Perioperative therapy landscape for locally advanced, resectable esophageal cancer: an updated literature review

Introduction

Esophageal cancer (EC) is the seventh most diagnosed cancer and the sixth most common cause of cancer-related death worldwide (1). In the United States (US), it accounts for 1.0% of all new cancer cases and 2.7% of all cancer-related deaths (2). Unfortunately, only about 51% of ECs are diagnosed early enough to be eligible for curative-intent surgery. Despite modern therapies, localized disease is associated with a 5-year overall survival (OS) rate of 47% and locally advanced disease, 26%. This less-than-ideal OS suggests a high rate of relapse (2).

Surgical and perioperative approaches vary based on initial TNM staging, tumor location, histology [adenocarcinoma (AC) vs. squamous cell carcinoma (SCC)], and surgical candidacy (3). For select early-stage, superficial tumors without lymph node (LN) metastases, an endoscopic resection, with or without ablation, is an acceptable option with curative intent (3). However, as the depth of invasion increases, specifically in the submucosa and beyond, and especially if there is LN involvement, the disease becomes locally advanced, whereby an esophagectomy with regional LN dissection and perioperative therapy become critical to optimize outcomes.

Landmark studies have confirmed survival advantages by adding perioperative therapies, such as chemotherapy (CTX) and chemoradiation (CRT), to surgery (4,5). Recent shifts in treatment paradigms are being implemented where non-surgical approaches are increasingly adopted given pathologic response successes with CRT alone with preservation of esophagectomy for recurrence (6,7). In addition, targeted therapies against human epidermal growth factor receptor 2 (HER2) amplifications, microsatellite instability-high (MSI-H) status, programmed death-ligand 1 (PD-L1) expression, and neurotrophic tyrosine receptor kinase gene fusions, as well as tumor mutational burden, are used to improve outcomes in advanced disease, and emerging studies demonstrate some efficacy in the perioperative setting (8-10).

Notably, historical trials leading to the perioperative standard of care (SOC) protocols used today have varied in design and patient populations. They have combined cases of EC, gastroesophageal junction cancers (GEJ), and gastric cancers (GC), and their histologies have varied. We now understand that these tumors are heterogeneous and that treatment response may vary depending on anatomic location, histology, and genomic profiles (11). While significant progress has been made (Figure 1), inconsistency remains in the management of EC by oncologists and surgeons alike. As the field evolves, providers must be cognizant of the rationale for perioperative therapies, up-to-date with the available options, and aware of how molecular profiling integrates into decision-making to ensure an optimal upfront treatment strategy. Herein, we perform an updated review of the main historical and recently emerging studies that may impact the perioperative management of patients with locally advanced, upfront-resectable EC (cT2-T4aN0-3M0). We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-27/rc).

Figure 1 Timeline of landmark prospective perioperative trials in esophageal and gastric cancers. >: superior to; nCTX trials: peri-op CTX trials, adjuvant systemic therapy trials, radiation-based trials. aCRT, adjuvant chemoradiation; aCTX, adjuvant chemotherapy; CAPOX, capecitabine + oxaliplatin; CF, cisplatin + 5-fluorouracil; CRT, chemoradiation; CTX, chemotherapy; ECF, epirubicin + cisplatin + 5-fluorouracil; ECX, epirubicin + cisplatin + capecitabine; FLOT, 5-fluorouracil + leucovorin + oxaliplatin + docetaxel; FOLFOX, 5-fluorouracil + leucovorin + oxaliplatin; nCRT, neoadjuvant chemoradiation; nCTX, neoadjuvant chemotherapy; peri-op, perioperative.

Methods

The authors performed a literature review of pivotal studies in the perioperative management of locally advanced EC (Table 1).

Neoadjuvant treatment

Neoadjuvant chemotherapy

Many clinical trials have demonstrated survival benefits when neoadjuvant CTX (nCTX) is added to surgery in locally advanced esophageal AC and SCC (Table 2). The landmark phase 3 OEO2 study included patients with resectable esophageal AC (66%) and SCC (31%), and surgical outcome and 2-year OS were better with 2 cycles of neoadjuvant cisplatin and 5-fluorouracil (5-FU) (regimen referred to as CF) than with surgery alone: complete resection rates were 60% with CF plus surgery vs. 54% with surgery alone (P<0.0001), and 2-year OS was 43% vs. 34% [difference 9%; 95% confidence interval (CI): 3–14%] (15). Five-year OS was 23% vs. 17.1% [hazard ratio (HR) 0.84; 95% CI: 0.72–0.98; P=0.03], and the benefit was unrelated to tumor histology (16). Notably, RTOG 8911, another large randomized controlled trial (RCT), had reported conflicting results almost a decade earlier: neoadjuvant CF added to surgery did not improve OS (12). Locoregional failures and rates of complete microscopic, margin negative (R0) resections were also not statistically significantly different. However, in subgroup analyses, patients with an R0 resection experienced good long-term survival, irrespective of whether they received nCTX, whereas patients with a microscopic positive margin resection (R1) had poor survival (13). Another study evaluating 2 to 3 cycles of neoadjuvant CF in 96 patients with EC SCC demonstrated no OS benefit (P=0.55), but subgroups with R0 resections and clinical responses to nCTX tended to benefit more (14). While these were negative nCTX studies, their subgroup analyses highlighted the prognostic value of clinical responses to nCTX and R0 resection status. Incomplete resections may offset potential CTX benefits.

Several prospective studies have evaluated nCTX in AC and SCC independently. The Japanese JCOG9204 trial in SCC patients, in which OS was higher with 2 cycles of neoadjuvant CF than with upfront surgery and 2 cycles of adjuvant CF, led to wide acceptance of the neoadjuvant CF approach in Eastern countries where SCC is more prevalent (19). In 2022, the JCOG1109 phase 3 study demonstrated improved OS when nCTX was intensified from 2 cycles of CF to 3 cycles of 5-FU, cisplatin, and docetaxel (DCF) (20). Although these studies support an nCTX approach in SCC, the general preference in Western countries is to use nCRT over nCTX for locally advanced SCC (3,5), which will be discussed later in this review.

In AC, the phase 3 EORTC 40954 study of 144 GEJ (53%)/GC (47%) failed to demonstrate patient survival benefit with 2 cycles of neoadjuvant CF over subtotal gastrectomy with D1 or D2 lymphadenectomy alone. However, the interpretation of this study for EC and GEJ tumors is limited by low statistical power and omission of EC patients undergoing esophagectomy (21). nCTX did, however, improve R0 resection rates (81.9% vs. 66.7%, P=0.036). The OEO5 trial, which accrued patients with resectable EC/GEJ AC, attempted to expand on the positive results of OEO2. However, the study failed to demonstrate OS benefit with 4 cycles of intensified CTX with epirubicin, cisplatin, and capecitabine (ECX) over 2 cycles of standard CF (17). In thoracic EC/GEJ AC, CF is still the recommended nCTX regimen (3).

In summary, nCTX is tolerable and may improve R0 resection rates and OS. Survival benefit is mainly seen in patients undergoing high-quality R0 resections. In the US, neoadjuvant CF in thoracic EC/GEJ AC is the recommended regimen. Nonetheless, as discussed later in this review, other approaches are often practiced, such as nCRT or perioperative CTX for AC and nCRT for SCC (3).

