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© 2000 American Society for Clinical Oncology Paclitaxel, Ifosfamide, and Cisplatin Second-Line Therapy for Patients With Relapsed Testicular Germ Cell CancerFrom the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; Departments of Epidemiology and Biostatistics, Urology, and Thoracic Surgery Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center; and Department of Medicine, Joan and Sanford I Weill Medical College of Cornell University, New York, NY. Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
PURPOSE: To evaluate the dose, toxicity, and efficacy of paclitaxel in combination with ifosfamide and cisplatin as salvage therapy for patients with relapsed testicular germ cell tumors (GCTs). PATIENTS AND METHODS: Thirty patients with previously treated GCTs were treated with paclitaxel and ifosfamide plus cisplatin (TIP) as second-line therapy. All had favorable prognostic features for response (testis primary tumor site and prior complete response to first-line chemotherapy program). Four cycles of paclitaxel, ifosfamide 5 g/m2, and cisplatin 100 mg/m2 were given 21 days apart with granulocyte colony-stimulating factor support, followed by resection of radiographic residua. The dose of paclitaxel was increased among cohorts with dose levels of 175, 215, and 250 mg/m2; the largest dose was selected for the phase II part of the trial. RESULTS: Twenty-three (77%) of 30 patients achieved a complete response to chemotherapy alone, and one patient achieved a durable partial response with normal tumor markers. Therefore, 24 (80%) achieved a favorable response. Eleven patients with normalized markers after chemotherapy underwent resection of residual tissue, with only necrosis found in 10 and mature teratoma in one. Two patients relapsed, and 22 (73%) of the favorable responses remain durable at a median follow-up duration of 33 months. Myelosuppression was the major toxicity, and two patients had grade 3 neurotoxicity. CONCLUSION: Four cycles of TIP was associated with a high proportion of patients who achieved a complete response, a lack of relapse, and relative tolerability as an ifosfamide-containing salvage regimen for testicular GCTs. The high durable complete response proportion emphasizes the importance of patient selection according to prognostic factors for a favorable outcome to conventional-dose salvage therapy.
DESPITE HIGH CURE rates for patients with advanced germ cell tumors (GCTs), between 20% and 30% of patients with disseminated disease do not achieve a durable complete response to cisplatin plus etoposide with or without bleomycin chemotherapy.1,2 For patients with resistant GCTs, two treatment programs show curative potential. Approximately 50% of patients achieve a complete response when ifosfamide and cisplatin plus vinblastine (VeIP) is administered as second-line therapy, and approximately one half of these responses remain durable.3-7 Two cycles of high-dose carboplatin plus etoposide with or without cyclophosphamide (or ifosfamide), followed by peripheral-blood–derived stem cell (PBSC) support given as third-line therapy, resulted in durable complete responses in 15% to 25% of patients as third-line therapy.8-11 Prognostic factors can be used to direct therapy to patients predicted to benefit, sparing others the toxicity of a futile therapy. Analyses showed that patients with gonadal primary tumor sites who relapse after complete response to first-line therapy are more likely to achieve a favorable treatment outcome after conventional-dose cisplatin plus ifosfamide salvage therapy.3,4,12 In contrast, patients with an incomplete response to first-line therapy or a mediastinal primary tumor site rarely achieve durable complete response to conventional-dose cisplatin plus ifosfamide salvage therapy.4,12 This latter group of patients is considered for clinical trials that included dose-intensive therapy as second-line treatment.13 In this phase I/II trial, patients with previously treated GCTs and favorable prognostic features for achieving a favorable treatment outcome to conventional-dose salvage chemotherapy were treated with a program of paclitaxel, ifosfamide, and cisplatin (TIP) as first-line salvage therapy. Paclitaxel was substituted for vinblastine in this regimen on the basis of in vitro studies that showed synergy for the three drugs against resistant GCTs14 and single-agent activity in phase II trials.15,16 The dose of paclitaxel, which was determined on the basis of a single-agent phase II study,15 was increased among cohorts to a maximum level, whereby subsequent patients were treated at a fixed dose in a phase II setting.
