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CONTENTS

INTRODUCTION.
EPIDEMIOLOGY AND ETIOLOGICAL FACTORS.
HISTORY OF DEVELOPMENT AND CLASSIFICATION.
PHARMACOKINETICS AND INNOVATION OF NEWER
AGENTS.
INTERFERENCE AND MECHANISM OF ACTION OF ACTION
ARRESTING IMMATURE CELL PROLIFERATION.
AGENTS WHICH POTENTIATE THE FUNCTION OF
CHEMOTHERAPEUTICAGENTS.
CLINICAL APPLICATION AS PRIMARY TREATMENT AND AS
ADJUVANT IN MALIGNANTLESIONS.
DRUGSENSITIVITY TO VARIOUS LESIONS AND
THERAPYREGIMES.
ROUTES OF ADMINISTRATION OF VARIOUS
CHEMOTHERAPEUTICAGENTS.
MARKERS USED TO INTERFERE WITH CELL GROWTH TO
STUDY THE PERFORMANCE OF THE DRUG.
TOXIC MANIFESTATIONS AND UNTOWARD REACTIONS
AND THEIR MANAGEMENT.
CONCLUSION.

INTRODUCTION
Malignancies of the head and neck region includes cancer of the
oral cavity; i.e., of the lip (International Classification of Diseases,
ninth revision (code140-ICD9:140), tongue (ICD9:141), and other
intra-oral sites (ICD9: 143-145). The salivary glands (ICD9:142) are
not normally included when describing oral cancer, i.e., of the
oropharynx (ICD9:146), nasopharynx (ICD9:147), and hypophaynx
(ICD9:148). Malignancies of these sites are generally clubbed together
as head and neck cancer, or mouth/pharyngeal cancer, or oropharyngeal cancer, or sometimes just oral cancer, because of the
common etiological/risk factors associated with these sites, with the
exception of nasopharyngeal cancers.17

The standard line of management depends on the extent of the disease.


Radiotherapy or surgery in advocated for the early lesions and
combination of both is practiced in advanced lesion. (Vanderval1984). 9
The philosophy of combining surgery and radiotherapy in advanced
lesions is that surgery fails at the periphery and radiotherapy at the

poorly oxygenated center of the tumour. So combination of both help


in total cure.
In search of better results, good cosmesis and better quality of
life systemic chemotherapy has been incorporated into the treatment
modalities along with surgery or radiotherapy. Systemic chemotherapy
is usually accepted as standard treatment for palliation in patients with
recurrent and metastatic head and neck cancer who have failed the
definitive therapy. Recently with the introduction of more active
chemotherapy agents and combination systemic chemotherapy, it is
being increasingly used before local therapy in previously untreated
and locally advanced head and neck cancer. (A1 Sarraf, 1988).
Today, the role of chemotherapy in the treatment of Head and
Neck Squamous Cell Carcinoma is being intensively reevaluated. The
possibility of inducing major tumour shrinkage with chemotherapy before
local treatments has led to the enthusiastic expectation that neoadjuvant
chemotherapy could have a major effect in improving survival rates in
patients with head and neck cancer. Conflicting data have been derived
from an analysis of some single-arm studies, whose results have been
compared with those obtained in historical control patients, treated with
local treatment alone. The last ten years have witnessed the changing role
of chemotherapy in patients with advanced head and neck Squamous cell
carcinomas. This is due in part to the introduction of better agents against
the disease and to the high over-all objective response and cure rates
produced by combination chemotherapy in patients with previously
untreated and advanced cancer.15

The aim of this library dissertation is to exhaustively review the


literature on chemotherapy from its historical and developmental
aspects, basic principles, its effectiveness in improving the cure rate
and also to enlighten upon the recent advances in the field of medical
oncology.

EPIDEMIOLOGY AND ETIOLOGICAL FACTORS


As see from Table, there is an enormous variation in the
incidence of mouth and pharyngeal cancer worldwide. The highest,
particularly those of South-East Asia. There are also, pockets of high
incidence rates in western populations, such as that of the Bas-Rhin in
France. Table 1.1 also shown that in males the incidence of cancer
of the tongue varies from a high of 8.0 to a low of 0.4 per 100,000; of
the mouth varies from 12.4
to 0.5 per 100,000; of the oropharynx varies from 13.3 to 0.3 per
100,000; and hypopharynx varies from 15.0 to 0.1 per 100,000. Lip
cancer is particularly common in Australian and Canadian populations
with its incidence in males going up to 13.5 per 100,000. It is not so
common in the South-East and East Asian countries. For example, in
Japanese, Chinese, and Indian populations, its incidence is barely 0.2
per 100,000. The incidence of cancer of the mouth and pharynx is
universally higher in males than in females, except in some countries
of South-East and East Asian countries. For example, in Japanese,
Chinese, and Indian populations, its incidence is barely 0.2 per
100,000.

The incidence of cancer of the mouth and pharynx is

universally higher in males than in females, except in some countries


of South-East Asia.

In Bangalore (in Indian), for example, the

incidence of cancer of the mouth (ICD9:143-145) in males is lower, at


2.8 per 100,000, as compared to the incidence rate of 8.9 per 100,000
in females (PArkin et al., 1997).
Globally, almost haft-a-million cancers of the mouth and
pharynx (ICD9:140-149) are diagnosed every year, and three-fourths
of these are from the developing world (Parkin et al., 1993). A similar

picture emerges as regards deaths from these cancers. Currently, over


400,000 individuals die from this disease every year, and again, over
80 per cent of these deaths are from the developing world (Pisani et
al., 1993).
Thus, cancer of the head and neck region is an important cancer
globally. For the developing world it is certainly of great significance,
and ranks fourth in frequency. In males, however, it is the third most
common cancer, and in females it ranks fourth (Parkin et al., 1993).
In countries like India, it is in fact the leading cancer site as reported
by the various cancer registries in the country (Biennial Report, 1992).
However, in western countries also, cancer of the mouth and pharynx
is now gaining importance. There is evidence that the incidence of
and mortality rates due to this cancer has started to increase in recent
decades particularly in men (Johnson, 1991; Moller, 1989; Hakulinen
et al., 1986). Va Vacchia et al. (1997) has compared the mortality
rates of the cancer of the head and neck region (ICD9: 140-149) at two
different time periods for thirty-two European countries and found that
in males of age group 35 to 64 years the mortality rate in the early
1990s were two-to-eight- fold higher than that reported in the late
1950s, except in Finland. An increase in the risk of tongue was
particularly noted in young adult (Davis and Severson, 1987; Coleman
et al., 1993).
The ratios of high and low incidence rates reported world-wide
shown in Table 1.1, vary from twenty-five-fold to over a hundredfold.

These high ratios indicate that a tremendous potential for

successful implementation of preventive strategies exists, once the


risk/protective factors have been identified. These are likely to be

more prevalent in males than in females in view of the pattern of


distribution of the disease in the two sexes.17
ETIOLOGY
The association of betal quid chewing with oral cancer was
observed in India as early as 1902 by Niblock and confirmed by Orr
(1933) in an excellent epidemiologic study. Niblock (1902) described
oral cancer in Madras and Travancore and attributed it to the habit of
chewing arecanut and betel leaf and often a lime rich paste with
tobacco. Orr (1933) in his study concluded that the use of shell lime
and Vadakkan or Jaffna tobacco along with a low vitamin content in
the diet due to tapico consumption, was primarily responsible for the
prevalence of oral cancer.
Sanghvi and his colleagues (1955) demonstrated for the first
time, the association of beedi smoking in addition to chewing with oral
cancer in a case-control study at the Tata Memoriral Hospital,
Mumbai, India.
Besides these risk factors, diet has been implicated in the
etiology of oral cancer (Notani 1987) also alcohol usage has been
shown to be an independent risk factor (Notani 1988).9

CHEMOTHERAPY, HISTORY OF DEVELOPEMENT AND


CLASSIFICATION
The word chemotherapy can be defined as the use of chemical
compounds in the treatment of infection diseases, so as to destroy off
evolving parasites or organisms without damaging the host, tissues.
The use of the term to cover all drug, or synthetic drug, therapy
needlessly removes a distinction which is convenient to the clinician
and has the sanction of long usage. By convention the term is used to
include therapy of cancer.11
This method of treating cancer has been used in head and neck
tumours for palliation and in a curative role, both as integral part of a
planned regime involving surgery or radiotherapy or both, and on its
own.

Certain tumors have been found to respond well to

chemotherapy and in management of these it is an accepted part of


total treatment. In the context of head and neck malignancies how ever
such tumours are rarities and it is the value of chemotherapy in the
common tumours such as squamous carcinoma and the salivary
tumours which is of real interest to the oral and maxillofacial
surgeon.18
History of drug Discovery

Chemotherapy has its origin in the work of Paul Ehrilich who coined
the term in reference to the systemic treatment of both infection
diseases and neoplasia. Many of the Ehrlichs concepts regarding the
experimental evaluation of new therapies using murine or rat models
have survived to the present day and have provided a number of

important biologic insights that have been applied successfully to the


clinical setting. Gilman and Philips conducted the first clinical trial of
nitrogen mustard in patients with malignant lymphomas at Yale
university in 1947. The results, initially published in 1946, could be
said to mark the beginning of modern chemotherapy.13

HISTORICAL OUTLINE OF DEVELOPMENT OF CANCER


CHEMOTHERAPY
A. Period 1946-1960
- Development of single-drug chemotherapy mainly on
empirical basis.
- Establishment of critical criteria for the clinical development
of new drugs: criteria of response; toxicity; performance
status; optimum tolerated dose.
- First results from the treatment of leukemias and malignant
lymphomas. Generally poor results in the treatment of
advanced solid tumours.
B. PERIOD 1960-1970
- Development of knowledge of cell kinetics and application of
kinetic concepts to the design of chemotherapy schedules.
- Broadening

of

chemotherapy.

the

experimental

basis

for

clinical

- Introduction of pharmacokinetic concepts into clinical


chemotherapy.
- First developments in the field of combination chemotherapy.
- Introduction of the concept of the controlled randomized
clinical trials into clinical chemotherapy assessment.
- Further improvement of treatment results in leukemias and
lymphomas and significant progress in the results obtained in
the treatment of certain solid tumours.
C. PERIOD 1970 TILL DATE
- Development of the concept of the combined modality
approach; improved cooperation between the onco- surgeon,
radiotherapist and chemotherapist.
- First indication of definitive role for adjuvant chemotherapy.
- Recognition, in long-term survivors, of the late toxicities of
anti-cancer

drugs

particularly

when

combined

with

radiotherapy.
- Development of the concepts of immunotherapy in man.
Disappointing results despite widespread application.14

Classification of chemotherapeutic agents 3


Major Classes

Examples

Malignancies Used

Toxicities

1.Alkylating

Nitrogen

in
Lymphomas

agents

mustard

Chronic

Anemia

Chlorambucil

lymphoblastic

Thrombocytopenia

Ifosfamide

leukemia

Nausea

Melphalan

Sarcomas

vomiting

Thiotepa

Myeloma

Neurotoxicity

Cisplatin

Breast cancer

Alopecia

Carboplatin

Ovarian cancer
Head

and

Leucopenia

and

neck

II.Antimetabolite Methotrexate

cancer
Breast

5-Fluorouracil

gastrointestinal

Diarrhea

Ara-C

cancer

Leucopenia

Hydroxyurea

Acute myeloblastic Anemia

Fludarabine

leukemia

Thrombocytopenia

Chriocarcinoma

Alopecia

and Mucositis

Genitourinary
cancer
Head

and

neck

cancer
Lymphoma
III. Antibiotics

Actinomycin-D Acute myeloblastic Leucopenia,


Doxorubin

leukemia

anemia,

and

(Adriamycin)

Germ cell cancer

thrombocytopenia

Daunorubicin

Gastrointestinal,

Mucositis

Mithramycin

lung,

Diarrhea

Mitomycin

Breast cancer

Skin disturbances

Bleomycin

Head

Mitoxantrone

cancers

Nausea

Sarcomas

vomiting

Lymphoma

Cardiac

and

neck Alopecia
and
and

pulmonary
toxicity
IV.

