Access to Oncology Medicines in Canada: Consensus Forum for Recommendations for Improvement.

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival.

Evaluating Wall-Mounted Prompts to Facilitate Physical Activity-Related Discussion between Individuals with Cancer and Oncology Health Care Providers: A Pre-post Survey Study.

Purpose: To evaluate the use of wall-mounted prompts in facilitating physical activity (PA)-related discussions between individuals with cancer and oncology care providers. Methods: Individuals with cancer were approached to participate in a survey-based pre-post study. Half of participants (n = 100) completed a survey prior to installation of wall-mounted prompts in clinic while the other half (n = 100) completed a survey following installation of the prompts. Survey questions included content of PA-related discussion, satisfaction with PA education across treatment, and current PA level. The post-prompt survey also asked questions related to the prompt. Survey responses were analyzed using descriptive statistics. Chi-squared tests were performed to determine significance between timepoints. Results: One hundred participants completed the survey at each timepoint. A significant difference was found pre and post-prompt in the number of PA discussions occurring overall during care (p = 0.03). Some participants (53%) were satisfied with the PA education received during treatment. There was no significant difference in occurrence of PA discussion (p = 0.36) pre and post-prompt and no difference in PA behaviour was observed (p = 0.130). Conclusions: Wall-mounted prompts may be effective in increasing the frequency of PA-related discussions between individuals with cancer and their oncology team across treatment. Additional strategies, such as easy referral to rehabilitation professionals, are also needed to facilitate safe and effective PA behaviour during and after cancer treatments.

Objectif: évaluer l'utilisation des messages muraux pour faciliter les discussions sur l'activité physique (AP) entre les personnes atteintes d'un cancer et les professionnels de la santé en oncologie. Méthodologie: des personnes cancéreuses ont été invitées à participer à une étude avant-après par sondage. La moitié (n = 100) a rempli un sondage avant l'installation de messages muraux en clinique, tandis que l'autre moitié (n = 100) l'a rempli après l'installation de ces messages. Les questions du sondage incluaient le contenu des discussions liées à l'AP, la satisfaction envers l'éducation à l'AP tout au long du traitement et le taux d'AP actuelle. Le sondage avant-après comportait aussi des questions au sujet des messages. Les chercheurs ont analysé les réponses au sondage au moyen de statistiques descriptives et ont procédé à des tests du chi carré pour déterminer le caractère significatif entre chaque sondage. Résultats: au total, 100 participants ont rempli chacun des sondages. Les chercheurs ont observé une différence significative avant et après les messages quant au nombre de discussions globales sur l'AP pendant les soins (p = 0,03). Certains participants (53 %) étaient satisfaits de l'éducation sur l'AP donnée pendant le traitement. Il n'y avait pas de différence significative quant à l'occurrence de discussions sur l'AP (p = 0,36) avant et après le message ni quant aux comportements relatifs à l'AP (p = 0,130). Conclusions: les messages muraux peuvent contribuer à accroître la fréquence des discussions sur l'AP entre les personnes atteintes du cancer et leur équipe d'oncologie tout au long du traitement. D'autres stratégies, comme une orientation facile vers des professionnels de la réadaptation, s'imposent également pour favoriser un comportement sécuritaire et efficace à l'égard de l'AP pendant et après les traitements en oncologie.

Factors Influencing the Decision of Individuals with Breast Cancer to Join an Exercise Oncology Trial.

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.

Three-Year Outcomes Following Permissive Cardiotoxicity in Patients on Trastuzumab.

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.

Optimizing Cancer Survivorship Care: Examination of Factors Associated with Transition to Primary Care.

Healthcare systems in Canada and elsewhere have identified the need to develop methods to effectively and safely transition appropriate cancer survivors to primary care. It is generally accepted that survivors with a low risk of adverse events, including recurrence and toxicity, should be more systematically identified and offered transition. There remains a lack of clarity about what constitutes an appropriate profile that would assist greater application in practice. To address this gap, we examined the clinical profiles of patients that were transitioned from a large regional cancer centre to the community. The factors examined included disease site, clinical stage, time since diagnosis/first consult, cancer treatments, and Edmonton Symptom Assessment System (ESAS) scores. In total, 2604 patients were identified as transitioned between 2013 and 2020. These patients tended to have common cancers (e.g., breast, endometrium, colorectal) that were generally of lower stage. Half of the patients had received chemotherapy and/or radiation treatment. Nearly one-third of survivors were transitioned within a year of first consult and a third after five years. Most patients reported minimal symptoms based on ESAS scores prior to being transitioned. This study represents one of the first to analyze the types of cancer patients that are being selected for transition to primary care.

