Gastric Cancer Treatment & Management

Updated: Nov 01, 2017
  • Author: Elwyn C Cabebe, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
  • Print
Treatment

Approach Considerations

National Comprehensive Cancer Network (NCCN) guidelines for treatment of early-stage (Tis, or T1) gastric cancer are as follows [4] :

  • Endoscopic mucosal resection or surgery are the standard treatment options
  • Complete surgical resection offers the potential for long-term survival
  • No further treatment is necessary if there is no residual disease

The NCCN guidelines for treatment of stage IB to IIIC gastric cancer are as follows [4] :

  • For medically fit patients with potentially resectable tumors, preoperative chemotherapy (category 1 recommendation) or chemoradiotherapy followed by surgery is appropriate
  • Postoperative chemoradiation or chemotherapy is indicated for patients who have undergone primary D2 lymph node dissection
  • For patients with unresectable tumors, treatment with fluoropyrimidine- or taxane-based chemoradiotherapy (category 1 recommendation) or chemotherapy is acceptable.

The European Society for Medical Oncology/ European Society of Surgical Oncology/ European Society for Therapeutic Radiology and Oncology (ESMO-ESSO-ESTRO) recommendations for treatment are as follows [32] :

  • Multidisciplinary treatment planning is mandatory; the management team should include surgeons, medical and radiation oncologists, gastroenterologists, radiologists, and pathologists plus, if available, dieticians and nurse specialists
  • T1a gastric cancers may be amenable to endoscopic resection if they are well-differentiated, ≤2 cm, confined to the mucosa, and not ulcerated
  • With T1 tumors that do not meet the criteria for endoscopic therapy, lymph node dissection during open surgery can be limited to perigastric nodes and include local N2 nodes
  • The preferred treatment for operable gastric cancers beyond stage T1N0 is surgery with both preoperative and postoperative chemotherapy
  • For patients with stage IB disease or higher who do not receive preoperative chemotherapy, the treatment options include either chemoradiotherapy or chemotherapy in the adjuvant setting
  • Radical gastrectomy is indicated for resectable stage IB–III disease, although subtotal gastrectomy may be performed if a macroscopic proximal margin of 5 cm can be achieved between the tumor and the esophagogastric junction (8 cm for diffuse-type cancers)
  • For medically fit patients, D2 lymph node dissection should be standard
  • For inoperable or metastatic gastric cancer, treatment is with palliative chemotherapy, or best supportive care if the patient is unfit for treatment
  • In HER-2 negative disease, combination regimens based upon a platinum–fluoropyrimidine doublet are generally used; triplet regimens are controversial, but the addition of an anthracycline (eg, epirubicin) has demonstrated benefit
  • In HER-2 positive disease, recommended chemotherapy is with trastuzumab plus cisplatin and either 5-fluorouracil or capecitabine
  • Second-line chemotherapy options include irinotecan and docetaxel or paclitaxel

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

Next:

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. [33]

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. [34, 35]

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. [36]

D2 dissections are recommended by the National Comprehensive Cancer Network 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. [37]

Previous
Next:

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.

A European randomized trial also 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 the US trial. [7] However, the Gastric Chemotherapy Group for Japan did not demonstrate a significant survival benefit with neoadjuvant chemotherapy.

Choice of preoperative and postoperative chemotherapy versus postoperative chemotherapy and radiation remains controversial, and an ongoing United States Intergroup study, CALGB 80101, will look more closely at that question.

Previous
Next:

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. [38]

Previous
Next:

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. [39]

The British Stomach Cancer Group reported lower rates of local recurrence in patients who received postoperative radiotherapy than in those who underwent surgery alone. [40]

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%). [41]

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%). [42]

Adjuvant radiotherapy is associated with improvements in both overall and relapse-free survival and reductions in locoregional failure. [43]

Previous
Next:

Adjuvant Chemotherapy

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

Recent 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. [44]

A study by Bang et al found that adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered among patients with operable gastric cancer; 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. [45]

Previous
Next:

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.

Previous
Next:

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.

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%. Early results reported in 2007 by Japanese clinicians suggest some improvement in both response rates and survival with the oral fluoropyrimidine S-1 used alone or in combination with cisplatin. [46] (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.) These results remain to be confirmed by ongoing studies in Europe and North America.

For metastatic gastric cancer, the NCCN recommends palliative chemotherapy or entry into a clinical trial. In April 2014, the FDA approved the angiogenesis inhibitor ramucirumab (Cyramza) for the treatment of advanced stomach cancer or gastroesophageal junction adenocarcinoma in patients with unresectable or metastatic disease following therapy with a fluoropyrimidine- or platinum-containing regimen. [47] This agent has also been designated as an orphan product.

Approval was based on two clinical trials. A study of 355 patients showed that those 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. [47]

Pembrolizumab (Keytruda) was approved in September 2017 for gastric or GE junction carcinoma in patients expressing PD-L1 with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. Approval was based on the KEYNOTE-059 study. In the multinational trial, 259 heavily pretreated patients received single-agent pembrolizumab 200 mg IV every 3 weeks. Before enrolling, 51.7% of patients had received 2 prior lines of therapy, and 29% and 19.3% had received 3 or more than 4 prior lines of therapy, respectively. Median follow-up was 5.8 months. In the study, 143 of 259 patients had PD–L1-positive tumors (CPS ≥1) and microsatellite stable tumor status or undetermined microsatellite instability or mismatch repair status. The objective response rate (ORR) in these patients was 13.3%, comprising 1.4% complete responses and 11.9% partial responses. Among the 19 patients who were responders, the duration of response ranged from 2.8+ to 19.4+ months, with 58% having responses 6 months or longer and 26% having responses 12 months or longer. [48]

Novel treatment strategies may be guided by the use of gene signatures. [49] 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 fluorouracil. [50]

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. [51]

Overexpression of human epidermal growth factor receptor 2 (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 (Herceptin). 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). [52]

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 was approved in October of 2010 for the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. It is administered in combination with cisplatin and capecitabine or 5-fluorouracil in patients who have not received prior treatment for metastatic disease. The trastuzumab dose consists of an initial cycle of 8 mg/kg intravenously (IV) infused over 90 minutes, followed by subsequent cycles of 6 mg/kg IV infused over 30-90 minutes every 3 weeks. Treatment is continued until the disease progresses.

A more recent study suggests that survival in advanced gastric cancer is also improved with an adjuvant chemotherapy regimen. Data from the open-label randomized Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) indicate that after surgery for advanced gastric cancer, treatment with capecitabine and oxaliplatin (XELOX) cuts the risk of death by 34% over 5 years, as compared with surgery alone. [53, 54]

In the CLASSIC study, 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. [53, 54]

At 5 years there was a 34% reduction in the risk of death with XELOX, as compared with surgery alone. [53, 54] The 5-year overall survival rate was also better with XELOX (78% vs 69%), as well as the 5-year disease-free survival rate (68% with XELOX and 53% without).

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). [55]

A biomarker evaluation performed as part of AVAGAST identified two biomarkers that are strong candidates for use in predicting response to bevacizumab. Patients with high baseline plasma levels of VEGF-A levels 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. [56]

Previous
Next:

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.

Previous
Next:

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. [57]

Previous