-2, and by regulating the polymerization state of microtubules-2) Failure of the drug to reach the target because of increased drug export through pumps like MDR3) Mutation of the drug target-4) Amplification of the drug target-5) A reduction in drug uptake. Source: Adapted from Scientific American.

Investigations into the methods of drug resistance have yielded a great deal of knowledge that will shape the way we treat cancer in the future. DNA injury caused by chemotherapeutic agents and ionizing radiation triggers activation of the p53 gene, leading to programmed cell death. The realization that exposure to chemotherapeutic agents initiates an active cellular suicide program, rather than simply causing cell death through massive DNA damage, raised the possibility that these cell death pathways may be disrupted in drug-resistant cancer cells. Inactivation of p53 in these cells is associated with resistance to these therapeutic agents. Loss of p53 is a common feature of human cancers, and a number of studies have suggested a correlation between inactivation of p53 and resistance to chemotherapeutic agents, as well as a more aggressive clinical course.

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The Next Wave of Agents


Over the past few decades, there has been somewhat of a paradigm shift in the way chemotherapeutic drug targets are identified. In the following paragraphs, we attempt to provide details on some of the key classes of developmental compounds. This is not intended to be a complete list, but rather an introduction into the various routes the pharmaceutical companies are taking to develop new therapies to treat cancer. As stated previously, advances in cell and molecular biology allow us to identify genetic abnormalities in cancer. A key starting point in unearthing potential drug targets is understanding the genes that underlie the abnormalities associated with cancer cells. In Exhibit 21, we provide a rough cellular diagram of some of these potential drug targets and their relationships to one another. These potential targets include gene products such as growth factors, growth factor receptors, signal transduction pathways and DNA transcription factors. Furthermore, telomerase, an enzyme that maintains the ends of chromosomes, must be active for tumors to continue to divide. Interestingly, elevated telomerase activity is observed in virtually all human cancers. Furthermore, the HER2/neu oncogene, which is a member of a family of epidermal growth factors, is overexpressed (concentrations are above normal) in 2030% of invasive breast cancers. Genentechs Herceptin is a monoclonal antibody targeted against this receptor.

Epidermal Growth Factor Receptor Targets


Several companies are currently developing compounds that inhibit the influences of epidermal growth factor by interacting with the epidermal growth factor receptor (EGFR). EGFR is a large protein receptor. It has an external binding domain where ligands lock on and an intracellular portion. When a ligandin this case, it would be epidermal growth factorbinds to the receptor, the receptor undergoes a transformation and a cascade of intracellular reactions begin. One key step in this cascade is the activation of the tyrosine kinase enzyme (see Exhibit 21).
Exhibit 21: Interactions at the Growth Factor Receptor
EXTRACELLULAR

M em brane
S u b s tra te

K
S u b s tra te

= g r o w th fa cto r

= ty ro s in e k in a s e = p h o sp h a te g ro u p

IN T R A C E L L U L A R

S ig n a llin g m o le c u le s

Source: Adapted from AstraZeneca.

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EGFR is important in tumor cells because of its role in apoptosis (cell death), angiogenesis (creation of a new blood supply) and metastasis. Researchers have shown that inhibiting EGFR can induce apoptosis. Second, in order for a tumor to continue to grow, it must acquire new blood vessels. The activation of EGFR appears to promote the release of vascular endothelial growth factor (VEGF), which is a key promoter of angiogenesis. Consequently, when EGFR is inhibited, it will likely inhibit angiogenesis as well. Currently, several different approaches are being used to inhibit EGFR. One avenue uses monoclonal antibodies to block EGF from binding to the receptor. Second, companies are using small molecule inhibitors of the EGFR tyrosine kinase enzyme and consequently blocking EGFR signaling. A third pathway uses ligand-toxin or immunotoxin conjugates. Lastly, some companies are using antisense oligonucleotides. These molecules bind to mRNA and thereby inhibit cellular expression of EGFR. These types of compounds have essentially the same effect of preventing signals from being transmitted from the receptor, but they act in different ways. The farthest along in development are the monoclonal antibodies and the small molecule inhibitors of tyrosine kinase. The monoclonal antibodies that have been designed to date bind to the portion of the EGFR that is outside of the tumor cell and prevent epidermal growth factor from binding to its receptor. The smaller molecule tyrosine kinase inhibitors are active on the inside of the tumor cell and prevent the enzyme cascade from proceeding. A host of both biotech and pharmaceutical companies have EGFR inhibitor molecules in various stages of clinical development.
Exhibit 22: New Cancer Drug Targets

GROWTH FACTORS

HER2

PDGF

EGF

PKC
GTP

ras
raf

mitochondria
Bcl2 MEK
cyclins Cdks p27/p16

MAPK FTase

bcr-abl
Cytoplasmic ras Precursor ras/CAAX

p53

NUCLEUS
telomerase

ER

Key: cdks, cyclin dependent kinases; EGF, epidermal growth factor receptor; ER, estrogen receptor; Ftase, farnesyltransferase; MEK, MAPK/Erk kinase; PDGF, platelet-derived epidermal growth factor receptor; PKC, proteinkinase C. Source: Adapted from SCIENCE (vol 270 pp 1970).

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Farnesyltransferase Inhibitors
Another avenue of drug development that has garnered attention recently is the farnesyltransferase inhibitors. These targets stem from identification of the molecular pathways that surround the ras oncogene. The ras oncogene is mutated in approximately 30% of human cancers. Ras activation stimulates signal transduction pathways and transcription factors (see Exhibit 22). Farnesyltransferase is a protein necessary for ras to function properly. Technically speaking, ras needs to be farnesylated to work. However, some versions of ras, such as K-ras, can function without farnesylation and can be activated by another process. At the annual American Association of Clinical Oncologists (ASCO) meeting this past May, several pharmaceutical companies presented early clinical data on their farnesyl transferase inhibitors, including Johnson & Johnson, Schering-Plough, Merck and Bristol-Myers, although Merck has since ceased development of its compound.

Matrix Metalloproteinase Inhibitors


Another promising avenue in drug development is the use of matrix metalloproteinase inhibitors (MMPIs). These compounds block enzymes, matrix metalloproteinases (MMPs) that are secreted by cancer cells. Cancer cells use these compounds to break down the extracellular matrix, which enables the cancer to slip through tissues and spread. However, recent studies have shown that these inhibitors can also act to inhibit tumor growth by a variety of measures, including preventing local invasion and inhibiting tumor neovascularization. It is important to note that MMPs are not solely characteristic of cancer cells. These enzymes are also responsible for the normal degradation of the extracellular matrix during connective tissue turnover and cell migration. There are 13 different subtypes of MMPs known (see Exhibit 23).
Exhibit 23: Various Matrix Metalloproteinases

Various Matrix Metalloproteinases


Name Collagenase 1 Collagenase 2 Collagenase 3 Matrilysin Stromelysin 1 Stromelysin 2 Stromelysin 3 Gelatinase A Gelatinase B Metalloelastase Aggrecanase Membrane Type MMP MMP 19
Source: UBS Warburg LLC.

Acronym MMP 1 MMP 8 MMP 13 MMP 7 MMP 3 MMP 10 MMP 11 MMP 2 MMP 9 MMP 12 MMP-MT1, MT2, MT3, MT4

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Currently, there is no proof that MMPIs will prolong survival in cancer patients. The majority of clinical data presented to date have been disappointing, either failing to meet the primary endpoint of the trial or being stopped early due to poor interim results. However, British Biotech/Schering-Ploughs marimastat has shown some good activity in clinical trials and may prolong survival in patients with locally advanced metastatic disease. Since MMPs are active in normal tissue remodeling, it is conceivable that complete inhibition may lead to some related toxicities. In a majority of the MMPI clinical trials to date, arthritis has been the dose-limiting toxicity. Researchers originally theorized that MMP-1 inhibition was the reason behind the dose-limiting arthritis seen with marimastat and Pfizers prinomastat. This would also explain why no dose-limiting arthritis was seen in Bayers MMPI, as that compound was a selective inhibitor of MMP-2, MMP-9 and MMP-3. Bayer has since ceased development of its compound. However, Bristol-Myers has a broad-spectrum MMPI in development that appears to be devoid of dose-limiting arthritis. The activity of Bristols compound leads to the hypothesis that the arthritis seen in the other agents is due to the inhibition of another related set of compounds known as sheddases. Sheddases are members of the MMP family and are involved in the proteolytic release of certain membrane proteins into the circulation in physiologically active forms. The Bristol compound does not inhibit the sheddases.

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How Cancer Is Staged


Oncologists describe the extent of the disease or the spread of cancer in stages. Staging of disease is essential in determining the proper choice of therapy and the specific prognosis. A cancers stage is constructed based on information regarding the primary tumors size, location and whether it has metastasized. There are several different staging systems that physicians can use. The TNM staging system assesses tumors in three ways: extent of the primary tumor (T), absence or presence of regional lymph node involvement (N), and absence or presence of distant metastases (M). Once the T, N and M are determined, a stage of I, II, III or IV is given; these stages correspond to in situ, local, regional and distant. In situ applies to a cancer that remains in the tissue where it originally developed. If the cancer cells have spread beyond the original layer of tissue, the cancer is then considered invasive. In addition to gross physiological examinations and X-rays, microscopic examination of the cancer cells is used to evaluate the cancer cells aggressiveness. Importantly, one way in which drug uses are classified is by first- or second-line use. First-line therapies are therapies given after the initial diagnosis, whereas second-line therapies are those treatments for any subsequent remission. These terms are sometimes confused with neoadjuvant or adjuvant therapy. Adjuvant therapy is defined as treatment given following primary treatment to enhance the efficacy of the primary treatment. It can be chemotherapy, radiation or hormone therapy. Neoadjuvant therapy, as the name indicates, is given before the primary treatment.

Terminology
Exhibit 24: Common Cancer Terminology
TERMINOLOGY
Adjuvant Neoadjuvant Palliative treatment Progression free survival Remisssion Survival rate Treatment given after the primary treatment to make it work better. Adjuvant therapy may include chemotherapy, radiation therapy, or hormone therapy. Treatment given before the primary treatment. Treatment given to relieve symptoms caused by advanced cancer. Palliative therapy does not alter the course of a disease, but improves the quality of life. Period of time where the disease does not increase in severity or scope. Disappearance of the signs and symptoms of cancer. When this happens, the disease is said to be "in remission." A remission may be temporary or permanent. Percentage of people alive for a given period of time after diagnosis of disease. This can be given as the observable survival rate, which considers deaths from all causes, cancer or otherwise. In cancer, this rate is commonly expressed in terms of five-year survival. Relative survival rate is calculated by adjusting the observed survival rate to remove the effects of all causes of death except cancer. Similar to "progression free survival".

Time to disease progression

Source: National Cancer Institute (NCI).

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The Individual Cancer Markets

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Introduction
In the following pages, we discuss the various aspects of each of the major cancers. Each section commences with a description of the disease followed by the anatomical layout of the cancer. We then provide details on the predominant therapeutic regimens for each cancer. It is extremely important to note that the majority of agents are widely used off label. More specifically, once a compound is approved for a particular indication, many physicians will attempt to use the drug in other settings. Furthermore, when data regarding the use of a drug in a new indication are presented at a large clinical symposium (ASCO or AACR), physicians will often adapt similar treatment regimens in their particular clinics. These types of off-label practices bring into question the issue of reimbursement. This is an extremely complex issue, which we do not develop in this report. Importantly, as part of the disease summaries, we have included proprietary data for the oncology market. The data provide an admittedly limited, but meaningful, analysis of what therapies are being used in what settings. We obtained these data from a privately held health care company, iKnowMed, located in Berkeley, California. The entire data set comprises approximately 10,000 patients that have undergone approximately 15,000 regimens. iKnowMed is attempting to build a leading clinical infomediary and repository for realtime, point-of-care health information. The company uses a Web-based program to capture, analyze and display patient treatment information. This system enables patients, physicians and the pharmaceutical industry to interact with one another. Currently, iKnowMed is established in the oncology market. In Exhibit 25, we provide a breakdown of the iKnowMed patient database that this report used as of November 1999.
Exhibit 25: Total iKnowMed Patient Pool
4000

iKnowMed Complete Patient Pool


3500 3436

3000

Numbers of Patients

2500

2305

2000

1768

1500 1156

1000 579 500 561 450 304 309 216 184 171 156 137 PROSTATE 114 MELANOMA 67 BRAIN 54 ENDOMETRIAL 49 SARCOMA 46 TESTICULAR 43 RENAL 40 CERVIX 28 KS

17 LIVER

0 BREAST LYMPH NSCL SCL OTHER LEUKEMIA PANCREAS HEAD & NECK STOMACH BLADDER OVARIAN COLORECTAL ESOPHAGUS

Cancer Type
Source: UBS Warburg LLC, iKnowMed.

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In the following exhibits, we provide expected incidence and death rates for all cancers in the U.S. this year.
Exhibit 26: Incidence of Various Cancers in the U.S.

U.S. Estimated New Cancer Cases by Gender in 2000


All sites Oral Cavity/ Pharynx Digestive System Esophagus Stomach Colon Rectum Liver Pancreas Respiratory Bone Skin (excluding basal & squamous) Breast Genital System Urinary System Brain Endocrine System Lymphoma Hodgkin's Disease Non-Hodgkin's Multiple Myeloma Leukemia Acute Lymphocytic Chronin Lymphocytic Acute Myeloid Chronic Myeloid Other Other
Source: CA Journal.

Total 1,220,100 30,200 226,600 12,300 21,500 93,800 36,400 15,300 28,300 179,400 2,500 56,900 184,200 265,900 86,700 16,500 20,200 62,300 7,400 54,900 13,600 30,800 3,200 8,100 9,700 4,400 5,400 34,000

Male 619,700 20,200 117,600 9,200 13,400 43,400 20,200 10,000 13,700 101,500 1,500 34,100 1,400 188,400 58,600 9,500 5,600 35,900 4,200 31,700 7,300 16,900 1,800 4,600 4,800 2,600 3,100 15,700

Female 600,400 10,000 109,000 3,100 8,100 50,400 16,200 5,300 14,600 77,900 1,000 22,800 182,800 77,500 28,100 7,000 14,600 26,400 3,200 23,200 6,300 13,900 1,400 3,500 4,900 1,800 2,300 18,300

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Exhibit 27: Incidence of Various Cancer Deaths in the U.S.

U.S. Estimated New Cancer Deaths by Gender in 2000


All sites Oral Cavity/ Pharynx Digestive System Esophagus Stomach Colon Rectum Liver Pancreas Respiratory Bone Skin (excluding basal & squamous) Breast Genital System Urinary System Brain Endocrine System Lymphoma Hodgkin's Disease Non-Hodgkin's Multiple Myeloma Leukemia Acute Lymphocytic Chronin Lymphocytic Acute Myeloid Chronic Myeloid Other Other
Source: CA Journal.

Total 552,200 7,800 129,800 12,100 13,000 47,700 8,600 13,800 28,200 161,900 1,400 5,800 41,200 59,000 24,600 13,000 2,100 27,500 1,400 26,100 11,200 21,700 1,300 4,800 7,100 2,300 6,200 36,600

Male 284,100 5,100 69,300 9,200 7,600 23,100 4,700 8,500 13,700 93,100 800 2,200 400 32,500 15,700 7,100 1,000 14,400 700 13,700 5,800 12,100 700 2,800 3,900 1,300 3,400 18,500

Female 268,100 2,700 60,500 2,900 5,400 24,600 3,900 5,300 14,500 68,800 600 3,600 40,800 26,500 8,900 5,900 1,100 13,100 700 12,400 5,400 9,600 600 2,000 3,200 1,000 2,800 18,100

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Breast Cancer
Breast cancer remains one of the most common forms of cancer affecting women. The American Cancer Society estimates that approximately 183,000 new cases of breast cancer will be diagnosed in 2000, with 41,000 deaths resulting from the disease. For the past ten years, incidence rates have been relatively level, which is a deceleration from the 4% annual growth seen during most of the 1980s. The flattening of the incidence curve is likely due to increased vigilance regarding detection and subsequent earlier diagnoses. The major risk factors for developing breast cancer are advancing age and a family history of the disease. Incidence increases with age, with approximately 75% of breast cancer cases diagnosed in women over 50.
The American Cancer Society estimates that approximately 183,000 new cases of breast cancer will be diagnosed in 2000, with 41,000 deaths resulting from the disease

Anatomy
Before a detailed discussion of breast cancer can begin, it is necessary to understand breast anatomy. The following figure accurately depicts the relevant structures.
Exhibit 28: Anatomical Structures of the Female Breast

Source: American Cancer Society.

Each breast has 15-20 overlapping regions referred to as lobes. Within each lobe are smaller lobules. The lobes and lobules are connected by ducts. Additionally, within each breast, there exist blood vessels and lymph vessels. The lymph vessels lead to small, bean-shaped reservoirs called lymph nodes. Lymph nodes are found throughout the body. Most lymphatic vessels of the breast lead to lymph nodes under the arm that are referred to as axillary nodes.

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Types of Breast Cancer


There are several forms of breast cancer. Often, if a tumor arises in the breast, it is benign. Benign breast tumors are merely abnormal growth; they do not spread outside of the breast and are rarely, if ever, life threatening. There are four distinct types of malignant breast cancer. Ductal carcinoma in situ (DCIS) is the earliest form of breast cancer. It is completely confined to the ducts of the breast. If a patient presents with DCIS, there is close to a 100% cure rate. DCIS is easily detected by mammogram. The second, more advanced, form of breast cancer is infiltrating (invasive) ductal carcinoma (IDC). This form of cancer begins in the ducts, but then migrates into the fatty tissue of the breast. IDC is the most common form of breast cancer, accounting for roughly 80% of the cases. The third type of cancer is lobular carcinoma in situ (LCIS). This form of cancer is not a true cancer, but it does increase a womans risk of developing cancer. Roughly 30% of women with LCIS develop breast cancer. The final form of breast cancer is infiltrating (invasive) lobular carcinoma, which starts in the lobules and represents 1015% of all breast cancers. The aforementioned tumor types are usually considered early breast cancer or stages I and II. A patient with stage III breast cancer characteristically presents with a primary tumor measuring greater than 5 cm, spreading to the skin or chest wall or lymph nodes. Stage III breast cancer accounts for roughly 10% of all cases. Approximately one-third of women that present with stage III have metastases at the time of diagnosis. The most severe and aggressive form of breast cancer is stage IV, or metastatic, breast cancer. The median survival time after diagnosis of metastatic disease is 18-24 months. If the disease has advanced this far, it is seldom curable.

Treatment
Exhibit 29: FDA-Approved Breast Cancer Therapies
FDA Approved Uses for Breast Cancer Therapies
Brand Name 5-FU Adriamycin, Rubex Arimidex Aromasin Cytoxan, Neosar Ellence Fareston Femara Herceptin Megace MTX Nolvadex Taxol Taxotere Thiotepa Velban Xeloda Zoladex Generic Name 5-Fluorouracil doxorubicin anastrozole exemestane cyclophosphamide epirubicin toremifene letrozole trastuzumab megestrol acetate methotrexate tamoxifen paclitaxel docetaxel thiotepa vinblastine capecitabine goserelin acetate Mnfr. Various Various AstraZeneca Pharmacia Various Pharmacia Roberts Novartis Genentech Various Various Various Indication Admin. Carcinoma IV, Oral Carcinoma IV 2nd line hormonal therapy in postmenopausal women Oral 2nd line carcinoma Oral Carcinoma IV, Oral Adjuvant therapy IV Metastatic Oral Advanced disease in postmenopausal women with progression after antiestrogens Oral Metastatic disease in women who overexpress HER2 receptor IV Advanced carcinoma (palliative) Oral Carcinoma IV, Inj, Oral Breast cancer, risk reduction in high risk women andisk reduction in women with DCIS Oral after surgery and radiation Bristol-Myers 2nd line carcinoma, 2nd line therapy following an anthracycline regimen and node positive IV cancer in combination with doxorubicin and cyclophosphamide Aventis Advanced , 2nd line IV Immunex Adenocarcinoma IV, Inj Various 3rd line IV Roche 2nd line metastatic Oral AstraZeneca Premenopausal carcinoma (palliative) Inj

Source: Food and Drug Administration.

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Exhibit 30: iKnowMed Breast Cancer Incidence by Stage

Stage IIIB 6%

Stage IV 13%

Stage I 16%

Stage IIIA 10% Stage IIA 31%

Stage IIB 24%

Source: iknowMed.

Early-Stage Disease
Many patients with breast cancer undergo surgery to remove the tumor from the breast. In many cases, the axillary (under the arm) lymph nodes are removed and analyzed for the presence of cancer. The types of surgery range from a simple lumpectomy (removal of the lump and some surrounding tissue) to a radical mastectomy, in which the breast, lymph nodes and chest muscles are removed. Approximately 60% of women diagnosed with breast cancer will present with localized disease that has not spread to the lymph nodes (node-negative); these women are often curable. Additionally, numerous trials have indicated that breast-conserving treatments consisting of lumpectomy and radiation therapy result in a survival rate that is comparable to that of more radical treatments like total mastectomies. At present, more than one-third of women with breast cancer in the U.S. are managed by lumpectomy and radiation. There are numerous options for women regarding the types of surgery and the use and duration of radiation therapy, but for the purpose of this report, they will not be discussed. However, there is evidence of substantial benefit to patients with early-stage disease that receive a combination of radiation therapy and chemotherapy. For the most part, patients receiving combination therapy experience higher survival rates. Data indicate that women experience fewer local and regional recurrences and improved overall survival when cytoxan, methotrexate and 5-FU (referred to as CMF) are given with radiation therapy. One study showed that survival at ten years was 54% among women who were given CMF and radiation compared to 45% for those patients who received radiation alone. Recently, it was noted that women whose tumors overexpress the HER2 proto-oncogene and receive Genentechs Herceptin may benefit further from an enhanced radiation effect.
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In women diagnosed with breast cancer that has spread to local lymph nodes, but not beyond, the cancer is also often curable. Data indicate that women experience fewer local and regional recurrences and improved overall survival when doxorubicin, cyclophosphamide and Taxol (ACT) are given.

Metastatic Breast Cancer


Chemotherapy
For the most part, women who have been disease-free for less than two years, have hormone receptor-positive disease, have had prior hormone therapy or have aggressive disease are good candidates for chemotherapy. Combination chemotherapy results in higher response rates when compared to single-agent use, varying from 5070% and up to nine to 12 months in duration. The rate of complete responses in patients receiving combination chemotherapy is approximately 1020%. Currently, the most commonly used regimens are methotrexate combined with 5-FU and leucovorin, cyclophosphamide combined with methotrexate and 5-FU, cyclophosphamide combined with doxorubicin and 5-FU, or some sort of taxane-containing regimen. Doxorubicin-containing regimens have shown a 1020% better response rate, but do not appear to offer a survival advantage over regimens that do not contain doxorubicin. In elderly women, a regimen with a less severe side-effect profile that is sometimes considered is Genentechs Herceptin or methotrexate plus 5-FU with leucovorin. In women where the disease has recurred after doxorubicin or taxane therapy, Navelbine (vinorelbine) with Alzas Doxil is sometimes used, even though those two agents are not currently approved for breast cancer therapy. Additionally, Roches oral therapy, Xeloda, is sometimes preferred and offers a 20% response rate.
Exhibit 31: Cytotoxic Therapy for Advanced Breast Cancer
Median Duration of Response (months) 5-8

Acronym CMF

Drugs cyclophosphamide methotrexate 5-FU FAC 5-FU Adriamycin (doxorubicin) cyclophosphamide AC Adriamycin (doxorubicin) cyclophosphamide CAF cyclophosphamide Adriamycin (doxorubicin) 5-FU Novantrone mitoxantrone Taxol paclitaxel Taxotere docetaxel
Source: Adapted from Ravdin: Breast Cancer.

Response Rate (%) 49-59%

50-75%

6-10

40-80% 60-80%

6-12 10-12

17-35% 30% 41%

4-5 6 6

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Endocrine Therapy
As stated earlier in this report, in many organs and cell types, hormones can stimulate cell division and growth. Consequently, some hormonal agents are effective at reducing or eliminating tumor cell growth in a specific tissue type. Most hormonal agents work as agonists to inhibit tumor growth or as antagonists that compete with endogenous hormones that promote growth. In the breast, the key receptor for hormones is the estrogen receptor (ER). In practice, women whose cancer is ER-positive have demonstrated a consistent survival advantage after recurrence compared to ER-negative women. Additionally, the presence of both progesterone receptor (PR) and ER indicate a higher response rate than in women with ER-positive tumors alone. For women with no prior history of hormonal therapy, use of the anti-estrogen tamoxifen is currently the standard of care. Tamoxifen is a nonsteroidal anti-estrogen that binds to the estrogen receptors that are present in the body, including those in cancerous tissue. Consequently, it effectively blocks estrogen from exerting its effects on cells, more specifically inhibiting tumor growth. Recently, compounds have been introduced that bind preferentially to forms of the ER present in breast tissue and modulate the actions of this receptor system. These compounds are referred to as selective estrogen receptor modulators (SERMs). Currently, the only marketed SERM is Lillys Evista (raloxifene). Notably, Evista appears to have a neutral effect on the uterus, whereas tamoxifen has a high affinity for uterine tissue. Consequently, tamoxifen use is associated with an increased risk of uterine cancer. Aromatase inhibitors are another type of therapy for women with breast cancer. In postmenopausal women, the primary source of estrogen is peripheral conversion of androstenedione to estrone by the enzyme aromatase, with further conversion of estrone to estradiol. As the name indicates, aromatase inhibitors inhibit the peripheral conversion to estrogen by inhibiting the aromatase enzyme. Recently, several new aromatase inhibitors have been developed. These agents, including Pharmacias Aromasin (exemestane), Novartiss Femara (letrozole) and AstraZenecas Arimidex (anastrozole), are highly selective and are substantially more potent inhibitors of aromatase than previous therapies. These therapies have become the gold standard therapy for postmenopausal women whose disease no longer responds to tamoxifen. While the cytotoxic chemotherapies for breast cancer are not administered as oral therapies, the adjuvant endocrine therapies are, for the most part, oral therapies. The following table indicates the market share trends for the oral breast cancer therapies.

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Exhibit 32: Total Prescription Trends for Oral Breast Cancer Therapies
Total Prescriptions (TRXs) in Thousands
Total Aromatase Inhibitors Total Breast Cancer Mkt Jun-99 135 346 Jul-99 139 348 Aug-99 144 349 Sep-99 141 342 Oct-99 145 354 Nov-99 143 356 Dec-99 146 377 Jan-00 140 340 Feb-00 142 342 Mar-00 154 366 Apr-00 144 346 May-00 161 378 Jun-00 160 372

Growth (year/year)
Total Generic Megace Megace Oral (BMY) Megace (BMY) Total Megace Arimidex (AZN) Aromasin (PHA) Femara (NVS) Fareston (SHPGY) Total Aromatase Inhibitors
Tamoxifen (BRL) Tamoxifen (N/R) Total Tamoxifen Nolvadex (AZN) Total Breast Cancer Mkt 9% 26% -24% 20% 7% N/A 84% 48% 16% 11% N/A 11% -9% 7% 11% 40% -22% 33% 7% N/A 84% 34% 21% 11% N/A 11% -5% 8% 15% 37% -22% 31% 10% N/A 82% 29% 22% 13% N/A 13% -2% 10% 11% 34% -22% 28% 6% N/A 75% 26% 18% 12% 238% 12% -3% 9% 10% 31% -19% 26% 9% N/A 65% 17% 18% 11% 633% 11% -3% 8% 12% 35% -11% 30% 15% N/A 70% 18% 21% 16% N/A 16% 4% 14% 10% 27% -16% 23% 14% N/A 58% 19% 17% 16% N/A 16% -1% 13% 9% 33% -13% 29% 10% N/A 49% 8% 18% 11% -100% 11% -7% 7% 12% 39% -12% 35% 16% N/A 49% 12% 23% 16% -85% 16% 1% 13% 5% 30% -19% 26% 10% N/A 30% -6% 16% 9% -100% 9% -8% 6% 2% 23% -15% 20% 10% N/A 36% -4% 13% 9% -100% 9% -9% 5% 16% 38% -17% 34% 21% N/A 46% 5% 26% 18% -100% 18% 3% 15% 6% 30% -25% 26% 15% N/A 40% -5% 18% 10% -100% 10% -4% 7%

Market Share
Total Generic Megace Megace Oral (BMY) Megace (BMY) Total Megace Arimidex (AZN) Aromasin (PHA) Femara (NVS) Fareston (SHPGY) Total Aromatase Inhibitors
Tamoxifen (BRL) Tamoxifen (N/R) Total Tamoxifen Nolvadex (AZN) Total Breast Cancer Mkt 37.9% 37.3% 2.9% 40.2% 15.5% 0.0% 3.0% 3.4% 100.0% 81.4% 0.0% 81.5% 18.5% 100.0% 37.3% 38.4% 2.7% 41.1% 15.2% 0.0% 3.0% 3.3% 100.0% 81.7% 0.0% 81.7% 18.3% 100.0% 37.2% 39.1% 2.7% 41.8% 15.0% 0.0% 2.9% 3.0% 100.0% 81.7% 0.0% 81.7% 18.3% 100.0% 36.8% 39.6% 2.6% 42.2% 14.8% 0.0% 3.0% 3.1% 100.0% 81.8% 0.0% 81.8% 18.2% 100.0% 36.5% 39.5% 2.5% 42.0% 15.4% 0.0% 3.1% 3.0% 100.0% 81.9% 0.0% 81.9% 18.1% 100.0% 36.0% 39.6% 2.6% 42.2% 15.6% 0.0% 3.3% 2.9% 100.0% 82.0% 0.0% 82.0% 18.0% 100.0% 36.2% 38.3% 2.6% 40.9% 16.2% 0.0% 3.5% 3.2% 100.0% 82.8% 0.0% 82.8% 17.2% 100.0% 35.8% 40.3% 2.4% 42.7% 15.2% 0.1% 3.4% 2.9% 100.0% 82.6% 0.0% 82.6% 17.4% 100.0% 35.2% 40.7% 2.3% 43.0% 15.1% 0.4% 3.3% 2.9% 100.0% 82.3% 0.0% 82.3% 17.7% 100.0% 34.6% 41.4% 2.2% 43.6% 14.9% 0.7% 3.4% 2.7% 100.0% 83.1% 0.0% 83.1% 16.9% 100.0% 34.5% 40.3% 2.2% 42.6% 15.5% 1.1% 3.5% 2.8% 100.0% 83.4% 0.0% 83.4% 16.6% 100.0% 34.7% 40.8% 2.0% 42.8% 14.9% 1.4% 3.5% 2.8% 100.0% 83.3% 0.0% 83.3% 16.7% 100.0% 34.1% 41.1% 1.8% 42.9% 15.1% 1.6% 3.6% 2.7% 100.0% 83.4% 0.0% 83.4% 16.6% 100.0%

Source: IMS America.

iKnowMed Data: Breast


The data we obtained from iKnowMed indicate that approximately 42% of the women being treated for breast cancer are receiving their first treatment. Of those women receiving first-line therapy, approximately 34% receive Adriamycin (doxorubicin) in combination with cyclophosphamide; 26% of patients receive cyclophosphamide, methotrexate and 5-FU. With regard to second-line therapies, the market is much more fragmented. Twenty-two percent of women receive Aventiss Taxotere, 15% receive Bristols Taxol and 11% receive Glaxos Navelbine.

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Exhibit 33: Number of Patients Being Treated, First Line Versus Second Line

2nd LINE 42%

1st LINE 58%

Note: First line refers to patients receiving their initial treatment. Second line refers to all subsequent treatments.

CNF 1% DOX-TXT 1% ACMF 2%

DOX 1%

Various 1st Line Regimens for Breast Cancer

HER-TAX 0% HER 0%

OTHER 2% TXT 3% ATC 8%

TAX 7% AC 34%

FAC 15%

CMF 26%

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Exhibit 33 contd: Number of Patients Being Treated, First Line Versus Second Line
HER-TXT 1% ATC 1% CARB-TAX 1%

DOXIL 1% 5FU-LEUC-TAX 1% XEL-GEM 2% NFL 2% DOX-TXT 2% 5FU-LEUC 2% DOX 2% DOX-TAX 2% HER-TAX 2%

Various 2nd line Regimens for Breast Cancer

GEM-NAV 1% 5FU-CIS 1%

TXT 22%

AC 5% FAC 5% CMF 5% HER 6% 5FU 4% OTHER 7%

TAX 15%

VIN 11%

GEM 2%

Source: iKnowMed.

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Exhibit 34: Acronyms for Breast Cancer Regimens

Acronym
5FU 5FU-CIS 5FU-LEUC 5FU-LEUC-TAX AC ACMF ATC CARB-TAX CMF CNF DOX DOXIL DOX-TAX DOX-TXT FAC GEMZAR GEMZ-NAV HER HER-TAX HER-TXT NFL OTHER TAXOL TXT VIN XELO-GEMZ

Regimen
5-fluorouracil 5-fluorouracil + cisplatin 5-fluorouracil + leucovorin 5-fluorouracil + leucovorin + Taxol adriamycin (doxorubicin) + cyclophosphamide adriamycin (doxorubicin) + cyclophosphamide + methotrexate + 5FU adriamycin (doxorubicin) + Taxol + cyclophosphamide Paraplatin + Taxol cyclophosphamide + methotrexate + 5-fluorouracil cyclophosphamide + Novantrone + 5-fluorouracil doxorubicin Doxil doxorubicin + Taxol doxorubicin + Taxotere 5-fluorouracil + adriamycin (doxorubicin) + cyclophosphamide Gemzar Gemzar + Navelbine Herceptin Herceptin + Taxol Herceptin + Taxotere Navelbine + 5FU + leucovorin Taxol Taxotere Navelbine Xeloda + Gemzar

Source: UBS Warburg LLC.

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Lung Cancer
In 2000, it is expected that approximately 164,000 new cases of lung cancer will be diagnosed (80,500 in men). Notably, lung cancer passed breast cancer in 1996 as the number one cause of death from cancer in women.

Lung cancer is responsible for approximately one-third of all cancer deaths in the United States. The incidence in men is beginning to decline, but the incidence in women continues to increase. In the year 2000, it is expected that approximately 164,000 new cases of lung cancer will be diagnosed (80,500 in men). Notably, lung cancer passed breast cancer in 1996 as the number one cause of death from cancer in women. Increasing incidence is a major reason for the high mortality rate in lung cancer, but lung cancer is notorious for its aggressive biology (or likelihood of spread/metastasis) and its relatively low cure rate.

Anatomy
The lung consists of three primary zones. The first zone consists of the cells that line the trachea (windpipe) and the first portion of the large airways (bronchi). These cells are flat, referred to as squamoid. These cells serve as a protective layer against inhaled substances. The second zone is more central and is usually referred to as the secretory zone. This zone is lined with a series of cells that produce mucus. The mucus moves constantly over the cells due to tiny hairs, known as cilia. The third and last portion of the lung consists of millions of tiny air sacs, known as alveoli. This is where breathing takes place and carbon dioxide is exchanged for oxygen.
Exhibit 35: Anatomical Structures in the Human Lung

Source: American Cancer Society.

