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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

Robert J. Motzer, Craig J. Nichols, Kim A. Margolin, Jennifer Bacik, Paul G. Richardson, Nicholas J. Vogelzang, Dean F. Bajorin, Primo N. Lara, Jr, Lawrence Einhorn, Madhu Mazumdar, George J. Bosl

From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, and Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center; Department of Medicine, Joan and Sanford I. Weill Medical College, Cornell University, New York, NY; Oregon Health Science Center, Portland, OR; City of Hope National Medical Center, Duarte, CA; Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, University of Chicago, Chicago, IL; University of California-Davis Cancer Center, Sacramento, CA; and Indiana University, Indianapolis, IN

Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: motzerr{at}mskcc.org

	ABSTRACT

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PURPOSE: To investigate the role of high-dose chemotherapy (HDCT) as first-line treatment in patients with metastatic germ cell tumor (GCT) and poor-prognostic clinical features. Serum tumor marker decline during chemotherapy was assessed prospectively as a predictor of treatment outcome.

PATIENTS AND METHODS: In this randomized phase III trial, previously untreated patients with intermediate- or poor-risk GCT received either four cycles of standard bleomycin, etoposide, and cisplatin (BEP alone), or two cycles of BEP followed by two cycles of HDCT containing carboplatin and then by hematopoietic stem-cell rescue (BEP + HDCT). Serum tumor markers alpha-fetoprotein and human chorionic gonadotrophin were correlated with treatment outcome as a secondary end point.

RESULTS: Two hundred nineteen patients were randomly assigned: 108 to BEP + HDCT and 111 to BEP alone. The 1-year durable complete response rate was 52% after BEP + HDCT and 48% after BEP alone (P = .53). Patients with slow serum tumor marker decline (alpha-fetoprotein and/or human chorionic gonadotrophin) during the first two cycles of chemotherapy had a shorter progression-free survival and overall survival compared with patients with satisfactory marker decline (P = .02 and P = .03, respectively). Among 67 patients with unsatisfactory marker decline, the 1-year durable complete response proportion was 61% for patients who received HDCT versus 34% for patients receiving BEP alone (P = .03).

CONCLUSION: The routine inclusion of HDCT in first-line treatment for GCT patients with metastases and a poor predicted outcome to chemotherapy did not improve treatment outcome. Frequent serum marker determinations to estimate marker decline during the first two cycles of BEP chemotherapy provide a clinically useful estimate of outcome.

	INTRODUCTION

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A collaborative effort led to the development of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk criteria,¹ which allowed metastatic germ cell tumors (GCT) to be classified as favorable, intermediate, and poor risk according to pretreatment clinical features. The proportion of patients with favorable-, intermediate-, and poor-risk features who achieve a long-standing complete response (CR) to chemotherapy is approximately 90%, 75%, and 40%, respectively.¹ Efforts are focused on directing treatment according to risk classification.

High-dose chemotherapy (HDCT) was studied in single-arm phase II trials as first-line therapy for patients with poor-prognostic features according to risk models developed before IGCCCG created the criteria.^2-5 The relative tolerability and improvement in relapse-free survival and overall survival (OS) compared with historical controls treated with conventional-dose programs suggested that this was a promising approach.

Retrospective studies showed that the rate of serum tumor marker decline is a post-treatment predictor of treatment outcome.^6-8 Most patients with a prolonged rate of decline for these markers have an inferior durable CR rate and survival compared with patients who have a satisfactory rate of decline. In two trials, patients were selected for a treatment change to HDCT based on the rate of serum tumor marker decline.^2,3 In both trials, patients with satisfactory marker decline during the first two cycles were deemed to be responding appropriately, and they completed their course of conventional-dose chemotherapy. In contrast, patients with an unsatisfactory rate of serum tumor marker decline had their treatment changed to a HDCT program.

The unresolved question as to what constitutes optimal therapy for patients with advanced GCT and intermediate- and poor-risk features (collectively referred to hereafter as "poor prognosis") led to this prospective randomized phase III trial to investigate the role of HDCT as first-line treatment. The trial was conducted by Memorial Sloan-Kettering Cancer Center (MSKCC), Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group (SWOG), and Cancer and Leukemia Group B (CALGB). The rate of serum tumor marker decline was not used in this trial to select patients for HDCT, but it was assessed prospectively as a post-treatment predictor of outcome.

