Clinical significance of palliative gastrectomy on the survival of patients with incurable advanced gastric cancer: a systematic review and meta-analysis

In spite of significant advances in experimental research, diagnosis and treatment, gastric cancer (GC) accounts for over 10% of cancer-related deaths worldwide and remains the second most frequent cause of cancer death after lung cancer [1, 2]. In recent years, however, the advances in new treatments and chemotherapy have improved the overall survival rate for GC patients with incurable factors compared with that of patients who receive only supportive treatment [3‐5]. The long-term outcomes for early GC are improved with earlier diagnosis, but for advanced GC combined with incurable factors the results are not optimistic [6, 7]. The incurable factors in patients with advanced GC are peritoneal dissemination, liver dissemination, distant lymph node metastases and a primary tumor of huge mass [8]. Therefore, palliative strategies are still necessary for patients with GC, especially in late stages [9].

The National Comprehensive Cancer Network (NCCN) guidelines suggest that gastric resections should be reserved for the palliation of symptoms (e.g., obstruction or uncontrollable bleeding) in patients with incurable disease [10]. The Japanese Gastric Cancer Association (JGCA) guidelines suggest that patients with metastases but without major symptoms may be treated with gastrectomy [11]. However, surgical resection is still considered to be the most suitable treatment for GC, but surgical resection for GC with incurable factors remains debatable. Palliative gastric resection could enable oral food intake, and decrease symptoms such as obstruction and bleeding [12, 13]. Some investigations reported that gastric resection may be beneficial for survival, reducing symptoms, and enhancing the quality of life [13‐17]. Simultaneously, some other studies reported that survival after palliative gastrectomy was associated with significant morbidity, longer hospital stays, and poor quality of life [18, 19], and gastrectomy was recommended only for cases with serious complications, such as tumor bleeding or organ perforation [20, 21].

Although many investigations have reported palliative gastrectomy for patients with incurable advanced GC, there is still not a clear consensus on the most suitable surgical treatment strategy. Also, determining which patients should receive palliative gastrectomy is also a question. Therefore, the present systematic review and meta-analysis was designed to analyze results according to surgical resection and factors that affect the survival of patients with incurable GC. The aim of our study was to determine the clinical significance of palliative gastrectomy for patients with incurable advanced GC focusing on patient selection and strategy selection.

In the last 30 years, the patterns of metastasis, recurrence, and survival in patients with GC have changed, and the incidences of GC has decreased worldwide. This phenomenon was promoted by therapies to eradicate approaches of Helicobacter pylori[40], improvements in standardized operative procedures and auxiliary instrument, and improvements in the quality of life among different societies, etc. [41]. However, patients with gastric cancer are always in the advanced stage when diagnosed. Recent advances in chemotherapy regimens have improved the survival rates of GC patients with incurable factors. However, whether it is suitable for patients with advanced GC to receive palliative resection is still under debate [42]. Therefore, our study was the first to perform a meta-analysis on palliative resection for patients with incurable advanced GC. The results showed the trend that palliative gastrectomy may improve survival in patients with incurable advanced GC. The impact on the improvement of survival may depend on the position of metastasis, chemotherapy and combined resection of metastasis.

In this study, almost all the articles used median survival time and 1-year, 3-year or 5-year survival rates to assess the effect. Therefore, the overall survival rates extracted from each article were suitable for analysis in this study. The articles that were included in our study all reported patients with incurable advanced GC. However, Kikuchi et al. [26] reported GC with metastasis to the distant peritoneum, so we also included it as an M1 GC. We obtained information about the median survival times of each study from the original articles, and calculated the weighted average values. The results showed that the weighted average of median survival time in patients with palliative gastrectomy was longer than that without palliative resection (14.96 vs. 7.07). Although there was significant heterogeneity, the meta-analysis still showed that palliative gastrectomy tended to improve overall survival rates, with an HR of 0.58 (95%CI 0.48–0.71).

Stage M1 in our study was considered as GC with distant organ metastasis, such as hepatic, peritoneal and distant lymph node metastasis. These had been shown previously to adversely affect survival in several studies [43‐45]. Therefore, the characteristic of patients with stage M1 GC was extracted to perform the analysis in our study. These results indicate that GC patients with metastasis who receive palliative gastrectomy may have better overall survival than patients who receive other treatments. In spite of M1 GC showing improvement in survival, fewer included trials may still make obstacles for proving the benefit of palliative gastrectomy in all metastasis types in our study. Furthermore, we investigated palliative gastrectomy combined with resection of metastasis. Sougioultzis et al. [32] reported that there were benefits in palliative gastrectomy for GC patients with distant metastases. Due to limitations of data from the original trials, only combined hepatic resection was in accordance with the selection criteria of our research. Although the efficacy of surgical treatment for hepatic metastasis from GC remains uncertain, palliative gastrectomy may be beneficial for patients with liver metastasis [46] and the results were also the same as in the present study. The results of our meta-analysis confirm that palliative gastrectomy combined with hepatectomy may provide better overall survival than palliative gastrectomy only in patients with advanced GC and liver metastasis.

