CANCER CHEMOTHERAPY

Outline

- INTRODUCTION: Defs, History, Routes, Cell cycle, Tumour kinetics

- TREATMENT STRATEGIES
- CLASSIFICATION
- PRINCIPLE: Preparation for chemotherapy, principles of combination
- RESPONSE MONITORING
- PERFORMANCE MONITORING
- RESISTANCE
- COMPLICATIONS
- FUTURE TRENDS

Intro

- Neoplasia: an abnormal mass of tissue, whose growth is un-coordinated and exceeds that of
normal tissue, and persists in the same excessive manner after cessation of the stimuli that
evoked the growth.
o Neoplasia literally means ‘’new growth”
o Tumour: aka neoplasm.
o Neoplasia/Tumour can be benign or malignant
- Oncology (Greek oncos = tumour) is the study of tumours or neoplasms. 
- Cancer is the common term for all malignant tumours (derived from the latin word for crab)
- Hallmark of malignant transformation:
o Abnormal cell characteristics: Pleomorphism; Hyperchromasia; frequent/atypical
mitosis; loss of polarity; tumour giant cells; Necrosis
o Invasion and metastasis
- Cancers are caused by interaction between genetic susceptibility and environmental toxins
- Worldwide Cancer is responsible for 1 in 8 deaths
- Modern cancer therapy is multidisciplinary. Modalities include loco-regional therapy
(surgery and radiotherapy) and systemic therapy (chemotherapy, immunotherapy, targeted
therapy)
- Cell cycle
o Cell cycle refers to the process through which a cell divides
o Lasts for 18-24 hrs (generation time). The generation time is the time taken to
complete one cell cycle.
 G1- 2-8hrs (but variable)
 S-phase: 8-30hrs
 G2 phase: 1-2hrs
 M- phase: 0.5-2hrs
 Thus, the generation time depends on the G1 phase since the S and G2
phases are relatively fixed
o Cell cycle starts at end of mitosis
o Stages include G1, S, G2 and M stages. G0 is not a part of the growth/cell cycle
 o G1 – interval between mitosis & DNA synthesis. RNA and protein synthesis take
place at this phase. Cells that are committed to divide enter this phase during which
there is synthesis of RNA and protein in preparation for the DNA synthesis that will
take place during the next (S) phase of the cell cycle. It is the 1 st resting phase. Lasts
for 2-8hrs
o S – DNA synthesis and replication of the genome occur. The genome becomes
tetraploid. Many anti-chemotherapeutic agents are S-phase specific, due to fact that
a high proportion of cancer cells are in S-phase. Lasts for 8-30hrs
o G2 – refers to the period between DNA synthesis and mitosis. RNA and protein
synthesis takes place with consequent formation of enzymes and factors that are
needed for mitosis. It is the second resting phase prior to mitosis. Lasts for 1-2hrs
o M – Mitosis. Refers to the process by which the 2 identical sets of chromosomes
produced in S-phase are divided into each of 2 daughter cells. Lasts for 0.5-2hrs
(shortest)
o G0: Quiescent phase. Eg 1. Fully differentiated cells (hepatocytes, neurons). 2.
Resting cells (mature lymphocytes)
- Tumour growth kinetics
o In most instances, tumour becomes detectable when there is at least 1billion (10 9)
cells (1gram/1cm size) while death can result when the tumor has 10 12 cells
o Skipper’s law: based on observations of the growth of a murine leukemia cell line in
mice. Laws are:
 Doubling time of a given cancer cell (or mass of cancer cells) is constant
 Percentage of tumour cells killed by a drug is constant
o Mendelsohn in 1960 modified skipper’s law by saying his postulates apply not to the
entire tumor mass, but only to the fraction of tumor cells in the growth cycle
o Cells within tumours consist of 3 subgroups
 Non-dividing terminally differentiated
 Continually proliferating
 Resting cells
o Tumour growth depends on:
 Growth fraction: refers to the proportion of a mass of tumour cells that are
in the cell cycle (as opposed to G0). Growth fraction ranges from < 10% in
slow-growing tumors (eg low grade astrocytoma) to 70-90% in fast growing
tumors (eg Burkitt’s lymphoma). Since chemotherapy has greatest efficacy
against cycling cell, high growth fraction leads to increase chemosensitivity
while low growth fraction implies reduced chemosensitivity
 Tumour doubling time
 Rate of cell loss due to immune system’s activity, tumour shedding,
apoptosis and necrosis
o Models of tumour growth
 Gompertzian kinetics: suggests that unimpeded exponential growth of a
small tumour eventually leads to a plateau phase of slow growth and
functionally stable cell population size when the tumour becomes large
 
Exponential growth of a small tumour is because a small tumor
receives an adequate supply of oxygen and nutrients (by direct
diffusion, and from adjacent or newly developed blood vessels)
 The subsequent slower growth of a large tumor is because in a large
tumor, cells at the centre cannot remain viable with simple diffusion
of nutrients. Blood vessel growth is also not commensurate with
tumor growth. Thus nutrient and oxygen supply is diminished. The
starved and hypoxic cells drop out of the cell cycle and become
quiescent or die. The growth fraction of the tumor is smaller, and
the growth rate of the tumor slows down because of this
 It is an important principle in guiding treatment of malignancies:
many chemotherapy protocols are based on the fact that smaller
tumours respond better to chemotherapy (because they have a
higher growth fraction, thus a higher percentage of cells susceptible
to chemotherapy)
 Skipper-schabel
 Molecular beam epitaxy
o Most chemotherapeutic agents act on cells in the S-phase in order to inhibit DNA
synthesis
o Chemotherapy acts more on fast-growing tumors (tumors with high growth fractions
and short generation time)

