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The aim of this guideline was to provide recommendations for the most effective therapy for patients with thymic epithelial tumours, including thymoma, thymic carcinoma, and thymic neuroendocrine tumours. This guideline is intended to be used by all healthcare professionals managing patients with thymic epithelial tumours.The guideline was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group through a systematic review of the evidence, expert consensus, and formal internal and external reviews.Evidence-based recommendations were developed to improve the management of patients with thymic epithelial tumours. The guideline includes recommendations for surgical, radiation, and systemic treatments for patients with thymoma, thymic carcinoma, and thymic neuroendocrine tumours separated by stage of disease using the TNM staging system. Recommendations for patients with thymic neuroendocrine tumours were endorsed from the 2021 National Comprehensive Cancer Network Neuroendocrine and Adrenal Tumors Guideline.This guideline reflects the new staging system for patients with thymoma and thymic carcinoma and includes supporting evidence from the best available studies.

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.

Background Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. Methods Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. Results Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. Conclusion One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.

Purpose:This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC).Patients and Methods:Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4–6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control.Results:Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50–0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36–0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09–1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic.Conclusions:Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

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. Résumé: 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.

Introduction Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free survival. Bradycardia is a potential adverse effect of these agents. We aimed to determine the risk of bradycardia associated with ALK inhibitors in patients with advanced NSCLC. Materials and methods We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, National clinical trial registry, and Web of Science Core Collection. We included all randomized controlled trials in which an ALK-inhibitor was compared with another ALK-inhibitor or standard chemotherapy. Meta-analyses were conducted to evaluate the pooled incidence rates of bradycardia and dizziness using fixed effect models. Results The pooled incidence of bradycardia among 1737 individuals prescribed ALK inhibitors was 8% during a mean follow-up of 1.26 years. Crizotinib led to more bradycardia than standard chemotherapy (relative risk, RR 24.68, 95% CI 7.11–85.), while no difference was seen between crizotinib and alectinib (RR 1.12, 95% CI 0.79–1.59). The next-generation ALK inhibitors alectinib, brigatinib and lorlatinib combined resulted in a similar rate of bradycardia when compared to crizotinib (RR 0.77, 95% CI 0.57–1.04). All ALK inhibitors (as an aggregate) caused more dizziness (as a potential symptom of bradycardia) than standard chemotherapy (RR 1.88, 95% CI 1.44–2.44). Conclusion: Crizotinib for the treatment of NSCLC is associated with a higher risk for bradycardia compared to standard chemotherapy. There is no evidence of a difference in bradycardia risk between crizotinib and newer ALK inhibitors.

Purpose: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC). Patients and Methods: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4–6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control. Results: Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50–0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36–0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09–1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic. Conclusions: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

Living guidelines are routinely updated guidelines that are developed for selected topic areas with rapidly evolving evidence that drives frequent change in clinical practice. These guidelines are updated on a regular schedule, based on the work of a standing panel that reviews the literature on a continuous basis. Updates will be made regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline . PURPOSE To provide evidence-based recommendations updating the 2021 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC) with driver alterations. METHODS ASCO updated recommendations on the basis of an ongoing systematic review of randomized control trials from 2020 to 2021. RESULTS This guideline update reflects changes in evidence since the previous update. Two studies provide the evidence base. Outcomes of interest include efficacy and safety. RECOMMENDATIONS For patients with an anaplastic lymphoma kinase rearrangement, a performance status (PS) of 0-2, and previously untreated NSCLC, clinicians should offer alectinib or brigatinib or lorlatinib. For patients with an anaplastic lymphoma kinase rearrangement, a PS of 0-2, and previously untreated NSCLC, if alectinib, brigatinib, or lorlatinib are not available, clinicians should offer ceritinib or crizotinib. For patients with a RET rearrangement, a PS of 0-2, and previously untreated NSCLC, clinicians may offer selpercatinib or pralsetinib. In second line, for patients with a RET rearrangement who have not received RET-targeted therapy, clinicians may offer selpercatinib or pralsetinib. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

Thymic epithelial tumors are rare and are classified as thymoma, thymic carcinoma, and thymic neuroendocrine tumors. The objective of this systematic review was to evaluate the treatment options for patients with thymic epithelial tumors.This systematic review was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing surgical, radiotherapy, or systemic treatments against any combination of these treatments in patients with thymic epithelial tumors. Meta-analyses were conducted with clinically homogenous studies.A total of 106 studies were included, mainly from observational studies. There was an overall survival benefit with postoperative radiotherapy for patients with thymic carcinoma (hazard ratio = 0.65, 95% confidence interval: 0.47-0.89) and for patients with thymoma (hazard ratio = 0.70, 95% confidence interval: 0.59-0.82), especially for those with a high risk for mortality. Patients with thymic carcinoma or thymoma had a response to chemotherapy. Selection bias affected the results for studies that evaluated neoadjuvant chemotherapy or minimally invasive surgical techniques. Furthermore, the overall survival benefit found for adjuvant chemotherapy may have been confounded by the administration of postoperative radiotherapy.For patients with thymoma or thymic carcinoma, the literature is of low quality and subject to bias. There were overall survival benefits with postoperative radiotherapy. The results of this systematic review were used to inform treatment recommendations in a clinical practice guideline. Future large-scale prospective studies that control for confounders are needed.

The onset of the COVID-19 in the UK has resulted in an inordinate amount of deaths affecting Black, Asian and Ethnic Minority (BAME) healthcare workers. The occupational risk to this group is thought to be a contributory factor, but other factors include race, genetics, medical co-morbidities, socio-economic status, and access to personal protection equipment. Why COVID-19 appears to be more deadly in BAME members remains unknown, but the UK government is investigating this now. It does appear that certain factors may worsen the disease process in BAME members, but which ones are pertinent to prevention remain to be determined, until a vaccine is available. Thus, the onus should rest on risk prevention, education, and support for all. Some of the safety strategies that may be instituted to help guide those in the workplace include education, treating potential therapeutic targets and ensuring protection in the working environment. The consideration of a compensation scheme, for families of healthcare workers that have suffered because of COVID-19, would go some way to support the recovery process.

