Case-Based Review

Neoadjuvant and Adjuvant Therapy for Gastric Cancer


 

References

INTRODUCTION

Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer death in both females and males. 1 More than 70% of gastric cancer cases occur in the developing world, with approximately 50% occurring in East Asia. 2 Gastric cancer is less common in the United States, with an incidence of 12.3 cases in males and 6.0 cases in females per 100,000 per year and a disproportionately higher incidence in Asians. 3 According to the Surveillance, Epidemiology, and End Results Program, approximately 26,370 new cases of stomach cancer were diagnosed in the United States in 2016, and an estimated 10,730 people died of this disease. 4 Since the 1970s, the 5-year relative survival rate for gastric cancer in the United States has improved from 15% in 1975 to 29% in 2009. 5 In contrast, in Japan and Korea, where screening programs have been implemented, the 5-year survival rate approaches 70%. 6

RISK FACTORS AND CLASSIFICATION

A variety of risk factors have been linked to gastric cancer. Diets high in salt, salt-preserved foods, and/or processed meats have been associated with an increased risk for developing gastric cancer. 7,8 Obesity and smoking have also been implicated in gastric cancer. 9,10 Several studies have demonstrated a strong association between Helicobacter pylori and the development of gastric cancer. 11–13 It is believed that H. pylori infection leads to chronic active gastritis, atrophic gastritis, and intestinal metaplasia. Interestingly, mass eradication of H. pylori has not been shown to reduce the risk for gastric cancer. 14 Therefore, treatment of H. pylori should only be considered in patients with active peptic ulcer disease. 15 Other risk factors include Epstein-Barr virus (EBV), prior gastric surgery, and radiation exposure. 16–18 Family history of gastric cancer, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, and hereditary diffuse gastric cancer caused by mutations in the E-cadherin gene increase the risk. 17

The anatomic distinction between gastric cancer and cancer of the gastroesophageal junction (GEJ) has been a topic of debate. The Siewert classification is the most widely used system and divides GEJ adenocarcinoma into 3 categories: 20 type I tumor: adenocarcinoma of distal esophagus, located 1 cm to 5 cm above the GEJ; type II tumor: true carcinoma of gastric cardia, located within 1 cm above and 2 cm below the GEJ; type III tumor: subcardial gastric carcinoma, located 2 cm to 5 cm below the GEJ, and infiltrates esophagus from below.

The American Joint Committee on Cancer (AJCC) has updated the latest (7th) edition of TMN staging for stomach cancer to include tumors arising more than 5 cm distally of the GEJ or within 5 cm of the GEJ but without extension to the esophagus or GEJ. 21

In the following sections, neoadjuvant and adjuvant therapy in gastric cancer are discussed using a case presentation to illustrate important concepts.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 43-year old male with no significant past medical history presents with epigastric abdominal pain and heart burn for the past few weeks. He denies nausea, vomiting, melena, or hematochezia. His primary care physician (PCP) diagnoses him with gastroesophageal reflux disease (GERD) and initiates a trial of pantoprazole. Over the next 2 to 3 months, his symptoms do not improve and he has an associated 40-lb weight loss. Both social history and family history are noncontributory. Physical exam reveals epigastric tenderness without rebound or guarding. Laboratory evaluation reveals a hemoglobin of 12.6 g/dL with a mean corpuscular volume of 72 fL. A comprehensive chemistry profile is within normal limits. Given the constellation of presenting symptoms, especially the unintentional weight loss and the presence of microcytic anemia, his PCP suspects a malignant process and refers the patient to a gastroenterologist.

• What are the next appropriate steps for diagnosis?