Neoadjuvant plus adjuvant chemotherapy

The MAGIC phase 3 study published in 2006 established perioperative CTX as another SOC approach in AC (4). The study randomized 503 patients with GC (372 patients; approx. 74%), lower EC (73; 14.5%), and GEJ AC (58; 11.5%) to surgery with or without perioperative epirubicin, cisplatin, and 5-FU (ECF). Perioperative ECF improved progression-free survival (PFS) (HR 0.66; 95% CI: 0.53–0.81; P<0.001) and OS (HR 0.75; 95% CI: 0.60–0.93; P=0.009). The 5-year OS was higher with perioperative CTX (36%) than without (23%). Similar survival benefits and improved curative resection rates were reported in the FNLCC/Francophone Federation of Digestive Cancer Research (FFCD) phase 3 trial, which compared perioperative CF to surgery alone (Table 3) (22).

However, in 2019, the landmark FLOT4 phase 2/3 trial led to the current SOC perioperative CTX regimen for AC: 4 cycles of neoadjuvant and adjuvant 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) (23). The FLOT regimen was compared with the MAGIC regimen in 716 patients with non-metastatic, resectable GC (44%) and GEJ cancer [Siewert I (23%) and II or III (33%)], the clinical stages of which were cT2 or higher with or without positive nodes (23). The FLOT regimen resulted in improved PFS (30 vs. 18 months; HR 0.75; 95% CI: 0.62–0.91; P=0.004), OS (50 vs. 35 months; HR 0.77; 95% CI: 0.63–0.94; P=0.012), and R0 resection rates (85% vs. 78%; P=0.0162). The FLOT group also had more downstaging with improved ypT1 (49% vs. 41%; P=0.025) and ypN0 rates (49% vs. 41%; P=0.025). Consequently, FLOT became a current SOC perioperative approach for clinically staged T2+/any N GEJ/GC AC (25).

Although limited in number, studies in SCC have demonstrated superior OS and recurrence-free survival in patients with EC when perioperative CTX is used over nCTX alone (3,24).

Neoadjuvant chemoradiation

Many trials also elucidated the benefits of neoadjuvant CRT (nCRT) (Table 4). The landmark CROSS trial, published in 2012, established the contemporary SOC nCRT approach and set the current benchmarks for 5-year survival and pathologic complete response (ypCR) rates (5). Three hundred and sixty-eight patients with EC (73%)/GEJ (24%)/unknown (3%) (75% AC, 23% SCC, 2% other) were randomized to 5 cycles of weekly paclitaxel plus carboplatin with concurrent 41.4 Gy radiation (23 fractions of 1.8 Gy) followed by surgery 4–6 weeks after completion vs. surgery alone. nCRT resulted in higher R0 resection (92% vs. 69%; P<0.001) and no notable differences in postoperative complications. The median OS was 49.4 vs. 24.0 months, and 5-year OS rates were 47% vs. 34% (HR 0.657; 95% CI: 0.495–0.871; P=0.003), favoring nCRT. At a median follow-up time of 84.1 months, further analysis demonstrated that the median OS benefit persisted, which was greater with nCRT than with surgery alone (48.6 vs. 24.0 months; HR 0.48, 95% CI: 0.53–0.88; P=0.003) (31). OS benefits were also sustained in AC (10-year OS 36% with nCRT vs. 26% with surgery alone) and notably to a greater extent in SCC (10-year OS 46% with nCRT vs. 23% with surgery alone) subgroups.

The CROSS arm demonstrated 29% ypCR rates. ypCR rates were significantly higher in SCC (49%) than in AC (23%), P=0.008 (5). Subsequent analysis of data from 422 patients from the CROSS and preceding phase 2 trials revealed that locoregional recurrence was lower for the nCRT arm (14%) than for the surgery-alone arm (34%), P<0.001, and the occurrence of peritoneal carcinomatosis (4% vs. 14%; P<0.001) and reduced distant metastases (29% vs. 35%; P=0.025) followed the same trend. The overall recurrence rates were also lower (35%) for nCRT than for surgery alone (58%) (32). Notably, patients who achieved a ypCR had lower recurrence rates (17%) than those with residual pathologic disease (42%). This study, among others, supported ypCR as a prognostic biomarker for survival and relapse (33-35).

nCRT with concurrent FOLFOX (5-FU, leucovorin, oxaliplatin) has also achieved a 28% ypCR rate and a 3-year OS rate of 45% in patients with stage 2/3 EC AC (28). FOLFOX and the CROSS regimens are being compared in the ongoing phase 2 PROTECT-1402 study (NCT02359968). The ypCR rates from nCRT trials are generally higher than those historically reported (2–20%) with nCTX alone, especially in SCC (19,36,37). Therefore, in addition to the option of perioperative CTX, the CROSS regimen or nCRT with FOLFOX is recommended for locally advanced EC/GEJ AC and particularly for SCC (3).

Chemoradiation versus chemotherapy

Only a few studies have directly compared nCTX with nCRT; however, these studies have yielded controversial results (36-41). Phase 2 studies such as that by Burmeister et al. (albeit underpowered and closed prematurely) and the NeoRes study have demonstrated higher ypCR rates with nCRT (28–31%) than with nCTX (8–9%). Improved R0 resection rates but no significantly improved survival rates have been observed, except in subgroups with ypCR (36,37). Meta-analysis of 5,496 patients from 31 RCTs reported better OS with nCRT than with nCTX, surgery alone, or neoadjuvant radiation, albeit at the expense of an increased risk of postoperative mortality (40). In addition, a systematic review of 5 RCTs, collectively accruing 709 patients, reported that nCRT in AC/SCC produced better R0 and ypCR rates than nCTX; however, nCRT improved 3-year OS in SCC only (41).

In SCC, an interim analysis from a recent Chinese RCT demonstrated improved pathological response rates with nCRT over nCTX (using a CF backbone) with no survival benefit (42). However, 3-year OS results (the primary endpoint) are pending. Similar patterns of improved pathologic responses but no survival benefit were noted in the JCOG 1109 phase 3 trial of nCTX vs. nCRT using CF in SCC (20). In AC, the phase 3 German POET study compared nCTX to nCRT using CF backbones in GEJ tumors, but the nCRT arm also received induction CF before nCRT. The nCRT arm had improved pathological outcomes (ypCR 15.6% vs. 2%; P=0.03) but no statistically significant OS benefit (46.7% vs. 26.1%; P=0.07), although this study was underpowered (38).

In the US, for AC, both perioperative FLOT and CROSS are SOC options for EC/GEJ AC. Although each approach achieved similar 5-year OS rates (45% and 47%, respectively), their respective trials varied in design, especially as FLOT4 included only gastric AC (44%) and GEJ AC (56%) and CROSS included both SCC and AC [mostly esophageal (73%) and GEJ (24%); no gastric]. The European NeoAegis phase 3 study was the first RCT to compare CROSS with perioperative CTX (either the MAGIC regimen or FLOT after its approval in 2019) in 377 patients with locally advanced EC/GEJ AC (43). Although CROSS resulted in improved R0 resection rates and pathologic outcomes, the estimated 3-year OS was not statistically significantly different after a median follow-up of 34.2 months. However, any strict interpretation of this study is limited because of the fact that 85% of patients in the perioperative CTX arm were treated with the sub-standard MAGIC regimen, the adjuvant SOC after CROSS has since changed, and the fact that patterns of recurrence and quality of life data are pending.

