Efficacy and safety of taxane-based systemic chemotherapy of advanced gastric cancer: A systematic review and meta-analysis

Taxanes are chemotherapeutic agents commonly used to treat several cancers. However, the effects of taxanes on advanced gastric cancer (AGC) are still not clear, especially when used as a first-line treatment. This systematic review and meta-analysis aims to investigate the efficacy and safety of taxanes as a first-line treatment of AGC. The quality of our included studies was assessed using the Cochrane risk of bias tool for RCTs and NOS scale for nRCTs, and the data of the included studies was of satisfactory quality to analyze. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicity. Taxanes significantly improved OS (HR = 0.84, 95% CI 0.76–0.92, P = 0.0004) and had a slight effect on ORR (RR = 1.23, 95% CI 1.00–1.51, P = 0.05). However, taxanes may also increase the risks of neutropenia and leucopenia, similar to effects observed in other conventional chemotherapeutic treatments such as oxaliplatin and epirubicin. Therefore, patient characteristics including concomitant diseases, physical condition, and prior therapies should be considered before selecting taxane-based treatments for AGC.


Results
Search results. We identified 1692 studies from a database search, and 1654 of these were excluded after reviewing the titles and abstracts. Ultimately, 11 studies met the inclusion criteria ( Fig. 1), including 6 randomized controlled trials (RCTs) and 5 non-randomized controlled trials (nRCTs) [22][23][24][25][26][27][28][29][30][31][32] . These trials included a total of 1932 patients, with 969 in the taxane group and 963 in the control group. All patients were diagnosed with AGC, specifically with unresectable local AGC, recurrent GC, or metastatic GC. We obtained data on patients' history of gastrectomy from four studies and found that approximately 29.4% patients in the taxane group and 27.2% patients in the control group had undergone gastrectomy. All 11 studies investigated the first-line treatment options for AGC. Detailed characteristics are shown in Table 1. The quality of the studies was assessed using the Cochrane risk of bias tool for RCTs and NOS scale for nRCTs, showing that the data was of satisfactory quality to analyze ( Fig. 2 Table S1). The quality of the evidence regarding overall survival, progression-free survival, and overall response rate were also evaluated following the GRADE approach and using GRADEpro software (Supplementary Table S2) 33 . Publication bias was observed by performing a funnel plot on ORR (Supplementary Figure S1). Since this test showed signs of bias, we conducted quantitative assessment using Begg's (p = 0.64) and Egger's (p = 0.20) tests using Stata software. The trim and fill analysis was also used for testing and adjusting for publication bias in our meta-analysis 34 . We observed that the logRR value (0.166, 95% CI 0.03-0.301, P = 0.017) was similar to the results after trim and fill analysis (0.152, 95% CI 0.018-0.286, P = 0.027), indicating that the results of our study were stable (Supplementary Figure S2). Based on these qualitative results of publication bias, we concluded that the slight publication bias did not affect our overall results.

and Supplementary
Overall survival. We extracted OS data from 10 studies (Roth et al. 31 did not analyze OS), including 928 patients in the taxane group and 923 patients in the control group. The results indicated an advantage of taxanes as first-line systemic chemotherapeutic agents for AGC patients compared with other agents (Fig. 3a). The Hazard Ratio (HR) was 0.84 (95% CI 0.76-0.92, P = 0.0004, I 2 = 0%). We performed a subgroup analysis comparing the different chemotherapy regiments and found that adding a taxane to known chemotherapy regimens had a moderate beneficial effect on OS. The HR was 0.81 (95% CI 0.72-0.91, p = 0.0004, I 2 = 0%, Fig. 3b). In the comparison between taxane-based chemotherapy and platinum-based chemotherapy, taxane-based chemotherapy trended toward a slight benefit over the platinum-based chemotherapy, but without statistical significance (HR = 0.92, 95% CI 0.73-1.16, p = 0.47, I 2 = 0%). We also performed a subgroup analysis between the study types. When grouped separately, the RCTs (HR = 0.81, 95% CI 0.72-0.92, p = 0.0007, I 2 = 0%) and the nRCTs (HR = 0.89, 95% CI 0.75-1.06, p = 0.18, I 2 = 0%) both showed a benefit when using a taxane, though the result in the nRCT group was not statistically significant (Fig. 3c). We then extracted the median length of the overall survival from the 11 studies and found that 9 of the 11 showed a longer median length of overall survival with a taxane (Supplementary  Table S3), further suggesting a benefit of treating with a taxane.
Progression-free survival. A total of 1487 patients from nine studies were included in the analysis of PFS.
Safety. We analyzed the grade 3 and grade 4 toxicities of these studies. The most common hematological toxicities were neutropenia, leucopenia, anemia, and thrombocytopenia. The most common non-hematological toxicities included nausea, vomiting, diarrhea, febrile neutropenia, anorexia, and neuropathy. Taxane-based chemotherapy increased the risk of developing neutropenia and leucopenia when compared to the control group (Table 2). While the risk of developing thrombocytopenia decreased in comparison to control, it was not statistically significant. Compared to platinum-based or epirubicin-based chemotherapy, taxane-based chemotherapy showed no significant advantage or disadvantage in terms of safety. Detailed results are shown in Table 3.  36 . First-line chemotherapy regimens that include a taxane might be good candidates for the combined treatment of AGC 37 . However, the results of a meta-analysis comparing taxane-based

