Randomized, Phase II Study Prospectively Evaluating Treatment of Metastatic Esophageal, Gastric, or Gastroesophageal Cancer by Gene Expression of <i>ERCC1</i>: SWOG S1201.

Abstract

Platinum-based therapy is the standard of care in patients who have HER2-negative, advanced esophagogastric cancer (AEGC). Retrospective data suggest that intratumoral <i>ERCC1</i> levels may determine platinum sensitivity. A randomized, phase II study was performed in patients with AEGC to explore whether the efficacy of a platinum-based therapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) versus a non-platinum-containing regimen of irinotecan and docetaxel (IT) differed according to <i>ERCC1</i> levels. Overall, 202 untreated patients with HER2-negative AEGC and a Zubrod performance status of 0-1 were evaluated prospectively for mRNA expression of <i>ERCC1</i> level and then randomly assigned to FOLFOX or IT, stratified by the intratumoral statuses of <i>ERCC1</i> low (< 1.7) or high (≥ 1.7). Objectives were to assess progression-free survival (PFS) and overall survival (OS) in all patients treated with FOLFOX compared with IT, stratified by low and high <i>ERCC1</i> levels, and to assess for interactive effects between <i>ERCC1</i> expression and treatment arm. Eighty-six percent of patients had <i>ERCC1</i> values < 1.7. Thus, evaluation of the <i>ERCC1</i>-high subgroup was limited. Grade ≥ 3 anemia, dehydration, diarrhea, and fatigue were greater in patients with IT. Occurrences of grade ≥ 3 neuropathy and decreased neutrophils were greater in patients with FOLFOX. In all patients, FOLFOX had a statistically superior median PFS compared with IT (5.7 <i>v</i> 2.9 months; hazard ratio, 0.68; <i>P</i> = .02). In patients with <i>ERCC1</i> levels < 1.7 receiving FOLFOX, PFS and response rate were statistically superior to IT, with no significant difference in OS. The evaluation of <i>ERCC1</i> in patients with upper GI tumors was thwarted by an overwhelming predominance of low <i>ERCC1</i> mRNA expression. Nonetheless, distribution of treatment effects on PFS did not vary with expression. For all patients and for those with low <i>ERCC1</i> expression, FOLFOX was superior in efficacy to IT.