Principles of Cancer Pharmacology

Cancer pharmacology is the use of cytotoxic, hormonal, targeted and immune-directed drugs to kill or restrain malignant cells while sparing normal tissue as far as the narrow therapeutic index allows. Treatment intent decides everything else: curative, adjuvant (after local treatment to remove micrometastases), neoadjuvant (before local treatment), or palliative (control of symptoms and survival gain with acceptable toxicity).

Growth kinetics. Tumours grow in a Gompertzian pattern: the growth fraction is highest when the tumour is small. Small-volume disease is therefore the most responsive, which is why adjuvant treatment works and why late bulky disease responds poorly.

Fractional cell kill. Each cycle of a drug kills a constant fraction of cells, not a constant number. A cycle that gives a 3-log kill from 10^9 cells leaves 10^6 cells, and regrowth between cycles erodes the gain. Cure needs eradication of the last clonogenic cell, so cycles are repeated at the shortest interval marrow recovery allows.

Resistance. Spontaneous mutation produces resistant clones (the somatic mutation model); the chance of resistance rises with tumour size. Mechanisms include drug efflux (P-glycoprotein), reduced uptake, increased DNA repair, target mutation, drug inactivation and altered apoptosis.

Combination therapy. Combinations use drugs with proven single-agent activity, different mechanisms, non-overlapping dose-limiting toxicities, and different resistance mechanisms, given at full dose on a set schedule.

Dose intensity. Delivered dose each unit of time determines outcome in chemosensitive tumours (lymphoma, germ cell tumour, breast cancer, leukaemia). Reductions of more than 15 to 20 percent under the planned dose intensity can lower cure rates, so supportive care is used to preserve dose when cure is the goal.

• Cytotoxic drugs: alkylating agents, platinum compounds, antimetabolites, anthracyclines and antitumour antibiotics, topoisomerase inhibitors, vinca alkaloids and taxanes.
• Hormonal drugs: oestrogen receptor modulators and degraders, aromatase inhibitors, androgen deprivation, antiandrogens, GnRH analogues.
• Targeted small molecules: tyrosine kinase inhibitors, PARP inhibitors, CDK4 and CDK6 inhibitors, BRAF and MEK inhibitors, proteasome inhibitors.
• Monoclonal antibodies and conjugates: anti-CD20, anti-HER2, anti-EGFR, anti-VEGF, antibody drug conjugates.
• Immune therapies: checkpoint inhibitors, immunomodulatory drugs, cellular therapy.

Differences. Cytotoxic drugs act on dividing cells and cause predictable marrow, mucosal, hair follicle and gonadal toxicity. Targeted and immune drugs need a biomarker or tumour type and cause a different set of effects (rash, hypertension, autoimmunity).

• Before treatment: confirm histological diagnosis and stage; record performance status (ECOG 0 to 4; chemotherapy is usually avoided at 3 to 4 unless the tumour is very chemosensitive); check full blood count, creatinine and creatinine clearance, liver function, and pregnancy status.
• Screening before chemotherapy or biologics: hepatitis B surface antigen and core antibody (reactivation risk is highest with anti-CD20 antibodies and anthracycline regimens; give entecavir or tenofovir prophylaxis when positive), hepatitis C and HIV.
• Dosing: most cytotoxic drugs are dosed by body surface area (mg/m2); carboplatin by target area under the curve; some by weight (mg/kg). Use actual body weight in obese adults unless the intent is non-curative and toxicity is a concern; dose capping is not usual.
• Response: judged by imaging (RECIST criteria), tumour markers and symptoms after 2 to 3 cycles. Stop for progression or unacceptable toxicity.
• Toxicity grading: CTCAE grades 1 to 5; delay the next cycle until neutrophils are 1.0 x 10^9/L or more and platelets 75 to 100 x 10^9/L or more, and reduce the dose after febrile neutropenia or grade 3 to 4 non-haematological toxicity.
• Pharmacogenomics: DPYD variants (fluoropyrimidines), TPMT and NUDT15 (thiopurines), UGT1A1 (irinotecan), and CYP2D6 (tamoxifen) alter toxicity.

Regional points. Cancers presenting late, HIV-associated malignancies (Kaposi sarcoma, aggressive B-cell lymphoma, cervical cancer), Burkitt lymphoma and retinoblastoma are common in East Africa. Antiretroviral therapy is part of treatment in HIV-associated cancers; check interactions with ritonavir- and cobicistat-boosted regimens, which raise vinca alkaloid, taxane and kinase inhibitor levels. Drug supply gaps are common: plan whole regimens before the first cycle, and avoid starting a curative regimen that cannot be completed.

Contraindications. Pregnancy in the first trimester (avoid; second and third trimester treatment is sometimes given for life-threatening disease), uncontrolled sepsis, and severe organ dysfunction for the specific drug.

Adverse effects. Myelosuppression and febrile neutropenia, mucositis, nausea and vomiting, alopecia, infertility, extravasation injury, hypersensitivity, tumour lysis syndrome, secondary malignancy, and organ-specific toxicity.

Prescribing errors. Confusing mg and mg/m2; intrathecal administration of vinca alkaloids (fatal; vincristine must be given intravenously only and dispensed in a minibag); using vincristine at weekly rather than the planned interval; wrong dose rounding; methotrexate daily instead of weekly dosing; omission of mesna or folinic acid rescue; and dose calculation errors with carboplatin.

Special groups.

• Pregnancy: avoid in the first trimester; counsel on contraception during and after treatment.
• Breastfeeding: stop breastfeeding during cytotoxic therapy.
• Children: dose by surface area, with specialist regimens; long-term effects on growth, fertility and the heart.
• Older adults: use geriatric assessment, expect more neutropenia and neuropathy, and prefer dose-adjusted regimens.
• Kidney and liver impairment: reduce or avoid renally cleared drugs (methotrexate, cisplatin, carboplatin by creatinine clearance) and hepatically cleared drugs (vinca alkaloids, taxanes, anthracyclines by bilirubin).

Monitoring. Full blood count before each cycle and at the nadir for high-risk regimens, creatinine, electrolytes, liver function, weight, symptom and toxicity review each cycle, and cumulative dose tracking for anthracyclines, bleomycin and alkylating agents.

Referral and escalation. All treatment should be delivered by a team with oncology training. Fever of 38.0 degrees Celsius or more with neutropenia, uncontrolled vomiting, mucositis that prevents drinking, and extravasation need same-day assessment.