Types of Lung Cancer


There are four distinct types of lung cancer, none of which are alike (see Exhibit 36). Small cell lung cancer (SCLC), which accounts for approximately 20% of all lung cancer, is cancer that invades the submucosa and is thought to arise from Kulchitsky cells, neuroendocrine cells that secrete peptide hormones in the lung. The three other types of lung cancer are grouped under non-small-cell lung cancer (NSCLC), which accounts for the other 80% of lung cancer. The first type of NSCLC is squamous-cell cancer, which originates in the larger airways. Adenocarcinomas, which include bronchoalveolar carcinomas, occur in the secretory portion of the lung, and are the
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second type of NSCLC. The final type of NSCLC is large cell carcinoma. Knowledge of the specific type of lung cancer and its site of origin are critical factors in the effective management of the disease. Unfortunately, by the time an individual presents with any of the warning signs of lung cancer, the disease is most likely at a late stage.
Exhibit 36: Pathologies of the Different Forms of Lung Cancer

Lung Cancer Pathology


Type Small Cell Lung Cancer Frequency Characteristics 20% Central location, strong relationship with smoking, metastasizes widely, most sensitive to chemo and radiation Squamous Adenocarcinoma 35% 35% Central location, more common in males, less metastases Peripheral in location, equal frequency in both sexes, metastatic potential common, most common type in nonsmokers Peripheral in location, equal frequency in both sexes, metastatic potential undifferentiated

Non-Small Cell Lung Cancer

Large Cell

10%

Source: Scientific American.

Staging of lung cancer is slightly different than for other cancers. For SCLC, a twostage system is typically used consisting of limited stage and extensive stage. Limited stage refers to a cancer that is localized to one lung and the lymph nodes on that side of the chest. Extensive stage refers to a cancer that has spread to the other lung, lymph nodes on the other side of the chest or to distant organs. SCLC is staged this way because it helps separate tumors that can be treated with radiation therapy from those that cannot.

Treatment
Exhibit 37: FDA-Approved Drug Uses for Lung Cancer
FDA Approved Uses for Lung Cancer Therapies
Brand Name Adriamycin, Rubex Etopophos, VePesid Gemzar Hycamtin MTX Mustargen Navelbine Photofrin Taxol Taxotere Generic Name doxorubicin etoposide gemcitabine topotecan methotrexate meclorethamine vinorelbine porfimer sodium paclitaxel docetaxel Mnfr. Various Various Eli Lilly GlaxoSmithkline Various Merck GlaxoSmithkline Sanofi-Synthelabo Bristol-Myers Aventis Indication Bronchogenic carcinoma 1st line small cell lung in combination with other therapies Non-small cell lung Small cell lung in patients with sensitive disease Small cell lung in patients with sensitive disease and squamous cell carcinoma Malignant effusions and bronchogenic carcinoma Advanced non-small cell lung Non-small cell lung, palliation of endobronchial obstruction 1st line non-small cell lung in combination with cisplatin 2nd line non-small cell lung Admin. IV IV, Oral IV IV IV, Inj, Oral IV IV Inj IV IV

Source: Food and Drug Administration.

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Small Cell Lung Cancer (SCLC)


Exhibit 38: Small Cell Lung Cancer Split

EXTENSIVE 50%

LIMITED 50%

Source: iKnowMed.

Small cell lung cancer (SCLC) has a high propensity for early metastatic spread. Due to its aggressive nature, small cell cancer has a greater tendency to be widely disseminated by the time of diagnosis, but it is much more responsive to chemotherapy and radiation. Furthermore, due to the likelihood of metastases, local treatments, such as surgery or radiation, rarely have an impact on long-term survival. At the time of diagnosis, approximately 40% of the patients with SCLC will have a tumor confined to one side of the chest. These patients are defined as having limited stage small cell carcinoma, as was stated above. The median survival time for patients with limited-stage disease is 16-24 months, whereas, in patients with significant disease spread, or extensive small cell lung cancer, median survival is six to 12 months with currently available therapies, and long-term disease-free survival is rare. The majority of patients with SCLC are treated with both radiation and chemotherapy. This dual treatment has been shown to be more effective than either type of therapy alone. The standard of care for the chemotherapy of limited-stage SCLC has not been defined. Currently, the most widely used regimen consists of a platinum-based agent and VePesid (etoposide), which is interesting considering there is no platinum-based compound with an FDA approval for this indication. This type of regimen has largely replaced the CAV regimen (cyclophosphamide, doxorubicin and vincristine) that was a mainstay of therapy in the 1970s and it has replaced the CAE regimen (cyclophosphamide, doxorubicin and etoposide) that was used in the 1980s because it is less toxic and more effective.

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As stated above, the CAV regimen was one of the most commonly used regimens in both limited- and extensive-stage disease in the 1970s. It produced response rates of 8090% in patients with a median survival time of eight to 14 months. However, relatively high rates of bone marrow suppression, neuropathy and pulmonary toxicity were seen. Notably, if a patient failed the CAV regimen, the response rate to second-line chemotherapy was less than 10% with a survival time of two to three months. A combination of Bristols Platinol and VePesid began being used in the 1970s and produced 90% response rates, with complete responses in 50% of the patients. This regimen also appeared to be active in patients that had failed the CAV regimen. There were associated toxicities with this regimen, such as bone marrow suppression, nephrotoxicity and ototoxicity. Importantly, though, the degree of bone marrow suppression was much less severe than in the CAV regimen. However, under both therapy regimens, the cancers developed resistance. Efforts to enhance efficacy in either regimen by increasing the dose or frequency of administration have, for the most part, failed to show any survival advantage. Currently, the use of Bristols second-generation, platinum-based compound Paraplatin (carboplatin) appears to be the standard therapy. Paraplatin produces less toxicity and is easier to administer when compared to Platinol. Newer agents are currently being studied in SCLC, including Bristols Taxol, Aventiss Taxotere, Pharmacias Camptosar, GlaxoSmithKlines Hycamtin and Lillys Gemzar.

iKnowMed Data: Small Cell Lung Cancer (SCLC)


The majority of patients (58%) with limited-stage small cell lung cancer (SCLC) receive Bristols Paraplatin in combination with etoposide. Twenty-two percent receive a combination of cisplatin and etoposide. In patients with extensive SCLC, there is widespread use of several therapies. Twenty-seven percent of patients receive SmithKlines Hycamtin; 14% receive Paraplatin in combination with etoposide; 10% receive a combination of cyclophosphamide, adriamycin and vincristine; and 10% receive Bristols Taxol.

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Exhibit 39: Various Regimens for SCLC


TAX-CARB-HYC 2%

TAX-HYC 3%

CAV 5% OTHER 7%

PCE 3%

EP 22%

CE 58%

Various Regimens for Extensive SCLC


VEP 2% VIN 2% TXT 3%

TAX-HYC 2%

HYC 27%

HYC-VCR 3% CARB-TAX 4% PCE 5%

GEM 5% EP 5% OTHER 8% TAX 10% CAV 10% CE 14%

Source: iKnowMed.

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Exhibit 40: Acronyms for Small Cell Lung Cancer Regimens

Acronym
CARB-TAX CAV CE EP GEM HYC HYC-VCR OTHER PCE TAX TAX-CARB-HYC TAX-HYC TXT VEP VIN

Regimen
Paraplatin + Taxol cyclophosphamide + adriamycin (doxorubicin) + vincristine Paraplatin + etoposide cisplatin + etoposide Gemzar Hycamtin Hycamtin + vincristine Taxol + Paraplatin + etoposide Taxol Taxol + Paraplatin + Hycamtin Taxol + Hycamtin Taxotere etoposide Navelbine

Source: UBS Warburg LLC.

Non-Small-Cell Lung Cancer (NSCLC)


In NSCLC, treatment outcomes are poor, except when the cancer is in its most localized stages. At this point, surgery is the major potentially curative treatment. In its advanced stages, chemotherapy can only offer modest survival advantages. At diagnosis, patients with NSCLC can be divided into three groups that, in essence, reflect the extent of the disease. The first group has tumors that are surgically resectable (stages I and II). This group is typically treated with radiation and surgery. The second group includes patients with either locally (T3T4, see Exhibit 41) or regionally (N2N3) advanced lung cancer. Typically, this group is treated with radiation and chemotherapy. Finally, the third group consists of those patients with distant metastases (M1) at the time of diagnosis. These patients are also treated with both radiation and chemotherapy.

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Exhibit 41: TNM Staging for Non-Small-Cell Lung Cancer (NSCLC)

TNM Staging for Non-Small Cell Lung Cancer


Primary Tumor (T) Primary tumor cannot be assessed (i.e. malignant cells present but can't be visualized by TX bronchoscope) No evidence of primary tumor T0 Carcinoma in situ Tis A tumor that is 3cm or less in greatest dimension T1 A tumor that is greater than 3cm in dimension or has invaded the pleura (lining of the lungs) T2 A tumor of any size that invades either the chest wall, diaphragm, pleura or pericardium T3 A tumor of any size that invades either the mediastinum, heart, great vessels, trachea, T4 esophagus or vertebral body Regional Lymph Nodes (N) Regional lymp nodes cannot be assessed NX No regional lymph node metastasis NO Metastasis to same side lymph nodes other than the suncarnial or mediastinal lymph nodes N1 Metastasis to same side suncarnial or mediastinal lymph nodes N2 Metastasis to opposite side lymph nodes N3 Distant Metastasis (M) Metastasis cannot be assessed MX No distant metastasis MO Distant metastasis M1
Source: American Cancer Society.

As stated previously, early-stage NSCLC is rarely treated with chemotherapy; consequently, we will not go into detail on the various treatment modalities for these types of NSCLC. In stage II cancer (T1, N1, M0 or T2, N1, M0 or T3, N0, M0), surgery is generally the treatment of choice, but many patients subsequently develop regional or distant metastases. Consequently, there has been some emphasis on the use of adjuvant chemotherapy (i.e., in conjunction with radiation and/or surgery). Two clinical trials in which surgically resected patients were treated with Bristols Platinol, doxorubicin and cyclophosphamide indicated that adjuvant chemotherapy can produce a modest increase in disease-free survival and trends of improved overall survival, especially in the first year after surgery. Approximately 40% of patients with NSCLC present with locally advanced or surgically unresectable tumors. The majority of these patients are stage IIIA and IIIB. In stage III (T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3,N2, M0), patients are most often treated with a combination of radiation, chemotherapy and surgery. Metaanalysis (a retrospective look at a combination of several previous studies) of several studies have shown that Platinol-based chemotherapy combinations in addition to radiation can result in a 10% risk reduction compared to radiation therapy alone. Additional studies have been performed to compare concomitant chemotherapy with radiation to sequential radiation and chemotherapy. In the majority of studies, concomitant chemotherapy was significantly better than sequential.

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iKnowMed Data: Non-Small-Cell Lung Cancer (NSCLC)


The vast majority of patients (67%) who are receiving initial therapy for non-small-cell lung cancer will likely receive a combination of Bristols Paraplatin and Taxol. The other 33% will receive one of several other various therapies. As for second-line therapy, 26% of patients will receive the Paraplatin/Taxol combination. 21% will receive Glaxos Navelbine and 17% will receive Lillys Gemzar.
Exhibit 42: Various Second-Line Regimens for NSCLC
HYC 1% GEM-CARB 1% CARB-VIN 2% GEM-CIS 2% CIS-VIN 3% TAX 6% CARB-TAX 26%

Various 2nd Line Regimens for NSCLC

CARB-TXT 1%

CE 2%

TXT 4% GEM-VIN 5%

OTHER 9% GEM 17%

VIN 21%

Source: iKnowMed.

Exhibit 43: Acronyms for Non-Small-Cell Lung Cancer Regimens

Acronym
5FU CARB-GEM CARB-TAX CARB-TAX-GEM CARB-TXT CARB-VIN CIS-VIN CE EP GEM GEM-CIS GEM-VIN HYC OTHER TAX TXT VIN

Regimen
5-fluorouracil Paraplatin + Gemzar Paraplatin + Taxol Paraplatin + Taxol + Gemzar Paraplatin + Taxotere Paraplatin + Navelbine cisplatin + etoposide Paraplatin + etoposide cisplatin + etoposide Gemzar Gemzar + cisplatin Gemzar + Navelbine Hycamtin Taxol Taxotere Navelbine

Source: UBS Warburg LLC.

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Colorectal Cancer
The American Cancer Society estimates that approximately 130,200 new cases of colorectal cancer will be diagnosed in 2000 (colon cancer will compose 72% of the total).

Colorectal cancers (cancers of the colon and rectum) are the most common form of cancers in the United States. The American Cancer Society estimates that approximately 130,200 new cases of colorectal cancer will be diagnosed in 2000 (colon cancer will compose 72% of the total). Colorectal cancer will likely cause 56,300 deaths this year. However, the death rate for colorectal cancer has been declining for the past 20 years. This is likely due to increased early detection and improvements in treatment. Ninety percent of people whose colorectal cancer is found and treated early will survive for at least five years. However, as is the case with other cancers, once the disease has metastasized, the five-year survival rate declines.

Anatomy
The colon, or large intestine, is approximately five feet long and consists of four distinct sections (see below): the ascending colon (which attaches to the small intestine), the transverse colon, the descending colon and the sigmoid colon.
Exhibit 44: Anatomy of the Human Colon

Source: American Cancer Society.

A malignancy can form in any of these sections of the colon, but the cancer will always originate in the innermost tissue layer. As the tumor grows, it often expands through the distinct layers that line the colon and in some cases breaks through. Before a true malignancy can develop, there are often subtle changes that occur in the intestine. One such change is the growth of a polyp, which is a precancerous lump of tissue.

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Treatment
Exhibit 45: FDA-Approved Colorectal Therapies
FDA Approved Uses for Colorectal Cancer Therapies
Brand Name Generic Name 5-Fluorouraci fluorouracil, 5-FU Camptosar irinotecan Ergamisol levamisole leucovorin Wellcovorin, L Mnfr. Various Pharmacia Indication Carcinoma, palliative 1st line therapy of metastatic disease in combination with 5-FU and leucovorin and advanced second line following 5-FU Johnson & Johnson Adanced in combination with 5-FU Various 1st line in combination with 5-FU Admin. IV, Oral IV, Oral Oral IV, Inj, Oral

Source: Food and Drug Administration.

For years, the standard adjuvant therapy for stage III colon cancer was 5-FU and Johnson & Johnsons Ergamisol (levamisole) until 1998 when studies indicated that by adding leucovorin to 5-FU, one can increase the period of tumor inhibition. Overall survival was not increased with the addition of leucovorin; however, the response rate increased significantly. Currently, the foundation of all colorectal cancer therapies is based on a combination of 5-FU and leucovorin, although that is changing. Data at this past American Society of Clinical Oncologists (ASCO) meeting in May indicated that Pharmacias Camptosar should be combined with 5-FU and leucovorin as part of the gold standard for therapy. As with many other cancers, there is an emphasis on using adjuvant therapies. Several large randomized studies have demonstrated the benefit of systemic adjuvant therapy with 5-FU combined with either leucovorin or levamisole after surgery versus patients that underwent surgery alone. A meta-analysis of the adjuvant therapy trials of chemotherapy versus surgery alone has revealed a reduction in mortality of 2233%. Pharmacia has commenced three international studies looking at Camptosar in combination with 5-FU and leucovorin in the adjuvant setting. In patients with advanced disease, some studies have shown that palliation (a reduction in symptoms with no curative effect) may be achieved in 1020% of patients with 5-FU alone. When leucovorin is added to the regimen, there appears to be an increase in response rates and palliation of symptoms but some confounding results in terms of survival. Camptosar has shown to be effective in terms of survival and palliation of symptoms in patients with advanced disease.

iKnowMed Data: Colorectal Cancer


When reading the following pie charts, please recall that these data are from November 1999 and, consequently, do not truly reflect the shift that may be occurring since Pharmacias Camptosar received approval for first-line therapy. As of November 1999, 5-FU/Leucovorin remained the gold standard for first-line therapy with 63% of patients receiving it. However, Camptosar was used widely in the second-line indication with 51% of patients receiving it. Twenty-three percent of the patients were on the combination of 5-FU/Leucovorin. Twelve percent received 5-FU. Notably, only 3% of patients received Roches Xeloda as a second-line therapy.

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Exhibit 46: Various First-Line Regimens for Colorectal Cancer


Various 1st Line Regimens for Colorectal Cancer

CAMPTO 3%

OTHER 4% 5FU-LEVAM 11%

5FU 19%

5FU-LEUC 63%

Various 2nd Line Regimens for Colorectal Cancer MITO-C


XELODA 3% 2%

OTHER 9%

5FU 12% CAMPTO 51%

5FU-LEUC 23%

Source: iKnowMed.

Exhibit 47: Acronyms for Colorectal Regimens

Acronym
5FU 5FU-LEUC 5FU-LEVAM CAMPTO MITO-C OTHER XELODA

Regimen
5-fluorouracil 5-fluorouracil + leucovorin 5-fluorouracil + Ergamisol Camptosar mitomycin Xeloda

Source: UBS Warburg LLC.

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Non-Hodgkins Lymphoma
Lymphoma is a general term for cancers that are derived from the lymphatic system. Hodgkins disease is one type of lymphoma with all other lymphomas being grouped together as non-Hodgkins lymphoma. Lymphomas account for about 5% of all cases of cancer in this country. It is expected that approximately 55,000 new cases of nonHodgkins lymphoma will be diagnosed in the U.S. this year (out of an approximate 62,000 total lymphoma cases). It is expected that roughly 49% of the patients diagnosed with non-Hodgkins lymphoma will die within five years. Patients with non-Hodgkins lymphoma usually present with advanced stage III or IV disease. Patients with indolent (low-grade) disease tend to have cancers that grow very slowly and cause fewer symptoms. Aggressive lymphomas, also referred to as intermediate and high-grade lymphomas, tend to grow and spread quickly and to cause severe symptoms.
Lymphomas account for about 5% of all cases of cancer in this country. It is expected that approximately 55,000 new cases of non-Hodgkins lymphoma will be diagnosed in the U.S. this year (out of an approximate 62,000 total lymphoma cases).

Anatomy
The lymphatic system consists of lymph nodes (or lymph glands), lymphatics (the small vessels that link the lymph nodes) and the spleen. This system is responsible for returning excess fluid to circulation and fighting infections and cancers. The lymph nodes (which generally occur in clusters in the neck, armpits and groin) produce some white blood cells and antibodies that help protect against infection. The right lymphatic duct and the thoracic duct drain lymph fluids into two veins that come together to form the superior vena cava, which passes into the heart. The cisterna chyli is a widened portion of the thoracic duct, where fluids from several lymph-collecting vessels are received. The spleen removes and destroys worn-out red blood cells and helps fight infection.

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Exhibit 48: The Human Lymph System

Source: American Medical Association.

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Treatment
Exhibit 49: FDA-Approved Non-Hodgkins Lymphoma Therapies
FDA Approved Uses for Non-Hodgkin's Therapies
B rand Nam e Adriam ycin, Rubex BCNU , BiCNU Blenoxane C ytoxan, Neosar L eukeran M TX O ncovin R ituxan Velban Generic N ame doxorubicin carm ustine bleom ycin cyclophospham ide chlorambucil m ethotrexate vincristine rituximab vinblastine Mnfr. Various Bristol-M yers Bristol-M yers Various GlaxoSm ithkline Various Eli Lilly IDEC Various Indication Non-Hodgkin's 2nd line Palliative therapy of lym phomas Advanced lym phom as Palliative therapy of lym phomas Advanced non-Hodgkin's lymphom a Non-Hodgkin's Relapsed or refractory non-Hodgkin's Non-Hodgkin's A dmin. IV IV IV, Inj IV, Oral Oral IV, Inj, Oral IV IV IV

Source: Food and Drug Administration.

For the most part, regional radiation therapy is successful in treating patients whose disease remains relatively localized (only about 10% of patients with low-grade disease). Radiation offers long-term control, with rates of freedom from relapse ranging between 44% and 47% at ten years and survival rates of 75% in patients younger than 60. In more advanced stages, adjuvant chemotherapy may be used. The efficacy of chemotherapy in low-grade lymphoma has yet to be determined because curative treatment has yet to be established. Low-grade or indolent lymphomas are not curable with conventional therapies, although most patients respond well initially. The average survival duration for a patient with indolent lymphoma is seven to ten years. In the past, physicians typically started patients on the gentler chemotherapy regimens such as chloramabucil and prednisone or cyclophosphamide+vincristine+prednisone (CVP), and if the patient failed or if there was a disease recurrence, the physician would go to the next more intense therapy. However, as with other cancers, there is no set schedule and most often it is a subjective decision based on the individual patient, their disease state, their symptoms and the type of lymphoma. It is possible that if the patient is symptomatic and has relatively widespread disease, one would put them on cyclophosphamide+doxorubicin+vincristine+prednisone (CHOP) initially on the chance that it may cause remission sooner. Patients who relapse are usually not curable with conventional treatments, except for stem-cell transplantation, which has a high incidence of mortality associated with it. In more aggressive stages of lymphoma, use of a combination of chemotherapy and radiation therapy has been highly successful. The most common chemotherapeutic regimen appears to CHOP. Several years ago, there was a movement away from alkylating agents as initial therapy to other drugs like Berlexs Fludara as an initial therapy. Consequently, when the monoclonal antibodies came along, they rapidly moved into second place for the patients who failed initial therapy, but some physicians are beginning to use the antibodies as first-line therapy. Three purine nucleoside analogs have received FDA approval for use in low-grade lymphoma: Fludara, SuperGens NiPent and Johnson & Johnsons Leustatin. Fludara therapy can result in complete remission in 1540% of patients with low-grade disease; the rate tends to be higher in previously untreated individuals. Use of chlorambucil, CVP, Fludara or Rituxan are all reasonable front-line therapies. In recent years, newly developed immunotherapies have generated a good deal of enthusiasm. Recently, there have been some studies that indicate some chemotherapy can
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make the tumors more sensitive to the monoclonal antibodies. For instance, SmithKline and Coulters Bexxar, which combines a monoclonal antibody with radioactivity, is used primarily to treat the tumor mass itself, often called debulking. However, there are some studies that have recently been completed that suggest that if chemotherapy is given early, it may actually make Bexxar more effective. Most of the data that are available are in the indolent or low-grade lymphomas. There is an increasing body of data suggesting activity for the monoclonal antibodies in aggressive lymphomas, which also, for example, express CD-20, and about a third of patients with aggressive lymphoma will experience a response to single-agent Rituxan. There is some data combining CHOP, which is the most commonly used chemotherapy for aggressive lymphoma, with Rituxan showing very impressive response rates virtually everybody responding when administered as front-line therapy. And as a result of these results, there is a large trial being conducted by the Cancer & Leukemia B Group (CALGB) and the Houston Cooperative Oncology Group looking at CHOP with or without Rituxan in patients with aggressive lymphomas. This trial is in elderly patients, while IDEC has a trial in all age groups. Front-line use of the monoclonal antibodies is currently getting a lot of attention. Antibodies like Rituxan, Bexxar and Zevalin all target the same molecule, referred to as CD-20, which is present on most B-cell lymphomas. CD is a term that basically indicates a marker. These markers are different on lymphocytes; B-lymphocytes have certain types of markers, such as CD-20, CD-22 and CD-19, while T-lymphocytes would have other markers. Some of the other antibodies like Campath target different molecules. It is important to note that all of these antibody-based agents have different levels of activity. Importantly, they also have different toxicities. For example, Rituxan is an unconjugated antibody, which means that it is not bound to anything, its just a protein and it works by a number of mechanisms. Bexxar and Zevalin are bound to radioisotopes, Bexxar is bound to iodine, whereas Zevalin is bound to yttrium. Consequently, these therapies have the potential to be more toxic because radioactivity can suppress the bone marrow and the thyroid gland, and the suppression can be rather lengthy in durationit may last several months after one shot of the antibody. Bexxar contains I-131 or radiolabeled iodine, which can suppress the thyroid gland. That effect is sometimes blocked by giving the pre-treatment. Bexxar and Zevalin are referred to as conjugated or radiolabeled. Conceptually, these agents are a more targeted form of therapy. Essentially, the antibody drags the radiation to the tumor sites, providing local radiation and hopefully sparing normal organ tissue because not all cells express this specific antigen that these agents target on their surface. Rituxan is an unconjugated antibody; consequently, its side effects are not related to radiation, but rather to the infusion, which includes fever, chills and shakes.

iKnowMed Data: Non-Hodgkins Lymphoma


It appears as though the majority of patients (60%) with non-Hodgkins lymphoma receive a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). As is the case with many cancers, there is an increase in the number of agents used as second-line therapy. Twenty-five percent of patients receiving second-line therapy receive IDECs Rituxan. Fourteen percent of patients receive CHOP and 9% receive Berlexs Fludara.
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Exhibit 50: Various Regimens for Non-Hodgkins Lymphoma


CTX 1% RITUX-CHOP 1% FLUD-CTX 1% PROM 3%

Various 1st Line Regimens for Non-Hodgkin's Lymphoma

CHLOR 1%

FLUD 3%

CVP 6% OTHER 8%

CHOP 60%

FAMP 4% RITUX 4%

CNOP 8%

CTX-VP 1% PROM 1% DICE 1%

Various 2nd Line Regimens for Non-Hodgkin's Lymphoma

RITUX-CHOP 1% IFN 1% EPOCH 1% DHAP 2% CVP 5% MINE 6% RITUX 25%

CNOP 5%

FAMP 8%

CHOP 14%

ESHAP 8% FLUD 9% OTHER 12%

Source: iKnowMed.

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Exhibit 51: Acronyms for Non-Hodgkins Lymphoma Regimens

Acronym
CHLOR CHOP CNOP CTX CTX-VP CVP DHAP DICE EPOCH ESHAP FAMP FLUD FLUD-CTX IFN MINE OTHER PROM

Regimen
Leukeran cyclophosphamide + doxorubicin + vincristine + prednisone cyclophosphamide + Novantrone + vincristine + prednisone cyclophosphamide cyclophosphamide + etoposide cyclophosphamide + Novantrone cisplatin + cytarabine cisplatin + etoposide + Ifex cyclophosphamide + doxorubicin + vincristine + etoposide cisplatin + cytarabine + etoposide Fludara + Novantrone Fludara Fludara + cyclophosphamide interferon alpha Novantrone + Ifex + etoposide

bleomycin + cyclophosphamide + cytarabine + doxorubicin + etoposide + leucovorin + methotrexate + vincristine RITUX Rituxan RITUX-CHOP Rituxan + cyclophosphamide + doxorubicin + vincristine + prednisone
Source: UBS Warburg LLC.

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Ovarian Cancer
The American Cancer Society predicts that approximately 23,100 women will be diagnosed with ovarian cancer and 14,000 will die. Ovarian cancer causes more deaths than any other reproductive organ cancer. More than 50% of the women diagnosed are over the age of 65. If ovarian cancer is detected when it is in a localized stage, treatment will usually result in 95% survival at five years. However, only 25% of ovarian cancers are detected at an early stage.
The American Cancer Society predicts that approximately 23,100 women will be diagnosed with ovarian cancer and 14,000 will die. Ovarian cancer causes more deaths than any other reproductive organ cancer.

Anatomy
The ovaries are located on either side of the female pelvis. The ovaries are responsible for producing eggs and are the main source of the female hormones progesterone and estrogen.
Exhibit 52: The Female Reproductive Organs

Source: The Merck Manual.

There are three main types of ovarian malignancies, each named for their site of origin. The most common type is epithelial cell cancer. This tumor type originates in the cells that line the ovary. Epithelial carcinoma is the fourth most frequent cause of cancerrelated death in women. A second form of ovarian cancer is germ cell, which originates in the eggs of the ovary. Germ cell cancers account for approximately 5% of ovarian cancers. The final type is referred to as stromal cell. Stromal cells are the cells that essentially hold the ovary together and are responsible for production of the ovarian hormones. Stromal tumors are rare, accounting for only about 5% of ovarian cancers. Approximately 510% of cancers have a distinct genetic component with three common hereditary patterns: ovarian cancer alone, ovarian and breast cancer, ovarian and colon cancer. The most important risk factor for ovarian cancer is a first-degree relative with the disease. In most families with breast and ovarian cancer, a genetic linkage has been identified on the BRCA1 locus on chromosome 17.

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It appears as though the ovarian cancer-associated antigen, CA 125, has no prognostic significance when measured at the time of diagnosis. However, it does have a high correlation with survival when measured one month after the third course of chemotherapy in patients with stage III and IV disease. Patients with ovarian cancer often go symptom-free if the disease is in its early stages. Consequently, the majority of patients have widespread disease at the time of diagnosis and yearly mortality is approximately 65%. Patients with stage III and IV disease on platinum-based therapies have a five-year survival rate of less than 10%. Importantly, however, if detected early, ovarian cancer is highly curable.

Treatment
Exhibit 53: FDA-Approved Ovarian Cancer Therapies
FDA Approved Uses for Ovarian Cancer Therapies
Brand Name Adriamycin, Rubex Alkeran Cytoxan, Neosar Doxil Hexalen Hycamtin Hydrea Paraplatin Platinol, Cisplatin Taxol Thiotepa Generic Name doxorubicin melphalan cyclophosphamide liposomal doxorubicin altretamine topotecan hydroxyurea carboplatin cisplatin paclitaxel thiotepa Mnfr. Various GlaxoSmithkline Various Alza US Bioscience GlaxoSmithkline Various Bristol-Myers Various Bristol-Myers Immunex Indication Carcinoma Non-resectable epithelial Carcinoma Epithelial carcinoma - 3rd line Palliative Carcinoma - 2nd line Advanced carcinoma Carcinoma - 1st line and palliative Carcinoma - metastatic Epithelial carcinoma - 1st line in combination with Platinol Adenocarcinoma Admin. IV Inj, Oral IV, Oral IV Oral IV IV IV IV IV IV, Inj

Source: Food and Drug Administration.

Currently, it is thought that all patients with advanced-stage and most patients with early-stage ovarian cancer should receive post-operative systemic chemotherapy. Prior to the 1980s, alkylating agents were the primary agents used. These agents produced response rates of 4050% in previously untreated patients. Currently, the majority of patients with ovarian cancer receive a platinum-based therapy as their initial course with overall response rates of 7080%. A large meta-analysis examined data from 8,000 patients and suggested that platinum-based combination therapy was superior to platinum-based chemotherapy alone in overall response and progression-free survival, but not in overall survival. During the 1980s, the taxanes were introduced. These agents demonstrated significant responses in platinum-refractory recurrent ovarian cancer; consequently, they were quickly adopted as part of first-line therapy. The only approved first-line therapies for ovarian cancer are Bristols Paraplatin (carboplatin) and Taxol. Taxols approved indication is for combination use with cisplatin. However, it appears that a majority of patients with ovarian cancer receive a combination of Taxol and Paraplatin as initial therapy. This may be due to Paraplatins more favorable side-effect profile. Other less widely used therapies in the initial treatment of ovarian cancer include cisplatin and cyclophosphamide, cisplatin and Taxol, Paraplatin and cyclophosphamide, SmithKlines Hycamtin and Alzas Doxil.

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Despite the advances in treatment, only a small fraction of patients are cured with current therapies. Typically, first-line therapy consists of a taxane in combination with a platinum-based compound. Unfortunately, 50% of women will relapse within six months after this treatment regimen, while the other 50% will relapse later. Once ovarian cancer recurs, the chances of a complete response with any therapy are extraordinarily small. The treatment options for second-line ovarian cancer are much greater. This may be due to the incidence of tumors that become resistant to platinumbased therapies. SmithKlines Hycamtin is approved for therapy after patients have failed their initial regimen. Doxorubicin has a similar indication. Notably, Alzas Doxil, which is a liposomal formulation of doxorubicin, has shown solid efficacy in refractory ovarian cancer. Patients are classified as having platinum-sensitive disease when recurrence occurs more than six months after the completion of platinum-based chemotherapy. The cancer is considered platinum-resistant if it progresses during platinum-based therapy or prior to six months after completion of treatment. Currently, it appears as though 15% of patients are platinum sensitive after relapse. Of the agents approved for secondline therapy, the ones that have the highest response rates in platinum- and taxanerefractory disease are Hycamtin, Vepesid, Doxil and Gemzar.

iKnowMed Data: Ovarian Cancer


An overwhelming majority (77%) of patients will receive a combination of Bristols Paraplatin and Taxol as first-line therapy for ovarian cancer. If a patient relapses, the therapeutic options increase significantly. Thirty-three percent of patients receive SBs Hycamtin as a second-line therapy. Nineteen percent receive the combination of Paraplatin and Taxol and 14% receive Alzas Doxil.
Exhibit 54: Various Regimens for Ovarian Cancer
DOXIL 1% HYC 3% CC 4% OTHER 4%

Various 1st Line Regimens for Ovarian Cancer

CIS-TAX 1%

CP 10%

CARB-TAX 77%

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Exhibit 54 contd: Various Regimens for Ovarian Cancer Various 2nd Line Regimens for AC 1% Therapy of Ovarian Cancer
VIN 1% ALT 2%

5FU 1% 5FU-LEUC 0%

GEM 2%

TAX 6% HYC 33%

CP 3%

TXT 6%

OTHER 12% CARB-TAX 19% DOXIL 14%

Source: iKnowMed.

Exhibit 55: Acronyms for Ovarian Cancer Regimens

Acronym
5FU 5FU-LEUC AC ALT CARB-TAX CC CIS-TAX CP DOXIL GEM HYC OTHER TAX TXT VIN

Regimen
5-fluorouracil 5-fluorouracil + leucovorin adriamycin (doxorubicin) + cyclophosphamide Hexalen Paraplatin + Taxol cisplatin + cyclophosphamide cisplatin + Taxol Paraplatin + cyclophosphamide Doxil Gemzar Hycamtin Taxol Taxotere Navelbine

Source: UBS Warburg LLC.

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Bladder Cancer
Every year, approximately 53,000 Americans learn that they have bladder cancer. The American Cancer Society estimates that approximately 12,200 will die of this disease. Bladder cancer appears to be more prevalent in men than in women. It is clear by looking at the survival curves for bladder cancer that early detection is key. Fortunately, bladder cancer is often found early, which results in a five-year survival rate of 94%. If the cancer spreads to nearby organs in the pelvis, the five-year survival rate drops to 49%. If distant metastases are present, the five-year survival rate is only 6%.

Anatomy
Bladder cancer, as the name indicates, originates in the bladder, the muscular pouch that stores the bodys urine.
Exhibit 56: The Male and Female Excretory Systems

Source: American Medical Association.

