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Preclinical evidence suggests statins may have anti-tumor properties. Large observational studies are also consistent with improved survival and cancer-specific outcomes among cancer patients on statins. We sought to evaluate the randomized controlled trials of statins in addition to usual anti-cancer therapy. A systematic search of MEDLINE, Embase, CINAHL, Cochrane Library, Web of Science, Papers First and Clinicaltrials.gov was performed from inception through to July 4, 2017 to identify randomized clinical trials that investigated statin therapy in cancer patients. Our primary outcome was overall survival and our secondary outcome was progression-free survival. We calculated summary hazard ratio's (HR) and 95% confidence intervals (CI) based on random-effects models using aggregate data. PROSPERO (CRD42017065503). Ten studies with 1,881 individuals were included with 1,572 deaths and a median follow-up of 23 months. All trials included patients with advanced (stage 3 or higher) disease. There was minimal between-study statistical heterogeneity (I2 = 1.8%, for OS; I2 = 0%, for PFS). The pooled HR for overall survival in patients randomized to statins plus standard anti-cancer therapy versus standard therapy alone was 0.94 (95% CI, 0.85 to 1.04). In the 9 studies that reported progression-free survival (1,798 participants), the pooled HR for statin plus standard therapy versus standard therapy alone was 0.97 (95% CI, 0.87 to 1.07). In patients with advanced cancer and a prognosis <2 years, the addition of statins to standard anti-cancer therapy does not appear to improve overall survival or progression-free survival. Future research should assess if cancer patients with better prognosis benefit from longer-term statin therapy.

No standard treatment exists for patients with platinum-refractory urothelial cancer. Taxanes and vinflunine are commonly used, but response is less than 20% with no survival benefit. In this phase 2 study, we assessed efficacy and tolerability of nanoparticle albumin-bound (nab) paclitaxel in platinum-refractory urothelial cancer. We did an open-label, single-group, two-stage study at five centres in Canada. We enrolled patients aged at least 18 years with histologically confirmed, locally advanced, or metastatic measurable urothelial cancer, with documented progression on or within 12 months of treatment with one previous platinum-containing regimen. Patients received nab-paclitaxel at 260 mg/m2 intravenously every 3 weeks. Treatment continued until disease progression or occurrence of unacceptable toxic effects. The primary endpoint was objective tumour response, defined by a complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (version 1.0) criteria. Tumour response and safety were assessed in all patients who received at least one cycle of nab-paclitaxel. This study is registered with ClinicalTrials.gov, number NCT00683059. We enrolled 48 patients between Oct 16, 2008, and June 23, 2010. Patients received a median of six cycles (range one to 15). 47 patients were evaluable; one (2·1%) had a CR and 12 (25·5%) had PRs, resulting in an overall response of 27·7% (95% CI 17·3–44·4). The most frequently recorded adverse events of any grade were fatigue (38 of 48; 79%), pain (37 of 48; 77%), alopecia (34 of 48; 71%), and neuropathy (30 of 48; 77%). The most frequently recorded adverse events of grade 3 or higher were pain (11 of 48; 23%), fatigue (five of 48; 23%), hypertension (three of 48; 6%), neuropathy (three of 48, 6%), and joint stiffness or pain (two of 48; 4%). Nab-paclitaxel was well tolerated in this population of patients with pretreated advanced urothelial cancer with an encouraging tumour response. These results warrant further study of nab-paclitaxel in second-line treatment of urothelial cancer. Abraxis Bioscience, Celgene.

