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Single Versus Sequential High-Dose Chemotherapy in Patients With Relapsed or Refractory Germ Cell Tumors: A Prospective Randomized Multicenter Trial of the German Testicular Cancer Study Group

Anja Lorch, Christian Kollmannsberger, Joerg Thomas Hartmann, Bernd Metzner, Ingo G.H. Schmidt-Wolf, Wolfgang E. Berdel, Florian Weissinger, Jan Schleicher, Gerlinde Egerer, Antje Haas, Rebekka Schirren, Jörg Beyer, Carsten Bokemeyer, Oliver Rick

From the Departments of Hematology and Oncology, Universitätsklinikum Giessen und Marburg GmbH, Marburg; Universitätsklinikum, Tübingen; Klinikum Oldenburg, Oldenburg; Universitätsklinikum, Bonn; Universitätsklinikum, Münster; Universitätsklinikum, Würzburg; Katharinenhospital, Stuttgart; Universitätsklinikum, Heidelberg; Klinikum Ernst-von-Bergmann, Potsdam; Vivantes Krankenhaus Am Urban, Berlin; Universitätskrankenhaus Eppendorf, Hamburg; Klinik Reinhardshöhe, Bad-Wildungen, Germany; and British Columbia Cancer Agency, Vancouver, British Columbia, Canada

Address reprint requests to J. Beyer, MD, Direktor Klinik für Hämatologie und Onkologie, Vivantes Klinikum Am Urban, Dieffenbachstrasse 1, 10967 Berlin, Germany; e-mail joerg.beyer{at}vivantes.de

	ABSTRACT

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Purpose To compare single versus sequential high-dose chemotherapy (HDCT) as first or subsequent salvage treatment in patients with relapsed or refractory germ cell tumors (GCTs).

Patients and Methods Between November 1999 and November 2004, 230 patients were planned to be recruited in a prospective, randomized, multicenter trial comparing one cycle of cisplatin 100 mg/m², etoposide 375 mg/m², and ifosfamide 6 g/m² (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m² and etoposide 1,500 mg/m² (CE; arm A) versus three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m², etoposide 1,800 mg/m², and cyclophosphamide 6,400 mg/m² (CEC; arm B).

Results The study was stopped prematurely after recruitment of 216 patients as a result of excess treatment-related mortality in arm B. One hundred eleven (51%) of 216 patients were randomly assigned to sequential HDCT, and 105 (47%) of 216 patients were randomly assigned to single HDCT. Five (2%) of 216 patients had to be excluded because of non-GCT histologies at review. With a median follow-up time of 36 months, 109 (52%) of 211 patients were alive, and 91 (43%) of 211 patients were progression free. At 1 year, event-free, progression-free, and overall survival rates were 40%, 53%, and 80%, respectively, in arm A compared with 37%, 49%, and 61%, respectively, in arm B (P > .05 for all comparisons). Treatment-related deaths, mainly as a result of sepsis and cardiac toxicity, were less frequent in arm A (four of 108 patients, 4%) compared with arm B (16 of 103 patients, 16%; P < .01).

Conclusion We found no difference in survival probabilities between single HDCT using CE and sequential HDCT using CEC. Sequential HDCT was better tolerated and resulted in fewer treatment-related deaths.

	INTRODUCTION

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High-dose chemotherapy (HDCT) followed by autologous stem-cell rescue is effective salvage treatment for patients with germ cell tumors (GCTs).¹ In the first salvage setting, 30% to 70% of patients may achieve durable remissions, often despite adverse prognostic factors.^2-5 Even when administered as second or subsequent salvage treatment, approximately 10% to 20% of patients may still be cured.^4,6,7 Single high-dose consolidation treatment after several cycles of conventional-dose salvage chemotherapy has been most commonly used in Europe and represented the experimental arm in the IT 94 trial.⁸ Single HDCT was usually applied as a combination of carboplatin and etoposide plus a third drug, such as cyclophosphamide, ifosfamide, or thiotepa, at maximum-tolerated doses.^6-8 Early intensification of salvage treatment with two or more HDCT cycles has been more extensively studied in the United States and has recently been reported to be an effective salvage strategy, particularly in patients with adverse prognostic features.^2-4 HDCT administered as sequential treatment was usually applied as a combination of carboplatin and etoposide without the use of a third drug.^2,3 To directly compare the efficacies of these two commonly practiced salvage approaches, we compared single versus sequential HDCT administered as first, second, or subsequent salvage treatment in a prospective randomized multicenter trial using published HDCT regimens or modifications thereof.^2,3,8

