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Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value (SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26–0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26–0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.

Background Surgical resection remains the only curative treatment for pancreatic cancer and is associated with significant post-operative morbidity and mortality. Patients eligible for surgery, increasingly receive neo-adjuvant therapy before surgery or adjuvant therapy afterward, inherently exposing them to toxicity. As such, optimizing physical function through exercise during treatment remains imperative to optimize quality of life either before surgery or during rehabilitation. However, current exercise efficacy and prescription in pancreatic cancer is unknown. Therefore, this study aims to summarise the published literature on exercise studies conducted in patients with pancreatic cancer undergoing treatment with a focus on determining the current prescription and progression patterns being used in this population. Methods A systematic review of four databases identified studies evaluating the effects of exercise on aerobic fitness, muscle strength, physical function, body composition, fatigue and quality of life in participants with pancreatic cancer undergoing treatment, published up to 24 July 2020. Two reviewers independently reviewed and appraised the methodological quality of each study. Results Twelve studies with a total of 300 participants were included. Heterogeneity of the literature prevented meta-analysis. Exercise was associated with improvements in outcomes; however, study quality was variable with the majority of studies receiving a weak rating. Conclusions High quality evidence regarding the efficacy and prescription of exercise in pancreatic cancer is lacking. Well-designed trials, which have received feedback and input from key stakeholders prior to implementation, are required to examine the impact of exercise in pancreatic cancer on key cancer related health outcomes.

Background Oesophageal Adenocarcinoma (OAC) incidence in the Western-world has increased markedly over 30 years. 5-year survival rates for patients remains below 20% with dismal response to neo-adjuvant or perioperative chemotherapy for operable tumours. The Dual ErbB Inhibition in Oesophago-gastric Cancer (DEBIOC) clinical trial assessed efficacy of combined oxaliplatin and capecitabine (Xelox) with dual ErbB inhibitor AZD8931 in providing additional benefit to operable patients compared to Xelox alone. We utilised a bioinformatic approach combing Almac Clara-T Transcriptional Discovery software with unsupervised machine learning methods to unveil translational clinical potential and biological insights from DEBIOC patient biopsy and resection specimens. Methods Using microarrays of DEBIOC patient specimens with documented clinical observations, we combined unsupervised machine learning techniques with state-of-the-art Almac Clara-T software to assess transcriptional changes between treatment types regarding the 10 hallmarks of cancer, characterised by representative gene-expression signatures and scores. These methods were employed to identify possible mechanisms of treatment resistance, evaluate changes in the tumour-microenvironment and determine clinically significant molecular subgroups in OAC. Differential expression and pathway analytics were used to describe signalling dissimilarities between clusters from unsupervised analysis and phenotypes respective to hallmarks of cancer, with alignment of sensitivities to single-gene drug targets for subgroups of interest. Results Unsupervised clustering analysis of biopsy specimens, resulted in the identification of two robust subgroups pre-treatment in OAC, determined to be significantly associated with the prediction of Mandard Score (Tumour Regression Grade 1-5) post-treatment (fishers exact p Conclusions Our analysis has revealed translational insights into possible mechanisms of drug resistance as well as cancer hallmark-specific phenotypes significantly associated with clinico-pathological factors during the DEBIOC clinical trial. Continued analysis into resulting phenotypes and clusters combined with the alignment of single gene drug target sensitivities is anticipated to reveal novel molecular pathways driving phenotypic differences in an effort to further inform biological understanding and improve treatment response and survival outcomes in OAC patients.

Introduction The diagnosis and treatment of Gastro-intestinal stromal tumours (GISTs) has been revolutionized by molecular pathology and targeted therapy. Description This patient was diagnosed with locally advanced gastric GIST in 2009. He was initially treated neoadjuvantly with imatinib from 2009- 2010. He underwent laparoscopic resection in 2010. Pathology showed almost complete response with only 1.5mm focus of viable tumour. He did not receive adjuvant imatinib as this was not established practice in 2010. Recurrent disease was resected in 2011. Mitotic count was 200/50hpf. Adjuvant imatinib was given for 5 years then discontinued in 2016. Imaging showed no recurrence over this time period. Molecular testing showed Kit Exon 11 mutation- this is common in GISTs and associated with response to imatinib. Recurrent disease was diagnosed 2018 with a 10x9cm mass between residual stomach and liver– he recommenced imatinib with partial response (maximal response was reached in 2020, but a new 3cm lesion was noted) He underwent further resection of the residual stomach and liver segmentectomy in 2020. Histology showed acellular areas of myxoid degeneration, indicating treatment response however viable tumour remained. Sequencing was performed. This showed the expected mutation in exon 11 but also a mutation in exon 13 of KIT- this has been shown recently to confer resistance to imatinib. Discussion Over 90% of GISTs harbour mutations in c-KIT. Recent work has demonstrated that some tumours acquire secondary mutations conferring resistance, following prolonged TKI therapy. Radiological and histopathological features correlate with such events and assist in deciding surgical management.

