Beyond 5 years after esophagectomy—is cure really achieved?

With great interest, we have read the manuscript by Robb et al. presenting a timely and thought-provoking secondary analysis from the FFCD9901 randomized trial, investigating oncological outcomes of patients who survived beyond 5 years after esophagectomy for stage I–II esophageal cancer (1,2).

A rare perspective on long-term survivorship

Most clinical trials in esophageal cancer report follow-up limited to 3–5 years, leaving the natural history of long-term survivors largely unexplored. The present study, therefore, fills an important gap by characterizing outcomes of patients who reached the 5-year survival mark. Among n=170 patients from the study, n=70 (41%) survived more than 5 years. Importantly, 13 (19%) of these 70 long-term survivors experienced recurrence after 5 years. This finding challenges the traditional assumption that 5-year survival equates to cure and underscores the biological heterogeneity of esophageal cancer (3). Late recurrences—often metastatic rather than locoregional—suggest that micrometastatic disease or tumor dormancy may persist long after apparently curative treatment (4).

Predictors of long-term outcome

In the multivariable analysis, two variables independently predicted death within 5 years: histological lymph-node positivity (pN+) and impaired baseline performance status. Both have long been recognized as key determinants of prognosis after esophagectomy (5,6).

Interestingly, postoperative complications were also associated with reduced 5-year survival in univariate analysis, aligning with prior evidence linking surgical morbidity to impaired long-term outcomes through mechanisms such as inflammation-induced tumor promotion, delayed adjuvant therapy, and diminished physiological reserve (7-9). This reinforces the critical importance of perioperative optimization and meticulous surgical technique not only for short-term recovery but also for long-term oncologic success.

When does cure begin? Implications for surveillance

Perhaps the most clinically impactful message of this study is that survival beyond 5 years does not guarantee cure. While most recurrences occur within the first 3 years after surgery, a non-negligible subset of patients develops recurrent disease beyond 5 years. The authors rightly question whether current follow-up strategies—which commonly taper or cease at 5 years—are appropriate for all patients.

Recent evidence from the large, multicenter ENSURE study demonstrated that intensive surveillance (IS) after esophagectomy reduced symptomatic recurrence and facilitated curative treatment in selected subgroups, particularly those with early-stage disease or favorable pathological response (10). However, routine IS for all patients is unlikely to be cost-effective or beneficial given competing risks of death from non-cancer causes. Thus, a risk-adapted surveillance model—ideally incorporating pathological stage, performance status, and histological subtype—appears rational.

The integration of liquid biopsy technologies, such as circulating tumor DNA (ctDNA), could revolutionize post-operative surveillance by enabling earlier, non-invasive detection of minimal residual disease and recurrence (11,12). These tools may eventually refine surveillance intensity beyond traditional imaging-based algorithms, allowing individualized follow-up intervals based on molecular risk rather than fixed timeframes.

Second primary malignancies—an overlooked threat

Another striking finding from the FFCD9901 analysis is the occurrence of second primary malignancies in 11% of resected patients and in 9% of the patients that were free of recurrence and alive after 5 years. Head-and-neck and lung cancers were the most frequent, consistent with previous population-based studies showing a three- to four-fold increased risk of metachronous malignancies in esophageal cancer survivors (13,14). These second primaries likely reflect shared etiologic exposures (tobacco, alcohol) rather than treatment-related toxicity.

The authors rightly highlight the need for vigilance toward second primaries in survivors of esophageal squamous cell carcinoma. Although national guidelines in France and Germany do not prescribe routine annual ear, nose, and throat (ENT) examinations, they recognize the elevated risk of head-and-neck malignancies and advocate individualized follow-up. Integrating such risk-based surveillance—together with smoking cessation and preventive care—should be a cornerstone of modern survivorship programs.

Lessons for clinical practice and future research

This study offers several important take-home messages:

• Five-year survival does not equal cure. Nearly one in five “long-term survivors” eventually recurred, highlighting the persistent risk of late disease.
• Performance status and nodal status remain key prognostic factors. These variables should inform both adjuvant treatment intensity and post-treatment follow-up.
• Surveillance must be individualized. Risk-adapted and ideally biomarker-informed strategies are needed to balance benefit, cost, and patient burden.
• Second primaries deserve systematic attention. Survivorship care must extend beyond cancer recurrence to prevention of new malignancies and management of comorbidities.

