Oncology-Chemotherapy: Cisplatin and its Analogues -

I. Cisplatin

A. Mechanism of Action:

• Cisplatin directly binds to DNA, forming intra-strand and inter-strand cross-links.
• This inhibits DNA synthesis by altering the DNA template. It acts as a bifunctional alkylating agent.
• Cytotoxic effects are cell cycle-independent.
• Synergistic effects with anti-metabolites are observed (mechanism not fully understood, possibly due to DNA repair malfunction).

B. Side Effects:

• Highly emetogenic (causes vomiting).
• Dose-dependent nephrotoxicity (kidney damage).
• Peripheral neuropathy (nerve damage).
• Ototoxicity (hearing damage, tinnitus).
• Can cause anaemia (low red blood cell count).
• Relatively low toxicity to white blood cells and platelets.

C. Dosage:

• Standard dose limit: 100 mg/m² as a single daily dose.
• Higher doses used in clinical trials, often with neuroprotective agents.
• Alternative schedules exist (e.g., five daily injections of 20 mg/m² for teratoma).
• Dosage based on empirical body surface area calculations; no clear pharmacokinetic/pharmacodynamic relationship.
• Clearance is rapid initially, then slower due to plasma protein binding. Prolonged in renal insufficiency.

D. Clinical Indications:

• Major advancement in testicular cancer treatment (80%+ complete response in metastatic disease).
• Used in ovarian cancer, genitourinary tumors, squamous carcinomas (head and neck, non-small-cell lung cancer).
• Frequently used in combination with other cytotoxic agents for various solid cancers and pediatric tumors.

II. Carboplatin

A. Overview:

• Cisplatin analogue with reduced toxicity compared to cisplatin.
• Clinically viable alternative to cisplatin in most situations, except for germ cell tumors where cisplatin may be preferred.
• Cross-resistance with cisplatin: patients resistant to one will likely be resistant to the other.

B. Side Effects:

• Significant: Thrombocytopenia (low platelet count), leucopenia (low white blood cell count) – both worse around day 14.
• Less Significant: Renal toxicity, neurological toxicity, otological toxicity, nausea and vomiting (occasional), mild alopecia (hair loss), rare visual disturbances, allergy (2% incidence).

C. Dosage:

• Initial dosage based on body surface area led to variable thrombocytopenia.
• Pharmacokinetic-based dosing is the standard: Dose calculated to achieve a specific AUC (area under the curve).
• Commonly used formula: Dose (mg) ≈ AUC (mg/mL.min) × (GFR + 25)
  • AUC: Typically 4-7 mg/mL.min (varies with administration frequency, prior treatment, combination drugs).
  • GFR: Glomerular filtration rate (mL/min), ideally measured by isotope clearance (e.g., 51CrEDTA), 24-hour urinary creatinine clearance acceptable.

D. Activity:

• Less toxic substitute for cisplatin with similar indications.
• Increased thrombocytopenia may be a disadvantage in some combinations.
• Reduced non-hematological toxicity is advantageous in high-dose regimens with bone marrow/stem cell rescue.

E. Pharmacokinetic Interactions:

• Unlike cisplatin, carboplatin does not affect hepatic cytochrome P450 enzymes.
• Pharmacokinetic interactions with other drugs are rare.

III. Oxaliplatin

A. Overview:

• Platinum analogue differing chemically and possibly mechanistically from cisplatin and carboplatin.
• Broad spectrum of in vitro activity, differing from cisplatin/carboplatin.
• Extensively used in colorectal cancer (adjuvant and advanced disease).
• Broad-spectrum activity, used in other cancers (e.g., upper GI).

B. Dosage:

• Common regimens:
  • 85 mg/m² every 2 weeks as a 2-6 hour infusion.
  • 130 mg/m² every 3 weeks as a 2-6 hour infusion.
• Many other dosing regimens exist, including chronomodulated infusion with fluorouracil.

C. Limitation:

• Cumulative dosage limited by the development of peripheral neuropathy (usually reversible upon drug withdrawal).

IV. Summary Table: