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ImportancePatients with cancer who continue to smoke tobacco experience greater treatment-related complications, higher risk of secondary cancers, and greater mortality. Despite research to improve smoking cessation care within clinical oncology, implementation of proposed interventions within routine care remains challenging.ObjectiveTo identify and recommend implementation strategies for smoking cessation interventions associated with improved screening, advice-giving, and referral for tobacco users recently diagnosed with cancer, as well as shifting smoking behaviors and attitudes in this patient population.Evidence ReviewMEDLINE, CINAHL, Embase, and PsycINFO databases, as well as Google Scholar, were searched for articles published before September 7, 2020, using terms related to cancer, smoking cessation, and implementation science. Outcomes of interest were study characteristics, implementation strategies, and outcome measures (screening, advice, referral, abstinence rates, and attitudes). The Cochrane Risk of Bias Tool for randomized and nonrandomized studies was used to assess bias. The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and Synthesis Without Meta-analysis (SWiM) guideline. Implementation strategies were categorized according to Expert Recommendations for Implementing Change (ERIC) study taxonomy. A systematic analysis was conducted focusing on studies with low or moderate risk of bias due to high heterogeneity in outcome measurement.FindingsIn total, 6047 records were screened, yielding 43 articles (10 randomized clinical trials and 33 nonrandomized studies). Four strategies were associated with improved screening, advice-giving, and referral: (1) supporting clinicians, (2) training implementation stakeholders (including clinicians), (3) changing the infrastructure, and (4) developing stakeholder interrelationships.Conclusions and RelevanceIn this systematic review, supporting clinicians by providing cessation care through a trained tobacco specialist was identified as important for achieving short-term abstinence and changing attitudes among patients with cancer. Combined with a theoretical framework and stakeholder involvement, these strategies provide the basis for successful implementation of cessation support; this systematic review serves as an illustration of the methodological application and synthesis of implementation studies and other medical conditions more generally.

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 October 2019.

Background The COVID‐19 pandemic has challenged cancer care globally, introducing resource limitations and competing risks into clinical practice. Aims To describe the COVID‐19 impact on medical oncology care provision in an Australian setting. Methods Calvary Mater Newcastle and Newcastle Private Hospital medical oncology data from 1 February to 31 April 2019 versus 2020 were retrospectively analysed. Results Three hundred and sixty‐four inpatient admissions occurred in 2020, 21% less than in 2019. Total inpatient days decreased by 22% (2842 vs 2203). April was most impacted (36% and 44% fewer admissions and inpatient days respectively). Mean length of stay remained unchanged (6.4 vs 6.2 days, P = 0.7). In all, 5072 outpatient consultations were conducted, including 417 new‐patient consultations (4% and 6% increase on 2019 respectively). Telephone consultations (0 vs 1380) replaced one‐quarter of face‐to‐face consultations (4859 vs 3623, −25%), with minimal telehealth use (6 vs 69). Day Treatment Centre encounters remained stable (3751 vs 3444, −8%). The proportion of new patients planned for palliative treatment decreased (35% vs 28%, P = 0.04), observation increased (16% vs 23%, P = 0.04) and curative intent treatment was unchanged (both 41%). Recruiting clinical trials decreased by one‐third (45 vs 30), two trials were activated (vs 5 in 2019) and 45% fewer patients consented to trial participation (62 vs 34). Conclusion Our medical oncology teams adapted rapidly to COVID‐19 with significant changes to care provision, including fewer hospital admissions, a notable transition to telephone‐based outpatient clinics and reduced clinical trial activity. The continuum of care was largely defended despite pandemic considerations and growing service volumes.

