The use of immunotherapy for esophageal cancer: a review of the current evidence and surgical implications

Introduction

Background

Esophageal cancer (EC) is the 8th most prevalent cancer and the 6th leading cause of cancer-related mortality in the United States (1). Despite a decreasing incidence of EC in the US, its incidence rates have escalated globally and are projected to rise further in the upcoming decades (2). In global hotspots such as East Asia and Africa, EC is currently predicted to claim more than 1 million lives each year (2).

Although EC is often discussed epidemiologically as a single entity, it comprises two main histologic subtypes: esophageal squamous cell carcinoma (eSCC) and esophageal adenocarcinoma (eAC). eSCC constitutes most EC cases worldwide and correlates with lifestyle factors such as tobacco and alcohol consumption, hot food intake, and consumption of nitrogenous compounds like processed meats and fish (3,4). Conversely, eAC is the predominant form of EC in Western countries and is primarily associated with obesity and gastroesophageal reflux disease (GERD) (3,5).

Rationale and knowledge gap

EC carries a grim prognosis, with an overall 5-year survival rate of 21%, plunging to 5.3% for advanced disease (6). This is largely due to the majority of patients presenting with locally advanced or metastatic disease (7). In 2012, the CROSS trial demonstrated a significant survival benefit in patients undergoing pre-operative chemoradiation compared to surgery alone for locally advanced, resectable EC (8). Since the original trial, subsequent studies have demonstrated that this survival benefit persists for at least 10 years (9). Additional efforts have been aimed at determining the optimal regimen, with multiple studies comparing the docetaxel-based fluorouracil + leucovorin + oxaliplatin + docetaxel (FLOT), anthracycline-based Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) and Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) chemoradiotherapy regimens. Emerging evidence from recent randomized trials, including Al-Batran et al. and ESOPEC, has demonstrated the favorable perioperative outcomes with neoadjuvant chemotherapy alone (i.e., FLOT regimen) for eAC, with superior overall survival (OS) compared to neoadjuvant chemoradiation of the CROSS regimen (10,11). Additionally, preliminary results from the European Neo-AEGIS trial have suggested that peri-operative chemotherapy may be non-inferior to chemoradiation regimens, such as CROSS (12). More recently, immunotherapy has been increasingly used and has shown promising results in various malignancies including EC (13-15).

Objective

There is increasing interest in developing novel systemic therapy modalities for patients with EC, with immunotherapy emerging as a promising avenue. There have been prior discussions regarding the role of immunotherapy for EC, however, they have not discussed its implication with regard to esophageal surgery and surgical outcomes (16-19). This review aims to provide an overview of the current state of immunotherapy in EC treatment, focusing on its surgical implications.

Mechanisms of action of immunotherapy

Immunotherapy is now considered the fourth pillar of cancer management alongside chemotherapy, radiation, and surgical resection (20). The body naturally has immunologic defense mechanisms that can detect malignant cells and signal them for destruction. Therefore, pre-cancerous cells need to develop necessary mutations to conceal themselves from the immune system before they progress into cancer. Immunotherapy focuses on therapeutic modalities that enhance the patient’s antitumor immune response. There are five major types of immunotherapies: immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell transfer (ACT), cytokine therapies, and viro-immunotherapy (21). In the treatment of EC, significant progress has been made in the realm of ICIs, cancer vaccines and ACT.

ICIs

Immune checkpoint proteins are molecules found on the surface of T- and B-cells that downregulate immune response and promote self-tolerance (22). These molecules, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1), are often overexpressed in cancer cells (23). This overexpression of immune checkpoints leads to a localized suppression of T-cell activity, which cancer cells utilize to grow and metastasize (24). Currently, the U.S. Food and Drug Administration (FDA) has approved two ICIs, nivolumab and pembrolizumab, for use in the treatment of EC.

Nivolumab

The use of nivolumab in EC was studied in the 2019 ATTRACTION-3 trial, where patients with unresectable advanced, recurrent, or metastatic eSCC who had previously undergone chemotherapy were randomized to either receive nivolumab or additional rounds of chemotherapy. In that study, nivolumab was shown to improve OS (10.5 vs. 8.0 months) with a favorable safety profile (25). These results have led to the FDA approving nivolumab as a second-line treatment for patients with unresectable or metastatic EC (26).