Durvalumab Plus Olaparib in Previously Untreated, Platinum-Ineligible Patients With Metastatic Urothelial Carcinoma: A Multicenter, Randomized, Phase II Trial (BAYOU).

PURPOSE: Homologous recombination repair gene mutations (HRRm) are common in urothelial carcinoma (UC), rendering tumor cells sensitive to poly (ADP-ribose) polymerase (PARP) inhibition. We assessed efficacy and safety of durvalumab (anti-programmed cell death ligand-1) plus olaparib (PARP inhibitor) in patients with metastatic UC (mUC). METHODS: This randomized, multicenter, double-blind, phase II trial enrolled untreated, platinum-ineligible patients with mUC. Patients (N = 154) were randomly assigned 1:1 to receive durvalumab (1,500 mg intravenously once every 4 weeks) plus olaparib (300 mg orally, twice daily) or durvalumab plus placebo. The primary end point was progression-free survival (PFS) assessed by investigators per RECIST version 1.1. Secondary end points included overall survival in all patients and PFS in patients with HRRm. RESULTS: Overall, median PFS was 4.2 months (95% CI, 3.6 to 5.6) for durvalumab plus olaparib and 3.5 months (95% CI, 1.9 to 5.1) for durvalumab plus placebo (hazard ratio [HR], 0.94; 95% CI, 0.64 to 1.39; log-rank P value, .789). Median overall survival was 10.2 months (95% CI, 7.0 to 13.9) and 10.7 months (95% CI, 7.2 to 17.3), respectively (HR, 1.07; 95% CI, 0.72 to 1.61). In the 20% of patients with HRRm, median PFS was 5.6 months (95% CI, 1.9 to 8.1) and 1.8 months (95% CI, 1.7 to 2.2), respectively (HR, 0.18; 95% CI, 0.06 to 0.47). Treatment-related grade 3 or 4 adverse events occurred in 18% and 9% of patients, respectively. CONCLUSION: Adding olaparib to durvalumab did not improve survival outcomes in an unselected mUC population. Efficacy outcomes with durvalumab were similar to those reported for other anti-programmed cell death-1/programmed cell death ligand-1 agents. However, the results of secondary analyses suggest a potential role for PARP inhibition in patients with UC harboring HRRm.

A Survey-Based Study on Physical Activity Promotion for Individuals with a Current or Past Diagnosis of Cancer in Canada.

PURPOSE: To determine the prevalence and content of discussions regarding physical activity (PA) promotion between individuals with a current or past diagnosis of cancer and their oncology care team. METHODS: Design and Procedure: A cross-sectional survey on PA discussion between individuals with a current or past diagnosis of cancer and their oncology care team was conducted at a single timepoint. PARTICIPANTS: Eligible participants were adults with a current or past diagnosis of cancer at any time point in their cancer treatment who had a pre-scheduled appointment with their oncology care team. RESULTS: A total of 100 participants completed the survey. PA-related discussions happened in 41% of the patient-provider interactions and 66% of respondents reported PA discussions at some point during care. No significant association occurred between cancer type, stage, or treatment status and PA discussions at any timepoint (all p's > 0.05). Most respondents were satisfied with the education provided on PA (54%); however, only 37% were sufficiently active. Those receiving education from their medical oncologist were more likely to be 'sufficiently active' (p = 0.020) according to the Godin Leisure Time Exercise Questionnaire. CONCLUSIONS: Most respondents discuss PA with an oncology care provider at some point during their cancer treatment; however, few are sufficiently active. Future research is needed to determine strategies to facilitate PA promotion and close the gap between discussions and actual physical activity behavior.

