The evolving role of systemic therapy in locoregionally advanced esophageal cancer: a narrative review

Introduction

Background

Esophageal cancer is common worldwide and the sixth leading cause of cancer deaths (1). While the distributions of disease and histology vary by country, nationally reported survival rates are low at 10–30% at 5 years (2). The incidence of esophageal cancer is estimated to increase with an aging population and ongoing risk factors of obesity, smoking, and alcohol use (3). Squamous cell carcinoma (SCC) is the most common histologic subtype of esophageal cancer worldwide accounting for 87% of global disease burden. Esophageal adenocarcinoma (AC) accounts for 11% of esophageal cancers globally but is the predominant histology in North America and much of Western Europe. The incidence of AC is increasing, likely related to escalating rates of obesity and gastroesophageal reflux disease in both developed and developing countries (4). While historically diagnosed at late stages, there is now a trend towards earlier diagnosis due to endoscopic surveillance for Barrett’s disease, increasing access to diagnostic studies for evaluation of symptomatic disease, and incidental radiographic findings (5). In light of these trends, the optimization of treatment for locoregionally advanced disease is increasingly important.

The standard of care for patients with resectable, locally advanced gastroesophageal junction or esophageal cancer is neoadjuvant chemotherapy or chemoradiotherapy prior to resection (6). Neoadjuvant therapy aims to balance local and systemic treatment effects with treatment-related toxicities. Local tumor response to treatment may down-stage lesions to facilitate complete (R0) resection and clear both occult and known nodal disease. Moreover, major pathologic response (mPR) and complete pathologic response to therapy (pCR) have repeatedly been shown to be associated with improved survival (7,8).

Underscoring the importance of systemic therapy, the majority of disease recurrence after neoadjuvant treatment and R0 resection is distant (9,10). Additionally, every neoadjuvant therapy regimen has inherent toxicity. The significant deconditioning, weight loss, neutropenia, and other side effects of chemotherapy and radiation have the potential to increase the risks of surgical complications, including anastomotic leak and cardiopulmonary events (10). Severe side effects may preclude patients from surgical candidacy.

Rationale and knowledge gap

Unfortunately, rates of cure even after optimal guideline-concordant treatment regimen are low. This has spurred extensive work in targeted neoadjuvant therapy, as well as expanded the role of adjuvant therapy for esophageal cancer, where previously the standard of care was observation.

Objective

In this review, we review key trials and emerging data on chemotherapy, radiotherapy, immunotherapy, and targeted therapy treatment approaches based on histology and biomarker status. We present this article in accordance with the Narrative Review reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-11/rc).

Methods

Information sources and search strategy

We searched Ovid MEDLINE and Ovid EMBASE on October 22, 2024 using a variety of subject headings and keywords (Table 1), identifying our major topics. Searches were restricted to randomized controlled trials, human studies, and English language articles. Excluded publication types included case reports. Articles were reviewed by the authors for inclusion based on relevance to the review topic. This search was supplemented by targeted review of topics pertaining to major recent trials including trial protocols and conference abstracts. The search strategy is detailed in Table 1. An example search string can be found in Appendix 1.

Neoadjuvant chemoradiotherapy (nCRT)

The ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial laid the foundation for the treatment of locoregional esophageal cancer, defined as cT1b–cT2, N+; cT3–cT4a, Any N; or high risk T2,N0 lesions (9,11,12). This trial randomized 368 patients to nCRT plus surgery versus surgery alone. The treatment regimen included five cycles of carboplatin and paclitaxel with a concurrent radiation dose of 41.4 Gy in 23 fractions. Neoadjuvant treatment was completed by 95% of patients, with the most common serious side effects including leukopenia (6%), anorexia (5%), and fatigue (3%). The rate of anastomotic leak was 22% in the treatment arm and 30% with surgery alone.

