Improving Outcomes in Resectable Gastric Cancer: A Review of Current and Future Strategies

July 15, 2016

Here we review the evidence supporting current approaches to resectable gastric cancer, including discussion of the optimal extent of surgery and lymphadenectomy, adjuvant chemotherapy, postoperative chemotherapy with chemoradiation, and perioperative chemotherapy.

Gastric cancer is a highly fatal malignancy, and surgery alone often does not provide a cure, even for relatively early stages of disease. Various approaches have been adopted around the world to improve surgical outcomes; however, there currently is no global consensus with regard to the extent of surgery or the timing and choice of chemotherapy and radiation. Here we review the evidence supporting current approaches to resectable gastric cancer, including discussion of the optimal extent of surgery and lymphadenectomy, adjuvant chemotherapy, postoperative chemotherapy with chemoradiation, and perioperative chemotherapy. Additionally, we discuss novel approaches, including intensified chemotherapy (in neoadjuvant, perioperative, and adjuvant settings), pre- and postoperative chemoradiation in combination with chemotherapy, and the role of biologics and targeted therapy. Finally, we examine the promise of molecular subtyping and potential biomarkers for improved patient selection. Upcoming and future trials should help answer questions regarding the optimal sequencing and choice of treatments, in order to further improve survival and move us towards ultimately curing more patients with resectable gastric cancer.

Introduction

Despite the declining incidence of gastric cancer, it remains the fifth most common malignancy worldwide-with 951,000 new cases in 2012-and represents nearly 7% of all cancer. The majority of cases arise in less developed countries, and there is a twofold higher incidence in men than in women. It continues to be the third leading cause of cancer death worldwide, behind lung and liver cancers.[1]

Gastric cancer is an insidious disease with a relative paucity of symptoms until late in the disease trajectory. As a result, nearly 40% of patients present with metastatic disease, and about 50% present with locoregional disease. While surgery remains the cornerstone of curative management, recurrence rates are high and the 5-year survival rate for all stages remains frustratingly low at 25% to 30%.[2]

The approach to resectable gastric cancer has evolved significantly over the past 20 years. In an attempt to improve long-term outcomes following surgery for resectable disease, different multimodality paradigms have been explored, including adjuvant chemotherapy, postoperative chemotherapy with chemoradiation, and perioperative chemotherapy. Each of these approaches has since been adopted in a different global region:

• Adjuvant chemotherapy after extended lymphadenectomy, including nodes adjacent to the stomach and around branches of the celiac axis (D2 resection)-in Asia.

• Perioperative chemotherapy-in Europe and Australasia.

• Postoperative chemotherapy with chemoradiation (CTRT)-in North America.

Clearly, there is no universally accepted standard of care, and uncertainty still exists regarding the optimal extent of surgery, the timing and choice of chemotherapy, and the incremental benefit of radiotherapy.

Several landmark phase III trials support each paradigm, and these will be reviewed here. In addition, the eagerly anticipated results of phase II/III trials that are investigating outstanding questions, as well as the role of targeted therapy, will be explored. Finally, we will consider novel approaches-including molecular subtyping, immunotherapy, and the quest for suitable predictive and prognostic biomarkers-all of which are part of the international effort to further advance progress in this highly fatal malignancy.

Current Approaches to Resectable Gastric Cancer

Surgery

Complete resection offers the only possibility for long-term survival in gastric cancer. At the time of diagnosis in the United States, only about one-quarter of patients have localized disease and about one-third already have involvement of regional lymph nodes.[2] An ideal surgical outcome would be complete excision of the primary and associated nodes without any residual disease.[3] However, even for stage I gastric cancer, 5-year survival is only around 65% and disease recurs in up to 25% to 50% of patients after a curative resection.[2,4] To improve surgical outcomes, many have explored optimizing patient selection through improved staging, more radical surgical techniques, and the combination of surgery with other modalities to reduce regional and systemic relapse.

It is widely accepted that for localized gastric cancer, having a multidisciplinary evaluation and consensus treatment plan is ideal before embarking on any therapy. Accurate staging that can better classify patients as potentially “resectable” or “unresectable” is critical because this determines their subsequent treatment pathway. Guidelines support diagnostic laparoscopy for locally advanced disease (T1b or higher) to exclude occult peritoneal and visceral metastases, which are difficult to detect with noninvasive imaging.[5,6] For those patients who already have distant metastatic disease, the morbidity of resection can be avoided, as there was no improvement in overall survival (OS) shown in the phase III randomized REGATTA trial, and symptoms can be successfully managed by other means in most patients.[7,8]

The optimal surgical approach to curative resection, in particular the extent of nodal dissection, is still debated. Retrospective studies suggested a benefit from more extensive routine lymph node dissection (with a minimum of 15 nodes), but it was uncertain whether the gains arose from more accurate stage assignment, from improved regional clearance, or from an associated overall superior technique of primary resection.[9,10] A prospective German study found that dissection of more than 26 lymph nodes (corresponding to Japanese D2 dissection) was an independent prognostic factor for improved survival in Union for International Cancer Control stage II and IIIA gastric cancer, without additional morbidity and mortality.[11] However, subsequent prospective randomized trials led by centers in the United Kingdom[12] and the Netherlands[13,14] showed no survival benefit even with 15-year follow-up, in the face of increased postoperative morbidity and even mortality. The more recent D1 vs D2 randomized trial conducted by the Italian Gastric Cancer Study Group demonstrated low and equivalent morbidity and mortality between groups, but it also failed to show an OS benefit with D2 dissection.[15]