With the publication of Checkmate 577 in 2021, nivolumab has become a core component of EC therapy. In this global, randomized control trial, adults who had complete (R0) surgical resection with residual disease (≥ ypT1 and/or ≥ ypN1) after neoadjuvant chemoradiation were assigned to an immunotherapy group with nivolumab treatment or placebo with a primary endpoint of disease-free survival (27). Results showed that median disease-free survival was significantly improved in the nivolumab group compared to placebo (22.4 vs. 11.0 months) (27). Interestingly, benefit seemed to be independent of PD-L1 expression and actually had a greater survival benefit in eSCC than eAC (27). A subsequent study by the same team demonstrated that nivolumab was relatively well tolerated by patients without significant side effects or negative impact on quality of life (13). Based on the results of the CheckMate 577 study, the FDA approved nivolumab for adjuvant treatment in patients with completely resected EC who had residual disease following neoadjuvant chemotherapy (28).

Spurred by these results, the subsequent CheckMate 648 trial was conducted to investigate the use of nivolumab as a potential first-line treatment for EC. In this study, 970 patients with unresectable, advanced, recurrent or metastatic eSCC were randomized to receive nivolumab + chemotherapy, nivolumab + ipilimumab, or traditional chemotherapy to investigate differences in OS. The study demonstrated that both nivolumab + chemotherapy and nivolumab + ipilimumab groups demonstrated increased OS in the overall population compared to chemotherapy alone (13.2 vs. 12.7 vs. 10.7 months) (29). Based on these results, the FDA approved the use of nivolumab in combination with either chemotherapy or ipilimumab for the first-line treatment of advanced or metastatic eSCC (30).

Pembrolizumab

Pembrolizumab, another PD-1 inhibitor, has also been studied. In the phase II KEYNOTE-180 study, researchers studied pembrolizumab as a treatment option for patients with metastatic disease who had received two or more previous therapies. Overall, there was a response rate of 10%, with higher response rates noted in eSCC (31). The follow-up phase III KEYNOTE-181 trial then compared it to chemotherapy for patients with advanced, metastatic disease who had progressed on previous therapy. After 16 months, median survival was noted to be comparable in both groups, with a significantly decreased treatment-related adverse events, in the immunotherapy group (32). Of note, in a subgroup analysis of patients with high PD-L1 expression [combined positive score (CPS) >10], survival was substantially higher in the immunotherapy group (43% vs. 20%) (32). Based on these results, pembrolizumab has received FDA approval as a second line agent for patients with eSCC expressing PD-L1 (CPS >10) (26).

Similar to the CheckMate 648 trial conducted using nivolumab, the KEYNOTE-590 trial was conducted to investigate pembrolizumab + chemotherapy vs. placebo + chemotherapy in patients with previously untreated, locally advanced or metastatic EC that is not amenable to surgical resection or definitive chemoradiation. The results demonstrated that the pembrolizumab group has prolonged OS (6.3 vs. 5.8 months) when compared to placebo, with a more noticeable effect in patients with high PD-L1 expression (CPS >10) (7.5 vs. 5.5 months) (33). The FDA subsequently approved pembrolizumab in combination with chemotherapy for patients with locally advanced or metastatic EC (26).

The FDA-approved immunotherapies have quickly integrated into the National Comprehensive Cancer Network (NCCN) guidelines and are outlined in Table 1.

Neo-adjuvant immunotherapy

Attention has recently turned towards using immunotherapy in addition to traditional chemoradiotherapy (nCRT) in the neoadjuvant setting. The PALACE-1 trial investigated the utilization of pembrolizumab combined with chemotherapy in the treatment of eSCC and found a pathologic complete response (pCR) rate of 55.6% (34). A similar trial, PEN-ICE, noted a pCR of 46.2% (35). Promising results have been shown with sintilimab in the ESONICT-1 trial, which showed a major pathologic response (MPR) rate of 52.2% and pCR rate of 21.7% in patients with eSCC (36). Spurred by these results, the ESONICT-2 trial showed a similar MPR of 70% and pCR of 16.7% with neoadjuvant toripalimab plus chemotherapy (37). High rates of MPR and pCR in neoadjuvant therapy have been associated with significantly improved outcomes (38). A study by Wong et al. using data from the National Cancer Database (NCDB) was able to show that patients undergoing immunotherapy plus nCRT had increased OS compared to nCRT alone (median OS: 69.1 vs. 56.3 months; 3-year OS of 65.6% vs. 55.0%) (39). On the other hand, in the PERFECT trial, the use of atezolizumab as part of a neo-adjuvant regimen was not associated with improvement in OS compared to chemoradiation alone (40). While studies on the use of neoadjuvant immunotherapy show promising outcomes, those results need to be validated in future long-term studies before such regimens can be integrated into the current practice guidelines (35,41,42).

Implications of immunotherapy on surgical outcomes

Several studies have investigated the implications of receiving neoadjuvant immunotherapy on surgical outcomes (19,43-47). Most of these neoadjuvant trials focused on safety, feasibility, and pathological outcomes, with common end points being MPR and R0 resection. In a pooled study, the completion rate of neoadjuvant therapy followed by surgery ranged from 49% to 100%, with key factors for early failure being treatment-related adverse events, disease progression or patient withdrawal (19). Of those that complete therapy, roughly 26.9% reported adverse events, with a pooled rate of MPR and pCR being 48.9% and 31.4%, respectively (43).