Background Many patients with incurable esophageal cancer (ECa) present with dysphagia as their predominant symptom. Currently there is no consensus on how best to initially manage this scenario with multiple therapeutic options available. We aimed to assess the safety and efficacy of using hypofractionated radiotherapy given over a progressively shorter timeframe with concurrent carboplatin and paclitaxel in the management of patients with ECa and dysphagia. Methods In this phase I trial we enrolled patients with histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus or the gastro-esophageal junction with symptomatic dysphagia from local disease and not for curative treatment. Patients needed to be 18 years or older, have an ECOG performance status of 0–2 and be suitable to receive carboplatin and paclitaxel chemotherapy. Patients were placed in four progressively shorter radiation schedules culminating in 30 Gy in 10 fractions in a step wise manner, all with concurrent carboplatin AUC 2 and paclitaxel 50 mg/m2 chemotherapy delivered weekly with the radiation therapy. The primary endpoint was the development of the dose limiting toxicities (DLTs) esophageal perforation or febrile neutropenia. Secondary endpoints were relief of dysphagia, time to improvement of dysphagia, dysphagia progression free survival and overall survival. Results Eighteen patients were enrolled in the study between October 2014 and March 2019. There were no DLTs experienced during the trial. The most common grade 3 + acute toxicity experienced by patients were nausea and vomiting (both in 4/18 patients). The most common radiation specific acute toxicity experienced was esophagitis with 67% of patients experiencing grade 1–2 symptoms. All patients experienced improvement in dysphagia. The median time to dysphagia improvement was 3 weeks from the start of chemoradiotherapy (CTRT) (range 2–10 weeks). The median dysphagia free survival was 5.8 months with a median overall survival of 8.9 months. Conclusion Hypofractionated palliative CTRT with 30 Gy/10# of radiation therapy with concurrent weekly carboplatin and paclitaxel chemotherapy is well tolerated and provides a good response in improvement of dysphagia. Further studies need to be undertaken which provide both symptomatic improvement in the primary tumor but also control of the metastatic burden in these patients. Clinical Trial Registration: This trial was prospectively registered with www.anzctr.org.au Identifier: ACTRN12614000821695.

LBA100 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. Methods: 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 tumor-informed 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%. Results: 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, respectively). Of those who received treatment, oxaliplatin-based doublet was more frequently administered than fluoropyrimidine alone for ctDNA-guided compared to standard management patients (62.2% vs. 9.8%; P < 0.001). ctDNA-guided management was non-inferior to standard management for 2-year RFS (93.5% vs 92.4%, difference 1.1%, 95% confidence interval, -4.1% to 6.2%). Following adjuvant CT, 3-year RFS for ctDNA-positive patients was 86.4%. Without adjuvant CT, 3-year RFS for ctDNA-negative patients was 92.5%, with a 3-year RFS of 96.7% in the clinical low risk subgroup. Conclusions: A ctDNA-guided approach to stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. The low recurrence rate in ctDNA-positive patients who received chemotherapy suggests a survival benefit from adjuvant therapy. ctDNA-negative patients are unlikely to benefit from chemotherapy. Clinical trial information: ACTRN12615000381583.

TPS9592 Background: CSCC is the second most common skin cancer with an estimated incidence of 1 million cases per year in the US. While the surgical cure rate for CSCC is > 95%, some pts have high risk of recurrence as assessed by immune status, primary disease stage, extent of nodal involvement, presence of extracapsular extension (ECE), and prior treatment. Postoperative RT is recommended for these pts but relapse with locoregional recurrence or distant metastases may still occur. C-POST is evaluating the efficacy of cemiplimab as adjuvant therapy for pts with high-risk CSCC. Here, we provide summary of the most recent study protocol amendment. Methods: C-POST is a randomized, placebo-controlled, double-blind, multicenter Phase 3 study to evaluate cemiplimab as adjuvant treatment for pts with high-risk CSCC, based on surgical and clinicopathologic findings, who completed surgery and postoperative RT (minimum total dose 50Gy, within 10 weeks before randomization) (NCT03969004). Pts with at least one of the following high-risk features are eligible: (1) nodal disease with (a) ECE and at least one node ≥20 mm or (b) at least three lymph nodes positive on surgical pathology report, regardless of ECE; (2) in-transit metastases; (3) T4 lesion; (4) perineural invasion; and (5) recurrent CSCC with at least one other risk factor. Pts with CSCC involvement in at least three lymph nodes (feature 1b) were added to the eligibility criteria, as this group was found to be at similar risk of CSCC recurrence as the initially planned study population. Protocol amendment now allows patients with chronic lymphocytic leukemia (CLL) who are not on active treatment to be enrolled. The study has two parts. In Part 1 (blinded), pts are randomly assigned 1:1 to receive cemiplimab 350 mg or placebo intravenously every 3 weeks for 12 weeks, followed by cemiplimab 700 mg or placebo every 6 weeks for 36 weeks. In optional Part 2 (unblinded), pts in the placebo arm who experience disease recurrence and pts in the cemiplimab arm who experience disease recurrence ≥3 months after completion of 48-week treatment in Part 1 are eligible to receive open-label cemiplimab for up to 96 weeks. The trial is expected to enrol 412 pts from about 100 sites in North and South America, Europe, and Asia-Pacific regions. Key primary objective is to compare disease-free survival; secondary objectives include evaluating overall survival, freedom from locoregional relapse, and distant relapse with adjuvant cemiplimab versus placebo in patients with high-risk CSCC. This study is once again open for enrolment following interruptions owing to the COVID-19 pandemic. Clinical trial information: NCT03969004.

