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Adjuvant and neoadjuvant treatment of gastric cancer

Adjuvant and neoadjuvant treatment of gastric cancer
Literature review current through: Jan 2024.
This topic last updated: Oct 21, 2022.

INTRODUCTION — The incidence of gastric cancer has been declining steadily since the 1930s, yet it remains a major cause of cancer death in the United States and globally. The high mortality rate reflects the prevalence of advanced disease at presentation. In population-based series of Western populations, the five-year survival rate for patients with completely resected stage I gastric cancer is approximately 70 to 75 percent, and it drops to 35 percent or less for stage IIB disease and beyond (table 1 and figure 1). (See "Surgical management of invasive gastric cancer", section on 'Prognosis' and "Epidemiology of gastric cancer".)

Efforts to improve treatment results beyond those obtained with surgery alone have included adjuvant (postoperative) and neoadjuvant (preoperative) strategies. The positive impact of such therapies on survival in patients with resected gastric cancer has become clearer over time, although there is no consensus as to the best approach.

This topic review will focus on adjuvant and neoadjuvant therapies for noncardia gastric cancer. The epidemiology, staging, and surgical treatment of invasive gastric cancers, the management of early gastric cancer (an adenocarcinoma that is restricted to the mucosa or submucosa, irrespective of lymph node metastasis [T1, any N]), and multimodality approaches for treatment of invasive thoracic esophageal cancers and cancers arising in the esophagogastric junction and proximal stomach (cardia) are covered separately.

(See "Epidemiology of gastric cancer".)

(See "Clinical features, diagnosis, and staging of gastric cancer".)

(See "Surgical management of invasive gastric cancer".)

(See "Early gastric cancer: Treatment, natural history, and prognosis".)

(See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus".)

(See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".)

OVERVIEW OF THE THERAPEUTIC APPROACH — For patients with potentially resectable noncardia gastric cancer, randomized trials and meta-analyses indicate a significant survival benefit over surgery alone for a number of approaches, including adjuvant chemoradiotherapy (as was used in two United States intergroup trials: Intergroup [INT] 0116 and Cancer and Leukemia Group B [CALGB] 80101), perioperative (preoperative plus postoperative) chemotherapy (as was used in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy [MAGIC], and docetaxel, oxaliplatin, leucovorin [LV], and short-term infusional fluorouracil [FU; FLOT] trials), and adjuvant chemotherapy alone (as is often used in East Asia). (See 'Adjuvant chemoradiotherapy' below and 'Neoadjuvant/perioperative chemotherapy' below and 'Adjuvant chemotherapy' below.)

Few trials have directly compared these approaches, and the optimal way to integrate combined modality therapy has not been definitively established. A major problem, at least in the United States, is that patients with gastric cancer are commonly taken to the operating room prior to consultation with medical or radiation oncologists. Multidisciplinary preoperative evaluation is strongly encouraged.

Enrollment in available clinical trials is preferred. If protocol treatment is not available or is declined, the following represents our general approach:

For most patients with potentially resectable, histologically proven noncardia gastric adenocarcinoma with invasion beyond the submucosa (clinical stage T2N0 or higher (table 1)) on preoperative staging evaluation, we recommend combined modality therapy over surgery alone.

For most patients, we suggest neoadjuvant therapy over initial surgery followed by adjuvant therapy, especially for those with a high likelihood of developing distant metastases (ie, those with bulky T3/T4 tumors, visible perigastric nodes by preoperative imaging studies, or a linitis plastica appearance).

Although there are no randomized trials demonstrating an overall survival benefit from neoadjuvant therapy versus initial surgery followed by any form of adjuvant therapy, we favor the neoadjuvant chemotherapy approach given the greater chance of delivering therapy in the preoperative setting and the fact that patients who are at high risk of developing distant metastases may be spared the morbidity of unnecessary gastrectomy if evidence of distant metastases emerges after chemotherapy. (See 'Versus surgery plus adjuvant chemotherapy' below.)

Upfront surgery followed by adjuvant therapy remains an accepted approach, especially for patients with clinically staged, nonbulky T2 or T3 tumors with no visible perigastric nodes.

Until further data are available, we suggest not pursuing preoperative chemoradiotherapy for patients with noncardia gastric cancer.

The best chemotherapy regimen for neoadjuvant therapy is not established, and practice is variable. For most patients with a good performance status and without significant comorbidities who are able to tolerate intensive chemotherapy, we suggest the FLOT regimen rather than an epirubicin-containing regimen (such as epirubicin, cisplatin, and infusional FU [ECF], or epirubicin, cisplatin, and capecitabine [ECX]), given the survival benefit for FLOT compared with ECF in the FLOT4-AIO trial. (See 'FLOT' below.)

For patients with a lower performance status or multiple comorbidities who are thought unlikely to tolerate FLOT, oxaliplatin plus infusional FU and LV (FOLFOX), capecitabine plus oxaliplatin (CAPOX), and S-1 plus oxaliplatin (where available) are appropriate alternative regimens. (See 'Lesser performance status' below.)

For patients who have already undergone potentially curative gastric resection with no neoadjuvant therapy, we recommend adjuvant therapy rather than surgery alone for all patients with positive nodes (which would include pathologic T1N1 [stage IB] disease) and for those with pathologic T3-4N0 disease (table 1).

Options for adjuvant therapy include chemotherapy with or without chemoradiotherapy.

For patients who have not undergone an adequate lymphadenectomy (D2 lymph node dissection including perigastric [D1] nodes as well as those along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery [D2 lymph nodes], with the goal of examining 16 or more lymph nodes), or who have node-positive or incompletely resected (ie, R1 or R2) disease, we suggest chemoradiotherapy plus chemotherapy rather than chemotherapy alone. (See 'Inadequate lymphadenectomy, node-positive, or incompletely resected disease' below.)

For patients who have had an adequate lymphadenectomy and who have node-negative disease, we suggest adjuvant chemotherapy alone. (See 'Adequate lymphadenectomy and node-negative disease' below.)

If chemoradiotherapy is chosen, we prefer the following regimen:

For patients with an excellent performance status and limited comorbidity, especially if they have more advanced disease (T4 or node positive), we initiate therapy with two 14-day cycles of FOLFOX (table 2) or two 14-day cycles of FLOT. (See 'FLOT' below and 'Adjuvant chemoradiotherapy' below.)

For patients with a lesser performance status or earlier stage (eg, T3N0) disease, an acceptable alternative is two 14-day cycles of the modified de Gramont FU/LV regimen (table 3).

During the chemoradiotherapy portion, we use continuous infusion FU (200 mg/m2 per day during the entire course of RT, as was used in the standard arm of CALGB 80101) or capecitabine (850 mg/m2 twice daily, as was used in the Adjuvant Chemoradiation Therapy in Stomach Cancer [ARTIST] trial) rather than bolus FU. (See 'Adjuvant chemoradiotherapy' below.)

We complete therapy with four additional cycles of FLOT (14-day cycles), FOLFOX (14-day cycles), two courses of CAPOX (21-day cycles), or four cycles of the de Gramont regimen of FU/LV (14-day cycles).

If chemotherapy alone is chosen, the optimal regimen is not established, but our preference is to give CAPOX (table 4) for six months, as was used in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) trial. Six months of FOLFOX (table 2) is an acceptable alternative. (See 'CAPOX/FOLFOX' below.)

One year of S-1 therapy may be an alternative for patients in Eastern Asian countries where this agent is approved. For those with stage III (table 1) disease, the combination of S-1 plus docetaxel may be more effective than S-1 alone, but the side effect profile is also worse. How one year of either S-1 monotherapy or S-1 plus docetaxel compares with CAPOX for six months is not clear. (See 'S-1 with or without docetaxel' below.)

For the subgroup of patients with pathologic T2N0 disease, observation is appropriate as long as they have undergone an adequate (D2) lymph node dissection with the goal of examining at least 16 nodes. However, we would suggest adjuvant treatment for pathologic T2N0 disease with an inadequate lymphadenectomy. For other high-risk cases (pathologic T2N0 with a high histologic grade or the presence of lymphovascular or perineural invasion), we encourage adjuvant therapy and individualize decision-making. (See 'Pathologic T2N0 disease' below.)

