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Journal of Clinical Oncology, Vol 23, No 27 (September 20), 2005: pp. 6549-6555 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.19.638 Combination of Paclitaxel, Ifosfamide, and Cisplatin Is an Effective Second-Line Therapy for Patients With Relapsed Testicular Germ Cell TumorsFrom the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; and the Department of Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY Address reprint requests to G. Varuni Kondagunta, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: kondaguv{at}mskcc.org
PURPOSE: The efficacy of paclitaxel was evaluated in combination with ifosfamide and cisplatin as second-line chemotherapy for patients with relapsed testicular germ cell tumors (GCTs). PATIENTS AND METHODS: Forty-six patients with progressive metastatic GCTs were treated with paclitaxel and ifosfamide plus cisplatin (TIP) as second-line therapy. Eligibility required that patients have both a testis primary tumor site and a prior complete response (CR) to a first-line chemotherapy program, which had been identified previously as favorable prognostic factors to conventional-dose salvage chemotherapy. RESULTS: Thirty-two (70%) of 46 patients achieved a CR to treatment. Three patients (7%) who achieved a CR relapsed after TIP chemotherapy. Twenty-nine patients are continuously disease free at a median follow-up time of 69 months, resulting in a 63% durable CR rate and a 2-year progression-free survival rate of 65% (95% CI, 51% to 79%). CONCLUSION: Four cycles of TIP as second-line therapy achieved a durable CR rate in a high proportion of patients with relapsed testicular GCT. The high CR rate emphasizes the importance of patient selection according to prognostic factors to achieve a favorable outcome to conventional-dose salvage therapy.
Between 70% and 80% of patients with advanced, metastatic germ cell tumors (GCTs) achieve a continuous complete response (CR) to initial treatment with cisplatin and etoposide with or without bleomycin.1,2 For patients with resistant GCT, potentially curative treatment options are available. Treatment with ifosfamide and cisplatin plus vinblastine (VeIP) chemotherapy results in a CR in 50% of patients, but only one half of these CRs remain durable.3,4 Two cycles of VeIP followed by two cycles of high-dose therapy is reported to result in a long-term response in approximately half of the relapsed patients.5 Two cycles of high-dose carboplatin-containing chemotherapy with peripheral-blood–derived stem-cell support resulted in durable CRs in 15% to 20% of patients as third-line therapy.6-9 Prognostic factors can be used to direct a specific therapy to the patients who are most likely to benefit. Analyses have shown that patients with gonadal primary tumor sites who relapse after CR to first-line therapy are more likely to achieve a favorable treatment outcome after conventional-dose cisplatin plus ifosfamide salvage therapy.3,4,10 These favorable prognostic features were used as eligibility criteria for this clinical trial in patients with relapsed GCTs previously treated with a conventional-dose chemotherapy program. While the trial was ongoing, the entity of late-relapse GCT was more widely recognized.11 These patients were defined as having recurrent GCT more than 2 years from completion of initial chemotherapy in the absence of a second gonadal primary tumor. In contrast to patients who relapse within 2 years of chemotherapy, patients with late-relapse GCT were described as highly chemoresistant (to VeIP), with surgical resection of metastases as the preferred therapy. During the accrual period of this trial, patients who had a prior CR and a gonadal primary tumor were treated with paclitaxel and ifosfamide plus cisplatin (TIP), regardless of the category of late-relapse GCT and multiple sites of disease. Paclitaxel was combined with cisplatin plus ifosfamide in this trial based on its single-agent activity against GCT12,13 and in vitro studies showing synergy with cisplatin and ifosfamide.14 Some data of patients who were treated on this trial have been previously reported, including data of patients treated on a phase I part of the study in which the paclitaxel dose was escalated among cohorts to determine the maximum-tolerated dose (MTD).15 In this article, we report the results of 46 patients treated on this completed trial with TIP chemotherapy.
Eligibility Forty-six patients with progressive GCTs were entered onto this prospective clinical trial. The study was approved by the Memorial Sloan-Kettering Cancer Center Institutional Review Board. All patients had histologically confirmed, advanced-stage GCT, established clinical resistance to platinum combination chemotherapy determined by a failure to achieve a continuous CR to a prior platinum-based regimen, and all of the following favorable prognostic features for achieving a favorable outcome to conventional-dose cisplatin-based salvage chemotherapy: (1) prior treatment limited to a single program of six or fewer prior cycles of cisplatin; (2) gonadal primary tumor site; and (3) either a CR or a partial response for more than 6 months after completion of chemotherapy in the setting of normal serum tumor markers (so-called partial response with negative markers). Progressive GCT in this patient population was documented by increasing serum concentrations of serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (HCG). In the absence of elevated serum tumor marker(s), biopsy was performed to document the presence of viable GCT and to exclude pure teratoma.