4539 Background: The Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) trial reported an acceptable safety profile for neoadjuvant Xelox +/- AZD8931 but limited efficacy. We utilized EAC patient samples from DEBIOC to evaluate the impact of neoadjuvant Xelox +/-AZD8931 on biological pathways using a unique software driven solution. Methods: 24 pre-treatment FFPE EAC biopsies and 17 matched surgical resection specimens were transcriptionally profiled using the Almac Diagnostics Xcel Array. Gene expression data was analyzed using the Almac claraT total mRNA report V3.0.0, reporting on 92 gene expression signatures and 7337 single genes associated with 10 key biologies. Paired Wilcoxon tests (5% significance level) were used to evaluate changes in claraT scores pre- and post-treatment. EGFR and Her2 expression were assessed by IHC and FISH. Results: 15 patients received Xelox+AZD8931 and 9 Xelox alone. Hierarchical clustering of biopsies identified 4 major clusters: Inflammation active, Genomic Instability active, EGFR & MAPK active, and EMT & Angiogenesis active. Comparison of signature scores pre- and post- neoadjuvant treatment demonstrated a significant reduction in scores relating to DNA damage repair (DDR) deficiency (Almac DNA Damage assay, p< 0.0001; BRCAness Profile, p= 0.0025; HRD Gene Signature, p< 0.0001; BRCA1ness Signature, p= 0.0004) and a significant increase in angiogenesis signatures (Almac Angiogenesis Assay, p= 0.0002; Angio Predictive G model, p= 0.0228; Angiogenesis Signature A, p= 0.0034) and EMT signatures (EMT Signature, p= 0.0031, EMT Enrichment Score, p= 0.0013, Pan-Can EMT Signature B, p= 0.0001). Comparing pre- and post-treatment signature scores in patients treated with Xelox +/-AZD8931 revealed a significant reduction in EGFR Sensitivity Signature ( p= 0.0088), ERBB2-specific Gene Expression Signature ( p= 0.0127) and Hallmark PI3K-AKT-MTOR Signaling ( p= 0.0195) in those treated with Xelox + AZD8931 in keeping with the mechanism of action of AZD8931. Downregulation of AKT signaling was confirmed in AZD8931 treated and resistant cell lines. Conclusions: We report the use of a novel software tool to apply 92 gene expression signatures to EAC biopsy and resection specimens from the DEBIOC trial to provide insight into mechanisms of action. Neoadjuvant treatment was associated with a reduction in DDR deficiency and an increase in angiogenesis and EMT signatures whilst a reduction in EGFR, Her2 and AKT pathways was noted with AZD8931 treatment.

Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches.

Background: Patients with resectable pancreatic ductal adenocarcinoma (PDAC), undergoing adjuvant chemotherapy can experience an array of complications including fatigue, pain and the loss of physical function. Accumulating evidence from largely early stage breast cancer studies supports exercise as an adjunct therapy to help mitigate treatment complications. However, there is a lack of evidence of its feasibility in pancreatic cancer. The purpose of this study is to explore the initial feasibility of delivering a supervised, individualized, and progressive concurrent exercise intervention to individuals with resectable PDAC who are undergoing adjuvant therapy. Methodology: Ten patients with resectable PDAC undergoing adjuvant chemotherapy will be recruited. Clinical care teams will screen patients against inclusion criteria to determine eligibility. All enrolled participants will complete a 16-week, supervised, tailored, moderate intensity exercise intervention consisting of aerobic and muscle strengthening activities. The primary outcome will be feasibility of delivering a supervised exercise intervention. Secondary outcomes will include measures of physical fitness, fatigue, and quality of life. Outcomes will be measured at baseline (T1), 16 weeks (T2) and 3 months (T3). The feasibility, acceptability and potential utility of the supervised exercise intervention will be explored qualitatively through semi-structured interviews with key stakeholders (e.g. active participants, eligible participants that declined participation and the research staff including exercise physiologists and recruiting clinicians). The use of health and social care services, medications and personal expenses incurred during the trial will also be used to determine cost-effectiveness of this intervention and a potential further RCT in PDAC. Discussion: The overall aim of this study is to determine the utility of a supervised, tailored, moderate intensity exercise intervention in PDAC patients undergoing adjuvant chemotherapy. This feasibility study will help inform the design of future randomised controlled trials to determine the efficacy of the exercise intervention in PDAC.

