BETTER LIFE- guidelines for chronic disease preventive care for people aged 18-39 years: a literature review.

BACKGROUND: The original 'BETTER' (Building on Existing Tools To Improve Chronic Disease Prevention and Screening in Primary Care) approach consisted of a prevention-focused visit between participants aged 40-65 years and a "Prevention Practitioner" (PP), who empowered the participant to set achievable prevention and screening goals for cancers and chronic diseases. BETTER was successfully adapted for economically deprived communities (BETTER HEALTH) in Canada. Our objective was to conduct a review of guidelines in preparation for adapting the 'BETTER HEALTH' approach for younger adults aged 18-39 years living with lower income, a group known to have earlier mortality due to a higher prevalence of preventable chronic diseases than their peers with higher income. METHODS: We searched multiple electronic databases and grey literature for clinical practice guidelines on prevention/screening and included those that met the following criteria: published in English from 2008-2020 in Canada or any of the following countries (Australia, Ireland, New Zealand, Scotland, United States and England); and addressed prevention or screening. We assessed quality using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool and extracted data (publication details, recommendations, and Quality/Level of evidence as reported by authors) from sources with overall scores of 5 or higher. Final recommendations were compiled after harmonization with input from diverse stakeholders (co-investigators, PPs, and the Community Advisory Committee). RESULTS: We included a total of 85 guidelines, and developed a final list of 42 recommendations for 18-39 year-olds across 21 topics. Specific recommendations fell under the following topics: cancers, cardiovascular disease, diabetes, obesity, lifestyle (alcohol; healthy nutrition/physical activity); healthy relationships and healthy sexuality, immunization, oral health, social determinants of health, and substance use. CONCLUSION: We identified evidence-based guidelines on individual-level prevention/screening actions for adults 18-39 years old and relevant for those living with lower income which will directly inform development and implementation of the BETTER LIFE intervention.

Safety of pembrolizumab as adjuvant therapy in a pooled analysis of phase 3 clinical trials of melanoma, non-small cell lung cancer, and renal cell carcinoma.

BACKGROUND: The safety profile of adjuvant pembrolizumab was evaluated in a pooled analysis of 4 phase 3 clinical trials. METHODS: Patients had completely resected stage IIIA, IIIB, or IIIC melanoma per American Joint Committee on Cancer, 7th edition, criteria (AJCC-7; KEYNOTE-054); stage IIB or IIC melanoma per AJCC-8 (KEYNOTE-716); stage IB, II, or IIIA non-small cell lung cancer per AJCC-7 (PEARLS/KEYNOTE-091); or postnephrectomy/metastasectomy clear cell renal cell carcinoma at increased risk of recurrence (KEYNOTE-564). Patients received adjuvant pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for approximately 1 year. Adverse events (AEs) were summarized for patients who received ≥ 1 dose of treatment. RESULTS: Data were pooled from 4125 patients treated with pembrolizumab (n = 2060) or placebo (n = 2065). Median (range) duration of treatment was 11.1 months (0.0-18.9) with pembrolizumab and 11.2 months (0.0-18.1) with placebo. Treatment-related AEs occurred in 78.6 % (1620/2060) of patients in the pembrolizumab group (grade 3-5, 16.3 % [336/2060]) and 58.7 % (1212/2065) in the placebo group (grade 3-5, 3.5 % [72/2065]). Immune-mediated AEs (e.g. adrenal insufficiency, hypophysitis, and thyroiditis) occurred in 36.2 % (746/2060) of patients in the pembrolizumab group (grade 3-5, 8.6 % [177/2060]) and 8.4 % (174/2065) in the placebo group (grade 3-5, 1.1 % [23/2065]). Of patients with ≥ 1 immune-mediated AE or infusion reaction, systemic corticosteroids were required for 35.2 % (268/761) and 20.2 % (39/193) of patients in the pembrolizumab and placebo groups, respectively. CONCLUSIONS: Adjuvant pembrolizumab demonstrated a manageable safety profile that was comparable to prior reports in advanced disease.

Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).

Long-Term Outcomes After Concurrent Once- or Twice-Daily Chemoradiation in Limited-Stage Small Cell Lung Cancer: A Brief Report From the CONVERT Trial.