The optimal management of patients with locally advanced, initially unresectable, but nonmetastatic gastric cancer is uncertain, and there is no standard approach. The role of induction therapy is unclear. An initial attempt at downstaging with chemotherapy, chemoradiotherapy, or a combination, followed by careful restaging and surgical exploration in responders who have no evidence of metastatic disease, is a reasonable approach for a fit patient who initially had locally unresectable but nonmetastatic disease. (See 'Initially locally unresectable nonmetastatic disease' below.)

POTENTIALLY RESECTABLE CLINICAL T2N0 DISEASE OR HIGHER THAT IS NOT YET RESECTED — For most patients with potentially resectable clinical T2N0 or higher (table 1) gastric cancer, we suggest neoadjuvant therapy rather than initial surgery. There are no randomized trials comparing neoadjuvant therapy with initial surgery followed by any form of adjuvant therapy. However, given the greater chance of delivering systemic therapy in the preoperative setting, we favor this approach. However, upfront surgery followed by adjuvant therapy remains an accepted approach, especially for patients with distal, clinically staged, nonbulky clinical T2 tumors and no visible perigastric nodes.

Neoadjuvant/perioperative chemotherapy

Rationale and outcomes — Neoadjuvant chemotherapy may be administered as a means of "downstaging" a locally advanced tumor prior to an attempt at curative resection. This approach has been applied to patients thought to have resectable disease as well as to those with apparently unresectable but nonmetastatic disease. (See 'Initially locally unresectable nonmetastatic disease' below.)

Another benefit of neoadjuvant chemotherapy is that patients who are at high risk of developing distant metastases (eg, those with bulky T3/T4 tumors, visible perigastric nodes by preoperative imaging studies [including endoscopic ultrasound], or a linitis plastica appearance) may be spared the morbidity of unnecessary gastrectomy if evidence of distant metastases emerges after chemotherapy. Laparoscopic evaluation prior to initiation of therapy should be considered in any patient with extensive or bulky lymphadenopathy, fat stranding, or abdominopelvic ascites. (See "Clinical features, diagnosis, and staging of gastric cancer", section on 'Staging laparoscopy'.)

Versus surgery alone — At least four trials have directly compared surgery alone with neoadjuvant or perioperative chemotherapy, three of which demonstrated a survival benefit for this approach [1-4]. Two other trials, which compared preoperative treatment using an oral fluoropyrimidine with surgery alone, failed to show a significant benefit for chemotherapy and are not discussed further here [5,6].

MAGIC trial – The largest and most influential trial has been the United Kingdom Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, in which 503 patients with potentially resectable gastric (74 percent), distal esophageal (11 percent), or esophagogastric junction (EGJ; 15 percent) adenocarcinomas were randomly assigned to surgery alone or surgery plus perioperative chemotherapy (three preoperative and three postoperative cycles of epirubicin, cisplatin, and infusional fluorouracil [FU; ECF] (table 5)) [1]. (See "Treatment protocols for esophagogastric cancer".)

A higher proportion of the chemotherapy-treated patients with gastric cancer who underwent radical surgery had a potentially curative procedure (79 versus 70 percent), and significantly more had T1/T2 tumors (52 versus 37 percent) and N0/N1 disease (84 versus 71 percent). Notably, only 104 patients (42 percent) were able to complete protocol treatment, including surgery and all three cycles of the postoperative chemotherapy. These data underscore one of the major problems with the perioperative approach: the difficulty in administering the full number of postoperative chemotherapy cycles.

Despite this, overall survival was significantly better with chemotherapy (hazard ratio [HR] for death 0.75, 95% CI 0.60-0.93; five year survival 36 versus 23 percent), as was progression-free survival.

Meta-analysis – A meta-analysis comparing a variety of preoperative chemotherapy regimens with surgery alone concluded that neoadjuvant chemotherapy was associated with a statistically significant benefit in terms of both overall survival (odds ratio [OR] 1.32, 95% CI 1.07-1.64) and progression-free survival (OR 1.85, 95% CI 1.39-2.46) [7]. Furthermore, neoadjuvant chemotherapy was associated with a significantly higher microscopically complete (R0) tumor resection rate (OR 1.38, 95% CI 1.08-1.78) and did not significantly worsen rates of operative complications, perioperative mortality, or grade 3 or 4 adverse effects.

Versus surgery plus adjuvant chemotherapy — The superiority of neoadjuvant versus adjuvant chemotherapy in patients with resectable gastric cancer was shown in the PRODIGY trial, in which 484 Korean patients with clinical stage IIa to IIIc gastric (94 percent) or EGJ (6 percent) adenocarcinoma were randomly assigned to three 21-day cycles of neoadjuvant docetaxel plus oxaliplatin and S-1 followed by gastrectomy with D2 lymphadenectomy and 48 weeks of adjuvant S-1 or gastrectomy/D2 lymphadenectomy followed by 48 weeks of S-1 [8]. S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine; a potent inhibitor of dihydropyrimidine dehydrogenase), and oteracil (potassium oxonate; which inhibits phosphorylation of intestinal FU, which is thought to be responsible for treatment-related diarrhea). One year of postoperative S-1 is considered a standard approach after gastric cancer resection in East Asia; the drug is not available in the United States. Overall, neoadjuvant therapy was reasonably well tolerated, although there were two treatment-related deaths (dyspnea, febrile neutropenia). While the group receiving neoadjuvant therapy were more likely to be pathologically node-negative (55 versus 22 percent) and less likely to have pT4 tumors (19 versus 40 percent), at a median follow-up of 39 months this only translated into a modest albeit significant benefit in three year progression-free survival (66 versus 60 percent, HR 0.70, 95% CI 0.52-0.95) and no overall survival benefit (three year 74 versus 73 percent, HR 0.84, 95% CI 0.60-1.19). Although more patients in the standard of care arm received no adjuvant chemotherapy as they were found to have pathologic stage I disease, the fraction of patients who started adjuvant chemotherapy and completed all cycles was similar in both groups (84 and 83 percent).

Choice of regimen and patient selection — The best chemotherapy regimen for use in the neoadjuvant setting has not been conclusively established, and practice is variable.

Excellent performance status — For patients with an excellent performance status (table 6) and without significant comorbidities, we suggest docetaxel, oxaliplatin, leucovorin [LV], and short-term infusional FU (FLOT) rather than an epirubicin-containing regimen (such as ECF or epirubicin, cisplatin, and capecitabine [ECX]), given the report of a survival benefit compared with ECF in the FLOT4-AIO trial [9].

FLOT — The FLOT regimen is outlined in the table (table 7).

The phase II/III FLOT4-AIO trial compared the docetaxel-based triplet FLOT regimen (four preoperative and four postoperative two-week cycles) versus epirubicin-based triplet therapy (three preoperative and three postoperative three-week cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2], both on day 1, and either FU [200 mg/m2 daily as a continuous infusion] on days 1 to 21 [ECF] or capecitabine [1250 mg/m2 orally daily] on days 1 to 21 [ECX]) [10,11]. In a report of the 300 patients with gastric or EGJ adenocarcinoma who were enrolled in the open-label phase II part of the trial, the FLOT regimen was associated with a higher pathologic complete response rate (16 versus 8 percent), and toxicity appeared approximately similar. At least one serious adverse event involving a perioperative medical or surgical complication developed in 25 and 40 percent of the patients in the FLOT and ECF/ECX groups, respectively, and there was less grade 3 or 4 nausea (9 versus 17 percent), fatigue (9 versus 14 percent), and vomiting (3 versus 10 percent) in the FLOT group. However, rates of grade 3 or 4 neutropenia were higher with FLOT (52 versus 38 percent).