Background AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). Methods AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival. Results During escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III–IV AEs. Six-month PFS was 85% (90% CI: 66%–94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024). Conclusion Xelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791)., Highlights • First study to assess safety and tolerability of the novel pan erbB inhibitor AZD8931 in oesophagogastric cancer (OGC). • Recommended phase II dose schedule determined to be 20-mg bd for 4 days on/3 days off, per cycle. • Feasibility of adding novel targeted therapies to standard-of-care for oesophago-gastric cancer is confirmed.

Aim: A matching-adjusted indirect comparison (MAIC) of sunitinib and everolimus has been previously reported based on the RADIANT-3 everolimus trial. We performed an analysis using updated overall survival (OS) data based on sunitinib's trial (A6181111). Methods: The MAIC matched on all baseline characteristics available from both studies. An anchored MAIC was performed for progression-free survival (PFS); an unanchored analysis was deemed more appropriate for OS due to crossover in both trials. A hazard ratio for sunitinib versus everolimus was derived from adjusted (weighted) sunitinib effects compared with the observed results for everolimus. Results: The adjusted hazard ratio for sunitinib versus everolimus was 0.85 (0.39–1.89) for PFS and 0.82 (0.53–1.27) for OS. Conclusion: Findings indicate comparable PFS and OS with sunitinib and everolimus.

709 Background: Olaparib is a potent inhibitor of PARP-1, which has a critical role in signalling DNA single strand breaks (SSB) as part of the base excision repair pathway, and may have radio-sensitizing effects due to impaired resolution of radiation induced SSB. We hypothesize that O may potentiate the effects of X-CRT in pts with LAPC. Methods: Eligible pts with LAPC, ECOG < 1, tumor diameter < 6cm, with stable disease (SD) or response after 12 weeks’ induction chemotherapy, were treated with 1 of 4 escalating doses of O given bid po starting on day -3, and then in combination with X (830 mg/m2 bid) and radiation (50·4 Gy in 28 fractions) all administered Mon-Fri. Dose limiting toxicities (DLT) were determined on clinical and lab toxicity assessments (NCI-CTC AE v4.03) performed weekly from the start of O until completion of O plus X-CRT (i.e. 6 weeks). Dose escalation continued with a rolling-six design until the Maximum Tolerated Dose (MTD) was reached. Blood samples for PK analyses of O and PD measurement (inhibition of PARP activity) were collected on day -3 (O monotherapy) and during week 1 of O + X-CRT. Results: 18 pts, (9 m, 9 f, ECOG 0/1 [n=6/12]), age range 49-81 (median=70) years, with histologic (14) or cytologic (4) proven LAPC, had received induction chemotherapy with gemcitabine [GEM] (n=2), GEM + X (12), or FOLFIRINOX (3) with partial response (n=4) or stable disease (14). Pts received 50 (3), 100 (4), 150 (6), or 200 (5) mgs bid of O with X+CRT. DLTs were observed in 2 pts (both at 200mgs bid): 1 pt with grade 3 nausea (on optimal anti-emetics) and grade 3 fatigue, 1 pt with grade 3 anorexia. 6 pts were subsequently recruited at 150mgs bid with no DLTs. No pts had complete response, 2 pts had partial response (1 pt each at 100 and 150 mgs bid) and 1 pt (at 100 mgs bid) had progressive disease; the remaining 14 pts had SD. Conclusions: The recommended dose (RP2) of O is 150mgs bid when given in combination with X + CRT in LAPC. Recruitment of up to 12 pts with borderline operable LAPC at the RP2 is ongoing. PK analyses of O, PD studies (PARP inhibition – PBMCs; cytokeratin 18 – serum; γH2AX foci – hair follicles), and exploratory predictive marker studies (tumor – NGS; RNA exome sequencing) are ongoing. Clinical trial information: ISRCTN10361292.