PURPOSE: CONVERT was a phase 3 international randomized clinical trial comparing once-daily (OD) and twice-daily (BD) radiation therapy (RT). This updated analysis describes the 6.5-year outcomes of these regimens delivered with conformal techniques. METHODS AND MATERIALS: CONVERT (NCT00433563) randomized patients 1:1 between OD RT (66 Gy/33 fractions/6.5 weeks) and BD RT (45 Gy/30 fractions/3 weeks), both delivered with concurrent cisplatin/etoposide. Three-dimensional conformal RT was mandatory, intensity-modulated RT was permitted, and elective nodal irradiation was not allowed. Prophylactic cranial irradiation was delivered at the discretion of treating clinicians. RT treatment planning was subject to central quality assurance. RESULTS: Five hundred forty-seven patients were recruited at 73 centers. The median follow-up for the surviving cohort (n = 164) was 81.2 months. The median survival for the OD and BD arms were 25.4 months (95% CI, 21.1-30.9) and 30.0 months (95% CI, 25.3-36.5; hazard ratio, 1.13; 95% CI, 0.92-1.38; P = .247). Performance status and tumor volume were associated with survival on multivariate analysis. No treatment-related deaths occurred subsequent to the initial analysis performed in 2017. Regarding late toxicity, 7 patients in the OD arm developed grade 3 esophagitis, 4 of which went on to develop stricture or fistulation, compared with no patients in the BD arm. Grade 3 pulmonary fibrosis occurred in 2 and 3 patients in the OD and BD arms, respectively. CONCLUSIONS: As the CONVERT trial did not demonstrate the superiority of OD RT and this regimen had a slightly worse toxicity profile after 80 months of follow-up, 45 Gy BD should remain the standard of care in limited stage small cell lung cancer.

Personalizing the Treatment of Women with Ductal Carcinoma In Situ (DCIS) Using the DCIS Score: A Qualitative Study on Score Use.

BACKGROUND: A twelve-gene molecular expression assay (DCIS score) may help guide radiation oncology treatment under specific circumstances. We undertook a study to examine radiation oncologist (RO), surgeon, and decision maker views on implementing the DCIS score in practice for women with low-risk DCIS. METHODS: We conducted a qualitative study involving telephone interviews that were audio-recorded and transcribed. Two researchers conducted a thematic analysis of transcripts. RESULTS: Twenty-eight individuals (ROs, breast cancer surgeons, and cancer policy decision makers) were invited to participate; 22 out of the 28 people (79%) agreed. The final sample included 20 participants: 11 of 13 (85%) ROs, 5 of 7 (71%) surgeons, and 4 of 8 (50%) decision makers. Most ROs expressed concerns about overtreatment but could not predict with certainty which low-risk patients could safely avoid radiation. The DCIS score was viewed as contributing valuable personalized risk information as part of treatment decision making that included clinicopathological factors and women's preferences. Future implementation would require guidelines with input from the oncology team. CONCLUSIONS: ROs had concerns about the overtreatment of women with DCIS, but lacked the tools to reliably predict which women could safely avoid radiation. By providing oncologists and women with personalized tumor information, the DCIS score was an important component of treatment decision making.

Vagus nerve damage increases alcohol intake and preference in a nonpreferring rat line: Relationship to vagal regulation of the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Clinical and preclinical research indicates that gastric weight loss surgeries, such as Roux-en-Y gastric bypass surgery, can induce alcohol use disorder (AUD). While numerous mechanisms have been proposed for these effects, one relatively unexplored potential mechanism is physical damage to the gastric branch of the vagus nerve, which can occur during bypass surgery. Therefore, we hypothesized that direct damage to the gastric branch of the vagus nerve, without altering other aspects of gastric anatomy, could result in increased alcohol intake. METHODS: To test this hypothesis, we compared alcohol intake and preference in multiple models in male Sprague-Dawley rats that received selective gastric branch vagotomy (VX) with rats who underwent sham surgery. Because the vagus nerve regulates hypothalamic-pituitary-adrenal (HPA) axis function, and alterations to HPA function are critical to the escalation of non-dependent alcohol intake, we also tested the hypothesis that gastric VX increases HPA function. RESULTS: We found that VX increases alcohol intake and preference in the every-other-day, two-bottle choice test and increases preference for 1 g/kg alcohol in the conditioned place preference test. The effects were selective for alcohol, as sucrose intake and preference were not altered by VX. We also found that VX increases corticotropin releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus (PVN), increases putative PVN CRF neuronal action potential firing, and increases corticosterone levels. CONCLUSIONS: Overall, these findings suggest that the vagus nerve may play a critical role in regulating HPA axis function via modulation of PVN CRF mRNA expression and putative PVN CRF neuronal activity. Furthermore, disruptions to vagal regulation of HPA axis function may increase alcohol intake and preference.