The most common presenting symptoms of gastric cancer are weight loss and abdominal pain. 22 Less commonly, patients exhibit nausea, anorexia, and dysphagia with proximal tumors. Melena is seen in only about 20% of patients. In Japan, where gastric cancer is more prevalent, mass screening programs allow for detection at an earlier stage, which partially accounts for the better survival rates seen in Asia as compared to the United States. Diagnostic work-up includes esophagogastroduodenoscopy (EGD) to assess Siewert category and to obtain a tissue sample for diagnosis. Full staging requires a complete blood count (CBC) with differential; comprehensive chemistry profile; computed tomography (CT) of chest/abdomen/pelvis with oral and intravenous contrast; endoscopic ultrasound (EUS) if no M1 disease is identified; positron emission tomography (PET)-CT if there is no evidence of M1 disease and if clinically indicated; and laparoscopy with cytology for clinical stage T1b or higher. 23 Patients should be staged according to the TMN staging system ( Table 1 ).

Table 1

MANAGEMENT OF NONMETASTATIC DISEASE

CASE CONTINUED

The patient undergoes EGD, which reveals a large ulcerated, partially circumferential mass measuring approximately 4 cm. The mass extends from the gastric body to the cardia. Biopsy of the mass reveals poorly differentiated adenocarcinoma as well as H. pylori –associated gastritis. He is given antibiotic therapy and undergoes complete work-up of his newly diagnosed gastric adenocarcinoma. CT of the chest/abdomen/pelvis demonstrates a large gastric mass with gastrohepatic and distal perigastric adenopathy, compatible with locally advance primary gastric cancer. There is no evidence of distant metastasis. PET scan shows a large hypermetabolic mass in the stomach body and increased FDG activity in 3 small nodes along the lesser gastric curvature and in 1 node in the gastrohepatic region. EUS reveals a malignant gastric tumor in the body of the stomach, which is staged as T3, and a few malignant-appearing lymph nodes in the perigastric region. Fine-needle aspiration of the perigastric lymph node is performed and the sample obtained is positive for malignant cells. Diagnostic laparoscopy with peritoneal washings is performed and cytology is negative for malignant cells. The patient is staged as clinical stage IIB (T3N1M0).

• How should this patient with newly diagnosed, locally advanced, resectable gastric cancer be managed?

SURGERY

Surgical resection for localized gastric cancer is the mainstay of treatment with curative intent. Only very early stage (Tis or T1a) tumors can be considered for endoscopic mucosal resection. Regarding surgical resection, distal gastric cancers are typically treated with subtotal gastrectomy because there is no survival difference between subtotal and total gastrectomy. 24,25 Moreover, subtotal gastrectomy is associated with better nutritional status and quality of life. For proximal tumors, total gastrectomy is preferred as subtotal gastrectomy has been associated with a higher incidence of reflux esophagitis and anastomotic stenosis. 26 In terms of surgical approach, multiple studies have shown that a laparoscopic approach has a lower complication rate and similar outcomes in terms of cancer recurrence and long-term survival when compared to open gastrectomy. 27–29 Thus, a laparoscopic approach is often used in academic centers with highly experienced surgeons.

The extent of lymph node dissection remains a topic of debate. A D1 dissection involves the removal of perigastric lymph nodes. A D2 dissection is a D1 dissection plus the removal of lymph nodes along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery. D2 lymphadenectomy has become the standard of care in Eastern countries where gastric cancer is more prevalent, such as Japan and Korea. 30 In Western countries, including the United States, less extensive lymphadenectomies are performed. Both randomized clinical trials and meta-analyses have failed to demonstrate an overall survival advantage of D2 dissection over D1 dissection. 31,32 A Dutch trial by Bonenkamp et al involving 711 patients, one of the largest randomized trials of D1 and D2 lymphadenectomy, showed that D2 patients had a higher operative mortality rate than D1 patients (10% versus 4%, P = 0.004) and experienced more complications (43% versus 25%, P < 0.001). 33 In a 15-year follow-up of this study, patients who had a D2 resection had lower locoregional recurrence and gastric-cancer–related death rates compared to those who had a D1 resection; however, D2 resection was associated with a significantly higher operative mortality and complication rate compared to D1. 34 In addition, a 2015 Cochrane meta-analysis has demonstrated improved disease-specific survival (DSS) with D2 dissection (hazard ratio [HR] 0.81 [95% confidence interval {CI} 0.71 to 0.92]). 35 Currently, the National Comprehensive Cancer Network (NCCN) recommends a D1 or a modified D2 gastrectomy with at least 15 lymph nodes removed for examination, with D2 lymphadenectomies only to be performed at experienced centers. 23

