Resection remains the primary curative treatment for localized esophageal adenocarcinoma (EAC). However, the 5-year survival rate with resection alone remains low at 26% due to a high risk of recurrence.1 Multimodal approaches incorporating perioperative chemotherapy, preoperative chemoradiotherapy (CRT), and adjuvant immunotherapy have improved survival compared with surgery alone.2–5 These strategies aim to downstage the primary tumor, increase the likelihood of margin-negative resection, eradicate micrometastatic disease, and ultimately improve survival in patients with EAC.
Although the ESOPEC study recently established the benefit of perioperative combination chemotherapy for locally advanced disease, nearly 50% of patients still experience recurrence and succumb to their disease.5 Strategies incorporating targeted therapies and new technology to individualize therapy will be critical in further improving survival.
This review discusses clinical trials that inform the current management of resectable EAC in patients fit for surgery. It will also explore unanswered questions, ongoing trials, and state-of-the-art technology that may inform perioperative therapy in the near future.
Neoadjuvant CRT or Perioperative Chemotherapy—Is There an Optimal Approach?
Randomized clinical trials have established the benefit of preoperative and perioperative therapy using chemotherapy or CRT (Table 1).2,3,5–7 Until recently, equipoise existed between these strategies, with the choice between perioperative chemotherapy or neoadjuvant CRT largely depending on physician and institutional preference. ASCO, ESMO, and NCCN have historically recommended preoperative CRT or perioperative chemotherapy.8–10 However, the results of the ESOPEC trial are poised to shift this paradigm.5
Key Clinical Trials Evaluating Preoperative CRT and Perioperative Chemotherapy
| Trial | Phase | Study Population | Treatment Arms | Endpoints and Efficacy | Reference |
|---|---|---|---|---|---|
| MAGIC | III | E/GEJ/G AC | Perioperative chemo with ECF + surgery vs surgery alone | OS: perioperative chemo superior HR, 0.75; 95% CI, 0.60–0.93; P=.009 | 7 |
| CROSS | III | E/GEJ SCC and AC (75% AC) | Neoadjuvant CRT with weekly carboplatin + paclitaxel + surgery vs surgery alone | OS for AC + SCC: neoadjuvant CRT superior 49.4 vs 24.0 mo HR, 0.657; 95% CI, 0.495–0.871; P=.003 OS for AC subgroup: HR, 0.741 (95% CI, 0.536–1.024; P=.07) |
2 |
| FLOT4 | II/III | GEJ/G AC | Perioperative chemo with FLOT vs ECF/ECX | pCR (phase II): FLOT superior 15% vs 6%; P=.02 OS (phase III): FLOT superior 35 vs 50 mo HR, 0.77; 95% CI, 0.63–0.94; P=.012 |
3,54 |
| ESOPEC | III | E/GEJ AC | Perioperative FLOT vs neoadjuvant CRT (CROSS) | OS: FLOT superior 66 vs 37 mo HR, 0.72; 95% CI, 0.54–0.96; P=.023 | 5 |
| TOPGEAR | III | GEJ/G AC | Preoperative chemo (ECF × 2 /FLOT × 3) + neoadjuvant CRT vs preoperative chemo (ECF × 3/FLOT × 4); both groups received postoperative chemo (ECF × 3/FLOT × 4) | OS: no difference 46 mo chemo + CRT vs 49 mo chemo HR, 1.04; 95% CI, 0.83–1.30 OS for GEJ subgroup: HR, 0.78; 95% CI, 0.55–1.12 |
15 |
| Neo-AEGIS | III | E/GEJ AC | CRT vs perioperative ECF/EOX/FLOT (15% FLOT) | OS: no difference 48.0 mo perioperative chemo vs 49.2 mo CRT HR, 1.03; 95% CI, 0.77–1.38; P=.82 | 11 |
| CALGB 80803 | II | E/GEJ AC | Neoadjuvant chemo (FOLFOX or carboplatin + paclitaxel) + CRT with continuation of induction chemo during CRT in PET responders, switch chemo in PET nonresponders | pCR in PET nonresponders: 18% (FOLFOX induction) and 20% (carboplatin + paclitaxel induction) | 14 |
| CRITICS | III | GEJ/G AC (17% GEJ) | Perioperative chemo (ECX/EOX) vs preoperative chemo and postoperative CRT | OS: no difference 43 mo perioperative chemo vs 37 mo postoperative CRT HR, 1.01; 95% CI, 0.84–1.22; P=.90 | 15 |
Abbreviations: AC, adenocarcinoma; chemo, chemotherapy; CRT, chemoradiotherapy; DFS, disease-free survival; E, esophagus; ECF/X, epirubicin/cisplatin/5-fluorouracil or capecitabine; EFS, event-free survival; EOX, epirubicin/oxaliplatin/capecitabine; FLOT, 5-FU/leucovorin/oxaliplatin/docetaxel; FOLFOX, 5-fluorouracil/leucovorin/oxaliplatin; G, gastric; GEJ, gastroesophageal junction; HR, hazard ratio; OS, overall survival; pCR, pathologic complete response; SCC, squamous cell carcinoma.