A range of barriers that impede collaborations between consumer researchers and other researchers have been identified, despite clear acknowledgement of the benefits of this approach in the literature. Recent research has questioned whether the costs of collaborative research outweigh the benefits. The overarching aim of the current study is to better understand non-consumer researchers' attitudes to, and issues concerning, engagement with consumer researchers. Non-consumer researchers from mental health disciplines were invited to participate in the cross-sectional Consumers as Researchers in Mental Health survey, and to respond to open-ended questions about their experiences of collaborative research with consumer researchers. The findings demonstrate a range of benefits associated with collaborations with consumer researchers - including increased relevance and credibility of research, and greater translation of research findings into changes in health policy, service, research and education. Collaborations were found to be varied and not limited by research design, decision-making styles, or research topic. Understanding these benefits within the context of identified barriers can make an important contribution to the proliferation of mental health consumer researcher roles.

Consumer collaboration in mental health research has demonstrated significant benefits and reflects both contemporary research practice and policy goals for the expected genuine involvement of consumers in all aspects of mental health service delivery. Notable barriers have been identified as impeding consumer researcher positions that must be better understood and ultimately addressed. The aim of this research was to better understand these barriers from the perspectives of non-consumer researchers who have worked collegially with consumer researchers. We developed a self-report survey, Consumers as Researchers in Mental Health (CaRiMH) and administered it to non-consumer mental health researchers in Australia and New Zealand. Findings suggest a lack of organizational structures to support both consumer research and capacity building of consumer researchers. Most consumer researchers were employed casually with no set hours. Although consumer researchers were typically remunerated, inadequate funding and inflexibility of employment were highlighted as major barriers. There was variation in opinion about token involvement of consumer researchers and some uncertainty about whether these roles, where they existed, were actively resisted. Despite the acknowledged barriers, participants were positive about collaborations with consumer researchers. Overall, findings suggest consumer research is unlikely to proliferate without greater attention to organizational structures. A systematic and strategic approach to advancing mental health consumer research is required, including extra-organizational policy factors.

Purpose The standard of care in management of patients with good performance status and unresectable stage III non-small cell lung cancer (NSCLC) therapy is concurrent chemoradiation. Newer techniques such as intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) are replacing 3-dimensional conformal radiation (3DCRT) despite low-quality evidence of improved outcomes. We used population-based data to examine survival outcomes by radiation technique. Methods and Materials A population-based retrospective cohort of patients with stage III NSCLC treated with concurrent chemoradiation from 2009 to 2017 in Ontario were identified. The primary outcome was a comparison of overall survival among 3DCRT, IMRT, and VMAT, calculated using the Kaplan-Meier method and compared using log-rank test. Cox regression was used to investigate effect of radiation type on overall survival adjusted for other covariates. Results A total of 3872 patients were treated with 3DCRT (n = 1178), IMRT (n = 1847), or VMAT (n = 847). A decline in 3DCRT and increase in VMAT use were observed over time. Median survival in months was 21.2 (95% confidence interval [CI], 20.0-22.8) for 3DCRT, 23.9 (95% CI, 22.3-25.6) for IMRT, and 24.9 (95% CI, 22.5-27.4) for VMAT, but these differences were not statistically significant (P = .06). Conclusions Our study demonstrates that survival is not compromised in patients receiving IMRT or VMAT (compared with 3DCRT). Thus, given the potential dosimetric advantages associated with these techniques, VMAT and IMRT are recommended for the management of patients with stage III NSCLC.

Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.

Introduction Anaplastic Lymphoma Kinase (ALK) inhibitors represent a major therapeutic advance in the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). Bradycardia was initially observed with crizotinib, the first ALK inhibitor. The risk of bradycardia and whether it differs among various generations of ALK inhibitors has not been systematically described. Purpose The primary objective of this systematic review is to compare the risk of bradycardia in patients who received an ALK inhibitor or standard chemotherapy for the treatment of NSCLC in randomized controlled trials. Methods We conducted a systematic literature search in MEDLINE, EMBASE, Cochrane Central, Web of Science, and Clinical Trials registry. We included randomized controlled trials that compared two different ALK inhibitors, or an ALK inhibitor with standard chemotherapies in patients with NSCLC. The primary outcome of interest was the number of bradycardia events. Because bradycardia was not systematically reported in many trials, we also documented reports of dizziness (as a potential symptom of bradycardia) in a secondary analysis. Results We identified 12 eligible studies including 2915 participants. Bradycardia was reported as a treatment-emergent adverse event in 9 trials; dizziness was reported in the remaining 3 trials. The type of bradycardia and use of heart rate-slowing medications were not documented in most studies. The incidence of bradycardia among 1080 individuals prescribed crizotinib in 8 trials was 13% (95% CI 9–17%) during a mean follow-up of 1.26 years. A meta-analysis of four trials that compared crizotinib with standard chemotherapies (Figure 1) showed a higher risk of bradycardia with crizotinib (RR 19.33; 95% CI 5.40–69.22). Newer generations of ALK inhibitors (alectinib, brigatinib and lorlatinib) showed similar rates of bradycardia compared to crizotinib (RR 0.51; 95% CI 0.21–1.26; Figure 2). Dizziness was more common in ALK inhibitors than standard chemotherapies (RR 1.83; 95% CI 1.38–2.42). Conclusions Our findings suggest that crizotinib is associated with a higher rate of bradycardia than standard chemotherapies, while no difference was found between crizotinib and newer generations of ALK inhibitors. The higher rate of dizziness in ALK inhibitors could represent a symptom of bradycardia. Further research is needed to evaluate the incidence and types of ALK inhibitor-associated bradycardia and its relationship with patient symptoms. Funding Acknowledgement Type of funding sources: None. Figure 2