Urine is emptied through a small tube called the urethra. The wall of the bladder consists of several layers. The innermost layer of cells is referred to as the transitional layer. These transitional cells are also present in the kidney and the tubes that connect the kidney to the bladder, the ureters. Consequently, if cancer develops in the bladder, it could likely affect these structures as well. There are three main types of tumors that can develop in the bladder. The first is the aforementioned transitional cell carcinoma, which accounts for approximately 90% of all bladder cancers. Cancer that is confined to the lining of the bladder is referred to as superficial bladder cancer. In some instances, cancer that begins as transitional cell spreads through the lining of the bladder and invades the muscular wall. This is known as invasive bladder cancer. The second major type of bladder cancer is squamous-cell carcinoma, which accounts for approximately 8% of cases. Squamous-cell carcinomas
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have a greater propensity to invade other cell layers of the bladder. The final major type of bladder cancer is adenocarcinoma, which accounts for approximately 12% of all cases. Some studies have indicated that the tumor suppressor gene p53 is associated with a poor prognosis in individuals diagnosed with bladder cancer. A retrospective study of 243 patients with invasive bladder cancer found that the presence of p53 was an independent predictor of recurrence.

Treatment
Exhibit 57: FDA-Approved Bladder Cancer Therapies
FDA Approved Uses for Bladder Cancer Therapies
Brand Name Adriamycin, Rubex BCG, TheraCys, TICE Platinol, Cisplatin Thiotepa Valstar Generic Name doxorubicin BCG vaccine cisplatin thiotepa valrubicin Mnfr. Various Organon Various Immunex Anthra Indication Transitional cell carcinoma Carcinoma in situ Carcinoma - metastatic Carcinoma - intravesicular BCG refractory in patients who cannot tolerate surgery Admin. IV IV, Inj IV IV IV

Source: Food and Drug Administration.

In noninvasive bladder cancer, intravesical treatment with chemotherapeutic agents such as thiotepa, mitomycin C, doxorubicin, or with immunotherapeutic agents such as Bacillus Calmette-Guerin (BCG) have demonstrated effectiveness when administered to patients with multiple tumors or prophylactically following transurethral resection (TURP). BCG has shown superior protection from tumor recurrence and prevention of disease progression as compared to thiotepa, mitomycin C and doxorubicin. BCG is a live, attenuated culture preparation of the bacillus Calmette-Guerin strain of mycobacterium bovis. Unlike conventional intravesical chemotherapeutic agents that attack tumor cells directly, BCG is a biological response modifier that is believed to exert its antitumor effect by stimulating various immune responses within the host. Invasive bladder cancer is one of the more chemosensitive forms of cancer and patients tend to display objective responses in about 50% of the cases. In clinical trials, chemotherapy is used as neoadjuvant or adjuvant treatment of invasive bladder cancer. Cisplatin as a single agent and/or in combination regimens is the cornerstone of invasive bladder cancer therapy. There are only a handful of therapies that are officially approved for the first-line treatment of bladder cancer. A combination of methotrexate, vinblastine, doxorubicin and cisplatin, commonly referred to as MVAC, is the current gold standard for transitional cell carcinoma. It is the only therapeutic regimen with a proven survival benefit in locally advanced or metastatic disease with median survival approaching one year.

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New agents in clinical trials are revealing equivalent response rates to MVAC, but with less toxicity. These agents include antifolates (trimetrexate and piritrexim), Lillys Gemzar, taxanes (Taxol and Taxotere), ifosfamide, 5-FU and gallium. However, MVAC continues to be the standard for neoadjuvant and adjuvant therapy of muscle invasive and metastatic bladder cancer. Apparently, in both first- and second-line therapies, the use of Paraplatin and Taxol is relatively widespread, even though neither drug is approved for bladder cancer. Recently, data on a combination of Gemzar and cisplatin versus MVAC showed that the Gemzar arm had equivalent efficacy but significantly better safety and tolerability. The FDA did not recommend approval for this indication. However, Lilly believes that approximately 50% of the U.S. bladder cancer market is currently using this product off-label.

iKnowMed Data: Bladder Cancer


As the following pie chart indicates, approximately 35% of patients receive MVAC as their initial therapy for bladder cancer, followed by 26% who receive Bristols Paraplatin. For patients who relapse, possible therapies include Paraplatin/Taxol (28%), Taxol (22%), MVAC (17%) and Gemzar (11%).
Exhibit 58: Various Regimens for Bladder Cancer
CIS-TAX 2% 5FU-CARB 2% 5FU-LEUC 2%

Various 1st Line Regimens for Bladder Cancer

CIS 4% CMV 5%

5FU 5% TAX 6% 5FU-CIS 6%

MVAC 35%

OTHER 7%

CARB-TAX 26%

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Exhibit 58 contd: Various Regimens for Bladder Cancer Various 2nd Line Regimens for Bladder Cancer

CMV 5% GEM 11% CARB-TAX 28%

OTHER 17%

MVAC 17%

TAX 22%

Source: iknowMed.

Exhibit 59: Acronyms for Bladder Cancer Regimens

Acronym
5FU 5FU-CARB 5FU-CIS 5FU-LEUC CARB-TAX CIS CIS-TAX CMV GEM MVAC OTHER TAX

Regimen
5-fluorouracil 5-fluoruracil + Paraplatin 5-fluorouracil + cisplatin 5-fluorouracil + leucovorin Paraplatin + Taxol cisplatin cisplatin + Taxol cisplatin + methotrexate + vinblastine Gemzar methotrexate + vinblastine + doxorubicin + cisplatin Taxol

Source: UBS Warburg LLC.

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Pancreatic Cancer
The American Cancer Society expects that approximately 28,000 people will be diagnosed with pancreatic cancer this year. The incidence is equally distributed between both men and women and is the fourth-leading cause of cancer death in both. In almost 50% of the patients, the tumor has already metastasized at the time of diagnosis. The one-year survival rate is only 18% and the five-year rate, only 3%.
Approximately 28,000 people will be diagnosed with pancreatic cancer this year. The oneyear survival rate is only 18%; the fiveyear rate, only 3%.

Anatomy
The pancreas is a glandular organ located deep in the abdomen, behind the stomach but in front of the spine. It is approximately six inches long and produces hormones and pancreatic juices that enable digestion. The pancreatic juices are transported along a series of ducts that ultimately empty in the small intestine. The pancreas is responsible for secreting two antagonistic hormones, insulin and glucagon, that are vital to proper metabolism.
Exhibit 60: The Human Pancreas

Source: American Medical Association.

Approximately 95% of pancreatic cancers originate in the ducts and are referred to as adenocarcinomas. A very rare type of pancreatic cancer originates in the cells that produce insulin and glucagon; these cells are termed the islets. Patients with these types of tumors have a better prognosis than patients with other types of pancreatic cancer.

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Treatment
Exhibit 61: FDA-Approved Pancreatic Cancer Therapies

FDA Approved Uses for Pancreatic Cancer Therapies


Brand Name Adrucil Gemzar Mitomycin, Mutamycin Zanosar Generic Name 5-FU, fluorouracil gemcitabine mitomycin streptozocin Mnfr. Various Eli Lilly Various Pharmacia Indication Admin. Carcinoma - palliative IV, Oral Carcinoma - advanced IV Adenocarcinoma IV Carcinoma - palliative IV

Source: Food and Drug Administration.

Unfortunately, as stated previously, most patients present with pancreatic cancer that cannot be removed surgically. Consequently, one of the few options is chemotherapy. However, clinical results have been poor. Most patients are severally debilitated and too weakened to undergo extensive chemotherapy. Additionally, individuals with pancreatic cancer exhibit physiological conditions that make it difficult to differentiate the side effects of therapy from disease progression. Several agents have been used as single agents where results have been minimally effective: 5FU, mitomycin C, streptozocin, ifosfamide and doxorubicin. Unfortunately, response rates using combinations of agents (streptozocin + mitomycin C + 5FU) have not shown any survival advantage over single agents. One agent that has shown some promise is Lillys Gemzar, which shows prolonged survival and a relatively mild side-effect profile.

iKnowMed Data: Pancreatic Cancer


In both first- and second-line cancer therapy, Lillys Gemzar is the predominant therapy, with 61% of patients and 49% of patients receiving it as first- and second-line therapy, respectively. Twenty-four percent of patients receive 5-FU in both first- and second-line regimens.

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Exhibit 62: Various Regimens for Pancreatic Cancer


GEM-XEL 2% OTHER 3% 5FU-LEUC 9%

Various 1st Line Regimens for Pancreatic Cancer

GEM-CDDP 1%

5FU 24%

GEM 61%

Various 2nd Line Regimens for Pancreatic Cancer

OTHER 13%

5FU-LEUC 14% GEM 49%

5FU 24%

Source: iKnowMed.

Exhibit 63: Acronyms for Pancreatic Cancer Regimens

Acronym
5FU 5FU-LEUC GEM GEM + CDDP GEM-XEL OTHER

Regimen
5-fluorouracil 5-fluorouracil + leucovorin Gemzar Gemzar + cisplatin Gemzar + Xeloda

Source: UBS Warburg LLC.

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Prostate Cancer
This year, the American Cancer Society expects 180,000 men to be diagnosed with prostate cancer and approximately 32,000 to die. There was a remarkable increase in the incidence of prostate cancer between 1976 and 1994, which was likely due to increased awareness and prostate-specific antigen (PSA) screening. The rate of incidence has since leveled off. Prior to 1990, the death rate from prostate cancer was increasing, but the death rate in the period from 1990 to 1995 dropped from 26.5% to 17.3%. A large part of the reduction was caused by early diagnosis, in addition to improved treatment modalities. The five-year survival rate for men with prostate cancer is 89%, and 63% of men will live at least ten years. If the cancer is found before it metastasizes outside of the prostate, the five-year survival rate is 100%. If it has spread to tissues near the prostate, the survival rate drops to 94%. Even if distant metastases are present, at least 31% of men will survive for five years.

Anatomy
The prostate gland is a walnut-sized gland located just below the bladder. The tube that carries urine, the urethra, runs through the prostate. The prostate is responsible for secreting some of the fluid contained in semen. Nerves found next to the prostate are responsible for causing an erection; consequently, damage to these nerves can result in impotence. The prostate gland is composed of three major sections: the central zone, the peripheral zone and the transitional zone. The large peripheral zone is the most common site for cancer.
Exhibit 64: The Male Genitourinary Tract

Source: American Medical Association.

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Treatment
Exhibit 65: FDA-Approved Prostate Cancer Therapies
FDA Approved Uses for Prosate Cancer Therapies
Brand Name Casodex Emcyt Eulexin Lupron Novantrone Stilphostrol Trelstar Generic Name bicalutamide estramustine flutamide leuprolide mitoxantrone diethylstilbestrol triptorelin Mnfr. AstraZeneca Pharmacia Schering-Plough TAP Immunex Various Pharmacia Indication 1st line in combination with LHRH analog Carcinoma - advanced, palliative 1st line in combination with LHRH analog Carcinoma - advanced, palliative Reduction of pain in combination with prednisone Carcinoma - advanced palliative treatment of advanced prostate cancer in patients whom orchiectomy or estrogen administration is not indicated or not acceptable Carcinoma - advanced, palliative Carcinoma - advanced, palliative

Viadur Zoladex

leuprolide implant goserelin

Alza AstraZeneca

Source: Food and Drug Administration.

Approximately 95% of prostate cancers can be defined as adenocarcinomas. Of the remaining 5%, greater than 90% are transitional cell carcinomas. All prostate cancers arise from what are referred to as glandular epithelial cells. Epithelial cells have a long progression before they become malignant. Premalignant changes can be present for up to ten years before cancer is diagnosed.

Hormone Therapy
In advanced prostate cancer, it is often necessary to manipulate the patients androgen levels, primarily testosterone. (Male sex hormones are often referred to as androgens.) There are three primary tissues that comprise prostate cancer cells: androgendependent, androgen-sensitive and androgen-independent. Androgen secretion is dependent on the secretion of luteinizing hormone releasing hormone (LHRH), which is secreted from the hypothalamus (a small gland at the base of the brain). LHRH stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These two hormones then act locally on the testis to produce most of the androgens. The ultimate goal of hormone therapy is to decrease the level of circulating androgens. By reducing levels of androgen, one can effectively eliminate those androgen-dependent cells in the tumor and halt the growth of the androgen-sensitive cells, thereby reducing the overall size of the tumor. Hormonal therapy is not curative, but can produce a reduction in symptoms. Clearly, one of the most efficient ways to reduce circulating androgen levels is by surgical removal of the testes (orchiectomy). Testosterone levels are reduced by 9095% after orchiectomy. Estrogen therapy blocks LHRH, effectively blocking production of testosterone; however, the cardiovascular side effects associated with estrogen make its use slightly more risky than some of the current hormonal agents. In the early 1990s, a definitive study was performed that showed AstraZenecas Zoladex (an LHRH agonist) was as effective in lowering blood levels of testosterone in previously untreated patients with metastatic carcinoma as surgical castration. Additionally, response rates, time to treatment failure and overall survival rates were equivalent in
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the two groups. Currently, the LHRH agonists are considered the standard of care. However, these agents are not without their drawbacks. These compounds will initially increase testosterone levels. It is not until after several days of therapy that testosterone levels begin to fall to a castration level. The surge of testosterone levels after therapy has commenced is referred to as a flare. During a flare, the patient is likely to experience increased pain and bladder obstruction. However, administering an antiandrogen (i.e., AstraZenecas Casodex or Scherings Eulexin) before the LHRH agonist may reduce the flare. Combining an antiandrogen with an LHRH agonist is referred to as total androgen ablation. Notably, a meta-analysis of 22 randomized trials, comprising 5,710 patients with advanced prostate cancer, failed to show a statistically significant difference in five-year survival rates between those patients who received total androgen ablation versus those who underwent surgical castration, although some believe that total androgen ablation may increase the time before tumor progression. Importantly, patients tend to respond well to hormonal therapy, on average, 7090% of the time, and sometimes responses can last for several years. A new addition to this market is Alzas Viadur. On March 6, the FDA approved Viadur, a once-yearly implant for the palliative treatment of advanced prostate cancer. This is the first product to provide continuous, 12-month testosterone suppression with a single treatment. Viadurs active compound is leuprolide, which is the same as TAPs Lupron, although the TAP products must be given every three or four months. The FDAs approval was based on two open-label, multicenter studies in 131 patients with advanced prostate cancer who were treated with Viadur and evaluated for up to two years. Following the initial surgical insertion of the implant, mean serum testosterone concentrations decreased to therapeutically desirable levels by week four in 99% of the patients. Once testosterone suppression was obtained, testosterone levels remained suppressed for the duration of the 12 months. This product is expected to launch in early 2001 and will be marketed by Bayer. Additionally, on June 15, Pharmacia received approval of Trelstar (triptorelin) for the palliative treatment of advanced prostate cancer in patients for whom orchiectomy or estrogen administration is not indicated or not acceptable. Trelstar is administered as an injection given once a month. The data for approval indicated that following a single IM injection of Trelstar to healthy male volunteers, serum testosterone levels first increased, peaking on day 4, and declined thereafter to low levels by week 4. Similar testosterone profiles were observed in patients with advanced prostate cancer when injected with Trelstar Depot. In healthy volunteers, testosterone serum levels returned to near baseline by week 8. Trelstar Depot was studied in a randomized, active control trial of 277 men, ages 47 to 89, with advanced prostate cancer. Patients were given either Trelstar or an approved GnRH agonist monthly for nine months. The primary efficacy results were both achievement of castration by day 29 and maintenance of castration from day 57 through day 253. Castration levels of serum testosterone were achieved in 91.2% of Trelstar patients at day 29 and in 97.7% of patients at day 57. One notable compound under development is Amgen/Praeciss Abarelix. This is a peptide antagonist, which inhibits the action of LHRH on the pituitary. Abarelixdepot-M is currently in phase III trials in patients with hormonally responsive prostate cancer. At ASCO this past year, two trials were presented on Abarelix. In one trial, 270
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patients with hormone-responsive prostate cancer were randomized to either Abarelix (n=180) or TAPs Lupron (n=91). All of the patients in the Abarelix arm avoided the testosterone flare, whereas in the Lupron arm, 18% of patients had such a flare. Seventy-two percent of patients on Abarelix achieved complete testosterone suppression after one week of therapy, whereas none of the patients in the Lupron arm did at one week. Similar results were reported in a second trial that looked at a total of 255 patients who were randomized to Abarelix (n=170) or Lupron plus AstraZenecas Casodex (n=85). Again, all patients in the Abarelix arm avoided the testosterone surge, whereas 14% of those in the Lupron-Casodex arm suffered flares. Sixty-eight percent of patients on Abarelix achieved complete testosterone suppression after one week, whereas no patient in the Lupron/Casodex arm did. All results were statistically significant. When a patient fails to respond to hormone therapy, the cancer is referred to as hormone-refractory prostate cancer (HRPC). At this point, antineoplastic therapy may be an option. Over the past several years, research has produced several drug regimens that enhance the quality of life of patients with HRPC. Unfortunately, none of these drug combinations has been shown to improve survival. Multidrug resistance is a possible explanation for the failure of patients to respond to chemotherapy. Some drugs that could be useful in HRPC include oral cyclophosphamide, estramustine in combination with Taxotere, or ketoconazole plus doxorubicin. Phase III trials are needed to compare the current standard of mitoxantrone plus steroid to these other drug combinations to identify the best combination for improving quality of life and perhaps affecting survival.
Exhibit 66: Total Prescription Trends for Oral Prostate Cancer Therapies
Total Prescriptions (TRXs) in Thousands
Total Prostate Cancer Market Jun-99 85 Jul-99 84 Aug-99 84 Sep-99 82 Oct-99 83 Nov-99 82 Dec-99 84 Jan-00 79 Feb-00 77 Mar-00 83 Apr-00 79 May-00 86 Jun-00 83

Growth (year/year)
Casodex (AZN) Emcyt (PHA) Eulexin (SGP) Total Generic Leuprolide Lupron Lupron Depot Lupron Depot-3 Mo. Lupron Depot-4mo. Lupron Depot-Ped Total Lupron (TAP) Total Generic Diethylstilbestrol Zoladex (AZN) Total Prostate Cancer Market 15% 11% -19% N/A -17% -2% -4% 173% 16% 0% -19% 10% 3% 11% 14% -16% N/A -28% -2% 13% 112% 19% 2% -60% -9% 3% 12% 8% -16% N/A -33% -1% 12% 113% 7% 2% -35% 12% 4% 9% 7% -13% N/A -19% -2% 5% 64% 4% 0% -44% 3% 3% 5% 10% -16% N/A -35% -5% -7% 67% 12% -3% -41% 5% 0% 9% 12% -13% 74400% -32% -4% 1% 69% 12% -1% 15% 21% 3% 6% 9% -13% 3304% -35% -6% -7% 41% -1% -5% -35% -9% 0% 3% 17% -18% 405% -30% -8% 8% 42% -5% -5% -31% 3% -1% 6% 39% -14% 151% -26% -5% 0% 35% 1% -3% -24% 7% 1% -2% 33% -17% 202% -30% -15% 1% 20% -7% -12% -45% -15% -5% -2% 28% -16% 193% -22% -13% -9% 33% -6% -11% -12% 0% -4% 8% 31% -8% 270% -7% -2% 4% 44% 3% 0% -37% 1% 5% 2% 26% -13% 96% -30% -7% 6% 14% -8% -6% -75% -15% -2%

Market Share
Casodex (AZN) Emcyt (PHA) Eulexin (SGP) Total Generic Leuprolide Lupron Lupron Depot Lupron Depot-3 Mo. Lupron Depot-4mo. Lupron Depot-Ped Total Lupron (TAP) Total Generic Diethylstilbestrol Zoladex (AZN) Total Prostate Cancer Market 49.3% 1.8% 22.0% 1.3% 7.3% 18.7% 2.2% 0.5% 2.2% 23.5% 0.3% 1.7% 100.0% 49.5% 1.8% 22.3% 1.6% 6.6% 18.3% 2.2% 0.5% 2.2% 23.2% 0.2% 1.4% 100.0% 49.6% 1.9% 21.8% 1.7% 6.0% 18.4% 2.4% 0.5% 2.1% 23.4% 0.2% 1.6% 100.0% 49.4% 1.8% 22.0% 2.1% 6.5% 18.3% 2.1% 0.5% 2.0% 22.9% 0.2% 1.6% 100.0% 49.4% 1.8% 21.6% 2.5% 6.8% 18.1% 2.3% 0.5% 2.2% 23.0% 0.2% 1.5% 100.0% 50.1% 1.9% 21.1% 1.8% 5.7% 18.2% 2.3% 0.5% 2.3% 23.3% 0.3% 1.6% 100.0% 51.1% 1.9% 21.4% 2.0% 5.0% 17.3% 2.1% 0.5% 2.1% 22.0% 0.2% 1.4% 100.0% 50.1% 2.1% 20.4% 3.2% 7.1% 17.4% 2.5% 0.5% 2.0% 22.5% 0.2% 1.6% 100.0% 50.7% 2.2% 20.1% 2.7% 6.4% 17.4% 2.3% 0.5% 2.2% 22.4% 0.2% 1.6% 100.0% 50.1% 2.3% 20.5% 3.0% 5.7% 17.3% 2.5% 0.6% 2.1% 22.6% 0.2% 1.4% 100.0% 50.2% 2.2% 19.8% 3.8% 6.6% 17.3% 2.3% 0.6% 2.0% 22.2% 0.3% 1.5% 100.0% 50.2% 2.4% 19.6% 3.7% 6.4% 17.4% 2.3% 0.6% 2.1% 22.5% 0.2% 1.4% 100.0% 51.2% 2.4% 19.6% 2.6% 5.2% 17.7% 2.3% 0.6% 2.0% 22.7% 0.1% 1.4% 100.0%

Source: IMS America.

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Company Cancer Portfolios

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Introduction
In this section, we provide an overview on each companys cancer product portfolio. Additionally, for the domestic companies officially covered by UBS Warburg LLC, we provide an analysis regarding the investment significance of these particular products to their respective companies.
Exhibit 67: Leaders in the Oncology Market

Top Ten Oncology Companies


Company Bristol-Myers Squibb AstraZeneca TAP Pharmaceuticals Aventis Pharmacia Roche/Genentech Eli Lilly Schering-Plough Takeda GlaxoSmithKline Total Market
Source: MedAdNews.

1999 Worldwide Sales in Millions 2,376.0 1,739.0 730.0 689.6 564.4 489.3 455.8 455.0 298.0 221.2 10,138.5

Market Share 23.4% 17.2% 7.2% 6.8% 5.6% 4.8% 4.5% 4.5% 2.9% 2.2% 100.0%

Alza
Drug Data
Doxil (Liposomal Doxorubicin)
Doxil is the anthracycline antibiotic encapsulated in Alzas patented stealth liposomes. At this years American Society of Clinical Oncology (ASCO) meeting in May, a large head-to-head trial comparing Doxil to SmithKlines Hycamtin found minimal differences between the two regimens for treating patients with relapsed ovarian cancer. However, Doxil did slightly better in patients with platinum-sensitive disease and it caused a much lower incidence of hematological toxicity. Currently, both Doxil and Hycamtin are approved in the U.S. for second-line treatment of ovarian cancer. In the trial, 474 patients who had failed first-line, platinumbased therapy were randomly assigned to Doxil once every four weeks as a one-hour infusion or a 30-minute IV infusion of Hycamtin for five days every three weeks. There was no significant difference between the two treatment arms for the median time to disease progression, 18.4 weeks for Doxil and 18.3 weeks for Hycamtin. Additionally, there was no significant difference between objective response or median overall survival. However, there was a significant difference in the subset of patients with platinum-sensitive disease. Patients in the Doxil arm showed a significantly better median overall survival of 86.1 weeks versus 63.6 weeks in the Hycamtin arm (p=0.012). Regarding adverse events, the Hycamtin arm experienced a high degree of hematological toxicity, with 81% of patients experiencing some level of neutropenia
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and 72% experiencing some level of anemia. In the Doxil arm, 49% of patients experienced hand-foot syndrome, also known as Palmar-Plantar Erythrodysesthesia (PPE), a tingly sensation in the palms of the hands and the soles of the feet, and 40% experienced stomatitis, soreness of the mouth. Importantly, patients on Doxil do not need any stem cell support, whereas patients on Hycamtin do. Regarding the interesting results in the platinum-sensitive patients, the trial was not designed to show this difference and, consequently, it was unexpected. The exact mechanism behind this result remains unclear. It is possible that Doxil is less likely to induce multi-drug resistance. Importantly, the point of the study was to show that there is no disadvantage to using Doxil before Hycamtin. Schering-Plough has rights to Doxil outside the U.S., where it is branded as Caelyx. Currently, Schering is conducting a large trial in breast cancer, as is the Eastern Oncology Cooperative Group (ECOG). Other researchers are looking at Doxils role in breast cancer therapy when combined with Genentechs Herceptin. Alza is looking at Doxil in patients with multiple myeloma who have failed anthracycline therapy, and a possible new drug application (NDA) could be filed in late 2000 or early 2001.

Ethyol (Amifostine)
Ethyol is the first broad-spectrum cytoprotective agent to gain regulatory approval. Broad spectrum refers to cytoprotection against a broad array of cytotoxic therapies (i.e., multiple drug classes as well as radiation, in multiple organ systems). However, it remains unclear as to the chemoprotective effects of Ethyol in the central nervous system. Ethyol is currently indicated for the reduction of chemotherapy-related toxicity in head and neck cancers as well as a reduction in the cumulative renal toxicity associated with the use of cisplatin, a commonly used platinum-based chemotherapy agent. The principal toxicities associated with Ethyol include nausea and vomiting and hypotension, typically characterized by a transient reduction in blood pressure. These toxicities are dose related. On October 4, data from a phase III, open-label, prospective multicenter randomized trial, which involved more than 300 patients with head and neck cancer, were presented. This trial demonstrated that approximately one month following treatment, 78% patients given radiation alone experienced moderate to severe xerostomia (dry mouth), compared with 51% of patients treated with Ethyol prior to radiation. This was a 35% reduction in the incidence of moderate to severe dry mouth. Additionally, one year after the completion of radiotherapy, 72% of the patients receiving Ethyol could produce a clinically relevant volume of saliva, compared with only 49% of patients who did not receive Ethyol.

Viadur (Leuprolide Implant)


On March 6, the FDA approved Viadur, a once-yearly implant for the palliative treatment of advanced prostate cancer. This is the first product to provide continuous, 12-month testosterone suppression with a single treatment. Viadurs active compound is the LHRH agonist, leuprolide. Currently, leuprolide is delivered by injections given every one, three or four months. The FDAs approval was based on two open-label, multicenter studies in 131 patients with advanced prostate cancer who were treated
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with Viadur and evaluated for up to two years. Following the initial surgical insertion of the implant, mean serum testosterone concentrations decreased to therapeutically desirable levels by week four in 99% of the patients. Once testosterone suppression was obtained, testosterone levels remained suppressed for the duration of the 12 months. On April 5, Alza and Bayer announced that the companies had entered into a U.S. commercialization agreement for Viadur. Under the terms of the agreement, Bayer will have the commercial rights to Viadur in the U.S. through 2015. Alza will manufacture the product for Bayer. The companies anticipate launching this product in early 2001.

American Home Products


Investment Summary
Minimal Investment Significance; Not Really a Key Player in Oncology Market
Mylotarg represents American Homes most recent foray into the oncology market, and it appears as though the major development pipeline centers around cell-cycle modifiers that are derivatives of Rapamune, such as the phase I product CCI-779. The market potential for Mylotarg is not that significant. The current indication for acute myeloid leukemia encompasses a patient population of approximately 10,000. Consequently, we do not have specific revenue assumptions for Mylotarg built into our model. American Home markets a handful of other cancer or cancer-related products such as Neumega, Isovorin/Leucovorin, Nipent, Novantrone and Thioplex. With the exception of Neumega, all of these products are marketed by American Home outside of the United States. As a point of reference, these products had U.S. sales of approximately $134 million during 1999, according to IMS Health.

Drug Data
Mylotarg (Gemtuzumab Ozogamicin)
Mylotarg is the first in a new class of anticancer therapies known as antibody-targeted chemotherapy. The product was jointly developed by American Home and Celltech. It is an injectable humanized monoclonal antibody targeting CD-33 linked to the cytotoxic agent clicheamicin, which is a highly potent antitumor antibiotic. It is currently approved for the treatment of CD-33 positive relapsed adult acute myeloid leukemia (AML). The CD-33 antigen is a glycoprotein commonly found on leukemic cells. This antigen is also found on other bone marrow hematopoietic cells, but not on pluripotent progenitor cells; consequently, the overall toxicity to blood cells is limited. In 1999, American Home obtained the license to market Mylotarg in the U.S. and Europe. Mylotarg, known generically as gemtuzumab ozogamicin, is currently approved for the treatment of patients 60 years and older in first relapse with CD33-positive acute myeloid leukemia (AML) who are not considered candidates for cytotoxic chemotherapy. On March 17, an FDA advisory committee recommended accelerated approval for acute relapsed AML in patients 60 years and older but against approval in the general population, citing efficacy concerns. The efficacy was not shown to be comparable to that of conventional salvage regimens; however, there was sufficient evidence to support improved safety in the treatment of CD-33 positive relapsed AML.
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At this years ASCO meeting, pooled data from three open-label international multicenter phase II clinical trials showed that the product resulted in prolonged survival. One hundred forty-two patients were given Mylotarg in two infusions at 14-day intervals. Remission was achieved in 30% of patients and median overall survival was 5.9 months. Importantly, there are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival, compared to any other treatment. Interestingly, Mylotarg can be administered in outpatient settings, which may be desirable to patients. AML is the most common type of acute leukemia in adults. The American Cancer Society estimates that close to 10,000 new patients will be diagnosed with the disease this year. More than 75% of patients are over the age of 60. Additionally, American Home is looking at other indications for Mylotarg, which include relapsed AML, using Mylotarg in combination with other therapies and earlier in the disease process, and using Mylotarg in pediatric patients.

Pipeline
The majority of these compounds are very early in development. Some preliminary data on CCI-779 were presented this past May at the American Society of Clinical Oncologists (ASCO) meeting. CCI-779 is an ester of Rapamune (rapamycin/sirolimus), American Homes new transplant therapy. It has shown good activity in vitro against T-cell leukemias, melanomas and malignancies of the central nervous system, breast and prostate. This product will likely be dosed intermittently to avoid the immunosuppression that is seen with chronic dosing. At the time the data were presented, the maximum tolerated dose (MTD) had not been encountered, although some patients developed an acneiform rash.

Amgen
Drug Data
Abarelix (LHRH Antagonist)
One notable compound under development is Amgen/Praeciss Abarelix. This is a peptide antagonist, which inhibits the action of LHRH on the pituitary. Abarelixdepot-M is currently in phase III trials in patients with hormonally responsive prostate cancer. At ASCO this past year, two trials were presented on Abarelix. In one trial, 270 patients with hormone-responsive prostate cancer were randomized to either Abarelix (n=180) or TAPs Lupron (n=91). All of the patients in the Abarelix arm avoided the testosterone flare, whereas in the Lupron arm, 18% of patients had such a flare. Seventy-two percent of patients on Abarelix achieved complete testosterone suppression after one week of therapy, whereas none of the patients in the Lupron arm did at one week. Similar results were reported in a second trial that looked at a total of 255 patients who were randomized to Abarelix (n=170) or Lupron plus AstraZenecas Casodex (n=85). Again, all patients in the Abarelix arm avoided the testosterone surge, whereas 14% in the Lupron-Casodex arm suffered flares. Sixty-eight percent of patients on Abarelix achieved complete testosterone suppression after one week, whereas no patient in the Lupron/Casodex arm did. All results were statistically significant. Amgen/Praecis expect to file Abarelix with the FDA during the fourth quarter.

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AstraZeneca
Drug Data
Arimidex (Anastrazole)
Arimidex was first approved for second-line treatment of advanced breast cancer in postmenopausal women during 1996. Recently, several European countries have approved Arimidex for first-line treatment of advanced breast cancer in postmenopausal women. On September 1, the FDA granted approval for this indication as well. At this years ASCO, data were presented from a meta-analysis of 1,021 patients. The results indicated that Arimidex was at least as effective as tamoxifen in time to tumor progression and in objective response. However, when a subgroup analysis was performed on 611 women with estrogen-receptor positive tumors, Arimidex was significantly more effective than tamoxifen in improving (reducing) time to progression and in objective response rates. Additionally, a separate study of neo-adjuvant treatment with Arimidex (given to women prior to surgery) indicated that Arimidex may shrink the tumor such that surgery can be avoided. AstraZeneca is conducting two larger studies to look at this indication.

Casodex (Bicalutamide)
Casodex is the leading anti-androgen worldwide. As of June this year, Casodex was the leading oral prostate cancer agent with a 51.2% total market share. AstraZeneca is conducting a study comparing Casodex with placebo in conjunction with standard treatment in more than 8,000 men with early prostate cancer; results are expected in 2002.

Nolvadex (Tamoxifen)
Tamoxifen is a nonsteroidal antiestrogen that binds to the estrogen receptors that are present in the body, including those present in cancerous tissue. Consequently, it effectively blocks estrogen from exerting its effects on cells, thereby inhibiting tumor growth. This product was launched in 1978. In 1993, as a result of the settlement of a patent challenge of tamoxifen by Barr Labs, AstraZeneca entered into a nonexclusive supply and distribution agreement. Under the terms of the agreement, Barr purchases tamoxifen directly from AstraZeneca and sells it as a generic product. Currently, Barr is the only distributor. Although Barr is a nonexclusive distributor, the agreement provides that should an additional distributor or distributors be selected by AstraZeneca, Barr will be granted terms no less favorable than those granted to any subsequent distributor. Additionally, Barr has a tentatively approved abbreviated new drug application (ANDA) for the manufacture of tamoxifen. Consequently, at the time of the patent expiration in August 2002, Barr can immediately begin the direct manufacture of tamoxifen. This past May at ASCO, data from several head-to-head trials of AstraZenecas Nolvadex versus some of the more recently launched agents were presented. A Finnish study compared Shires Fareston to Nolvadex. In this study, the mean time to breast cancer recurrence and overall survival were also similar for both groups of patients. When analyzed according to the endpoints of death from breast cancer, there was a trend for fewer breast cancer deaths with Fareston (5.3%) compared to Nolvadex
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(9.6%), (p=.05). The investigators concluded that Fareston is effective and safe for the adjuvant treatment of node-positive breast cancer in postmenopausal women. On June 30, the FDA granted AstraZeneca a new indication for Nolvadex in the treatment of ductal carcinoma in situ (DCIS). Nolvadex is the first therapy approved for this indication. DCIS is an invasive cancer involving only the cells lining the milk ducts of the breast. The exact indication is for the reduction of risk of invasive breast cancer in women with DCIS following breast surgery and radiation.

