The ESOPEC trial and the role of the FLOT regimen in the management of locally advanced esophageal adenocarcinoma: have we finally CROSSed the bridge?

Esophageal adenocarcinomas (EAs) are aggressive malignant neoplasms with a significant epidemiological burden, especially in the West (1). In the setting of localized disease, evidence supporting neoadjuvant therapy for EA was scarce and controversial until the publication of the CROSS trial data (2). In this study, 366 patients with EA (representing 75% of the study population) or squamous cell carcinoma (ESCC) were randomized to upfront surgery or neoadjuvant chemoradiation with weekly carboplatin and paclitaxel. The study showed improved overall survival, progression-free survival, and R0 resection rate favoring the neoadjuvant strategy in the overall population and the subgroup of patients with adenocarcinoma. Interestingly, the benefit of the CROSS regimen was more robust for patients with ESCC and clinically negative regional lymph nodes. Thereafter, neoadjuvant chemoradiotherapy was established as the standard perioperative therapy for EAs in the West, while preoperative or postoperative chemotherapy continued to be the preferred treatment approach in the East.

Initial investigations on the role of neoadjuvant chemotherapy for patients with EAs had mixed results (RTOG 8911 and OE02) (3,4), but results from the MAGIC and FNLCC ACCORD07-FFCD 9703 trials indeed suggested this could be active (5,6). This perception was strengthened after the publication of the FLOT4 trial. In this study, 716 patients with gastroesophageal junction (55% of the study population) or gastric cancer were randomized to perioperative treatment with FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) or ECF/ECX (epirubicin, cisplatin, and either 5-fluorouracil or capecitabine) (7). The study showed improved overall survival, disease-free survival, and pathological complete response (pCR) rate for patients treated in the FLOT arm. As EAs are prone to systemic dissemination, the FLOT regimen was thought to be an intense chemotherapy regimen that could lead to lower rates of systemic relapse, something that was not seen with the CROSS regimen (8).

Since then, multiple retrospective studies have failed to demonstrate the superiority of one regimen over the other (9-12). However, this riddle started to be solved after the results of the Neo-AEGIS study. This was a phase III randomized clinical trial (RCT) designed to compare the outcomes of perioperative chemotherapy and the CROSS regimen in the management of patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction (13). Noteworthy, only 15% of the patients in the chemotherapy arm received FLOT (the study was amended after the results of the FLOT4 trial). There were no differences in overall survival or disease-free survival. However, a higher pCR rate was shown in the chemoradiation arm, while treatment failure in the liver and the lungs was less frequent in the chemotherapy arm. Despite the lack of differences in survival between groups, the fact that only a minority of patients received the FLOT regimen suggested that indeed perioperative chemotherapy could lead to superior outcomes in this setting.

This hypothesis was put to the test in the ESOPEC trial. In this phase III RCT, 438 patients with adenocarcinomas (including T4a) arising in the esophagus or gastroesophageal junction that extended to the esophagus were randomized to receive perioperative FLOT or preoperative chemoradiation according to the CROSS trial protocol. Mature results from this trial were presented at the 2024 American Society of Clinical Oncology Annual Meeting (14). Treatment with FLOT was associated with improved overall survival and progression-free survival (Table 1). In the subgroup analysis, patients with clinically positive lymph nodes seemed to benefit the most from the FLOT regimen. Interestingly, the pCR rate in the FLOT arm was numerically higher than that of the CROSS arm. Also, despite the lack of differences in the frequency of postoperative complications, the number of postoperative deaths was numerically higher in the CROSS arm.

While we wait for the publication of the study manuscript, including its full data on efficacy and toxicity, many concerns have been raised regarding the ESOPEC trial. First, while compliance to radiotherapy was very high in the ESOPEC trial (98.0% vs. 92.0% in the CROSS trial), only 67.7% of patients received the full 5-week course of radiosensitizing chemotherapy (2,14). As of now, it is not clear why so many patients failed to comply with chemotherapy in the radiotherapy arm, especially considering that 91% of patients in the CROSS trial completed the chemotherapy protocol. Interestingly, the number of patients who completed perioperative FLOT in the ESOPEC trial was numerically higher (52.5%) when compared to the FLOT4 trial (46.0%) (7). This data possibly conveys better clinical management of the FLOT regimen after it has been widely adopted in the perioperative treatment of esophagogastric cancer.