Plant Vincristine

alkaloids

V.Micellaneous

Testicular,

lung, Leukopenia

Vinblastine

breast and bladder Anemia

VP-16

cancers

Thrombocytopenia

Taxol

Lymphoma

Alopecia

DTIC

Sarcomas

Nausea
Leucopenia

M-AMSA

Acute myeloblastic Anemia

Procarbazine

leukemia

Thrombocytopenia

Hexamethylme Hodgkin;s

Nausea

lamine

lymphoma

Bleeding

Asparaginase

Ovarian cancer
Acute
lymphoblastic
leukemia

PHARMACOKINETICS AND INNOVATION OF NEWER


AGENTS
Pharmacokinetic of cancer chemotherapy
Because there are such narrow margins between effective and
toxic dosages for many antineoplastic agents, rational therapy should
be assisted by the ability to maintain drug concentrations in specified
therapeutic ranges. Thorough pharmacokinetic analyses have been
performed for a number of anticancer drugs in a variety of clinical
situations.
Modeling
The classical pharmacokinetic device for describing the disappearance
of drugs from plasma is the two-compartment open model.

The

concept assumes that a drug is instantaneously injected and distributed


in Compartment 1(with concentration, C1, and volume, V1) and that all
elimination of the drug from the system occurs from this central
compartment. Immediately after injection the drug may distribute into
compartment 2(concentration, C2, and volume, V2) at a rate defined by
k12.

Drug may move from Compartment 2 (the peripheral

compartment) at the rate k21 into the central compartment, thence to be


eliminated. The elimination rate is indicated as k el. Movement of drug
into and out of either compartment is a first-order process and the rate
constants k12, k21, and kel have dimensions of inverse time (e.g., min -1,
hr-1). A typical two-compartmental curve for plasma disappearance of
a drug is depicted in fig which plots concentrations on a logarithmic
ordinate and time on a linear abscissa. This smooth curve can be
divided into two discrete exponential terms. Ae -at and Be-t, indicated
by hatched lines. The concentration, C, at any time is the sum of these

terms. Dividing the curve allows for definition of the earlier portion as
the distribution phase of drug disposition, and of the later portion as
the elimination phase.

Five parameters are commonly found in

pharmacokinetic descriptions of antineoplastic agents, and can be


calculated from the relationship, C= Aeot + Be-. The concentration at
the moment of injection, C0, is usually the peak concentration during
rapid intravenous bolus injections and equals the sum of the constants
A and B: C0 = A+B.

The terminal elimination half life, t 1/2, is

determined by the elimination rate constants, : t1/2 = 0.693/. The


initial volue of distribution of the drug, V d, is related to the initial
(peak) concentration, Co, and the dose given: dose = Vd x Co, or Vd =
dose/Do (dimensional units of dose and C o must be similar, e.g., mg
and mg/ml or nmol and nmol/ml).

The area under the plasma

concentration-time plot provides a measures of the exposure of the


body or of a particular tissue to a drug over a period of time. This
quantity, often referred to as the area under curve (AUC) or
concentration x time product (C x t) of a drug, is calculated by
integrating the equation C = Ae-nt + Be-. Because e-t approaches zero
at very late times of observation, this integral can be reduced to C x t
(or AUC)=A/ + B/. The C x t can be estimated equally well by the
trapezoidal rule. Finally, the clearance of a drug Cl =k el x V1. In
practice kel and V1 are difficult to determine and clearance values can
be

estimated

as

Cl

Vd.2

New Chemotherapy Agents


To date, the combination of cisplatin and 5-FU represents
standard polychemotherapy in association with RT in HN cancers. 5
Recently, pre-clinical studies have demonstrated an enhanced activity
of RT with new cytotoxic agents such as taxol, which has
radiosensitizing properties and anti-cancer activity. A phase I study
was conducted with 24-hours paclitaxel infusion and simultaneous RT
in

locally

advanced,

recurrent

metastatic

Head

andNeck

malignancies. The dose limiting toxicity was febrile granulocytopenia


and the maximum tolerated dose of paclitaxel was 75 mg/m 2. All the
patients with locally advanced disease demonstrated either a complete
or a partial response, and at a median follow-up of more than 1 year
only 9 per cent of patients had progressed (Seinberg et al., 1977). The
results were confirmed by an additional preliminary report in a study
using concurrently taxol at 60 mg/70 per cent showing complete
response. Mucositis was the main toxicity (Amrein et al., 1998). A
potentially synergistic activity between RT and gemicitabine has been
suggested in recent trials. A pilot study performed at the Institute of
Cancer Research, Genoa, Italy and Croce General Hospital, Cuneo,
Italy demonstrated a high response rate (90 per cent) in advanced,
inoperable Head and Neck cancer patients, treated with alternating RT
and a combination of gemcitabine and cisplatin (Benasso et al., 1997;
1998). A complete response was observed in 85 per cent of the
patients, of which more than 70 per cent are alive and disease-free
after a median follow-up of 1 year. However, modifications to the

schedule are mandatory in light of the heavy toxicity observed, but


the high anti-tumour activity obtained suggests further investigations
on the combination of RT and gemcitabine.17

INTERFERENCE

AND

MECHANISM

OF

ACTION

ARRESTING IMMATURE CELL PROLIFERATION


General
Chemotherapy is planned on the basis of observed differences
between normal and tumour cells in response to anti-tumour agents
used both as single and in combination. Part of the difference between
normal and neoplastic cells can be emphasized that cell kinetics cannot
explain all the consequences of tumour-cell exposure to a drug, since
these are also dependent upon pharmacokinetics, biochemistry and
tumour biology.
The proliferation of tumour cells is not entirely autonomous,
neither is it constant; it varies with the size of the tumour and is related
to its blood supply. Animal studies show that the characteristics of
tumour cell proliferation have an important influence on the response
to chemotherapy. Skipper (1971) has reviewed some of the principles
concerned and the following generalizations can be made for
experimental tumours.14|

The Cell Cycle

An understanding of cell-cycle kinetics is essential for the


proper use of the current generation of antineoplastic agents. Many of
the most potent cytotoxic agents act at specific phases of the cell cycle
and, therefore, have activity only against cells that are in the process
of division. Accordingly, human neoplasms that are currently most
susceptible to chemotherapeutic measure are those with a large growth
fraction, that is, a high percentage of cells in the process of division.
Similarly, normal tissues that proliferate rapidly (bone marrow, hair
follicles, and intestinal epithelium) are subject to damage by some of
these potent antineoplastic drugs, and such toxicity often limits the
usefulness of drugs. On the other hand, slow growing tumors with a
small growth fraction (for example, carcinomas of the colon or lung)
are often unresponsive to cytotoxic drugs. Although difference in the
duration of the cell cycle occur between cells of various types, all cells
display a similar pattern during the division process. This cellcycle
may be characterized as follows : (1) there is a presynthetic phase
(G1); (2) the synthesis of DNA occurs (S); (3) an interval follows the
termination of DNA synthesis, the postsynthetic phase (G 2); and (4)
mitosis (M) ensues the G2 cell, containing a double complement of
DNA, divides into two daughter G 1 cells. Each of theses cells may
immediately reenter the cell cycle or pass into a nonproliferative stage,
referred to as G0.

The cells of certain specialized tissues may

differentiate into functional cells that are no longer capable of


division. On the other hand, many cells, especially those in slowgrowing tumors, may remain in the G0 state for prolonged periods,
only to be recruited into the division cycle again at a much later time.
Most antineoplastic agents act specifically on processes such as the

synthesis of DNA or of the mitotic spindle. Other block the synthesis


of DNA precursors or damage the integrity of DNA. While most of
the known anticancer drugs are G1 is the period between mitosis and
the beginning of DNA synthesis. Resting cells (cells that are not
preparing for cell division) are said to be in subphase of G 1, G0. S is
the period of DNA synthesis; G2 the premitotic interval; and M the
period of mitosis. Example of cell-cycle-dependent anticancer drugs
are listed in blue below the phase in which they act. Drugs that are
cytotoxic for cells at any point in the cycle are called cycle phasenonspecific drugs. (Modified from Pratt et al., 1994 with permission.)
most effective against actively proliferating cells, some (called cell
cycle phase-specific, such as cytosine arabinoside and methotrexate)
affect cells only during the S phase or during mitosis (e.g., pactiaxel
and vinca alkalids) and will not kill nondividing cells. Damaged cells
that cross the G1/S boundary will undergo apoptosis, or programmed
cells death, if the p53 gene is intact and exerts its normal checkpoint
function. If the p53 gene is mutated and the diversion down the
apoptotic pathway does not take place, the damaged and potentially
mutated cells will proceed through S phase and emerge as a drugresistant population.8
All tissues are basically composed of three populations of cells.
The first of these consist of cells that are continuously traversing the
cell cycle. The second population is composed of cells that leave the
cell cycle after a certain number of divisions to differentiate and later
never to divide again, and die. In the third population group, the cells
remain dormant and leave the cell cycle temporarily to return when a
stimulus or other environmental conditions dictates their re-entry into

the cell cycle. An example of these populations is seen in the bone


marrow. The marrow is composed of a sub-set of cells which are
continuously traversing the cell cycle by dividing and producing more
blast cells from precursors.