AIM The routine use of prophylactic percutaneous endoscopic gastrostomy (PEG) tubes for nutrition support during radical chemoradiation for head and neck cancer has been suggested to result in PEG dependency. This research aimed to determine the rates of gastrostomy dependency at the Calvary Mater Newcastle (CMN) where PEGs are routinely used and to identify potentially modifiable risk factors. METHODS All patients with head and neck cancer planned for curative chemoradiation with a prophylactic PEG inserted were included in this review. Medical records of 250 patients treated between 2000 and 2015 were examined. RESULTS Overall, eight patients (3%) were unable to wean. At 12 months following treatment, 16 patients (6%) still required PEG tubes for feeding. A greater T extent (T4 or synchronous head and neck tumors) and number of days Nil By Mouth (NBM) remained as significant independent risk factors for PEG dependency at 12 months (Textent OR 6.96 P

Background The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild-type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer. Patients and Methods Patients were enrolled in an open-label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m2, then 250 mg/m2 cetuximab weekly, with or without irinotecan 180 mg/m2 every 2 weeks. The primary endpoint was 6-month progression-free survival; secondary endpoints were response rate, overall survival, toxicity, and quality of life. Results From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab-irinotecan, progression-free survival was 14% versus 41% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P = .008); response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial); P = .04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%); global and specific quality of life scores did not differ. Conclusion In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. This echoes data from molecularly unselected patients.

e14029 Background: A significant delay in oncology patient journey through emergency department (ED) due to various reasons such as multiple specialists involved, difficulty in accessing timely advice from extremely busy inpatient/outpatient oncology teams, etc. In order to streamline admissions and discharges for oncology patients, a new model of care was created with the introduction of oncology nurse practitioner (ONP) at Calvary Mater Newcastle ED. This model operated during business hours three days a week with an aim to improve continuity of care, to enhance patients’ experience and meet organisations key performance indicators (KPIs). Limited research into the impact of these services on patient care and patient experience, particularly from service users’ perspective. Methods: A retrospective audit (6 months) has been undertaken to determine the impact of this model of care on time to specialty transfer, number of admissions versus discharges and patients representations through ED when ONP was available versus standard care. Results: During the audit period, ONP reviewed 149 patients. Fifty-four (36%) patients were discharged and of those 6 (11%) returned (within 28 days) with same or related issues. There was an average reduction in time to disposition planning for ED oncology patients of approximately 83 (193 vs 110) minutes when ONP was present at ED (one month review). Using a raw bed day costing, this resulted in a significant financial saving. Further cost analysis of this model is underway. Conclusions: The introduction of ONP into an acute care hospital ED has proven to be effective in terms of continuity of patient care, financial savings and assisted ED in meeting KPIs. The perception within the senior emergency management team is that this new model of care has been an unqualified success. ONP has rapidly and effectively joined emergency team and has seamlessly adjusted practice to the new environment. ED remains highly supportive of this new model of care. This model of care is one that could be translated easily to other specialities. Further analysis will be presented at the time of ASCO meeting.

A 72-year-old male patient was receiving second-line chemotherapy for metastatic squamous cell carcinoma of the skin (SCCS) when he was diagnosed with concurrent metastatic melanoma (BRAF mutant). Chemotherapy was ceased and he was treated with 4 cycles of ipilimumab immunotherapy. The patient experienced clinical benefit and durable remission in both malignancies and remains free of cancer progression 8 months after the last cycle of ipilimumab. Response of SCCS to ipilimumab has not been previously described, however this case and recent reports of pembrolizumab efficacy confirm the critical role of the immune system in SCCS pathogenesis and suggest further exploration of checkpoint immunotherapy for the treatment of this disease.

Activation of the canonical TGF-β signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2, and SMAD3 and analyzed for allelic loss by single-nucleotide polymorphism (SNP) microarray analysis. Mutation spectra were compared between the genes, the pathogenicity of mutations was assessed, and relationships with clinicopathologic features were examined. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. A significant overrepresentation of two genetic hits was detected for SMAD4 and SMAD3, consistent with these genes acting as tumor suppressors. SMAD4 mutations were associated with mucinous histology. The mutation spectra of SMAD2 and SMAD3 were highly similar to that of SMAD4, both in mutation type and location within the encoded proteins. In silico analyses suggested the majority of the mutations were pathogenic, with most missense changes predicted to reduce protein stability or hinder SMAD complex formation. The latter altered interface residues or disrupted the phosphorylation-regulated Ser-Ser-X-Ser motifs within SMAD2 and SMAD3. Functional analyses of selected mutations showed reductions in SMAD3 transcriptional activity and SMAD2–SMAD4 complex formation. Joint biallelic hits in SMAD2 and SMAD3 were overrepresented and mutually exclusive to SMAD4 mutation, underlining the critical roles of these three proteins within the TGF-β signaling pathway. Cancer Res; 73(2); 725–35. ©2012 AACR.

