c-Met overexpression has been observed in renal cell carcinoma (RCC). However, its clinicopathological impacts remain uncertain. We performed this meta-analysis to evaluate the pathologic and prognostic impacts of high c-Met expression in patients with RCC. A systematic computerized search of the electronic databases PubMed and Embase was performed. From 12 studies, 1,724 patients with RCC were included in the meta-analysis. Compared with RCCs showing low c-Met expression, tumors with high c-Met expression showed significantly higher nuclear grade (odds ratio = 2.45 [95% CI: 1.43-4.19], P = 0.001) and pT stage (odds ratio = 2.18 [95% CI: 1.27-3.72], P = 0.005). In addition, patients with c-Met-high RCC showed significantly worse overall survival than those with c-Met-low tumor (hazard ratio = 1.32 [95% CI: 1.12-1.56], P = 0.0009). In conclusion, this meta-analysis demonstrates that high c-Met expression correlate with significantly worse pathological features and overall survival, indicating c-Met overexpression is a potential adverse prognostic marker for patients with RCC.

The role of anti-epidermal growth factor receptor (EGFR) therapy is controversial in patients with esophago-gastric adenocarcinoma. We performed this meta-analysis to evaluate whether the addition of an anti-EGFR agent to chemotherapy can produce survival benefits in patients with advanced esophageal adenocarcinoma, gastric adenocarcinoma, or gastroesophageal junction adenocarcinoma. Electronic databases were searched for eligible randomized studies. From six studies, 1,817 patients were included in the meta-analysis of hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS). Compared with chemotherapy alone, anti-EGFR agents in combination with chemotherapy were significantly associated with shorter PFS (HR = 1.14 [95% confidence interval {CI}, 1.01-1.28], P = 0.03). In terms of OS, the addition of an anti-EGFR agent to chemotherapy showed no advantage (HR = 1.10 [95% CI, 0.98-1.23], P = 0.11). In addition, the combination of an anti-EGFR agent with chemotherapy significantly increased some grade 3/4 toxicities including diarrhea (risk ratio {RR} = 1.42, [95% CI, 1.03-1.94], P = 0.03), mucositis (RR = 3.30 [95% CI, 1.54-7.07], P = 0.002), and skin rash (RR = 6.82 [95% CI, 3.15-14.78], P < 0.00001). In conclusion, this meta-analysis indicates that the addition of an anti-EGFR agent to chemotherapy conveys no additional benefit for patients with advanced esophago-gastric adenocarcinoma. As of now, anti-EGFR agents should not be used in the first-line treatment of adenocarcinoma of the upper gastrointestinal tract.

The overexpression of c-Met protein has been detected in pancreatic adenocarcinoma (PAC). However, its prognostic impact remains unclear. We performed this meta-analysis to evaluate the prognostic value of c-Met overexpression in PAC. A systematic computerized search of the electronic databases such as PubMed, Embase, and Google Scholar was carried out. From 5 studies, 423 patients who underwent surgical resection for PAC were included in the meta-analysis. Compared with patients with PAC showing low c-Met expression, patients with c-Met-high tumor had significantly worse disease-free survival (hazard ratio = 1.94 [95% confidence interval, 1.46-2.56], P = 0.00001) and overall survival (hazard ratio = 1.86 [95% confidence interval, 1.19-2.91], P = 0.006). In conclusion, this meta-analysis demonstrates that c-Met overexpression is a significant prognostic marker for poor survival in patients who underwent surgical resection for PAC.

The overexpression of c-Met protein has been detected in hepatocellular carcinoma (HCC). However, its prognostic impact remains uncertain. We performed this meta-analysis to evaluate the prognostic value of c-Met overexpression in patients who underwent curative surgical resection for HCC. A systematic computerized search of the electronic databases was carried out. From 5 studies, 1,408 patients who underwent surgical resection for HCC were included in the meta-analysis. Compared with patients with HCC having low c-Met expression, patients with c-Met-high tumor showed significantly worse relapse-free survival (hazard ratio = 1.26 [95% confidence interval, 1.02-1.56], P = 0.03) and overall survival (hazard ratio = 1.16 [95% confidence interval, 1.03-1.31], P = 0.01). In conclusion, our meta-analysis indicates that c-Met overexpression is a significant adverse prognostic factor for recurrence and survival in patients who underwent surgical resection for HCC.

