Gastroesophageal cancers are a heterogeneous group of cancers that develop insidiously and carry poor prognoses.1,2 Worldwide, gastric adenocarcinoma and esophageal cancer represent the fourth and sixth most common causes of cancer-related death, respectively.3 Surgery is the primary curative treatment modality, except for esophageal squamous cell carcinomas (SCCs), for which definitive chemoradiotherapy (CRT) can be considered.4,5 Despite advances in surgical techniques, prognosis with surgery alone remains poor, with 5-year overall survival (OS) rates ranging from 30% to 40%.6,7 Multimodality approaches incorporating preoperative and postoperative chemotherapy and/or radiotherapy have been established; however, there is no standardized approach and notable geographic variation in treatment exists. Up-front surgery with adjuvant chemotherapy is favored in Asian countries, whereas neoadjuvant or perioperative treatment is preferred in Europe and North America.8–11 The perioperative approach to gastroesophageal cancers is further complicated by the fact that esophageal cancers comprise 2 different histologies, each with different molecular characteristics. The genomic profile of esophageal SCC has been shown to share more similarities to other aerodigestive SCCs, whereas that of esophageal adenocarcinomas resembles the chromosomally unstable variant of gastric adenocarcinoma.12,13 Although in clinical trials gastroesophageal junction (GEJ) cancers have traditionally been grouped with either esophageal or gastric cancer depending on the tumor’s anatomic Siewert classification, molecular profiling studies suggest that basing treatment on histology may be more appropriate.
The high morbidity of surgery often limits the ability to deliver treatment postoperatively, highlighting the need for novel strategies to either develop more active preoperative treatment or more tolerable postoperative therapies. This article reviews currently available evidence supporting preoperative and postoperative approaches in gastroesophageal cancer, with an emphasis on recent practice-changing trials and ongoing areas of investigation, including the role of immune checkpoint inhibition and biomarker-driven approaches to treatment.
Approaches to Resectable Gastric Cancer
Postoperative Chemotherapy
Given the high risk of recurrence following surgical resection, several randomized phase III trials investigating adjuvant chemotherapy have been conducted (Table 1). The Japanese ACTS-GC trial assigned 1,059 patients following gastrectomy and D2 lymphadenectomy to receive adjuvant S-1 for 12 months or surgery alone.8 There was a significant survival advantage with S-1, with superior relapse-free survival (RFS) (65.4% vs 53.1%; hazard ratio [HR], 0.653) and OS (71.7% vs 61.1%; HR, 0.669) with S-1 at 5 years.14 The CLASSIC study, conducted in South Korea, China, and Taiwan, investigated adjuvant chemotherapy (8 cycles of capecitabine and oxaliplatin) following D2 gastrectomy compared with surgery alone.9 The chemotherapy group had improved disease-free survival (DFS) (68% vs 53%; HR, 0.58) and OS (78% vs 69%; HR, 0.66) at 5 years, although with high rates of toxicity (56% with ≥1 grade 3 or 4 adverse events).15 Based on these trials, surgery with adjuvant chemotherapy is the preferred approach for resectable gastric cancer in Asian countries.
Phase III Trials Supporting Postoperative Therapy in Resectable Gastric and GEJ Cancer
Postoperative CRT
Treatment strategies involving postoperative CRT have also been explored, based on the observation that locoregional recurrence occurred in up to 40% to 65% of patients after curative-intent gastric resection in North America (Table 1).16,17 The INT-0116 study randomized 556 patients with gastric or GEJ adenocarcinoma to postoperative CRT (1 cycle of fluorouracil/leucovorin, then 45 Gy of radiation + fluorouracil/leucovorin, followed by 2 cycles of fluorouracil/leucovorin) or observation following surgical resection.18 Rates of grade 3 and 4 toxicity with CRT were high (41% and 32%, respectively) and only 64% of patients completed the planned treatment. Although the study reported significant improvement in RFS and OS with CRT, primarily driven by decreased local recurrences, a major limitation of INT-0116 was that only 10% of patients underwent D2 lymphadenectomy, whereas 36% had a D1 and 54% had a D0 dissection, calling into question whether the benefits of CRT would still be seen if all patients had received optimal surgery.19 The follow-up CALGB 80101 study showed that changing the postoperative CRT regimen to epirubicin/cisplatin/infusional fluorouracil (ECF) did not improve OS, although ECF was better tolerated.20
The ARTIST trial sought to elucidate the role of CRT in 458 patients who underwent curative resection with D2 lymph node dissection.21 Following surgery, patients were randomized to receive chemotherapy alone (6 cycles of capecitabine + cisplatin [XP]) or chemotherapy + CRT (2 cycles of XP, 45 Gy of radiation with concurrent capecitabine, 2 further cycles of XP). Overall, no DFS benefit was seen with the addition of CRT (3-year DFS, 78.2% CRT vs 74.2% chemotherapy; P=.0862). A subgroup analysis suggested DFS improvement in those with pathologic lymph node positivity, prompting the subsequent ARTIST 2 study.22 In ARTIST 2, 546 patients with D2-resected node-positive gastric cancer were randomized to 1 of 3 arms: S-1 for 1 year, S-1 + oxaliplatin (SOX) for 6 months, or SOX + CRT (SOXRT).23 The trial was terminated prematurely, and did not show a DFS difference between SOX and SOXRT (3-year DFS, 74.3% vs 72.8%, respectively; HR, 0.971).