Background Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are “wild type”). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a “quadruple wild type” tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent. Methods and design ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with “quadruple wild type” or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine-based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer. Discussion This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the “quadruple wild type”, which may ‘superselect’ for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug. The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes, reduce toxicity and contain treatment costs. Tissue and blood will yield a resource for molecular studies. Recruitment, particularly of patients with the rare G13D mutation, will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups. Trial registration Australian and New Zealand Clinical Trials Registry: ACTRN12612000901808, registered 16 August 2012.

Purpose Universal screening for chronic hepatitis B virus (HBV) infection before chemotherapy has been recommended. We evaluated the cost-effectiveness of HBV screening before chemotherapy given for nonhematopoietic solid tumors (STs). Methods A decision-analytic model was used to compare the cost-effectiveness of universal screening conducted per professional guidelines versus no screening in hypothetical patient cohorts beginning adjuvant chemotherapy for early breast cancer or palliative chemotherapy for advanced non–small-cell lung cancer. Survival times were extrapolated using Markov models. Probabilities were derived from published studies and costs estimated from the perspective of the Australian health care system. One-way and probabilistic sensitivity analyses were performed, including with the application of an alternative HBV screening strategy. Results Using an incremental cost-effectiveness ratio threshold of $50,000 (Australian dollars) per life-year (LY) saved, universal HBV screening was not cost-effective for adjuvant patients ($88,224/LY, 13% probability of being cost-effective), palliative patients ($1,344,251/LY, 0%), or pooled (all) patients ($149,857/LY, 1%). Sensitivity analyses found that screening approached cost-effectiveness among adjuvant patients with the highest reported rates of undiagnosed chronic HBV (65%, $59,445/LY) or HBV reactivation with chemotherapy (41%, $56,537/LY). Cost- effectiveness was also significantly influenced by HBV population prevalence. An alternative screening strategy using hepatitis B surface antigen testing only produced the most economically favorable results, with $30,126/LY (80% probability) for adjuvant patients and $51,201/LY (43%) for the pooled cohort. Conclusion Universal HBV screening conducted per current guidelines is not cost-effective in patients with STs. Screening may be economically favorable in selected patient subpopulations and/or with simplification of the screening strategy.

Universal screening for chronic hepatitis B virus (HBV) before chemotherapy has been recommended by the Centers for Disease Control. We sought to determine the prac- tice of Australian oncologists with regard to HBV screening in patients with solid tumors (STs) and their clinical experience of HBV reactivation (HBVR). Methods: A survey was sent to all consultant members of the Medical Oncology Group of Australia. One hundred eighty-eight responses (63% response rate) were received. We also reviewed the incidence of HBV in patients with STs screened at the Peter MacCallum Cancer Centre (Melbourne, Australia). Results: Fifty-three percent of medical oncologists screen for HBV, but only 19% screen all patients. The most common rea- sons given for performing screening were anecdotal experience of HBVR (46%) and perceived sufficient evidence for screening of some patient subgroups (42%). Sixty-five percent of those who screened did so only in subgroups, usually selecting patients on the basis of ethnicity (82%). Oncologists who did not screen most commonly cited inadequate evidence for a benefit of screening (72%). Twenty-two percent of oncologists had wit- nessed one or more HBVR events, representing one event per 45 years of respondents' practice. HBVR events reported (n 54) consisted of asymptomatic liver test abnormalities only (44%), symptomatic hepatitis (28%), decompensated liver failure (19%), and death (7%). In 206 patients with STs screened for HBV, 1.0% (n 2) were HBV surface antigen positive, and 14.9% hepatitis B core antibody positive. Conclusion: The majority of Australian medical oncologists have not adopted universal HBV screening before chemothera- py. Further evidence of the benefit and cost effectiveness of universal screening in patients with STs will be required to alter practice.

Background: Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy. Methods: Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15–30 mg m−2 per week and cisplatin 15–30 mg m−2 per week in six planned dose levels (DLs) in 3–6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy. Results: A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m−2, cisplatin 15 mg m−2) and grade 3 nausea in DL2 (20 mg m−2, 15 mg m−2). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial). Conclusion: Cisplatin and docetaxel each 30 mg m−2 per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.

