|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2971-2972 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.3231
Carboplatin for Stage I SeminomaCleveland Clinic Foundation, Department of Solid Tumor Oncology, Cleveland, OH
Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA To the Editor: The editorial by Drs Loehrer and Bosl1 opposing carboplatin for stage I seminoma omitted critical facts regarding the risks and benefits of carboplatin and radiation therapy (RT). First, disease-specific survival was 100% after carboplatin in nine studies enrolling more than 1,000 patients. Median follow-up ranged from 2 years to 10 years.2-10 Second, a randomized trial comparing RT with one cycle of carboplatin enrolled 1,477 men and reported equivalent survival and disease control for the two arms with a median follow-up of 4 years.2 Phase II trials studying two cycles of carboplatin have reported lower relapse rates than have trials of RT (2% v 4%) even though two of the larger carboplatin trials targeted men with a high or intermediate risk of relapse.2-4 Third, carboplatin does not appear to lead to a higher risk of late relapse than RT. Among studies of two cycles of carboplatin, including three studies with more than 5 years median follow-up, no relapses later than 28 months have been reported. Later relapses have been reported with a single cycle of carboplatin (none later than 5 years), but late relapses are also seen after RT as demonstrated in the randomized trial.2 Fourth, RT for seminoma has been associated with decreased overall survival compared with the age- and race-specific life expectancy of the general population, even among men whose RT was restricted to subdiaphragmatic sites.11 This excess mortality is due to increased deaths from cardiovascular disease and secondary cancers. This finding is supported by extensive work documenting a strong association between RT for testicular cancer and an increased subsequent risk of other cancers.12-16 The relative risk for cancer following RT for testis cancer has been reported to range from 1.5 to 2.0 in large series, translating into an additional six to nine cancers over the 25 years after treatment for every 100 men treated. These studies and others have looked for an association between testis cancer chemotherapy and the overall risk of second cancers, but the results have been mixed and no consistent relationship has been identified. Chemotherapy using etoposide and cisplatin for testis cancer has been associated with an increased risk of leukemia but even in patients receiving four cycles of those two drugs, the leukemia risk appears to be less than five cases of leukemia for every 1,000 men treated. Carboplatin at the doses used for seminoma has not been associated with leukemia. In addition, unlike RT, chemotherapy for testicular cancer has not been associated with increased cardiovascular mortality. Zagars11 reported that 15 years after infradiaphragmatic RT, the risk of cardiac death was 80% higher than in the age- and race-matched general population. And contrary to Loehrer and Bosl's assertion, carboplatin has not been associated with myocardial infarction as a distinct end point.17-19 While some studies using combined end points have reported an increased incidence of cardiovascular events in general in patients receiving chemotherapy for germ cell tumors, the vast majority of patients in these studies received more than two cycles of regimens consisting of multiple chemotherapeutic agents. Moreover, the risk after RT appears to be just as great. Huddert18 reported that the relative risk of cardiovascular events after platinum-based chemotherapy was 2.59 (95% CI, 1.15 to 5.84) while the risk after RT was 2.40 (95% CI, 1.04 to 5.45). Whereas the work showing an increased cancer risk after radiation is based on studies of thousands of patients, the purported higher risk of cardiovascular events after chemotherapy cited by Drs Loehrer and Bosl comes from an analysis of five events in 87 patients, all of whom received multiagent cisplatin-based chemotherapy for disseminated testis cancer.19 Even if those five events somehow provide an accurate estimation of risk, it remains unclear how that data applies to two cycles of single-agent carboplatin. Finally, the fact that carboplatin is less effective than cisplatin for metastatic disease does not speak to the effectiveness of carboplatin for stage I seminoma; carboplatin is favored for stage I disease because of its near 100% effectiveness at preventing relapse and its lesser toxicity relative to cisplatin. Where does that leave us? With little reason to favor RT. If 100 men with stage I seminoma receive RT, 82 patients who were not destined to relapse will be treated unnecessarily, 14 relapses will be