Prognostic and Predictive Factors for the Curative Treatment of Esophageal and Gastric Cancer in Randomized Controlled Trials: A Systematic Review and Meta-Analysis.

BACKGROUND: An overview of promising prognostic variables and predictive subgroups concerning the curative treatment of esophageal and gastric cancer from randomized controlled trials (RCTs) is lacking. Therefore, we conducted a systematic review and meta-analysis. METHODS: PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to March 2019 for RCTs on the curative treatment of esophageal or gastric cancer with data on prognostic and/or predictive factors for overall survival. Prognostic factors were deemed potentially clinically relevant according to the following criteria; (1) statistically significant (p < 0.05) in a multivariate analysis, (2) reported in at least 250 patients, and (3) p < 0.05, in ≥ 33% of the total number of patients in RCTs reporting this factor. Predictive factors were potentially clinically-relevant if (1) the p-value for interaction between subgroups was <0.20 and (2) the hazard ratio in one of the subgroups was significant (p < 0.05). RESULTS: For gastric cancer, 39 RCTs were identified (n = 13,530 patients) and, for esophageal cancer, 33 RCTs were identified (n = 8618 patients). In total, we identified 23 potentially clinically relevant prognostic factors for gastric cancer and 16 for esophageal cancer. There were 15 potentially clinically relevant predictive factors for gastric cancer and 10 for esophageal cancer. CONCLUSION: The identified prognostic and predictive factors can be included and analyzed in future RCTs and be of guidance for nomograms. Further validation should be performed in large patient cohorts.

The Efficacy and Safety of (Neo)Adjuvant Therapy for Gastric Cancer: A Network Meta-analysis.

Background: Alternatives in treatment-strategies exist for resectable gastric cancer. Our aims were: (1) to assess the benefit of perioperative, neoadjuvant and adjuvant treatment-strategies and (2) to determine the optimal adjuvant regimen for gastric cancer treated with curative intent. Methods: PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to August 2017 for randomized-controlled-trials on the curative treatment of resectable gastric cancer. We performed two network-meta-analyses (NMA). NMA-1 compared perioperative, neoadjuvant and adjuvant strategies only if there was a direct comparison. NMA-2 compared different adjuvant chemo(radio)therapy regimens, after curative resection. Overall-survival (OS) and disease-free-survival (DFS) were analyzed using random-effects NMA on the hazard ratio (HR)-scale and calculated as combined HRs and 95% credible intervals (95% CrIs). Results: NMA-1 consisted of 9 direct comparisons between strategies for OS (14 studies, n = 4187 patients). NMA-2 consisted of 16 direct comparisons between adjuvant chemotherapy/chemoradiotherapy regimens for OS (37 studies, n = 10,761) and 14 for DFS (30 studies, n = 9714 patients). Compared to taxane-based-perioperative-chemotherapy, surgery-alone (HR = 0.58, 95% CrI = 0.38⁻0.91) and perioperative-chemotherapy regimens without a taxane (HR = 0.79, 95% CrI = 0.58⁻1.15) were inferior in OS. After curative-resection, the doublet oxaliplatin-fluoropyrimidine (for one-year) was the most efficacious adjuvant regimen in OS (HR = 0.47, 95% CrI = 0.28⁻0.80). Conclusions: For resectable gastric cancer, (1) taxane-based perioperative-chemotherapy was the most promising treatment strategy; and (2) adjuvant oxaliplatin-fluoropyrimidine was the most promising regimen after curative resection. More research is warranted to confirm or reproach these findings.

Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease.

Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.

The Efficacy and Safety of First-line Chemotherapy in Advanced Esophagogastric Cancer: A Network Meta-analysis.

BACKGROUND: A globally accepted standard first-line chemotherapy regimen in advanced esophagogastric cancer (AEGC) is not clearly established. We conducted a systematic review to investigate the efficacy and safety of first-line chemotherapy using Network meta-analysis (NMA). METHODS: Medline, EMBASE, CENTRAL, and conferences were searched until June 2015 for randomized controlled trials that compared regimens containing: fluoropyrimidine (F), platinum (cisplatin [C] and oxaliplatin [Ox]), taxane (T), anthracycline (A), irinotecan (I), or methotrexate (M). Direct and indirect evidence for overall survival (OS) and progression-free-survival (PFS) were combined using random-effects NMA on the hazard ratio (HR) scale and calculated as combined hazard ratios and 95% credible intervals (CrIs). RESULTS: The NMA incorporated 17 chemotherapy regimens with 37 direct comparisons between regimens for OS (50 studies, n = 10 249) and 29 direct comparisons for PFS (34 studies, n = 7795). Combining direct and indirect effects showed increased efficacy for fluoropyrimidine noncisplatin doublets (F-doublets) over cisplatin doublets (C-doublets): FI vs CF (combined HR = 0.85, 95% CrI = 0.71 to 0.99), FOx vs CF (combined HR = 0.83, 95% CrI = 0.71 to 0.98) in OS and FOx vs CF (combined HR = 0.82, 95% CrI = 0.66 to 0.99) in PFS. Anthracycline-containing triplets (A-triplets: ACF, AFOx, AFM) and TCF triplet showed no benefit over F-doublets in OS and PFS. The triplet FOxT showed increased PFS vs F-doublets FT (combined HR = 0.61, 95% CrI = 0.38 to 0.99), FI (combined HR = 0.62, 95% CrI = 0.38 to 0.99), and FOx (combined HR = 0.67, 95% CrI = 0.44 to 0.99). Increased grade 3 to 4 toxicity was found for CF vs F-doublets, for ACF vs FI for TCF vs CF, and for FOxT vs FOx. CONCLUSIONS: Based on efficacy and toxicity, F-doublets FOx, FI, and FT are preferred as first-line treatment for AEGC compared with C-doublets, A-triplets, and TCF. FOxT is the most promising triplet.

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.