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Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 421-427
© 2008 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2007.13.8461
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Randomized Trial Comparing Bleomycin/Etoposide/Cisplatin With Alternating Cisplatin/Cyclophosphamide/Doxorubicin and Vinblastine/Bleomycin Regimens of Chemotherapy for Patients With Intermediate- and Poor-Risk Metastatic Nonseminomatous Germ Cell Tumors: Genito-Urinary Group of the French Federation of Cancer Centers Trial T93MP

Stéphane Culine, Andrew Kramar, Christine Théodore, Lionel Geoffrois, Christine Chevreau, Pierre Biron, Binh Bui Nguyen, Jean-François Héron, Pierre Kerbrat, Armelle Caty, Rémy Delva, Pierre Fargeot, Karim Fizazi, Jeannine Bouzy, Jean-Pierre Droz

From the Centre Regional de Lutte contre le Cancer Val d'Aurelle, Montpellier; Institut Gustave Roussy, Villejuif; Centre Alexis Vautrin, Nancy; Institut Claudius Régaud, Toulouse; Centre Léon Bérard, Lyon; Institut Bergonié, Bordeaux; Centre François Baclesse, Caen; Centre Eugène Marquis, Rennes; Centre Oscar Lambret, Lille; Centre Eugène Papin, Angers; and the Centre Georges François, Leclerc, France

Corresponding author: Stéphane Culine, MD, PhD, Department of Medical Oncology, CRLC Val d'Aurelle, Parc Euromédecine, 34298 - Montpellier Cedex 5, France; e-mail: stculine{at}valdorel.fnclcc.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Purpose Two chemotherapy regimens for intermediate- and poor-risk metastatic nonseminomatous germ cell tumors were compared for efficacy and toxicity.

Patients and Methods From February 1994 to February 2000, 190 patients were randomly assigned between either four cycles of BEP (bleomycin 30 mg d1, d8, d15; etoposide 100 mg/m2 d1-5; cisplatin 20 mg/m2 d1-5) or four to six alternating cycles of CISCA/VB (cyclophosphamide 400 mg/m2 d1-2, doxorubicin 35 mg/m2 d1-2, cisplatin 100 mg/m2 d3/vinblastine 2.5 mg/m2 d1-5, bleomycin 25 mg/m2 d1-5). Risk was initially defined according to the Institut Gustave Roussy (Villejuif, France) prognostic model based on serum alpha-fetoprotein and human chorionic gonadotropin levels only. Patients were retrospectively assigned into the International Germ Cell Consensus Classification.

Results Among 185 assessable patients, favorable responses did not differ statistically between the two arms: 49 in the CISCA/VB arm (56%; 95% CI, 45% to 66%), 57 in the BEP arm (65%; 95% CI, 55% to 75%). The CISCA/VB regimen induced more significant hematologic and mucous toxicities compared with the BEP arm. The 5-year event-free survival rates were 37% (95% CI, 27% to 47%) and 47% (95% CI, 37% to 57%) in CISCA/VB and BEP arms, respectively (hazard ratio [HR] = 0.76; 95% CI, 0.52 to 1.11; P = .15). With a median follow-up of 7.8 years, the 5-year overall survival rates were 59% (95% CI, 47% to 67%) and 69% (95% CI, 58% to 77%) in CISCA/VB and BEP arms, respectively (HR = 0.73; 95% CI, 0.46 to 1.18; P = .24).

Conclusion Because of equivalent efficacy and lesser toxicity, the standard treatment for patients with intermediate- and poor-risk metastatic nonseminomatous germ cell tumors remains four cycles of BEP.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Since the introduction of cisplatin into clinical practice in the 1970s, approximately 80% of patients with unselected metastatic nonseminomatous germ cell tumors (NSGCT) can expect long-term disease-free survival.1-3 Refinements in prognostic staging led to the publication by the International Germ Cell Cancer Collaborative Group (IGCCCG) of a consensus prognostic index in 1997.4 This index stratifies patients into good-, intermediate-, and poor-prognosis subgroups on the basis of three criteria: the primary tumor site, the levels of serum tumor markers, and whether extrapulmonary visceral metastases are present. Patients allocated to the good-prognosis group have a more than 90% probability of cure, but patients in the intermediate- and poor-prognosis group have 3-year survival rates of only 81% and 48%, respectively.