Professionally led support groups for people living with advanced or metastatic cancer: a systematic scoping review of effectiveness and factors critical to implementation success within real-world healthcare and community settings.

PURPOSE: To examine the effectiveness of professionally led support groups for people with advanced or metastatic cancer, and identify factors critical to implementation success within real-world settings. METHODS: Databases (MEDLINE; PsychINFO; CINAHL) and grey literature were searched for empirical publications and evaluations. Articles were screened for eligibility and data systematically extracted, charted and summarised using a modified scoping review methodology. Implementation factors were mapped using Proctor's implementation framework and the Consolidated Framework for Implementation Research 2.0. RESULTS: A total of 1691 publications were identified; 19 were eligible for inclusion (8 randomised controlled trials, 7 qualitative studies, 2 cohort studies, 2 mixed methods studies). Most (n=18) studies focused on tumour-specific support groups. Evidence supported professionally led support groups in reducing mood disturbances (n=5), distress (i.e. traumatic stress, depression) (n=4) and pain (n=2). Other benefits included social connectedness (n=6), addressing existential distress (n=5), information and knowledge (n=6), empowerment and sense of control (n=2), relationships with families (n=2) and communication with health professionals (n=2). Thirteen studies identified factors predicting successful adoption, implementation or sustainment, including acceptability (n=12; 63%), feasibility (n=6; 32%) and appropriateness (n=1; 5%). Key determinants of successful implementation included group leaders' skills/experience, mode of operation, travelling distance, group composition and membership and resourcing. CONCLUSIONS: Professionally led tumour-specific support groups demonstrate effectiveness in reducing mood disturbances, distress and pain among patients. Successful implementation hinges on factors such as leadership expertise, operational methods and resource allocation. IMPLICATIONS FOR CANCER SURVIVORS: Professionally led support groups may fill an important gap in supportive care for people with advanced or metastatic cancer.

Smoking, Diabetes Mellitus, and Previous Cardiovascular Disease as Predictors of Anticancer Treatment-Induced Cardiotoxicity in Non-Small-Cell Lung Cancer: A Real-World Study.

PURPOSE: Cardiotoxicity is a common and under-reported side effect of tyrosine-kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI). Baseline risk factors may help in risk-stratifying patients at increased risk of cardiotoxicity. This real-world study investigated the effects of baseline risk factors in cardiotoxicity on patients with non-small-cell lung cancer (NSCLC) treated with TKIs and ICIs. METHODS: This is a retrospective study carried out at The Royal Marsden Hospital, UK. Newly diagnosed patients with localized or metastatic NSCLC who received anticancer therapy with TKIs and/or ICIs were eligible. Patients who received only chemotherapy were excluded. Patients were followed up from the time of diagnosis until death or discharge. The relationship between cardiotoxicity and risk factors were tested by logistic regression. RESULTS: Of 88/451 (19.5%) patients developed cardiotoxicity. Risk factors hypothesized to have a causal relationship with anticancer treatment-induced cardiotoxicity were analyzed. Cardiotoxicity risk was increased with prior diabetes mellitus (OR = 1.93, 95% CI, 1.04-3.61, P = .038), history of smoking (OR = 1.91, 95% CI, 1.13-3.22, P = .016) and presence of baseline cardiovascular disease (OR = 2.03, 95% CI, 1.13-3.64, P = .018). The risk of developing cardiotoxicity increased in patients for smokers with diabetes mellitus (OR = 3.03, 95% CI, 1.40-6.55, P < .01) and for smokers with previous cardiovascular disease (OR = 1.99, 95% CI, 1.03-3.84, P = .041). CONCLUSION: Diabetes mellitus, smoking and baseline cardiovascular disease may synergistically contribute to cardiotoxicity when a patient is exposed to potentially cardiotoxic anticancer agents. Risk stratification at baseline may improve cardio-oncology care.

