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Phase I/II Study of Sequential Dose-Intensified Ifosfamide, Cisplatin, and Etoposide Plus Paclitaxel As Induction Chemotherapy for Poor Prognosis Germ Cell Tumors by the German Testicular Cancer Study Group

Jörg T. Hartmann, Thomas Gauler, Bernd Metzner, Arthur Gerl, Jochen Casper, Oliver Rick, Marius Horger, Jan Schleicher, Günter Derigs, Regine Mayer-Steinacker, Jörg Beyer, Markus A. Kuczyk, Carsten Bokemeyer

From the Departments of Oncology and Hematology and Urology, South West German Comprehensive Cancer Center, University of Tuebingen, Tuebingen; Department of Oncology, West German Cancer Center, Essen; Department of Oncology/Hematology, Klinikum Oldenburg, Oldenburg; Department of Hematology and Oncology, University Hospital Grosshadern, Munich; Department of Hematology and Oncology, University of Rostock, Rostock; Department of Hematology/Oncology, Charite Berlin, Berlin; Department of Oncology, Katharinenhospital Stuttgart, Stuttgart; Department of Hematology and Oncology, University of Mainz, Mainz; Department of Hematology and Oncology, University of Ulm, Ulm; Department of Hematology and Oncology, University of Marburg, Marburg; and Department of Oncology and Hematology, University of Hamburg, Hamburg, Germany

Address reprint requests to Jörg T. Hartmann, MD, PhD, Department of Medical Oncology, Hematology, Immunology, Rheumatology, and Pulmonology, South West German Comprehensive Cancer Center, Eberhard-Karls-University of Tuebingen, Otfried-Mueller-Str 10, 72076 Tuebingen, Germany; e-mail: joerg.hartmann{at}med.uni-tuebingen.de

	ABSTRACT

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Purpose: To evaluate the feasibility and the toxicity of sequential, dose-intensified chemotherapy combined with paclitaxel plus peripheral blood–derived hematopoietic stem-cell support (PBSC) for patients with untreated metastatic germ cell tumors (GCTs) who have poor International Germ Cell Consensus Cancer Group prognostic features.

Patients and Methods: Paclitaxel was added to high-dose (HD) etoposide, ifosfamide, and cisplatin (VIP; etoposide 1,500 mg/m², ifosfamide 10,000 mg/m², and cisplatin 100 mg/m²; cumulative dose; days –6 through –2 per cycle) at three dose levels (135, 175, and 225 mg/m²) applied on day –6. Cycles were supported by PBSC and granulocyte colony-stimulating factor. One cycle of standard VIP was administered before start of HD-VIP plus paclitaxel cycles to collect autologous PBSC.

Results: Fifty-two of 53 patients receiving 152 cycles were assessable. As expected, myelosuppression was the major adverse effect. Median durations of leukocytes less than 1,000/µL and thrombocytes less than 25,000/µL were 6 and 4 days, respectively, independently of the dose of paclitaxel applied. WHO grade 2 neurotoxicity and grade 3 encephalopathy were observed in 5% of patients each. Other main adverse effects observed were stomatitis, diarrhea, and obstipation. Seventy-nine percent of patients achieved a favorable response to chemotherapy plus secondary surgery. After a median follow-up time of 41 months in surviving patients, the calculated 2- and 5-year survival rates were 77.6% (95% CI, 65.4% to 89.9%) and 75.2% (95% CI, 62.5% to 87.8%), respectively.

Conclusion: Dose-intensive, sequential HD-VIP plus paclitaxel up to a dose of 225 mg/m² in patients with poor prognosis GCT is a feasible approach. The regimen warrants investigation for its therapeutic potential in an expanded cohort of poor prognosis GCT patients.

	INTRODUCTION

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Four cycles of cisplatin, etoposide, and bleomycin (PEB) chemotherapy result in a 5-year overall survival (OS) rate of only approximately 48% in poor prognosis patients with germ cell tumors (GCTs) according to the International Germ Cell Consensus Cancer Group (IGCCCG) classification.^1-6 The German Testicular Cancer Study Group (GTCSG) has tested a concept of early dose intensification with three sequential high-dose (HD) treatment cycles based on etoposide, ifosfamide, and cisplatin (VIP), escalating the dose of etoposide and ifosfamide. The current protocol used is composed of a first cycle of standard-dose VIP for granulocyte colony-stimulating factor (G-CSF) –supported peripheral hematopoietic cell mobilization, followed by three to four cycles of HD-VIP with peripheral-blood stem-cell (PBSC) rescue. From 1993 to 1999, 182 poor prognosis patients were treated within eight different dose-intensity levels.⁷ The 5-year disease-specific survival rate was 73% after a median observation period of 47 months.

