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© 2001 American Society for Clinical Oncology 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 CancerFrom the Departments of Hematology and Oncology, Charité, Campus Virchow Klinikum, Berlin; Eberhard-Karls Universität, Tübingen; Städtische Kliniken, Oldenburg; Universität Rostock, Rostock; Klinikum Nord, Nürnberg, Universität des Saarlandes, Homburg; Martin Luther Universität, Halle; Johannes Gutenberg Universität, Mainz; Klinikum Grosshadern, München; and Universität Münster, Münster, Germany. Address reprint requests to J. Beyer, MD, Department of Hematology and Oncology, Philipps Universität Marburg, Baldinger Strasse, 35033 Marburg, Germany; email joerg.beyer{at}mailer.uni-marburg.de
PURPOSE: To study feasibility and efficacy of a new salvage regimen in patients with relapsed and/or refractory germ cell tumors. PATIENTS AND METHODS: Between May 1995 and February 1997, 80 patients were entered onto a phase II study. Conventional-dose salvage treatment with three cycles of paclitaxel 175 mg/m2, ifosfamide 5 x 1.2 g/m2, and cisplatin 5 x 20 mg/m2 (TIP) was followed by one cycle of high-dose chemotherapy (HDCT) with carboplatin 500 mg/m2 x 3, etoposide 600 mg/m2 x 4, and thiotepa 150 to 250 mg/m2 x 3 (CET). In 23 patients, one additional cycle of paclitaxel 175 mg/m2 and ifosfamide 5 g/m2 (TI) was given immediately before TIP to improve stem-cell mobilization. RESULTS: Fifty-five (69%) of 80 patients responded to TIP, 24 (30%) of 80 patients had stable disease (n = 5) or tumor progression (n = 19), and one patient died. Only 62 (78%) of 80 patients received subsequent HDCT. Among those, 41 (66%) of 62 patients responded and 20 (32%) of 62 patients had stable disease (n = 3) or tumor progression (n = 17). One patient died after HDCT from multiorgan failure. Survival probabilities at 3 years were 30% for overall and 25% for event-free survival. Peripheral neurotoxicity with sensorimotor impairment grade 2 through 4 in 29%, paresthesias grade 2 through 4 in 24%, and skin toxicity grade 2 through 3 in 15% of patients were the most relevant side effects. CONCLUSION: Treatment with TIP followed by high-dose CET is feasible and can induce long-term remissions in 25% of patients with relapsed or refractory germ cell tumors. Peripheral nervous toxicity in approximately one third of patients is a disadvantage of this salvage strategy.
HIGH-DOSE CHEMOTHERAPY (HDCT) followed by autologous stem-cell rescue (ASCR) can be curative in patients with germ cell tumors who relapse or who have an inadequate response after conventional-dose salvage treatment.1-3 HDCT may also increase response rates and survival when given as first-salvage treatment in cisplatin-sensitive patients.4-6 However, despite the use of HDCT, long-term remissions after salvage treatment can only be expected in approximately 10% to 40% of patients depending on risk factors such as the location of the primary tumor, the degree of sensitivity to cisplatin, and human chorionic gonadotropin (HCG) levels before HDCT. Particularly in patients who have become refractory to cisplatin, the results of HDCT are still disappointing.1,7 Paclitaxel is among the few drugs with single-agent activity in cisplatin-refractory germ cell tumors and has been successfully used in combination chemotherapy regimens together with cisplatin and ifosfamide. In cisplatin-refractory patients, paclitaxel has even been reported to restore sensitivity to cisplatin.8-11 Although information on single-agent activity in germ-cell tumors is lacking for thiotepa, at least one group has reported on activity in refractory germ cell tumors when thiotepa was given in combination with high-dose carboplatin and cyclophosphamide.12 We therefore investigated whether an induction salvage treatment with paclitaxel, ifosfamide and cisplatin (TIP) followed by HDCT with carboplatin, etoposide, and thiotepa (CET) would be feasible in patients with relapsed and/or refractory germ cell tumors. In addition, we were interested in the response rates with the novel strategy of TIP followed by high-dose CET, particularly in patients with tumors refractory or absolute refractory to cisplatin. Finally, we hoped that the nephrotoxicity that occurs with HDCT combinations that include ifosfamide or cyclophosphamide would be reduced by using thiotepa instead of an oxazaphosphorine as an alkylating drug.