Introduction Pancreatic neuroendocrine tumours (pNETs) are rare and the majority of patients present with advanced disease. Such patients have limited treatment options. We conducted a systematic review of published clinical trials of non-surgical interventions in pNET, to understand the efficacy, safety and health related quality of life (HRQoL) outcomes from the current evidence base. Methods Electronic databases and manual bibliographic searches were conducted to identify relevant studies. Data were extracted by two independent reviewers. Results Forty seven clinical studies met the predefined inclusion criteria. The following interventions were included: targeted therapies (two RCTs and six single-arm studies), chemotherapy (two RCTs, one prospective nonrandomised, comparative study and 14 single-arm studies);somatostatin analogues (SSA) and radiolabeled SSA therapies (nine single-arm studies), liver-directed therapies (six single-arm studies), mixed treatment regimens (one RCT, four single-arm studies) and other interventions such as interferon and recombinant human endostatin (one single-arm study for each). The paucity of RCT data and lack of consistency in reporting validated study outcomes and differing patient inclusion criteria between studies made it difficult to compare the relative efficacy of therapies. Discussion The majority of published studies assessing treatment regimens for the management of pNET are single arm, non-randomised studies, often enrolling a small number of patients and not reporting clinically meaningful outcomes. However data from recently conducted studies assessing targeted therapies indicate that it is possible to conduct adequately powered RCTs reporting standardised oncological endpoints in this rare cancer. Further, similarly robust studies should be conducted to define the optimal treatment algorithm.

Background TP300, a recently developed synthetic camptothecin analogue, is a highly selective topoisomerase I inhibitor. A phase I study showed good safety and tolerability. As camptothecins have proven active in oesophago-gastric adenocarcinomas, in this phase II study we assessed the efficacy and safety of TP300 in patients with gastric or gastro-oesophageal junction (GOJ) adenocarcinomas. Methods Eligible patients had metastatic or locally advanced gastric or Siewert Types II or III GOJ inoperable adenocarcinoma. Patients were chemotherapy naïve unless this had been administered in the perioperative setting. TP300 was administered as a 1-h intravenous infusion every 3 weeks (a cycle) for up to 6 cycles at a starting dose of 8 mg/m2 with intra-patient escalation to 10 mg/m2 from cycle 2 in the absence of dose-limiting toxicity. Tumour responses (RECIST 1.1) were assessed every 6 weeks. Toxicity was recorded by NCI-CTCAE version 3.0. Using a modified two-stage Simon design (Stage I and II), a total of 43 patients were to be included providing there were 3 of 18 patients with objective response in Stage I of the study. Results In Stage I of the study 20 patients (14 males, 6 females), median age 67 years (range 40 − 82), performance status ECOG 0/1, with GC [14] or GOJ carcinoma [6] were enrolled. Of the 16 evaluable patients, 11 received the planned dose increase to 10 mg/m2 at cycle 2, 2 decreased to 6 mg/m2, and 3 continued on 8 mg/m2. There were no objective responses after 2 cycles of treatment. Twelve patients had stable disease for 1 − 5 months and 4 had progressive disease. Median progression free survival (PFS) was 4.1 months (CI [1.6 − 4.9]), median time to progression (TTP) was 2.9 months (CI [1.4 − 4.2]). Grade 3/4 toxicities (worst grade all cycles) included 7 patients (35 %) with neutropenia, 4 patients (20 %) with anaemia, 2 patients (10 %) with thrombocytopenia, and 3 patients (15 %) with fatigue. This study was terminated at the end of Stage I due to a lack of the required (3/18) responders. Conclusions This study of TP300 showed good drug tolerability but it failed to demonstrate sufficient efficacy as measured by radiological response. Trial registration EU-CTR 2009-012097-12 2009-09-03

