Patients with unresectable gastric cancers and no evidence of metastatic disease can be expected to survive approximately 6 months without any treatment.
Palliative Gastrectomy and Regional Therapies for Advanced Disease
Palliative resection, bypass, and/or stenting may be appropriate for some patients with obstructive lesions. Palliative resection may also be suitable for patients with bleeding gastric cancers that are not resectable for cure. Generally, resection appears to offer better palliative results than bypass. Regional therapy with preoperative intraperitoneal and systemic therapy and hyperthermic intraperitoneal chemotherapy (HIPEC) have recently been explored as methods to reduce rates of peritoneal failures in patients with peritoneal carcinomatosis. Although promising results have been generated in trials utilizing regional therapy, it has not yet become a part of standard therapy.
Radiation therapy alone can provide palliation in patients with bleeding or obstruction who are not operative candidates. Radiotherapy may convert unresectable cancers to resectable tumors.
Patients with locally advanced disease may be appropriately treated with chemoradiation therapy. This approach can provide relatively long-lasting palliation and may render some unresectable cancers resectable. Older studies have shown that postoperative chemoradiation therapy can reduce relapse rates and prolong survival in patients with incompletely resected stomach cancer.
When possible, all newly diagnosed patients with disseminated gastric cancer should be considered candidates for clinical trials, and those with good performance status should be offered systemic therapy. Even though cure is not expected with chemotherapy, such treatment may provide palliation in selected patients, and sometimes durable remissions. Several randomized chemotherapy trials have suggested improvement in survival and probably quality of life vs best supportive care alone across first and second lines of therapy.
Single-agent drug therapy
Several agents have established activity in gastric cancer: 5-FU, platinums (cisplatin, oxaliplatin(Drug information on oxaliplatin), and carboplatin(Drug information on carboplatin)), mitomycin, etoposide, some anthracyclines (doxorubicin and epirubicin), taxanes (paclitaxel and docetaxel), irinotecan(Drug information on irinotecan), antimetabolites (pemetrexed [Alimta], methotrexate(Drug information on methotrexate), trimetrexate), and oral fluoropyrimidines (uracil and tegafur(Drug information on tegafur) [UFT], S-1, capecitabine(Drug information on capecitabine)). The agents 5-FU and cisplatin(Drug information on cisplatin) have been used most commonly. Responses seen with single-agent chemotherapy have been traditionally partial and mostly short-lived, with little, if any, impact on overall survival.
Response rates are consistently higher when combination chemotherapy regimens are used in gastric cancer. Combination therapy has been generally preferred over single agents, though it remains unclear whether doublets or triplets represent ideal therapy (Table 3).
In the 1980s, the combination of 5-FU, doxorubicin(Drug information on doxorubicin), and mitomycin(Drug information on mitomycin) (FAM) was considered the standard regimen in the treatment of advanced gastric cancer. However, the NCCTG (North Central Cancer Treatment Group) randomly compared this regimen with 5-FU plus doxorubicin and single-agent 5-FU and found no difference in survival among the patients treated with the three regimens.
Several different regimens, including FAMTX (5-FU, doxorubicin, and methotrexate) and ELF (etoposide, leucovorin, and 5-FU), have been tested. Most regimens are associated with markedly better response rates and longer survival in early trials than in phase III studies. No combination has been confirmed as superior. However, ECF (epirubicin, cisplatin, 5-FU) approaches standard of care in Canada and in some parts of Europe. This regimen has proved superior to FAMTX in terms of objective response rate and survival and superior to the mitomycin, cisplatin, 5-FU (MCF) regimen in terms of toxicity. A combination of docetaxel(Drug information on docetaxel), cisplatin, and 5-FU was shown to offer superior survival rates vs cisplatin and 5-FU; however, grade 3/4 toxic events occurred in 81% of patients treated with triple therapy. Modifications of this regimen have been proposed. The search for the optimal combination regimen continues, with the promising newer agents usually being introduced in combination regimens.
Newer agents with somewhat similar mechanisms of action to those of classic drugs have been tried in patients with advanced gastric cancer. Oxaliplatin- and cisplatin-containing regimens have been compared, with the former perhaps being more efficacious. Additionally, regimens substituting oral capecitabine for intravenous 5-FU are popular because of ease of administration and fewer catheter-related complications. S-1 is another version of an oral fluoropyrimidine. Phase III studies of S-1 in the West have been promising in regard to reduction of toxicity, but efficacy has not been superior. S-1 plus cisplatin improved survival for patients with advanced incurable gastric cancer patients vs S-1 alone in the Japanese SPIRITS trial. Likewise, no standard second-line therapy for advanced gastric cancer patients exists. Taxanes and the topoisomerase-1 inhibitor irinotecan have shown some activity in this setting.
