Sections

Treatment

Approach Considerations

Surgical resection is the principal therapy for gastric cancer, as it offers the only potential for cure.^[4]The most common procedures are total, subtotal, or distal gastrectomy. The choice of procedure and the extent of nodal dissection are determined by the ability to obtain clear microscopic margins. In patients who present with regionally advanced disease, removal of involved adjacent organs (eg, the spleen) may be required.

Neoadjuvant chemotherapy has an established role in the management of gastric cancer. Perioperative chemotherapy, or postoperative chemotherapy plus chemoradiation, are preferred for localized gastric cancer. Because of lower toxicity, two-drug cytotoxic regimens (eg, fluoropyrimidine and oxaliplatin) are preferred for patients with advanced disease.^[4]

For description of chemotherapy and chemoradiotherapy regimens, see Gastric Cancer Treatment Protocols.

Surgical Care

In general, most surgeons in the United States perform a total gastrectomy (if required for negative margins), an esophagogastrectomy for tumors of the cardia and gastroesophageal junction, or a subtotal gastrectomy for tumors of the distal stomach. A randomized trial comparing subtotal with total gastrectomy for distal gastric cancer revealed similar morbidity, mortality, and 5-year survival rates.^[37]

Because of the extensive lymphatic network around the stomach and the propensity for this tumor to extend microscopically, traditional teaching is to attempt to maintain a 5-cm surgical margin proximally and distally to the primary lesion.

Lymph node dissection

The extent of the lymph node dissection is somewhat controversial. Many studies demonstrate that nodal involvement indicates a poor prognosis, and more aggressive surgical approaches to attempt to remove involved lymph nodes are gaining popularity.

Two randomized trials compared D1 (perigastric lymph nodes) with D2 (hepatic, left gastric, celiac, and splenic arteries, as well as those in the splenic hilum) lymphadenectomy in patients who were treated for curative intent. In the largest of these trials, postoperative morbidity (43% versus 25%) and mortality (10% versus 4%) were higher in the D2 group.^{[38, 39]}

Most critics argue that these studies were underpowered and overestimated benefit. In addition, a more recent randomized trial found a much lower rate of complications than those earlier trials. Degiuli et al reported complication rates of 17.9% and 12% with D2 and D1 dissections, respectively—a statistically insignificant difference— and postoperative mortality rates of 2.2% and 3%, respectively.^[40]

D2 dissections are recommended by the National Comprehensive Cancer Network (NCCN) over D1 dissections.^[4]A pancreas- and spleen-preserving D2 lymphadenectomy is suggested, as it provides greater staging information, and may provide a survival benefit while avoiding its excess morbidity when possible.

D1 gastrectomy is associated with less anastomotic leaks, a lower postoperative complication rate, a lower reoperation rate, decreased length of hospital stay, and a lower 30-day mortality rate. The 5-year survival rate in patients who underwent D1 gastrectomy was similar to the D2 cohort.^[41]

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy may allow downstaging of disease to increase resectability, decrease micrometastatic disease burden prior to surgery, allow patient tolerability prior to surgery, determine chemotherapy sensitivity, reduce the rate of local and distant recurrences, and ultimately improve survival. However, the choice of preoperative and postoperative chemotherapy versus postoperative chemoradiation therapy remains controversial.

A European randomized trial demonstrated survival benefit when patients were treated with three cycles of preoperative chemotherapy (epirubicin, cisplatin, and 5-fluorouracil) followed by surgery and then three cycles of postoperative chemotherapy compared with surgery alone. The benefit was comparable to that obtained with postoperative chemoradiation in a US trial.^[7]However, the Gastric Chemotherapy Group for Japan did not demonstrate a significant survival benefit with neoadjuvant chemotherapy.

A meta-analysis of 15 randomized controlled trials concluded that the addition of neoadjuvant chemotherapy to surgery reduces overall mortality at 3 and 5 years in patients with advanced gastric cancer (relative risk [RR] = 0.74 and 0.82, respectively) and reduces overall mortality at 1, 2, 3, and 5 years in patients with esophagogastric cancer (RR = 0.79, 0.83, 0.84, 0.91 respectively). In patients with esophagogastric cancer, neoadjuvant therapy reduces the overall recurrence rate (RR = 0.80). However, neoadjuvant therapy does not influence morbidity and perioperative mortality rates in either gastric or esophagogastric cancer.^[42]

Intraoperative Radiotherapy

Some authors suggest that intraoperative radiotherapy (IORT) shows promising results. This alternative method of delivering radiotherapy allows for a high dose to be given in a single fraction while in the operating room so that other critical structures can be avoided.

