Can recurrence-free survival replace overall survival for resectable esophageal cancer?

Esophageal cancers are highly complex, inherently resistant and heterogeneous. Progress has been painfully slow and meager. Recent years have seen some movement, but many questions remain. In this context, Okui et al. recently published their original investigation involving individual patient data (IPD) from randomized phase 3 perioperative trials in the surgically resectable esophageal cancer patients (1). The authors, who consisted of a geographically diverse group but highly experienced investigators with considerable expertise in esophageal cancer, attempted to answer a very relevant question. Can recurrence-free survival (RFS) represent a surrogate marker for overall survival (OS) in localized esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC)? This question has been asked before but has not been investigated in the manner presented in this article using IPD from several trials. We congratulate their undertaking.

The authors highlight the need for such investigation as OS as an endpoint requires long-term follow-up, large trial populations, post-recurrence therapies, and can be clouded by non-cancerous causes of death. In addition, the authors note the lack of evidence-based data from randomized controlled trials in this realm. The long follow-up remains a challenge in cancer medicine. Two recent practice changing trials in the esophageal cancer space, the CHECKMATE 577 and the ESOPEC trial, highlight the substantial time needed to complete these types of trials (2,3). ESOPEC enrolled for ~4 years (February 2016 to April 2020) with a median follow up of ~5 years (55 months) (2). CHECKMATE 577 enrolled for ~3 years (July 2016 to August 2019) with a median follow up of ~2 years (24.4 months) (3). CHECKMATE 577’s primary endpoint was event-free survival (EFS) while ESOPEC’s primary endpoint was OS (2,3). These time periods also do not include time it takes to conceive and launch these trials. Waiting close to 10 years as is the case for ESOPEC to generate results is an impediment to make relatively rapid advances our patients expect. Therefore, given long time needed for OS to result, we applaud the authors who attempt to answer whether RFS/EFS correlates with OS in esophageal cancers (1). Another strength of this investigation was utilizing the Kendall rank correlation coefficient as the statistical model to determine the association between the two variables (RFS and OS). Additionally, the investigation consisted of a sizable population with over 2,000 patients enrolled in 10 prospective studies. The task of compiling and analyzing IPD is not a simple one. The authors were able to suggest collective and trial level surrogacy between RFS and OS and with subgroup analysis by treatment modality.

However, we must acknowledge some limitations of such projects and the results they generate. The ten trials spanned a decade for publication dates (2003–2023) with differing treatment modalities making the results variable for clinical practice (1). As an example, given that trial design concepts can vastly differ and run simultaneously, results of trials like CHECKMATE-577 can become out of date quickly given newer results such as ESOPEC as seen with EAC. Additionally, simultaneous investigations can be going with mixed strategies (preoperative chemotherapy, preoperative chemoradiotherapy, adjuvant chemotherapy, and surgery alone) and the inclusion of diverse group of strategies. All this making it difficult to harmonize the results as well as the message. Essentially, with all these subgroups with smaller cohorts, one cannot be entirely certain that RFS/EFS correlates with OS in every circumstance. The authors did not include the immune checkpoint inhibitor trials whether this can influence the results remains unclear. EACs are now frequently treated without the addition of chemoradiation but chemoradiation remains a major component of ESCC. Combining the two strategy raises some issues. We hope in the future we will have results in large cohorts focused on separate histologies and treated with similar strategies. In this study, ESCC patients predominated (73% of the population), thus we can say that the results are more relevant to ESCC and not so much for EAC. One concern is the inclusion of chemoradiation strategy for EAC limits the results in the context of currently popular strategy established after the ESOPEC results (2). It is acknowledged that the authors utilized results for EAC available when this project was launched. However, many factors could affect OS after a relapse, particularly in EAC, as biomarker-driven approaches can prolong OS and confound the results. The authors have not provided data on subsequent therapy in various groups. We acknowledge that the authors have tackled a very complicated retrospective exercise but given the nature of retrospective design it is destined to have a number of limitations.

No question that OS remains the gold standard for introduction of new therapies and most regulatory agencies want an OS advantage in this setting. CHECKMATE 577 is one good example (3). Adjuvant nivolumab was approved in some countries in EU after the initial results of considerable EFS advantage but the approval was rescinded in some countries as OS results did not come through for a long time. More importantly, OS analysis of this study demonstrated no benefit for the intent-to-treat population (4). The other example is the Matterhorn trial, which showed significant EFS advantage but only very minor in programmed death ligand-1 (PD-L1) positive population (but significant advantage) in OS (5,6).

Are the results presented in Okui et al.’s paper change the stance of various regulatory agencies to allow EFS as the only primary endpoint for approval of a drug? We are uncertain. A very robust analysis (that adjusts for post-event therapy) might be acceptable however, OS has been established surrogate at this time.

What does future hold? All these trials discussed above have the age-old problem of assuming that every patient’s tumor has similar biology/genetics which is entirely untrue. More we study individual patient’s tumor (and sometime germline DNA), we understand that not only each patient with esophageal cancer is unique, but there are also biomarker-driven subgroups and deeper dives will uncover more subgroups/drivers that can be targeted uniquely. Our future is in biomarker/NGS in tissue/blood-driven approaches to individualize therapies. If we adopt such strategies then correlating RFS/EFS to OS will become even more complex. Nevertheless, the future holds a lot of excitement.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0002/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0002/coif). The authors have no conflicts of interest to declare.

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References

1. Okui J, Matsuda S, Nagashima K, et al. Recurrence-free Survival as a Surrogate Endpoint for Overall Survival in Resectable Esophageal Cancer: Integrated Analysis of Individual Patient Data From Phase III Trials. Ann Surg 2025; Epub ahead of print. [Crossref] [PubMed]
2. Hoeppner J, Brunner T, Schmoor C, et al. Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer. N Engl J Med 2025;392:323-35. [Crossref] [PubMed]
3. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med 2021;384:1191-203. Erratum in: N Engl J Med 2023;388:672. [Crossref] [PubMed]
4. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): First results of overall survival (OS) from CheckMate 577. J Clin Oncol 2025;43:4000. [Crossref]
5. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer. N Engl J Med 2025;393:217-30. [Crossref] [PubMed]
6. Tabernero J, Al-Batran SE, Wainberg ZAA, et al. Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: a randomise, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) in resectable gastric/gastroesophageal junction (G/GEJ) adenocacinoma. Ann Oncol 2025;36:LBA81. [Crossref]