Although … limitations may confound the results, our findings do elucidate a possible association between surgery and radiation therapy and improved survival for metastatic gastric cancer patients.
—Ravi Shridhar, MD, PhD, and colleagues
A Surveillance, Epidemiology, and End Results (SEER) database analysis reported by Ravi Shridhar, MD, PhD, and colleagues in Cancer indicates that patients receiving surgery and radiation therapy for metastatic gastric cancer have prolonged survival compared with those receiving either alone or neither surgery nor radiotherapy.1
In the study, the Moffitt Cancer Center investigators queried the SEER 2004 to 2008 data set to identify patients aged 18 years or older with stage IV (M1) gastric cancer who did or did not undergo surgery or radiotherapy. Patients had to have histologic subtypes of adenocarcinoma (not otherwise specified [NOS], intestinal-type, mucinous or mucin-producing, mixed cell or with mixed subtypes, in adenoma or polyp, and with neuroendocrine differentiation) or carcinoma (NOS, diffuse type, or signet ring cell). Patients receiving radiotherapy had received postoperative or preoperative external-beam radiotherapy and were excluded if they had received intraoperative radiotherapy. All surgical patients had some form of gastrectomy with or without lymph node dissection.
Patients with survival of less than 3 months were excluded from the analysis; of 3,337 such patients, 2,750 received neither surgery nor radiotherapy, 241 received radiotherapy alone, 330 received surgery alone, and 16 received both. Data not included in the database included comorbidities, performance status, surgical margin status, postoperative complications, type of lymphadenectomy, chemotherapy, and radiotherapy field design and dose.
Of the initial 8,978 patients identified in the SEER database, 5,072 remained in the analysis after exclusion based on histology and survival of less than 3 months. Of these, 3,069 patients received neither surgery nor radiotherapy (no surgery/no radiotherapy group), 806 received radiotherapy alone, 957 received surgery alone, and 240 received both (surgery/ radiotherapy group). There were significant differences across these four groups in mean age, sex, year of diagnosis, type of metastases, tumor location, tumor histology, T stage, N stage, and tumor grade.
Increased Survival with Surgery/Radiotherapy
Median and 2-year overall survival durations were 16 months and 31.7% in the surgery/radiotherapy group, 10 months and 18.2% in the surgery-alone group, 8 months and 8.9% in the radiotherapy-alone group, and 7 months and 8.2% in the no surgery/no radiotherapy group (overall P < .00001). Kaplan-Meier analysis showed that survival curves for each of the groups differed significantly from each other. When patients with survival of less than 3 months were included in the analysis, the differences among groups remained significant.
Multivariate analysis of overall survival including all patients showed that surgery was associated with a significant 43.5% reduction in risk for mortality (hazard ratio [HR] = 0.565 vs no surgery, P < .0001) and radiotherapy with a significant 11.8% reduction (HR = 0.882 vs no radiotherapy, P = .042). Increasing age (HR = 1.01 as a continuous variable, P < .0001), T4 tumors (HR = 1.18 vs T1, P = .021), N3 nodes (HR = 1.27 vs N0, P = .024), signet ring histology (HR = 1.22 vs adenocarcinoma NOS, P = .002), and peritoneal carcinomatosis (HR = for peritoneal metastasis 1.33 vs nodal metastasis, P < .0001; HR = 1.40 for peritoneal and nodes vs nodes, P < .0001) were associated with significantly increased risk of mortality. Sex, tumor grade, and tumor location were not predictive of mortality.
Reduced Mortality with Surgery plus Radiotherapy
Multivariate analysis among all patients undergoing surgery showed that radiotherapy was associated with a significant 26.7% reduction in risk for mortality (HR = 0.733 vs no radiotherapy, P = .004), whereas increasing age, removal of less than 15 nodes (HR = 1.24 vs ≥ 15 nodes, P = .022), tumor stage (T2, T3, and T4 vs T1), nodal stage (N2 and N3 vs N1), signet ring histology, and peritoneal carcinomatosis were associated with significantly increased risk of mortality. Sex, tumor location, and tumor grade were not predictive of mortality.
Among patients not undergoing surgical resection, radiotherapy had no significant effect on mortality. Increasing age was associated with increased risk, and there was a trend for increased risk with signet ring histology. Sex, tumor stage, nodal stage, tumor location, histology, tumor grade, and peritoneal carcinomatosis were not predictive.
The authors noted that there have been few reports on the role of locoregional therapy in metastatic gastric cancer, with available data from small series suggesting a survival benefit with palliative resection and no evidence of a survival benefit of radiotherapy. In addition to suggesting a significant survival benefit of surgery and radiotherapy in this setting, the SEER analysis suggests that patients with metastatic disease may benefit from removal of 15 or more nodes, a strategy that has been associated with a survival benefit in the nonmetastatic setting.
Limitations of Analysis
The authors acknowledged that the analysis has a number of limitations, including the absence of data on performance status, nutritional status, systemic chemotherapy, resection margin status, extent of lymphadenectomy, whether resection was complete or not, use of concurrent chemotherapy with radiotherapy, and radiotherapy field design, technique, and dose.
They noted, “[I]t is impossible to fully understand from SEER why some people may have received surgery and/or radiation therapy as part of their treatment management. It is possible that healthier patients, hence better prognosis patients, received these locoregional treatments. However, despite these inherent biases, SEER documents the real world outcomes of these patients. Although these limitations may confound the results, our findings do elucidate a possible association between surgery and radiation therapy and improved survival for metastatic gastric cancer patients…. [The findings] warrant…prospective clinical trials addressing the role of locoregional treatment in well-defined patient cohorts with metastatic gastric cancer.”
Two trials are currently examining the role of palliative surgery in stage IV gastric cancer. The phase III REGATTA trial in Japan and Korea is examining use of palliative surgery followed by chemotherapy. In a phase II/III trial in Japan, patients with a partial or complete response to S-1 and docetaxel or cisplatin are to be randomly assigned to either continued chemotherapy or surgical resection followed by additional chemotherapy. ■
Disclosure: The authors of the study reported no potential conflicts of interest.
1. Shridhar R, Almhanna K, Hoffe SE, et al: Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: A Surveillance, Epidemiology, and End Results database analysis. Cancer January 29, 2013 (early release online).