Patients with cTanyN3M0 esophageal cancer represent a relatively uncommon subgroup with extensive regional lymph node involvement and a high risk of distant progression. Despite the absence of distant metastases at diagnosis, outcomes remain poor, and the optimal treatment strategy is not clearly established.
Current curative-intent approaches include neoadjuvant chemoradiotherapy (nCRT) followed by planned esophagectomy, definitive chemoradiotherapy (dCRT), and perioperative chemotherapy. However, patients with cN3 disease have been underrepresented in major clinical trials, leaving limited evidence to guide treatment decisions in this population.
A nationwide population-based study from the Netherlands evaluated real-world survival outcomes and recurrence patterns among patients with cTanyN3M0 esophageal cancer, with particular emphasis on comparing nCRT and dCRT.
The study, titled “Survival outcomes of treatment strategies for cTanyN3M0 esophageal cancer: A nationwide population-based study,” was published online on November 1, 2026, in Radiotherapy and Oncology.
The research was conducted by C.J.H. Hafkamp, E.D. Geijsen, H.W.M. van Laarhoven, S. Derks, R.J. Bennink, R.H.A. Verhoeven, S.L. Meijer, S.S. Gisbertz, M.I. van Berge Henegouwen, P.B. Olthof, A. van der Veen, and P.S.N. van Rossum.
The findings were previously presented as an oral presentation at the European Society for Radiation Oncology (ESTRO) Congress on May 3, 2025, in Vienna.
Study Design and Patient Population
This retrospective cohort study used data from the nationwide Netherlands Cancer Registry, including patients diagnosed between 2015 and 2022 with biopsy-confirmed cTanyN3M0 esophageal or gastroesophageal junction cancer.
Eligible histologies included adenocarcinoma, squamous cell carcinoma, and adenosquamous carcinoma.
Among 19,867 patients diagnosed with esophageal cancer, 316 (1.6%) had cTanyN3M0 disease. Of these, 265 patients met the study inclusion criteria.
Approximately half of the eligible patients (n=134; 50.6%) received nCRT, while 59 (22.3%) received dCRT. An additional 11 patients (4.2%) received induction or perioperative chemotherapy, and 61 (23.0%) received palliative therapy.
Importantly, patients were classified according to the treatment strategy initiated rather than whether they ultimately underwent esophagectomy. This approach was intended to better reflect real-world treatment decisions and reduce selection and immortal time bias associated with comparing patients based solely on surgery received.
The primary endpoint was overall survival (OS), measured from diagnosis. The investigators also evaluated progression-free survival (PFS) and recurrence patterns in patients diagnosed between 2015 and 2018, for whom recurrence data were available.
To improve comparability between nCRT and dCRT, propensity score matching was performed using baseline clinical and tumor characteristics, resulting in 38 patients in each matched group.
Survival Outcomes: nCRT vs dCRT
At a median follow-up of 40.2 months among surviving patients in the overall cohort, no statistically significant difference in OS was observed between the nCRT and dCRT strategies. In the unmatched population, median OS was 18.8 months with nCRT versus 15.2 months with dCRT (HR 0.76; 95% CI 0.54–1.08).
After propensity score matching, the difference in survival was smaller, with median OS of 17.6 months with nCRT versus 16.1 months with dCRT (HR 0.78; 95% CI 0.46–1.31). The proportional hazards assumption was violated in the matched analysis. However, complementary restricted mean survival time analyses at 36, 48, and 60 months also found no statistically significant differences between the two approaches.
Among patients receiving induction or perioperative chemotherapy, median OS was 18.9 months, compared with 7.1 months among those receiving palliative therapy. The perioperative chemotherapy group was too small to support reliable comparative conclusions.
Regarding treatment completion, 92 of 134 patients (68.6%) in the nCRT group ultimately underwent esophagectomy, compared with three of 59 patients (5.1%) in the dCRT group.
Adjuvant nivolumab was administered to 10.4% of patients in the nCRT group and 1.7% in the dCRT group. These results reflect outcomes according to the initiated treatment strategy rather than a direct comparison of completed trimodality treatment versus definitive chemoradiotherapy.