SYSTEMIC CHEMOTHERAPY

Locally advanced gastric cancer (T3-T4 or node positive) requires systemic chemotherapy in addition to surgery, as this intervention improves the 5-year overall survival by 10% to 15%. 36 Systemic therapy should also be considered in patients with T2N0 disease with high-risk features: poorly differentiated or high-grade cancer; lymphovascular invasion; neural invasion; age younger than 50 years; and patients who did not undergo D2 dissection. 23 Currently, there is no global consensus on the best treatment approach. In the United States, where a less aggressive lymph-node dissection is performed, adjuvant chemoradiotherapy after surgery is more commonly seen. In Europe, perioperative (preoperative and postoperative) chemotherapy is the standard treatment. In Japan, adjuvant chemotherapy after D2 lymphadenectomy is the standard of care. 37 These regional preferences are largely due to randomized clinical trials that have shown benefit for each approach. The landmark trials are discussed in the following sections and are summarized in Table 2 .

Table 2

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy has the benefit of “downstaging” locally advanced tumors to allow for curative resection. Phase 2 clinical trials have also demonstrated good pathologic response rates and high R0 resection rates following neoadjuvant chemotherapy. 38,39 However, phase 3 trials to support this treatment approach are lacking. In the European Organisation for Research and Treatment of Cancer (EORTC) 40954 trial, patients with stage III or IV gastric or GEJ cancer were randomly assigned to surgery with or without preoperative cisplatin, leucovorin, and infusional fluorouracil (5-FU). 40 The trial was stopped early due to poor accrual after 144 patients were randomized. The neoadjuvant chemotherapy arm had a higher R0 resection rate compared to the surgery alone arm (82% versus 67%, respectively, P = 0.036) but a higher postoperative complication rate (27% versus 16%, respectively, P = 0.09). More important, after a median follow-up of 4.4 years, a survival benefit could not be shown, with 2-year survival rates of 72.7% and 69.9% in the neoadjuvant and surgery-only arms, respectively (HR 0.84 [95% CI 0.52 to 1.35], P = 0.466). Due to the lack of large trials, a meta-analysis assessing the effectiveness of neoadjuvant chemotherapy combined with surgery versus surgery alone in advanced gastric and gastroesophageal cancer was performed. 41 The analysis included 12 randomized controlled trials with a total of 1820 patients. Neoadjuvant chemotherapy was shown to slightly improve the survival rate (odds ratio [OR] 1.32 [95% CI 1.07 to 1.64], P = 0.01). It significantly improved the 3-year progression-free survival (PFS; OR 1.85 [95% CI 1.39 to 2.46], P < 0.0001), tumor down-staging rate (OR 1.71 [95% CI 1.26 to 2.33], P = 0.0006), and R0 resection rate (OR 1.38 [95% CI 1.08 to 1.78], P = 0.01). There were no differences between the 2 arms in terms of relapse rates, operative complications, perioperative mortality, and grade 3/4 adverse effects. While these results are encouraging, further randomized clinical trials are needed to clarify the role of neoadjuvant chemotherapy and its impact on overall survival.