A number of attempts have been made to improve the cure rate of patients with intermediate and poor prognosis during the last two decades. In 1987, investigators from Indiana University5 reported the results of a randomized trial comparing four cycles of either cisplatin/vinblastine/bleomycin (PVB) or bleomycin/etoposide/cisplatin (BEP) in unselected metastatic NSGCT. A subgroup analysis showed that the BEP combination produced better outcomes in patients with poor prognostic features.5 From then on, the BEP regimen became the standard treatment for poor-risk patients. Subsequent studies that attempted to identify a regimen superior to BEP in randomized trials have focused on increasing cisplatin dose-intensity,6 substituting bleomycin for ifosfamide,7-9 or using high-dose chemotherapy with autologous hematopoietic stem-cell support.10,11 However, all of them have failed to demonstrate any survival advantage over standard BEP.

In the early 1980s, a cyclical chemotherapy regimen was developed at The University of Texas M.D. Anderson Cancer Center that combined two independently effective regimens, cisplatin/doxorubicin/cyclophosphamide (CISCA) and vinblastine/bleomycin (VB).12 Initial results indicated a 92% complete response rate in 48 patients.13 These encouraging results were subsequently confirmed in a larger study including 100 unselected patients with advanced NSGCT because 89% achieved continuous disease-free status with a median follow-up of 31.5 months.14 However, results were inferior in subgroups of patients with either visceral disease or extragonadal tumors (73% and 56%, respectively). At Institut Gustave Roussy (IGR; Villejuif, France), the continuous disease-free status was 47% in a small cohort of 17 patients with poor-risk features.15 The acute toxicity associated with the original CISCA/VB regimen was substantial and included mainly febrile neutropenia and stomatitis.12-14 However, a 20% dose reduction was shown to be associated with reduced toxicity and comparable survival in a randomized trial including metastatic patients with good and intermediate features according to the IGCCCG classification.16

In this setting, in 1993 the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG) designed a randomized trial to compare the efficacy and toxicity of BEP and CISCA/VB regimens. Here we report the final results of this study.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Patients
Eligible patients had an NSGCT with the following features: testicular, retroperitoneal, or mediastinal primary; no previous chemotherapy; metastatic disease evidenced by radiographic assessment and/or raised serum tumor markers; and poor-risk disease according to the Institut Gustave Roussy (IGR) prognostic model based on serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) levels.17 All patients were required to sign written, informed consent before randomization and treatment according to French legal procedures.

Treatment
Treatment after randomization consisted of either four cycles of BEP (ie, bleomycin [30 mg intravenously (IV) on d1, d8, d15], etoposide [100 mg/m2 IV d1-5], and cisplatin [20 mg/m2 IV d1-5]) every 3 weeks or cycles of CISCA and VB alternatively delivered every 3 weeks. The CISCA regimen included cyclophosphamide (400 mg/m2 IV on d1-2), doxorubicin (35 mg/m2 IV d1-2) and cisplatin (100 mg/m2 IV d3). The VB regimen was a combination of vinblastine (2.5 mg/m2/d) and bleomycin (25 mg/d) as a continuous IV infusion from days 1 to 5. Two cycles of CISCA and two cycles of VB were systematically planned. Patients could then receive up to two supplementary cycles of CISCA until normalization of serum tumor marker levels. At the end of chemotherapy, the surgical resection of all residual masses was mandatory in both arms. In cases where viable cancer cells were found, patients received two additional cycles of chemotherapy with ifosfamide- and cisplatin-based chemotherapy. Treatment toxicity was graded according to standard WHO criteria.18 Chemotherapy cycles were to be delayed until recovery if the neutrophil count was lower than 1.0 x 109/L or the platelet count was lower than 100 x 109/L by day 21 of the previous cycle. In the event of febrile neutropenia, the use of hematopoietic growth factors (HGFs) was mandatory for subsequent cycles. No erythropoietin support was used. Bleomycin was to be stopped if there was clinical evidence of pulmonary toxicity. Dose reduction for cisplatin was to be undertaken if creatinine clearance fell below 1 mL/s. No other dose modifications were envisioned.