Importance Unresected locally advanced non–small cell lung cancer (LA-NSCLC) shows poor survival outcomes even after aggressive concurrent chemoradiotherapy. Whether metformin, a diabetes agent that inhibits the mitochondria oxidative phosphorylation chain, could improve radiotherapy and chemotherapy response in LA-NSCLC remains to be studied. Objective To examine whether metformin, given concurrently with chemoradiotherapy and as consolidation treatment, could improve outcomes in patients with LA-NSCLC. Design, Setting, and Participants The Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy (OCOG-ALMERA) study was a multicenter phase 2 randomized clinical trial. Patients were stratified for stage IIIA vs IIIB LA-NSCLC and use of consolidation chemotherapy. The trial was designed to enroll 96 patients with unresected LA-NSCLC who did not have diabetes. The trial was conducted from September 24, 2014, to March 8, 2019. Interventions Patients were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy (60-63 Gy), with or without consolidation chemotherapy or the same treatment plus metformin, 2000 mg/d, during chemoradiotherapy and afterward for up to 12 months. Main Outcomes and Measures The primary outcome was the proportion of patients who experienced a failure event (ie, locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months). Proportions were compared using a 2-sided Fisher exact test. Conventional progression-free and overall survival were estimated using the Kaplan-Meier method. Adverse events were graded with Common Terminology Criteria for Adverse Events, version 4.03. All randomized patients were included in an intention-to-treat analysis. Results The trial was stopped early due to slow accrual. Between 2014 and 2019, 54 patients were randomized (26 in experimental arm and 28 in control arm). Participants included 30 women (55.6%); mean (SD) age was 65.6 (7.6) years. Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients (P = .05). The 1-year progression-free survival rate was 34.8% (95% CI, 16.6%-53.7%) in the metformin arm and 63.0% (95% CI, 42.1%-78.1%) in the control arm (hazard ratio, 2.42; 95% CI, 1.14-5.10) The overall survival rates were 47.4% (95% CI, 26.3%-65.9%) in the metformin arm and 85.2% (95% CI, 65.2%-94.2%) in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event. Conclusions and Relevance In this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC who are candidates for chemoradiotherapy. Trial Registration ClinicalTrials.gov Identifier:NCT02115464

Objectives This study sought to evaluate the safety of continuing trastuzumab in patients with human epidermal growth factor receptor–positive breast cancer who developed mild cardiotoxicity. Background Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Current standard of care is discontinuation of trastuzumab, which can lead to worse cancer outcomes. It is unknown whether it is safe to continue trastuzumab despite mild cardiotoxicity. Methods Patients were eligible for this phase I, prospective, single-arm trial if left ventricular ejection fraction (LVEF) was between 40% and the lower limit of normal or if it fell ≥15% from baseline. Participants were treated with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers in a cardio-oncology clinic and were followed clinically and with serial echocardiograms for 1 year. The primary outcome was cardiac dose-limiting toxicity, defined as cardiovascular death, LVEF, Central Illustration

WHAT IS KNOWN ON THE SUBJECT?: Contemporary mental health policy stipulates consumer participation in all aspects of mental health services including service evaluation and other forms of mental health research. Research is identified as underpinning quality mental health services, and therefore, consumers researchers could enhance the mental health sector by contributing to the quality, credibility and relevance of mental health research. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Non-consumer researchers generally supported the concept of a consumer expert reference group for researchers at the individual and institutional level. A consumer expert reference group should reflect diversity and offer expertise relevant to the topic of research and may represent one way to normalize partnerships with consumer researchers and realize the benefits they can bring to research. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Quality mental health services are underpinned by robust research evidence. It is crucial that consumers are active participants in research activity. The availability of a consumer expert reference group could facilitate collaborations between consumer and non-consumer researchers and contribute to a stronger consumer focus embedded in mental health research. Abstract Introduction Contemporary mental health policy identifies consumers as active participants in all aspects of mental health services from design to evaluation. Consumer researchers should be actively involved in mental health research and contribute to quality service delivery. Aim To gain a snapshot of mental health researcher views on strategies for increasing research by or with consumers in mental health through the establishment of an Expert Consumer Researcher Group (ECRG). Methods Cross-sectional survey of 41 non-consumer mental health researchers from Australia or New Zealand. Results The introduction of an ECRG was considered an effective strategy for linking consumer and non-consumer researchers and providing specialist advice on research design and methodology. The most suitable location for this group was identified as within consumer advocacy agencies (71%), universities (66%) or research funding bodies (66%). Participants rated their likelihood of seeking advice from the ECRG as high. Discussion Research participants supported the value of an ECRG. They emphasized the importance of ensuring the group reflected a diversity of views and offered specialized expertise related to the specific topic. The ECRG could benefit both individual researchers and larger research organizations. Implications for practice An ECRG could facilitate collaborations with consumer researchers and in turn enhance the quality of mental health research.

The major limitation in the use of trastuzumab therapy is cardiotoxicity. We evaluated the safety of a strategy of continuing trastuzumab in patients with breast cancer despite mild, asymptomatic left ventricular impairment. Charts of consecutive patients referred to a cardio-oncology clinic from January 2015 to March 2017 for decline in left ventricular ejection fraction (lvef), defined as a fall of 10 percentage points or more, or a value of less than 50% during trastuzumab therapy, were reviewed. The primary outcome of interest was change in lvef, measured before and during trastuzumab exposure and up to 3 times after initiation of cardiac medications during a median of 9 months. All 18 patients referred for decline in lvef chose to remain on trastuzumab and were included. All patients were treated with angiotensin converting&ndash, enzyme inhibitors or beta-blockers, or both. After initiation of cardiac medications, lvef increased over time by 4.6 percentage points (95% confidence interval: 1.9 percentage points to 7.4 percentage points), approaching baseline values. Of the 18 patients, 17 (94%) were asymptomatic at all future visits. No deaths occurred in the group. Many patients with mildly reduced lvef and minimal heart failure symptoms might be able to continue trastuzumab without further decline in lvef, adverse cardiac events, or death when treated under the supervision of a cardiologist with close follow-up.

