FLOT vs CROSS After pCR in Esophageal Adenocarcinoma: JAMA Surgery | July 2026

Introduction:

Pathological complete response (pCR) following neoadjuvant therapy is considered a favorable prognostic marker in esophageal adenocarcinoma. However, whether patients achieving pCR derive similar long-term benefit regardless of the neoadjuvant regimen remains uncertain. This multicenter European study compared survival and recurrence among patients with pCR treated with perioperative FLOT chemotherapy versus CROSS chemoradiotherapy.

Why was this study needed?

. pCR is widely used as a surrogate marker for favorable outcomes in esophageal adenocarcinoma.

. It is unclear whether the prognostic significance of pCR differs between chemotherapy and chemoradiotherapy.

. Comparative real-world data between FLOT and CROSS in patients achieving pCR are limited.

. Understanding these differences could refine treatment selection and interpretation of pCR as a clinical endpoint.

Results:

Among 297 patients with esophageal or gastroesophageal junction adenocarcinoma who achieved pCR after neoadjuvant therapy and curative esophagectomy, those treated with perioperative FLOT experienced significantly better overall and disease-free survival than those receiving CROSS chemoradiotherapy. FLOT was associated with a substantially lower recurrence rate, with recurrences occurring later than after CROSS. While distant metastases predominated among patients treated with CROSS, recurrence following FLOT was less frequent and showed a more heterogeneous pattern. After adjustment for baseline differences, FLOT remained an independent predictor of improved survival, with the greatest benefit observed in patients with clinically node-negative or limited nodal disease.

Clinical Impact:

These findings suggest that achieving pCR does not confer equivalent prognosis across different neoadjuvant strategies. Patients achieving pCR after FLOT appear to have more favorable tumor biology or superior systemic disease control than those treated with CROSS. Treatment strategy should therefore be considered when interpreting pCR, counseling patients, and designing future clinical trials that use pCR as a surrogate endpoint.

Bottom Line:

Among patients with esophageal adenocarcinoma achieving pathological complete response, perioperative FLOT was associated with superior survival, lower recurrence, and delayed disease relapse compared with CROSS, indicating that the prognostic value of pCR depends on the neoadjuvant treatment strategy.