The National Cancer Institute randomized patients with grossly resected stage III/IV gastric cancer to receive either 20 Gy of IORT or 50 Gy of postoperative external beam radiation. Local failure was delayed in the patients treated with IORT (21 mo vs 8 mo). Although the median survival duration also was higher (21 mo vs 10 mo), this figure did not reach statistical significance.^[43]

Adjuvant Radiotherapy

Moertel and colleagues randomized postoperative patients with advanced gastric cancer to receive 40 Grays (Gy) of radiotherapy or 40 Gy of radiotherapy with 5-FU as a radiosensitizer and demonstrated improved survival associated with the combined-modality therapy.^[44]

The British Stomach Cancer Group reported lower rates of local recurrence in patients who received postoperative radiotherapy than in those who underwent surgery alone.^[45]

The update of the initial Gastrointestinal Tumor Study Group series revealed higher 4-year survival rates in patients with unresectable gastric cancer who received combined-modality therapy than in those who received chemotherapy alone (18% vs 6%).^[46]

In a series from the Mayo Clinic, patients were randomized to receive postoperative radiotherapy with 5-FU or surgery alone, and improved survival was demonstrated in patients receiving adjuvant therapy (23% vs 4%).^[47]

Adjuvant radiotherapy is associated with improvements in both overall and relapse-free survival and reductions in locoregional failure.^[48]

Adjuvant Chemotherapy

Numerous randomized clinical trials comparing combination chemotherapy in the postoperative setting to surgery alone did not demonstrate a consistent survival benefit.

Meta-analyses have shown a hint of statistical benefit. In one meta-analysis of 13 randomized trials, adjuvant systemic chemotherapy was associated with a significant survival benefit (odds ratio for death, 0.80; 95% CI, 0.66-0.97). In subgroup analysis, there was a trend toward a larger magnitude of effect for trials in which at least two thirds of the patients had node-positive disease.^[49]

In the open-label randomized Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC), treatment with capecitabine and oxaliplatin (XELOX) after surgery for advanced gastric cancer cut the risk of death by 34% over 5 years, as compared with surgery alone. In CLASSIC, patients with stage II to IIIB gastric cancer who had undergone curative D2 gastrectomy were assigned to adjuvant XELOX for eight cycles or surgery alone. The XELOX regimen consisted of oral capecitabine (1000 mg/m² twice daily on days 1-14 of each cycle) plus intravenous oxaliplatin (130 mg/m² on day 1 of each cycle) for 6 months.^[50] However, D2 surgeries are not common in the United States due to morbidity concerns and a lack of level 1 evidence of a survival advantage.

Adjuvant Chemoradiotherapy

A postoperative chemoradiation study was prompted in part by the patterns of local failure often preceding systemic spread. A randomized phase III study performed in the United States, Intergroup 0116, demonstrated a survival benefit associated with postoperative chemoradiotherapy compared with surgery alone (en bloc resection).^[6]

In Intergroup 0116, patients with T3 and/or N+ adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive a bolus of 5-fluorouracil (5-FU) and leucovorin (LV) and radiotherapy or observation. Patients who received the adjuvant chemoradiotherapy demonstrated improved disease-free survival (from 32% to 49%) and improved overall survival rates (from 41% to 52%) compared to those who were merely observed. This regimen is considered the standard of care in the United States.

The phase III CALGB 80101 study found that in patients who had undergone curative resection of gastric or gastroesophageal junction adenocarcinoma, postoperative chemoradiotherapy with epirubicin, cisplatin, and infusional 5-FU before and after radiotherapy did not improve survival compared with standard 5-FU and LV before and after radiotherapy. With a median follow-up duration of 6.5 years, 5-year overall survival rates were 44% in both treatment arms.^[51]

Advanced Unresectable Disease

Many patients present with distant metastases, carcinomatosis, unresectable hepatic metastases, pulmonary metastases, or direct infiltration into organs that cannot be resected completely.

In the palliative setting, radiotherapy provides relief from bleeding, obstruction, and pain in 50-75% of patients. The median duration of palliation is 4-18 months.

Surgical procedures such as wide local excision, partial gastrectomy, total gastrectomy, simple laparotomy, gastrointestinal anastomosis, and bypass also are performed with palliative intent, with a goal of allowing oral intake of food and alleviating pain.