Patients Between May 1995 and February 1997, 80 patients were entered onto a phase II trial at seven centers in Germany: Virchow Klinikum Berlin (n = 46), University Tübingen (n = 23), Klinikum Oldenburg (n = 4), Klinikum Nürnberg (n = 2), University Rostock (n = 2), University Homburg (n = 2), and University Halle (n = 1). All patients with germ cell tumors were eligible if there was unequivocal evidence of relapse or progression after cisplatin-based combination chemotherapy as defined by increasing tumor markers. In marker-negative patients with radiologic relapse or progression, additional histologic evidence of undifferentiated germ cell tumor was required. As in previous trials, patients were required to have a Karnofsky performance status of at least 60%, a creatinine clearance of at least 70 mL/min as calculated by the Cockroft formula, and no major organ dysfunction.5 The treatment protocol was approved by the ethics committee of the Virchow Klinikum, Berlin, Germany, as well as by the local ethics committees of each participating center. All patients gave their written informed consent before participating in the trial.
Treatment As mobilization of peripheral-blood progenitor cells (PBPCs) proved to be difficult after TIP, one additional cycle of paclitaxel 175 mg/m2 over 3 hours on day 1 followed by a 24-hour continuous infusion of ifosfamide at a dose of 5 g/m2 (TI) was given in the latter part of the study before treatment with TIP. After TI, G-CSF at a dose of 10 µg/kg was given from day 3 until a sufficient number of PBPCs could be collected. Chemotherapy with TIP immediately followed PBPC collections as described above in patients who were mobilized with TI. In the remaining patients PBPC collections were performed after the first and/or second TIP cycle. In two patients, bone marrow collection was needed to obtain sufficient numbers of progenitor cells. HDCT consisted of carboplatin 500 mg/m2/d from day -6 until day -4 (a total of 1,500 mg/m2), etoposide 600 mg/m2/d from day -6 until day -3 (a total of 2,400 mg/m2), and thiotepa 250 mg/m2/d from day -6 until day -4 (a total of 750 mg/m2). However, as unacceptable skin toxicity was observed among 11 initial patients, the dose of thiotepa was subsequently reduced to 150 mg/m2/d from day -6 until day -4 (a total of 450 mg/m2). In patients with a calculated creatinine clearance between 70 and 100 mL/min according to the Cockroft formula, the carboplatin dose was reduced to 3 x 400 mg/m2 and the etoposide dose was reduced to 4 x 450 mg/m2. No other dose modifications were scheduled. ASCR was performed on day 0 as previously described with an unmanipulated graft and a target number of at least 2.5 x 106 CD34+ cells/kg of bodyweight.5,13 G-CSF was given after ASCR from day +1 at a dose of 5 µg/kg of body weight until neutrophil recovery to more than 1,000/µL for 2 consecutive days.
Supportive Care
Clinical Monitoring and Follow-Up Follow-up evaluations were performed at 6 and 12 weeks post-HDCT and consisted of a detailed physical examination, a standard chemistry profile in addition to tumor markers, and computed tomography scans of the thorax and abdomen. Additional investigations were performed as clinically indicated. Thereafter, patients were re-evaluated every 3 months during the first year and every 6 months during subsequent years. In all patients with a partial remission and negative tumor markers (PRm-) as well as those patients with a partial remission and positive tumor markers (PRm+) in whom this was considered appropriate, complete surgical resection of all residual disease was attempted.