Taken together, these studies do not support the routine use of postoperative CRT in patients who have undergone D2 lymphadenectomy.
Perioperative Chemotherapy
Another strategy is the use of perioperative chemotherapy (Table 2). The UK Medical Research Council (MRC) MAGIC trial was a landmark trial that randomized 503 patients with adenocarcinoma of the stomach (74%), GEJ (11.5%), or lower esophagus (14.5%) to receive 3 cycles of preoperative and postoperative ECF or surgery alone.24 The perioperative chemotherapy arm had significantly improved progression-free survival (PFS) (HR, 0.66; P<.001) and OS (HR, 0.75; P=.009), with a 13% improvement in 5-year OS. This benefit was seen despite only 42% of patients in the perioperative arm completing all 6 cycles of chemotherapy. The French FNCLCC ACCORD-07/FFCD 9703 trial of perioperative cisplatin and fluorouracil similarly found significant improvement in DFS (HR, 0.65; P=.003) and OS (HR, 0.69; P=.02) compared with surgery alone.25 Again, only 23% completed all postoperative therapy.
Phase III Trials Supporting Perioperative Therapy in Gastroesophageal Cancer
The FLOT4-AIO study was a practice-changing trial comparing the perioperative ECF regimen used in the MAGIC trial with 4 cycles of preoperative and postoperative FLOT (fluorouracil/leucovorin/oxaliplatin/docetaxel).11 In total, 716 patients with gastric (44%) or GEJ adenocarcinoma (23% Siewert 1; 32% Siewert 2 or 3) were included. FLOT significantly improved PFS (HR, 0.75; P=.004) and OS (HR, 0.77; P=.012). Consistent with previous trials, only 60% of patients in the FLOT group started postoperative chemotherapy, and only 46% completed all 8 cycles of FLOT.
Taken together, these studies show significant survival benefit with the use of perioperative chemotherapy, with FLOT being the preferred regimen. Notably, completing planned chemotherapy following surgery was a challenge in each study. To address this issue, the EORTC 40954 trial investigated a neoadjuvant chemotherapy approach using cisplatin, fluorouracil and leucovorin; however, the study was closed early due to poor accrual and failed to demonstrate a survival benefit.26 Given the challenges of treating these patients postoperatively, and lack of success using preoperative chemotherapy only, strategies are needed to either improve neoadjuvant therapies or develop more tolerable postoperative regimens.
How to Improve Perioperative Treatment
Even in patients who receive perioperative FLOT, the estimated 5-year OS rate is only 45%, highlighting the need for further improvements to treatment efficacies. The CRITICS study examined the addition of postoperative CRT to perioperative chemotherapy.27 A total of 788 patients (83% gastric, 17% Siewert 2 or 3 GEJ adenocarcinoma) underwent 3 cycles of preoperative chemotherapy (epirubicin, cisplatin, or oxaliplatin, and capecitabine; Table 2) followed by surgery and went on to receive either 3 cycles of the same chemotherapy or 45 Gy of radiotherapy with concurrent cisplatin and capecitabine. There was no difference in OS between the 2 cohorts (43 vs 37 months, respectively; HR, 1.01; P=.90).