The second population consists of cells such as granulocytes


which have differentiated and are destined to perform a specific
function, not undergo further mitosis, and finally to die. Cells in the
third population include stem cells which do not cycle until marrow
depletion causes them to re-enter the cell cycle and proliferate again.
In terms of tissue growth in both normal and abnormal
situations, 3 factors regulate the population: 1. The cell cycle and its
duration, 2. The growth fraction, 3. The rate of cell loss. The cell cycle

time refers to the interval between mitoses. The faster that the cell
cycles, the faster the increase in the total number of cells. The growth
fraction refers to the subset of the population of cells which are
actually traversing the cell cycle. The larger the number of cycling
cells, the more cells will be produced. The rate of cell loss refers to the
number of cells that die or leave the cell loss population by migrating
to other tissue. In an adult organism where growth has ceased to exist,
there is a steady state produced where cell loss is equal to cell
production. Growth of both normal and neoplastic tissue occurs as a
results of an increase in the total cell number.1
Host-Tumor-Drug

Relationship

and

the

response

to

Chemotherapy. A number of pharmacokinetic parameters such as


activation, inactivation, binding to carrier proteins, excretion, and
delivery of drug have obvious impact in the clinical response to even
the most active agents. As well, the response to an agent given in an
appropriate schedule seems to depend heavily on the proliferative
status of tumor cell populations, which in turn seems to vary as a
function of tumor burden. Thus, understanding the host-tumor
relationship with the purpose of designing more effective schedules
might be profitable.
The early pioneering work of Skipper et al in the L1210
leukemia model led to their statement of the log-kill hypothesis in
1964. This holds that a constant fraction of the tumor cells will survive
a given level of effective therapy irrespective to the size of the tumor.
Thus, the greatest number of cells will be killed in large tumors, while

small tumors should be curable if the same level of therapy is


repeatedly applied until virtually every cell is killed.
In 1977 Norton and Simon suggested that tumor killing for a
given level of effective therapy varies with the growth rate of the
tumor. For L1210 or other tumors which follow logarithmic growth,
growth fraction (GF) is large and stays constant. Thus, growth rate
accelerates as the tumor grows, rendering large tumors sensitive. In
contrast, for Gompertzian tumor growth, which probably more
accurately describes human tumors, GF is large initially, but
progressively diminishes. Growth rate progressively increases reaching
its maximum at about 37% of total volume and subsequently
decreases, as decreased GF become significant. Consequently, large
tumors, as well as very small tumors, have low growth rates wand are
relatively resistant to effective treatment.16

- The doubling time of a tumour increases with the tumour


mass up to a critical point while the thymidine labeling index
decreases. The growth of most experimental tumours can be
described as Gompertzian (after the statistician who first
described the mathematics) rather than linear.
- The response to chemotherapy is reflected by the change in
the

thymidine-labelling

index

(the

number

of

cells

synthesizing DNA).
- The shorter the doubling time at the onset of treatment, the
better the initial response to chemotherapy is likely to be.

- As the tumour volume increases the disease becomes less


easy to eradicate by single modality therapy.
- Non-phase dependent agents are theoretically more effective
than phase-dependent agents against tumours with long times
and low thymidine-labelling indices.

Gompertzian growth curve

Animal tumours do not grow in a linear manner. As they become


larger the growth rate slow. Though few data are available for human
tumours, there are suggestions that the above generalizations may
apply to human cancer, and proliferation studies may come to be
helpful in the choice of chemotherapy and in predicting duration of
remission and survival.

Phase-specificity / Phase dependency of cytotoxic drugs

Phase dependent agents exert an increasingly toxic effect with


prolonged exposure of the cells to an effective concentration while in
the sensitive phase. This results from an accumulation of cells in that
phase (provided the drug does not prevent entry). Given over a short
period, even at high dose level, these agents are not very toxic. Cells
not in the sensitive phase, at the time of the brief exposure, will be
minimally affected.
The toxicity of cycle-dependent or non-phase-dependent drugs
for both malignant and normal cells depends on the drug concentration
and the duration of exposure. To achieve maximum effect it is
therefore logical to administer the drugs intermittently at the highest
dose. Some drugs interfere with progression from one phase of the cell
cycle to another. Cytosine arabinoside and hydroxyurea, for example,
inhibit the progression of G1 cells into S and therefore cells not is S are
protected. This protective effect can be overcome by giving the drug
intermittently at intervals that permit the non-S phase cells to enter S
during the drug-free period.

Note that for both A and B rapidly proliferating cells are more
sensitive than slowly proliferating cells

Classification of anti-tumour agents according to their effect on the


cell cycle

Predominantly non-phase
dependent
Alkylating agents
Nitrosoureas
Anthracyclines
Imidazole carboxamide (DTIC)
Mitomycin C
Actinomycin D

Predominantly phase-dependent
Vinca alkaloids
Hydroxyurea
Cytosine arabinoside
Methotrexate
6-Mercaptopurine
6-Thioguanine
Procarbazine
Podophyllotoxins - VM26
- VPP 16-213

Drug metabolism
Most anti-cancer agents are metabolized in the body, usually to
products which are inactive having lower lipid solubility. These are
then excreted. In some instances, active metabolites are produced (e.g.
cyclophosphamide).
Drug absorption, distribution and excretion

EXCRETION
Biotransformation to
active or inactive
product(s)

Renal and extra-renal


Free drug in plasma
ABSORPTION
Plasma protein binding

Tissue binding (specific


and non-specific)
tumour and normal
tissues
Anabolic activation is particularly important in the case
of anti-

metabolites. The role of anabolic and catabolic activation and


deactivation is of great importance since it may form the basis of
selective activity in different cell types (normal and malignant).
Usually, drug metabolism occurs in two phases:
A.

Biotransformation

involving

hydroxylation,

oxidation, reduction or hydrolysis


B.

Conjugation e.g. with sulphate, acetyl or a


glucuronyl group.

Drug metabolism occurs chiefly in the liver but may also take
place in the plasma, gastro-intestinal tract, kidneys and lungs. For this

reason, hepatic function is an important consideration in the choice of


dose of some anti-tumor agents. The anthracyclines (e.g. Adriamycin
and Daunorubicin) are excreted mainly in the bile and these drugs
produce enhanced toxicity in patients with hepatic failure or biliary
obstruction.
EXCRETION
Most anti-tumour agents are excreted in the bile and urine.
Drugs not

bound to albumin are filtered by the glomerulus. The

proximal tubule possesses two pump systems which transport drugs


from plasma to urine, one for the secretary mechanism and probenecid
can be used to reduce the elimination of acidic drugs (e.g. penicillins
and, possibly, anti-cancer agents such as Methotrexate). Passive
reabsorption of lipid-soluble drugs and the non-ionized fraction of
drugs which are weak electrolytes takes place in the renal tubule.
Elimination of weak acids by the kidney is increased by alkalinizing
the urine. The reverse is true for weak bases. Active tubular
reabsorption of ions and various solutes can also take place in the
proximal tubule.
Excretion in tears, sweat, saliva and in the breath is relatively
unimportant but may be the cause of unusual toxicity such as the
conjunctivitis seen following the use of high dose Methotrexate.
Several host dependent factors have important influences on drug
absorption, distribution, metabolism and excretion. Illness which
affects renal and hepatic function, bone-marrow reserve or gastrointestinal function may well have a marked influence on the efficacy
and toxicity of a drug. Methotrexate, for example, is largely excreted in

the urine and its toxicity may be markedly enhanced in patients with
renal failure.14

AGENT

WHICH

PONTENTIATE

THE

FUNCTION

OF

CHEMOTHERAPEUTIC AGENTS
Chemosensitization
Hypoxic cell Chemosensitizers
In the animal model the hypoxic cell sensitizers misonidazole
and SR-2508 enhance of the cytotoxicities of alkylating agents and
nitrosoureas. However, the optimal method of administration is not
known.

Dose-response curves for the different sensitizers and

alkylating agents are needed to optimize efficacy and reduce toxicity.


A randomized trial using intravenous melphalan with or without
misonidazole in metastiatic non-small-cell lung cancer showed a
small, but statistically significant, improvement in response rate with
misonidazole. Other single-arm trials of misonidazole and alkylating
agents have been negative or inconclusive.
Perfluorochemicals as Chemosensitizers
Fluosol-DA and carbogen breathing increased the antitumor
efficacy of bleomycin and cyclophophamide in the animal model.
With cyclophosphamide when the Fluosol dose was increased from
0.1 to 0.3 ml and carbogen breathing extended from 6 hr the tumor
growth delay tripled. Similar effects were seen with bleomycin.
Chemosensitization by Vasocative Drugs
Several vasoactive drungs can selectively reduced blood flow
and increases the percent of hypoxic areas in experimental tumor
systems. By promoting hypoxia in the tumor, the cytotoxicity of
drugs which are active in hypoxic conditions is potentiated. When
hydralazine was given prior to or after the alkylating agents
melphalan, melphalns antitumour activity increased by a factor of 2

and 3, respectively. However, systemic toxicity was only increased by


a factor of 1.2. Additional animal studies have shown that hydralazine
cause a dose-dependent decrease in tumour energy metabolism
(measured by PNMR spectroscopy). PH, and perfusion pressure in
tumors. Despite these alternations in tumor metabolism, toxicity is
minimal in the treated animals. These data suggest that hydralazine
might be beneficial combined with therapy which is specifically toxic
by hypoxic cells (e.g., hyperthermia, mitomycin C, and perhaps after
alkylting agents).

Verapamil and other calcium chemotherapeutic

agents also potentiate the efficacy of certain chemotherapeutic agents


by preventing drug efflux and altering tumor blood flow .
Agents That Are Toxic to Hypoxic Cells
The bioreductive alkylating agents mitomycin and porfiromycin
may target to hypoxic cells. In a randomized trial of radiation with or
without mitomycin in head and neck cancer, improved disease-free
survival was observed in the patients treated with mitomycin .
SR-4233 is a new benzotriazine which is 15-to 50-fold more
toxic to anoxic than to well-oxygenated human tumor cells in vitro.
However, the invivo results with SR-4233 were less impressive.
A new analog, SR-4482 is more toxic than SR-4233 in vitro, and
less toxic in vivo.Several important effects of the nitroimidazole
compounds

(hypoxic

cytotoxicity,

thiol

depletion,

and

chemosensitization) are felt to be due to reduction of the parent


compound. The benzotriazines are activated by enzymatic reduction.
The differential activity of various reductases in normal and malignant
tissues may lead to the logical selection of the appropriate sensitizer in
this class.