Second, while the radiotherapy schedule used in the ESOPEC trial mirrors that used in the CROSS trial (41.4 Gy in 23 fractions of 1.8 Gy using 3D conformal radiation technique) (15), there remains to be shown data on tumor volumes and radiotherapy protocol deviations. Furthermore, limited retrospective data suggest more modern radiation techniques, such as IMRT, might be associated with improved overall survival and, therefore (16), the use of older radiation technology could have negatively affected the results of the CROSS arm in both NEO-Aegis and ESOPEC trials. Also, it is possible that the use of non-CROSS chemotherapy regimens might have led to superior outcomes. Indeed, in the CALBG 80803 trial, patients who underwent neoadjuvant radiotherapy with concomitant FOLFOX fared better, especially those who had a metabolic response to induction FOLFOX (17).

Third, trials that assessed the role of neoadjuvant radiotherapy have systematically shown improved pCR rates with neoadjuvant chemoradiation (ranging from 12% to 22% in chemoradiation and 0% to 7% in chemotherapy arms) (13,18,19). While the pCR rate of the FLOT arm in the ESOPEC trial is similar to the one found in the FLOT4 trial, the results in the chemoradiation arm fall short of the expectations according to previous studies. Likewise, in these trials, R0 resections were more frequent in patients undergoing neoadjuvant chemoradiation. In the ESOPEC trial, the rates of R0 resection were very high in both arms at approximately 95%. It is possible that with recent advances in surgical techniques, better local control can be achieved without radiotherapy. Along with better systemic treatment using a more powerful chemotherapy regimen, this can help explain the results of the ESOPEC trial. However, the median overall survival of patients with EA in the CROSS trial was superior to that observed in ESOPEC (43.2 vs. 37.0 months). Apart from the underperformance of the chemoradiation arm in the ESOPEC, this is rather surprising as during the time elapsed from the publication of these trials, improvements in other treatment modalities have led to improvements in survival. One possible explanation might be related to the inclusion criteria, as the ESOPEC trial included patients with T4 tumors. Despite the apparent balance in terms of T3/4 tumors between the two arms of the ESOPEC trial, the presence of T4 tumors in the chemoradiation arm of the ESOPEC trial might have contributed to the inferior outcomes when compared with the CROSS trial.

Last, the ESOPEC trial was designed before the results of CheckMate-577 were available. In this study, patients with EAs or ESCC with residual pathologic disease after neoadjuvant chemoradiation and surgery were randomized to nivolumab for 1 year or placebo (20). The use of adjuvant nivolumab was associated with improved disease-free and metastasis-free survival. Thereafter, nivolumab has been used in this setting in many countries, and, therefore, the ESOPEC trial does not correspond to the current clinical practice in many parts of the world. However, it is important to bear in mind that the ESOPEC trial showed improved overall survival for the FLOT arm, which has not been demonstrated so far with the use of adjuvant nivolumab. Also, the subgroup analysis suggests the benefit of adjuvant nivolumab after chemoradiation seems to be somewhat less robust for patients with EA when compared to ESCC (20). Moreover, despite the disappointing results with perioperative immunotherapy seen in the KEYNNOTE-585 trial (21), eagerly awaited data from the MATTERHORN and DANTE trials might justify the use of immunotherapy along with chemotherapy in the perioperative setting and further improve the results identified using FLOT.

One should highlight the results of the ESOPEC trial have not been completely presented and additional data on patterns of recurrence, causes of death, and post-progression therapy are awaited. While we believe the results of the ESOPEC trial suggest FLOT is the new standard of care in the perioperative treatment of patients with EA, some patients, such as those less fit for FLOT, with clinically negative regional lymph nodes or invasion of the adjacent structures (such as diaphragm, pericardium, or aorta) might still benefit from the CROSS regimen. However, this might not be the definitive answer to this conundrum. Modern radiotherapy techniques might have an additional impact in the treatment of localized EA and, therefore, radiotherapy will continue to play a role in the management of localized EA. Ongoing studies are assessing the efficacy and toxicity of combining both strategies in the neoadjuvant setting and we wait for the results of these studies, along with the aforementioned immunotherapy trials.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus. The article has undergone external peer review.

Peer Review File: Available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-23/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-23/coif). V..H.F.d.J was supported by IQVIA and received consulting fees from Knight Medical, Bayer, Servier, MSD, and Astellas, and received payments from BMS, MSD, Roche, Pfizer, Sirtex, Merck, Daiichi-Sankyo, Amgen, Servier, he also was supported by AstraZeneca, Pfizer, and Daiichi Sankyo and he is on the editorial board of the Scientific Committee – Brazilian Society of Clinical Oncology. E.Z.C. has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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