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© 2000 American Society for Clinical Oncology
High-Dose Chemotherapy as Initial Salvage Chemotherapy in Patients With Relapsed Testicular CancerFrom the Department of Medicine, Division of Hematology/Oncology, Indiana University Medical Center, Indianapolis, IN. Address reprint requests to Lawrence H. Einhorn, MD, Indiana University, Indiana Cancer Pavilion, 535 Barnhill Dr RT 473, Indianapolis, IN 46202.
PURPOSE: To assess the role of high-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. PATIENTS AND METHODS: From August 1992 to April 1998, 65 patients with testicular cancer were treated with high-dose carboplatin and etoposide followed by peripheral-blood stem-cell transplantation or autologous bone marrow transplantation rescue as initial salvage chemotherapy at Indiana University. An identical course was given after hematopoietic reconstitution. Postchemotherapy resection of residual disease was performed in selected patients with incomplete radiographic response associated with normalization of markers. The median follow-up was 39 months (range, 16 to 91 months). RESULTS: Thirty-seven (57%) of the 65 patients are continuously disease-free. Three additional patients are disease-free with subsequent surgery. High-dose chemotherapy was associated with significant morbidity but no treatment-related mortality. CONCLUSION: High-dose chemotherapy as initial salvage chemotherapy achieved impressive long-term survival with acceptable toxicity in patients with relapsed testicular cancer.
GERM CELL NEOPLASMS are rare cancers, accounting for only 1% of male malignancies.1 Seventy percent to 80% of patients with disseminated cancer can be cured with standard-dose, cisplatin-based combination chemotherapy and aggressive surgical extirpation of residual disease if necessary.2 Unfortunately, 20% to 30% of these patients will become candidates for second-line therapy, either because of incomplete response to primary treatment or because of relapse from a complete remission (CR). Conventional second-line therapy with vinblastine, ifosfamide, and cisplatin (VeIP) in germ cell tumors achieves a CR rate of approximately 50% with a long-term survival rate of 24%, including 32% in patients with primary testicular cancer.3 Early studies with autologous bone marrow transplantation (ABMT) in heavily pretreated patients at Indiana University Medical Center found significant morbidity and mortality but a long-term survival rate of 15% to 20%.4 However, with better patient selection and improved supportive care, the treatment-related mortality for high-dose chemotherapy (HDCT) for patients with germ cell tumor is now 1% to 2%. The modest results of conventional-dose salvage regimens and the 15% cure rates with HDCT as third-line or later therapy, combined with the decreasing mortality and morbidity of the procedure, prompted us to advance this modality to the treatment of patients in initial relapse. However, in our earlier experience of patients with mediastinal nonseminomatous tumors treated with HDCT as initial salvage therapy, there were no long-term survivors.5 Hence, these patients were excluded. In the initial 25 patients, 52% remained disease-free with a median follow-up of 26 months.6 Our updated experience with 65 patients treated with tandem transplants as initial salvage therapy for testicular germ cell tumor is the subject of this article. We have also divided the patient populations into categories of known prognostic significance.
