Esophageal cancer is the seventh most common malignancy and the sixth most common cause of cancer-related mortality globally [1]. Trimodality treatment (TMT) of chemoradiotherapy (CRT) followed by surgery is currently accepted as the standard treatment in locally advanced esophageal cancer [2–4]; however, some studies reported that surgical resection may be omitted without serious impact on survival in cases showing response to CRT [5,6]. This may be considered a reasonable approach considering the high rates of mortality and morbidity associated with surgical resection [2,7,8]. In addition, patients are often reluctant to undergo surgery after the completion of neoadjuvant CRT, especially when they show good clinical response to CRT, experience the disappearance of the main symptoms, or show incomplete recovery of performance after chemoradiation.

However, the term “response” includes a wide range of disease status in the real-world setting, from partial responses of a slight decrease in the disease status to complete disappearance of the tumor. Moreover, it may be difficult to evaluate the clinical response due to treatment-induced edema and esophagitis, which do not subside at the time of post-treatment reevaluation. Therefore, it is necessary to accurately define the criteria for “response”, which is complicated due to the individual variability among clinicians in interpreting treatment responses. To minimize these variations and possible confusion, the use of the criteria of “complete response” may be more reasonable and practical despite the controversy on the evaluation methods.

We assume that surgical resection may be omitted only in responders to CRT, because patients may miss the optimal timing for surgical resection and cure. However, there is a limited amount of available data on the survival benefit of esophagectomy in patients who show a clinically good response after CRT for locally advanced esophageal squamous cell carcinoma (ESCC), and the available results are not consistent [9–12]. Therefore, in this study, we evaluated the long-term effect of esophagectomy in patients with ESCC who received concurrent CRT followed by surgery (TMT) in terms of their clinical response to CRT.

Currently, TMT is regarded as the standard treatment for locally advanced esophageal cancer, with its role having been established by the results of randomized controlled trials (RCTs) on adenocarcinoma [2,4] and squamous cell carcinoma (SCC) [13]. However, considering the high rate of pathologic CR in patients with SCC (~50%), it may be possible to omit esophagectomy in good responders if they could be identified prior to surgical resection. In the real-world setting, the role of esophagectomy in good responders after CRT is yet to be firmly established. Many RCTs that compared between esophagectomy and no surgery reported that esophagectomy did enhance the survival rate in no responders but not in good responders [5,6]. Yet, those RCTs included partial responders and viable tumor cells might have remained in the esophagus and regional lymph nodes.

In order to focus on testing the possibility of safely omitting esophagectomy, remnant tumors in the mediastinum should be considered for performing a successful study. Accordingly, the study by Piessen et al. [9] was meaningful as it only enrolled cCR cases and reported the benefit of esophagectomy in terms of survival (58.9% vs. 33.4%, p= 0.001); however, their study had limited generalizability because it excluded patients with short follow-up durations of 3 years or less, and included both adenocarcinoma and squamous cell carcinoma, which have different chemoradiosensitivity [14].

Other investigators also tried to identify the benefit of esophagectomy in cCR patients with SCC, but none has demonstrated significant advantages in terms of survival. Castoro et al. [10] investigated 77 SCC patients who achieved cCR after neoadjuvant CRT, and did not observe a significant difference in 5-year survival (50% vs. 57%, p=0.99). Chao et al. [11] also analyzed 150 SCC patients who underwent endoscopic CR after CRT and reported no significant survival benefit with esophagectomy. It should be noted that PET scan was not fully available during the study periods of the studies by Castoro et al. [10] and Chao et al. [11], and that the response evaluation was primarily dependent on endoscopy findings. Therefore, it is possible that their study patients might not have achieved cCR according to current standards that include metabolic response on PET scan, and might have had residual tumors in the extraluminal area such as the regional lymph nodes.