Efficacy
Favorable responses included any of the following situations: clinical complete responses (normal levels of serum tumor markers, no clinical nor radiologic evidence of residual disease), pathologic complete responses (normal levels of serum tumor markers and complete resection of residual masses with pathologic analysis revealing necrotic debris, fibrosis, or teratoma), surgical complete responses (normal levels of serum tumor markers and complete resection of residual masses with persistent viable cancer cells), or partial responses (normal levels of serum tumor markers and incomplete resection of nonviable residual masses). Any other situation was judged an incomplete response. Relapses were defined as recurrences of the disease observed after favorable responses and requiring second-line chemotherapy (with or without surgery). Pure teratoma relapses requiring surgery only as therapy were not considered relapses.

Statistical Design and Analysis
A sample size of 180 patients was necessary for a superiority formulation with an expected favorable response rate of 50% in the control arm and a projected 20% improvement in the CISCA/VB arm using a two-sided type I error equal to .05 and a type II error equal to .20 (or 80% power). All survival times were calculated from the date of randomization. Survival estimates were obtained using the Kaplan-Meier method, and comparisons between treatment groups were evaluated with the stratified log-rank test on the intent-to-treat population. Overall survival was calculated until death resulting from any cause. Patients alive at last follow-up were excluded. Event-free survival rates were calculated until incomplete response, relapse, or death occurred. Patients alive at last follow-up who had never experienced an incomplete response or a relapse were excluded at the last follow-up visit. Median follow-up was estimated from the Kaplan-Meier method, using death as an exclusion indicator.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
A total of 190 male patients from 27 GETUG centers were randomly assigned between February 1994 and February 2000. Two patients in the BEP arm were ineligible because of an error in diagnosis and were not treated. Three randomly assigned patients in the CISCA/VB arm did not receive treatment: one patient died on day 2 before receiving treatment and two patients refused. These patients were not analyzed for toxicity nor for response because no data have been collected. Thus, 185 patients, 91 in the CISCA/VB arm and 94 in the BEP arm, were assessable for toxicity and efficacy (Fig 1).


Figure 1
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  		Fig 1. CONSORT diagram. CISCA, cisplatin/cyclophosphamide/doxorubicin; VB, vinblastine/bleomycin; BEP, bleomycin/etoposide/cisplatin.

 
Patient Characteristics
Patient characteristics were well balanced between the two treatment arms (Table 1). The median initial AFP value tended to be higher in the CISCA/VB arm; conversely, the median initial hCG value was higher in the BEP arm. Four patients had pure seminomatous tumors but elevated AFP serum levels. The IGCCCG classification criteria retrospectively identified 32% and 61% of patients with intermediate- and poor-risk characteristics, respectively.


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  		Table 1. Patient Characteristics

 
Treatment Delivery
A total of 22 (12%) patients received fewer than four chemotherapy cycles: 10 for progressive disease (six patients in the CISCA/VB arm and four in the BEP arm, respectively), four for toxicity (two and two, respectively), seven for toxic deaths (four and three, respectively), and one for unspecified reasons. Thirty-seven patients (41%) in the CISCA/VB arm received more than four cycles. More than 90% of the planned dose-intensity was achieved for the following drugs (CISCA/VB v BEP): cisplatin (91% v 86%), etoposide (0% v 84%), and bleomycin (49% v 57%). Overall treatment duration was significantly longer in the CISCA/VB arm (13 v 12.1 weeks; P < .001). Surgical resection of residual masses was performed for 60% and 64% of patients after a median of 6 and 8 weeks (P = .008) after the end of chemotherapy in the CISCA/VB and BEP arms, respectively. Abdominal and thoracic surgery was performed in 50% and 20% of patients, respectively, and 13 patients had both (four in the CISCA/VB arm, nine in the BEP arm). Complete resection was obtained in 83% and 90% of patients undergoing abdominal surgery and in 82% and 79% of patients undergoing thoracic surgery in the CISCA/VB and BEP arms, respectively.