A 52-year-old lady presented with a history of occasional, severe abdominal cramps, postprandial diarrhoea and weight loss. After routine gastrointestinal investigations, she was diagnosed with irritable bowel syndrome. Over six months, she developed occasional facial flushing prompting assessment of neuroendocrine tumour markers. Urinary 5HIAA, 5HT, chromogranin A and neurokinin A were significantly elevated. Scans showed extensive hepatic metastases but did not show the location of a primary tumour. Somatostatin analogue therapy was commenced but despite increasing doses, symptoms increased and biomarkers rose dramatically. Interferon alpha was introduced concomitant with somatostatin analogue therapy. Biomarkers were monitored regularly. Within six months, symptoms abated and biomarkers reduced, continuing to fall over the next year, close to reference range. To manage side-effects of interferon alpha, dose was reduced from time to time. During these short periods, neurokinin A showed significant transient increases (75–150 ng/L) and carcinoid symptoms returned. For more than seven years, and with the co-operation of the patient, a balance was achieved between interferon alpha side-effects and disease control. Scans showed tumour load to be stable. The patient survived for 10 years post diagnosis. She chose to discontinue interferon alpha and received peptide receptor radiation therapy in her final year. Throughout, neurokinin A remained the most sensitive monitor of her disease progression.

PURPOSE: Although oral fluoropyrimidine prodrugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. METHOD: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m2) OGT 719. RESULTS: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. CONCLUSION: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Background Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. Methods This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Committee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecitabine (1000 mg/m2 po, twice daily, days 1–14) and oxaliplatin (130 mg/m2 i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Results Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8 % (95 % CI 12.05–39.5 %). Stable disease was observed in a further 13 patients (31 %) and progressive disease observed in 12 (28.6 %) of patients. The median progression-free survival was 4.6 months (95 % CI 2.8–6.4 months; Fig. 1) and the median overall survival 7.9 months (95 % CI 5.3–10.4 months; Fig. 2).Fig. 1Progression-free survivalFig. 2Overall survival Conclusion Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. However, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated.

Purpose: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). Patients and Methods: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ≤1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. Results: Twenty-five patients received 17-DMAG (range 2.5–106 mg/m2). At 106 mg/m2 of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m2. Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m2 or less. In peripheral blood mononuclear cells significant (P < 0.05) HSP72 induction was detected (≥20 mg/m2) and sustained for 96 hours (≥40 mg/m2). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m2 client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively). Couclusions: The recommended phase II dose of 17-DMAG is 80 mg/m2 weekly i.v. Clin Cancer Res; 17(6); 1561–70. ©2011 AACR.

Background: On the basis of preclinical studies of NC-6004, a cisplatin-incorporated micellar formulation, we hypothesised that NC-6004 could show lower toxicity than cisplatin and show greater anti-tumour activity in phase I study Methods: A total of 17 patients were recruited in a range of advanced solid tumour types. NC-6004 was administered intravenously (i.v.) every 3 weeks. The dose escalation started at 10 mg m−2 and was increased up to 120 mg m−2 according to the accelerated titration method and modified Fibonacci method. Results:One dose-limiting toxicity (DLT) occurred in a patient who was given 90 mg m−2 of NC-6004, otherwise any significant cisplatin-related toxicity was not observed or generally mild toxicity was observed. Despite the implementation of post-hydration and pre-medication regimen, renal impairment and hypersensitivity reactions still developed at 120 mg m−2, which led to the conclusion that the maximum tolerated dose was 120 mg m−2, and the recommended dose was 90 mg m−2, although DLT was not defined as per protocol. Stable disease was observed in seven patients. The maximum concentration and area under the concentration–time curve of ultrafilterable platinum at 120 mg m−2 NC-6004 were 34-fold smaller and 8.5-fold larger, respectively, than those for cisplatin. Conclusion:The delayed and sustained release of cisplatin after i.v. administration contributes to the low toxicity of NC-6004 Refereed/Peer-reviewed

Despite recent advances in the treatment of both early and advanced colorectal cancer, it remains the second leading cause of cancer deaths in the western world. There is, therefore, a pressing need to optimize the use of the currently available systemic therapies and to identify active new agents for the treatment of this disease. Pharmacogenomic studies have shown that genetically determined variability in key cellular functions can influence toxicity, response to treatment and survival. Numerous examples of these single ‘classical’ markers have been identified for a wide range of agents and each has been studied with regard to its effect on response. However, in any individual or tumor it is likely that a number of complex, interacting factors are involved in determining the likelihood of benefit with a given therapeutic agent. Microarray-based gene-expression profiling has allowed the complex range of molecular changes occurring in the cell and surrounding stroma to be assessed in relation to response and prognosis. Predictive gene sets have been developed and, along with other markers, are being assessed in prospective clinical trials. Treatment may soon be individualized by using this technology to predict which patients will benefit from a particular systemic therapy or which are likely to develop recurrence.