The purpose of this study was to determine the feasibility (recruitment, retention, and adherence rates) and effectiveness of institution-based exercise and self-management (SM) on physical activity (PA) level, exercise knowledge and intention, health status, functional capacity, patient engagement, and lower extremity strength for individuals with breast cancer receiving treatment. We conducted a hybrid implementation-effectiveness trial (type 1), including female participants with a current diagnosis of breast cancer undergoing treatment. Participants were randomized to (1) exercise and SM (EXSM; 8 in person exercise sessions and SM education), (2) SM only (8 sessions of SM), or (3) usual care (UC; no intervention). The RE-AIM model was used to explore the interventions success. The primary outcome was PA level at post-intervention. An ANCOVA determined effectiveness of the intervention at each timepoint. Eighty-five participants were included in the study. Study recruitment was 72%. Both the EXSM and SM interventions had high levels of retention (EXSM: 72%; SM: 93%) and adherence (EXSM: 76%; SM: 93%). A significant effect of group was found between EXSM and UC for PA level at post-intervention timepoint (adjusted mean difference: 9.28 (95% CI 6.45, 12.10); p  < 0.001), and was maintained at 6- and 12-month follow-ups (11.78 (8.93, 14.64); p  < 0.001; 11.10 (8.28, 13.92); p  < 0.001). Exercise and SM using strategies that maximize availability and accessibility of exercise and SM services for survivors of breast cancer can successfully be implemented during treatment within the cancer institution in Canada. Future research should explore implementation of this program at multiple centers, maximizing referral of diverse participants from diverse providers, and consider cost-effectiveness of the interventions provided over the long term in order to facilitate sustained implementation across cancer centers.

Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9–24·8] with docetaxel, prednisone, and custirsen vs 22·0 months [19·5–24·0] with docetaxel and prednisone; hazard ratio [HR] 0·93, 95% CI 0·79–1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. OncoGenex Technologies.

IntroductionThe prevalence of cancer in Canada is growing, leading to multiple lasting side effects in survivors. The physical and psychosocial benefits of regular physical activity (PA) during and after treatment for individuals with cancer are well established, however, not well implemented in a clinical setting. The overall aim of this project is to build on previous work and conduct a multicentred randomised controlled trial (RCT) and evaluate the effectiveness of a novel implementation strategy using PA and self-management versus usual care during cancer treatment.Methods and analysisStudy design: a hybrid implementation–effectiveness RCT will occur at five cancer centres across Ontario, Canada. Participants: eligible participants include adults with a cancer diagnosis (any type or stage) who are receiving treatment and cleared for exercise by their oncology care team. Intervention: participants (n=129) will be randomised to one of three groups: (1) institution-based exercise and self-management (SM) (eight in-person sessions of aerobic exercise and eight SM modules), (2) SM alone (SM only: eight virtual modules) or (3) usual care (no intervention). Outcomes: the Reach, Effectiveness, Adoption, Implementation and Maintenance framework will assess implementation outcomes. The primary effectiveness outcome is self-report PA level postintervention. Data analysis: outcomes will be measured at four time points (baseline, postintervention, 6- and 12-month follow-up). Descriptive statistics will be used to present implementation outcomes. An analysis of covariance will assess change between groups over time.Ethics and disseminationFindings from this trial will build on previous work and inform the way PA services are provided within cancer institutions across Ontario, Canada, and inform decision-making on how to incorporate exercise evidence into real-world clinical practice in cancer care. The Hamilton Integrated Research Ethics Board (ID: 7673 & 17454) has approved this study. Results will be disseminated using a combination of peer-reviewed publications, conference presentations and community organisation presentations. Participants will contribute to dissemination by sharing ‘participant perspectives’, highlighting their experience in the project and thoughts on the implementation strategies used.Trial registration numberThe study is registered on clinicaltrials.gov (ID: NCT06323707).

Exercise has been found to have numerous benefits for individuals with cancer undergoing treatment. The primary objective of this study was to explore factors that influence the decision to join an exercise trial for individuals with a current diagnosis of breast cancer. A theory-informed survey was administered exploring factors (i.e., attitudes, subjective norms, perceived behavioral control) that influenced participants’ decision to join the “NEXT-BRCA” exercise trial. Eligible participants included self-reported females over 18 years, diagnosed with stage 1–3 breast cancer undergoing treatment and cleared for exercise by their oncologist. Survey questions were analyzed using descriptive statistics and exploratory analysis was performed to determine if associations existed between personal characteristics (age, physical activity level, co-morbid conditions) and cancer characteristics (treatment received). Seventy-four participants completed the survey. Most participants (85% of respondents) were interested in increasing their level of physical activity. The most common attitudes contributing to participant’s decision to participate in the trial included feelings that exercise was beneficial for improving physical (91%) and mental health (89%). Advice from the treating oncologist was ranked as the most important factor influencing their decision to join the trial (73%). Respondents hoped to gain exercise knowledge through educational materials (72%) and a structured exercise program (70%). Findings explore why individuals with breast cancer participate in exercise trials during treatment. This knowledge will enhance recruitment of future studies using similar interventions and assist clinicians to maximize education regarding exercise and access to exercise programs for individuals with breast cancer in the future.