The phase III component of the trial enrolled 716 patients with resectable gastric (44 percent) or gastroesophageal junction (56 percent) tumors and randomly assigned them to the same docetaxel- or epirubicin-based triplets as were used in the phase II component. Overall, 91 and 37 percent of patients receiving ECF/ECX and 90 and 50 percent of patients receiving FLOT completed the planned preoperative and postoperative cycles, respectively [12]. The primary endpoint was overall survival. At a median follow-up of 43 months, FLOT was associated with a significantly greater median overall survival (50 versus 35 months, HR 0.77, 95% CI 0.63-0.94) and three-year overall survival (57 versus 48 percent). The rates of perioperative complications were similar (51 percent with ECF/ECX and 50 percent for FLOT). There was significantly more grade 3 or 4 nausea (16 versus 7 percent), vomiting (8 versus 2 percent), and thromboembolic events (6 versus 3 percent) with ECF/ECX and more grade 3 or 4 diarrhea (10 versus 4 percent), neutropenia (51 versus 39 percent), infections (18 versus 9 percent), and sensory neuropathy (7 versus 2 percent) with FLOT.

Efforts to improve upon the FLOT regimen are underway:

The randomized phase II RAMSES study explored the addition of ramucirumab to FLOT in 180 patients with gastric or gastroesophageal junction cancer [13]. Initial results suggest higher rates of margin-free (R0) resections (97 versus 83 percent), but pathologic complete response rates were similar (27 versus 30 percent).

Ongoing studies are testing the value of FLOT plus immune checkpoint inhibitors including pembrolizumab (KEYNOTE-585), atezolizumab (the DANTE study) [14], and durvalumab [15].

ECF/ECX — Prior to the data from the FLOT4-AIO trial, many clinicians utilized the ECF regimen (table 5), as was used in the MAGIC trial, or one of the ECF variants, as described in the Randomized ECF for Advanced and Locally Advanced Esophagogastric Cancer 2 (REAL 2) study, including ECX (table 8) and epirubicin, oxaliplatin, and capecitabine (EOX) (table 9). The MAGIC trial administered three cycles of chemotherapy prior to resection and three cycles after surgery. (See 'Rationale and outcomes' above.)

However, the ECF/ECX regimens have fallen out of favor with new data suggesting the superiority of FLOT; we no longer use these combinations.

Lesser performance status — For patients with a lesser performance status (table 6) or extensive comorbidity, we prefer non-epirubicin- and non-docetaxel-containing regimens, such as oxaliplatin plus infusional FU and LV (FOLFOX, (table 2)) [16-18], capecitabine plus oxaliplatin (CAPOX (table 4); as was used in the CLASSIC adjuvant trial), or S-1 plus oxaliplatin (where available) [19]. In such cases, we would administer four cycles prior to surgery and four courses following resection. (See 'CAPOX/FOLFOX' below.)

Is there a role for neoadjuvant chemoradiotherapy — Until further data are available, we suggest not pursuing preoperative chemoradiotherapy as an alternative to perioperative chemotherapy for patients with noncardia gastric cancer.

Preoperative combined chemotherapy and radiation therapy is more commonly used for esophageal, EGJ, and gastric cardia cancers than for potentially resectable noncardia gastric adenocarcinomas. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus" and "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".)

The only available trials included gastric cardia and EGJ tumors only:

Neoadjuvant chemoradiotherapy was compared with induction chemotherapy alone in the multicenter German PreOperative therapy in Esophagogastric adenocarcinoma Trial (POET), which was limited to patients with EGJ adenocarcinoma [20]. Although there were potentially clinically meaningful survival differences that favored chemoradiotherapy, they were only borderline significant (p = 0.055 for overall survival). Furthermore, whether the results can be extrapolated to patients with true noncardia gastric cancer is uncertain. These data are discussed in detail elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'Neoadjuvant CRT versus chemotherapy alone'.)

Additional data are available from the NEO-AEGIS trial, which directly compared the CROSS chemoradiotherapy regimen with perioperative chemotherapy (modified ECF as used in the MAGIC trial or FLOT) in 362 patients with adenocarcinoma of the esophagus or EGJ [21]. In a preliminary report, presented at the 2021 annual American Society of Clinical Oncology meeting (median follow-up 25 months), chemoradiotherapy was associated with a higher rates of R0 resection (95 versus 82 percent), higher pathologic complete response rate (16 versus 5 percent), and more patients with pathologically node-negative disease (60 versus 45 percent), but this did not translate into better three-year survival (56 versus 57 percent, HR 1.02, 95% CI 0.74-1.42), the primary endpoint. Mature data are awaited.

There are no randomized trials addressing the benefit of preoperative chemoradiotherapy for noncardia gastric cancers. In three separate phase II studies using different chemoradiotherapy protocols, the pathologic complete response rates ranged from 20 to 30 percent, and 70 to 78 percent were able to undergo an R0 resection after chemoradiotherapy [22-24]. Whether these results are better than what could be achieved with surgery alone, neoadjuvant chemotherapy, or surgery followed by adjuvant chemoradiotherapy is the subject of current randomized studies (Trial of Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma [TOPGEAR], CRITICS-II, and ESOPEC). (See 'Ongoing research' below.)

The use of induction chemoradiotherapy for patients with initially unresectable gastric cancer is discussed below. (See 'Initially locally unresectable nonmetastatic disease' below.)

Postoperative management of poor responders — Regardless of the perioperative regimen that is chosen, patients should complete the postoperative component of the selected regimen after surgery, if feasible. Whether outcomes can be improved in poor responders by switching to a different non-cross-resistant regimen or by administering chemoradiotherapy (if it was not administered preoperatively) is not established. It is reasonable to offer adjuvant chemoradiotherapy to individuals with extensive residual disease if they are sufficiently fit to tolerate it, and wish to pursue an aggressive approach. Management of these patients needs to be individualized.

Patients who have substantial residual disease at resection after neoadjuvant therapy (particularly nodal metastases [25-27]) have a relatively poor prognosis, and the best way to manage this situation is unclear. If two or three months of preoperative chemotherapy had minimal impact on the tumor, administering more courses of the same chemotherapy seems unlikely to be more effective following surgery [28]. However, at least one analysis of two separate cohorts undergoing perioperative chemotherapy using several different oxaliplatin-containing chemotherapy regimen for locally advanced gastric cancer concluded that those who received the adjuvant therapy component of the regimen after surgery had better survival than did those who did not (after propensity score matching for a variety of potentially confounding covariates, three year overall survival was 60.1 versus 49.3 percent) [29]. The better survival was seen only in those with a lymph node ratio (LNR; number of positive nodes divided by the total number of nodes in the surgical specimen) ≥9 percent, and not in those with a lower LNR. These data support the view that the perioperative chemotherapy regimen should be completed postoperatively, if possible, even in the presence of a high number of residually positive lymph nodes.

The only data to inform a potential benefit from chemoradiotherapy in this setting come from the Dutch CRITICS trial, in which 788 patients with stage IB to IV (table 10) potentially resectable gastric cancer received induction chemotherapy (three courses of ECX/EOX) followed by surgery and randomization to postoperative chemotherapy (three cycles of the same regimen) or chemoradiotherapy (45 Gy in 25 fractions with weekly cisplatin and daily capecitabine) regardless of the pathologic result [30]. All patients were to have a D1 or better lymphadenectomy with at least 15 nodes in the resection specimen. At a median follow-up of 61 months, there were no significant differences in five-year overall survival (the primary endpoint, 42 versus 40 percent with chemotherapy and chemoradiotherapy, respectively) or progression-free survival; local recurrence rates were 15 versus 11 percent.

Postoperatively, only approximately 60 percent of the patients in each group even started the adjuvant therapy regimen. Given that all patients received neoadjuvant therapy initially, this trial was not designed to address the benefit of adjuvant chemoradiotherapy compared with adjuvant chemotherapy alone. Furthermore, the initial report did not stratify outcomes according to post-treatment pathologic stage, and therefore, they cannot be used to conclude whether there is or is not a benefit for chemoradiotherapy in nonresponders to initial neoadjuvant chemotherapy.

INITIAL POTENTIALLY CURATIVE RESECTION

Pathologic T3N0 or node-positive disease — For patients who have already undergone potentially curative gastric resection and who did not receive neoadjuvant therapy and for whom protocol participation is not feasible, we suggest adjuvant therapy rather than surgery alone for patients with N1 disease (which would include T1N1 stage IB) and for all patients with T3-4N0 disease (table 1).

