The use of (Network) meta-analysis in clinical oncology

Meta-analysis is important in oncological research to provide a more reliable answer to a clinical research question that was assessed in multiple studies but with inconsistent results. Pair-wise meta-analysis can be applied when comparing two treatments at once, whereas it is possible to compare multiple treatments at once with network meta-analysis (NMA). After careful systematic review of the literature and quality assessment of the identified studies, there are several assumptions in the use of meta-analysis. First, the added value of meta-analysis should be evaluated by examining the comparability of study populations. Second, the appropriate comparator in meta-analysis should be chosen according to the types of comparisons made in individual studies: (1) Experimental and comparator arms are different treatments (A vs. B); (2) Substitution of a conventional treatment by an experimental treatment (A+B vs. A+C); or (3) Addition of an experimental treatment (A+B vs. B). Ideally there is one common comparator treatment, but when there are multiple common comparators, the most efficacious comparator is preferable. Third, treatments can only be adequately pooled in meta-analysis or merged into one treatment node in NMA when considering likewise mechanism of action and similar setting in which treatment is indicated. Fourth, for both pair-wise meta-analysis and NMA, adequate assessment of heterogeneity should be performed and sub-analysis and sensitivity analysis can be applied to objectify a possible confounding factor. Network inconsistency, as statistical manifestation of violating the transitivity assumption, can best be evaluated by node-split modeling. NMA has advantages over pair-wise meta-analysis, such as clarification of inconsistent outcomes from multiple studies including multiple common comparators and indirect effect calculation of missing direct comparisons between important treatments. Also, NMA can provide increased statistical power and cross-validation of the observed treatment effect of weak connections with reasonable network connectivity and sufficient sample-sizes. However, inappropriate use of NMA can cause misleading results, and may emerge when there is low network connectivity, and therefore low statistical power. Furthermore, indirect evidence is still observational and should be interpreted with caution. NMA should therefore preferably be conducted and interpreted by both expert clinicians in the field and an experienced statistician. Finally, the use of meta-analysis can be extended to other areas, for example the identification of prognostic and predictive factors. Also, the integration of evidence from both meta-analysis and expert opinion can improve the construction of prognostic models in real-world databases

Comparing cytotoxic backbones for first-line trastuzumab-containing regimens in HER2-positive advanced esophagogastric cancer: A meta-analysis

According to the ToGA study, trastuzumab plus cisplatin and capecitabine/5-fluorouracil (5-FU) is standard first-line treatment for HER2-positive advanced esophagogastric cancer. We examined the relative efficacy and safety of alternative trastuzumab-based cytotoxic backbone regimens compared to the standard ToGA regimen using meta-analysis. We searched Medline, EMBASE, CENTRAL and ASCO and ESMO up to March 2017 for studies investigating alternative first-line trastuzumab-based regimens for HER2-positive esophagogastric cancer, defined as high protein expression IHC3+ or IHC2+ and gene amplification by in-situ-hybridisation. We compared primary outcome overall survival (OS) of alternative trastuzumab-based regimens to the ToGA regimen. Hazard ratios (HR) and 95% confidence intervals (95%CI) were calculated by extraction of the published Kaplan-Meier curves. Incidence counts and toxicity sample-sizes were extracted for adverse events and compared using single-arm proportion meta-analysis in R. Fifteen studies (N=557 patients) were included. OS was significantly longer with regimen trastuzumab plus doublet oxaliplatin and capecitabine/5-FU (median OS=20.7 months) versus ToGA (16.0 months, HR=0.75, 95%CI=0.59-0.99) and was less toxic. Trastuzumab plus doublet cisplatin and S-1 showed no OS difference versus ToGA, but showed a different toxicity profile, including less hand-foot syndrome. Trastuzumab plus cisplatin or capecitabine as singlet backbone showed significantly worse survival and more toxicity versus ToGA regimen. Trastuzumab with triplet cytotoxic backbones or with bevacizumab and doublet cytotoxic backbone showed no survival benefit and more toxicity. In conclusion, trastuzumab plus doublet cytotoxic backbone containing oxaliplatin is preferable over the ToGA regimen with cisplatin. S-1 can substitute capecitabine or 5-FU when specific toxicities are encountered. This article is protected by copyright. All rights reserve

Continuation of trastuzumab beyond progression in HER2-positive advanced esophagogastric cancer: a meta-analysis