PD-1-expressing macrophages and CD8 T cells are independent predictors of clinical benefit from PD-1 inhibition in advanced mesothelioma.

BACKGROUND: Few tissue biomarkers exist to date that could enrich patient with cancer populations to benefit from immune checkpoint blockade by programmed cell death protein 1/ligand-1 (PD-/L-1) inhibitors. PD-L1 expression has value in this context in some tumor types but is an imperfect predictor of clinical benefit. In malignant pleural mesothelioma, PD-L1 expression is not predictive of the benefit from PD-1 blockade. We aimed to identify novel markers in malignant pleural mesothelioma to select patients better. METHODS: We performed a multiplex-immune histochemistry analysis of tumor samples from the phase III PROMISE-meso study, which randomized 144 pretreated patients to receive either pembrolizumab or standard second-line chemotherapy. Our panel focused on CD8+T cell, CD68+macrophages, and the expression of PD-1 and PD-L1 on these and cancer cells. We analyzed single and double positive cells within cancer tissues (infiltrating immune cells) and in the stroma. In addition, we performed cell neighborhood analysis. The cell counts were compared with clinical outcomes, including responses, progression-free and overall survivals. RESULTS: We confirmed the absence of predictive value for PD-L1 in this cohort of patients. Furthermore, total CD8 T cells, CD68+macrophages, or inflammatory subtypes (desert, excluded, inflamed) did not predict outcomes. In contrast, PD-1-expressing CD8+T cells (exhausted T cells) and PD-1-expressing CD68+macrophages were both independent predictors of progression-free survival benefit from pembrolizumab. Patients with tumors simultaneously harboring PD1+T cells and PD-1+macrophages benefited the most from immune therapy. CONCLUSION: We analyzed a large cohort of patients within a phase III study and found that not only PD-1+CD8 T cells but also PD-1+CD68+ macrophages are predictive. This data provides evidence for the first time for the existence of PD-1+macrophages in mesothelioma and their clinical relevance for immune checkpoint blockade.

REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment.

Increasing evidence suggests that some immunotherapy dosing regimens for patients with advanced cancer could result in overtreatment. Given the high costs of these agents, and important implications for quality of life and toxicity, new approaches are needed to identify and reduce unnecessary treatment. Conventional two-arm non-inferiority designs are inefficient in this context because they require large numbers of patients to explore a single alternative to the standard of care. Here, we discuss the potential problem of overtreatment with anti-PD-1 directed agents in general and introduce REFINE-Lung (NCT05085028), a UK multicentre phase 3 study of reduced frequency pembrolizumab in advanced non-small-cell lung cancer. REFINE-Lung uses a novel multi-arm multi-stage response over continuous interventions (MAMS-ROCI) design to determine the optimal dose frequency of pembrolizumab. Along with a similarly designed basket study of patients with renal cancer and melanoma, REFINE-Lung and the MAMS-ROCI design could contribute to practice-changing advances in patient care and form a template for future immunotherapy optimisation studies across cancer types and indications. This new trial design is applicable to many new or existing agents for which optimisation of dose, frequency, or duration of therapy is desirable.

Patient Engagement in Health Research: Perspectives from Patient Participants.

BACKGROUND AND PURPOSE: Over the past decade, patient engagement (PE) has emerged as an important way to help improve the relevance, quality, and impact of health research. However, there is limited consensus on how best to meaningfully engage patients in the research process. The goal of this article is to share our experiences and insights as members of a Patient Advisory Committee (PAC) on a large, multidisciplinary cancer research study that has spanned six years. We hope by sharing our reflections of the PAC experiences, we can highlight successes, challenges, and lessons learned to help guide PE in future health research. To the best of our knowledge, few publications describing PE experiences in health research teams have been written by patients, survivors, or family caregivers themselves. METHODS: A qualitative approach was used to gather reflections from members of the Patient Advisory Committee regarding their experiences in participating in a research study over six years. Each member completed an online survey and engaged in a group discussion based on the emergent themes from the survey responses. RESULTS: Our reflections about experiences as a PAC on a large, pan-Canadian research study include three overarching topics (1) what worked well; (2) areas for improvement; and (3) reflections on our overall contribution and impact. Overall, we found the experience positive and experienced personal satisfaction but there were areas where future improvements could be made. These areas include earlier engagement and training in the research process, more frequent communication between the patient committee and the research team, and on-going monitoring regarding the nature of the patient engagement. CONCLUSIONS: Engaging individuals who have experienced the types of events which are the focus of a research study can contribute to the overall relevance of the project. However, intentional efforts are necessary to ensure satisfactory involvement.

