An update on developments in curative treatment for locally advanced esophageal cancer: a narrative review

Introduction

The overall 5-year survival of esophageal cancer remains poor at approximately 20%. However, in patients with locally advanced esophageal cancer (i.e., cT1-4N0-3M0), a 5-year survival rate of 40–50% can be achieved through the combination of neoadjuvant chemo(radio)therapy and resection by esophagectomy (1). Significant progress in the treatment of esophageal cancer has been made over the past several decades, driven by the implementation of multimodality treatment, centralization of specialized care, the growing use of minimally invasive surgical techniques, and the adoption of enhanced recovery after surgery (ERAS) protocols. Despite these advancements, an international benchmarking study revealed that morbidity rates following esophagectomy remain high, with approximately 60% of patients experiencing postoperative complications, even in high-volume centers (2). These data indicate that there is still room for improvement regarding both long-term survival and perioperative surgical care in the treatment of esophageal cancer.

Although extensive research has been performed and multiple reviews are already available on this topic (1,3,4), several important trials have been published in the most recent years. Hence, an updated comprehensive review is necessary to discusses and place these studies into broader perspective.

This narrative review aims to provide an update on the current state and developments concerning various key aspects of curatively intended treatment for patients with locally advanced esophageal cancer. We present this article in accordance with the Narrative Review reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-3/rc).

Methods

For this narrative review, literature searches on PubMed/EMBASE and Scopus were performed until 27^th April 2025 with search terms including esophagectomy, neoadjuvant or perioperative therapy, and perioperative care in the context of locally advanced esophageal cancer. Case reports were excluded. Meta-analyses, randomized controlled trials, and cohort studies were eligible for inclusion and included based on quality and relevance, as judged by the authors. Only articles in English writing were included. Due to the nature of this article, no institutional review board approval was necessary. The search strategy is detailed in Table 1.

Multimodality treatment

In most centers, strategies that combine neoadjuvant or perioperative therapy with surgical resection have become standard for managing locally advanced esophageal and gastroesophageal junction (GEJ) cancers, as they offer significant survival benefits over surgery alone. The CROSS trial still represents an important study, demonstrating a median overall survival of 49.4 months for esophageal cancer patients treated by neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy as compared to 24.0 months for patients undergoing surgery alone, which translates to 5-year survival rates of 47% in the nCRT group vs. 33% in the surgery-only cohort (5). These findings may partially be attributed to the remarkably higher complete resection (R0) rate achieved in the nCRT compared to the surgery-alone group (92% vs. 67%), along with an overall pathological complete response rate of 29% (i.e., 49% in squamous cell carcinomas and 23% in adenocarcinomas). Nonetheless, the survival outcomes of the CROSS trial were largely reproduced in other centers and gave rationale for wide implementation of nCRT according to the CROSS regimen (i.e., 5 courses of carboplatin and paclitaxel, combined with 41.4 Gy of concurrent radiotherapy). Over the recent years, however, several important studies have challenged the superiority of nCRT over neoadjuvant chemotherapy (nCT) or perioperative chemotherapy (pCT).

For esophageal squamous cell carcinoma, the Japanese landmark NExT trial was published in 2024 and compared 3 arms of neoadjuvant therapy: triplet nCT (3 courses of docetaxel, cisplatin, fluorouracil) versus doublet nCT (2 courses of cisplatin and fluorouracil) versus nCRT (2 courses of cisplatin and fluorouracil combined with 41.4 Gy) (6). This trial concluded that triplet nCT achieves superior overall 3-year survival as compared to doublet nCT (i.e., 72.1% vs. 62.6%), while the overall survival difference between nCRT and doublet nCT did not reach statistical significance. Although the authors concluded that triplet nCT holds to potential to become the standard of care for esophageal squamous cell carcinomas, it should be noted that triplet nCT was associated with a substantially higher incidence of febrile neutropenia (16%) than doublet nCT (2%) or nCRT (5%) in the NExT trial.