Introduction: After progression on first-line trastuzumab-based therapy, no HER2-targeted agent is available for patients with HER2-positive esophagogastric cancer. However, continuation of trastuzumab after progression is an established strategy in HER2-positive breast cancer. We conducted a meta-analysis to investigate whether continuation of trastuzumab beyond first-line therapy in combination with chemotherapy is more effective compared to chemotherapy-alone. Methods: PubMed, EMBASE, CENTRAL and meeting abstracts from ASCO and ESMO were searched up to June 2018 for studies (any design) investigating second-line trastuzumab plus chemotherapy compared to chemotherapy-alone for patients with HER2-positive esophagogastric cancer that progressed on first-line trastuzumab-based therapy. Meta-analysis was performed on the primary outcome, overall survival (OS), and on secondary outcomes progression-free survival (PFS), objective-response rate (ORR), and adverse events. Results: Four cohort studies and one randomized controlled trial (RCT) were included with n = 200 patients who received second-line trastuzumab plus chemotherapy and n = 183 who received chemotherapy-alone. Meta-analysis showed that trastuzumab plus chemotherapy did not prolonged OS [HR = 0.72, 95% confidence interval (95% CI) = 0.47–1.08, p=.11). PFS was longer with trastzumab plus chemotherapy compared to chemotherapy-alone (HR = 0.64, 95% CI = 0.45–0.91, p<.05). There was no significant difference in ORR between the trastuzumab plus chemotherapy-group and the chemotherapy-alone group (ORR = 19.1% versus ORR = 13.4%, p=.13) and no significant differences in grade 3/4 and grade 1/2 adverse events. Conclusions: This meta-analysis showed that patients who progressed on first-line trastuzumab-based therapy but of whom trastuzumab was continued in second-line and added to chemotherapy did not show longer OS or a higher ORR compared to patients receiving second-line chemotherapy-alone. However, PFS was prolonged and trastuzumab was not associated with additional safety concerns. In absence of available second-line HER2-targeted agents, a large prospective RCT should investigate if continuation of trastuzumab might be an attractive strategy, as this meta-analysis was mostly based on non-randomized studies and a RCT with a small sample size

The efficacy and safety of S-1-based regimens in the first-line treatment of advanced gastric cancer : a systematic review and meta-analysis

BACKGROUND: S-1 is first-line therapy for advanced gastric cancer in Asia and is used with increased frequency in Western counties. We conducted a meta-analysis to investigate the efficacy and toxicity of S-1-based therapy compared with 5-fluorouracil (5-FU)/capecitabine-based therapy and S-1-based combination therapy compared with S-1 monotherapy. METHODS: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, American Society of Clinical Oncology meeting abstracts, European Society for Medical Oncology meeting abstracts and ClinicalTrials.gov were searched for randomized clinical trials until May 2015. Data were extracted for overall survival (OS), progression-free-survival (PFS), objective response rate (ORR) and grade 1-2 and grade 3-4 adverse events. Stratified OS data for subgroups were extracted. RESULTS: S-1 was not different from 5-FU (eight studies, n = 2788) in terms of OS [hazard ratio (HR) 0.93, 95 % confidence interval (CI) 0.85-1.01] and PFS (HR 0.87, 95 % CI 0.73-1.04), whereas ORR was higher (risk ratio 1.43, 95 % CI 1.05-1.96). There was no subgroup difference in efficacy among Asian and Western patients, but in Western patients S-1 was associated with a lower rate of febrile neutropenia, toxicity-related deaths and grade 3-4 stomatitis and mucositis compared with 5-FU. S-1 showed no difference in efficacy compared with capecitabine (three studies, n = 329), but was associated with a lower rate of grade 3-4 neutropenia and grade 1-2 hand-foot syndrome. S-1-combination therapy was superior to S-1 monotherapy (eight studies, n = 1808) in terms of OS (HR 0.76, 95 % CI 0.65-0.90), PFS (HR 0.68, 95 % CI 0.56-0.82) and ORR (risk ratio 1.20, 95 % CI 1.04-1.38) but was more toxic. Survival benefit of S-1 combination therapy over S-1 monotherapy was most pronounced in patients with non-measurable disease, diffuse-type histological features and peritoneal metastasis. CONCLUSIONS: S-1 is effective and tolerable as first-line therapy for advanced gastric cancer in both Asian and Western countries

Reporting of health-related quality of life in randomized controlled trials involving palliative systemic therapy for esophagogastric cancer: a systematic review

