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Original Investigation
December 2016

Second Malignant Neoplasms and Cause of Death in Patients With Germ Cell CancerA Danish Nationwide Cohort Study

Author Affiliations
  • 1Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  • 2Unit of Survivorship, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
  • 3Unit of Statistics, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
  • 4Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
  • 5Department of Oncology, Odense University Hospital, Odense, Denmark
JAMA Oncol. 2016;2(12):1624-1627. doi:10.1001/jamaoncol.2016.3651
Key Points

Question  What are the treatment-specific risks for second malignant neoplasm (SMN) and death in patients treated for germ cell cancer?

Findings  In this Danish nationwide population-based, retrospective cohort study, an almost 2-fold increase was found for risks for SMN after radiotherapy and chemotherapy with bleomycin, etoposide, and cisplatin (BEP) compared with a control group. There was no excess risk after surveillance alone.

Meaning  We found an almost doubling of risk for SMN after BEP and radiotherapy with SMN being the main reason for excess non-GCC mortality.


Importance  Patients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options.

Objective  To evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens.

Design, Setting, and Participants  This study examined a Danish nationwide cohort of 5190 men with GCC who entered the Danish Testicular Cancer database between January 1, 1984, and December 31, 2007. Treatment results were compared with a randomly sampled, age-stratified, population-based control group. Cases of gonadal and extragonadal primary were included in the nationwide cohort. The treatments were surveillance only; retroperitoneal radiotherapy (RT); bleomycin, etoposide, and cisplatin (BEP); or more than 1 line of treatment (MTOL).

Main Outcomes and Measures  Cumulative incidence and hazard ratios (HRs) for SMN and death calculated by the Cox proportional hazards model were compared with those of age-matched controls.

Results  The study population comprised 2804 patients with seminoma and 2386 with nonseminoma. The median follow-up was 14.4 years (interquartile range, 8.6-20.5 years). The 20-year cumulative incidence of SMN with death as a competing risk was 7.8% (surveillance), 7.6% (BEP), 13.5% (RT), 9.2% (MTOL), and 7.0% (controls). We found no increased risk for SMN after surveillance, while the HRs were 1.7 (95% CI, 1.4-2.0), 1.8 (95% CI, 1.5-2.3), and 3.7 (95% CI, 2.5-5.5), respectively, after BEP, RT, and MTOL. Mortality owing to non-GCC causes was decreased after surveillance, but increased by 1.3 times after BEP and RT and by 2.6 times after MTOL. Excess mortality due to SMN was found after BEP (HR, 1.6; 95% CI, 1.2-2.2), RT (HR, 2.1; 95% CI, 1.5-2.9), and MTOL (HR, 5.8; 95% CI, 3.6-9.6).

Conclusions and Relevance  We found no increased risk for SMN or death among patients undergoing surveillance only. The risks for SMN and death due to SMN were increased after BEP alone, RT alone, and MTOL. Approaches to define patients who might benefit from less intensive treatment are needed.