The CROSS regimen demonstrated impressive efficacy for locoregional disease control. R0 resection was achieved in 92% of the intervention group, compared to 69% in surgery alone. A cPR was observed in 23% of patients with AC and in 49% of SCC (P=0.008). Fewer patients had residual nodal disease when treated with CROSS (31%) compared to those receiving surgery alone (75%, P<0.001). At five-year follow-up, the rate of locoregional progression was lower with CROSS (22% vs. 38%, P<0.001). Additionally, there was also a decrease in observed distant progression at 5 years [39% CROSS vs. 48% surgery alone, hazard ratio (HR) 0.63; 95% confidence interval (CI): 0.46–0.87; P=0.004], though the statistical significance of this effect did not persist at 10 years (HR 0.76; 95% CI: 0.52 to 1.13).

The CROSS trial showed a significant survival advantage with nCRT in both SCC and AC. Median overall survival was 48.6 months with the CROSS regimen vs. 24 months with surgery alone (HR 0.68, 95% CI: 0.53–0.88, P=0.003); 5-year overall survival was 47% with CROSS and 33% with surgery alone. The regimen was particularly effective for SCC: median overall survival for patients with SCC was 81.6 months in the nCRT group and 21.1 months with surgery alone (HR 0.48; 95% CI: 0.28–0.83). Median survival for patients with AC was 43.2 months with nCRT and 27.1 months with surgery alone (HR 0.73, 95% CI: 0.55–0.98). The CROSS regimen became the standard of care for neoadjuvant treatment of esophageal cancer in 2012 following publication of this trial.

Perioperative chemotherapy for AC

Perioperative chemotherapy for esophageal and gastroesophageal junction (GEJ) cancer was established with the MAGIC trial, as early studies showed only a modest survival benefit (13-15). The MAGIC trial found neoadjuvant epirubicin, cisplatin, and 5-FU (ECF) to lead to improved progression-free and overall survival than surgery alone in patients with locoregional gastric (74%) or esophageal and GEJ (26%) AC (16). Further trials investigated intensification of the chemotherapeutic regimen and addition of antiangiogenic therapy, finding no improvement in survival but an increase in complications (17-20). Following the publication of the CROSS trial in 2012, however, neoadjuvant chemotherapy for locoregional esophageal cancer fell out of favor.

A paradigm shift in perioperative chemotherapy occurred with the FLOT4-AIO trial, which showed the FLOT regimen (fluorouracil, leucovorin, oxaliplatin, docetaxel) to be both well-tolerated and produce comparable survival results to CROSS. FLOT4-AIO randomized 716 patients with gastric or GEJ AC to perioperative therapy with FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) or ECF/ECX (epirubicin, cisplatin, fluorouracil or capecitabine) and showed improved outcomes in the group receiving FLOT (10). Among the FLOT group, 90% completed all cycles of neoadjuvant treatment and 97% proceeded to surgery. Patients with GEJ AC accounted for 23% of the group, and 31% underwent Ivor-Lewis esophagectomy. An R0 resection was achieved by 85% of the FLOT group, and 15% had a pCR. The 30-day postoperative mortality was 3%. Median overall survival was 50 months in patients receiving FLOT compared to 35 months with ECF/ECX. Five-year overall survival was 45% with FLOT and 36% with ECF/ECX. Notably, 24% of patients in the FLOT4-AIO were over the age of 70 and experienced a treatment benefit upon stratified analysis, demonstrating feasibility in treating older adults. While better tolerated than ECF/ECX, 25% of patients treated with FLOT were hospitalized for toxicities in FLOT4-AIO. The most common grade 3 or 4 toxicities observed were neutropenia (51%), alopecia (28%), leukopenia (27%), and infections (18%).

FLOT4-AIO changed the standard neoadjuvant chemotherapeutic regimen for esophageal AC to FLOT, and challenged CROSS as the optimal neoadjuvant treatment modality.