Implementation of a Web-Based Communication System for Primary Care Providers and Cancer Specialists.

Healthcare providers have reported challenges with coordinating care for patients with cancer. Digital technology tools have brought new possibilities for improving care coordination. A web- and text-based asynchronous system (eOncoNote) was implemented in Ottawa, Canada for cancer specialists and primary care providers (PCPs). This study aimed to examine PCPs' experiences of implementing eOncoNote and how access to the system influenced communication between PCPs and cancer specialists. As part of a larger study, we collected and analyzed system usage data and administered an end-of-discussion survey to understand the perceived value of using eOncoNote. eOncoNote data were analyzed for 76 shared patients (33 patients receiving treatment and 43 patients in the survivorship phase). Thirty-nine percent of the PCPs responded to the cancer specialist's initial eOncoNote message and nearly all of those sent only one message. Forty-five percent of the PCPs completed the survey. Most PCPs reported no additional benefits of using eOncoNote and emphasized the need for electronic medical record (EMR) integration. Over half of the PCPs indicated that eOncoNote could be a helpful service if they had questions about a patient. Future research should examine opportunities for EMR integration and whether additional interventions could support communication between PCPs and cancer specialists.

Web-Based Asynchronous Tool to Facilitate Communication Between Primary Care Providers and Cancer Specialists: Pragmatic Randomized Controlled Trial.

BACKGROUND: Cancer poses a significant global health burden. With advances in screening and treatment, there are now a growing number of cancer survivors with complex needs, requiring the involvement of multiple health care providers. Previous studies have identified problems related to communication and care coordination between primary care providers (PCPs) and cancer specialists. OBJECTIVE: This study aimed to examine whether a web- and text-based asynchronous system (eOncoNote) could facilitate communication between PCPs and cancer specialists (oncologists and oncology nurses) to improve patient-reported continuity of care among patients receiving treatment or posttreatment survivorship care. METHODS: In this pragmatic randomized controlled trial, a total of 173 patients were randomly assigned to either the intervention group (eOncoNote plus usual methods of communication between PCPs and cancer specialists) or a control group (usual communication only), including 104 (60.1%) patients in the survivorship phase (breast and colorectal cancer) and 69 (39.9%) patients in the treatment phase (breast and prostate cancer). The primary outcome was patient-reported team and cross-boundary continuity (Nijmegen Continuity Questionnaire). Secondary outcome measures included the Generalized Anxiety Disorder Screener (GAD-7), Patient Health Questionnaire on Major Depression, and Picker Patient Experience Questionnaire. Patients completed the questionnaires at baseline and at 2 points following randomization. Patients in the treatment phase completed follow-up questionnaires at 1 month and at either 4 months (patients with prostate cancer) or 6 months following randomization (patients with breast cancer). Patients in the survivorship phase completed follow-up questionnaires at 6 months and at 12 months following randomization. RESULTS: The results did not show an intervention effect on the primary outcome of team and cross-boundary continuity of care or on the secondary outcomes of depression and patient experience with their health care. However, there was an intervention effect on anxiety. In the treatment phase, there was a statistically significant difference in the change score from baseline to the 1-month follow-up for GAD-7 (mean difference -2.3; P=.03). In the survivorship phase, there was a statistically significant difference in the change score for GAD-7 between baseline and the 6-month follow-up (mean difference -1.7; P=.03) and between baseline and the 12-month follow-up (mean difference -2.4; P=.004). CONCLUSIONS: PCPs' and cancer specialists' access to eOncoNote is not significantly associated with patient-reported continuity of care. However, PCPs' and cancer specialists' access to the eOncoNote intervention may be a factor in reducing patient anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT03333785; https://clinicaltrials.gov/ct2/show/NCT03333785.

Investigating the efficacy of osimertinib and crizotinib in phase 3 clinical trials on anti-cancer treatment-induced cardiotoxicity: are real-world studies the way forward?