Definitions and Evaluation of Toxicities Sensitivity to cisplatin was assessed as reported previously.1,7 Any disease was considered sensitive to cisplatin when more than SD was achieved for more than 4 weeks. Any disease was considered refractory to cisplatin when SD or better was achieved but when there was evidence of tumor progression within 4 weeks of the last cisplatin-based treatment. Any disease was considered absolutely refractory to cisplatin when not even SD was achieved despite cisplatin-based chemotherapy. Evaluations of toxicities were classified according to modified criteria of the World Health Organization. Peripheral neurotoxicity (paresthesias and sensorimotor toxicity) and ototoxicity were classified, with minor modifications, according to the National Cancer Institute of Canada Expanded Common Toxicity Criteria. Paresthesias were considered grade 2 if they were mild and tolerable, grade 3 if paresthesias were prominent and disturbed daily activities, and grade 4 if paresthesias became intolerable and required treatment. Sensorimotor toxicity was considered grade 2 if minor impairment of daily activities were noted, grade 3 if objective loss of function occurred that interfered with daily activities, and grade 4 if loss of function required supportive measures. Ototoxicity was considered grade 2 if there was tinnitus or mild hearing impairment that did not interfere with daily activities, grade 3 if tinnitus or hearing impairment interfered with daily activities, and grade 4 if a hearing aid was required.
Statistical Analysis
Patient Characteristics at Study Entry The patient characteristics at study entry and the distribution of known prognostic factors are listed in Table 1. At study entry, patients had previously been treated with a median of five cycles (range, two to 14 cycles) of cisplatin-based chemotherapy; 79 (99%) of 80 patients had received etoposide and 53 (66%) of 80 patients had received ifosfamide as part of their prior treatment; 54 (67%) of 80 patients had experienced treatment failure with first-line treatment and 26 (33%) of 80 had also experienced treatment failure with one or more previous salvage regimens (Table 1). Sequential HDCT with conventional-dose cisplatin plus dose-intensive etoposide and ifosfamide had failed as first-line treatment in four (5%) of 80 patients with poor-prognosis tumors at initial presentation.15 The distribution of known prognostic factors at study entry is shown as Table 1.
Entering the study, the majority of patients were considered sensitive to cisplatin. However, 13% were considered refractory and 11% were considered absolutely refractory to cisplatin ( Table 2).
Conventional-Dose Treatment and Responses Before HDCT All 80 patients were assessable for response to TIP. Overall, a median number of three TIP cycles (range, one to five cycles) were given; three (4%) of 80 patients received only one cycle, seven (9%) of 80 patients received two cycles, 66 (83%) of 80 patients received three cycles, three (4%) of 80 patients received four cycles, and one patient received five cycles. An additional TI cycle was given before TIP in 23 (29%) of 80 patients to improve stem- cell mobilization. A favorable response (CR, PRm-, or PRm+) was obtained in 74% (95% CI, 63% to 85%) of patients who were considered cisplatin-sensitive and in 80% (95% CI, 55% to 100%) of patients who were considered cisplatin-refractory. Favorable responses were achieved in only 22% (CI, 0% to 50%) of patients who were considered absolutely refractory to cisplatin at study entry (Table 2). Among patients who were sensitive to cisplatin at study entry, 71% proceeded to HDCT and were in remission immediately before HDCT. In contrast, only 50% of patients who were refractory to cisplatin and only 22% of patients who were absolutely refractory to cisplatin at study entry proceeded to HDCT and were in remission at the time of HDCT.
Responses in Patients With and Without HDCT Among the 18 patients who did not receive HDCT, 15 patients had progressive disease, one patient died after the first TIP cycle, one patient had stable disease for 1 month, and one patient in whom sufficient PBPCs could not be collected had a PRm- for 8 months. All 18 patients without HDCT died (Fig 1).
Among 62 patients who did receive HDCT, a cCR was observed in 11 (18%) of 62 patients (95% CI, 8% to 27%), seven (11%) of 62 patients (95% CI, 3% to 19%) achieved a pCR after resection of necrosis/mature teratoma, and an additional 10 (16%) of 62 patients (95% CI, 7% to 25%) achieved an sCR after resection of undifferentiated viable tumor. A PRm- was obtained as best response in 11 (18%) of 62 patients (95% CI, 8% to 27%), and two (3%) of 62 patients (95% CI, 0% to 8%) had a PRm+ lasting for 2 and 3 months. The remaining 20 (32%) of 62 patients (95% CI, 20% to 44%) had SD (n = 3) or PD (n = 17), and one patient died of multiorgan toxicity after HDCT.