Perioperative Chemotherapy
The phase III MAGIC trial established the benefit of perioperative chemotherapy over surgery alone. Although most patients in the trial had gastric or gastroesophageal junction (GEJ) adenocarcinoma, approximately 25% had EAC.7 Perioperative epirubicin, cisplatin, and 5-FU (ECF) significantly improved overall survival (OS) compared with surgery alone (hazard ratio [HR], 0.75; 95% CI, 0.60–0.93; P=.009), with a 5-year OS rate of 36% versus 23%, respectively. Subsequently, the phase II/III FLOT4 trial compared perioperative ECF to perioperative FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) in patients with resectable GEJ and gastric adenocarcinoma.3 Survival was significantly longer with FLOT (median OS, 50 vs 35 months; HR, 0.75; 95% CI, 0.60–0.93; P=.009), establishing FLOT as the standard perioperative chemotherapy regimen for locally advanced esophageal carcinoma.
Neoadjuvant CRT
The phase III CROSS trial evaluated the benefit of neoadjuvant CRT in patients with resectable esophageal cancer.2 Patients with T2–3 or N+ disease (75% adenocarcinoma) were randomized to neoadjuvant chemotherapy (weekly carboplatin + paclitaxel [CP]) with concurrent radiotherapy (41.4 Gy in 23 fractions) or resection alone. The CROSS regimen was well-tolerated and did not increase postoperative complications. Overall, neoadjuvant CRT doubled median OS to 49.4 months versus 24.0 months with surgery alone (HR, 0.657; 95% CI, 0.495–0.871; P=.003). Although the benefit of neoadjuvant CRT was observed in all patients, the survival benefit was largely driven by those with SCC (HR for death, 0.422; 95% CI, 0.226–0.788; P=.007), compared with a more modest effect in EAC (HR, 0.741; 95% CI, 0.536–1.024; P=.07). CRT reduced the local recurrence rate but did not impact distance recurrence rates (27% vs 28%; HR, 0.76; 95% CI, 0.52–1.13). With long-term follow-up, the benefit of CRT relative to surgery alone in EAC remains marginal, with a 10-year OS rate of 36% versus 26% (HR, 0.75; 95% CI, 0.56–1.00).1 The attenuated benefit in EAC and lack of impact on distant recurrence risk leave the optimal paradigm for resectable EAC in question.
Is There an Optimal Approach?
The phase III Neo-AEGIS and ESOPEC trials compared neoadjuvant CRT with perioperative chemotherapy in patients with resectable EAC. Neo-AEGIS randomized patients either to neoadjuvant CRT with the CROSS regimen or perioperative chemotherapy, initially using the MAGIC regimen and later incorporating perioperative FLOT.11 The trial design was modified to assess noninferiority after the first interim analysis, but closed prematurely due to slow accrual. Survival was similar between perioperative chemotherapy and CRT (48.0 vs 49.2 months; HR, 1.03; 95% CI, 0.77–1.38; P=.82), leaving clinical equipoise between these approaches. However, because only 15% of the perioperative chemotherapy arm received FLOT, whether perioperative FLOT could be more effective remained an open question.