Chemoradiotherapy vs. chemotherapy for AC (CROSS vs. FLOT)

The initial studies comparing neoadjuvant chemotherapy and chemoradiotherapy evaluated pre-FLOT chemotherapy regimens. These trials demonstrated higher rates of pCR with chemoradiotherapy with reduced rates of local recurrence, but consistently showed no difference in overall survival (21-24). These findings were recapitulated in a large propensity-matched analysis of the National Cancer Database (25). Retrospective studies comparing CROSS and FLOT neoadjuvant regimens in esophageal AC have reported better pathologic response with CROSS but similar overall survival (26-29). However, they highlight a greater incidence of post-operative respiratory failure with CROSS (13% vs. 3%, P<0.001) (26), and more post-operative pulmonary and cardiac complications overall (27). Several prospective studies were designed to compare the CROSS and FLOT regimens head-to-head. Neo-AEGIS and ESOPEC have been completed and are discussed below and presented in Table 2; the RACE (30) trial is ongoing.

Neo-AEGIS (31) randomized esophageal and GEJ AC patients to neoadjuvant therapy with chemotherapy (ECF/ECX initially, then FLOT after 2018) or chemoradiotherapy according to the CROSS regimen. After accruing 377 patients, the study was closed early in December 2020 due to futility and the effect of the COVID-19 pandemic. The study was underpowered to detect a difference in the primary outcome of overall survival, reporting comparable median overall survival of 48.0 months in the chemotherapy group and 49.2 months in the CROSS group. However, pathologic complete response was much more likely in the CROSS group (OR 0.33, 95% CI: 0.14–0.81), as was mPR (OR 0.21, 95% CI: 0.12–0.39) and R0 resection rate (OR 0.21, 95% CI: 0.08–0.53). While neutropenia, vomiting, and diarrhea were significantly increased with chemotherapy, there was a trend towards more acute respiratory distress syndrome (ARDS) with CROSS (4.3% vs. 0.6%; P=0.07). The rates of anastomotic leak were identical at 11%.

The recently reported ESOPEC (32) trial provides the current best quality randomized evidence for neoadjuvant CROSS vs. perioperative FLOT therapy for locally advanced esophageal AC. This study randomized 438 patients with resectable esophageal AC to CROSS vs. FLOT followed by surgery. Patients treated with induction chemotherapy alone were also given FLOT postoperatively. Of those treated, 93% proceeded to surgery in the FLOT group and 92% in CROSS; R0 resection rates were comparable at 94.3% and 95.0%. pCR was seen in 16.7% of the FLOT group and 10.1% of CROSS. Serious adverse events were observed in 47.3% of the FLOT group (most commonly neutropenia, leukopenia, and pneumonia) and 41.8% of CROSS (most commonly leukopenia and pneumonia). Post-operative adverse events were similarly distributed among the groups, with an anastomotic leak rate of 11.4% after FLOT and 13.8% after CROSS (Table 2).

Isolated locoregional progression was more common in patients treated with FLOT (7.7% vs. 4.1%), while isolated distal metastases were more common with CROSS (32.7% vs. 20.3%). Proportions of simultaneous locoregional and distant failure were similar. There was a marked improvement in median survival with FLOT at 66 months (95% CI: 36–not estimable) versus 37 months with CROSS (95% CI: 28–43). Three-year overall survival was 57.4% (95% CI: 50.1–64.0%) with FLOT vs. 50.7% (95% CI: 43.5–57.5%) with CROSS. The hazard ratio for overall survival was 0.70 (95% CI: 0.53–0.92, P=0.01) favoring FLOT, and 0.66 (95% CI: 0.51–0.85) favoring FLOT for progression-free survival. This effect was particularly pronounced among patients with Siewert type I disease (overall survival HR 0.48, 95% CI: 0.32–0.71; progression-free survival HR 0.54, 95% CI: 0.36–0.79).