Survival
Toxicities All 80 patients were evaluated for toxicity after TIP and 62 patients were evaluated for toxicity after CET. TIP was tolerated with acceptable hematologic toxicity. Transfusions of packed RBCs were required in 51% of patients and of platelet concentrates in 23% of patients. Neutropenia  grade 3 developed in 79% of patients and hospitalization for neutropenic fever was required in 10% of patients. There were no severe infections or severe organ toxicities grade 3 during conventional treatment with TIP. One patient with diffuse lung metastases developed intrapulmonary hemorrhage, became respirator-dependent, and died 3 weeks after initiation of the first TIP cycle.
Peripheral nervous toxicity was the most relevant side effect after TIP. Sensorimotor neuropathy
After HDCT, sensorimotor toxicity
Other No further severe toxicities were observed. In particular, renal dysfunction was limited. One patient reversibly deteriorated to a creatinine clearance of less than 50 mL/min, and one patient required hemodialysis in the context of multiorgan failure after HDCT. During the follow-up period, one patient developed a myelodysplastic syndrome 30 months after HDCT, and one patient developed acute myeloid leukemia 16 months after HDCT.
During the past 10 years, HDCT has emerged as a feasible and potentially curative option for second or subsequent salvage treatment in patients with multiply relapsed germ cell tumors.1,2,16 Among patients with gonadal primary tumors who are still sensitive to cisplatin, the rate of long-term remissions may be as high as 30% or more.7 Patients who have become refractory or even absolutely refractory to cisplatin-based combination chemotherapy will profit much less from further salvage treatment despite intensification with HDCT. In the first-salvage setting of patients with relapse or progression after first-line treatment, the situation is more controversial.3 Conventional-dose chemotherapy (CDCT) can result in durable remissions in approximately 10% to 24% of patients.17,18 No prospective or randomized data are available that unequivocally show that HDCT is indeed superior to CDCT when given as first-salvage treatment in cisplatin-sensitive patients, but data from phase II trials and retrospective comparisons point to a superiority of HDCT over CDCT even in the first-salvage setting of these less intensively pretreated patients.4-6,10 Yet these data also demonstrate that the majority of patients who relapse after first-line cisplatin-based chemotherapy will still ultimately die of their disease.3 This applies particularly to patients who have become refractory to cisplatin.7 Therefore, salvage treatment strategies clearly need to be improved. Similarly, the toxicities of HDCT are substantial. In particular, nephrotoxicity has been a problem in using HDCT regimens that included ifosfamide or cyclophosphamide in addition to the template of high-dose carboplatin and etoposide.19 The development of myelodysplasias or secondary leukemias after high-dose etoposide treatment has become another area of concern.20 In the present phase II trial, we have tried to optimize our previous salvage strategy using several different approaches, first by using intensive CDCT for remission induction before HDCT. Remission status has been one independent prognostic factor in a recent multivariate analysis for treatment response after HDCT.7 Second, we incorporated paclitaxel into the conventional-dose salvage treatment regimen before HDCT with the intention to increase the remission rate, particularly in cisplatin-refractory patients. Paclitaxel has been shown to be one of the few active drugs in cisplatin-refractory germ cell tumors and may have synergistic activity with cisplatin and, potentially, also with ifosfamide.8-11,21,22 Third, we substituted high-dose thiotepa for ifosfamide as an alkylating agent in the HDCT combination to reduce the incidence of severe nephrotoxicity and to increase treatment efficacy. Thiotepa seemed well suited for HDCT, as its limited nonhematologic side effects allow dose escalations to approximately 10 to 20 times the conventional dose.12 The aim of the study was to determine the feasibility and the therapeutic potential of intensive conventional-dose induction treatment with TIP followed by high-dose CET. Conventional-dose treatment with TIP was active and resulted in an overall response rate of 69%. In particular, cisplatin-sensitive patients and those with only a limited degree of refractoriness to cisplatin benefited from induction treatment with TIP. These results compare favorably with those of other conventional-dose salvage regimens that combine cisplatin and ifosfamide with either vinblastine or etoposide and correspond to previous reports using a similar regimen with higher doses of paclitaxel.10,17,18,23 However, the response rate to TIP in patients who were considered absolutely refractory at the time of study entry was only 22%. Alternative approaches using higher doses of paclitaxel and a higher