What are the potential side effects of cisplatin in adult cancer patients?

Side Effects of Cisplatin

Cisplatin causes multiple dose-limiting toxicities including nephrotoxicity, ototoxicity, neurotoxicity, myelosuppression, severe nausea/vomiting, and cardiovascular complications that can significantly impact patient quality of life and may be irreversible. 1

Major Organ Toxicities

Nephrotoxicity

• Renal tubular damage occurs in the majority of patients, with up to 30% experiencing persistent reduction in glomerular filtration rate even years after treatment 2, 1
• Acute reversible decreases in GFR are common, but some patients sustain irreversible damage that remains stable or improves over 5-10 years post-treatment 2
• Electrolyte disturbances are frequent and related to tubular damage: hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia 1
• Hypomagnesemia can persist for more than 6 years after chemotherapy in some patients 2
• Elderly patients are more susceptible to nephrotoxicity 1

Ototoxicity

• Hearing loss occurs in 31-93% of patients and is manifested by tinnitus and/or high-frequency hearing loss (4,000-8,000 Hz) 1, 3, 4
• Children have particularly high prevalence at 40-60%, with more severe effects in those under 5 years of age 1
• Hearing loss can be unilateral or bilateral, becomes more frequent and severe with repeated doses, and may be irreversible 1
• Deafness after the initial dose has been reported 1
• Ototoxicity is attributed to selective damage to outer hair cells of the cochlea 2
• Risk factors include: cumulative dose, schedule of administration, prior cranial irradiation, concurrent ototoxic drugs (aminoglycosides, vancomycin), renal impairment, and genetic variants in TPMT gene 1, 5
• Audiometric monitoring should be performed prior to initiation, before each dose, and for several years post-therapy 1

Neurotoxicity

• Peripheral neuropathy occurs in approximately 20% of long-term survivors, characterized by sensory paresthesias 2, 6
• Neuropathies usually occur after prolonged therapy (4-7 months), but can occur after a single dose 1
• Symptoms may begin 3-8 weeks after the last dose and may progress even after stopping treatment 1
• Peripheral neuropathy may be irreversible in some patients 1
• The principal pathophysiological effect is degeneration of the dorsal nerve ganglion, a site of drug accumulation 2
• Additional neurologic manifestations include: Lhermitte's sign, dorsal column myelopathy, autonomic neuropathy, loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome 1
• Muscle cramps occur with high cumulative doses and advanced neuropathy 1
• Elderly patients are more susceptible to peripheral neuropathy 1
• No effective treatment exists to ameliorate symptoms 2

Ocular Toxicity

• Optic neuritis, papilledema, and cerebral blindness have been reported with standard doses 1
• Improvement or total recovery usually occurs after discontinuing cisplatin 1

Hematologic Toxicity

Myelosuppression

• Occurs in 25-30% of patients, with leukopenia and thrombocytopenia more pronounced at doses >50 mg/m² 1
• Nadirs in platelets and leukocytes occur between days 18-23 (range 7.5-45), with most patients recovering by day 39 (range 13-62) 1
• Anemia (decrease of 2 g hemoglobin/100 mL) occurs at the same frequency and timing as leukopenia and thrombocytopenia 1
• Coombs' positive hemolytic anemia has been reported 1
• Fever and infection secondary to neutropenia can be fatal 1
• Elderly patients are more susceptible to myelosuppression 1
• Acute leukemia coincident with cisplatin use has been reported, particularly when combined with other leukemogenic agents 1

Gastrointestinal Toxicity

Nausea and Vomiting

• Marked nausea and vomiting occur in almost all patients and may be severe enough to require discontinuation 1
• Symptoms begin within 1-4 hours after treatment and last up to 24 hours 1
• Various degrees of vomiting, nausea, and/or anorexia may persist for up to 1 week after treatment 1
• Delayed nausea and vomiting (beginning or persisting ≥24 hours after chemotherapy) occurs even in patients with complete emetic control on the day of therapy 1
• Diarrhea has also been reported 1
• Younger patients (<50 years) may be more susceptible to anticipatory nausea and vomiting, occurring in 20% at any cycle and 25-30% by the fourth cycle 2

Cardiovascular Toxicity

Vascular Complications

• Cisplatin-treated testicular cancer survivors have up to 8% absolute risk of coronary artery disease over 20 years 2
• 2% risk of arterial thrombosis with subsequent myocardial and cerebrovascular ischemia 2
• Vascular toxicities include: myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic-uremic syndrome), and cerebral arteritis 1
• Raynaud phenomenon occurs in up to 37% of patients treated with bleomycin and vinblastine combinations 2
• 18.1% of testicular cancer survivors develop cardiovascular disease within 20 years of treatment 2
• Mechanisms include: direct vascular injury, endothelial damage (increased circulating endothelial cells), inflammatory response with cytokine release, oxidative damage, electrolyte changes, and platelet aggregation 2

Metabolic Complications

• Hyperlipidemia occurs in 80% of chemotherapy-treated testicular cancer survivors 2
• Metabolic syndrome occurs in 40% of survivors 2

Other Toxicities

Hyperuricemia

• Occurs at approximately the same frequency as increases in BUN and serum creatinine 1
• More pronounced after doses >50 mg/m², with peak levels occurring 3-5 days after the dose 1
• Allopurinol therapy effectively reduces uric acid levels 1

Risk Factors for Increased Toxicity

• Older age is associated with increased risk of ototoxicity, neurotoxicity, and nephrotoxicity 5
• Cumulative dose and schedule of administration affect multiple toxicities 2, 1
• Prior or concurrent cranial irradiation increases ototoxicity risk 1
• Renal impairment increases risk of multiple toxicities 1
• Genetic factors (TPMT gene variants) may contribute to ototoxicity 1

Clinical Monitoring Requirements

• Renal function assessment before each dose with adequate hydration and mannitol to reduce nephrotoxicity 1
• Audiometric monitoring before initiation, before each dose, and for several years post-therapy 1
• Electrolyte monitoring with supplementation as needed 1
• Neurologic assessment for early detection of peripheral neuropathy, with discontinuation when symptoms first appear 1
• Hematologic monitoring for myelosuppression 1