The Graying of Testis Cancer Patients: What Have We Learned?

Abstract

Remarkable advances in testicular cancer therapy occurred in the 1970s and 1980s, leading to a new age in cancer treatment in which cure of metastatic cancer became possible with chemotherapy. The discovery of cisplatin ushered in an exciting era during which it was combined with other drugs, including vinblastine and bleomycin. These three drugs were the cornerstone of curable regimens in their day, only to be replaced rapidly with etoposidecontaining combinations. The new regimens of bleomycin, etoposide, and cisplatin (BEP) and etoposide plus cisplatin were quickly established. Ifosfamide and paclitaxel were also discovered to have activity and could cure patients who experienced treatment failure after first-line treatment. These discoveries were an affirmation that germ cell tumors truly served as a “model for a curable neoplasm.” The germ cell model established far more than just curative chemotherapy combinations, however. Oncology was coming of age by the 1980s, and this emergence was best represented by testicular cancer therapy; randomized clinical trials created level 1 evidence for new standards of care. Chemotherapy cured 80% of men but failed to cure 20% of men. The concept of modeling response to chemotherapy using serum tumor markers emerged and risk-directed treatment strategies and risk-directed clinical trials soon followed, particularly to reduce toxicity in highly curable patients. Risk-directed trials proliferated internationally, but with an extraordinary disparity in clinical criteria assigning patients to good-risk and poor-risk categories. Investigators responded to this challenge by creating the International Germ Cell Cancer Consensus Group that combined data from thousands of patients worldwide, compared models, and found all models lacking to a degree. Thus, the group created a new international model and published the first consensus on risk definitions—a milestone in testis cancer and a model for other malignancies. Therapy for testis cancer was not alone in this coming of age. The young men that were treated for testicular cancer have also aged. Oncology was quite naive, projecting the major benefit to society in work-years for each man cured of testis cancer. We underestimated the immense impact of this curative therapy on our society. These men are directly responsible for these great advances by having volunteered for clinical trials in such high numbers that important clinical advances were made at an unparalleled pace for a rare adult disease, and they helped establish randomized trials as the gold standard in oncology research. Testis cancer survivors still also actively participate in longterm follow-up studies, giving back to the cancer community in ways that were unforeseen in the 1970s and 1980s. Our elder testis cancer survivors continue to make major contributions to society by helping younger men faced with this disease, informing the lay public about cancer detection and successes in cancer treatment, and increasing awareness about the trends in cancer research funding. Lance Armstrong, an internationally acclaimed athlete who was cured of testis cancer, not only serves as an inspiration for cancer patients worldwide, but has also created a foundation to provide funding for testis cancer research as well as for other malignancies. The confluence of these factors—improved cancer treatment, testis cancer survivors, and lay organizations funding studies on long-term toxicity—is well represented in the study by van den Belt-Dusebout et al in this issue of the Journal of Clinical Oncology (JCO). This study is an extension of this group’s prior analysis on late cardiovascular events in testis cancer patients. The current study of more than 2,700 testis cancer survivors from the Netherlands, supported by the Lance Armstrong Foundation and the Dutch Cancer Society, quantifies the long-term risks of second malignancies and serious cardiovascular disease (angina, myocardial infarct, and congestive heart failure) after curative treatment for testis cancer. At a median follow-up time of 17 years, this study has medical follow-up available on 90% of Dutch testis cancer patients; these observations have substantial importance to the international testis cancer community. The authors report that the cumulative 20-year incidence of these long-term toxicities was 4% greater in patients treated with chemotherapy and 1.5% greater in patients treated with infradiaphragmatic radiation compared with patients treated with surgery alone. The increased risk of a major late secondary cancer or cardiac event was 1.8-fold for patients treated with infradiaphragmatic radiotherapy and 1.9-fold for those treated with chemotherapy in comparison to patients treated with surgery alone. Placed in context, smoking causes a 1.7-fold increase in these events. These long-term toxicities have direct survival implications; median survival was 1.4 years after a diagnosis of a second malignancy and 4.7 years after a cardiovascular event. At a minimum, this sentinel JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 28 OCTOBER 1 2007