Chemoradiation with curative intent is considered the standard of care in patients with locally advanced, stage iii non-small-cell lung cancer (nsclc). However, some patients with stage iii (N2 or N3, excluding T4) nsclc might be eligible for surgery. The objective of the present systematic review was to investigate the efficacy of surgery after chemoradiotherapy compared with chemoradiotherapy alone in patients with potentially resectable locally advanced nsclc. A search of the medline, embase, and PubMed databases sought randomized controlled trials (rcts) comparing surgery after chemoradiotherapy with chemoradiotherapy alone in patients with stage iii (N2 or N3, excluding T4) nsclc. Three included rcts consistently found no statistically significant difference in overall survival between patients with locally advanced nsclc who received surgery and chemoradiotherapy or chemoradiotherapy alone. Only one rct found that progression-free survival was significantly longer in patients treated with chemoradiation and surgery (hazard ratio: 0.77, 95% confidence interval: 0.62 to 0.96). In a post hoc analysis of the same trial, the overall survival rate was higher in the surgical group than in matched patients in a chemoradiation-only group if a lobectomy was performed (p = 0.002), but not if a pneumonectomy was performed. Furthermore, fewer treatment-related deaths occurred in patients who underwent lobectomy than in those who underwent pneumonectomy. For patients with locally advanced nsclc, the benefits of surgery after chemoradiation are uncertain. Surgery after chemoradiation for patients who do not require a pneumonectomy might be an option.

PURPOSE To provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC) with driver alterations. A guideline update for systemic therapy for patients with stage IV NSCLC without driver alterations was published separately. METHODS The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel updated recommendations based on a systematic review of randomized controlled trials (RCTs) from December 2015 to January 2020 and meeting abstracts from ASCO 2020. RESULTS This guideline update reflects changes in evidence since the previous update. Twenty-seven RCTs, 26 observational studies, and one meta-analysis provide the evidence base (total 54). Outcomes of interest included efficacy and safety. Additional literature suggested by the Expert Panel is discussed. RECOMMENDATIONS All patients with nonsquamous NSCLC should have the results of testing for potentially targetable mutations (alterations) before implementing therapy for advanced lung cancer, regardless of smoking status recommendations, when possible, following other existing high-quality testing guidelines. Most patients should receive targeted therapy for these alterations: Targeted therapies against ROS-1 fusions, BRAF V600e mutations, RET fusions, MET exon 14 skipping mutations, and NTRK fusions should be offered to patients, either as initial or second-line therapy when not given in the first-line setting. New or revised recommendations include the following: Osimertinib is the optimal first-line treatment for patients with activating epidermal growth factor receptor mutations (exon 19 deletion, exon 21 L858R, and exon 20 T790M); alectinib or brigatinib is the optimal first-line treatment for patients with anaplastic lymphoma kinase fusions. For the first time, to our knowledge, the guideline includes recommendations regarding RET, MET, and NTRK alterations. Chemotherapy is still an option at most stages. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

Background: Widespread concerns about new medical graduates' 'work readiness' may reflect, in part, differences in mandatory learning outcomes for medical students and new medical graduates.Purpose: To examine differences between required medical student and PGY1 (first year resident) training program outcomes, and the nature and magnitude of these differences.Method: Comparison, systematic identification and thematic analysis of differences between the graduate outcomes in the Australian Medical Council Standards for the Assessment and Accreditation of Primary Medical Programs and those in the New Zealand Curriculum Framework for Prevocational Training.Results: The relationship between these outcome statements were categorized as: essentially similar; continuity; partial discontinuity; and complete discontinuity of learning trajectory. Areas requiring substantial new learning may reflect medical schools' focus on individual student performance, and on learning and assessments based on single episodes of often uncomplicated illness. This contrasted with a post-graduate focus on integrated health care delivery by teams and management of complex illnesses over the whole patient care journey.Conclusions: Characterizing these marked differences between pre-graduate and postgraduate standards, within a trajectory of learning, explains some of the difficulties in students' preparation for work readiness. These could inform learning interventions to support new graduates' professional development to ensure patient safety. Development and revision of accreditation standards should include formal review against the expectations of the preceding and succeeding phases of learning.

Purpose To explore the views and opinions of nonconsumer researchers to the concept of an Expert Consumer Researcher Group. Design and methods Qualitative exploratory involving individual interviews with nonconsumer mental health researchers experienced in working collaboratively with consumer researchers. Data were analyzed thematically. Findings Participants viewed the concept positively, albeit with caution. Perceived advantages included: greater visibility and enhanced access; collegiality; sharing and creating expertise; broader acceptance; making it mandatory; and structure and location. Participants were concerned about potential tokenism and implementation barriers. Practice implications Consumer involvement enhances the quality and relevance of research, potentially impacting clinical practice.