Background Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples. Methods VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181–221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman’s rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables. Results 237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively ( p  = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm ( p  = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) ( p  = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124–137), and placebo arms, 131 g/L (124–137) ( p  = 0.38), and at 6 months, metformin, 131 g/L (91–162), and 131 g/L (106–169) in placebo group ( p  = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15μmol/L). At 6 months, one patient (metformin) had MMA >0.4μmol/L and 3 (2 metformin, 1 placebo) had HC > 15μmol/L. Conclusions There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.

The hidden curriculum is the set of implicit influences which occur within health care organizations. The hidden curriculum has a tremendous impact on medical trainees and practicing physicians alike due to its influence in the domains of policy development, evaluation, resource allocation and institutional slang. We explore and reflect on the various ways in which the hidden curriculum impacts medical trainees and professionals in academic medical institutions.

Abiraterone has been approved as second-line chemotherapy in patients with metastatic castration-resistant prostate cancer. This study shows significant improvement in progression-free survival with abiraterone as first-line chemotherapy in these patients. Metastatic castration-resistant prostate cancer, defined by tumor growth despite a testosterone level of less than 50 ng per deciliter (1.7 nmol per liter), causes approximately 258,400 deaths annually worldwide. 1 , 2 Death of patients with this condition, which typically occurs within 24 to 48 months after the onset of castration resistance, is commonly preceded by a sequence of landmark events associated with deterioration of overall health and worsening symptoms (Figure S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). 3 – 7 Among the treatment options for patients with metastatic castration-resistant prostate cancer who have not undergone chemotherapy . . .

Introduction Cardiotoxicity, manifest by reduced left ventricular ejection fraction (LVEF), is the most common reason for the premature discontinuation of trastuzumab. While permissive cardiotoxicity (where mild cardiotoxicity is accepted to enable ongoing trastuzumab) has been shown feasible, the longer-term outcomes are unknown. We aimed to study the intermediate-term clinical outcomes of patients who underwent permissive cardiotoxicity. Materials and Methods We performed a retrospective cohort study of patients referred to the cardio-oncology service at McMaster University from 2016 to 2021 for LV dysfunction following trastuzumab administration. Results Fifty-one patients underwent permissive cardiotoxicity. The median (25th-75th percentile) follow-up time from cardiotoxicity onset was 3 years (1.3-4 years). Forty-seven (92%) patients completed trastuzumab; 3 (6%) developed severe LV dysfunction or clinical heart failure (HF) while on trastuzumab and prematurely discontinued therapy. One discontinued trastuzumab by patient choice. At final follow-up after therapy completion, 7 (14%) patients still had mild cardiotoxicity, including 2 who had clinical heart failure and stopped trastuzumab early. Among those with recovered LV function, 50% had normalized LVEF or GLS by 6 and 3 months, respectively, after initial cardiotoxicity. There was no difference in characteristics between those who did or did not recover their LV function. Conclusions Among patients exposed to permissive trastuzumab cardiotoxicity for HER2-positive breast cancer, 6% were unable to complete planned trastuzumab due to severe LV dysfunction or clinical HF. Although most patients recover their LV function after trastuzumab discontinuation or completion, 14% still have persistent cardiotoxicity by 3-year follow-up. This article reports oncological and cardiac outcomes of 51 patients with HER2-positive breast cancer who developed mild cardiac dysfunction after trastuzumab administration, and pursued a strategy of permissive cardiotoxicity.