For adenocarcinomas of the esophagus and gastro-esophageal junction, which are predominant in Western countries and show less response to nCRT than squamous cell carcinomas, the discussion on the optimal multimodality treatment is also ongoing. The Neo-AEGIS trial was designed to compare nCRT according to the CROSS regimen versus pCT in the form of the MAGIC regimen before 2018 and the FLOT regimen thereafter, in patients with adenocarcinoma of the esophagus or gastro-esophageal junction (7). The trial was prematurely terminated due to recruitment issues, and thus its findings remain inconclusive. The preliminary data suggested that survival is comparable between groups, despite favorable pathological response rates in the nCRT group. Since then, the randomized controlled FLOT-4 and ESOPEC trials have generated more evidence regarding the benefits of FLOT for esophageal and gastro-esophageal junction adenocarcinoma. In the FLOT-4 trial that randomized patients with gastric (44%) or gastro-esophageal junction (56%) adenocarcinoma, the MAGIC regimen (3 preoperative and 3 postoperative courses of epirubicin 50 mg/m² on day 1, cisplatin 60 mg/m² on day 1, and fluorouracil 200 mg/m² as continuous intravenous infusion on days 1 to 21) was compared to the FLOT regimen (4 preoperative courses and 4 postoperative courses, with each 2-week cycle of consisting of docetaxel 50 mg/m² on day 1, oxaliplatin 85 mg/m² on day 1, leucovorin 200 mg/m² on day 1, and 5-FU 2,600 mg/m² as 24-h infusion on day 1) (8). The FLOT regimen was superior in terms of survival, demonstrating a median overall survival of 50 months and a 5-year survival of 45%, as compared to 35 months and 36% in the MAGIC group. The very recently published multicenter ESOPEC trial randomized 438 patients with esophageal adenocarcinoma to nCRT according to CROSS versus pCT according to FLOT in 25 German centers over a 4-year inclusion period (9). A radical resection (i.e., R0) was achieved in a high proportion of patients in both groups (94% with FLOT and 95% with CROSS). The FLOT group performed substantially better than the CROSS group regarding 3-year overall survival (57.4% vs. 50.7%) and 5-year overall survival (50.6% vs. 38.7%). These findings are promising, yet several remarks should be made. First, adherence to pCT remains a challenge, as only 53% of patients completed their postoperative FLOT cycles. Most importantly, however, the chemoradiotherapy group performed relatively poor in comparison to previous studies that generally found overall 5-year survival rates >40%. This might be explained by the relatively low pathological complete response rate of only 16% following chemoradiotherapy in the ESOPEC trial, as compared to 23% in the adenocarcinoma subgroup of the CROSS trial. Although the ESOPEC researchers suggested that the inclusion of relatively more advanced tumors in their cohort may be responsible for these findings, the disappointing outcomes in the chemoradiotherapy group remain quite remarkable. Hence, while the overall 5-year survival of 50% in the FLOT group seems very promising, future real-world studies are needed to confirm the generalizability of the ESOPEC results.

Immunotherapy is another form of systemic therapy that has gained an increasing role in oncology. For resectable esophageal cancer in particular, recent evidence from the CheckMate 577 trial showed that adjuvant nivolumab in patients with residual disease after nCRT and surgery is associated with increased disease-free survival (10). Several trials are exploring the neoadjuvant and perioperative use of immunotherapy (11). More evidence on this topic is expected in the near future.

In summary, nCRT has emerged as the standard for esophageal cancer in many centers worldwide. However, several recent trials have suggested that better alternatives exist. For squamous cell carcinomas, triplet nCT seems to achieve superior overall survival at the cost of a substantially higher incidence of febrile neutropenia. For esophageal and gastro-esophageal junction adenocarcinomas, current evidence suggests that pCT according to the FLOT regimen achieves significantly better survival than nCRT and could become the standard of care if data from randomized controlled trials can be reproduced in the real-world setting. Furthermore, the role of immunotherapy might increase in the context of esophageal cancer.

Surgical techniques

Surgical radical resection by means of esophagectomy remains the mainstay of curatively intended treatment for locally advanced esophageal cancer. Open transthoracic esophagectomy has traditionally been considered the gold standard for optimal oncological efficacy, as an extended mediastinal lymphadenectomy can be performed in contrast to the transhiatal approach. However, with the rise of laparo- and thoracoscopic techniques, minimally invasive esophagectomy (MIE) was first reported in 1992 and has since then been widely implemented (12). A recent international survey amongst surgeons showed that MIE was considered to be the preferred technique by 53% of the respondents in 2022, as compared to merely 14% of the respondents in 2007 (13,14). Compared to open esophagectomy, MIE was previously shown to be oncologically safe while being superior in terms of blood loss, pulmonary complications, length of hospital stay, and quality of life in the randomized controlled TIME trial (15,16). Several large (national) studies have since then been performed, which suggested that MIE was associated with increased pulmonary complications and re-intervention rates (17-21). The learning curve of MIE, which has been suggested to be around 119 cases (22), has been proposed as the explanation for the discrepancy between findings from the randomized controlled trial TIME trial and real-world data. With growing experience and continued centralization, the outcomes of MIE are expected to improve.