Options for adjuvant therapy include chemoradiotherapy plus chemotherapy and chemotherapy alone. For patients who have not undergone an adequate D2 lymph node dissection (including perigastric [D1] nodes as well as those along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery [D2 lymph nodes], with the goal of examining 16 or more lymph nodes), we suggest chemoradiotherapy plus chemotherapy rather than chemotherapy alone. For patients who have had an adequate lymphadenectomy, we suggest chemotherapy alone but chemoradiotherapy plus chemotherapy is still an option, particularly for patients who have node-positive disease.

Adequate lymphadenectomy and node-negative disease — For patients who have had an adequate lymphadenectomy and who have node-negative disease, we suggest adjuvant chemotherapy alone.

Adjuvant chemotherapy — More than 30 randomized trials have compared adjuvant systemic chemotherapy with surgery alone in resectable gastric cancer, with variable, mostly negative results when overall survival is considered the primary endpoint (table 11). While some of the trials were clearly underpowered to detect a significant survival difference, others utilized inferior surgical techniques, or much of the planned chemotherapy was not given because of a prolonged recovery from surgery.

Meta-analyses – Given the variability in outcomes in these phase III trials, several meta-analyses have been undertaken, all of which support a significant survival benefit for perioperative or adjuvant chemotherapy [31-33], including one that was limited to trials from Western (ie, non-Eastern Asian) countries [34]. Several studies indicate a somewhat better prognosis in Eastern Asian as compared with Western populations with gastric cancer. This subject is discussed in detail elsewhere. (See "Surgical management of invasive gastric cancer", section on 'Prognosis'.)

As an example, one of these analyses evaluated data from 34 randomized trials comparing adjuvant systemic chemotherapy with surgery alone conducted in both Eastern Asian and Western populations [32]. The risk of death in patients receiving adjuvant chemotherapy was reduced by 15 percent (hazard ratio [HR] for death 0.85, 95% CI 0.80-0.90). However, all trials had a high risk of bias.

Choice of regimen — The optimal regimen is not established. Acceptable alternatives include CAPOX, as was used in the CLASSIC trial [35]; FOLFOX [36]; and for Eastern Asian patients (where available), S-1 with or without docetaxel. (See 'Rationale and outcomes' above.)

CAPOX/FOLFOX — The benefit of adjuvant therapy using CAPOX was addressed in the multicenter CLASSIC trial, in which 1035 patients with stage II, IIIA, or IIIB (table 1) gastric cancer were randomly assigned to eight 21-day cycles of capecitabine (1000 mg/m2 twice daily on days 1 to 14) plus oxaliplatin (130 mg/m2 on day 1) or to surgery alone after D2 gastrectomy [35]. The study was conducted in South Korea, China, and Taiwan. Only 67 percent of the patients assigned to chemotherapy received all eight cycles of chemotherapy as planned, and adverse events (most commonly neutropenia, nausea, vomiting, thrombocytopenia, and anorexia) led to chemotherapy dose modifications in 90 percent of patients. Despite this, at a median follow-up of 34 months, chemotherapy was associated with a significant improvement in three-year disease-free survival (DFS; 74 versus 59 percent, HR for death 0.56, 95% CI 0.44-0.72), with only a borderline statistically significant improvement in overall survival (83 versus 78 percent, HR 0.72, 95% CI 0.52-1.00). However, with longer follow-up, the improved overall survival with chemotherapy was statistically significant (five-year overall survival 78 versus 69 percent, HR for death 0.66, 95% CI 0.51-0.85) [37].

FOLFOX is an acceptable alternative. In a prospective randomized trial comparing FU/leucovorin with or without oxaliplatin after complete (R0) resection on gastric cancer, recurrence-free and overall survival rates all favored the addition of oxaliplatin, and there were no significant differences between the groups in toxicity rates [36].

S-1 with or without docetaxel

S-1 monotherapy – The benefit of adjuvant treatment with S-1 was demonstrated in the Japanese Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC) trial, in which 1059 patients with stage II or III gastric cancer who had undergone potentially curative surgery with D2 lymphadenectomy were randomly assigned to S-1 (80 to 120 mg daily for four weeks, repeated every six weeks for one year) or surgery alone [38]. Five-year overall survival was significantly better with S-1 (72 versus 61 percent), with better-than-expected survival in both groups. By comparison, the five-year survival rates for the Intergroup (INT) 0116 and MAGIC trials were 43 versus 28 and 36 versus 23 percent for the treatment versus control groups, respectively [1,39].

These results led to the adoption of one year of postoperative S-1 as a standard adjuvant therapy approach for gastric cancer in Eastern Asian patients. It is difficult to know whether the benefit of adjuvant therapy with S-1 demonstrated in the ACTS-GC trial can be extrapolated to other populations, given the markedly better outcomes seen in both the treated and the surgery-alone control groups, stage for stage, when compared with outcomes in other non-Japanese populations [40].

S-1 is approved in Japan for adjuvant therapy of gastric cancer and in Europe for treatment of advanced gastric cancer; it is not available in the United States.

Docetaxel plus S-1Docetaxel plus S-1 may provide better outcomes than S-1 alone, at least for stage III disease. In the multicenter phase III JACCRO GC-07 trial, after a microscopically complete (R0) resection with D2 lymphadenectomy, 1100 patients with pathologic stage III gastric cancer were randomly assigned to oral S-1 alone (eight courses of 80 to 120 mg per day on days 1 to 28 of each 42-day cycle) or S-1 plus docetaxel (oral S-1 at 80 to 120 mg per day on days 1 to 14 with seven days of rest, followed by six courses of S-1 at the same dose and schedule combined with docetaxel 40 mg/m2 on day 1 of each cycle, then four further courses of S-1 at 80 to 120 mg per day on days 1 to 28 of each 42-day cycle) [41].

In the latest analysis of long-term outcomes presented at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, three-year recurrence-free survival (the primary endpoint) was significantly better with S-1 plus docetaxel (68 versus 57 percent, HR 0.715, 95% CI 0.587-0.871) as was three-year overall survival (78 versus 71 percent, HR 0.742, 95% CI 0.596-0.925) [42]. Grade 3 or worse adverse events, including leucopenia, anorexia, stomatitis, and anemia, were more frequent with combined therapy [41].

Inadequate lymphadenectomy, node-positive, or incompletely resected disease — For patients who have not undergone an adequate D2 lymph node dissection (including perigastric [D1] nodes as well as those along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery [D2 lymph nodes], with the goal of examining 16 or more lymph nodes), or who have node-positive or incompletely resected (ie, R1 or R2) disease, we suggest chemoradiotherapy plus chemotherapy rather than chemotherapy alone.

Adjuvant chemoradiotherapy — One of the most controversial areas in gastrointestinal oncology is the benefit of postoperative chemoradiotherapy over chemotherapy alone after resection of gastric cancer. Interest in adjuvant RT stems from the observation that over 80 percent of patients who die from gastric cancer experience a local recurrence at some point [43]. However, despite the multiple randomized trials and meta-analyses, the survival benefit from adding chemoradiotherapy to chemotherapy after surgery for gastric cancer remains uncertain.

The following studies have informed this debate:

INT-0116 – In the United States the seminal trial that influenced the use of chemoradiotherapy after resection of a gastric cancer was INT 0116 trial, in which 556 patients were randomly assigned following potentially curative resection of gastric or esophagogastric junction (EGJ) cancer (T1-4N0-1), to observation alone or adjuvant chemoradiotherapy (one cycle of FU/LV bolus chemotherapy followed by chemoradiotherapy and then two more cycles of chemotherapy) [44].

The majority of tumors were T3/T4 (68 and 69 percent of the treated and control groups, respectively), and 85 percent had nodal metastases. Three-year DFS (48 versus 31 percent) and overall survival rates (50 versus 41 percent) were significantly better with combined modality therapy, and median survival was significantly longer (36 versus 27 months). Benefits were maintained with longer follow-up (five-year overall survival 43 versus 28 percent, HR for survival 1.32, 95% CI 1.10-1.60) [39].

In the chemoradiotherapy group, grade 3 and 4 acute toxic effects occurred in 41 and 32 percent of patients, respectively, while three patients (1 percent) died from treatment-related toxicity [44]. The most frequent grade 3 or worse adverse effects were hematologic (54 percent), gastrointestinal (33 percent), infectious (6 percent), and neurologic (4 percent).

