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Cisplatin: Mechanism, Adverse Effects, Contraindications, and Dosing

Mechanism of Action:

Cisplatin reacts with DNA and forms covalent crosslinks between adjacent guanines—which inhibits DNA replication and transcription. The resulting DNA damage triggers apoptosis.

Urologic Indications for Cisplatin:

• Metastatic germ cell tumors (advanced seminoma or nonseminoma) are treated with BEP- or PEI-based regimens.
• Metastatic urothelial carcinoma of the bladder, or upper tract urothelial carcinoma are treated with MVAC combination or in combination with gemcitabine.

Pharmacokinetics:

Intravenous administration; cellular uptake occurs via passive diffusion and transporters; covalent binding to plasma proteins up to approximately 90%, predominantly renal elimination, terminal half-life approximately 24–36 hours.

Adverse Effects of Cisplatin:

Because cisplatin causes substantial chemotherapy-induced nausea and vomiting (CINV) and myelosuppression, supportive care is indicated, including evidence-based antiemetic prophylaxis and neutropenia prevention strategies.

Nausea and Vomiting:

Cisplatin is highly emetogenic. Clinicians distinguish acute CINV occurring within hours after administration from delayed CINV occurring 1–5 days afterward. Prophylactic antiemetic therapy is mandatory.

Electrolyte Losses:

Most notably magnesium, calcium, potassium, and phosphate.

Nephrotoxicity:

Risk factors for cisplatin nephrotoxicity include pre-existing renal impairment, dehydration, hyperuricemia, concomitant use of other nephrotoxic drugs (e.g., aminoglycosides or amphotericin B), and hypoalbuminemia. Typical findings include a rise in serum creatinine and hypomagnesemia; hypokalemia and hypocalcemia may also occur.

Intravenous hydration before and after cisplatin administration is essential to mitigate nephrotoxicity, with a target urine output of at least 100 mL/h. Clinicians should provide concurrent magnesium supplementation. Routine use of forced diuresis with mannitol is not recommended; reserve mannitol for inadequate diuresis or select high-dose settings. Nephrotoxicity may be reversible or irreversible.

Neurotoxicity:

Peripheral sensory-predominant neuropathy (dose-dependent, with risk increasing with cumulative exposure), ototoxicity with tinnitus and high-frequency hearing loss, and rarely visual disturbances; Raynaud phenomenon may occur. These toxicities can be partially irreversible.

Myelosuppression:

Leukopenia, thrombocytopenia, and anemia occur. The nadir typically occurs around day 14 after administration, and recovery may take up to 40 days.

Mutagenic Risk:

Therapy-related secondary malignancies, including leukemia, are very rare. After three cycles of BEP, the estimated risk is low (0.5%) with etoposide being the significant risk factor. Cisplatin is also mutagenic to germ cells, so effective contraception is required during treatment and for an appropriate interval afterward.

Fertility:

Cisplatin can cause dose-dependent, sometimes partially irreversible impairment of spermatogenesis; recovery may require more than one year. After three cycles of BEP, the risk of persistent infertility is approximately 10–30%.

Other Adverse Effects of Cisplatin:

Mucositis, gingival bleeding, diarrhea, alopecia, allergic reactions, and hepatic dysfunction. Extravasation can cause local tissue injury and skin necrosis.

Drug Interactions:

Avoid nephrotoxic or strongly myelosuppressive agents during cisplatin-based chemotherapy whenever possible. Loop diuretics (e.g., furosemide) increase ototoxicity and should not be used to augment diuresis. Live vaccines are contraindicated during—and for an appropriate interval after—cytotoxic chemotherapy.

Contraindications to Cisplatin:

Depending on the curative intent of the cisplatin-based regimen, the following may represent relative contraindications.

• Severe hypersensitivity reactions to cisplatin
• Severe renal impairment (consider dose adjustment or alternative therapy)
• Pre-existing significant hearing loss
• Severe cisplatin-induced neuropathy
• Severe bone marrow suppression
• Pregnancy and lactation

Dosing of Cisplatin:

To reduce nephrotoxicity, provide intravenous hydration: for example, 1,000 mL 6–12 hours before cisplatin administration and 2,000 mL within 6–12 hours afterward. Consider mannitol only if urine output remains below approximately 100–200 mL/h after cisplatin or for high-dose regimens exceeding 60 mg/m².

Dosing in the BEP and PEI Combinations for Germ Cell Tumors:

Administer cisplatin 20 mg/m² on days 1–5 as a short infusion over about 1 hour. The cycle length is 21 days.

Dosing of Cisplatin in Combination with Gemcitabine for Urothelial Carcinoma:

Administer cisplatin 70 mg/m² on day 2 with a cycle length of either 21 or 28 days.

Dosing in the MVAC Combination for Urothelial Carcinoma:

Administer cisplatin 70 mg/m² on day 2 with a 28-day cycle length.

References

Go und Adjei 1999 GO, R. S. ; ADJEI, A. A.: Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin.
In: J Clin Oncol
17 (1999), Nr. 1, S. 409–22

E. Huyghe et al., “Fertility after testicular cancer treatments: results of a large multicenter study.,” Cancer, vol. 100, no. 4, pp. 732–737, 2004, doi: 10.1002/cncr.11950.

C. N. Sternberg et al., “Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse,” Cancer, vol. 64, no. 12, pp. 2448–58, 1989.

von der Maase et al., “Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study,” J Clin Oncol, vol. 18, no. 17, pp. 3068–77, 2000.

  Deutsche Version: Nebenwirkungen und Kontraindikationen von Cisplatin

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