Whether nCRT or perioperative CTX should be used in lower EC/GEJ AC is still under debate. Ongoing phase 3 studies, such as the ESOPEC trial—which uses current protocols—will hopefully answer this question (NCT02509286). Providers often consider nCRT in EC, bulky tumors, and GEJ (Siewert I/II), whereas FLOT is considered in GEC (Siewert III) and GC, although these approaches may vary by institution. In SCC, nCRT remains the preferred approach in the US. This standard is based on CROSS and other trials demonstrating improved downstaging and ypCR rates with nCRT. In fact, with high ypCR rates, many SCC patients may be cured with CRT alone, and this non-surgical approach is increasingly adopted (3).

Sequential chemotherapy and chemoradiation

Although nCRT yields better survival rates and local control than surgery alone, it has failed to significantly improve distant metastatic recurrence rates, which are commonly around 27–28% (44). The idea of sequentially delivering nCTX and nCRT is theoretically attractive as it may increase systemic therapy compliance, induce earlier clinical responses in symptomatic patients, and address micro-metastatic disease earlier. Only a few studies have tested nCRT with and without induction CTX but have failed to provide robust data to support a ypCR or OS advantage with induction CTX (45,46).

Ajani et al. randomized 162 EC/GEJ AC/SCC patients in a phase 2 trial to nCRT (50.4 Gy with FOLFOX) with and without 8 weeks of induction FOLFOX and found no improvement in the primary endpoint of ypCR rates and no OS benefit (45). An Alliance phase 2 trial randomized 55 EC/GEJ AC patients to nCRT (50.4 Gy with FOLFOX) with and without induction docetaxel, oxaliplatin, and capecitabine. The study demonstrated futility and was terminated when its primary endpoint of ypCR was not met (28.6% vs. 40.7%, P=0.34). However, long-term follow-up demonstrated a more prolonged median OS with induction CTX, especially in well-to-moderately differentiated tumors (46). Although no RCT has demonstrated an adequately powered survival benefit with an induction CTX approach, emerging clinical response data following induction therapy to optimize neoadjuvant regimens are promising.

Positron emission tomography (PET)-guided neoadjuvant therapy

Studies suggest that patients who lack early radiographic or PET-metabolic tumor responses after a course of nCTX have poor prognoses compared to their counterparts and may not be benefiting from a given therapy (13,47,48). Metabolic non-responders have worse survival, higher recurrence rates, and lower ypCR rates. The concept of switching nCTX according to early PET-response evaluation was evaluated in the recent CALGB 80803 trial (49). EC/GEJ AC patients with PET-avid locally advanced disease were randomized to induction FOLFOX versus induction carboplatin and paclitaxel. After a course of induction CTX, if patients in either arm had a response by PET [≥35% decrease in standardized uptake value (SUV)], they were to continue with the same CTX backbone with concurrent radiation added prior to surgery. If patients were non-responders, they were switched over to the other CTX regimen with radiation.

After a median follow-up time of 5.2 years, there was no statistically significant difference in OS between responders and non-responders (HR 1.34; 95% CI: 0.94–1.92), suggesting that a switch in therapy in non-responders improved their survival. ypCR rates in non-responders also improved. While FOLFOX responders who continued FOLFOX with CRT had the best 5-year OS of 53%, the study was not powered to compare the induction CTX regimens head-to-head. Overall, this trial supported utilizing a PET-adapted approach in optimizing an individual’s neoadjuvant regimen. This approach could also potentially be applied when testing novel therapies in this setting.

Role of targeted therapies

With several Food and Drug Administration (FDA) approvals for targeted therapy in the advanced setting, there is growing interest in studying these therapies in the perioperative setting. Although targeted therapies like anti-epidermal growth factor receptor antibodies and anti-vascular endothelial growth factor antibodies have failed to improve outcomes, testing of alternative systemic agents continues (50,51).

Amplifications of HER2, a receptor tyrosine kinase in the epidermal growth factor family, drive oncogenesis in about 10–40% of EC (8,52). Trastuzumab, an anti-HER2 monoclonal antibody, improved OS when added to front-line CTX in advanced/metastatic disease and is now SOC in patients with HER2-amplified GEJ/GC (53). Unfortunately, a phase 3 trial failed to demonstrate that adding trastuzumab to trimodal therapy in HER2-amplified disease improved ypCR rates (27% with trastuzumab vs. 29% without trastuzumab) and DFS (HR 0.99; 95% CI: 0.71–1.39; P=0.97) (54). However, the single-arm, phase 2 TRAP study demonstrated promising results with nCRT, trastuzumab, and pertuzumab (another anti-HER2 monoclonal antibody), with a 100% R0 resection rate, 34% ypCR, and 71% 3-year OS rates (8).

The PETRARCA randomized phase 2 study compared FLOT to FLOT with perioperative trastuzumab and pertuzumab in HER2-amplified GEJ/GC AC. The trial demonstrated similar post-surgical R0 resection rates and mortality but improved ypCR (35% vs. 12%; P=0.02; primary endpoint) and tumor downstaging in favor of the HER2-targeting arm (9). In a highly HER2 amplified subgroup [HER2 3+ immunohistochemistry (IHC)], ypCR rates were strikingly higher in the experimental arm (41%) than in the FLOT arm (12%) (P=0.066) (55). Unfortunately, the study closed prematurely and did not proceed to the phase 3 portion after negative results from the JACOB trial, which used trastuzumab, pertuzumab, and CTX to treat patients with advanced disease (56). Nonetheless, the median DFS in the PETRARCA study was greater (not reached) in the experimental arm than in the control arm (26 months; P=0.14). The median OS was not reached in both arms at a median 22-month follow-up. The results of the ongoing phase 2 EORTC 1203 trial are pending. When released, it is hoped that they will help ascertain the benefits of adding either trastuzumab alone or trastuzumab plus pertuzumab to perioperative CTX compared to CTX alone (57). Until there is robust RCT survival data supporting the incorporation of HER2-targeting agents into treatment regimens for HER2-amplified tumors, nCRT and nCTX will likely remain the perioperative SOC.

More recently, immunotherapy with immune checkpoint inhibitor (ICI) monoclonal antibodies has been studied in the neoadjuvant setting, given its successes and FDA approvals in advanced-stage disease (58,59). ICIs target and inhibit tumor and immune cell-surface markers; for example, programmed death-1 (PD-1), PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which are often implicated in tumor immune evasion. A phase 2 trial demonstrated 30% ypCR rates when atezolizumab (anti-PD-L1) was added to CROSS. However, when outcomes were compared to a propensity score-matched nCRT cohort, there was no significant difference in response or survival (60). Exploratory tumor-biopsy and PD-L1 expression biomarker analyses failed to identify response or survival differences, although there were trends toward improved outcomes with higher PD-L1 expression. Higher baseline tumor type II interferon gene signatures were linked with tumor response. In contrast, on-treatment biopsies enriched with cytotoxic lymphocytes and genes associated with T-cell exhaustion were linked to non-response.

A US phase 2 trial treated locally advanced EC/GEJ AC patients with nCRT combined with pembrolizumab (PD-1 inhibitor) and adjuvant pembrolizumab (61). The primary endpoint of major pathologic response (MPR) (defined as ypCR or near-ypCR) in 31 evaluable patients was striking at 50% and was much higher than historical controls (around 30%). MPR rates were higher in EC than GEJ (73.3% vs. 33.3%; P=−0.02) and predicted improved DFS (1-year DFS 100% vs. 31.8% in non-MPR patients; P=0.002). Correlative tissue analysis suggested that tumor microenvironment immune signatures varied by tumor location (EC vs. GEJ) and correlated with response. For example, responders were enriched with CD8⁺ T cells and monocytes, whereas poor responders were enriched with dendritic cells and activated B-cells.

