Explore the vast range of titles available.

In preclinical work and retrospective population studies, the anti-diabetic drug metformin has been associated with antineoplastic activity and decreased burden of many cancers, including pancreatic cancer. There is therefore interest in the hypothesis that this drug might be repurposed for indications in oncology. We aimed to assess the efficacy of the addition of metformin to a standard systemic therapy in patients with advanced pancreatic cancer, and provide the first report of a clinical trial with a survival endpoint of metformin for an oncological indication. We did this double-blind, randomised, placebo-controlled phase 2 trial at four centres in the Netherlands. Patients aged 18 years or older with advanced pancreatic cancer were randomly assigned (1:1), via a permutated computer-generated block allocation scheme (block size of six) to receive intravenous gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks and oral erlotinib (100mg) once daily in combination with either oral metformin or placebo twice daily. Metformin dose was escalated from 500 mg (in the first week) to 1000 mg twice daily in the second week. Randomisation was stratified by hospital, diabetes status, and tumour stage. The primary endpoint was overall survival at 6 months in the intention-to-treat population. This trial is complete and is registered with ClinicalTrials.gov, number NCT01210911. Between May 31, 2010, and Jan 3, 2014, we randomly assigned 121 patients to receive gemcitabine and erlotinib with either placebo (n=61) or metformin (n=60). Overall survival at 6 months was 63·9% (95% CI 51·9–75·9) in the placebo group and 56·7% (44·1–69·2) in the metformin group (p=0·41). There was no difference in overall survival between groups (median 7·6 months [95% CI 6·1–9·1] vs 6·8 months [95% CI 5·1–8·5] in the metformin group; hazard ratio [HR] 1·056 [95% CI 0·72–1·55]; log-rank p=0·78). The most frequent grade 3–4 toxic effects were neutropenia (15 [25%] patients in placebo group vs 15 [25%] in metformin group), skin rash (six [10%] vs four [7%]), diarrhoea (three [5%] vs six [10%]), and fatigue (two [3%] vs six [10%]). Addition of a conventional anti-diabetic dose of metformin does not improve outcome in patients with advanced pancreatic cancer treated with gemcitabine and erlotinib. Future research should include studies of more potent biguanides, and should focus on patients with hyperinsulinaemia and patients with tumours showing markers of sensitivity to energetic stress, such as loss of function of AMP kinase, a key regulator of cellular energy homoeostasis. Academic Medical Centre, Amsterdam, and The Terry Fox Foundation, Vancouver, Canada.

Background Previous studies demonstrated better outcomes for mCRPC (metastatic castration resistant prostate cancer) patients with higher abiraterone exposure (minimal plasma concentration (C min ) > 8.4 ng/mL), but around 40% of patients experience exposure below this target. Pharmacokinetic (PK)-guided interventions following Therapeutic Drug Monitoring (TDM) could optimise exposure and outcomes. We aimed to evaluate the feasibility and effect on treatment outcomes of abiraterone TDM. Methods Patients with low exposure levels (Low-group, C min  < 8.4 ng/mL) got a PK-guided intervention. We compared exposure, adverse event (AE) incidence, time on treatment (ToT) and Prostate-Specific Antigen response rate (PSArr) between the Low-group and Adequate-group. Results We included 167 mCRPC patients, with 56 in the Adequate-group and 111 in the Low-group. Interventions were successful 86% of the time. Exposure between groups became corresponding (Low-group: 7.95 to 20.5 ng/mL, Adequate-group: 20.8 ng/mL, p  = 0.72) with comparable AE incidence (17% vs. 23%, p  = 0.4). Median ToT and PSArr were similar (351 vs. 379 days, p  = 0.35; 61.3% vs. 67.9%, p  = 0.51). Conclusions PK-guided interventions improved above target exposure from 33.5% to 81.4% of patients without additional AEs. While historically, low exposure patients had significantly shorter survival, PK-guided interventions eliminated this disparity. As interventions are effective, low-cost and safe, TDM for abiraterone should be considered to enhance treatment outcomes.

Previous studies demonstrated better outcomes for mCRPC (metastatic castration resistant prostate cancer) patients with higher abiraterone exposure (minimal plasma concentration (C ) > 8.4 ng/mL), but around 40% of patients experience exposure below this target. Pharmacokinetic (PK)-guided interventions following Therapeutic Drug Monitoring (TDM) could optimise exposure and outcomes. We aimed to evaluate the feasibility and effect on treatment outcomes of abiraterone TDM. Patients with low exposure levels (Low-group, C  < 8.4 ng/mL) got a PK-guided intervention. We compared exposure, adverse event (AE) incidence, time on treatment (ToT) and Prostate-Specific Antigen response rate (PSArr) between the Low-group and Adequate-group. We included 167 mCRPC patients, with 56 in the Adequate-group and 111 in the Low-group. Interventions were successful 86% of the time. Exposure between groups became corresponding (Low-group: 7.95 to 20.5 ng/mL, Adequate-group: 20.8 ng/mL, p = 0.72) with comparable AE incidence (17% vs. 23%, p = 0.4). Median ToT and PSArr were similar (351 vs. 379 days, p = 0.35; 61.3% vs. 67.9%, p = 0.51). PK-guided interventions improved above target exposure from 33.5% to 81.4% of patients without additional AEs. While historically, low exposure patients had significantly shorter survival, PK-guided interventions eliminated this disparity. As interventions are effective, low-cost and safe, TDM for abiraterone should be considered to enhance treatment outcomes.

Summary Background Improvements in knowledge of molecular mechanisms in cancer are the basis for new studies combining chemotherapy with targeted drugs. Inhibition of the epidermal growth factor receptor (EGFR) by erlotinib or cetuximab has limited or no activity, respectively, in pancreatic cancer. The crosstalk between EGFR and mammalian target of rapamycin (mTOR) pathways is a potential mechanism of resistance; therefore we conducted a study to explore safety and efficacy of multiple pathway inhibition by cetuximab and everolimus in combination with capecitabine. Methods Safety and efficacy of fixed standard dose cetuximab in combination with various dose levels of everolimus (5–10 mg/day) and capecitabine (600–800 mg/m 2 bid, 2 weeks every 3 weeks) were investigated in a phase I/II study in patients with advanced pancreatic cancer. The primary endpoint was objective response. Results Sixteen patients were treated in the phase I part at two dose levels. Mucositis, rash and hand-foot syndrome were dose-limiting toxicities. Dose level 1 (everolimus 5 mg/day, capecitabine 600 mg/m 2 bid for 2 weeks every 3 weeks and cetuximab 250 mg/m 2 weekly) was considered the maximum tolerated dose (MTD). Of 31 patients in the phase II part, partial response was documented in two patients (6.5%) and five (16.1%) had stable disease. Median overall survival was 5.0 months (CI 3.1–6.8). Conclusion The schedule of capecitabine, everolimus and cetuximab resulted in considerable epidermal and mucosal toxicities and prevented escalation to optimal dose levels. Because of toxicity and low efficacy this treatment combination cannot be recommended for treatment in pancreatic cancer patients.