This study was a retrospective review of 65 patients with primary testicular cancer treated between August 1992 and April 1998 with two cycles of high-dose carboplatin and etoposide followed by peripheral-blood stem-cell (PBSC) transplantation or ABMT rescue as initial salvage treatment. Extragonadal germ cell tumors were excluded. The initial 22 patients have been previously described.6 Thirty-three subsequent patients were treated on the same protocol after giving informed consent. The last 10 patients were treated on a gene therapy protocol. In these patients, ex vivo cytokine-stimulated, mdr-1–transduced CD34-positive cells were transfused for the hematopoietic rescue after the second cycle of HDCT. This was followed by three cycles of maintenance oral etoposide. Each cycle consisted of etoposide administered at 50 mg/m2/d for 3 out of 4 weeks. An additional 16 patients of the earlier 55 patients also received maintenance oral etoposide after HDCT.7
Relapse after primary chemotherapy was documented by increasing serum marker levels or by an increasing mass on radiographic assessment. Eligibility criteria for consideration for HDCT included Eastern Cooperative Oncology Group (ECOG) performance status Patients who had progressed during initial cisplatin induction went straight to tandem transplantation. However, most patients were treated with one cycle of standard-dose salvage chemotherapy (usually VeIP) before HDCT for cytoreduction and to assess chemosensitivity. Sixteen patients received a second cycle of VeIP before HDCT. This was in the earlier phase of the study and was done because of lengthy delays from third-party payers to cover HDCT. Most patients were taken to HDCT regardless of their response to the pre-HDCT regimen. PBSCs were mobilized with granulocyte colony-stimulating factor (10 µg/kg/d) subcutaneously. On the fourth day of mobilization, daily pheresis was initiated through a dual-lumen pheresis catheter using a Cobe Spectra machine (Cobe Industries, Lakewood, CO). Collections were continued until 5 x 108 mononuclear cells/kg/cycle had been collected and cryopreserved. Autologous bone marrow was also collected in the first 25 patients. A minimum of 2 x 108 nucleated cells/kg/cycle were cryopreserved in a standard fashion.8 HDCT consisted of carboplatin 700 mg/m2 and etoposide 750 mg/m2 given intravenously on days -6, -5, and -4 on each cycle of therapy. There were no planned dose escalations or reductions. The day of PBSC or autologous bone marrow infusion was designated as day 0; days before that are minus and the days following are plus. All patients had PBSCs infused on day 0 through a free-flowing intravenous central catheter after premedication with diphenhydramine 50 mg given intravenously. A second cycle of the same chemotherapy was given after hematopoietic recovery unless there was progressive disease or unexpected toxicity. Patients were treated on either the Bone Marrow Transplant Unit or a dedicated hematology/oncology floor in either laminar air-flow or high-efficiency, particulate air–filtered private rooms. The last 12 patients were managed on an outpatient basis for the course of their transplant, except in the event of a complication. Prophylactic antibiotics were used routinely and included acyclovir, fluconazole, ciprofloxacin, and either penicillin or vancomycin. Neutropenic fever was treated empirically with imipenem 500 mg given intravenously every 6 hours or ceftazidime 2 gm given intravenously every 8 hours. All patients received granulocyte colony-stimulating factor 5 µg/kg/d beginning on day 0 and continuing until they had achieved an absolute granulocyte count of 2,000/mm3 for 2 days. Toxicity was graded according to ECOG toxicity criteria.9 CR was defined as the absence of clinically and radiographically detectable disease, including normalization of beta-human chorionic gonadotropin and alpha-fetoprotein levels for at least 1 month. Those patients in whom surgical resection of residual masses after HDCT yielded necrosis/fibrosis and who had negative markers were also labeled as having CR. The term no evidence of disease (NED)–teratoma was used to describe patients in whom complete surgical resection of residual masses yielded teratoma, and NED–carcinoma described those in whom complete surgical resection of residual masses yielded carcinoma. A partial response (PR) marker negative (m-) was defined as the presence of negative markers and large-volume radiographic disease that was stable or decreasing on serial radiographic studies. Postchemotherapy resection of residual disease was performed in selected patients with an incomplete radiographic response associated with normalization of serum markers. Patients who did not fall in the above categories after HDCT were considered to have failed treatment. Patients were considered to be refractory to cisplatin if stable disease or better was achieved but with evidence of tumor progression within 4 weeks of the last cisplatin-based chemotherapy. The tumor was considered absolutely refractory if progression was observed during cisplatin-based chemotherapy. Overall and progressive-free survival were assessed from the first day of salvage therapy. Survival curves were constructed using the Kaplan-Meier product-limit method.10 The patients were also stratified into good-, intermediate-, and poor-risk categories on the basis of a cumulative score calculated using a prognostic index derived from a multivariate analysis of 283 patients from four institutions.11 One point each was given for progressive disease before HDCT and nonseminomatous mediastinal primary or refractory disease before HDCT. Two points were given for human chorionic gonadotropin levels greater than 1,000 mIU/mL before transplantation or absolute refractory disease. Patients with a cumulative score greater than 2 were in the poor-prognosis group and those with a score of 0 were in the good-prognosis group. This is different from the International Germ Cell Consensus Classification staging system, which uses similar terms of good, intermediate, and poor risk but is for a different patient population, namely those receiving first-line therapy.12
Patient Characteristics Patient characteristics are described in Table 1. All patients had primary testicular cancer. Of the 65 patients, 10 had pure seminoma, six had pure choriocarcinoma, and 49 had nonseminomatous germ cell tumor. The majority of the patients were treated with bleomycin, etoposide, and cisplatin as first-line therapy. The relationship between response to first-line therapy and subsequent outcome after HDCT is described in Table 2. Of the 51 patients who achieved CR or PRm- with first-line therapy, 31 (60%) are continuously disease-free, in contrast to six (43%) of the 14 (P = .12) patients who had a marker positive (m+) PR or progression during initial chemotherapy. Although the sample size is very small, both patients who were absolutely refractory to their cisplatin combination therapy are continuously NED after HDCT.