dose-intensity with short intercycle intervals, as reported recently, might be superior in the subgroup of patients who are absolutely refractory to cisplatin.9,10 Survival rates achieved after TIP/CET in the present trial were very similar compared with those observed in previous HDCT trials.5,16 With a minimum follow-up of almost 2 years, 26% of patients are continuously disease-free and 30% patients are currently disease-free. Survival after TIP/CET depended largely on the presence of prognostic factors for treatment response after HDCT that have been evaluated previously.7 As in previous analyses with other high-dose regimens, good-prognosis patients without any adverse prognostic factors did particularly well, with a projected overall survival rate of 53% and an event-free survival rate of 47% at 3 years. Patients with an intermediate prognosis still had projected overall and event-free survival rates of 23% and 8% at 3 years, respectively. Among poor-prognosis patients there were no long-term survivors. Thus particularly for this latter and prognostically worst group of patients, intensification with high-dose CET was insufficient, and in these patients, new treatment approaches should be explored.9,10 The protocol extended over a time period of 2 years at several treatment centers and included CDCT as well as HDCT. Interobserver variations might therefore have interfered with reporting of toxic side effects and, particularly, with the interpretation of neurotoxicity. However, the overall neurotoxicity observed in the trial was confirmed by a toxicity analysis in a subset of 46 patients treated at a single center in whom detailed assessments of neurotoxicity were performed after each treatment cycle and in whom neurologic evaluations were performed by the same two investigators throughout the study period. Overall, salvage treatment with TIP/CET was feasible and tolerable in the majority of patients. Whereas hematologic toxicities and other nonhematologic toxicities were comparable or, with respect to nephrotoxicity, were clearly less frequent, we observed more peripheral neurotoxicity in the present study as compared with our previous strategy of conventional-dose cisplatin, etoposide, and ifosfamide followed by high-dose carboplatin, etoposide, and ifosfamide in a similar group of patients.5,16 Although peripheral neurotoxicity occurred with increasing numbers of TIP cycles, this toxicity was significantly precipitated with the use of the high-dose CET regimen. Grade 4 peripheral neurotoxicity occurred in five patients after HDCT and improved only gradually during the follow-up period. Several possible mechanisms may explain this finding. Paclitaxel is known to induce sensory and possibly also motor peripheral neuropathy.24-26 Prior exposure to cisplatin or vinca alkaloids, a short interval between the administration of paclitaxel and the last treatment with other potentially neurotoxic drugs, concomitant illnesses such as alcoholism or diabetes, a short infusion time, and high cumulative doses of paclitaxel have all been associated with an increase of peripheral neurotoxicity.24,25 In the present trial, peripheral nerve damage from conventional-dose salvage treatment with TIP was substantially aggravated by high-dose carboplatin and/or thiotepa. Whereas carboplatin has little or no neurotoxicity at conventional doses, peripheral neurotoxic side effects occur after high-dose treatment.5,16 Similarly, thiotepa has not been reported to cause peripheral nervous toxicity even at doses higher than those used in the present study.12,27 However, thiotepa is known to cause central nervous toxicity, and there is limited experience with the use of high-dose thiotepa in patients intensively pretreated with one or more neurotoxic drugs. It is a weakness of the present trial that neurotoxicity was assessed on clinical grounds alone. Systematic neurophysiologic studies will be required in intensively pretreated patients with germ cell tumors to clarify the mechanisms of neurotoxicity.26 In conclusion, conventional-dose TIP followed by high-dose CET is a feasible and active salvage regimen in patients with relapsed and/or refractory germ cell tumors. Survival rates after TIP/CET largely depend on the degree of sensitivity of a tumor to prior cisplatin-based chemotherapy and are comparable to the ones observed in previous HDCT trials. As compared with other HDCT regimens, there is a shift of nonhematologic toxicities with a reduction of nephrotoxicity after TIP/CET but more prominent peripheral neurotoxicity, particularly after high-dose CET. High-dose CET might therefore be less optimal than other high-dose regimens in patients pretreated with potentially neurotoxic drugs. The present trial was not designed to determine the role of paclitaxel in the treatment of refractory germ cell tumors. Regimens with dose-intensive paclitaxel, early intensification of first-salvage treatment, and repetitive HDCT cycles with carboplatin and etoposide alone warrant further exploration.