In vitro studies with paclitaxel have demonstrated marked activity on cisplatin-resistant teratocarcinoma cell lines.⁸ Clinical trials have been conducted in GCT patients who experienced treatment failure on first- or second-line cisplatin combination chemotherapy.^9,10 We report here the results of a dose-finding study using escalating doses of paclitaxel with HD-VIP. This trial was conducted in a multicenter setting within the GTCSG. The primary study aims were to assess the feasibility of the addition of paclitaxel to HD-VIP, to determine the maximum-tolerated dose, and to assess response rates and survival.

	PATIENTS AND METHODS

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Eligibility
Patients with poor prognosis nonseminomatous GCTs according to the IGCCCG classification were registered on this prospective, internal review board–approved trial. All patients were chemotherapy naïve and had assessable disease and documented GCT either histologically or by increased values of alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (HCG). In the absence of elevated serum tumor markers, biopsy was performed to document the presence of active GCT (and exclude teratoma).^11,12

Additional eligibility criteria included WBC greater than 3,000/µL, platelets greater than 100,000/µL, creatinine clearance greater than 50 mL/min, and signed informed consent. Patients were excluded for the presence of active infection or prior cytostatic therapy. The study protocol was approved by Tuebingen University Ethics Committee and all local ethics committees.

Pretreatment Evaluation
Pretreatment evaluation included history and physical examination; lactate dehydrogenase; AFP; HCG; audiometry; serum screening chemistry panel (eg, AST, ALT, bilirubin, creatinine, urea, electrolytes); computed tomography scan of the chest, abdomen, and pelvis; and brain imaging and bone scans based on clinical indications.

Treatment Program
Treatment consisted of one cycle of standard-dose VIP (cisplatin 20 mg/m², etoposide 75 mg/m², and ifosfamide 1,200 mg/m², daily for 5 days, administered 21 days apart) followed by three cycles of paclitaxel plus HD-VIP (dose level 6) with PBSC support administered at 21-day intervals. Commencing 24 hours after the completion of standard VIP, patients received G-CSF 5 µg/kg once daily by subcutaneous injection. Leukapheresis was performed on cycle days 13 through 16, provided that the total leukocyte count had recovered to 1,000/µL. Peripheral blood was processed and cryopreserved according to standard methods. Paclitaxel was added to three cycles of HD-VIP with increasing doses among patient cohorts in the manner of a phase I trial. Dose escalation comprised three dose steps (level 1 [L1]: 135 mg/m²; L2 [L2]: 175 mg/m²; and L3 [L3]: 225 mg/m²) on day –6 of each cycle before HD-VIP. Paclitaxel was administered on an inpatient basis by a 3-hour infusion, followed by HD-VIP (Table 1, Fig 1). Premedications for paclitaxel were dexamethasone, diphenhydramine, and cimetidine. G-CSF was administered again commencing 24 hours (day –1) after PBSC retransfusion in cycles 2 through 4 of paclitaxel plus HD-VIP and was continued until the absolute neutrophil count was 2,000/µL one time or more than 1,000/µL for 3 successive days. PBSC support using unmanipulated grafts was administered 48 hours after each paclitaxel plus HD-VIP cycle (day 0). The minimal cell number for each reinfusion was 1 x 10⁶ CD34⁺ cells/kg of body weight per cycle (at least 3 x 10⁶ CD34⁺ cells for three consecutive HD-VIP cycles). Patients with insufficient peripheral-blood progenitor cells to support HD chemotherapy could undergo repeat leukaphereses but were excluded from the study if repeat leukaphereses failed. Leukaphereses and cryopreservation were performed according to standard protocols.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Paclitaxel dose was escalated among patients cohorts: level (L) 1, paclitaxel 135 mg/m2; L2, paclitaxel 175 mg/m2; and L3, paclitaxel 225 mg/m2. Cycles of standard-dose (SD) etoposide, ifosfamide, and cisplatin (VIP) and high-dose (HD) VIP plus paclitaxel were administered in 21-day intervals, starting on day (D) 1 and D –6, respectively. Autologous hematopoietic peripheral-blood stem-cell (PBSC) rescue during HD chemotherapy was performed on D 0. Granulocyte colony-stimulating factor (G-CSF) was administered every cycle, starting on D 7 during SD-VIP and D –1 during HD-VIP plus paclitaxel.