Single-arm trials have demonstrated promising ypCR rates (33.3%) for non-radiation regimens when combining nCTX with PD-1 inhibitors in EC (62). The DANTE phase 2 study randomized patients with GEJ/GC AC to perioperative FLOT with and without atezolizumab. Interim results recently published showed similar rates of R0 resection but higher rates of pathologic tumor regression, especially in patients with tumors with higher PD-L1 expression (63). A recent meta-analysis of phase 2 non-randomized trials using neoadjuvant ICI either alone or in combination with other therapies in over 800 resectable EC patients reported pooled ypCR rates of 31.4% [with higher rates in SCC (32.4%) compared to AC (25.2%)] and high rates of R0 resections (98.6%) (57). Collectively, these data demonstrate promising early results and potential predictive biomarkers which require further study. More extensive confirmatory studies with longer follow-ups demonstrating survival advantages may be needed before ICIs are incorporated as SOC in neoadjuvant regimens, and there are many ongoing trials (Table 5).

MSI-H/deficient mismatch repair status (dMMR) is a well-established predictive biomarker associated with improved ICI efficacy across many tumor types, partly attributed to resultant hypermutated tumors, higher neoantigen loads, and enhanced tumor immunogenicity (64). However, this biomarker is not always checked in early-stage EC, and CRT/CTX remains the SOC regardless of microsatellite status. In 2022, a phase 2 study evaluating combined nivolumab and ipilimumab (anti-CTLA4) without nCTX/CRT and postoperative nivolumab in MSI-H/dMMR GEJ/GC patients revealed 100% R0 resection rates and a remarkable 59% ypCR rate, with 94% of patients remaining event-free at a 12-month median follow-up (10). More recently, in 2023, the phase 2 INFINITY trial using neoadjuvant durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA4) resulted in 60% ypCR and 80% major-complete pathologic response rates (65). Although longer follow-up is needed, ICIs alone will probably become a treatment of choice in the MSI-H/dMMR tumor subset (66).

Several ongoing trials are assessing the role of immunotherapy in the perioperative setting, with a potential shift in the treatment paradigm in the coming years (Table 5). Currently, molecular profiling to guide targeted therapy is primarily reserved for patients with advanced disease. However, with expanding commercialized tissue/plasma next-generation sequencing assays and targeted perioperative clinical trials, its role may become increasingly relevant in earlier disease stages.

Definitive chemoradiation

The idea of forgoing surgery after CRT has been evaluated over decades, particularly in SCC. Esophageal SCC tends to be more radiosensitive and develops higher in the esophagus, where surgery may be morbid and challenging (Table 4). Two major RCTs have compared definitive CRT with nCRT and surgery. Stahl et al. randomized 172 upper and mid-third T3-4N0-1 SCC patients to induction CTX followed by CRT (40 Gy) and surgery or definitive induction CTX followed by CRT (65 Gy). The investigators found that pursuing surgery improved local control but resulted in higher post-treatment mortality without OS improvement (30). Similar findings were reported by the FFCD 9102 study, which mainly included SCC patients (89%) (7). A multicenter, retrospective study of 616 patients also reported no DFS or OS difference between trimodal therapy and definitive CRT with salvage surgery in the event of persistent or recurrent resectable disease (67). However, salvage surgery was associated with more anastomotic leaks and surgical site infections. Other prospective studies like RTOG 0246 have demonstrated promising survival rates when using a selective surgical approach in patients with AC/SCC, showing clinical complete responses (cCR) by biopsy and imaging after nCRT (68). Only 20% of patients with cCR required a salvage procedure, and of patients who did not achieve cCR patients, 80% were able to have their tumor resected with minimal morbidity. However, to successfully employ a selective surgical approach, accurate prediction of residual disease is critical.

Our current radiology and biopsy techniques and attempted prediction models using clinical and molecular data are insufficient for predicting residual disease independently (44,69,70). However, the Pre-SANO trial determined that combining modern diagnostics (endoscopy, ultrasound, improved biopsy techniques, and PET scans) was adequate in detecting residual disease (71). These diagnostics are now being used in ongoing, randomized, phase 3 trials (SANO and ESOSTRATE) to evaluate active surveillance vs. surgery in patients with cCR prospectively.

Today, definitive CRT, with surgery reserved as a salvage measure, is an acceptable approach for select patients with cCR after nCRT, particularly for SCC patients. Although this approach can be discussed with AC patients who achieve cCR, the lower ypCR rates and fewer data in AC mean that SOC trimodal therapy is often preferred and still considered SOC. A definitive CRT approach is desirable for poor surgical candidates with comorbidities or patients who decline surgery. Of note, the recommended radiation dose of 50.4 Gy for definitive CRT is higher than that of a standard nCRT regimen (5,72).

Surgical approach

While open esophagectomy has historically been the SOC surgical approach, minimally invasive esophagectomy (MIE) has been increasingly pursued. Compared to an open approach, MIE has demonstrated excellent oncologic outcomes and decreased blood loss, lengths of hospital stays, and perioperative mortality (73-78). Much of these data come from single-institution studies. A multicenter RCT (TIME) comparing the approaches identified lower rates of pulmonary complications (9% vs. 29%, P=0.005) and shorter hospital stays (median 11 vs. 14 days, P=0.044) in the MIE group with a similar rate of anastomotic leaks (12% vs. 7%, P=0.39) (79). A subsequent study focusing on long-term outcomes found no significant differences in 3-year OS (41% vs. 43%) and DFS (37% vs. 43%) between the open and MIE groups, respectively (80). Large database studies comparing the techniques have also reported shorter hospital stays and similar rates of anastomotic leaks, 30-day mortality, and oncologic survival with MIE (77,81). Recently, the ROBOT trial evaluating robotic-assisted MIE and open esophagectomy reported lower rates of postoperative blood loss, cardiopulmonary complications, and pain scores with the robotic approach (82). Although MIE is technically demanding, multiple studies have demonstrated its safety and feasibility, comparable oncologic outcomes, and association with improved postoperative morbidity.

Adjuvant therapy

Following neoadjuvant chemoradiation

While nCRT emerged as a SOC approach in the US and Western Europe, the benefits of adjuvant CTX (aCTX) in this setting were not well defined. There is an understanding that patients with pathologic residual disease or involved LNs after neoadjuvant therapy are at high risk for poor outcomes. Nevertheless, contemporary studies, such as CROSS, which guide our SOC management today, evaluated all therapies pre-operatively without mandating adjuvant treatment or randomizing patients into adjuvant treatment arms (33-35,83).

Large retrospective studies like a propensity-matched National Cancer Database (NCDB) cohort study that included EC/GEJ AC treated with nCRT before curative-intent surgery suggested better OS with aCTX than mere observation (84). Another similar retrospective, propensity-score-matched NCDB study of EC AC treated with nCRT and R0 resection but only including patients with ypN+ status demonstrated greater OS benefit with aCTX than observation (85). A third NCDB retrospective study, this time including AC (85%) and SCC (15%) regardless of ypT or N status, reported improved OS, especially in ypN+ cases, with aCTX (86). While these studies suggested survival benefits, especially in patients with pathologic residual disease, robust prospective data are lacking, and the optimal CTX regimen is unclear. In addition, it is challenging to administer cytotoxic CTX after a major esophagectomy: less than 50% of patients can tolerate and complete intended adjuvant regimens (4,87). Therefore, many providers previously recommended practicing patient observation regardless of pathologic status after nCRT.