Background. Recent data have suggested that regular aspirin use improves overall and cancer-specific survival in the subset of colorectal cancer (CRC) patients harboring PIK3CA mutations. However, the number of PIK3CA-mutated CRC patients examined in these studies was modest. Our collaborative study aims to validate the association between regular aspirin use and survival in patients with PIK3CA-mutated CRC.Patients and methods. Patients with PIK3CA-mutated CRC were identified at Moffitt Cancer Center (MCC) in the United States and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data and survival data were available. At MCC, PIK3CA mutations were identified by targeted exome sequencing using the Illumina GAIIx Next Generation Sequencing platform. At RMH, Sanger sequencing was utilized. Multivariate survival analyses were conducted using Cox logistic regression.Results. From a cohort of 1487 CRC patients, 185 patients harbored a PIK3CA mutation. Median age of patients with PIK3CA-mutated tumors was 72 years (range: 34–92) and median follow up was 54 months. Forty-nine (26%) patients used aspirin regularly. Regular aspirin use was not associated with improved overall survival (multivariate HR 0.96, p = 0.86). There was a trend towards improved cancer-specific survival (multivariate HR 0.60, p = 0.14), but this was not significant.Conclusions. Despite examining a large number of patients, we did not confirm that regular aspirin use was associated with statistically significant improvements in survival in PIK3CA-mutated CRC patients. Prospective evaluation of this relationship is warranted.

3572 Background: Cetuximab (cet) increases survival in RAS wild-type (WT) metastatic colorectal cancer (mCRC) in first-line and chemorefractory patients (pts). Adding irinotecan (iri) to cet in refractory pts who had progressed on iri increased response and delayed progression in the BOND trial, which was conducted prior to recognition that RAS mutations are predictive of EGFR-inhibitor (EGFR-I) resistance. Subsequent trials in chemorefractory pts used single agent EGFR-I as standard. In the era of biomarker selection, the benefit of continuing iri versus single agent EGFR-I had not been resolved. Methods: ICECREAM is a randomised phase II trial evaluating cet v cet + iri in chemotherapy-refractory mCRC, stratified for KRAS G13D mutation (previously reported) or no mutations in KRAS, NRAS, BRAF and PI3KCA (Quad WT ). EGFR-I naïve, ECOG PS 0-1 pts, progressing within 6 months of iri and refractory (or intolerant) to fluoropyrimidine and oxaliplatin were randomised to cet 400mg/m2 IV loading then 250mg/m2 weekly +/- iri 180mg/m2q2 wks. The primary endpoint was progression-free survival at 6 months (6m PFS); secondary endpoints were response rate (RR), overall survival (OS), toxicity and quality of life (QOL). Results: From Nov 2012 to June 2016, 48 Quad WT pts were recruited: 2 ineligible (not iri-refractory, BRAF mutation) wre not included for analyses and a further 2 not evaluable for response. Characteristics were balanced between cet (n = 21) v cet-iri (n = 25), except for sex (male 62 v 72%) and primary site (left 95 v 68%). 6m PFS rate was 14% v 41%; HR 0.39 (95% CI: 0.20–0.78, p = 0.008). RR was 10% (2 PR) v 36% (1 CR, 8 PR); p = 0.04. Toxicities were higher with cet-iri; at least one grade 3/4 adverse event in 50 v 23%. No differences in global or specific QOL were seen. Conclusions: The AGITG ICECREAM trial confirms a significant synergy for the addition of iri to cet and improved PFS in Quad WT chemorefractory mCRC, echoing data in molecularly unselected pts. Clinical trial information: ACTRN12612000901808.

Gastrointestinal stromal tumors lacking mutations in KIT or PDGFRα are known as wild type (WT) and are less responsive to imatinib. These WT tumors are hypothesized to be dependent on signaling through the insulin-like growth factor 1 receptor (IGF-1R). We report the case of a 29-year-old woman with neurofibromatosis type 1-associated WT GIST treated with an anti-IGF-1R monoclonal antibody. Treatment was ineffective, and the potential basis for lack of response is discussed in the context of IGF-1R expression levels measured within this patients' primary tumor. We suggest that future clinical trials of anti-IGF-1R therapies prospectively determine tumor IGF-1R expression levels for correlation with response to treatment.