Perioperative Chemotherapy

The results of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial published in 2006 established perioperative chemotherapy as standard of care in patients with resectable gastric and gastroesophageal adenocarcinoma. 42 A total of 503 patients with potentially resectable gastric and lower esophageal adenocarcinoma were randomly assigned to perioperative chemotherapy plus surgery or surgery alone. Perioperative chemotherapy consisted of 3 preoperative and postoperative cycles of epirubicin, cisplatin, and infusional 5-FU (ECF). At a median follow-up of 4 years, the perioperative-chemotherapy group had a significantly better PFS (HR 0.66 [95% CI 0.53 to 0.81], P < 0.001) as well as overall survival (HR 0.75 [95% CI 0.60 to 0.93], P = 0.009). The 5-year overall survival rate was 36.3% in the perioperative chemotherapy group and 23% in the surgery group. Of note, there was a greater proportion of stage T1/T2 tumors (52% versus 37%, P = 0.002) and N0/N1 disease (84% versus 71%) in the perioperative-chemotherapy group compared to the surgery alone group. In addition, only 42% of patients in the perioperative chemotherapy group completed all 6 cycles of chemotherapy.

The administration of ECF is often difficult since the 5-FU component requires a central venous access device and an ambulatory infusion pump and the cisplatin component is associated with nephrotoxicity and ototoxicity. The REAL-2 trial was a randomized phase 3 clinical trial that assessed whether 5-FU could be replaced by capecitabine and cisplatin by oxaliplatin in the ECF regimen. 43 Between June 2000 and May 2005, a total of 1002 patients with locally advanced esophageal/GEJ/gastric cancer were enrolled. Patients were randomly assigned to 1 of 4 triplet therapies: epirubicin and cisplatin plus either 5-FU (ECF) or capecitabine (ECX) or epirubicin and oxaliplatin plus either 5-FU (EOF) or capecitabine (EOX). After a median follow-up of approximately 18 months, the overall survival in the capecitabine groups did not differ significantly from that in the 5-FU groups (HR 0.88 [95% CI 0.77 to 1.00], P = 0.06), nor did overall survival in the oxaliplatin groups differ significantly from that in the cisplatin groups (HR 0.91 [95% CI 0.79 to 1.04], P = 0.16). Interestingly, the 1-year survival rate was longer in the EOX group than in the ECF group (46.8% versus 37.7%, respectively; HR 0.80 [95% CI 0.66 to 0.97], P = 0.02). This translated into an overall survival of 11.2 months for the EOX group and 9.9 months for the ECF group. Therefore, EOX is preferred over ECF in clinical practice.

The French FNLCC/FFCD trial published in 2011 provided further support for perioperative chemotherapy. 44 A total of 224 patients with adenocarcinoma of the lower esophagus, GEJ, or stomach were randomly assigned to perioperative chemotherapy plus surgery or surgery alone. The perioperative-chemotherapy group received 2 to 3 cycles of preoperative chemotherapy and 3 to 4 cycles of postoperative chemotherapy, consisting of infusional 5-FU (800 mg/m 2 daily for days 1 to 5) and cisplatin (100 mg/m 2 on day 1). In patients receiving preoperative chemotherapy, 38% experienced at least grade 3 to 4 toxicity. Among the 109 patients who received at least 1 cycle of preoperative chemotherapy, only 54 patients (50%) received postoperative chemotherapy. Despite this, the perioperative-chemotherapy group had a statistically significant higher R0 resection rate (84% versus 74%, P = 0.04) compared to the surgery alone group. At a median follow-up of 5.7 years, the perioperative chemotherapy group had an improved overall survival (HR for death 0.69 [95% CI 0.50 to 0.95], P = 0.02) and disease-free survival (DFS; HR for recurrence or death 0.65 [95% CI 0.48 to 0.89], P = 0.003). This translated into 5-year overall survival rates of 38% versus 24% and 5-year DFS rates of 34% versus 19%. One caveat to this study is that the majority of patients (64%) had GEJ cancer and only 25% had gastric cancer. In the multivariate analysis, the 2 significant prognostic factors for overall survival were the administration of preoperative chemotherapy ( P = 0.01) and tumor site at the GEJ ( P < 0.01).