Purpose Combination chemotherapy regimens can improve survival in patients with advanced gastric and oesophageal adenocarcinoma. Docosahexaenoic acid (DHA)-paclitaxel is a novel conjugate formed by the covalent linkage of the fatty acid DHA to paclitaxel and may result in increased tumour exposure to paclitaxel without increased toxicity. Patients and methods In this single arm, phase II study of DHA-paclitaxel, eligible patients with previously untreated, inoperable locally advanced or metastatic adenocarcinoma of the oesophagus, oesophago-gastric junction or stomach were treated with DHA-paclitaxel (1,100 mg/m(2)) administered by 2-h intravenous infusion every 21 days. Results Fifty-four patients were recruited of whom 53 were evaluable for toxicity, and 48 for response. There were five confirmed partial responses (9.4%) by the RECIST criteria. The median duration of response was 87 days (range 49-97 days), the median time to progression was 84 days (95% CI 78-124 days), and median overall survival was 262 days (95% CI 205-357 days). Grade >= 3 neutropaenia occurred in 93% of patients, and febrile neutropaenia in 17% of patients. Conclusions DHA-paclitaxel has modest activity in patients with oesophago-gastric cancer and with haematological toxicity that is comparable to paclitaxel and docetaxel.

TO THEEDITOR: We congratulate Davies et al 1 on the retrospective analysis of 400 patients treated with neoadjuvant chemotherapy followed by surgery at two high-volume London centers over the course of a decade. Rather than examining the prognostic effect of tumor regression, the authors focused on the downstaging effect of neoadjuvant chemotherapy as a predictor of recurrence-free and overall survival. Following adjustment for known clinicopathologic variables, tumor downstaging was associated with a reduction in the risk of recurrence and death, suggesting that major clinical decisions should be based on postchemotherapy staging. As mentioned by the authors, advanced diagnostic staging procedures, such as positron emission tomography-computed tomography (PET-CT),areimportantfordetectingnodaldiseaseanddistantmetastases.Toclassifyatumorasdownstaged,itisessentialtonotonlyaccurately define the pathologic stage following surgical resection but also to define the clinical stage before chemotherapy. Although much work has been carried out to standardize the reporting of pathologic stage, the use of clinical staging methodologies has varied over time and between centers. 2,3 StagingthatusesPET-CTcandetectoccultmetastaticdiseaseinup

A two-stage Simon design was used to evaluate the response rate of OSI-7904L, a liposome encapsulated thymidylate synthase inhibitor, in advanced gastric and/or gastroesophageal adenocarcinoma (A-G/GEJA), administered intravenously at 12 mg m(-2) over 30 min every 21 days. Fifty patients were treated. Median age was 64 years (range 35-82), 62% were male and 89% had ECOG PS of 0/1. A total of 252 cycles were administered; median of 4 per patient (range 1-21). Twelve patients required dose reductions, mainly for skin toxicity. Investigator assessed response rate was 17.4% (95% CI 7.8-31.4) with one complete and seven partial responses in 46 evaluable patients. Twenty-one patients (42%) had stable disease. Median time to progression and survival were 12.4 and 36.9 weeks, respectively. NCI CTCAE Grade 3/4 neutropenia (14%) and thrombocytopenia (4%) were uncommon. The main G3/4 nonhaematological toxicities were skin-related 22%, stomatitis 14%, fatigue/lethargy 10%, and diarrhea 8%. Pharmacokinetic data showed high interpatient variability. Patients with higher AUC were more likely to experience G3/4 toxicity during cycle 1 while baseline homocysteine did not predict toxicity. Response did not correlate with AUC. Elevations in 2'-dU were observed indicating target inhibition. Analysis of TS genotype, TS protein and expression did not reveal any correlation with outcome. OSI-7904L has activity in A-G/GEJA similar to other active agents and an acceptable safety profile.