In summary, the ESOPEC trial suggests that perioperative FLOT may be preferable to CROSS for patients with esophageal AC. The improved survival reported in this study likely reflects the importance of an intense systemic regimen in the treatment of patients with esophageal cancer due to their high risk of distant relapse. While informative and likely practice changing, ESOPEC should be interpreted with major caveats: pCR rates were lower than reported in prior studies potentially due to more advanced disease, and current standard-of-care adjuvant immunotherapy (33) was not used, as discussed subsequently in this review.

Sequential chemotherapy and chemoradiation for AC

Looking to maximize both local disease control with radiotherapy and systemic disease control with aggressive chemotherapy, several groups have implemented a sequential neoadjuvant treatment approach. A secondary analysis of a randomized trial comparing nCRT to induction chemotherapy followed by nCRT found that the subgroup of patients with well- or moderately-differentiated tumors had a survival advantage with the combined treatment strategy (5-year overall survival 74% vs. 50%, P=0.001) (34). A subsequent small randomized controlled trial was terminated early due to not finding adequate effect in pathologic response, but also found longer disease-free and overall survival in patients with well/moderately-differentiated tumors treated with induction chemotherapy (docetaxel, oxaliplatin, capecitabine) prior to chemoradiation and surgery (35). While no randomized controlled trial has demonstrated a definitive advantage to this treatment strategy, there is likely a subgroup that would stand to benefit.

Because early radiographic response to neoadjuvant therapy is predictive of treatment effect and survival (14), some groups have also attempted to tailor the neoadjuvant treatment regimen to patient response. The CALGB 80803 study randomized esophageal and GEJ AC patients to neoadjuvant oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel, then used interval positron emission tomography (PET) imaging to determine whether to cross over to the other chemotherapy during a subsequently planned course of chemoradiation (36). This study demonstrated pCR rates of 18–20% in the crossover group, and 40% in the FOLFOX-responder plus chemoradiation group. The median survival in the FOLFOX-responder group was not reached after median follow-up of 5.17 years. A follow-up retrospective of 35 patients with induction FOLFOX or FLOT followed by a tailored chemoradiation approach found an overall pCR rate of 31%, 39% among FOLFOX/FLOT-responders (37). While these studies demonstrate a potential advantage to combining chemotherapy with chemoradiation, the patients in these studies were largely not treated with the current optimal chemotherapy regimen (FLOT). No adequately powered study of FLOT non-responders crossing over to CROSS, another treatment regimen, has yet been performed.

Chemoradiotherapy vs. chemotherapy for SCC

The CROSS trial demonstrated a particularly strong effect of chemoradiotherapy in SCC, reporting a 23% improvement in survival at 10 years. Based on the results of the CROSS trial and other trials demonstrating survival advantage with chemoradiotherapy (38,39), nCRT is currently the standard of care for locoregional esophageal SCC in the United States. However, neoadjuvant chemotherapy has also been demonstrated to be effective and is commonly used in Asian countries (40,41). There is not yet definitive head-to-head data comparing nCRT to chemotherapy for SCC.

JCOG1109 compared neoadjuvant doublet chemotherapy (5-FU and cisplatin) vs. triplet chemotherapy (5-FU, cisplatin, docetaxel) vs. nCRT in esophageal SCC (42). Triplet chemotherapy was clearly superior to doublet. Comparing triplet chemotherapy to nCRT, overall survival trended towards better with triplet chemotherapy (HR 0.80, 95% CI: 0.59–1.10), though this comparison was not statistically significant. There was, however, a trend towards better survival in patients with tumors of the upper thoracic esophagus treated with nCRT. nCRT was associated with lower rates of locoregional recurrence, but higher distant recurrence when compared to triplet chemotherapy.

The CROSS trial did not include bulky tumors (by a size cutoff of 8 cm in length, 5 cm in width), and only included one patient with cT4 disease; as such, the benefit of the CROSS regimen in bulky tumors is not well described. CMISG1701 compared nCRT vs. paclitaxel and cisplatin for 264 patients with bulky SCC tumors (cT3–T4N0–1M0) prior to minimally invasive esophagectomy, finding no difference in overall or progression-free survival between the study groups. pCR was significantly higher with CRT (27.7% vs. 2.9%, P<0.001) (43). Yamasaki et al. conducted a study of T4b SCC comparing CRT with triplet chemotherapy, finding a trend towards better survival with CRT, particularly among patients who were able to undergo R0 resection (44).