The ongoing TOPGEAR trial is examining the addition of neoadjuvant CRT to perioperative chemotherapy and will provide insight about whether adding another treatment modality in the neoadjuvant setting when patients are better able to tolerate therapy will improve outcomes (Table 3).28 CRITICS II is another ongoing trial studying 3 preoperative approaches: chemotherapy alone versus chemotherapy followed by CRT versus CRT alone (Table 3).29
Ongoing Trials Investigating Novel Approaches to Resectable Gastroesophageal Cancer
Approaches to Esophageal Cancer
Management of Esophageal SCC
Definitive CRT can be considered for curative-intent treatment of esophageal SCC, leaving surgery for salvage. The few randomized trials comparing definitive CRT with trimodality (CRT followed by surgery) treatment have not shown a significant OS difference, although a trimodality approach may improve locoregional control (Table 4).4,5,30
Phase III Trials Supporting Definitive or Preoperative CRT for Resectable Esophageal and GEJ Cancer
Aside from definitive CRT trials, esophageal SCC has generally been grouped with esophageal adenocarcinoma in clinical trials. Based on the differing molecular characteristics suggesting that these are distinct diseases, future trials should separate the 2 histologies.
Neoadjuvant CRT
The pivotal CROSS trial established the benefit of neoadjuvant CRT in esophageal and GEJ cancer, randomizing 366 patients (75% adenocarcinoma, 23% SCC) to receive preoperative CRT (41.4 Gy) with weekly carboplatin and paclitaxel followed by resection, or surgery alone10 (Table 4). Neoadjuvant CRT was well tolerated, with 91% completing the full treatment regimen and no significant increase in postoperative morbidity compared with surgery alone. The CRT arm had significantly improved OS over surgery alone (HR, 0.657; P=.003), with absolute 5- and 10-year OS benefit of 14% (47% vs 33%) and 13% (38% vs 25%), respectively.31,32 A greater magnitude of benefit was seen in the SCC subgroup, although those with adenocarcinoma derived benefit as well. As a result, the CROSS protocol became the standard of care for resectable esophageal cancer in North America.
Adjuvant Immunotherapy
Although the use of multimodality treatment has achieved incremental progress in improving outcomes in gastroesophageal cancers, up to half of patients will experience cancer recurrence, highlighting the persisting unmet need for better therapies. CheckMate 577 was a global trial investigating a 1-year course of adjuvant nivolumab compared with surveillance in patients with resected esophageal (60%) or GEJ (40%) cancer who had residual pathologic disease after neoadjuvant CRT and surgery.33 Of the 794 patients, 71% had adenocarcinoma and 29% SCC. A significant DFS improvement was seen with nivolumab, with a median DFS of 22.4 versus 11.0 months (HR, 0.69; P<.001). Nivolumab was well tolerated, with no reduction in health-related quality of life.34 Although OS data are pending, we anticipate adjuvant nivolumab will yield a significant OS benefit, given the doubling in DFS. This trial establishes adjuvant nivolumab as a new standard of care in this patient population.
Remaining Questions and Future Approaches
Neoadjuvant CRT Versus Perioperative Chemotherapy in GEJ Adenocarcinoma
Although both perioperative chemotherapy and preoperative CRT have been established as standard of care in resectable gastroesophageal cancer, a subset of patients will fit the criteria for both approaches. The optimal strategy for these patients remains a crucial question that several trials have been designed to address.
The Neo-AEGIS study presented at the 2021 ASCO Annual Meeting randomized 377 patients with esophageal or GEJ adenocarcinoma to receive perioperative chemotherapy (85% MAGIC, 15% FLOT) or preoperative CRT with CROSS.35 Initially designed as a superiority trial, this was modified to a noninferiority analysis with a margin of 5%. Survival was similar between the 2 arms, meeting noninferiority criteria, with 3-year OS of 56% with CROSS and 57% with perioperative chemotherapy (HR, 1.02; 95% CI, 0.74–1.42). Outcomes including rates of pathologic complete response, R0 resection, and nodal downstaging favored the CROSS arm. Overall, this study showed that either approach is likely reasonable, leaving clinicians to consider factors such as patient fitness, regimen tolerability, and differing patterns of recurrence with each approach to guide decision-making. Because this trial opened before the FLOT4-AIO results were available, most patients in the perioperative chemotherapy arm received ECF/ECX. Whether similar results would be achieved using FLOT is under investigation in the ongoing ESOPEC and POWERRANGER trials (Table 3). However, the target HR of 0.645 in ESOPEC will be difficult to meet, and it is uncertain whether this study will be able to adequately address this question.36
With the results of CheckMate 577, which included only patients who underwent neoadjuvant CRT, an additional question raised is the role of immune checkpoint inhibition in those receiving chemotherapy without radiation. The KEYNOTE-585 study is investigating the combination of pembrolizumab with perioperative chemotherapy.37 MATTERHORN is studying the addition of durvalumab to perioperative FLOT.38 The phase II DANTE trial is studying atezolizumab with perioperative FLOT.39 These trials will help answer whether patients undergoing perioperative chemotherapy derive a similar benefit to that seen in CheckMate 577, or whether the abscopal effect induced by radiotherapy is a crucial component driving this benefit (Table 3).