Toxicity
The CISCA/VB regimen induced more significant hematologic toxicity compared with the BEP arm (Table 2). There were an increased frequency of grade 4 neutropenia (57% v 25% of cycles, P < .0001) with a longer duration (median, 10 [range, 1 to 37] v 3 days, [range, 1 to 18]; P < .001); more frequent cycles with febrile neutropenia (19.2% v 5.3%; P < .0001) and infections (7.2% v 2.5%; P = .0037); and increased number of cycles with granulocyte colony-stimulating factor requirement (39.9% v 22.5%; P < .0001); more cycles with blood transfusions (13.6% v 8.8%; P = .043); more frequent grade 3/4 thrombocytopenia (13.1% v 6.5%; P = .0033); and a trend toward more platelet transfusions (4.6% v 2.3%; P = .082). Similarly, mucositis was more severe in the CISCA/VB arm with 15 (17%) and nine (10.1%) patients experiencing grade 3 or 4 toxicity, respectively. Regarding nonhematologic toxicities, more cutaneous adverse effects were observed with the BEP regimen. There were seven toxic deaths, four in the CISCA/VB arm caused by sepsis and three in the BEP arm related to acute respiratory failure.


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  		Table 2. Toxicity by Treatment Group, per Cycle and per Patient

 
Efficacy
Favorable responses did not differ statistically between the two arms: 49 among patients allocated to CISCA/VB (56%; 95% CI, 45% to 66%) and 57 among patients allocated to BEP (65%; 95% CI, 55% to 75%) (Table 3). Relapses occurred in 21 and 20 patients in the CISCA/VB and BEP arms, respectively. The 5-year event-free survival rates were 37% (95% CI, 27% to 47%) and 47% (95% CI, 37% to 57%) in CISCA/VB and BEP arms, respectively (hazard ratio [HR] = 0.76; 95% CI, 0.52 to 1.11; P = .15; Fig 2). When limited to the 115 poor-risk patients according to the IGCCCG classification, the 5-year event-free survival rates were 24% (95% CI, 14% to 36%) and 32% (95% CI, 20% to 44%), respectively (P = .29). After a median follow-up of 7.8 years (range, 4 to 12 years), the 5-year overall survival rates were 59% (95% CI, 47% to 67%) and 69% (95% CI, 58% to 77%) in the CISCA/VB and BEP arms, respectively (HR = 0.73; 95% CI, 0.46 to 1.18; P = .24). When limited to the 115 poor-prognosis patients according to the IGCCCG classification, the 5-year survival rates were 45% (95% CI, 31% to 58%) and 58% (95% CI, 45% to 70%), respectively (P = .19).


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  		Table 3. Efficacy and Survival

 

Figure 2
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  		Fig 2. Event-free survival (A) according to treatment; (B) by treatment for intermediate-risk International Germ Cell Cancer Collaborative Group (IGCCCG) patients; and (C) by treatment for poor-risk IGCCCG patients. Overall survival (D) according to treatment; (E) by treatment for intermediate-risk IGCCCG patients; and (F) by treatment for poor-risk IGCCCG patients.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Because approximately 75% of metastatic NSGCT patients in the intermediate-risk group and 45% in the poor-risk group achieve a durable complete response with standard BEP (four cycles), the development of clinical investigations assessing new regimens have remained a priority during the last two decades (Table 4). Most of the randomized trials reported so far included intermediate- and poor-risk patients since the IGCCCG classification was published in 1997.4 This is also the case in the present study, which was based on the IGR prognostic system. In this model, the serum AFP and hCG levels were retained as the only independent prognostic variables after a forward stepwise procedure.17 The patients were classified into the poor-risk group according to a less than 70% probability of achieving a complete response. The IGR prognostic system was used from 1985 to 1994 to design three generations of clinical trials in poor-risk NSGCT tumor patients, including the present study.10,19


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  		Table 4. Randomized Trials in Intermediate- and Poor-Risk Germ Cell Tumors