Traditionally, surgical resection is performed 4–6 weeks after completion of neoadjuvant therapy, to optimize pathologic reseponse as well as patients’ short- and long-term outcomes (48,49). There have also been several studies suggesting that a prolonged interval of 6–12 weeks might improve histological outcomes (50,51). However, the NeoRes II trial suggests that a prolonged interval to surgery following nCRT did not demonstrate significant improvement in pCR rate while being associated with a significant decrease in OS (14.2 vs. 26.5 months) (52). In the SCALE-1 trial and Xu et al., surgical resection was performed 4–6 weeks after completion of neoadjuvant immunochemoradiation (44,45). In both studies, the incorporation of neoadjuvant immunotherapy agents did not seem to affect the operative/perioperative outcomes.

Cheng et al. conducted a retrospective cohort study comparing neoadjuvant immunochemotherapy using pembrolizumab, tislelizumab, camrelizumab, sintilimab, or toripalimab to nCRT (46). They were unable to detect any difference in pathologic characteristics such as staging, rates of lympho-vascular invasions or MPR/pCR (46). Interestingly, they did note a statistically significant decrease in adverse operative outcomes, including decreased blood loss, operative time, and perioperative complication rates in the immunotherapy group (46). They attributed these findings to decreased adhesions and tissue edema secondary to a lack of radiation in the immunotherapy group. A similar study conducted by Wu and colleagues demonstrated that patients who received neoadjuvant immunotherapy regimens with camrelizumab, pembrolizumab, or sintilimab have a similar rate of perioperative complications and sustained a higher rate of MPR when compared with nCRT (53).

Reviewing data from the NCDB, immunotherapy did not appear to increase time to surgery, length of hospital stay, or rates of unplanned readmission (39). Data does suggest an association with increased lymph node harvest (17 vs. 15) and N-stage downstaging (49.7% vs. 40.2%) in patients undergoing immunotherapy (39). Researchers were ultimately able to conclude that, in this patient population, neoadjuvant immunotherapy was associated with an increase in long-term OS over 5 years (39). Once patients survive the first 5 years, recurrence is considered rare (54).

A phase I/II retrospective study was conducted by Sihag et al. at Memorial Sloan Kettering to investigate the safety of a durvalumab-based neoadjuvant regimen for EC (47). In terms of safety, they did not detect any difference in rates of major cardiopulmonary complications, anastomotic leak, or 30-/90-day mortality (47). Immunotherapy did not appear to affect the interval time to surgery nor the feasibility of minimally invasive approaches. At the same time, the rate of immune-related adverse events also appeared low, with only one patient requiring withdrawal due to hypersensitivity (47). Unlike Cheng et al.’s study, neither Sihag et al. nor Wu et al were able to demonstrate a statistical difference in operative blood loss or length of hospital stay (46,47,53). While these results may be promising, generalizability is limited by the relatively low sample sizes (<50 patients) and differences in surgeons’ experience and technique. A summary of the major immunotherapy trials for EC is outlined in Table 2.

Novel immunotherapeutic agents

In addition to those advancements in utilizing ICIs in different clinical settings, promising prospects are also present in the development of novel ICIs. The checkpoint inhibitor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) was found to be highly expressed in certain cancers, including EC, and is associated with worse outcomes (55). Novel inhibitors, including domvanalimab, have already been developed to target these receptors. For example, the ongoing STAR-221 trial aims to investigate the utility of these new inhibitors compared to nivolumab in the treatment of treatment-naïve, locally advanced, unresectable eAC (56).

Cancer vaccines

Traditionally, vaccines have been viewed as prophylactic agents that are administered to healthy patients to prevent disease. Recently, there has been a significant push towards the development of therapeutic vaccines, which are given to patients with pre-existing disease to promote a stronger immune response (57). Currently, the FDA has approved three different cancer vaccines: the Bacillus Calmette-Guerin vaccine for bladder cancer, Sipuleucel-T for metastatic prostate cancer, and Talimogene Laherparepvec for metastatic melanoma (58).

In the treatment of EC, two potential targets, New York esophageal squamous cell carcinoma 1 (NY-ESO-1) and melanoma-associated antigen (MAGE-A), have been identified as tumor-specific biomarkers and possible targets for molecular therapy (23,59-61). Kageyama et al. was able to demonstrate in a phase I clinical trial that an NY-ESO-1 based vaccine could be safe and promote an immune response in patients with metastatic EC, with higher doses promoting a stronger response (60). While CD4⁺ and CD8⁺ responses were seen in most patients, disease progression was eventually observed (60). Similar results were demonstrated with other agents such as Montanide ISA-51 and Pacibanil OK-432 (62).