Modalities for Rx of Cancer

- Loco-regional
o Surgery
o Radiotherapy
- Systemic
o Chemotherapy: Neo-adjuvant and adjuvant
o Hormonal therapy
o Immunotherapy
o Targeted therapy

CHEMOTHERAPY

- Cancer chemotherapy: refers to the treatment of cancer with one or more cytotoxic anti-
neoplastic drugs
- The word chemotherapy was traditionally used to encompass any chemical treatment of
disease (eg the use of antimicrobial agents in treatment of infections. However, this use has
become archaic)
- History of cancer chemotherapy:
o Mustard gas was incidentally discovered to cause myelosuppression during World
War 1.
o Nitrogen mustards (similar family to mustard gas) were then studied after the war;
which led to its use in patients with lymphoma in December 1942 with some
success.
- Routes of administration of anticancer drugs:
o IV, Oral, IM, SC, Topical
o Intrathecal, intraventricular in meningeal metastases from leukemia, lymphoma,
breast CA etc
o Intra-arterial in liver cancer
o Isolated limb perfusion in melanoma
o Intraperitoneal in ovarian cancer, colorectal ca, mesothelioma
o Intrapericardial: in malignant pericardial effusions
- Types of Chemotherapy
o Neoadjuvant Vs adjuvant
 Neoadjuvant chemotherapy: refers to chemotherapy given before definitive
management is done which aims to shrink the tumor and make it amenable
to other treatments or make those other local treatments (surgery or
radiotherapy) less destructive
 Adjuvant chemotherapy: refers to the chemotherapy given after
surgery/radiotherapy has been done and there is little evidence of cancer
present, but there is risk of recurrence. It targets the micro-metastasis in the
circulation
o Palliative or Curative chemotherapy:
 Palliative chemotherapy: use of chemotherapy without curative intent but
to decrease tumour load and increase life expectancy
o Combination VS monochemotherapy
 Combination chemotherapy is preferred. This is because chemotherapy
destroys cells by 1st order kinetics (with administration of the drug, a
constant percentage of cells is killed, not a constant number of cells).
Combination thus provides: Maximal cell kill, Broader range of coverage,
Prevents or delay drug resistance
 Drug selection
 Drugs known to be active as single agents usually are selected
 Drugs with different mechanisms of action are combined to allow
for additive or synergistic effects
 Combining cell-cycle–specific and cell-cycle–non specific agents may
be especially advantageous
 Drugs with differing dose-limiting toxic effects are combined to
allow for each drug to be given at therapeutic doses
 Drugs with different patterns of resistance are combined whenever
possible to minimize cross-resistance
- Uses of chemotherapy
o Killing of neoplastic cells
o Treatment of other non-neoplastic conditions such as crohn’s disease, multiple
sclerosis, psoriasis, rheumatoid arthritis, ankylosing spondylitis and scleroderma
- Chemotherapy acts by killing rapidly dividing cells. This means that apart from killing cancer
cells that are rapidly dividing, it also attacks normal body cells that are rapidly dividing such
 as bone marrow cells, GI mucosa and hair follicles. This leads to side effects such as
myelosuppression, mucositis and alopecia

Classification of Chemotherapeutic agents

- Based on: Structure, Mechanism of action and Site of action on the cell cycle
- Structure and mechanism of action
o Alkylating agents
 They act by covalent bonds formed between their alkyl groups and nucleic
acid of DNA, thereby impeding DNA replication
 They inhibit DNA replication by forming cross-linkages with DNA and inhibit
un-winding
 Sub-classified as follows:
 Nitrogen mustards (chloroethyl amines): cyclophosphamide,
ifosphamide, chlorambucil, melphalan, mechlorethamine, thiotepa
(ovarian and breast CA), busulfan (CML only)
 Nitrosoureas:
o Carmustine, lomustine, semustine: they cross BBB, so used
for brain tumours
o Streptozocin: pancreatic CA, NHL
 Related compounds
o Platinum compounds: Cisplatin, Carboplatin, oxaliplatin.
They are heavy platinum metal complexes which acts like
alkylating agents. They cause severe nausea and vomiting
with bone marrow suppression
o Dacarbazin, Procarbazin
 Cyclophosphamide: a pro-drug activated by liver cytochrome P450 enzymes
into its active form (phosphoramide mustard and acrolein). Acrolein causes
haemorhagic cystitis which is Rx by N-acetylcystein (which neutralizes
acrolein) or mesna (Na-2-mercapto-ethane sulphonate)

