Principles of cancer

systemic therapy

dr. Dita Ria S., Sp.PD, M.Sc

Therapy of cancer (and not only...)
► local ► systemic
 surgery  chemotherapy
 radiotherapy
 hormonal therapy
 biological therapy
 Kinetika Sel dan
Transformasi Keganasan
 To understand how chemotherapy
works as a treatment, it is helpful
to understand the normal life cycle
of a cell in the body.
 All living tissue is composed of
cells. Cells grow and reproduce to
replace cells lost during injury or
normal "wear and tear." The cell
cycle is a series of steps that both
normal cells and cancer cells go
through in order to form new cells.
The cell cycle phases
are: resting (G0;
nothing is happening),
G1 (or gap 1; a
growth phase), S
(synthesis; the
replication of DNA
occurs), G2 (gap 2;
another growth
phase), and M
(mitosis; the actual
division from 1 cell
into 2).
 The Cell Cycle

G0 phase (resting stage): The cell has

not yet started to divide. Cells
spend much of their lives in this
phase. Depending on the type of cell,
G0 can last for a few hours to a
few years. When the cell is signaled
to reproduce, it moves into the G1
phase.
G1 phase: During this phase, the cell
starts making more proteins and
growing larger, so the new cells will
be of normal size. This phase lasts
about 18 to 30 hours.
S phase: In the S phase, the
chromosomes containing the genetic
code (DNA) are copied so that both of
the new cells formed will have
matching strands of DNA. This phase
lasts about 18 to 20 hours.
G2 phase: In the G2 phase, the cell
checks the DNA and prepares to start
splitting into 2 cells. It lasts from 2
to 10 hours.
M phase (mitosis): In this phase, which
lasts only 30 to 60 minutes, the cell
actually splits into 2 new cells.
 Cancer Chemotherapy
• After completion of mitosis, the resulting daughter cells have two
options:
• •(1) they can either enter G1 & repeat the cycle or
• •(2) they can go into G0 and not participate in the cell cycle.
• •Growth fraction - at any particular time some cells are going
through the cell cycle whereas other cells are resting.
• •The ratio of proliferating cells to cells in G0, is called the growth
fraction.
• •A tissue with a large percentage of proliferating cells & few
cells in G0 has a high growth fraction.
• •Conversely, a tissue composed of mostly of cells in G0 has a low
growth fraction.
Cell Cycle Specific (CCS) & Cell Cycle Non-
Specific Agents (CCNS)
 Log kill hypothesis
• According to the log-kill hypothesis,
chemotherapeutic agents kill a constant fraction of
cells (first order kinetics), rather than a specific
number of cells, after each dose

• 1. Solid cancer tumors - generally have a low growth

fraction thus respond poorly to chemotherapy & in
most cases need to be removed by surgery
• 2. Disseminated cancers- generally have a high
growth fraction & generally respond well to
chemotherapy
LIAQUAT NATIONAL HOSPITAL
Principles of cancer chemotherapy
Institute for postgraduate Medical Sciences

•Effects of various treatments on the cancer

cell burden:
LOG kill hypothesis
LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences
Chemotherapeutic Agents
• Cell Cycle Specific Drugs:

• Antimetabolites Effective for high

growth-fraction-
• Bleomycin peptide antibiotics malignancies,
such as
• Vinca alkaloids
hematologic
cancers.

• Cell Cycle non-Specific Drugs:

Effective for
• Alkylating agents both low-growth
• Antibiotics (Dactinomycin) (solid tumors)
and high growth
• Cisplatin fraction
malignancies
 Chemotherapy
– mechanism of action
► cycle/phase non-specific
 alkylating agents
► phase specific
 G1 phase  G2 phase
► L-asparaginase ► bleomycin