Adjuvant Chemoradiotherapy

The INT-0116 (Intergroup 0116) study published in 2001 established adjuvant chemoradiotherapy as the standard approach for resectable gastric cancer in the United States. In this study, a total of 556 patients with resected gastric or GEJ cancer were randomly assigned to surgery alone or surgery followed by adjuvant 5-FU/leucovorin bolus chemotherapy, sandwiched with 5-FU–based chemoradiation (45 Gy). 45 In the chemoradiotherapy group, 64% of patients completed treatment and grade 3 and 4 toxicity occurred in 41% and 32%, respectively. However, only 3 patients (1%) died from treatment-related toxicity. At a median follow-up of 5 years, the median overall survival was 36 months in the chemoradiation group and 27 months in the surgery group. Overall survival rate was 50% in the combined modality group and 41% in the surgery-alone group, with a HR of 1.35 (95% CI 1.09 to 1.66 , P = 0.005). The 3-year DFS was 48% in the chemoradiotherapy group and 31% in the surgery-alone group, corresponding to a DFS of 30 months and 19 months, respectively. Even after a median follow-up of 10 years, these positive results were maintained, with a HR for survival of 1.32 (95% CI 1.10 to 1.60, P = 0.0046) and HR for DFS of 1.51 (95% CI 1.25 to 1.83, P < 0.001). 46 A criticism of the INT-0116 study is that 54% of patients had less than a D1 lymph node dissection, suggesting that adjuvant chemoradiation may have compensated for suboptimal surgery.

CALGB 80101, a United States Intergroup study, compared the INT-0116 protocol regimen (bolus 5-FU/leucovorin with 5-FU plus concurrent radiotherapy) to postoperative ECF sandwiched with 5-FU plus concurrent radiotherapy. 47 The study included patients with resected gastric or GEJ adenocarcinoma that extended beyond the muscularis propria or was node positive. The percentage of patients with gastric versus GEJ cancer was not reported. A total of 546 patients were randomized. Preliminary results were presented at the 2011 American Society of Clinical Oncology meeting. The ECF arm had lower rates of grade 3/4 toxicities, including neutropenia, diarrhea, and mucositis. However, there was no difference in overall survival (3-year overall survival of 52% versus 50% for ECF and 5-FU/leucovorin, respectively) or DFS (3-year DFS of 47% versus 46% for ECF and 5-FU/leucovorin, respectively). The trial was not adequately powered to assess noninferiority. The location of the primary tumor (GEJ versus proximal versus distal stomach) did not have any effect on treatment outcome.

The Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) trial was the first study to compare adjuvant chemoradiotherapy with adjuvant chemotherapy in patients with D2-resected gastric cancer. 48 A total of 458 patients were randomly assigned to 6 cycles of XP chemotherapy (capecitabine 2000 mg/m 2 per day on days 1–14 and cisplatin 60 mg/m 2 on day 1, every 3 weeks) or XP/radiotherapy/XP (2 cycles of XP followed by 45 Gy radiotherapy with concurrent daily capecitabine [825 mg/m 2 twice daily] and 2 cycles of XP). After a median follow-up of 84 months, there was no difference in DFS or overall survival between treatment arms (HR for progression 0.74 [95% CI 0.52 to 1.05], P = 0.09; HR for death 1.13 [95% CI 0.78 to 1.65], P = 0.53). 49 However, subgroup analysis showed that chemoradiotherapy significantly improved DFS in patients with node-positive disease (3-year DFS 76% versus 72%, P = 0.004).

Adjuvant Chemotherapy

Data supporting the use of adjuvant chemotherapy alone is largely derived from trials done in Asia, typically after a D2 lymph node dissection, and thus adjuvant chemotherapy has become the standard of care in that region. In the Japanese Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC), a total of 1059 patients with stage II or III gastric cancer who had undergone surgery with a D2 lymphadenectomy were randomly assigned to 1 year of S-1 (an oral fluoropyrimidine) or surgery alone. 50 The 5-year overall survival rate was 72% in the S-1 group and 61% in the surgery-only group (HR 0.669 [95% CI 0.54 to 0.83]). 51 The 5-year relapse-free survival was 65% in the S-1 group and 53% in the surgery-only group (HR 0.65 [95% CI 0.537 to 0.793]). Of note, both arms of the ACTS-GC trial had significantly higher 5-year overall survival rates compared to the INT-0116 and MAGIC trials: 43% versus 28% and 36% versus 23% for the treatment and control groups, respectively. 42,45 Consequently, it is unclear if the benefit of adjuvant chemotherapy can be translated to Western countries.