In the past, when quality of surgery was not recognized as an important prognostic factor in gastric cancer, nonspecialized Western surgeons often performed only dissection of epigastric nodes plus omentectomy (D1), or even omitted lymph node dissection altogether.[16,17] By contrast, in Japan and in some parts of Asia, extended (D2 or D3) lymph node dissection by an experienced surgeon had already been accepted as a standard for curative settings. The difference in the extent of lymphadenectomy between the “West” and the “East” was thought to potentially contribute in part to the improved survival rates seen in Asian as compared with Western patients, despite the lack of robust level I evidence to that effect.[9,16,18]

A recent Cochrane systematic review and meta-analysis examined eight randomized controlled trials (N = 2,515), including the aforementioned ones, and found no improvement in survival with a D3 (para-aortic nodes) lymphadenectomy compared with a D2 lymphadenectomy (gastric and celiac axis nodes).[19] In addition, when a D2 lymphadenectomy was compared with a D1 lymphadenectomy, there were no statistically significant differences in OS or disease-free survival (DFS). However, a D2 lymphadenectomy was associated with superior disease-specific survival (hazard ratio [HR], 0.81 [95% CI, 0.71–0.92])-defined as time from surgery to either death by disease or last follow-up-which the authors argue is a more meaningful outcome when comparing extent of dissection.[19] The number needed to treat was 14, which suggests that 71 events could be avoided per 1,000 patients treated with D2, instead of D1, surgery. A caveat is that this improvement needs to be balanced against an increased postoperative mortality rate (relative risk, 2.02 [95% CI, 1.34–3.04]).[19] Given these reservations, Western guidelines currently recommend D2 lymphadenectomy but suggest that gastrectomy for gastric cancer be performed in high-volume centers where perioperative mortality rates are less than 2%.[15,20,21]

Adjuvant chemotherapy

In an attempt to reduce systemic recurrence following surgery alone, adjuvant chemotherapy has been used in trials since the 1980s. However, adjuvant chemotherapy alone has been relatively disappointing for gastric cancer, unlike other solid tumors. The results of individual trials have been predominantly negative, and meta-analyses have shown small survival benefits with postoperative anthracycline and fluoropyrimidine–based regimens.[22-24] Many of the trials included were small, underpowered, and of varying quality, which limits interpretation.[22-24]

Earlier adjuvant trials were not in the setting of an aggressive D2 gastrectomy; thus, Japanese researchers continued to investigate the role of adjuvant chemotherapy. In 2007, the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) group published their landmark phase III trial that supported the use of adjuvant S-1 (an oral fluoropyrimidine combination of tegafur, gimeracil, and oteracil) after D2 gastrectomy (Table 1).[25] In ACTS-GC, 1,059 patients were randomized to either surgery alone or 80 mg/m2 of S-1 for 4 weeks followed by a 2-week break, every 6 weeks for 12 months. The trial was stopped at its first interim analysis because the S-1 group showed a significantly higher OS rate (HR, 0.68 [95% CI, 0.52–0.87]; P = .003). An updated analysis at 5 years demonstrated that the survival advantage was maintained at 71% for adjuvant S-1 vs 61% for surgery alone.[26]

The CLASSIC study was another large phase III randomized controlled trial (N = 1,035) that evaluated the role of adjuvant chemotherapy; it was conducted in Korea, China, and Taiwan.[27] This trial also required at least a D2 gastrectomy but used a regimen of capecitabine with oxaliplatin as opposed to S-1, which is infrequently used outside of Japan. DFS was the primary endpoint, and both the 3-year and the updated 5-year DFS showed a significant benefit from chemotherapy (5-year HR, 0.58 [95% CI, 0.47–0.72]; P < .0001).[27,28] In addition, the secondary outcome of 5-year OS was improved, with an HR for death of 0.66 (95% CI, 0.51–0.85; P = .0015).[28]

Another Japanese study, the Stomach Cancer Adjuvant Multi-Institutional Group Trial (SAMIT), investigated the additional benefit of taxanes, which have been shown to be active in advanced gastric cancer.[29] In SAMIT, 1,495 patients with T4a/b gastric cancer were randomized to one of four groups: paclitaxel followed by S-1, paclitaxel followed by UFT (tegafur with uracil), S-1 monotherapy, or UFT monotherapy. The trial was negative for its primary endpoint of 3-year DFS, which suggests that S-1 monotherapy remain the standard adjuvant treatment regimen in Japan.[29]

No trial to date has directly compared adjuvant chemotherapy regimens. Thus, at this time the two common adjuvant regimens are S-1 in Japan and capecitabine with oxaliplatin elsewhere. Although there has been uncertainty about the efficacy of S-1 in non-Asian patients, a recent systematic review and meta-analysis have suggested that it is as effective and tolerable in Western patients as in Asian ones, at least in the setting of advanced gastric cancer.[30]

