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OBJECTIVES: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials. STUDY DESIGN: Retrospective observational study; review of patient records in fifteen Australian institutions. SETTING, PARTICIPANTS: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme. MAIN OUTCOME MEASURES: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival. RESULTS: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8

Introduction: Normalisation Process Theory (NPT) is widely used to explore how new healthcare practices are understood, enacted, reflected upon and embedded in usual practice, typically focussing on professionals’ behaviours. NPT is less commonly used to explore patients’ experiences during implementation of new interventions. The RETurn to work After stroKE (RETAKE) trial used NPT’s four constructs (coherence, cognitive participation, collective action, reflexive monitoring) in comparing experi-ences of stroke survivors who received Early Stroke Specialist Vocational Rehabilitation (ESSVR) with recipients of usual care (UC) only.Method: Semi-structured interviews with 44 stroke survivors (23 who received ESSVR and 21 UC participants). NPT underpinned data collec-tion and analysis.Results: RETAKE OTs helped participants in the ESSVR arm make sense of stroke, accept stroke-related limitations, and develop intervention understanding (coherence) more easily than most UC participants. RETAKE OTs typically involved all stakeholders in return-to-work (RTW) plans, facilitating co-operation and engagement (cognitive participation), whereas UC participants described poor co-ordination between services and limited or no focus on RTW. ESSVR participants completed individu-ally tailored work-related tasks, with RETAKE OTs mediating workplace adjustments and monitoring employment progress (collective action). In contrast, OT involvement in work preparation and employer negotiations for UC participants was rare. RETAKE OTs supported ESSVR participants to reflect on the appropriateness of RTW post-stroke or explore alterna-tives (reflexive monitoring). However, few UC recipients were supported to consider the suitability of their current work roles; consequently, some reported feeling ‘abandoned’ by health services.Conclusion: NPT was useful in exploring participants’ perspectives of a complex intervention in the RETAKE trial.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index–increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10−36). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

Background: The role of adjuvant chemotherapy (CT) in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival (RFS), while its absence predicts a low recurrence risk. For ctDNA-positive cases the benefit of adjuvant CT is unknown. DYNAMIC was designed to assess if a ctDNA-guided approach could reduce the use of adjuvant CT without compromising recurrence risk. Method(s): DYNAMIC is a multi-center randomized controlled phase II trial. Eligible patients had resected stage II colon cancer and were suitable for adjuvant CT. Patients were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician-guided based on conventional criteria), after stratification for T stage and participating center location. Criteria for clinical low versus high risk were predefined. The Safe-SeqS tumorinformed personalized ctDNA assay was used. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine CT; ctDNA-negative patients were not treated. The primary efficacy endpoint was non-inferiority in RFS rate at 2 years. A key secondary endpoint was adjuvant CT use. The target sample size of 450 provided 80% power with 95% confidence to confirm non-inferiority between the two arms with a margin of 8.5%. Result(s): Of 455 patients randomized between Aug 2015 and Aug 2019, 302 were assigned to ctDNA-guided and 153 to standard management. Median follow-up was 37 months. In the ctDNA-guided arm, ctDNA analysis was successful in all but three patients; only two patients did not receive ctDNA-guided management. In the intention to treat population, fewer patients overall in the ctDNA-guided arm received adjuvant CT compared to standard management (15.3% vs 27.9%, odds ratio 2.14; P = 0.002), with the largest difference seen in patients with T4 or poorly differentiated tumors (odds ratios 6.22 and 6.31, respective

BACKGROUND: Oesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations. METHODS: PALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy. DISCUSSION: This unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12619001371189 , registered 8 Octobe

Background: Cigarette smoking in people with cancer is associated with negative treatment-related outcomes including increased treatment toxicity and complications, medication side effects, decreased performance status and morbidity. Evidence-based smoking cessation care is not routinely provided to patients with cancer. The purpose of this study is to determine the effectiveness of a smoking cessation implementation intervention on abstinence from smoking in people diagnosed with cancer. Methods: A stepped wedge cluster randomised design will be used. All sites begin in the control condition providing treatment as usual. In a randomly generated order, sites will move to the intervention condition. Based on the Theoretical Domains Framework, implementation of Care to Quit will include (i) building the capability and motivation of a critical mass of key clinical staff and identifying champions; and (ii) identifying and implementing cessation care models/pathways. Two thousand one hundred sixty patients with cancer (diagnosed in the prior six months), aged 18+, who report recent combustible tobacco use (past 90 days or in the 30 days prior to cancer diagnosis) and are accessing anti-cancer therapy, will be recruited at nine sites. Assessments will be conducted at baseline and 7-month follow-up. The primary outcome will be 6-month abstinence from smoking. Secondary outcomes include biochemical verification of abstinence from smoking, duration of quit attempts, tobacco consumption, nicotine dependence, provision and receipt of smoking cessation care, mental health and quality of life and cost effectiveness of the intervention. Discussion: This study will implement best practice smoking cessation care in cancer centres and has the potential for wide dissemination. Trial registration: The trial is registered with ANZCTR (www.anzctr.org.au): ACTRN (ACTRN12621000154808) prior to the accrual of the first participant and will be updated regularly as per registry guidelines.