Dose Modifications
Dose-limiting toxicity (DLT) was defined as WHO grade 4 nonhematologic toxicity or grade 3 neurotoxicity or complicated neutropenia (eg, septicemia or septic shock, WHO grade 4). At least 10 assessable patients were entered at each dose level. Subsequent dose levels were not opened until safety and tolerability had been assessed for the previous dose level for all patients for all cycles. If DLT of any type was seen in four (40%) of the 10 planned patients, six more patients were enrolled. If more than six (37%) of these 16 patients experienced DLT, this level was considered as dose limiting, and the previous level was considered as the maximum-tolerated dose level. The dose escalation of paclitaxel was limited to a maximal dose of 225 mg/m² per cycle.

Management of complications included platelet transfusion for counts of less than 10,000/µL and packed RBCs for hemoglobin levels of less than 8 g/dL. Neutropenic fevers were routinely treated with empiric broad-spectrum antibiotics.

The criteria for paclitaxel plus HD-VIP treatment with cycle 2 and subsequent cycles were a neutrophil count of at least 1,500/µL and a platelet count greater than 80,000/µL. In case of incomplete hematologic recovery, a maximal treatment delay of 1 week was allowed. Dose modifications for subsequent HD chemotherapy cycles included individual stop of paclitaxel treatment in case of grade 3 neurotoxicity and a 50% dose reduction of cisplatin and ifosfamide in case of severe hematuria exceeding 3 days. The decision of whether to substitute cisplatin with carboplatin in case of severe ototoxicity or nephrotoxicity was left up to the local investigator, as was further treatment after septic events.

Evaluation of Response and Toxicity
Physical examination was performed and vital signs were taken daily for inpatients and twice weekly for outpatients, or more frequently as indicated. A CBC was obtained at least twice weekly while G-CSF was administered and daily during leukapheresis. Comprehensive hematologic and chemistry panels and creatinine, AFP, HCG, and lactate dehydrogenase levels were obtained before each cycle, along with a 24-hour urine collection for creatinine clearance.

Response to HD-VIP plus paclitaxel was defined according to WHO criteria.¹³ Computed tomography scans were required every two cycles. Follow-up duration, progression-free survival (PFS), and OS were calculated from the beginning of treatment to the date of last follow-up evaluation, date of relapse, and the date of death, respectively. The survival calculation used death as a result of any reason as the end point. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test.¹⁴ The level of significance was set to P = .05 (two-sided). All tests were performed using SPSS software (SPSS for Windows, version 13.0; SPSS Inc, Chicago, IL).

	RESULTS

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Patient Characteristics
Fifty-three patients with nonseminomatous histology and IGCCCG poor prognosis criteria were entered onto this multicenter phase I trial at 20 German cancer centers between July 1998 and January 2003. Fifty-two of 53 patients were assessable for analysis. One patient did not begin treatment with HD-VIP plus paclitaxel as a result of early death (neutropenic sepsis, multiorgan failure, and septic shock) during the SD-VIP cycle. Median age was 30 years (range, 18 to 55 years). Ten patients were treated at dose level L1, 19 patients were treated at dose level L2, and 23 patients were treated at dose level L3. The patient numbers at dose levels L2 and L3 were expanded to 19 and 23, respectively, to gain more clinical experience with this regimen. Patient characteristics are listed in Table 2.