Several trials reported the function of chemotherapy for patients after palliative gastrectomy. Chemotherapy may be a protective factor for patients with unresectable or metastatic disease, and may offer a comparable survival benefit [47]. Some trials showed there was no survival benefit associated with palliative gastrectomy and recommended chemotherapy [37, 42]. In contrast, some articles suggested palliative gastrectomy without chemotherapy was beneficial [48, 49]. There were also some trials, such as Lin et al., recommended palliative gastrectomy with chemotherapy to improve the survival rates of patients [29]. The majority of original studies included in the present study reported chemotherapy as used in the trials. We analyzed survival rate of patients that received palliative gastrectomy with or without chemotherapy. The results showed that patients with palliative gastrectomy combined with chemotherapy might have a beneficial survival compared to patients with simple palliative gastrectomy.

Whether a course of treatment is valuable for incurable patients depends on whether it improves their periods of survival and quality of life (QOL). In clinical practice, we must balance the benefits with the risk and costs of surgery, before the decision to treat is taken. Quality of life is an important factor in evaluating the impact of resection, but very few of the articles included in our analysis mentioned. In the present study, we calculated the survival rates to evaluate the efficacy of the treatment, but because we had limited data from only retrospective trials, the quality of life, duration of hospital stay, and costs could not be determined, so the currently available evidence cannot clarify the potential clinical benefits or harms. However, Chang [34] used hospitalization-free survival (HFS) as a parameter to evaluate QOL. The results reported by Chang suggested that palliative gastrectomy may not compromise QOL. However, whether palliative gastrectomy affects QOL, is still contentious, and more research into this tissue is required in the future.

Early diagnosis and prevention strategies are systematically performed in several Asian countries [50], and have been shown to produce a higher rate of early tumor categories and better prognoses among patients with gastric cancer than Europeans and other Western countries. However, many investigations from the countries with the greatest experience and incidence of GC in Asia are published in Asian languages, and are often neither analyzed nor cited. Differences in results may be attributable to different districts. In the present study, eight of the included articles [26, 29, 31, 33, 34, 36‐38] reported in Asian and six [27, 28, 30, 32, 35, 39] were from Western countries. We analyzed subgroups based on different regions, such as Asian and Western countries, to determine whether they influenced the analysis. Our results showed that palliative gastrectomy may improve survival in both regions, even though relatively clear heterogeneity was observed in the data from Western countries (Table 3). The differences among regions may influence outcomes, but the results of our analysis suggest that the effect is slight. More data from Western countries are required for comparison with Asian data before a final conclusion can be drawn.

To date there have been no randomized, controlled trials evaluating the difference between survival of patients managed with or without palliative resection for incurable advanced GC. Therefore, this work was limited to data from retrospective studies and it is difficult to extract strong conclusions from survival data. The patient status and tumor burden at the time of diagnosis may influence the decision as to whether to operate and it may influence the survival advantage after surgery [51]. Only a few trials reported the detailed characteristics of patients before and after surgery [26, 29, 36‐38] (1571 patients, 52.31%), combined resection [36, 38] (92 patients, 3.06%), or chemotherapy [27, 29, 30] (259 patients, 8.62%). We tried to connect with the authors, but few replied. To reduce publication bias, we selected studies carefully and evaluated the trails with the STROBE guidelines. The degree of asymmetry among the individual study results around the combined HR for overall survival in shown in Figure 5. The degree of asymmetry was not statistically significant on Egger’s test (p = 0.177) or Begger’s test (p = 0.855) which means that there was no significant publication bias among the articles included in the present analysis. The selection of patients for the different groups was a problem, because each included study had its own distinct indications and goals, and should be evaluated independently. Without a better understanding of the performance status of the patients selected in the two study groups, selection bias in our analysis cannot be excluded. Furthermore, the quality of articles must be improved in the future. For instance, in the study by Saidi et al., the confidence interval for the median survival time ranged between 4.3 and 28.8 months, which may be attributable to the small sample used in the study (24 patients) or other factors, and sample sizes should be increased to eliminate this effect. Recently, a randomized controlled trial has begun in Japan and Korea to determine the value of gastrectomy performed in patients with advanced GC, and the results are keenly awaited [52]. In the future, well designed and high-quality multicenter clinical trials are still required.

The present meta-analysis showed that palliative gastrectomy had a statistically significant survival benefit on patients with incurable advanced GC, especially stage M1 GC patients. Survival advantage is longer when chemotherapy was used. For patients with liver metastasis, palliative gastrectomy may provide better survival than with metastasis in other organs. Otherwise, palliative gastrectomy combined with hepatic resection may improve survival.