499 Background: Borderline resectable pancreas cancers (BRPC) often require vascular reconstruction, have higher rates of operative margin positivity and confer a poor prognosis. In 2014, our high-volume pancreatectomy, gastrointestinal tumor multidisciplinary treatment (GI MDT) group endorsed a consensus anatomical definition of BRPC consistent with NCCN criteria. Diagnostic and staging tests were standardized and a neoadjuvant chemoradiotherapy protocol adopted with the goals to (1) improve R0 resection rate and (2) prevent futile surgery in rapidly progressive disease. Methods: Neoadjuvant chemoradiotherapy (CRT) consisted of 50.4Gy in 28# and concurrent capecitabine 830mg/m2 bd. Pancreatectomy was planned 4-8 weeks later unless repeat imaging showed progressive disease. Comprehensive, prospectively defined data items were collected on all patients (pts) diagnosed with BRPC. Results: Nine pts have been diagnosed with BRPC by the GI MDT. Seven pts received full dose of CRT, one pt progressed during CRT hence stopped early and one pt didn’t receive CRT due to significant deterioration beforehand. CRT was tolerable in all eight pts who received it; there were no dose modifications for toxicity. Post-CRT, three pts underwent curative-intent resection and all are still alive (494, 319 and 172 days post-CRT). One was found to have a solitary liver metastasis during surgery (resected), R1 resection (SMV margin involvement) of T3N1 tumor and is receiving palliative chemotherapy. Two other pts underwent R0 resections (T3N0, T3N1) with histopathologic response to CRT. Four pts showed progressive disease on post-CRT imaging (all local & distant progression) and subsequently received palliative therapy. Median survival (first dose CRT to death) in the 5 CRT pts who have succumbed was 509 days (range 363-577). Conclusions: In this small prospective, unselected cohort the majority of pts diagnosed with BRPC demonstrated disease progression during/after neoadjuvant CRT and did not proceed to surgical resection, underscoring the poor prognosis of this pancreas cancer subset. Neoadjuvant CRT is well tolerated and did not preclude subsequent surgery in those patients with stable disease.

578 Background: Aspirin use reduces the incidence of colorectal adenomas, and of colorectal cancer (CRC) in patients with hereditary non-polyposis colorectal cancer. There is limited data on the effect of aspirin in the secondary prevention of CRC, currently the subject of multiple prospective randomized trials. We aimed to test the hypothesis that aspirin reduces disease recurrence in patients diagnosed with early CRC at a high volume, single institution. Methods: A retrospective analysis was conducted of all patients (pts) treated with at least one cycle of adjuvant chemotherapy for stage II or III CRC over a 5yr period (2009–13). Patients with synchronous CRC were excluded. Aspirin use at the onset of adjuvant chemotherapy was sourced from the universal electronic recording of concomitant medications. Kaplan-Meier curves and the log-rank test were used to compare crude relapse free survival (RFS) between pts who were using aspirin to those who were not. Propensity score analyses was used to balance the groups according to potentially confounding variables: tumor site (colon vs rectum), tumor stage (II vs III), and adjuvant chemotherapy (oxaliplatin-based vs no oxaliplatin). The propensity scores were estimated through a multivariable logistic regression model, and a Cox proportional hazards model used to assess the effect of aspirin use on RFS in the sample weighted according to the inverse probability of receiving aspirin. Results: A cohort of 231 pts met eligibility criteria; median age 64yr; 50% colon, 50% rectal; 19% stage II, 81% stage III; 35% received oxaliplatin; 13% (n=31) were using aspirin and 26% of pts (n=61) developed CRC recurrence in median follow-up of 2.9yr. Unadjusted RFS was not significantly different for those using aspirin (log rank p value 0.88). There was good overlap in propensity scores for the two groups. The hazard ratio for RFS with aspirin use from the weighted Cox regression model was 1.2 (95% CI 0.62-2.29), indicating no statistically significant effect of aspirin on CRC relapse. Conclusions: In this single institution series, we did not find evidence that aspirin use at onset of chemotherapy had an effect on CRC relapse free survival. These results do not exclude an aspirin effect that is modest or restricted to select CRC subgroups.

Background: The aim was to investigate the correlation between 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus. Methods: A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan–Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response. Results: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P

