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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4341-4343 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.7795
The Graying of Testis Cancer Patients: What Have We Learned?Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; Memorial Sloan-Kettering Cancer Center; and Department of Medicine, Joan and Sanford Weill Medical College of Cornell University, New York, NY 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 etoposide-containing 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."1 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 emerged2 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.3 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 naïve, 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 long-term 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).4 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 publication of 20-year cumulative risks of malignancy and cardiac disease greatly increases the level of detail required in our discussions with patients on their treatment options. Increasingly mature long-term data are now available on etoposide-induced leukemia and cisplatin-associated bladder cancer, among others.5-7 In addition, the discussion can no longer be restricted to just second malignancies. Cardiovascular morbidity and mortality is associated with the recently defined metabolic syndrome consisting of insulin resistance, hypertensin, dyslipidemia, and abdominal obesity.8 This association is of concern because hypercholesterolemia, increased low-density and decreased high-density lipoprotein levels, excessive weight gain, and increased systolic and diastolic blood pressure are all more common in treated testis cancer patients than in the general population.9-11 These potentially treatable risks also need to be communicated to internists by oncologists because internists frequently provide health care to testis cancer patients long after completion of curative treatment. The greatest immediate impact of this study will be in stage I testis cancer, both high-risk nonseminomatous germ cell tumors (NSGCT) and seminomas, for which recent studies have reported on the benefits of adjuvant chemotherapy. Adjuvant BEP and carboplatin have been included by some as treatment options in published treatment paradigms for NSGCT and seminoma, respectively. Long-term toxicity data from this Dutch study should be included in future discussions of chemotherapy in this setting. In explaining the long-term risks of adjuvant chemotherapy compared with surgery for high-risk stage I NSGCT, testis cancer patients should now be informed that the cumulative risk of cancer and heart disease from the chemotherapy may be similar to that of smoking, and that this increased risk is nonexistent for surgery. Dismissing the toxicity with an explanation that adjuvant BEP chemotherapy is only administered for two cycles is not sufficient. For example, there is no known established lower limit of drug exposure that may lead to these long-term effects; secondary leukemia has been observed with only limited exposure to etoposide.12 The long-term risks for prophylactic radiation in patients with stage I seminoma seem to be less and thus do not seem to influence the risk-benefit ratio to the same degree as NSGCT. The following observations are in support of less associated long-term cumulative risks: testis cancer patients treated with infradiaphragmatic radiation less than 35 Gy do not have an increased risk of cardiac disease4; seminoma patients treated with radiation do not have an age-adjusted risk of developing metabolic syndrome, in contrast to cisplatin-treated patients13; there were fewer secondary malignancies observed with the decreased radiation doses used in the stage I setting4; and melanomas were seen outside the radiation port, an observation that has been reported previously7 and suggests predisposing risk rather than direct causality. More importantly, this study and other testis cancer survivorship studies6,7,9,10,13,14 should serve as a platform for the academic oncology community to re-examine how we weigh risks and benefits in creating chemotherapy recommendations for patients with stage 1 testis cancer. Stage-directed and risk-directed treatment paradigms are based predominantly on disease-free and overall survival rates at 5 years, as well as short-term toxicity. For example, published National Cancer Center Network and European Society of Medical Oncology treatment options include short-term chemotherapy for high-risk stage I NSGCT.15,16 These recommendations are based predominantly on trials such as that reported by the Medical Research Council in the United Kingdom using two cycles of BEP instead of surgery: of the patients receiving two cycles of cisplatin-based chemotherapy, fewer than 5% experienced relapse and approximately 1% died.17 Yet, the median follow-up on this study was 4 years, and was insufficient to weigh long-term toxicity. Instead, toxicity assessments focused on more immediate adverse effects, such as myelosuppression, infections, fertility, and ototoxicity. Treatment options for stage I seminoma include the use of single-agent carboplatin, but the randomized trial forming the basis of this option