Modifiable risk factors for prostate cancer in low- and lower-middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Most of the epidemiological data on prostate cancer risk factors come from high-income countries (HIC). Reducing exposure to prostate cancer modifiable risk factors may significantly lower PCa morbidity and mortality in LIC and MIC. The objective of this study was to summarize the evidence on modifiable risk factors (RFs) for PCa in LIC and lower-middle-income countries (LMIC). METHODS: We conducted a systematic search on MEDLINE, EMBASE, and Global Health databases. We selected case-control and cohort studies from 2010 onwards that studied modifiable RFs for PCa in LIC and LMIC with a population of 30 million or more, as defined by the World Bank in January 2021. Risk of bias was assessed by the Ottawa-Newcastle tool. Individual study estimates were pooled when estimates were available for at least two studies. RESULTS: 5740 studies were initially identified; 16 studies met inclusion criteria. All were case-control studies except one retrospective cohort study. Higher fat intake was associated with a higher risk of PCa incidence with an odds ratio (OR) of 3.13 (95% CI 1.33-7.33). Higher vegetable intake (OR 0.48, 95% CI 0.24-0.97) and tea consumption (OR 0.51, 95% CI 0.32-0.83) were associated with a lower risk for PCa. There was no association between fruits, fish, and chicken consumption and risk of PCa. Alcohol consumption, smoking, red meat intake, and a BMI ≥ 25-30 kg/m2 showed a trend towards an increased risk, although these were not statistically significant. CONCLUSIONS: In LIC and LMIC, high fat intake was associated with higher risk of PCa while a diet rich in vegetables and tea intake was associated with a lower risk. Future prospective studies will be important to elucidate whether other modifiable risk factors for PCa specific to LIC and LMIC can be identified to inform impactful and cost-effective preventive strategies in these countries.

Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial.

Importance: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions: Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures: The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01101438.

Impact of stereotactic body radiotherapy (SBRT) in oligoprogressive metastatic disease.

PURPOSE: There is increasing interest in using stereotactic body radiation therapy (SBRT) in areas of oligoprogressive metastatic disease (OPD). Our main objective was to investigate the impact of SBRT on overall survival (OS) and the incidence of systemic therapy treatment switches in this population. METHODS: A retrospective institutional review of patients treated with SBRT for OPD was performed. Patients were included if they received SBRT for 1-3 discrete progressing metastases, using a dose of at least 5 Gy per fraction. The study aimed to calculate progression-free survival (PFS), overall survival (OS), local control (LC), and incidence of treatment switch (TS). PFS and OS were calculated using the Kaplan-Meier methodology, while LC and TS were determined using cumulative incidence. RESULTS: Eighty-one patients with a total of 118 lesions were treated with SBRT from July 2014 to November 2020. The Median SBRT dose was 40 (18-60) Gy in 5 (2-8) fractions. Patients had primarily kidney, lung, or breast cancer. Most patients were treated with a tyrosine kinase inhibitor (TKI) (30.9%) or chemotherapy (29.6%) before OPD. The median follow-up post-SBRT was 14 months. Median OS and PFS were 25.1 (95% CI 11.2-39.1) months and 7.8 (95% CI 4.6-10.9) months, respectively. The cumulative incidence of local progression of treated lesions was 5% at 1 year and 7.3% at 2 years. Sixty patients progressed after SBRT and 17 underwent additional SBRT. Thirty-eight patients (47%) changed systemic therapy following SBRT; the cumulative incidence of TS was 28.5% at 6 months, 37.4% at 1 year, and 43.9% at 2 years. CONCLUSIONS: SBRT effectively controls locally progressing lesions but distant progression still occurs frequently. A sizeable number of patients can be salvaged by further SBRT or have minimally progressing diseases that may not warrant an immediate initiation/switch in systemic therapy. Further prospective studies are needed to validate this benefit.

The Cardiologist's Role in the Management of Patients with a Genitourinary Cancer.

BACKGROUND: Increased life expectancy due to improved cancer prognosis, shared determinants (e.g., tobacco use), and cardiovascular toxicities related to cancer therapies, including the adverse cardiometabolic effects of androgen deprivation therapy for prostate cancer, make cardiovascular disease an frequent and important co-morbidity in patients with a genitourinary malignancy. Complex cardiovascular disease can pose significant challenges in the management of these patients given the uncertainties related to the best approach to reconcile ischemic and bleeding risks, and the role of invasive cardiovascular interventions in individuals with advanced cancer. In this review, we discuss the current evidence that informs decision-making in this clinical context.