Postoperative chemotherapy and chemoradiation therapy

In the West, as recently as 15 years ago, as many as 40% to 65% of recurrences following curative-intent resections for gastric cancer were due to locoregional relapse.[16,17] Given the relatively lackluster outcomes with adjuvant chemotherapy at the time, the landmark phase III Intergroup 0116 (INT-0116) study explored the use of postoperative chemotherapy and CTRT.[17] After gastrectomy, 556 patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma were randomized to either no further treatment (surgery alone) or surgery then CTRT (see Table 1). CTRT involved 1 cycle of fluorouracil (5-FU) and leucovorin, followed by 45 Gy (25 fractions of 1.8 Gy; to the tumor bed, 2 cm beyond the margins and nodes) with concurrent 5-FU and leucovorin, followed by 2 cycles of 5-FU and leucovorin. Although the protocol recommended a D2 lymphadenectomy, only 10% of patients had undergone this procedure; 36% had a D1 operation, and the majority (54%) had a D0 lymphadenectomy, which reflected practices in the United States at that time. The study originally reported a significant improvement in relapse-free survival (RFS) and OS with CTRT after surgery.[17] These findings were confirmed with 10-year follow-up results that showed that for surgery alone compared with CTRT, the HR for death was 1.32 (95% CI, 1.10–1.60; P = .0046) and for RFS was 1.51 (95% CI, 1.25–1.83; P < .001).[31] A major criticism of the INT-0116 study that limited its global uptake was the uncertainty about whether the survival difference seen with CTRT would persist in patients who received optimal surgery (ie, adequate lymphadenectomy).

The additional benefit of adjuvant CTRT in the setting of a D2 lymphadenectomy was first investigated in the Adjuvant Chemoradiation Therapy in Stomach Tumors (ARTIST) trial (see Table 1).[32] Building on the tolerability and efficacy of capecitabine and cisplatin (XP) with or without radiotherapy,[33] the ARTIST trial randomized 458 patients with gastric cancer after curative D2 resection to 6 cycles of adjuvant XP vs 2 cycles of XP, followed by concurrent chemoradiation with capecitabine (XRT; 45 Gy in 25 fractions), followed by 2 further cycles of XP.[32] The majority of patients completed treatment as planned in the XP and XP/XRT/XP arms (75.4% and 81.7%, respectively). The addition of chemoradiation to XP chemotherapy did not significantly improve overall 3-year DFS (78.2% in the experimental arm vs 74.2% in the control arm; P = .0862). However, in a subgroup analysis in patients with pathologic node positivity, XP/XRT/XP showed a statistical benefit over XP alone (3-year DFS of 77.5% vs 72.3%, respectively; P = .0365).[32] An update after 7 years of follow-up showed a consistent benefit in DFS (P = .0922) but no difference in OS, with an HR of 1.130 (95% CI, 0.775–1.647; P = .5272).[34] The ARTIST trial also showed that after a D2 resection, the addition of radiation continued to significantly reduce locoregional relapse (13% in the XP arm vs 7% in the XP/XRT/XP arm; P = .0033), although there were no significant differences in distant relapse (27% and 24%, respectively; P = .5568).[34] In subgroup analyses, patients with node positivity and intestinal-type gastric cancer seemed to benefit most. The extent of benefit from chemoradiation in node-positive patients, and the optimal adjuvant regimen for gastric cancer following a D2 resection, are questions that are being addressed in the follow-up ARTIST-II trial (ClinicalTrials.gov identifier: NCT01761461).

While the INT-0116 trial showed a reduction in locoregional recurrences with postoperative chemotherapy combined with chemoradiation, the same could not be said for distant relapses. The ensuing Intergroup Cancer and Leukemia Group B (CALGB) 80101 trial examined whether a more active chemotherapy regimen (with the addition of an anthracycline and platinum to 5-FU), in addition to chemoradiation, could improve outcomes in gastric and GEJ adenocarcinoma (see Table 1).[35] Essentially, the trial compared different adjuvant chemotherapy regimens in combination with postoperative chemoradiation: the control arm received the standard INT-0116 regimen (with 5-FU and leucovorin) and the experimental arm received dose-attenuated ECF (epirubicin, cisplatin, and 5-FU). In a preliminary report presented at the American Society of Clinical Oncology (ASCO) 2011 Annual Meeting, the CALGB 80101 trial did not show any improvement in 5-year OS or RFS compared with standard 5-FU– and leucovorin-based treatments.[35] Thus, the change in the chemotherapy backbone did not translate into improved outcomes. Some would argue that the trial design was suboptimal in terms of chemotherapy scheduling, given the large gaps between the first and subsequent cycles (because of chemoradiation) and insufficient cycles of chemotherapy (only 3 in total, compared with 6 in perioperative chemotherapy trials).[36]

Perioperative chemotherapy

The Medical Research Council (MRC) Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial was the first to validate the perioperative chemotherapy paradigm (see Table 1).[36] In this trial, 503 patients from the United Kingdom and Europe with gastric (74%), GEJ (11%), and lower-third esophageal (15%) adenocarcinoma were randomized to surgery alone or 3 cycles of ECF before and after surgery. The extent of lymph node dissection was at the discretion of the surgeon; approximately 43% of patients in both arms had a D2 resection.[36] Postoperative complication rates were no different between the arms, but only 42% of patients allocated to the perioperative ECF arm completed all 6 cycles as planned, because of interval progression, patient preference, or complications. Despite these limitations, the trial was positive and showed a significant benefit from perioperative ECF in progression-free survival (PFS) (HR, 0.66 [95% CI, 0.53–0.81]; P < .001) and OS (HR, 0.75 [95% CI, 0.60–0.93]; P = .009).[36]