o Antimetabolites
 They form fraudulent nucleotides (they masquerade as nucleotides-purines
& pyrimidines), thereby preventing the normal nucleotides (purines and
pyrimidines) from becoming incorporated into DNA in the S-phase of the cell
cycle. Nucleic acid/DNA synthesis is thus inhibited
 They can also inhibit RNA synthesis
 Sub-classified as follows:
 Folic acid antagonists: methotrexate
 Pyrimidine antagonists: 5-FU, Cytosine Arabinoside (cytarabine),
Gemcitabine
 Purine antagonists: 6-mercaptopurine (6-MP), 6-thioguanine (6-TG),
fludarabine, cladribine, pentostatin, azathiopine
 o Methotrexate: inhibits dihydrofolate reductase, (the enzyme
responsible for reduction of folic acid to tetrahydrofolic
acid), leading to reduced availability of folate. Folate is
needed for thymidylate and purine synthesis.
 It is given with leucovorin (folinic acid/citrovorum
factor) which provides a substrate for thymidine
synthesis, thereby limiting the side effects of the
drug
o 5-FU: inhibits thymidylate synthetase, the enzyme that
converts deoxyuridine to thymidylate which is necessary in
nucleic acid synthesis. 5-FU is a pro-drug, which is converted
to its active metabolite (5-deoxy uridylate) within the cell
o Capecitabine (xeloda): an oral prodrug, a fluoropyrimidine
carbamate that achieves higher intratumoral 5-FU
concentration because it is enzymatically converted to 5-FU
within tumour cells. It also has lower systemic toxicity than
IV 5-FU
 It is 1st converted into two inactive precursors in the
liver (5-deoxy-5-fluorocytidine and 5-deoxy-5-
fluorouridine-5-DFCR & 5-DFUR). These inactive
precursors are then converted by thymidine
phosphorylase enzyme into 5-FU within the tumor
cells. Thymidine phosphorylase is found only in
tumor cells, thus the systemic side effects of
capecitabine is less
 Dose: 2.5g/m2/day in 2DD for 14days, then 7 days
rest after which the drug is repeated
 Use:
 Metastatic colorectal CA
 Metastatic Breast cancer: used with
docetaxel after failure of anthracycline-
based Rx
 Side effects: hand and foot syndrome (numbness,
tingling and painful swelling of the hand and feet
which can be severe enough as to cause the finger
prints to disappear in some patients)
o Cytarabine: inhibits DNA polymerase
o Gemcitabine: a cytarabine analogue. Inhibits ribo-nucleotide
reductase. Used for Rx of NSC lung CA and pancreatic CA.
1g/m2. Causes an influenza-like syndrome
o Cytotoxic Antibiotics
 They are derived from microbial origin (streptomyces, a soil fungus)
 They include
 Anthracyclines:
 o They intercalate between adjacent DNA, thereby generating
free O2 radicals and also alters ion transport across
membranes
o Adriamycin (Doxorubicin), Epirubicin, Daunorubicin,
Idarubicin, Mitoxantrone
o Lifetime dosage of doxorubicin: 550mg/m 2
 Chromomycins: Dactinomycin, Plicamycin
 Miscellaneous: Bleomycin, mitomycin
o Bleomycin
 It also oxidizes DNA-bleomycin-Fe complex, forming
free radicals that induce damage and chromosomal
aberrations
 Causes skin atrophy (75-100% of cases), skin
pigmentation, interstitial pulmonary fibrosis (if
cumulative dose of 200mg/m2 is exceeded) and
mucositis. It does not cause bone marrow
suppression
 They act by
 Inhibiting DNA/RNA synthesis by intercalating between base pairs of
the DNA/RNA strand, thus preventing cell division
 Inhibiting topoisomerase II enzyme, thereby preventing the
relaxation of the super-coiled DNA, thus preventing DNA
transcription and replication
 Creates iron-mediated free oxygen radicals which damage DNA,
proteins and cell membranes
 They are cardiotoxic, which is irreversible, cumulative and dose-dependent.
 An irreversible cardiomyopathy develops when the cumulative dose
exceeds 550mg/m2
 The cardiotoxicity is due to the intercalation between actin and myosin of
cardiac muscle and the O2-radical mediated damage to cell membranes
(which is catalysed by a doxorubicin-iron complex)
 The cardiotoxicity is Rx/prevented by:
 Staying below the lifetime cumulative dose of 550mg/m 2
 Use of dexrazoxane (which is a chelating agent that acts by
removing the iron from the doxorubicin-iron complex)
 Cardiac monitoring at 3,6 and 9 months
 Use of liposomal preparations of doxorubicin: the liposomal
formulations are less cardiotoxic because a lower proportion of drug
administered in liposomal form is delivered to the heart
 Administration of doxorubicin over longer infusion rates: this results
in a reduced plasma -+level and a lower left ventricular peak
concentration
o Vinca (plant) alkaloids
  They inhibit assembly of tubulin into microtubules, thus blocking spindle
formation, leading to mitotic arrest at metaphase.
 Eg vincristine, vinblastine, vindesine, vinorelbine, vinflunine
o Taxanes
 They cause over-stabilization of the microtubules, thereby inhibiting
disassembly of the microtubules.
 They thus prevent separation of the chromosomes during anaphase
 Vesicles, organelles such as secretory granules, and mitochondria
cannot move from one part of the cell to another. Because of their
stabilization, the microtubules cannot form mitotic spindles which
move the chromosomes in mitosis. The cell therefore ultimately dies
 Eg paclitaxel, docetaxel, cabazitaxel, lorataxel, ortataxel, tasetaxel
o Podophyllotoxins
 Eg Etoposide, Teniposide
 Prevents the cell from entering the G1 phase of the cell cycle. Also prevents
DNA replication during the S-phase of the cell cycle
 Inhibits topoisomerase II which results in DNA damage
o Topoisomerase inhibitors
 Topoisomerases are enzymes essential for maintaining the topology of DNA
 Inhibition of type I or II topoisomerases interferes with both transcription
and replication of DNA by upsetting proper DNA super coiling
 Topoisomerase I inhibitors: Camptothecins e.g irinotecan, topotecan
 Topoisomerase II inhibitors: etoposide, teniposide
- Classification based on site of action on the cell cycle
o Cell cycle specific: destroys cells only when they are dividing
 Phase specific
 S-phase dependent: methotrexate, 5-FU, cytarabine, capecitabine,
doxorubicin/adriamycin
 M-phase dependent: vinca alkaloids, taxanes
 G2 phase dependent: irinotecan, bleomycin
 Phase non specific eg Alkylating agents
o Cell cycle non-specific: destroys cells that are not actively dividing