prevented, and four patients will relapse despite RT and will go on to receive cisplatin-based chemotherapy. Of the original 100 patients, between six and nine will develop radiation-induced cancers. Thus, while radiating 100 men prevents 14 relapses, it will cause as many as nine other cancers that are much more difficult to cure than seminoma. The risk to benefit ratio is highly unfavorable. The fact that many patients are lost to follow-up by the time they suffer their radiation-induced malignancies should not lull us into complacency. While we are regularly told that modern RT will cause fewer deaths than historical RT, there is no persuasive data to confirm these assurances. In contrast, single-agent carboplatin is a brief and well-tolerated regimen whose late toxicity remains hypothetical. Certainly this is a critical area for future research, but we see no evidence to support the contention that one or two cycles of single-agent carboplatin will be as dangerous as RT. In the final analysis, we believe that surveillance represents the best option for most stage I seminoma patients until additional follow-up is available from the current carboplatin studies to reassure us regarding the possibility of late toxicity and/or there is good data to support the benignity of modern RT. Compared with RT, surveillance does not appear to increase the risk of ultimately needing cisplatin-based chemotherapy.20 For patients uncomfortable with or poorly suited to surveillance, carboplatin represents an excellent alternative and is now endorsed as a standard of care option by the European Germ Cell Tumor Consensus Group.21 Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Loehrer PJ, Bosl GJ: Carboplatin for stage I seminoma and the sword of Damocles. J Clin Oncol 23:8566-8569, 2005 2. 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] 3. Aparicio J, Germa JR, del Muro XG, et al: Risk-adapted management for patients with clinical stage I seminoma: The second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol 23:8717-8723, 2005 4. Aparicio J, Garcia del Muro X, Maroto P, et al: Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma. Ann Oncol 14:867-872, 2003 5. Steiner H, Holtl L, Wirtenberger W, et al: Long-term experience with carboplatin monotherapy for clinical stage I seminoma: A retrospective single-center study. Urology 60:324-328, 2002[CrossRef][Medline] 6. Reiter WJ, Brodowicz T, Alavi S, et al: Twelve-year experience with two courses of adjuvant single-agent carboplatin therapy for clinical stage I seminoma. J Clin Oncol 19:101-104, 2001 7. Dieckmann KP, Bruggeboes B, Pichlmeier U, et al: Adjuvant treatment of clinical stage I seminoma: Is a single course of carboplatin sufficient? Urology 55:102-106, 2000[CrossRef][Medline] 8. Krege S, Kalund G, Otto T, et al: Phase II study: Adjuvant single-agent carboplatin therapy for clinical stage I seminoma. Eur Urol 31:405-407, 1997[Medline] 9. Dieckmann KP, Krain J, Kuster J, et al: Adjuvant carboplatin treatment for seminoma clinical stage I. J Ca Res Clin Oncol 122:63-66, 1996[CrossRef][Medline] 10. Schmoll HJ, Harstrick A, Bokemeyer C, et al: Single-agent carboplatinum for advanced seminoma: A phase II study. Cancer 72:237-243, 1993[CrossRef][Medline] 11. Zagars GK, Ballo MT, Lee AK, et al: Mortality after cure of testicular seminoma. J Clin Oncol 22:640-647, 2004 12. Bokemeyer C, Schmoll HJ: Secondary neoplasms following treatment of malignant germ cell tumors. J Clin Oncol 11:1703-1709, 1993 13. Travis LB, Curtis RE, Storm H, et al: Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 89:1429-1439, 1997 14. van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout AW, et al: Second cancer risk following testicular cancer: A follow-up study of 1,909 patients. J Clin Oncol 11:415-424, 1993 15. Wanderas EH, Fossa SD, Tretli S: Risk of subsequent non-germ cell cancer after treatment of germ cell cancer in 2006 Norwegian male patients. Eur J Cancer 33:253-262, 1997[CrossRef][Medline] 16. 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 17. Fossa SD, Aass N, Harvei S, et al: Increased mortality rates in young and middle-aged patients with malignant germ cell tumours. Br J Cancer 90:607-612, 2004[CrossRef][Medline] 18. 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 19. Meinardi MT, Gietema JA, van der Graaf WT, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000 20. Warde PR, Chung P, Sturgeon J, et al: Should surveillance be considered the standard of care in stage I seminoma? J Clin Oncol 23:382s, 2005 (suppl; abstr 4520) 21. Schmoll HJ, Souchon R, Krege S, et al: European consensus on diagnosis and treatment of germ cell cancer: A report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 15:1377-1399, 2004
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