Given the survival benefit seen in the MAGIC trial,[36] in which fewer than one-half of participants completed the postoperative treatment, the European Organisation for Research and Treatment of Cancer (EORTC) conducted a randomized trial (EORTC 40954) to look at a purely neoadjuvant chemotherapy strategy (see Table 1).[37] The study was closed prematurely because of poor accrual; however, the researchers managed to randomize 144 patients to either surgery alone or two 48-day cycles of neoadjuvant cisplatin, infusional 5-FU, and leucovorin. The chemotherapy arm showed a significant increase in complete (R0) resection rates (81.9% vs 66.7% with surgery alone; P = .036), but no difference was observed in the primary endpoint of OS, with an HR of 0.84 (95% CI, 0.52–1.35; P = .466).[37] This also came at the cost of higher rates of postoperative complications (27.1% in the chemotherapy arm vs 16.2% in the surgery-alone arm; P = .09). The researchers commented that in addition to the trial being underpowered, the lack of a survival advantage could be related to the much higher rates of D2 resection (over 92% in both arms compared with approximately 43% in the MAGIC trial), which could mask the benefit of neoadjuvant therapy.[36,37]

Another pivotal trial that supports perioperative chemotherapy is the French (Fédération Nationale des Centres de Lutte Contre la Cancer [FNCLCC] and Fédération Francophone de Cancérologie Digestive [FFCD]) phase III trial that randomized 224 patients with lower esophageal (11%), GEJ (64%), or gastric (25%) adenocarcinoma to either surgery alone or 6 cycles of perioperative chemotherapy and surgery (see Table 1).[38] Chemotherapy consisted of 2 or 3 preoperative 28-day cycles of infusional 5-FU (800 mg/m2 on days 1–5) and cisplatin (100 mg/m2 on day 1), followed by a further 3 or 4 cycles postoperatively, for a total of 6. While the vast majority (87%) of patients received preoperative treatment, much as in the MAGIC trial,[36] only 23% were able to complete all postoperative chemotherapy.[38] The perioperative chemotherapy group had significantly higher 5-year OS (38% vs 24%, with an HR of 0.69 [95% CI, 0.50–0.95]; P = .02) and 5-year DFS (34% vs 19%, with an HR of 0.65 [95% CI, 0.48–0.89]; P = .003) than the surgery-alone group.[38] Chemotherapy was associated with an improved rate of R0 resection compared with surgery alone (84% vs 73%; P = .04). The main toxicity was grade 3/4 neutropenia (20%), but postoperative complications and death rates were similar in the two arms.[38] The results of this trial also raised further questions about the use of anthracyclines and the value of triplet therapy, and whether these are worth the additive toxicity. Either ECF or a platinum doublet (cisplatin, 5-FU) is a reasonable perioperative regimen, particularly for GEJ tumors.

An ongoing challenge in the United States is the relatively poor uptake of evidence-based treatments. A retrospective study of patients who underwent resection for stage IB–IV gastric adenocarcinoma between 1991 and 2009 showed that only 19.1% received postoperative CTRT and 1.9% received perioperative chemotherapy, while the vast majority (60.9%) had surgery alone.[39] Ideally, patients with resectable gastric cancer should be evaluated by multidisciplinary tumor boards to decide on the staging and optimal management plan before treatment commences.

Anticipated Investigational Approaches

As discussed, there are multiple approaches to resectable gastric cancer: adjuvant chemotherapy, adjuvant CTRT, and perioperative chemotherapy. Although cross-trial comparisons are not ideal, each approach yields an approximate HR for death of about 0.65 to 0.75. To date, chemotherapy regimens have been based on older agents, such as 5-FU, leucovorin, and cisplatin. Some of the approaches currently being investigated build on these agents; they involve newer cytotoxic, biologic, and targeted agents and the use of neoadjuvant chemoradiation.

Intensified neoadjuvant chemotherapy

The neoadjuvant approach continues to be investigated because of improvements seen with perioperative treatment and the fact that fewer than one-half of patients in previous trials received postoperative chemotherapy.[36,37] Reasons include improved preoperative “downstaging,” which results in smaller tumor size, better R0 resection rates, and less lymph node involvement; reduction in micrometastases; and time to assess the biology of the disease and sensitivity to chemotherapy (the morbidity of surgery can be avoided if metastatic disease is detected during preoperative restaging). As was seen in the MAGIC[36] and FNCLCC/FFCD[38] trials, preoperative chemotherapy is better tolerated and easier to deliver. Following on from the EORTC 40954 trial with neoadjuvant cisplatin, 5-FU, and leucovorin, several groups have ongoing phase III trials that are seeking to improve the chemotherapy regimen to both reduce toxicity and improve efficacy.[37]

The Japan Clinical Oncology Group 0501 study is a phase III neoadjuvant chemotherapy trial (ClinicalTrials.gov identifier: NCT00252161) that is looking at the addition of cisplatin to S-1 and comparing that to surgery alone (minimum D2 gastrectomy). Korean investigators are combining modern agents with docetaxel, oxaliplatin, and S-1 as neoadjuvant therapy in addition to standard S-1 adjuvant therapy for resectable but locally advanced gastric cancer (T2–3/N+ or T4/N either +/-) in the PRODIGY trial (ClinicalTrials.gov identifier: NCT01515748). Finally, the German NEO-FLOT trial (ClinicalTrials.gov identifier: NCT01160419) mirrors the PRODIGY trial but uses 5-FU and leucovorin instead of S-1, with slightly lower doses of oxaliplatin. The results of all three trials are eagerly awaited to see whether newer combinations bring superior efficacy with tolerable toxicity for both Asian and Western patients.