A later pattern of failure analysis disclosed a similar frequency of distant metastasis (16 versus 18 percent in the chemoradiotherapy and control groups, respectively) but fewer local (2 versus 8 percent) and regional (22 versus 39 percent) recurrences with chemoradiotherapy [39].

The initial report of this study changed the standard of care in the United States following potentially curative resection of gastric cancer from observation alone to surgery followed by adjuvant combined chemoradiotherapy and FU/LV chemotherapy. The impact of these results on the management of patients with EGJ tumors is addressed in detail elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas", section on 'Adjuvant CRT'.)

However, a significant criticism of this trial was the limited extent of the surgical procedure in most cases. Although D2 lymph node dissection was recommended, it was only performed in 10 percent of cases, and 54 percent did not even have clearance of the D1 nodal regions. This noncompliance likely contributed to inferior survival and a 64 percent relapse rate in the surgery-alone arm. (See "Surgical management of invasive gastric cancer", section on 'Extent of lymph node dissection'.)

CALGB 80101 – Another criticism of the INT-0116 trial is that it used inferior chemotherapy by modern standards, and the chemoradiotherapy component was given with bolus intravenous FU and LV on days 1 through 4 and on the last three days of RT, an approach that has fallen out of favor given the better tolerability and superior efficacy of daily low-dose infusional FU in other gastrointestinal sites, such as rectal cancer [45].

As discussed above, the MAGIC trial demonstrated a significant survival benefit for the use of perioperative chemotherapy with ECF (table 5) versus surgery alone in patients with resectable gastric and EGJ cancer. (See 'Rationale and outcomes' above and "Treatment protocols for esophagogastric cancer".)

CALGB 80101, a United States intergroup study, compared the INT 0116 protocol regimen (bolus FU and LV plus concurrent FU-based chemoradiotherapy) with postoperative ECF before and after concurrent FU-based chemoradiotherapy in 546 patients with completely resected gastric or EGJ tumors that extended beyond the muscularis propria or were node positive [46]. Both arms received continuous infusion FU during the chemoradiotherapy part of the adjuvant regimen. There were approximately 22 percent EGJ tumors, and the remainder were gastric or multicentric.

Patients receiving ECF had lower rates of diarrhea, mucositis, and grade 4 or worse neutropenia. However, overall survival, the primary endpoint, was not significantly better with ECF (at five years, 44 percent in both groups). The trial was not adequately powered to assess noninferiority.

Chemotherapy versus chemoradiotherapy – The benefits of postoperative chemoradiotherapy were called into question by the results of several trials directly comparing postoperative adjuvant chemotherapy with chemoradiotherapy [30,47-53], only one of which has shown a significant overall survival benefit for the addition of RT to chemotherapy [49]. However, most of the trials are flawed in some way:

ARTIST trial – In one of the largest trials, the Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) trial, 458 patients with completely resected gastric cancer and a D2 lymph node dissection were randomly assigned to six courses of postoperative capecitabine plus cisplatin or two courses of postoperative capecitabine plus cisplatin followed by chemoradiotherapy (45 Gy RT with concurrent daily capecitabine [825 mg/m2 twice daily]) and two additional courses of capecitabine plus cisplatin [47].

In the latest update, at a median follow-up of 84 months, three-year DFS (the primary endpoint) was not significantly better in patients who received combined modality therapy (HR 0.74, 95% CI 0.52-1.05), although an unplanned subset analysis did indicate a significantly better DFS with chemoradiotherapy in those with node-positive disease (three-year DFS 76 versus 72 percent, p = 0.004) [47]. Overall survival, a secondary endpoint, was also not significantly different (HR 1.13, 95% CI 0.775-1.647). Notably, even though the ARTIST trial met its accrual goal, both arms did better than anticipated, so the number of events was smaller than planned, resulting in the study being underpowered for the planned endpoints.

In our view (and that of others [54]), this trial should not be interpreted as definitively disproving the benefit of chemoradiotherapy relative to chemotherapy alone.

ARTIST 2 trial – The hypothesis that adjuvant chemoradiotherapy may represent a better approach than adjuvant chemotherapy for patients with node-positive disease was tested in a successor trial, the ARTIST 2 trial, in which 900 Korean patients with pathologically staged II or III, node-positive, D2-resected gastric cancer were randomly assigned to adjuvant S-1 for one year, S-1 plus oxaliplatin (SOX) for six months, or SOX chemotherapy plus chemoradiotherapy (two months of SOX followed by 45 Gy RT plus S-1 and then four additional months of SOX) [55]. In an analysis of the first 546 enrolled patients, with a median follow-up of 47 months, there was no significant benefit for the addition of RT to SOX in terms of DFS, the primary endpoint (at three years, 73 versus 74 percent, HR 0.971). Results were inferior with S-1 alone (three-year DFS 65 percent). Overall survival endpoints were not reported. Although the boundaries for stopping the trial were not reached, further trial enrollment was discontinued at the recommendation of the Data Monitoring Committee.

It is difficult to put this trial into context for patients outside of Korea who do not have access to S-1, and in areas where there is less confidence that patients are getting a full lymphadenectomy. Little information is provided on RT delivery in the trial, and there was no RT quality assurance program to monitor RT quality [56]. In addition, the statistical design of the trial was to evaluate the superiority of either SOX or SOX plus RT compared with S-1 alone and was not to directly compare SOX versus SOX plus RT. Furthermore, at the time of the interim analysis, there were only 178 DFS events (the trial was powered statistically based on 226 DFS events). For all of these reasons, in our view, these results do not change our recommendation that chemoradiotherapy is still worthy of consideration in addition to chemotherapy for patients with node-positive disease who did not receive neoadjuvant chemotherapy.

Dutch CRITICS trial – In the Dutch CRITICS trial, 788 patients with stage IB to IV (table 10) potentially resectable gastric cancer received induction chemotherapy (three courses of epirubicin, cisplatin/oxaliplatin, and capecitabine) followed by surgery and randomization to postoperative chemotherapy (three cycles of the same regimen) or chemoradiotherapy (45 Gy in 25 fractions with weekly cisplatin and daily capecitabine) [30]. All patients were to have a D1 or better lymphadenectomy with at least 15 nodes in the resection specimen. At a median follow-up of 61 months, there were no significant differences in five-year overall survival (the primary endpoint, 42 versus 40 percent with chemotherapy and chemoradiotherapy, respectively) or progression-free survival; local recurrence rates were 15 versus 11 percent.

However, as with the ARTIST trial, this trial should not be interpreted as definitively disproving the benefit of adjuvant chemoradiotherapy relative to chemotherapy alone for the following reasons:

-Only approximately one-half of the patients in both groups could complete the full postoperative treatment. In a later per-protocol analysis limited to the 478 patients who actually started their allocated postoperative treatment, there was a five-year overall survival advantage favoring chemotherapy (57.9 versus 45.5 percent), but this type of analysis produces uncertainty about whether the two treatment arms were balanced in other important factors that might influence outcomes [57].

-Another important point is that because all patients received upfront chemotherapy, this trial did not adequately address the relative merits of chemoradiotherapy versus adjuvant chemotherapy alone in patients who undergo initial resection of gastric cancer.

-Finally, there was a large proportion of patients with early stage disease enrolled in the trial, who would be the least likely to benefit from RT.

China trial – The only trial to show a significant survival benefit for the addition of RT randomly assigned 68 Chinese patients undergoing complete resection with a D1 or D2 lymph node dissection for previously untreated gastric cancer to chemoradiotherapy (administered according to the INT 0116 trial but using intensity-modulated RT) or chemotherapy alone (five cycles of FU 425 mg/m2 per day and LV calcium 25 mg/m2 per day, given five days in a row once monthly) [49]. All patients were followed for at least three years. The three-year DFS rate was significantly higher in the chemoradiotherapy group (56 versus 29 percent), as was overall survival (68 versus 44 percent).