Eligibility Thirty patients with advanced GCTs were registered onto this prospective trial between May 1994 and October 1998. The study was approved by the Memorial Sloan-Kettering Cancer Center internal review board. All patients had histologically confirmed GCTs, assessable disease, recurrent GCTs after treatment with a cisplatin-based regimen, and favorable prognostic features for treatment with conventional-dose, first-line salvage therapy. All favorable prognostic factors for achieving a complete response to cisplatin plus ifosfamide conventional-dose salvage therapy had to be met and were as follows: (1) gonadal primary tumor site; (2) prior treatment limited to one program or six or fewer prior cycles of cisplatin; and (3) either a complete response or a partial response with normal serum tumor markers to first-line chemotherapy program. Relapse was documented by rising serum concentrations of serum alpha-fetoprotein (AFP) and/or and human chorionic gonadotropin (HCG). In the absence of elevated serum tumor marker(s), biopsy was performed to document the presence of active GCTs (and to exclude teratoma). Additional eligibility criteria included a WBC count of 3,000/µL or higher, hemoglobin level of 8.0 g/dL or higher, platelet count of 100,000/µL or higher, creatinine clearance rate of more than 50 mL/min, and signed informed consent. Patients were excluded if their prior treatment had included paclitaxel or ifosfamide.
Pretreatment Evaluation
Treatment Program Patients received granulocyte colony-stimulating factor (G-CSF) 5 µg/kg daily by subcutaneous injection on days 7 through 18. If the WBC count exceeded 10,000/µL for 2 days, G-CSF therapy was discontinued. The criteria for re-treatment with subsequent cycles was a neutrophil count of 450/µL or higher and platelet count of more than 75,000/µL. Dose reductions were not made; recovery from toxicity was allowed before re-treatment at the full dose occurred.
Dose Escalation of Paclitaxel
Supportive Care
Evaluation of Response and Toxicity Evaluations approximately 28 days after the first day of the last cycle of chemotherapy included a physical examination, CBC count, comprehensive chemistry panel, AFP and HCG measurements, and a computed tomography scan of the chest, abdomen, and pelvis as required for assessment of tumor response. After the completion of four cycles of chemotherapy and radiographic and marker assessment, surgical resection of all residual masses was considered. Responses were categorized as complete or incomplete. Response duration and survival were measured from the initiation of therapy. A complete response 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 residuum yielded necrotic debris, fibrosis, or mature teratoma but no evidence of viable malignant tumor. A complete response to chemotherapy plus surgery was defined as the complete excision of all masses, at least one of which contained viable tumor other than mature teratoma. An incomplete response was therefore observed in patients who did not achieve a complete response to chemotherapy with or without surgery or who were observed to have failure of serum tumor marker normalization.
Patient Characteristics Twenty-seven males had nonseminoma and three had seminoma histologies (Table 1). Two patients had recurrent GCTs associated with a second gonadal primary. The prior chemotherapy had been as follows: cisplatin and etoposide for 15 patients17; bleomycin, cisplatin, and etoposide for 10 patients; vinblastine, cisplatin, bleomycin combination therapy (VAB-6)18 for one patient; VAB-6 plus cisplatin and etoposide for one patient; VAB-6 plus high-dose carboplatin and etoposide with autologous bone marrow transplantation19 for one patient; and carboplatin plus etoposide for two patients.20 Six patients were considered to have a late relapse, defined as a recurrence of disease more than 2 years after a complete response to first-line chemotherapy.21
Treatment and Toxicity Three patients were treated at the paclitaxel 175 mg/m2 dose level and three at the paclitaxel 215 mg/m2 dose level; none of the six experienced dose-limiting toxicity. The remaining 24 patients were treated with paclitaxel 250 mg/m2. A total of 111 cycles of therapy were administered to 30 patients, and the median number of days between cycles was 21 (range, 19 to 61 days). Myelosuppression was the major toxicity (Table 2). There were 21 hospitalizations for nadir fever/sepsis in 16 patients. All episodes were treated successfully with antibiotics.