Other modalities for Rx CA

a. Hormonal therapy:
- Hormonal therapy refers to the use of hormonal manipulation in the eradication of cancer
cells that arise from hormonally responsive tissues
- They also influence synthetic processes which convert RNA to protein.
- Classified as follows
o Surgical or Medical
 Medical is sub-classified into steroidal and non-steroidal
o Additive or Ablative
 Ablative: surgical removal or radiation induced destruction of a particular
endocrine organ
 Additive: exogenous hormone added to another modality of Rx
 o Reversible or irreversible

- Surgical hormonal therapy

o Ablation of the organ producing the hormone eg bilateral total orchidectomy,
adrenalectomy, hypophysectomy
- Medical hormonal therapy
o Anti-oestrogens: tamoxifen (non-steroidal, agonist-antagonist), fulvestrane
(steroidal, pure antagonist), nafoxiden, clomiphene
o Selective aromatase inhibitors (SAIs):
 Reversible, non-steroidal SAI: Anastrozole, letrozole
 Irreversible, steroidal SAI: exemestane, formestane
o Anti-androgens: flutamide, 5a reductase inhibitors
o Gonodotropin releasing hormone analogues: goserelin, leuprolide
o Others: Aminoglutetimide, Oestrogens, Progestins, Corticosteroids

- Tamoxifen
o A non-steroidal agent that has agonist-antagonist properties on the oestrogen
receptor
o Uses
 Rx of breast cancer in both pre- and post-menopausal women, though more
efficacious in post-menopausal women
 Prophylaxis of invasive breast cancer in high risk women.
o Mechanism of action
 It binds the estrogen receptors in the cancer cells, thereby inhibiting the
uptake of estrogens by the cancer cells which they need for their growth
 Causes breast epithelial cells to rest in the Go phase of the cell cycle
 Inhibits angiogenesis thereby aiding its effect on apoptosis of tumor.
 Reduces the level of circulating insulin-like growth factor which stimulates
growth and spread of malignant cells.
 It stimulates fibroblasts to produce TGF-B which acts in a paracrine manner
to stimulate fibroblast proliferation
o It is more efficacious in ER+/PR+ tumors, but there will be response to its use in 10%
of ER- tumours
o Taken for 5 years at a dose of 20mg/day
o Toxic effects include hot flushes, nipple pigmentation, fluid retention and over a long
period liver, endometrial, colorectal and gastric cancer, hypercalcaemia and vaginal
bleeding.
- Fulvestrane (Fasodex)
o A steroidal pure anti-oestrogen
o MOA
 It binds to the oestrogen receptors and prevents dimerization of the
oestrogen receptor and DNA binding to the oestrogen receptor.
 They also degrade the receptor proteins.
o It is given IM once every month.
o Used as 2nd line hormonal treatment after tamoxifen relapse instead of selective
aromatase inhibitors (SAl).

- Selective Aromatase inhibitors

 o They inhibit aromatase, the enzyme that catalyzes the conversion of
androstenedione to oestrone and peripheral conversion of testosterone to
oestradiol. (Thus, they do not interfere with the production of corticosteroids)
o They therefore prevent the production of oestrogens by peripheral (non-ovarian)
tissues especially adipose tissues
o They are used as second line drugs in ER+/PR+ breast cancer, especially in post-
menopausal women.
o They are sub-classified as follows:
 Reversible, non-steroidal SAI: Anastrozole, letrozole
 Irreversible, steroidal SAI: exemestane, formestane

o Anastrozole: a non-steroidal, reversible inhibitor of aromatase enzyme, the enzyme

which catalyzes the peripheral conversion of androstenedione to oestrone and of
testosterone to oestradiol. It may be used in postmenopausal or oophorectomized
patients who have relapsed during tamoxifen therapy. The dose is 1mg daily. Side
effects include somnolence, headaches, hot flushes, vaginal dryness, hair thinning,
vomiting and diarrhea.

- Flutamide
o It is a non-steroidal anti-androgen which inhibits androgen uptake in target tissues.
o Used in combination with goserelin acetate in the treatment of metastatic
carcinoma of the prostate.
o Its dose is 250mg orally 3x a day
o Side effects include hot flushes, loss of libido, impotence, nausea, vomiting and
diarrhea.

- Gonadotrophin Releasing Hormones (LHRH) analogues eg Goserelin

o Goserelin is a synthetic analogue of LHRH and inhibits gonadotrophin secretion
within 4 weeks when given continuously. Androgen and oestrogen secretion is
thereby suppressed.
o The dose is 1mg daily S.C. or depot injection of 3.6mg S.C monthly.
o Indicated in prostate and breast carcinomas.
o Side-effects include fluid retention, paraesthesia, hot flushes, impotence, rash,
alopecia, fever and erythema at the injection site.