 
As with previous studies, the present trial was based on the hypothesis that the efficacy of the experimental arm was superior to that of standard BEP. No difference was noted concerning the primary (favorable response rate) end point. Moreover the 37% 5-year event-free-survival rate was the lowest one observed in the literature review (Table 4). A possible explanation is the cisplatin dose-intensity, which was halved in the CISCA/VB arm (16.4 v 32.5 mg/m2/wk in the BEP arm). Indeed, a Southwest Oncology Group study previously showed that the major prognostic factor for response and survival was a cisplatin dose-intensity threshold of 30 mg/m2/wk, especially in the subgroup of patients with maximal extent of disease.22 An additional explanation could be the absence of etoposide in the CISCA/VB arm. Besides the lack of superiority, a greater toxicity, including myelosuppression and mucositis, occurred in patients treated in the CISCA/VB arm, despite a 20% dose reduction compared with the original regimen.

Unquestionably the failure to define clear advances in the management of patients with poor-risk NSGCT during the last 20 years emphasizes the need for carrying on prospective randomized trials. A Medical Research Council phase III study is comparing standard BEP with a dose-dense sequential regimen including carboplatin and vincristine along with BEP (C-BOP/BEP protocol). A German group embarked on a randomized study testing the impact of repetitive doses of dose-intense chemotherapy with autologous hematopoietic stem-cell support. Finally, the GETUG initiated a multi-institution international clinical trial introducing the issue of the clinical relevance of serum tumor marker decline after the first cycle of BEP.23 Patients with a favorable decline are treated with three additional cycles of BEP. In contrast, patients with an unfavorable decline are randomly assigned to receive either three additional cycles of BEP or a more intensive regimen including drugs, such as oxaliplatin, that have been selected for their known efficacy in the refractory setting.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
Author Contributions
 REFERENCES
 
The author(s) indicated no potential conflicts of interest.


   Author Contributions
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 Author Contributions
REFERENCES
 
Conception and design: Stéphane Culine, Andrew Kramar, Jeannine Bouzy, Jean-Pierre Droz

Administrative support: Jeannine Bouzy

Provision of study materials or patients: Stéphane Culine, Christine Théodore, Lionel Geoffrois, Christine Chevreau, Pierre Biron, Binh Bui Nguyen, Jean-François Héron, Pierre Kerbrat, Armelle Caty, Rémy Delva, Pierre Fargeot, Karim Fizazi, Jean-Pierre Droz

Collection and assembly of data: Stéphane Culine, Andrew Kramar, Christine Théodore, Lionel Geoffrois, Christine Chevreau, Pierre Biron, Binh Bui Nguyen, Jean-François Héron, Pierre Kerbrat, Armelle Caty, Rémy Delva, Pierre Fargeot, Karim Fizazi, Jeannine Bouzy, Jean-Pierre Droz

Data analysis and interpretation: Stéphane Culine, Andrew Kramar, Jean-Pierre Droz

Manuscript writing: Stéphane Culine, Andrew Kramar

Final approval of manuscript: Stéphane Culine, Andrew Kramar, Christine Théodore, Lionel Geoffrois, Christine Chevreau, Pierre Biron, Binh Bui Nguyen, Jean-François Héron, Pierre Kerbrat, Armelle Caty, Rémy Delva, Pierre Fargeot, Karim Fizazi, Jeannine Bouzy, Jean-Pierre Droz


   ACKNOWLEDGMENTS
 
We thank the following clinicians, who contributed patients to the trial: T. Facchini (Metz); F. Fruge (Poitiers); A. Goupil (Saint-Cloud); D. Hauteville (Saint-Mandé); F. Khoser (Colmar); C. Linassier (Tours); J.P. Malhaire (Brest); C. Martin (Annecy); Y. Merrouche (Besançon); N. Mottet (Nîmes); M. Mousseau (Grenoble); C. Platini (Thionville); F. Rolland (Nantes); and A. Thyss (Nice).


   NOTES
 
Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, May 12-15, 2001, San Francisco, CA.