From a research standpoint, several questions remain. First, can molecular residual disease monitoring using ctDNA or methylation assays predict late recurrence and identify patients needing extended surveillance? Second, what is the optimal duration and modality of follow-up that maximizes benefit without overwhelming healthcare systems? Third, how do histological subtypes differ in their long-term recurrence kinetics? Importantly, interpretation of these findings must consider the histological composition of the FFCD9901 cohort, which was predominantly composed of squamous cell carcinoma. As recurrence patterns, second primary risks, and survivorship trajectories differ substantially between squamous cell carcinoma and adenocarcinoma, the observed rates of late recurrence and second malignancies may not be fully generalizable to contemporary Western adenocarcinoma-dominated populations. In particular, adenocarcinoma is more frequently associated with distant metastatic relapse and may exhibit different late recurrence kinetics, underscoring the need for histology-specific survivorship models. Future studies should therefore stratify long-term outcomes by histological subtype to refine surveillance strategies accordingly. Large pooled analyses integrating histology-specific data from Western and Asian cohorts could shed light on these issues.

Finally, the landscape of multimodal therapy is rapidly evolving. The addition of neoadjuvant durvalumab in the Matterhorn trial has redefined the standard of care for patients with locally advanced disease (15). Whether such immune checkpoint inhibition can also mitigate late recurrence or second malignancies remains to be seen, but long-term follow-up of these modern cohorts will be crucial.

Concluding remarks

The analysis of long-term survivors from the FFCD9901 trial delivers an important message: being alive 5 years after esophagectomy does not necessarily mean being cured. A subset of patients continues to harbor biological risk for recurrence or second primary cancer even after apparent cure. Conversely, many others remain disease-free, attesting to the progress achieved in early detection, staging, and surgical quality.

As outcomes improve and survivorship becomes an increasingly prominent part of esophageal cancer care, follow-up strategies must evolve from rigid timelines to personalized, risk-stratified pathways that integrate molecular monitoring and survivorship care. The study by Robb et al. provides a valuable foundation for this transition—reminding us that the true measure of success in esophageal cancer is not merely survival at 5 years, but sustained wellness beyond it.

Acknowledgments

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.com/article/view/10.21037/aoe-2025-1-38/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2025-1-38/coif). The authors have 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Robb WB, Veziant J, Dahan L, et al. What are the outcomes for long-term survivors after esophagectomy? - Evidence from a randomized controlled trial (FFCD9901). Eur J Surg Oncol 2025;51:109736. [Crossref] [PubMed]
2. Mariette C, Dahan L, Mornex F, et al. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol 2014;32:2416-22. [Crossref] [PubMed]
3. Pectasides E, Stachler MD, Derks S, et al. Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. Cancer Discov 2018;8:37-48. [Crossref] [PubMed]
4. Manjili MH. Tumor Dormancy and Relapse: From a Natural Byproduct of Evolution to a Disease State. Cancer Res 2017;77:2564-9. [Crossref] [PubMed]
5. Eloubeidi MA, Desmond R, Arguedas MR, et al. Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer 2002;95:1434-43. [Crossref] [PubMed]
6. Zhao Y, Zhong S, Li Z, et al. Pathologic lymph node ratio is a predictor of esophageal carcinoma patient survival: a literature-based pooled analysis. Oncotarget 2017;8:62231-9. [Crossref] [PubMed]
7. Broadbent A, Rahman S, Grace B, et al. The effect of surgical complications on long-term prognosis following oesophagectomy. Eur J Surg Oncol 2023;49:106930. [Crossref] [PubMed]
8. Abou Chaar MK, Godin A, Harmsen WS, et al. Determinants of Long-term Survival Decades After Esophagectomy for Esophageal Cancer. Ann Thorac Surg 2023;116:1036-44. [Crossref] [PubMed]
9. Crnovrsanin N, Giring S, Oppel A, et al. Effects of postoperative complications in oesophageal cancer on survival, hospital outcomes, and long-term quality of life: retrospective cohort study. BJS Open 2025;9:zraf083. [Crossref] [PubMed]
10. Elliott JA, Markar SR, Klevebro F, et al. An International Multicenter Study Exploring Whether Surveillance After Esophageal Cancer Surgery Impacts Oncological and Quality of Life Outcomes (ENSURE). Ann Surg 2023;277:e1035-44. [Crossref] [PubMed]
11. Allan Z, Sloane HS, Harper K, et al. Circulating tumor DNA (ctDNA) analysis for improved treatment response assessment and prediction of clinical outcomes in patients with esophageal cancer. J Clin Oncol 2025;43:4077.
12. Ng HY, Ko JMY, Lam KO, et al. Circulating Tumor DNA Dynamics as Prognostic Markers in Locally Advanced and Metastatic Esophageal Squamous Cell Carcinoma. JAMA Surg 2023;158:1141-50. [Crossref] [PubMed]
13. Matsubara T, Yamada K, Nakagawa A. Risk of second primary malignancy after esophagectomy for squamous cell carcinoma of the thoracic esophagus. J Clin Oncol 2003;21:4336-41. [Crossref] [PubMed]
14. Mitani S, Kadowaki S, Oze I, et al. Risk of second primary malignancies after definitive treatment for esophageal cancer: A competing risk analysis. Cancer Med 2020;9:394-400. [Crossref] [PubMed]
15. 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]