High c-Met expression has been observed in head and neck squamous cell carcinoma (HNSCC). However, its clinicopathological impact remains controversial. We performed this meta-analysis to evaluate the pathologic and prognostic impacts of c-Met overexpression in patients with HNSCC. A systematic computerized search of the electronic databases was carried out. From 16 studies, 1,948 patients with HNSCC were included in the meta-analysis. Compared with HNSCCs showing low c-Met expression, tumors with high c-Met expression were significantly associated with higher rate of lymph node metastasis (odds ratio = 3.26, 95% CI: 2.27-4.69, P < 0.00001) and higher T stage (odds ratio = 1.33, 95% CI: 1.03-1.71, P = 0.03). In addition, patients with c-Met-high HNSCC showed significantly worse disease-free survival (hazard ratio = 1.49, 95% CI: 1.04-2.14, P = 0.03) and overall survival (hazard ratio = 1.83, 95% CI: 1.29-2.60, P = 0.0007) than those with c-Met-low tumor. In conclusion, this meta-analysis demonstrates that high c-Met expression is significantly associated with worse pathological features and prognosis, indicating c-Met overexpression is an adverse prognostic marker for patients with HNSCC.

There is a debate as to whether anti-angiogenic molecular agents can produce survival benefits in patients with previously treated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). We performed this meta-analysis of randomized trials to evaluate the survival outcomes of an anti-angiogenic agent versus placebo in the salvage treatment of advanced GC or GEJC. Electronic databases were searched for eligible studies. From the four studies, 910 patients with previously treated advanced GC or GEJC were included in the meta-analysis. Compared with placebo, anti-angiogenic targeted agents significantly improved progression-free survival (hazard ratio = 0.37 [95% confidence interval, 0.26-0.53], P < 0.00001). In terms of overall survival, anti-angiogenic agents induced 36% reduction in the risk for death (hazard ratio = 0.64 [95% confidence interval, 0.48-0.86], P = 0.002). In conclusion, this meta-analysis demonstrates that anti-angiogenic agents can prolong survival in patients with previously treated advanced GC or GEJC. This finding suggests that anti-angiogenic therapy can be a considerable option in patients who are not candidates for further chemotherapy.

Immune checkpoint inhibitors (ICIs) have been approved for patients with advanced non-small-cell lung cancer (NSCLC), regardless of histology. However, histologic subtypes of NSCLC may influence treatment outcomes of ICIs. We conducted this meta-analysis to investigate if there is difference in survival benefits of ICIs between squamous (SQ) and non-squamous (non-SQ) NSCLC. We searched PubMed, MEDLINE, EMBASE and ESMO databases. We included randomized controlled trials with the data of survival outcomes in advanced NSCLC patients treated with ICIs. From 7 eligible studies, 998 patients with SQ NSCLC and 2,769 with non-SQ NSCLC were included in the meta-analysis. ICIs improved progression-free survival (PFS) significantly in patients with SQ NSCLC (HR = 0.68 [95% confidence interval (CI), 0.51-0.91], P = 0.01), compared to chemotherapy. For patients with non-SQ NSCLC, however, ICIs were not associated with significant improvement of PFS (HR = 0.88 [95% CI, 0.67-1.16], P = 0.37). In terms of overall survival (OS), ICIs prolonged OS significantly in both SQ (HR = 0.71 [95% CI, 0.60-0.83], P < 0.0001) and non-SQ NSCLC (HR = 0.77 [95% CI, 0.63-0.94], P = 0.01). In conclusion, this meta-analysis indicates that ICIs significantly prolong OS in both SQ and non-SQ NSCLC.

Bevacizumab has shown survival benefits when added to chemotherapy in patients with metastatic colon cancer (mCRC). However, the efficacy of bevacizumab may depend on the accompanying chemotherapeutic regimen. We performed this meta-analysis to examine the impact of the choice of chemotherapy regimen on the survival benefits of bevacizumab in the first-line treatment for patients with mCRC. Electric databases were searched for eligible randomized trials. From 9 studies, 3,710 patients with mCRC were included in the meta-analysis of hazard ratios (HRs) for progression-free survival (PFS) or overall survival (OS). Compared with chemotherapy alone, the addition of bevacizumab to chemotherapy significantly prolonged PFS (HR = 0.66 [95% confidence interval (CI), 0.55-0.77], P < 0.0001) and OS (HR = 0.84 [95% CI, 0.77-0.92], P = 0.0001). In the subgroup analysis according to the chemotherapeutic regimens, bevacizumab showed both PFS (HR = 0.57 [95% CI, 0.41-0.77], P = 0.0004) and OS (HR = 0.79 [95% CI, 0.67-0.93], P = 0.004) advantages only in combination with irinotecan-based regimen. In conclusion, this meta-analysis confirms that the addition of bevacizumab to chemotherapy significantly prolongs PFS and OS in the first-line treatment for mCRC. The subgroup analyses suggest that irinotecan-based regimen may be a better partner of bevacizumab in terms of both PFS and OS.