Meta-analysis – Additional information is available from a meta-analysis of six trials (excluding the CRITICS trial [30,53]) directly comparing adjuvant chemoradiotherapy with chemotherapy, which concluded that while chemoradiotherapy was associated with significantly higher rates of five-year DFS (odds ratio [OR] 1.56, 95% CI 1.09-2.24) and fewer locoregional recurrences (OR 0.46, 95% CI 0.32-0.67), there was only a trend toward a survival benefit for chemoradiotherapy, which was not statistically significant (OR for overall survival 1.32, 95% CI 0.92-1.99) [58].

Influence of lymphadenectomy extent — As noted above, the INT 0116 trial, which demonstrated a survival benefit from postoperative chemoradiotherapy, was compromised by the fact that >50 percent of the enrolled patients had an inadequate (less than D1) lymphadenectomy, suggesting that postoperative chemoradiotherapy might be mainly compensating for suboptimal surgery. (See "Surgical management of invasive gastric cancer", section on 'Extent of lymph node dissection'.)

This point of view is supported by retrospective data from the Dutch D1D2 trial, which demonstrated that chemoradiotherapy reduces local recurrence rates following a D1 lymphadenectomy (2 versus 8 percent) but provides no benefit after a D2 dissection [59]. However, other conflicting data suggest potential benefits for chemoradiotherapy even after an optimal D2 dissection [47,48,59,60].

The Dutch D1D2 analysis also suggested significant improvement in recurrence and survival with the use of chemoradiotherapy in those with an R1 resection [59], a finding that has also been confirmed in other retrospective series [61].

Largely based on these data, the NCCN guidelines suggest postoperative chemoradiotherapy plus chemotherapy for patients with pathologic T3-4 or node-positive disease if they have undergone less than a D2 dissection, chemoradiotherapy alone for patients undergoing an incomplete (microscopically incomplete [R1] or macroscopically incomplete [R2]) resection, and chemotherapy alone (with the omission of chemoradiotherapy) for those who have undergone a primary D2 lymph node dissection [62].

Choice of regimen — If chemoradiotherapy is chosen, we prefer the following regimen:

For patients with an excellent performance status (table 6) and limited comorbidity, especially if they have more advanced disease (T4 or node positive), we initiate therapy with two 14-day cycles of FOLFOX (table 2), or two courses of CAPOX (21-day cycles), or FLOT (table 7). (See 'Adjuvant chemoradiotherapy' above.)

For patients with a lesser performance status or earlier stage (eg, T3N0) disease, an acceptable alternative is two 14-day cycles of the modified de Gramont FU/LV regimen (table 3).

During the chemoradiotherapy portion, we suggest continuous infusion FU (200 mg/m2 per day during the entire course of RT, as was used in the standard arm of CALGB 80101) or capecitabine (850 mg/m2 twice daily, as was used in the ARTIST trial) rather than bolus FU. (See 'Adjuvant chemoradiotherapy' above.)

We complete therapy with four additional cycles of FOLFOX (14-day cycles, (table 2)), or FLOT (14-day cycles, (table 7)), or the de Gramont regimen of FU/LV (14-day cycles, (table 3)), or two 21-day cycles of CAPOX.

Timing of adjuvant therapy — The optimal timing of adjuvant therapy is not established. Most clinicians prefer to start within six to eight weeks of surgery since many of the clinical trials in the adjuvant setting started adjuvant therapy within this time frame. In practice, however, only a minority of patients are sufficiently recovered from surgery to start adjuvant chemotherapy within eight weeks; many more are able to start within 12 weeks [63]. Whether a delay in starting adjuvant chemotherapy beyond 8 or even 12 weeks compromises outcomes is not clear [64-66].

Pathologic T2N0 disease — For the subgroup of patients with pathologic T2N0 disease, observation is appropriate as long as they have undergone an adequate (D2) lymph node dissection with the goal of examining at least 16 nodes. However, we would suggest adjuvant treatment (chemotherapy plus chemoradiotherapy) for pathologic T2N0 disease with an inadequate lymphadenectomy. For other high-risk cases (pathologic T2N0 with a high poorly differentiated or histologic high-grade cancer, or the presence of lymphovascular or perineural invasion, or <50 years of age), we encourage adjuvant therapy and individualize decision making based on patient preference and goals of care.

This recommendation is consistent with consensus-based guidelines from the NCCN [62]. Guidelines from ESMO suggest adjuvant therapy (chemotherapy for most, but consideration of chemoradiotherapy for positive [R1] resection margins) for all patients with resected stage IB disease, including those with pathologic T2N0 tumors [67]. (See "Surgical management of invasive gastric cancer", section on 'Nodal (N) status' and "Surgical management of invasive gastric cancer", section on 'Extent of lymph node dissection'.)

There is controversy surrounding the benefit of adjuvant therapy for patients with resected stage IB, especially pathologic T2N0, disease (invasion of the muscularis propria but not the subserosal connective tissue) (table 1). While patients with T2N0 gastric cancer were included in the INT 0116 trial of observation versus chemoradiotherapy, the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system in use at that time (the third edition) defined T2 disease as invading the muscularis propria or subserosa. It was not clearly specified in the paper whether the enrolled T2N0 patients were limited to patients with subserosal invasion or also included those with invasion limited to the muscularis propria.

A subsequent nonrandomized trial that reportedly used the same eligibility criteria as the INT 0116 trial excluded patients with T2aN0 disease (which according to the fifth edition of the AJCC staging system, which was in use at that time, reflected invasion into the muscularis propria but not beyond; invasion into the subserosa was T2b disease) [60]. Thus, it could be that while patients with stage IB disease were included in the INT 0116 trial, they may have really been patients with subserosal involvement, and those with only muscularis propria invasion may have been observed. Also, these patients made up a tiny proportion of the trial, and no subgroup analysis was made for this group. (See 'Adjuvant chemoradiotherapy' above.)

Similarly, many of the adjuvant chemotherapy trials limited enrollment to patients with resected stage II or III gastric cancer, while some included patients with stage IB disease [35,68,69]. None of the trials that demonstrated a survival benefit for adjuvant chemotherapy was appropriately powered to analyze subgroups according to disease stage. (See 'Adjuvant chemotherapy' above.)

Some have attempted to stratify outcomes among patients with resected stage IB to IIA gastric cancer according to the presence or absence of adverse clinicopathologic features using data from the Surveillance, Epidemiology, and End Results (SEER) registry of the National Cancer Institute (NCI) [70]. The authors concluded that patients with stage IB to IIA gastric adenocarcinoma and ≥2 adverse features (age >60 years, tumor size >5 cm, proximal location, and high histologic grade of differentiation) have a five-year disease-specific survival of ≤76 percent, and they recommended this subset as appropriate for adjuvant therapy. However, information on the use of adjuvant chemotherapy and RT was not available for patients reported to this database, and outcome estimates could have been influenced by the use of adjuvant therapy. Furthermore, the analysis was limited to those patients with pathologic evaluation of 15 or more regional lymph nodes.

The influence of a suboptimal lymphadenectomy on benefit from adjuvant therapy was addressed in a retrospective analysis of data on 1687 patients who underwent R0 resection for T2N0 gastric cancer between 2003 and 2011 and were reported to the National Cancer Database (NCDB) [71]. Fourteen percent received adjuvant chemoradiotherapy, and 65 percent had fewer than 15 nodes examined. Adjuvant chemoradiotherapy (but not adjuvant chemotherapy alone) was associated with a significant survival benefit among those with <15 nodes examined but not among those with 15 or more nodes in the surgical specimen.

INITIALLY LOCALLY UNRESECTABLE NONMETASTATIC DISEASE — The optimal management of patients with locally advanced, unresectable, but nonmetastatic gastric cancer is uncertain, and there is no standard approach. The role of induction therapy is unclear. An initial attempt at downstaging with chemotherapy, chemoradiotherapy, or a combination, followed by careful restaging and surgical exploration in responders who have no evidence of metastatic disease, is a reasonable approach for a fit patient who initially had locally unresectable but nonmetastatic disease. Whenever possible, such patients should be encouraged to enroll in clinical trials testing new approaches.

The best way to manage locally advanced, initially unresectable disease is not established. Palliative methods for control of local symptoms are discussed elsewhere. (See "Local palliation for advanced gastric cancer".)