NONHYPOXIC RADIATION SENTIZIERS


Halogenated pyrimidines
Bromodeoxyuridine (BUdR) and iododeoxyuridine (IUdR), are
halogenated pyrimidines, which were designed as thymidine analogs.
The initial hypothesis was that these drugs could be incorporated into
the DNA of actively dividing cells and act as radiosensitizers. Clinical
trails should attempt to achieve sustained plasma levels of 10m IUdR
for optimal radiosensitization.
Early clinical trials using the halogenated pyrimidines
demonstrated excessive normal tissue reactions without increased
antitumor efficacy in patients with head and neck cancer. Since the
halogenated pyrimidines are absorbed preferentially in actively
dividing cells, it is not surprising that severe mucosal toxicity was
encountered. Since BUdR is associated with photosensitivity, recent
interest has focused on IUdR.

More encouraging results may be

observed in the Phase II trials combining halogenated pyrimidine with


radiotherapy for gliomas and sarcomas, since the irradiated,
surrounding normal tissues have lower mitotic rates .
Two clinical studies of continuous intrahepatic artery infusions
of IUdR have shown that human colon cancer cells absorb almost six
times the amount of IUdR compared with adjacent normal liver.
Regional infusion also decreases systemic IUdR leves 50-78% .
DNA repair inhibitors
Inhibitors of DNA repair may act as radiosensitizers. Inhibitors
of DNA replications which act by inhibiting DNA-dependent DNA
polymerases can decrease the radiation damage at the chromosome
level. However, the effectiveness of inhibiting both replication and

repair of DNA does not always correlate with clinical response. In


human cervical cancer cell lines, the DNA repair inhibitors reduced
radiation survival. Various DNA repair inhibitors have been studies in
the laboratory. Hydroxyurea reduced survival at both high and low
radiation doses.

Beta-ARA-A and caffeine are more effective in

reducing all survival at low doses.


Nicotinamide
In several animal models nicotinamide has bee shown to
preferentially radiosensitize tumors, perhaps by reducing hypoxia.
The radiation enhancement ratio ranged from 1.2 to 1.7 in animal
tumors and 1/0 to 1.3 in normal tissues.
Platinum analog
Cis-plantinum is one of the most
agents.

active chemotherapeutic

However, its radiosensitizing properties have not been

exploited with fractionated radiation because cis-plantinums normal


tissue toxicity. The less toxic transiomer trans-platinum and other
platinum analogs interact with radition in vitro. Trans-platinum might
be an ideal sensitizer for most radiation fractionation schedules used
in clinical practice.
Thiol Depletors
As the thiol content in cells increases, most cells are protected
from the cytotoxicity of radition of alkylting agents. In vitro, thiol
depletion leads to radiosensitization. When BSO depletes cellular
glutathione in vitro, radiation injury increases. However, the presence
of other reducing agents (such as ascorbic acid or -tocophero) blunts
the sentizing effect of BSO in vivo. Lowering glutathione levels in
tumours might potentiate the effect of hypoxic radiosensitizers.

However, glutathione depletions major likely role will be in


chemosensitization.4
Chemoprevention
The most effective methods of preventing oral cancer are
avoidance of the major etiological factors, tobacco and alcohol.
However patients with premalignant conditions in the mouth have a
high risk of developing carcinoma, and patients successfully treated
for oral cancer have a high risk of developing seconds primary
neoplasms.

Accordingly there is now a considerable interest in

measures to prevent the development of cancer in this high risk group,


including the use of chemical agents.
Retinoids
Vitamin A and related compounds have several properties which
suggests that they may be useful as chemopreventive agents in oral
squamous cell carcinoma.

They are modulators of epithelial cell

differentiation, both in vitro and in vivo.

They probably act by

regulating gene expression. Cell nuclei contain retinoic acid receptors


that mediate the biological effects of retinoids. The ligand for these
receptors is probably all-trans-retinoic acid, to which retinoids must be
metabolized to exert their biological effect. In experimental animals
vitamin A deficiency causes squamous metaplasia similar to that
induced by chemical carcinogens. It has been found that vitamin A
and related retinoids can reverse the metaplsia in vitamin A deficient
animals.

They have also been shown to inhibit the growth of

squamous carcinoma cell lines in vitro.


There have been several studies of treatment of oral dysplastic
leukoplakia by retinoids. Hong et al. used isotretinoin in a dose of 1-2

mg/kg per day for 3 months in a placebo-controlled trail involving 44


patients. The drug produced major clinical responses in 67 per cent of
patients compared with 10 per cent who received placebo (P=0.0002)
and reversed the dysplastic change in 56 per cent. At this dosage
isotretinoin has appreciable toxicity, with peeling of the skin, chelitis,
facial erythema and hypertriglyceridaemia in about 75 percent of
patients, headaches and dyspepsia also occasionally occur.
leukoplakic changes recur after stopping treatment.

The

However a

subsequent study demonstrated that low dose maintenance treatment


(0.5 mg/kg) after the end of the 3 months of high dose therapy was
well tolerated and prevented recurrences.
Vitamin A in high dosage was shown to reverse premalignant
change in Indian betel chewers. Vitamin A is generally less loxic than
isotretinoin, but effective dose levels, i.e.300 000 IU per day, produce
similar if less severe side effects. In both of the above studies carotene was also tested as maintenance treatment because of its lower
either vitamin A or isotretinoin, probably because it is less easily
metabolised to the active ligand.
Experience with isotretinoin in the treatment of leukoplakia has
led to being tested as adjuvant treatment in patients with oral and
laryngeal carcinoma who were disease-free after primary treatment.
There was no influence on recurrence rates of the original tumours,
but there was a significant reduction in the incidence of second
primary tumours.

This experience led to the setting up of larger

multicentre chemopreventive trails in cured head and neck cancer


patients, for examples the Euroscan trail using vitamin A.
Antioxidants

Agents with antioxidant properties can inhibit the effects of


many toxins including carcinogens. N-acetylcysteine, a precursor of
intracellular glutathione, inhibits the mutagenic effect of carcinogens
such as benzpvrene in vitro.10

CLINICAL APPLICATION AS PRIMARY TREATMENT AND


AS ADJUVANT IN MALIGNANT LESIONS
One of the most important factors in selecting chemotherapy is
the incidence of clinical and histological cure rate achieved by such
treatment. Present chemotherapy regimes do not produce cure rate in
all patients treated and considerable improvement is required in this
area. Also, it is very important to mention that after clinical cure rate is
achieved, the additional number of courses of chemotherapy
administered is critical in determining the frequency of histological
cure rate and duration of overall survival. A clinical cure rate occurring
after one course of chemotherapy, when additional courses of the same
chemotherapy are planned, is a more favorable prognostic factor than
clinical cure rate occurring at the end of the last planned course of
chemotherapy. It is important in evaluating chemotherapy as part of
multimodality treatment that in addition to the minimum number of
courses needed to achieve clinical cure rate.
The goals of including chemotherapy as part of the
multimodality treatment in patients with locally advanced head and
neck cancers are better overall survival and/or quality of life. When our
best chemotherapy is proven to be of value as part of multimodality
therapy, then the possibility of delaying or performing less extensive
surgery can be studied. The main purpose would be to lessen the
cosmetic and/or functional morbidity caused by radical surgical
procedures without jeopardizing the survival of the patients.
Induction (initial) chemotherapy
To investigate the effectiveness of chemotherapy as part of
multimodality treatment, the drugs must be administered before

definitive surgery and/or radiotherapy when gross and measurable


disease in present. As with most new therapies patients with more
advanced disease (stage III and IV) are usually selected for trials.
The use of chemotherapy as initial treatment started in the mid
1970s because of the increased local toxicities of simultaneously
administered chemotherapy and radiotherapy and lack of benefit of the
combined approach at that time.
Initially high dose methotrexate with leucovorin rescue as
utilized. In general, the overall response rate to this agent alone in
previously untreated patients with locally advanced disease was poor,
with no clinical cure rate and no evidence of improved survival of
these patients as compared with historical controls.
With the demonstration that cisplatin was effective as a single
agent in patients with recurrent cancer of the head and neck, many
trails were initiated with cisplatin containing combinations in patients
with previously untreated and locally advanced disease, summarizes
the overall results of trials with cisplatin alone or in combination with
other agent(s) that are known to be effective against head and neck
cancers. More than sixty such trials were reported up to 1985. All
except two trials were single arm pilot studies.
Because of patient heterogeneity and marked variation in the
doses and schedules of drug administration it is difficult to draw
conclusions. It does seem that cisplain combinations are superior to
cisplatin alone in achieving clinical cure rate and in overall response
rate. The most common agent(s) combined with cisplatin are
bleomycin alone or with other agents like methotrexate, vinblastine or
Oncovin. The overall clinical cure rate rate seems high with cisplatin

and 5-FU infusion than with any of the cisplatin and bleomycin
combinations. Also, the incidence of histological cure rate in those
clinical cure rate patients who underwent surgical resection is high
after cisplatin and 5-FU infusion than with any cisplatin and bleomycin
combinations. The side effects of these combinations are acceptable
and reversible.
From the clinical trails, patients achieving clinical cure rate to
the initial chemotherapy had significantly superior survival than those
patients with less than cure rate to the treatment regardless of the
subsequent definitive therapy. More important those cure rate patients
who were found to have no histological disease after surgical resection
have statistically superior survival when compared with those clinical
cure rate patients who had residual disease at surgery.
Oral cancers constitute about 10% and 6% of all cancer cases in
males and females respectively in India (ICMR 1989). Carcinoma of
buccal mucosa is more commonly seen among females than males with
a 3:1 incidence. About 80% of these tumors are locally advanced
(Stage III and IV) at the time of presentation, inspite of oral cavity
being easily accessible for examination and early identification.
Buccal mucosa is made up of stratified squamous epithelium
covering the internal surface of lips and cheeks. Pathologically buccal
mucosal cancers vary from verruccous exophytic indolent types with
well demarcated borders to deeply infiltrating ulcerative painful tumor
with poorly defined margins. More than 90% of these tumors are
squamous cell carcinomas and the remaining make up for minor
salivary gland tumors, melanoma, sarcoma etc., (Strong and Spiro