However, in 2021, the Checkmate 577 study changed the treatment paradigm in this space and reduced the clinical relevance of aCTX. The ICI nivolumab (anti-PD-1) was studied in the adjuvant setting after trimodal therapy for EC in the randomized, double-blind, phase 3 trial (66). Patients with at least ypT1 or ypN1 resected AC/SCC were randomly assigned to nivolumab or placebo irrespective of PD-L1 status for up to 1 year. The median DFS doubled in the treatment arm (24.4 vs. 11 months; P<0.001) without compromising patient quality of life. All subgroups benefited irrespective of the pathological tumor status, LN involvement, stage at initial diagnosis, location of the tumor, or PD-L1 expression. The FDA approved nivolumab on May 20, 2021, and the current National Comprehensive Cancer Network (NCCN) guidelines recommend up to 1 year of adjuvant nivolumab for SCC and AC patients who received nCRT followed by an R0 resection with pathological residual disease. However, observation until progression is an alternative option (3,88). The role of ICI in definitive CRT is unknown but is currently being evaluated. After trimodal therapy, surveillance is recommended for AC/SCC patients with R0 resections and ypT0N0 status. With an R1 resection, re-resection (for AC) or observation until progression are options, while palliative management is considered for R2 resections per NCCN guidelines (3).

Following neoadjuvant chemotherapy

For those pursuing perioperative CTX, the landmark studies (such as the MAGIC and FLOT trials) were designed to continue the same CTX regimen post-operatively regardless of whether there were pathologic responses or nodal involvement at the time of surgery. Currently, there are no available trial data to guide switching adjuvant therapies on the basis of pathological or clinical responses, although studies in this space are likely warranted (Table 6).

The CRITICS phase 3 trial aimed to determine if GEJ/GC AC patients receiving nCTX (using a MAGIC CTX backbone) and surgery benefited from adjuvant CRT (aCRT) rather than aCTX (94). The results showed no significant local control, distant metastases, or survival benefit with aCRT over aCTX. However, patients in this study may have been under-staged (only 10% had diagnostic laparoscopy, which is more commonly used today to diagnose metastatic disease upfront), and most patients underwent an inferior LN dissection by today’s standards (less than 10% had D2 lymphadenectomies). Additionally, the MAGIC regimen is currently substandard. While this study does not support a standard nCTX and aCRT approach in patients with R0 resections, if pathology reveals an R1 resection after the nCTX component of perioperative therapy, aCRT should be considered today for local control. aCRT, palliative systemic therapies, or best supportive care are options for patients with an R2 resection, depending on the individual’s functional status (3).

Following upfront surgery

Although most patients clinically staged with locally advanced disease should undergo some form of neoadjuvant treatment for various reasons, some patients may undergo an upfront resection or be upstaged at the time of pathologic review. In these cases, adjuvant therapy in the form of CTX or CRT is often recommended, especially for AC EC/GEJ.

In the phase 3 Intergroup 0116 study, 556 patients with resected T3+ and/or N+ GEJ/GC AC who underwent upfront R0 resections were randomly assigned to observation vs. aCRT (89). There was a relapse-free survival benefit (30 vs. 19 months; P<0.001) and OS benefit (36 vs. 27 months; P=0.005) in favor of aCRT arm (P=0.005). Although only 10% of patients underwent what is today an optimal lymphadenectomy, this study established aCRT as a potential SOC approach, especially in node-positive disease, and the results are extrapolated to manage higher EC ACs as well. Of note, a recent meta-analysis including 13 studies and 2,165 AC and SCC also demonstrated notable improvement in 5-year OS when comparing patients who received aCRT to those who had no aCRT. (95). There was also a reduction in local-regional recurrence rates (OR 0.58; 95% CI: 0.46–0.72; P<0.00001) but no significant difference in distant metastasis (OR 0.94; 95% CI: 0.68–1.30; P=0.70).

aCTX without radiation may also improve survival, but randomized studies in EC are scant. For AC, the single-arm, phase 2 ECOG 8296 study reported an encouraging 2-year OS rate (60%), which was improved from historical controls (P=0.0008) when 4 cycles of adjuvant cisplatin and paclitaxel were used in 59 distal EC/GEJ AC patients with R0 resections (96). The NCCN guideline recommendations of aCTX for EC/GEJ AC using FOLFOX or capecitabine plus oxaliplatin are mostly extrapolated from the CLASSIC trial. This trial primarily enrolled GC patients who had undergone tumor resection, including a D2 lymphadenectomy, and in whom 6 months of aCTX provided better 5-year DFS (68% vs. 53%; HR 0.58; 95% CI: 0.51–0.85; P=0.037) and 5-year OS (78% vs. 69%; HR 0.66; 95% CI: 0.51–0.85; P=0.0015) than no adjuvant therapy (93).

While there are demonstrable benefits with aCRT/aCTX over observation for patients with lower EC/GEJ/GC treated upfront with surgery, this is understudied for higher ECs, specifically SCC. In SCC, the JCOG 9904 study, including 242 patients, is the only major RCT evaluating aCTX versus no aCTX in EC SCC and reported a 5-year DFS (55% vs. 45%; P=0.037) but not OS benefit (P=0.13) with aCTX (92). There are also scant data comparing aCRT to CTX to guide the decision of choosing one over the other. Currently available data have led the NCCN to recommend surveillance following surgery in SCC with an R0 resection, regardless of pathological staging; aCRT with an R1 resection; and aCRT or palliative systemic treatment, if appropriate, with an R2 resection (3). For locally advanced AC diagnosed after upfront surgery, including some T2N0 disease with high-risk features (>2 cm, poorly-differentiated, lymphovascular invasion, perineural invasion) or in patients <50 years of age, some form of postoperative therapy is often indicated, including aCRT or CTX, although surveillance remains an alternative (3).

Potential role of circulating tumor DNA (ctDNA)

To date, physicians primarily use risk factors, as noted on a pathology report to guide whether to give adjuvant therapy. In addition, radiography and endoscopic evaluation, which lack accuracy in detecting residual disease or complete eradication of disease, are used to guide surgical or organ-sparing decisions. Improved modern tools are needed to risk-stratify patients for treatment escalation or de-escalation.

ctDNA, or circulating cell-free DNA derived from tumor cells, is a promising tool with prognostic and predictive potential. With advancements in genomic profiling, commercialized tests have emerged that can detect microscopic levels of cancer cells through ctDNA detection in the peripheral blood (97-99). In general, assays may be tumor-informed tests, in which specific mutations known to exist in a patient’s tumor are assessed in the blood using highly specific and sensitive personalized assays or plasma-only. Single genes, hot-spot mutations, or a broad collection of cancer-associated genes can also be assessed in the blood without requiring knowledge of pre-existing tumor mutations. Positive tests, signifying the presence of ctDNA, have demonstrated strong prognostic value as they identify residual disease with a lead time of months prior to radiographic relapse and predict worse DFS and OS (100). Amongst gastrointestinal cancers, most data published to date about the utility of ctDNA is in colorectal cancer, although studies evaluating ctDNA in EC/GEJ/GC are emerging. In a prospective study including 97 EC patients, cancer-specific survival (HR 5.55; 95% CI: 2.42–12.71; P=0.0003) and DFS (HR 2.35; 95% CI: 1.18–4.72; P=0.01) were worse in postoperative ctDNA-positive patients than in ctDNA-negative patients (101). ctDNA detection was also associated with worse PFS in a larger study, including 254 patients with EC/GEJ/GC (102). In another prospective study of 45 EC patients, ctDNA positivity after CRT equated to an 18.7 times higher risk of progression and 32.1 times higher risk of distant metastases, with ctDNA detection preceding radiographic release by an average of 2.8 months (103). Interestingly, ctDNA combined with metabolic imaging after CRT had higher accuracy in detecting tumor progression than ctDNA or metabolic imaging used independently (P<0.001). These studies demonstrate ctDNA as a potential tool in identifying a high-risk group of patients destined for relapse who may benefit from completion surgery or augmented adjuvant therapy.