A study conducted by Kono et al. suggests that a multi-peptide vaccine could be well-tolerated and help control disease in patients with advanced eSCC (63). In their sample of 10 patients, they were able to achieve temporary disease control in half of the patients, with a couple of patients developing complete response in metastatic lesions for several months (63). Similarly, a study using cancer vaccines in patients with metastatic eSCC demonstrated stable disease in 5 out of 9 patients, although complete/partial response was not observed (64). Promising results have also been shown with adjuvant vaccine therapy, with one phase II study demonstrating therapy in patients with resected eSCC showing improved cancer-specific survival (65).

Despite these findings, a phase II study was unable to detect a difference between NY-ESO-1 vaccine-treated patients who subsequently underwent nCRT and surgical resection vs. unvaccinated controls (66). It appears that, although short-term immune responses are generated, long-term effects and tumor immunosuppressive mechanisms limit vaccination effectiveness (67). Even with setbacks, new immunotherapy mechanisms such as pulse vaccinations and multi-target vaccination regimens are still being developed to overcome such shortcomings and offer promising results (66).

ACT

ACT involves the utilization of a patient’s immune cells to target and eliminate cancer cells (68). Two examples of ACT therapy include chimeric antigen receptor therapy (CAR-T) and T cell receptor therapy (TCR-T). Traditionally, ACT has been used in the treatment of hematologic cancers such as leukemia, lymphomas, and multiple myeloma, with multiple FDA-approved regimens (69-72). Fueled by this success, numerous ongoing studies aim to test the utility of CAR-T and additional ACT methods on solid tumors, including EC. Pre-clinical studies have identified numerous potential targets for ACT therapy for the treatment of EC. This includes the embryologic NY-ESO-1, which has previously been studied in the development of cancer vaccines, as well as ACT treatment of other solid tumors such as synovial sarcoma and melanoma (59,73,74). There are currently several ongoing phase I/II trials testing the efficacy of NY-ESO-1-based ACT, including NCT03638206 and NCT03638206, for the treatment of EC. Additional therapeutic strategies targeting other proteins including human epidermal growth factor receptor 2 (HER-2), epithelial cell adhesion molecule (EpCAM), and Mucin short variant S1 (MUC-1), have shown promising in vitro results as well and are currently being investigated in early phase I trials (75).

Strengths and limitations

Fortunately, while discussing EC, there is a strong body of literature to draw from. Given its global presence, there is ongoing discussion in multiple different patient populations and countries, notably in East Asia and the United States. In this study, we reviewed multiple recent pivotal trials which have contributed significantly to the integration of immunotherapy in clinical practice, as well as a discussion regarding emerging therapeutic agents. With that said, this analysis does have some limitations. First, the studies that review outcomes regarding neoadjuvant chemoimmunotherapy vs. chemoradiation vs. chemotherapy are often retrospective, which makes them vulnerable to selection bias (46,47,53). Additionally, many of the studies discussed are subject to subgroup variability. For example, multiple studies have noted that patients with high levels of PD-L1 receptors have improved outcomes regarding immunotherapy (26,32,33). Similarly, immunotherapy appears to have more favorable outcomes with eSCC compared to eAC (35-40). It is thought that this may be secondary to different tumor microenvironments with increased infiltration of CD8⁺/CD45RO⁺ cells and increased presence of lymphoid structures such as lymphoid tissue in eSCC (76,77). On the other hand, eAC tumors often have lower levels of CD8⁺ T cells and increased immune suppressive cell populations (78). The presence of such differences makes the generalizability of such discussions difficult.

Conclusions

Immunotherapy has emerged as a promising modality in the treatment of EC, offering new hope for patients. ICIs such as nivolumab and pembrolizumab have demonstrated improved outcomes in the neoadjuvant and adjuvant treatment of EC as well as cases of metastatic disease, prolonging survival. The success of these agents has led to their integration into NCCN guidelines. Beyond ICIs, ongoing research into cancer vaccines and ACT holds promise for expanding treatment options, with promising early preclinical trials.

The integration of immunotherapy into the multidisciplinary management of EC presents a significant opportunity for surgeons. Multiple studies have demonstrated an increase in pathologic response. At the same time, preliminary data suggest that inclusion of immunotherapy does not significantly impact surgical parameters such as leak rate and other post-operative complications. Future trials are essential to further refine these treatment strategies, expand their indications and improve outcomes for patients with this challenging disease.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-33/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-33/coif). M.K.K. serves as an unpaid editorial board member of Current Challenges in Thoracic Surgery from March 2025 to February 2027. 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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