	PATIENTS AND METHODS

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Patients and Eligibility Criteria
The trial started in September 1999 and was scheduled to recruit 230 patients with relapsed or refractory GCT at centers throughout Germany. In November 2004, the trial was stopped prematurely after recruitment of 216 patients because of excess toxicity in arm B. Patients with GCTs were eligible for the trial if there was unequivocal evidence of relapse or progression after cisplatin-based combination chemotherapy for metastatic GCT as defined by either increasing tumor markers and/or progressing radiologic manifestations. Marker-negative patients needed additional histologic evidence of undifferentiated GCT. Patients with late relapses 2 or more years after their initial treatment and patients with mediastinal primary tumors could be included. 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. Patients who had already experienced treatment failure with previous HDCT and patients with absolute refractory disease who experienced disease progression while on cisplatin-based treatment were excluded from participation. The treatment protocol was approved by the Ethics Committee of the Charité University Hospital, Berlin, Germany, as well as by the local ethic committees of each participating center.

Treatment Protocol
Random assignment was performed centrally and stratified according to location of the primary tumor, response to previous treatment, and number of previous cisplatin cycles. Treatment schedules in the two arms of the study were chosen according to published regimens and doses.^2,3,8 Treatment in arm A consisted of one cycle of conventional-dose cisplatin 20 mg/m², etoposide 75 mg/m², and ifosfamide 1.2 g/m² for 5 days (VIP) plus three additional cycles of high-dose carboplatin 1,500 mg/m² and etoposide 1,500 mg/m² (CE) administered in three divided doses over 3 days followed by reinfusion of autologous peripheral-blood progenitor cells (PBPC) 2 days later. Cycles were to be repeated at intervals of 21 days. Treatment in arm B was identical to the experimental arm of the IT 94 trial.⁸ Patients received three identical conventional-dose cycles of VIP plus one additional cycle of high-dose carboplatin 2,200 mg/m², etoposide 1,800 mg/m², and cyclophosphamide 6,400 mg/m² administered in four divided doses over 4 days followed by reinfusion of autologous PBPC 2 days later.⁸ Patients with a creatinine clearance between 70 mL/min and 100 mL/min were scheduled to receive HDCT at a reduced dose of carboplatin 1,200 mg/m² and etoposide 1,200 mg/m² in arm A and carboplatin 1,600 mg/m², etoposide 1,600 mg/m², and cyclophosphamide 1,300 mg/m² in arm B. Patients with brain metastases received whole-brain irradiation at a dose of 40 Gy immediately after random assignment in addition to their planned treatments.

PBPC Collection and Reinfusion
Mobilization of PBPC was scheduled after the first cycle of VIP in all patients using granulocyte colony-stimulating factor at a dose of 2 x 5 µg/kg/d subcutaneously.^6,9 The minimal total number of CD34⁺ cells required for each HDCT cycle was 2 x 10⁶ CD34⁺ cells/kg body weight. Patients in arm A with insufficient CD34⁺ cells to support all three HDCT cycles were switched to arm B. Patients with insufficient PBPC to support even a single HDCT cycle could undergo repeat leukaphereses after the second cycle of VIP but were excluded from the study and received further conventional-dose salvage treatment if repeat leukaphereses failed. Leukaphereses and cryopreservation were performed according to standard protocols. Autologous stem-cell rescue was performed on day 0 using unmanipulated grafts.