Objective Clozapine is the favoured antipsychotic for treatment-refractory schizophrenia but its safe use requires careful adverse-effect management. Clozapine-induced gastrointestinal hypomotility (CIGH or ‘slow-gut’) is one of the most common and serious of clozapine's adverse effects. CIGH can lead to paralytic ileus, bowel obstruction, gastrointestinal ischaemia, toxic megacolon, and death. Enquiring about constipation is a simple and commonly used screening method for CIGH but its diagnostic accuracy has not previously been assessed. Methods First, we examined the reliability of asking about constipation compared with asking about Rome constipation criteria in inpatients treated with clozapine (n = 69). Second, we examined the diagnostic accuracy of (1) self-reported constipation and (2) the Rome criteria, compared with the reference standard of gastrointestinal motility studies. Results After 30 motility tests, it was clear constipation screening had very poor diagnostic properties in this inpatient group and the study was terminated. Although 73% of participants had objective CIGH on motility testing, only 26% of participants self-reported constipation, with sensitivity of 18% (95% CI: 5–40%). Specificity and positive predictive values were higher (95% CI: 63–100% and 40–100%, respectively). Adding in Rome criteria improved sensitivity to 50% (95% CI: 28.2–71.8%), but half the cases were still missed, making this no more accurate than tossing a coin. Conclusions CIGH is often silent, with self-reported constipation having low sensitivity in its diagnosis. Treating CIGH based on self-reported symptoms questions will miss most cases. However, universal bowel motility studies are impractical. In the interests of patient safety, prophylactic laxatives are suggested for people taking clozapine.

PURPOSE The aim of this work is to provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC) without driver alterations. A guideline update for patients with stage IV NSCLC with driver alterations will be published separately. METHODS The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel made updated recommendations based on a systematic review of randomized controlled trials from December 2015 to 2019. RESULTS This guideline update reflects changes in evidence since the previous guideline update. Five randomized controlled trials provide the evidence base. Additional literature suggested by the Expert Panel is discussed. RECOMMENDATIONS Recommendations apply to patients without driver alterations in epidermal growth factor receptor or ALK. For patients with high programmed death ligand 1 (PD-L1) expression (tumor proportion score [TPS] ≥ 50%) and non–squamous cell carcinoma (non-SCC), the Expert Panel recommends single-agent pembrolizumab. Additional treatment options include pembrolizumab/carboplatin/pemetrexed, atezolizumab/carboplatin/paclitaxel/bevacizumab, or atezolizumab/carboplatin/nab-paclitaxel. For most patients with non-SCC and either negative (0%) or low positive (1% to 49%) PD-L1, the Expert Panel recommends pembrolizumab/carboplatin/pemetrexed. Additional options are atezolizumab/carboplatin/nab-paclitaxel, atezolizumab/carboplatin/paclitaxel/bevacizumab, platinum-based two-drug combination chemotherapy, or non–platinum-based two-drug therapy. Single-agent pembrolizumab is an option for low positive PD-L1. For patients with high PD-L1 expression (TPS ≥ 50%) and SCC, the Expert Panel recommends single-agent pembrolizumab. An additional treatment option is pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel). For most patients with SCC and either negative (0%) or low positive PD-L1 (TPS 1% to 49%), the Expert Panel recommends pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel) or chemotherapy. Single-agent pembrolizumab is an option in select cases of low positive PD-L1. Recommendations are conditional on the basis of histology, PD-L1 status, and/or the presence or absence of contraindications. Additional information is available at www.asco.org/lung-cancer-guidelines .

This multicenter phase Ib study aimed to establish a recommended phase II dose for durvalumab (Du) ± tremelimumab (Tr) in combination with standard platinum-doublet chemotherapy. Eligible patients were enrolled into one of six dose levels (DL) of Du ± Tr which included concomitant treatment with standard platinum-doublet regimens; (pemetrexed, gemcitabine, etoposide, (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)). Dose escalation was according to a Rolling Six type design. Both weight-based and fixed dosing of Du and Tr were explored. Du was continued until progression. Tr dosing was finite (up to 6 doses) with increasing dose and/or frequency by DL. 136 patients were enrolled. The majority of drug-related adverse events (AEs) were ≤ grade 2 and attributable to chemotherapy. AEs considered related to immunotherapy were mainly ≤ grade 2; the most frequent (occurring ≥10 %) were colitis/diarrhea, skin, and thyroid dysfunction. Seven patients had DLTs including pneumonitis, myocarditis, diarrhea, encephalitis, motor neuropathy, and enterocolitis. There were 2 treatment-related deaths. Tr and Du exposures did not appear affected by chemotherapy. Among the 73 non-small cell lung cancer (NSCLC) patients treated, the objective response rate was 51 % (95 %CI = 38.7-62.6 %) with a median progression-free and overall survival of 6.5 months (95 % CI = 5.5-9.4 months) and 19.8 months (95 % CI = 14.8 months - not yet reached) respectively. Anti-tumour activity was observed across PD-L1 subtypes. Du 1500 mg q3w and Tr 75 mg q3wx5 can be safely combined with platinum-doublet chemotherapy. Efficacy among NSCLC patients appears comparable to results from other immunotherapy and chemotherapy combination trials. NCT02537418.

Background Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series. Patients and methods KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post hoc, exploratory analysis. The main outcome measures were best overall response rate (complete response + partial response) and clinical benefit rate (complete response + partial response + stable disease lasting ≥6 months) by RECIST v1.1 criteria, progression-free survival, overall survival, and safety. Results Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the best overall response rate and clinical benefit rate were 21.4% [95% confidence interval (CI) 14.6–29.6] and 42.9% (95% CI 34.1–52.0), respectively. A reduction in the sum of the major diameters of BM ≥30% occurred in 42.9% (95% CI 34.1–52.0), including 49.3% (95% CI 36.9–61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median progression-free survival and overall survival were 5.5 (95% CI 5.3–5.6) months and 18.9 (95% CI 17.1–21.3) months, respectively. The adverse event profile was broadly similar in patients with and without baseline BM, although nervous system adverse events were more common in patients with [208 (52.3%)] versus without [701 (43.7%)] baseline BM. Conclusion This exploratory analysis of patients with HER2-positive metastatic breast cancer and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting. Trial registration ClinicalTrials.gov identifier: NCT01702571.