Variations on nCRT have also been investigated in SCC. Gao et al. (39) compared the CROSS regimen to cisplatin/5-fluorouracil (PF) in combination with varying doses of radiotherapy: CROSS conferred survival benefit over the PF + 45 Gy radiation dose. Groups receiving higher doses of radiation therapy experienced more esophageal leaks.

In summary, while the CROSS regimen offers an impressive advantage for the treatment of locoregional esophageal SCC, there is a demonstrated need for optimization of systemic regimens to reduce the likelihood of distant recurrence in high-risk patients.

Adjuvant therapy—CheckMate 577

Even after optimal neoadjuvant therapy and R0 resection of esophageal cancer, the risk of recurrence remains above 50% (38). Patients with poor pathologic response to therapy and those with lymph node-positive disease are at increased risk of recurrence and cancer-related death (8). Until CheckMate 577, no adjuvant therapy was reliably demonstrated to be effective. CheckMate 577 (33) was a global randomized controlled trial evaluating the use of nivolumab, a checkpoint inhibitor, in patients with Stage II or III esophageal or GEJ squamous or AC. Patients were eligible for randomization if they had been treated with nCRT, experienced an R0 resection, and were found to have any evidence of residual disease (at least ypT1 or ypN1). Randomization was stratified according to tumor cell programmed death-ligand 1 (PD-L1) expression, lymph node status, and histologic type. The primary endpoint was disease-free survival assessed by cross-sectional imaging every 12 weeks for the first two years and at increasing intervals thereafter. A total of 794 patients in 29 countries were randomized, 71% of whom had AC. The treatment was well-tolerated, with 86% of the treatment group receiving at least 90% of the planned dosing regimen.

CheckMate 577 found that patients treated with nivolumab experienced a longer disease-free survival compared to those receiving placebo (22.4 vs. 11.0 months, respectively, HR for disease recurrence or death 0.69 (95% CI: 0.56–0.86, P<0.001). This advantage was found for both AC and squamous cell histologies, with a median disease-free survival improvement of 8.3 months for AC (HR 0.75, 95% CI: 0.59–0.96) and 18.7 months for SCC (HR 0.61, 95% CI: 0.42–0.88). Notably, patients with ypN1 or greater disease experienced a benefit from adjuvant nivolumab [median disease-free survival HR 0.67 (95% CI: 0.53–0.86)] while the survival benefit for patients with ypN0 disease did not reach statistical significance (HR 0.74, 95% CI: 0.51–1.06). The treatment effect for ypT0 patients (who must have been ≥ ypN1 by study inclusion criteria) was the greatest among the T stages. Distant recurrence was less frequent with nivolumab than placebo (29% vs. 39%), as was locoregional recurrence (12% vs. 17%). These findings suggest that adjuvant nivolumab exerts a robust systemic effect with reductions in disease recurrence. Overall survival results from this trial have not yet been published.

Further work to refine the indications and optimal regimen for adjuvant treatment of high-risk patients is ongoing. Interim analysis of the VESTIGE study (45) evaluating the efficacy of adjuvant nivolumab and ipilimumab among patients with tumor-positive lymph nodes or incomplete surgical resection did not demonstrate a survival benefit to adjuvant immunotherapy.

Biomarkers and therapeutic considerations

Three biomarkers have emerged as therapeutic targets for gastroesophageal cancer and are now routinely measured: microsatellite instability (MSI), HER-2, and PD-L1. In a recent report of metastatic gastroesophageal ACs treated 2012–2022 at a single institution, 64.0% had at least one of the three biomarkers (46). Testing for these biomarkers now forms part of the standard of care for gastroesophageal AC, as results provide prognostic information and access to an increasing array of targeted therapies. While many patients have two or three concurrent biomarkers (46,47), literature on how those targets should be prioritized for treatment is sparse.

Mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H)

dMMR/MSI-H phenotypes account for approximately 10% of gastric and GEJ ACs and 4% of esophageal cancers, and increase in frequency with age (48,49). dMMR/MSI-H tumors are less responsive to certain cytotoxic agents as evidenced by decreased effect on pathologic response, disease-free and overall survival (50-52). However, limited data suggest that these tumors are more responsive to FLOT with better rates of nodal downstaging and survival compared to alternative cytotoxic regimens (53,54).

The dMMR/MSI-H phenotype is strongly predictive of response to immune checkpoint inhibitors (55-57). CheckMate 649 (57) showed that nivolumab in combination with chemotherapy was associated with superior progression-free and overall survival compared to chemotherapy alone in the first-line treatment of HER2-negative unresectable or metastatic gastric, GEJ, or esophageal cancers. The recently reported interim analysis of the DANTE trial (FLOT vs. FLOT + atezolizumab in resectable disease) (54) included a small number of dMMR/MSI-H patients (n=23). In this subgroup, patients treated with FLOT +atezolizumab had pCR rate of 63%, compared to 27% with FLOT alone, suggesting a role for neoadjuvant combination FLOT plus immunotherapy in this population.

There is also evidence supporting the use of perioperative immunotherapy alone in dMMR/MSI-H disease. NEONIPIGA (58) was a single-arm study of 32 patients with locoregionally advanced MSI-H GEJ (50%) or gastric AC treated with neoadjuvant ipilimumab plus nivolumab, followed by surgery, followed by adjuvant nivolumab. The planned neoadjuvant therapy was completed by 85% of patients, and 91% proceeded to surgery. pCR was achieved in 58.6% of patients, a notable improvement when compared to the AC pCR rate of 23% in CROSS.

Several ongoing trials have confirmed the promising effects of perioperative immunotherapy without concurrent chemotherapy on pathologic response in dMMR/MSI-H disease, though have not yet reached survival endpoints. IMHOTEP (59), a single-arm study of perioperative pembrolizumab for treatment of dMMR/MSI-H tumors at interim analysis showed pCR of 25% in esophagogastric tumors. INFINITY (60) is evaluating dual CTLA-4/PD(L)-1 inhibition with tremelimumab and durvalumab on dMMR/MSI-H resectable gastric and GEJ AC. Of 18 patients recruited at interim analysis, pCR rate was 89% in T2–3 tumors and 17% in T4 tumors.

HER-2

Amplification of HER2, a receptor tyrosine kinase in the EGFR family, is found in approximately 20% of gastroesophageal ACs (61). While targeted therapy with trastuzumab has been beneficial for treatment of HER2-positive breast cancer, the optimal treatment strategy for HER2 positive esophageal cancers is still being refined. Targeting HER2 appears to be beneficial in the treatment of metastatic esophageal cancer, based on the ToGA trial demonstrating a survival advantage to adding trastuzumab to chemotherapy in HER2-positive metastatic gastroesophageal cancers (62). The DESTINY-Gastric01 and 02 trials (63,64) have shown promising efficacy for the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (ENHERTU) in salvage therapy for previously treated metastatic or unresectable gastroesophageal cancer. The addition of pertuzumab to a trastuzumab/chemotherapy regimen in the JACOB trial was not effective (65).