Treatment and Toxicity
All 52 patients were assessable for toxicity. All toxicities, with the earlier mentioned exception of a patient who had died after a standard-dose cycle, were attributed to HD-VIP and were taken into account to define DLT, independently of whether the adverse event was judged to be related to the drug being escalated (paclitaxel) or related to VIP. The most common nonhematologic toxicities were GI adverse effects such as mucositis, nausea and vomiting, obstipation, and diarrhea, as well as peripheral neurotoxicity grade 1 or 2 and central neurotoxicity. At dose level L1, all patients (100%) enrolled were treated with three subsequent cycles of paclitaxel plus HD-VIP without experiencing a DLT. At L2 and L3, two patients each stopped treatment after completion of two HD cycles as a result of documented progression (n = 2) or toxicity (n = 2; encephalopathy and GI toxicity). Two patients (5%) developed allergic reactions after paclitaxel application; in one of these patients, paclitaxel was suspended because of the severity of the hypersensitivity reaction. This patient has been further treated according to the HD-VIP protocol plus hematopoietic rescue (without paclitaxel). Other causes for dose reductions were grade 2 paresthesia in two patients (4%), diarrhea and obstipation (pre-ileus) in four patients (8%), and encephalopathy in two patients (4%). A total of 72% of patients were treated for nadir fever in 21 (70%) of 30 cycles at dose level L1, 33 (60%) of 55 cycles at L2, and 48 (72%) of 67 cycles at L3. Grade 3 or 4 infections occurred in 12 cycles (8%). Twenty percent, 32%, and 26% of patients at dose levels L1, L2, and L3, respectively, experienced WHO grade 4 mucositis requiring transient intravenous morphine derivatives; grade 3 mucositis was seen in 30%, 16%, and 13% of patients at L1, L2, and L3, respectively. Grade 3 nausea and vomiting occurred in 50%, 42%, and 34% of patients at L1, L2, and L3, respectively (Table 3). In addition, approximately 25% of patients developed WHO grade 1 or 2 neurotoxicity, which seemed to be independent from the paclitaxel dose administrated; however, given the low number of patients included per dose level, the statistical power for comparison was limited.

Response and Survival
Overall, 41 (79%) of 52 patients treated with HD-VIP plus paclitaxel achieved a favorable response, which was defined as a complete remission (CR), a partial remission with tumor marker normalization, or no evidence of disease after resection of residual masses. Nine (22%) of 41 patients were rendered disease free by secondary surgery resecting mature teratoma in five patients and vital carcinoma in four patients. Another 17 patients (33%) allocated to surgery yielded necrosis only. Twelve patients reaching a partial remission status with complete marker normalization did not undergo surgery because of unresectable extension of disease. The rate of unfavorable responses was 21%.

The 5-year PFS and OS rates for the 52 patients were 64.1% (95% CI, 50.3% to 77.9%) and 75.2% (95% CI, 62.5% to 87.8%), respectively (Fig 2). For dose levels L1 to L3, the OS rates were 70.0%, 83.3%, and 77.3%, respectively. The median follow-up time for survivors at the time of this analysis was 41 months (range, 4 to 65 months).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Overall survival and (B) progression-free survival of 52 patients with poor prognosis germ cell tumors treated with induction high-dose etoposide, ifosfamide, and cisplatin plus paclitaxel chemotherapy with autologous hematopoietic stem-cell rescue.

	DISCUSSION

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The treatment program of the GTCSG in poor prognosis GCT patients comprised multiple cycles of sequential, dose-intensive HD-VIP therapy with PBSC support. To maximize the dose-intensity of chemotherapy, three HD cycles were administered in short time intervals starting immediately after hematopoietic cell collection using one cycle of standard-dose VIP. The use of hematopoietic growth factors and PBSC reduced the time to blood count recovery and allowed rapid recycling of therapy. In the trial presented here, paclitaxel was added to the HD-VIP regimen at the doses that were identified in the previous phase I/II trial of HD-VIP.⁷ The inclusion of paclitaxel in dose-intensive programs for GCT may be an essential component for achieving durable CR against refractory GCT in GCT reference centers¹⁷ but has not been investigated as a first-line approach in poor prognosis patients.