Low Serum Testosterone in Men with Newly Diagnosed Androgen-Deprivation Therapy-Naïve Prostate Cancer and Its Relationship to Cardiovascular Risk Factors: A RADICAL-PC Substudy.

PURPOSE: Cardiovascular disease is a common cause of death in prostate cancer patients. Low testosterone is associated with increased cardiovascular risk in the general male population. We investigated the relationship between serum testosterone, cardiovascular disease and risk factors in androgen-deprivation therapy-naïve prostate cancer patients. MATERIALS AND METHODS: We performed a cross-sectional analysis of a subgroup of 1,326 androgen-deprivation therapy-naïve men from RADICAL-PC (Role of Androgen-Deprivation Therapy In CArdiovascular Disease-A Longitudinal Prostate Cancer study) in whom serum testosterone was measured at baseline. RADICAL-PC is a prospective multicenter cohort study of men (2,565) enrolled within 1 year of prostate cancer diagnosis, or within 6 months of commencing androgen-deprivation therapy for the first time. Cardiovascular risk factors, cancer characteristics and total serum testosterone were collected at baseline. Low testosterone was defined as total serum testosterone <11 nmol/L (<320 ng/dL). A Framingham cardiovascular risk score ≥15 was considered high risk for future cardiovascular events. We performed logistic regression to calculate odds ratios for the association between testosterone and cardiovascular risk. RESULTS: Among 1,326 participants (median age 67 years, range 45-93), 553 (42%) had low testosterone. Low testosterone was associated with existing cardiovascular disease, diabetes, elevated hemoglobin A1c, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension and Framingham score >15. Among patients with low testosterone, the odds ratio for high cardiovascular risk was 1.33 (1.02-1.73) after adjusting for ethnicity, education, alcohol use, cancer characteristics, physical activity and body mass index. CONCLUSIONS: Among androgen-deprivation therapy-naïve prostate cancer patients, low testosterone is common and associated with increased cardiovascular risk factors.

Pertuzumab Cardiotoxicity in Patients With HER2-Positive Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpressing malignancies, including breast and gastro-esophageal, are associated with a poor prognosis. The cardiotoxicity of trastuzumab, a HER2-targeting monoclonal antibody, is well established. However, the cardiotoxic effect of pertuzumab, another HER2-directed therapy, is less well documented. The objective of this systematic review and meta-analysis was to determine the risk of cardiac events in patients with HER2-positive cancer who are receiving pertuzumab. METHODS: We performed a systematic review of phase 2 and 3 randomized controlled trials in which the addition of pertuzumab to other standard therapies in patients with stage I-IV HER2-positive cancer was evaluated, and cardiac adverse effects reported. We searched MEDLINE (1946-2020), Embase (1974-2020), and CENTRAL. Two independent reviewers assessed the risk of bias and extracted the data. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated from the pooled data using the inverse variance method and random-effects models. RESULTS: Eight randomized controlled trials (8420 patients) were included: 1 was gastro-esophageal; 7 were breast cancer trials. Participants' median age ranged from 49 to 61.5 years. All participants received trastuzumab and chemotherapy in addition to pertuzumab or placebo. Compared with placebo, pertuzumab increased the risk of clinical heart failure (HF; RR [95% CI]: 1.97 [1.05-3.70]; I2 = 0%). However, pertuzumab had no demonstrable effect on asymptomatic/minimally symptomatic left ventricular systolic dysfunction (RR [95% CI]: 1.19 [0.89-1.61]; I2 = 19%). CONCLUSIONS: Pertuzumab increases the risk of clinical HF, but not asymptomatic/minimally symptomatic left ventricular systolic dysfunction, in HER2-positive cancer patients. Further research into the mechanisms underlying pertuzumab-related HF is needed to understand its clinical spectrum of cardiotoxicity.