BACKGROUND.: Oncology clinical trials demonstrate the risk of cardiotoxicity but are not sufficient to reveal the true risk. In this article, we compared the incidence of cardiotoxicity of crizotinib and osimertinib from a real-world study to data reported by phase 3 clinical trials. METHODS.: Data from an ongoing real-world lung cancer study was used as a comparator. Patients were recruited retrospectively with the criteria of being diagnosed with non-small cell lung cancer and having received at least a course of treatment of tyrosine-kinase inhibitor and/or immune check-point inhibitor. Characteristics of the patients who developed cardiotoxicity associated with osimertinib and crizotinib in the real-world lung cancer study were analysed against the inclusion criteria of the corresponding phase 3 clinical trials. Variations of cardiotoxicity incidence among the real-world lung cancer study and clinical trials were investigated. RESULTS.: 18%, n = 37/206, of the patients developed cardiotoxicity. QTc prolongation was the most frequently observed cardiotoxicity (n = 12/37). Osimertinib and crizotinib were the most cardiotoxic agents, each responsible for seven cases of cardiotoxicity. FLAURA, AURA3, PROFILE 1007 and PROFILE 1014 were the included clinical trials for analysis. None of the patients who developed cardiotoxicity in the real-world study would have been eligible to participate in FLAURA and PROFILE 1014 study whereas n = 4/7 and n = 5/7 patients were eligible to participate in AURA3 and PROFILE 1007 trials, respectively. CONCLUSION.: Although phase 3 clinical trials play an important role in understanding the effectiveness and give insights on side-effect profiles, real-world studies can show the real risk of cardiotoxicity more accurately and realistically.

Assessment of RANK/RANK-L prevalence and clinical significance in NSCLC European Thoracic Oncology Platform Lungscape cohort and SPLENDOUR randomized clinical trial.

BACKGROUND: The primary objective of this study is to evaluate the clinical significance of RANK/L expression, in both a retrospective cohort of surgically resected stage I-III NSCLC (Lungscape) and a randomized clinical trial-cohort (SPLENDOUR) of advanced NSCLC treated with chemotherapy alone or in combination with denosumab. METHODS: RANK-L expression was assessed on tissue microarrays (TMAs) in Lungscape and whole sections in SPLENDOUR, using immunohistochemistry, with H-scores values > 0 indicating positivity. Prevalence of RANK positivity and its association with clinicopathological characteristics, and patient outcome was explored in a subset of the ETOP Lungscape cohort and in SPLENDOUR. Also investigated were the prevalence of RANK overexpression (proportion of positive cancer cells ≥ 50%) in the Lungscape cohort, and RANK-L in the SPLENDOUR trial. RESULTS: In the Lungscape cohort, RANK expression was assessed at a median follow-up of 46 months (N = 488 patients; 4 centers); 35% were female, 44/49/6% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 48/27/25% with stage I/II/III. Median RFS/TTR/OS were 58/Not reached/74 months. Prevalence of RANK expression was 31% (95%CI:27%-35%); significantly higher in AC: 50% (95%CI:43%-57%) vs SCC: 12% (95%CI:8%-16%) (p < 0.001); more frequent in females (42% vs 25%, p < 0.001) and tumors ≤ 4 cm (35.3% vs 23.3%, p = 0.0065). No association with outcome was found. In the SPLENDOUR trial (463 patients), the prevalence of membranous and cytoplasmic RANK positivity was 34% (95%CI:30%-38%) and 9% (95%CI:7%-12%), respectively, while prevalence for RANK-L was 5% (95%CI:3%-7%) and 36% (95%CI:31%-40%), respectively. Cytoplasmic RANK-L positivity was more common among females (47% vs 31%, p = 0.001) and in non-SCC histology (45% vs 10%, p < 0.0001). At the pre-specified 1% significance level, no prognostic or predictive effect was found. CONCLUSIONS: Both cohorts indicate that RANK expression is more common in adenocarcinoma/non-squamous NSCLC and in female patients. No prognostic effect is found, and in the clinical trial involving addition of denosumab to chemotherapy no predictive effect is detected.

Patient and Healthcare Provider Perspectives on the Implementation of a Web-Based Clinical Communication System for Cancer: A Qualitative Study.

