Platinum Compounds

Platinum compounds form intrastrand and interstrand DNA cross-links that block replication and transcription. They are among the most active anticancer drugs in germ cell tumours, ovarian, lung, head and neck, cervical, bladder and gastrointestinal cancers, and they are used with radiotherapy as radiosensitisers.

Classification. Cisplatin, carboplatin, oxaliplatin.

Pharmacokinetics. Cisplatin is highly protein bound and eliminated by the kidney; carboplatin is excreted by glomerular filtration, so dose is calculated from renal function. Oxaliplatin is cleared mostly by the kidney.

• Cisplatin 50 to 100 mg/m2 every 3 weeks, or 40 mg/m2 weekly with radiotherapy; give with prehydration (1 to 2 litres of isotonic sodium chloride over 2 to 4 hours), magnesium and potassium supplements, and an antiemetic regimen for high emetic risk.
• Carboplatin dose in mg = target area under the curve (usually 5 to 6) x (glomerular filtration rate + 25); cap the filtration rate at 125 mL/min, so the largest dose for an area under the curve of 5 is 750 mg.
• Oxaliplatin 85 mg/m2 every 2 weeks, or 130 mg/m2 every 3 weeks.

Differences. Cisplatin is the most emetogenic and nephrotoxic and causes ototoxicity and neuropathy. Carboplatin is mainly myelosuppressive, with less nausea, kidney injury and neuropathy. Oxaliplatin causes acute cold-induced paraesthesia and cumulative sensory neuropathy but little marrow, kidney or ear toxicity.

• Germ cell tumour: cisplatin, etoposide and bleomycin.
• Ovarian cancer: carboplatin with paclitaxel.
• Cervical, head and neck cancer: weekly cisplatin with radiotherapy (carboplatin if kidney function is poor).
• Colorectal cancer: oxaliplatin with fluorouracil and folinic acid.
• Cisplatin dose adjustment: avoid at creatinine clearance under 60 mL/min; use carboplatin; sometimes split dosing.
• Nephroprotection: hydration and forced diuresis; avoid nephrotoxic drugs (aminoglycosides, NSAIDs, amphotericin B).
• Hypersensitivity: carboplatin and oxaliplatin reactions usually appear after 6 or more cycles; desensitisation is used in specialist centres.

Selection. Replace cisplatin with carboplatin in older, hearing-impaired or kidney-impaired patients, accepting somewhat lower efficacy in some tumours.

Contraindications. Hypersensitivity to platinum compounds; cisplatin with creatinine clearance under 60 mL/min, pre-existing hearing loss, or neuropathy.

Adverse effects. Nausea and vomiting, myelosuppression (carboplatin), nephrotoxicity, hypomagnesaemia, hypokalaemia, ototoxicity with high-frequency hearing loss and tinnitus, peripheral neuropathy, anaphylaxis, and secondary leukaemia.

Interactions. Aminoglycosides, loop diuretics and vancomycin increase kidney and ear toxicity; cisplatin lowers phenytoin levels; avoid live vaccines.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: audiological monitoring is essential; hearing loss is common.
• Older adults: carboplatin is preferred.
• Kidney impairment: avoid cisplatin; use carboplatin with the area-under-the-curve formula.
• Liver impairment: no adjustment for carboplatin or cisplatin; oxaliplatin needs no change.

Monitoring. Creatinine, magnesium, potassium and calcium before each cisplatin dose, full blood count at the nadir (day 14 to 21 for carboplatin), audiology, neurological examination, and urine output during hydration.

Referral and escalation. Rising creatinine, new hearing loss or tinnitus, anaphylaxis and severe neuropathy need review; stop the drug at grade 3 neuropathy.