Additional eligibility criteria included a WBC count of
Pretreatment Evaluation
Treatment Program Dexamethasone 20 mg orally 14 and 7 hours before treatment with paclitaxel, diphenhydramine 50 mg intravenously 1 hour before paclitaxel, and cimetidine 300 mg intravenously 1 hour before paclitaxel were administered as pretreatment therapy to avoid acute allergic reactions. Standard antiemetic and hydration protocols were followed. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) 5 µg/kg daily by subcutaneous injection on days 7 to 18. If the WBC exceeded 10,000/µL for 2 days, G-CSF therapy was discontinued. Re-treatment with the subsequent cycle on day 22 required a neutrophil count of 450/µL or higher and a platelet count of more than 75,000/µL. Dose reductions were not made; recovery from toxicity was required before re-treatment at the full dose occurred.
Supportive Care
Protocol Design
Evaluation of Response, Toxicity, and Survival Computed tomography scan of the chest, abdomen, and pelvis was performed at the conclusion of treatment for assessment of tumor response. Radiographic studies were not routinely performed between cycles of therapy unless indicated by patient status. After the completion of four cycles of chemotherapy and complete radiographic and marker assessment, surgical resection of all residual masses was recommended to patients with normalized serum tumor markers. A CR to chemotherapy alone was defined as the disappearance of all clinical, radiographic, and biochemical evidence of disease for at least 4 weeks; this included patients in whom surgical resection of residual disease yielded necrotic debris, fibrosis, or mature teratoma but no evidence of viable malignant tumor. A CR to chemotherapy plus surgery was defined as the complete excision of all masses, at least one of which contained viable GCT other than mature teratoma. Therefore, an incomplete response (IR) was observed in patients who failed to achieve a CR to chemotherapy with or without surgery, including patients who were observed to have failure of serum tumor marker normalization. Overall survival was defined as time from initiation of therapy to last follow-up or death from any cause. Progression-free survival was measured from the initiation of therapy to relapse or last follow-up for the patients with CRs and time until treatment failure for the patients with IRs. Survival distributions were estimated using the Kaplan-Meier method.16 Late relapse was defined as having a recurrent GCT more than 2 years from completion of initial chemotherapy in the absence of a second gonadal primary tumor.
Patient Characteristics Forty-six patients were treated; 41 patients had nonseminoma, and five had pure seminoma (Table 1). Forty-three patients had no evidence of a second primary GCT, and three patients developed metastatic disease in the setting of a second gonadal primary GCT, after having had cisplatin-based chemotherapy to treat the first primary GCT. Fourteen patients had late-relapse GCT. Thirty-four patients (74%) were previously treated with a combination chemotherapy program consisting of cisplatin and etoposide with or without bleomycin; nine patients (19%) were previously treated with VAB-6 (cisplatin, vinblastine, dactinomycin, bleomycin, and cyclophosphamide) or other vinblastine-based therapy; and three patients (7%) previously received etoposide and carboplatin with or without bleomycin (Table 1).17
Treatment and Toxicity All 46 patients were treated with TIP chemotherapy. Fewer than four cycles were administered to five patients who developed progressive disease during TIP and to three patients because of toxicity. Myelosuppression was the primary toxicity (Table 2). Neutropenia resulted in 26 hospitalizations in 22 patients (48%) for neutropenic fever with or without sepsis.
Two of three patients who discontinued treatment with TIP because of toxicity experienced grade 3 neurotoxicity. The third patient experienced renal toxicity. All three patients remain free of disease at 27+, 75+, and 83+ months. An additional patient experienced grade 3 neurotoxicity but received all four cycles. Three patients (7%) experienced grade 4 or 5 renal toxicity. The one patient with grade 5 renal toxicity developed acute renal failure in the setting of neutropenic sepsis and died of multiorgan failure, representing the one patient with a treatment-related death. There was one patient who experienced a grade 3 transaminitis; no grade 4 hepatic toxicity was seen.
Response
The remaining 14 patients achieved an IR. Among these patients were two patients with a partial response and normal serum tumor markers who progressed at 12.6 and 63.6 months.
Relapse, Progression-Free Survival, and Overall Survival
Late Relapses Fourteen of 46 patients were treated with TIP after a late relapse to first-line platinum combination chemotherapy (Table 4). At the time of enrollment in the TIP clinical trial, none of these patients were considered suitable candidates for surgical resection of disease. All of the patients had nonseminomatous histology, and the serum AFP was abnormally elevated in 11 patients (79%). Thirteen patients (93%) had metastases to the retroperitoneal lymph nodes. Seven patients (50%) had one site of disease, and six patients (43%) had two or more sites of metastases, with one patient (7%) having elevated markers only. The median time to relapse from first-line chemotherapy was 11.8 years (range, 2.7 to 22.8 years).