The Korean Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) trial published in 2012 also established the role of adjuvant chemotherapy after D2 gastrectomy. 52 A total of 1035 patients with stage II-IIIB gastric cancer who had curative D2 gastrectomy were randomly assigned to 8 cycles of adjuvant XELOX (capecitabine 1000 mg/m 2 twice daily on days 1–14 plus oxaliplatin 130 mg/m 2 on day 1, 21-day cycle) or surgery alone. Median follow-up was 34 months in both arms and 67% of patients in the chemotherapy arm completed all 8 cycles of planned chemotherapy. The 3-year DFS was 74% in the chemotherapy group and 59% in the surgery-only group (HR 0.56 [95% CI 0.44 to 0.72], P < 0.0001). There was a trend toward improvement in overall survival (83% versus 78%, HR 0.72 [95% CI 0.52 to 1.00]). After 5 years of follow-up, the improvement in overall survival became statistically significant (78% versus 69%, HR 0.66 [95% CI 0.51 to 0.85]). 53

The benefit of adjuvant chemotherapy was reinforced by a 2010 meta-analysis comparing adjuvant chemotherapy to surgery alone in patients with resected gastric cancer. 54 A total of 17 randomized controlled trials were included. Adjuvant fluorouracil-based chemotherapy was associated with a statistically significant improved overall survival (HR 0.82 [95% CI 0.76 to 0.90], P < 0.001) and DFS (HR 0.82 [95% CI 0.75 to 0.90], P < 0.001). Five-year overall survival increased from 49.6% to 55.3% with chemotherapy.

SELECTION OF TREATMENT APPROACH

Since data exists for all 3 approaches (perioperative chemotherapy, adjuvant chemoradiotherapy, and adjuvant chemotherapy), various meta-analyses have been done to clarify which approach is the best. In a recent meta-analysis of 6 randomized controlled trials reported between 2010 and 2012, which involved 1171 patients with resected gastric cancer, adjuvant chemotherapy was compared to adjuvant chemoradiotherapy. 55 Five of the studies were from East Asia, while one was from a Western country. Adjuvant chemoradiation was associated with a lower local-regional recurrence rate (OR 0.46 [95% CI 0.32 to 0.67]) and better 5-year DFS rate (OR 1.56 [95% CI 1.09 to 2.24]). However, there was no statistical difference in 5-year overall survival rate (OR 1.32 [95% CI 0.92 to 1.88]). Similar results were reported by Zhou et al in 2016. 56 This meta-analysis included 4 randomized controlled trials reported between 2010 and 2015, with a total of 960 patients who had undergone a D2 resection for gastric cancer. Compared to adjuvant chemotherapy, adjuvant chemoradiotherapy significantly reduced the loco-regional recurrence rate (LRRR; relative risk [RR] 0.50 [95% CI 0.34 to 0.74], P = 0.0005) and improved DFS (HR 0.73 [95% CI 0.60 to 0.89], P = 0.002). Again, no difference in overall survival was seen (HR 0.91 [95% CI 0.74 to 1.11], P = 0.34).