► steroids ► topo I inhibitors

 S phase  M phase
► antimetabolites ► Vinca alkaloids
► anthracyclins ► taxanes
► topo II inhibitors
 Chemotherapy - strategy
drug – used rarely
► single
► combination
 provides maximal cell kill within tolerable
toxicity
 provides broader range of coverage of resistant
cells in a heterogeneous tumor
 prevents/slows the development of resistant
cells
 Development
of combination chemotherapy
► drugs effective in particular tumor
► different mechanisms of action
► non-overlapping toxicity
► different patterns of resistance
► drugs used in their optimal dose and
schedule
► drugs given at consistent (as short as possible)
intervals
 Setting of use of systemic
therapy
► as a single modality
 radical/definitive
 palliative
► in combined (multimodality) therapy
 primary induction therapy
 before local treatment (induction, neoadjuvant)
 after local treatment (adjuvant)
 during local treatment (concomitant)
Multimodality therapy
 Multimodality therapy
► Terapi neoajuvan saat ini umumnya diberikan
pada pengobatan kanker anal, kandung kemih,
payudara, esofagus, larings, non small cell lung
cancer dan sarkoma osteogenik.

► Respon pengobatan dapat diukur dengan

perubahan obyektif dari ukuran tumor atau produk
tumor, masa ketahanan hidup & respon subyektif

► Tolak ukur keberhasilan pada kemoterapi ajuvan :

relaps free survival dan overall survival
 Multimodality therapy
 concomitant
 no delay of any treatment modality
 synergistic effect of various modalities

 increased toxicity
 need to modify doses of individual treatment
modalities
 Chemotherapy - indications
Neoplasms in Which Chemotherapy is the Primary
Therapeutic Modality for Localized Tumors
• Large cell lymphomas
• Burkitt's lymphoma
• Childhood and some adult stages of Hodgkin's disease
• Wilms' tumor
• Embryonal rhabdomyosarcoma
• Small cell lung cancer
• Central nervous system lymphomas
 Chemotherapy - indications
Neoplasms in Which Primary Chemotherapy Can
Allow for Less Mutilating Surgery

•Anal carcinoma
•Bladder carcinoma
•Breast cancer
•Laryngeal cancer
•Osteogenic sarcoma
•Soft tissue sarcomas
 Chemotherapy - indications
Neoplasms in Which Clinical Trials Indicate an
Expanding Role for Primary Chemotherapy in the
Future
•Non–small cell lung cancer
•Breast cancer
•Esophageal cancer
•Nasopharyngeal cancer
•Other cancers of the head and neck region
•Pancreatic cancer
•Gastric cancer
•Prostate cancer (hormones)
•Cervical carcinoma
 Chemotherapy - indications
Neoplasms in Which Chemotherapy May Be
Used for Metastases and/or Widespread Disease

•Embryonal carcinoma

•Choriocarcinoma

•Non-Hodgkin's lymphoma

•Leukemias (acute lymphoblastic leukemia, acute myeloid

leukemia)
Treatment of cancer – assessment of
response
► complete response (CR)

► partial response (PR)

► stable disease/no change (SD)

► progressive disease (PD)

Pola Sensitivitas Kanker Terhadap Kemoterapi

► Kelompok I : kanker dengan sitostatika

menghasilkan efek sitoreduktif yang cepat (sensitif
terhadap kemoterapi), ex : LLA pd anak, HL, NHL
tipe large B cell, kanker testis)

► Kelompok II : berespon baik pada awal namun

berubah menjadi refrakter terhadap kemo
berikutnya, ex : kanker payudara, small cell lung
cancer, kanker ovarium yang kambuh

► Kelompok III : tumor yang resisten terhadap

hampir semua kemoterapi, ex : melanoma maligna
 Chemosensitivity of tumors
► high  medium  low
ALL  ovarian cancer  NSCLC

Hodgkin’s  breast cancer  cervical cancer

disease  osteosarcoma  endometrial
NHL  head & neck cancer
testicular cancer  adult soft

cancer  multiple myeloma tissue sarcoma

 malignant
SCLC  bladder cancer
melanoma
Wilms’ tumor  colorectal cancer
 liver cancer
 pancreatic
cancer
 Faktor-faktor yang harus diperhatikan
dalam melakukan kemoterapi
► Pilihan rejimen pengobatan, Dosis, Cara
pemberian, Jadwal pemberian

► Faktor yang harus diperhatikan pada pasien 

usia, jenis kelamin, status sosioekonomi, status
gizi, status penampilan, sumsum tulang, fungsi
paru, hati, ginjal, jantung & penyakit penyerta