Fifty-six of the 65 patients in this series were treated with one or two cycles of standard-dose salvage chemotherapy, before HDCT. Of the 56 patients who received induction therapy, 33 patients were treated with one cycle of VeIP, 16 with two cycles of VeIP, three with cisplatin, vinblastine, and bleomycin, and two each with etoposide, ifosfamide, and cisplatin and bleomycin, etoposide, and cisplatin. Three of the 56 patients had progressed during induction salvage chemotherapy. An additional 13 patients demonstrated evidence of progression while awaiting HDCT after induction therapy. The median duration between day 1 of the last cycle of induction chemotherapy and initiation of HDCT was 31 days (range, 24 to 57 days). Nine patients (including seven who had progressed during their initial cisplatin-based chemotherapy and two patients with seminoma who had earlier received abdominal radiation) received HDCT without induction therapy. Thus, 25 patients (38.4%) had evidence of progression at the time of starting HDCT. The patient characteristics immediately before HDCT are shown in Table 3. All patients had an ECOG performance status of 0 or 1 and a creatinine clearance rate of greater than 60 mL/min. Forty patients (61%) were in the good-prognosis group, 20 (31%) were intermediate, and five (8%) were in the poor-prognosis group, as previously described.11
HDCT: Response and Outcome Of the 65 patients who underwent HDCT, 58 (89.2%) received both cycles of chemotherapy. Reasons for not receiving a second cycle were poor platelet engraftment (n = 2), renal insufficiency (n = 1), overwhelming sepsis in cycle 1 (n = 1), progression (n = 1), and patient refusal (n = 2). CR was achieved in 28 patients (43%). One additional patient who could be given only one cycle of HDCT because of renal insufficiency achieved CR with one cycle of VeIP. An additional 13 patients (20%) were rendered NED by surgery. Teratoma was resected in nine and carcinoma in four. Fifteen additional patients were in PR with negative human chorionic gonadotropin and alpha-fetoprotein levels (PRm-).
With a median follow-up of 39 months (range, 16 to 91 months), 20 (35%) of these 57 patients who were NED or PRm- at the end of HDCT relapsed. Three of these patients were rendered disease-free by subsequent surgery, which revealed carcinoma in two and teratoma in one. These three patients remain disease-free 16, 45, and 80 months after surgery. Thus with HDCT as initial salvage therapy, 37 patients (57%) are continuously NED and 40 (60%) are currently NED. The median progression-free survival (range, 16 to 91 months) and the median overall survival (range, 5 to 91 months) (Fig 1) have not been reached.
Prognostic Factors for Treatment Response Of the 41 patients who were rendered disease-free by HDCT or by surgery immediately after HDCT, 30 are continuously and 33 are currently NED. One additional patient who could not receive a second course of HDCT is continuously disease-free after one additional cycle of VeIP. Nine (60%) of the 15 patients who were PRm- have relapsed. All eight patients who were m+ after HDCT have relapsed (Table 4). Thus, as expected, disease status after HDCT predicts long-term outcome.
A poor response to first-line therapy was associated with inferior results, but they were not statistically significant (P = .12). Of the 51 patients who achieved CR or PRm- with first-line therapy, 31 (62%) are continuously disease-free, in contrast to six (43%) of the 14 patients (P = .12) who progressed or achieved PRm+ (Table 2). Of the 56 patients who were treated with one or two cycles of VeIP or similar chemotherapy before HDCT, 27 were in CR or PRm- before transplantation. Twenty-one (78%) of these patients are currently and continuously disease-free, while 13 (44%) of the remaining 29 patients are continuously disease-free (P = .02). Results for our 65 patients as stratified by the prognostic index suggested by Beyer et al11 are presented in Table 5. Twenty-seven (68%) of 40 in the good-prognosis group are continuously disease-free. Ten (40%) of the 25 in the intermediate- and poor-prognosis groups are continuously NED (P < .01). However, our patients are different from those used in the original multivariate analysis because we excluded patients with primary mediastinal germ cell tumors and included only initial salvage therapy patients.