The most recent surgical advancement is robotic assistance. Benefits of surgical robots include improved three-dimension view, greater dexterity, and tremor filtration. Furthermore, the Da Vinci Xi system adds a fourth robotic arm, which can be operated by the console surgeon and thereby improve autonomy. Robot assisted minimally invasive esophagectomy (RAMIE) was introduced in 2003 and has gained popularity over the last decades (14,23,24). The single-center randomized controlled ROBOT trial compared RAMIE to open esophagectomy primarily regarding postoperative complications, and largely reproduced the findings of the TIME trial that favored minimally invasive surgery (25,26). The key question currently is how RAMIE compares to conventional MIE. Surgeons particularly experience the benefits of robotic surgery during challenging parts of complex procedures, such as the upper mediastinal lymph node dissection in esophagectomy. In the REVATE trial, RAMIE was compared to conventional MIE in terms of mediastinal lymph node yield and recurrent laryngeal nerve (RLN) injury, showing a higher number of mediastinal lymph nodes retrieved while significantly reducing the incidence of RLN palsies (27). Although further randomized studies such as the ROBOT-2 trial are still awaited (28), several large cohort studies suggested that RAMIE and MIE perform comparable and some studies suggested that RAMIE was associated with high mediastinal lymph node yield and possibly less pulmonary complications than MIE (25,26,29-31). A recent meta-analysis confirmed that RAMIE is a safe alternative to MIE and also suggested potential benefits of RAMIE in terms of lymph node yield that might translate to increased disease-free survival especially in squamous cell carcinoma (32). These findings should be further investigated in high-quality studies, ideally in a randomized controlled multicenter setting to achieve optimal generalizability. At this moment, available real-world international multicenter data from the Upper GI International Robotic Association (UGIRA) show that the outcomes of RAMIE are promising on a global scale, with textbook outcome being achieved in 49% of Ivor-Lewis procedures and in 61% of McKeown procedures in the most recent years (33,34). Although these data are encouraging, surgeons might be hesitant to implement RAMIE due to the learning curve and high costs of robotic surgery that exist in combination with a lack of overwhelming high-quality evidence for superiority of RAMIE over conventional MIE from randomized trials (35,36). The costs of robotic surgery are expected to decrease as more robotic systems become available. Furthermore, as postoperative complications are expensive, future improvement of postoperative outcomes can reduce the overall costs of RAMIE (37,38). Moreover, anticipated developments such as augmented reality require a computer between the patient and the surgeon’s hands, which may drive wider adoption of robotic surgery in the near future.

Overall, MIE and RAMIE are nowadays the preferred techniques for more than half of esophageal surgeons worldwide. Wider implementation of these techniques is anticipated as the evidence for minimally invasive surgery continues to grow. Although the high costs of robotic surgery remain a major limitation, this is expected to be less of an issue in the future with the increased availability of robotic system and a likely reduction in costs.

ERAS

ERAS is a multidisciplinary approach to the surgical patient, aiming to shorten hospitalization by improving patient outcomes through standardized perioperative care protocols. ERAS protocols have been published for many procedures, including esophagectomy for cancer. Key elements of ERAS include prehabilitation (i.e., physical and nutritional), minimally invasive surgery (i.e., MIE or RAMIE in the context of esophagectomy), effective pain management, minimization of drains and other lines, and early postoperative mobilization with clear goals regarding the length of hospital stay. ERAS protocols for esophagectomy were first employed and described in Seattle, showing significant reduction in length of hospital stay from a median of 17 days to 7 days (39). Since then, many esophageal expert centers adopted the ERAS principles and numerous studies have been performed to support their safety and merits. In 2019, the ERAS Society published an evidence-based guideline to be used for patients undergoing esophagectomy (40). Several recent systematic meta-analyses consistently concluded that ERAS protocols are effective in reducing postoperative (pulmonary) complications and length of hospital stay (41-43). Nonetheless, certain aspects of the perioperative care pathway remain subjects of ongoing debate. This section explores some of these issues.

