Describe the general principles of cancer chemotherapy including the cell cycle, log kill hypothesis, combination therapy, resistance and toxicity.

Cell Cycle and Drug Classification

• Cell cycle specific (CCS) agents kill only cells in a particular phase; they are most effective against rapidly proliferating tumours, and their effect is schedule-dependent — prolonged infusion or divided doses expose more cells as they pass through the sensitive phase
• Cell cycle non-specific (CCNS) agents — alkylating agents, platinum compounds, anthracyclines, nitrosoureas — act on cells in any phase including G0; their effect is dose-dependent, so large intermittent doses are used

The Log Kill Hypothesis

A given dose of a drug kills a constant fraction of tumour cells, not a constant number → So a dose reducing the population by 99.9% (3 logs) takes 1010 cells to 107 → The same next dose takes 107 to 104 → Cells regrow between cycles, so each cycle starts from a higher number than the previous one ended → Cure therefore requires repeated cycles continued beyond apparent remission, until the last clonogenic cell is eliminated → Since one surviving cell can restore the tumour, treatment continues after the tumour is undetectable

Principles of Combination Chemotherapy

• Each drug must be active alone against the tumour
• Different mechanisms of action, to attack several targets at once
• Non-overlapping toxicity, so each can be given at full dose — the central practical principle. Combining two myelosuppressive drugs forces both doses down
• No cross-resistance between the agents
• Given at optimal dose and schedule, with intervals just long enough for normal marrow to recover
• Classic examples — ABVD (Hodgkin lymphoma), chop (non-Hodgkin lymphoma), FOLFOX (colorectal), BEP (testicular)

Mechanisms of Resistance

General Toxicity of Chemotherapy

• The therapeutic index is narrow because these drugs target proliferation, and normal tissues that proliferate rapidly are hit alongside the tumour — bone marrow, gut mucosa, hair follicles, skin, and germ cells
• Myelosuppression — the dose-limiting toxicity of most agents; the nadir is typically 7 to 14 days with recovery by 21 days, which sets the cycle length. Causes neutropenic sepsis, anaemia and thrombocytopenia
• Gastrointestinal — nausea and vomiting, mucositis, diarrhoea, anorexia
• Alopecia — reversible, but of great importance to patients
• Gonadal — infertility and premature menopause; gamete storage should be discussed before treatment
• Teratogenicity — effective contraception is essential
• Second malignancy — particularly acute leukaemia after alkylating agents and etoposide, appearing years later; a real cost of cure
• Tumour lysis syndrome — hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia with acute renal failure, in rapidly responding bulky tumours; prevented by hydration and allopurinol or rasburicase

Adjuvant, Neoadjuvant and Palliative Intent

Applied Aspects

• Chemotherapy prescriptions must be checked independently and the dose calculated by body surface area; errors are catastrophic and are a recognised cause of death
• Vincristine must never be given intrathecally — it causes an ascending paralysis that is almost invariably fatal. It is dispensed in a minibag labelled "for intravenous use only", and never at the same time as an intrathecal drug
• Neutropenic fever is an emergency — broad-spectrum antibiotics within an hour, before the source is known
• Extravasation of a vesicant (anthracyclines, vinca alkaloids) causes severe tissue necrosis; central venous access is used where possible, and specific antidotes exist
• Discuss fertility preservation and contraception before starting; the opportunity is lost once treatment begins
• Cost and access shape oncology practice in India; generic and biosimilar production has made many regimens affordable, and India supplies much of the world with affordable cancer drugs
• Reduce doses for renal and hepatic impairment according to the drug's route of elimination; failure to do so is a common source of severe toxicity
• Assess performance status before treating; a patient too frail to tolerate chemotherapy is harmed rather than helped by it, and this judgement matters more than the histology
• Explain the intent clearly — curative, adjuvant or palliative; patients and families frequently assume cure is intended when it is not, and decisions about toxicity cannot be shared without that understanding
• Dose intensity matters in curative regimens, and unnecessary dose reductions or delays reduce the chance of cure; growth factor support exists partly to avoid them