688 Background: Recent phase III clinical trials have shown that the use of capecitabine with long course radiotherapy in the neoadjuvant treatment of rectal cancer provides equivalent outcomes to the traditionally used CI5FU. In the Australian health system the dispensed price of capecitabine is higher; however CI5FU administration requires a peripherally inserted central catheter (PICC). This analysis was designed to test the comparative cost of capecitabine over CI5FU from the perspective of the Australian healthcare system. Methods: We determined fully itemised direct treatment costs for the administration of neoadjuvant long course chemoradiotherapy with each of capecitabine and CI5FU. A decision analytic model was then used to compare potential clinical adverse events with the respective agents. Clinical probabilities were derived from published studies and the management of adverse events costed using Australian refined diagnosis-related group (AR-DRG) coding. The results of the decision analytic model were integrated with the drug administration costs to produce an inclusive discriminating cost for capecitabine versus CI5FU. Results: The total cost to the Australian healthcare system for the administration of CI5FU was $2,110 per patient, compared with $1,170 for capecitabine. The costs of managing treatment complications were similar: mean $174 per patient for CI5FU and $72 for capecitabine. The integrated discriminating cost difference was a mean saving of $1,042 per patient with prescription of capecitabine. The presented base-case model utilised higher capecitabine costs where input data could vary, and hence in all sensitivity analyses capecitabine continued to demonstrate cost savings (minimum $286 and maximum $1,975 per patient) over CI5FU. Conclusions: Capecitabine is a cost effective alternative to CI5FU. Considering also the expected lower indirect costs with oral therapy, use of capecitabine in chemoradiotherapy for rectal cancer is economically superior.

386 Background: Recent data has demonstrated that regular ASA use improves overall and cancer-specific survival in the subset of CRC patients harboring PIK3CA mutations. However, as this series only analyzed 15 PIK3CA mutant CRC patients with metastatic disease at diagnosis, it remains uncertain whether the survival benefit associated with regular ASA use extends to patients with metastatic disease. We combined data from two large academic institutions to explore the association between regular ASA use and survival in metastatic CRC. Methods: Patients with PIK3CA mutated CRC were identified at Moffitt Cancer Center (MCC) in Tampa, FL and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data (including age, sex, site of disease) and survival data were available. At MCC, PIK3CA mutations were identified by exome sequencing using an Illumina Next Generation Sequencing platform with 50-100X coverage. At RMH, Sanger sequencing was used to identify PIK3CA mutations. Survival analyses were conducted using Cox regression. Results: We identified 187 CRC patients who harbored a PIK3CA mutation. Median age was 72 years and median follow up was 48 months. 49 (26%) patients used ASA regularly. 47 (25%) patients had metastatic disease at diagnosis. In univariate analyses, regular ASA use was not associated with improved overall survival (HR 0.87, p = 0.60), although there was a trend towards improved cancer-specific survival (HR 0.48, p = 0.06). In patients with stage-II or stage-III disease, regular ASA use did not improve overall, cancer-specific or recurrence-free survival. However, in stage-IV patients, regular ASA use was significantly associated with improved overall (HR 0.35, p = 0.04) and cancer-specific (HR 0.28, p = 0.02) survival in a univariate analysis. Conclusions: Our study demonstrates that in patients with metastatic CRC harboring a PIK3CA mutation, regular ASA use is associated with a significant overall and cancer-specific survival advantage. However, we were not able to confirm the survival advantage across all stages. To our knowledge, our study is the largest to examine ASA use in PIK3CA mutated CRC.

3598 Background: Aspirin has an established role in preventing CRC. Recent data suggests aspirin use may also benefit a subset of pts diagnosed with CRC. In one series, the authors identified PIK3CA mutations as a potential predictive biomarker for aspirin use, reporting that PIK3CA mutant CRC pts receiving aspirin had superior cancer specific survival (CSS) compared to those not receiving aspirin (HR 0.18, p

Background The BRAF V600E mutation is a well-validated negative prognostic biomarker in metastatic colorectal cancer (mCRC), and is a highly attractive drug target. Barriers to the development of agents targeting BRAF V600E in mCRC are the low rate of mutations (approximately 10%) and reliance on to sequencing-based technologies, which are not routinely available outside of large cancer centres. A simple immunohistochemistry (IHC) test, more suited to routine pathology practice, would provide much broader access to patient (pt) identification, and would also enable studies of tumor heterogeneity. Aims: To validate an IHC-based method of detecting the BRAF V600E mutation in a large cohort of community-based CRC patients. Methods Tissue microarrays, comprising matched normal and tumor paraffin embedded tissue samples obtained from colectomy specimens from a community cohort of 505 pts with stage I–IV CRC, were tested with 2 antibodies (Ab): pBR for total BRAF and VE1 for BRAF V600E, using the Ventana UltraView and OptiView kits, respectively. IHC was assessed independently by 2 blinded pathologists, and results compared to BRAF V600E status determined by Sanger sequencing (SS). pBR negative samples were considered non - evaluable. Nine discordant cases were re-tested with a BRAF V600E SNaPshot assay. Results Demographic features were evenly matched. SS was evaluable in 504/505; IHC in 477/505; with both evaluable in 476/505 pts. 56/476 (11.8%) pts had V600E mutations detected by SS, 65/476 (13.7%) by IHC. The positive predictive value was 84.6% (55/65). 1 pt was negative by IHC and positive on SS and SNaPshot; resulting in a negative predictive value of 99.8% (410/411 cases). There was 100% concordance between SS and SNaPshot. Further validation is ongoing, and outcome data will be available at the time of presentation. Conclusions We have conducted a comprehensive analytical and clinical validation and feasibility analysis of an IHC-based method to detect the BRAF V600E mutation in a large community-based population of pts with CRC. Shown to be highly sensitive, we are planning to adopt this approach as our initial screening step in an upcoming prospective combination trial targeting BRAF V600E in pts with mCRC. Disclosure J. Desai: Research Support: Roche, Ventana Medical Systems, A. Muranyi: Employee: Ventana Medical Systems, K. Shanmugam: Employee and Shareholder, Ventana Medical Systems, T. Grogan: Shareholder and Chief Scientific Officer, Ventana Medical Systems, P. Gibbs: Research Support, Ventana Medical Systems, P. Waring: Research Support: Ventana Medical Systems, All other authors have declared no conflicts of interest.