Intensified perioperative chemotherapy

In an effort to improve on the results of the MAGIC trial, the German AIO phase II/III FLOT4 study (ClinicalTrials.gov identifier: NCT01216644) randomized 714 patients with resectable locally advanced gastric or GEJ cancer either to the standard 6 cycles of perioperative ECF or to 4 cycles of 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) preoperatively and 4 cycles of FLOT postoperatively. Phase II data presented at the 2015 ASCO Annual Meeting showed that centrally reviewed pathologic complete response (pCR) rates were 12.8% with FLOT vs 5.1% with ECF.[40] Although these data are promising, changes to standard regimens can be made only after considering the phase III toxicity and OS outcomes.

Intensified adjuvant chemotherapy

In the adjuvant chemotherapy setting, the ongoing Chinese phase III CAPITAL study (ClinicalTrials.gov identifier: NCT01795027) is investigating the addition of oxaliplatin to adjuvant S-1 (SOX). Another Chinese study (ClinicalTrials.gov identifier: NCT01711242) is comparing intensified adjuvant chemotherapy alone vs CTRT in the setting of D2 lymphadenectomy. Adjuvant chemotherapy consists of four 21-day cycles of XELOX (capecitabine, 1,000 mg/m2 twice daily on days 1–14, with oxaliplatin, 130 mg/m2 on day 1), while postoperative CTRT involves 2 cycles of XELOX, followed by chemoradiation (45 Gy in 1.8-Gy fractions with concurrent capecitabine, 825 mg/m2 twice daily on days of radiation), then 2 further cycles of XELOX. This trial attempts to address some of the questions arising from previous studies, including INT-0116, ARTIST, and CLASSIC.[17,27,32] Although the trial tries to clarify the incremental benefit of postoperative chemoradiation after D2 surgery in the setting of modern chemotherapy regimens, the results will likely apply only in Asia, where upfront D2 surgery is routine. Meanwhile, other regions are now focusing more on improving therapy in the neoadjuvant and perioperative settings.

Addition of perioperative chemoradiation to chemotherapy

The merits of a three-step approach involving preoperative induction chemotherapy, followed by chemoradiation, then surgery for resectable gastric cancer were shown in a series of phase II trials.[41-43] Of note, no therapy is indicated after surgery in this setting because all chemotherapy and chemoradiation are delivered preoperatively. Induction chemotherapy involved 2 cycles of cisplatin, 5-FU, and either leucovorin or paclitaxel. Published results showed greatly improved R0 resection and pCR rates of 70% and 30%, respectively.[41] The subsequent phase II Radiation Therapy Oncology Group (RTOG) trial (RTOG 9904) reported an R0 resection rate of 77% and a pCR rate of 26%.[43] This has led to two large international phase II/III trials that are investigating this approach of combining induction chemotherapy with chemoradiation and adequate surgery.

The randomized phase III trial of Chemoradiotherapy After Induction Chemotherapy in Cancer of the Stomach (CRITICS) is being conducted by the Dutch Colorectal Cancer Group (ClinicalTrials.gov identifier: NCT00407186), while another collaboration led by the Australasian Gastro-Intestinal Trials Group (AGITG) is conducting a multinational phase II/III trial (ClinicalTrials.gov identifier: NCT01924819) of preoperative therapy for gastric and GEJ adenocarcinoma (TOPGEAR). In the CRITICS trial, all patients receive 3 cycles of preoperative epirubicin, cisplatin, and capecitabine (ECX) chemotherapy followed by surgery; then patients are randomized to either 3 cycles of postoperative ECX (similar to the MAGIC trial) or chemoradiation with cisplatin and capecitabine. The TOPGEAR trial in Australia, Canada, and Europe is similar in that patients in the control arm receive 3 cycles of preoperative and 3 cycles of postoperative ECX/ECF (similar to the MAGIC trial), but those in the experimental arm receive 2 cycles of preoperative ECX/ECF followed by chemoradiation with a fluoropyrimidine, then 3 cycles of postoperative ECX/ECF. In both trials, surgery includes at least D1 lymphadenectomy. The results of both are eagerly anticipated, since they should clarify the incremental benefit of chemoradiation in the setting of adequate predefined surgery and effective perioperative chemotherapy.

Biologics and targeted therapy

Targeting the EGFR pathway. Blockade of the epidermal growth factor receptor (EGFR) pathway with either cetuximab or panitumumab yielded disappointing results in the setting of advanced gastric cancer.[44-46] In addition, small-molecule tyrosine kinase inhibitors, such as erlotinib, also failed to show any significant antitumor effects.[47] These negative signals have led to the early termination of many trials in the localized setting. Although an ongoing phase II study is exploring the role of preoperative cetuximab in combination with cisplatin and irinotecan (ClinicalTrials.gov identifier: NCT00857246), it is unlikely that this approach will be strongly pursued in the future.