Immune checkpoint inhibitors (ICIs) have emerged as a new treatment option for patients with advanced non-small-cell lung cancer (NSCLC). Some studies with ICIs in NSCLC suggested that smoking history was associated with improved survival outcomes. We conducted this meta-analysis to investigate if survival benefits of ICIs in patients with advanced NSCLC are different according to smoking status. Electronic databases were searched for eligible studies. We included randomized controlled trials with the data of survival outcomes and extracted progression-free survival (PFS) or overall survival (OS) stratified by smoking status. From 6 studies, 2,389 ever-smokers and 413 never-smokers were included in the meta-analysis. In first-line treatment setting, ICIs tended to improve PFS in patients with smoking history (HR = 0.85 [95% CI, 0.71-1.10], P = 0.07). For never-smokers with advanced NSCLC, chemotherapy, not ICIs, was significantly associated with improvement of PFS (HR = 2.30 [95% CI, 1.23-4.28], P = 0.009). In more than second-line setting, ICIs significantly prolonged OS over that with chemotherapy in ever-smokers (HR = 0.70 [95% CI, 0.63-0.79], P < 0.00001). For never-smokers with NSCLC, however, ICIs failed to significantly improve OS (HR = 0.79 [95% CI, 0.59-1.06], P = 0.12). In conclusion, this meta-analysis indicates that ICIs can prolong survival over that with chemotherapy in ever-smokers with advanced NSCLC. However, ICIs failed to improve survival in never-smokers. These results suggest that smoking status may be a predictive marker for survival benefits to ICIs.

It is unclear whether targeted agents can produce survival advantage in patients with advanced HCC previously treated with sorafenib. We performed this meta-analysis of randomized trials and reviewed clinical outcomes of molecular targeted agents in the second-line treatment for advanced HCC. A systematic computerized search of the electronic databases PubMed, Embase, Google Scholar, and Cochrane Library (up to May 2017) was carried out. From six studies, 2,388 patients were included in the meta-analysis. Almost all patients were treated with sorafenib as first-line therapy. Compared with placebo, targeted agents significantly improved time-to-progression (hazard ratio = 0.62, 95% confidence interval: 0.49-0.78, P < 0.0001). In terms of overall survival, targeted therapy tended to improve prognosis (hazard ratio = 0.86, 95% confidence interval: 0.74-1.01, P = 0.06). In conclusion, this meta-analysis indicates that molecular targeted agents have a potential to improve prognosis after failure of first-line treatment with sorafenib in patients with advanced HCC.

The alterations of MET have been detected in non-small-cell lung cancer (NSCLC). However, survival benefit of MET inhibitors remains controversial. We performed this meta-analysis to evaluate the survival benefit of MET inhibitors combined with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) or standard chemotherapy in patients with advanced or metastatic NSCLC. A systematic computerized search of the electronic databases was carried out. From seven studies, 2,577 patients were included in the meta-analysis. Compared with patients in the placebo group, patients who received an additional MET inhibitor did not show significantly improved progression-free survival (hazard ration (HR) = 0.92 [95% confidence interval (CI): 0.79-1.08], P = 0.33) and overall survival (HR = 1.0 [95% CI: 0.90-1.11], P = 0.97). In the subgroup analysis, patients with MET-high NSCLC tended to show longer survival when treated with an additional MET inhibitor than those in the placebo group (HR = 0.76, [95% CI: 0.58-1.01], P = 0.06). In conclusion, this meta-analysis indicates that the addition of a MET inhibitor to an EGFR TKI or chemotherapy has no survival benefit over placebo in patients with advanced or metastatic NSCLC. Although patients with MET-high tumor tended to show better survival, further studies to explore more specific biomarkers are warranted to identify ideal candidates for MET inhibitors in NSCLC.

There has been a debate over whether the addition of anti-epidermal growth factor receptor (EGFR) agents to the conventional treatments has beneficial effects in patients with head and neck squamous cell carcinoma (HNSCC). This meta-analysis was performed to investigate the role of anti-EGFR agents in patients with locoregionally advanced HNSCC (LA-HNSCC). A systematic search of the electronic databases was carried out. From eight randomized controlled trials, 2,263 patients were included in the meta-analysis. Compared with chemoradiotherapy (CRT), the addition of an EGFR inhibitor to radiotherapy (RT) or CRT did not improve locoregional control (hazard ratio (HR) = 1.19 [95% confidence interval (CI): 0.99-1.42], P = 0.06), progression-free survival (HR = 1.07 [95% CI: 0.92-1.24], P = 0.37), and overall survival (HR = 1.04 [95% CI, 0.88-1.23], P = 0.65) in patients with LA-HNSCC. Moreover, the addition of anti-EGFR agents increased the risk of skin toxicities (odds ratio = 4.04 [95% CI: 2.51-6.48], P < 0.00001) and mucositis (odds ratio = 1.58 [95% CI: 0.99-2.52], P = 0.06). In conclusion, this meta-analysis indicates that the addition of an anti-EGFR agent to RT or CRT do not improve clinical outcomes compared with CRT in patients with LA-HNSCC. Except for patients with coexisting medical conditions or decreased performance status, concurrent CRT should remain the standard of care for patients with LA-HNSCC.