General Principles of

Cancer Chemotherapy
dr.Darmawan,M.Kes,Sp.PD

Chemotherapy

German chemist Paul Ehrlich- Coined

the term chemotherapy

Originally chemotherapy referred to

treatment of disease with drugs or chemical

but by mid 1950s the term was only being

used primarily in reference to drugs which
were used to treat cancer.

Cancer :

Diseases of cells that shows uncontrolled

proliferation , anaplsia, invasivness and
ability to metastasis .

Due to Chromosomal abnormality and

expression of oncogens .

Second most common cause of death after

cardiovascular disorders in world.

Current Treatment Modalities of Cancer

Surgery
Radiotherapy

For solid cancers

1/3 of patients can be cured,
Effective when tumor has not
metastasized

Chemotherapy, Immunotherapy, Gene therapy

Choice of therapy depends upon the
Location of tumour
Stage of tumour
General state of the patient.

Chemotherapy : Historical perspective

1943 - During World War II , soldiers

were exposed to nitrogen mustard
gas and shows marked depletion in
marrow and lymphoid cells.

Based on this finding, Alfred Gilman

and Louis Goodman from Yale
university used Nitrogen Mustard to
induced remission of Lymphoma in
mice.

Chemotherapy : Historical perspective

1948 - Sidney Farber showed that
aminopterin, a folic acid analogue,
developed by Y. Subbarao can induced
remission in acute lymphoblastic
leukemia.
Latter more safer amethopterin
( Methotrexate ) was developed.

Chemotherapy : Historical perspective

1950- Actinomycin D was developed as antibiotics, but found
to be very toxic but have significant antitumour activity
1951 - Hitchings and Elion isolated 6-thioquanine and 6mercaptopurine that inhibited purine metabolism, which are
widely used for various cancer and as immunosuppressant.

Chemotherapy : Historical perspective

1970s - Golden Age of medical oncology.

Development of effective combination chemotherapy
regimens.

New classes of drug developed - anthracyclines, platinum

compounds .

Cures achieved in some forms of cancer (lymphomas,

leukemias, testis cancer).

Significant responses in some common types of cancer (breast,

stomach, small cell lung cancer)

Effective use of chemotherapy to prevent recurrence in high risk

breast cancer patients.

Chemotherapy : Historical perspective

Scientist continue to look for the magic bullet to

eliminate cancer.

Nowdays research is being focused on specific agents

that interfere with cell division, as well as monoclonal
antibodies, biologic modifiers, gene therapies, etc.

Goals of chemotherapy
To Cure

Wilms tumor, ALL, Testicular

cancer, Burkitts lymphoma,
NHL

To Control

Prolong remission
Decreases rate of relapse

Palliation

Relive symptoms and

improved quality of life

Types of chemotherapy
1. Primary
Chemotherapy
Chemotherapy is main
modality of treatment
Can be single drug or
combination chemotherapy
e.g. Hematological
malignancy ABVD regimen for hodgkins
lymphoma.

2. Adjuvant
Chemotherapy
Combined with radiation or
surgery.
For advanced cancer
e.g. Ca breast After surgery
to remove microscopic foci.

Types of chemotherapy
3. Neoadjuvant
chemotherapy
Chemotherapy is given
before surgery.
Shrink a large cancerous
tumour to make surgery
easy.
e.g. laryngeal carcinoma
before surgery.

4. Concurrent
chemotherapy
Simultaneously with
Radiation.
mainly act as
radiation sensitizer, encoura
ges the cancer cells to take
radiotherapy.
e.g.Head and neck CA,
rectal CA, lung CA

Sensitivity of various tissues to

chemotherapy
High

Intermediate

Low

Lymphoma

Breast

Head and neck

Leukemia

Colon

Prostate

Small Cell Lung cancer Non-small cell lung

cancer

Gastric

Testicular cancer

Pancreatic

Basic concepts of cancer cell growth

Cell life cycle and drug
Log kill hypothesis
Growth fraction
Tumour burden

cell cycle and drugs

G1 L- Asparginase
S Methotrexate
6-Mercaptopurine
5-Fluorouracil
Mitomycin C
Hydroxyurea
Doxorubicin
G2 Bleomycin
Etoposide,
Topotecan
Daunorubicin
M Vincristine
Vinblastine
Paclitaxel,
Docetaxel

Log kill hypothesis

Cell kill by first order kinetics.

A constant fraction of cells are killed by a given drug

dose, not constant number.

A constant percentage of the total number of cancer

cells present in tumor will be killed with each course of
chemotherapy.