Adjuvant chemotherapy and perioperative chemotherapy have also been compared. In a recent meta-analysis of 14 randomized controlled trials (8 Asian, 6 European) involving 2093 patients with resected gastric or GEJ cancer, perioperative chemotherapy was associated with improved overall survival when compared to adjuvant chemotherapy (HR 0.48 [95% CI 0.35 to 0.67], P < 0.001). 57 The benefit of perioperative chemotherapy over adjuvant chemotherapy has also been reported in a 2016 meta-analysis by Zhao et al. 58 A total of 1240 patients were included from 5 randomized controlled trials and 6 clinical controlled trials, all from Asian countries. The 5-year overall survival rate was significantly better in the perioperative chemotherapy group compared to the adjuvant chemotherapy group (RR 0.77 [95% CI 0.64 to 0.92], P < 0.01). Furthermore, the 2 groups showed no significant differences in the postoperative complication rates (RR 0.98 [95% CI 0.63 to 1.51], P = 0.91) or adverse effects of chemotherapy ( P > 0.05 for all adverse effects).

While these meta-analyses may offer some insight on the best treatment approach, they should be interpreted with caution. Most studies included in these meta-analyses were from Asian countries, and their findings may not be applicable to Western countries. Furthermore, the heterogeneity of trials and inclusion of nonrandomized trials make it difficult to draw conclusions. There are several ongoing trials that will help to define the optimal treatment approach.

CASE CONTINUED

The patient is presented at tumor board and the consensus is to proceed with the perioperative chemotherapy approach. The patient undergoes echocardiography, which reveals a normal ejection fraction. He receives 3 cycles of neoadjuvant EOX (epirubicin, oxaliplatin, and capecitabine). After 3 cycles of neoadjuvant EOX, the patient has a repeat CT that shows marked interval reduction in the size of the primary gastric neoplasm and interval decrease in the size of the small perigastric lymph nodes. He subsequently undergoes a total gastrectomy with J-tube placement. Pathology shows ypT3N0 disease with 0 out of 47 lymph nodes involved and negative margins. He then receives 3 cycles of adjuvant EOX.

• What are the recommendations for surveillance?

According to the current NCCN guidelines, a history and physical exam should be performed every 3 to 6 months for 1 to 2 years, then every 6 to 12 months for 3 to 5 years, and then annually. 23 Labs, CT chest/abdomen, and EGD should be done as clinically indicated. Patients who have undergone surgical resection should be monitored for nutritional deficiencies (vitamin B12 and iron).

GASTROESOPHAGEAL JUNCTION TUMORS

Tumors arising in the GEJ or gastric cardia within 5 cm of the GEJ that extend into the GEJ or distal esophagus are staged and treated as esophageal cancers. 21 The primary treatment for T1/T2N0 tumors is surgical resection. In patients with T3 or higher or node-positive adenocarcinoma of the GEJ, a combined modality approach is preferred, with preoperative chemoradiotherapy followed by surgical resection. 59 The CROSS trial demonstrated a significant survival benefit with preoperative chemoradiation using carboplatin/paclitaxel compared to surgery alone in patients with esophageal or GEJ cancer (49 months versus 24 months, HR 0.66, P = 0.003). 60

ONGOING TRIALS

As mentioned previously, several randomized clinical trials are in progress to clarify the optimal treatment approach. The MAGIC-B/MRC-ST03 is a randomized phase 2/3 trial looking at perioperative epirubicin, cisplatin, and capecitabine (ECX) with or without bevacizumab in patients with resectable lower esophageal, GEJ, or gastric cancer. 61 The TOPGEAR trial, a randomized phase 2/3 study being conducted in Canada and Europe, is comparing perioperative ECF chemotherapy with preoperative chemoradiation plus perioperative ECF chemotherapy. 62 In Asia, the PRODIGY trial is a phase 3, open-label, randomized study comparing neoadjuvant docetaxel, oxaliplatin, and S-1 followed by surgery and adjuvant S-1 versus surgery plus adjuvant S-1 in patients with locally advanced gastric cancer (T2-T4 or node positive). 63 Primary endpoint is PFS and secondary endpoints are overall survival, R0 resection rate, and safety.