- Others
o Aminoglutetimide (Trade name- Cytadren)
 Mechanism of action
 It blocks steroid production in the adrenal gland by blocking the
conversion of cholesterol to pregnenolone (by blocking the
cytochrome P450 desmolase enzyme), thereby inhibiting synthesis
of cortisone, oestrogens and androstenedione (a form of medical
adrenalectomy).
 It inhibits aromatase enzyme, thereby preventing conversion of
androstenedione to testosterone
 Used in breast and adrenal carcinomas. Also used in Cushing’s syndrome
 The dose is 750-1000mg/day with steroid replacement. Doses up to 2g/day
may be needed in the suppression of adrenal tumours .
 Toxic effects are somnolence, agranulocytosis, lethargy, ataxia, blurred
vision, hepatotoxicity, orthostatic hypotension and skin rash.
 o Oestrogens eg DES
 They are used in breast CA in post-menopausal women and men and also in
prostatic cancer
 Cause a pituitary mediated anti-prolactin effect in breast CA and anti-
interstitial cell hormone in CAP
 Toxic effects include fluid retention, thromboembolism, hypercalcaemia,
feminization and loss of libido in male and uterine bleeding in females
o Progestins
 Examples are medroxyprogesterone acetate (depo provera) and megestrol
acetate.
 They have anti-oestrogen, anti-prolactin, anti-androgen and anti-
gonadotrophin effects and reduce the oestrogen and progesterone
receptors. They therefore have a direct cytotoxic effect on breast cancer.
 They are used in breast cancer and endometrial cancer.
 Side-effects are weight gain, moon face and breakthrough vaginal bleeding.

o Anti-prolactin
 CB 154, L-Dopa, and CG 603 used in advanced breast CA
o Corticosteroids
 Corticosteroids have anti-tumor activity in lympho-proliferative disorders
and breast cancer. They are most effective when they form part of
combination chemotherapy.
 They are also beneficial in controlling some of the complications of cancer
e.g hypercalcaemia, increased intracranial pressure from brain metastases
and the complication of auto-immune haemolytic anaemia that
accompanies some of the lymphoid neoplasms.
 Dexamethasone and prednisolone are the ones commonly used.
 The dose is dependent on the effect anticipated i.e. anti-tumor activity or
control of the complication of neoplastic disorder.
 The long-term complications include hyperglycaemia, osteoporosis,
hypertension, sodium retention, psychosis and adrenal atrophy

b. Immunotherapy
- Aims to induce or potentiate intrinsic (inherent) anti-tumor immunity that can destroy
cancer cells
o The value of immune defenses in CA has been demonstrated by
 High incidence of cancers in immunosuppressed patients eg post-transplant
patients, HIV
 Spontaneous cancer regression (though a rare occurrence)

- Immunotherapy is better able to destroy very small qty of malignant cells, usually in sub-
clinical forms after completion of other therapies. They can be specific or non-specific
o Non-specific: stimulates general immune mechanisms. BCG, levamisole, cytokines,
retinoids
o Specific
 Active – anti-tumour vaccines
 Adaptive: transfusion of some sensitized or immunized cytotoxic cells
  Passive – antibodies to specific tumour associated antigen eg anti-
lymphocytes serum in leukemia

- BCG: melanoma, bladder CA, intra-pleural injection post-pneumonectomy for lung CA

- Levamisole: an antihelminthic drug which has immune-regulating activity against some
tumour cells. It is currently used in adjuvant therapy for large bowel cancer in combination
with 5-FU. The dose is 50mg 8-hourly for 72h, repeated every 2-3weeks for one year. Side-
effects are leucopoenia and dermatitis.
- Cytokines
o Interleukin-2 (IL-2): it enhances the activity of tumor specific T-cell and NK-cells.
Used in Rx of melanoma, renal cell carcinoma, non-Hodgkin's lymphoma and
neuroblastoma. The dosage is 200-800ug/m2/day as three 5-day courses. Side-
effects include fever, thrombocytopenia, hypotension, fluid retention and
pulmonary edema.
o Interferon:
 Interferons are proteins that enhance immunity by increasing NK-
lymphocyte activity and causing the re-expression of HLA genes which are
sometimes lost during neoplastic transformation.
 Types
 Alpha: produced by leukocytes
 Beta: produced by fibroblasts
 Gamma: produced by Ag or mitogen lymphocytes
 Used in Rx of chronic granulocytic leukaemia, hairy cell leukaemia, multiple
myeloma, Kaposi's sarcoma, NHL, RCC, lung CA and breast CA.
 The dose is 3 mega units I.M or S.C daily for at least 12months.
 Adverse effects include flu-like symptoms, alopecia, depression, abnormal
liver function test and cytopenias.
o Retinoids: they are non-toxic chemical modifications of pre-formed vitamin A. Used
in BCC, malignant melanoma and actinic keratoses

