What is cisplatin and what are its side effects?

What is Cisplatin and Its Side Effects

What Cisplatin Is

Cisplatin is a platinum-based chemotherapy drug used to treat multiple solid tumors including metastatic testicular cancer, metastatic ovarian cancer, and advanced bladder cancer. 1 It works primarily by crosslinking with purine bases on DNA, interfering with DNA repair mechanisms and causing DNA damage that leads to cancer cell death. 2

• Cisplatin is indicated as combination therapy with other chemotherapeutic agents for metastatic testicular and ovarian tumors in patients who have already received appropriate surgical and/or radiotherapeutic procedures. 1
• As a single agent, cisplatin is indicated for metastatic ovarian tumors refractory to standard chemotherapy and for transitional cell bladder cancer no longer amenable to local treatments. 1
• The drug is also used in treating lung, head and neck, and cervical cancers, among others. 2

Major Side Effects

Nephrotoxicity (Kidney Damage)

Dose-related and cumulative renal insufficiency is the major dose-limiting toxicity of cisplatin, occurring in 28% to 36% of patients treated with a single dose of 50 mg/m². 1

• Renal toxicity manifests during the second week after dosing with elevations in BUN, creatinine, serum uric acid, and decreased creatinine clearance. 1
• Cisplatin causes damage to renal tubular epithelial cells, affecting electrolyte reabsorption and causing excessive urinary losses, particularly of magnesium, potassium, sodium, and calcium. 3, 4
• Adequate IV hydration (6-8 hour infusion) with mannitol is used to reduce nephrotoxicity, though renal toxicity can still occur. 1
• Elderly patients are more susceptible to nephrotoxicity. 1
• Cisplatin is contraindicated in patients with pre-existing renal impairment. 1

Ototoxicity (Hearing Loss)

Ototoxicity occurs in up to 31% of patients treated with a single dose of cisplatin 50 mg/m², manifested by tinnitus and/or hearing loss in the high frequency range (4,000 to 8,000 Hz). 1

• The prevalence of hearing loss in children is particularly high at 40-60%, and decreased ability to hear normal conversational tones may occur. 1
• Deafness can occur after the initial dose and may be unilateral or bilateral, becoming more frequent and severe with repeated doses. 1
• It is unclear whether cisplatin-induced ototoxicity is reversible. 1
• Audiometric testing should be performed prior to initiation of therapy, prior to each subsequent dose, and for several years post-therapy. 1
• Risk factors include age less than 5 years, concurrent ototoxic drugs (aminoglycosides, vancomycin), renal impairment, and prior cranial irradiation. 1

Myelosuppression (Bone Marrow Suppression)

Myelosuppression occurs in 25% to 30% of patients, with nadirs in circulating platelets and leukocytes occurring between days 18 to 23, with most patients recovering by day 39. 1

• Leukopenia and thrombocytopenia are more pronounced at higher doses (>50 mg/m²). 1
• Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and timing as leukopenia and thrombocytopenia. 1
• Elderly patients are more susceptible to myelosuppression, with higher incidences of severe neutropenia, thrombocytopenia, and leukopenia. 1
• Fever, infection, and potential fatalities due to infection secondary to myelosuppression have been reported. 1

Neurotoxicity (Nerve Damage)

Severe peripheral neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. 1

• These neuropathies occur particularly with higher doses or greater dose frequencies than recommended. 1
• Loss of motor function has also been reported. 1
• Elderly patients are more susceptible to peripheral neuropathy. 1
• Neurologic examination should be performed regularly during treatment. 1

Cardiovascular Disease

Among testicular cancer survivors treated with cisplatin-based therapy, 18.1% developed cardiovascular disease within 20 years of treatment, with an observed-to-expected ratio of major cardiovascular events of 7.1 (95% CI = 1.9 to 18.3) at a median age of only 41 years. 5

• Hyperlipidemia and metabolic syndrome have been reported in 80% and 40% of chemotherapy-treated testicular cancer survivors, respectively. 5
• Mechanisms include direct vascular injury through inflammatory response with cytokine release, oxidative damage, electrolyte changes (particularly hypomagnesemia), and platelet aggregation. 5
• Raynaud phenomenon developed in 37% of testicular cancer survivors treated with bleomycin and vinblastine with or without cisplatin. 5

Gastrointestinal Toxicity

Nausea and vomiting are common side effects of cisplatin that can significantly affect patient quality of life. 6

• These symptoms can be severe enough to lead to treatment interruptions and reduced effectiveness. 6
• NK-1 receptor antagonists show promise in preventing cisplatin-induced nausea and vomiting. 6

Other Significant Side Effects

Anaphylactic-like reactions can occur within minutes of administration in patients with prior cisplatin exposure, requiring immediate treatment with epinephrine, corticosteroids, and antihistamines. 1

• Hypersensitivity reactions become more common with repeat platinum exposure and can be life-threatening. 5
• Injection site reactions and extravasation may occur during administration, requiring close monitoring of the infusion site. 1
• Hepatic toxicity and metabolic toxicities can occur, particularly with intraperitoneal administration. 5

Critical Monitoring Requirements

Serum creatinine, BUN, creatinine clearance, and magnesium, sodium, potassium, and calcium levels must be measured prior to initiating therapy and prior to each subsequent course. 1

• Peripheral blood counts should be monitored weekly. 1
• At recommended dosage, cisplatin should not be given more frequently than once every 3 to 4 weeks. 1
• Patients require careful monitoring for myelosuppression, dehydration, electrolyte loss, and end-organ toxicities after each cycle. 5
• Hypomagnesemia should be aggressively corrected as it can exacerbate potassium wasting. 3

Contraindications and Special Populations

Cisplatin is contraindicated in patients with pre-existing renal impairment, myelosuppression, hearing impairment, or history of allergic reactions to platinum-containing compounds. 1

• Cisplatin is Pregnancy Category D and can cause fetal harm; it is mutagenic, teratogenic, and embryotoxic. 1
• Patients receiving cisplatin should not breast-feed as the drug is found in human milk. 1
• Elderly patients require particular caution due to increased susceptibility to nephrotoxicity, myelosuppression, peripheral neuropathy, and infectious complications. 1
• Patients must have normal renal function, adequate performance status, and no preexisting medical problems that could significantly worsen during chemotherapy (such as preexisting neuropathy) before starting treatment. 5