Clinical Evaluations and Follow-Up
Clinical evaluations included a detailed history and physical examination; conventional chest radiograms; an ECG; computed tomography scans of the brain, chest, abdomen, and pelvis; measurements of the serum tumor markers alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase; and screening serum chemistry. Laboratory investigations were performed as required, and determinations of the tumor markers alpha-fetoprotein and human chorionic gonadotropin were repeated at least before each treatment cycle.

Follow-up evaluations were performed at 6 and 12 weeks after HDCT. Patients were re-evaluated every 3 months during the first year and every 6 months during subsequent years until the final study observation period of 3 years. In all patients with a partial remission and negative tumor makers as well as in patients with a partial remission and positive tumor marker considered appropriate surgical candidates, complete surgical resection of all residual disease was attempted.

Definitions and Evaluation of Toxicities
Standard WHO criteria were used to assess treatment response.^6,10 Sensitivity to cisplatin was assessed as reported previously.^6,7 Any disease was considered sensitive to cisplatin when more than stable disease was achieved for more than 4 weeks. Patients were considered refractory to cisplatin when stable disease or better was achieved but when there was evidence of tumor progression within 4 weeks. Patients were considered absolutely refractory to cisplatin when disease progression occurred during cisplatin-based chemotherapy.

Evaluations of toxicities were classified according to the modified criteria of WHO. Peripheral neurotoxicity and ototoxicity were classified according to the National Cancer Institute of Canada Expanded Common Toxicity Criteria, Version 2.0.

Statistical Analysis
To focus on the clinical feasibility of the respective salvage approaches, the primary end point of the study was event-free survival (EFS) at 1 year. Secondary end points were progression-free survival, overall survival, and toxicities. EFS was calculated from the date of random assignment to any unplanned event such as switch from arm A to arm B, major toxicity such as dialysis or ventilation requirement, disease progression, death from any cause, or the date of last follow-up. Progression-free survival was calculated from the date of random assignment to disease progression or the date of last follow-up. Patients who died from treatment-related toxicity were censored at the time of death. Overall survival was measured from the date of random assignment to the death of the patient from any cause or the date of last follow-up.

The planned study size was 230 patients to detect a difference of 15% in EFS with an overall alpha error of 5% and a power of 80%. Data were analyzed using the Statistica software (Statsoft, Tulsa, OK). Survival analyses were performed on an intent-to-treat basis. Survival probabilities were calculated according to the Kaplan-Meier method. The log-rank test was used to compare survival probabilities. For comparison of categoric variables, Fisher's exact test or ² test was used. A difference of P < .05 was considered statistically significant.

One planned interim analysis was scheduled after the inclusion of 50% of the required total number of patients. The steering committee responsible for data management and safety decided to stop the trial prematurely after a substantially higher than anticipated rate of severe organ toxicities and deaths in arm B became apparent.

	RESULTS

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Patient Characteristics at Study Entry
Five (3%) of 216 randomly assigned patients had to be excluded because of non-GCT histologies on data review. The characteristics of the remaining 211 patients are listed in Table 1. Known prognostic factors at study entry were equally distributed between the two study arms.^4,8 Patients had been treated with a median of four cycles (range, two to nine cycles) of cisplatin-based chemotherapy; 204 (97%) of 211 patients had received etoposide, and 58 (27%) of 211 patients had received ifosfamide during previous treatments. One hundred eighty-one (86%) of 211 patients had experienced treatment failure with first-line treatment, and 30 (14%) of 211 patients experienced disease recurrence after conventional-dose salvage regimens (Table 1). At study entry, the majority of patients were sensitive to cisplatin. However, on data review, 46 (22%) of 211 patients had to be considered refractory or absolutely refractory to cisplatin (Table 1).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Events after random assignment. HDCT, high-dose chemotherapy; no., number; VIP, etoposide, ifosfamide, and cisplatin.