Technological advancements in recent years have sparked the use of large databases for research. The availability of these large databases has administered a need for anonymization and de-identification techniques, prior to publishing the data. This de-identification alters the data, which in turn can impact the results derived post de-identification and potentially lead to false conclusions. The objective of this study is to investigate if alterations to a de-identified time-to-event data set may improve the accuracy of the estimates. In this data set, a missing time bias was present among censored patients as a means to preserve patient confidentiality. This study investigates five methods intended to reduce the bias of time-to-event estimates. A simulation study was conducted to evaluate the effectiveness of each method in reducing bias. In situations where there was a large number of censored patients, the results of the simulation showed that Method 4 yielded the most accurate estimates. This method adjusted the survival times of censored patients by adding a random uniform component such that the modified survival time would occur within the final year of the study. Alternatively, when there was only a small number of censored patients, the method that did not alter the de-identified data set (Method 1) provided the most accurate estimates.

Angiogenesis is frequent in non-small-cell lung cancer (nsclc) and is associated with more aggressive disease. Many clinical trials have evaluated the addition of antiangiogenic therapy to standard therapies for patients with nsclc. Bevacizumab, a monoclonal antibody directed against serum vascular endothelial growth factor, in combination with carboplatin&ndash, paclitaxel chemotherapy, has been shown to improve survival for patients with nsclc. However, bevacizumab-based therapy is not suitable for many nsclc patients, including those with squamous histology, poor performance status, brain metastases, and the presence of bleeding or thrombotic disorders. Similar efficacy has also been seen with carboplatin&ndash, pemetrexed followed by maintenance pemetrexed chemotherapy. In the second-line setting, the addition of ramucirumab to docetaxel&mdash, or the addition of bevacizumab to paclitaxel&mdash, has resulted in a modest improvement in efficacy, although the clinical importance of those findings is questionable. Many trials in nsclc have also evaluated oral antiangiogenic compounds, both in the first line in combination with chemotherapy and upon disease progression either as combination or single-agent therapy. No clear improvements in overall survival have been observed, although a subgroup analysis of a trial evaluating the addition of nintedanib to docetaxel showed improved survival that was limited to patients with adenocarcinoma. Those findings require validation, however.

Coproduction of research between consumers of mental health services and nonconsumer mental health researchers is increasing. There is some research available describing consumer perspectives of this experience. However, there is a notable lack of research on other (nonconsumer) researcher experiences of and views about consumer involvement in coproduced research. A qualitative exploratory study was undertaken to examine perspectives of mental health researchers about consumer involvement in research. In-depth individual interviews were undertaken with 11 nonconsumer mental health researchers in Australia and New Zealand. Interview transcripts were analysed to identify major themes. There were three interacting themes: the salience of experiential difference, expanded learning, and enhanced research. The dynamic between different perspectives and learning had the effect of enhancing research across the spectrum of study phases and in ensuring research was of value to different groups. The findings emphasize the important contribution consumer researchers can make to mental health research by bringing their unique perspective and enhancing an environment of mutual learning. Findings also point to the need for foregrounding the numerous benefits of joint research between consumer and other researchers to enhance and improve clinical practice and the development of policy.

Introduction: Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor (HER)-2 and significantly improves survival in HER-2 positive early stage breast cancer. However, trastuzumab is also known to cause cardiotoxicity. Guidelines recommend withholding or discontinuing trastuzumab if left ventricular ejection fraction (LVEF) falls ≥15% from baseline, or to Methods: In this retrospective chart review, we identified 18 consecutive patients with stage 1-3 HER-2 positive breast cancer patients who had a decline in LVEF meeting the criteria above to withhold trastuzumab, and who were referred to our cardio-oncology service from the beginning of 2015 to March 2017. These patients were offered and consented to receive ongoing trastuzumab accompanied by ACE-I and/or beta blocker. Data on patient demographics, cancer therapies, clinical features, LVEF, and cardiac medications were extracted from medical charts. Results: Among the 18 patients identified, all were women, 12 (67%) were estrogen receptor positive, and 7 progesterone receptor positive (39%). 11 (61%) of patients had a left-sided breast cancer, 6 (33%) had right-sided breast cancer, and 1 (5%) had an unspecified side breast cancer. 17 (94%) of patients had previously undergone radiation therapy, and 4 (22%) had experienced a recurrence. 16 patients had received a prior anthracycline regimen (10 sequentially, 6 concurrently). The patients were treated with one or a combination of the following medications: carvedilol (n=13), ramipril (n=12), bisoprolol (n=1), candesartan (n=2), rosuvastatin (n=2), atorvastatin (n=2). The patients were followed up for an average of 7 months after starting cardiac therapy. Table 1 summarizes the mean±SD LVEF values over the follow up time period. All patient except one (94%) completed trastuzumab treatment successfully. This patient with concomitant moderate-severe mitral regurgitation was hospitalized for pulmonary edema. Trastuzumab was discontinued and LVEF has subsequently returned to normal values. Table 1: LVEF progression from baseline to end of follow-upMean±SD LVEF at baseline57.59±5.49%Mean±SD LVEF on referral to cardio-oncology clinic50.75±4.76%Mean±SD LVEF at end of follow-up56.35±3.50% Conclusion: Treating cardiac dysfunction related to trastuzumab in a cardio-oncology clinic, using beta blockers and ACE-I may enable completion of trastuzumab therapy. Randomized trials are necessary before it can be widely recommended, however findings from our experience suggest this may be a promising new treatment strategy. Citation Format: Bharaj UK, Leong D, Dhesy-Thind S, Ellis P, Mukherjee S, Bordeleau L, Phillips C, Brown M, Kumar Tyagi N. Safety of continuing chemotherapy in overt left ventricular dysfunction using antibodies to human epidermal growth factor receptor-2: A retrospective study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-17.