Zoladex (Goserelin)
Zoladex is an LHRH agonist for the treatment of prostate cancer. It was launched in 1990 and is administered as an injection given once every three months. As of June 2000, the product had 1.4% of the prostate cancer market. At this years ASCO, Zoladex received further support for its use with standard radiation to improve the recurrence rate in locally advanced prostate cancer; 1,520 patients received four months of Zoladex and Schering-Ploughs anti-androgen Eulexin for two months before and for two months during radiation treatment. The patients were then randomized to receive either no therapy or 24 months of additional Zoladex therapy alone. Patients were followed for an average of 4.8 years. During the study period, the group on long-term Zoladex therapy did significantly better than those receiving short-term hormone treatment in terms of disease-free survival (54% versus 34%, p=0.0001), local disease progression (6% versus 13%, p=0.0001), distant metastases (11% versus 17%, p=0.001) and biochemical failure (21% versus 46%, p=0.0001). However, five-year survival rates were not that much different between the arms: 78% versus 79%. But patients at the highest risk for relapse who were treated with long-term Zoladex had significantly better five-year survival (80% versus 69%) and better disease-specific survival (90% versus 78%) than those who had short-term therapy. Notably, patients in the Zoladex arm had a significant increase in bowel complications.

Pipeline
Faslodex
Faslodex is a new class of breast cancer therapy (selective estrogen receptor down regulator) in phase III as a long-acting, once-monthly injection for advanced disease. Submission for regulatory approval is expected in 2000.

Iressa (ZD1839)
AstraZeneca has several early-stage compounds in development, such as ZD0473, a new generation platinum agent designed to deliver an extended spectrum of antitumor activity and to overcome classical platinum resistance; ZD9331, a thymidilate synthase inhibitor, is being developed as IV and oral formulations and Iressa (ZD1839), a novel oral cancer therapy. Iressa has garnered the most attention of any of the compounds. It is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The following exhibit highlights how prevalent this receptor is in various tumor types. Increased expression of this receptor is usually associated with invasion, metastasis, later-stage disease and poor outcome.

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Exhibit 68: Epidermal Growth Factor Receptor Expression

Incidence of EGFR Expression in Various Tumor Types


Non-small Cell Lung Cancer Colorectal Gastric (advanced) Pancreatic Ovarian Breast Prostate
Source: Adapted from AstraZeneca.

40-80% 25-77% 33% 30-50% 35-70% 15-30% 40%

At ASCO, preliminary phase I trials of the once-daily oral agent, Iressa, as a single agent in several cancer types were presented. Anti-tumor activity was most profound in non-small-cell lung cancer (NSCLC). Many cancers are known to overexpress epidermal growth factor (EGF), which promotes cell proliferation. Iressa is designed to block the signal that causes EGF to bind to its protein receptors. Two NSCLC patients had partial responses to Iressa, two showed improvement in disease control and two others had disease stabilization. The most common adverse events were mild to moderate diarrhea and an acne-like rash. Serious adverse events were rare and usually related to disease progression. The dose-limiting toxicity (DLT) was diarrhea at 700 mg. Phase III trials in first-line NSCLC are commencing. Iressa will also be combined with traditional chemotherapy in a whole range of clinical trials in various cancers as well as being tested as monotherapy. Phases I and II are now complete and AstraZeneca has stated that the FDA has given it preliminary notice that this product would receive fasttrack status. AstraZeneca anticipates filing this product with the FDA during the fourth quarter of 2001.

Aventis
Drug Data
Campto (Irinotecan)
Aventis has the marketing rights to Camptosar in Europe, Pharmacia has rights in the Americas, Australia and New Zealand. Aventis markets this product under the brand name Campto (please see the Pharmacia section for detailed clinical data). Currently, Campto is in phase III for gastric cancer and phase II for non-small-cell lung and small-cell lung cancer. Aventis is also in early-stage clinical development of an oral formulation.

Taxotere (Docetaxel)
Taxotere is classified as a taxane and one of the newer entrants to the cancer market. It is a semisynthetic derivative of a precursor to Taxol (paclitaxel). It is extracted from the needles of the European yew, which is abundantly available. It was launched in June 1996 and is currently the mainstay of Aventiss cancer portfolio. In 1999, it generated approximately $500 million in worldwide sales. In the U.S., Taxotere is currently indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy and for patients with locally advanced or metastatic non-small-cell lung cancer after failure of prior platinum-based chemotherapy. Notably,
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our iKnowMed database indicates that the majority of Taxoteres use is in breast cancer. Additionally, it appears that the majority of its use is as a second-line therapy.
Exhibit 69: Various Uses of Taxotere
600

Taxotere Use
500

Numbers of Patients

400

300

200

100

0 BREAST NSCLC OVARIAN OTHER PROSTATE SCLC

Disease
ADJ 2nd LINE

Source: iKnowMed.

At this past Mays ASCO, several studies were presented on Taxotere looking at its use in prostate and gynecological cancers in addition to further studies in lung cancer. One study in advanced prostate cancer indicated that weekly treatment with Taxotere reduces pain and disease markers. The study showed that 44% of patients achieved a palliative response in terms of pain reduction. Additionally, 43% of patients had a prostate serum antigen (PSA) response defined as a PSA decline of 50% or more. Another notable study in prostate cancer was also presented. A study performed at Columbia Presbyterian showed that combination treatment with Taxotere and estramustine (a nitrogen mustard derivative) resulted in improved survival for patients with advanced prostate cancer. In the study, Taxotere was given weekly along with estramustine three times a day. At the time these results were presented, the median time to survival had not yet been reached and 77% of men were alive at one year versus 68% in a previous study. The Southwest Oncology Group (SWOG) presented data in non-small-cell lung cancer. In a phase II study, patients received cisplatin, radiation and Taxotere. The patients in the Taxotere arm had progression-free survival of 13 months, with a median survival time of 20 months. These results are superior to an earlier SWOG trial in which concurrent cisplatin, radiotherapy and etoposide resulted in median survival of only 15 months. Importantly, the two-year survival rates were 47% and 34% for the two studies, respectively.

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Pipeline
Flavopiridol
This compound is currently in phase IIa. Aventis expects to launch this product during 2003. Flavopiridol has three mechanisms of action. First, it inhibits cyclin-dependent kinase, which effectively inhibits the cells ability to reproduce. Second, it inhibits blood vessel formation within tumors. Lastly, it induces caspase-3 activation and cell death. Aventis plans to apply for first-line indications and the company believes that flavopiridol may have utility in multi-drug resistant tumors. The compound seems to be effective regardless of the patients prior treatment history and does not appear to have any overlapping toxicity with other chemotherapeutic agents.
Exhibit 70: Flavoperidol Patient Data
Flavopiridol Patient Response by Tumor Site
Number of Patients 1 1 Response CR PR Tumor Adenocarcinoma (esophageal) Adenocarcinoma (gastro-esophageal junction) Adenocarcinoma (esophageal) Adenocarcinoma (esophageal) Neuroendocrine Prostate Pancreas Sarcoma Metastatic Sites Duration (months) Primary, Mediastinal 13.6 Lymph nodes 7

3 1 9 4 3 3

MR SD SD SD SD SD

Lung, nodes Liver Lymph nodes Bone Liver Lung

2, 2+, 4.5 2.8+ 9.2 1.9, 2.1, 2.6, 7.2 2.0, 2.1, 6.3 3.2, 3.9, 6.7

Source: Aventis R&D Day, May 2000.

Aventis has also shown data from a phase II dose escalation trial in patients with chronic lymphocytic leukemia (CLL), which was summarized at the companys R&D day. Flavopiridol caused shrinkage in lymph node size without causing any doserelated toxicity. In dose-ranging studies presented at ASCO, the dose-limiting toxicities were nausea and vomiting, neutropenia and diarrhea.

p53 Gene Therapy


Introgen, in collaboration with Aventis, is developing cancer gene therapies. Its lead product, INGN 201, combines the p53 gene with a gene delivery system the company has developed. The gene delivery system uses a modified adenovirus, a common cold virus, to deliver the p53 gene to cancer cells. The companies have commenced phase III trials in head and neck cancers. Phase II trials are ongoing in non-small-cell lung cancer. Ten of the first 16 patients with inoperable non-small-cell lung cancer (NSCLC) who received Introgens adenoviral p53 gene therapy were alive at the end of one year. In total, five of 17 patients who were too ill to receive chemotherapy had greater-than50% regression of their total disease after three months, and had a negative biopsy without evidence of tumor progression at any site, after receiving intratumorial injections of p53 with radiation therapy in phase II. The most common side effects were cardiac arrhythmia and nausea.

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Bayer AG
Drug Data
Viadur (Leuprolide Implant)
Viadur is a version of leuprolide used in the treatment of prostate cancer. Viadur, which was developed by Alza, uses Alzas patented DUROS implant technology. The leuprolide is encased in a miniature titanium implant. This product provides a convenient alternative to the injectable versions of leuprolide. Viadur is placed under the skin delivering a continuous 12-month suppression of testosterone. (Please see Alza company section for a more detailed clinical summary.)

Pipeline
Bayer has four other development programs in its cancer portfolio: a camptothecin glycoconjugate in phase 1, a taxane analogue (preclinical), an IL-2 inhibitor and a RAF kinase inhibitor. The next-generation taxane (IDN 5109) was in-licensed from Indena. Preclinical data have shown that it has potential efficacy in taxane-resistant tumors and potential efficacy in patients with brain metastases and can be delivered orally.

Bristol-Myers Squibb
Investment Summary
Number one marketer in the world for cancer products, patent expiration hurts near term, but one of the deepest oncology pipelines in the industry should benefit the company longer term. In 1999, Bristol marketed nearly 25% of the worlds oncology products. The company is recognized by physicians worldwide as a premier force in this market. However, over the past several months, investors have focused on the U.S. patent expiry of Bristols flagship chemotherapeutic agent, Taxol. We have accounted for this in our U.S. revenue assumptions for Taxol. Importantly, we believe the Taxol market will continue to grow, albeit at a slower pace, down from 20% to the double digits and then to the mid-single digits in the out years. At the time of the patent expiry, we lowered our U.S. revenue estimate by taking half of the market share away from Bristol by 2001, which would mean a loss of $350 million (see the following exhibit).
Exhibit 71: UBS Warburg LLC Assumptions of Generic Taxol Impact

Total Taxol Market Market Growth Revised Taxol Revenue Implied lost revenue
Source: UBS Warburg LLC.

2000 2001 2002 $1,050 $1,150 $1,250 12% 10% 9% $1,009 $41 $784 $366 $638 $612

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Importantly, we believe that Bristol has an oncology pipeline sound enough to compensate for the lost opportunities with Taxol, although the products will not hit until late 2002 at the earliest. Near-term components of growth in oncology are few, namely Orzel and Oncology Therapeutic Network (OTN). However, Bristol has several earlystage compounds that hold considerable promise, such as Epothilone (a compound with a similar mechanism of action to Taxol), BMS-275291 (a matrix metalloproteinase inhibitor), and the next-generation taxanes. None of these products are currently in our revenue model, but it is important to note that some of these products dont necessarily have to have a prolonged clinical development cycle and could proceed rapidly to the market. Consequently, if the clinical data play out, there could be significant upside.
Exhibit 72: Bristol-Myers Cancer Portfolio

Bristol-Myers Cancer Portfolio Worldwide Sales Forecast


(dollars in millions)

Taxol Paraplatin VepeSid Platinol Orzel OTN GMK Vaccine Other Total Oncology Growth Total Pharmaceuticals Oncology as % of Pharma Sales
Source: UBS Warburg LLC.

2000 1,605 647 78 99 20 1,055 311 3,865 14,346 27%

2001 2002 2003 2004 1,475 1,400 1,425 1,450 660 680 680 690 84 86 88 90 155 160 160 160 100 175 275 400 1,225 1,400 1,575 1,750 60 100 360 370 400 430 4,059 4,271 4,663 5,070 5% 5% 9% 9% 14,834 15,656 16,683 17,765 27% 27% 28% 29%

Drug Data
Paraplatin (Carboplatin)/Platinol (Cisplatin)
Bristols oncology platform is composed of several agents, including two platinumbased agents, the second-generation Paraplatin and its predecessor, Platinol. Both agents continue to be widely used. However, both Bristol and physicians are switching over to Paraplatin because of its milder side-effect profile. Nephrotoxicity, ototoxicity, neurotoxicity, and dose-limiting nausea and vomiting are lessened with Paraplatin. Additionally, Platinol has gone generic. Paraplatin and Platinol have similar spectrums of activity. The following pie charts highlight Paraplatins use in both first- and secondline chemotherapy. Paraplatins major dose-limiting toxicity is myelosuppression.

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Exhibit 73: Paraplatin Use


ENDOMETRIAL 1% BREAST 1% ESOPHAGEAL 2% BLADDER 2% OTHER 9% H&N 2% OVARIAN 11% NSCLC 55% COLORECTAL 1%

1st Line Paraplatin Use


PERITONEAL 1%

SCLC 15%

ENDOMETRIAL 1%

2nd Line Paraplatin Use

COLORECTAL 1%

BREAST 4%

ESOPHAGEAL 4%

H&N 5% NSCLC 45%

BLADDER 5%

OTHER 8%

OVARIAN 16% SCLC 11%

Source: iKnowMed.

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Currently, Paraplatin is only indicated for first- and second-line treatment of ovarian cancer. However, several clinical studies have shown that Paraplatin has activity in lung cancers, squamous-cell cancers of the head and neck, gastrointestinal cancer and testicular cancer.

Taxol
Currently, the companys flagship chemotherapeutic agent is Taxol (paclitaxel). Taxol is the prototype of the taxanes. It was originally derived from the bark of the Pacific or Western yew tree, which was rare. However, semisynthetic production of Taxol can be done using the needles and twigs of the Himalayan yew, a much more abundant and renewable source. In 1995, the FDA approved the production of semisynthetic Taxol. Taxol is currently indicated for first-line treatment of ovarian cancer in combination with cisplatin, ovarian cancer that has spread beyond the ovaries (metastasized) and is not responsive to other types of chemotherapy drugs, breast cancer that has spread to the lymph nodes (node positive) following surgery and doxorubicin-containing chemotherapy, and non-small-cell lung cancer. It is also indicated as a second-line treatment of AIDS-related Kaposis sarcoma. Taxol is one of the most widely studied and widely prescribed cancer therapies in the history of the industry.
Exhibit 74: Various Uses of Taxol
1000

Taxol Use

800

Numbers of Patients

600

400

200

0 BREAST BLADDER ENDOMETRIAL OVARIAN PROSTATE NSCL OTHER H&N SCL GI

Disease ADJ 2nd LINE

Source: iKnowMed.

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Even though Taxol is widely used, there are some impediments to the success of the therapy in all cancers. First, many cancers become resistant to Taxol, due to multidrug-resistance-associated proteins, which effectively pump the drug out of the cell before it has any effect. Second, because it is not soluble in water, Taxol must be administered with the lung surfactant Chremophor, which sometimes causes severe hypersensitivity reactions. During July, the FDA approved a more convenient dosing regimen for Taxol in advanced ovarian cancer. Patients will now be able to take the drug in an outpatient setting, using a higher dose for a shorter, three-hour infusion. This approval was based on results from a multinational phase III trial in 600 women with stage IIb-IV ovarian cancer. In the study, women received Taxol, given in a three-hour infusion every three weeks in combination with cisplatin. This regimen significantly improved survival compared with the standard therapy of cyclophosphamide and cisplatin. Taxol had been previously approved for use in advanced ovarian cancer, but was given in a 24hour infusion every three weeks. This past March, Bristol-Myers lost a patent dispute with IVAX, a generic drug maker. On September 15, IVAX received approval of its generic from the FDA. After several months of legal jockeying, it appears as though IVAX will be able to launch its generic version of paclitaxel sometime in late 2000. IVAX has 180 days of market exclusivity for its version, after which other generic versions will be able to enter the market. On September 20, Bristol and Roche announced a European clinical research partnership. The alliance is designed to facilitate the development of clinical trials involving Taxol and Roche/Genentechs Herceptin. The companies will attempt to elucidate how Taxol and Herceptin work together. The collaboration will cover breast cancer as well as other solid tumors where scientific evidence of the combination suggests there may be efficacy.

Pipeline
BMS-275291
This is Bristols matrix metalloproteinase inhibitor (MMPI) that was in-licensed from Celltech (formerly Chiroscience). Matrix metalloproteinases (MMPs) are enzymes that degrade proteins of the extracellular matrix, thus facilitating tumor growth, metastases and neovascularization. BMS-275291 is an oral MMP inhibitor that has been shown to inhibit a broad range of MMPs and to reduce tumor growth rates in preclinical studies. Theoretically, Bristol may have the one MMP that makes it through to the market, after disappointments from Bayer and British Biotech. BMS-275291 is a potent inhibitor of MMPs, but it does not inhibit the group of related enzymes known as sheddases. It is the inhibition of the sheddases that apparently leads to the dose-limiting arthralgia that we have seen in the trials of other MMPs. Consequently, one could conceivably deliver higher doses of the Bristol drug without encountering the doselimiting side effects seen in other drugs in this arena. The following two exhibits indicate this compounds selectivity for MMP inhibition while having a minimal impact on sheddase inhibition. (Note: IC50 refers to the concentration of a drug needed to inhibit 50% of the activity of a target molecule.)
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Exhibit 75: Profiles of Various Matrix Metalloproteinase Inhibitors

MMP Selectivity Profile


Compound BMS-275291 Marimastat AG3340 MMP1 9 2 N/D MMP8 10 4 2 IC 50 Values (nanomolar) MMP13 MMP7 MMP3 4 23 157 2 2 36 0.2 60 30 MMP2 41 9 2 MMP9 25 7 4 MMP14 40 14 8

Source: UBS Warburg LLC.

Exhibit 76: Profiles of Various Matrix Metalloproteinase Inhibitors

Sheddase Selectivity Profile


Compound BMS-275291 Marimastat AG3340 TNF-alpha release >100 4 1.6 IC 50 Values (micromolar) L-Selectin TNF-alpha RII Shedding shedding >100 >100 6 1 14 0.8 IL1-RII shedding >100 3.4 1.8 IL-6R shedding >100 3.6 12

Source: UBS Warburg LLC.

This compound is currently in phase II/III for advanced or metastatic non-small-cell lung cancer (NSCLC). Currently, a non-U.S. trial is enrolling patients with stage IIIb or IV NSCLC. Patients will be randomized to one of two arms. In the active arm, patients will receive Bristols Taxol and Paraplatin in addition to receiving oral BMS-275291 for a 21-day cycle. Patients in the control arm will receive Taxol and Paraplatin plus an oral placebo. A total of 700 patients (60 for phase II and 640 for phase III) will be accrued over two years.

Epothilone (BMS-247550)
Epothilones were discovered approximately 15 years ago when German scientists were looking at soil bacteria. The epothilones were extracted from a bacterium found in southern Africa named Sorangium cellulosum. S. cellulosum produces four different versions of the epothilone, A-D. All four stabilize microtubules in the same manner as Taxol, but they are also effective against Taxol-resistant tumors and are water-soluble. BMS-247550, an oral semi-synthetic analog of epothilone B, has demonstrated significant improvement over Taxol in several critical aspects. It is active against human cancer models that are naturally insensitive to or have developed resistance to Taxol, both in cell culture systems in vitro and in human tumor xenografts grown in nude mice. This compound has the ability to overcome all major forms of Taxol-resistance mechanisms, including the 170 kD P-glycoprotein-mediated multidrug resistance and tubulin mutation. Furthermore, it exhibits a very broad spectrum of antitumor activity against Taxol-sensitive ovarian and colorectal cancers, as well as Taxol-resistant ovarian and colorectal cancers. Apparently, BMS-247550 can be combined with several antineoplastic agents and has demonstrated therapeutically significant interaction in vitro.

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Farnesyltransferase Inhibitor (BMS-214662)


This compound is in early-stage development as both an oral and an IV anticancer agent. Specifically, it blocks growth signals from the ras oncogene and induces programmed cell death. As stated previously, ras oncogenes are found in a high percentage of pancreatic, lung and colon cancers.

GMK Vaccine
This vaccine is designed to stimulate the bodys immune system to control or eliminate residual cancer cells after the tumor has been resected. GMK incorporates the GM2 ganglioside, which is a cancer antigen found in about 95% of melanoma cells. Bristol is in a collaboration with Progenics Pharmaceuticals for the development of this vaccine in addition to an MGV vaccine. On May 26, Progenics announced that the Eastern Cooperative Oncology Group (ECOG) concluded their participation in the phase III clinical trial for the GMK melanoma vaccine. At that time, the trial was roughly halfway enrolled. ECOG stated that the interim analysis indicated that the relapse-free and overall survival rates for patients receiving the vaccine were lower than for patients receiving high-dose alpha interferon. As expected, GMK had a much better side-effect profile. Progenics plans to continue the trial under the assumption that the follow-up period had been too brief. Currently, 880 patients are enrolled in the trial. The early results versus alpha interferon were anticipated, considering that GMK requires the body to build up an immune response to the vaccine. Consequently, the vaccine shows its clinical benefit much later than standard therapies. At the next interim analysis, Bristol will ultimately decide whether to keep this product and its follow-on MGV vaccine or give the two products back to Progenics.

Orzel (UFT)
This is Bristols new antimetabolite. This drug is an oral formulation of UFT capsules and leucovorin. UFT, which Bristol in-licensed from Japans Taiho Pharmaceuticals in 1995, combines the 5-FU prodrug tegafur with uracil. Uracil is an enzyme inhibitor that increases the half-life of 5-FU. On March 17, Bristol withdrew its NDA for the drug after receiving a favorable review from an FDA advisory committee. On April 20, the company resubmitted its NDA, apparently to allow the FDA time to review additional analyses, particularly on the role of uracil in the combination and proof that it is not inferior to 5-FU. If approved, this product could have significant promise as one of two potential oral antimetabolite therapies (Roches Xeloda is the other). The product was recently approved in Spain, which will serve as the reference member state for the mutual recognition process in the European Union.

Next-Generation Taxanes
Bristol has two compounds that can be considered next-generation Taxols. These molecules appear to work in animal models where Taxol and Aventiss Taxotere do not, perhaps including gastrointestinal tumors, yet they have a better side-effect profile. The first is BMS 184476, which is currently in phase II and is administered over only two hours. The second compound, BMS 188797, trails BMS 184476 by several months, but is administered by short infusion (more than one hour), and requires no premedication. BMS 188797 is similar to BMS 184476 biologically but different chemically.

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At ASCO in 1999, results from a phase I pharmacokinetic study of BMS-188797 were shown. In the trial, the drug was administered as a one-hour infusion every 21 days. A total of 28 patients were enrolled into seven dosage tiers. The nonhematologic toxicities at the lower dosage tiers were minor, with only grade 2 or lower toxicities (e.g., neutropenia, fever, diarrhea, nausea, myalgia, arthralgia and edema) observed. Notably, several pretreated patients experienced grade 3 or 4 hematologic toxicity; however, none were of sufficient duration to be considered a dose-limiting toxicity (DLT). The pharmacokinetic profile of BMS-18797 was similar to that of Taxol, and the product appears to have a 27-hour half-life. But importantly, in this trial, no routine premedication was administered and no hypersensitivity reactions were reported. However, this formulation did contain Cremophor to make it more water soluble, but that only makes the lack of hypersensitivity reactions all the more interesting.

Eli Lilly
Investment Summary
This is not currently a critical franchise for the company, but it is one area of consistent high-double-digit growth. Its importance to Lilly will likely increase over time. In 1999, Lilly ranked seventh in the world as a marketer of cancer therapies

with 7.5% of the market. Currently, the companys franchise revolves around Gemzar, which we expect to generate $555 million in worldwide revenue during 2000. However, Lilly has a handful of unique compounds in early-stage clinical development, such as a molecule to overcome multi-drug resistance. If the clinical data on compounds such as this come through, Lillys position in the cancer market could change dramatically.
Exhibit 77: Eli Lillys Cancer Portfolio
Eli Lilly Cancer Portfolio Worldwide Sales Forecast
(dollars in millions)

Gem zar Alim ta (M TA) Other Total Oncology Total Pharm aceuticals Oncology as % of Pharma Sales
Source: UBS Warburg LLC.

2000 555 31 586 10,267 6%

2001 650 25 30 705 20% 10,960 6%

2002 750 75 30 855 21% 11,665 7%

2003 850 150 30 1,030 20% 13,240 8%

2004 950 200 30 1,180 15% 14,055 8%

Drug Data
Gemzar (Gemcitabine)
Gemzar is an antimetabolic agent that is currently approved for the treatment of locally advanced or metastatic pancreatic cancer, as well as first-line treatment of inoperable, locally advanced or metastatic non-small-cell lung cancer in combination with cisplatin. Gemzar is currently the key member of Lillys oncology franchise. The product launched in 1995 with the pancreatic cancer indication and has since become one of the largest revenue generators of any chemotherapy agent. The data in pancreatic cancer are quite convincing. In a study of Gemzar versus 5-FU in previously untreated
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patients, nearly one in five patients was alive at one year after starting therapy with Gemzar, compared to one in 50 given 5-FU. The majority of patients had overall survival of six months, which was approximately six weeks longer than the patients given 5-FU. Similar results were seen in patients previously treated with 5-FU, although survival times were slightly lower. Additionally, Gemzar is effective at relieving some of the symptoms associated with advanced pancreatic cancer. Gemzar is one of the more widely studied agents and consequently receives a lot of attention in off-label use as the following bar chart indicates.
Exhibit 78: Various Uses for Gemzar
300

Gemzar Use
250

Numbers of Patients

200

150

100

50

0 NSCLC PANCREATIC OTHER BREAST BLADDER SCLC OVARIAN

Disease
ADJ 2nd LINE

Source: iKnowMed.

In 1998, Gemzar received a supplemental indication for the treatment of non-smallcell lung cancer (NSCLC) in combination with cisplatin. In the phase III trials that supported this indication, 522 previously untreated patients were randomized to receive Gemzar-cisplatin or cisplatin alone. The patients who received Gemzar-cisplatin showed a statistically significant one-year survival rate of 39% versus 28% in the control arm. The median survival rate was nine months in the Gemzar arm versus 7.6 months in the control arm. The median time to disease progression in the Gemzar group was 5.2 months, compared to 3.7 in the cisplatin group. There was no difference between the two groups in terms of their duration of response to either regimen. Another study that supported the NSCLC indication looked at Gemzar plus cisplatin versus cisplatin plus etoposide. The Gemzar-cisplatin group showed a statistically significantly higher tumor response rate compared with the cisplatin-etoposide group, 33% versus 14%, respectively. Median time to disease progression was significantly longer for Gemzar-cisplatin patients compared with cisplatin-etoposide patients, 5.0 months versus 4.1 months. Median survival was 8.7 months for patients treated with Gemzarcisplatin, compared with 7.0 months for patients treated with cisplatin-etoposide.

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Pipeline
Alimta (Premetrexed Disodium)
Alimta, formerly known as MTA or multi-target antifolate, is currently in phase III for mesothelioma and in phase II for non-small-cell lung cancer and metastatic breast cancer. This compound is the furthest along in development of any in Lillys oncology pipeline. It has a similar mechanism of action to 5-FU/leucovorin and methotrexate, but also has the added benefit of being able to inhibit glycinamide ribotide formyltransferase (GARFT), a key enzyme for de novo purine synthesis. Purines are necessary components of DNA and RNA; consequently, Alimta theoretically has three mechanisms of inhibiting cellular division. Lilly is currently looking at Alimtas utility in combination with other chemotherapeutic agents. Notably, a combination of Gemzar and Alimta may be effective in cancers of the breast, lung and pancreas. Lilly plans on filing Alimta with the FDA for mesothelioma by the end of 2001.
Exhibit 79: Phase II Experience of ALIMTA

ALIMTA Phase II Experience in Breast Cancer


Anthracycline Refractory 28 1 4 18 7 2.4 5.3 Anthracycline Failure 44 3 7 23 16 4.6 6.2

Evaluable Patients # of complete responses # of partial responses Overall response rate (%) Median survival Time to disease progression (months) Median duration of response (months)
Source: Eli Lilly analyst presentation.

Arzoxifene (LY353381)
Arzoxifene is Lillys selective estrogen receptor modulator (SERM) that is in phase II for metastatic breast cancer. Lilly is currently enrolling patients with newly diagnosed advanced breast cancer into a phase II trial. The compound appears to compare favorably to tamoxifen in advanced breast cancer. In the phase II trials that have already been completed, the adverse side effects appear to be minimal and manageable. The incidence of breast pain and endometrial hyperplasia was only 2% and there was no incidence of vaginal bleeding.

MDR (LY335979)P-Glycoprotein Multidrug Resistance Inhibitor


As was stated earlier in this report, one of the main reasons chemotherapy fails is due to the P-glycoprotein pump. P-glycoprotein resides in the cells membrane and recognizes a broad spectrum of anticancer drugs, many of which are naturally occurring substances. P-glycoprotein pumps the drugs to the extracellular space, so that an effective concentration at the intracellular target is never achieved. There are only a few drugs that are not affected by P-glycoprotein, such as the alkylating agents, the platinum-containing agents and the antimetabolites.

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Lillys compound is currently in late phase I trials and appears to be a potent, specific antagonist of the P-glycoprotein pump. Lilly is developing both IV and oral formulations. Importantly, this compound does not appear to change the pharmacokinetics of the chemotherapeutic agent being used. Conceivably, the use of Lillys drug could enable physicians to lower the doses of the chemotherapy drug, because the resistance hurdle would be minimal. Consequently, the overall tolerability of the regimen would increase.

Genentech
Drug Data
Herceptin (Trastuzumab)
Herceptin is the first humanized monoclonal antibody approved for the treatment of breast cancer. Herceptin monotherapy is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 (human epidermal growth factor receptor2) protein and who have received one or more chemotherapy regimens for their metastatic disease. Additionally, Herceptin in combination with paclitaxel is indicated for treatment of patients with metastatic breast cancer. In 25 30% of women with metastatic breast cancer, there is a genetic alteration in the HER2 gene, which produces an increased amount of the growth factor receptor protein on the tumor cell surface. This HER2 protein overexpression is associated with more aggressive disease. The following table highlights Herceptins efficacy in the first-line treatment of metastatic breast cancer. This trial was performed in 469 patients with metastatic disease.
Exhibit 80: Herceptin Phase III Results

Phase III Clinical Efficacy in 1st Line Treatment


Combined Results Herceptin + Chemo Chemo 235 234 7.2 <0.0001 45 <0.001 79 <0.01 68 73 0.08 29 4.5 Paclitaxel Subgroup AC Subgroup Herceptin + Herceptin + Paclitaxel Paclitaxel AC AC 92 96 143 138 6.7 2.5 <0.0001 38 <0.001 61 83 0.04 15 7.6 0.002 50 0.1 73 38 5.7

Number of patients Primary Endpoint Time to Progression p-value Secondary Endpoint Overall Response Rate p-value Percent Alive at 1-year p-value
Source: Herceptin package insert.

Notably, on May 3, Genentech issued a dear health care provider letter in the U.S. alerting doctors to reports of severe adverse events, including 15 deaths, associated with Herceptin, its monoclonal antibody for the treatment of metastatic breast cancer. Postmarketing surveillance has revealed 62 cases of severe side effects characterized by at least one of the following: hypersensitivity and infusion and/or pulmonary reactions. Accordingly, the label has been changed so that the boxed warning and other sections include details of the reactions, which have included anaphylaxis and adult respiratory distress syndrome. Genentech estimates that 25,000 patients have received the drug worldwide since its launch in 1998 for use as second- or third-line therapy in advanced
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breast cancer in patients whose tumors overexpress the HER-2 growth factor receptor. The product is available in Canada and Switzerland and is awaiting approval in the European Union for this indication. To date, the hypersensitivity reaction has been very low and comparable to what is seen with Rituxan. A year after Rituxans launch, severe side effects, including eight fatal cases of cytokine release syndrome, were reported, which led to strengthening the warning on the label. But since non-Hodgkins lymphoma is an incurable disease with few other treatment options, sales of the product were not adversely affected. Herceptins status will likely depend on how the product fares in ongoing studies in the adjuvant setting. The potential for hypersensitivity reactions could ultimately deter patients. Importantly, physicians and patients will need to weigh this risk against the fact that patients with tumors that overexpress the HER-2/neu receptor have a relatively poor prognosis. Additionally, these hypersensitivity concerns supplement the risks associated with Herceptin and cardiotoxicity. The package insert also contains a black box warning regarding cardiomyopathy; the risk of heart problems is particularly high in patients who also receive anthracyclines. On September 20, Bristol-Myers and Roche announced a European clinical research partnership. The alliance is designed to facilitate the development of clinical trials involving Taxol and Roche/Genentechs Herceptin. The companies will attempt to elucidate how Bristols Taxol and Herceptin work together. The collaboration will cover breast cancer as well as other solid tumors where scientific evidence of the combination suggests there may be efficacy.

Rituxan (Rituximab)
Genentech markets this product in the U.S. (Roche has rights outside of the U.S.) for IDEC Pharmaceuticals. Please see the IDEC subsection.

Pipeline
Anti-VEGF
Genentech has a phase III anti-vascular endothelial growth factor (anti-VEGF) compound. This is an antibody developed to inhibit angiogenesis in tumors. Phase III trials are ongoing in patients with colorectal cancer. Genentech is currently preparing Phase III trials for non-small-cell lung cancer and metastatic breast cancer. Data that showed promising results were presented at this springs American Society of Clinical Oncology (ASCO) meeting. However, there were safety concerns and four deaths associated with sudden bleeding. When added to standard chemotherapy (Paraplatin and Taxol) in non-small-cell metastatic lung cancer, the high-dose anti-VEGF arm had a longer time to disease progression than the control arm and the gold standard. In the 35 patients randomized to the high-dose anti-VEGF (15 mg/kg), arm time to progression was 7.5 months, compared with 4.4 months for 32 patients on the lower dose (7.5 mg/kg) and 4.3 months for patients on chemotherapy alone. Median survival in the high-dose arm was 18 months compared to 12 months in the low-dose arm versus 14 months in the control arm.
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Additionally, phase II results from a trial in 104 untreated metastatic colorectal cancer patients were presented. Patients were randomized to one of three arms, 5 mg of antiVEGF antibody plus 5-FU/leucovorin, 10 mg of the anti-VEGF antibody plus 5FU/leucovorin or the control arm of 5-FU and leucovorin. The low-dose anti-VEGF arm showed the best response rate of 40%, followed by the high-dose arm (24%) and the control arm (17%). Time to disease progression was highest in the low-dose arm at nine months compared to 7.2 months and 5.2 months in the high-dose and control arm, respectively. In this trial, the antibody was generally well tolerated except for a 25% incidence of blood clots in the low-dose arm and an 11% incidence in the highdose arm. Additionally, Genentech has commenced phase III trials in colorectal cancer looking at its monoclonal antibody to vascular endothelial growth factor (anti-VEGF) in combination with Camptosar. The trial will have three arms: anti-VEGF plus Camptosar and 5-FU/leucovorin, Camptosar plus 5-FU/leucovorin and anti-VEGF plus 5-FU/leucovorin.