Previous research has identified communication and care coordination problems for patients with cancer. Healthcare providers (HCPs) have reported communication issues due to the incompatibility of electronic medical records (EMR) software and not being consistently copied on patient reports. We evaluated an asynchronous web-based communication system ("eOncoNote") for primary care providers and cancer specialists to improve cancer care coordination. The objectives were to examine patients' perceptions of the role of eOncoNote in their healthcare, and HCPs' experiences of implementing eOncoNote. Qualitative interviews were conducted with patients with breast and prostate cancer, primary care providers, and cancer specialists. Eighteen patients and fourteen HCPs participated. Six themes were identified from the patient interviews focusing on HCP and patient roles related to care coordination and patient awareness of communication among their HCPs. Four themes were identified from HCP interviews related to the context of care coordination and experience with eOncoNote. Both patients and HCPs described the important role patients and caregivers play in care coordination. The results show that patients were often unaware of the communication between their HCPs and assumed they were communicating. HCPs encountered challenges incorporating eOncoNote into their workflow.

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial.

BACKGROUND: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC. METHODS: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting. FINDINGS: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo. INTERPRETATION: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Use of eConsult to enhance genetics service delivery in primary care: A multimethod study.

PURPOSE: Electronic consultation (eConsult) is a freely-available secure online platform connecting primary care providers (PCPs) to geneticists. Our purpose was to determine whether eConsult is effective in improving genetics service delivery in primary care. METHODS: PCP questionnaires regarding eConsult's utility, geneticists' tracking form assessments of eConsult type and appropriateness, and geneticists' interviews on implementing eConsult were carried out. RESULTS: In 2 regions of Ontario, Canada, from January 2019 to June 2020, there were 305 genetics eConsults. For 169 (55%), PCPs indicated receiving good advice for a new course of action; for 110 (36%), referral was now avoided; and for 261 (86%), eConsult was perceived valuable for patient management. Of the 131 geneticist-completed tracking forms, cancer questions were most common (68, 52%). For 63 (48%), geneticists disagreed/strongly disagreed PCPs should know the answer to the referral question. From the interview data, it was observed that geneticists described eConsult positively and suggested how it might improve access and efficiencies if integrated into genetic service delivery. Dealing with eConsults virtually could reduce waitlists, and suggesting appropriate investigations for PCPs could improve efficiencies. CONCLUSION: eConsult offers a potential solution for receiving timely genetics advice and avoiding unnecessary patient referrals, however, greater effect on access and wait times will need systematic integration into PCP and geneticist practice.

Splenic volume as a predictor of treatment response in patients with non-small cell lung cancer receiving immunotherapy.

INTRODUCTION: The spleen is a lymphoid organ and we hypothesize that clinical benefit to immunotherapy may present with an increase in splenic volume during treatment. The purpose of this study was to investigate whether changes in splenic volume could be observed in those showing clinical benefit versus those not showing clinical benefit to pembrolizumab treatment in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: In this study, 70 patients with locally advanced or metastatic NSCLC treated with pembrolizumab; and who underwent baseline CT scan within 2 weeks before treatment and follow-up CT within 3 months after commencing immunotherapy were retrospectively evaluated. The splenic volume on each CT was segmented manually by outlining the splenic contour on every image and the total volume summated. We compared the splenic volume in those achieving a clinical benefit and those not achieving clinical benefit, using non-parametric Wilcoxon signed-rank test. Clinical benefit was defined as stable disease or partial response lasting for greater than 24 weeks. A p-value of <0.05 was considered statistically significant. RESULTS: There were 23 responders and 47 non-responders based on iRECIST criteria and 35 patients with clinical benefit and 35 without clinical benefit. There was no significant difference in the median pre-treatment volume (175 vs 187 cm3, p = 0.34), post-treatment volume (168 vs 167 cm3, p = 0.39) or change in splenic volume (-0.002 vs 0.0002 cm3, p = 0.97) between the two groups. No significant differences were also found between the splenic volume of patients with partial response, stable disease or progressive disease (p>0.017). Moreover, there was no statistically significant difference between progression-free survival and time to disease progression when the splenic volume was categorized as smaller or larger than the median pre-treatment or post-treatment volume (p>0.05). CONCLUSION: No significant differences were observed in the splenic volume of those showing clinical benefit versus those without clinical benefit to pembrolizumab treatment in NSCLC patients. CT splenic volume cannot be used as a potentially simple biomarker of response to immunotherapy.