Introduction: Detection of circulating tumor DNA (ctDNA) presents a strategy to identify Molecular Residual Disease (MRD) in patients with breast cancer. Tools capable of detecting ctDNA at lower concentrations are needed to increase sensitivity and lengthen lead time between ctDNA detection and relapse. We present results from a highly sensitive personalized sequencing approach for ctDNA detection of MRD based on multiple patient specific mutations. Methods: 22 early breast cancer patients (12 hormone receptor positive HER2 negative (HR+HER2-), 7 HER2+ and 3 triple negative breast cancer (TNBC)) enrolled in the ChemoNEAR sample collection study were included. Tumor DNA from FFPE samples was Whole Exome Sequenced to identify patient specific mutations and design personalized Residual Disease and Recurrence (RaDaRTM) multiplex PCR assays. Cell free DNA was extracted from 147 plasma samples (median volume 4ml, range 0.5-5ml) and sequenced with RaDaR assays, with 10-61 variants (median 41) per panel, to 100,000x per locus. A matched single timepoint buffy coat was sequenced to identify confounding CHIP mutations. A proprietary algorithm was used to identify ctDNA. Tumor Sequencing of multiple biopsy timepoints was carried out for 14 patients (mean 2.8 samples per patient) and clonal populations estimated with Pyclone. For clusters of greater than 10 mutations, RaDaR panels were supplemented with additional variants for clonal tracking. Results: At a median follow-up of 24.6 months post-surgery, MRD was identified in 100% (17/17) of relapsed patients, and in none of the 54 time points in the 5 patients that did not relapse (p=0.0002, Log rank test). Detection of ctDNA levels ranged from 7.4 parts per million (ppm), equivalent to Allele Frequency (AF) of 0.0007%, to 13,195ppm (1.3%) (median 625ppm and 0.06% AF). Median lead-time from ctDNA detection to clinical relapse in patients with extracranial disease relapse was 12.89 months (range 3.72-26.04). In three patients with brain only relapse, ctDNA was detected prior to relapse in all patients (3/3, 100%) albeit with a reduced lead time over clinical relapse (3.85, 4.21 and 5.65 months), which was not previously achievable with single mutation dPCR MRD-detection assays. In 8/14 patients with multiple tumor samples sequenced, multiple clones (mean 3.4 clones/patient) were identified, with heterogenous polyclonal relapse in 4/8 patients, and a single clone detectable in 4/8 patients. Conclusions: In a retrospective, multi-center, proof-of-principle study of early stage breast cancer patients with personalized sequencing assays, ctDNA-detected MRD associates with relapse free survival and long lead time over clinical relapse. Sequencing based ctDNA testing can detect patients with brain-only relapses, with increased sensitivity over first generation dPCR-based ctDNA assays. Citation Format: Rosalind J. Cutts, Maria Coakley, Isaac Garcia-Murillas, Lara Ulrich, Karen Howarth, Warren Emmett, Malcolm Perry, Pete Ellis, Charlene Knape, Stephen R. Johnston, Alistair Ring, Simon Russell, Abigail Evans, Anthony Skene, Duncan Wheatley, Mitch Dowsett, Ian E. Smith, Nicholas C. Turner. Molecular residual disease detection in early stage breast cancer with a personalized sequencing approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 536.

Traditional teaching in psychiatry does little to address recovery concepts. The aim of this study was to evaluate the incorporation of a recovery-focused teaching program for medical students in psychiatry. Recovery, as understood by medical students who had participated in a recovery-focused teaching program, was assessed by thematic analysis of recovery-focused assessment reflections. Six major themes emerged from the recovery reflections from final year medical students are as follows: (1) recovery as a person-centered approach, (2) the need for social integration, (3) non-diagnostic framing of mental illness, (4) tensions between the medical model and personal recovery, (5) a patient’s willingness to engage with mental health services, and (6) the development of a positive sense of self. A recovery teaching program was associated with students expressing knowledge of recovery principles and positive attitudes towards people with experience of mental illness. Psychiatric placements for medical students may benefit from a recovery focus.

Purpose The panel updated the American Society of Clinical Oncology (ASCO) adjuvant therapy guideline for resected non–small-cell lung cancers. Methods ASCO convened an update panel and conducted a systematic review of the literature, investigating adjuvant therapy in resected non–small-cell lung cancers. Results The updated evidence base covered questions related to adjuvant systemic therapy and included a systematic review conducted by Cancer Care Ontario current to January 2016. A recent American Society for Radiation Oncology guideline and systematic review, previously endorsed by ASCO, was used as the basis for recommendations for adjuvant radiation therapy. An update of these systematic reviews and a search for studies related to radiation therapy found no additional randomized controlled trials. Recommendations Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections. For individuals with stage IB, adjuvant cisplatin-based chemotherapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a medical oncologist, is recommended to assess benefits and risks of adjuvant chemotherapy for each patient. The guideline provides information on factors other than stage to consider when making a recommendation for adjuvant chemotherapy, including tumor size, histopathologic features, and genetic alterations. Adjuvant chemotherapy is not recommended for patients with stage IA disease. Adjuvant radiation therapy is not recommended for patients with resected stage I or II disease. In patients with stage IIIA N2 disease, adjuvant radiation therapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a radiation oncologist, is recommended to assess benefits and risks of adjuvant radiation therapy for each patient with N2 disease. Additional information is available at www.asco.org/lung-cancer-guidelines and www.asco.org/guidelineswiki .