1987). Million and Cassissi (1984) reported that 95% of oral cancers
were squamous cell carcinomas.
The standard line of management of buccal mucosa cancer
depends on the extent of the disease. Radiotherapy or surgery is
advocated for early lesions (Stage I & II) and combination of both
practiced in advanced lesions (Stage III & IV) (Vanderwaal 1984). The
philosophy of combining surgery and radiotherapy in advanced lesions
is that surgery fails at the periphery and radiotherapy at the poorly
oxygenated center of the tumor.
As seen earlier, majority of the patients present with advanced
lesions and even combination of surgery and radiotherapy may not be
possible in most of the patients, as the tumors either will be
unresectable or the patient will not be fit to undergo surgery due to
associated medical conditions.
Over the years the results with surgery and radiotherapy has not
improved much and has reached a plateau (RTOG, 1980, Perez). The
locoregional recurrence with the above modality is as high as 60%
(Vikram, 1984; Kramer, 1985). The combined modality of surgery and
radiotherapy in advanced cases has given better results only when
surgery was very extensive and cosmetically inacceptable (Pinsolle,
1992).
In search of better results, good cosmesis and better quality of
life systemic chemotherapy has been incorporated into the treatment
modalities along with surgery or radiotherapy. Systemic chemotherapy
is usually accepted as standard treatment for palliation in patients with
recurrent and metastatic head and neck cancers who have failed the
definitive therapy. Recently with introduction of more active

chemotherapy agents and combination systemic chemotherapy is being


increasingly used before local therapy in previously untreated and
locally advanced head and neck cancers (Al Sarraf 1988).
Systemic chemotherapy has been used in various forms as
detailed below.
Induction chemotherapy: This is other wise called as
neoadjuvant chemotherapy. This started being used from mid 1970s
because of increased local toxicities seen with simultaneously
administered chemotherapy and radiotherapy and lack of benefit of
combined approach during 1960s (Al Sarraf 1988). The drugs are
administered prior to start of definitive therapy. The rational for
neoadjuvant chemotherapy is that a) ability to deliver drug to untreated
tumors with intact vascularity, b) Better tolerance to chemotherapy, c)
to enhance the efficacy of planned definitive local therapy after
cytoreduction and eradication of sub clinical metastasis and d) for
better overall survival and quality of life.
Concurrent chemotherapy: The drugs are used simultaneously
with definitive therapy (Radio Therapy or Surgery).
Chemotherapy

after

surgery

and

before

radiotherapy

(Sandwich)
Sandwich method: Here chemotherapy is administered after
surgery and before delivering radiotherapy.
Various agents have been used either singly or in combination as
chemotherapy. The agents used are Methotrexate, bleomycin, 5flurouracil (5-Fu), vinblastine and cisplatinum. The commonly used
combinations being methotrexate and

5-Fluorouracil

(Tarpley 1975; Al Sarraf 197; Alan Coates 1984; Ervin 1987; Jaulerry

1991) and Cisplatinum and 5-Fluorouracil (Singhal 1993). Ten years of


clinical trails have not yet identified the best chemotherapy regimen
to be combined with definitive treatment (Al Sarraf 1988).
Methotreaxate and Fluorouracil has been used in combination in
advanced head and neck cancers as neoadjuvant chemotherapy agents
(Alan Coats 1984; Jacobs 1982; Pitman 1983; Mackintosh 1988) with
varying success.
Oral cancers are common tumors presenting in advanced stages.
The effect of treatment is easily assessable in oral cancers.
Neoadjuvant chemotherapy has shown its effectiveness in head and
neck cases. So we want to assess the effect of combined neoadjuvant
chemotherapy with definitive radiotherapy in carcinoma of buccal
mucosa.
In patients with previously untreated respectable and operable,
locally advanced head and neck cancer, the timing and sequence of
effective chemotherapy as part of multimodality treatment is important
and needs to be investigated. The following problems existed with
induction chemotherapy when given as the initial treatment in
combined modality therapy:
1.

Patients refuse surgical resection or any further


therapy, especially those achieving the best response to
chemotherapy.

2.

The

planned

surgery

after

initial

successful

chemotherapy is not the same as that done in


previously untreated patients with identical tumors.
3.

The results of surgery after three courses of


chemotherapy, even with achievement of up to a 50%

clinical cure rate, are no different than adequate


surgery without preoperative treatment.
4.

Chemotherapy yields higher objective response rates in


patients with smaller tumor masses (stage III v stage
IV). Thus a higher effectiveness is expected of the
same chemotherapy when it is given to patients with
minimal residual disease after surgery (microscopic)
rather than gross bulky disease present before surgery.

Because of the above, a pilot study for patients with locally


advanced but respectable cancer in which three courses of cisplatin and
120 hour 5-FU infusion were given after surgery and before
radiotherapy. Following the demonstration of the feasibility of this
approach two pilot studies were activated by the RTOG in 1981, one
using induction chemotherapy followed by surgery and postoperative
radiotherapy in respectable patients, while the second uses the same
chemotherapy after surgery and

before radiotherapy. The

side effects of chemotherapy were the same regardless of the sequence


of chemotherapy in relation to the definitive treatments. Survival
favored chemotherapy in the middle sandwich, in spite of more stage
IV patients and poorer performance status in this group. This led to a
phase II trail RTOG 83-22, Head and Neck Cancer Inter Group I-0034)
in which after surgical resection patients are stratified and randomized
to receive radiotherapy or three courses of cisplatin and 5-FU infusion
followed by radiotherapy.
Combined chemo-radiotherapy

Since the late 1960s several efforts were made to commune


chemotherapy

with

radiotherapy.

The

concept

of

combining

chemotherapy and radiation in the treatment of locally advanced


squamous cell carcinoma of the head and neck, particularly
unresectable or inoperable lesions, is attractive.
Many single agents or combinations of drugs were used with
radiotherapy . The most common single agents selected for combination
with irradiation were, hydroxyurea, methotrexate or bleomycin. The efficacy
of these agents combined with radiotherapy has not been established in
randomized oral cancer, which often results in interruption of therapy.
The search for better and safer agents to combine with radiotherapy
led to the administration of Cisplatin. Cisplatin is an active agent in
squamous cell cancers of the head and neck. It does not produce mucositis
of the oral cavity and should not interfere with the delivery of radiotherapy.
Cisplatin possesses properties of radiosensitization that have been observed
both in vitro and in vivo. It has been suggested that the cytotoxic activity of
cisplatin is independent of cellage, and that radiation enhancement is both
dose and cell cycle phase dependent.
The combination of cisplatin and radiotherapy produced high CR
rates when given preoperatively in resectable stage III head and neck
malignancy and IV head and neck cancer or as the total treatment in
unresectable and/or inoperable disease. Also, this combination is
being tested as postoperative treatment at Wayne State University in
Detroit.
Because of the high complete response rate obtained with the
combination of cisplatin and 5-FU, this two drug regimen was added
to radiotherapy, and resulted in improved local control. The

combination of the cisplatin and radiotherapy is being compared to


radiation alone in phase III randomize trails by ECOG, RTOG, and
SWOG.
We feel that chemo-radiotherapy may play an important role
in the treatment of patients with locally advanced head and neck
cancer and clinical investigation in this area continues.

Chemotherapeutic agents used concurrently with radiotherapy in


advanced cancers

Methotreaxate
Hydroxyurea
5-Fluorouracil
Bleomycin
Cisplatin
Combined Agents
Bleomycin, vincristine, and methotrexate (BVM)
Bleomycin, and methotrexate
Bleomycin, Adriamycin,* and 5-FU
Bleomycin, and cytoxan
Bleomycin, cytoxan, and vincristine
Mitomycin-C, and 5-FU
Cisplatin, and 5-FU
5.

Adrimycin (Adria Laboratories, Columbus, OH)

Chemotherapy After Radiotherapy


It has been reported that chemotherapy is most effective in
animal models when used for the eradication of small tumor masses.
Thus, chemotherapy administered after the definitive treatments of
surgery and/or radiotherapy may be efficacious in eradicating
minimal residual disease.

Randomized trails of single agent chemotherapy (methotrexate


or

cisplatin)

post

definitive

treatments

of

surgery

and/or

radiotherapy were initiated in many cooperative groups. In the


NCI head and neck contract trial one of the experimental arms
required that six doses of cisplatin be administered following one
course of cisplatin plus bleomycin, surgery and postoperative
radiotherapy. Only about 10% of the patients finished the total six
courses while about 30% either progressed or died, or refused
therapy respectively. Chemotherapy postdefinitive treatment is an
important concept that needs further evaluation. 15

DRUG SENSITIVITY TO VARIOUS LESIONS, THERAPY


REGIMES
Chemotherapy for recurrent or metastatic SCC H&N
When a patient relapses after extensive surgery or radiation
therapy, treatment options are limited. Traditionally, chemotherapy
has been used in this patient population, with chemotherapeutic single
agents and combination chemotherapy being evaluated for their
response as well as their impact on the patients quality of life. Four
drugs have been noted to have major activity in recurrent and
metastatic SCC H&N. They are (1) methotrexate, (2) cisplatin, (3)
belomycin, and (4) 5-fluorouracil. Other chemotherapeutic agents are
noted to have activity but are not as frequently used.
Methotrexate
Include in the antimetabolite class of agents, methotrexate exerts
its cytotoxic effect through inhibition of the enzyme dihydrofolate
reductase. This enzyme is responsible for maintaining the intercellular
pool of folates in reduced state, which is required for the synthesis of
the purine nucleotides.
For most oncologists, this is the standard chemotherapeutic
agents to which other single agents and combinations are compared.
The overall response rate using methotrexate as single agents
approximately 31%, with predominantly partial response seen and few
complete response noted.

The initial dose is 40mg/m 2, given

intravenously weekly until toxicity is noted, usually in the form of


mucositis or leucopenia. Various doses and schedules have been used,
including leucovorin as a bone marrow protector in the higher doses.
Nevertheless, pooled response rates are very similar between the
moderate and high doses of methotrexte, and toxicity plus cost are
more appreciable at the higher doses.
Cisplatin
Cisplatin is considered a heavy metal compound and is believed
to exert its activity by causing DNA cross-linking. This agent has been
extensively evaluated for patients with recurrent SCC H&N, with
single-agents activity in the range of 28%.
Cisplatin has been evaluated when given on a weekly basis,
every 3 weeks as an intravenous bolus, or by continuous infusion. All
schedules have shown similar response rates.