	PATIENTS AND METHODS

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Patients
Two hundred nineteen male patients were enrolled onto this trial between 1994 and 2003 on the basis of intermediate- and poor-risk classifications according to the IGCCCG criteria.¹ Definitions of intermediate- and poor-risk criteria are summarized in Table 1. All patients had GCT with evidence of metastases that could be evaluated for response, no prior chemotherapy, and an absence of underlying organ dysfunction precluding the use of HDCT. Written informed consent was obtained from all patients, and the trial was approved by the individual institutional review boards and sponsored by the National Cancer Institute.

Evaluation
The pretreatment evaluation included physical examination and pulmonary function tests; measurement of serum tumor markers LDH, alpha-fetoprotein (AFP), and human chorionic gonadotrophin (HCG); CBC; serum-screening chemistry panel; and a computed tomography scan of the chest, abdomen, and pelvis.

Study Design and Treatment
Patients were randomly assigned to receive either standard chemotherapy with four cycles of bleomycin, etoposide, and cisplatin (BEP alone) or two cycles of BEP followed by two cycles of high-dose carboplatin, etoposide, and cyclophosphamide (BEP + HDCT) administered with autologous hematopoietic stem-cell transplantation. The BEP-alone regimen was described earlier.⁹ Granulocyte colony-stimulating factor (G-CSF) was administered with each cycle.

In the BEP + HDCT arm, BEP was administered in a similar fashion to the conventional treatment arm, but only for two cycles. After completing the second cycle of BEP, patients were treated with HDCT consisting of carboplatin 600 mg/m², etoposide 600 mg/m², and cyclophosphamide 50 mg/kg administered on days 1, 2, and 3 and followed by an infusion of autologous stem cells on day 5. All patients received G-CSF during the recovery period. Once the patients' CBC recovered, a second cycle of HDCT was administered. If the patients' medical condition did not allow treatment with HDCT after the second cycle of BEP, then the patient continued BEP chemotherapy for two more cycles rather than proceed to HDCT.

Because this was a multicenter trial, the means for hematopoietic reconstitution varied. For the majority of patients treated on the high-dose treatment arm, reconstitution consisted of autologous stem cells that were obtained from peripheral blood by leukapheresis, which was performed after the first and/or second cycle of BEP. Details of supportive care after HDCT were determined according to the preference of the individual participating centers.

Assessment of Safety and Treatment Response
During treatment with BEP, assessments included a physical examination, a comprehensive serum-screening chemistry panel, and measurements for AFP, HCG, and serum LDH. HDCT was routinely administered on an inpatient basis. Baseline assessments were the same as for BEP, and the serum chemistry profile and CBC were obtained frequently.

A computed tomography scan was performed at the conclusion of treatment. Surgical resection of residual masses was recommended to all patients with normalized serum tumor markers. After surgery, no further chemotherapy was administered if either mature teratoma or necrotic debris was present in the resected specimen. When complete resection of residual disease contained viable GCT at any site, two additional cycles of etoposide and cisplatin were recommended for patients treated with BEP alone. Patients who received BEP + HDCT did not receive additional chemotherapy if viable GCT was completely resected.

Response was classified as either a CR or an incomplete response (IR). A CR to chemotherapy was defined as the disappearance of all clinical, radiographic, and biochemical evidence of disease or when all resected masses contained necrotic debris, fibrosis, or mature teratoma. A CR to chemotherapy plus surgery was indicated when serum tumor marker concentrations were normal and all residual disease was resected, but viable GCT was found at one or more sites. Any response less than a CR was considered to be an IR. A partial response with negative markers (or partial response-negative markers) was defined as radiographic evidence of response and normalization of serum tumor markers but no surgical evaluation or resection. Patients who had partial response-negative markers were still considered in the general category of an IR.

