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© 2002 American Society for Clinical Oncology Salvage Chemotherapy for Patients With Advanced Pure SeminomaByFrom the Genitourinary Oncology Service, Divisions of Solid Tumor Oncology and Biostatistics, Departments of Medicine, Biostatistics and Epidemiology, and Surgery, and Urology Service, Memorial Sloan-Kettering Cancer Center, and Departments of Medicine and Pathology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY. Address reprint requests to Robert J. Motzer, MD, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: motzerr{at}mskcc.org
PURPOSE: We describe the response to conventional or high-dose salvage chemotherapy in patients with advanced seminoma who experience disease progression after receiving first-line platinum-based treatment. PATIENTS AND METHODS: Twenty-seven patients with progressive, advanced, pure seminoma were treated with salvage chemotherapy. Fifteen patients were treated with conventional-dose cisplatin-and-ifosfamide combination chemotherapy. Twelve patients were treated with high-dose chemotherapy followed by autologous stem-cell rescue. RESULTS: Fifteen patients (56%) achieved a complete response (CR), nine achieved CR with a conventional-dose cisplatin and ifosfamide program, and six experienced CR after high-dose chemotherapy. Fourteen patients (52%) are alive and disease-free, with 13 (48%) continuously disease-free at a median follow-up of 72 months. Twelve (57%) of 21 patients whose pretreatment tumors were studied morphologically were found to have seminoma with atypia. Eight patients underwent resection after salvage chemotherapy; six with histologic findings of necrotic debris/fibrosis alone are alive and disease-free at last follow-up. Both patients with viable seminoma found at surgery died of disease. CONCLUSION: Most patients with advanced seminoma are cured with standard first-line programs of cisplatin and etoposide with or without bleomycin. A small minority of patients with pure seminoma have resistant tumors and require salvage chemotherapy. In this setting, approximately 50% of patients with recurrent pure seminoma achieve durable CR with conventional or high-dose salvage chemotherapy. Identification of biologic markers to predict clinical outcome and an enhanced understanding of the basic biologic features of seminoma may lead to improvements in the management of this disease.
SINCE THE INTRODUCTION of cisplatin-based combination chemotherapy, 70% to 80% of patients with metastatic testicular germ cell cancers (GCT) are cured.1 In this regard, pure seminoma histology is recognized as particularly chemotherapy sensitive and is associated with a high chance of cure, using standard chemotherapy programs of cisplatin and etoposide with or without bleomycin.2 When patients with pure seminoma are stratified according to internationally accepted risk criteria, 90% of patients are classified as good risk, and more than 85% are cured with cisplatin-based combination chemotherapy.2,3 A minority of patients with advanced pure seminoma, however, do not achieve a complete response (CR) with initial chemotherapy or will relapse after a CR and require salvage therapy.3 In this setting, patients are treated on programs that have been largely used in nonseminoma, because their histology is more likely to be refractory to standard chemotherapy programs. Effective second-line chemotherapy in patients with resistant GCT using ifosfamide and cisplatin with either etoposide or vinblastine results in a CR of 50%, with durable complete remission in approximately 25% of patients.4,5 In patients who are not cured by ifosfamide-based and cisplatin-based salvage chemotherapy, high-dose chemotherapy (HDCT) with autologous stem-cell rescue can cure 15% to 25% of patients.6,7 However, published series of both regimens to date have been composed almost entirely of patients with nonseminoma histology. The small number of patients who require salvage chemotherapy has limited the study of optimal management of pure seminoma in the salvage setting.8 We describe the experience at our center in the management of 27 patients with resistant seminoma. Treatment outcomes and surgical resection after salvage chemotherapy are discussed.