In contrast, the ESOPEC trial established perioperative FLOT as a more effective strategy than neoadjuvant CRT for fit patients with resectable EAC.5 ESOPEC randomized patients to perioperative FLOT or neoadjuvant CRT with the CROSS regimen, excluding those with SCC or gastric cancer. FLOT significantly improved survival (median, 66 vs 37 months; HR, 0.70; 95% CI, 0.53–0.92; P=.012). Although the pCR rate in the CRT arm was lower than expected based on the pCR rate in the CROSS trial (10% vs 23% in CROSS), direct comparisons are limited because ESOPEC included patients with more advanced tumors [cT4] and a greater proportion of cN+ disease (79.7% vs 64.5% in CROSS). Although FLOT improved survival over CRT in the ESOPEC study, some limitations should be considered. Nearly one-third of patients did not complete planned chemotherapy during radiation. Furthermore, patients in the CRT arm did not receive adjuvant nivolumab, which is the current standard of care for patients with residual disease after neoadjuvant CRT and surgery based on CheckMate 577.4 Thus, the true benefit of perioperative FLOT over standard CRT with adjuvant nivolumab remains unknown.
Together, Neo-AEGIS and ESOPEC suggest that perioperative chemotherapy is at least as effective, and possibly superior, to neoadjuvant CRT in locally advanced EAC. As such, neoadjuvant CRT with adjuvant nivolumab should likely be reserved for patients unable to tolerate FLOT.
Preoperative Chemotherapy + Chemoradiotherapy
Given the proven benefits of perioperative chemotherapy and neoadjuvant CRT individually, there is growing interest in combining these strategies. Total neoadjuvant approaches are particularly appealing for esophagogastric tumors, given the high morbidity of resection and the challenges of delivering postoperative therapy. For example, in the FLOT4 and ESOPEC studies, only 62% and 59% of patients initiated postoperative chemotherapy, and even fewer completed all planned cycles (46% and 52%, respectively).3,7 Retrospective and single-arm studies in EAC support the safety and feasibility of preoperative chemotherapy combined with CRT, demonstrating high adherence rates to planned preoperative therapy.12,13
CALGB 80803
The phase II CALGB 80803 trial evaluated whether FDG-PET following induction chemotherapy could be used to guide neoadjuvant therapy and improve pCR rates in patients receiving neoadjuvant chemotherapy followed by CRT.14 Patients were initially randomized to 6 weeks of modified FOLFOX (5-FU/leucovorin/oxaliplatin) or CP, followed by a PET scan. Based on standard uptake value (SUV) changes, patients were classified as PET responders if the SUV decreased by ≥35%, or nonresponders if the SUV decreased by <35%. Responders continued with the same chemotherapy during CRT, and nonresponders switched to the alternate chemotherapy regimen during CRT.
Results of the primary endpoint, pCR rate in PET nonresponders after switching chemotherapy, are discussed later. Interestingly, a notable finding was the striking difference in pCR rates among PET responders, with a 40.3% pCR rate in FOLFOX responders compared with 14% in CP responders. After a median follow-up of 5.17 years, FOLFOX responders had a median OS that was not reached, with a 5-year OS of 53%, whereas CP responders had a median OS of 38.7 months and a 5-year OS of 42.9%. Although the trial was not designed to directly compare outcomes between chemotherapy regimens, the higher pCR and survival rates in FOLFOX responders suggest a potential advantage over CP.
TOPGEAR
The phase III TOPGEAR trial evaluated the benefit of adding preoperative CRT to perioperative chemotherapy (ECF or FLOT) in patients with gastric or GEJ adenocarcinoma.15 Overall, the addition of preoperative CRT did not improve OS (HR, 1.05; 95% CI, 0.83–1.31; Table 2). Although TOPGEAR primarily focused on gastric cancer, approximately one-third of the cohort had GEJ tumors. Subgroup analyses suggest that preoperative CRT may provide some benefit in the GEJ subgroup (HR, 0.78; 95% CI, 0.55–1.22) and in patients with T1–2 tumors (HR, 0.63; 95% CI, 0.29–1.37). Only one-third of patients received FLOT, and the radiation dose was only 45 Gy, so it is possible that more effective systemic control with FLOT combined with a conventional radiation dose (50.4 Gy) could improve efficacy. Ongoing trials will more specifically evaluate the role of preoperative CRT combined with preoperative chemotherapy in patients with EAC and GEJ adenocarcinoma, often as total neoadjuvant therapy, to determine whether these combined strategies improve outcomes and whether CRT has a role in treating fit patients with resectable EAC (Table 2).1,15–18