Recently, a prospective, randomized trial evaluating two cycles of BEP plus two cycles of HD chemotherapy consisting of cyclophosphamide, etoposide, and carboplatin plus PBSC rescue compared with four cycles of BEP in both intermediate and poor prognosis GCT patients has been carried out in the United States. This US Intergroup study has stopped recruitment after inclusion of 219 of the planned 270 patients, and the results have not shown an advantage for the whole group of intermediate and poor prognosis GCT patients. The observation of a slow marker decline (AFP and/or HCG) during the first two cycles of BEP was associated with a shorter PFS and OS compared with a sufficient decline. Among 67 patients with unsatisfactory marker decline in the first two cycles, the 1-year partial response/CR rate was 61% for patients receiving HD cyclophosphamide, etoposide, and carboplatin chemotherapy for the subsequent two cycles compared with 34% for patients receiving two more additional cycles of BEP (P = .03).¹⁹ Thus, a slow marker decrease might be a predictive factor to identify patients who are more likely to have a negative outcome after standard-dose protocols. Other investigations have also shown that patients fulfilling IGCCCG poor prognosis criteria may still be, in some degree, a prognostically heterogeneous group.^20,21 An ongoing European-American phase III trial, started in November 2003, compares four cycles of BEP with a dose-dense regimen including oxaliplatin, paclitaxel, ifosfamide, bleomycin, etoposide, and cisplatin in case of slow marker decline (K. Fizazi, personal communication, October 2006).

On the basis of this observation and in view of the activity of paclitaxel in patients with GCT who experienced treatment failure with cisplatin-based combination chemotherapy, the incorporation of paclitaxel in a standard upfront regimen represents an important new experimental approach in patients with poor prognosis criteria. In our schedule design, we opted for the addition of paclitaxel to the HD-VIP regimen at dose level 6. Because the toxicity of paclitaxel is dependent on both the duration of infusion and the sequence in the administration with cisplatin, we chose a 3-hour infusion immediately before the start of cisplatin on day 1 (ie, the start of the 5-day cycle of HD-VIP). The present series demonstrates that, with this schedule, paclitaxel up to a dose of 225 mg/m² can safely be added to HD-VIP in a multicenter setting. With the use of G-CSF and PBSC rescue, the toxicity of paclitaxel followed by HD-VIP did not differ significantly from the profile of the previously used HD-VIP regimen alone. When paclitaxel was added to HD-VIP at the highest dose level tested, GI toxicity and more prolonged myelotoxicity were observed. However, this was mainly restricted to the last HD chemotherapy cycle. Because the analysis of the planned and applied dose-intensity has revealed values of more than 90% regardless of cycle and dose level, we determined paclitaxel 225 mg/m² to be the recommended dose level. However, it remains unclear whether there is a dose-response relationship with paclitaxel in GCT. Our data suggest no obvious excess in neuromotor toxicity with the use of one cycle of standard VIP and three cycles of paclitaxel plus HD-VIP. We conclude that paclitaxel plus HD-VIP is feasible and a tolerable induction regimen for poor prognosis GCT patients. The initial results in 52 assessable patients with poor prognosis GCT, showing a favorable response in 79% of patients with 69% of patients being relapse free after a median follow-up time of 41 months (range, 4 to 65 months), are encouraging. Hence, paclitaxel plus HD-VIP is being investigated for its therapeutic potential in an expanded cohort of poor prognosis GCT patients.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Jörg T. Hartmann, Carsten Bokemeyer

Administrative support: Jörg T. Hartmann

Provision of study materials or patients: Jörg T. Hartmann, Thomas Gauler, Bernd Metzner, Arthur Gerl, Jochen Casper, Oliver Rick, Jan Schleicher, Günter Derigs, Regine Mayer-Steinacker, Jörg Beyer, Marjus A. Kuczyk, Carsten Bokemeyer

Collection and assembly of data: Jörg T. Hartmann, Thomas Gauler, Arthur Gerl, Jochen Casper, Marius Horger, Jan Schleicher, Guenter Derigs, Regine Mayer-Steinacker, Carsten Bokemeyer

Data analysis and interpretation: Jörg T. Hartmann, Arthur Gerl, Oliver Rick, Marius Horger, Carsten Bokemeyer

Manuscript writing: Jörg T. Hartmann

Final approval of manuscript: Jörg T. Hartmann, Thomas Gauler, Bernd Metzner, Arthur Gerl, Jochen Casper, Oliver Rick, Marius Horger, Jan Schleicher, Günter Derigs, Regine Mayer-Steinacker, Jörg Beyer, Markus A. Kuczyk, Carsten Bokemeyer

	Appendix

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View larger version (34K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Achieved dose-intensity in percentage of the planned intensity according to dose levels L1 to L3 for the high-dose etoposide, ifosfamide, and cisplatin plus paclitaxel treatment cycles 1 to 3 per specific drug.