Prehabilitation

Patient fitness is generally considered to be an important predictor for outcomes after surgery and, as such, preoperative efforts are made to optimize the physical condition in the context of ERAS. In esophagectomy in particular, pulmonary complications occur in up to 40% and therefore represent an important reason for prolonged hospitalization. The introduction of minimally invasive techniques has reduced the incidence of pulmonary complications, but achieving a further reduction has been challenging. Prehabilitation has been introduced as a key element of ERAS in this context, which dictates narrow collaboration with physiotherapists and dietetic professionals to monitor and improve the patients’ fitness prior to surgery (44). Previous research showed that there is a clear association between preoperative deterioration of physical fitness and postoperative pulmonary complications, which suggests that physical fitness could be a modifiable risk factor to improve postoperative outcomes (45,46). In line with evidence from cardiac and abdominal surgery, extensive (randomized) research has been performed to evaluate the effect of preoperative inspiratory muscle training on postoperative pulmonary complications after esophagectomy. Although inspiratory muscle training did improve inspiratory muscle strength, unfortunately no effect on the incidence of pulmonary complications after esophagectomy was found (47-50). The conclusions of other studies that investigated prehabilitation programs for patients undergoing esophagectomy varied in a recent systematic review with meta-analyses, with positive effects on pulmonary complications and length of hospital stay being reported in observational studies, while randomized controlled studies could not unequivocally confirm these findings (51). In line with this, a recent Cochrane review on the effects of prehabilitation in colorectal surgery patients showed that physical fitness may be improved, although no solid effect on postoperative outcomes was identified (52,53). Nonetheless, prehabilitation is nowadays a standard part of ERAS protocols for patients undergoing esophagectomy in many centers. Future studies should evaluate which parts of prehabilitation programs can be optimized in order to further reduce postoperative complications and accelerate recovery.

Pain management

Pain management is an integral part of ERAS protocols for esophagectomy, since ineffective analgesia can lead to inadequate ventilation and pulmonary complications. For a long time, thoracic epidural analgesia has been considered the gold standard for pain management in this setting, offering superior pain relief and fewer pulmonary complications compared to systemic opioids following open esophagectomy in relatively old studies (54-56). With the rise of (RA)MIE, however, the optimal analgesic strategy has been questioned. Paravertebral analgesia is widely used in lung surgery and potentially achieves similar pain relieve while avoiding epidural-related side-effect such as hypotension, which could be beneficial to enhance recovery following esophageal surgery. The recent multicenter PEPMEN-trial randomized patients undergoing (RA)MIE between thoracic epidural analgesia versus paravertebral analgesia with opioid by patient controlled analgesia (PCA), primarily comparing the quality of recovery on postoperative day 3 as evaluated by the Quality-of-Recovery-40 (QoR-40) questionnaire (57). This trial concluded that paravertebral analgesia was not superior to thoracic epidural analgesia, but suggests that paravertebral analgesia can be used in clinical practice (58). These findings were reproduced by a large observational cohort study (59). Based on these studies, both thoracic epidural and paravertebral analgesia can be applied in the context of ERAS protocols for (RA)MIE.

Nutritional aspects

Esophageal cancer patients are at substantial risk for malnutrition, due to cancer cachexia, potential mechanical obstruction of the upper gastro-intestinal tract, and side-effects of neoadjuvant therapy (60). The preoperative nutritional status of esophageal cancer patients is associated with the risk of postoperative complications, warranting identification and monitoring of these malnourished patients (61). As such, nutritional intervention in malnourished esophageal cancer patients is an integral part of ERAS. Although a recent Cochrane review was unable to identify a clear effect of preoperative nutritional intervention on postoperative outcomes in a variety of patients undergoing gastro-intestinal surgery, another meta-analysis specifically on cancer patients receiving nutritional intervention during nCRT showed a significant reduction in postoperative length of hospital stay (62,63). Furthermore, a meta-analysis specifically on patients undergoing esophagectomy showed that nutritional prehabilitation was significantly associated with less overall postoperative morbidity, although no significant reduction in length of hospital stay could be found (64). To adequately evaluate patients who are at risk of malnutrition during the preoperative phase, early involvement of a dietetic professional is essential in the multidisciplinary approach of esophageal cancer patients. Depending on severity of the clinical situation, nutritional intervention can be in the form of personal dietary advice, oral supplements, enteral feeding (i.e., by naso-enteric or jejunostomy tube) or parenteral feeding. In the recent years, enteral immunonutrition has gained interest aiming to improve immunity and thereby the inflammatory response in patients undergoing surgery. However, based on several recent meta-analyses, there is no evidence to support the routine use of enteral immunonutrition in patients undergoing esophagectomy (65-67).