Author
Year Type chemotherapy and ECF indicated no benefits of taxanes 38 . Therefore, we aimed to investigate the effect of adding a taxane to known chemotherapy regimens for systemic chemotherapy for AGC. It has been demonstrated that taxane-based chemotherapy is effective against several types of tumors. In this respect, Tian et al. found that the use of a taxane improved short-term local control in Chinese patients with locally advanced nasopharyngeal carcinoma 39 . Moreover, it has been reported that taxanes were beneficial for locally advanced squamous cell carcinomas of the head and neck (SCCHN) and advanced non-small cell lung cancer [40][41][42] .
We concluded that taxanes significantly improved survival and OS (HR = 0.84, p = 0.0004) compared with the control group in patients with AGC. Moreover, taxanes also have a slight effect on ORR (RR = 1.23, 95% CI 1.00-1.51, p = 0.05), although these effects are not statistically significant. The significant improvement in ORR suggests that patients may be more sensitive to taxane-based treatments. However, the safety-risk analysis uncovered negative effects, indicating that taxanes significantly increased the risk of developing neutropenia and leucopenia.
We performed a subgroup analysis to further the investigation, comparing data from the six RCTs and five nRCTs separately. The RCTs reported that taxanes significantly improved OS, which is similar to the results above. Furthermore, taxanes improved the ORR compared to the control group, suggesting that patients are more responsive to taxane-based treatments than control treatments. The results of the analysis of the RCTs indicated that taxanes increased the risk of developing febrile neutropenia and neuropathy. This result was different from that obtained for the nRCTs, which may be due to the small sample size.
Further subgroup analyses were subsequently performed. One subgroup analysis compared the effect of adding taxanes into known chemotherapy regimens. The results indicated that adding taxanes significantly improved OS, ORR, and PFS, demonstrating that the incorporation of taxanes improved the systemic chemotherapeutic treatment of AGC patients. Another two subgroup analyses evaluated the effects of platinum-or epirubicin-based chemotherapy regimens with taxane-based chemotherapy. Taxane-based chemotherapy did not improve OS, PFS, or ORR when compared with platinum-based chemotherapy, a result which was also observed by Mao et al. 43 . Likewise, Roberto P et al. found that docetaxel and epirubicin-based chemotherapeutic regimens had similar effects on metastatic gastric cancer 38 . Thus, adding a taxane to known chemotherapy regimens improved the systemic chemotherapeutical treatment of AGC patients, but taxane-based chemotherapy did not have any advantage compared to the platinum-or epirubicin-based chemotherapies. With regard to toxicity, we found that the inclusion of a taxane increased the risk of neutropenia and leucopenia compared with the original chemotherapy regimens. Alternately, the inclusion of a taxane seemed to decrease the risk of thrombocytopena, but was not statistically significant.
The results of the comparison between single and combined treatment for AGC were similar to those of other studies. Bittoni et al. found that first-line triple therapy might be superior to dual therapy for the treatment of AGC patients regarding the ORR and PFS 44 . Mohammad et al. also found that first-line triple chemotherapy may be superior to a dual regimen in the treatment of advanced esophagogastric cancer patients 45 . These two studies also found that the triple therapy regimens increased the risk of toxicity, similar to our results. Conversely, Sun et al. reported that single-agent treatment should be chosen as the first-line palliative chemotherapy option for older patients with GC 46 . Therefore, the inclusion of a taxane in systemic chemotherapeutic treatments for AGC could improve the therapeutic effect; however, the benefits should be weighed against the risks of treatment-related toxicity. Similar to the survival analysis results, we did not find significant improvements in safety by replacing the drugs in known chemotherapy regimens with a taxane. However, each drug has unique characteristics. For example, compared with platinum-based chemotherapy, taxane-based chemotherapy increased the risk of neutropenia, leukopenia, and diarrhea but decreased the risk of neuropathy, nausea, and vomiting (Table 3). This result was similar to that of Mao et al. 43 . Moreover, taxane-based chemotherapy significantly increased the risk of developing neutropenia but decreased the risk of developing thrombocytopenia compared with epirubicin-based chemotherapy (Table 3). Therefore, replacing chemotherapeutic drugs with a taxane did not significantly decrease the net overall risk of toxicity. For this reason, systemic chemotherapeutic regimens should be chosen according to the patients' health status and drug characteristics. Further studies should evaluate better combinations of chemotherapeutic drugs. In addition, the effects of newly emerging antineoplastic drugs and their correlation with traditional chemotherapeutic drugs, such as targeted therapies and Chinese medicine 47 , should also be investigated. Our systematic review and meta-analysis has some limitations. First, the variance in the control group was not uniform due to the limited number of studies that evaluated the use of a taxane alone. Therefore, the heterogeneity might be higher than what was reported herein. Second, some subgroup analyses could not be done due to the limited number of studies, and some of our analyses included only two studies, which might decrease the stringency of the meta-analysis. Third, the quality of the included studies (both RCTs and nRCTs) was poor. Therefore, more high-quality RCTs should be conducted to elucidate the role of taxane in the treatment of AGC.