Seven (50%) of the 14 patients with late-relapse disease achieved a CR to TIP followed by resection of residual masses. Four of the seven patients achieved a CR to chemotherapy (resection of necrotic debris and/or teratoma), and three other patients had normalized markers to chemotherapy and had resection of viable GCT. None of these CR patients have relapsed, and all seven remain continuously free of disease at a median follow-up time of 51 months (range, 27.0 to 75.1 months). Eight patients had no evidence of disease at last follow-up; one patient had an IR to TIP but now has no evidence of disease after being treated with high-dose chemotherapy and autologous stem-cell transplantation. Figure 3 shows the progression-free survival for the 46 patients according to early (32 patients) or late (14 patients) relapse before TIP chemotherapy. There were 25 (78%) of 32 patients who did not have a late relapse who achieved a CR to TIP chemotherapy.
The results of this trial show that TIP has a high level of activity as second-line therapy for patients with metastatic testicular GCT, as demonstrated by a high CR rate of 70% and a low relapse rate. These results seem better than results with VeIP for both response rates and toxicity. CRs were reported in 36% and 50% of patients in two phase II trials of VeIP administered as second-line treatment to patients with metastatic GCTs.3,4 The proportion of durable CRs was 23% in both studies and less than the 63% rate in this study of TIP. One factor that contributed to the high proportion of CRs observed in this trial was the patient selection criteria used to prospectively identify a population more likely to benefit from conventional-dose second-line therapy. With these selection criteria, it was anticipated that our results would be better than the results of the two previously reported trials of VeIP.3,4 In both of those trials, patients with mediastinal nonseminomatous GCTs or metastatic testicular cancer and IR to first-line therapy were included.3,4 Patients with these features are recognized as being more resistant to cisplatin- and ifosfamide-containing chemotherapy, and inclusion of these patients would undoubtedly have lessened the overall CR rate and survival time (Table 5). 3,4,19
The substitution of paclitaxel for vinblastine in combination with ifosfamide plus cisplatin may contribute to the efficacy of this regimen. However, a subset of patients with a prior CR in the report by McCaffrey et al,3 showed a durable CR rate of 35% after VeIP salvage therapy. In the present study, the 70% response rate suggests a better efficacy of TIP. The high degree of activity of paclitaxel in this disease is supported by single-agent activity in patients with refractory GCT.12,13,20,21 In addition, paclitaxel, when used as part of high-dose chemotherapy regimens, has shown promising activity even in a heavily pretreated patient population with unfavorable prognostic features.22-24 Significant hematologic, renal, and neurologic toxicities (with rare treatment-related mortality) have been reported with ifosfamide-based treatments in the second-line setting. Although TIP was associated with moderately severe toxicities that were predominantly related to myelosuppression, the nephrotoxicity and neurotoxicity were not more severe than that previously described with ifosfamide-based therapies, and one patient (2%) experienced a treatment-related mortality. The GI adverse effects (ie, ileus) associated with vinblastine were avoided completely. Because a randomized trial showed a benefit in reducing hematologic toxicity, the use of hematopoietic growth factors is now standard.25 Two treatment approaches may be undertaken in patients with relapsed GCT. One option is to direct treatment using a conventional-dose regimen or a high-dose program based on a patient's clinical features. A second option is to administer two cycles of VeIP followed by two cycles of high-dose carboplatin and etoposide. In a trial using the latter approach, the regimen showed a durable CR rate of 57%.5 This study also selected patients by favorable features for response, excluding patients with extragonadal primary nonseminomatous GCT. The patients in this trial received two cycles of high-dose chemotherapy. This is considered a standard approach, but our data suggest that a significant proportion of patients with relapsed testicular GCT may achieve a CR without the morbidity associated with high-dose therapy. Surgery to remove postchemotherapy residual masses remains an essential part of the successful management of metastatic GCT. There is significant benefit to complete resection of residual disease because persistent teratomatous elements in the retroperitoneum may grow or undergo malignant transformation, developing non–germ cell somatic elements such as sarcoma or carcinoma. Last, there is a higher risk of late relapse if residual disease is not fully resected.26 Recently, attention has focused on late-relapse GCT as a distinct clinical entity that is characterized by a high degree of resistance to chemotherapy. Patients with late-relapse GCT are generally managed by surgical resection of metastasis, even in the setting of an elevated marker. In a relatively large series in the study by George et al,27 83 patients were reported to have late-relapse GCT; 49 patients underwent surgery, and 43 patients were rendered disease free. Of these 43 patients, 20 (46.5%) remain continuously free of disease. Thirty-two patients received salvage chemotherapy, but only six of these patients (18.8%) were rendered disease free. In our trial, 14 patients were treated with TIP after a late relapse. Seven (50%) of 14 patients with late-relapse disease achieved a CR to treatment. Three of these CRs were to chemotherapy plus resection of necrotic debris or teratoma, and four of the CRs were to chemotherapy plus resection of viable GCT. To date, none of these patients have relapsed, and they remain continuously free of disease at a median follow-up time of 51 months. Although surgical removal of solitary metastasis remains the preferred treatment for late-relapse GCT, our data suggest that patients who are not considered suitable candidates for primary surgery may benefit from TIP chemotherapy followed by surgical resection of residual masses. In summary, TIP is a highly effective regimen for treatment of relapsed GCT in patients selected by prognostic features for favorable outcome. Patients with late-relapse GCT and multiple sites involved or unresectable disease should be considered for treatment with TIP before resection.
