A Phase II Study Demonstrates No Feasibility of Adjuvant Treatment with Six Cycles of S-1 and Oxaliplatin in Resectable Esophageal Adenocarcinoma, with ERCC1 as Biomarker for Response to SOX

Abstract

We assessed the feasibility of adjuvant S-1 and oxaliplatin following neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Patients treated with nCRT (paclitaxel, carboplatin) and esophagectomy received six 21-day cycles with oxaliplatin (130 mg/m2) on day 1 and S-1 (25 mg/m2 twice daily) on days 1–14. The primary endpoint was feasibility, defined as ≥50% completing treatment. We performed exploratory propensity-score matching to compare survival, ERCC1 and Thymidylate Synthase (TS) immunohistochemistry analyses, proteomics biomarker discovery and 5-FU pharmacokinetic analyses. Forty patients were enrolled and 48% completed all adjuvant cycles. Median dose intensity was 98% for S-1 and 62% for oxaliplatin. The main reason for early discontinuation was toxicity (67%). The median recurrence-free and overall survival were 28.3 months and 40.8 months, respectively (median follow-up 29.1 months). Survival was not significantly prolonged compared to a matched cohort (p = 0.09). Patients with ERCC1 negative tumor expression had significantly better survival compared to ERCC1 positivity (p = 0.01). Our protein signature model was predictive of survival [p = 0.04; Area under the curve (AUC) 0.80]. Moreover, 5-FU pharmacokinetics significantly correlated with treatment-related toxicity. To conclude, six cycles adjuvant S-1 and oxaliplatin were not feasible in pretreated esophageal adenocarcinoma. Although the question remains whether additional treatment with chemotherapy should be provided in the adjuvant setting, subgroups such as patients with ERCC1 negativity could potentially benefit from adjuvant SOX based on our exploratory biomarker research.

A population-based study in resected esophageal or gastroesophageal junction cancer aligned with CheckMate 577

“… 13 Adjuvant chemotherapy is not standard of care for esophageal cancer in the Netherlands and patients who received adjuvant S1 and oxaliplatin according to the SOX trial or who received adjuvant nivolumab according to CheckMate 577 were excluded ( n = 22). 6 , 10 To align our population with CheckMate 577, patients with cervical esophageal cancer ( n = 0), irradical resection (R1/R2) or unknown radicality ( n = 66), and without residual pathological disease (ypT0N0) ( n = 212) were excluded. To account for time from resection until randomization of 4 to 16 weeks in CheckMate 577, patients who were deceased within 12 weeks after resection ( n = 44) or patients who had recurrence within 12 weeks after resection ( n = 17) were excluded.…”

“… 1 , 3 Currently, adjuvant treatment is not part of the standard of care for esophageal cancer due to unconvincing results of clinical studies. 4 – 6 The addition of adjuvant treatment could particularly be interesting for patients with residual pathological disease after neoadjuvant chemoradiotherapy who have poorer outcomes compared with patients without residual pathological disease. 7 – 9 …”

Nivolumab adjuvant therapy for esophageal cancer: a review based on subgroup analysis of CheckMate 577 trial

“…However, patients without a pathological complete response after surgery confront a high risk of treatment failures (8)(9)(10)(11)(12)(13)(14)(15). Unfortunately, adjuvant therapies have shown limited effectiveness (16)(17)(18). Therefore, the quest for a potent adjuvant treatment to enhance survival outcomes continues.…”