Organ failures were also more frequent with the use of high-dose CEC in arm B. Hemodialysis and mechanical ventilation were required in five (5%) of 108 patients in arm A compared with 27 (26%) of 103 patients in arm B (P < .001). Although grade 3 and 4 infections were more common in arm A than arm B (89 of 108 patients, 82% v 59 of 103 patients, 57%, respectively; P < .001), most of the severe grade 3 and 4 organ toxicities, such as cardiac, hepatic, and neurologic toxicities, occurred more frequently in arm B compared with arm A (Table 3). Other expected toxicities such as severe mucositis, nausea, GI toxicity, and myelosuppression occurred with similar frequencies in both treatment arms. Because of the excess organ toxicity and the higher number of treatment-related deaths in arm B, the trial was stopped prematurely by decision of the steering committee.

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Survival probabilities for the entire study population (211 patients). (B) Overall survival. (C) Progression-free survival. (D) Event-free survival. HDCT, high-dose chemotherapy.

	DISCUSSION

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

Several possible explanations must be considered for this observation. First, the dosages per HDCT cycle were higher in the CEC regimen compared with the CE regimen, resulting in a higher risk of severe organ damage. Second, renal and cardiac toxicities are known adverse effects of cyclophosphamide, particularly when used at maximal dosages as in the CEC regimen. Although predefined dose reductions were made in patients with poor renal function, these adverse effects may have been increased by subclinical organ dysfunction in the intensively pretreated study population.

A substantial, albeit lower, mortality rate of 7% after high-dose CEC was also observed in the IT 94 trial, in which the high-dose CEC regimen was identical to the one in the present study.⁸ In contrast to previous studies, experience of the treatment center as defined by the number of patients included did not influence mortality or the rate of severe toxicities.¹¹ Therefore, sequential treatment at submaximal doses of the most established drugs, carboplatin and etoposide, might be a less toxic and safer strategy to deliver HDCT in pretreated patients with GCTs rather than single HDCT.^2,3

Resections of residual tumors after HDCT played an integral part of the salvage strategy in both arms of the study.^12,13 Similar numbers of patients in either treatment arm underwent secondary surgery that resulted in a comparable rate of resection of vital undifferentiated tumor, mature teratoma, or both in approximately one quarter of patients.

Modifications of the intended treatment plan were needed in 30% of patients in arm A and 19% of patients in arm B. In addition, approximately 10% of patients in each arm who completed the study required dose modifications as a result of poor renal function. Despite standard mobilization chemotherapy and the use of granulocyte colony-stimulating factor, insufficient PBPCs were obtained to support all three HDCT cycles in 14% of patients in arm A. The majority of these patients was switched to arm B and received single HDCT. In the remaining patients of arm A as well as in the majority of patients in arm B, disease progression, organ toxicity, and severe infections were the most important reasons for premature discontinuation of the study treatment. This and the occurrence of treatment-related deaths even after conventional-dose cycles in both arms of the study are reminders that salvage chemotherapy is complicated and toxic treatment in a difficult-to-handle patient population.

Several limitations are inherent to the present study. First, a heterogeneous patient population was included. There is strong evidence that prognostic factors impact on the outcome after salvage treatment. Histology, location of the primary tumor, location of metastatic sites, tumor load as defined by the level of serum tumor markers, response to first-line treatment, progression-free interval, and sensitivity to cisplatin have been reported to be of prognostic relevance.^4,7,14 Conventional-dose first salvage treatment will cure a relevant number of seminoma as well as nonseminoma patients.^15-19 At least one prospective, randomized trial showed that HDCT was not superior to conventional-dose chemotherapy in the first salvage treatment of patients with good prognosis features.⁸ However, HDCT can still induce long-term remissions in patients with adverse prognostic features to first salvage treatment as well as in patients who require second or subsequent salvage treatment.^4,6,7 In the present study, known prognostic factors were well distributed between the two arms, and the trial does not answer the question of whether conventional-dose or high-dose chemotherapy should be used as salvage treatment in any particular patient population.