c. Targeted therapy
- Targeted therapy exploits the molecular difference between normal cells and cancer cells to
block the growth of tumor by interfering with specific molecules, genes or proteins that are
expressed by cancer cells and essential for their growth
o Usually directed at the processes involved in tumour growth rather than killing all
rapidly dividing cells
- Protein kinases (eg tyrosine kinase) are at the forefront as attractive therapeutic targets
- Sub-groups of major targeted therapy agents
o Inhibitors of growth factor receptors
o Inhibitors of intracellular signal transduction
o Cell-cycle inhibitors
o Apoptosis-based therapies
o Anti-angiogenic compounds
- Types
o Small molecules: imatinib, gefitinib, erlotinib, bortezonib
 They target the epidermal growth factor receptors (EGFR) in tumors that
have over expression of EGFR. Over expression of EGFR leads to excessive
activation of the apoptotic RAS signal transduction cascade. This results in
uncontrollable excessive growth and proliferation of the cancer cells.
  Gefitinib or Erlotinib binds to the ATP kinase binding site of the EGFR,
thereby inhibiting EGFR tyrosine kinase and so the Ras signal transduction
cascade. The growth of the cancer cells is accordingly inhibited. Both drugs
are efficacious in non-small cell lung cancer.
 Imatinib mesylate (Gleevec or STI-571): used for chronic myelogenous
leukaemia, gastrointestinal stromal rumours and dermatofibrosarcoma
protuberans. Targets the bcr-abl gene (Philadelphia xsome)
 Bortezonib: used for multiple myeloma unresponsive to current treatment.
o Monoclonal antibodies: trastuzumab, rituximab, bevacizumab
 They are tumor-specific monoclonal antibodies which selectively kill
neoplastic cells without harming normal host cells.
 Can also be used for targeted radio-immunotherapy of residual disease and
radio-iodine labeled monoclonal antibody has been used in neuroblastoma
with some success.
 Trastuzumab (Herceptin): monoclonal Ab against HER-2/neu receptor
positive breast CA. Can be used in combination with paclitaxel. Loading dose
is 4mg/kg by i.v. infusion over 90minutes followed by weekly doses
of2mg/kg i. v infusion over 30 minutes. Given after adjuvant chemotherapy
for one year at weekly or 3-weekly intervals, it significantly improves
disease-free survival
 Rituximab (Mabthera): This is an anti-CD-20 monoclonal Ab which has anti-
tumor activity in CD20+ B cell non-Hodgkin's lymphomas (used in
combination with CHOP-cyclophosphamide, daunorubicin Hydrochloride,
Oncovin/vincristine, Prednisolone). Its dose is 375mg/m 2 intravenously given
weekly for 4 weeks.
 Bevacizumab (Avastin): it counteracts VEGF. (VEGF is essential for the
induction and maintenance of angiogenesis needed for growth and
development). Used for colorectal CA, non-small cell lung cancer, sarcoma,
used with interferons for metastatic clear cell renal cancer.
 Cetuximab: targets and inhibits the EGF receptors. Used for colorectal and
non-small cell lung carcinomas.

d. Supportive therapy: refers to the non-specific symptomatic measures used to control the
primary complications of cancer. Include blood transfusion to correct anemia, nutritional
rehabilitation for malnutrition (cancer cachexia), analgesics, antibiotics, terminal care
measures

Preparation for chemotherapy (Principle of Chemotherapy)

- Established indication, with clinical and histologic confirmation of malignancy

o Detailed patient evaluation in order to stage and accurately define extent of disease,
detect concurrent disease and identify paraneoplastic syndromes
- Counsel the patient, together with close family members such as the spouse. Appreciate the
patient 's anxieties and apprehension; and instill hope and confidence in the patient
o Explain the nature of illness, side effect profile of the medications, duration of Rx
and expectations from Rx
o Goals of treatment must be clearly defined; cure vs palliation, acceptable toxicity,
quality of life
 o Introduce to other individuals with similar illness, and care support groups. This is a
morale-booster for the patient
o Where two or more Rx options are possible, the pros and cons of each should be
explained and a joint decision taken.
- Assess for fitness of the patient and ability to withstand the drugs
o Performance status
o Clinical evaluation: pallor, dehydration, etc
o Weight: calculate the appropriate dosage, based on BSA of the patient
 BSA= 4n+7/n+90
 BSA= ⇃weight X Height/3600
 Nomograms can be used, which make use of the weight and height of the
patient
o Ensure adequate hydration
o Laboratory
 FBC: PCV > 30%, WBC > 4,000 (or absolute neutrophil count < 1000),
Platelets > 150,000
 E/U/Cr
 LFT
 Tumour markers
 Urinalysis
 ECG: before giving anthracyclines
- Appropriate drug selection (decide on regimen)
o Drugs, dose
o Combination cyclic; single agent
- Drug administration
o Drug should be used at their optimal dose and schedule.
o Dilute the drugs appropriately to prevent thrombophlebitis
o Use a large vein
o Give appropriate pre-medication
 Anti-emetics: Ondasetron, Granisetron, Metochlopramide
 Give allopurinol and alkalinize the urine in order to prevent tumour lysis
syndrome in patients with tumours expected to lyse rapidly
- Repeat the cycle at a consistent time interval as indicated, while ensuring that the treatment
free period is as short as possible to allow for recovery of the most sensitive normal tissues
- Before each dose:
o Ensure FBC and other investigations are adequate before repeating each cycle
o Assess tumour response before each dose, and document as appropriate
 WHO
 RECIST (Response Evaluation Criteria in Solid Tumours)
 Objective response: change in longest diameter of target lesion(s)
 Complete Response: complete disappearance of all target lesions
confirmed 4 or more weeks after treatment
 Partial Response: >30% decrease from baseline at more than 4
weeks
  Progressive disease: >20% increase in size or appearance of new
lesions
 Stable disease: neither PR nor PD
o Assess the patient’s quality of life and performance status, so as to be able to
determine whether the patient is fit enough to withstand the chemotherapy.
Popular instruments in oncology include:
 Karnofsky performance index; ranges from 100%(normal) to 0%(death)
 Eastern Cooperative Oncology Group (ECOG)
 Ranges from 0(asymptomatic) to 5 (death)
 0. Fully active, able to carry on all pre-disease performance without
restriction
 1. Restricted in physically strenuous activity but ambulatory and
able to carry out work of a light or sedentary nature, eg light
housework, office work
 2. Ambulatory and capable of all seIf care but unable to carry out
any work activities; up and about more than 50% of waking hours
 3. Capable of only limited self-care, confined to bed or chair,
requires assistance more than 50% of waking hours
 4. Completely disabled; cannot carry on any self-care; totally
confined to bed or chair
 5. Dead
- Patient care after chemotherapy
o Follow-up for evidence of recurrence and development of 2 nd cancers
o Manage long term complications of the disease and chemotherapy