Options for anticancer therapy include chemotherapy alone or chemoradiotherapy:

Unresectable, locally advanced gastric cancer is often treated primarily with chemotherapy, using the same regimens as are used for metastatic disease. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer".)

Initial chemotherapy treatment may render some patients resectable. However, the benefit of neoadjuvant chemotherapy in patients who are deemed initially unresectable but are without distant metastatic disease is uncertain. No randomized trials have been completed.

Several uncontrolled studies have explored the use of preoperative chemotherapy for patients with locally advanced gastric cancer without distant metastases [72-75]. All have shown that some patients initially thought to be unresectable respond to chemotherapy sufficiently enough that they are able to undergo potentially curative surgery. However, pathologic complete response rates are low (between 5 and 15 percent), and treatment-related toxicity may be prominent [75].

Preliminary uncontrolled data suggest that with preoperative combined modality therapy (chemoradiotherapy with or without induction chemotherapy), approximately 70 percent of patients with localized but initially unresectable gastric cancer can undergo potentially curative resection, with pathologic complete response rates as high as 30 percent [22-24,76-78].

Although these early data seem encouraging, the studies have been conducted in highly selected patients, and randomized trials will ultimately be necessary to confirm a benefit from any of these approaches over chemotherapy alone.

ONGOING RESEARCH — The focus of ongoing research is optimizing the chemotherapy regimen, further defining the role of radiation therapy (RT), and exploring the effect of treatment timing (preoperative, postoperative, or both) and the contribution of targeting HER2 and immunotherapy for patients whose tumors have deficient mismatch repair (dMMR), the biologic footprint of which is high levels of microsatellite instability (MSI-H). The following are examples of ongoing trials.

New adjuvant and neoadjuvant approaches

In Asia, several trials are underway comparing adjuvant therapy with capecitabine plus oxaliplatin (CAPOX) with and without docetaxel, capecitabine versus observation, S-1 versus S-1 plus oxaliplatin, S-1 for 6 versus 12 months, and CAPOX for four versus six months.

Elsewhere, neoadjuvant therapy is under study:

A European trial is comparing preoperative fluorouracil (FU) and cisplatin with surgery alone [79], and in a joint Swiss/Italian trial of preoperative docetaxel, cisplatin, and FU compared with surgery alone, which has completed accrual and is awaiting data maturation.

A randomized trial, the Trial of Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma (TOPGEAR) trial, has been completed in Europe and Canada to directly compare preoperative chemotherapy alone (epirubicin, cisplatin, and infusional FU [ECF]) with chemoradiotherapy (two cycles of ECF followed by concurrent fluoropyrimidine-based chemoradiotherapy) in patients with resectable adenocarcinoma of the stomach and esophagogastric junction; both groups received three further cycles of ECF postoperatively. A preliminary report demonstrated that preoperative chemoradiotherapy can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity [80].

The CRITICS II trial is comparing preoperative docetaxel/oxaliplatin/capecitabine, the same chemotherapy regimen followed by chemoradiotherapy and then surgery, and chemoradiotherapy followed by surgery.

The ESOPEC trial is comparing neoadjuvant chemoradiotherapy followed by surgery with perioperative oxaliplatin, docetaxel, FU, and leucovorin (FLOT).

Immunotherapy for dMMR tumors — Between 3 and 7 percent of gastric cancers have deficiency in mismatch repair (dMMR), the biologic footprint of which is MSI-H. Among patients with advanced esophagogastric cancer, dMMR/MSI-H status predicts potential benefit from immune checkpoint inhibitor immunotherapy. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Deficient mismatch repair' and "Second and later-line systemic therapy for advanced unresectable and metastatic esophageal and gastric cancer", section on 'Defective mismatch repair'.)

Interest in neoadjuvant immunotherapy was prompted by an individual patient data meta-analysis of four randomized trials of perioperative therapy in patients with resectable gastric cancer (MAGIC, CLASSIC, ARTIST and ITACA-S [1,35,81,82]), which found that individuals with early stage dMMR/MSI-H esophagogastric cancers derived little benefit from either neoadjuvant or adjuvant chemotherapy, and actually did worse than those undergoing surgery alone [83]. MSI status was available for 1556 patients treated on one of the four randomized trials, and 121 (7.8 percent) were MSI-H. In subset analysis, patients with MSI-low gastric cancer benefitted from perioperative therapy compared with surgery alone (five-year overall survival [OS] 62 versus 53 percent, HR for death 0.75, 95% CI 0.60-0.94) while those with MSI-H disease did not (five-year OS 75 versus 83 percent, HR 1.50, 95% CI 0.55-4.12), although the confidence intervals were wide and the analysis failed to exclude important differences in the two groups.

Notably, a lack of benefit for adjuvant chemotherapy in resected dMMR/MSI-H gastric cancer could not be confirmed in a second meta-analysis of seven studies that reported on the survival outcomes of adjuvant chemotherapy compared with surgery alone for dMMR or MSI-H patients, but only one was a prospective randomized trial, and the remainder were retrospective reports [84]. Among patients with dMMR, compared with surgery alone, the addition of adjuvant chemotherapy led to a significantly higher overall survival at 3, 5, and 10 years (81, 84, and 64 percent versus 64, 65, and 50 percent, respectively).

Early data on neoadjuvant immunotherapy are available from the phase II NEONIPIGA trial, in which 32 patients with gastric (n = 16) or esophagogastric junction (EGJ) dMMR adenocarcinomas received six infusions of nivolumab (240 mg IV every two weeks) and two infusions of ipilimumab (1 mg/kg every six weeks); following surgery, adjuvant nivolumab was administered every four weeks for nine months [85]. At a median follow-up of 14.9 months, 19 percent of individuals experienced grade 3 or 4 treatment-related adverse events during immunotherapy, and of the 29 who proceeded to surgery a median of 35 days (range 25 to 170) after the last infusion of nivolumab, all had microscopically complete (R0) resection and 17 (59 percent) achieved a pathologic complete response. Notably, three did not have surgery and had complete endoscopic response with tumor-free biopsies and a normal CT scan (two refused surgery and one had metastasis at enrollment).

While exciting, additional follow-up and randomized trials comparing this approach to perioperative chemotherapy are needed before it can be concluded that neoadjuvant immunotherapy is a preferred approach for patients with dMMR gastric or EGJ tumors.

HER2-targeted therapy — There are emerging data on the benefit of combinations of trastuzumab with cytotoxic chemotherapy in the perioperative setting for HER2-positive gastric adenocarcinoma, but this remains an investigational approach.

Among patients with advanced gastric adenocarcinoma, the addition of trastuzumab to a cytotoxic chemotherapy backbone improves survival for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing tumors. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'HER2-overexpressing adenocarcinomas'.)

The available data on the perioperative setting in esophagogastric cancer are as follows:

The PETRARCA trial randomly assigned 81 patients to neoadjuvant FLOT alone or with both trastuzumab and pertuzumab [86,87]. (See 'FLOT' above.)

In an early analysis, the addition of HER2-trargeted therapy significantly increased the complete pathologic rate (35 versus 12 percent), and increased the rate of node-negative resections (68 versus 39 percent)but there was a higher rate of toxicity (especially grade 3 or 4 diarrhea [41 versus 5 percent] and leucopenia [23 versus 13 percent]) that led to more cycles with dose modification. Rates of complete (R0) resection, surgical morbidity and surgical mortality were comparable in both groups. Following the initial assessment, it was decided not to move forward with the phase III portion of this study (largely because of the demonstrated inefficacy of adding pertuzumab to trastuzumab in HER2-positive metastatic gastric cancer), and accrual was prematurely terminated. (See "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'HER2-overexpressing adenocarcinomas'.)

However, in a later report with median 22 month follow-up [87], disease-free and overall survival rates at 24 months were 54 and 77 percent for FLOT, versus 70 and 84 percent with combined therapy. The authors concluded that further trials with HER2-targeted agents were warranted in the neoadjuvant setting, but that the results were insufficient to justify routine targeting of HER2 as a standard neoadjuvant approach.