Selected Clinical Trials Evaluating Strategies Combining Preoperative Chemotherapy With CRT
| Trial | Phase | Study Population | Treatment Arms | Primary Endpoint and Efficacy | Reference |
|---|---|---|---|---|---|
| TOPGEAR | II/III | GEJ/G AC | Perioperative chemo (ECF/X × 3 or FLOT × 4 preoperative and postoperative) + preoperative CRT (5-FU infusion) vs perioperative chemo [add RT dose] | OS: no difference 46 mo chemo + CRT vs 49 mo chemo alone HR, 1.05; 95% CI, 0.83–1.31 | 15 |
| TNT-OES 2 | II | E/GEJ AC | TNT with FLOT followed by CRT (CROSS) and CRT (CROSS) followed by FLOT [add RT dose] | DFS: ongoing NCT06161818 | 1 |
| CRITICS-II | II | E/GEJ AC | Preoperative chemo (DOC × 4) vs chemo + CRT vs CRT [add RT dose] | EFS: ongoing NCT02931890 | 16 |
| RACE | III | GEJ (Siewert I–III) AC | Perioperative chemo (FLOT) vs Preoperative chemo + CRT [add RT dose] | DFS: ongoing NCT04375605 | 32 |
| PREACT | III | GEJ/G (Siewert II/III) AC | Perioperative chemo (SOX) + preoperative CRT vs preoperative chemo [add RT dose] | DFS: ongoing NCT03013010 | 18 |
Abbreviations: AC, adenocarcinoma; chemo, chemotherapy; CRT, chemoradiotherapy; DFS, disease-free survival; DOC, docetaxel/oxaliplatin/capecitabine; E, esophagus; EFS, event-free survival; ECF/X, epirubicin/cisplatin/5-fluorouracil or capecitabine; EFS, event-free survival; FLOT, 5-FU/leucovorin/oxaliplatin/docetaxel; G, gastric; GEJ, gastroesophageal junction; HR, hazard ratio; OS, overall survival; RT, radiotherapy; SCC, squamous cell carcinoma; SOX, S-1/oxaliplatin; TNT, total neoadjuvant therapy.
Notably, no studies to date have definitively demonstrated that trimodality therapy (chemotherapy, radiation, and surgery) is superior to bimodality therapy (eg, perioperative chemotherapy + surgery or preoperative CRT + surgery). This suggests that a subset of patients may have an innate resistance to cytotoxic therapy, and implies that alternative approaches are needed to improve survival.
Role of Immune Checkpoint Inhibitors and Targeted Therapies in Resectable EAC
Despite multimodality therapy, fewer than half of patients with resectable EAC are cured, underscoring the urgent need for more effective strategies.2,3,5 Given the promising activity of immune checkpoint inhibitors (ICIs) and targeted therapies in advanced disease, there is growing enthusiasm for incorporating these novel therapies into the perioperative setting.19,20
Immune Checkpoint Inhibitors
Postoperative Immunotherapy: CheckMate-577
Patients with EAC and residual pathologic disease following neoadjuvant CRT face an exceptionally high risk of recurrence, with 75% developing recurrent disease.2,21 Until recently, there were no proven adjuvant strategies for this high-risk group. The phase III CheckMate-577 trial tested whether 1 year of adjuvant nivolumab in patients who received neoadjuvant CRT and did not experience a pCR could improve disease-free survival (DFS).4 Adjuvant nivolumab doubled DFS compared with placebo (22.4 vs 11 months; HR, 0.69; 96.4% CI, 0.56–0.86; P<.001). In the adenocarcinoma subgroup, adjuvant nivolumab improved median DFS from 11.1 months with placebo to 19.4 months with nivolumab (HR, 0.75; 95% CI, 0.59–0.96). Although OS data are still awaited, adjuvant nivolumab has become the current standard for patients with EAC treated with neoadjuvant CRT who have residual pathologic disease.10
Preoperative ICI: EA2174
EA2174 is a recently completed phase II/III trial evaluating the benefit of adding an ICI to neoadjuvant CRT and comparing the effectiveness of single-agent versus dual checkpoint blockade in the adjuvant setting.22 Patients with EAC were randomized to concurrent CRT with or without nivolumab, followed by surgery. After resection, they were randomized again to receive either nivolumab or nivolumab + ipilimumab. Initial results presented at the 2024 ASCO Annual Meeting showed that the addition of nivolumab to neoadjuvant CRT did not improve the pCR rate in patients with resected EAC or GEJ adenocarcinoma (21% for CRT alone vs 25% for CRT with nivolumab; P=.27). The study is ongoing to analyze the adjuvant endpoint, DFS.