Ten of the 65 patients had pure seminoma. Nine (90%) of the 10 are continuously disease-free as compared with 28 (51%) of the 55 with nonseminomatous germ cell tumor.
Toxicity Six patients developed significant renal toxicity (creatinine level > 2.0 mg/dL), including one patient who needed short-term dialysis (creatinine level before transplantation was 1.2 mg/dL). The final 12 patients on this study were treated on an outpatient basis. Six of these 12 patients required subsequent admission because of neutropenic fever, intractable nausea, or grade 3 mucositis. There was no treatment-related mortality. Engraftment data were available for 114 cycles. The median time to achieving an absolute neutrophil count of greater than 500/mm3 was 10 days for both the first and second cycles of PBSC, and it was 17 and 17.5 days for the first and second cycles, respectively, with bone marrow. Similarly, time to achieving a platelet count of greater than 20,000/mm3 independent of transfusion was 10 and 9 days for the first and second cycles, respectively, with PBSC but was 12.5 and 14 days with bone marrow. Thus, there was improved engraftment with PBSC as compared with ABMT for both platelets (P = .05) and granulocytes (P = .04) for both cycles 1 and 2. The median time to absolute neutrophil count greater than 500/mm3 and platelet independence in patients who received mdr-1–transduced CD34-positive cells was 9 days (range, 8 to 11 days) and 13 days (range, 10 to 35 days), respectively.
Long-term disease-free survival rates of 12% to 52% have been reported with high-dose carboplatin and etopo- side with or without ifosfamide or cyclophosphamide from various centers in a heterogeneous group of patients with metastatic germ cell tumor.6,11,13-16 In this report, we have presented the results of the single largest series of patients with primary testicular germ cell tumor who received HDCT as initial salvage therapy using a uniform regimen. Administration of two cycles of HDCT with carboplatin and etoposide resulted in an overall disease-free survival rate of 60% (40 of 65 patients) and a continuous disease-free survival rate of 57% (37 of 65 patients). The minimum follow-up was 16 months. The median overall survival and progression-free survival have not been reached. These results are consistent with the 66% 2-year survival rate for HDCT as initial salvage therapy in good-risk patients reported by Rick et al.15 The results compare favorably with those observed after standard-dose salvage chemotherapy with VeIP. There was a 24% 5-year survival rate with VeIP as initial salvage chemotherapy, including 32% for patients with a testicular primary tumor.3 However, the trial described by Loehrer et al3 included patients with a poor performance status who may not have been eligible for HDCT and was conducted in an earlier time period. Our results are considerably better than those observed in patients with multiple recurrent and refractory germ cell tumors treated with HDCT and ABMT.11 Thus, they suggest that there may be an advantage to treatment of relapsed germ cell tumor with early HDCT. However, randomized trials are needed to evaluate the role of this approach. Currently an international randomized trial (IT 94) is being conducted to answer this question. We analyzed our results according to the prognostic score derived from the previously published multivariate analysis.11 Because of the small number of patients in the poor-risk category, they were grouped with patients in the intermediate-risk category. In the good-risk category, 27 patients (68%) are continuously disease-free and 28 (70%) are currently disease-free. In the intermediate-/poor-risk categories, 10 patients (40%) are continuously disease-free and 12 (48%) are currently disease-free (P < .01). Thus, the prognostic score predicts outcome after HDCT. However, it is rare that patients with a poor prognostic score can be cured with HDCT. The response to first-line treatment and outcome after HDCT were evaluated. Of the 51 patients who achieved CR or PRm- with first-line therapy, 31 (62%) are continuously disease-free, in contrast to six (43%) of the 14 (P = .12) patients who progressed or had PRm+. However, failure to reach statistical significance may have been due to the small number of patients. These findings are consistent with the results of a multivariate multi-institution analysis in which response to first-line therapy did not predict outcome.11 As expected, response to VeIP chemotherapy before HDCT as well as response to HDCT itself (P < .002) predicted long-term disease-free survival. Thirty of the 42 patients who were rendered free of disease by HDCT or by surgery after HDCT are continuously NED, whereas 33 are currently NED. One additional patient who could not receive the second cycle of HDCT but received VeIP continues to be free of disease. Six of the 15 patients who were PRm- are continuously and currently free of disease. All patients who had PRm+ after HDCT have since relapsed. Although the toxicity of HDCT is considerable, in recent years there has been marked mitigation of side effects. We have currently shifted HDCT for germ cell tumor to the outpatient setting. This is probably related to a patient population that is less heavily pretreated, use of peripheral stem cells instead of bone marrow, and use of hematopoietic growth factors. In contrast to the experience of other centers,15 only one of our last 12 patients had to be admitted for grade 3 or 4 mucositis. Also, nephrotoxicity was uncommon and in all cases transient. The difference may be related to the absence of ifosfamide in our preparative regimen. In conclusion, HDCT as initial salvage therapy achieved impressive long-term survival with acceptable toxicity in patients with relapsed testicular tumors. Patients in the intermediate- and poor-prognosis categories tend to do less well. Potential experimental approaches could include allogeneic minitransplantation or further dose escalation of carboplatin/etoposide in the autologous setting.
