DOES THE KINETIC OF TUMOR MARKER DECLINE PREDICT OUTCOME IN PATIENTS WITH RELAPSED DISSEMINATED GERM-CELL TUMORS TREATED BY HIGH-DOSE OR CONVENTIONAL CHEMOTHERAPY? AN ANALYSIS OF THE IT94 RANDOMIZED TRIAL

Introduction: Conventional dose chemotherapy is the standard salvage therapy for patients with progressive or relapsed germ-cell tumors (GCT). The IT94 phase III randomized trial compared conventional chemotherapy (4 cycles of cisplatin, ifosfamide, and vinblastine (VeIP)) versus high-dose chemotherapy (3 cycles of VeIP followed by 1 cycle of high-dose carboplatin, etoposide, and cyclophosphamide (PEC)). There was no progression-free survival (PFS) or overall survival (OS) difference between the two arms in this trial (Pico, Ann Oncol 2005; 16: 1152-9). Early serum tumor marker decline during chemotherapy was previously shown to predict survival in patients with poor prognosis disseminated non-seminomatous GCT in first line (Fizazi, J Clin Oncol 2004, 22: 3868-76). The aim of this study was to assess whether serum tumor marker decline also correlates with outcome in the salvage setting.

Methods: Serum tumor markers were obtained before chemotherapy and after two cycles of treatment from 235 patients accrued in the IT94 trial (114 and 121 in the 4VeIP and the 3 VeIP+PEC arms, respectively). The decline of serum alfa-fetoprotein (AFP) and human chorionic gonadotropin (hCG) was assessed and classified into the ‘‘favorable marker decline’’ and the ‘‘unfavorable marker decline’’ groups classified using a mathematical model.

Results: Serum AFP decline was significantly associated with PFS (HR=2.17; p=0.0003)while serum hCG decline did not affect the outcome. Among patients with a favorable AFP decline, those who were treated in the high-dose chemotherapy arm had a better PFS (2-year PFS rate: 56% versus 36%; HR=0.58; p=0.007), and a trend for a better OS (2-year OS rate: 70% versus 56%; HR=0.69; p=0.11) as compared to patients who were in the conventional chemotherapy arm. In contrast, among patients with an unfavorable AFP decline, those who received conventional chemotherapy had a better PFS (2-year PFS: 56% versus 36%; HR=2.22; p=0.025) and a non-significant trend for a better OS (2-year OS: 54% versus 21%; HR=2.43; p=0.34), as compared to those who received high-dose chemotherapy.

Conclusion: These data suggest that AFP decline during the first 6 weeks of salvage chemotherapy predicts PFS in patients with disseminated GCT. High-dose chemotherapy may be beneficial only to selected patients with a favorable AFP decline. This would require a prospective validation.