2 Minute Medicine Rewind July 2, 2018

Effect of Fruquintinib vs Placebo on Overall Survival in Patients with Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial

Colorectal cancer is the third most common cancer worldwide.  The cancer undergoes neoangiogenesis via the vascular endothelial growth factor (VEGF) pathway in order to grow and proliferate. In this phase 3 randomized, double-blind, placebo-controlled trial, oral fruquintinib, a VEGF receptor inhibitor, was investigated for its safety and efficacy. In a 2:1 ratio, Chinese patients (n=416) age 18 to 75 years with metastatic colorectal cancer that had progressed after at least two lines of chemotherapy were assigned to receive 5 mg of either oral fruquintinib or placebo daily for 21 days, followed by 7 days without treatment. These 28-day cycles were continued until disease progressed, patients withdrew from the study, or toxicity became intolerable. Researchers found that patients in the intervention group demonstrated significantly prolonged median survival as compared to placebo (9.3 months (95% CI 8.2 months to 10.5 months) versus 6.6 months (95% CI 5.9 months to 8.1 months); HR 0.65 (95% CI 0.51 to 0.83, p<0.001)). Results also showed a significant increase in median progression-free survival (3.7 months (95% CI 3.7 months to 4.6 months) versus 1.8 months (95% CI 1.8 months to 1.8 months); HR for progression or death 0.26 (95% CI 0.21 to 0.34, p<0.001)). However, the incidence of grade 3 and 4 adverse events was significantly higher in the group treated with fruquintinib, occurring in 61.2% of patients receiving fruquintinib and 19.7% of patients receiving placebo. Investigators therefore concluded that fruquintinib is effective in prolonging overall survival in patients with metastatic colorectal cancer that have been treated with at least two chemotherapy regimens previously. Further research is needed to evaluate efficacy and safety in other populations.

Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer

Enzalutamide, an androgen receptor blocker, has been shown to prolong survival in patients with metastatic, castration-resistant prostate cancer. In this phase 3 randomized, double-blind, placebo-controlled trial, enzalutamide was investigated for its efficacy in delaying metastasis in patients with non-metastatic, castration-resistant prostate cancer. Patients (n=1401) who met these criteria with a prostate specific antigen (PSA) doubling time of 10 months or less on androgen deprivation therapy were randomized 2:1 to receive 160 mg of enzalutamide or placebo daily. Researchers found that median metastasis-free survival was significantly increased in the intervention arm of the study (36.6 months vs. 14.7 months; HR for metastasis or death 0.29 (95% CI 0.24 to 0.35, p<0.001)). In addition, time to PSA progression was significantly prolonged (37.2 months vs. 3.9 months, HR 0.07, 95% CI, p<0.001), as was time to first use of subsequent antineoplastic therapy (39.6 months vs. 17.7 months, HR 0.21, p<0.001). Grade 3 or 4 adverse event rates were comparable, with a rate of 31% in those receiving enzalutamide and a rate of 23% in those receiving placebo. Investigators therefore concluded that enzalutamide prolongs metastasis-free survival in men with non-metastatic, castration-resistant prostate cancer with a rapidly rising PSA level.

Metformin Exposure in First Trimester of Pregnancy and Risk of All or Specific Congenital Anomalies: Exploratory Case-Control Study

Metformin is frequently used in the management of type 2 diabetes and polycystic ovarian syndrome (PCOS). Its use during pregnancy, however, is controversial due to fetal exposure at term. This case-control study aimed to investigate the effect of metformin on the risk of non-genetic congenital anomalies when used during the first trimester of pregnancy. Live births, fetal deaths after 20 weeks and terminations of pregnancy for fetal anomaly were included in the analysis (n=50,167). Researchers found that there was no significant difference in first trimester exposure to metformin between those with non-genetic anomalies and genetic controls (OR 0.84, 95% CI 0.55 to 1.30). Twenty-nine subgroups of non-genetic congenital anomalies, such as oro-facial clefts, hypospadias, neural tube defects, and atrial septal defect were also evaluated, with 28 out of 29 showing no association with exposure to metformin. Pulmonary valve atresia was, however, associated with metformin exposure when compared to non-genetic controls (OR 3.54, 95% IC 1.05 to 12.00), but not when compared to those with genetic anomalies (OR 2.86, 95% CI 0.79 to 10.3). Investigators therefore concluded that the use of metformin during the first trimester was not associated with non-genetic anomalies. They also concluded that the increased risk of pulmonary valve atresia was not more than what would be expected by chance.

Association of Facility Type with Procedural-Related Morbidities and Adverse Events Among Patients Undergoing Induced Abortions

Though several states have laws mandating facilities that perform abortions meet criteria for an ambulatory surgery center (ASC), there is limited data on whether any association exists between the type of facility and outcomes such as morbidity and mortality. This retrospective cohort study aimed to investigate adverse events and abortion-related morbidity for abortions performed in ASCs, as compared to office settings. Researchers reviewed data from 49,287 women with private health insurance who underwent 50,311 induced abortions in either an ASC or office setting between 2011 and 2014. Researchers found no statistically significant difference in the rate of abortion-related adverse events or morbidity between the two settings, with ASCs having a rate of 3.25% and the office setting yielding a rate of 3.33% (difference -0.8%, 95% CI -0.58 to 0.43, OR 0.95, 95% CI 0.81 to 1.17). Additionally, there were no significant differences in the rate of infections (OR 0.75, 95% CI 0.52 to 1.09) or major adverse events or morbidities (OR 0.78, 95% CI 0.45 to 1.37). Investigators therefore concluded that among this patient population there was no difference in induced abortion-related morbidity or adverse events between these two clinical settings.

Recurrent Glioblastoma Treated with Recombinant Poliovirus

There are currently no effective treatments for the treatment of grade IV malignant glioma, with survival being typically less than 20 months. The in vitro infection of neoplastic cells with PVSRIPO, a recombinant non-pathogenic polio-rhinovirus chimera, has been shown to result in lethal cytotoxic effects in solid tumours expressing the poliovirus receptor CD155. This clinical trial aimed to study dosing and investigate the toxicity of intratumoral delivery of PVSRIPO. Patients (n=61) were enrolled if they had supratentorial grade IV malignant glioma, as confirmed by histopathological testing, that had recurred. Patients were required to have measurable disease with a tumor that enhanced greater than or equal to 1 cm and was less than or equal to 5.5 cm in its greatest dimension. Seven doses between 107 and 1010 50% tissue-culture infectious doses (TCID50) were investigated. Researchers found that the dose of 5×107 TCID50 was found to be the dose for the previous phase 2 trial for drug efficacy. In the dose-expansion phase, this dose resulted in a grade 3 or higher adverse event rate of 19%. Additionally, results showed a survival rate of 21% at 24 months (95% CI 11% to 33%), with sustained survival at 36 months exceeding that seen in historical controls where the survival rate was 14% at 24 months (95% CI 8% to 21%) and 4% (at 36 months 95% CI 1% to 9%). Investigators therefore concluded that survival among patients who received PVSRIPO immunotherapy at the dose of 5×107 TCID50 was greater at 24 and 36 months when compared to historical controls.

Image: PD

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