► Faktoryang berhubungan dengan tumor  jenis

dan derajat histologi, tumor primer atau
metastasis, lokasi metastasis, ukuran tumor, efusi
 Kontraindikasi
► Kontraindikasi absolut : penyakit terminal,
kehamilan trimester pertama, septikemia, koma

► Kontraindikasi relatif : bayi < 3 bulan, usia tua,

status penampilan buruk (<40), gagal organ
parah, metastasis otak, pasien tidak dapat datang
reguler, pasien tidak kooperatif, jenis tumor yang
resisten terhadap kemoterapi
LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences
Chemotherapeutic Agents
LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences
Chemotherapeutic Agents
1. Alkylating agents:

Cyclophosphamaide
Carboplatin
• Major interaction: Alkylation of DNA
Cisplatin • Binds to nucleophilic groups on various cell
Oxaliplatin
constituents. Including DNA
Dacarbazine
• These drugs react with carboxyl, sulfhydryl, amino,
hydroxyl, and phosphate groups of cellular
constituents.
• Primary DNA alkylation site: N7 position of guanine
(other sites as well)
• Major Toxicity: bone marrow suppression
LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences
Chemotherapeutic Agents
2. Antimetabolites:

5-Fluoro Uracil •Structurally related to normal compounds that

Gemcitabine exist within the cell.
Cyterabine
Methotrexate
•Interfere with the availability of normal purine or
pyrimidine nucleotide precursors, either by
inhibiting their synthesis or by competing with
them in DNA or RNA synthesis.

•Their maximal cytotoxic effects are in S-phase

and therefore are cell-cycle specific.
LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences
Chemotherapeutic Agents
3. Microtubule Inhibitors:
Vinca Alkaloids
Vincristine
Vinblastine
Vinorelbine • These are plant-derived substances .
Taxanes
Paclitaxel • Cause cytotoxicity by affecting the equilibrium
Docetaxel between the polymerized and depolymerized forms
of the microtubules.

• Vinca alkaloids inhibit microtubule polymerization

and increase microtubule disassembly. The mitotic
spindle apparatus is disrupted, and segregation of
chromosomes in metaphase is arrested.
LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences
Chemotherapeutic Agents
4. Antineoplastic Antibiotics:
Bleomycin
Doxorubicin
Dactinomycin • Interacts with DNA, leading to disruption of DNA
Daunorubicin function.
• Also Inhibit topoisomerases (I and II) and
produce free radicals.
• Cell-cycle nonspecific.

• Eg: Actinomycin D binds with double-stranded

DNA and blocks the action of RNA polymerase,
which prevents DNA transcription.
LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences
Chemotherapeutic Agents

Prednisone
5. Hormonal Agents:
Tamoxifen
Estrogens
• Commonly involves the use of glucocorticoids.
Flutamide • Direct antitumor effects are related to their
Nilutamide
Bicalutamide lympholytic properties;.
• Glucocorticoids can inhibit mitosis, RNA synthesis,
and protein synthesis in sensitive lymphocytes.
• Considered cell-cycle nonspecific .
• Resistance to a given glucocorticoid may develop
rapidly and typically extends to other
glucocorticoids.
 Hormono therapy
– mechanism of action
► hormone deprivation
removal of hormone producing tissue (ablation)
inhibition of hormone production
blocking of hormone receptors
► exogenous hormone treatment (additive
therapy)
 Hormonotherapy – indications

► breast cancer
► prostate cancer
► endometrial cancer
► renal cancer
► ovarin cancer
► cancer cachexia
Hormonotherapy of breast cancer
= estrogen depletion
► estrogen source ablation
castration (surgery or RT)
adrenalectomy
► removal or inhibition of gonadotropin action
hypophysectomy
LHRH agonists
danazol
progestagens
► estrogen receptor blocking
tamoxifen and other SERM
fulvestrant
► inhibition of peripheral estrogen synthesis
aromatase inhibitors
 Premenopausal
estrogen production
Gonadotrophins
a/LHRH (FSH + LH) Oestrogens

Ovary

Tamoxifen
Pituitary gland Adrenal
LHRH glands
(hypothalamus) Androgens Oestrogens