Recurrence Patterns and Progression-Free Survival
Recurrence data were available for patients diagnosed between 2015 and 2018. Among 97 patients treated with curative intent during this period, 65 (67%) had a documented first recurrence. Distant metastatic progression was the predominant pattern of treatment failure among documented first recurrences. Distant metastatic recurrence was reported in 59% (43/73) of patients receiving nCRT and 50% (12/24) of those receiving dCRT.
One-year progression-free survival (PFS) was 50.2% following nCRT and 55.8% following dCRT (HR 1.15; 95% CI 0.65–2.02). These findings highlight the high risk of distant recurrence in patients with extensive regional lymph node involvement, even following treatment with curative intent. The investigators also reported a five-year survival rate of approximately 8% despite curative-intent treatment, indicating that long-term survival remains possible in a small proportion of patients.
Clinical Implications: Is Treatment Intensification Needed?
The findings contribute to an important clinical discussion regarding the role of esophagectomy following chemoradiotherapy in patients with cN3M0 esophageal cancer.
Previous observational studies have suggested improved survival among patients undergoing esophagectomy after chemoradiotherapy. However, those analyses frequently compared patients who received surgery with those who did not, potentially introducing selection bias because only patients remaining sufficiently fit and without interval progression could proceed to surgery.
By evaluating treatment strategies from their initiation, the current study offers a different perspective. Although no statistically significant OS advantage was observed with the nCRT strategy compared with dCRT, these findings do not establish equivalent efficacy or demonstrate that surgery can safely be omitted.
The high frequency of distant recurrence also raises questions about whether intensifying systemic treatment could improve outcomes in this subgroup. The investigators discussed the potential relevance of more intensive chemotherapy strategies, immunotherapy, and targeted therapies. However, the study could not determine the benefit of these approaches specifically in cN3M0 disease.
The ESOPEC trial demonstrated improved OS with perioperative FLOT compared with the CROSS regimen in patients with resectable esophageal adenocarcinoma. However, outcomes were not reported separately for patients with cN3M0 disease. The potential morbidity and long-term quality-of-life consequences of esophagectomy are additional considerations when selecting a treatment strategy. However, this study did not directly evaluate comparative quality-of-life outcomes.
Study Limitations
Several limitations should be considered when interpreting these findings. The retrospective, nonrandomized design introduces potential residual confounding, including factors not captured in the registry, such as frailty, nutritional status, patient preferences, and the extent or location of lymph node involvement.
Although propensity score matching improved comparability, the matched analysis included only 76 patients, limiting statistical power and resulting in wide confidence intervals. The limited sample size restricted conclusions for patients with squamous cell carcinoma, while the exclusion of cT4b disease from matching further limited generalizability.
Treatment classification was also largely based on radiation dose, while recurrence information was available only for patients diagnosed between 2015 and 2018. Because follow-up imaging and endoscopy were performed according to clinical indications rather than a standardized surveillance schedule, recurrence may have been underestimated. Furthermore, the cohort predominantly reflected adenocarcinoma and gastroesophageal junction disease, while perioperative chemotherapy was not yet standard of care in the Netherlands during the study period.
Conclusion
This nationwide population-based study found no statistically significant overall survival difference between neoadjuvant chemoradiotherapy intended for subsequent esophagectomy and definitive chemoradiotherapy among patients with cTanyN3M0 esophageal cancer.
In the propensity score-matched analysis, median OS was 17.6 months with nCRT versus 16.1 months with dCRT (HR 0.78; 95% CI 0.46–1.31). The predominance of distant metastatic recurrence emphasizes the need to improve systemic disease control in this high-risk population. Although the findings raise questions about the additional contribution of surgery following chemoradiotherapy, they are hypothesis-generating and should not be interpreted as evidence supporting routine omission of esophagectomy.
Further prospective research is needed to define the optimal integration of local and systemic therapies and identify patients with cN3M0 esophageal cancer who may benefit most from curative-intent treatment.