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
 REFERENCES
 
1. Einhorn LH: Treatment of testicular cancer: A new and improved model. J Clin Oncol 8:1777-1781, 1990[Abstract]

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3. Schmoll HJ, Souchon R, Krege S, et al: European consensus on diagnosis and treatment of germ cell cancer: A report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 15:1377-1399, 2004[Abstract/Free Full Text]

4. 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]

5. Williams SD, Birch R, Einhorn L, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316:1435-1440, 1987[Abstract]

6. Nichols CR, Williams SD, Loehrer PJ, et al: Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: A Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 9:1163-1172, 1991[Abstract]

7. Nichols CR, Catalano PJ, Crawford ED, et al: Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: An Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B study. J Clin Oncol 16:1287-1293, 1998[Abstract/Free Full Text]

8. de Wit R, Stoter G, Sleijfer DTh, et al: Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non-seminoma: A randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. Br J Cancer 78:828-832, 1998[Medline]

9. 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]

10. Droz JP, Kramar A, Biron P, et al: Failure of high-dose cyclophosphamide and etoposide combined with double-dose cisplatin and bone marrow support in patients with high-volume metastatic nonseminomatous germ-cell tumours: Mature results of a randomised trial. Eur Urol 51:739-748, 2007[CrossRef][Medline]

11. Motzer RJ, Nichols CR, 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]

12. Samuels ML, Holoye PY, Johnson DE: Bleomycin combination chemotherapy for metastatic testicular carcinoma. Cancer Bull 25:53-55, 1973

13. Logothetis CJ, Trindade A, Samuels ML: Improved survival with cyclic chemotherapy for nonseminomatous germ cell tumors of the testis. J Clin Oncol 3:326-335, 1985[Abstract]

14. Logothetis CJ, Samuels ML, Selig D, et al: Cyclic chemotherapy with cyclophosphamide, doxorubicin, and cisplatin plus vinblastine and bleomycin in advanced germinal tumors: Results with 100 patients. Am J Med 81:219-228, 1986[CrossRef][Medline]

15. Culine S, Théodore C, Bekradda M, et al: Experience with bleomycin, etoposide, cisplatin (BEP) and alternating cisplatin, cyclophosphamide, doxorubicin (CISCAII)/vinblastine, bleomycin (VBIV) regimens of chemotherapy in poor-risk nonseminomatous germ cell tumors. Am J Clin Oncol 20:184-188, 1997[CrossRef][Medline]

16. Fizazi K, Do KA, Wang X, et al: A 20% dose reduction of the original CISCA/VB regimen allows better tolerance and similar survival rate in disseminated testicular non-seminomatous germ cell tumors: Final results of a phase III randomized trial. Ann Oncol 13:125-134, 2002[Abstract/Free Full Text]

17. Droz JP, Kramar A, Ghosn M, et al: Prognostic factors in advanced nonseminomatous testicular cancer. A multivariate logistic regression analysis. Cancer 62:564-568, 1988[CrossRef][Medline]

18. Miller AB, Hoogstraten B, Staquet B, Winkler A: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline]

19. Droz JP, Pico JL, Ghosn M, et al: A phase II trial of early intensive chemotherapy with autologous bone marrow transplantation in the treatment of poor prognosis non seminomatous germ cell tumors. Bull Cancer 79:497-507, 1992[Medline]

20. de Wit R, Stoter G, Sleijfer DT, et al: Four cycles of BEP versus an alternating regime of PVB and BEP in patients with poor-prognosis metastatic testicular non-seminoma: A randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. Br J Cancer 71:1311-1314, 1995[Medline]

21. Kaye SB, Mead GM, Fossa SD, et al: Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: A randomized Medical Research Council/European Organization for Research and Treatment of Cancer study. J Clin Oncol 16:692-701, 1998[Abstract]

22. Samson MK, Rivkin SE, Jones SE, et al: Dose-response and dose-survival advantage for high versus low dose cisplatin combined with vinblastine and bleomycin in disseminated testicular cancer. Cancer 53:1029-1035, 1984[CrossRef][Medline]

23. Fizazi K, Culine S, Kramar A, et al: Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors. J Clin Oncol 22:3868-3876, 2004[Abstract/Free Full Text]

Submitted August 3, 2007; accepted October 12, 2007.


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