ACTH aromatase
inhibitors
Peripheral
ACTH = adrenocorticotrophic hormone; conversion
FSH = follicle-stimulating hormone;
LH = luteinising hormone;
(aromatase enzyme)
LHRH = LH-releasing hormone
 Methods of achieving ovarian
ablation

Surgical
Irradiation,
(oophorectomy)
Chemotherapy,
or Goserelin
 Response to hormonal therapy in relation to
estrogen and progesterone receptor expression
80

70

60

50

40

30

20

10

ER - + - +
PR
- - + +
Clark, 1984
Hormonotherapy – past and present

► 1896– Beatson: oophorectomy causes

remission of breast cancer in young women
► ER/PgR – first predictive factors in oncology
► low toxicity long term use
 advanced disease
 adjuvant treatment of early disease
 chemoprevention
Prostate cancer – hormonal
therapy
► estrogens

► orchidectomy

► androgen receptor antagonists

► LHRH agonists (medical castration)

► „total androgen blockage”

LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences
Chemotherapeutic Agents
6. Monoclonal Antibodies:

Rituximab • Antibodies that are made in the lab rather than

Trastuzumab by a person's own immune system.
Cetuximab
Bevacizumab
• Directed at specific targets and often have fewer
adverse effects.

• Designed to recognise and find specific

abnormal proteins on cancer cells.

• Each monoclonal antibody recognizes one

particular protein.
LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences
Chemotherapeutic Agents

• Three types of monoclonal A-bodies:

Rituximab
Trastuzumab
Cetuximab 1. Trigger the immune system to attack and kill cancer
Bevacizumab
cells. E.g. Rituximab (Mabthera)

2. Stop cancer cells from taking up proteins

E.g. Trastuzumab (Herceptin).

3. Carry cancer drugs or radiation to directly to cancer

cells These are called conjugated MABs.
E.g. Ibritumomab (Zevalin)
 Chemotherapy – toxicity
► myelosuppression

► immunosuppression

► nausea/vomiting

► alopecia

► mucositis

► diarrhea
HEMATOPOIETIC SYSTEM

 Myelosuppression- depression
of bone marrow function,
resulting in decreased
production of blood cells.
- Decreases the number of RBCs
(anemia), WBCs (leukopenia) and
platelets (thrombocytopenia)
Colony-stimulating factor:
 G-CSF (granulocyte-colony
stimulating factor)
 GM-CSF (granulocyte
macrophage colony-stimulating
factor)
 EPO (erythropoietin)
GASTROINTESTINAL SYSTEM
 can cause irritation which can
eventually lead to inflammation
of the mouth, a condition known
as stomatitis .
 A stinging sensation in the
throat may develop and lead to
dysphagia (difficulty in
swallowing).
Management:
 Good oral hygiene
 Nausea & Vomiting- most
common side effects of
chemotherapy and may
persist for as long as 24-
48 hrs. after its
administration.
 Mucositis – inflammation
of the mucosal lining
 Diarrhea can also be a side effect
of chemotherapy. Caused by the
destruction of normal, dividing
cells of the gastrointestinal (GI)
tract, diarrhea varies from
patient to patient. It is better
managed if treated early

RENAL SYSTEM
 Rapid tumor cell lysis- increased
urinary excretion of uric acid,
which can cause renal damage
SKIN
 Alopecia
 Hair loss occurs because
chemotherapy can sometimes
damage healthy cells.
 It is so common because hair
follicle cells multiply very
quickly like cancer cells and
chemotherapy drugs have
difficulty in discerning the
difference.
REPRODUCTIVE SYSTEM
 take effective
contraceptive
precautions when
having chemotherapy,
as the chemotherapy
drugs might harm the
baby if pregnancy
occurs.
 In some women, chemotherapy brings
on an early menopause. This may cause
symptoms such as dryness of the
vagina and a decreased interest in
sex.
NEUROLOGIC SYSTEM
 Peripheral neuropathies
 Loss of deep tendon reflexes
 Paralytic ileus

MISCELLANEOUS
 Fatigue
 Alopecia
LIAQUAT NATIONAL HOSPITAL
Institute for postgraduate Medical Sciences