Targeting angiogenesis. Investigators from the MRC who conducted the original MAGIC study recently completed another phase II/III trial (ST03) that investigated the role of bevacizumab, an anti–vascular endothelial growth factor (VEGF) A monoclonal antibody, in operable esophagogastric cancer (ClinicalTrials.gov identifier: NCT00450203). This trial was designed based on the initial promise of improved PFS and response rates with bevacizumab in advanced gastric cancer seen in the Avastin in Gastric Cancer (AVAGAST) trial.[48] ST03 also included a pilot safety and feasibility study of lapatinib (a human epidermal growth factor receptor 2 [HER2] tyrosine kinase inhibitor) for patients with HER2-positive tumors. Thus, patients were randomized to one of four arms. Those who were HER2-negative received 6 cycles of perioperative ECX or ECX with bevacizumab; those who were HER2-positive received 6 cycles of perioperative ECX or ECX with lapatinib. Both experimental arms included bevacizumab or lapatinib monotherapy for an additional 6 cycles after postoperative chemotherapy was completed. Like the results of the AVAGAST trial, which did not show an improvement in OS, the final results of ST03, presented at the 2015 European Cancer Congress, were disappointing.[48,49] The addition of bevacizumab did not improve OS, PFS, or DFS, but did increase the risk of postoperative anastomotic leaks.[49]

Ramucirumab is a recombinant antibody that targets VEGF receptor 2. While it has shown a survival advantage in advanced gastric cancer,[50,51] it will now be tested in the perioperative setting together with FLOT chemotherapy in the RAMSES trial (ClinicalTrials.gov identifier: NCT02661971). It will be interesting to see if this alternative approach to angiogenesis, with a proven OS benefit in advanced gastric cancer, can translate to a survival improvement in the setting of resectable gastric cancer, in which bevacizumab has failed.

Targeting the HER2 pathway. Given the survival benefit of trastuzumab in HER2-amplified metastatic gastric cancer,[52] several groups are now investigating its use in resectable HER2-amplified gastric cancer. The ongoing single-arm phase II TOXAG study (ClinicalTrials.gov identifier: NCT01748773) is looking primarily at safety but also at secondary outcomes of DFS and OS associated with 3 cycles of adjuvant trastuzumab, oxaliplatin, and capecitabine (TOX), then chemoradiation with capecitabine, then monotherapy with trastuzumab every 3 weeks for a total of 12 months.

The AIO phase II HER-FLOT study included 58 patients who were treated with 8 cycles of perioperative trastuzumab, 5-FU, leucovorin, oxaliplatin, and docetaxel (HER-FLOT) followed by 9 further cycles of trastuzumab monotherapy, with pCR as the primary endpoint. Promising results (a pCR of 21%) were presented at the 2014 ASCO Annual Meeting.[53] Despite severe grade 3/4 neutropenia in 35% of patients and diarrhea in 17%, the authors reported that 69% of patients received all scheduled therapy. If these phase II trials are positive, future phase III trials with trastuzumab and novel anti-HER2 agents, such as pertuzumab and the antibody conjugate of trastuzumab emtansine (T-DM1), will likely follow. Although these newer agents offer additional improvements in outcome in the treatment of breast cancer, their benefit remains to be proven in gastric cancer. In the recent phase II/III GATSBY trial, there was no significant benefit in OS, PFS, or response rate with T-DM1 compared with taxane monotherapy in the setting of second-line therapy for advanced gastric cancer.[54]

Future Opportunities

Molecular subtyping and biomarkers

The classification of gastric adenocarcinomas has historically included the Lauren and World Health Organization systems.[55,56] Both have been based primarily on etiologic or histologic features. While the Lauren classification does permit a degree of prognostication-with poorer prognosis associated with the diffuse subtype compared with the intestinal subtype-both systems are limited in their ability to guide management or the selection of specific therapies.

Most other solid tumors have undergone a revolution in molecular classification and subsequent personalized selection of treatment. With the exception of those with HER2-positive advanced gastric cancer, most patients with early gastric adenocarcinomas have largely been treated similarly. Thus, not surprisingly, there is significant variability and uncertainty regarding response to treatments.

The Cancer Genome Atlas (TCGA) Research Network analyzed 295 samples to identify dysregulated pathways and potential driver mutations in gastric cancer.[57] The TCGA group identified four distinct molecular subtypes of gastric adenocarcinoma (Table 2): microsatellite instability (MSI), Epstein-Barr virus–associated (EBV), chromosomal instability (CIN), and genomically stable (GS) tumors.[57] The Asian Cancer Research Group (ACRG) analyzed 300 specimens to identify four discrete subtypes (see Table 2): MSI, intact TP53 activity (TP53-positive), functional loss of TP53 (TP53-negative), and mesenchymal-like (EMT).[58] Both groups used a combination of molecular analytical methodology, including single-nucleotide polymorphism analysis, gene expression and methylation profiling, messenger RNA and microRNA sequencing, and copy number analyses, as well as whole-exome and genome sequencing.[57,58] In addition, the ACRG found a significant association between their subtypes and recurrence patterns and even survival when data were merged across multiple gastric cancer cohorts, including TCGA and another Singaporean dataset.[58]

The goal of subtyping is to enrich future trial populations by selecting patients who are more likely to respond to particular treatments. For example, within the ACRG’s MSS/TP53-negative subtype (microsatellite stable, TP53 functional loss) and TCGA’s CIN subtype, up to 60% to 70% of cases harbor somatic mutations in the TP53 tumor suppressor gene.[57,58] Thus, trials with upcoming drugs that target this pathway could either specifically select for or enrich subgroups with this particular molecular subtype.