INTRODUCTION: Les tumeurs malignes qui surexpriment le récepteur 2 du facteur de croissance épidermique humain (HER2, de l'anglais Human epidermal growth factor receptor 2), notamment le cancer du sein et le cancer de la jonction gastro-œsophagienne, sont associées à un mauvais pronostic. La cardiotoxicité du trastuzumab, un anticorps monoclonal qui vise le HER2, est bien établie. Toutefois, les effets cardiotoxiques du pertuzumab, un autre traitement qui vise le HER2, sont moins bien démontrés. L'objectif de cette revue systématique et de cette méta-analyse était de déterminer le risque d'événements cardiaques chez les patients atteints d'un cancer HER2 positif qui prennent du pertuzumab. MÉTHODES: Nous avons réalisé une revue systématique d'essais comparatifs à répartition aléatoire de phase 2 et de phase 3 lors desquels nous avons évalué l'ajout du pertuzumab à d'autres traitements standards chez les patients atteints d'un cancer HER2 positif de stades I-IV, et signalé les effets indésirables sur le cœur. Nous avons fait des recherches dans MEDLINE (1946-2020), Embase (1974-2020) et CENTRAL. Deux examinateurs indépendants ont évalué le risque de biais et extrait les données. Les données groupées ont permis de calculer les intervalles de confiance (IC) à 95 % des risques relatifs (RR) au moyen de la méthode de la variance inverse et des modèles à effets aléatoires. RÉSULTATS: Nous avons inclus huit essais contrôlés randomisés (8420 patients), soit un qui portait sur le cancer de la jonction gastro-œsophagienne, et sept sur le cancer du sein. L'âge médian des participants se situait entre 49 à 61,5 ans. Tous les participants ont pris le trastuzumab et ont suivi une chimiothérapie en plus de la prise du pertuzumab ou du placebo. Comparativement au placebo, le pertuzumab a fait augmenter le risque de manifestations cliniques de l'insuffisance cardiaque (IC) (RR [IC à 95 %] : 1,97 [1,05-3,70]; I2 = 0 %). Toutefois, le pertuzumab n'a démontré aucun effet sur la dysfonction systolique du ventricule gauche asymptomatique/minimalement symptomatique (RR [IC à 95 %] : 1,19 [0,89-1,61]; I2 = 19 %). CONCLUSIONS: Le pertuzumab fait augmenter le risque de manifestations cliniques de l'IC, mais pais la dysfonction systolique du ventricule gauche asymptomatique/minimalement symptomatique, chez les patients atteints d'un cancer HER2 positif. Des recherches plus approfondies sur les mécanismes sous-jacents à l'IC liée au pertuzumab sont nécessaires pour comprendre son spectre de manifestations cliniques de cardiotoxicité.

Ten ways to get a grip on designing and implementing a competency-based medical education training program.

BACKGROUND: Globally there is a move to adopt competency-based medical education (CBME) at all levels of the medical training system. Implementation of a complex intervention such as CBME represents a marked paradigm shift involving multiple stakeholders. METHODS: This article aims to share tips, based on review of the available literature and the authors' experiences, that may help educators implementing CBME to more easily navigate this major undertaking and avoid "black ice" pitfalls that educators may encounter. RESULTS: Careful planning prior to, during and post implementation will help programs transition successfully to CBME. Involvement of key stakeholders, such as trainees, teaching faculty, residency training committee members, and the program administrator, prior to and throughout implementation of CBME is critical. Careful and selective choice of key design elements including Entrustable Professional Activities, assessments and appropriate use of direct observation will enhance successful uptake of CBME. Pilot testing may help engage faculty and learners and identify logistical issues that may hinder implementation. Academic advisors, use of curriculum maps, and identifying and leveraging local resources may help facilitate implementation. Planned evaluation of CBME is important to ensure choices made during the design and implementation of CBME result in the desired outcomes. CONCLUSION: Although the transition to CBME is challenging, successful implementation can be facilitated by careful design and strategic planning.