Chemotherapy and biologic therapy

Platinum-based chemotherapy, in combinations such as epirubicin/cisplatin/5-FU or docetaxel/cisplatin/5-FU, represents the current first-line regimen. Other active regimens include irinotecan and cisplatin and other combinations with oxaliplatin and irinotecan. Results of cisplatin-based chemotherapy have been largely discouraging, with median time to progression of 3-4 months and overall survival of approximately 6-9 months despite reported response rates of up to 45%. For metastatic gastric cancer, the NCCN recommends palliative chemotherapy or entry into a clinical trial.^[4]

Early results reported in 2007 by Japanese clinicians suggested some improvement in both response rates and survival with the oral fluoropyrimidine S-1 used alone or in combination with cisplatin.^[52](S-1 combines three investigational drugs: tegafur, a prodrug of 5-FU; gimeracil, an inhibitor of fluorouracil degradation; and oteracil or potassium oxanate, a GI tract adverse-effect modulator.) A 2017 systematic review and meta-analysis found evidence of a modest survival benefit with S-1 compared with 5-FU-containing regimens.^[53] However, studies of S-1 have largely been limited to Japan, China, and Korea.

Novel treatment strategies may be guided by the use of gene signatures.^[54] Kim et al reported that combined overexpression of MYC, EGFR, and FGFR2 predicts a poor response of metastatic gastric cancer to treatment with cisplatin and 5-FU.^[55]

Ishido et al reported that in patients receiving S-1 chemotherapy after gastrectomy for advanced gastric cancer, intratumoral mRNA expression of thymidylate synthase (TS) is an independent prognostic factor for response to chemotherapy. In 39 patients who received postoperative S-1, recurrence-free survival and overall survival were significantly longer in patients with low TS expression than in those with high TS expression (P=0.021 and 0.016, respectively), whereas in 40 patients treated with surgery only, TS expression did not correlate with survival.^[56]

Ramucirumab

The angiogenesis inhibitor ramucirumab (Cyramza) is approved by the US Food and Drug Administration (FDA) for the treatment of advanced stomach cancer or gastroesophageal (GE) junction adenocarcinoma in patients with unresectable or metastatic disease following therapy with a fluoropyrimidine- or platinum-containing regimen.^[57]

Approval was based on two clinical trials. In one study (n=355), patients treated with ramucirumab (two thirds of patients) had better median overall survival (5.2 vs 3.8 mo) and better progression-free survival compared with patients who received placebo. A second study that compared the efficacy of ramucirumab plus paclitaxel with that of paclitaxel alone also showed improved overall survival in the group that received ramucirumab. The most common adverse events associated with ramucirumab included diarrhea and hypertension.^[57]

Pembrolizumab

Pembrolizumab is approved, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of locally advanced unresectable or metastatic gastric or GE junction adenocarcinoma that is positive for human epidermal growth factor receptor 2 (HER2).

Pembrolizumab received accelerated approval in 2017 for gastric or GEJ carcinoma in patients expressing PD-L1 with disease progression on or after 2 or more prior lines of therapy. The approval was based on results in the phase 2, single-arm KEYNOTE-059 study.^[58] In 2021, however, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted against maintaining this indication for pembrolizumab, and the manufacturer withdrew the drug from the North American market for this indication.^[59]

Rapid progression of cancer (ie, hyperprogression) occurs in a fraction of patients treated with PD-1/PD-L1 inhibitors such as pembrolizumab, including approximately 10% of those with advanced gastric cancer. Kamada et al propose that hyperprogression may occur when when PD-1 blockade activates and expands the population of tumor-infiltrating PD-1+ regulatory T (Treg) cells, which then overwhelm tumor-reactive PD-1+ effector T cells. These authors report that the presence of actively proliferating PD-1+ effector Treg cells in tumors is a reliable marker for hyperprogression, and suggest that inhibiting Treg cell proliferation (eg, with nivolumab plus ipilimumab) could be an important strategy for prevention and treatment of hyperprogression in high-risk patients receiving PD-1 inhibitor therapy.^[60]

Trastuzumab

Trastuzumab, a monoclonal antibody against HER2, was approved in 2010 for the treatment of HER2-overexpressing metastatic gastric or GE junction adenocarcinoma. It is administered in combination with cisplatin and capecitabine or 5-FU in patients who have not received prior treatment for metastatic disease.

Overexpression of HER2 is a significant negative prognostic factor for gastric cancer. In the international ToGA trial (trastuzumab with chemotherapy in HER2-positive advanced gastric cancer), about 22% of patients with advanced gastric cancer were found to have tumors that overexpressed HER2. In this phase III trial, 594 patients with HER2-positive advanced gastric cancer were randomized to receive standard chemotherapy alone or chemotherapy plus trastuzumab. Overall survival with trastuzumab was 13.8 months, compared with 11.1 months in the chemotherapy group (hazard ratio [HR], 0.74, P = 0.0046).^[61]

Although modest, this 2.7-month improvement in overall survival is clinically meaningful in this group of patients, who have a poor prognosis. In addition to the impact on overall survival, trastuzumab improved all of the secondary end points, including progression-free survival (increased from 5.2 mo to 6.7 mo; P = 0.002) and overall response rate (increased from 34.5% to 47%; P = 0.0017).