Patients Twenty-seven patients with metastatic pure seminoma who required salvage chemotherapy were identified from July 1987 to December 1999 on a clinical trial approved by the institutional review board at Memorial Sloan-Kettering Cancer Center (MSKCC). For all patients, salvage chemotherapy consisted of conventional-dose cisplatin and ifosfamide or high-dose chemotherapy with autologous stem-cell rescue.5,7,9,10 All patients met criteria for prechemotherapy histologic diagnosis of pure seminoma, including (1) normal alpha fetoprotein at initial diagnosis, (2) histologic diagnosis confirmed at MSKCC, and (3) clinical evidence of chemotherapy resistance by demonstration of progressive disease after treatment with platinum-based combination chemotherapy. Progression of disease was evident by increasing human chorionic gonadotropin (HCG), viable unresected seminoma, and/or increasing mass on radiologic studies. The salvage chemotherapy programs, toxicities, and treatment results of the trials have previously been reported.5,7,9,10 Fifteen patients (56%) were treated on conventional-dose cisplatin and ifosfamide regimens with vinblastine, etoposide, or paclitaxel.5,10 Twelve patients (44%) were treated on high-dose chemotherapy with autologous stem-cell rescue programs that consisted of etoposide and carboplatin with or without cyclophosphamide (Table 1). 7,9 Since 1993, patients were prospectively identified by clinical features and risk-stratified to conventional or high-dose second-line chemotherapy.9,10 Patients with a gonadal primary site who experience relapse after CR with first-line therapy have a chance for cure with conventional-dose cisplatin and ifosfamide salvage therapy. These patients were entered onto a trial of combined paclitaxel with ifosfamide and cisplatin in a first-line salvage program.10 In contrast, patients with an incomplete response (IR) to first-line therapy rarely achieve a durable CR to conventional-dose cisplatin plus ifosfamide salvage therapy.5 These patients were treated on a clinical trial of repetitive cycles of dose-intense therapy that consisted of paclitaxel and ifosfamide followed by high-dose carboplatin and etoposide with autologous stem-cell rescue.9
After chemotherapy, clinical restaging, including serum tumor markers (HCG, lactate dehydrogenase [LDH], alpha fetoprotein) and radiographic studies, were performed to evaluate initial sites of disease. Patients with normalization of serum tumor markers and radiographic evidence of residual disease after salvage chemotherapy were referred for surgical resection at the discretion of the treating physician. Responses were categorized as either CR or IR. A CR to chemotherapy was defined as the disappearance of all clinical, radiographic, and biochemical evidence of disease for a minimum of 4 weeks after chemotherapy; this included patients for whom surgical resection of residuum yielded only necrotic debris or fibrosis. A CR to chemotherapy plus surgery was defined as the complete excision of all masses that contained seminoma.5 An IR was, therefore, observed in patients who did not achieve a CR with chemotherapy with or without surgery. This included patients who experienced disease progression on therapy, had unresectable seminoma at surgery, or had a partial response with negative markers. The latter consisted of patients who had a residual radiographic abnormality after chemotherapy but were not evaluated by surgery and who remained progression-free at the time of analysis, with normal values of LDH and HCG.5
Surgical Resection After Salvage Chemotherapy
Pathology Review Twelve (57%) of 21 patients with tumors studied morphologically were found to have the presence of seminoma with atypia. Seven of these patients had pathologic material reviewed from testis, and five, from retroperitoneal lymph node. Eleven were obtained before the patient received any chemotherapy, and one was obtained after chemotherapy but before entry onto this study.
Statistical Methods and Prognostic Analysis Factors considered in univariate analysis included site of metastatic disease (presence or absence of nonpulmonary visceral metastases) and histology before salvage chemotherapy (classical seminoma v seminoma with atypia11). The relationship between survival and each of the variables was analyzed using a permutation test on the basis of the log-rank statistic.13
Patient Characteristics Patient characteristics are shown in Table 2. Primary site was testis in 26 (96%) and extragonadal (retroperitoneum) in one patient. Initial response to first-line therapy was CR in eight patients (30%) and IR in 19 (70%). Six patients (22%) had prior radiation therapy. Twenty-three patients (85%) had been treated with one prior cisplatin-based or carboplatin-based regimen, and four patients (15%) had received two prior regimens. Twelve (44%) and 17 (65%) had abnormally elevated serum concentrations of HCG and LDH, respectively, before salvage chemotherapy.