In the phase II part of the trial, one patient had grade 3 infectious toxicity, and two patients had grade 4 infectious toxicity related to septicemia. Both patients with grade 4 infections developed grade 4 renal toxicity in the setting of antibiotic therapy. Two patients had grade 3 neurotoxicity. One patient had grade 3 nausea and two patients had grade 3 myalgia/arthralgia during treatment that was attributable to paclitaxel and/or G-CSF therapy.
Response and Survival
Two patients with incomplete response and one with relapse were subsequently rendered free of disease by additional therapy. One patient had TIP treatment discontinued after one cycle because of grade 4 infectious toxicity and was rendered free of disease by surgical resection of a metastasis. A second patient had TIP treatment discontinued after three cycles because of a rising serum AFP concentration and underwent resection of a metastasis. In both instances, the site resected was the retroperitoneum, histology showed mature teratoma, and the previously elevated AFP concentration normalized. The third patient achieved a complete response to dose-intensive chemotherapy with PBSC rescue following relapse after TIP therapy. One additional patient was treated with dose-intensive therapy plus PBSC rescue after TIP but achieved an incomplete response. Twenty-four patients (80%) are currently alive and free of disease, one patient remains alive with disease in durable partial response, and five died of disease (Fig 1). The proportion of patients alive at 2 years was 85%. The median follow-up period for the 25 survivors was 34 months (range, 12 to 65 months).
Adjunctive Surgery Eleven patients with normalized serum tumor markers after TIP therapy underwent surgery and resection of residua. The sites of surgery were the retroperitoneum in six patients, lung parenchyma in five patients, and mediastinum in two patients. Nine patients had one site evaluated, and two patients had two sites resected. The findings were necrosis in 10 patients and mature teratoma in one patient. None of the patients had evidence of viable GCTs (other than mature teratoma, such as embryonal cell carcinoma) found at resection.
Late Relapses
A complete response was achieved in 23 (77%) of 30 relapsed testicular GCT patients treated with TIP, and 85% are alive at 2 years, with a median follow-up of 33 months. These data demonstrate that prognostic factors can be applied prospectively to select patients for a favorable treatment outcome to a conventional-dose second-line chemotherapy program. The complete response proportions achieved in two prior studies of cisplatin, ifosfamide, plus vinblastine or etoposide given as second-line therapy to patients who were not selected by prognostic features were 36% and 50%, with approximately 25% of patients remaining in durable complete response.3,4 Because of patient selection and single-arm design, we cannot compare the efficacy of TIP to the standard VeIP regimen. However, TIP therapy was associated with a relatively high proportion of patients who achieved a complete response, a lack of relapse, and relative tolerability as an ifosfamide-containing salvage regimen. The toxicity associated with cisplatin plus ifosfamide salvage therapy is reported to be substantial and includes hematologic, renal, gastrointestinal, and neurologic toxicities, with rare treatment-related deaths.3,4 Hematologic toxicity in this trial was ameliorated with the use of hematopoietic growth factor, which is considered standard practice for cisplatin plus ifosfamide combination salvage programs.22 Neurotoxicity associated with paclitaxel and cisplatin combinations was anticipated, particularly since patients had received prior treatment with cisplatin. However, the neurotoxicity from TIP was not excessive because two (7%) of 30 patients developed grade 3 neurotoxicity. Also, neurotoxicity can occur with vinblastine, and the other toxicities associated with high doses of vinblastine in the VeIP regimen, including gastrointestinal toxicity, were avoided.3,4 Between 10% and 20% of patients with GCTs relapse after first-line chemotherapy. Most relapses occur within 2 years of treatment. Recently, "late relapses" have been described, defined as appearing after a more than 24-month disease-free interval.21,23,24 Patients with isolated mature teratoma do well after undergoing excision, whereas patients with marker-positive disease or histology other than teratoma are characterized by a high degree of resistance to