Adjuvant Therapy After Neoadjuvant Therapy for Esophageal Cancer: Who Needs It?

Abstract

Objective: We hypothesized that, on average, patients do not benefit from additional adjuvant therapy after neoadjuvant therapy for locally advanced esophageal cancer, although subsets of patients might. Therefore, we sought to identify profiles of patients predicted to receive the most survival benefit or greatest detriment from adding adjuvant therapy.

Background: Although neoadjuvant therapy has become the treatment of choice for locally advanced esophageal cancer, the value of adding adjuvant therapy is unknown.

Methods: From 1970 to 2014, 22,123 patients were treated for esophageal cancer at 33 centers on 6 continents (Worldwide Esophageal Cancer Collaboration), of whom 7731 with adenocarcinoma or squamous cell carcinoma received neoadjuvant therapy; 1348 received additional adjuvant therapy. Random forests for survival and virtual-twin analyses were performed for all-cause mortality.

Results: Patients received a small survival benefit from adjuvant therapy (3.2±10 months over the subsequent 10 years for adenocarcinoma, 1.8±11 for squamous cell carcinoma). Consistent benefit occurred in ypT3-4 patients without nodal involvement and those with ypN2-3 disease. The small subset of patients receiving most benefit had high nodal burden, ypT4, and positive margins. Patients with ypT1-2N0 cancers had either no benefit or a detriment in survival.

Conclusions: Adjuvant therapy after neoadjuvant therapy has value primarily for patients with more advanced esophageal cancer. Because the benefit is often small, patients considering adjuvant therapy should be counseled on benefits versus morbidity. In addition, given that the overall benefit was meaningful in a small number of patients, emerging modalities such as immunotherapy may hold more promise in the adjuvant setting.

Figure 1:

Box and whiskers plot of gain (positive) or detriment (negative) in lifetime within 10 years by adding adjuvant therapy after neoadjuvant therapy according to ypT along horizontal axis, and ypN0 and ypN+ along right-hand edge for adenocarcinoma (left) and squamous cell carcinoma (right). Solid bar is median, box encloses the 25th and 75th percentiles of values, whiskers are 1.5 times the interquartile range, and filled circles are values beyond this. Box width is proportional to sample size. When median (solid bar) is above zero there is a gain in lifetime, and when below zero a detriment in lifetime, for that ypT category.

Figure 2:

Box and whiskers plot of gain (positive) or detriment (negative) in lifetime within 10 years by adding adjuvant therapy after neoadjuvant therapy according to ypT category along horizontal axis, and number of cancer-positive lymph nodes (right-hand edge) for adenocarcinoma (left) and squamous cell carcinoma (right). Format is as in Figure 1.