IDEC Pharmaceuticals
Drug Data
Rituxan (Rituximab)
Rituxan is a monoclonal antibody indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkins lymphoma (NHL). At ASCO this past spring, a small, 20-patient study was presented looking at Rituxans use in first-line treatment of low-grade, follicular, non-Hodgkins lymphoma. The overall response rate was 50%. The results indicated that Rituxan used prior to chemotherapy is feasible and the side effects and response rates are similar to when Rituxan is used after chemotherapy. A phase III trial is currently under way to address this possible new indication. IDEC and its co-promotion partner, Genentech, have initiated a trial that compares the chemotherapy cocktail of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) to Rituxan plus CHOP. In October 1999, IDEC filed an supplemental Biologic License Application (sBLA) for Rituxan in bulky non-Hodgkins lymphoma, for treatment and retreatment up to eight times. Genentech markets Rituxan in the U.S., while Roche markets Rituxan outside the U.S. and in Japan.

Zevalin
Zevalin is the anti-CD-20 mouse parent antibody of Rituxan. This therapy is a new way of treating people with lymphoma who have already tried chemotherapy. Generically known as ibritumomab tiuxetan, Zevalin is a monoclonal antibody with a chelating agent that links the antibody to yttrium 90, a beta-emitting radioisotope. The subsequent radioimmunoconjugate uses the antibody to deliver the radioisotope directly to the lymphoma. Data from a study performed by the Mayo Clinic indicate that Zevalin in combination with Rituxan produces higher overall response rates than Rituxan alone. In a study of 143 patients with relapsed or refractory low-grade, non-Hodgkins lymphoma, an interim analysis indicated that the overall response rate in the
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Zevalin/Rituxan arm was 80% compared to 44% in the Rituxan alone arm. Twentyone percent of the patients in the combination arm had a complete response rate versus 7% in the Rituxan arm. A complete analysis of these data will be available at the American Society of Hematology meeting in December.

Merck & Co.


Investment Summary
Although Merck has a few compounds in early clinical development, oncology doesnt appear to be one of the areas of emphasis for Mercks R&D program.

Drug Data
Vioxx (Rofecoxib)
Although Merck has not announced any clinical development for Vioxx in cancer, one can infer from Pharmacias efforts with Celebrex that Merck may be investigating this possible indication. Theoretically, there appear to be three ways in which the COX-2 enzyme has a role in cancer. First, cells with high levels of COX-2 are less susceptible to cell death (or apoptosis). Second, when the COX-2 enzyme synthesizes prostaglandins, it releases free radicals as a by-product. Free radicals, such as oxygen ions, have been shown to cause mutations in cells. Finally, COX-2 has been shown to promote the production of blood vessel formation in tumors. The initiation of blood flow is critical for a tumor to grow.

Pipeline
One interesting point is Mercks discontinuation of its farnesyltransferase inhibitor (L-778,123) this past spring. In a small trial of 15 patients who took the Merck drug in combination with Bristols Taxol, significant dose-limiting toxicities were seen at the starting dose and included neutropenia. It may be the case that this drug was not truly a specific inhibitor of farnesyltransferase.

Novartis
Drug Data
Aredia (Pamidronate)
Aredia is currently the gold standard for the treatment of hypercalcemia due to bone metastases. This intravenous bisphosphonate was launched in 1991 and generated $491 million in worldwide sales during 1999. Novartis plans to convert patients to its newer agent, Zometa, when it gets FDA approval (see below for more details).

Femara (Letrozole)
Femara is an oral, nonsteroidal aromatase inhibitor that was launched in 1997 for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Femara has been slowly gaining market share in the oral breast cancer market and as of June had 3.6% of the total market. It competes

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directly against branded and generic megestrol, which had 42.9% of the market as of June. Patients on Femara who were refractory to antiestrogen therapy display objective response rates of 23.8% versus 14.8% for women on megestrol. Femara significantly reduces plasma estrogen levels. On September 11, Novartis announced that Femara had been given a priority review by the FDA for use as a first-line treatment of advanced breast cancer.

Pipeline
Amdray (Valspodar)
Amdray is a derivative of cyclosporine that is nonimmunosuppressive and nontoxic to the kidneys. It binds to P-glycoprotein with very high affinity. As stated previously, the P-glycoprotein pump is one of the main mechanisms of multi-drug resistance in tumors. Amdray is five to 30 times more potent than cyclosporine A in decreasing the efflux of chemotherapeutic agents from resistant cells. It will likely be available in IV and oral formulations. Novartis is currently conducting phase III trials for the treatment of multi-drugresistant ovarian cancer and acute myelogenous leukemia. The ovarian cancer trials are being conducted in combination with Bristols Taxol. The endpoint in this trial is time to disease progression. The results are expected to be available by the third quarter of 2001 with a filing in the same timeframe.

STI-571
Novartis has generated a good deal of attention with this product. STI-571 is a signal transduction inhibitor and a breakthrough treatment of early-stage chronic myelogenous leukemia (CML). Approximately 90% of patients with CML have a diagnostic marker, the Philadelphia chromosome (Ph1). This is characterized by chromosome number 22 missing a portion, which has been translocated to chromosome number 9. This results in the activation of a proto-oncogene known as c-abl. When the protooncogene c-abl is translocated from chromosome 9 to 22, a new oncogene, bcr-abl, is formed. This gene produces a protein that is associated with triggering growth factor receptors. It is hypothesized that this gene may induce uncontrolled growth of leukemic cells. However, not everyone with the diagnostic marker develops CML. Interestingly, 96% of CML patients have been shown to have an abnormality of genetic material swapping between chromosome 9 and 22. Researchers have found that bcr-abl is also activated in 20% of patient with acute lymphoblastic leukemia (ALL). STI-571 is a very specific inhibitor of abl-kinase. At ASCO this past spring, data were presented from 33 acute leukemia patients, including 21 myeloid blast crisis CML patients and 12 Bcr-Abl positive ALL or lymphoid blast crisis CML patients. These individuals were give daily, oral, forms of the drug. All but seven patients had received at least one prior chemotherapy regimen for their acute leukemia. There were four early deaths, two from disease progression prior to completing one week of therapy and two from infections in heavily pretreated patients. The median duration of treatment when the study was presented was 68 days with a range

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of one to 182 days. Nineteen of 29 evaluable patients had responded to therapy, as defined by a decrease in the percentage of bone marrow blasts to 15% or less. Responses had been observed in 55% of myeloid blast crisis patients with complete responses in 22% of patients. However, all of the patients with lymphoid leukemias have relapsed on drug between 45 and 81 days. In terms of adverse events, of 19 responding patients, ten have experienced grade 3-4 neutropenia. These data come on top of data presented at the December 1999 meeting of the American Society of Hematologists (ASH). All 31 patients with early-stage CML who were treated with the product had complete normalization of white blood cells and platelet counts for up to eight months. Taken in their entirety, these results suggest that STI-571 works better in patients with myeloid leukemia compared to those with lymphoid leukemia. Novartis expects to file this product with the FDA sometime during 2001.

Zometa (Zoledronic Acid)


Zometa is an intravenous bisphosphonate for the treatment of hypercalcemia of malignancy (HCM), which is the most common life-threatening metabolic complication associated with cancer. On September 22, Novartis announced that it had received an approvable letter from the FDA. The FDA withheld the full approval until it finalizes its review of additional data, including serum creatinine data from Novartiss ongoing trials for the treatment of bone metastases. Elevated serum creatinine levels are indicative of changes in kidney function. The FDA is basing its decision on data derived from two identical pivotal studies comparing the drug with Novartiss Aredia (pamidronate), which is the current treatment standard. The combined results showed that by day 10 of treatment, a statistically significantly higher percentage of patients responded to Zometa at 4 mg (88.4%) versus pamidronate at 90 mg (70%) in reducing serum calcium levels to the normal range. The FDA has given Zometa a priority review. Hypercalcemia of malignancy affects more than 10% of all cancer patients, generally late in the course of the disease. It is characterized by elevated serum calcium levels, with symptoms of nausea, vomiting and confusion. It occurs most often in cases of breast cancer, multiple myeloma and non-small-cell lung cancer. It may also occur in head and neck cancer, lymphoma, leukemia, kidney cancer and gastrointestinal cancer. Novartis plans to convert patients on Aredia to Zometa. Additionally, phase III trials are currently under way evaluating Zometas effectiveness in treating bone metastases and preventing their complications.

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Pfizer
Investment Summary
Pfizers drug development platform in oncology is in its infancy. The Agouron pipeline acquired as part of the Warner-Lambert merger helps, but it remains to be seen if Pfizer will be able to achieve a meaningful presence in this potentially lucrative market.

Drug Data
Celebrex (Celecoxib)
A full description of Celebrexs role in cancer exists in the Pharmacia subsection below.

Pipeline
Prinomastat (AG3340)
Prinomastat is Pfizers matrix metalloproteinase inhibitor (MMPI). Prinomastat is an orally active, synthetic molecule designed to potently and selectively inhibit certain members of a family of enzymes known as matrix metalloproteinases (MMPs) that are believed to be involved in tumor angiogenesis, invasion and metastasis. On August 4, Pfizer announced that preliminary results of phase III trials in advanced hormone refractory prostate cancer and advanced non-small-cell lung cancer (NSCLC) had failed to meet their primary endpoints. However, patients with earlier-stage NSCLC who had been recruited into another trial will continue to be studied. Pfizer is planning to look at prinomastat in other tumor types and in earlier-stage disease. Six phase II trials are currently under way. The most common side effects of prinomastat have been observed in the joints, and include joint stiffness, joint swelling, and in a few patients, some limits on the mobility of certain joints, most often in the shoulders and hands. All of these effects were reversible and were managed effectively by treatment rests and dose reductions.

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Pharmacia Corp.
Investment Summary
The New Oncology Challenger; Camptosar Remains a Key Growth Driver
Pharmacia has recently dubbed itself The New Oncology Challenger and the foundation of Pharmacias oncology portfolio rests on Camptosar (irinotecan). In 1999, the company ranked fifth in the world for oncology products with 5.6% of the market. The acquisition of Sugen in the spring of 1999 has allowed Pharmacia to accelerate its cancer development platformspecifically, the development of its kinase platform, of which the angiogenesis signaling inhibitor SU-5416 is the lead candidate.
Exhibit 81: Pharmacia Cancer Portfolio
Pharmacia Cancer Portfolio Worldwide Sales Forecast
(dollars in millions)

Camptosar Ellence/Pharmorubicin Leridistim Aromasin SU5416 Total Oncology Growth Total Pharmaceuticals Oncology as % of Pharma Sales
Source: UBS Warburg LLC.

2000 436 206 5 647 10,711 6%

2001 2002 2003 2004 515 585 670 730 220 230 240 250 50 100 200 60 90 120 150 5 15 25 35 800 970 1,155 1,365 24% 21% 19% 18% 11,965 13,070 14,010 15,195 7% 7% 8% 9%

Drug Data
Aromasin
Pharmacias aromatase inactivator, Aromasin (exemestane), is approved for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. Pharmacia launched this product in January. Aromasin is the first approved oral aromatase inactivator. This past May, data were presented at ASCO that compared the activity and safety of Aromasin 25 mg/day with tamoxifen 20 mg/day as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Of 97 randomized patients, data were available on 63 for response and 76 for toxicity. In the study, the median time to tumor progression in patients treated with Aromasin was 8.9 months compared with 5.2 months in patients treated with tamoxifen. Women treated with Aromasin experienced the following side effects in comparison to those treated with tamoxifen: grade 2/3 fatigue (5% versus 13%), pain (11% versus 18%), hot flashes (3% versus 15%), sweating (0 versus 10%), edema (3% versus 8%), nausea (3% versus 8%) and dyspnea (11% versus 5%). There was no difference between patients treated with Aromasin and patients treated with tamoxifen in the incidence of weight gain. We currently have relatively modest estimates for Aromasin revenue; however, if head-to-head data on Aromasin versus tamoxifen continue to roll out in favor of the drug, our estimates could prove conservative.

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Camptosar (Irinotecan)
Exhibit 82: Camptosar Use
Camptosar Adjuvant Versus 2nd Line Use

ADJ 8%

2nd LINE 92%

Source: iKnowMed.

Exhibit 83: Various Uses of Camptosar


OTHER-2nd LINE 5% COLORECTAL-ADJ 8%

Various Uses of Camptosar

OTHER-ADJ 1%

COLORECTAL 2nd LINE 86%

Source: iKnowMed. Note: These data are from November 1999; consequently, they may underrepresent the trends in Camptosar use that are currently occurring.

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This past May at the annual American Society of Oncologists (ASCO) meeting, it became apparent that Camptosar is quickly becoming the gold standard for colorectal cancer, one of the more prevalent forms of cancer. The American Cancer Society estimates that approximately 130,200 new cases of colorectal cancer will be diagnosed in 2000. Up until this past spring, Camptosars only approved indication was for secondline therapy of colorectal cancer. However, on April 20, the FDA gave approval for Camptosars use as a first-line therapy in combination with 5-FU and leucovorin. The FDA based its approval on two clinical trials in which patients with metastatic disease were infused with Camptosar in addition to the standard treatment of 5-FU and leucovorin. These studies indicated that patients in the Camptosar arm had median survival prolonged by approximately three months. Pharmacia said that it expects a 60% increase in patients using Camptosar as a result of this new indication. That level of growth may be accelerated by the enormous interest displayed at the ASCO meeting, where a meta-analysis of data from the FDA registration trial was presented. When researchers looked at subgroup analyses of the entire patient pool, they noticed that response rates and median time to disease progression improved in every subgroup. Consequently, clinicians believe that all patients with metastatic colorectal cancer would benefit from receiving Camptosar as a first-line therapy. Pharmacia has also commenced adjuvant studies with Camptosar, 5-FU and leucovorin with three major clinical trials. Some clinicians have postulated that this type of aggressive initial therapy may potentially have a curative effect. Additionally, Camptosar appears to be active in other cancers as well. Data were presented at ASCO from a phase II study using a combination of Camptosar and Lillys Gemzar in the treatment of pancreatic cancer. The results showed a 20% response rate, which is double the response rate seen in Gemzar alone. Importantly, there was no increase in toxicity; phase III international trials are enrolling now. Interestingly, Genentech has commenced phase III trials in colorectal cancer looking at its monoclonal antibody to vascular endothelial growth factor (anti-VEGF) in combination with Camptosar. The trial will have three arms: anti-VEGF plus Camptosar and 5-FU/leucovorin, Camptosar plus 5-FU/leucovorin and anti-VEGF plus 5-FU/leucovorin. Additionally, a Japanese phase III study using Camptosar in combination with cisplatin showed increased survival compared with the current standard treatment for patients with extensive small-cell lung cancer of etoposide plus cisplatin. A total of 154 patients were enrolled, with the primary endpoint being survival. In the Camptosar arm, 58.4% of patients lived one year or longer compared with 37.7% of patients receiving standard treatment. At two years, the survival benefit was 18.9% in the Camptosar arm versus 6.5% in the control arm. The study was stopped at a pre-planned interim analysis point due to the survival benefit. The overall response rate in the Camptosar arm was 83.1% with 2.7% complete responders and 80.5% partial responders. The overall response rates in the control arm were 67.5% (58.4% partial responders and 9.1% complete responders). In this trial, the side-effect profile favored the patients taking Camptosar. Pharmacia plans to file for the non-small-cell lung cancer indication during 2002. Apparently, Pharmacia is investigating an oral formulation. At this past Mays ASCO, a phase I study in pediatric patients with solid tumors was shown. It was a small trial in 17 patients, so it is difficult to extrapolate the significance. However, the compound was only 10% bioavailable, which is slightly disappointing. We currently have a worldwide revenue forecast for Camptosar of $490 million for 2001, growing to $730 million by 2004.
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Celebrex (Celecoxib)
Theoretically, there appear to be three ways in which the COX-2 enzyme has a role in cancer. First, cells with high levels of COX-2 are less susceptible to cell death (or apoptosis). Second, when the COX-2 enzyme synthesizes prostaglandins, it releases free radicals as a by-product. Free radicals, such as oxygen ions, have been shown to cause mutations in cells. Finally, COX-2 has been shown to promote the production of blood vessel formation in tumors. The initiation of blood flow is critical for a tumor to grow. On December 23, 1999, the FDA granted approval for Celebrex for a reduction in the number of polyps in patients with familial adenomatous polypsis (FAP), as an adjunct to surgery. Approximately 40,000 patients in the U.S. are affected by FAP; consequently, the market opportunity in this specific population is not large. This past year, the National Cancer Institute (NCI), in collaboration with Pharmacia and Pfizer, initiated a phase III study looking at Celebrexs role in preventing the occurrence of new sporadic adenomatous polyps in the colon. This trial is currently known as the Adenoma Prevention with Celecoxib (APC) trial. The trial will recruit more than 1,000 patients over the age of 40 at centers across the United States. Patients will be required to have had at least one colorectal adenomatous polyp removed within the past three months and cannot have any history of FAP or hereditary nonpolyposis colorectal cancer. Patients will be randomized to receive either Celebrex or a placebo twice a day for three years and will be evaluated for adenomatous colorectal polyps at one and three years. Additionally, Pharmacia researchers have also shown that the COX-2 gene is overactive in skin cancer and breast cancer as well.

Ellence (Epirubicin)
Ellence is an anthracycline chemotherapeutic agent. On September 15, 1999, the FDA approved Ellence as a component of adjuvant therapy following resection of early breast cancer that has spread to the axillary lymph nodes. Notably, in June, prior to the approval, an FDA advisory committee unanimously recommended approval of Ellence for the aforementioned indication. However, the committee voted against a broader indication in patients with locally advanced or metastatic breast cancer, due to questions regarding overall survival data. The FDA based its approval of Ellence on two, randomized, open-label multicenter studies involving 1,281 women. The first trial in 716 women compared the combination of Ellence, cyclophosphamide and 5-FU to cyclophosphamide, methotrexate and 5-FU. The Ellence arm showed significantly longer five-year relapse-free survival with an overall reduction in risk of death of 29%. The second study enrolled 565 patients on Ellence (low dose), cyclophosphamide and 5-FU to Ellence (high dose), cyclophosphamide and 5-FU. The high-dose arm had a significantly longer five-year survival rate (65% versus 52%) and overall survival rate (76% versus 65%). The overall reduction in the risk of relapse was 32% and the relative reduction in the risk of death was 31%. Adverse effects of Ellence therapy include severe local tissue necrosis, myocardial toxicity, secondary acute myelogenous leukemia and myelosuppression.

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Trelstar (Triptorelin)
Although not a significant driver to the franchise, Trelstar is one of the newer additions to Pharmacias cancer portfolio. On June 15, Pharmacia received FDA approval of Trelstar for palliative treatment of advanced prostate cancer in patients for whom orchiectomy or estrogen administration is not indicated or not acceptable. Trelstar is administered as an injection given once a month. The data for approval indicated that following a single IM injection of Trelstar to healthy male volunteers, serum testosterone levels first increased, peaking on day 4, and declined thereafter to low levels by week 4. Similar testosterone profiles were observed in patients with advanced prostate cancer, when injected with Trelstar Depot. In healthy volunteers, testosterone serum levels returned to near baseline by week 8. Trelstar Depot was studied in a randomized, active control trial of 277 men, ages 47 to 89, with advanced prostate cancer. Patients were given either Trelstar or an approved GnRH agonist monthly for nine months. The primary efficacy results were both achievement of medical castration by day 29 and maintenance of castration from day 57 through day 253. Castration levels of serum testosterone were achieved in 91.2% of Trelstar patients at day 29 and 97.7% of patients at day 57.

Pipeline
Leridistim
Another potential cancer product is leridistim, which is a blood cell growth factor being developed to help stimulate white blood cells in cancer patients receiving chemotherapy. We expect a filing with the FDA in late 2000 or early 2001. This product will likely compete with Amgens Neupogen. We have yet to see any data on leridistim; consequently, our revenue assumptions remain conservative. Importantly, Pharmacia announced on May 1 that leridistim had failed in a pediatric study.

SU-5416
SU-5416 is the lead candidate from Sugens platform. It is a synthetic, small-molecule, angiogenesis-signaling inhibitor. At ASCO, several preliminary trials were presented for SU-5416 indicating that when the drug is given to patients with untreated, advanced colorectal cancer, the drug may extend the time patients remain free of tumor growth and spread. One study evaluated 28 patients with untreated advanced colorectal cancer receiving increasing doses of SU-5416 intravenously twice each week, with standard doses of 5-FU and leucovorin. Twelve patients achieved a complete or partial remission. Patients remained free of tumor growth and spread for an average of approximately nine months, compared with standard chemotherapy, which delays the progression for about six months. Seven percent of the patients showed no response. The drug appears to be well tolerated when combined with 5-FU and leucovorin. There is currently an ongoing phase II/III study that will enroll 710 patients in North America and Europe comparing 5-FU/leucovorin with 5-FU/leucovorin in combination with SU-5416. The study will be large enough to detect changes in survival, response rates, time to progression and quality of life.

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Pharmacia is also conducting a pilot study of SU-5416 in combination with Camptosar, 5-FU and leucovorin, for the treatment of metastatic colorectal cancer. The pharmaceutical company is also researching oral forms of SU-5416. We have relatively conservative estimates for SU-5416 with worldwide revenue of $35 million in 2004.

Roche
Drug Data
Herceptin (see Genentech) Xeloda (Capecitabine)
In August 1998, Roche launched Xeloda for the treatment of metastatic breast cancer. According to IMS Health, the product had U.S. sales of $42 million in 1999. Xeloda is an oral pro-drug of 5-FU. It is ingested in a relatively inactive form and absorbed readily in the intestinal tract. It is metabolized in the liver to 5-DFCR. Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5-DFCR to 5-DFUR. The enzyme, thymidine phosphorylase, then hydrolyzes 5-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Although it is only currently approved in breast cancer, many studies are ongoing in the cancers where 5-FU has shown good activity. Roche submitted an NDA for the first-line treatment of colorectal cancer on September 20, 1999. On September 25, 2000, the company received an approvable letter from the FDA.
Exhibit 84: Various Uses of Xeloda
30

25

Xeloda Use

Numbers of Patients

20

15

10

0 BREAST COLORECTAL PANCREATIC LIVER RENAL GASTRIC

Disease
ADJ 2nd LINE

Source: iKnowMed.

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At the 1999 ASCO, phase II trials of Xeloda in taxane-refractory metastatic breast cancer results were shown. An overall response rate of 25% was seen in Xeloda patients, with a median duration of response of 8.3 months and a median survival time of 12.3 months. Roche is conducting phase III trials, which will compare Xeloda and Aventiss Taxotere in combination versus Taxotere monotherapy in advanced and/or metastatic breast cancer. The primary endpoint in this trial will be superiority in time to progression. In a phase III colorectal cancer study involving 1,200 patients, Xeloda showed a greater overall response rate (shrinking tumors by at least 50%) in 21% of patients, compared with 11% of patients given 5-FU/leucovorin (the Mayo regimen). Xeloda also showed similar time to progression and survival when compared to the Mayo regimen. Xelodas safety profile differs from that of the Mayo regimen, as it was associated with fewer grade 3/4-related stomatitis and neutropenia, but had a higher incidence of grade 3 hand-foot syndrome. In the trial, Xeloda had a lower hospitalization rate due to drug-related adverse events and fewer concomitant medications were required to manage Xeloda patient side effects.

Schering-Plough
Investment Summary
Successful use of in-licensing has enabled Schering to have a presence in this market, but it has yet to reach critical mass.

Drug Data
Caelyx (Liposomal Doxorubicin)
Schering-Plough has successfully used in-licensing strategies to build its cancer portfolio. Currently, Schering has three marketed compounds and four compounds in development (two that were in-licensed). One marketed compound is Caelyx (branded domestically as Doxil), where Schering in-licensed international marketing rights from SEQUUS Pharmaceuticals (now merged with Alza). Caelyx was recommended for European Union approval in June to treat advanced ovarian cancer. A large head-to-head trial comparing this liposomal formulation of doxorubicin (Doxil/Caelyx) with SBs Hycamtin found minimal differences between the regimens for treating patients with relapsed ovarian cancer. However, Doxil did slightly better in patients with platinum-sensitive disease and it caused a much lower incidence of hematological toxicity. Both Doxil and Hycamtin are approved in the U.S. for second-line treatment of ovarian cancer. In the trial, 474 patients who had failed first-line platinum-based therapy were randomly assigned to Doxil once every four weeks as a one-hour infusion or a 30minute IV infusion of Hycamtin for five days every three weeks. There was no significant difference between the two treatment arms for the median time to disease progression, 18.4 weeks for Doxil and 18.3 weeks for Hycamtin. Additionally, there was no significant difference between objective response or median overall survival. However, there was a significant difference in the subset of patients with platinum-sensitive disease. Patients in the Doxil arm showed a significantly better median overall survival of

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86.1 weeks versus 63.6 weeks in the Hycamtin arm (p=0.012). Regarding adverse events, those in the Hycamtin arm experienced a high degree of hematological toxicity with 81% of patients experiencing some level of neutropenia and 72% experiencing some level of anemia. In the Doxil arm, 49% of patients experienced hand-foot syndrome, also known as Palmar-plantar erythrodysesthesia (PPE), a tingly sensation in the palms and soles, and 40% experienced stomatitis, soreness of the mouth. Importantly, patients on Doxil do not need any stem cell support, whereas the patients on Hycamtin do. Regarding the interesting results in this trial subset, the trial was not designed to show this difference and, consequently, the results were unexpected. The exact mechanism behind this remains unclear. It is possible that Doxil is less likely to induce multi-drug resistance. Importantly, the point of the study was to show that there is no disadvantage to using Doxil before Hycamtin. Currently, Schering is conducting a large trial in breast cancer, as is the Eastern Oncology Cooperative Group (ECOG). Other researchers are looking at Doxils role in breast cancer therapy when combined with Genentechs Herceptin. Alza is looking at Doxil in patients with multiple myeloma who have failed anthracycline therapy, and an NDA could be filed during the fall of 2000.

Intron A (Interferon-Alpha)
Intron A is Scherings brand of interferon-alpha. This product launched in 1986 and approximately 50% of its use is in cancer-related disorders. Interferons are natural substances produced by the body in response to infection or disease. They were originally discovered by their ability to prevent viral replication, but they are currently viewed as being good anti-cancer agents as well. Alpha-interferons are used to treat several diseases such as hepatitis and genital warts. They are also effective in treating hairy cell leukemia, melanoma, non-Hodgkins lymphoma and AIDS-related Kaposis sarcoma. Currently, Intron-As cancer indications consist of hairy cell leukemia, malignant melanoma, follicular lymphoma, condylomata acuminata and AIDS-related Kaposis sarcoma. Scherings follow-on compound, Peg-Intron A, uses a new delivery technology that allows for less frequent dosing (once a week versus three times a week). The new formulation may allow for a reduction in the adverse events, but maintain equivalent efficacy.

Temodar (Temozolomide)
This product was in-licensed from Cancer Research Campaign Technology Ltd. Temodar is an oral therapy indicated for the treatment of adult patients with anaplastic astrocytoma (a form of brain cancer) at the first relapse with disease progression on a nitrosourea- and procarbazine-containing drug regimen. It launched in the U.S. during August 1999. In a trial of 162 patients with anaplastic astrocytoma, a complete response was seen in 9% of the patients and a partial response was seen in 13% of the patients. In this trial, a complete response was noted by tumor loss for two consecutive months. Tumor shrinkage was measured by gadolinium-enhanced magnetic resonance and clinical improvement. A decrease of more than 50% in the tumor area for two consecutive months constitutes a partial response. The median duration for all
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responders was 50 weeks, with a range of 16 to 114 weeks, and the median duration for complete responders was 64 weeks, with a range of 52 to 114 weeks. Additionally, 45% of patients were progression free at six months. 74% of patients were alive at six months and the overall median survival was 15.9 months. Sixty percent of patients in this trial had undergone previous chemotherapy. The dose-limiting toxicity (DLT) was myelosuppression (reduction in blood counts). This usually occurred within the first few cycles of therapy, was not cumulative, and was resolved within 14 days. Notably, in phase III trials, treatment of patients with glioblastoma multiforme (another form of brain cancer) with Temodar did not show statistical significance. Additionally, on March 23, 1999, the FDA advisory panel voted 10-1 not to recommend approval of Scherings NDA for the treatment of melanoma. Temodar did not meet the primary endpoints of superior overall survival in a 305-patient trial comparing Temodar to intravenous dacarbazine. The intent-to-treat analysis showed an increased survival of 1.4 months for patients on Temodar (7.7 versus 6.3), but these results failed to be statistically significant. However, Temodar did show an increased duration of response over the control arm, 5.5 months versus 3.2 months.

Pipeline
Farnesyltransferase Inhibitor (SCH66336)
This is Scherings phase II farnesyltransferase inhibitor (FTI). At the American Society of Clinical Oncology (ASCO) meeting this past spring, promising phase I results were presented. This compound is orally bioavailable and inhibits growth of cells transformed by an activated h-ras oncogene and of human tumor cell lines expressing activated k-ras proteins. Schering is currently looking at this compound in monotherapy as well as in combination with other agents, such as Lillys Gemzar. In the trials presented at ASCO, 60% of patients exhibited objective responses.

Marimastat
In September 1999, in a reported $60 million dollar deal, Schering licensed worldwide rights (except for certain Far East territories) from British Biotech to several matrix metalloproteinase inhibitors (MMPIs), including marimastat and BB-3644. Schering will assume European and U.S. regulatory filings. To date, marimastat has failed to show any significant potential. In four phase III studies in patients with advanced cancers, the drug failed to meet its primary endpoint. In January 2000, results were presented in a pancreatic cancer trial looking at a combination of Lillys Gemzar and marimastat. The study was conducted in 293 patients with the primary endpoint being survival. Marimastat combined with Gemzar failed to show any significant statistical differences from the Gemzar-alone group. Additionally, there was no statistical difference in the secondary endpoints, safety or quality of life. The trial was powered so that a positive result would be a 15% improvement in the combination group, which may have been too ambitious a goal considering the aggressive nature of pancreatic cancer. Results showed that the survival curves were almost identical. Median survival was 164 days in the control arm versus 165.5 days in the active arm. However, subset analyses did reveal some interesting trends. In patients with earlier-stage disease (stages I and II), the median survival was 451 days in patients receiving the combination versus 250

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days in patients receiving Gemzar alone. But the results are not statistically significant, as only 30 patients were considered early stage. Marimastat has failed to show statistical benefit in the treatment of glioblastoma and gastric cancer. Recently, the drug failed again. On September 26, British Biotech announced the results of a trial in advanced ovarian cancer. Patients enrolled in this trial had failed to respond to at least one prior treatment with Bristols Paraplatin. In the active arm of this trial, patients received Paraplatin in combination with marimastat. This combination showed no statistically significant advantage over Paraplatin alone in either primary or secondary endpoints. British Biotech believes that the drug still has potential in earlier-stage cancers. Notably, marimastat is associated with tendonitis, which could restrict its use in earlystage disease. British Biotech is hoping that this side effect may be eliminated with its follow-on compound BB-3644, which has not shown this tendency in animal models. The product is currently being tested in humans in a phase Ib trial. Phase II trials are expected to start in mid-2001.

Melacine
This is a vaccine that Schering has in-licensed from Corixa (formerly Ribi ImmunoChem Research). Melacine consists of lysed cells from two human melanoma cell lines combined with Corixas proprietary Detox adjuvant. Detox adjuvant includes MPL adjuvant (monophosphoryl lipid A) and mycobacterial cell wall. During February 2000, phase III results of Melacine were reported. The study endpoint was a comparison of disease-free survival in patients with Stage II melanoma who, following surgical removal of the patients primary tumor, received adjuvant immunotherapy with Melacine, versus no adjuvant therapy. Patients in the active arm received ten treatments of Melacine over a 27-week cycle. This cycle was to be repeated three times. This trial was the largest study of a cancer vaccine completed to date. Patient accrual was completed in November 1999; the intent-to-treat population comprised 689 patients, who were randomized. An analysis of the eligible patient population found no statistically significant difference in disease-free survival between the patients who received Melacine versus those who did not. However, the results of the intent-to-treat analysis on the total population indicated there was a statistically significant difference in disease-free survival between the patients treated with the Melacine vaccine (103/346 patients died or relapsed) and patients randomized to the control arm (125/343 patients died or relapsed) (p=0.04). The product received approval in Canada during October 1999. On September 27, 2000, Corixa announced its intention to file a biological license application (BLA). The filing will be based predominantly on the aforementioned data. The entire data pool will comprise patients that began enrollment in April 1992. Corixa will submit data on these patients through January 2001. The company plans to file the BLA during the second quarter of 2001 and a full 12-month review by the FDA.

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p53
Schering is currently in phase II and earlier studies with its p53 tumor suppressor gene therapy for treating various solid tumors. Schering has a number of agreements that continue to advance this therapeutic platform. Currently, Schering has a collaboration with Gene Logic, Inc. to help identify patients with a missing or defective p53 gene in tumors.

SmithKline Beecham
Drug Data
Hycamtin (Topotecan)
Hycamtin is the companys semisynthetic derivative of camptothecin, a topoisomerase I inhibitor. It is more water-soluble than camptothecin, and unlike Pharmacias Camptosar, it is not a pro-drug; consequently, it is clinically active in the current form. Hycamtin is currently indicated for the second-line treatment of ovarian cancer and small cell lung cancer. In a refractory ovarian cancer trial, 454 patients who had failed one or two platinum-based regimens, had complete or partial response rates combined ranged between 13.3% and 20.5%. These response rates were equivalent to what was seen with Bristols Taxol. However, Hycamtin does cause a higher incidence of myelosuppression and neutropenia. Furthermore, it appears as though response rates decline in patients who are truly refractory to platinum-based therapies. In small cell lung cancer (SCLC), 211 patients were treated with either Hycamtin or cyclophosphamide, doxorubicin and vincristine (CAV). The overall response rate in the Hycamtin arm was 24% compared with 18% in the CAV arm. The median time to progression also favored Hycamtin at 13.3 weeks compared with 12.3 weeks. Median survival was basically equivalent, at 25.0 weeks in the Hycamtin arm versus 24.7 weeks in the CAV arm. On September 14, results from a phase II trial that combined Hycamtin with Bristols Paraplatin in the first-line treatment of advanced non-small-cell lung cancer (NSCLC) were presented at the 9th World Congress on Lung Cancer in Tokyo. This was a noncomparative, multi-center study, which evaluated this combination in chemotherapynave patients. Results from the trial indicate that combination treatment with Hycamtin produced an overall response rate of 14% in evaluable patients, with 49% of patients achieving an arrest in tumor progression. Results were presented on 42 of 47 patients. The median duration of response with this combination was 16 weeks, with a median survival rate of 32.7 weeks. These results are similar to what was presented at ASCO this past spring in a study of 1,594 patients comparing four first-line therapies where the median survival rate ranged from 31 to 36 weeks.

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SB continues to develop the Hycamtin franchise. The compound is in phase I trials for second-line colorectal cancer, phase I for the first-line indication in SCLC, phase II for first-line therapy of non-small-cell lung cancer, phase II for first-line therapy of ovarian cancer and phase III for myelodysplastic syndrome. Notably, the company is developing an oral formulation, which is currently in phase III trials for second-line therapy of SCLC.