Statistical Design and Analysis
This trial was initially targeted only for poor-risk patients and designed with the primary end point of durable CR at 1 year from entry onto the trial. We planned to accrue 100 patients per arm to detect an improvement from 30% to 50%, with a 5% level of significance and 80% power. When eligibility was later expanded to include the modified intermediate-risk patients, as described earlier, target accrual was modified to 218 patients based on a historical 1-year durable CR rate of 45% in the poor- and intermediate-risk groups combined. In 2002, CALGB joined the study and began accruing patients. At that point, we hoped to address our original question in the poor-risk group of patients and planned to accrue 270 patients, consisting of 216 poor-risk patients (200 per original calculation plus 16 to account for withdrawals) and 54 intermediate-risk patients. However, as accrual did not meet expectations, even with the additional cooperative group participating, the study closed in August 2003.

The data were reviewed annually by an independent data and safety monitoring committee. The design included an O'Brien and Fleming stopping rule,¹⁰ with the sequence of nominal significance levels of .005 and .048 for the interim analyses and the final analysis, respectively. In May 2000, the principal investigator (R.J.M.) and the biostatistician (M.M.) on the study presented a formal comparative interim analysis on durable CR proportion and OS.

Randomization was performed at a centralized office at MSKCC using the method of random permuted block, with risk status (poor v intermediate) and center (MSKCC, ECOG, SWOG, and CALGB) used as stratification factors.

Response rates were compared using Fisher's exact test. OS was defined as time from randomization to last follow-up or death from any cause. Time-to-treatment failure (TTF) was defined as time from randomization to relapse or last follow-up for patients with a CR and time from randomization to treatment failure for patients with an IR. Both curves were estimated using the Kaplan-Meier method¹¹ and compared using the log-rank test. The 1-year rates from the TTF analysis represent the primary end point of the study. They were compared using a z score with the SE from Greenwood's formula.¹² One patient who withdrew consent before receiving any drug and one patient whose response data were unavailable are not included in this analysis. The intent-to-treat principle was followed for these analyses. The primary analyses included both intermediate- and poor-risk patients, with secondary analyses looking at the two risk groups separately.

Marker-Decline Cohort Analysis
Only those patients with elevated baseline AFP or HCG who received two cycles of BEP and at least one additional cycle of either BEP or HDCT and who had adequate markers to determine marker-decline status were included. The serum tumor marker values between day 7 and the first day of cycle 3 (or day 49, whichever was lower) were used. Markers between days 1 and 7 were excluded because of the possibility of an unpredictable increase in serum tumor marker levels during the initial days of chemotherapy.¹³ For patients who did not achieve a normal marker value by the start of the third cycle of chemotherapy, the marker half-life was calculated using the method described previously.⁷ Only patients who had at least one cycle 1 marker and one cycle 2 marker were included in the regression. Marker decline was defined as satisfactory if both AFP and HCG demonstrated satisfactory decline (declined to normal by the start of cycle 3 or had a half-life 7 days for AFP and 3.5 days for HCG) or if one marker had a satisfactory decline and the other was not elevated at baseline. The marker decline was unsatisfactory if one or both markers demonstrated a slow decline (half-life > 7 days for AFP or > 3.5 days for HCG).

For this analysis, OS and TTF were redefined using a landmark time of 49 days. Patients were included in each of the survival analyses if they had at least 49 days of follow-up and did not experience treatment failure during this period. It was of interest to first determine whether marker decline predicted OS and TTF, and, if so, to then determine if the impact of marker decline differed by treatment. Treatment groups were defined based on the intent-to-treat principle as well as treatment actually received. The marker decline and treatment interaction was explored within the context of a Cox proportional hazards model, adjusting for variables identified in a multivariate stepwise procedure whereby a significant relationship with OS (P .05) was used as the criterion for including the variable. All analyses were performed using SAS (version 8.2; SAS Institute, Cary, NC).

	RESULTS

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Patient Characteristics
Two hundred nineteen patients were entered onto the trial: 108 were randomly assigned to the BEP + HDCT arm, and 111 were randomly assigned to the BEP-alone arm (Table 2). Patient characteristics were similar for the two arms, except for a higher median-elevated HCG value in the BEP + HDCT arm compared with the BEP-alone arm. Of the 219, 174 (79%) were poor risk, and 45 (21%) had intermediate-risk features.