Perioperative ICI
Three phase III trials—KEYNOTE-585, MATTERHORN, DANTE—are currently ongoing to evaluate the combination of ICIs with perioperative chemotherapy (Table 4).17,23,24 Although none of these trials focus specifically on esophageal tumors, their results may provide valuable insights for EAC treatment. All 3 trials demonstrate that adding an ICI to preoperative chemotherapy improves the pCR rate (Table 3). Unfortunately, adding pembrolizumab to perioperative chemotherapy in KEYNOTE-585 did not improve event-free survival (EFS).23 Although the data from DANTE are still maturing, top-line results from MATTERHORN suggest that the study met its primary endpoint of EFS.
Selected Clinical Trials of Immune Checkpoint Inhibitors for Resectable E/GEJ AC
| Trial | Phase | Study Population | Treatment Arms | Primary Endpoints and Efficacy | Reference |
|---|---|---|---|---|---|
| CheckMate-577 | III | E/GEJ SCC and AC (71% AC) without pCR to neoadjuvant CRT | Adjuvant nivolumab vs placebo | DFS: nivolumab superior 22.4 vs 11.0 mo HR, 0.69; 95% CI, 0.56–0.86; P<.001 | 4 |
| EA2174 | II/III | E/GEJ AC | Perioperative CRT ± nivolumab Adjuvant nivolumab ± ipilimumab |
pCR rate (neoadjuvant): no difference 21% CRT vs 24.8% CRT + nivolumab (P=.27) DFS (adjuvant): ongoing NCT03604991 |
22 |
| KEYNOTE-975 | III | E/GEJ SCC and AC Ineligible for curative surgery |
Definitive CRT (FOLFOX) + pembrolizumab vs definitive CRT + placebo | OS, EFS: ongoing NCT04210115 | 39 |
| KEYNOTE-585 | III | GEJ/G AC | Perioperative chemo (cisplatin + 5-FU or capecitabine) + pembrolizumab vs chemo + placebo | pCR rate: chemo + pembrolizumab superior 12.9% vs 2.0 %; P<.00001 EFS: no benefit 44.4 vs 25.3 mo HR, 0.81; 95% CI, 0.67–0.99; P=.0190 OS: no benefit 60.7 vs 58.0 mo HR, 0.90; 95% CI, 0.73–1.12; P=.174 |
23 |
| MATTERHORN | III | GEJ/G AC | Perioperative chemo (FLOT) + durvalumab vs chemo | EFS (phase III): ongoing Interim pCR rate: 19% durvalumab + chemo arm vs 7% chemo arm OR, 3.08; P=.00001 NCT04592913 |
24 |
| DANTE | II/III | GEJ/G AC | Perioperative chemo (FLOT) + atezolizumab vs FLOT | pCR or major pathologic response (phase II): chemo + atezolizumab superior 24% vs 15%; P=.032 EFS (phase III): ongoing |
17 |
| INFINITY | II | dMMR/MSI-H GEJ/G AC | Neoadjuvant tremelimumab + durvalumab followed by surgery (cohort 1) and nonoperative management (cohort 2) | pCR (cohort 1): ongoing 2-y complete clinical response rate (cohort 2): ongoing NCT04817826 |
28,30 |
Abbreviations: AC, adenocarcinoma; chemo, chemotherapy; CRT, chemoradiotherapy; DFS, disease-free survival; dMMR, mismatch repair deficient; E, esophagus; ECF/X, epirubicin/cisplatin/5-fluorouracil or capecitabine; EFS, event-free survival; EOX, epirubicin/oxaliplatin/capecitabine; FLOT, 5-FU/leucovorin/oxaliplatin/docetaxel; FOLFOX, 5-fluorouracil/leucovorin/oxaliplatin; G, gastric; GEJ, gastroesophageal junction; HR, hazard ratio; MSI-H, microsatellite instability-high; OR, odds ratio; OS, overall survival; pCR, pathologic complete response; SCC, squamous cell carcinoma.