Pipeline
Bexxar
Bexxar is a monoclonal antibody that is conjugated to a radioisotope. It has completed phase III trials for non-Hodgkins lymphoma. Trials for Bexxar are ongoing, including a phase II study for first or second relapsed indolent B-cell lymphomas, phase I for intermediate and high-risk B-cell chronic lymphocytic leukemia and an open-label expanded-access study of Bexxar in chemotherapy-relapsed/refractory low-grade or transformed low-grade non-Hodgkins lymphoma. In a phase II study presented at ASCO in May, Bexxar achieved a 97% overall response rate and a 76% complete response rate when given to patients with advanced-stage, low-grade non-Hodgkins lymphoma. Seventy-six patients had been enrolled in the study at the time the data were presented and the median duration of response had not yet been reached. Notably, at the time the data were presented, 68% of patients had survived for three years without progression of their disease, but 62% of the patients developed human antimouse antibodies after therapy. Coulter has co-developed Bexxar with SmithKline Beecham. Coulter submitted a biologic license application (BLA) for Bexxar for the second-line treatment of nonHodgkins lymphoma on June 30, 1999. The company was granted a priority review, but received a refusal to file letter from the FDA on August 27. The FDA requested that Coulter reformat selected data and reorganize certain analyses. On September 18, SmithKline Beecham and Coulter announced that they had resubmitted the BLA to the FDA. On October 5, the companies announced that the FDA had granted the product a priority, or six-month, review. Coulter believes they could possibly launch Bexxar sometime next year.

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Cancer Terms

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A
abdomen: The part of the body that contains the pancreas, stomach, intestines, liver, gallbladder and other organs. accelerated phase: Refers to chronic myelogenous leukemia that is progressing. The number of immature, abnormal white blood cells in the bone marrow and blood is higher than in the chronic phase, but not as high as in the blast phase. acetylcysteine: A drug usually used to reduce the thickness of mucus and ease its removal. It is also used to reverse the toxicity of high doses of acetaminophen. Also called N-acetylcysteine. acitretin: A drug used in cancer prevention that belongs to the family of drugs called retinoids. It is also used in the treatment of psoriasis. acridine carboxamide: DACA. A substance that is being studied as an anticancer drug. It belongs to the family of drugs called topoisomerase inhibitors. actinic keratosis: A precancerous condition of thick, scaly patches of skin. Also called solar or senile keratosis. acustimulation: Mild electrical stimulation of acupuncture points to control symptoms such as nausea and vomiting. acute: Having the abrupt onset of symptoms and a short course; not chronic. acute leukemia: Cancer of the bloodforming tissue (bone marrow) that progresses rapidly. acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells, called lymphoblasts, are found in the blood and bone marrow. Also called acute lymphocytic leukemia. acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells, called lymphoblasts, are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. adenocarcinoma: Cancer that begins in cells that line certain internal organs and that have glandular (secretory) properties. adenoid cystic cancer: A rare type of cancer that usually begins in the salivary glands.

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adenoma: A noncancerous tumor. adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumorfighting gene. adjuvant therapy: Treatment given after the primary treatment to make it work better. Adjuvant therapy may include chemotherapy, radiation therapy or hormone therapy. adrenal glands: A pair of small glands, one located on top of each kidney. The adrenal glands produce the hormones epinephrine and norepinephrine that help control heart rate, blood pressure, the way the body uses food, and other vital functions. adrenaline: A hormone. Also called epinephrine. Adverse effect: An unwanted side effect of treatment. aflatoxins: Substances made by a fungus that is often found on poorly stored grains and nuts. Aflatoxins have been implicated as a factor in the etiology of primary liver cancer. AFP: Alpha-fetoprotein. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. aggressive: A quickly growing cancer. aggressive lymphoma: A quickly growing cancer that arises in the cells of the lymphatic system.

agonists: Drugs that trigger an action from a cell or another drug. agranulocyte: A type of white blood cell; monocytes and lymphocytes are agranulocytes. alkylating agents: A family of anticancer drugs that interfere with the cells DNA and inhibit cancer cell growth. allogeneic: Taken from different individuals of the same species. allogeneic bone marrow transplantation: A procedure in which a person receives stem cells, the cells from which all blood cells develop, from a compatible, though not genetically identical, donor. allopurinol: A drug that lowers high uric acid (a by-product of metabolism) levels in the blood caused by some cancer treatments. alpha-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. altretamine: An anticancer drug that belongs to the family of drugs called alkylating agents. alum: A type of immune adjuvant (a substance used to help boost the immune response to a vaccine). Also called aluminum sulfate. alveoli: Tiny air sacs at the end of the bronchioles in the lungs. amikacin: An antibiotic drug used to treat infection. It belongs to the family of drugs called aminoglycoside antibiotics.
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aminocamptothecin: An anticancer drug that belongs to the family of drugs called topoisomerase inhibitors. aminoglutethimide: An anticancer drug that belongs to the family of drugs called nonsteroidal aromatase inhibitors. Aminoglutethimide is used to decrease estrogen production and to suppress the growth of tumors that need estrogen to grow. aminolevulinic acid: A drug used in photodynamic therapy that is absorbed by tumor cells; when exposed to light, it becomes active and kills the cancer cells. aminopterin: An anticancer drug that belongs to the family of drugs called antimetabolites. amphotericin B: An antifungal drug used to treat infection. amsacrine: An anticancer drug that belongs to the family of drugs called topoisomerase inhibitors. amylase: An enzyme that helps the body digest starches. amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart and liver; secondary amyloidosis often affects the spleen, kidneys, liver and adrenal glands. analgesics: Drugs that reduce pain. These drugs include aspirin, acetaminophen and ibuprofen.
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analog: In chemistry, a substance that is similar, but not identical, to another. anaplastic: A term used to describe cancer cells that divide rapidly and bear little or no resemblance to normal cells. anastomosi: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. androgen suppression: Treatment to suppress or block the production of male hormones. Androgen suppression is achieved by surgical removal of the testicles, by taking female sex hormones or by taking other drugs. Also called androgen ablation. androgens: A family of hormones that promote the development and maintenance of male sex characteristics. anemia: A condition in which the number of red blood cells is below normal. angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue into a solid tumor. This is caused by the release of a chemical by the tumor cells. angiogenesis inhibitor: A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue into a solid tumor. angiosarcoma: A type of cancer that begins in the lining of blood vessels. ansamycins: A group of anticancer drugs that belong to the family of drugs called antineoplastic antibiotics.

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anterior mediastinotomy: A procedure in which a tube is inserted into the chest to view the tissues and organs in the area between the lungs and between the breastbone and spine. The tube is inserted through an incision next to the breastbone. This procedure is usually used to get a tissue sample from the lymph nodes on the left side of the chest. Also called the Chamberlain procedure. anthracenediones: A subgroup of the family of anticancer drugs called anticancer antibiotics. anthracycline: A member of a family of anticancer drugs that are also antibiotics. anthraquinones: A family of anticancer drugs. anti-CEA antibody: An antibody against carcinoembryonic antigen (CEA), a protein present on certain types of cancer cells. anti-idiotype vaccine: A vaccine made of antibodies that see other antibodies as the antigen and bind to it. Anti-idiotype vaccines can stimulate the body to produce antibodies against tumor cells. antiandrogen therapy: Treatment with drugs used to block production or interfere with the action of male sex hormones. antiangiogenesis: Prevention of the growth of new blood vessels into a solid tumor. antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind only to a specific anti-

gen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. antibody therapy: Treatment with an antibody, a substance that can directly kill specific tumor cells or stimulate the immune system to kill tumor cells. anticancer antibiotics: A group of anticancer drugs that block cell growth by interfering with DNA, the genetic material in cells. Also called antitumor antibiotics or antineoplastic antibiotics. anticoagulants: Drugs that help prevent blood clots from forming. Also called blood thinners. antiemetics: Drugs that prevent or reduce nausea and vomiting. antifungals: Drugs that treat infections caused by fungi. antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. antigen-presenting cell vaccine: A vaccine made of antigens and antigenpresenting cells (APCs). Also called APC vaccine. antigens: Substances that cause the immune system to make a specific immune response. antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction.

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antineoplastic antibiotics: A group of anticancer drugs that block cell growth by interfering with DNA, the genetic material in cells. Also called anticancer antibiotics or antitumor antibiotics. APC vaccine: A vaccine made of antigens and antigen-presenting cells (APCs). Also called antigen-presenting cell vaccine. aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. aplidine: An anticancer drug obtained from a marine animal. apoptosis: A normal series of events in a cell that lead to its death. arterial embolization: The blocking of an artery by a clot of foreign material. This can be done as treatment to block the flow of blood to a tumor. ascites: Abnormal buildup of fluid in the abdomen. asparaginase: An anticancer drug that is an enzyme. aspergillosis: An infectious fungal disease that occurs most often in the skin, ears, nasal sinuses and lungs of persons with a suppressed immune system. aspirate: Fluid withdrawn from a lump, often a cyst. astrocytomas: Tumors that begin in the brain or spinal cord in small, star-shaped cells called astrocytes.

asymptomatic: Having no signs or symptoms of disease. ataxic gait: Awkward, uncoordinated walking. atypical hyperplasia: A benign (noncancerous) condition in which cells have abnormal features and are increased in number. autologous: Taken from an individuals own tissues, cells or DNA. autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored and then given back to the person following intensive treatment. autologous lymphocytes: A persons white blood cells. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and disease. autologous tumor cells: Cancer cells from the persons tumor. axilla: The underarm or armpit. axillary: Pertaining to the armpit. axillary lymph node dissection: Surgery to remove lymph nodes found in the armpit region. axillary lymph nodes: Lymph nodes found in the armpit that drain the lymph channels from the breast. azacitidine: An anticancer drug that belongs to the family of drugs called antimetabolites.

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B
B cells: White blood cells that make antibodies and are an important part of the immune system. B cells come from bone marrow. Also called B lymphocytes. B lymphocytes: White blood cells that make antibodies and are an important part of the immune system. B lymphocytes come from bone marrow. Also called B cells. B3 antigen: A protein found on some tumor cells. bacterial toxin: A toxic substance, made by bacteria, that can be modified to kill specific tumor cells without harming normal cells. Barretts esophagus: A condition in which the cells lining the lower part of the esophagus have changed or been replaced with abnormal cells that could lead to cancer of the esophagus. The backing up of stomach contents (reflux) may irritate the esophagus and over time cause Barretts esophagus. basal cell carcinoma: A type of skin cancer that arises from the basal cells, small round cells found in the lower part, or base, of the epidermis, the outer layer of the skin. basal cells: Small, round cells found in the lower part, or base, of the epidermis, the outer layer of the skin. basophil: A type of white blood cell. Basophils are granulocytes. BCG vaccine: An anticancer drug (Bacille Calmette-Guerin) that activates the immune system. Filling the bladder with a solution of BCG is a form of biological therapy for superficial bladder cancer. benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy, or BPH. benign tumor: A noncancerous growth that does not invade nearby tissue or spread to other parts of the body. beta carotene: A vitamin A precursor. Beta carotene belongs to the family of fat-soluble vitamins called carotenoids. biafine cream: A topical preparation to reduce the risk of and treat skin reactions to radiation therapy. bilateral: Affecting both the right and left side of body. bilateral cancer: Cancer that occurs in both paired organs, such as both breasts or both ovaries. bile: A fluid made by the liver and stored in the gallbladder. Bile is excreted into the small intestine, where it helps digest fat. bile duct: A tube through which bile passes in and out of the liver. biological response modifier: BRM. A substances that stimulates the bodys response to infection and disease.
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biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also called immunotherapy or biological response modifier (BRM) therapy. biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids or tissues, and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. biopsy: A procedure used to remove cells or tissues in order to look at them under a microscope to check for signs of disease. When an entire tumor or lesion is removed, the procedure is called an excisional biopsy. When only a sample of tissue is removed, the procedure is called an incisional biopsy or core biopsy. When a sample of tissue or fluid is removed with a needle, the procedure is called a needle biopsy or fine-needle aspiration. bladder: The organ that stores urine. blast crisis: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast phase. blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. blasts: Immature blood cells.

bleomycin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. blood transfusion: The administration of blood or blood products into a blood vessel. blood-brain barrier: A network of blood vessels with closely spaced cells that makes it difficult for potentially toxic substances (such as anticancer drugs) to penetrate the blood vessel walls and enter the brain. bolus: A single dose of drug usually injected into a blood vessel over a short period of time. bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. bone marrow: The soft, sponge-like tissue in the center of bones that produces white blood cells, red blood cells and platelets. bone marrow ablation: The destruction of bone marrow using radiation or drugs. bone marrow aspiration: The removal of a small sample of bone marrow (usually from the hip) through a needle for examination under a microscope. bone marrow biopsy: The removal of a sample of tissue from the bone marrow with a needle for examination under a microscope. bone marrow metastases: Cancer that has spread from the original (primary) tumor to the bone marrow.

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bone metastases: Cancer that has spread from the original (primary) tumor to the bone. bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream. It collects in the bones and is detected by a scanner. bowel: The long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. brachytherapy: Radioactive material, sealed in needles, seeds, wires or catheters, is placed directly into or near the tumor. Also called internal radiation therapy or implant radiation. brain metastases: Cancer that has spread from the original (primary) tumor to the brain stem. The part of the brain that is connected to the spinal cord. brain stem glioma: A tumor located in the part of the brain that connects to the spinal cord (the brain stem). It may grow rapidly or slowly, depending on the grade of the tumor. brain stem tumor: A tumor in the part of the brain that connects to the spinal cord (the brain stem). BRCA1: A gene located on chromosome 17 that normally helps to suppress cell growth. Inheriting an altered version of BRCA1 predisposes an individual to breast, ovarian or prostate cancer. breast reconstruction: Surgery to rebuild a breasts shape after a mastectomy.

breast-conserving surgery: An operation to remove the breast cancer but not the breast itself. Types of breastconserving surgery include lumpectomy (removal of the lump), quadrantectomy (removal of one quarter of the breast), and segmental mastectomy (removal of the cancer as well as some of the breast tissue around the tumor and the lining over the chest muscles below the tumor). brief pain inventory: A questionnaire used to measure pain. bronchi: The large air passages that lead from the trachea (windpipe) to the lungs. bronchioles: The tiny branches of air tubes in the lungs. bronchoscopy: A procedure in which a thin, lighted tube is inserted through the nose or mouth. This allows examination of the inside of the trachea and bronchi, air passages that lead to the lung, as well as the lung itself. Bronchoscopy may be used to detect cancer or to perform some treatment procedures. bronchus: A large air passage that leads from the trachea (windpipe) to the lung. broxuridine: A drug that makes cancer cells more sensitive to radiation and is also used as a diagnostic agent to determine how fast cancer cells grow. bryostatin-1: A drug used for its antitumor activity. buccal mucosa: The inner lining of the cheeks and lips. Burkitts lymphoma: A type of nonHodgkins lymphoma that most often occurs in young people between the ages

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of 12 and 30. The disease usually causes a rapidly growing tumor in the abdomen. buserelin: An anticancer drug that belongs to the family of drugs called gonadotropin-releasing hormones. In prostate cancer therapy, buserelin blocks the production of testosterone in the testicles. busulfan: An anticancer drug that belongs to the family of drugs called alkylating agents. buthionine sulfoximine: A drug that may help prevent resistance to some anticancer drugs. bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids.

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C
c-erbB-2: The gene that controls cell growth by making the human epidermal growth factor receptor 2. Also called HER2/neu. CA-125: Substance sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. calcitonin: A hormone secreted by the thyroid that lowers blood calcium levels. calcitriol: A vitamin D analogue (a drug made in the laboratory that is chemically similar to vitamin D). calcium: A mineral found in teeth, bones and other body tissues. camptothecin: An anticancer drug that belongs to the family of drugs called topoisomerase inhibitors. camptothecin analogue: An anticancer drug related in structure to camptothecin, a topoisomerase inhibitor. One such drug is aminocamptothecin. cancer: A term for diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. cancer of unknown primary origin: Cancer cells are found in the body, but the place where the cells first started growing (the origin or primary site) cannot be found. cancer vaccine: A vaccine designed to prevent or treat cancer.
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capecitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. capsaicin: A component of certain plants, including cayenne and red pepper, used topically for peripheral nerve pain. Also being studied for controlling mucositis pain following chemotherapy and radiation therapy. carbendazim: An anticancer drug that belongs to the family of drugs called antifungal agents. carboplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. carboxyamidotriazole: An anticancer drug that belongs to the family of drugs called angiogenesis inhibitors. carboxypeptidase-G2: A bacterial enzyme that belongs to the family of drugs called chemoprotective agents. It is used to neutralize the toxic effects of methotrexate. carcinoembryonic antigen peptide-1: CAP-1. A protein that can stimulate an immune response to certain tumors. carcinogen: Any substance that causes cancer. carcinogenesis: The process by which normal cells are transformed into cancer cells. carcinoma: Cancer that begins in the skin or in the tissues that line or cover internal organs.

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carcinoma in situ: Cancer that involves only the cells in which it began and has not spread to neighboring tissues. cardiac: Pertaining to the heart. cardiopulmonary: Pertaining to the heart and lungs. Carmustine: An anticancer drug that belongs to the family of drugs called alkylating agents. carotenoids: Substance found in yellow/orange fruits and vegetables and dark green leafy vegetables that may reduce the risk of developing cancer. carzelesin: An anticancer drug that belongs to the family of drugs called alkylating agents. Castlemans disease: A rare disorder in which noncancerous growths develop in lymph node tissue. castration: Removal or destruction of the testicles or ovaries using radiation, surgery or drugs. Medical castration refers to the use of drugs to suppress the function of the ovaries or testicles. CC-49 monoclonal antibody: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. CD34 antigen: A protein found on the surface of some bone marrow and blood cells. CEA: Carcinoembryonic antigen. A substance that is sometimes found in an increased amount in the blood of people with certain cancers.

CEA assay: A laboratory test to measure carcinoembryonic antigen (CEA), a substance that is sometimes found in an increased amount in the blood of people who have certain cancers. celecoxib: A drug that reduces pain. Celecoxib belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied for cancer prevention. cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. cell differentiation: The process during which young, immature (unspecialized) cells take on individual characteristics and reach their mature (specialized) form and function. cell proliferation: An increase in the number of cells as a result of cell growth and cell division. cellular adhesion: The close adherence (bonding) to adjoining cell surfaces. central nervous system: CNS. The brain and spinal cord. central venous access catheter: A tube surgically placed into a blood vessel for the purpose of giving intravenous fluid and drugs. It also can be used to obtain blood samples. This device avoids the need for separate needle insertions for each infusion. cerebellum: The portion of the brain in the back of the head between the cerebrum and the brain stem. The cerebellum controls balance for walking and standing, and other complex motor functions.

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cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing and learning. cervical intraepithelial neoplasia: CIN. A general term for the growth of abnormal cells on the surface of the cervix. Numbers from 1 to 3 may be used to describe how much of the cervix contains abnormal cells. cervix: The lower, narrow end of the uterus that forms a canal between the uterus and the vagina. chemoembolization: A procedure in which the blood supply to the tumor is blocked surgically or mechanically, and anticancer drugs are administered directly into the tumor. This permits a higher concentration of drug to be in contact with the tumor for a longer period of time. chemoprevention: The use of drugs, vitamins or other agents to try to reduce the risk of or delay the development or recurrence of cancer. chemoprotective: A quality of some drugs used in cancer treatment. Chemoprotective agents protect healthy tissue from the toxic effects of anticancer drugs. chemosensitivity assay: A laboratory test to analyze the responsiveness of a tumor to a specific drug.

chemosensitizer: A drug that makes tumor cells more sensitive to the effects of chemotherapy. chemotherapy: Treatment with anticancer drugs. chlorambucil: An anticancer drug that belongs to the family of drugs called alkylating agents. cholangiosarcoma: A tumor of the connective tissues of the bile ducts. chondrosarcoma: A type of cancer that forms in cartilage. chordoma: A type of bone cancer that usually starts in the lower spinal column. choriocarcinoma: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus following conception. Also called gestational trophoblastic disease, gestational trophoblastic neoplasia, gestational trophoblastic tumor or molar pregnancy. choroid plexus tumor: A rare type of cancer that occurs in the ventricles of the brain. It usually occurs in children younger than two years old. chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. chronic: A disease or condition that persists or progresses over a long period of time. chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia.
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chronic leukemia: Cancer of the bloodforming tissues that progresses slowly. chronic lymphoblastic lymphoma: A slowly progressing disease in which too many immature white blood cells called lymphoblasts are found in the body. chronic lymphocytic leukemia: A slowly progressing disease in which too many white blood cells called lymphocytes are found in the body. chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. chronic myeloid leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic granulocytic leukemia. chronic phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature, abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. chronic phase chronic myelogenous leukemia: A phase of chronic myelogenous leukemia that may last from several months to several years. Although there may be no symptoms of leukemia, there are too many white blood cells. cidofovir: A drug used to treat infection caused by viruses. cirrhosis: A type of chronic, progressive liver disease.
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cisplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. cladribine: An anticancer drug that belongs to the family of drugs called antimetabolites. clinical resistance: The failure of a cancer to shrink after treatment. clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis or treatment of a disease. clodronate: A drug used as treatment for hypercalcemia (abnormally high levels of calcium in the blood) and for cancer that has spread to the bone (bone metastases). It may decrease pain, the risk of fractures, and the development of new bone metastases. CMA-676: An anticancer drug used in the treatment of acute myelogenous leukemia. CNS: Central nervous system. The brain and spinal cord. CNS metastases: Cancer that has spread from the original (primary) tumor to the central nervous system. CNS prophylaxis: Chemotherapy or radiation therapy given to the central nervous system (CNS) as a preventive treatment. It is given to kill cancer cells that may be in the brain and spinal cord, even though no cancer has been detected there. CNS tumors: Tumors of the central nervous system, including brain stem glioma, craniopharyngioma, medulloblastoma and meningioma.

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coactivated T cells: T cells that have been coated with monoclonal antibodies to enhance their ability to kill tumor cells. colectomy: An operation to remove the colon. An open colectomy is the removal of the colon through a surgical incision made in the wall of the abdomen. Laparoscopic-assisted colectomy uses a thin, lighted tube attached to a video camera. It allows the surgeon to remove the colon without a large incision. colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. colonoscope: A thin, lighted tube used to examine the inside of the colon. colonoscopy: An examination of the inside of the colon using a thin, lighted tube (called a colonoscope) inserted into the rectum. If abnormal areas are seen, tissue can be removed and examined under a microscope to determine if disease is present. colony-stimulating factors: Substances that stimulate the production of blood cells. Colony-stimulating factors include granulocyte colony-stimulating factors (also called G-CSF and filgrastim), granulocyte-macrophage colonystimulating factors (also called GM-CSF and sargramostim), and promegapoietin. colorectal: Having to do with the colon or the rectum. colostomy: An opening into the colon from the outside of the body. A colostomy provides a new path for waste ma-

terial to leave the body after part of the colon has been removed. colposcopy: Examination of the vagina and cervix using a lighted magnifying instrument called a colposcope. combination chemotherapy: Treatment using more than one anticancer drug. combretastatin A4 phosphate: An anticancer drug that reduces the blood supply to tumors; it is a tubulin binding agent. common bile duct: Carries bile from the liver and gallbladder into the duodenum (the upper part of the small intestine). complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes such practices as dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing and meditation. complete remission: The disappearance of all signs of cancer. Also called complete response. complete response: The disappearance of all signs of cancer. Also called complete remission. computed tomography: A series of detailed pictures of areas inside the body; the pictures are created by a computer linked to an X-ray machine. Also called computed tomography (CT) scan or computed axial tomography (CAT) scan. condylomata acuminata: Genital warts caused by certain human papilloma viruses (HPV).
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cone biopsy: Surgery to remove a coneshaped piece of tissue from the cervix and cervical canal. Cone biopsy may be used to diagnose or treat a cervical condition. Also called conization. congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. conization: Surgery to remove a coneshaped piece of tissue from the cervix and cervical canal. Conization may be used to diagnose or treat a cervical condition. Also called cone biopsy. consolidation therapy: Chemotherapy treatments given after induction chemotherapy to further reduce the number of cancer cells. continent reservoir: A pouch formed from a piece of small intestine to hold urine after the bladder has been removed. continuous hyperthermic peritoneal perfusion: CHPP. A procedure that bathes the abdominal cavity in fluid that contains anticancer drugs. This fluid is warmer than body temperature and appears to kill cancer cells without harming normal cells. continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period. conventional treatment: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. cooperative group: A group of physicians and/or hospitals formed to treat a large number of persons in the same way so that new treatment can be evaluated quickly. Clinical trials of new cancer
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treatments often require many more people than can be cared for by a single physician or hospital. cordycepin: An anticancer drug that belongs to a family of drugs called antitumor antibiotics. core biopsy: The removal of a tissue sample with a needle for examination under a microscope. corpus: The body of the uterus. corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. craniopharyngioma: A benign brain tumor that may be considered malignant because it can damage the hypothalamus, the area of the brain that controls body temperature, hunger and thirst. craniotomy: An operation in which an opening is made in the skull. crisnatol mesylate: An anticancer drug that interferes with the DNA in cancer cells. cryosurgery: Treatment performed with an instrument that freezes and destroys abnormal tissues. This procedure is a form of cryotherapy. cryotherapy: Any method that uses cold temperature to treat disease. cryptorchidism: A condition in which one or both testicles fail to move from the abdomen, where they develop before birth, into the scrotum. Cryptorchidism may increase the risk for development of

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testicular cancer. Also called undescended testicles. CSF: Cerebrospinal fluid. The fluid flowing around the brain and spinal cord. CSF is produced in the ventricles of the brain. CT scan: Computed tomography scan. A series of detailed pictures of areas inside the body; the pictures are created by a computer linked to an X-ray machine. Also called computed axial tomography (CAT) scan. curettage: Removal of tissue with a curette, a spoon-shaped instrument with a sharp edge. cutaneous: Related to the skin. cutaneous T-cell lymphoma: A disease in which certain cells of the lymph system (called T lymphocytes) become cancerous (malignant) and affect the skin. cyclophosphamide: An anticancer drug that belongs to the family of drugs called alkylating agents. cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. cyproterone acetate: A drug used to block the production of or interfere with the action of male sex hormones. cyst: A sac or capsule filled with fluid. cystectomy: Surgery to remove the bladder.

cystoscope: A thin, lighted instrument used to look inside the bladder and remove tissue samples or small tumors. cystoscopy: Examination of the bladder using a thin, lighted instrument (called a cystoscope) inserted into the urethra. Tissue samples can be removed and examined under a microscope to determine if disease is present. cytarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. cytokines: A class of substances that are produced by cells of the immune system and that can affect the immune response. Cytokines can also be produced in the laboratory by recombinant DNA technology and given to people to affect immune responses. cytomegalovirus: A virus that may be carried in an inactive state for life by healthy individuals. It is a cause of severe pneumonia in people with a suppressed immune system, such as those undergoing bone marrow transplantation or people with leukemia or lymphoma. cytopenia: A reduction in the number of blood cells. cytotoxic chemotherapy: Anticancer drugs that kill cells, especially cancer cells. cytotoxic T cells: A type of white blood cell that can directly destroy specific cells. T cells can be separated from other blood cells, grown in the laboratory and then given to a patient to destroy tumor cells. Certain cytokines can also be given to a patient to help form cytotoxic T cells in the patients body.

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D
DACA: Acridine carboxamide. A substance that is being studied as an anticancer drug. It belongs to the family of drugs called topoisomerase inhibitors. dacarbazine: An anticancer drug that belongs to the family of drugs called alkylating agents. daclizumab: A monoclonal antibody that is being studied for treatment of adult T-cell leukemia. Also called dacliximab. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. dactinomycin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. dalteparin: A drug that helps prevent the formation of blood clots; it belongs to the family of drugs called anticoagulants. danazol: A synthetic hormone that belongs to the family of drugs called androgens and is used to treat endometriosis. It is being evaluated in the treatment of endometrial cancer. daunorubicin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. decapeptyl: Belongs to the family of drugs called luteinizing hormonereleasing hormone agonists. Used to block hormone production in ovarian ablation. decitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. deferoxamine: An iron chelating agent that removes iron from tumors by inhibiting DNA synthesis and causing cancer cell death. It is used in conjunction with other anticancer agents in pediatric neuroblastoma therapy. defibrotide: A drug under study for the prevention of veno-occlusive disease, a rare complication of high-dose chemotherapy and stem cell transplantation in which small veins in the liver become blocked. dendritic cell: A special type of antigenpresenting cell (APC) that activates T lymphocytes. dendritic cell vaccine: A vaccine made of antigens and dendritic antigenpresenting cells (APCs). denileukin diftitox: A substance used in the treatment of cutaneous T-cell lymphoma that has not responded to previous therapy. deoxycytidine: A drug that protects healthy tissues from the toxic effects of anticancer drugs. depsipeptide: Anticancer drugs obtained from microorganisms. dermatitis: Inflammation of the skin. DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who had used DES. DES may also increase the risk of breast cancer in women who used DES.

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desmoid tumor: A tumor of the tissue that surrounds muscles, usually in the abdomen. Desmoid tumors rarely metastasize. dexamethasone: A synthetic steroid similar to steroid hormones produced naturally in the adrenal gland. Dexamethasone is used to treat leukemia and lymphoma and may be used to treat some of the problems caused by other cancers and their treatment. dexrazoxane: A drug used to protect the heart from the toxic effects of anthracycline drugs such as doxorubicin. It belongs to the family of drugs called chemoprotective agents. di-dgA-RFB4 monoclonal antibody: An anticancer drug that is a combination of a monoclonal antibody (RFB4) and an immunotoxin (dgA). diaphragm: The thin muscle below the lungs and heart that separates the chest from the abdomen. diathermy: The use of heat to destroy abnormal cells. Also called cauterization or electrodiathermy. diaziquone: AZQ. An anticancer drug that is able to cross the blood-brain barrier and kill cancer cells in the central nervous system. diethylstilbestrol (DES): A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who had used DES. DES may also increase the risk of breast cancer in women who used DES.

differentiation: In cancer, refers to how mature (developed) the cancer cells are in a tumor. Differentiated tumor cells resemble normal cells and grow at a slower rate than undifferentiated tumor cells, which lack the structure and function of normal cells and grow uncontrollably. diffusion magnetic resonance imaging: A noninvasive imaging technique that is capable of detecting changes in body tissues that are not clearly distinguished by conventional magnetic resonance imaging (MRI). difluoromethylornithine: DFMO. An anticancer drug that has been shown to reduce the risk of cancer in animals. dihematoporphyrin ether: A drug used in photodynamic therapy that is absorbed by tumor cells; when exposed to light, it becomes active and kills the cancer cells. dilation and curettage: D&C. A minor operation in which the cervix is expanded enough (dilation) to permit the cervical canal and uterine lining to be scraped with a spoon-shaped instrument called a curette (curettage). dimesna: A drug that belongs to the family of drugs called chemoprotective agents. dimethylxanthenone acetic acid: An anticancer drug that belongs to the family of drugs called angiogenesis inhibitors. dipyridamole: A drug that prevents blood cell clumping and enhances the effectiveness of fluorouracil and other chemotherapeutic agents.

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disease progression: Cancer that continues to grow or spread. distant cancer: Refers to cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. disulfiram: A drug that slows the metabolism of retinoids, allowing them to act over a longer period of time. diuretic: A drug that increases the production of urine. DNA: Deoxyribonucleic acid. The molecules inside cells that carry genetic information and pass it from one generation to the next. docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. dose-rate: The strength of a treatment given over a period of time. double-blinded: A doubled-blinded trial is a clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. doxorubicin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. It is an anthracycline. doxycycline: An antibiotic drug used to treat infection. DPPE: Belongs to a group of antihormone drugs.

dronabinol: A synthetic pill form of delta-9-tetrahydrocannabinol (THC), an active ingredient in marijuana that is used to treat nausea and vomiting associated with cancer chemotherapy. duct: A tube through which body fluids pass. ductal carcinoma in situ: DCIS. Abnormal cells that involve only the lining of a duct. The cells have not spread outside the duct to other tissues in the breast. Also called intraductal carcinoma. dumping syndrome: A group of symptoms that occur when food or liquid enters the small intestine too rapidly. These symptoms include cramps, nausea, diarrhea and dizziness. Dumping syndrome sometimes occurs in people who have had a portion of their stomach removed. duodenum: The first part of the small intestine. dysplasia: Cells that look abnormal under a microscope, but are not cancer. dysplastic nevi: Atypical moles; moles whose appearance is different from that of common moles. Dysplastic nevi are generally larger than ordinary moles and have irregular and indistinct borders. Often their color is not uniform, and ranges from pink to dark brown; they usually are flat, but parts may be raised above the skin surface. dyspnea: Difficult, painful breathing, or shortness of breath.

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E
echocardiography: A procedure that uses ultrasonic waves directed over the chest wall to obtain a graphic record of the hearts position, and the motion of the walls, or internal parts such as the valves. edatrexate: An anticancer drug that belongs to a family of drugs called antimetabolites. edema: Swelling caused by excess fluid in body tissues. electroporation therapy: EPT. Treatment that generates electrical pulses through an electrode placed in a tumor to enhance the ability of anticancer drugs to enter tumor cells. embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. endocrine cancer: Cancer that occurs in endocrine tissue, the tissue in the body that secretes hormones. endometrial disorder: Abnormal cell growth in the endometrium (the lining of the uterus). endometriosis: A benign condition in which tissue that looks like endometrial tissue grows in abnormal places in the abdomen. endometrium: The layer of tissue that lines the uterus. endoscopy: The use of a thin, lighted tube (called an endoscope) to examine the inside of the body. endostatin: A drug that is being studied for its ability to prevent the growth of new blood vessels into a solid tumor. Endostatin belongs to the family of drugs called angiogenesis inhibitors. eniluracil: An anticancer drug that increases the effectiveness of fluorouracil. Also called ethynyluracil. enoxaparin: A drug used to prevent blood clots. It belongs to the family of drugs called anticoagulants. enzyme: A protein that speeds up chemical reactions in the body. ependymal tumors: A type of brain tumor that usually begins in the central canal of the spinal cord. Ependymomas may also develop in the cells lining the ventricles of the brain, which produce and store the special fluid (cerebrospinal fluid) that protects the brain and spinal cord. Also called ependymomas. ependymomas: A type of brain tumor that usually begins in the central canal of the spinal cord. Ependymomas may also develop in the cells lining the ventricles of the brain, which produce and store the special fluid (cerebrospinal fluid) that protects the brain and spinal cord. Also called ependymal tumors. epidermal growth factor receptor: A protein found on the surface of some breast cancer cells that allows epidermal growth factor to stimulate cell growth. Also called HER2/neu or c-erb B-2.