CONTEXTE: Partout dans le monde, on observe une tendance en faveur de l'éducation médicale axée sur les compétences (EMAC) à tous les niveaux du système d'éducation médicale. Une intervention complexe comme l'élaboration d'un programme d'EMAC représente un important changement de paradigme qui nécessite l'implication de plusieurs parties prenantes. MÉTHODE: L'objectif de cet article est de partager des conseils dégagés par les auteurs d'une revue de la littérature et de leur propre expérience afin d'aider les éducateurs à mieux s'orienter dans cette entreprise de taille qu'est la mise en œuvre de l'EMAC et à éviter les écueils. RÉSULTATS: Une planification minutieuse avant, pendant et après la transition des programmes vers l'EMAC contribue à garantir son succès. L'implication des principales parties prenantes, telles que les stagiaires, le corps enseignant, les membres du comité du programme de résidence et l'administrateur du programme, avant et pendant la mise en œuvre est essentielle. La sélection attentive des éléments clés, comme les activités professionnelles confiables, les évaluations et l'utilisation appropriée de l'observation directe, favorisera l'adoption de l'EMAC. Des tests pilotes peuvent permettre la participation du corps professoral et des apprenants, et à déceler les problèmes logistiques qui peuvent entraver la mise en œuvre. Les conseillers pédagogiques, le recours à la cartographie des programmes d'études et le repérage et la mobilisation de ressources locales peuvent faciliter la mise en œuvre des programmes d'EMAC. L'évaluation planifiée de ces programmes est importante pour garantir que les choix faits lors de leur conception et mise en œuvre aboutissent aux résultats souhaités. CONCLUSION: Puisque la transition vers l'EMAC peut comporter de nombreux défis, elle peut néanmoins être opérée avec succès grâce à une conception et une planification stratégique minutieuses.

The Hidden Curriculum in Postgraduate Medical Education: a Commentary.

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.

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. METHODS: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice-web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. FINDINGS: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9-43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4-17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4-15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71-1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1-18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9-14·0) in the chemotherapy group (0·85, 95% CI 0·72-1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury). INTERPRETATION: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted. FUNDING: AstraZeneca.

Efficacy and Safety of nab-Paclitaxel vs Paclitaxel on Survival in Patients With Platinum-Refractory Metastatic Urothelial Cancer: The Canadian Cancer Trials Group BL.12 Randomized Clinical Trial.

IMPORTANCE: Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial. OBJECTIVES: To evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC. DESIGN, SETTING, AND PARTICIPANTS: In this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract. Mixed histologic findings, except small cell, were permitted provided UC was the predominant histologic finding. All patients had received platinum-based chemotherapy either in the metastatic setting or were within 12 months of perioperative chemotherapy. Patients with prior taxane chemotherapy were not included. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 and adequate organ function. INTERVENTIONS: Patients were randomized to nab-paclitaxel, 260 mg/m2, or paclitaxel, 175 mg/m2, every 3 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS). RESULTS: Among 199 patients, median age was 67 (range, 24-88) years; 144 (72%) were men; 167 (84%) were ECOG PS 0-1; 59 (30%) had liver metastases; and 110 (55%) were within 6 months of prior platinum-based chemotherapy. At a median follow-up of 16.4 months, there was no significant difference between nab-paclitaxel vs paclitaxel for median PFS (3.4 months vs 3.0 months; hazard ratio [HR], 0.92; 90% CI, 0.68-1.23; 1-sided P = .31). Median overall survival was 7.5 months for nab-paclitaxel vs 8.8 months for paclitaxel (HR, 0.95; 90% CI, 0.70-1.30; 1-sided P = .40); and objective response rate (ORR) was 22% for nab-paclitaxel vs 25% for paclitaxel (P = .97). Grade 3/4 adverse events were more frequent with nab-paclitaxel (64/97 [66%]) compared with paclitaxel (45/97 [46%]), P = .009; but peripheral sensory neuropathy was similar (all grades, 72/97 [74%] vs 64/97 [66%]; grade 3/4, 7/97 [7%] vs 3/97 [3%]; P = .27). There were no apparent differences in scores for health-related quality of life. CONCLUSIONS AND RELEVANCE: In this open-label, phase 2 randomized clinical trial of patients with platinum-refractory mUC, nab-paclitaxel had similar efficacy to paclitaxel; but worse toxic effects. The ORR with either taxane, however, was higher than previously reported and similar to those reported for the immune checkpoint inhibitors, suggesting that the taxanes remain a reasonable option in this setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02033993.