Selected Clinical Trials of Targeted Therapies for Resectable E/GEJ AC
| Trial | Phase | Study Population | Treatment Arms | Primary Endpoint and Efficacy | Reference |
|---|---|---|---|---|---|
| Trials incorporating HER2-targeted therapies | |||||
| RTOG1010 | III | HER2+ E/GEJ AC | CRT (carboplatin + paclitaxel) with or without trastuzumab | DFS: no difference 19.6 mo with CRT + trastuzumab vs 14.2 mo with CRT alone (HR, 0.99; 95% CI, 0.71–1.39; P=.97) | 34 |
| PETRARCA | II/III | HER2+ E/GEJ AC | Perioperative chemo (FLOT) + trastuzumab + pertuzumab vs chemo alone | pCR rate: favors FLOT + trastuzumab + pertuzumab arm 35% vs 12% (P=.019) Did not proceed to phase III | 40 |
| PHERFLOT | II | HER2 + EG AC | Pembrolizumab + FLOT + trastuzumab | pCR and 2-y DFS: ongoing NCT05504720 | 56 |
| EPOC2003 | II | HER2+ or HER2-low GEJ/G AC | Neoadjuvant trastuzumab deruxtecan | Major pathologic response: ongoing NCT05034887 | 58 |
| Trials incorporating EGFR-targeted therapies | |||||
| RTOG 0436 | III | E SCC and AC (62% AC) | Neoadjuvant CRT with weekly cetuximab vs CRT | OS: no benefit HR, 0.90; 95% CI, 0.70–1.16; P=.47 | 37 |
| SAKK 75/08 | III | E/GEJ AC and SCC (64% AC) | Neoadjuvant chemo (cisplatin + docetaxel) + CRT with pre- and postoperative cetuximab vs chemo + CRT | PFS: no benefit 2.9 y cetuximab vs 2.0 y control; HR, 0.79; 95% CI, 0.58–1.07; P=.13 | 36 |
| Neoadjuvant and perioperative trials incorporating VEGF/VEGFR2-targeted therapies | |||||
| ST03 | II/III | GEJ/G AC | Perioperative chemo (ECX) + bevacizumab vs chemo alone | OS (phase III): no benefit HR, 1.01; 95% CI, 0.61–1.67 | 38 |
| RAMSES/FLOT7 | II/III | GEJ/G AC | Perioperative chemo (FLOT) vs FLOT + ramucirumab | Major pathologic response (phase II): no benefit 29% FLOT vs 26% FLOT + ramucirumab Did not proceed to phase III | 57 |
Abbreviations: AC, adenocarcinoma; chemo, chemotherapy; CRT, chemoradiotherapy; DFS, disease-free survival; E, esophagus; ECX, epirubicin/cisplatin/capecitabine; FLOT, 5-FU/leucovorin/oxaliplatin/docetaxel; G, gastric; GEJ, gastroesophageal junction; HR, hazard ratio; OS, overall survival; pCR, pathologic complete response; PFS, progression-free survival; SCC, squamous cell carcinoma.
Currently, perioperative ICI alone is not recommended, except in the rare subset of patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors (<2% EAC).25–30 The relatively limited benefit of perioperative chemotherapy, coupled with the activity of ICIs in the advanced setting, provides initial support for this strategy, and underscores the importance of testing all esophagogastric adenocarcinomas for dMMR and/or MSI-H.10,25,26,31 Published data reviewed by Strickland et al27 support neoadjuvant ICI in patients with dMMR/MSI-H esophagogastric cancers, based on pCR rates of approximately 60% and encouraging EFS data.28,29 The ongoing phase II INFINITY trial includes a cohort with a clinical response to preoperative ICI and will evaluate nonoperative management.30 Although available data on perioperative ICI in dMMR/MSI-H tumors are encouraging, the current evidence is insufficient to broadly recommend nonoperative management following neoadjuvant ICI. Ongoing trials in patients with dMMR/MRI-H tumors (ClinicalTrials.gov identifiers: NCT04817826, NCT04062656, NCT04795661, NCT04736485), along with subset analyses from the ongoing KEYNOTE-585, MATTERHORN, and DANTE trials, may further inform the optimal strategy.17,23,24
Targeted Therapies
The therapeutic landscape for advanced esophagogastric cancer has rapidly expanded with the introduction of therapies targeting HER2, VEGF, PD1/PD-L1, and Claudin 18.2.19,32–40 However, no targeted therapy has proven beneficial in patients with resectable EAC (Table 4).
