In the multimodality management of Resectable Esophageal Adenocarcinoma (EAC), preoperative chemoradiation (CRT) consisting of the quintessential CROSS protocol and perioperative chemotherapy with FLOT were considered to be in equipoise until the publication of the ESOPEC study in January 2025. The overall survival outcomes for EAC had remained dismal for over a decade. Van Hagen et al.1 published the CROSS trial findings, demonstrating the superiority of CRT over surgery alone, with a median overall survival of 49.4 months versus 24 months, respectively. The FLOT4 trial came into the picture when perioperative FLOT showed superior outcomes compared to the MAGIC protocol.2 However, concerns persisted regarding FLOT-related toxicities, and the clinical trial results were difficult to translate into real-world practice. Consequently, FLOT was prescribed more frequently in academic centres with good clinical support, whereas CROSS was preferred by physicians in private practice—a distinction that was quite understandable. A definitive answer to the optimal treatment approach has long been awaited, which culminated in the ESOPEC trial published recently,3 in which both first-line treatment modalities were pitted against each other, with CROSS serving as the standard arm. However, at that time, CROSS alone was no longer considered the standard of care, given the additional role of adjuvant Nivolumab, which demonstrated superior disease-free survival of 22.4 months compared with 11 months in placebo as seen in Checkmate 577 trial in patients who had residual pathological disease after surgery.4 The FLOT arm in ESOPEC demonstrated a superior median overall survival of 66 months compared to a dismal 37 months in the CROSS arm. This difference may be attributed to the CRT arm having more advanced primary and node-positive disease, which is expected to fare worse considering the poor response rates. Moreover, such patients would not typically be considered for CRT as the first-line option in a multidisciplinary tumour board (MDT).Questions still remain regarding how to accurately stage nodal disease (N stage) preoperatively till date. In the CRT arm, only 67.7% patients completed their treatment compared to 91% in CROSS study.1 This was explained by the study design—patients who missed even one weekly chemotherapy cycle due to anticipated toxicity were considered to have not completed their planned treatment. Owing to this disparity in tumor stage between the two arms, the CROSS arm fared poorly. Strategies are now shifting toward strengthening FLOT with immunotherapy Durvalumab (D-FLOT), as ESOPEC demonstrated favorable toxicity profiles and lower postoperative mortality compared to CROSS.3 The recently published MATTERHORN trial5 showed that D-FLOT reduced the risk of death by 22% compared with FLOT (based on a hazard ratio HR of 0.78; 95% confidence interval CI 0.63-0.96; P = 0.021). Median OS was not yet reached for either arm. An estimated 69% of patients treated with D-FLOT at three years compared with 62% in the FLOT-only arm. However, pre-planned subgroup analyses revealed heterogeneity in treatment benefit. Patients with PD-L1–negative tumors (TAP <1%) had a HR of 0.77 with a wide confidence interval (95% CI 0.40-1.46), whereas those with PD-L1 ≥1% tumors showed a clearer advantage (HR 0.70; 95% CI 0.57-0.87). In-spite of these results the standard treatment while incorporating these novel strategies have changed to D-FLOT for EAC. Moving on to neoadjuvant strategies, the JCOG1109 NExT trial6 evaluated in Oesophageal Squamous Cell Carcinoma (OSCC) that compared Doublet Cisplatin Fluorouracil chemotherapy (Neo-CF) against Triplet Chemotherapy with the addition of Docetaxel (NeoCF-D) and the same Doublet with Radiation (NeoCF-RT). At follow-up period of 50·7 months, the 3-year overall survival rate was significantly higher in the NeoCF+D group (72·1% vs 62·6%) but not in the NeoCF+RT group (68·3%). Treatment-related adverse events leading to termination of neoadjuvant therapy were more common in the NeoCF+D group 9% compared to NeoCF-RT (6%) and Neo-CF (4%). This shows that proper patient selection is required before subjecting them to intense chemotherapy. In addition, the benefit of preoperative CRT resulting in superior pathological complete response rates as seen in CROSS could not be translated to superior outcomes when compared to chemotherapy alone especially when a taxane is added. Although the evidence seen so far seems obvious to many MDTs, it further opened the discussion on the role of CROSS—and CRT in particular. In settings like ours, where patients are often not fit enough for intensive regimens, rather than pushing them through the long-abandoned MAGIC protocol, CRT can be offered as a viable alternative even in EAC. Also, the clinical utility of high financial burden (D-FLOT) regimen has not yet been studied in our patient population. There is also the risk of patients not completing the planned perioperative chemotherapy, and in cases with a high risk of R1 resection, CRT can be delivered preoperatively, serving as a bridge to surgery. Based on the current evidence and the evolving treatment paradigm, radiation oncologists do have a pertinent role to play. In conclusion rather than adopting a one-size-fits-all approach and blindly adopting approaches based on clinical trials, treatment planning should be individualized in MDT discussions, taking into account patient profiles—with radiotherapy still having a role in selected cases. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Kaliyath et al. (Thu,) studied this question.