Second, patients with late relapse GCTs were included in the study if they had rapid disease progression and/or unresectable tumors. In contrast to patients with slowly progressing and potentially resectable disease in whom aggressive surgery offers the best chances of cure, the optimal approach in this prognostically unfavorable subset of late relapse patients is undetermined and needs to be studied in future trials.

In conclusion, sequential HDCT using three cycles CE was superior to single HDCT with CEC in the treatment of patients with relapsed or refractory GCTs in terms of a lower rate of severe organ toxicities and fewer treatment-related deaths. However, the optimal approach to salvage treatment in such patients still needs to be determined, particularly with respect to the integration of prognostic factors.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Christian Kollmannsberger, Pfizer Inc Stock: N/A Honoraria: Wolfgang E. Berdel, Amgen Inc, Merck Germany, AstraZeneca; Carsten Bokemeyer, Amgen Inc, Bristol-Myers Squibb Co Research Funds: Wolfgang E. Berdel, Funds, Amgen Inc; Carsten Bokemeyer, Funds, Amgen Inc, Bristol-Myers Squibb Co, Sanofi-Aventis Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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

 
Conception and design: Jörg Beyer, Carsten Bokemeyer, Oliver Rick

Financial support: Jörg Beyer

Administrative support: Jörg Beyer, Carsten Bokemeyer, Joerg Thomas Hartmann, Oliver Rick

Provision of study materials or patients: Anja Lorch, Christian Kollmannsberger, Joerg Thomas Hartmann, Bernd Metzner, Ingo G.H. Schmidt-Wolf, Wolfgang E. Berdel, Florian Weissinger, Jan Schleicher, Gerlinde Egerer, Antje Haas, Jörg Beyer, Carsten Bokemeyer, Oliver Rick

Collection and assembly of data: Anja Lorch, Christian Kollmannsberger, Joerg Thomas Hartmann, Wolfgang E. Berdel, Gerlinde Egerer, Rebekka Schirren, Jörg Beyer, Carsten Bokemeyer, Oliver Rick

Data analysis and interpretation: Anja Lorch, Christian Kollmannsberger, Joerg Thomas Hartmann, Rebekka Schirren, Jörg Beyer, Carsten Bokemeyer, Oliver Rick

Manuscript writing: Anja Lorch, Jörg Beyer

Final approval of manuscript: Anja Lorch, Christian Kollmannsberger, Joerg Thomas Hartmann, Bernd Metzner, Ingo G.H. Schmidt-Wolf, Wolfgang E. Berdel, Florian Weissinger, Jan Schleicher, Gerlinde Egerer, Antje Haas, Rebekka Schirren, Jörg Beyer, Carsten Bokemeyer, Oliver Rick

	Appendix

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Participating centers, with number of patients in parentheses, were as follows: Unversitätsklinikum Charité, Standort Mitte, Berlin (52), Universitätsklinikum Tübingen (33), Universitätsklinikum Marburg (12), Städtische Kliniken Oldenburg (10), Universitätsklinikum Bonn (10), Universitätsklinikum Münster (9), Universitätsklinikum Würzburg (6), Katharinenhospital Stuttgart (5), Klinikum Ernst von Bergmann Potsdam (5), Universitätsklinikum Heidelberg (5), Klinikum Minden (4), Städtisches Klinikum Karlsruhe (4), Universitätsklinikum Göttingen (4), Krankenhaus München-Harlaching (3), Robert-Bosch Krankenhaus Stuttgart (3), Universitätsklinikum Hamburg (3), Universitätsklinikum Dresden (3), Städtisches Klinikum Dessau (3), Carl-Thiem Klinikum Cottbus (3), Universitätsklinikum Aachen (2), Klinikum Ludwigshafen (2), Diakonissenkrankenhaus Bremen (2), Dr.-Horst-Schmidt Kliniken Wiesbaden (2), Universitätsklinikum Rostock (2), Klinikum Großhadern München (2), Universitätsklinikum Mainz (2), KMT Klinik Idar-Oberstein (2), Klinikum Siloah Hannover (2), Franziskus Hospital Bielefeld (2), Universitätsklinikum Charité, Standort Benjamin-Franklin, Berlin (1), Zentralkrankenhaus Bremen Mitte (1), Städtische Kliniken Höchst, Frankfurt (1), Universitätsklinikum Homburg (1), Universitätsklinikum Regensburg (1), Universitätskinderklinik Bonn (1), Klinikum Wuppertal (1), Universitätsklinikum Ulm (1), Städtische Kliniken Lübeck Süd (1), Klinikum Krefeld (1), Universitätsklinikum Jena (1), Medizinische Hochschule Hannover (1), Allgemeines Krankenhaus der Stadt Hagen (1), Städtische Kliniken Gütersloh (1), Universitätsklinikum Greifswald (1), Universitätsklinikum Düsseldorf (1), St. Johannes Hospital Duisburg (1), and Robert-Rössle Klinik, Berlin-Buch (1).