RTOG 1010 compared trimodality treatment (neoadjuvant RT plus weekly paclitaxel and carboplatin) with and without trastuzumab in 203 patients with HER2-positive esophageal adenocarcinoma (patients with gastric cancer were eligible if the tumor epicenter was within 5 cm of the EGJ) [88]. There was no benefit from the addition of trastuzumab to chemoradiotherapy.

Three other phase II trials did not include a control group treated without HER2-targeted therapy, and thus, the true benefit of HER2-targeted therapy could not be ascertained [89-91].

Additional information is expected from the randomized INNOVATION (INtegratioN of trastuzumab, with or without pertuzumab, into periOperatiVe chemotherApy of HER-2 posiTIve stOmach caNcer) trial, which is testing the value of adding HER2-targeted agents to perioperative chemotherapy (cisplatin plus a fluoropyrimidine) in patients with gastric cancer.

POST-TREATMENT CANCER SURVEILLANCE — There are no randomized trials to guide a postoperative surveillance strategy. We follow consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [62], which suggest the following:

History and physical examination every three to six months for one to two years, then every 6 to 12 months for three to five years.

Complete blood count and chemistry profile as clinically indicated.

Monitor for iron and vitamin B12 deficiency in surgically treated patients (especially after total gastrectomy), and treat as indicated.

For patients who had a partial or subtotal gastrectomy, upper gastrointestinal endoscopy as clinically indicated (particularly those patients treated without chemoradiotherapy).

Guidelines for radiologic imaging differ according to pathologic disease stage:

For resected pathologic stage I (T1aN0, T1bN0) treated with surgical resection or T1a treated with endoscopic resection, computed tomography (CT) of the chest/abdomen/pelvis with oral and intravenous contrast as clinically indicated.

For resected pathologic stage II/III (treated with neoadjuvant and/or adjuvant therapy), CT of the chest/abdomen/pelvis with oral and intravenous contrast is recommended every 6 to 12 months for the first two years, then annually up to five years.

Similarly, updated guidelines from the European Society for Medical Oncology (ESMO) suggest regular post-treatment follow-up with dietary support (assessment for vitamin and mineral deficiencies), and periodic radiologic investigations (CT of the thorax and abdomen) in patients who are candidates for further cancer-specific therapies [67].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastric cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Stomach cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

General approach

For patients with potentially resectable clinical stage T2N0 or higher noncardia gastric cancer, we recommend combined modality therapy over surgery alone (Grade 1A). (See 'Adjuvant chemoradiotherapy' above and 'Adjuvant chemotherapy' above and 'Neoadjuvant/perioperative chemotherapy' above.)

The optimal way to integrate combined modality therapy has not been definitively established. Multidisciplinary preoperative evaluation is strongly encouraged, as is participation in clinical trials (when possible). If protocol treatment is not available or is declined, the following represents our general approach to therapy.

Patients not yet resected

For most patients with potentially resectable (clinical stage T2 or higher (table 1)) gastric cancer, we suggest neoadjuvant chemotherapy over initial surgery followed by adjuvant therapy (Grade 2C). However, upfront surgery followed by adjuvant therapy remains an accepted approach, especially for patients with distal, clinically staged, nonbulky T2 tumors with no visible perigastric nodes.

For most patients with noncardia gastric cancer, we suggest not pursuing preoperative chemoradiotherapy as an alternative to chemotherapy (Grade 2C). (See 'Is there a role for neoadjuvant chemoradiotherapy' above.)

For patients with an excellent performance status (table 6) without significant comorbidities and able to tolerate intensive chemotherapy, we suggest docetaxel, oxaliplatin, leucovorin (LV), and short-term infusional fluorouracil (FU; FLOT, (table 7)) rather than an epirubicin-containing regimen (such as epirubicin, cisplatin, and infusional FU [ECF]) (Grade 2B). (See 'FLOT' above.)

Other acceptable alternatives, especially for patients with a lesser performance status or extensive comorbidity, include oxaliplatin plus infusional FU and LV (FOLFOX) (table 2), capecitabine plus oxaliplatin (CAPOX) (table 4), or S-1 plus oxaliplatin (where available). (See 'Lesser performance status' above and "Treatment protocols for esophagogastric cancer".)

Regardless of the perioperative regimen that is chosen, patients should complete the postoperative component of the regimen after surgery, if feasible. It is reasonable to offer adjuvant chemoradiotherapy to poor responders with extensive residual disease if they are sufficiently fit to tolerate it, and wish to pursue an aggressive approach. Management of these patients needs to be individualized. (See 'Postoperative management of poor responders' above.)

Patients already resected: pN+ or T3/T4 N0 disease

For patients who have had potentially curative gastric resection, we recommend adjuvant therapy rather than surgery alone for those with pathologic (p) node-positive disease (including pT1N1 [stage IB] disease) and for those with pT3-4N0 disease (table 1) (Grade 1B). (See 'Pathologic T3N0 or node-positive disease' above.)

Options for adjuvant therapy include chemoradiotherapy plus chemotherapy and chemotherapy alone.

-If an adequate D2 lymph node dissection (including perigastric [D1] nodes as well as those along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery [D2 lymph nodes], with the goal of examining 16 or more lymph nodes) has not been done, we suggest chemoradiotherapy plus chemotherapy rather than chemotherapy alone (Grade 2C). (See 'Inadequate lymphadenectomy, node-positive, or incompletely resected disease' above.)

-Patients who have had an adequate lymphadenectomy may omit radiation therapy (RT), but chemoradiotherapy plus chemotherapy is still an option, particularly for those with node-positive disease. (See 'Adequate lymphadenectomy and node-negative disease' above.)

-If chemoradiotherapy is chosen, for patients with an excellent performance status and limited comorbidity, especially if they have more advanced disease (T4 or node positive), we initiate therapy with two 14-day cycles of FOLFOX (table 2), or FLOT (table 7), or two 21-day courses of CAPOX (table 4). (See 'Choice of regimen' above.)

For patients with a lesser performance status or earlier stage (eg, T3N0) disease, an acceptable alternative is two 14-day cycles of the modified de Gramont FU/LV regimen (table 3).

During the chemoradiotherapy portion, we suggest continuous infusion FU (200 mg/m2 per day during the entire course of RT) or capecitabine (850 mg/m2 twice daily) rather than bolus FU (Grade 2C).

We complete therapy with four additional 14-day cycles of FOLFOX (table 2), or FLOT (table 7), or the de Gramont regimen of FU/LV (table 3), or two 21-day cycles of CAPOX.

-If chemotherapy alone is chosen, the optimal regimen is not established, but our preference is to give CAPOX (table 4) for six months. Six months of FOLFOX (table 2) is an acceptable alternative. (See 'Choice of regimen' above.)

One year of S-1 therapy may be an alternative for patients in Eastern Asian countries where this agent is approved. For those with stage III (table 1) disease, the combination of S-1 plus docetaxel is more effective than S-1 alone, but the side effect profile is also worse. How one year of S-1 with or without docetaxel compares with CAPOX for six months is not clear. (See 'S-1 with or without docetaxel' above.)

Patients already resected: pT2N0 disease

For patients with pathologic T2N0 disease, we suggest adjuvant chemoradiotherapy for pathologic T2N0 disease with an inadequate D2 lymphadenectomy (Grade 2C).

For patients with other high-risk features (eg, high histologic grade or the presence of lymphovascular or perineural invasion, or age <50) who have had an adequate lymphadenectomy, we encourage adjuvant chemotherapy but the decision should be individualized. (See 'Pathologic T2N0 disease' above.)

Locally unresectable tumors – The optimal approach to patients with locally advanced, unresectable, but nonmetastatic disease is uncertain. A reasonable approach for a fit patient with a good performance status is initial attempt at downstaging with chemotherapy, chemoradiotherapy, or a combination, followed by careful restaging and surgical exploration in responders who have no evidence of metastatic disease. (See 'Initially locally unresectable nonmetastatic disease' above.)

Post-treatment surveillance – We follow published guidelines from the National Comprehensive Cancer Network (NCCN) [62]. (See 'Post-treatment cancer surveillance' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Craig Earle, MD, MSc, FRCPC, who contributed to an earlier version of this topic review.

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Topic 2523 Version 88.0

References

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