The issue of dose

intensity has also been addressed, with dose-realted toxicity being a


limiting factor, particularly involving renal toxicity and neurotoxicity.
The typical dose used has been between 80 and 100mg/m 2, with no
clear advantage see when higher doses are used. Cisplatin is usually
given every 3 to 4 weeks, with pre and post-hydration plus mannitol
infusion to protect renal function.
Bleomycin
Bleomycin is a mixture of glycopeptides considered in the class
of antibiotic considered in the class of antibiotic neoplastic agents with
activity in the G2 and mitotic phases of the cell cycle. It has been one
of the more frequently used agents for head and neck cancer and has a
single agent response rate of approximately 21%. Bleomycin has been
administered as a bolus or by continuous infusion, with equal activity

in both continuous infusion, with equal activity in both schedules but


with a suggestion of an improved toxicity profile when the continuous
infusion, with equal activity in both schedules but with a suggestion of
an improved toxicity profile when the continuous infusion schedule is
used.
The dose-limiting toxicity of bleomycin is its cumulative effect
on pulmonary function, making it difficult to administer after several
courses. The single-course dosage frequently used is 10 to 15 mg/m 2
daily for 3 to 4 days every 3 to 4 weeks.
5-Fluorouracil
One of the most frequently used chemotherapeutic agents for
head and neck cancer, 5-FU is usually used in combination with
cisplatin. 5-FU is pyrimidine antimetabilite that is converted
intracellularly to fluorodeoxyuridine monophosphate (5-F-DUMP); a
potent inhibitor of thymidylate synthetase, thereby inhibiting DNA
synthesis.
Another way -5-FU mediates its activity is by forming
fluorouridine triphosphate (FUTP), which is incorporated into a
interferes with the function of RNA. Single-agent response rate with
5-FU is approximately 15%. 5-FU has been extensively used with
cisplatin because of preclinical synergy noted.
Recently, it has been observed that 5-FU can be potentiated
when used in conjunction with leucovorin, which is the reduced form
of folate. Leucovorin stabilizes the 5-FU and thymidylate synthetase
tenary complex. When 5-FU is administered as a bolus daily for 5
days, the dose-limiting side effect is predominalty bone marrow
suppression. If the schedule is altered to a continuous venous infusion

over 24 hours daily for 4 to 5 days, the limiting toxicity changes to


mucositis, diarrhea, and cutaneous erythema. Cardiac toxicity has also
been noted. The continuous infusion schedule was used in an effort to
reduce myelosuppression, but, indeed, it seems to have improved the
activity of this drug in SCC H&N. The dosage most frequently used
has been 800 to 1000 mg/m 2 by continuous intravenous infusion for 72
to 96 hours.
Other single agents, not as widely used but with reported activity
in SCC H&N in the range of 15% to 36%, are the following: (1)
carboplatin, an analogue of cisplatin whose dose-limiting toxicity is
myelosuprresion, specifically thrombocytopenia (2) cyclophosphamide
and its analogue, ifosfamide, and hydroxyurea; (3) general classes of
drugs with limited single agent activity, including the anthracylines
(doxorubicin), the vinca alkaloids, mitomycin, and the nitrosureas.
Combination chemotherapy for recurrent or metastatic SCC H&N
In the 1970s, the many trails using combination chemotherapy
for patients with recurrent or metastatic SCC H&N combined the
active single agents cisplatin, bleomycin, and methotrexate.

The

response rates noted were encouraging, with the cisplatin-based


combination thought to be superior to the non-cisplatin-based
regimens.
In the 1980s, investigators at Wayne State University combined
cisplatin with 5-fluorouracil, both as a bolus and by continuous
intravenous infusion for 96 hours.

The initial results were very

encouraging, with an objective response rate of 78% noted; more


importantly, a 29% complete response rate was obtained for patients
with recurrent and metastatic disease. Other investigators have used

the cisplastin/5-FU combination with the same dose and schedule but
have obtained overall response rates, usually in the range of 25% to
30%, with approximately 10% achieving a complete response.
Efforts have been made over the past several years to improve
the response rates of the cisplatin 5-FU combination. Some of this
research efforts has focused on (1) substituting the analogue
carboplatin for cisplatin, (2) modulating 5-FU with leucovorin, and (3)
dose escalating the cisplatin combined with the use of chemoprotectors
to try to prevent cisplatin-related toxicities.

Unfortuanately, these

efforts have failed to significantly improve the response rate of this


combination, and no overall improvements have been seen with these
approaches.
Eleven randomized trails have looked at comparing single
agents, such as cisplain, 5-FU, and methotrexate, versus combination
chemotherapy, including cisplatin and 5-FU, for patients with recurrent
or metastatic SCC H&N.

Review of these studies reveals that,

although slightly higher response rates have been noted using


combination chemotherapy, this has not translated into an improved
disease-free or overall survival advantage. In addition, combination
chemotherapy has added toxicity and cost for the patient when
compared with single agents.
Although higher responses and, in particular, complete
responses, can be obtained with the use of cisplatin and 5-fluororuacil,
more toxicity is noted with this combination than with single agents.
Primary Chemotherapy
Primary chemotherapy refers to the use of chemotherapy, given
either before local therapy, concurrent, with radiation, or after local

treatment has been completed. The rationale for using chemotherapy


prior to local treatment is based on factors such as (1) an improved
patient performance status, (2) an intact vascular supply to the tumor
bed, and (3) the eradication of micrometastasis to prevent regional and
distant metastases.
Induction (Neoadjuvant)
The initial observation made was that response rates using single
agents, such as cisplatin, bleomycin, and methotrexate, were higher for
patients who had not received prior local therapy than for patients in
whom disease recurred.

In the 1970s, Randolph et al combined

cisplatin and bleomycin for two cycles prior to local treatment. In this
study, the combination of cisplatin and bleomycin as induction
chemotherapy yielded an overall objective response rate of 71%, with a
20% complete response rate. Subsequently, investigators at Wayne
State University combined cisplatin and infusional 5-FU for three
cycles prior to local treatment and reported an 88% overall response
rate, with 54% of the patients achieving a complete response.
Other investigators have also used the cisplatin and 5-FU
regimen for three courses prior to local therapy with less favorable
results. Parts of the disparity can be explained by patients selection
factors, because patients with N2 or greater disease have been noted to
obtain a complete response rate in the range of 20%.

The pilot

feasibility studies pointed to an improved overall and complete


response rate obtained with induction chemotherapy, without
compromising local therapy.
Concurrent Chemoradiation Therapy

Although there have been no new agents developed to add to the


response rate of combination chemotherapy for patients with locally
advanced, unresectable SCC H&N, the concurrent use of single agents,
such as bleomycin, 5-FU, methotrexate, hydroxy- urea, mitomycin-C,
and cisplatin, with radiation therapy has been investigated.
The rationale for combining these two modalities is based on
preclinical data suggesting the radiation-sensitizing effects of certain
chemotherapeutic agents. Also, combining these two modalities of
treatment simultaneously applies the concept of dose-intensity
administering the largest amount of treatment per unit time in an effort
to over-come any inherent drug or radition resistance.
Adjuvant Chemotherapy
Chemotherapy given after local therapy has been tried with the
rationale of eradicating micrometastases and thereby possibly reducing
the local, regional and distant metastatic rate. Unfortunately, of the six
randomized trials using chemotherapy in this fashion, none has shown
a survival advantage.

Nevertheless, one large study showed a

statistically significant decrease in distant metastases for patients


receiving chemotherapy after local therapy, even though overall
survival rates in both arms were not different.
Nasopharyngeal cancer
Standard treatment for nasopharyngeal carcinoma worldwide has
been radiation therapy because of this tumors known radiation
sensitivity and poor anatomic location, making surgical intervention
difficult. In fact, early-stage disease is well controlled with radiation
therapy alone, but in advanced stage disease, survival is considerably
less. For example, for Stage III disease using radiation therapy alone,

5-year survival has been reported in the range of 15% to 40% and for
Stage IV disease, it is only 0% to 30%.
Patients with nasopharyngeal carcinoma have a high likelihood
to developing distant metastasis, which seems to correlate with the
amount of cervical adenopathy.

In patients with bilateral neck

involvement, there is an established 80% chance for developing distant


metastases at a later date, usually involving the lung, liver, or bone.
Nasopharyngeal carcinoma is believed to be a chemosensitive
tumor; in fact, multiple single agents, such as cisplatin, 5-FU,
methotrexate, bleomycin, the vinca alkaloids, and doxorubicin, have
known activity in this disease. Various studies have reported rate, of
which less than 20% are complete responders, with the use of cisplatin
and non-cisplatin-based regimes for patients with recurrent or
metastatic nasopharyngeal carcinoma.
Salivary gland carcinoma
Salivary gland carcinomas make up approximately 5% to 10%
of all head and neck malignancies. These tumors demonstrate very
diverse anatomic, histologic, and biologic behaviour. Traditionally,
treatment for these tumours has been surgery with or without radiation
therapy. Chemotherapy has been reserved for patients with recurrent
and/or metastatic disease, and the benefits of chemotherapy have been
predominantly palliative for this group of patients. A number of single
agents have shown activity in this disease, but the most active and
frequently used are cisplatin, doxorubicin, 5-FU, cyclophosphamide,
and methotrexate.
Depending upon the histologic type of the tumor, methotrexate,
for example, has been shown to have a single-agent response rate of

approximately 36% in mucoepidermoid cancer, which is similar to the


activity seen for this agent in SCC H&N.

However, for other

histologic types of salivary tumours, the response rate with


methotrexate is much lower, approximately 6%.

In contrast,

doxorubicin is relatively inactive in mucoepidermoid carcinoma but is


active in other salivary gland histologic types. Single-agent cisplatin
has also been extensively used with a wide range of response rates
from 17% to 70%. Multiple combinations of the most active agents
have been tested, with the most frequent combination being cisplatin
and doxorubicin, with or without 5-FU or cyclophosphamide. The
responses with doxorubicin-based combinations have been in the range
of 35% to 100% with a median response of approximately 50%.

Miscellaneous groups
A number of diverse histologic tumors present less commonly in
the head and neck area for which chemotherapy has been utilized.
These

include

sarcomas,

lymphomas,

esthesioneuroblastomas,

neuroendocrine carcinomas, and Merkel cell carcinomas.


Sarcomas
Sarcomas can arise from either the bone or soft tissues in the
head and neck but are rare. When they d occur, the most common of
these tumors are the osteogenic sarcomas, malignant fibrous
hitiocytomas, rhabdomyosarcomas, fibrosarcomas, synovial sarcomas,
and angiosarcomas.
Surgery and radiation therapy remain the treatment of choice for
local disease, but depending upon the extent of disease, grade and
location, local and regional recurrences can be significant, with distant
metastases predominantly involving the lung, liver and bone.
Chemotherapy, particularly with doxorubicin-based regimens,
has been used and can provide palliation.

Response rates with

chemotherapy are similar to those seen for other sites and are largely
partial response.

For one particular subtype, rhabdomyosarcoma,

chemotherapy added to surgery and radiation therapy has been reported


to improve 5-year survival compared with that seen with surgery
and/radiation therapy alone.
Lymphomas
Both Hodgkins and non-Hodgkins lymphomas can present in
the head and neck area. When the disease is localized to the head and
neck, the treatment usually consists of radiation therapy only.
However, this disease is frequently found in multiple areas, and

chemotherapy and radiation therapy are used with substantial success.