	ACKNOWLEDGMENTS

 
We thank Tanja Braun, Günter Janitzki, and Antje Fleming for their help with the data management as well as W. Siegert, MD, for his support of the study.

	NOTES

 
C.B., O.R., and J.B. equally contributed to the conception and design of the study, the provision of patients, and the data interpretation and analysis on behalf of the German Testicular Cancer Study Group.

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. Horwich A, Shipley J, Huddart R: Testicular germ-cell cancer. Lancet 367:754-765, 2006[CrossRef][Medline]

2. 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[Abstract/Free Full Text]

3. 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]

4. Vaena DA, Abonour R, Einhorn LH: Long-term survival after high-dose salvage-chemotherapy for germ cell malignancies with adverse prognostic variables. J Clin Oncol 21:4100-4104, 2003[Abstract/Free Full Text]

5. Beyer J, Stenning S, Gerl A, et al: High-dose versus conventional-dose chemotherapy as first-salvage treatment in patients with non-seminomatous germ-cell tumors: A matched-pair analysis. Ann Oncol 13:599-605, 2002[Abstract/Free Full Text]

6. 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[Abstract/Free Full Text]

7. 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[Abstract/Free Full Text]

8. Pico JL, Rosti G, Kramar A, et al: A randomized trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumors. Ann Oncol 16:1152-1159, 2005[Abstract/Free Full Text]

9. 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[Abstract/Free Full Text]

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

11. Collette L, Sylvester RJ, Stenning SP, et al: Impact of the treating institution on survival of patients with "poor prognosis" metastatic nonseminoma. J Natl Cancer Inst 91:839-846, 1999[Abstract/Free Full Text]

12. Hartmann J, Schmoll HJ, Kuczyk MA, et al: Postchemotherapy resections of residual masses from metastatic non-seminomatous testicular germ cell tumors. Ann Oncol 8:531-538, 1997[Abstract/Free Full Text]

13. Rick O, Bokemeyer C, Weinknecht S, et al: Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer. J Clin Oncol 22:3713-3719, 2004[Abstract/Free Full Text]

14. Fossa SD, Stenning SP, Gerl A, et al: Prognostic factors in patients progressing after platinum-based chemotherapy for malignant non-seminomatous germ cell tumours. Br J Cancer 80:1392-1399, 1999[CrossRef][Medline]

15. Miller KD, Loehrer PJ, Gonin R, et al: Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma. J Clin Oncol 15:1427-1431, 1997[Abstract]

16. Kondagunta GV, Bacik J, Donadio A, et al: Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 23:6549-6555, 2005[Abstract/Free Full Text]

17. Vuky J, Tickoo SK, Sheinfeld J, et al: Salvage chemotherapy for patients with advanced pure seminoma. J Clin Oncol 20:297-301, 2002[Abstract/Free Full Text]

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. 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[CrossRef][Medline]

Submitted October 21, 2006; accepted April 5, 2007.

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