Toxicity was more severe for patients treated on the BEP + HDCT arm (Table 3). Ten (5%) of 219 patients died during treatment. Six of the patients who died during treatment had been assigned to the BEP + HDCT arm, and four were treated on the BEP-alone arm. On the experimental arm, four of the deaths occurred during treatment with BEP before administration of HDCT, and one patient died during the second cycle of HDCT. The causes of death in these five patients were infection² and hemorrhage (two pulmonary and one gastrointestinal). The sixth patient died of complications after abdominal surgery 7 months after completing chemotherapy. Of the four patients who died during treatment on the BEP-alone arm, two died from cardiac ischemia, one from neutropenic sepsis, and one of hemorrhage and bleeding without grade 3 to 4 thrombocytopenia.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Time-to-treatment failure experienced by patients randomly assigned to four cycles of bleomycin, etoposide, and cisplatin (BEP) compared with two cycles of BEP followed by two cycles of high-dose carboplatin, etoposide, and cyclophosphamide (chemotherapy [CT]) plus autologous hematopoietic stem-cell rescue. One patient who withdrew consent before receiving any drug and one patient whose response data were unavailable are not included in this analysis.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival for patients randomly assigned to four cycles of bleomycin, etoposide, and cisplatin (BEP) compared with two cycles of BEP followed by two cycles of high-dose carboplatin, etoposide, and cyclophosphamide (chemotherapy [CT]) plus autologous hematopoietic stem-cell rescue.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Time-to-treatment failure for poor-risk patients randomly assigned to four cycles of bleomycin, etoposide, and cisplatin (BEP) compared with two cycles of BEP followed by two cycles of high-dose chemotherapy (CT). One patient who withdrew consent before receiving any drug is not included in this analysis.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Overall survival for patients with elevated baseline markers who have a satisfactory marker decline compared with those who have an unsatisfactory decline. One patient who died before landmark time is not included in this analysis.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Time-to-treatment failure for patients with elevated baseline markers and (A) a satisfactory decline and (B) unsatisfactory decline treated with four cycles of bleomycin, etoposide, and cisplatin (BEP) compared with two cycles of BEP followed by two cycles of high-dose chemotherapy (CT) plus stem-cell rescue. Four patients who experienced treatment failure before landmark time are included in these analyses.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 6. Overall survival for patients with elevated baseline markers and (A) a satisfactory decline and (B) unsatisfactory decline treated with four cycles of bleomycin, etoposide, and cisplatin (BEP) compared with two cycles of BEP followed by two cycles of high-dose chemotherapy (CT) plus stem-cell rescue. One patient who died before landmark time is not included in these analyses.

	DISCUSSION

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The results of our trial showed that the routine inclusion of HDCT after two cycles of BEP in first-line treatment for GCT patients with metastases and a poor predicted outcome to chemotherapy did not improve survival over four cycles of BEP alone. BEP administered for four cycles remains the standard of care for intermediate- and poor-risk GCT patients.

This was the first randomized phase III trial that used the IGCCCG criteria to define risk and allocate patients to a prospective trial. Applying the IGCCCG criteria was critical to conducting this cooperative group trial, and the criteria should be used to define patient populations in future clinical GCT trials and to direct standard management as well. The progression-free survival at 2 years in patients with poor-risk GCT treated with standard BEP in this trial (45%; 95% CI, 35% to 56%) was similar to that predicted by the IGCCCG criteria (52%).¹ As a result, this consistency in outcome provides the basis for the development of international GCT trials, as national germ cell studies are limited by accrual.

A secondary objective of this trial was to assess prospectively the rate of serum tumor marker decline during the first two cycles of chemotherapy as an early predictor of treatment outcome to full-course chemotherapy. Patients with a faster rate of AFP and/or HCG regression during chemotherapy were observed in previous retrospective studies to be more likely to achieve a favorable treatment outcome when compared with patients who experience a slow clearance of tumor marker concentrations.^6,7,13-15 Therefore, a secondary subset analysis of survival outcome was planned and performed, and included the simultaneous assessment of both marker decline and the use of HDCT, similar to that performed in the two phase II single-arm trials that predated this randomized study.