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epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. epidural: The space between the wall of the spinal canal and the covering of the spinal cord. An epidural injection is given into this space. epidural block: An injection of an anesthetic drug given into the space between the wall of the spinal canal and the covering of the spinal cord. epinephrine: A hormone and neurotransmitter. Also called adrenaline. epirubicin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. epithelial: Refers to the cells that line the internal and external surfaces of the body. epithelial carcinoma: Cancer that begins in the cells that line an organ. epithelial ovarian cancer: Cancer that occurs in the cells lining the ovaries. epithelium: A thin layer of tissue that covers organs, glands and other structures within the body. epoetin alfa: A colony-stimulating factor that is made in the laboratory. It increases the production of red blood cells. Epstein-Barr virus: EBV. A common virus that remains dormant in most people. It has been associated with certain cancers, including Burkitts lymphoma, immunoblastic lymphoma and nasopharyngeal carcinoma.

erythrocytes: Cells that carry oxygen to all parts of the body. Also called red blood cells (RBCs). erythroleukemia: Cancer of the bloodforming tissues in which large numbers of immature, abnormal red blood cells are found in the blood and bone marrow. erythroplakia: A reddened patch with a velvety surface found in the mouth. erythropoietin: A colony-stimulating factor, produced in the adult kidney, that stimulates the production of red blood cells. esophageal: Related to the esophagus, the muscular tube through which food passes from the throat to the stomach. estramustine: A combination of the hormone estradiol (an estrogen) and nitrogen mustard (an anticancer drug). Used in the palliative therapy of prostate cancer. estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. estrogen receptor negative: ER-. Breast cancer cells that do not have a protein (receptor molecule) to which estrogen will attach. Breast cancer cells that are ER- do not need the hormone estrogen to grow and usually do not respond to hormone (antiestrogen) therapy that blocks these receptor sites. estrogen receptor positive: ER+. Breast cancer cells that have a protein (receptor molecule) to which estrogen will attach. Breast cancer cells that are ER+ need the hormone estrogen to grow and will usually respond to hormone (antiestrogen) therapy that blocks these receptor sites.

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estrogen replacement therapy: ERT. Hormones (estrogen and/or progesterone) given to postmenopausal women, or women who have had their ovaries surgically removed. Hormones are given to replace the estrogen no longer produced by the ovaries. estrogens: A family of hormones that promote the development and maintenance of female sex characteristics. ethynyluracil: An anticancer drug that increases the effectiveness of fluorouracil. Also called eniluracil. etidronate: A drug that belongs to the family of drugs called bisphosphonates. Bisphosphonates are used as treatment for hypercalcemia (abnormally high levels of calcium in the blood) and for cancer that has spread to the bone (bone metastases). etiology: The cause or origin of disease. etoposide: An anticancer drug that is a podophyllotoxin derivative and belongs to the family of drugs called mitotic inhibitors. evaluable disease: Disease that cannot be measured directly by the size of the tumor but can be evaluated by other

methods specific to a particular clinical trial. Ewings sarcoma: A type of bone cancer that usually forms in the middle (shaft) of large bones. Also called Ewings sarcoma/primitive neuroectodermal tumor (PNET). excisional biopsy: A surgical procedure in which an entire lump or suspicious area is removed for diagnosis. The tissue is then examined under a microscope. exemestane: An anticancer drug used to decrease estrogen production and to suppress the growth of estrogendependent tumors. extensive-stage small cell lung cancer: Cancer that has spread outside the lung to other tissues in the chest or to other parts of the body. external radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called externalbeam radiation. external-beam radiation: Radiation therapy that uses a machine to aim highenergy rays at the cancer. Also called external radiation.

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F
fallopian tubes: Part of the female reproductive tract. The long slender tubes through which eggs pass from the ovaries to the uterus. familial dysplastic nevi: A condition that runs in certain families in which at least two members have dysplastic nevi (atypical moles) and have a tendency to develop melanoma. familial polyposis: An inherited condition in which numerous polyps (tissue masses) develop on the inside walls of the colon and rectum. It increases the risk for colon cancer. Fanconi anemia: A rare and often fatal inherited disease in which the bone marrow fails to produce red blood cells, white blood cells, platelets or a combination of these cells. The disease may transform into myelodysplastic syndrome or leukemia. fatty acids: A major component of fats that are used by the body for energy and tissue development. fazarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. fentanyl: A narcotic opioid drug that is used in the treatment of pain. fibroid: A benign smooth muscle tumor, usually in the uterus or gastrointestinal tract. Also called leiomyoma. fibrosarcoma: A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles and other organs in place. fibrosis: The growth of fibrous tissue. filgrastim: A colony-stimulating factor that stimulates the production of neutrophils (a type of white blood cell). It is a cytokine that belongs to the family of drugs called hematopoietic (blood forming) agents. Also called granulocyte colony-stimulating factor (G-CSF). filgrastim-SD/01: A substance that is being studied for its ability to increase numbers of white blood cells in people who are receiving chemotherapy. It belongs to the family of drugs called colony-stimulating factors. finasteride: A drug used to reduce the amount of male hormone (testosterone) produced by the body. fine-needle aspiration: The removal of tissue or fluid with a needle for examination under a microscope. Also called needle biopsy. flavopiridol: Belongs to the family of anticancer drugs called flavinols. floxuridine: An anticancer drug that belongs to the family of drugs called antimetabolites. fluconazole: A drug that treats infections caused by fungi. flucytosine: A drug that treats infections caused by fungi. fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. fludeoxyglucose F 18: The radioactive form of glucose used in positron emis-

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sion tomography (PET), a diagnostic imaging procedure. fludrocortisone: A synthetic corticosteroid. It is used to replace steroid hormones normally produced by the adrenal gland. fluoroscope: An X-ray machine that makes it possible to see internal organs in motion. fluorouracil: An anticancer drug that belongs to the family of drugs called antimetabolites. flutamide: An anticancer drug that belongs to the family of drugs called antiandrogens.

folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition and/or blood flow. fundus: The larger part of a hollow organ that is farthest away from the organs opening. The bladder, gallbladder, stomach, uterus, eye and the cavity of the middle ear all have a fundus.

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G
G-CSF: Granulocyte colony-stimulating factor. A substance that stimulates the production of neutrophils, a type of white blood cell. Also called filgrastim. gadolinium texaphyrin: A substance that makes tumor cells more sensitive to radiation; it can also enhance tumor images using magnetic resonance imaging (MRI). Gadolinium texaphyrin belongs to the family of drugs called metalloporphyrin complexes. gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. gallium nitrate: A drug that lowers blood calcium. Used as treatment for hypercalcemia (too much calcium in the blood) and for cancer that has spread to the bone (bone metastases). gamma knife: Radiation therapy in which high-energy rays are aimed at a tumor from many angles in a single treatment session. gastric: Having to do with the stomach. gastric atrophy: A condition in which the stomach muscles shrink and become weak. The digestive (peptic) glands may also shrink, resulting in a lack of digestive juices. gastrointestinal tract: The stomach and intestines. Gastroscope (GAS-tro-skope): A thin, lighted tube used to view the inside of the stomach. geldanamycin analogue: An antineoplastic antibiotic drug that belongs to the family of drugs called ansamycins. genetic markers: Alterations in DNA that may indicate an increased risk of developing a specific disease or disorder. Genito-urinary system: The parts of the body that play a role in reproduction, in getting rid of waste products in the form of urine, or both. germ cell tumors: Tumors that begin in the cells that give rise to sperm or eggs. They can occur virtually anywhere in the body and can be either benign or malignant. gemcitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. gene deletion: The total loss or absence of a gene. gene therapy: Treatment that alters a gene. In studies of gene therapy for cancer, researchers are trying to improve the bodys natural ability to fight the disease or to make the cancer cells more sensitive to other kinds of therapy. gene-modified: Cells that have been altered to contain different genetic material than they did originally. genetic: Inherited; having to do with information that is passed from parents to children through genes in sperm and egg cells.

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germ cells: The reproductive cells of the body, specifically either egg or sperm cells. germinoma: The most frequent type of germ cell tumor in the brain. germline mutation: A gene change in the bodys reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. Gleason score: A system of grading prostate cancer cells to determine the best treatment and to predict how well a person is likely to do. A low Gleason score means the cancer cells are very similar to normal prostate cells; a high Gleason score means the cancer cells are very different from normal. glial tumors: A general term for many types of tumors of the central nervous system, including astrocytomas, ependymal tumors, glioblastoma multiforme and primitive neuroectodermal tumors. glioblastoma: A general term that refers to malignant astrocytoma, a type of brain tumor. glioblastoma multiforme: A type of brain tumor that forms from the glial (supportive) tissue of the brain. It grows very quickly and has cells that look very different from normal cells. Also called grade IV astrocytoma. glioma: A cancer of the brain that comes from glial, or supportive, cells. gliosarcoma: A type of glioma. glucocorticoid: A compound that belongs to the family of compounds called

corticosteroids (steroids). Glucocorticoids affect metabolism, and have antiinflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). glufosfamide: An anticancer drug that belongs to the family of drugs called alkylating agents. glutamine: An amino acid used in nutrition therapy. It is also being studied for the treatment of diarrhea caused by radiation therapy to the pelvis. GM-CSF: Granulocyte-macrophage colony-stimulating factor. A substance that stimulates the production of white blood cells, especially granulocytes and macrophages, and cells (in the bone marrow) that are precursors of platelets. Also called sargramostim. gonads: The part of the reproductive system that produces and releases eggs (ovaries) or sperm (testicles/testes). goserelin: A drug that belongs to the family of drugs called gonadotropinreleasing hormone analogues. Goserelin is used to block hormone production in the ovaries or testicles. gp 100: Glycoprotein 100 (gp 100) is a tumor-specific antigen used in the development of cancer vaccines. grade: The grade of a tumor is determined by how abnormal the cancer cells appear when examined under a microscope, the probable growth rate of the tumor, and its tendency to spread. The systems used to grade tumors vary with each type of cancer. grading: A system for classifying cancer cells in terms of how abnormal they appear when examined under a microscope. The objective of a grading system
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is to provide information about the probable growth rate of the tumor and its tendency to spread. The systems used to grade tumors vary with each type of cancer. Grading plays a role in treatment decisions. graft: Healthy skin, bone or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a persons tissue. graft-versus-tumor: An immune response to a persons tumor cells by immune cells present in a donors transplanted tissue, such as bone marrow or peripheral blood. granisetron: A drug that prevents or reduces nausea and vomiting.

granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils and basophils are granulocytes. granulocyte colony-stimulating factor: G-CSF. A substance that stimulates the production of blood cells, especially platelets, during chemotherapy. It is a cytokine that belongs to the family of drugs called hematopoietic (blood forming) agents. Also called filgrastim. granulocytopenia: A deficiency in the number of granulocytes, a type of white blood cell. growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. gynecologic cancer: Cancer of the female reproductive tract, including the cervix, endometrium, fallopian tubes, ovaries, uterus and vagina.

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H
hairy cell leukemia: A type of chronic leukemia in which the abnormal white blood cells appear to be covered with tiny hairs when viewed under a microscope. hemangiopericytoma: A type of cancer involving blood vessels and soft tissue. hematogenous: Originating in the blood or spread through the bloodstream. hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. hematoporphyrin derivative: A drug used in photodynamic therapy that is absorbed by tumor cells. When exposed to light, it becomes active and kills the cancer cells. hepatic: Refers to the liver. hepatoblastoma: A type of liver tumor that occurs in infants and children. hepatocellular carcinoma: This is a type of adenocarcinoma, the most common type of liver tumor. hepatocyte: A liver cell. HER2/neu: Human epidermal growth factor receptor 2. The HER2-neu protein is involved in growth of some cancer cells. Also called c-erbB-2. HER2/neu gene: The gene that makes the human epidermal growth factor receptor 2. The protein produced is HER2/neu antigen, which is involved in growth of some cancer cells. Also called c-erbB-2. hormonal therapy: Treatment of cancer by removing, blocking or adding hormones. Also called endocrine therapy. hormone receptor test: A test to measure the amount of certain proteins, called hormone receptors, in cancer tissue. Hormones can attach to these proteins. A high level of hormone receptors may mean that hormones help the cancer grow. hereditary mutation: A gene change in the bodys reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. hereditary nonpolyposis colon cancer: An inherited disorder in which affected individuals have a higher-than-normal chance of developing colon cancer and certain other types of cancer, usually before the age of 60. Also called Lynch syndrome. histamine dihydrochloride: A drug being studied for its ability to enhance the effectiveness of IL-2 in treating acute myeloid leukemia. Hodgkins disease: A malignant disease of the lymphatic system that is characterized by painless enlargement of the lymph nodes, the spleen or other lymphatic tissue. It is sometimes accompanied by symptoms such as fever, weight loss, fatigue and night sweats. homoharringtonine: An anticancer drug that belongs to the plant alkaloid family of drugs.

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hormone replacement therapy: HRT. Hormones (estrogen and/or progesterone) given to postmenopausal women or women who have had their ovaries surgically removed, in order to replace the estrogen no longer produced by the ovaries. hormone therapy: Treatment of cancer by removing, blocking or adding hormones. Also called endocrine therapy. hormones: Chemicals produced by glands in the body and circulated in the bloodstream. Hormones control the actions of certain cells or organs. human papilloma virus: HPV. A virus that causes abnormal tissue growth (warts) and that is often associated with some types of cancer. hydrocephalus: The abnormal buildup of cerebrospinal fluid in the ventricles of the brain. hydrocortisone: A drug used to relieve the symptoms of certain hormone shortages, and to suppress an immune response. hydroxyurea: An anticancer drug that belongs to the family of drugs called antimetabolites. hypercalcemia: High levels of calcium in the blood. hyperfractionation: A way of giving radiation therapy in smaller-than-usual doses two or three times a day instead of once a day.

hyperplasia: An abnormal increase in the number of cells in an organ or tissue. hypersensitivity: An exaggerated response by the immune system to a drug or other substance. hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells, or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. hyperthermic perfusion: A procedure in which a warmed solution containing anticancer drugs is used to bathe, or is passed through the blood vessels of, the tissue or organ containing the tumor. hyperthyroidism: A condition in which the thyroid gland produces too much thyroid hormone. hyperuricemia: A buildup of uric acid (a by-product of metabolism) in the blood; a side effect of some anticancer drugs. hypervascular: Having a large number of blood vessels. hypopharynx: The bottom part of the throat. Cancer of the hypopharynx is also called hypopharyngeal cancer. hypothalamus: The area of the brain that controls body temperature, hunger and thirst. hysterectomy: An operation in which the uterus is removed.

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I
idarubicin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. Also called 4-demethoxydaunorubicin. IDEC-Y2B8 monoclonal antibody: An anticancer drug that is a combination of a monoclonal antibody and a radioisotope (yttrium Y 90). Also called ibritumomab tiuxetan. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. idoxifene: A drug that blocks the effects of estrogen. idoxuridine: A drug that reduces the risk of cancer cell growth by interfering with the cells DNA. ifosfamide: An anticancer drug that belongs to the family of drugs called alkylating agents. ileostomy: An opening into the ileum, part of the small intestine, from the outside of the body. An ileostomy provides a new path for waste material to leave the body after part of the intestine has been removed. immune adjuvant: A drug that stimulates the immune system to respond to disease. immune function: Production and action of cells that fight disease or infection. immune response: The activity of the immune system against foreign substances (antigens). immune system: The complex group of organs and cells that defend the body against infection or disease. immunocompromised: Having a weakened immune system caused by certain diseases or treatments. immunodeficiency: The decreased ability of the body to fight infection and disease. immunodeficiency syndrome: The inability of the body to produce an immune response. immunoglobulin: A protein that acts as an antibody. immunological adjuvant: A substance used to help boost the immune response to a vaccine so that less vaccine is needed. immunosuppression: Suppression of the bodys immune system and its ability to fight infections or disease. Immunosuppression may be deliberately induced with drugs, such as in preparation for bone marrow or other organ transplantation in order to prevent rejection of the donor tissue. It may also result from certain diseases, such as AIDS or lymphoma, or from anticancer drugs. immunosuppressive therapy: Therapy used to decrease the bodys immune response, such as drugs given to prevent transplant rejection. immunotherapy: Treatment to stimulate or restore the ability of the persons immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also called biological therapy or biological response modifier (BRM) therapy.

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immunotoxin: An antibody linked to a toxic substance. Some immunotoxins can bind to cancer cells and kill them. implant radiation: Radiation therapy that is given internally. This is done by placing radioactive material that is sealed in needles, seeds, wires or catheters directly into or near the tumor. Also called internal radiation or brachytherapy. implantable pump: A small device installed under the skin to administer a steady dose of drugs. in situ cancer: Early cancer that has not spread to neighboring tissue. in vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). in vivo: In the body. The opposite of in vitro (outside the body). incidence: The number of new cases of a disease diagnosed each year. incomplete Freunds adjuvant: A drug used in vaccine therapy to stimulate the immune system. indolent: A type of cancer that grows slowly. indolent lymphoma: Lymphoma that grows slowly and has few symptoms. induction therapy: Treatment designed to be used as a first step toward shrinking the cancer and in evaluating response to drugs and other agents. Induction therapy is followed by additional therapy to eliminate whatever cancer remains. infiltrating cancer: Cancer that has spread beyond the layer of tissue in
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which it developed and is growing into surrounding, healthy tissues. Also called invasive cancer. inflammatory breast cancer: A type of breast cancer in which the breast looks red and swollen, and feels warm. The skin of the breast may also show the pitted appearance called peau dorange (like the skin of an orange). The redness and warmth occur because the cancer cells block the lymph vessels in the skin. infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. inguinal orchiectomy: An operation in which the testicle is removed through an incision in the groin. interferon: A biological response modifier (a substance that stimulates the bodys response to infection and disease). Interferons affect the division of cancer cells and slow tumor growth. There are several types of interferons, including interferon-alpha, interferonbeta and interferon-gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. interleukin-11: IL-11. A type of biological response modifier (a substance that can improve the bodys natural response to disease) that stimulates immune response and may reduce toxicity to the gastrointestinal system resulting from cancer therapy. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. Also called oprelvekin. interleukin-12: IL-12. A type of biological response modifier (a substance that

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can improve the bodys natural response to disease) that enhances the ability of the immune system to kill tumor cells, and that may interfere with blood flow to the tumor. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. interleukin-2: IL-2. A type of biological response modifier (a substance that can improve the bodys natural response to disease) that stimulates the growth of certain disease-fighting blood cells in the immune system. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. Also called aldesleukin. interleukin-3: IL-3. A type of biological response modifier (a substance that can improve the bodys natural response to disease) that enhances the immune systems ability to fight tumor cells. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. interleukin-4: IL-4. A type of biological response modifier (a substance that can improve the bodys natural response to disease) that enhances the immune systems ability to fight tumor cells. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. interleukins: Biological response modifiers (substances that can improve the bodys natural response to disease) that help the immune system fight infection and cancer. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases.

intermediate-grade lymphomas: Includes diffuse small, cleaved cell lymphoma and diffuse large, noncleaved cell lymphoma. These are more aggressive than low-grade lymphomas, but they have a better response to anticancer drugs. internal radiation: Radiation therapy that is given internally. This is done by placing radioactive material that is sealed in needles, seeds, wires or catheters directly into or near the tumor. Also called implant radiation or brachytherapy. intracarotid infusion: The introduction of fluids and drugs directly into the carotid artery, the main artery in the neck; it carries blood from the heart to the brain. intracranial tumors: Tumors that occur in the brain. intraductal carcinoma: Abnormal cells that involve only the lining of a duct. The cells have not spread outside the duct to other tissues in the breast. Also called ductal carcinoma in situ. intraepithelial: Within the layer of cells that form the surface or lining of an organ. intrahepatic: Within the liver. intrahepatic bile ducts: The bile ducts that pass through and drain bile from the liver. intrahepatic infusion: The delivery of anticancer drugs directly to the blood vessels of the liver. intraoperative radiation therapy: IORT. Radiation treatment aimed directly at a tumor during surgery.

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intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). intrathecal: The thin space between the lining of the spinal cord and the brain. intrathecal chemotherapy: Anticancer drugs infused into the thin space between the lining of the spinal cord and the brain to treat or reduce the risk of cancers in the brain and spinal cord. intravenous: IV. Injected into a vein. intravenous pyelogram: IVP. A series of X-rays of the kidneys, ureters and bladder. The X-rays are taken after a dye is injected into a blood vessel. The dye, which is concentrated in the urine, outlines the kidneys, ureters and bladder on the X-rays. intraventricular infusion: The delivery of a drug into a space within an organ. intravesical: Within the bladder. invasive cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called infiltrating cancer. invasive cervical cancer: Cancer that has spread from the surface of the cervix to tissue deeper in the cervix or to other parts of the body. ionomycin: An antibiotic drug used to treat infection. IORT: Intraoperative radiation therapy. Radiation treatment aimed directly at a tumor during surgery.

irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. irreversible toxicity: Side effects that are caused by toxic substances or something harmful to the body, and that do not go away. islet cell cancer: Cancer arising from cells in the islets of Langerhans, which are found in the pancreas. islets of Langerhans: Cells in the pancreas that produce hormones (including insulin). isoflavones: Compounds found in soy beans that may help prevent cancer. isolated hepatic perfusion: A procedure in which a catheter is placed into the artery that provides blood to the liver; and another catheter is placed into the vein that takes blood away from the liver. This temporarily separates the livers blood supply from blood circulating throughout the rest of the body and allows high doses of anticancer drugs to be directed to the liver only. isolated limb perfusion: A technique that may be used to deliver anticancer drugs directly to an arm or leg. The flow of blood to and from the limb is temporarily stopped with a tourniquet, and anticancer drugs are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where the cancer occurred.

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isolated lung perfusion: A surgical procedure during which the circulation of blood to the lungs is separated from the circulation of blood through the rest of the body, and a drug is delivered directly into the lung circulation. This allows a higher concentration of chemotherapy to reach tumors in the lungs.

isotretinoin: A drug that belongs to the family of drugs called retinoids. It is used in the treatment of acne and psoriasis and is being studied in cancer prevention. Also called 13-cis retinoic acid.

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J
jaundice: A condition in which the skin and the whites of the eyes become yellow, urine darkens and stool becomes clay colored. Jaundice occurs when the liver is not working properly or when a bile duct is blocked.

K
Kaposis sarcoma: A type of cancer characterized by the abnormal growth of blood vessels that develop into skin lesions or occur internally. keloid: A thick, irregular scar caused by excessive tissue growth at the site of an incision or wound. keratinocyte growth factor: A substance that stimulates the growth of epithelial cells that line the surface of the mouth and intestinal tract. killer cells: White blood cells that attack tumor cells and body cells that have been invaded by foreign substances. Krukenberg tumor: A tumor in the ovary caused by the spread of stomach cancer.

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L
laparoscopy: The insertion of a thin, lighted tube (called a laparoscope) through the abdominal wall to inspect the inside of the abdomen and remove tissue samples. laparotomy: A surgical incision made in the wall of the abdomen. large cell carcinomas: A group of lung cancers in which the cells are large and look abnormal when viewed under a microscope. laryngeal: Refers to the larynx. leflunomide: An anticancer drug that works by inhibiting a cancer cell growth factor. Also called SU101. leiomyoma: A benign smooth muscle tumor, usually in the uterus or gastrointestinal tract. Also called a fibroid. leiomyosarcoma: A tumor of the muscles in the uterus or abdomen/pelvis. leptomeningeal cancer: A tumor that involves the tissues that cover the brain and spinal cord. leptomeningeal metastases: Cancer that has spread from the original (primary) tumor to the tissues that cover the brain and the spinal cord. leridistim: A substance that is being studied for its ability to increase the number of white blood cells in people who are receiving chemotherapy. It belongs to the family of drugs called colony-stimulating factors. lerisetron: A drug that prevents or reduces nausea and vomiting.
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lesion: An area of abnormal tissue change. letrozole: An anticancer drug that belongs to the family of drugs called nonsteroidal aromatase inhibitors. Letrozole is used to decrease estrogen production and suppress the growth of estrogen dependent tumors. leucovorin: A drug used to protect normal cells from high doses of the anticancer drug methotrexate. It is also used to increase the antitumor effects of fluorouracil and tegafur-uracil, an oral treatment alternative to intravenous fluorouracil. leukapheresis: Removal of the blood to collect specific blood cells; the remaining blood is returned to the body. leukemia: Cancer of blood-forming tissue. leukocytes: Cells that help the body fight infections and other diseases. Also called white blood cells (WBCs). leukoplakia: A white patch that may develop on mucous membranes, such as the cheek, gums or tongue, and may become cancerous. leuprolide: A drug that belongs to a family of drugs called gonadotropinreleasing hormone analogues. Used to block hormone production in the ovaries or testicles. leuvectin: An agent that delivers the gene for interleukin-2 (IL-2) into cells to increase production of IL-2 by the cells.

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levamisole: An antiparasitic drug that is also being studied in cancer therapy with fluorouracil. LH-RH: Abbreviation for luteinizing hormone-releasing hormone, a hormone that controls the production of sex hormones in men and women. Li-Fraumeni syndrome: A rare, inherited predisposition to multiple cancers caused by an alteration in the p53 tumor suppressor gene. ligation: The process of tying off blood vessels so that blood cannot flow to a part of the body or to a tumor. limb perfusion: A technique that may be used to deliver anticancer drugs directly to an arm or leg. The flow of blood to and from the limb is temporarily stopped with a tourniquet, and anticancer drugs are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where the cancer occurred. limited-stage small cell lung cancer: Cancer is found in one lung and in nearby lymph nodes. liposarcoma: A rare cancer of the fat cells. liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better and its distribution to the tumor site is improved. liver metastases: Cancer that has spread from the original (primary) tumor to the liver. lobaplatin: An anticancer drug that belongs to the family of drugs called platinum compounds.
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lobular carcinoma in situ: LCIS. Abnormal cells found in the lobules of the breast. This condition seldom becomes invasive cancer. However, having lobular carcinoma in situ increases ones risk of developing cancer in either breast. lobule: A small lobe or subdivision of a lobe. local cancer: An invasive malignant cancer confined entirely to the organ where the cancer began. local therapy: Treatment that affects cells in the tumor and the area close to it. localized: Restricted to the site of origin without evidence of spread. localized gallbladder cancer: Cancer is found only in the tissues that make up the wall of the gallbladder; it can be removed completely in an operation. locally advanced cancer: Cancer that has spread only to nearby tissues or lymph nodes. lomustine: An anticancer drug that belongs to the family of drugs called alkylating agents. low-grade lymphomas: Lymphomas that tend to grow and spread slowly, including chronic lymphocytic lymphoma and follicular small cleaved cell lymphoma. Also called indolent lymphomas. lumbar puncture: The insertion of a needle into the lower part of the spinal column to collect cerebrospinal fluid or to give anticancer drugs intrathecally. Also called a spinal tap. lumpectomy: Surgery to remove the tumor and a small amount of normal tissue around it.

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lung metastases: Cancer that has spread from the original (primary) tumor to the lung. luteinizing hormone-releasing hormone agonist: LH-RH agonist. A substance that closely resembles luteinizing hormone-releasing hormone (LH-RH), which controls the secretion of sex hormones. However, LH-RH agonists affect the body differently than does LH-RH. LH-RH agonists eventually cause a decrease in the secretion of sex hormones. lutetium texaphyrin: A substance that is being studied in photodynamic therapy. It belongs to the family of drugs called metallotexaphyrins. lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and they contain many lymphocytes, which filter the lymphatic fluid (lymph). lymphadenectomy: A surgical procedure in which the lymph nodes are removed and examined to see if they contain cancer. Also called lymph node dissection. lymphangiography: An X-ray study of the lymphatic system. A dye is injected into a lymphatic vessel and travels throughout the lymphatic system. The dye outlines the lymphatic vessels and organs on the X-ray. lymphatic system: The tissues and organs that produce, store and carry white blood cells that fight infection and other

diseases. This system includes the bone marrow, spleen, thymus and lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. lymphedema: A condition in which excess lymph collects in tissue and causes swelling. It may occur in the arm or leg after lymph vessels or lymph nodes in the underarm or groin are removed. lymphocyte: A type of white blood cell that has a number of roles in the immune system. Some lymphocytes act as tumor-killing cells. Other lymphocytes produce antibodies or other substances that fight cancer, infection and other diseases. The main types of lymphocytes are T cells, B cells and natural killer (NK) cells. lymphokine-activated killer cells: White blood cells that are stimulated in a laboratory to kill tumor cells. Also called LAK cells. lymphoma: Cancer that arises in cells of the lymphatic system. lymphomatoid granulomatosis: Destructive growth of lymph cells, usually involving the lungs, skin, kidneys and central nervous system. Grades I and II are not considered cancerous, but grade III is considered a lymphoma. lymphoproliferative disorders: Diseases in which cells of the lymphatic system grow excessively. These disorders are often treated similarly to cancer. Lynch syndrome: An inherited disorder in which affected individuals develop colon cancer, usually before the age of 60. Also called hereditary nonpolyposis colon cancer.
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M
M proteins: Antibodies or parts of antibodies found in unusually large amounts in the blood or urine of people with multiple myeloma. MAGE-3: A gene found in some types of tumors. magnetic resonance imaging: MRI. A procedure in which a magnet linked to a computer is used to create detailed pictures of areas inside the body. maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. malabsorption syndrome: A group of symptoms such as gas, bloating, abdominal pain and diarrhea resulting from the bodys inability to absorb nutrients properly. malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. malignant ascites: A condition in which fluid containing cancer cells collects in the abdomen. malignant fibrous histiocytoma: A sarcoma that usually begins in soft tissue. It usually appears as an enlarging, painful mass that can cause fracture due to destruction of the bone by a spreading tumor. malignant meningioma: A rare, rapidly growing tumor that occurs in the membranes that cover and protect the brain and the spinal cord (meninges). malignant mesothelioma: A rare type of cancer in which malignant cells are found in the sac lining the chest or abdomen. Exposure to airborne asbestos particles increases ones risk of developing malignant mesothelioma. MALT lymphoma: Mucosa-associated lymphoid tissue lymphoma. A type of cancer that arises in cells in mucosal tissue that are involved in antibody production. mammogram: An X-ray of the breast. mantle field: The area of the neck, chest and lymph nodes in the armpit that is exposed to radiation. marimastat: An anticancer drug that belongs to the family of drugs called angiogenesis inhibitors. Marimastat is a matrix metalloproteinase inhibitor. marker: A diagnostic indication that disease may develop. mastectomy: Surgery to remove the breast (or as much of the breast tissue as possible). measurable disease: A tumor that can be accurately measured in size. This information can be used to judge response to treatment. medial supraclavicular lymph nodes: Lymph nodes located above the collar bone and between the center of the body

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and a line drawn through the nipple to the shoulder. median: A statistics term. The middle value in a set of measurements. mediastinum: The area between the lungs. The organs in this area include the heart and its large blood vessels, the trachea, the esophagus, the bronchi and lymph nodes. medical castration: Refers to the use of drugs to suppress the function of the ovaries or testicles. medroxyprogesterone: A hormonal anticancer drug that is also used in cancer prevention. It belongs to the family of drugs called progestins. medulloblastoma: A malignant brain tumor that begins in the lower part of the brain and that can spread to the spine or to other parts of the body. Medulloblastomas are sometimes called primitive neuroectodermal tumors (PNET). megestrol: A drug that belongs to the group of hormones called progestins, used as hormone therapy to block estrogen and to suppress the effects of cancer. melanin: The substance that gives the skin its color. melanocytes: Cells in the skin that produce and contain the pigment called melanin. melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. melanoma vaccine: A cancer vaccine prepared from human melanoma cancer

cells. It is used either alone or with other therapy in treating melanoma. melphalan: An anticancer drug that belongs to the family of drugs called alkylating agents. membrane: A very thin layer of tissue that covers a surface. meningeal: Refers to the meninges, the tissue covering the brain and spinal cord. meningeal metastases: Cancer that has spread from the original (primary) tumor to the tissue covering the brain and/or spinal cord. meningioma: A type of tumor that occurs in the meninges, the membranes that cover and protect the brain and the spinal cord. Meningiomas usually grow slowly. menopause: The time of life when a womans menstrual periods stop for at least a year. Also called change of life. menstrual cycle: The monthly cycle of hormonal changes from the beginning of one menstrual period to the beginning of the next. menstruation: Periodic discharge of blood and tissue from the uterus. Until menopause, menstruation occurs approximately every 28 days when a woman is not pregnant. mercaptopurine: An anticancer drug that belongs to the family of drugs called antimetabolites. Merkel cell cancer: A rare type of cancer that develops on or just beneath the skin. mesenchymal: Refers to cells that develop into connective tissue, blood vessels and lymphatic tissue.