While these studies highlight the prognostic value of a positive ctDNA test, they are primarily observational and include small numbers of patients. Providers must know the sensitivity limitations related to tumor stage, histology, and anatomic location. These tumor characteristics may affect the degree of “ctDNA tumor shedding”. So, too, providers must be aware of false positives due to clonal non-malignant processes in hematological cells in aging populations, called clonal hematopoiesis of indeterminate potential (104-106). Well-populated, prospective, randomized studies are needed to validate ctDNA as a predictive tool before physicians can use it to guide surgery and perioperative escalation or de-escalation strategies.

Conclusions

In summary, nCRT or definitive CRT with salvage surgery are the preferred approaches for SCC based on higher radiosensitivity, impressive ypCR rates, and survival benefits based on CROSS and definitive CRT trials. In AC, completion surgery is recommended due to lower ypCR rates with nCTX/nCRT, and nCRT is recommended for proximal tumors, while nCRT or perioperative CTX are both acceptable options for lower EC/GEJ tumors based on the CROSS, FLOT4, and NeoAegis trials. Novel strategies to build upon the successes of perioperative CTX and CRT are imperative for EC patients. Precision medicine using tissue/blood-based genomic biomarkers is becoming increasingly relevant and has the potential to revolutionize perioperative treatments for EC. With continued research and improved funding for such a fatal disease, we hope to better understand the molecular mechanisms of this aggressive malignancy and personalize therapies to improve oncologic outcomes.

