Stage IV and Recurrent Gastric Cancer
Standard treatment options:
- Palliative chemotherapy with:
- Fluorouracil (5-FU).[1-3]
- Epirubicin, cisplatin, and 5-FU (ECF).[4,5]
- Epirubicin, oxaliplatin, and capecitabine (EOX).
- Cisplatin and 5-FU (CF).[7,3]
- Docetaxel, cisplatin, and 5-FU.
- Etoposide, leucovorin, and 5-FU (ELF).
- 5-FU, doxorubicin, and methotrexate (FAMTX).
- Trastuzumab, cisplatin, and either 5-FU or capecitabine in patients with HER2-positive tumors (3+ on immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH]-positive).
- Endoluminal laser therapy, endoluminal stent placement, or gastrojejunostomy, may be helpful to patients with gastric obstruction.
- Palliative radiation therapy may alleviate bleeding, pain, and obstruction.
- Palliative resection should be reserved for patients with continued bleeding or obstruction.
Standard chemotherapy versus best supportive care for patients with metastatic gastric cancer has been tested in several clinical trials, and there is general agreement that patients who receive chemotherapy live for several months longer on average than patients who receive supportive care.[11-13][Level of evidence: 1iiA] During the last 20 years, multiple randomized studies evaluating different treatment regimens (monotherapy vs. combination chemotherapy) have been performed in patients with metastatic gastric cancer with no clear consensus emerging as to the best management approach. A meta-analysis of these studies demonstrated an hazard ratio (HR) of 0.83 for overall survival (OS) (95% confidence interval [CI], 0.74–0.93) in favor of combination chemotherapy.
Of all the combination regimens, ECF is often considered the reference standard in the United States and Europe. In one European trial, 274 patients with metastatic esophagogastric cancer were randomly assigned to receive either ECF or FAMTX. The group who received ECF had a significantly longer median survival (8.9 vs. 5.7 months, P = .0009) than the FAMTX group.[Level of evidence: 1iiA] In a second trial that compared ECF with mitomycin, cisplatin, and 5-FU (MCF), there was no statistically significant difference in median survival (9.4 vs. 8.7 months, P = .315).[Level of evidence: 1iiA]
Oxaliplatin and capecitabine are often substituted for cisplatin and 5-FU within the ECF regimen as a result of data from the REAL-2 trial (ISRCTN51678883). This randomized trial of 1,002 patients with advanced esophageal, gastroesophageal junction, or gastric cancer utilized a 2 × 2 design to demonstrate noninferior median OS in patients treated with capecitabine rather than 5-FU (HRdeath = 0.86; 95% CI, 0.82–0.99) and in patients treated with oxaliplatin in place of cisplatin (HRdeath = 0.92; 95% CI, 0.80–1.10).
An international collaboration of investigators randomly assigned 445 patients with metastatic gastric cancer to receive docetaxel, cisplatin, and 5-FU (DCF) or CF. Time-to-treatment progression (TTP) was the primary endpoint. Patients who received DCF experienced a significantly longer TTP (5.6 months; 95% CI, 4.9–5.9; vs. 3.7 months; 95% CI, 3.4–4.5; HR, 1.47; 95% CI, 1.19–1.82; log-rank P < .001; risk reduction 32%). The median OS was significantly longer for patients who received DCF versus patients who received CF (9.2 months; 95% CI, 8.4–10.6; vs. 8.6 months; 95% CI, 7.2–9.5; HR, 1.29; 95% CI, 1.0–1.6; log-rank P = .02; risk reduction = 23%).[Level of evidence: 1iiA] There were high toxicity rates in both arms. Febrile neutropenia was more common in patients who received DCF (29% vs. 12%), and the death rate on the study was 10.4% for patients on the DCF arm and 9.4% for patients on the CF arm.
Whether the CF regimen should be considered as an index regimen for the treatment of patients with metastatic gastric cancer is the subject of debate. The results of a study that randomly assigned 245 patients with metastatic gastric cancer to receive CF, FAMTX, or ELF demonstrated no significant difference in response rate, progression-free survival, or OS between the arms. Grades 3 and 4 neutropenia occurred in 35% to 43% of patients on all arms, but severe nausea and vomiting was more common in patients in the CF arm and occurred in 26% of those patients.[Level of evidence: 1iiDiv]
In an open-label, international phase III trial, patients with HER2-positive metastatic, inoperable locally advanced, or recurrent gastric or gastroesophageal junction cancer were randomly assigned to chemotherapy with or without the anti-HER2 monoclonal antibody trastuzumab. HER2 positivity was defined as either 3+ staining by IHC or a HER2 to CEP17 ratio of two or more using FISH. Tumors from 3,665 patients were HER2 tested; of the patients, 810 were positive (22%) and 594 met eligibility criteria for randomization. Chemotherapy consisted of cisplatin plus 5-FU or capecitabine chosen at the investigator’s discretion. The study treatment was administered every 3 weeks for six cycles, and trastuzumab was continued every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Crossover to trastuzumab at disease progression was not permitted. Median OS was 13.8 months (95% CI, 12–16) in patients assigned to trastuzumab and 11.1 months (95% CI, 10–13) in patients assigned to chemotherapy alone (HR, 0.74; 95% CI, 0.60–0.91; P = .0046).[Level of evidence: 1iiA] There was no significant difference in rates of any adverse event, and cardiotoxicity was equally rare in both arms.
When patients develop progression of disease after first-line chemotherapy, there is no standard treatment option. Investigators in Korea randomly assigned patients with advanced gastric cancer who had received one or two prior chemotherapy regimens involving both a fluoropyrimidine and a platinum agent to either salvage chemotherapy or best supportive care in a 2:1 fashion. Salvage chemotherapy consisted of either docetaxel (60 mg/m2 every 3 weeks) or irinotecan (150 mg/m2 every 2 weeks) and was left to the discretion of the treating physicians. Of the 202 patients enrolled, 133 received salvage chemotherapy and 69 received best supportive care. Median OS was 5.3 months in the group that received salvage chemotherapy and 3.8 months in the group that received best supportive care (HR, 0.657; P = .007). There was no difference in median OS between docetaxel and irinotecan (5.2 months vs. 6.5 months, P = .116).[Level of evidence: 1iiA]
Treatment options under clinical evaluation:
- Palliative chemotherapy with:
- Irinotecan and cisplatin.
- Folic acid, 5-FU, and irinotecan (FOLFIRI).
- Leucovorin, 5-FU, and oxaliplatin (FOLFOX).
Phase II studies evaluating irinotecan-based or oxaliplatin-based regimens demonstrate similar response rates and TTP to those found with ECF or CF, but the former may be less toxic.[20-25] There are conflicting data regarding relative efficacy of any one regimen for another. Ongoing studies are evaluating these newer regimens.Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV gastric cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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