Response and Survival Analysis CR to salvage chemotherapy was achieved in 15 (56%) of 27 patients; none of these patients required resection of residual viable seminoma (Table 3). Twelve patients (44%) achieved an IR. This included nine patients who experienced failure of normalization or increased serum tumor marker values and/or increased radiographic masses and three who had a partial response with normal serum tumor markers but did not have surgery to evaluate residual radiographic abnormalities. Of the 15 patients treated with cisplatin-containing and ifosfamide-containing chemotherapy, nine (60%) achieved a CR, with eight (53%) alive and without evidence of disease at last follow-up. None of the six patients with an IR to cisplatin-containing and ifosfamide-containing chemotherapy are alive at last follow-up. Of the 12 patients treated with high-dose chemotherapy, six (50%) of the 12 patients achieved a CR, and all six patients remain alive and disease-free at last follow-up. One patient treated with high-dose chemotherapy achieved a partial response with normalization of markers and is progression-free at 33+ months but is considered alive with disease. Therefore, seven (58%) of 12 patients treated with high-dose chemotherapy are alive at last follow-up (Table 3). Two patients experienced relapse from a CR to conventional-dose cisplatin and ifosfamide combination chemotherapy. One patient achieved a CR to subsequent high-dose chemotherapy with autologous stem-cell transplant and remains disease-free at 85+ months.
The median survival time for the 27 patients has not been reached, with a median follow-up of survivors of 72 months (range, 9 to 157 months) (Fig 1). The 2-year survival rate is 57% (95% confidence interval, 38 to 77). Overall, 14 patients (52%) are alive without evidence of disease, 13 (48%) of whom are alive and continuously disease-free after CR with salvage chemotherapy at last follow-up (Table 4). Seven patients are alive and continuously disease-free after conventional-dose cisplatin and ifosfamide chemotherapy, and six patients are alive and continuously disease-free after high-dose chemotherapy at last follow-up.
Six (22%) of 27 patients had nonpulmonary visceral (bone and liver) metastases before treatment with salvage chemotherapy. Twelve (57%) of 21 patients with tumors studied morphologically were found to have the presence of seminoma with atypia. No statistically significant difference in survival was found when comparing those patients with and without nonpulmonary visceral metastases or when comparing classical versus seminoma with atypia. However, it must be noted that prior response was used to stratify patients to conventional-dose or high-dose chemotherapy.
Surgery After Salvage Chemotherapy
A minority of patients with pure seminoma have an IR to initial cisplatin-based chemotherapy or relapse from a CR and require salvage chemotherapy. One prior report also addressed treatment results of salvage cisplatin and ifosfamide therapy in patients with pure seminoma.8 The CR proportion in patients treated with cisplatin and ifosfamide chemotherapy in the present series was lower than that reported by Miller et al,8 but the durable response rate was identical. The difference in CR between the two series may reflect patient selection because our series included some patients who were more heavily pretreated. Until specific prognostic features are identified for pure seminoma, our approach to using high-dose chemotherapy for these patients follows the same paradigm used in the management of patients with resistant nonseminoma.9,10 Nine patients with seminoma in this series were selected to receive dose-intensive chemotherapy, with paclitaxel, ifosfamide, carboplatin, and etoposide as second-line therapy on the basis of unfavorable prognostic features; all nine patients had achieved a prior IR to initial cisplatin-combination chemotherapy.9 Six (67%) of the nine patients are alive, and all are progression-free. In this regard, seminoma patients with an IR to initial chemotherapy, characterized by progressive disease or residual radiographic disease and normal markers of less than 6 months, are offered treatment with a high-dose program. The role for postchemotherapy surgery in seminoma after first-line chemotherapy is controversial.14 We are not aware of any series that addresses the issue following salvage chemotherapy. None of the patients with findings of viable seminoma after salvage chemotherapy surgery are alive. However, all six patients with necrosis found at surgery remain alive without evidence of disease at 9+ to 87+ months after salvage chemotherapy. Because both patients with histologic findings of viable seminoma at surgery died, a therapeutic benefit for surgery was not evident in this small series. However, distinguishing seminoma from necrosis is useful in the assessment of response and prognosis and could be used to direct high-dose chemotherapy to patients with unresectable viable seminoma after