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Originally published as JCO Early Release 10.1200/JCO.2003.08.902 on October 20 2003 © 2003 American Society for Clinical Oncology
Poor-Risk Testicular Cancer and High-Dose ChemotherapyMemorial Sloan-Kettering Cancer Center, New York, NY SCHMOLL ET al1 have reported the results of a single-arm study of high-dose chemotherapy with stem-cell support as first-line therapy for patients with advanced germ cell tumors (GCTs) with poor prognostic features. This long-term study suggests a favorable outcome in these patients given high-dose chemotherapy, when compared with historical control of poor-risk patients treated with conventional-dose therapy. As expected, treatment-related toxicity was considerably worse than anticipated, compared with standard therapy consisting of four cycles of cisplatin, etoposide, and bleomycin (BEPx4). The authors acknowledge two ongoing phase III trials in the United States and Europe that are seeking to more definitively define the role of high-dose chemotherapy given as first-line treatment to patients with poor-risk GCTs. Advanced GCTs are classified according to International Consensus Criteria2 using serum tumor marker values, site of metastasis, histology, and primary site, leading to risk-directed therapy as the standard approach. The successful management of advanced GCTs with cisplatin-based combination therapy, followed by surgical resection of residual tumor, stands as a milestone in medical oncology. The complete response rate for patients selected by good-risk features and who are treated with four cycles of etoposide plus cisplatin or three cycles of BEP is approximately 90%.3 However, between 20% and 30% of advanced GCT patients either relapse or achieve an incomplete response to cisplatin-based chemotherapy. These patients can usually be identified at initial presentation by the presence of poor-risk clinical features, such as nonseminoma histology with very high serum tumor markers; metastases to liver, bone, or brain; or mediastinal primary site. Since about one half of all patients with poor-risk GCTs die of their cancer, current clinical investigations seeking to improve survival in poor-risk GCT patients focus on developing more effective chemotherapy treatments. An improved treatment outcome for poor-risk GCTs was observed in a randomized trial in which etoposide was substituted for vinblastine in combination with bleomycin and cisplatin, establishing BEPx4 as standard treatment in 1987.4 Further efforts to improve outcome in poor-risk GCTs have been unsuccessful. Regimens which showed promise in single-arm studies, but failed to show superior efficacy compared to BEPx4 in phase III trials, include etoposide, ifosfamide plus cisplatin (VIP),5 double-dose platinum, etoposide plus bleomycin,6 and sequential treatment with BOP/VIP-B.7 High-dose therapy was first given to heavily pretreated patients as third-line therapy, and long-standing complete remission were reported in 15% to 25% of patients.8 Toxicity and treatment-related mortality have since been reduced by use of hematopoietic growth factors and peripheral blood-derived stem cells (rather than bone marrow). Studies of first-line (such as that reported by Schmoll et al1) or second-line high-dose chemotherapy show earlier intervention reduces the cumulative toxicity of high-dose chemotherapy. Patients with advanced testicular GCTs who achieve a partial response to first-line BEPx4, and who develop progressive disease are considered refractory, and are conventionally treated with a high-dose carboplatin-containing program as second-line therapy. These patients rarely achieve a complete response to vinblastine, ifosfamide, and cisplatin (VeIP) salvage chemotherapy.9,10 There is no consensus as to whether high-dose chemotherapy should be given to all patients who relapse following a complete response to first-line chemotherapy. A single-arm study supports this approach, showing a high complete response rate after two cycles of high-dose carboplatin and etoposide with stem cell support given to patients with relapsed testicular GCTs.11 But, a randomized trial of three cycles of VeIP plus one cycle of high-dose chemotherapy compared with four cycles of VeIP showed no survival benefit.12 It may be likely that multiple cycles of high-dose chemotherapy are necessary to achieve a favorable outcome, and, therefore, the single cycle of high-dose therapy given in that trial may have negatively affected the outcome.12 Four cycles of a conventional-dose regimen of paclitaxel, ifosfamide, and cisplatin resulted in a high proportion of durable complete responses as second-line therapy for patients with relapsed testicular GCT.13 This study showed that patients can be selected for a favorable outcome to conventional-dose