Trastuzumab deruxtecan

Trastuzumab deruxtecan, the first HER2-directed antibody conjugate, consists of trastuzumab covalently linked to the topoisomerase I inhibitor deruxtecan. It was approved by the FDA in 2021 for locally advanced and metastatic HER2-positive gastric or GE junction adenocarcinoma in patients who were previously treated with a trastuzumab-based regimen.

Approval was based on the phase 2 DESTINY-Gastric01 trial, which randomized patients (n=187) to receive either trastuzumab deruxtecan or physician’s choice of chemotherapy. Objective response was higher in the trastuzumab deruxtecan group compared with the chemotherapy group (51% versus 14%). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (12.5 months versus 8.4 months).^[62]

Tipiracil/trifluridine

The FDA approved tipiracil/trifluridine in 2019 for metastatic gastric or GE junction adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine; a platinum agent; either a taxane or irinotecan; and if appropriate, HER2/neu-targeted therapy.

Approval of tipiracil/trifluridine was based on the phase 3 TAGS (TAS-102 Gastric Study) clinical trial (n=507). Patients in the tipiracil/trifluridine group had a median overall survival 5.7 months compared with 3.6 months in the placebo group (one-sided P=0.00029, two-sided P=0.00058).^[63]

Nivolumab

The FDA approved nivolumab in 2021 for first-line immunotherapy in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. In the phase 3 CheckMate 649 trial, which involved 1581 previously untreated patients with unresectable HER2-negative gastric cancer, GE junction cancer, or esophageal adenocarcinoma, 60% of which had a PD-L1 combined positive score (CPS) ≥5, nivolumab plus oxaliplatin-based chemotherapy was associated with significantly better overall survival (OS) than chemotherapy alone (13.8 months vs 11.6 months, respectively; P = 0.0002). In patients with a PD-L1 CPS ≥5, progression-free survival (PFS) was also significantly improved with nivolumab plus chemotherapy (median 7.7 months vs 6.0 months, P < 0.0001).^{[64, 65]}

In contrast, the phase 3 ATTRACTION-4 study, conducted in Japan, Korea, and Taiwan, which involved involved 724 previously untreated patients with HER2-negative gastric or GE junction cancer, nivolumab plus chemotherapy did not significantly improve OS, but did significantly improve PFS, at a median 10.5 months vs 8.3 months with chemotherapy alone (P = 0.0007).^[64]

Bevacizumab

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF) has been evaluated for use in advanced gastric cancer. The Avastin in Gastric Cancer (AVAGAST) trial, a randomized study of bevacizumab added to capecitabine and cisplatin as first-line treatment of advanced gastric cancer in 774 patients, showed a trend toward achieving its primary endpoint of improving median survival, but did not reach statistical significance (12.1 months with bevacizumab vs 10.1 months with placebo-chemotherapy; HR, 0.87, P = 0.1). However, other endpoints were met and favored bevacizumab, including median progression-free survival (6.7 vs 5.3 months; HR, 0.80; P = 0.0037) and overall response rate (46.0% vs 37.4%; P = 0.0315).^[66]

An evaluation of biomarkers performed as part of AVAGAST identified two strong candidates for use in predicting response to bevacizumab. Patients with high baseline plasma levels of VEGF-A showed a trend toward improved overall survival (HR, 0.72) versus patients with low VEGF-A levels (HR, 1.01; interaction P = 0.07). Patients with low baseline expression of neuropilin-1 also showed a trend toward improved overall survival (HR, 0.75) versus patients with high neuropilin-1 expression (HR, 1.07; interaction P = 0.06). Subgroup analyses demonstrated that for both biomarkers, significance was present only in patients from non-Asian regions.^[67]

Consultations

Specialists recommend obtaining consultations freely in the management of most malignancies, and gastric carcinoma is no exception. The gastroenterologist, surgical oncologist, radiation oncologist, and medical oncologist work closely as a team.

Prevention

A diet that includes fruits and vegetables rich in vitamin C may have a protective effect. A review of eight trials by Rothwell et al found allocation to aspirin reduced death caused by cancer. A latent period of more than 5 years was observed for stomach cancer.^[68]The National Cancer Institute concludes that evidence suggests smoking prevention or cessation would result in a decreased risk of gastric cancer. However, the impact on risk reduction of dietary changes to decrease salt and increase consumption of fruits, vegetables, and whole grains is uncertain.^[20]

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