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IN REPLY

Memorial Sloan-Kettering Cancer Center, New York, NY

The letter by Drs Einhorn and Foster outlines their opinion as to the optimal management for patients with good-risk germ cell tumor (GCT) and highlights the generally minor differences in our treatment approach. However, we disagree with some of their conclusions, particularly those not supported by data. Drs Einhorn and Foster state that bleomycin, etoposide, and cisplatin (BEP) for three cycles (x 3) is better tolerated than etoposide and cisplatin (EP) for four cycles (x 4), but there are no published data to support this statement. We outlined the limitations in comparing EP x 4 and BEP x 3 based on the existing data.¹ Bleomycin toxicity has been and remains the most significant issue. The totality of bleomycin toxicity must be considered. While acute pulmonary toxicity is reduced in BEP x 3, bleomycin can still contribute to morbidity in postchemotherapy resection and deaths can occur.² Long-term cardiovascular disease, including myocardial infarction and hypertension, is now recognized, and Raynaud's phenomenon ranges in frequency from 6% to 24%, occurring only when bleomycin was administered in the study reported by de Wit et al.^3-7 Regarding efficacy, the importance of etoposide dose cannot be overemphasized. Toner et al⁸ have shown the inferior survival results from the use of etoposide 360 mg/m², and more than 40% of patients who received 360 mg/m² had additional dose reductions during therapy in the study reported by de Wit et al.³ The problems with data analysis and trial design of the Culine study,⁹ in which patients were randomly assigned to either BEP x 3 or EP x 4, which were presented at the Annual Meeting of the American Society of Clinical Oncology in 2003, are clearly outlined and summarized in the annual meetings publication.¹⁰ The study was underpowered to detect either superiority of one regimen or noninferiority, and had a significant probability of false-positive conclusions. Survival was not statistically significantly better in either arm of this study.⁹ The use of BEP x 4 for patients with intermediate- and poor-risk disease remains the standard, as there are no studies of lesser therapy. The goal for these patients is improved efficacy, with reduction of toxicity a secondary priority, and this goal has been the focus of all of the investigators who have developed clinical trials for these higher risk groups. Hence, we recommend BEP x 4 for those patients.

Everyone agrees that surgical resection of residual disease (teratoma and/or viable GCT) is required to achieve the highest likelihood of cure in GCT patients. Studies have demonstrated that the incidence of teratoma or viable GCT at postchemotherapy resection is present in at least 15% to 20% of cases.^11-13 In the Oldenburg study,¹³ five of six patients with viable residual disease had residual masses < 1 cm. Clinical criteria to exclude teratoma and viable GCT after chemotherapy have not been determined. We argue that the biologic potential of teratoma is critical in deciding whether or not postchemotherapy surgery (particularly retroperitoneal lymph node dissection) is necessary. Viable GCT will always progress. Teratoma, despite its benign histologic appearance, can grow, invade adjacent structures, and become unresectable. Teratoma is always aneuploid,¹⁴ has a highly variable proliferative index as measured by Ki67 expression,¹⁵ and malignant transformation cannot be predicted. Hence, teratoma cannot be known a priori to be inert or benign.

In our opinion, based on the available data, both EP x 4 and BEP x 3 represent standard treatment options for patients with metastatic good-risk GCT. We continue to recommend retroperitoneal lymph node dissection to patients who have retroperitoneal disease at the start of therapy and whose markers normalize after chemotherapy, even if the residual retroperitoneal disease is < 1 cm.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Kondagunta GV, Bacik J, Bajorin D, et al: Etoposide and cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol 23:9290-9294, 2005[Abstract/Free Full Text]

2. Baniel J, Foster RS, Rowland RG, et al: Complications of post-chemotherapy retroperitoneal lymph node dissection. J Urol 153:976-980, 1995[CrossRef][Medline]

3. de Wit R, Stoter G, Kaye SB, et al: Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: A randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol 15:1837-1843, 1997[Abstract/Free Full Text]

4. Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316:1435-1440, 1987[Abstract]

5. 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[Abstract/Free Full Text]

6. 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[Abstract/Free Full Text]

7. van den Belt-Dusebout AW, Nuver J, de Wit R, et al: Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 24:467-475, 2006

8. Toner GC, Stockler MR, Boyer MJ, et al: Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: A randomised trial. Australian and New Zealand Germ Cell Trial Group. Lancet 357:739-745, 2001[CrossRef][Medline]

9. Culine S, Kerbrat P, Bouzy J, et al: The optimal chemotherapy regimen for good-risk metasatic non-seminomatous germ cell tumors (MNSGCT) is 3 cycles of bleomycin, etoposide, and cisplatin: Mature results of a randomized trial. Proc Am Soc Clin Oncol 21:382, 2003 (abstr 1536)

10. Kosty MP: Genitourinary (nonprostate) Cancer. Proc Am Soc Clin Oncol 21:118-120, 2003

11. Beck SD, Foster RS, Bihrle R, et al: Teratoma in the orchiectomy specimen and volume of metastasis are predictors of retroperitoneal teratoma in post-chemotherapy nonseminomatous testis cancer. J Urol 168:1402-1404, 2002[CrossRef][Medline]

12. Debono DJ, Heilman DK, Einhorn LH, et al: Decision analysis for avoiding postchemotherapy surgery in patients with disseminated nonseminomatous germ cell tumors. J Clin Oncol 15:1455-1464, 1997[Abstract]

13. Oldenburg J, Alfsen GC, Lien HH, et al: Postchemotherapy retroperitoneal surgery remains necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses. J Clin Oncol 21:3310-3317, 2003[Abstract/Free Full Text]

14. Rodriguez E, Mathew S, Mukherjee AB, et al: Analysis of chromosome 12 aneuploidy in interphase cells from human male germ cell tumors by fluorescence in situ hybridization. Genes Chromosomes Cancer 5:21-29, 1992[Medline]

15. Bosl G: Significant differences in Ki67, P53 expression and apoptosis characterize germ cell tumor (gct) differentiation and progression. Proc Am Soc Clin Oncol 19:660a 2000 (abstr 2602)

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Related Correspondence

• Bleomycin, Etoposide, and Cisplatin for Three Cycles Compared With Etoposide and Cisplatin for Four Cycles in Good-Risk Germ Cell Tumors: Is There a Preferred Regimen?
  Lawrence H. Einhorn and Richard S. Foster
  JCO 2006 24: 2597-2598 [Full Text]

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