3623 Background: The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been implicated in the development of colorectal cancer (CRC), however a systematic analysis of pathway members and their association with clinical, pathological and other molecular features has been lacking. Methods: We determined the prevalence of PIK3CA (exons 9, 20) mutations in a large cohort (n=1092) of community-based patients (pts) with stage I-IV CRCs. A subset (n=744, 68%) were also tested for mutation in PTEN (exons 3,4,5,6,7,8), PTEN LOH and CIMP. All tumors were characterised for MSI, KRAS and BRAF mutations, and annotated for clinico-pathologic features and patient outcomes in a prospectively-recorded database. Detected novel PIK3CA exon-specific correlates were further explored in a combined analysis integrating the data of other published cohorts (total n=3677). Results: PIK3CA mutations occurred in 11.6% of primary tumors and were associated with older pt age (p=0.009), proximal site (p

4105 Background: 18-fluorodeoxyglucose positron emission tomography (FDG-PET) improves the accuracy of staging and radiotherapy planning in anal cancer, and in other malignancies has prognostic val...

9121 Background: Although universal screening for chronic HBV prior to chemotherapy has been recommended by the Centers for Disease Control and other bodies, the compliance rate among medical oncol...

The B-type Raf kinase (BRAF) V600E mutation is a well-established biomarker for poor prognosis in metastatic colorectal cancer (mCRC) and is a highly attractive drug target. A barrier to the development of new therapies targeting BRAF V600E in mCRC is the low prevalence of mutations (approximately 10 %) and the current need for access to sequencing-based technologies which are not routinely available outside of large cancer centres. Availability of a standardised immunohistochemistry (IHC) test, more suited to routine pathology practice, would provide much broader access to patient identification. We sought to evaluate the accuracy and clinical utility of a recently developed BRAF V600E IHC method as a prognostic biomarker in a large cohort of community-based CRC patients. Archival tumour samples from 505 patients with stage I-IV CRC were immunohistochemically tested with two antibodies, pBR1 for total BRAF and VE1 for BRAF V600E. Cases were assessed by two blinded pathologists, and results were compared to BRAF V600E mutation status determined using DNA sequencing. Discordant cases were retested with a BRAF V600E SNaPshot assay. BRAF mutation status was correlated with overall survival (OS) in stage IV CRC. By DNA sequencing and IHC, 505 and 477 patients were respectively evaluable. Out of 477 patients, 56 (11. 7 %) had BRAF V600E mutations detected by sequencing and 63 (13.2 %) by IHC. Using DNA sequencing results as the reference, sensitivity and specificity for IHC were 98.2 % (55/56) and 98.1 % (413/421), respectively. IHC had a positive predictive value (PPV) of 87.3 % (55/63) and a negative predictive value (NPV) of 99.8 % (413/414). Compared to DNA sequencing plus retesting of available discordant cases by SNaPshot assay, IHC using the VE1 antibody had a 100 % sensitivity (59/59), specificity (416/416), NPV (416/416) and PPV (59/59). Stage IV CRC patients with BRAF V600E protein detected by IHC exhibited a significantly shorter overall survival (hazard ratio = 2.20, 95 % CI 1.26-3.83, p = 0.005), consistent with other published series. Immunohistochemistry using the BRAF V600E VE1 antibody is an accurate diagnostic assay in CRC. The test provides a simple, clinically applicable method of testing for the BRAF V600E mutation in routine practice.