Trials comparing adjuvant chemotherapy to adjuvant chemoradiotherapy are also being conducted. In the Dutch CRITICS study, a randomized phase 3 trial, patients with stage Ib-Iva resectable gastric cancer were given 3 cycles of epirubicin, cisplatin/oxaliplatin, and capecitabine (ECC/EOC), followed by D2 resection and either 3 cycles of ECC/EOC or chemoradiation with weekly cisplatin and daily capecitabine. 64 Between January 2007 and April 2015, a total of 788 patients were enrolled. In a preliminary report presented at ASCO in 2016, the 5-year survival rate was similar between the 2 arms (41.3% for chemotherapy arm and 40.9% for chemoradiotherapy arm, P = 0.99). The Korean ARTIST II trial is comparing adjuvant S-1 and S-1/oxaliplatin with or without radiotherapy in patients with D2-resected gastric cancer. 65 Similarly, the NCT01711242 trial is comparing adjuvant XELOX alone versus XELOX with concurrent capecitabine/radiotherapy in patients with resected D2 gastric cancer. 66

The ToGA trial established a survival benefit of trastuzumab in combination with chemotherapy in HER2-positive metastatic gastric cancer. 67 Consequently, there are ongoing clinical trials to assess the role of trastuzumab in nonmetastatic gastric cancer. The TOXAG study is a phase 2 trial looking at the safety and tolerability of adjuvant oxaliplatin, capecitabine, and trastuzumab with radiation in patients with resected HER2-positive gastric or GEJ adenocarcinoma. 68 The NCT01130337 clinical trial is evaluating perioperative XELOX/trastuzumab in patients with resectable gastric or GEJ adeno-carcinoma. 69

SUMMARY

Gastric cancer is the fifth most common cancer worldwide, with the greatest incidence in East Asia. Survival outcomes are better in Asian countries when compared to the United States. This difference in survival may be related to the presence of mass screening programs in Asia, which allows for detection at an earlier stage and the use of a more extensive surgical approach (ie, D2 resection). Risk factors for developing gastric cancer include: diets high in salt/salt-preserved foods or processed meats, obesity, smoking, H. pylori infection, EBV, prior gastric surgery, radiation exposure, and positive family history.

According to the latest edition of TMN staging, gastric cancer includes tumors arising more than 5 cm distally of the GEJ or within 5 cm of the GEJ but without extension to the esophagus or GEJ. Diagnostic work-up includes: EGD with biopsy; basic labs; CT chest/abdomen/pelvis with oral and intravenous contrast; EUS if no M1 disease is identified; PET-CT if there is no M1 disease and if clinically indicated; and diagnostic laparoscopy with cytology for clinical stage T1b or higher.

The mainstay of treatment is surgical resection. Laparoscopic approach is preferred over open gastrectomy due to lower complication rates and similar survival outcomes. Current NCCN guidelines recommend a D1 or a modified D2 lymph node dissection with at least 15 lymph nodes removed for examination. Systemic chemotherapy is required in locally advanced gastric cancer (T3-T4 or node positive) and should be considered in T2N0 disease with high-risk features. Currently, there is no global consensus on the optimal treatment approach. Data from various trials have shown benefit for each approach. Regional preferences are: perioperative chemotherapy in Europe; adjuvant chemoradiotherapy in the United States; and adjuvant chemotherapy in Asia. In an effort to better define the optimal treatment approach, several randomized clinical trials are being conducted. According to the current NCCN guidelines, the following treatment approaches are acceptable and are supported by data in the trial listed in parentheses:

• Perioperative chemotherapy

° 5-FU/cisplatin (French FNLCC/FCCD trial) 44 or

° ECF (MAGIC trial) 42 or

° ECF modifications: EOX, EOF, ECX (REAL-2 trial) 43

• Adjuvant chemoradiotherapy

° 5-FU/leucovorin sandwiched with 5-FU-based chemoradiation (INT-0116 trial) 45

• Adjuvant chemotherapy (after D2 resection)

° Capecitabine/oxaliplatin (CLASSIC trial) 52 or

° Capecitabine/cisplatin (ARTIST trial) 48,49

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