Emil ter Veer

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.

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.

Comparing cytotoxic backbones for first-line trastuzumab-containing regimens in human epidermal growth factor receptor 2-positive advanced oesophagogastric cancer: A meta-analysis: HER2-positive advanced oesophagogastric cancer

According to the Trastuzumab for Gastric Cancer (ToGA) study, trastuzumab plus cisplatin and capecitabine/5‐fluorouracil (5‐FU) is standard first‐line treatment for human epidermal growth factor receptor 2 (HER2)‐positive advanced oesophagogastric 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 oesophagogastric 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 (HRs) 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.

S-1 with leucovorin and oxaliplatin for advanced gastric cancer

1 Hironaka S, Sugimoto N, Yamaguchi K, et al. S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; 17: 99–108. 2 Yamada Y, Higuchi K, Nishikawa K, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer. Ann Oncol 2015; 26: 141–48. 3 Longley DB, Harkin DP, Johnston PG. 5-fl uorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3: 330–38. 4 Al-Batran SE, Hartmann JT, Probst S, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fl uorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008; 26: 1435–42. 5 Thirion P, Michiels S, Pignon JP, et al. Modulation of fl uorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol 2004; 22: 3766–75. 6 Montagnani F, Turrisi G, Marinozzi C, Aliberti C, Fiorentini G. Eff ectiveness and safety of oxaliplatin compared to cisplatin for advanced, unresectable gastric cancer: a systematic review and meta-analysis. Gastric Cancer 2011; 14: 50–55. meta-analysis of 19 randomised studies of 3300 patients with advanced colorectal cancer showed a small but signifi cant increase in overall survival and the proportion of patients with a response for fluorouracil plus leucovorin compared with fluorouracil alone. However, a significant interaction between treatment benefit and fluorouracil dose was noted; tumour response and overall survival advantages in patients treated with fluorouracil plus leucovorin compared with fl uorouracil alone was restricted to trials in which a similar dose of fl uorouracil was prescribed in both groups. Second, the non-inferiority of oxaliplatin compared with cisplatin in combination with fl uoropyrimidines for treatment of advanced gastric cancer has already been shown in phase 2 and phase 3 trials and a meta-analysis. Oxaliplatin might be preferred to cisplatin because of a small increase in survival and a more favourable toxic effect profile. Furthermore, oxaliplatin has been shown to be safe and effective in combination with S-1 in advanced gastric cancer. Thus, based on the extensive evidence for fl uoropyrimidine modulation by leucovorin and the available comparative studies of oxaliplatin and cisplatin, we feel that additional evidence for a regimen with S-1 plus leucovorin and oxaliplatin compared with S-1 plus cisplatin is redundant. In view of the poor outcome of advanced gastric cancer and the low availability of resources for clinical studies, we advocate that research efforts be directed at cytotoxic or targeted treatment combinations that are expected to lead to truly new insights into the systemic treatment of this disease.

Interferon Gamma-Induced Protein (IP-10) as Potential Biomarker for Cancer-Related-Fatigue: Results from a 6-month Randomized Controlled Trial

Abstract We examined if serum concentrations Interferon gamma-induced protein (IP-10) is a potential clinical biomarker for cancer-related-fatigue (CRF). Fatigue scores and IP-10 concentrations were measured from curatively treated fatigued cancer patients randomized to either cognitive behavioral therapy (CBT, n = 26) or waiting-list (WL, n = 13). No correlation was found between baseline IP-10 level and fatigue severity and no significant differences in IP-10 serum levels were observed between fatigued and matched non-fatigued patients (n = 22). Relative changes in IP-10 concentrations from baseline to six-month follow-up were not significantly different between the CBT and WL conditions. In this study, IP-10 showed low potential as clinical CRF biomarker. Trial registration: This study is registered at ClinicalTrials.gov (NCT01096641).

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.