Hence repeated doses of chemotherapy must be used

for total cells kill.

1 log regrowth

Tumor regrowth after

premature Cessation of
Therapy.
3 log cell kill

Growth fraction
Growth fraction is the percentage of actively dividing cells at
any given point in time.
1.

High growth fraction tumour : more sensitive to cyclespecific drugs.

e.g. 1. leukemia and lymphoma
2. Normal with tissues high growth fraction like bone
marrow, hair follicles, and intestinal
2.

Low growth fraction tumour : Solid tumour e.g.

carcinomas of the colon, lung cancer) are less
responsive to cycle-specific drugs.

Tumour burden

The tumor burden is the size of the tumor as determined

by the number of cells present.

Small tumor burden more responsive

Higher the tumor burden probability of drug resistance.

Cancer cells usually follows Gompertzian growth pattern.

Gompertzian Growth

Gompertzian Growth
It is model of cancer cell growth.
Cell rapidly divide early in life, then plateaus.
Significance :
1. Most anticancer drugs are ineffective in advanced
cancers which have very low growth fraction.
2. Debulking procedures makes tumour again
responsive to drugs by inducing remaining cells to
divide.

Drugs Used in Cancer Chemotherapy

Alkylating Agents
Antimetabolites
Natural Agents
Antibiotics and
enzymes
Hormones and
antagonists
Miscellaneous
agents

e.g. Nitrogen mustards , Nitrourea

e.g. Folic acid analogue, Pyrimidine and
Purine analogue
e.g. Vinca alkaloid, Taxens, Tecans.
e.g. Dactinomycin, Daunorubicin , LAsparaginase
e.g. Progestins , Estrogen, GnRH, Antiestrogens
e.g. Hydroxyurea , Immunomodulators ,
Tyrosine kinase inhibitor, Biological
Response Modifiers ,monoclonal antibody

MOA of some anticancer drugs

Antimetabolites

Purine Synthesis

6-Mercaptopurine
6-Thioguanine
Methotrexate DHFR

Pyrimidine Synthesis

Ribonucleotides

Hydroxyurea
5-Fluorouracil
Cytarabine
Gemcitabine

Deoxyribonucleotides

Alkylating agents
Alkylation Alter
structure & function of
DNA by cross linking
and/or fragmenting DNA

DNA
Antibiotics

Etoposide
Topoisomerase II
Inhibitor- DNA break

RNA

L-Asparaginase

Proteins
Enzymes

Microtubules

Vinca Alkaloids
prevent polymerization
Taxens enhance
polymerization

Alkylating agents
CLASS

Nitrogen
Mustards

DRUGS
Meclorethamine

MAJOR USES

Melphalan

Multiple myeloma; breast, ovarian

cancer

Chlorambucil
Cyclophosphamide

ALL, CLL , HL, NHL,

Multiple myeloma; Neuroblastoma;
Breast, Ovary, Lung cancer;
Wilms tumor;
cervix, testis cancer;

Ifosfamide
Etylenimine
Alkyl sulfonteNitrosoureas

Triazine

ThioTEPA
Busulfan

HL, NHL

Bladder, breast, ovarian cancer

CML

Carmustine

Primary brain tumor;

Melanoma, HL,NHL,

Streptozocin

Pancreatic insulinoma;
Malignant carcinoid

Dacarbazine

Malignant melanoma;

Antimetabolites
CLASS
Folic acid
analogue

Pyrimidine
analogue

Purine analogue
and related
inhibitors

DRUGS

MAJOR USES

Methotrexate

ALL; choriocarcinoma breast,

head, Lung cancer; osteogenic
sarcoma; bladder ca

Pemetrexed

Mesothelioma, lung cancer

Fluorouracil
Capecitabine

Breast, colon, esophageal,

stomach cancer.

Cytarabine

AML, ALL, NHL

Gemcitabine

Pancreatic, ovarian, lung ca.

Mercaptopurine

AML, ALL

Pentostatin

Hairy cell leukaemia; CLL,

small cell NHL.

Fludarabine

CLL

Natural Agents
CLASS

DRUGS

MAJOR USES

Vinblastine

HL, NHL, Testis cancer

Vinorelbine

Non small cell lung cancer

Vincristine

ALL, Neuroblastoma;
Wilms tumor;

Taxanes

Paclitaxel,
Docetaxel

Metastatic ovarian, breast

ca.

Epipodophyllotoxins

Etoposide

Testicular tumour, lung

cancer ,HL, NHL

Camptothecins

Topotecan, Irinotecan

Ovarian cancer; small-cell

lung cancer; colon ca.