TCGA’s EBV subtype displays strong expression of interleukin-12 signaling components, as well as overexpression of programmed death ligands 1 (PD-L1) and 2 (PD-L2), which suggests a rationale for testing immune checkpoint inhibitors in this particular subgroup. Exciting phase I/II results suggest a positive signal for PD-1 inhibition using either pembrolizumab or nivolumab in advanced gastric cancer.[59,60] In the CheckMate-032 study with nivolumab, improved responses were seen in patients whose tumors were positive for PD-L1, thus highlighting a potentially useful biomarker. The next vitally important hypothesis to test is whether checkpoint inhibitors as adjuvant therapy can improve survival for early-stage gastric cancer, as they have for resectable melanoma.[61]

Conclusion

Gastric cancer remains a major cause of cancer-related mortality. Surgery continues to be pivotal to the curative management of resectable gastric cancer, but over time the importance of a multimodality approach has become evident. In fact, it could be argued that for optimal outcomes, patients with resectable gastric cancer should be evaluated and managed by specialized multidisciplinary teams in large-volume centers. Although there is a lack of global consensus on the preferred paradigm to improve survival following surgery alone, level I evidence exists for various approaches, including adjuvant chemotherapy, postoperative chemotherapy with chemoradiation, and perioperative chemotherapy.

Improved survival with adjuvant chemotherapy alone in Asia is likely the result of adequate local control achieved via radical surgery and potentially of biologic factors. In Western countries, survival gains have been realized by the inclusion of either postoperative chemoradiation to reduce local failure rates or perioperative chemotherapy to minimize systemic relapses. There is also a heightened awareness of the importance of good-quality surgery to achieve R0 resection, which is associated with improved survival, even in Western centers. Previous studies have indicated the difficulties in completing postoperative therapy; as a result, modern approaches are looking at combining preoperative or perioperative chemoradiation with chemotherapy. The results of the ongoing TOPGEAR and CRITICS trials are therefore eagerly anticipated and likely to be practice-changing.

Exciting new investigational approaches include intensified chemotherapy regimens with modern cytotoxic agents, incorporation of targeted therapies, and the use of preoperative chemoradiation in combination with chemotherapy. Significant developments in molecular pathology have enhanced our understanding of dysregulated pathways and driver mutations underlying the heterogeneity of gastric adenocarcinoma.

To further advance clinical practice, there is an urgent need for consensus on a molecular classification system to provide better predictive and prognostic biomarkers. These must be incorporated to refine and enrich patient selection for entry into future trials. Finally, although immunotherapy with checkpoint inhibitors is still in its infancy for gastric cancer, it holds much promise, particularly in combination with other modalities, as we aim to improve survival and effect a cure in resectable gastric cancer.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-E386.

2. National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER 18: 2005-2011). Stat fact sheets: stomach cancer. http://seer.cancer.gov/statfacts/html/stomach.html. Accessed June 7, 2016.

3. Biondi A, Persiani R, Cananzi F, et al. R0 resection in the treatment of gastric cancer: room for improvement. World J Gastroenterol. 2010;16:3358-70.

4. Spolverato G, Ejaz A, Kim Y, et al. Rates and patterns of recurrence after curative intent resection for gastric cancer: a United States multi-institutional analysis. J Am Coll Surg. 2014;219:664-75.

5. Ajani J, D’Amico TA. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): gastric cancer version 3.2015. http://www.nccn.org. Accessed June 7, 2016.

6. De Andrade JP, Mezhir JJ. The critical role of peritoneal cytology in the staging of gastric cancer: an evidence-based review. J Surg Oncol. 2014;110:291-7.

7. Fujitani K, Yang HK, Mizusawa J, et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016;17:309-18.

8. Sarela AI, Yelluri S; Leeds Upper Gastrointestinal Cancer Multidisciplinary Team. Gastric adenocarcinoma with distant metastasis: Is gastrectomy necessary? Arch Surg. 2007;142:143-9.

9. Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the “different disease” hypothesis. Cancer. 2000;88:921-32.

10. Smith DD, Schwarz RR, Schwarz RE. Impact of total lymph node count on staging and survival after gastrectomy for gastric cancer: data from a large US-population database. J Clin Oncol. 2005;23:7114-24.

11. Siewert JR, Bottcher K, Roder JD, et al. Prognostic relevance of systematic lymph node dissection in gastric carcinoma. German Gastric Carcinoma Study Group. Br J Surg. 1993;80:1015-8.

12. Cuschieri A, Weeden S, Fielding J, et al. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer. 1999;79:1522-30.

13. Hartgrink HH, van de Velde CJ, Putter H, et al. Extended lymph node dissection for gastric cancer: Who may benefit? Final results of the randomized Dutch Gastric Cancer Group trial. J Clin Oncol. 2004;22:2069-77.

14. Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010;11:439-49.

15. Degiuli M, Sasako M, Ponti A, et al. Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer. Br J Surg. 2014;101:23-31.

16. Wanebo HJ, Kennedy BJ, Chmiel J, et al. Cancer of the stomach. A patient care study by the American College of Surgeons. Ann Surg. 1993;218:583-92.

17. 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.

18. Wu CW, Hsiung CA, Lo SS, et al. Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol. 2006;7:309-15.

19. Mocellin S, McCulloch P, Kazi H, et al. Extent of lymph node dissection for adenocarcinoma of the stomach. Cochrane Database Syst Rev. 2015;8:CD001964.