Resistance to Chemotherapy

- Primary resistance: when the cancer does not respond to standard chemotherapy from the
first exposure
- Acquired resistance: when the tumor initially responds then become resistant
- Cellular and biochemical mechanisms
o Decreased drug accumulation
 Decreased drug influx
 Increased drug efflux: P-glycoprotein may actively pump the drug out of the
cancer cell
 Over-expression of adenosine triphosphate-binding cassette (ABC)
transporter proteins at the cancer cell membrane, principally in the
liver, kidneys and GIT, are normally responsible for excreting toxic
substances from the cells by efflux/influx at the cell membrane and
also act as blood-brain and blood-testis barriers.
 About 40 such ABC transporter proteins have been described, the
best studied being P-glycoprotein. They excrete drugs and other
proteins from the cell by an efflux pump. Cancers with over
expression of the ABC transporter proteins have chemoresistance to
 anthracyclins, taxanes, vinca alkaloids, methotrexate, cisplatin,
mitoxantrone etc.
 About 41% of breast cancers express P-glycoprotein and are three
times more likely to be chemo-resistant.
 Altered intracellular trafficking of drug
o Decreased drug activation
o Increased inactivation of drug or toxic intermediate
o Increased repair of drug-induced damage to DNA, Protein and Membranes
o Alteration of drug targets (quantitatively or qualitatively)
o Alteration of cofactor or metabolite levels
o Alteration of gene expression
 DNA mutation, amplification, or deletion
 Altered transcription, post-transcription processing or translation
 Altered stability of macromolecules
 Dys-regulation or inactivation of apoptosis: apoptosis of cells is mediated by
p53, the protein produced by the gene p53. P53 is also a nuclear
transcription factor which activates a protein that causes slowing or arrest of
the cell cycle temporarily or permanently and permits repair of mutations
and other defects of the DNA. Mutation of p53 or inactivation is involved in
the induction of >50% of cancers. Apoptolic dysregulation or inactivation is
responsible for chemoresistance of cytotoxic drugs such as the anti-
metabolites, which cause cell death through apoptosis.
 BCL-2 is an anti-apoptotic protein and its over-expression enhances chemo-
resistance.
 Tumours with normal p53 (ie the wild p53) and low levels of BCL-2 should be
expected to respond to cytotoxic chemotherapy.
- 3. Activation of Nuclear Factor - kB transcription or
- sinilar transcription factor in the cancer cell.
- 4. Cancer stem cells.

3. Nuclear Factor - kB (NF -kB) regula tion

The several protein heterodimers of the family of NF-kB
when activated, initiate transcription of several genes affecting
inflammation, tissue repair, and cell survival and death. NFkB
is inhibited in the cell by IkB but phosphorylat ion ofUill by
IkE kinase activates it resulting in induction of anti-a pop to tic
proteins and suppression of pro-apoptotic genes resulting in the genesis and progression of tumors.
Some cytotoxic agents eg. doxorubicin, taxanes v inca
alkaloids, cisplatin can activate NF-kB in the cancer cells
leading to its translocation and induction of the larget genes.
The tumour cells are thus able, through enhanced NF-kB, to
resist the action of the drugs. Activated NF-kB also inhibits p53
and promotes anti-apoptotic proteins eg. BCL-2 thereby cnhancing
tumour cell survival and chemoresistance.
It is established that NF-kB inh ibition by target drugs
enhances the efficacy of cytotoxic drugs .
4. Cancer stem cells
It appears that some cancers have a small population of
cancer stem cells which di fferentiate, proliferate and produce
daughter cells. These stem cells, which are no rmally quiescent,
have a high expression of ABC transporters, can repair
DNA and resist apoptosis. They therefore resist the action of
aptotoxicdrugs.
Prediction of response to cytotoxic drugs
It would be desirable to know wh ich cancers are likely to
respond to cytotoxic chemotherapy and thc type of drug to use.
Some biomarkers have been srudicd especially in relaton to
breast cancer but the result have not been rewarding. Breast
cancer with the epidermal growth facto r! , HER-2/neumarker,
however, respond if the humanised murine monoclonal antibody,
herceptin, is added to the cytotoxic drugs.
Tumour type and diffe rentiatio n have not shown predictive
value. The value of Ki67 which indicates tumour proliferation
has not been established.
The apoptotoxic gcnes p53, BCL-2 and BAX are also not
helpful. In breast cancer, it was thought that ER negative rumours responded benerto chemotherapy
than ER + ones. But
it appears this is not so.
Genomic technology is currently being used to investigac
- tumourchemoresponsiveness. Results are awaited