had a follow-up of only 4.0 years.18 Long-term toxicity data on second malignancy and cardiovascular disease from this trial are not available. The risks and benefits of all modalities of therapy for early-stage testis cancer was a topic of discussion in a recent JCO review.19 For example, adjuvant BEP for stage I NSGCT is common in Europe and increasingly used in the United States. Yet, it is characterized as investigational by some investigators from the United States who believe that the greater oncology community may be lulled by the fact that testis cancer rarely relapses after 2 years, not by the observations that true risk-benefit assessment may take a decade of follow-up or even longer. Twenty-year chemotherapy toxicity data in a young population are critically important to recommendations when cure is possible with other conventional approaches. For example, retroperitoneal lymph node dissection for stage I NSGCT achieves similar overall survival without these long-term consequences. In summary, the emerging data on the long-term toxicity of patients cured with modern therapy is of great benefit to patients and physicians in discussing risks and benefits of treatment. The authors should be commended for providing mature data that can be used in the decision-making process for young men and clinicians alike. The oncology community also needs to reflect more on these important observations and how such data may influence current recommendations. Perhaps the time has come for another international collaboration or an international data repository, this time focusing on the long-term adverse effects from all therapies, including single-agent carboplatin, short-term (two cycles) adjuvant chemotherapy, and modern radiation therapy. Finally, the Lance Armstrong Foundation and Dutch Medical Society deserve special recognition for funding this important research. Curative treatment for testis cancer has resulted in a rapidly increasing prevalence of cancer survivors who are expected to live for decades. Consequently, testis cancer again serves as a model for a curable neoplasm, but now as a leading example for how the greater testis cancer community can collaborate to provide survivorship studies that are of critical importance for the continued health of all patients cured of cancer. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Einhorn LH: Testicular cancer as a model for a curable neoplasm: The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 41: 3275-3280, 1981 2. Bosl GJ, Geller NL, Cirrincione C, et al: Multivariate analysis of prognostic variables in patients with metastatic testicular cancer. Cancer Res 43: 3403-3407, 1983 3. International Germ-Cell Cancer Collaborative Group: International Germ-Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ-cell cancers. J Clin Oncol 15: 594-603, 1997 4. van den Belt-Dusebout AW, de Wit R, Gietema AJ, et al: Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 25: 4370-4378, 2007 5. Travis LB, Andersson M, Gospodarowicz M, et al: Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst 92: 1165-1171, 2000 6. Travis LB, Fossa SD, Schonfeld SJ, et al: Second cancers among 40,576 testicular cancer patients: Focus on long-term survivors. J Natl Cancer Inst 97: 1354-1365, 2005 7. Robinson D, Moller H, Horwich A: Mortality and incidence of second cancers following treatment for testicular cancer. Br J Cancer 96: 529-533, 2007[CrossRef][Medline] 8. Alberti KG, Zimmet P, Shaw J, et al: The metabolic syndrome-a new worldwide definition. Lancet 366: 1059-1062, 2005[CrossRef][Medline] 9. Meinardi MT, Gietma JA, van der Graaf WTA, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18: 1725-1732, 2000 10. Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21: 1513-1523, 2003 11. Sagstuen H, Aass N, Fossa SD, et al: Blood pressure and body mass index in long-term survivors of testicular cancer. J Clin Oncol 23: 4980-4990, 2005 12. Le Deley M-C, Leblanc T, Shamsaldin A, et al: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: A case-control study by the Société Française d'Oncologie Pédiatrique. J Clin Oncol 21: 1074-1081, 2003 13. Haugnes HS, Aass N, Fossa SD, et al: Components of the metabolic syndrome in long-term survivors of testicular cancer. Ann Oncol 18: 241-248, 2007 14. Fosså SA, Gilbert E, Dores GM, et al: Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst 99: 533-544, 2007 15. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer. http://www.nccn.org/professionals/physician_gls/PDF/testicular.pdf 16. Huddart RA, Purkalne G, ESMO Guidelines Task Force: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of mixed or non-seminomatous germ cell tumors (NSGCT). Ann Oncol 16: i37-i39, 2005 (suppl 1) 17. Cullen MH, Stenning SP, Parkinson MC, et al: Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: A Medical Research Council report. J Clin Oncol 14: 1106-1113, 1996 18. Oliver RT, Mason MD, Mead GM, et al: Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: A randomised trial. Lancet 366: 293-300, 2005[CrossRef][Medline] 19. de Wit R, Fizazi K: Controversies in the management of clinical stage I testis cancer. J Clin Oncol 24: 5482-5492, 2006
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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