20. Degiuli M, Calvo F. Survival of early gastric cancer in a specialized European center. Which lymphadenectomy is necessary? World J Surg. 2006;30:2193-203.

21. Coupland VH, Lagergren J, Luchtenborg M, et al. Hospital volume, proportion resected and mortality from oesophageal and gastric cancer: a population-based study in England, 2004-2008. Gut. 2013;62:961-6.

22. Hermans J, Bonenkamp JJ, Boon MC, et al. Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol. 1993;11:1441-7.

23. Earle CC, Maroun JA. Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer. 1999;35:1059-64.

24. Mari E, Floriani I, Tinazzi A, et al. Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Ann Oncol. 2000;11:837-43.

25. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357:1810-20.

26. Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011;29:4387-93.

27. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379:315-21.

28. Noh SH, Park SR, Yang H-K, 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.

29. Tsuburaya A, Yoshida K, Kobayashi M, et al. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol. 2014;15:886-93.

30. Ter Veer E, Mohammad NH, Lodder P, et al. The efficacy and safety of S-1-based regimens in the first-line treatment of advanced gastric cancer: a systematic review and meta-analysis. Gastric Cancer. 2016 Jan 11. [Epub ahead of print]

31. Smalley SR, Benedetti JK, Haller DG, et al. Updated analysis of SWOG-directed Intergroup Study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012;30:2327-33.

32. Lee J, Lim do H, Kim S, et al. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012;30:268-73.

33. Kang YK, Kang WK, Shin DB, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20:666-73.

34. Park SH, Sohn TS, Lee J, et al. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: final report of the Adjuvant Chemoradiotherapy in Stomach Tumors Trial, including survival and subset analyses. J Clin Oncol. 2015;33:3130-6.

35. Fuchs CS, Tepper JE, Niedwiecki D, et al. Postoperative adjuvant chemoradiation for gastric or gastroesophageal adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (RT): interim toxicity results from Intergroup trial CALGB 80101. J Clin Oncol. 2011;29(suppl):abstr 4003.

36. 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.

37. 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.

38. 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.

39. Snyder RA, Penson DF, Ni S, et al. Trends in the use of evidence-based therapy for resectable gastric cancer. J Surg Oncol. 2014;110:285-90.

40. Pauligk C, Tannapfel A, Meiler J, et al. Pathological response to neoadjuvant 5-FU, oxaliplatin, and docetaxel (FLOT) versus epirubicin, cisplatin, and 5-FU (ECF) in patients with locally advanced, resectable gastric/esophagogastric junction (EGJ) cancer: data from the phase II part of the FLOT4 phase III study of the AIO. J Clin Oncol. 2015;33(suppl):abstr 4016.

41. Ajani JA, Mansfield PF, Janjan N, et al. Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol. 2004;22:2774-80.

42. Ajani JA, Mansfield PF, Crane CH, et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol. 2005;23:1237-44.

43. Ajani JA, Winter K, Okawara GS, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006;24:3953-8.

44. Lordick F, Kang YK, Chung HC, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:490-9.

45. Waddell T, Chau I, Cunningham D, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:481-9.

46. Tebbutt NC, Price TJ, Ferraro DA, et al. Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial. Br J Cancer. 2016;114:505-9.

47. Dragovich T, McCoy S, Fenoglio-Preiser CM, et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006;24:4922-7.

48. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968-76.

49. Cunningham D, Smyth E, Stenning SP, et al. Peri-operative chemotherapy ± bevacizumab for resectable gastro-oesophageal adenocarcinoma: results from the UK Medical Research Council randomised ST03 trial (ISRCTN 46020948). Eur J Cancer. 2015;51(suppl 3):abstr 2201.

50. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab Monotherapy for Previously Treated Advanced Gastric or Gastro-Oesophageal Junction Adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31-9.

51. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab Plus Paclitaxel Versus Placebo Plus Paclitaxel in Patients With Previously Treated Advanced Gastric or Gastro-Oesophageal Junction Adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224-35.

52. 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.

53. Hofheinz R, Hegewisch-Becker S, Thuss-Patience P, et al. HER-FLOT: trastuzumab in combination with FLOT as perioperative treatment for patients with HER2-positive locally advanced esophagogastric adenocarcinoma: a phase II trial of the AIO Gastric Cancer Study Group. J Clin Oncol. 2014;32(suppl):abstr 4073.

54. Kang YK, Shah MA, Ohtsu A, et al. A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (LA/MGC/GEJC). J Clin Oncol. 2016;34(suppl 4):abstr 5.

55. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31-49.

56. World Health Organization. WHO classification of tumours of the digestive system. Lyon, France: IARC Press; 2010.

57. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202-9.

58. Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449-56.

59. Muro K, Bang YJ, Shankaran V, et al. Relationship between PD-L1 expression and clinical outcomes in patients (pts) with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012. J Clin Oncol. 2015;33(suppl 3):abstr 3.

60. Le D, Bendell J, Calvo E, et al. Safety and activity of nivolumab monotherapy in advanced and metastatic (A/M) gastric or gastroesophageal junction cancer (GC/GEC): results from the CheckMate-032 study. J Clin Oncol. 2016;34(suppl 4):abstr 6.

61. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522-30.