We have published a similar study with more advanced evaluation methods such as PET scan, and reported that while esophagectomy resulted in significantly improved disease-free survival, it did not result in a significant improvement in OS [12]. We reasoned that such statistically null findings in OS likely stemmed from the small number of patients, and therefore expected to find a positive result in this updated study with a larger cohort size. As a result, we found that esophagectomy was associated with a significantly better OS as well as LRFR and DMFR in the entire cohort. However, we could not find a significant beneficial effect of surgical resection in the subgroup analysis on patients with cCR, which indicates that the improvement in LRFR was not directly translated to an improvement in OS. We could only reaffirm that esophagectomy was beneficial for patients without cCR.

Although the exact reason why we could not observe a significant difference in OS in the cCR patients is unclear, the following factors may have been involved. First, surgical mortality might have been involved in the nullification of the survival benefits of esophagectomy. For example, robot-assisted surgery was introduced to our center for esophageal cancer in 2010, and there may have had been a period of higher rates of complication and mortalities during the learning curves of the surgeons. Yet, the transient increase in mortality was not enough to offset the difference in LRFR. Second, salvage esophagectomy might reduce the mortality from local recurrence in CRT patients. As salvage esophagectomy was performed in 15.8% of cases with locally recurrent tumors and was not enough to explain the negative result, it is worth noting that 80% of those cases had R0 resection without any in-hospital mortality or death within 90 days after salvage surgery. Markar et al. [15] conducted a multicenter study that demonstrated the role of salvage esophagectomy, in which salvage esophagectomy after definitive CRT did not result in significant differences with TMT in terms of in-hospital mortality, 3-year overall survival, and disease-free survival in 848 patients [15]. Third, the characteristics of the CRT group (e.g., higher age, poor differentiation, and higher Charlson-Deyo score) may have predisposed the patients to poor prognosis despite the correction effort. Fourth, the effect of distant metastasis on survival in the cCR cases might have been strong, and surgery as a local treatment could be limited in significantly affecting the overall survival. However, as the rate of distant metastasis was around 9% in both groups (Table 2), the effect of distant metastasis on survival does not seem to be large enough to offset the increase in LRFR. Collectively, we assume that these four possible explanations are likely to have led to the null findings in survival in this study.

In terms of radiation dose, our patients received a neoadjuvant dose of around 45 Gy and some patients received 50–54 Gy for definitive aim. Some investigators insisted on the use of 60 Gy or higher for definitive CRT considering that local recurrence occurs in about half of patients as in our current study. Yet, there is not enough empirical evidence to change the current standard dose, which was established based on RCTs; in the near future, however, it may be feasible to administer higher doses through more advanced techniques such as IMRT and Proton. In order to determine the role of esophagectomy after CRT, we chose a rather narrow range of conventional radiation doses because we sought to perform response evaluation at one month after treatment. In order to use a higher radiation dose, a treatment break of 1 month should be considered prior to the additional dose, whose effect is not established at present.

The present study has several limitations. First, it is a retrospective analysis and the result might have been influenced by potential selection bias. Although IPTW-adjusted analysis was performed to adjust for the differences in patient characteristics, unobserved confounding factors may have still been present. Second, the rate of pCR was higher than that of cCR, which suggests that our criteria for cCR may have been overly strict and not representative of the real-world setting. Third, we focused on high-grade treatment-related toxicities and may have underestimated lower grade toxicities and their possible effects. Forth, histological confirmation of recurrent lesions could not be performed in every patient.

Despite these limitations, our study provides clinically meaningful results because the treatments were performed according to a prospectively established study protocol by an experienced multidisciplinary esophageal cancer team. Moreover, we applied the IPTW adjustment to perform a reliable analysis. Although some of our results did not support our initial hypothesis, this study showed that esophagectomy after CRT was associated with improved survival compared with CRT and we hope that our study may be used as a reliable reference for future studies.

Esophagectomy after CRT was associated with significantly better survival results and lower rates of local recurrence and distant metastasis rates compared with CRT. As such effects were more prominent in patients who did not achieve cCR, esophagectomy may be considered in such patients. In complete responders, however, the treatment decision should be made by considering the pros and cons of esophagectomy, which was effective for improving LRFR but not OS.