Health-related quality of life (HRQoL) assessments are increasingly incorporated into oncological randomized controlled trials (RCTs). The quality of HRQoL reporting in RCTs concerning palliative systemic treatment for advanced esophagogastric cancer is currently unknown. Therefore, we conducted a systematic review to investigate the quality of HRQoL reporting over time. PubMed, CENTRAL and EMBASE were searched for RCTs concerning systemic treatment for advanced esophagogastric cancer up to February 2017. The Minimum Standard Checklist for Evaluating HRQoL Outcomes in Cancer Clinical Trials was used to rate the quality of HRQoL reporting. Univariate and multivariate generalized linear regression analysis was used to investigate factors affecting the quality of reporting over time. In total, 37 original RCTs (N = 10,887 patients) were included. The quality of reporting was classified as 'very limited' in 4 studies (11%), 'limited' in 24 studies (65%), and 'probably robust' in 9 studies (24%). HRQoL reporting did not improve over time, and it did not improve following the publication of the CONSORT-PRO statement in 2013. The publication of HRQoL findings in a separate article and second-line treatment were associated with better reporting. HRQoL reporting in RCTs concerning palliative systemic therapy for advanced esophagogastric cancer is limited and has not improved over time. This systematic review provides specific recommendations for authors to improve HRQoL reporting: formulate hypotheses a priori, clearly describe instrument administration, and handle missing data and interpret findings appropriatel

Second- and third-line systemic therapy in patients with advanced esophagogastric cancer : a systematic review of the literature

The optimal second- and third-line chemotherapy and targeted therapy for patients with advanced esophagogastric cancer is still a matter of debate. Therefore, a literature search was carried out in Medline, EMBASE, CENTRAL, and oncology conferences until January 2016 for randomized controlled trials that compared second- or third-line therapy. We included 28 studies with 4810 patients. Second-line, single-agent taxane/irinotecan showed increased survival compared to best supportive care (BSC) (hazard ratio 0.65, 95 % confidence interval 0.53-0.79). Median survival gain ranged from 1.4 to 2.7 months among individual studies. Taxane- and irinotecan-based regimens showed equal survival benefit. Doublet chemotherapy taxane/irinotecan plus platinum and fluoropyrimidine was not different in survival, but showed increased toxicity vs. taxane/irinotecan monotherapy. Compared to BSC, second-line ramucirumab and second- or third-line everolimus and regorafenib showed limited median survival gain ranging from 1.1 to 1.4 months, and progression-free survival gain, ranging from 0.3 to 1.6 months. Third- or later-line apatinib showed increased survival benefit over BSC (HR 0.50, 0.32-0.79). Median survival gain ranged from 1.8 to 2.3 months. Compared to taxane-alone, survival was superior for second-line ramucirumab plus taxane (HR 0.81, 0.68-0.96), and olaparib plus taxane (HR 0.56, 0.35-0.87), with median survival gains of 2.2 and 4.8 months respectively. Targeted agents, either in monotherapy or combined with chemotherapy showed increased toxicity compared to BSC and chemotherapy-alone. This review indicates that, given the survival benefit in a phase III study setting, ramucirumab plus taxane is the preferred second-line treatment. Taxane or irinotecan monotherapy are alternatives, although the absolute survival benefit was limited. In third-line setting, apatinib monotherapy is preferred

Capecitabine, 5-fluorouracil and S-1 based regimens for previously untreated advanced oesophagogastric cancer: A network meta-analysis

As evidence is inconsistent and based on either isolated Asian or Western studies, we conducted a network meta-analysis (NMA) to examine efficacy and safety of 5-FU (5-fluorouracil), capecitabine and S-1-based first-line treatment of advanced esophagogastric cancer in Asian and Western patients. Medline, EMBASE, CENTRAL and conferences ASCO and ESMO were searched up to January 2016 for randomized-controlled-trials comparing 5-FU, capecitabine or S-1-based regimens with equal chemotherapy backbones. Direct and indirect data for overall survival (OS) and progression-free-survival (PFS) were combined on the Hazard Ratio (HR)-scale using random-effects NMA and calculated as combined HRs and 95% credible intervals (95% CrI). Grade 1-2 and grade 3-4 adverse events were compared with pair-wise meta-analysis. Fifteen studies were identified including capecitabine (n = 945), 5-FU (n = 2,132) or S-1 (n = 1,636). No differences were found in respectively OS and PFS for capecitabine-based versus 5-FU-based regimens (HR = 0.89, 95% CrI = 0.76-1.04 and HR = 0.98, 95% CrI = 0.75-1.32), S-1-based versus 5-FU-based regimens (HR = 0.92, 95% CrI = 0.82-1.04 and HR = 0.88, 95% CrI = 0.70-1.11) and S-1-based versus capecitabine-based regimens (HR = 1.03, 95% CrI = 0.87-1.22 and HR = 0.89, 95% CrI = 0.65-1.20). Effects were similar in Asian and Western subgroups. Toxicity profiles were different but a lower frequency of relevant adverse events was observed with S-1 In conclusion, as efficacy was similar, choosing fluoropyrimidines should be based on their individual toxicity profiles

SOURCE: A Registry-Based Prediction Model for Overall Survival in Patients with Metastatic Oesophageal or Gastric Cancer

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