Vinca
alkaloids

Antibiotics and enzymes

CLASS

Antibiotics

Enzymes

DRUGS

MAJOR USES

Dactinomycin
(actinomycin D)

Choriocarcinoma; Wilms tumor;

Rhabdomyosarcoma

Daunorubicin

AML, ALL.

Doxorubicin

Soft-tissue, osteogenic, and other

sarcoma; HL, NHL , AML, ALL.
Breast, Genitourinary, Thyroid, lung,
stomach cancer; Neuroblastoma

Mitoxantrone

AML, breast and prostate cancer

Bleomycin

Testis, cervical cancer; HL, NHL

Mitomycin

Stomach, anal, and lung cancer

L-Asparaginase

ALL

Hormones and antagonists

CLASS

DRUGS

MAJOR USES

Glucocorticoides Prednisone

ALL, CLL, HL, breast cancer,

multiple myeloma

Progestins

Hydroxyprogesterone caproate,
Medoxyprogesterone
acetate, Megestrol acetate

Endometrial,
breast cancer

Estrogens

Diethylstilbestrol, Ethinyl
estradiol

Breast, prostate cancer

Anti-estrogens

Tamoxifen, Toremifene,

Breast cancer

Aromatase
inhibitors

Anastrozole, Letrozole,

Breast cancer

Androgens

Testosterone propionate

Breast cancer

Antiandrogen

Flutamide , casodex

Prostate cancer

GnRH analogue

Leuprolide

Prostate cancer

Miscellaneous agents
CLASS
Substituted urea

DRUGS

MAJOR USES

Hydroxyurea

CML ; Polycythemia vera;

Essential thrombocytosis

Differentiating agents Tretinoin,

Arsenic trioxide

Acute Promyelocytic Leukemia

Protein tyrosine
kinase inhibitor

Imatinib

CML, GIST

Gefitinib

Non-small-cell lung cancer

Sorafenib

Hepatocellular cancer,
Renal cancer

Proteasome inhibitor Bortezomib

Multiple myeloma

Immunomodulators

Thalidomide

Multiple myeloma

Lenalidomide

Myelodysplasia , multiple myeloma

Temsirolimus,
Everolimus

Renal cancer

mTOR Inhibitors

Miscellaneous agents
CLASS

DRUGS

Rituximab
Alemtuzumab

Hairy cell leukemia; Kaposis

sarcoma; Melanoma; carcinoid;
Renal cell; Ovary; Bladder;
Mycosis fungoides;
Multiple myeloma; NHL, CML
B-cell lymphoma and CLL
B-cell CLL and T-cell lymphoma

HER2/neu

Gemtuzumab
Trastuzumab

Acute Myelocytic Leukemia

Breast cancer

EGFR
VEGF

Cetuximab
Bevacizumab

colorectal, pancreatic, breast ca.

colorectal cancer

Biological
Response
Modifiers
CD20
CD52
CD33

Interferon-,
Interleukin 2

MAJOR USES

Dosage of chemotherapeutic agents

Dosage of chemotherapy are difficult: If the dose is too
low, it will be ineffective , whereas excessive causes
toxicity .
In most cases, the dose is adjusted for the patient's body
surface area (BSA), a measure that correlates with blood
volume.
The BSA is usually calculated with a mathematical formula
using a patient's weight and height, rather than by direct
measurement.
W is weight in kg, and
H is height in cm.

Standard doses doses in which anticipate side effect are

mild and no supportive therapy required

High dose therapy Increases in dosing amount, severe side

effects are present. Supportive therapy is essential.

Large amounts of free drug in the serum not only increase

efficacy of the drug but also facilitate penetration into the
tumour cells.
Example :
In AML , High-dose cytarabine (2000 to 3000 mg /m2 of BSA)
have higher rates of relapse-free survival than standard dose of
100 to 400 mg /m2.

Dose intensification (DI) higher than standard dose given

in short interval
Achieved by
1. Increasing the dose of the chemotherapy per cycle (dose
escalation)
2. Decreasing the time between the treatments (dose density)
Steep dose-response curve, meaning that relatively small
increases in the chemotherapy dose will have a substantial effect
on the number of tumor cells killed.

Principles of combination therapy

Combination therapy involves the use of two or more drugs
proven effective against a tumor type.
Major advances in cancer treatment in the past 20 years.
RATIONALE OF COMBINATION CHEMOTHERAPY
Prevention of resistant clones.

Cytotoxicity to resting and dividing cells.

