Progression-Free and Overall Survival in
Patients With Relapsed/Refractory Germ
Cell Tumors Treated With Single-Agent
Chemotherapy: Endpoints for Clinical
Darren R. Feldman, MD1,2; Sujata Patil, PhD3; Michael J. Trinos, BS1; Maryann Carousso, NP1; Michelle S. Ginsberg, MD4;
Joel Sheinfeld, MD5; Dean F. Bajorin, MD1,2; George J. Bosl, MD1,2; and Robert J. Motzer, MD1,2
BACKGROUND: Refractory germ cell tumor (GCT) patients have a poor prognosis and limited treatment options. The
identification of novel active agents may be impaired by use of response as the primary endpoint in phase 2 trials.
Improved endpoints could enhance the development of new effective agents. METHODS: The characteristics and out-
come of refractory GCT patients enrolled in 7 single-agent phase 2 trials conducted at Memorial Sloan-Kettering Can-
cer Center from 1990 to 2008 were reviewed. The study agents were suramin, all-transretinoic acid, topotecan,
pyrazoloacridine, temozolomide, ixabepilone, and sunitinib. The major endpoints evaluated were response, progres-
sion-free survival (PFS), and overall survival (OS). RESULTS: Ninety patients (87 male, 3 female) were treated. The pri-
mary tumor site was testis in 65 patients, mediastinum in 17 patients, retroperitoneum in 4 patients, and other in 4
patients. Eighty-six patients had nonseminoma, and 4 patients had pure seminoma. Best responses were 1 (1%) partial
response (ixabepilone), 15 (17%) stable disease, and 74 (82%) progressive disease. Median PFS and OS were 1.0
month (95% confidence interval [CI], 0.8-1.3) and 4.7 months (95% CI, 3.5-6.4), respectively. Eighty-six of the 90
patients have died. The 12- and 16-week PFS rates were 9% (95% CI, 3-15%) and 6% (95% CI, 1%-11%), respectively.
CONCLUSIONS: Patients with refractory GCT progressed rapidly to these single agents. PFS and OS may be useful
endpoints for designing phase 2 trials testing novel agents in this population. Twelve-week PFS (with comparison to
the 9% benchmark rate reported herein) is the recommended endpoint for phase 2 trial design and median OS (using
4.7 months as the predicted median for the control arm) is suggested for phase 3 trials. Cancer 2012;118:981-6.
C 2011 American Cancer Society.
KEYWORDS: germ cell tumors, phase II trial, clinical trial design, progression-free survival, overall survival, relapsed
Germ cell tumors (GCTs) are considered a model for the treatment of other malignancies because of the high propor-
tion of patients who can achieve cure even in the face of widely metastatic disease. Currently, more than 70% of such
patients are cured with initial cisplatin-based chemotherapy with or without adjunctive surgery.1Furthermore, 30%-50%
oftheremaindercanstillachievedurableremissionswithsalvageapproaches, including high-dosechemotherapy.1Incon-
trast, nearly all patients progressing after high-dose chemotherapy (referred to as relapsed/refractory), will ultimately die
from progressive disease. An average of more than 35 years of life is lost when a patient dies from GCT, well over a decade
longer thananyother adultmalignancy.2
DOI: 10.1002/cncr.26375, Received: April 13, 2011; Revised: May 23, 2011; Accepted: May 31, 2011, Published online July 26, 2011 in Wiley Online Library
Corresponding author: Darren R. Feldman, MD, Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial
Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065; Fax: (212) 988-0701; email@example.com
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York;
3Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York;4Department of Radiology, Memorial Sloan-Kettering
Cancer Center, New York, New York;5Department of Urology,MemorialSloan-Kettering Cancer Center, New York, New York
2Weill Medical College of Cornell University, New York, New York;
The results of this study were presented in part at the 45thAnnual Meeting of the American Society of Clinical Oncology, June 7, 2010; Orlando, FL.
February 15, 2012
Furthermore, an analysis of various clinical factors for
association with a more favorable or adverse outcome
among this group revealed a very limited potential to dis-
criminate patients. As mentioned above, only elevated
LDH was prognostic for both PFS and OS. This is in
agreement with another retrospective analysis of 54 GCT
patients who underwent systemic treatment after progres-
sion to high-dose chemotherapy in which no clinical fac-
torcould beidentified asprognosticforsurvival.16
trials conducted in rare disease states such as relapsed/re-
fractory GCT, where patient accrual can be challenging.
quickly close a trial of an inactive agent and move on to a
new study that may hold more promise. More widespread
adoption of this strategy could therefore improve the effi-
ciency of trial conduct in this setting and expedite the de-
velopment of novel active agents for GCT. Similarly, the
early stopping rule limits the number of patients exposed
to agents unlikely to offer therapeutic benefit, allowing
patients topursuemoreworthwhile treatments,andpoten-
In conclusion, these data illustrate the rapid progres-
sion that nearly all patients with relapsed/refractory GCT
experience when treated with ineffective drugs and indi-
cate that when prolonged stable disease (?12 weeks) is
achieved, it is likely to be a manifestation of effective drug
therapy. Therefore, we recommend that 12-week PFS
(with comparison with the 9% benchmark rate reported
herein) be used as the primary endpoint for future phase 2
clinical trial design in this population. This is particularly
important for the study of agents with cytostatic antitu-
mor properties to avoid the inappropriate dismissal of
potentially beneficial novel therapeutics. Similarly, these
data support using OS as the primary endpoint for phase
3 trials in this population, with a median survival of
Supported by the Sidney Kimmel Center for Prostate and Urologic
Cancers (New York, NY) andthe Craig TiffordFoundation.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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February 15, 2012