HER2
HER2 overexpression or amplification occurs in approximately 23% and 11% of esophagogastric cancers. Trastuzumab, a monoclonal antibody targeting HER2, combined with frontline chemotherapy, improves survival in HER2-positive advanced EAC.33,41 Two trials testing HER2-directed therapy in resectable EAC showed no significant benefit (Table 4). RTOG 1010 compared neoadjuvant CRT with trastuzumab, followed by adjuvant trastuzumab, versus CRT alone in patients with HER2-positive resectable EAC.34 DFS was numerically longer in the trastuzumab group, but the benefit was not statistically significant. PETRARCA added trastuzumab and pertuzumab, another monoclonal antibody against HER2, to perioperative FLOT.35 This strategy improved pCR rates (35% vs 12%; P=.019), but the trial was stopped early due to slow accrual. Ongoing studies will further explore strategies incorporating HER2-directed therapy into the perioperative setting for patients with localized HER2-positive esophagogastric adenocarcinoma.
EGFR, VEGF
Two phase III trials, RTOG 0436 and SAKK 75/08, examined the benefit of adding the anti-EGFR antibody cetuximab to neoadjuvant chemoradiation in esophageal cancer; however, neither demonstrated a survival benefit.36,37 The addition of the anti-VEGFA antibody bevacizumab to perioperative chemotherapy in patients with resectable gastric and esophageal tumors in the phase II STO trial did not improve OS.38
Individualizing Multimodality Management of Resectable EAC
Although the pivotal trials discussed herein inform the current approach to the management of EAC, several key questions remain, particularly for underrepresented groups in clinical trials. Racial and ethnic disparities exist in the presentation, treatment, and outcomes of patients with EAC. Non-White patients often present with more advanced disease, and stage-for-stage, they are less likely to undergo surgery.42 Notably, neither CROSS, TOPGEAR, nor ESOPEC report on the race and ethnicity of the subjects enrolled.2,5,15 Given the geographic locations of these studies (Western Europe, Canada, Australia, and New Zealand), African American, American Indian, and Hispanic patients are likely underrepresented. In the US-based CALGB 80803, 93% of the 225 patients were White, and 97% were non-Hispanic.14 This underrepresentation limits the generalizability of the results. Expanding enrollment to a more diverse patient population to better represent the population affected by the disease is critical, as are strategies that ensure all patients have access to appropriate multidisciplinary care.
Although ESOPEC establishes perioperative FLOT as the more effective regimen for fit patients undergoing resection for EAC, several important clinical questions remain. The most effective approach for patients who cannot tolerate FLOT is unknown. Neo-AEGIS11 suggests that CRT is more effective than perioperative ECX, but based on CALGB 80803,14 FOLFOX may be a more effective chemotherapy backbone to consider for patients who cannot tolerate FLOT. ESOPEC5 does not address the management of tumors that do not respond to preoperative therapy, as all patients in the perioperative chemotherapy group were assigned to receive postoperative FLOT, regardless of response. ESOPEC also highlights the challenge of delivering postoperative therapy following esophagectomy. Only 63% of patients in the perioperative FLOT arm began postoperative therapy, raising the question of whether a total neoadjuvant approach could further improve efficacy.
Another open question is the role of nonoperative management for patients who may not tolerate resection due to advanced age, frailty, or medical comorbidities, or for those who experience a complete clinical response to preoperative therapy. Given the increasing uptake of organ preservation approaches in rectal cancer and the risk of morbidity and impact on quality of life of esophagectomy, there is increasing interest in the nonoperative management of esophageal cancer. Although growing evidence supports the nonoperative management of esophageal SCC, there are currently fewer data for EAC. Definitive CRT should be considered for patients unable to undergo resection, and the benefit of incorporating pembrolizumab into the CRT paradigm is being evaluated in the ongoing KEYNOTE-975 study.39
Another major challenge in treating esophagogastric cancers is managing patients whose tumors do not respond to preoperative therapy. In the MAGIC trial,7 patients with node-positive disease at resection survived a median of 16 months. However, in practice, the standard paradigm is to resume the same chemotherapy regimen used in the preoperative setting.43 Conversely, a proportion of patients who have exceptional responses to neoadjuvant therapy may be overtreated with adjuvant therapy. FDG-PET and circulating tumor DNA (ctDNA) are proven prognostic tools that could inform adaptive perioperative strategies. The ability to detect the presence of residual disease noninvasively in the preoperative and postoperative settings could help guide risk-adapted approaches for resectable EAC.