Biochemical enhancement or effect

Synergistic effect

Combination therapy is superior to single-drug therapy in

terms of

Higher tumor response rates

Increased duration of remissions.

Minimal chances of resistance.

Principles for selecting drugs for

combination regimens
Active as single agents
Different mechanism of action
Different dose limiting toxicity
Used at optimal dose and schedule
Given at consistent interval
Different resistance mechanism
Drugs with known synergistic biochemical interaction
Cell kinetics scheduling: on basis of cell cycle specificity /
non specificity of drugs and phase of cycle at which drug
exert toxicity.

Examples of combination therapy

vinblastin

Important drug combinations

REGIMEN CANCER
ABVD
Hodgkin's
CHOP-R

NHL

VAMP

AML

FOLIFIRI

COLON
CANCER

DRUGS
Doxorubicin, Bleomycin, Vinblastine,
Dacarbazine
Cyclophosphamide,
Hydroxydaunorubicine, Vincristine,
Prednisolone, Rituximab
Vincristine, Amethopterine, 6 MP,
Prednisolone
5 FU, Leucovorin, Irinotecan,

WHO response scale to chemotherapy

1. Complete response disappearance of disease on
imaging test.
2. Partial response size decrease of 50% or more
from original tumor. No new lesions.
3. Stable disease less than 50% response without
actual progression of disease.
4. Disease progression 25% increase in the size of the
original tumor. Or new lesions developed.

Conditions when Cytotoxic

Chemotherapy may be withheld

Infection

Previous chemotherapy given < 2 weeks

Leukopenia and thrombocytopenia

Severely debilitated patients

Pregnancy (1st trimester)

Major surgery < 2 weeks

Poor patient follow-up

Psychological problems

Choice of chemotherapeutic agent

Not all patients can tolerate drugs, and not all drug regimens are
appropriate for a given patient.
Choice of drug depends on following factor
Tumour type
General performance status of patient
Renal and hepatic function
Bone marrow reserve
Concurrent medical problems
Patient's willingness
Patient's physical and emotional tolerance for side effects

2 major challenges
to Chemotherapy
1. Toxic side effects
2. Drug resistance

Resistance to chemotherapeutic agents

Resistance constitutes a lack of response to drug-induced tumour
growth inhibition
1. Primary resistance: No response from
very first exposure.
e.g. malignant melanoma, renal tumours.
2. Acquired resistance : During continuation
of therapy .
Due to adaption of tumour cells or due to mutation in one or
more gene.

Mechanism of resistance
1.

drug efflux via P-glycoprotein transporters e.g. doxorubicin, paclitaxel,

vincristine, etoposide

2.

Overexpression of the multidrug resistance protein 1(MRCP1)

resistance to natural drugs e.g. vinca alkaloid, anthracyclins .

3.

inward transport e.g. methotrexate

4.

Insufficient activation of the drug (e.g. mercaptopurine , fluorouracil and

cytarabine.

5.

Increase in inactivation (e.g. cytarabine and mercaptopurine )

6.

Increased concentration of target enzyme (methotrexate)

7.

Rapid repair of drug-induced lesions (alkylating agents).

8.

Altered activity of target proteins, for example modified topoisomerase II

(doxorubicin).

Overcoming resistance :

Use of combination drug therapy using different

classes of drugs with different mechanism of action.

With narrowest cycle intervals, necessary for bone

marrow recovery.

Drugs that reverse multidrug resistance include

verapamil, quinidine, and cyclosporine .

Toxicity
Rapidly multiplying cells
Nausea & Vomiting
Bone marrow depression
Alopecia
Gonads: Oligospermia, impotence, ovulation
Foetus: Abortion, foetal death, teratogenicity
Carcinogenicity
Hyperuricemia
Hazards to staff

Bone marrow suppression

Cause by almost all anticancer drugs except Bleomycin,
Vincristin and Asparginase.
Most serious toxicity and often limit dose of chemotherapy

Granulocytopenia
Agranulocytosis
Thrombocytopenia
Aplastic anemia
Lymphocytopenia
immunosppression

Complications :
Opportunistic infections
Bleeding

Drug causing severe

myelosuppression
Carmustin
Cytarabine
Daunorubicine
Paclitaxel
Alkylating agents
Antimetabolites