standard salvage chemotherapy programs.23,24 "Desperation surgery,"25,26 the resection of metastasis in the setting of rising serum tumor markers, has been effective in a minority of instances.21,24 Patients more likely to benefit from desperation surgery include those with a solitary tumor site, retroperitoneal metastasis, and elevated serum AFP concentration.26 In the study presented here, Six patients with a late relapse were treated with TIP therapy, and three were rendered continuously disease-free. These data suggest that selected patients with late relapse who are not candidates for surgical salvage may benefit from TIP therapy, and treatment of a larger number of patients is underway to further address this issue. It is possible that paclitaxel plays a role in this regard, consistent with a report of a durable response to single-agent paclitaxel in a late-relapse patient who did not respond to high-dose chemotherapy.27 High-dose carboplatin plus etoposide with autologous bone marrow transplantation has been studied in treatment programs for the management of GCT patients in first-relapse after complete response.28,29 In one study of GCT patients in first relapse, 18 of 23 patients completed high-dose therapy, and seven (39%) were progression-free at their 26-month follow-up.28 In a second study undertaken in gonadal GCT patients in their first-relapse, 13 (52%) of 25 patients treated with high-dose therapy remain progression-free at a median follow-up duration of 26 months.29 The results of the trial reported herein showed a high response proportion in patients with relapsed GCTs treated with a conventional-dose TIP program. A European trial comparing four cycles of cisplatin plus ifosfamide-containing therapy with three cycles of cisplatin plus ifosfamide-containing therapy plus one cycle of high-dose carboplatin-containing therapy may provide additional insight into the role of high-dose therapy in relapsed GCTs. Until such benefit is demonstrated, the inclusion of high-dose therapy in the routine treatment of patients with testicular cancer in first relapse remains uncertain. Alternatively, less than 10% of patients with an incomplete response to first-line therapy or extragonadal (mediastinal) primary tumor site who were treated with cisplatin plus ifosfamide salvage chemotherapy achieved prolonged survival.4,12 At our center, patients with poor prognostic features who required salvage therapy were treated on a clinical trial of repetitive cycles of dose-intensified therapy consisting of paclitaxel, ifosfamide, carboplatin, and etoposide with autologous stem-cell rescue. Twenty-one (57%) of 37 patients treated with this program achieved a complete response, and 13 (35%) remain in durable complete response with a follow-up duration of longer than 18 months.30 In summary, four cycles of TIP was an effective treatment program for patients with relapsed testicular GCTs. TIP therapy was associated with a high proportion of patients who achieved a complete response, a lack of relapse, and relative tolerability as an ifosfamide-containing regimen. The high durable complete response proportion emphasizes the importance of patient selection according to prognostic factors.
Supported by grant no. CA 05826 from the National Cancer Institute, Bethesda, MD, and Bristol-Myers Corporation. We thank Patricia Fischer for nursing care and Carol Pearce for her review of the manuscript.
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Motzer RJ, Mazumdar M, Gulati SC, et al: Phase II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Natl Cancer Inst 85:1828-1835, 1993 20. Bajorin DF, Sarosdy MF, Pfister DG, et al: Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: A multi-institutional study. J Clin Oncol 11:598-606, 1993[Abstract] 21. Baniel J, Foster RS, Gonin R, et al: Late relapse of testicular cancer. J Clin Oncol 13:1170-1176, 1995[Abstract] 22. Bosl GJ, Bajorin DF, Sheinfeld J, et al: Cancer of the testis, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA,J.B. Lippincott, 1996, pp 1397-1426 23. Nichols CR, Saxman S: Primary salvage treatment of recurrent germ cell tumors: Experience at Indiana University. Semin Oncol 25:210-214, 1998[Medline]
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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 Submitted November 4, 1999; accepted February 24, 2000. This article has been cited by other articles:
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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
