Comparing FLOT and CROSS Protocols: Survival and Recurrence in Esophageal Adenocarcinoma with Pathological Complete Response

Highlight

Among patients with esophageal or gastroesophageal junction adenocarcinoma who achieve pathological complete response (pCR) after neoadjuvant treatment, perioperative FLOT chemotherapy is associated with significantly improved overall and disease-free survival compared to CROSS chemoradiotherapy. Furthermore, FLOT yields a lower recurrence rate, with later recurrence onset and more heterogeneous patterns than CROSS. Subgroup analyses emphasize greater survival benefits of FLOT in patients with clinical node-negative or low nodal burden.

Study Background

Esophageal adenocarcinoma is a malignancy with a high mortality rate and considerable burden worldwide. Neoadjuvant therapy followed by curative esophagectomy has become standard to improve prognosis. Pathological complete response (pCR), defined as no residual viable tumor cells in resected specimens post-neoadjuvant therapy, is a robust prognostic marker linked to improved survival outcomes. However, the impact of different neoadjuvant regimens on long-term outcomes in pCR achievers remains underexplored, especially comparing emerging perioperative chemotherapy regimens like FLOT (5-fluorouracil, leucovorin, oxaliplatin, docetaxel) against CROSS (chemoradiotherapy) protocols.

Study Design

This multicenter cohort study was conducted across 14 high-volume European esophagogastric centers from January 2018 to December 2024, enrolling patients with esophageal or gastroesophageal junction adenocarcinoma who underwent neoadjuvant therapy followed by esophagectomy with curative intent. Inclusion criteria focused on patients achieving pathological complete response (pCR). Exclusions included squamous cell carcinoma histology, noncurative resection, incomplete pathological response, and early postoperative mortality within 90 days. The comparator groups consisted of patients treated with either perioperative FLOT chemotherapy or CROSS chemoradiotherapy protocols. The primary endpoint was overall survival; secondary endpoints included disease-free survival, recurrence incidence and patterns, and survival analyzed according to nodal status (cN0 vs cN1). Statistical analyses utilized Kaplan-Meier survival estimation and multivariable Cox proportional hazards regression to adjust for confounders.

Key Findings

Of 2,717 eligible patients, 297 (mean age 64.4 years, 79.5% male) achieved pCR and formed the study cohort: 150 received CROSS and 147 received FLOT. Baseline characteristics showed that FLOT recipients were younger and had a higher proportion of clinical node positivity. Postoperative outcomes were comparable between groups.

Unadjusted analysis revealed that FLOT was associated with a lower mortality risk compared to CROSS (hazard ratio [HR] for overall survival 0.32, 95% CI 0.17–0.60, P < .001), and similarly better disease-free survival (HR 0.32, 95% CI 0.19–0.55, P < .001). After multivariable adjustment considering age, clinical nodal status, and other confounders, FLOT maintained a significant independent association with improved overall survival (HR 0.34, 95% CI 0.16–0.69, P = .003) and disease-free survival (HR 0.35, 95% CI 0.19–0.62, P < .001).

Recurrence rates were markedly lower in the FLOT group (8.8%) compared with CROSS (24.7%). The pattern of relapse differed: CROSS recurrences were predominantly distant metastases (70%), whereas FLOT recurrences were more balanced among locoregional, distant, and combined sites. Time to recurrence was longer after FLOT (median 16.8 months) than CROSS (median 12.8 months).

Subgroup analysis focusing on patients with clinical node-negative or low nodal disease showed a pronounced survival benefit from FLOT (HR 0.32, 95% CI 0.15–0.67, P = .002). This suggests that the advantage of FLOT over CROSS may be particularly relevant in early nodal categories.

Expert Commentary

This study delivers important insights into the prognostic landscape of pCR in esophageal adenocarcinoma by directly comparing two widely used neoadjuvant strategies. The robust association of FLOT with substantially improved survival and lower recurrence risk, even after adjustment, suggests an intrinsic difference in treatment efficacy or durability of response among pCR patients. The more heterogeneous recurrence pattern and delayed relapse with FLOT point to a potentially broader systemic control effect compared to CROSS, which combines local radiotherapy with chemotherapy.

Methodologically, the study benefits from a large contemporary cohort and high external validity given its multicenter, European setting and standardized treatment protocols. Nonetheless, residual confounding inherent to observational designs cannot be entirely excluded. The imbalance in baseline clinical nodal status, although adjusted for, warrants cautious interpretation. Additionally, longer follow-up beyond the median recurrence times would strengthen understanding of late events.

Biologically, FLOT’s multimodal chemotherapy regimen may induce more systemic immune and cytotoxic effects compared to CROSS’s chemoradiotherapy approach, potentially contributing to deeper systemic micrometastatic eradication. Emerging research into tumor microenvironment modulation by chemotherapy supports this hypothesis, but further mechanistic studies are needed.

Conclusion

In patients with esophageal adenocarcinoma who achieve pathological complete response after neoadjuvant therapy, perioperative FLOT chemotherapy offers superior long-term survival and reduces recurrence risk compared to CROSS chemoradiotherapy. The prognostic implication of pCR appears influenced by the neoadjuvant strategy utilized, emphasizing the need to interpret pathological remission status within the treatment context. These findings have practical implications for tailoring neoadjuvant approaches and post-surgical surveillance strategies in esophageal cancer management.

Funding and ClinicalTrials.gov

This study was supported by the collaborative efforts of the ALES Study Collaborative Group and European esophagogastric cancer centers. No specific funding details or clinical trial registration numbers were provided in the publication.

References

Alhayo S, Chou WK, Giorgi L, et al. FLOT vs CROSS Among Patients With Pathological Complete Response in Esophageal Adenocarcinoma. JAMA Surg. 2026; published online July 15. PMID: 42455557. https://pubmed.ncbi.nlm.nih.gov/42455557/

Additional literature on neoadjuvant therapy strategies in esophageal adenocarcinoma and pathological complete response is available through recent oncology and gastroenterology guidelines and meta-analyses. For example:
• Klevebro F, Alexandersson von Döbeln G, Chegwidden L, et al. Neoadjuvant treatments for resectable esophageal and gastroesophageal junction adenocarcinoma: a systematic review and network meta-analysis. J Clin Oncol. 2020;38(19):2160-2170.
• van Hagen P, Hulshof MCCM, van Lanschot JJB, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074-2084.