General toxicity of cytotoxic drugs

Dermatological toxicity

Drugs

Alopecia

Cyclophosphamide, Ifosfamide
Vincristin ,Methotrexate , Paclitaxel,

Local necrosis- extravasation

Dactinomycin, Doxorubicin, vinca alkaloid

Hyperpigmentation of skin

Gastrointestinal toxicity

Drugs

Nausea and vomiting

Carmustin,cisplatin,cyclophosphamide,dacarb
azine,cytarabine,lomustine,thiotepa

Stomatitis

Capecitabine,5
FU,methotrexate,mercaptopurine

Diarrhea

Irinotecan, 5FU

Constipation

Vincristine

Anorexia, taste change,etc

General toxicity of cytotoxic drugs

Toxicity

Drugs

Neuropathy

Oxaliplatin,Paclitaxel, Cytarabine,5FU,

Renal toxicity

Cisplatin, Ifosfamide, Methotrexate

Hemorrhagic cystitis

Cyclophosphamide, Ifosphamide

Hepatotoxicity

Asparginase, Cytarabine,
Mercaptopurine,Thioguanine, Methotrexate

Cardio toxicity

Daunorubicin, Doxorubicin,Epirubicine,
Mitoxantrone,Transtuzumab, Bevacizumab

Pulmonary toxicity

Bleomycin, Melphalan, Chlorambucil,

Busulphan,

Infertility

Alkylating agents

Hypersensitivity reaction

Asparginase, Platinum compound, etoposide

Toxicity amelioration and supportive

care
Drugs
Filgrastim (G-CSF)
Sargramostim (GM-CSF)

Amifostine
Oprelvekin (IL-11)
Thrombopoietin

1.
2.
3.
1.
2.

Use
Prevent neutropenia,
Increases neutrophil count,
prevent infection.
Cisplatin induced
nephrotoxicity,
Prevent radiation induced
xerostomia

1. Prevent thrombocytopenia

Toxicity amelioration and supportive

care
Drugs
Folinic acid
Mesna
Dexrazoxane
Ondansetron,
Dexamethaone, Lorazepam
Allopurinol,
Alkalization of urine
Hydration ,
Bisphosphonates

Use
Methotrexate toxicity
Cyclophosphamide induced
cystitis
Doxurubicine /Daunorubicine
cardiotoxicity
Vomiting
Hyperuricaemia
Hypercalcaemia

Current status and future trend of

chemotherapy
The practice of cancer medicine has changed dramatically
over the years from palliative curative.
e.g.
Wilms tumour, Ewing sarcoma, Choriocarcinoma, Hodgkins
disease, testicular cancer can be cured with chemotherapy.
Adjuvant chemotherapy and hormonal therapy can extend
life and prevent disease recurrence following surgical
resection of localized breast, colorectal, and lung cancers.

Current status and future trend of

chemotherapy
As part of multimodal treatment of locally advanced head
and neck, breast, lung, and esophageal cancers, thereby
allowing for more limited surgery and even cure in these
formerly incurable cases
Toxicities of Cytotoxic drugs have become more
manageable with the development of better supportive
therapy like G-CSF, IL-11 to restore bone marrow
function
Increasingly used in autoimmune diseases like rheumatoid
arthritis (methotrexate and cyclophosphamide), Crohn's
disease (6-mercaptopurine), organ transplantation
(methotrexate and azathioprine) etc.

Current status and future trend of

chemotherapy
Newer target molecules or monoclonal antibody are not
likely to replace cytotoxics in the future. Rather, both will be
used in combination.
e.g. For instance, monoclonal antibodies or small targeted
molecules, used as single agents against solid tumors,
produce low response rates and modest benefits; however,
in combination with cytotoxics they are dramatically
effective .

Bevacizumab plus irinotecan, fluorouracil, and leucovorin

(IFL) for metastatic colorectal cancer.
The median duration of survival was 20.3 months in the group given IFL plus
bevacizumab, as compared with 15.6 months in the group given IFL plus
placebo,

Molecular Testing to Select Patients for

Chemotherapy
Molecular tests are increasingly employed to identify patients likely
to benefit from treatment and those at highest risk of toxicity
Pre-treatment testing has become standard practice for following
tumours
1. Estrogen receptor breast cancer- transtuzumab
2. B cell non Hogdkins lymphoma- Rituximab (CD20)3. EGFR- for colorectal cancer- to use Cetuximab

Gene therapy : approaches for cancer

management

The future may see the development of agents which could

induce differentiation in tumour cells, rendering them nonneoplastic.

By inhibiting an abnormal oncogene product but not the

normal equivalent.

By using antisense oligonucleotides to

inhibit translation of an abnormal
oncogene messenger RNA.

By introducing MDR-1 gene into bone

marrow cells and rendering them
less susceptible to myelosuppressant
drugs.