The most commonly used chemotherapeutic agents for the lymphomas
are the alkylating agents (i.e., cyclophosphamide) in combination with
doxorubicin and vincristine. Prednisone is also incorporated into these
regimens.

Drug combinations

No.

No. with

evaluated

50%
regression

15

Methotrexate + vincristine

28

15(53%)

Dibromodulcitol + bleomycin

20

5(25%)

Adriamycin + bleomycin

MeCCNU + cyclophosphamide +

32

11(35%)

10

18

4(22%)

13

Methotrexate + bleomycin

bleomycin + vincristine (COMB)


Methotreaxate + 5-fuorouracil +
cyclophosphamide + vincristine
(modified COMF)
Methotrexate + cyclophosphamide +
vincristine+prednisone (Coopers
regimen)
CCNU+HN-2+ adriamycin + bleomycin
+ vincristine (BACON)

Methotrexate+6-mercaptopurine +
procarbazine + chlorambucil + thiotepe + streptonigrin +
rufochromomycin + vinblastine

82

45(55%)

SINGLE AGENT ACTIVITY


Drug

Dose Schedule

Evaluable

Responsea

Patients
Cyclophosphamid

8-10 mg/kg IV

56

2 CE, 35
improved

4 mg/kg/dy IV
4-60 mg/kg single
dose
150-300mg/dy;

15

2 improved

3 PR, 3

then 100-200
mg/day PO
2g in divided
doses for 8 days;

improved

then 100 mg/day


PO
Cyclophosphamid

IV, PO, IP, or

2 excellent and

intrapleural

2 moderate

ranging from

responses

100mg daily PO to
8g IV loading dose
preceding PO
therapy
Cyclophosphamid

50-200 mg/day PO

e
30mg/kg IVP; then
10-15 mg//kg q1-2

Improved

wks
Cyclophosphamid

Various IV and PO

doses

Chlorambucil

0.2 mg/kg/day X

1 improved

34

1 CR, 4 PR

None

41

5 improved

84

1 CR, 4 PR, 20

42 days PO
Nitrogen mustard

Total dose, 0.5-0.8


mg/kg
0.6mg/kg in 3
divided doses

5-FU

15mg/kg/day X 5
IV; then 7.1mg/kg

improved

every other day


until toxicity.
Maximum loading
dose per day,
1,000 mg
5-FU

1,000 mg/day X 5;

2 improved

17

3 improved

12

1 CR, 1 PR

then 500mg every


other day until
toxicity
5-FU

4-8mg/kg/day X
14-42 days

5-FU

15-20 mg/kg/wk

Responsea

Evaluable
Patients

1 improved

10

3 improved

23

4 PR 7,
improved

Mitomycin C

50mg/kg/day X 6;

31

3 improved

12

76

11 PR

then 50 mg/kg every


other day until
toxicity

CR = Complete response; PR = Partial response (50% or more in

tumor measurements); Improved = Less than a PR not quantitated

ROUTE OF ADMINISTRATION OF VARIOUS


CHEMOTHERAPEUTIC AGENTS
The administration of chemotherapy has not always been as it is
today. As recently as the 1950s, the physician administered the
medications and the nurse was left to care for any side effects (Lind
and Bush 1987). The first chemotherapy drug. A nitrogen mustard
(mechlorethamine), was discovered in the 1940s and in comparison to
other areas of medicine, the field of oncology was still in its infancy.
As the number of available drugs increased and the technology of
chemotherapy administration became more complex.
ROUTES OF ADMINISTRATION
The goal of chemotherapy administration is to optimize drug
availability. In an attempt to deliver drugs in high concentrations to
areas of greatest clinical need and to improve the antitumor effects,
many diverse routes of drug administration have been developed
(Haskel 1980). The current routes of administration include:
intrathecal (IT)
intra-arterial (IA)
intracavitary (IC)
subcutaneous (SQ)
intramuscular (IM)
topical (TOP)
oral (PO)
intravenous (IV)

The following three routes of administration allow for high drug


concentrations in the disease area while minimizing the systemic
concentrations, and thus the side effects:
intrathecal
intra-arterial
intracavitary
Administering chemotherapy intrathecally allows the drugs to
reach the central nervous system to prevent or treat local disease. The
majority of chemotherapy agents do not cross the blood-brain barrier,
so they must be delivered directly into the cerebrospinal fluid. This is
accomplished by either:1) a lumbar puncture or 2)utilizing an
indwelling subcutaneous cerebrospinal fluid reservoir, such as the
Ommaya reservoir (Heyer-Schulte del Caribe, Anasco PR). The
benefits and risks to the patient must be determined before either
method of administration is chosen. To put it concisely, include: 1)
having a lumbar puncture performed for each treatment (weighing the
pain and potential complications that procedure involves) or 2) the
potential complications of surgically inserting and Ommaya reservoir,
but utilizing a consistent port for each treatment. The Ommaya
reservoir is a mushroom-shaped, reusable, self-sealing, silicone port
which is connected to a catheter placed in the ventricle (Figure ). The
reservoir is accessed by inserting a hypodermic needle, usually a
small-gauged butterfly needle with an attached three-way stopcock and
syringe, directly into the dome. During the procedure an amount of
cerebrospinal fluid, equal to the amount of medication to be injected, is
removed. The medication is injected into the reservoir and, once the
needle is removed, the domed reservoir is manually compressed and

released to mix the medication with the cerebrospinal fluid (Brown


1987). This procedure is usually performed by a physician using strict
aseptic technique.

Cerebrospinal fluid reservoir and mode of use


Intra-arterial infusions treat an isolated organ or inoperable
tumor. The chemotherapy agents are administered through a catheter
inserted into an artery usually in the liver, head, neck, or brain. The
celiac artery is used to treat the liver, the external carotid artery for the
head and neck area, and the internal carotid artery for brain tumors
(Johnston and Pratt 1981). The catheters are inserted into the artery
surgically with general anesthesia or using angiographic catheterization
and a local anesthetic. The catheters are then connected to either an
implanted or portable pump. There are two impantable pumps
currently being used: the Infusaid pump (Shiley Infisaid Inc, Norwood,
MA), and the Medtronic pump (Medtronic, Minneapolis). The

Autosyringe Division, Hooksett, NH), is an example of a portable


systems used for intra-arterial infusions.

Portable infusion pump

Three other modes of drug administration are used less


frequently:
subcutaneous
intramuscular
topical
Many of the antineoplastic agents are irritating or damaging to
body tissue, so it is inadvisable to give a subcutaneous or intramuscular
injection of these agents. Some drugs that can be given by the
subcutaneous route are cytosine arabinoside

(ARA-C) and the

interferons, while bleomycin and methotrexate can be given


intramuscularly. L-asparaginase is one drug that may be given either

by the subcutaneous or intramuscular route. Topical administration has


limited usefulness with only mechlorethamine and 5-fluorouracil
cream having this method as one of their routes of administration,
(Dorr and Fritz 1980). Occasionally, a specific protocol or drug may be
administered using one of the methods.
The last two routes of chemotherapy administration are the most
common:
Oral
Intravenous
The oral route is usually preferred but absorption can be
unpredictable. Several factors must be considered before choosing the
oral route: patency and functioning of the GI tract, presence of nausea,
vomiting, or dysphagia, the patients state of consciousness, the
patients willingness to comply to the schedule, and the availability of
the medication in oral form.
The intravenous (IV) route of administration is the most
common method used to deliver chemotherapy. It allows absorption of
the drug thus providing predictable blood levels (Brown 1987).
Intravenous drugs may be administered through a peripheral access, a
vein in the patients arm or hand, or through a central venous access
device, such as a silicone, silastic catherter, or an implanted infusion
port. The three major adviser reactions to the intravenous route of
administration are: phlebitis, venous flare, and extravasation
(Troutman 1985).
There are four methods of intravenous administrations:
push (IVP)
piggyback (IVB)

sidearm
infusion, continuous or intermittent
Intravenous push refers to directly administering the medication
into the intravenous cannula, through either an angiocath or a butterfly
needle. A piggyback method denotes there is a main line of
intravenous fluid connected into the intravenous cannula. The solution
to be piggybacked is connected, usually in the port closest to the
patient, into the main intravenous line. The sidearm method of
administration is the route of choice for chemotherapy with vesicant
properties. Again, a main line of intravenous fluid, freely flowing, is
connected into the intravenous cannula. The physician directly
administers the medication, slowly, into the part closest to the patient
while continually assessing the peripheral IV site for complications
and extravasation. This method, as could the piggyback method, allows
for further dilution of the chemotherapeutic agent with the main fluid.
The two solutions must be compatible. The infusion method may last
from several minutes (bolus infusions) to several days, 24 hours a day
(continuous infusions).

Selecting a Vein Assess veins in both arms and hands. Do not use
veins in compromised limbs/lower extremities

Criteria for Vein Selection

Appropriate
Choice of
Venipuncture Site

Ideal Vein/Best Location

forearm

Large, soft resilient veins in forearm,


hand
Ideal Vein/Undesirable Location
Large, soft, resilient veins in

hand

hand/antecubital fossa; small, thin


veins in forearm
Satisfactory Vein/Best Location
Small, thin veins in forearm/hand

forearm

Satisfactory Vein/Undesirable

hand

Location
small thins veins in hand; veins in
forearm not palpable or visible
Unsatisfactory Vein/Undesirable

Consider central

Location
small, fragile veins, which easily

venous line*

rupture, in hand/forearm
Unsatisfactory Vein/Undesirable
Location
veins in forearm/hand not palpable or

Consider central
venous line*

visible
*In some situations, central venous lines are inserted before the patient
is started on a chemotherapy protocol.
Dealing with the veinless patient
One of the most common dilemmas facing oncology nurses is
trying to administer chemotherapy to the veinless patient (described
by Lokich 1978). With the variety of central venous access devices,
both catheters and subcutaneous ports, this issue doesnt have to be a
problem.
1. In an attempt to dilate the veins, apply moist heat to the arms
for 5-10 minutes (Johnston Early, Cohen and White 1981).
2. Once the soaks are removed, work efficiently while the veins
are dilated.
3. Local vein manipulation may also aid dilation:
a. Appropriate use of a tourniquet or blood pressure cuff
to encourage pooling of venous blood.
b. Milking the veins from proximal to distal (elbow to
hand)
c. Gently striking the surface of the vein
4. Catheter selection is very important in this setting. The veins
may well be small and an appropriately sized needle will
decrease trauma.
5. Perform

the

actual

techniques

and

preparation

for

venipuncture according to the institutions policies and


procedures.
Controversial Issues in Chemotherapy Administration

Issue
Solution
Administration Use antecubital

Rationale
Larger veins permit more rapid

site

infusion and administration of

fossa

drugs
Larger veins permit more rapid
circulation of potentially
Avoid antecubital

irritating drugs
Mobility of arm restricted

fossa
Risk of extravasation increased
due to patient mobility
Ealry infiltration and
extravasation difficult to assess
due to subcutaneous tissue
Repair of infiltration would be
difficult and debilitating for the
Needle size