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mesna: A drug that helps protect the kidneys and bladder from the toxic effects of anticancer drugs, such as ifosfamide and cyclophosphamide. metabolism: The total of all chemical changes that take place in a cell or an organism. These changes produce energy and basic materials that are needed for important life processes. metaplasia: A change of cells to a form that does not normally occur in the tissue in which it is found. metastasis: The spread of cancer from one part of the body to another. When cancer cells metastasize and form secondary tumors, the cells in the metastatic tumor are like those in the original (primary) tumor. The plural is metastases. metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. methotrexate: An anticancer drug that belongs to the family of drugs called antimetabolites. methylprednisolone: A corticosteroid hormone replacement. metoclopramide: A drug that prevents or reduces nausea and vomiting. microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but that can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. mifepristone: An anticancer drug that blocks the action of progesterone, a hormone that affects the growth of some cancers.
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misoprostol: A radioprotective agent that belongs to the family of drugs called prostaglandins. mitolactol: An anticancer drug that belongs to the family of drugs called alkylating agents. mitomycin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. mitotic inhibitors: Drugs that kill cancer cells by interfering with cell division (mitosis). mitoxantrone: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. mivobulin isethionate: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. Also called CI980. mixed gliomas: Brain tumors that occur in more than one type of brain cell, including astrocytes, ependymal cells, and/or oligodendrocytes. modified radical mastectomy: Surgical procedure in which the breast, some of the lymph nodes in the armpit, and the lining over the chest muscles are removed. mole: A benign growth on the skin (usually tan, brown or flesh-colored) that contains a cluster of melanocytes and surrounding supportive tissue. monoclonal antibodies: Laboratoryproduced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal

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antibodies can be used alone, or they can be used to deliver drugs, toxins or radioactive material directly to the tumor. monocyte: A type of white blood cell. MRI: Magnetic resonance imaging. A procedure in which a magnet linked to a computer is used to create detailed pictures of areas inside the body. mucin/peptide: A protein/sugar compound made by some cancer cells. mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. mucus: A thick, slippery fluid produced by the membranes that line certain organs of the body, including the nose, mouth, throat and vagina. multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. multidrug resistance inhibition: Treatment used to make cancer cells less resistant to anticancer drugs. multimodality treatment: Therapy that combines more than one method of treatment. multiple myeloma: Cancer that arises in plasma cells (white blood cells that produce antibodies). muromonab-CD3 monoclonal antibody: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. mutations: Changes in the structure of genes. A mutation may be inherited or

caused by an environmental exposure. Certain changes may lead to cancer or other diseases. Also called a gene alteration. mycosis fungoides: A type of nonHodgkins lymphoma that first appears on the skin and can spread to the lymph nodes or other organs such as the spleen, liver or lungs. myelin: The fatty substance that covers and protects nerves. myelodysplasia: Abnormal bone marrow cells that may lead to myelogenous leukemia. myelodysplastic syndrome: Disease in which the bone marrow does not function normally. Also called preleukemia or smoldering leukemia. myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. myelogenous: Produced by or originating in the bone marrow. myeloid: Pertaining to, derived from or manifesting certain features of the bone marrow. In some cases also pertains to certain types of non-lymphocyte white blood cells found in the bone marrow, including granulocyte, monocyte and platelet lineages. Also called myelogenous. myeloma: Cancer that arises in plasma cells, a type of white blood cell. myeloproliferative disorders: Diseases in which too many blood cells are made in the bone marrow. myelosuppressive therapy: Treatment that inhibits blood cell production.
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N
N-acetyl cysteine: An antioxidant drug that may keep cancer cells from developing or reduce the risk of growth of existing cancer. neoadjuvant therapy: Treatment given before the primary treatment. Neoadjuvant therapy can be chemotherapy, radiation therapy or hormone therapy. neoplasm: A new growth of benign or malignant tissue. neoplastic meningitis: Tumor cells that have spread from the original (primary) tumor to the tissue that covers the brain and/or spinal cord. nephrectomy: Surgery to remove the kidney. Radical nephrectomy removes the kidney, the adrenal gland, nearby lymph nodes and other surrounding tissue. Simple nephrectomy removes only the kidney. Partial nephrectomy removes the tumor, but not the entire kidney. neuroblastoma: Cancer that arises in immature nerve cells and that affects mostly infants and children. neuroectodermal tumor: A tumor of the central or peripheral nervous systems. neuroendocrine: Describes the production of hormone-like substances by neurons or neuron-like cells and the way the nervous system and the endocrine system work together. neuropathy: A problem in any part of the nervous system except the brain and the spinal cord. Neuropathies can be caused by infection, toxic substances or disease.
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neurotoxicity: The tendency of some treatments to cause damage to the nervous system. neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. neutrophil: A type of white blood cell. nevus: A benign growth on the skin, such as a mole. A mole is a cluster of melanocytes and surrounding supportive tissue that usually appears as a tan, brown or flesh-colored spot on the skin. NG-monomethyl-L-arginine: An amino acid derivative used to counteract high blood pressure caused by interleukin-2. niacinamide: A vitamin. It is being studied to increase the effect of radiation therapy on tumor cells. Also called nicotinamide. nitrocamptothecin: An alkaloid drug belonging to a class of anticancer agents called topoisomerase inhibitors. nitrosoureas: A group of anticancer drugs that can cross the blood-brain barrier. Carmustine and lomustine are nitrosoureas. node-negative: Cancer that has not spread to the lymph nodes. node-positive: Cancer that has spread to the lymph nodes. non-Hodgkins lymphoma: A group of cancers of the lymphoid system, including acute lymphoblastic leukemia, B cell lymphoma, Burkitts lymphoma, diffuse cell lymphoma, follicular lymphoma,

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immunoblastic large cell lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, mycosis fungoides, posttransplantation lymphoproliferative disorder, small non-cleaved cell lymphoma and T-cell lymphoma. nonmalignant hematologic disorders: Noncancerous disorders of the blood. They do not destroy or invade nearby tissue and do not spread to other organs. nonmelanoma skin cancer: Skin cancer that arises in basal cells or squamous cells but not in melanocytes (pigmentproducing cells of the skin). nonmetastatic: Cancer that has not spread from the primary (original) site to other sites in the body.

nonseminoma: A group of testicular cancers that begin in the germ cells (cells that give rise to sperm). Nonseminomas are identified by the type of cell they begin in and include embryonal carcinoma, teratoma, choriocarcinoma and yolk sac carcinoma. Non-small-cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma and large cell carcinoma. nonspecific immune cells: Cells such as phagocytes and macrophages that respond to many antigens, not just one. novobiocin: An antibiotic drug used to treat infection.

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O
oat cell cancer: A type of lung cancer in which the cells look like oats when viewed under a microscope. Also called small cell lung cancer. octreotide: A drug similar to the naturally occurring growth hormone inhibitor somatostatin. Octreotide is used to treat diarrhea and flushing associated with certain types of tumors. oligodendroglial tumors: Rare, slowgrowing tumors that begin in brain cells called oligodendrocytes, which provide support and nourishment for cells that transmit nerve impulses. Also called oligodendroglioma. oligodendroglioma: A rare, slow-growing tumor that begins in brain cells called oligodendrocytes, which provide support and nourishment for cells that transmit nerve impulses. Also called oligodendroglial tumor. Ommaya reservoir: A device surgically placed under the scalp and used to deliver anticancer drugs to the fluid surrounding the brain and the spinal cord. oncogene: A gene that normally directs cell growth. If altered, it can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by environmental exposure to carcinogens. oncology: The study of cancer. ondansetron: A drug that prevents or reduces nausea and vomiting. oxaliplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. oophorectomy: Surgery to remove one or both ovaries. orchiectomy: Surgery to remove one or both testicles. oropharynx: The middle part of the throat that includes the soft palate, the base of the tongue and the tonsils. osteolytic: Causing the breakdown of bone. osteoporosis: A condition that is characterized by a decrease in bone mass and density, causing bones to become fragile. osteosarcoma: A cancer of the bone that primarily affects children and adolescents. Also called osteogenic sarcoma. ovarian ablation: Surgery, radiation therapy or drug treatment to stop the functioning of the ovaries. Also called ovarian suppression. ovarian epithelial cancer: Cancer that occurs in the cells lining the ovaries. ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. overexpress: An excess of a particular protein on the surface of a cell.

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P
P-32: A radioactive form of phosphorus used in the treatment of cancer. p-value: A statistics term. A measure of probability that a difference between groups during an experiment happened by chance. For example, a p-value of .01 (p = .01) means there is a 1/100 chance the result occurred by chance. The lower the p-value, the more likely it is that the difference between groups was caused by treatment. p53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. paclitaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. palliative therapy: Treatment given to relieve symptoms caused by advanced cancer. Palliative therapy does not alter the course of a disease, but improves the quality of life. pamidronate: A drug that belongs to the family of drugs called bisphosphonates. Pamidronate is used as treatment for abnormally high levels of calcium in the blood. Pancoast tumor: Non-small-cell lung cancer that originates in the upper portion of the lung and extends to other nearby tissues such as the ribs and vertebrae. Also called a pulmonary sulcus tumor. pancreas: A glandular organ in the abdomen. It makes pancreatic juices with enzymes that help digestion and it produces several hormones, including insulin. The pancreas is surrounded by the stomach, intestines and other organs. pancreatectomy: Surgery to remove the pancreas. In a total pancreatectomy, a portion of the stomach, the duodenum, common bile duct, gallbladder, spleen and nearby lymph nodes also are removed. pancreatic enzymes: A group of proteins secreted by the pancreas that aid in digestion of food. pancreatic juices: Fluids made by the pancreas. Pancreatic juices contain proteins called enzymes that aid in digestion. papillary tumor: A tumor shaped like a small mushroom with its stem attached to the epithelial layer (inner lining) of an organ. paracentesis: Insertion of a thin needle or tube into the abdomen to remove fluid from the peritoneal cavity. paraneoplastic syndrome: A group of symptoms that may develop when substances released by some cancer cells disrupt the normal function of surrounding cells and tissue. partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. passive antibody therapy: Treatment with injections of antibodies made in another animal or in the laboratory. peau dorange: A dimpled condition of the skin of the breast, resembling the
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skin of an orange, sometimes found in inflammatory breast cancer. PEG-interferon alfa-2B: An anticancer drug that belongs to the family of drugs called biological response modifiers. PEG-interferon alfa-2B is a cytokine. PEG-MGDF: A synthetic form of a protein that is normally made in the body to regulate the production of platelets. pegaspargase: A modified form of asparaginase, an anticancer drug that belongs to the family of drugs derived from enzymes. pelvis: The lower part of the abdomen, located between the hip bones. penclomedine: Penclomedine is an anticancer drug that belongs to the family of drugs called alkylating agents. pentetic acid calcium: A drug that protects healthy tissues from the toxic effects of anticancer drugs. pentosan polysulfate: A drug used to relieve pain or discomfort associated with chronic inflammation of the bladder. It is also being evaluated for its protective effects on the gastrointestinal tract in people receiving radiation therapy. pentostatin: An anticancer drug that belongs to the family of drugs called antimetabolites. peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins.

peptide 946: A protein that causes white blood cells to recognize and destroy melanoma cells. perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. pericardial effusion: An abnormal collection of fluid inside the sac that covers the heart. perifosine: An anticancer drug that belongs to the family of drugs called alkylphospholipids. perillyl alcohol: A drug used in cancer prevention that belongs to the family of plant drugs called monoterpenes. perimenopausal: The time of a womans life when menstrual periods become irregular. Refers to the time near menopause. perineal prostatectomy: Surgery to remove the prostate through an incision made between the scrotum and the anus. peripheral blood: Blood circulating throughout the body. peripheral blood lymphocyte therapy: A treatment for Epstein-Barr virus infection or overgrowth of white blood cells (lymphocytes) following transplantation of organs or bone marrow. Specific lymphocytes from a sibling donor are infused into the patient in an attempt to cause remission. peripheral stem cell support: A method of replacing blood-forming cells destroyed by cancer treatment. Immature

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blood cells (stem cells) in the circulating blood that are similar to those in the bone marrow are removed from the persons blood before treatment. The cells are given back to the person after treatment. Also called peripheral stem cell transplantation. peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. peristalsis: The rippling motion of muscles in the intestine or other tubular organs characterized by the alternate contraction and relaxation of the muscles that propel the contents onward. peritoneal cavity: The space within the abdomen that contains the intestines, the stomach and the liver. It is bound by thin membranes. peritoneal perfusion: A method of delivering fluids and drugs directly to tumors in the peritoneal cavity. pernicious anemia: A type of anemia (low red blood cell count) caused by the bodys inability to absorb vitamin B12. PET scan: Positron emission tomography scan. A computerized image of the metabolic activity of the body tissues used to determine the presence of disease. phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. pharynx: The hollow tube about five inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach).

phase I trial: Phase I trials are the first step in testing a new treatment in humans. These studies test the best way to give a new treatment (for example, by mouth, intravenous infusion or injection) and the best dose. The dose is usually increased a little at a time in order to find the highest dose that does not cause harmful side effects. Because little is known about the possible risks and benefits of treatments being tested, phase I trials usually include only a small number of patients, who have not been helped by other treatments. phase I/II trial: A trial to study the safety, dosage levels and response to a new treatment. phase II trial: Phase II cancer trials test whether a new treatment has an anticancer effect (for example, whether it shrinks a tumor or improves blood test results), and whether it works against a certain type of cancer. phase II/III trial: A trial to study response to a new treatment and the effectiveness of the treatment compared to the standard treatment regimen. phase III trial: Phase III trials compare the results of people taking a new treatment with results of people taking standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III trials only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people. phase IV trial: Once a treatment has been approved and is being marketed, it is studied in a phase IV trial to evaluate side effects of the new treatment that were not apparent in the phase III trial.

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Thousands of people are involved in a phase IV trial. phenylacetate: A drug being studied in the treatment of cancer. phenylbutyrate: An anticancer drug that belongs to the family of drugs called differentiating agents. photodynamic therapy: Treatment with drugs that become active when exposed to light and kill cancer cells. photofrin: A drug used in photodynamic therapy that is absorbed by tumor cells; when absorbed by cancer cells and exposed to light, it becomes active and kills the cancer cells. photosensitizer: A drug used in photodynamic therapy. When absorbed by cancer cells and exposed to light, the drug becomes active and kills the cancer cells. phyllodes tumor: Rare, benign or malignant tumors of the breast. pilocarpine: A drug used to increase salivation in people who have dry mouth. Dry mouth can be caused by opioids or radiation therapy. It belongs to the family of drugs called alkaloids. pilot study: The initial study examining a new method or treatment. pineal gland: A small gland located in the cerebrum that produces melatonin. Also called pineal body or pineal organ. pineal region tumors: Types of brain tumors that occur in or around the pineal gland, a tiny organ near the center of the brain.

pineoblastoma: A fast-growing type of brain tumor that occurs in or around the pineal gland, a tiny organ near the center of the brain. pineocytoma: A slow growing type of brain tumor that occurs in or around the pineal gland, a tiny organ near the center of the brain. piperacillin-tazobactam: A combination of drugs used to fight infections in people who have cancer. Piperacillin is a synthetic penicillin; tazobactam enhances the effectiveness of piperacillin. piritrexim: An anticancer drug. pituitary gland: The main endocrine gland; it produces hormones that control other glands and many body functions, especially growth. placebo: An inactive substance that looks the same as, and is administered in the same way as, a drug in a clinical trial. plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. plasma cells: A type of white blood cell that produces antibodies. plasmacytoma: A tumor that is made up of cancerous plasma cells. plasmapheresis: The process of separating certain cells from the plasma in the blood by a machine. Only the cells are returned to the person. Plasmapheresis can be used to remove excess antibodies from the blood. platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes.

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platinum: A metal that is an important component of some anticancer drugs, such as cisplatin and carboplatin. pleura: A thin layer of tissue covering the lungs and the wall of the chest cavity to protect and cushion the lungs. A small amount of fluid that acts as a lubricant allows the lungs to move smoothly in the chest cavity during breathing. pleural cavity: A space enclosed by the pleura (thin tissue covering the lungs and lining the interior wall of the chest cavity). It is bound by thin membranes. pleural effusion: An abnormal collection of fluid between the thin layers of tissue (pleura) lining the lung and the wall of the chest cavity. pneumatic larynx: A device that uses air to produce sound to help a laryngectomee talk. polyp: A growth that protrudes from a mucous membrane. polyposis: The development of numerous polyps (growths that protrudes from a mucous membrane). porfimer sodium: An anticancer drug that is also used in cancer prevention. It belongs to the family of drugs called photosensitizing agents. positive axillary lymph nodes: Lymph nodes in the area of the armpit (axilla) to which cancer has spread. This is determined by surgically removing some of the lymph nodes and examining them under a microscope to see whether cancer cells are present. positron emission tomography scan: PET scan. A computerized image of the

metabolic activity of body tissues used to determine the presence of disease. postmenopausal: Refers to the time in life after menopause. Menopause is the time in a womans life when menstrual periods stop for at least a year; also called change of life. postremission therapy: Anticancer drugs to kill cancer cells that survive after remission induction therapy. precancerous: A term used to describe a condition that may or is likely to become cancer. Also called premalignant. prednisone: Belongs to the family of drugs called steroids. It is used to treat several types of cancer and other disorders. Prednisone also inhibits the bodys immune response. preleukemia: Disease in which the bone marrow does not function normally. Also called myelodysplastic syndrome or smoldering leukemia. premalignant: A term used to describe a condition that may or is likely to become cancer. Also called precancerous. primary tumor: The original tumor. prinomastat: An anticancer drug that belongs to the family of drugs called angiogenesis inhibitors. Prinomastat is a matrix metalloproteinase inhibitor. Also called AG3340. procarbazine: An anticancer drug that belongs to the family of drugs called alkylating agents. progesterone: A female hormone. progesterone receptor negative (PR-): Breast cancer cells that do not have a protein (receptor molecule) to which

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progesterone will attach. Breast cancer cells that are PR- do not need the hormone progesterone to grow and usually do not respond to hormonal therapy. progressive disease: Cancer that is increasing in scope or severity. promegapoietin: A colony-stimulating factor that stimulates the production of blood cells, especially platelets. It is given during chemotherapy to increase blood cell regeneration. It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. promyelocytic leukemia: A type of acute myeloid leukemia, a rapidly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. prophylactic cranial irradiation: Radiation therapy to the head to reduce the risk that cancer will spread to the brain. prophylactic oophorectomy: Surgery intended to reduce the risk of ovarian cancer by removing the ovaries before disease develops. prophylaxis: An attempt to prevent disease.

prostate gland: A gland in the male reproductive system just below the bladder. It surrounds part of the urethra, the canal that empties the bladder. It produces a fluid that forms part of semen. prostate-specific antigen: PSA. A substance that may be found in an increased amount in the blood of men who have prostate cancer or benign prostatic hyperplasia. prostatectomy: An operation to remove part or all of the prostate. Radical (or total) prostatectomy is the removal of the entire prostate and some of the tissue around it. prostatic acid phosphatase: PAP. An enzyme produced by the prostate. It may be found in increased amount in men who have prostate cancer. prosthesis: An artificial replacement of a part of the body. proteins: Molecules made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair, and of substances such as enzymes, cytokines and antibodies.

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R
radiation fibrosis: The formation of scar tissue as a result of radiation therapy. radiation surgery: A radiation therapy technique that delivers radiation directly to the tumor while sparing the healthy tissue. Also called radiosurgery and stereotactic external beam irradiation. radiation therapy: The use of high-energy radiation from X-rays, neutrons and other sources to kill cancer cells and to shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from material called radioisotopes. Radioisotopes produce radiation and are placed in or near a tumor or near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. radical cystectomy: Surgery to remove the bladder as well as nearby tissues and organs. radical mastectomy: Surgery to remove the breast, chest muscles, and all of the lymph nodes in the armpit. Also called the Halsted radical mastectomy. radical prostatectomy: Surgery to remove the entire prostate. The two types of radical prostatectomy are retropubic prostatectomy and perineal prostatectomy. radioactive iodine: A radioactive form of the chemical element iodine often used for imaging tests or as a treatment for cancer. radiofrequency ablation: The use of electrical current to destroy tissue. radioimmunoguided surgery: A procedure that uses radiolabeled substances to detect tumors for surgical removal. radioimmunotherapy: Treatment with a radioactive substance that is linked to an antibody that will attach to the tumor when injected into the body. radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. radiolabeled: Any compound that has been joined with a radioactive substance. radiosensitization: The use of a drug that makes tumor cells more sensitive to radiation therapy. radiosensitizers: Drugs that make tumor cells more sensitive to radiation. raloxifene: A drug that belongs to the family of drugs called selective estrogen receptor modulators (SERMs). It is used in the prevention of osteoporosis in postmenopausal women. Raloxifene is also being studied as a cancer prevention drug. ras gene: A gene that has been found to cause cancer when it is altered (mutated). Agents that block its activity may stop the growth of cancer. A ras peptide is a protein fragment produced by the ras gene.

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rebeccamycin: An anticancer drug that belongs to the family of drugs called antineoplastic antibiotics. recurrence: The return of cancer, at the same site as the original (primary) tumor or in another location, after it had disappeared. red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. Reed-Sternberg cell: A type of cell that appears in people with Hodgkins disease. The number of these cells increases as the disease advances. refractory cancer: Cancer that has not responded to treatment. regimen: A treatment plan that specifies the dosage, the schedule and the duration of treatment. regional chemotherapy: Treatment with anticancer drugs that is directed to a specific area. regression: A decrease in the extent or size of cancer. relapse: The return of signs and symptoms of cancer after a period of improvement. remission: Disappearance of the signs and symptoms of cancer. When this happens, the disease is said to be in remission. A remission may be temporary or permanent. remission induction therapy: The initial chemotherapy a person receives to bring about a remission.

renal cell cancer: Cancer that develops in the lining of the renal tubules, which filter the blood and produce urine. resected: Surgical removal of part of an organ. resection: Surgical removal of part of an organ. residual disease: Cancer cells that remain after attempts have been made to remove the cancer. resistance: Clinical resistance is the failure of a cancer to shrink after treatment. response rate: The percentage of patients whose cancer shrinks or disappears after treatment. retinoblastoma: An eye cancer that most often occurs in children under the age of five. It occurs in both hereditary and nonhereditary (sporadic) forms. retinoid: Vitamin A or a vitamin A-like compound. retinol: Vitamin A. It is essential for proper vision, healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. retroviral vector: RNA from a virus that is used to insert genetic material into cells. RevM10 gene: An antiviral gene being studied for treatment of cancer in patients who have HIV, the AIDS virus. rhabdoid tumor: A malignant tumor of either the central nervous system (CNS) or the kidney. Malignant rhabdoid tumors of the CNS often have an abnormality of chromosome 22. These tumors

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usually occur in children younger than two years old. rhabdomyosarcoma: A malignant tumor of muscle tissue. ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. risk factor: Anything that increases the chance of developing a disease.

rituximab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. RNA: Ribonucleic acid. One of the two types of nucleic acids found in cells. The other is DNA (deoxyribonucleic acid). RNA plays a role in sending information from DNA to the protein-forming system of the cell.

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S
sarcoma: A cancer of the bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. sargramostim: A colony-stimulating factor that stimulates the production of blood cells, especially platelets, during chemotherapy. It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called GM-CSF. Schiller test: A test in which iodine is applied to the cervix. The iodine colors healthy cells brown; abnormal cells remain unstained, usually appearing white or yellow. schwannoma: A type of benign brain tumor that begins in the Schwann cells that produce the myelin that protects the acoustic nerve (the nerve of hearing). second cancer: Refers to a new primary cancer that is caused by previous cancer treatment, or a new primary cancer in a person with a history of cancer. second-look surgery: Surgery performed after primary treatment to determine whether tumor cells remain. secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. segmental mastectomy: The removal of the cancer as well as some of the breast
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tissue around the tumor and the lining over the chest muscles below the tumor. Usually some of the lymph nodes under the arm are also taken out. Sometimes called partial mastectomy. seminoma: A type of cancer of the testicles. sentinel lymph node: The first lymph node that cancer is likely to spread to from the primary tumor. Cancer cells may appear first in the sentinel node before spreading to other lymph nodes. sequential treatment: One treatment after the other. Sezary syndrome: A form of cutaneous T-cell lymphoma, a cancerous disease that affects the skin. shave biopsy: A procedure in which the parts of a mole that are above and just below the surface of the skin are removed with a small blade. There is no need for stitches with this procedure. shunt: A surgically created diversion of fluid, for example blood or cerebrospinal fluid, from one area of the body to another. side effects: Problems that occur when treatment affects healthy cells. Common side effects of cancer treatment are fatigue, nausea, vomiting, decreased blood cell counts, hair loss and mouth sores. small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer.

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small intestine: The part of the digestive tract that is located between the stomach and the large intestine. smoldering leukemia: Disease in which the bone marrow does not function normally. Also called preleukemia or myelodysplastic syndrome. sodium salicylate: A drug that belongs to the family of drugs called nonsteroidal anti-inflammatory drugs. Sodium salicylate may be tolerated by people who are sensitive to aspirin. soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels or other supporting tissue of the body. soft tissue sarcoma: A sarcoma that begins in the muscle, fat, fibrous tissue, blood vessels or other supporting tissue of the body. solid tumor: Cancer of body tissues other than blood, bone marrow or the lymphatic system. somatic cells: All the body cells except the reproductive (germ) cells. somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells. spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells and destroys old blood cells. The spleen is located on the left side of the abdomen near the stomach. sputum: Mucus coughed up from the lungs. squamous cell carcinoma: Cancer that begins in squamous cells, which are thin,

flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. stable disease: Cancer that is not decreasing or increasing in extent or severity. stage: The extent of a cancer within the body, including whether the disease has spread from the original site to other parts of the body. Staging refers to the determination of the extent of cancer. staging: Doing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. stem cell transplantation: A method of replacing immature blood-forming cells that were destroyed by cancer treatment. The stem cells are given to the person after treatment to help the bone marrow recover and continue producing healthy blood cells. stem cells: The cells from which all blood cells come. stent: A device placed in a body structure such as a blood vessel or the gastrointestinal tract, in order to provide support and keep the structure open.

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stereotaxis: Use of a computer and scanning devices to create three-dimensional pictures. This method can be used to direct a biopsy, external radiation or the insertion of radiation implants. steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain and other symptoms of inflammation. steroids: Drugs used to relieve swelling and inflammation. STI571: A substance that is being studied for its ability to inhibit the growth of certain leukemias. It interferes with a portion of the protein produced by the bcr/abl oncogene. stoma: A surgically created opening from an area inside the body to the outside. Colostomy and urostomy are types of stomas. Also called an ostomy. streptavidin: A small bacterial protein that binds with high affinity to the vitamin biotin. This streptavidin-biotin combination can be used to link molecules such as radioisotopes and monoclonal antibodies together. These bound products have the property of being attracted, and attached, to cancer cells, rather than normal cells. The radiolabeled products are more easily removed from the body, thus decreasing their toxicity. streptozocin: An anticancer drug that belongs to the family of drugs called alkylating agents. stromagen: A drug that is derived from a patients stem cells (specialized cells in the bone marrow which form new blood cells) and may be given back to them to help restore bone marrow that has been damaged by high-dose chemotherapy.

stromal tumors (STRO-mal): Tumors that arise in the supporting connective tissue of an organ. strontium: A metal often used in a radioactive form for imaging tests or as a treatment for cancer. strontium-89: A radioactive compound that is absorbed by the bone. It is used to treat bone pain associated with prostate cancer. SU5416: An anticancer drug that belongs to the family of drugs called angiogenesis inhibitors. subcutaneous: Beneath the skin. subcutaneous port: A tube surgically placed into a blood vessel and attached to a disk placed under the skin. It is used for the administration of intravenous fluids and drugs. It can also be used to obtain blood samples. suberoylanilide hydroxamic acid: A substance that is being studied as an anticancer drug. sucralfate: A drug used to treat ulcers. It adheres to proteins at the ulcer site and forms a protective coating over the ulcer. It is also used to treat mucositis. sulindac sulfone: An analgesic drug that belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. supraclavicular lymph nodes: Lymph nodes located above the clavicle (collar bone).

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surgical castration: Surgical removal of the testicles (orchiectomy) or ovaries (oophorectomy) to stop the production of sex hormones. Decreasing the levels of hormones may stop the growth of certain cancers.

systemic: Affecting the entire body. systemic therapy: Treatment that uses substances that travel through the bloodstream, reaching and affecting cells all over the body.

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T
T cell: A type of white blood cell that attacks virus-infected cells, foreign cells and cancer cells. T cells also produce a number of substances that regulate the immune response. T-cell depletion: Treatment to destroy T cells, which play an important role in the immune response. Elimination of T cells from a bone marrow graft from another person may reduce the chance of an immune reaction against the persons tissues. T-cell lymphoma: A disease in which certain cells of the lymph system (called T lymphocytes) become cancerous. tamoxifen: An anticancer drug that belongs to the family of drugs called antiestrogens. Tamoxifen blocks the effects of the hormone estrogen in the body. It is used to prevent or delay the return of breast cancer or to control its spread. taxanes: Anticancer drugs that inhibit cancer cell growth by stopping cell division. Also called antimitotic or antimicrotubule agents, or mitotic inhibitors. tegafur: An anticancer drug that belongs to the family of drugs called antimetabolites. temozolomide: An anticancer drug that belongs to the family of drugs called alkylating agents. teniposide: An anticancer drug that is a podophyllotoxin derivative and belongs to the family of drugs called mitotic inhibitors. testosterone: A hormone that promotes the development and maintenance of male sex characteristics. thalidomide: A drug that belongs to the family of drugs called angiogenesis inhibitors. It prevents the growth of new blood vessels into a solid tumor. thioguanine: An anticancer drug that belongs to the family of drugs called antimetabolites. thiotepa: An anticancer drug that belongs to the family of drugs called alkylating agents. thoracic: Pertaining to the chest. thoracoscopy: The use of a thin, lighted tube (called an endoscope) to examine the inside of the chest. thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. thrombocytopenia: A decrease in the number of platelets in the blood, which may result in easy bruising and excessive bleeding from wounds or bleeding in mucous membranes and other tissues. thrombophlebitis: Inflammation of a vein that occurs when a blood clot forms. thrombopoietin: A colony-stimulating factor that stimulates the production of blood cells, especially platelets, during chemotherapy. It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. thymoma: A tumor of the thymus, an organ that is part of the lymphatic system and is located in the chest, behind the breastbone.

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thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is located in the chest behind the breastbone. thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. tirapazamine: A drug that makes tumor cells more sensitive to radiation therapy. topical chemotherapy: Treatment with anticancer drugs in a lotion or cream applied on the skin. topoisomerase inhibitors: A family of anticancer drugs. The topoisomerase enzymes are responsible for the arrangement and rearrangement of DNA in the cell and for cell growth and replication. Inhibiting these enzymes may kill cancer cells or stop their growth. topotecan: An anticancer drug that belongs to the family drugs called topoisomerase inhibitors. toremifene: An anticancer drug that belongs to the family of drugs called antiestrogens. Toremifene blocks the effect of the hormone estrogen in the body. It may help control some cancers from growing, and it may delay or reduce the risk of cancer recurrence. total estrogen blockade: Therapy used to eliminate estrogen in the body. This may be done with surgery, radiation therapy, chemotherapy or a combination of these. total hysterectomy: Surgery to remove the entire uterus.

total mastectomy: Removal of the breast. Also called simple mastectomy. total nodal irradiation: Radiation therapy to the mantle field, the spleen, the lymph nodes in the upper abdomen and the lymph nodes in the pelvic area. total pancreatectomy: Surgery to remove the entire pancreas. total-body irradiation: Radiation therapy to the entire body. Usually followed by bone marrow or peripheral stem cell transplantation. toxicity: Negative side effect. trachea: The airway that leads from the larynx to the lungs. Also called the windpipe. transformation: The change that a normal cell undergoes as it becomes malignant. transfusion: The infusion of components of blood or whole may have been taken from the person earlier and stored until needed. transitional cell carcinoma: A type of cancer that develops in the lining of the transitional cells: cells lining some organs. transplantation: The replacement of an organ with one from another person. transrectal ultrasound: A procedure used to examine the prostate. An instrument is inserted into the rectum, and sound waves bounce off the prostate. These sound waves create echoes, which a computer uses to create a picture called a sonogram.

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transurethral prostatic resection: Surgical procedure to remove tissue from the prostate using an instrument inserted through the urethra. Also called TURP. transurethral resection: Surgery performed with a special instrument inserted through the urethra. Also called TURP. trastuzumab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. Trastuzumab blocks the effects of the growth factor protein HER2, which transmits growth signals to breast cancer cells. tretinoin: A drug that belongs to the family of drugs called retinoids. It is used in the treatment of acne and is being studied in cancer prevention. tributyrin: A triglyceride drug that may inhibit cell growth and induce cell differentiation. Differentiating agents may be effective in changing cancer cells back into normal cells. trimetrexate glucuronate: A drug that belongs to the family of drugs called antimetabolites. It is used in the treatment of pneumocystis carinii pneumonia and is being studied in the treatment of cancer. triptorelin: A hormonal anticancer drug that belongs to the family of drugs called gonadotropin-releasing hormones. tubal ligation: An operation to tie the fallopian tubes closed. This procedure prevents pregnancy by blocking the passage of eggs from the ovaries to the uterus.

tumor: An abnormal mass of tissue that results from excessive cell division. Tumors perform no useful body function. They may be either benign (not cancerous) or malignant (cancerous). tumor antigen vaccine: A vaccine made of tumor antigens (proteins isolated from tumor cells). tumor debulking: Surgically removing as much of the tumor as possible. tumor infiltrating lymphocytes: White blood cells that have left the bloodstream and migrated into a tumor. tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and that may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. tumor necrosis factor: A type of biological response modifier (a substance that stimulates the bodys response to infection and disease). tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. tumor-derived: Taken from a persons tumor tissue; may be used in the development of a vaccine that enhances the bodys ability to build an immune response to the tumor. tyrosinase peptide: A tumor-specific antigen used in the development of cancer vaccines.

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U
unresectable: Unable to be surgically removed. uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. ureter: The tube that carries urine from the kidney to the bladder. urethra: The tube through which urine leaves the body. It empties urine from the bladder. urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder and urethra. uterus: The small, hollow, pear-shaped organ in a womans pelvis. This is the organ in which a fetus develops. Also called the womb.

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V
vaccine: A substance or group of substances designed to stimulate an immune response to a tumor or to microorganisms, such as bacteria or viruses. vaccine adjuvant: A substance added to a vaccine to improve the immune response so that less vaccine is needed. vasectomy: An operation to cut or tie off the two tubes that carry sperm out of the testicles. vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. vinca alkaloids: Anticancer drugs that inhibit cancer cell growth by stopping cell division. They are also called antimitotic or antimicrotubule agents, or mitotic inhibitors. vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. vindesine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. vinorelbine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. viruses: Submicroscopic organisms that cause infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to kill tumor cells. visual pathway glioma: A rare, slowgrowing tumor of the eye. vitamin A: A vitamin used in cancer prevention; it belongs to the family of drugs called retinoids. vitamin E: A vitamin used in cancer prevention; it belongs to the family of drugs called tocopherols. vitamin K: A substance that promotes the clotting of blood. von Hippel-Lindau syndrome: A rare inherited disorder in which blood vessels grow abnormally in the eyes, brain, spinal cord, adrenal glands or other parts of the body. People with von HippelLindau syndrome have a higher risk of developing some types of cancer. vorozole: A hormone therapy drug used to decrease the production of estrogen.

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W
Waldenstroms macroglobulinemia: A rare cancer of the lymph cells that causes the body to produce abnormal levels of plasma cells (plasmacytosis) and lymphocytes (lymphocytosis) in the bone marrow. Waldenstroms macroglobulinemia may also cause a decrease in red blood cells (anemia) and enlargement of the liver (hepatomegaly), spleen (splenomegaly), or glands (adenopathy). white blood cell: A type of cell in the immune system that help the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages and others. Whitmore-Jewett staging system: A system used for the staging of prostate cancer. whole cell vaccine: Vaccine made from whole tumor cells that have been changed in the laboratory. Wilms tumor: A kidney cancer that occurs in children, usually before the age of five.

X
xeroderma pigmentosum: A genetic condition characterized by a sensitivity to all sources of ultraviolet radiation.

Z
zoledronate: A drug that belongs to the family of drugs called bisphosphonates. It is used to prevent bone fractures and to reduce bone pain in people who have cancer that has spread to the bone.

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Additional information available upon request.


Prices of companies mentioned as of November 8, 2000: ALZA Corp AZA $89.00 American Home Products AHP $61.38 Amgen 1 AMGN $61.63 AstraZeneca AZN $49.19 Aventis AVE $74.63 Bristol-Myers Squibb BMY $62.31 Eli Lilly & Co LLY $90.44 Genentech Inc DNA $86.75 Glaxo Wellcome GLX $59.50 Idec Pharmaceuticals Corp IDPH $220.25 Johnson & Johnson JNJ $93.44 Merck & Co MRK $90.81 Novartis NVS $40.25 Pfizer Inc PFE $45.38 Pharmacia Corp. PHA $59.44 Roche ROHHY $94.68 Schering-Plough SGP $51.88 Smithkline Beecham 2 SBH $67.13 1. UBS Warburg LLC, PaineWebber Incorporated and/or one of their affiliates usually makes a market in the securities of this company. 2. UBS Warburg LLC, PaineWebber Incorporated and/or one of their affiliates has acted as a manager/co-manager or placement agent in underwriting securities of this company or one of its subsidiaries in the past three years.

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