Acknowledgments

We thank Marion L. Hartley, PhD (The Ruesch Center for the Cure of GI Cancers, Georgetown University, Washington, DC, USA) for editing this manuscript during the writing process.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-27/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-27/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-27/coif). RM has consulted for Aptitude Health, received research funding paid to her institution from Genentech, Inc and Natera, Inc. for an investigator initiated trial, and participates on the Georgetown Data Safety Monitoring Committee. RM and AA have consulted for WebMD Medscape for reviewing educational transcripts. MSN has consulted for Ipsen, Merus, and Daiichi Sankyo and received research support paid to his institution from Erytech for an investigator initiated trial. The other authors have 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/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Cancer Stat Facts: Esophageal Cancer. In: NIH Surveillance, Epidemiology, and End Results Program. 2021. Available online: https://seer.cancer.gov/statfacts/html/esoph.html (accessed May 4, 2022).
3. NCCN. NCCN Guidelines Version 2.2022 Esophageal and Esophagogastric Junction Cancers. 2022. Available online: https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf (accessed Apr 4 2022).
4. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20. [Crossref] [PubMed]
5. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074-84. [Crossref] [PubMed]
6. Stahl M, Wilke H, Lehmann N, et al. Long-term results of a phase III study investigating chemoradiation with and without surgery in locally advanced squamous cell carcinoma (LA-SCC) of the esophagus. J Clin Oncol 2008;26:abstr 4530.
7. Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 2007;25:1160-8. [Crossref] [PubMed]
8. Stroes CI, Schokker S, Creemers A, et al. Phase II Feasibility and Biomarker Study of Neoadjuvant Trastuzumab and Pertuzumab With Chemoradiotherapy for Resectable Human Epidermal Growth Factor Receptor 2-Positive Esophageal Adenocarcinoma: TRAP Study. J Clin Oncol 2020;38:462-71. [Crossref] [PubMed]
9. Hofheinz RD, Haag GM, Ettrich TJ, et al. Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone for HER2-positive resectable esophagogastric adenocarcinoma: Final results of the PETRARCA multicenter randomized phase II trial of the AIO. J Clin Oncol 2020;38:abstr 4502.
10. Andre T, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): The GERCOR NEONIPIGA phase II study. J Clin Oncol 2022;40:abstr 244.
11. Barrak DK, Deldar R, Halbert SA, et al. Field Defect in Esophageal Cancer: A Stochastic Evolution in Cancer Biology. Ann Thorac Surg 2022;113:1069-72. [Crossref] [PubMed]
12. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979-84. [Crossref] [PubMed]
13. Kelsen DP, Winter KA, Gunderson LL, et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol 2007;25:3719-25. [Crossref] [PubMed]
14. Ancona E, Ruol A, Santi S, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer 2001;91:2165-74. [Crossref] [PubMed]
15. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002;359:1727-33. [Crossref] [PubMed]
16. Allum WH, Stenning SP, Bancewicz J, et al. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 2009;27:5062-7. [Crossref] [PubMed]
17. Alderson D, Cunningham D, Nankivell M, et al. Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial. Lancet Oncol 2017;18:1249-60. [Crossref] [PubMed]
18. Boonstra JJ, Kok TC, Wijnhoven BP, et al. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer 2011;11:181. [Crossref] [PubMed]
19. Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 2012;19:68-74. [Crossref] [PubMed]
20. Kato K, Ito Y, Daiko H, et al. A randomized controlled phase III trial comparing two chemotherapy regimen and chemoradiotherapy regimen as neoadjuvant treatment for locally advanced esophageal cancer, JCOG1109 NExT study. J Clin Oncol 2022;40:abstr 238.
21. Schuhmacher C, Gretschel S, Lordick F, et al. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol 2010;28:5210-8. [Crossref] [PubMed]
22. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011;29:1715-21. [Crossref] [PubMed]
23. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 2019;393:1948-57. [Crossref] [PubMed]
24. Zhao Y, Dai Z, Min W, et al. Perioperative versus Preoperative Chemotherapy with Surgery in Patients with Resectable Squamous Cell Carcinoma of Esophagus: A Phase III Randomized Trial. J Thorac Oncol 2015;10:1349-56. [Crossref] [PubMed]
25. NCCN. NCCN Guidelines Version 2.2022 Gastric Cancer. 2022. Available online: https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf (accessed Apr 11 2022).
26. Yang H, Liu H, Chen Y, et al. Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial. J Clin Oncol 2018;36:2796-803. [Crossref] [PubMed]
27. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 2008;26:1086-92. [Crossref] [PubMed]
28. Leichman LP, Goldman BH, Bohanes PO, et al. S0356: a phase II clinical and prospective molecular trial with oxaliplatin, fluorouracil, and external-beam radiation therapy before surgery for patients with esophageal adenocarcinoma. J Clin Oncol 2011;29:4555-60. [Crossref] [PubMed]
29. Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol 2014;15:305-14. [Crossref] [PubMed]
30. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 2005;23:2310-7. [Crossref] [PubMed]
31. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 2015;16:1090-8. [Crossref] [PubMed]
32. Oppedijk V, van der Gaast A, van Lanschot JJ, et al. Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol 2014;32:385-91. [Crossref] [PubMed]
33. Chirieac LR, Swisher SG, Ajani JA, et al. Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation. Cancer 2005;103:1347-55. [Crossref] [PubMed]
34. Rohatgi P, Swisher SG, Correa AM, et al. Characterization of pathologic complete response after preoperative chemoradiotherapy in carcinoma of the esophagus and outcome after pathologic complete response. Cancer 2005;104:2365-72. [Crossref] [PubMed]
35. Blum Murphy M, Xiao L, Patel VR, et al. Pathological complete response in patients with esophageal cancer after the trimodality approach: The association with baseline variables and survival-The University of Texas MD Anderson Cancer Center experience. Cancer 2017;123:4106-13. [Crossref] [PubMed]
36. Burmeister BH, Thomas JM, Burmeister EA, et al. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial. Eur J Cancer 2011;47:354-60. [Crossref] [PubMed]
37. Klevebro F, Alexandersson von Döbeln G, Wang N, et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann Oncol 2016;27:660-7. [Crossref] [PubMed]
38. Stahl M, Walz MK, Riera-Knorrenschild J, et al. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. Eur J Cancer 2017;81:183-90. [Crossref] [PubMed]
39. von Döbeln GA, Klevebro F, Jacobsen AB, et al. Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or gastroesophageal junction: long-term results of a randomized clinical trial. Dis Esophagus 2019; [Crossref] [PubMed]
40. Chan KKW, Saluja R, Delos Santos K, et al. Neoadjuvant treatments for locally advanced, resectable esophageal cancer: A network meta-analysis. Int J Cancer 2018;143:430-7. [Crossref] [PubMed]
41. Deng HY, Wang WP, Wang YC, et al. Neoadjuvant chemoradiotherapy or chemotherapy? A comprehensive systematic review and meta-analysis of the options for neoadjuvant therapy for treating oesophageal cancer. Eur J Cardiothorac Surg 2017;51:421-31. [PubMed]
42. Wang H, Tang H, Fang Y, et al. Morbidity and Mortality of Patients Who Underwent Minimally Invasive Esophagectomy After Neoadjuvant Chemoradiotherapy vs Neoadjuvant Chemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial. JAMA Surg 2021;156:444-51. [Crossref] [PubMed]
43. Reynolds JV, Preston SR, O’Neill B, et al. Neo-AEGIS (Neoadjuvant Trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): Final primary outcome analysis. J Clin Oncol 2023;41:abstr 295.
44. Eyck BM, van Lanschot JJB, Hulshof MCCM, et al. Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial. J Clin Oncol 2021;39:1995-2004. [Crossref] [PubMed]
45. Ajani JA, Xiao L, Roth JA, et al. A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer. Ann Oncol 2013;24:2844-9. [Crossref] [PubMed]
46. Yoon HH, Ou FS, Soori GS, et al. Induction versus no induction chemotherapy before neoadjuvant chemoradiotherapy and surgery in oesophageal adenocarcinoma: a multicentre randomised phase II trial (NCCTG N0849 [Alliance]). Eur J Cancer 2021;150:214-23. [Crossref] [PubMed]
47. Ott K, Weber WA, Lordick F, et al. Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction. J Clin Oncol 2006;24:4692-8. [Crossref] [PubMed]
48. Lordick F, Ott K, Krause BJ, et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol 2007;8:797-805. [Crossref] [PubMed]
49. Goodman KA, Ou FS, Hall NC, et al. Randomized Phase II Study of PET Response-Adapted Combined Modality Therapy for Esophageal Cancer: Mature Results of the CALGB 80803 (Alliance) Trial. J Clin Oncol 2021;39:2803-15. [Crossref] [PubMed]
50. Suntharalingam M, Winter K, Ilson D, et al. Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial. JAMA Oncol 2017;3:1520-8. [Crossref] [PubMed]
51. Bendell JC, Meluch A, Peyton J, et al. A phase II trial of preoperative concurrent chemotherapy/radiation therapy plus bevacizumab/erlotinib in the treatment of localized esophageal cancer. Clin Adv Hematol Oncol 2012;10:430-7. [PubMed]
52. Gerson JN, Skariah S, Denlinger CS, et al. Perspectives of HER2-targeting in gastric and esophageal cancer. Expert Opin Investig Drugs 2017;26:531-40. [Crossref] [PubMed]
53. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-97. [Crossref] [PubMed]
54. Safran HP, Winter K, Ilson DH, et al. Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial. Lancet Oncol 2022;23:259-69. [Crossref] [PubMed]