Chemotherapy works modestly well in advanced gastric cancer, but only one biologic agent, trastuzumab (Herceptin), has appeared effective to date, and is considered standard of care in the 10% to 15% of patients with HER2-positive tumors. Kang and associates (Kang YK et al: J Clin Oncol 2011) presented AVAGAST (Avastin in Gastric Cancer), a randomized double-blind, placebo-controlled study of first-line chemotherapy with or without bevacizumab(Drug information on bevacizumab) (Avastin), in patients with incurable disease: 774 patients from 17 countries were enrolled and given capecitabine (Xeloda) (or 5-FU)/cisplatin plus or minus the biologic. Investigators were looking for an improvement in overall survival from 10 to 12.8 months. The addition of bevacizumab did result in statistically significant improvements in the overall response rate and progression-free survival (the latter from 5.3 to 6.7 months), but it did not meet its primary objective. Overall survival was 10.1 months for patients given placebo and 12.1 months for those getting the antiangiogenic agent (P = .1002). The trial reported interesting overall regional survival differences in efficacy for chemobiologic therapy (Americans did worst), and pre-planned biomarker analysis is awaited.
Gastric cancer patients should be encouraged to participate in well-designed clinical trials. Outside experimental regimens, the recommended therapy for patients with good performance status is a 5-FU/platinum-based regimen.
Targeted therapy in gastric cancer
In general, targeted agents are not used in the majority of patients with gastric cancer. One exception is trastuzumab(Drug information on trastuzumab). The addition of trastuzumab to chemotherapy was explored in the ToGA (Trastuzumab for Gastric Cancer) randomized trial. A total of 594 patients with gastric or gastroesophageal junction cancers with overexpression of HER2 protein or gene amplification were randomized to capecitabine or 5-FU with cisplatin vs capecitabine or 5-FU and cisplatin every 3 weeks for 6 cycles, given with trastuzumab. As reported by Bang et al, at a median follow-up of 18.6 months in the trastuzumab-plus-chemotherapy arm and 17.1 months in the chemotherapy arm, there was a benefit in median overall survival in the group receiving trastuzumab (13.8 months vs 11.1 months, P = .0046). There was no significant difference in the rates of toxicity between the groups. The most common adverse effects were nausea, vomiting, and neutropenia in both groups. Although trastuzumab has been approved in the United States, only 15% to 20% of patients have HER2 positivity considered positive enough for treatment. Other agents have been disappointing; bevacizumab (Avastin) did not improve upon capecitabine plus cisplatin in the AVAGAST or AVATAR trials, and anti-EGFR therapy has also failed.
Targeted agents continue to perform well in patients with advanced GIST, for example as reported in the phase III GRID (GIST—Regorafenib in Progressive Disease) trial.
Sidebar: Epidermal growth factor overexpression occurs in up to half of patients with advanced upper gastrointestinal cancers, and it correlates with poor prognosis. The REAL3 trial compared panitumumab (Vectibix), a human anti–epidermal growth factor receptor (EGFR) antibody, added to epirubicin(Drug information on epirubicin), oxaliplatin (Eloxatin), and capecitabine (Xeloda) vs the same drugs (slightly different dosing) in patients with advanced esophagogastric adenocarcinomas. The trial was actually halted after Data Safety and Monitoring Board review; those given the anti-EGFR antibody had worsened median progression-free survival (7.4 vs 6 months) and overall survival (11.3 vs 8.8 months); KRAS and PI3K3CA mutations were prognostic for poorer overall survival, and no biomarker predicted for better results with antibody treatment. Patients on the panitumumab arm experienced better median overall survival (10.2 vs 4.3 months) if they had grade 1-3 rash (Waddell TS et al: J Clin Oncol 30[suppl]: abstract LBA4000, 2012).
Sidebar: The GRID trial was a phase III, double-blinded trial comparing the oral multikinase inhibitor regorafenib (Stivarga) vs placebo, in patients with advanced GIST failing to respond to treatment with imatinib(Drug information on imatinib) (Gleevec) and sunitinib (Sutent). Patients given drug experienced median survival of 4.8 months vs 0.9 for those on placebo. Cross-over washed out any potential overall survival advantage. Common toxicities (> grade 3) included hypertension, hand-foot reactions, and diarrhea. Regorafenib should become available soon for third-line treatment of those with incurable GIST (Demetri GD et al: J Clin Oncol 30[suppl]: abstract LBA10008, 2012).