These previous trials showed improved durable CR rates when HDCT was included in first-line treatment compared with historical survivals observed with conventional-dose chemotherapy alone.^2,3 In both of these earlier trials, patients were selected for a treatment change to HDCT based on slow marker decline during the first two cycles of conventional-dose chemotherapy.^2,3 In contrast, patients with a satisfactory decline of serum tumor markers during the first two cycles of conventional-dose chemotherapy were considered responders and were continued on conventional-dose chemotherapy. Following this principle, the patients eligible for marker-decline analysis in this trial were assessed according to both their marker-decline status (ie, satisfactory v unsatisfactory) and treatment (conventional v high dose) received after the initial two cycles of BEP.

This trial prospectively validated the prognostic value of serum tumor marker decline during chemotherapy in predicting outcome for the cohort of patients with elevated baseline markers. The patients with appropriate serum tumor marker decline had a significantly longer survival and TTF compared with patients who experienced an unsatisfactory, or slow, rate of decline. This study population comprised both patients with intermediate- and poor-risk features, with most having poor-risk features. We conclude that frequent serum marker determinations during the first two cycles of BEP chemotherapy provide a clinically useful estimate of disease-free survival observed 1 and 2 years after therapy.

The results of this secondary analysis demonstrated that patients with early chemotherapy resistance, evidenced by an unsatisfactory decline of serum tumor markers during the first two cycles of BEP, experienced a higher durable CR proportion when treatment was changed to HDCT. In contrast, patients showing a satisfactory decline in serum tumor markers had a similar durable CR proportion after treatment with BEP alone compared with patients who changed to HDCT treatment.

This observation implies that there is a form of chemotherapy resistance manifested by slow marker decline that may be overcome by late intensification of chemotherapy. These findings were similar to the estimated benefits observed in the two phase II clinical trials that formed the basis of this randomized trial.^2,3 In fact, random assignment to HDCT only for slow–marker-decline patients was the design originally proposed for this trial, but testing that specific hypothesis was thought to be impossible, given the expected national accrual rates. The limited accrual rate of this trial confirmed those suspicions.

The rate of serum tumor marker decline was not used to select patients for HDCT nor was it used as criteria by which to randomly assign patients to standard versus HDCT treatment. Random assignment did not occur within the marker-decline groups separately; therefore, there is no guarantee of balance in prognostic factors between the two treatment groups. To minimize this effect, however, we controlled for imbalance by adjusting for known prognostic variables in the marker decline and treatment arm outcome analyses. The limitations of a nonrandomized study hold, most notably, the possibility of selection bias. Moreover, the observed benefit for a change to HDCT in patients with slow marker decline was based on a modest sample size of 70 patients.

Lacking this validation, we do not feel that the body of data generated from this study (and its precursor trials) is sufficiently robust to extend this approach to conventional treatment. However, given the prognosis of patients with slow marker decline in the first two cycles of conventional therapy, we do feel it is appropriate that such patients be considered for clinical trials that explore novel investigational chemotherapy approaches designed to circumvent early chemotherapy resistance evidenced by slow marker decline.

In summary, the routine inclusion of HDCT in first-line treatment for GCT patients with intermediate- and poor-prognostic features did not improve treatment outcome. Frequent serum marker determinations to estimate marker decline during the first two cycles of BEP chemotherapy provide a clinically useful estimate of survival outcome. We highly recommend referral to experienced centers for these GCT patients who require specialized chemotherapy and/or surgical management.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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: Dean F. Bajorin, Bristol-Myers Squibb Co; Lawrence Einhorn, Bristol-Myers Squibb Co Stock: Lawrence Einhorn, Amgen Inc, GlaxoSmithKline, Biogeidec Honoraria: N/A Research Funds: Dean F. Bajorin, Bristol-Myers Squibb Co Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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

 
Conception and design: Robert J. Motzer, Craig J. Nichols, Kim A. Margolin, Jennifer Bacik, Paul G. Richardson, Nicholas J. Vogelzang, Dean F. Bajorin, Lawrence Einhorn, Madhu Mazumdar, George J. Bosl

Provision of study materials or patients: Robert J. Motzer, Craig J. Nichols, Kim A. Margolin, Paul G. Richardson, Nicholas J. Vogelzang, Dean F. Bajorin, Primo N. Lara Jr, Lawrence Einhorn, George J. Bosl

