Long-term survivors of testicular cancer treated with 4 cycles of etoposide and cisplatin faced significantly higher odds of renal impairment, ototoxicity, and peripheral neuropathy compared with those who received 3 cycles of bleomycin, etoposide, and cisplatin, according to a real-world multicenter analysis.

The Platinum Study enrolled survivors at 8 cancer centers between 2012 and 2018. For the current report, researchers analyzed 798 patients with histologically or serologically confirmed germ cell tumors who had completed first-line cisplatin-based chemotherapy at least 6 months prior and who completed both baseline clinical evaluation and follow-up questionnaires through February 17, 2025. Median age at follow-up was 45 years, and median time since chemotherapy completion was 11 years; 65% were 10-year or longer survivors.

The majority received one of three standard regimens: bleomycin/etoposide/cisplatin for 3 cycles (BEPx3; 40%), etoposide/cisplatin for 4 cycles (EPx4; 25%), or BEPx4 (12%). An additional 3% received etoposide/ifosfamide/cisplatin for 4 cycles (VIPx4; n = 27). Investigators quantified adverse health outcomes (AHOs) and cumulative burden of morbidity (CBM) scores—composite measures reflecting both the number and severity of health conditions—using validated questionnaires, physical examinations, and laboratory data.

Comparing Standard Regimens

In multivariable-adjusted analyses, patients treated with EPx4 vs BEPx3 had:

• 1.55 times the odds of worse renal impairment

• 1.48 times the odds of worse hearing loss

• 1.77 times the odds of worse neuropathy

Patients treated with BEPx4 vs BEPx3 had:

• 1.95 times the odds of renal impairment

• 1.95 times the odds of neuropathy

• 3.92 times the odds of thromboembolic disease

Despite differences in individual AHOs, overall CBM scores were statistically similar following EPx4 vs BEPx3. By contrast, CBM scores were significantly worse following BEPx4 (1.77 times the odds of a higher score vs BEPx3) and VIPx4 (2.24 times the odds). These findings remained directionally consistent when analyses were restricted to survivors of 10 or more years, though they did not reach statistical significance in that subgroup, likely owing to reduced sample size.

Across all regimens, higher cumulative cisplatin dose was independently associated with dose-dependent increases in platinum-specific CBM scores. This dose-response relationship persisted among patients surviving at least 10 years.

Renal Impairment and Downstream Cardiovascular Risk

Reduced estimated glomerular filtration rate below 90 mL/min/1.73 m² was observed in 41% of patients—a prevalence the authors noted exceeded US population norms of approximately 35%. The correlation between cumulative cisplatin dose and glomerular filtration rate (eGFR), while highly statistically significant, was modest in magnitude.

Graded eGFR reductions at baseline enrollment were strongly associated with subsequent development of grade 2 or higher hypertension at follow-up, with odds of:

• 2.01 for eGFR 60–89 mL/min/1.73 m²

• 2.84 for eGFR 45–59

• 20.0 for eGFR 30–44

compared with patients with normal eGFR.

Patients with eGFR in the 30–44 mL/min/1.73 m² range also had 6.10 times the odds of subsequent hyperlipidemia and 7.09 times the odds of cardiovascular disease (CVD).

Notably, few patients with impaired eGFR reported kidney disease at the time of assessment. Among those with eGFR of 30–59 mL/min/1.73 m², only 29% reported a diagnosis of kidney disease.

Raynaud Phenomenon Risk Factors

In multivariable analysis, BEPx4 was associated with 2.18 times the odds of Raynaud phenomenon compared with EPx4. Increasing cumulative bleomycin dose was also associated with higher odds.

Novel nonchemotherapy risk factors included:

• Beta-blocker use (2.17 times the odds)

• Comorbid peripheral artery disease (3.14 times the odds)

• Reduced eGFR, with each 10-unit increase associated with approximately a 10% reduction in odds

BEPx3 showed a borderline, nonsignificant association vs EPx4. The authors noted that prior analyses of Raynaud phenomenon in testicular cancer survivors examined limited risk factors and did not account for eGFR, PAD, or medication use.

Patient-Reported Health

Chemotherapy regimen was a statistically significant predictor of lower self-reported global physical health, with the most pronounced reductions following BEPx4 and VIPx4. Higher CBM scores correlated with lower global physical health scores.

Physical activity emerged as a modifiable protective factor for both individual AHOs and overall mortality, the authors noted, citing a related publication from the same cohort.

Methodology and Limitations

eGFR was calculated using the updated Chronic Kidney Disease Epidemiology Collaboration creatinine equation consistent with 2024 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. AHOs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, modified to incorporate medication use and kidney disease diagnoses. CBM scores were derived using previously validated methods.

Multivariable models adjusted for demographic factors, smoking, and heavy alcohol use.

The authors acknowledged the absence of pretreatment creatinine measurements, limited pulmonary assessment data, and small numbers in the VIPx4 group as limitations.

“This multicenter, real-world study shows that long-term CBM scores after NCCN-endorsed EPx4 or BEPx3 are comparable, but statistically significant differences in cisplatin-related toxicities exist. Cisplatin dose-dependent reductions in eGFR are followed by significant excesses of hypertension, hyperlipidemia, and CVD,” the authors wrote.

Disclosures are available in the original publication.

Source: JNCCN