The results for HER2-targeted therapy in resectable esophageal cancers are mixed. There is not yet a clearly demonstrated advantage to adding HER2 therapy to neoadjuvant chemoradiation. RTOG 1010 (66) was a randomized controlled trial evaluating the addition of perioperative trastuzumab for HER2-positive resectable esophageal and GEJ AC treated with neoadjuvant chemoradiation and surgery. This study reported a median disease-free survival of 19.6 months in the trastuzumab group vs. 14.2 months in the placebo group (P=0.97), suggesting HER2 therapy did not benefit patients. However, this trial reported a much lower survival in the placebo group than anticipated based on CROSS (median progression-free survival 29.9 months) and had a lower proportion of patients proceeding to resection (82% vs. 94% in CROSS), potentially indicative of a patient cohort with more advanced disease or suboptimal resection/perioperative care. A more promising effect was demonstrated in a propensity-matched cohort study adding trastuzumab and pertuzumab to chemoradiotherapy (67). TRAP-2, a randomized trial evaluating the addition of trastuzumab and pertuzumab to nCRT for resectable esophageal and GEJ cancer is ongoing (68).

The addition of HER2 therapy to neoadjuvant chemotherapy also yields mixed results, with a trend towards improved pathologic response but no clear survival benefit. AIO-PETRARCA (69) evaluated the addition of trastuzumab and pertuzumab to FLOT as perioperative treatment for HER-2 positive resectable gastroesophageal AC, showing significant improvement in pCR in the treatment group (35% vs. 12%, P=0.02). The trial was closed early due to poor enrollment following the publication of JACOB. JCOG2302-TRIGGER (70) evaluated the addition of trastuzumab to preoperative S-1/cisplatin for locally advanced gastric and GEJ tumors and similarly showed a trend towards improvement in pathologic response (partial/complete response 66.7% vs. 36.4% with chemo alone, P=0.08). This trial was also closed early due to poor accrual. The small single-arm HerFLOT study added trastuzumab to FLOT for neoadjuvant treatment of locally advanced gastric and GEJ AC (71% GEJ) and showed a pCR rate of 21.4%, though median disease-free survival was longer than expected at 42.5 months (71). In contrast, interim results from the EORTC1203-INNOVATION study (72) did not show a significant effect of adding trastuzumab/pertuzumab to neoadjuvant chemotherapy on pathologic response.

For patients with metastatic or locally advanced HER2-positive and PD-L1 positive tumors, KEYNOTE-811 demonstrated a survival advantage to adding pembrolizumab to trastuzumab and chemotherapy (73).

Thus, there is not yet a clear therapeutic benefit for targeting HER2 in addition to neoadjuvant chemotherapy or chemoradiotherapy for resectable esophageal cancer, though clinical trials with novel therapeutics are ongoing.

PD-L1 immunotherapy

The programmed death protein 1 (PD-1)/PD-L1 pathway controls the induction and maintenance of immune tolerance within the tumor microenvironment (74). PD-L1 overexpression is found in approximately 40% of esophageal cancers and increases with increased tumor stage. High PD-L1 expression is significantly associated with poor overall survival, but is positively correlated with response to anti-PD-L1 treatment regimens (75). Agents targeting the PD-1/PD-L1 pathway have been approved for unresectable or metastatic gastroesophageal cancers (56,57,76).

When used for locoregional disease, immunotherapy appears to improve local disease control when used alone or in combination with chemotherapy: a 2022 systematic review and meta-analysis of Phase II and III trials evaluating preoperative immunotherapy alone or in combination with other therapies for esophageal cancers reported pooled pCR rates of 32.4% for SCC and 25.2% for AC (77).

Several recent trials have evaluated the addition of anti-PD-L1 agents to perioperative FLOT for esophageal AC: sintilimab (78), DANTE (54) (atezolizumab), KEYNOTE-585 (79) (pembrolizumab), and MATTERHORN (80) (durvalumab) have all demonstrated improved pCR rates with combined chemo-immunotherapy than with FLOT alone. A small single-armed trial combined neoadjuvant pembrolizumab with CROSS for patients with GEJ AC and found no benefit in the overall cohort; however, patients with high baseline expression of PD-L1 (n=8) achieved significantly higher rates of pCR (50% vs. 13.6%) and experienced longer survival (81). The effect on survival outcomes on a larger scale is not yet clear.

