CANCER CHEMOTHERAPY

The goals of chemotherapy To eliminate neoplastic cells in the body without permanently damaging the normal host cells To achieve remission induction in cancer patients

The goals of chemotherapy(CONTD)

CURE
CONTROL PALLIATION

TUMOUR KINETICS
Tumors usually arise from clonal proliferation of abnormal cells. Determinants of tumor growth are Generation time Growth fraction

GENERATION TIME/CELL CYCLE

G2 (RNA + PROTEIN SYNTHESIS)

S PHASE DNA SYNTHESIS Gi
(RNA + PROTEIN SYNTHESIS)

MITOSIS

GO

Shorter generation time, better response to chemotherapy

GROWTH FRACTION
The portion of the cells in a tumor proliferating at a particular given time. The higher the growth fraction, theoretically the better response to chemotherapy

CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

BASED ON

STRUCTURE MODE OF ACTION

SITE OF ACTION

CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

Antineoplastic drugs may be classified according to their effects on the cell cycle.
Cell cycle specific / Phase specific eg alkylating agents Non cell cycle specific eg Steriods , antitumor antibiotics

CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

Antimetabolites Folic Acid Antagonists Methotrexate 5 Fluorouracid Purine Antagonists 6 Mercaptopurine

ALKYLATING AGENTS
Cyclophosphamide
Thio TEPA (Triethylene thio phosphoramide)

ANTIBIOTICS
Actinomycin D
Adriamycin Epirubicin

VINCA ALKALOIDS
Vincristine
Vinblastine Vinorelbine

Podophyllotoxins
Etoposide
Teniposide

Inhibit cells from entering the G1 and the S phase of the cell cycle

Platinum Compounds
Cisplatin
Carboplatin Oxaliplatin (Alkylating agents)

STEROID / NON STEROIDAL SYSTEMIC THERAPY

Anti-androgens Flutamide Eostrogens Anti-oestrogens Tamoxifen Anastrazole Aminogluthemide

Topoisomerase inhibitors
Irinotecan

(Inhibits DNA synthesis and replication)

Biological response modifiers

Non-specific immunomodulators eg Levamisole, BCG, Cimetidine
Lymphokines and Cytokines

Antitumor therapy

Biological agents
EGFR tyrosine kinase inhibitors
VEGF inhibitor

ROUTES OF ADMINISTRATION
Oral Intravenous Intra-aterial Intracavitary Subcutaneous Topical Intraperitoneal Others

PATIENT EVALUATION AND STAGING

HISTOLOGICAL DIAGNOSIS ACCURATE STAGING OF THE EXTENT OF THE DISEASE EVALUATION OF CONCURENT DISEASES OTHERS CBC, SERUM E&U, LFT , IMAGING TECHNIQUES

SINGLE AGENT VS COMBINATION THERAPY

AVOID DRUGS WITH SIMILAR TOXICITY USE DRUGS WITH DIFFERENT MECHANISMS OF ACTION THERAPUETIC DOSES SHOULD BE USED

RESPONSE TO CHEMOTHERAPY
SKIPPER-SCHABEL MODEL Ie d------t then dz-------------zt GOMPERTZ MODEL Resulting in a group of stable cells

RESPONSE TO CHEMOTHERAPY

OBJECTIVE RESPONSE COMPLETE RESPONSE PARTIAL RESPONSE STABLE DISEASE PROGRESSIVE DISEASE

Resistance to Chemotherapy
Pharmakokinetic resistance .i.e The drug concentration is too low to kill the cells. Eg altered rates of absorption, distribution or delivery
Cytokinetic resistance. Eg dormant cells, dose limiting drug toxicity and the inability to achieve a 100% kill. Resistance via biochemical modification eg multidrug resistant amplification gene which eliminates all structurally unrelated substances out of the cell.

SOME CONCEPTS IN CHEMOTHERAPY

Fractional kill hypothesis
3Log kill : 1 Log regrowth

COMPLICATIONS OF CHEMOTHERAPY

Gastrointestinal compliocations
Nausea, vommiting, anorexia, mucositis,eosophagitis

Hematological
Aneamia, Leukopenia; Thrombocytopenia

Skin
Alopesia, darkening of skin and appendages

Neural
Neuropathy

Pulmonary, Nephrologic, Pulmonary and Cardiotoxicity

DOSE MODIFICATION IN DRUG TOXICITY

DOSAGE MODIFICATIONS Dose Levels for Toxicities Agent Dose Level +1 Dose Level Irinotecan 180 mg/m2 180 mg/m2 Folinic Acid*) 400 mg/m2 400 mg/m2 FLUOROURACIL BOLUS 400 mg/m2 400 mg/m2 FLUOROURACIL INFUSION 3000 mg/m2 2400 mg/m2

Dose Level 1 Dose Level2 Dose Level 3 150 mg/m2 120 mg/m2 Discontinue Therapy 400 mg/m2 400 mg/m2 Discontinue Therapy 320 mg/m2 240 mg/m2 Discontinue Therapy 2000 mg/m2 1600 mg/m2 Discontinue Therapy

EMERGENCIES IN CHEMOTHERAPY
TUMOR LYSIS SYNDROME Ie Rapid destruction of tumor cells leading to massive release of intrcellular cellular breakdown products eg uric acid, calcium phosphate and free radicals

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