Complications of Chemotherapy

- The most common medications affect mainly the fast-dividing cells of the body
- Gastrointestinal: nausea, vomiting, mucositis, diarrhoea, constipation, malnutrition
- Hematological: anaemia, leucopenia, thrombocytopenia
- Integument: alopecia, hyperpigmentation, nail changes
- Neurological: peripheral neuropathy, loss of deep tendon reflexes, paralytic ileus, confusion,
loss of interest: vincristine is a common cause of these
- Ototoxicity: platinum compounds
- Cardiac toxicity: anthracyclines, cyclophosphamide
- Pulmonary toxicity: bleomycin, busulfan
- Nephrotoxicity: platinum compounds
- Bladder toxicity: cyclophosphamide. Haemorhagic cystitis: caused by cyclophosphamide and
ifosphamide.
o Both are pro-drugs activated by liver cytochrome P450 enzymes into their active
form (phosphoramide mustard and acrolein).
o Acrolein causes haemorhagic cystitis
o It is Rx by N-acetylcystein (which neutralizes acrolein) or mesna (Na-2-mercapto-
ethane sulphonate)
- Endocrine: infertility, irregular menses, amenorrhoea
- Fluid retention (from capillary leak): it is dose dependent and may lead to peripheral edema,
pleural effusion and weight gain.
- Second tumours: alkylating agents, procarbazine, topoisomerase inhibitors
- Acute tumor lysis syndrome:
o Refers to the biochemical (metabolic) disturbance characterized by hyperkalemia,
hyperuricemia, hyperphosphatemia & hypocalcemia which occur due to rapid
destruction of tumor cells with subsequent synchronized massive release of cellular
 breakdown products that is sufficient to overwhelm both excretory mechanisms and
the body’s normal capacity to re-utilize such products
 Hyperkalemia: can cause sudden death
 Hyperuricemia: can cause urate nephropathy
 Hyperphosphataemia: can cause nephrocalcinosis & ARF
o A common complication following effective therapy of fast growing tumours such as
lymphomas and leukemias; though can sometimes occur without Rx
o The risks of developing the condition are associated with
 Sensitivity of the tumor to the Rx modality
 Disease bulk or clinical stage
 Renal function
 Serum lactate dehydrogenase levels
o Prevention: adequate hydration to maintain renal perfusion, urine alkalinization,
allopurinol to promote purine excretion without urate nephropathy

Prevention/Rx of complications

- Myelosuppression:
o Anemia: hematinics without folic acid, transfusion, recombinant erythropoietin
o Neutropenia: recombinant G-CSF & GM-CSF
o Thrombocytopenia:
 Platelet concentrate
 Recombinant human thrombopoietin
 IL-11: a growth factor which also has effect in reducing chemotherapy-
induced thrombocytopenia.
- Nausea/Vomiting:
o Metochlorpramide
o 5-HT3 receptor inhibitors e.g Ondasetron- 8-32mg/day oral or IV, Granisetron,
Tropisetron 5mg
o IV Phenergan or dexamethasone
- Haemorrhagic cystitis: caused by cyclophosphamide and ifosphamide. Prevented by
adequate hydration and mesna (a short-acting sulfhydryl compound given orally or IV). It
may give false positive result for urinary ketones.
- Secondary cancer: careful follow-up
- Hypercalcemia: tumor-induced hypercalcaemia frequently accompanies bone metastases.
o Biphosphonates such as pamidronate and clodronate inhibit osteoclast induced
bone resorption and normalize plasma calcium between 3-7 days following initiation
of treatment. The dose of pamidronate is 30-90mg given as a 2-h intravenous
infusion.
o Gallium nitrate; Calcitonin (8u/kg IM 6 hourly for 2-3days): reserved for patients
who do not respond to two scheduled infusions of pamidronate
o Mithramycin: reserved for patients without thrombocytopenia or significant renal or
hepatic dysfunction
- Supportive treatments:
o Addition of leucovorin to increase the total amount of anti-metabolites that can be
given to patients
 The leucovorin (folinic acid/citrovorum factor) provides a substrate for
thymidine synthesis, thereby limiting the side effects of the drug
 o Colony stimulating factors and erythropoietin can be used to supplement high dose
chemotherapy

New/Future trends

- Isolated infusion approaches: aims to deliver a high dose of chemotherapy to the site of
tumor without causing overwhelming systemic damage
o Isolated limb perfusion: used in melanoma
o Isolated infusion of chemotherapy into the liver or the lung
- Targeted delivery mechanisms: specially targeted delivery vehicles aim to increase effective
levels of chemotherapy for tumor cells while reducing effective levels for other cells
- Nanoparticles: vehicle for poorly soluble agents. E.g abraxane (nab-paclitaxel) uses human
albumin to increase the solubility of paclitaxel. Nano particles made of magnetic material
can be used to concentrate agents at the tumour site using an externally applied magnetic
field
- Electro-chemotherapy: combined treatment in which injection of a chemotherapeutic drug
is followed by application of high-voltage electric pulses locally to the tumor

Conclusion

- Though the management of cancer is multidisciplinary, the surgeon must not only know the
techniques for performing a cancer operation but also the alternatives to surgery such as
chemotherapy
- Chemotherapy is an important modality in systemic cancer therapy