55. Hofheinz RD, Merx K, Haag GM, et al. FLOT Versus FLOT/Trastuzumab/Pertuzumab Perioperative Therapy of Human Epidermal Growth Factor Receptor 2-Positive Resectable Esophagogastric Adenocarcinoma: A Randomized Phase II Trial of the AIO EGA Study Group. J Clin Oncol 2022;40:3750-61. [Crossref] [PubMed]
56. Tabernero J, Hoff PM, Shen L, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol 2018;19:1372-84. [Crossref] [PubMed]
57. Wagner AD, Grabsch HI, Mauer M, et al. EORTC-1203-GITCG - the "INNOVATION"-trial: Effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer group. BMC Cancer 2019;19:494. [Crossref] [PubMed]
58. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398:27-40. [Crossref] [PubMed]
59. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021;398:759-71. [Crossref] [PubMed]
60. van den Ende T, de Clercq NC, van Berge Henegouwen MI, et al. Neoadjuvant Chemoradiotherapy Combined with Atezolizumab for Resectable Esophageal Adenocarcinoma: A Single-arm Phase II Feasibility Trial (PERFECT). Clin Cancer Res 2021;27:3351-9. [Crossref] [PubMed]
61. Shah MA, Almhanna K, Iqbal S, et al. Multicenter, randomized phase II study of neoadjuvant pembrolizumab plus chemotherapy and chemoradiotherapy in esophageal adenocarcinoma (EAC). J Clin Oncol 2021;39:abstr 4005.
62. Shen D, Chen Q, Wu J, et al. The safety and efficacy of neoadjuvant PD-1 inhibitor with chemotherapy for locally advanced esophageal squamous cell carcinoma. J Gastrointest Oncol 2021;12:1-10. [Crossref] [PubMed]
63. Al-Batran SE, Lorenzen S, Thuss-Patience PC, et al. Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: Interim results from DANTE, a randomized, multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK. J Clin Oncol 2022;40:abstr 4003.
64. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-13. [Crossref] [PubMed]
65. Pietrantonio F, Raimondi A, Lonardi S, et al. INFINITY: A multicentre, single-arm, multi-cohort, phase II trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). J Clin Oncol 2023;41:abstr 358.
66. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med 2021;384:1191-203. [Crossref] [PubMed]
67. Markar S, Gronnier C, Duhamel A, et al. Salvage Surgery After Chemoradiotherapy in the Management of Esophageal Cancer: Is It a Viable Therapeutic Option? J Clin Oncol 2015;33:3866-73. [Crossref] [PubMed]
68. Swisher SG, Moughan J, Komaki RU, et al. Final Results of NRG Oncology RTOG 0246: An Organ-Preserving Selective Resection Strategy in Esophageal Cancer Patients Treated with Definitive Chemoradiation. J Thorac Oncol 2017;12:368-74. [Crossref] [PubMed]
69. Skinner HD, Lee JH, Bhutani MS, et al. A validated miRNA profile predicts response to therapy in esophageal adenocarcinoma. Cancer 2014;120:3635-41. [Crossref] [PubMed]
70. Ajani JA, Correa AM, Hofstetter WL, et al. Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer. Ann Oncol 2012;23:2638-42. [Crossref] [PubMed]
71. Noordman BJ, Spaander MCW, Valkema R, et al. Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study. Lancet Oncol 2018;19:965-74. [Crossref] [PubMed]
72. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002;20:1167-74. [Crossref] [PubMed]
73. Decker G, Coosemans W, De Leyn P, et al. Minimally invasive esophagectomy for cancer. Eur J Cardiothorac Surg 2009;35:13-20; discussion 20-1. [Crossref] [PubMed]
74. Rizk NP, Ishwaran H, Rice TW, et al. Optimum lymphadenectomy for esophageal cancer. Ann Surg 2010;251:46-50. [Crossref] [PubMed]
75. Luketich JD, Pennathur A, Franchetti Y, et al. Minimally invasive esophagectomy: results of a prospective phase II multicenter trial-the eastern cooperative oncology group (E2202) study. Ann Surg 2015;261:702-7. [Crossref] [PubMed]
76. Perry KA, Enestvedt CK, Pham T, et al. Comparison of laparoscopic inversion esophagectomy and open transhiatal esophagectomy for high-grade dysplasia and stage I esophageal adenocarcinoma. Arch Surg 2009;144:679-84. [Crossref] [PubMed]
77. Sihag S, Kosinski AS, Gaissert HA, et al. Minimally Invasive Versus Open Esophagectomy for Esophageal Cancer: A Comparison of Early Surgical Outcomes From The Society of Thoracic Surgeons National Database. Ann Thorac Surg 2016;101:1281-8; discussion 1288-9. [Crossref] [PubMed]
78. Luketich JD, Alvelo-Rivera M, Buenaventura PO, et al. Minimally invasive esophagectomy: outcomes in 222 patients. Ann Surg 2003;238:486-94; discussion 494-5. [Crossref] [PubMed]
79. Biere SS, van Berge Henegouwen MI, Maas KW, et al. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet 2012;379:1887-92. [Crossref] [PubMed]
80. Straatman J, van der Wielen N, Cuesta MA, et al. Minimally Invasive Versus Open Esophageal Resection: Three-year Follow-up of the Previously Reported Randomized Controlled Trial: the TIME Trial. Ann Surg 2017;266:232-6. [Crossref] [PubMed]
81. Yerokun BA, Sun Z, Yang CJ, et al. Minimally Invasive Versus Open Esophagectomy for Esophageal Cancer: A Population-Based Analysis. Ann Thorac Surg 2016;102:416-23. [Crossref] [PubMed]
82. van der Sluis PC, van der Horst S, May AM, et al. Robot-assisted Minimally Invasive Thoracolaparoscopic Esophagectomy Versus Open Transthoracic Esophagectomy for Resectable Esophageal Cancer: A Randomized Controlled Trial. Ann Surg 2019;269:621-30. [Crossref] [PubMed]
83. Rizk NP, Venkatraman E, Bains MS, et al. American Joint Committee on Cancer staging system does not accurately predict survival in patients receiving multimodality therapy for esophageal adenocarcinoma. J Clin Oncol 2007;25:507-12. [Crossref] [PubMed]
84. Mokdad AA, Yopp AC, Polanco PM, et al. Adjuvant Chemotherapy vs Postoperative Observation Following Preoperative Chemoradiotherapy and Resection in Gastroesophageal Cancer: A Propensity Score-Matched Analysis. JAMA Oncol 2018;4:31-8. [Crossref] [PubMed]
85. Drake J, Tauer K, Portnoy D, et al. Adjuvant chemotherapy is associated with improved survival in patients with nodal metastases after neoadjuvant therapy and esophagectomy. J Thorac Dis 2019;11:2546-54. [Crossref] [PubMed]
86. Burt BM, Groth SS, Sada YH, et al. Utility of Adjuvant Chemotherapy After Neoadjuvant Chemoradiation and Esophagectomy for Esophageal Cancer. Ann Surg 2017;266:297-304. [Crossref] [PubMed]
87. Glatz T, Verst R, Kuvendjiska J, et al. Pattern of Recurrence and Patient Survival after Perioperative Chemotherapy with 5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) for Locally Advanced Esophagogastric Adenocarcinoma in Patients Treated Outside Clinical Trials. J Clin Med 2020;9:2654. [Crossref] [PubMed]
88. US Food and Drug Administration. FDA approves nivolumab for resected esophageal and GEJ cancer. May 20, 2021. Accessed April 15, 2022. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-resected-esophageal-or-gej-cancer
89. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725-30. [Crossref] [PubMed]
90. Lv J, Cao XF, Zhu B, et al. Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma. World J Gastroenterol 2010;16:1649-54. [Crossref] [PubMed]
91. Ni W, Yu S, Xiao Z, et al. Postoperative Adjuvant Therapy Versus Surgery Alone for Stage IIB-III Esophageal Squamous Cell Carcinoma: A Phase III Randomized Controlled Trial. Oncologist 2021;26:e2151-60. [Crossref] [PubMed]
92. Ando N, Iizuka T, Ide H, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204. J Clin Oncol 2003;21:4592-6. [Crossref] [PubMed]
93. Noh SH, Park SR, Yang HK, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:1389-96. [Crossref] [PubMed]
94. Cats A, Jansen EPM, van Grieken NCT, et al. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol 2018;19:616-28. [Crossref] [PubMed]
95. Kang J, Chang JY, Sun X, et al. Role of Postoperative Concurrent Chemoradiotherapy for Esophageal Carcinoma: A meta-analysis of 2165 Patients. J Cancer 2018;9:584-93. [Crossref] [PubMed]
96. Armanios M, Xu R, Forastiere AA, et al. Adjuvant chemotherapy for resected adenocarcinoma of the esophagus, gastro-esophageal junction, and cardia: phase II trial (E8296) of the Eastern Cooperative Oncology Group. J Clin Oncol 2004;22:4495-9. [Crossref] [PubMed]
97. Tie J, Cohen JD, Lahouel K, et al. Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer. N Engl J Med 2022;386:2261-72. [Crossref] [PubMed]
98. Sethi H, Salari R, Navarro S, et al. Analytical validation of the SignateraTM RUO assay, a highly sensitive patient-specific multiplex PCR NGS-based noninvasive cancer recurrence detection and therapy monitoring assay. Cancer Res 2018;78:abstr 4542.
99. Corcoran RB, Chabner BA. Application of Cell-free DNA Analysis to Cancer Treatment. N Engl J Med 2018;379:1754-65. [Crossref] [PubMed]
100. Moati E, Taly V, Garinet S, et al. Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives. Cancers (Basel) 2021;13:4743. [Crossref] [PubMed]
101. Ococks E, Frankell AM, Masque Soler N, et al. Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling. Ann Oncol 2021;32:522-32. [Crossref] [PubMed]
102. Huffman BM, Budde G, Chao J, et al. 1415P Performance of a tumor-informed circulating tumor DNA assay from over 250 patients with over 600 plasma time points in esophageal and gastric cancer. Ann Oncol 2021;32:S1062. [Crossref]
103. Azad TD, Chaudhuri AA, Fang P, et al. Circulating Tumor DNA Analysis for Detection of Minimal Residual Disease After Chemoradiotherapy for Localized Esophageal Cancer. Gastroenterology 2020;158:494-505.e6. [Crossref] [PubMed]
104. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014;6:224ra24. [Crossref] [PubMed]
105. Van't Erve I, Rovers KP, Constantinides A, et al. Detection of tumor-derived cell-free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid. J Pathol Clin Res 2021;7:203-8. [Crossref] [PubMed]
106. Hu Y, Ulrich BC, Supplee J, et al. False-Positive Plasma Genotyping Due to Clonal Hematopoiesis. Clin Cancer Res 2018;24:4437-43. [Crossref] [PubMed]