Controversies in preoperative therapy in esophageal cancer: Current evidence and ongoing research

Abstract Esophageal cancer incidence is growing worldwide, especially adenocarcinomas in the western world. Outcomes overall are universally poor, with the best survival seen in earlier stages of the disease, where surgery is the mainstay of treatment. Although squamous cell cancers and adenocarcinomas of the esophagus have different etiology, clinical features, biological behavior and prognosis, earlier research studies have frequently combined the two histologies. Several trials in the past three decades have been carried out in the neoadjuvant, adjuvant and perioperative settings in attempts to improve survival further. Most of the initial studies were small and underpowered, and showed no benefit with neoadjuvant or adjuvant treatment over surgery alone. More recent well‐designed trials have now established that the neoadjuvant (in squamous and adenocarcinomas) and the perioperative (in adenocarcinomas) strategies result in superior outcomes compared to surgery alone. However, the optimum neoadjuvant strategy has still not been identified, with both neoadjuvant chemotherapy and chemoradiotherapy (both followed by surgery) showing superior outcomes over surgery alone. Direct comparisons of these two neoadjuvant protocols have not shown a clear benefit of one over the other, although more trials are ongoing and may settle this debate. Future studies using personalized medicine and immunotherapy are required to evaluate their role in the management of esophageal cancers.


| INTRODUC TI ON
The global incidence of esophageal cancer is on the rise, ranking seventh in terms of incidence and sixth in overall mortality worldwide. 1  Preoperative therapy (neoadjuvant) appears to offer theoretical advantages over postoperative therapy (adjuvant) to control the micrometastases early. Intact blood supply to the tumor may improve the delivery and effectiveness of chemotherapy and radiotherapy. There is a potential to downstage the tumor and facilitate curative (R0) resection. It may also help to identify tumors with aggressive biological behavior and therefore guide further treatment. However, associated disadvantages of preoperative therapy have to be taken into consideration as it can increase both morbidity and mortality of surgery. There could be technical difficulties of operating in a pretreated field, especially with the addition of radiation, resulting in impaired healing of anastomosis and an increase in postoperative pulmonary complications. Hence, the ideal neoadjuvant treatment should be able to treat micrometastasis, improve survival by preventing local as well as distant failures, and have minimum toxicity and postoperative complications.
Although it is possible that chemotherapy and radiation could act synergistically at a locoregional level, the question remains as to whether there is value in combining two local treatments-radiation and surgery. Hence, the optimal treatment regimen for esophageal cancer is still controversial.

| NEOADJ U VANT CHEMOTHER APY
Over the last three decades, extensive research has been done on neoadjuvant treatment for resectable esophageal cancers.
Chemotherapy in the preoperative as well as adjuvant setting has been studied. Several randomized trials have compared neoadjuvant chemotherapy (NACT) followed by surgery with surgery alone (Table 1). Two-drug or three-drug combinations have been these results, the standard of care for esophageal and GEJ adenocarcinomas seems to be moving towards FLOT rather than the conventional ECF regimen. Most recent trials as well as meta-analyses 11,12 clearly show the superiority of neoadjuvant chemotherapy followed by surgery over surgery alone. Importantly, this benefit is seen without an increase in treatment-related morbidity or mortality.

| NEOADJ U VANT CHEMOR ADIATION
Neoadjuvant chemoradiation (NACRT) has the advantage of combining chemotherapy and radiation prior to surgery, and addressing both locoregional disease as well as micrometastases. Several trials were carried out to evaluate whether neoadjuvant chemoradiation followed by surgery could improve survival over surgery alone ( Table 2) The EORTC trial 14 also evaluated patients with squamous cell carcinoma and compared neoadjuvant CRT followed by surgery TA B L E 1 Summary of neoadjuvant chemotherapy (NACT) trials in esophageal cancer  with surgery alone. Here, radiation was delivered in two one-weekly courses, 2 weeks apart, with five daily fractions of 3.7 Gy each; cisplatin was given before each course of radiation. A total of 282 patients were randomized, 139 to surgery alone and 143 to combined treatment. Complete pathological response was seen in 26% of patients with combined treatment. In this trial, recruitment was stopped earlier than anticipated because of higher mortality in the combined treatment group. After a median follow up of 55.2 months, there was no significant difference in overall survival between the two groups.

TA B L E 2 Summary of neoadjuvant chemoradiation (NACRT) trials in esophageal cancer
Esophagus cancer-related deaths were lower in the neoadjuvant group, although mortality due to other causes was higher. The probable cause of the higher mortality rate was attributed to the higher dose of radiation per fraction. 12 Drawbacks of this study included the unconven-

| NEOADJ U VANT CHEMOTHER APY VER SUS NEOADJ U VANT CHEMOR ADIOTHER APY
The important controversy of the optimal neoadjuvant treatment regimen to treat esophageal cancer remains unresolved-there are very few trials comparing NACT with NACRT therapy. The POET trial 20,21 compared NACT followed by surgery with NACRT followed by sur- Our calculated guess is that NACRT is likely to be superior to NACT in squamous cell carcinomas and of no additional benefit to NACT in adenocarcinomas.

| TARG E TED THER APY AND IMMUNOTHER APY
Several years ago, there was a lot of promise and hype about targeted therapy and this has been assessed in a few studies.
Panitumumab was evaluated in a German phase II trial (NEOPECX) 28 and phase III multicentre study (REAL 3), 29 where patients were randomized to receiving conventional MAGIC (ECX/EOX) with or without panitumumab, three cycles pre-and three cycles postoperatively; however, the studies showed no difference in outcomes with the addition of panitumumab. Similarly with bevacizumab, there was a non-randomized phase II study 30  and nivolumab 33 -both drugs have shown response rates superior to chemotherapy alone. However, these were observational studies and need to be validated in well-conducted randomized trials.

| SUMMARY
Surgery remains the mainstay of treatment for non-metastatic esophageal cancer. The addition of neoadjuvant treatment is now clearly known to improve outcomes over surgery alone. However, what is unclear is whether neoadjuvant chemoradiation is superior to neoadjuvant chemotherapy alone. Several trials are ongoing which are likely to answer this question. Future trials should also evaluate the potential of immunotherapy to improve outcomes.

D I SCLOS U R E
Funding: No funding was received for this study.
Conflicts of Interest: Authors declare no conflicts of interest for this article.