Larger gauge (#19-

patient
Potentially irritating drugs

21 scalp vein

reach circulation sooner, with

needles)

less irritation to peripheral

Small gauge (#23-

veins
Smaller gauge needles less

25)

likely to puncture wall of vein;


less scar tissue at insertion site;
and less pain on insertion
Increased blood flow around
needle increases dilution of the
drug
Reduced incidence of

mechanical phlebitis
Slower infusion rate may
reduce side effects, i.e., nausea
Sequencing of

and vomiting
Administer vesicant Vascular integrity decreases

medications

first

over time, i.e., more stable and


less irritated at the beginning of
treatment
Initial assessment of vein
patency is most accurate
Irritating agents may cause

venous spasm and pain


Administer vesicant Vesicants are irritating, may
last

increase vein fragility, and


cause spasm at onset of drug
administration. The nurse must
assess whether the spasm and
complaint of pain is an

Particular

Use sidearm

infiltrate or not
Freely running intravenous

intravenous

method

lines allow for dilution of drugs

Use direct IV push

Integrity of the vein can be

method

more easily assessed


Extravasation can be noted

method of
administration

earlier

DRUG DELIVERY SYSTEMS


One of the fastest growing areas in the oncology setting today is
the area of drug delivery systems catheters, implantable ports, and
infusion pumps. By the time this book is published, numerous new
products will be available that were only a thought at the time the
authors were formulating this section.
Previously, a venous access device was only indicated when the
patient had unsatisfactory veins for further cancer therapy. Now there
are several indications for early placement of a venous access device
(Simon

1987).

Patients

receiving

continuous

infusions

of

chemotherapy, nutritional supplements, or antibiotics either at home or


in the hospital are also ideal candidates for such devices.
Two central venous access devices will be discussed in this
section: silastic right atrial catheters and implantable venous access
ports (VAP).
Growth factors
Transforming growth factor-1 (TGF-1) is a potent cytokine
that affects growth inhibition of various cells and stimulates
extracellular matrix production and angiogenesis. Loss of TGF-
receptor type II (TGF- RII) expression has been related to tumor
progression.
Advances in molecular biology and genetics have provided new
insights into the carcinogenesis and behavior of malignant tumors of
the salivary glands. The WHO system provides a consistent taxonomy
for tumors of the salivary glands, which may facilitate sharing of our

experience with these relatively rare tumors. Clinical parameters such


as advanced stage, high grade, nodal metastasis, positive margins, and
perineural spread characterize patients with aggressive and potentially
lethal tumors. The relatively high rate of failure to control the disease
in these patients indicates the need for improvement in adjuvant
therapy.6

Treatment of nausea and vomiting


A.

Mild

Pretreatment

with

10mg

prochloreperazie

(Compazine) orally or parenterally before therapy, and one or two


doses every 4 to 6 hours posttherapy is usually sufficient.
B. Moderate retreatment with 10mg prochloreperazine PO or
parenterally, 10mg dexamethazone (decadron) IV, and 0.3mg/kg
ondansetron (Zofran) IV. At end of chemotherapy, 0.15mg/kg
ondansetron. Then, 10mg prochlorperazine every 6 hours as needed.
Ondancetron can also be given as a single injection of 30mg once a
day.
C. Severe Same as for moderate, but with addition of 0.5mg
lorazepam IV before treatment. The lorazepam and ompazine are
repeated in 3 hours, then taken every 6 hours by mouth at home. On
occasion, 10 to 20mg metoclopramide (raglan) orally can be helpful.
In patients with severe, rather refractory nausea and emesis,
continuous infusion ondansetro (1mg/hr) has been very helpful. Such
treatment can be associated with headache.
Ondansetron has recently become available in an oral form
which is quite effective.
Diarrhea: Causes = amethopterin, fluorouracil (especially with folinic
acid), FUDR, 6-mercaptopurine, mitotane, and somatostatin.

Treatment
a) Stop oral intake
b) Diphenoxyate with Atropine (lomotil) 1 t.i.d. to .i.d. PO or
loperamide (Imodium) 2 to 4mg q.i.d. PO
c) Patients failing to respond to Lomotil have been reported by
Petrilli et al. to resolve the diarrhea in 24 hours by having the
somatostain analog (Sandostatin) at a dose of 150 g/hr IV.
Stomatitis: Causes =actinomycin D (Cosmogen), amethopeterin,
cyclophosphamide, cytosine arabinoside, daunorubicin, doxorubicin,
fluorouracil, FUDR, hydroxyurea, 6-mercaptopurine, mitomycin C,
and procarbazine fludarabine.
Treatment
a) Switch to soft bland foods; avoid citrus products
b) Viscous xylocaine swish before meals and PRN
c) Tyleno #3 1 to 2 tabs every 4 hours RN or stronger pain
medication
d) To prevent or reduce the severity of stomatitis with
fluorouracil, the patient should place ice chips in the mouth 5
minutes before receiving the IV dose of Fluorouracil and
continue the ice chips for 30 minutes after the injection
(Mahood et al., 1991).
CNS Toxicity:
a)

Peripheral

neuropathy

cisplatin,

carboplatin,

hexamethlmelamine, procarbazine, vinblastine, vincristine, and VP 16.


b) Change in consciouness amethopterine, L-asparaginase,
cytosine arabinoside, ifosfamide, interferon, mitotane, ad procarbazine.

c) Seizures cisplatin, interferon, hydroyurea, procarbazine, and


vincristine.
d) Cerebellar ataxia cisplatin, fluorouracil, and Ara-c.
e) Ototoxicity carboplatin.
f) Retinopathy tamoxifen.
Pulmonary Fibrosis or pulmonary interstitial disease. Causes =
amethopterine, BCNU, bleomycin, CCNU, methyl CCNU, cytosine
arabinoside, and myleran.
Treatment: This is often unsatisfactory. Large doses of steroids have
been felt to be beneficial by some.
Alopecia:

Actinomycin,

cyclophosphamide,

daunorubicin,

doxorubicin, fluorouracil, interfereon alpha 2, mitoxanthrone, and


VP16.
Liver dysfunction: Amethopterin, androgens, BCNU, CCNU, methyl
CCNU, cyctosine arabinoside, DTIC, 6-mercaptopurine, mithramycin,
and 6-thioguanine.
Treatment: Stop agent or decrease dose,.
Skin ulceration with extravasation: Actinomycin D, daunorubicin,
doxorubicin, nitrogen mustard, vinblastine, and vincristine.
Treatment: Stop agent. Elevate arm. Intermittent ice packs for 8 to
12hrs.If extravasation severe, consider infiltrating area with saline and
injecting with hyaluronidase.
Marrow Toxicity: Actinomycin D, amethoptein, BCNU, carboplatin,
CCNu, methyl CCNu, chlorambucil, cisplatin, cyclophosphamide,
cytosine arabinoside, daunorubicin, doxorubicin, DTIC, fludarabone,
5-fluorouracil,
interferon,

hexamethylmelamine,

6-mercaptopurine,

hydroxyurea,

mitomycin

C,

ifosfamide,

nitrogen

mustard,

novatrone, procarbazine, streptozotocin, 6-thioguanine, vinblastine,


and VP-216.
Treatment: Stop or reduce doses, use hematopoetic growth factors.
Renal toxicity: Amethopterin, BCNU, carboplatin, CCNU, methyl
CCNU, cisplatin, mitomycin C, nephrotoxocity, and streptozotocin.
Treatment: Stop medication or reduce dosage.
Anaphylaxis: L-Asparaginase, bleomycin, and VP-16.
Treatment: Epinephrine, steroids
Cardiac injury: Cyclophosphamide, daunorubicin, doxorubicin, 5fluorouracil, and novantrone.
Treatment: Stop drug. Supportive care with diuretics, digitalis (not
very effective). Limit total dosage of medications (e.g., 450mg/m 2
doxorubicin).
Dermatitis:

Amethopterin,

bleomycin,

5-fluorouracil,

hexamethylmelamine, hydroxyurea, mitotane, and procarbazine.


Treatment: (1) Stop drug
(2) 25-50mg benadryl PO every 6 hours for itching.
(3} Topical agents for itching, and glucocorticoid creams
or ointments.
Fever: Bleomycin, cytosine arabinoside, interferon, mithramycin,
mitomycin C, and mitotone.
Treatment: (1) Stop drug
(2) Premedicate with acetaminophen
Syndrome inappropriate antidiuretic hormone: Cyclophosphamdie,
vinblastine, vincristine.
Treatment: (1) Stop medication
(2) Fluid restriction.7

CONCLUSION
Despite

20 years of active investigation, the role of

chemotherapy for head neck malignancies remains largely undefied


and continues to be an area for active investigation.

Clearly, for

patients with recurrent and metastatic disease, palliation can be


achieve, with single agents methotrexate being the standard for SCC
H&N.
Primary chemotherapy still remains largely experimental, except
for patients with advanced respectable SCC H&N, new combinations
that can achieve greater than 50% complete response rtes with
acceptable toxicity remain the goal. The concurrent use of
chemotherapy and radiation appears promising with survival
advantages noted for patients with unrespectable SCC H&N. Organ
preservation without compromising survival has been noted for
advanced laryngeal primaries and is now under active investigation for
other sites of disease in the head and neck. The use of intra-arterial
chemotherapy may play a role in this regard, particularly for patients
with maxillary sinus tumors.
The area with the most promise is chemo-prevention, with the
retinoids showing an impact on reducing second primary aerodigestive
tract tumors.

New chemopreventive agents and analogues are

currently being developed, with combined chemopreventive agent


trails forthcoming. Continued emphasis must concurrently be placed
on smoking cessation along with these trials.The most effective way of
reducing mortality and morbidity from oral cancer is early diagnosis
followed by adequate treatment.20

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3. Alan Mitchell Kramer: The role of chemotherapy in head and
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4. Donna J. Glover: Radiation therapy and chemotherapy
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5. Dorr, Von Hoff: Cancer Chemotherapy hand book. II
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6. Eugene N. Myers, James Y. Suen: Cancer of the head and
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8. Goodman & Gilman : Chemotherapy of Neoplastic
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9. Kimio: Chemotherapy and oral malignancies, 2000.
10.Langer, J.D., J.M. Henk: Malignant tumors of the mouth,
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11.Lawrence, D.R., P.N. Bennet: Clinical pharmacology. Fifth
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