1. Nichols CR, Tricot G, Williams SD, et al: Dose-intensive chemotherapy in refractory germ cell cancer: A phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol 7: 932-939, 1989[Abstract] 2. 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 3. Siegert W, Beyer J: Germ cell tumors: Dose-intensive therapy. Semin Oncol 25: 215-223, 1998[Medline] 4. Broun ER, Nichols CR, Turns M, et al: Early salvage therapy for germ cell cancer using high dose chemotherapy with autologous bone marrow support. Cancer 73: 1716-1720, 1994[Medline]
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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 6. Beyer J, Stenning S, Gerl A, et al: High-dose versus conventional-dose first-salvage treatment in nonseminoma: A matched-pair analysis. Proc Am Soc Clin Oncol 19: 326a, 1999 (abstr 1255)
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Beyer J, Kramar A, Mandanas R, et al: High-dose chemotherapy as salvage treatment in germ cell tumors: A multivariate analysis of prognostic factors. J Clin Oncol 14: 2638-2645, 1996
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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 9. Motzer RB, Bajorin DF, Bosl GJ, et al: Paclitaxel (T) containing first-line salvage therapy selected by risk for patients (pts) with germ cell tumors (GCT). Proc Am Soc Clin Oncol 17: 322a, 1997 (abstr 1146)
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Motzer RB, 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
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Bokemeyer C, Beyer J, Metzner B, et al: Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer. Ann Oncol 7: 31-34, 1996
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Rodenhuis S, Westermann A, Holtkamp MJ, et al: Feasibility of multiple courses of high-dose cyclophosphamide, thiotepa, and carboplatin for breast cancer or germ cell cancer. J Clin Oncol 14: 1473-1483, 1996
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Schwella N, Beyer J, Schwaner I, et al: Impact of preleukapheresis cell counts on collection results and correlation of progenitor-cell dose with engraftment after high-dose chemotherapy in patients with germ cell cancer. J Clin Oncol 14: 1114-1121, 1996 14. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 15. Bokemeyer C, Harstrick A, Beyer J, et al: High-dose (HD) VIP-chemotherapy (Ctx) plus peripheral stem cell (PBPC) support as first-line therapy for advanced germ cell cancer. Proc Am Soc Clin Oncol 18: 326a, 1998 (abstr 1258) 16. 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
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McCaffrey JA, Mazumdar M, Bajorin D, 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 18. 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] 19. Beyer J, Rick O, Weinknecht S, et al: Nephrotoxicity after high-dose carboplatin, etoposide and ifosfamide in germ-cell tumors: Incidence and implications for hematologic recovery and clinical outcome. Bone Marrow Transplant 20: 813-819, 1997[Medline] 20. Kollmannsberger C, Beyer J, Droz JP, et al: Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors. J Clin Oncol 16: 3386-3391, 1998[Abstract]
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Shin EM, Glisson BS, Khuri FR, et al: Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. J Clin Oncol 16: 1325-1330, 1998 22. Bajorin DF, McCaffrey JA, Hilton S, et al: Treatment of patients with transitional-cell carcinoma of the urothelial tract with ifosfamide, paclitaxel, and cisplatin: A phase II trial. J Clin Oncol 16: 2722-2727, 1998[Abstract] 23. Farhat F, Culine S, Theodore C, et al: Cisplatin and ifosfamide with either vinblastine or etoposide as salvage therapy for refractory or relapsing germ cell tumor patients. Cancer 77: 1193-1197, 1996[Medline] 24. Rowinsky EK, Eisenhauer EA, Chaudhry V, et al: Clinical toxicities encountered with paclitaxel (TAXOL). Semin Oncol 20: 1-15, 1993[Medline]
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Postma TJ, Vermorken JB, Liefting AJM, et al: Paclitaxel-induced neuropathy. Ann Oncol 6: 489-494, 1995
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Cavaletti G, Bogliun G, Crespi V, et al: Neurotoxicity and ototoxicity of cisplatin plus paclitaxel in comparison to cisplatin plus cyclophosphamide in patients with epithelial ovarian cancer. J Clin Oncol 15: 199-206, 1997
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Dunkel IJ, Boyett JM, Yates A, et al: High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. J Clin Oncol 16: 222-228, 1998 Submitted November 9, 1999; accepted July 17, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