The authors indicated no potential conflicts of interest.
Supported by Bristol Myers Squibb, National Institutes of Health Grants No. K24 CA-82431 and 5T32-CA-09207-26, and the Craig D. Tifford Foundation. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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3. 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 4. Loehrer PJ Sr, 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]
5. 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
6. 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 7. 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 8. Beyer J, Schwella N, Zingsem J, et al: Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: A randomized comparison. J Clin Oncol 13:1328-1335, 1995[Abstract]
9. Siegert W, Beyer J, Strohscheer I, et al: High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: A phase I/II study—The German Testicular Cancer Cooperative Study Group. J Clin Oncol 12:1223-1231, 1994 10. Motzer RJ, Geller NL, Tan CC, et al: Salvage chemotherapy for patients with germ cell tumors: The Memorial Sloan-Kettering Cancer Center experience (1979-1989). Cancer 67:1305-1310, 1991[CrossRef][Medline] 11. Baniel J, Foster RS, Gonin R, et al: Late relapse of testicular cancer. J Clin Oncol 13:1170-1176, 1995[Abstract]
12. Motzer RJ, Bajorin DF, Schwartz LH, et al: Phase II trial of paclitaxel shows antitumor activity in patients with previously treated germ cell tumors. J Clin Oncol 12:2277-2283, 1994
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14. Chou TC, Motzer RJ, Tong Y, et al: Computerized quantitation of synergism and antagonism of Taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: A rational approach to clinical protocol design. J Natl Cancer Inst 86:1517-1524, 1994
15. 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 18:2413-2418, 2000 16. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]
17. Bosl GJ, Gluckman R, Geller NL, et al: VAB-6: An effective chemotherapy regimen for patients with germ-cell tumors. J Clin Oncol 4:1493-1499, 1986
18. Donadio AC, Motzer RJ, Bajorin DF, et al: Chemotherapy for teratoma with malignant transformation. J Clin Oncol 21:4285-4291, 2003 19. Mardiak TS, Sycova-Mila Z, Hlavata Z, et al: Paclitaxel, ifosfamide, and cisplatin (TIP) salvage therapy for patients (pts) with relapsed testicular germ cell tumors (GCT). J Clin Oncol 22, 2004 (suppl, abstr 4632) 20. Bokemeyer C, Schmoll HJ, Natt F, et al: Preliminary results of a phase I/II trial of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer. J Cancer Res Clin Oncol 120:754-757, 1994[CrossRef][Medline] 21. Sandler AB, Cristou A, Fox S, et al: A phase II trial of paclitaxel in refractory germ cell tumors. Cancer 82:1381-1386, 1998[CrossRef][Medline]
22. Motzer RJ, Mazumdar M, Sheinfeld J, et al: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18:1173-1180, 2000
23. Rick O, Bokemeyer C, Beyer J, et al: Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J Clin Oncol 19:81-88, 2001 24. Margolin K: High dose chemotherapy and stem cell support in the treatment of germ cell cancer. J Urol 169:1229-1233, 2003[CrossRef][Medline] 25. Fossa SD, Kaye SB, Mead GM, et al: Filgrastim during combination chemotherapy of patients with poor-prognosis metastatic germ cell malignancy: European Organization for Research and Treatment of Cancer, Genito-Urinary Group, and the Medical Research Council Testicular Cancer Working Party, Cambridge, United Kingdom. J Clin Oncol 16:716-724, 1998[Abstract] 26. Stephenson AJ, Sheinfeld J: The role of retroperitoneal lymph node dissection in the management of testicular cancer. Urol Oncol 22:225-235, 2004[Medline]
27. George DW, Foster RS, Hromas RA, et al: Update on late relapse of germ cell tumor: A clinical and molecular analysis. J Clin Oncol 21:113-122, 2003 Submitted March 21, 2005; accepted May 13, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3,000/µL, hemoglobin level of 
