In this focused study, on clinical T1N+, T2 (both node negative and node positive) esophagus cancer patients, there was no evident superiority associated with neoadjuvant therapy over adjuvant therapy by multivariate analysis using Cox regression model. This relationship held true in both squamous cell carcinoma and adenocarcinoma groups. For T1N+ ESCC, this conclusion is limited by the relatively small number of patients in the NCDB cohort and may require additional studies.
The introduction of both chemotherapy and radiation in the neoadjuvant and adjuvant settings has positively impacted survival in patients with locally advanced esophageal cancer. There is significant literature on the use of multimodal therapy for the treatment of esophageal cancer and the strategies for treatment have been previously summarized (3,5, 11). There are proponents of various approaches and many reasons fuel this debate including difficulty in studying the disease due to anatomic and histologic heterogeneity. One major source of discussion is the use of neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy alone prior to surgery. Advocates for the use of chemoradiotherapy frequently quote the CROSS trial which showed significantly higher median overall survival in patients who received chemoradiotherapy followed by surgery when compared to surgery alone (10). While these results of neoadjuvant chemoradiotherapy are quite remarkable, one of the criticisms of this study is the lack of a neoadjuvant chemotherapy arm in this study (14,15). The ability to achieve a R0 resection at the time of surgery is one of the most important factors for decisions on adjuvant therapies. In our study, we found a significant lower R0 rate associated with the AT only group when compared to the NT and CT groups. This is consistent with consensus that induction therapy will increase R0 rate at the time of surgery.
However, there is concern suggesting an increase in operative complexity and intraoperative and postoperative complications in the setting of neoadjuvant chemoradiation in an already complex operation of esophagectomy (15-17). In a study by Reynolds and colleagues an increase in postoperative complications including respiratory complications were noted in patients with preoperative chemoradiation followed by esophagectomy, when compared with patients treated with surgery alone (17). We also found significantly higher 30 and 90 day mortality in the NT group than that in the AT and the CT groups. The results support the idea that NT may have negative impact on surgical results. We also need to be very cautious when interpreting above results. While the NCDB provides an extensive group of patients to study, it fails to capture patients who opted out of AT due to a protracted postoperative course. These patients have an associated higher 30d mortality and 90d mortality rate and their improper exclusion into the AT or CT groups may introduce some selection bias.
The sequence between chemotherapy and radiation with surgery has also been in debate. Accurate staging is important for selection of appropriate treatment strategy, however, there are significant inaccuracies in clinical staging modalities. One cohort where clinical staging with endoscopic ultrasound is notably inaccurate are patients with clinical T2 disease, where inaccuracies as high as 50% been reported (12, 13). With the inaccuracies of clinical staging particularly for cT1N+ and cT2 tumors, upfront surgery, and subsequent treatment based on more reliable pathological staging information may be considered. In patients undergoing surgery first, their pathologic findings are definitive and provide definitive pathologic staging data. Therefore, this affords the multidisciplinary oncologic team to selectively choose the best treatment regimen based on final pathology. The role of adjuvant chemotherapy in esophageal cancer is not clearly established (5,11). However, a Phase2 study ECOG E8296 with adjuvant chemotherapy after completely resected adenocarcinoma showed encouraging results (5,18). Further, several meta-analyses investigated neoadjuvant vs adjuvant therapy in the setting of esophageal cancer with no significant differences in outcome (19,20). Speicher et al. compared induction therapy with patients that underwent surgery first in patients with clinical T2N0 disease (13). While they were unable to show a benefit to receiving induction therapy in these patients, they were unable to further stratify the induction therapy as that data was not available until 2006 in the NCDB. In the current study, our findings also support the idea that there is a role for adjuvant therapy following surgery in various subgroups particularly those with cT1N+ and cT2Nany disease. Therefore, adjuvant therapy following surgery may be a viable treatment sequence for a select group of patients especially those with cT1N+ and cT2Nany disease. Ultimately, careful patient selection is necessary to identify those that would best benefit from this approach. This is highlighted by Semenkovich et al. who, through a decision analysis model, recommended the use of upfront induction in patients that are found to have high risk features for upstaging found on EUS (21).
There are limitations to note for the current study. First, this is a retrospective analysis utilizing a large administrative database, lacking of granular patient data, standardized staging or treatment regimens, and is therefore subjected to reporter and selection bias. In addition, the data being collected is limited and does not include important variables such as cancer-specific mortality data. Therefore, we were unable to evaluate any relationship between oncologic outcomes such as recurrence-free survival or have any insight into specific therapy regimens. Similarly, we were also unable to track specific intraoperative and postoperative complications with regards to surgery as well as the multi-modal therapies (22). Additionally, Samson et al showed worse survival for upfront esophagectomy patients whom were upstaged with only 44.2% receiving adjuvant therapy and median overall survival of 27.5 months vs 43.9 months in neoadjuvant cT2 N0 patients. And so we acknowledged the concept of surgery first and allowing pathologic findings to determine adjuvant therapy has some risks (23). Base on NCDB, we also found up to 60% patients who received chemoradiation therapy could not undergo esophagectomy. Nonetheless, the results of this study reflect outcomes based on the most up-to-date cohort of patients with T1N+, T2 (both node negative and node positive) esophageal cancer in US.