Other trials of immunotherapy in resectable gastroesophageal cancer include ATTRACTION-05, a trial being conducted in Japan, Korea, and China investigating nivolumab in combination with adjuvant S-1 or CAPOX chemotherapy, as well as the phase II/III EA2174 study of preoperative CRT with nivolumab followed by postoperative nivolumab ± ipilimumab (Table 3).40,41
Biomarker-Driven Preoperative and Postoperative Approaches
In the era of personalized cancer medicine, predictive biomarkers are urgently needed to help determine the optimal treatment to maximize benefit for individual patients and to spare patients from toxicities of unnecessary therapies. In advanced gastroesophageal cancer, a higher combined positive score (CPS), a measure of PD-L1 expression on tumor cells and tumor-associated immune cells, has been shown to predict benefit from immune checkpoint inhibitors.42 A post hoc analysis of PD-L1 CPS expression in CheckMate 577 has yielded similar findings, wherein adjuvant nivolumab was associated with significant DFS improvement in the CPS ≥5 subgroup (HR, 0.62; 95% CI, 0.45–0.83) but not necessarily in CPS <5 (HR, 0.89; 95% CI, 0.65–1.22).33 Future studies should prospectively incorporate biomarker analysis into trial design, and further development of new predictive biomarkers is needed.
Microsatellite Instability
Patients with mismatch repair deficiency (dMMR) or high levels of microsatellite instability (MSI-H) represent another subgroup of patients who warrant special consideration in the perioperative setting. An individual patient data meta-analysis of the MAGIC, CLASSIC, ARTIST, and ITACA-S trials has suggested lack of benefit from perioperative or adjuvant chemotherapy in patients with MSI-H/dMMR gastric cancer.43 In the advanced/metastatic setting, treatment with immune checkpoint inhibitors achieve response rates of >55% in patients with MSI-H/dMMR gastric cancer; however, there is a paucity of prospective data in patients treated with curative intent.44,45 Wherever possible, patients with resectable MSI-H/dMMR gastric cancer should be referred for clinical trials of chemotherapy omission or immune checkpoint inhibition strategies. Outside of a trial setting, patients should be individually counseled about the risks and potential benefits to come to an informed decision about cytotoxic chemotherapy.
HER2 Inhibition
In advanced or metastatic HER2-overexpressed or HER2-amplified gastroesophageal adenocarcinoma, the addition of HER2-targeted therapy to chemotherapy is an established standard of care.46 HER2-directed therapies are under investigation in the curative-intent setting, with several single-arm phase II studies demonstrating the feasibility of incorporating HER2 blockade in the perioperative setting.47–50 Unfortunately, no randomized studies have demonstrated a survival benefit (Table 5). The phase II PETRARCA study found that adding trastuzumab and pertuzumab to perioperative FLOT increased the pathologic complete response rate; however, with increased toxicity and no significant DFS advantage, the trial closed before proceeding to phase III.51 Similarly, the phase III RTOG 1010 trial combining trastuzumab with preoperative CRT failed to show survival benefit.52 The ongoing phase II INNOVATION trial is studying the addition of trastuzumab ± pertuzumab to perioperative chemotherapy.53 Given the results from previous studies, we anticipate this too will fail to improve survival. In the current treatment landscape of resectable gastroesophageal cancer, there is no role for HER2-targeted therapy in routine practice. Patients with HER2-positive cancers should be considered for clinical trials if available, or should otherwise receive the same treatment as HER2-negative patients.
Phase II/III Trials Investigating HER2 Inhibition in Resectable Gastroesophageal Cancer
Conclusions
The management of resectable gastroesophageal cancers has seen incremental changes over the past 2 decades, with clear evidence that multimodal approaches improve survival and that postoperative chemotherapy is difficult to complete, highlighting the need to develop either more active preoperative treatment or more tolerable postoperative therapies. The question of neoadjuvant versus perioperative therapy remains, and ongoing trials comparing the 2 strategies will provide further insight. Adjuvant immunotherapy following trimodality treatment has emerged as a practice-changing therapy, and OS results are eagerly awaited, as are results from perioperative immunotherapy trials. Prospective incorporation of biomarker analysis in the design of future clinical trials is encouraged to aid in the development of predictive biomarkers to guide decision-making and optimize treatment selection in the curative-intent setting.
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