treatment with cisplatin and ifosfamide salvage chemotherapy. Seminoma with atypia is distinguished by atypical morphologic features and a distinct immunohistochemical staining pattern (c-kit negativity or decreased positivity, rare single-cell positivity of CD30, increased expression of blood group antigens, and greater nuclear positivity of Ki-67)11,15 The clinical course has been suggested to be more aggressive in some cases than classic seminoma.15,16 Seminoma with atypia has been proposed to represent early transformation to nonseminomatous histology.3,15-17 Given the small sample size in this study, we were unable to identify an unfavorable prognosis for seminoma with atypia to treatment with salvage chemotherapy. However, the number of patients with seminoma with atypia in this series (selected by chemotherapy resistance) was substantial. It is possible that atypia may result from chemotherapy-induced changes in this setting. However, our prior observations on such changes in untreated cases11 raise the possibility that seminoma with atypia may be a poor prognostic feature for patients with advanced seminoma that warrants prospective study in untreated patients. In conclusion, seminoma is highly chemosensitive, and most patients are cured with standard first-line programs of cisplatin and etoposide with or without bleomycin. A minority of patients with pure seminoma have resistant tumors and require salvage chemotherapy. In this setting, approximately 50% of patients with recurrent pure seminoma achieve durable CR to conventional or high-dose salvage chemotherapy. Until specific prognostic features are identified for pure seminoma in directing salvage chemotherapy, our approach has been to follow the same paradigm used in the management of patients with resistant nonseminoma. A high number of patients with seminoma with atypia were identified in this series, which was selected by chemotherapy resistance, and this histology warrants study as a prognostic feature in untreated patients. Identification of biologic markers to predict clinical outcome and an enhanced understanding of the basic biologic features of seminoma may lead to improvements in the management of this disease.
Supported in part by a grant from the Brian Piccolo Cancer Research Fund and grant nos. NIH CA-09207-23 and NIH K24 CA-82431 from the National Institutes of Health, Bethesda, MD. We thank Carol Pearce for her review of the manuscript and Jessica Zwaska for data collection.
1. Bosl GJ, Motzer RJ: Testicular germ-cell cancer. N Engl J Med 337: 242-253, 1997
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. Mencel PJ, Motzer RJ, Mazumdar M, et al: Advanced seminoma: Treatment results, survival, and prognostic factors in 142 patients. J Clin Oncol 12: 120-126, 1994[Abstract] 4. Loehrer PJ, Lauer R, Roth BJ, et al: Salvage therapy in recurrent germ cell cancer: Ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 109: 540-546, 1988
5.
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
6.
Nichols CR, Williams S: Dose intensive chemotherapy in refractory germ cell cancer: A phase I/II trial of carboplatin and etoposide with autologous bone marrow transplant. J Clin Oncol 14: 2625-2626, 1987
7.
Motzer RJ, Mazumdar M, Bosl GJ, et al: High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: Treatment results and prognostic factors for survival and toxicity. J Clin Oncol 14: 1098-1105, 1996 8. Miller KD, Loehrer PJ, Gonin R, et al: Salvage therapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma. J Clin Oncol 15: 1427-1431, 1997[Abstract]
9.
Motzer RJ, Mazumdar M, Sheinfeld J, et al: Sequential dose-intensive paclitaxel, ifosfamide, and carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18: 1173-1180, 2000 10. Motzer RJ, Sheinfeld J, Mazumdar M, et al: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 18: 2412-2418, 2000 11. Tickoo SK, Bosl GJ, Reuter VE: Testicular seminoma: A clinicopathological and immunohistochemical study of 105 cases. Mod Pathol 13: 116A, 2000 (abstr) 12. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 13. Heller G, Venkatraman ES: Resampling procedures to compare two survival distributions in the presence of right censored data. Biometrics 52: 1204-1213, 1996[CrossRef]
14.
Puc HS, Heelan R, Mazumdar M, et al: Management of residual mass in advanced seminoma: Results and recommendations from the Memorial Sloan-Kettering Cancer Center. J Clin Oncol 14: 454-460, 1996
15.
Motzer RJ, Reuter VE, Cordon-Cardo C, et al: Blood group-related antigens in human germ cell tumors. Cancer Res 48: 5342-5347, 1988 16. Srigley JF, Mackay B, Toth P, et al: The ultrastructure and histogenesis of male germ cell neoplasia with emphasis on seminoma with early carcinomatous differentiation. Ultrastruct Pathol 12: 67-86, 1988[Medline]
17.
Yuasa T, Yoshiki T, Ogawa O, et al: Detection of alpha-fetoprotein mRNA in seminoma. J Androl 20: 336-340, 1999. Submitted May 21, 2001; accepted August 13, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
