The evolving landscape of esophageal cancer treatment continually challenges clinicians to adapt and reassess their therapeutic strategies. In this context, the recent study by van der Zijden et al.1 on the use of adjuvant therapy for patients with tumor-positive resection margins after chemoradiotherapy and esophagectomy has raised a topic for debate: the use of adjuvant nivolumab in this setting.

The study assessed this topic in the National Cancer Registry of the Netherlands between 2015 and 2022. It highlights that before 2021, patients with tumor-positive resection margins did not receive adjuvant therapy. However, this trend changed remarkably from 2021 and onward, with 62 % of these patients administered adjuvant nivolumab. Importantly, due to the limited follow-up period, the study could not make conclusions about the potential survival benefits of this practice.

This shift in treatment practice is intriguing given the ongoing debates and the lack of consensus on adjuvant treatment in this context. The current body of literature, comprising mainly retrospective cohort studies with small sample sizes, presents conflicting data on the efficacy of adjuvant therapy for positive resection margins, which includes radiotherapy, chemotherapy, or chemoradiotherapy.2,3,4 This ambiguity is further demonstrated by the varying recommendations in both national and international guidelines. In the Netherlands, for instance, adjuvant therapy was not traditionally recommended, a stance mirrored in the findings of van der Zijden et al.,1 which show that no patients received such therapy before 2021.

The adoption of nivolumb after 2021 is understandable considering the typically poor prognosis of patients with positive resection margins and the attention gained by the promising results of the ATTRACTION-3 and Checkmate 577 trials.5,6 The latter study showed that disease-free survival was significantly longer for those who received nivolumab in an adjuvant setting after chemoradiotherapy followed by a radical esophagectomy. However, this shift toward the adjuvant use of nivolumab for patients with tumor-positive resection margins warrants a critical reflection.

The inherent limitations of the Checkmate 577 trial that set this trend in motion cannot be overlooked. Notably, the lack of long-term survival data is a significant evidence gap because overall survival is a crucial metric in assessing the efficacy of cancer therapies. Additionally, the trial’s patient selection criteria and the homogeneity of the study population limit the generalizability of its findings to broader patient groups such as those with positive resection margins. Because patients with positive resection margins were not part of the inclusion criteria for the Checkmate 577 trial, the use of nivolumab for this group of patients has therefore been off-label.

Beyond clinical effectiveness, the burden for patients should be acknowledged. The addition of adjuvant immunotherapy means an extra year of treatment after an already intensive regimen of chemoradiation and major surgery. This extension translates into monthly hospital visits and additional evaluation scans, adding to the patient’s health care journey. Although the absolute percentage of patients experiencing side effects from nivolumab may be limited, the additional treatment burden necessitates substantial proof of its efficacy.

Financial implications also warrant a discussion. The costs of nivolumab treatment amounts to more than 5000 euros per patient per month, accumulating to more than 68,000 euros annually.7 In a health care environment that is increasingly conscious of cost-effectiveness, the justification of allocating significant resources to a treatment with yet-to-be-confirmed (long-term) benefits is a matter of ethical and economic concern. This is especially pertinent in esophageal cancer care, in which the burden and costs of treatment are already substantial.

Although, the potential of adjuvant nivolumab for patients with positive resection margins should not be dismissed outright, the decision to adopt it must be grounded in a comprehensive evaluation of its clinical benefits, cost-effectiveness, and long-term outcomes. Innovation in cancer treatment is crucial, but it should not come at the cost of evidence-based practice. As we await more robust data, a cautious yet open-minded approach is essential in navigating this complex therapeutic landscape.