Several single-arm studies demonstrate promising activity for neoadjuvant immunotherapy in squamous cell esophageal cancer, reporting pCR rates 22–50% (9,82-86). Tislelizumab, recently approved for use in unresectable or metastatic esophageal squamous cell carcinoma (ESCC) based on the RATIONALE 302 study (87), is being studied for use in selecting patients for definitive chemoradiotherapy (SCENIC trial) (88), treatment of borderline resectable squamous cell tumors (89), combined with chemotherapy for resectable squamous cell tumors (90), and in variable regimens for perioperative treatment of ESCC including patients with pCR (PILOT trial) (91). Camrelizumab was found in the ESCORT-NEO/NCCES01 study (92) to increase pCR rates when used in the neoadjuvant setting with chemotherapy; the NICE-2 study (93) will compare camrelizumab and chemotherapy vs. camrelizumab and chemoradiotherapy vs. chemoradiotherapy alone. A trial of combined neoadjuvant chemoradiation and pembrolizumab is ongoing [PALACE-2 (94)].

Given the improvement in pCRs reported in these interim analyses and smaller studies, the early evidence suggests that immunotherapy will potentially have a role in the neoadjuvant space. The specific population of patients, PD-L1 expression levels, and lengths of treatment have yet to be defined until the completion of the aforementioned trials and information regarding survival and recurrence data are available.

Conclusions

The last decade has witnessed considerable advancements in the perioperative management of locoregional esophageal cancers. Key trials are summarized in Figure 1. While historically treated as a part of the conglomerate of “gastroesophageal cancer”, esophageal and GEJ cancers are increasingly understood to have diverse disease biology and behavior and merit treatment optimized for tumor location, histology, and biomarkers. The FLOT4 trial redefined the optimal chemotherapy regimen for ACs. Following the results of the ESOPEC and ongoing RACE trials, FLOT may supersede CROSS as the neoadjuvant regimen of choice for AC. Patients at high risk of recurrence after neoadjuvant chemoradiation and resection should now be treated with adjuvant nivolumab to improve survival based on CheckMate 577. Multiple therapies are emerging for the treatment of dMMR/MSI-H, HER2+, and PD-L1⁺ disease that may augment or replace our current neoadjuvant regimens in patients with locoregionally advanced esophageal cancer.

Figure 1 Key trials in perioperative therapy for locally advanced esophageal cancer. AC, adenocarcinoma; CROSS, chemoradiotherapy for oesophageal cancer followed by surgery study; FLOT, fluorouracil, leucovorin, oxaliplatin, and docetaxel; MSI-H, microsatellite instability-high; PD-L1, programmed death-ligand 1; SCC, squamous cell carcinoma.

Several clinical scenarios are poorly studied and are therefore not well-characterized in this review, including bulky primary and nodal disease, extremes of age, and tumors harboring combinations of biomarkers. Additionally, while there is clearly significant financial and lifestyle toxicity to esophageal cancer treatment, the comparative influence of the various treatment regimens on patient quality of life and financial outcomes is poorly studied (95).

With the proliferation of treatment regimens in emerging trials, it is becoming increasingly evident that perioperative therapies must be selected and customized for each patient’s individual combination of comorbidities, tumor biology, histology, and biomarker status. Multidisciplinary treatment teams have been demonstrated to improve outcomes for esophageal cancer treatment (96) and are increasingly important as the complexity of decision-making around perioperative therapies increases. While the advantages of multidisciplinary care compound with higher guideline-concordant care and better procedural outcomes at large-volume and academic centers (97-99), patients with lower socioeconomic status remain at risk of worse outcomes due to logistical and socioeconomic barriers to care (100). In addition to further refining the optimal treatment regimens, ongoing efforts in improving the implementation of guideline-concordant esophageal cancer therapies are necessary to improve population-level outcomes.

Acknowledgments

The authors thank Kate J. Krause, in the Research Medical Library at MD Anderson Cancer Center, for her assistance with the literature search.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-11/rc

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-11/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-11/coif). The authors have no conflicts of interest to declare.

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