salvage therapy by prognostic features—testis primary site plus a history of complete response to first-line chemotherapy. The approach followed at our center is a risk-directed strategy in selecting patients for conventional-dose or high-dose second-line therapy. Two large ongoing randomized trials in the United States and Europe are designed to show whether the higher burden of toxicity associated with high-dose therapy in first-line treatment for patients with poor-risk GCTs is balanced by improved long-term survival. The phase I/II trial in this issue of the Journal of Clinical Oncology by Schmoll et al1 provided the rationale for the high-dose VIP arm in the ongoing poor-risk trial in Europe. The trial in the United States compares BEPx4 with two cycles of BEP plus two cycles of high-dose carboplatin, etoposide, and cyclophosphamide with stem cell support. Unfortunately, accrual to the phase III trial in the United States has been slow, despite broad cooperative group participation. Treatment failure for patients with advanced GCTs is particularly devastating, given the usually young age of the patient population and the high expectations for cure. Our goal must be to cure all patients with advanced GCT, with research efforts focusing on more effective first-line treatments for patients with poor- and intermediate risk GCTs, and effective second-line therapy for patients showing platinum resistance. Multiple reports have documented that expertise in treating GCTs provides patients with their best chance of cure.14–16 An analysis performed on 380 patients with poor-risk GCTs treated on a randomized trial showed a poorer chance of survival at institutions entering less than five patients compared with those institutions entering a larger number of patients.17 Poor- and intermediate-risk patients should be referred to experienced centers, to gain access to clinical trials and expertise in management from GCT specialists. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. Schmoll H-J, Kollmannsberger C, Metzner JT, et al: Long-term results of first-line sequential high-dose VIP-chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: An extended phase I/II study of the German Testicular Cancer Study Group. J Clin Oncol 21:4083–4091, 2003
2. 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
3. Bosl GJ, Motzer RJ: Testicular germ-cell cancer. N Engl J Med 337:242–253, 1997 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. Hinton S, Catalano PJ, Einhorn LH, et al: Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer 97:1869–1875, 2003[CrossRef][Medline] 6. Nichols CR, Williams SD, Loehrer PJ, et al: Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: A Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 9:1163–1172, 1991[Abstract] 7. Kaye SB, Mead GM, Fossa S, et al: Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: A randomized Medical Research Council/European Organization for Research and Treatment of Cancer study. J Clin Oncol 16:716–724, 1998[Abstract]
8. Motzer RJ, Bosl GJ: High-dose chemotherapy for resistant germ cell tumors: recent advances and future directions. J Natl Cancer Inst 84:1703–1709, 1992
9. McCaffrey JA, Mazumdar M, Bajorin DF, et al: Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: Response and survival. J Clin Oncol 15:2559–2563, 1997 10. Loehrer PJ, Gonin R, Nichols CR, et al: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16:2500–2504, 1998[Abstract]
11. Bhatia S, Abonour R, Porcu P, et al: High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18:3346–3351, 2000 12. Rosti G, Pico J-L, Wandt H, et al: High-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumors: First results of a prospective randomised trial of the European Group for Blood and Marrow transplantation—IT-94 study. Proc Am Soc Clin Oncol 21:180a, 2003 (abstr) 13. Donadio AC, Sheinfeld J, Bacik J, et al: Paclitaxel, ifosfamide, and cisplatin (TIP): an effective second-line therapy for patients with relapsed testicular germ cell tumors. Proc Am Soc Clin Oncol 22:383, 2003 (abstr 1537) 14. Harding M, Paul J, Gillis CR, et al: Management of malignant teratoma: does referral to a specialist unit matter? Lancet 341:999–1002, 1993[CrossRef][Medline] 15. Aass N, Klepp O, Cavallin-Stahl E, et al: Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: A multicenter experience. J Clin Oncol 9:818–826, 1991[Abstract] 16. Norum J, Nordoy T, Wist E: Testicular cancer treated in a minor general oncology department. Eur J Cancer 31A:293–295, 2003 17. Collette L, Sylvester RJ, Stenning SP, et al: Impact of the treating institution on survival of patients with "poor prognosis" metastatic nonseminoma. J Natl Cancer Inst 91:39–46, 2003
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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