Introduction Clozapine is the preferred antipsychotic for treatment-resistant schizophrenia, but has significant adverse effects, including gastrointestinal hypomotility or ‘slow gut’, which may result in severe constipation, ileus, bowel obstruction, and even death. These gastrointestinal effects remain inadequately recognized. Methods We reviewed all reports of serious clozapine-induced gastrointestinal hypomotility (CIGH) submitted to the Australian Therapeutic Goods Administration and New Zealand Pharmacovigilance Centre between 1992 and 2013. We extracted relevant demographic, clinical, and outcome data and derived a numerator from clozapine registries. We examined whether clozapine drug safety information in Australia, New Zealand, the US, and the UK was adequate and consistent with pharmacoepidemiologic evidence. Results A total of 43,132 people commenced clozapine over the study period. 160 were reported as having serious gastrointestinal hypomotility with clozapine the suspected cause (37/10,000 clozapine users). Of these, 66.3% were male, age range was 17–76 years, clozapine dose range 25–1000 mg/day (mean 439 mg/day) and median duration of clozapine treatment 2.5 years. Few had received laxatives. At least 29 patients died (7/10,000 clozapine users), a reported case fatality rate of 18%. The CIGH prevalence, while similar to other smaller studies, differs significantly from clozapine prescribing information issued by regulators and pharmaceutical companies, none of which mention CIGH, and which report serious gastrointestinal complications at rates of

Introduction T-DM1 treatment significantly improved overall survival and had a lower incidence of grade ≥3 adverse events (AEs) vs capecitabine plus lapatinib in patients (pts) with HER2-positive advanced breast cancer (BC) in the EMILIA study, including pts with treated, asymptomatic CNS metastases (mets). KAMILLA is an ongoing, single-arm, open-label, phase 3b global safety study of T-DM1 in pts with HER2-positive locally-advanced or metastatic BC (target n=2220). In this interim analysis we describe clinical characteristics, safety, and efficacy in pts with stable CNS mets at baseline (BL). Methods Eligible pts received prior HER2-directed therapy and chemotherapy and progressed on or after most recent treatment for advanced BC, or within 6 months of completing adjuvant therapy. Pts with asymptomatic CNS mets were eligible, including pts with stable CNS disease with prior radiation therapy. Pts received T-DM1 3.6 mg/kg every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression. This exploratory analysis describes pts with BL CNS mets. Median progression-free survival (PFS) was estimated using the Kaplan-Meier method. Results As of April 4, 2016, data were available for 2017 treated pts, of whom 399 (20%) had BL CNS mets, with a median follow-up of 33 months. Table 1 presents demographic and BL characteristics. The incidence of AEs was similar between pts with and without BL CNS mets. Serious AEs (SAEs) occurred in 112 pts with BL CNS mets (28%) vs 311 of 1618 pts without BL CNS mets (19%), and the frequency of SAEs was comparable to that observed in EMILIA. However, nervous system disorder SAEs, such as seizure, epilepsy, and brain edema, occurred more frequently in pts with BL CNS mets (30 pts [8%]) vs 18 pts [1%] with no BL CNS mets. Mean T-DM1 treatment duration was 8.0 months (median 8 cycles; range 1–55) in pts with BL CNS mets and 9.4 months (median 9 cycles; range 1–57) in pts with no BL CNS mets. Median PFS was 5.5 months in pts with BL CNS mets vs 7.9 months in pts with no BL CNS mets. A decrease in the size of brain target lesions was observed during T-DM1 treatment in 84 of 126 pts with measurable CNS lesions. Table 1. BL characteristics CNS mets at BL (n=399)No BL CNS mets (n=1618)Median age, yrs (range)52 (28–83)55 (26–88)ECOG performance status, n (%) 0193 (48)929 (57)1174 (44)605 (37)232 (8)83 (5)Hormone receptor status, n (%) ER and/or PR positive246 (62)992 (61)ER and PR negative149 (37)593 (37)Median time since initial BC diagnosis, yrs (range)4.8 (0–28)5.0 (0–53)Median time since first metastasis, yrs (range)2.4 (0–25)2.6 (0–35)Median number of prior therapies for metastatic BC (range)3 (0–>10)2 (0–>10) Conclusions This subgroup analysis of KAMILLA is the largest reported cohort of pts with CNS mets treated with T-DM1. The overall safety profile of T-DM1 in pts with BL CNS mets was comparable to that of pts without CNS mets. As might be expected in pts with CNS disease, serious neurological AEs occurred more frequently in pts with BL CNS mets vs those without. Response to T-DM1 was seen in the CNS in pts with BL CNS mets, however, median PFS was lower in pts with BL CNS mets vs those without BL CNS mets. Citation Format: Montemurro F, Ellis P, Delaloge S, Wuerstlein R, Anton A, Button P, Lindegger N, Barrios C. Safety and efficacy of trastuzumab emtansine (T-DM1) in 399 patients with central nervous system metastases: Exploratory subgroup analysis from the KAMILLA study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-10.

End-of-life cancer care involves multidisciplinary teams working in various settings. Evaluating the quality of care and the feedback from such processes is an important aspect of health care quality improvement. Our retrospective cohort study reviewed health care use by lung cancer patients at end of life, their reasons for visiting the emergency department (ed), and feedback from regional health care professionals. We assessed 162 Ontario patients with small-cell and relapsed or advanced non-small-cell lung cancer. Demographics, disease characteristics, and resource use were collected, and the consenting caregivers for patients with ed visits were interviewed. Study results were disseminated, and feedback about barriers to care was sought. Median patient age was 69 years, 73% of the group had non-small-cell lung cancer, and 39% and 69% had received chemotherapy and radiation therapy respectively. Median overall survival was 5.6 months. In the last 3 months of life, 93% of the study patients had visited an oncologist, 67% had telephoned their oncology team, 86% had received homecare, and 73% had visited the ed. Death occurred for 55% of the patients in hospital, 23%, at home, and 22%, in hospice. Goals of care had been documented for 68% of the patients. Homecare for longer than 3 months was associated with fewer ed visits (80.3% vs. 62.1%, p = 0.022). Key themes from stakeholders included the need for more resources and for effective communication between care teams. Use of acute-care services and rates of death in an acute-care facility are both high for lung cancer patients approaching end of life. In our study, interprofessional and patient&ndash, provider communication, earlier connection to homecare services, and improved access to community care were highlighted as having the potential to lower the need for acute-care resources.