Supported in part by National Cancer Institute (Bethesda, MD) grant no. 2R35CA-39844-14 and the Walther Cancer Institute, Indianapolis, IN.
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
1. Einhorn LH: Testicular cancer: An oncological success story. Clin Cancer Res 3: 2630-2632, 1997 2. Hainsworth JD: Testicular germ cell neoplasms. Am J Med 75: 817-832, 1983[Medline] 3. Loehrer P, Nichols C, Weathers T, et al: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16: 2500-2504, 1998[Abstract]
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Nichols CR, Williams S: Dose intensive chemotherapy in refractory germ cell cancer: A phase I/II trail of carboplatin and etoposide with autologous bone marrow transplant. J Clin Oncol 14: 2625-2626, 1987 5. Saxman SB, Nichols CR, Einhorn LH: Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: The Indiana University experience. J Clin Oncol 12: 1390-1393, 1994[Abstract] 6. Broun ER, Nichols CR, Gize G, et al: Tandem high dose chemotherapy with autologous bone marrow transplantation for initial relapse of testicular germ cell cancer. Cancer 79: 1605-1610, 1997[Medline] 7. Cooper MA, Einhorn LH: Maintenance chemotherapy with daily oral etoposide following salvage therapy in patients with germ cell tumors. J Clin Oncol 13: 1167-1169, 1995[Abstract] 8. English DLR, Graves V: Semi-automated processing of bone marrow for transplantation. Transfusion 29: 12-16, 1989[Medline] 9. Oken MN, Tormey DC: Toxicity and response criteria of the Eastern Oncology Group. Am J Clin Oncol 5: 649-655, 1982[Medline] 10. Kaplan E: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53: 457-481, 1958
11.
Beyer J, Mandanas R, Linkesch W, et al: High dose chemotherapy as salvage treatment in germ cell tumor: A multivariate analysis of prognostic variables. J Clin Oncol 14: 2638-2645, 1996 12. International Germ Cell Collaborative Group-International Germ Cell Consensus Classification-a prognostic factor based staging system for metastatic germ cell tumors-a multiinstitutional study. J Clin Oncol 11:598, 1993 13. Broun ER, Nichols CR, Kneebone P, et al: Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 117: 124-128, 1992
14.
Motzer RJ, Mazumdar M, Bajorin DF, et al: High-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Clin Oncol 15: 2546-2552, 1997 15. Rick O, Beyer J, Kingreen D, et al: High-dose chemotherapy in germ cell tumours: A large single centre experience. Eur J Cancer 34: 1883-1888, 1998 16. Beyer J, Kingreen D, Krause M, et al: Long-term survival of patients with recurrent or refractory germ cell tumors after high dose chemotherapy. Cancer 79: 161-168, 1997[Medline] Submitted January 1, 2000; accepted May 31, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2, normal cardiac function, normal liver function test results, creatinine clearance greater than 60 mL/min, diffusion capacity of more than 50%, and absence of active infections. All patients met the pretransplant assessment criteria per our institutional protocol and signed an informed consent conforming to our institutional review board guidelines. 