FDG-PET
FDG-PET imaging is routinely used to stage and assess the response to neoadjuvant therapy for esophageal cancer.44 In esophagogastric cancer treated with neoadjuvant therapy, a reduction in the SUV ≥35% from baseline is associated with a histologic response and improved survival.45–47 Metabolic nonresponders represent a very-high-risk group, with an expected pCR rate of only 4%.48 Using the study design described earlier,14 CALGB 80803 evaluated whether adapting preoperative therapy based on PET response to induction chemotherapy could improve the pCR rate in PET nonresponders. The study met its primary endpoint (pCR rate in PET nonresponders), showing a pCR rate of 18% for FOLFOX to CP and 20% for CP to FOLFOX, compared with the expected rate of only 4%.48 These results demonstrate that response assessment using PET following neoadjuvant chemotherapy and adapting therapy based on treatment response is a viable and promising strategy.
ctDNA
ctDNA is an emerging tool with significant potential to dynamically evaluate cancer. However, available evidence in esophageal cancer is largely limited to retrospective data and post hoc analyses, often from heterogeneous cohorts. Two prospective studies of patients with EAC have shown that ctDNA detection following neoadjuvant CRT completion was associated with shorter DFS.49,50 In patients with EAC treated with neoadjuvant chemotherapy and resection, 90% of those with detectable ctDNA following resection went on to develop recurrence, with significantly shorter survival in patients with detectable ctDNA (10.0 vs 20.9 months; HR, 5.55; 95% CI, 2.42–12.71; P=.0003).50 In another analysis of patients with stage I–III esophagogastric cancer (adenocarcinoma and SCC), ctDNA detection within 16 weeks of resection was associated with significantly shorter DFS in all patients, including the subset with esophageal cancer (HR, 55.6; 95% CI, 6.9–7,198.7; P<.001).51
Though largely focused on gastric and GEJ adenocarcinoma, additional studies show a significant association between ctDNA dynamics and clinical and pathologic outcomes.52,53 In a cohort of patients with gastric and GEJ adenocarcinoma, early ctDNA clearance during neoadjuvant therapy was associated with the longest DFS and OS. Conversely, ctDNA persistence at mid-neoadjuvant therapy, postneoadjuvant therapy, and postoperative time points was associated with incrementally shorter recurrence-free survival and OS.52 In an analysis of ctDNA dynamics among a subset of patients treated with preoperative chemotherapy in the CRITICS trial, detection of ctDNA following resection was significantly associated with recurrence (median EFS, 18.7 months vs not reached; HR, 21.8; P<.001).53 In both studies, the presence or absence of ctDNA following neoadjuvant therapy strongly correlated with the degree of histologic regression in the resected tumor.
Although preliminary, these data suggest that ctDNA has significant potential to inform risk-adapted perioperative strategies for patients with localized EAC. However, data are insufficient to recommend the routine use of ctDNA for guiding treatment decisions in EAC at this time. This caution stems from the lack of evidence demonstrating that ctDNA-guided strategies translate to improved patient outcomes. Furthermore, the added cost of ctDNA testing without established clinical benefit should preclude its routine clinical use. Therefore, well-designed, prospective clinical trials that are specifically powered to evaluate the clinical impact of ctDNA-guided approaches are essential for validating its utility.
A phase II trial in development will evaluate a ctDNA-guided approach to postoperative therapy in patients with locally advanced esophagogastric adenocarcinoma who received preoperative chemotherapy and resection. Following resection, patients with undetectable ctDNA will receive de-escalated postoperative therapy with capecitabine, whereas those with detectable ctDNA will be randomized to either standard postoperative FLOT or salvage therapy. The salvage therapy regimen will consist of a proven regimen used in the frontline setting for advanced esophagogastric adenocarcinoma tailored to the individual patient’s tumor, based on PD-L1, HER2, and Claudin 18.2 expression. The primary objectives are to demonstrate that in patients with undetectable ctDNA, de-escalated therapy does not compromise DFS, and in patients with detectable ctDNA, salvage therapy improves DFS compared with standard postoperative FLOT therapy.
Conclusions
Multimodality therapy has led to improved survival for patients with EAC, with recent data from landmark trials establishing the importance of effective systemic therapy in improving survival for patients with EAC. The ESOPEC trial represents a significant milestone in the evolution of treatment for resectable EAC, highlighting the importance of effective systemic control in this disease. Despite these advancements, fewer than half of patients are cured with multimodality therapy, underscoring the urgent need for more effective strategies. Targeted therapies have significantly improved survival in the metastatic setting and are currently being explored in the localized, curative setting. Incorporating these advancements and novel approaches that individualize perioperative treatment to individual patients offers considerable promise for the future management of EAC.
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