The optimal postoperative feeding protocol remains a topic of debate for patients undergoing esophagectomy. Although immediate resumption of oral intake is part of most ERAS protocols, esophagectomy patients are at considerable risk of anastomotic leakage and aspiration. Some previous studies, including a randomized controlled trial, showed that immediate resumption of oral intake after esophagectomy is safe, although no clear benefits in terms of functional recovery or postoperative complications were found in comparison to patients who had enteral tube feeding until delayed resumption of oral intake (68,69). One meta-analysis did suggest that early resumption of oral feeding improves quality of life in patients undergoing esophagectomy, although the number and quality of included studies was limited (70). In contrast to these studies, however, another randomized controlled trial compared an early oral feeding group to a delayed oral feeding group (who received jejunostomy tube feeding) and found that the delayed group suffered less weight loss and resultant malnutrition following esophagectomy, while complication rates and length of hospital stay were similar between groups (71). Concerns regarding a potentially increased risk of anastomotic leakage when immediately resuming oral intake have not been definitively taken away, especially in case of a cervical anastomosis (72). These previous studies give space for believers of the merits of immediate resumption of oral intake, but lead many centers to opt for delayed oral intake following esophagectomy while providing nutritional support during the early postoperative phase. Enteral tube feeding is preferred over parenteral feeding, as line infections are avoided and gut functionality is preserved (60,73). While naso-enteric and jejunostomy tubes both seem effective in achieving nutritional aims, jejunostomy tubes are associated with less dislocations and possibly higher short-term quality of life, at the price of more infections and bowel obstruction due to torsions (74,75). In summary, current literature suggests that early resumption of oral intake after esophagectomy may be safe, although generalizability and clear benefits in terms of recovery and length of hospital stay have not been proven. For postoperative feeding support, both naso-enteric and jejunostomy tubes may be used depending on experience and preference of the team.

Discussion and future perspectives

There is still room for improvement in the treatment of locally advanced esophageal cancer. Although neoadjuvant and perioperative treatment options are improving, esophagectomy will remain the cornerstone of treatment in patients with resectable esophageal cancer and future studies should therefore focus on further reducing perioperative morbidity and mortality. (RA)MIE has decreased surgical complications, yet surgeons are constantly looking for better alternatives. A novel technique for esophagectomy has recently been introduced, which involves performing the mediastinal dissection through transcervical mediastinoscopic approach. This transcervical technique potentially reduces pulmonary complications that are associated with a transthoracic approach, while still offering adequate exposure for an extended mediastinal lymphadenectomy. Observational studies are promising, showing good short-term outcomes (76-78). A potential downside of this technique, however, is that it requires the construction of a cervical esophagogastric anastomosis. An intrathoracic anastomosis is currently the standard for mid- to distal esophageal tumors in many centers, as anastomotic leakage and RLN injury rates were previously found to be lower than for cervical anastomoses (79). Hence, high-level comparative studies comparing both short- and long-term outcomes of (RA)MIE through a transcervical versus a transthoracic approach are warranted to evaluate whether this novel technique deserves to be implemented widely.

Technological developments in the context of artificial intelligence (AI) may play an important role in further improving treatment for locally advanced esophageal cancer. As AI is especially useful in image analyses, it might help to boost the quality of clinical response assessment following neoadjuvant therapy. Furthermore, as surgical robots are increasingly implemented and place a computer system between the patient and the surgeon’s hands, an increasing number of surgical videos will be available to analyze. Recent studies showed the potential of AI in recognizing anatomic structures during RAMIE, which might lead to augmented-reality based surgical navigation modules in the future (80). However, challenges remain on how to adequately train algorithms in such a way that it is generalizable and can be used in other settings. A thorough understanding of AI-learning is essential to prevent erroneous use of algorithms in a clinical setting. More studies on AI-applications are expected in the near future.

Strengths and limitations

This review represents an overview of up-to-date literature and discusses key developments in the treatment of esophageal cancer. The narrative nature of this article can be a limitation, as the conclusions may be influenced by personal view of the data.

Conclusions

The standard treatment of locally advanced esophageal cancer involves neoadjuvant or perioperative chemo(radio)therapy in combination with planned esophagectomy. Recent studies have identified pCT according to the FLOT regimen as possibly the optimal choice for esophageal and gastro-esophageal junction adenocarcinomas. For squamous cell carcinomas, neoadjuvant triplet chemotherapy seems to achieve the highest overall survival rates at the cost of an increased incidence of febrile neutropenia. A minimally invasive technique, which includes MIE or RAMIE, provides benefits in terms of postoperative complications and recovery when compared to open esophagectomy. With the technical merits that surgical robots have to offer, more surgeons will implement RAMIE as their preferred technique in the upcoming years. In perioperative care, a multidisciplinary approach is warranted and the use of an ERAS protocol is advised to accelerate postoperative recovery and limit the length of hospitalization. Future developments include the implementation of transcervical MIE and the introduction of AI-based resources to improve treatment of locally advanced esophageal cancer.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-3/rc

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-3/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-3/coif). B.F.K. serves as an unpaid editorial board member of Annals of Esophagus from October 2024 to December 2026. J.P.R. and R.v.H. are proctors for Intuitive specifically for robotic esophagectomy and gastrectomy. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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