Collection and assembly of data: Robert J. Motzer, Craig J. Nichols, Jennifer Bacik, Paul G. Richardson, Nicholas J. Vogelzang, Dean F. Bajorin, Primo N. Lara Jr, Lawrence Einhorn, Madhu Mazumdar, George J. Bosl

Data analysis and interpretation: Robert J. Motzer, Craig J. Nichols, Kim A. Margolin, Jennifer Bacik, Paul G. Richardson, Nicholas J. Vogelzang, Dean F. Bajorin, Primo N. Lara Jr, Lawrence Einhorn, Madhu Mazumdar, George J. Bosl

Manuscript writing: Robert J. Motzer, Craig J. Nichols, Kim A. Margolin, Jennifer Bacik, Paul G. Richardson, Nicholas J. Vogelzang, Dean F. Bajorin, Primo N. Lara Jr, Lawrence Einhorn, Madhu Mazumdar, George J. Bosl

Final approval of manuscript: Robert J. Motzer, Craig J. Nichols, Kim A. Margolin, Jennifer Bacik, Paul G. Richardson, Nicholas J. Vogelzang, Dean F. Bajorin, Primo N. Lara Jr, Lawrence Einhorn, Madhu Mazumdar, George J. Bosl

	ACKNOWLEDGMENTS

 
We thank the physicians, research staff, and patients from ECOG, CALGB, and SWOG who participated in this trial; Deborah L. Dobrzynski and Lesley Spodek for data management; and Carol Pearce for assistance in the preparation of the manuscript.

	NOTES

 
Supported by Grants No. CA-05826, CA-23318, CA-66636, CA-2115, and CA-49883 from the National Institutes of Health.

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. IGCCCG: 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]

2. Motzer RJ, Mazumdar M, Lyn P, et al: High-dose carboplatin, etoposide, and cyclophosphamide in first-line therapy for poor-risk germ cell tumors. J Clin Oncol 14:2546-2552, 1996[Abstract]

3. Motzer RJ, Mazumdar M, Gulati SC, et al: Phase II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Natl Cancer Inst 85:1828-1835, 1993[Abstract/Free Full Text]

4. Decatris MP, Wilkinson PM, Welch RS, et al: High-dose chemotherapy and autologous haematopoietic support in poor-risk nonseminomatous germ cell tumours: An effective first-line therapy with minimal toxicity. Ann Oncol 11:427-434, 2000[Abstract/Free Full Text]

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

6. Toner GC, Geller NL, Tan C, et al: Serum tumor marker half-life during chemotherapy allows early prediction of complete response and survival in nonseminomatous germ cell tumors. Cancer Res 50:5904-5910, 1990[Abstract/Free Full Text]

7. Murphy BA, Motzer RJ, Mazumdar M, et al: Serum tumor marker decline is an early predictor of treatment outcome in germ cell tumor patients treated with cisplatin and ifosfamide salvage therapy. Cancer 73:2520-2526, 1994[CrossRef][Medline]

8. Mazumdar M, Bajorin D, Bacik J, et al: Predicting outcome to chemotherapy in patients with germ cell tumors: The value of the rate of decline of human chorionic gonadotrophin and alpha-fetoprotein during therapy. J Clin Oncol 19:2534-2541, 2001[Abstract/Free Full Text]

9. Williams SD, Birch R, Einhorn LH, 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]

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13. Vogelzang NJ, Lange PH, Goldman A, et al: Acute changes of alpha-fetoprotein and human chorionic gonadotropin during induction chemotherapy of germ cell tumors. Cancer Res 42:4855-4861, 1982[Abstract/Free Full Text]

14. Picozzi VJ, Freiha FS, Hannigan JF, et al: Prognostic significance of a decline in serum human chorionic gonadotropin levels after initial chemotherapy for advanced germ cell carcinoma. Ann Intern Med 100:183-186, 1984[Abstract/Free Full Text]

15. Fizazi K, Culine S, Kramar A, et al: Early predicted time to normalization of tumor marker predicts outcome in poor-prognosis nonseminomatous germ cell tumors. J Clin Oncol 22:3868-3877, 2004[Abstract/Free Full Text]

Submitted December 22, 2005; accepted June 15, 2006.

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