Conclusions
The addition of taxane to current first-line treatment options for AGC can improve OS, PFS, and ORR; however, these treatments concomitantly increase the risk of toxicity. The effect of taxane is similar to that of conventional drugs such as oxaliplatin and epirubicin in known chemotherapy regimens. Therefore, other patient characteristics, including concomitant diseases, physical condition, and prior therapies, should be considered before choosing taxane.

Methods
Study selection. We searched the PubMed, EMBASE, and the Cochrane Library databases for citations published before February 2016. The keywords searched included "taxane", "taxol", "paclitaxel", "docetaxel", "gastric cancer", and "gastric carcinoma". The full search strategy is shown in the Supplementary Materials. Different search strategies were conducted for different databases, and the references of the included studies were also searched.
Date extraction and outcomes. The primary outcomes of our study were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). ORR was defined as the sum of both partial and complete responses. We also included grade 3 and grade 4 adverse events as safety outcomes. Two investigators (Jinxin Shi and Peng Gao) extracted the data from the full articles independently. Any disagreements were resolved by a third investigator.
Eligibility criteria. Eligibility criteria included (1) studies that were published in English; (2) patients were diagnosed with AGC; (3) studies that evaluated at least one of the three primary outcomes; (4) studies that compared taxane-based therapy with other agent-based therapies as chemotherapy regimens; (5) studies that evaluated first-line chemotherapeutic agents; and (6) in cases of duplicates, the most recent and higher-quality study was included. We excluded case reports, review articles, and letters. The studies were excluded in cases in which none of the outcomes (OS, PFS, ORR, or safety) were provided or could not be calculated, and in cases in which the classification of the chemotherapeutic agents was not provided. Two reviewers (Jinxin Shi and Peng Gao) evaluated the studies independently. The PRISMA 2009 checklist was used as a guideline for reporting the findings for included studies 48 .  Quality assessment. The quality of the articles were assessed by two researchers independently using the Cochrane risk of bias tool for RCTs and NOS scale for nRCTs 49 . The quality of the evidence used for calculating OS, PFS and ORR was also evaluated using GRADEpro software.
Statistical analysis. The meta-analysis was performed using Review Manager Software version 5.2 (Cochrane Collaboration). The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of OS and PFS were calculated using the log HR and standard error in Review Manager Software version 5.2 (Cochrane Collaboration) following the method of Tierney 50 . ORR and safety were analyzed by calculating the risk ratio (RR). The random-effects model was selected prior to analysis because it provides more conservative estimates and is tailored to multicenter studies in which heterogeneity is usually present 51 . The p-values less than 0.05 were considered significant. The Begg's and Egger's tests were performed using Stata software version 12.0.