	ACKNOWLEDGMENTS

 
We thank the following physicians for actively participating in the study: T. Kubin, Städtisches Klinikum Karlsruhe; C. Binder, University of Goettingen; M. Hentrich, Krankenhaus Harlaching, Munich; K. Kaesberger, Diakonissenkrankenhaus, Stuttgart; A. Glassmacher, University of Bonn; E. Thiel, Klinikum Steglitz, Berlin; V. Grünwald, Medizinische Hochschule Hannover; R. Naumann, Universität Dresden; and A. Jakob, Klinikum Offenburg. We thank H. Hecker, University Medical School Hanover, for statistical support. We are indebted to I. Boehlke and A. Flemming for the study data documentation.

	NOTES

 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Birch R, Williams S, Cone A, et al: Prognostic factors for favorable outcome in disseminated germ cell tumors. J Clin Oncol 4:400-407, 1986[Abstract/Free Full Text]

2. International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 15:594-603, 1997[Abstract/Free Full Text]

3. Hinton S, Catalano PJ, Einhorn LH, et al: Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: Final analysis of an intergroup trial. Cancer 97:1869-1875, 2003[CrossRef][Medline]

4. Sonneveld DJ, Hoekstra HJ, van der Graaf WT, et al: Improved long term survival of patients with metastatic nonseminomatous testicular germ cell carcinoma in relation to prognostic classification systems during the cisplatin era. Cancer 91:1304-1315, 2001[CrossRef][Medline]

5. Bosl GJ, Motzer RJ: Testicular germ-cell cancer. N Engl J Med 337:242-253, 1997[Free Full Text]

6. Kopp HG, Kuczyk M, Classen J, et al: Advances in the treatment of testicular cancer. Drugs 66:641-659, 2006[CrossRef][Medline]

7. Schmoll HJ, Kollmannsberger C, Metzner B, et al: Long-term results of first-line sequential high dose VIP chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: An extended phase II study of the German Testicular Cancer Study Group. J Clin Oncol 21:4083-4091, 2003[Abstract/Free Full Text]

8. Motzer RJ, Chou TC, Schwartz L, et al: Paclitaxel in germ cell cancer. Semin Oncol 22:12-15, 1995[Medline]

9. 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[Abstract/Free Full Text]

10. 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[Abstract/Free Full Text]

11. Hartmann JT, Nichols CR, Droz JP, et al: Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors. J Natl Cancer Inst 92:54-61, 2000[Abstract/Free Full Text]

12. Hartmann JT, Fossa SD, Nichols CR, et al: Incidence of metachronous testicular cancer in patients with extragonadal germ cell tumors. J Natl Cancer Inst 93:1733-1738, 2001[Abstract/Free Full Text]

13. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline]

14. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

15. Houldsworth J, Xiao H, Murty VV, et al: Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation. Oncogene 16:2345-2349, 1998[CrossRef][Medline]

16. Kondagunta GV, Bacik J, Sheinfeld J, et al: Paclitaxel plus ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol 25:85-90, 2007[Abstract/Free Full Text]

17. 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[Abstract/Free Full Text]

18. de Wit R, Louwerens M, de Mulder PH, et al: Management of intermediate-prognosis germ-cell cancer: Results of a phase I/II study of Taxol-BEP. Int J Cancer 83:831-833, 1999[CrossRef][Medline]

19. Motzer RJ, Nichols CJ, Margolin KA, et al: Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol 25:247-256, 2007[Abstract/Free Full Text]

20. Hartmann JT, Nichols CR, Droz JP, et al: Prognostic variables for response and outcome in patients with extragonadal germ-cell tumors. Ann Oncol 13:1017-1028, 2002[Abstract/Free Full Text]

21. Kollmannsberger C, Nichols C, Meisner C, et al: Identification of prognostic subgroups among patients with metastatic ‘IGCCCG poor-prognosis’ germ-cell cancer: An explorative analysis using cart modeling. Ann Oncol 11:1115-1120, 2000[Abstract/Free Full Text]

Submitted April 18, 2007; accepted September 17, 2007.

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