Palliative chemotherapy for inoperable/metastatic oesophageal cancer has limited activity. This study assesses the feasibility and activity of gemcitabine and cisplatin in this group of patients. In total, 42 patients with locally advanced/metastatic squamous or adenocarcinoma of the oesophagus were treated with gemcitabine 1250 mg m(-2) days 1 and 8 and cisplatin 75 mg m(-2) day 1 in a 21-day cycle. Interim safety analysis was carried out after the first 19 patients suggested significant toxicity. The dose of gemcitabine was subsequently reduced to 1000 mg m(-2). Patients were assessed for toxicity and response. The median number of treatment cycles per patient was 4 (range 1-6). Grade 3-4 neutropenia occurred in 37% of cycles; however, there was only one episode of neutropenic fever. Nonhaematological toxicities included fatigue, nausea and vomiting. Among 32 patients eligible for response, there were three complete responses and 16 partial responses (overall response rate of 45%); nine patients had stable disease. Median survival was 11 months. The response rate appears to be greatest in those with squamous carcinoma compared to adenocarcinoma (71 vs 33%, P=0.036). The combination of gemcitabine and cisplatin in this schedule has manageable toxicity and significant activity in patients with locally advanced/metastatic oesophageal cancer and is worthy of further study.

Background Troxacitabine (Troxatyl™) is a novel L -enantiomer nucleoside analog with activity in pancreatic cancer xenograft models. Patients and methods Troxacitabine 1.5 mg/m2 was administered by 30-min infusions daily ×5 every 4 weeks to 54 patients with advanced pancreatic cancer. Patients were evaluated for objective tumor response, time to tumor progression (TTP), changes in tumor marker CA 19-9, survival, safety, pain, analgesic consumption, Karnofsky performance status and weight change. Results Median TTP was 3.5 months (95% CI 2.0–3.8), median survival 5.6 months (95% CI 4.9–7.4), and the 1 year survival rate 19%. Best responses were stable disease in 24 patients with eight patients having stable disease for at least 6 months (15%). A 50% or greater decrease in CA 19-9 was seen in seven of 44 assessed patients (16%). Grade 3 and 4 neutropenia were observed in 37% and 30% of patients with one episode of febrile neutropenia. The most common drug-related non-hematological toxic effects reported were cutaneous, with 22% and 6% of patients reporting grade 2 and 3 skin rash, respectively and 4% grade 2 hand–foot syndrome. Conclusion Troxacitabine administered by a bolus daily ×5 monthly regimen has modest activity in advanced pancreatic adenocarcinoma.

The orally bioavailable matrix metalloproteinase inhibitor MMI270 reduces tumour growth metastasis in preclinical models. We assessed the feasibility and pharmacokinetic interactions of combining MMI270 with 5-fluorouracil (5-FU) and folinic acid (FA). Entered into the study were 33 patients with advanced colorectal cancer. They received FA 200 mg/m2 over 2 h followed by 5-FU 400 mg/m2 over 15 min and 5-FU 600 mg/m2 over 22 h on days 1 and 2 of a 14-day cycle. MMI270 commenced with the second cycle at either 50 mg once daily, 150 mg three times daily or 300 mg twice daily. No dose-limiting toxicity was observed at any MMI270 dose level. Ten patients (61%) experienced joint symptoms independent of MMI270 dose, leading to interruption, modification, or discontinuation of treatment in seven patients (23%). MMI270 did not alter 5-FU pharmacokinetics. Six patients had a partial response and seven had stable disease. 5-FU/FA with MMI270 at a dose of 300 mg twice daily is well tolerated. MMI270 has no significant effect on 5-FU pharmacokinetics.

4026 Background: Current strategies to guide the selection of neo-adjuvant or adjuvant therapy in esophageal and gastric adenocarcinomas (EAC/GAC) are inadequate. We assessed a clinically validated 44 gene DNA Damage Response Deficiency (DDRD) assay to predict prognosis following neo-adjuvant DNA damaging chemotherapy (CT) in EAC and adjuvant CT or chemo-radiotherapy (CRT) in GAC. Methods: Transcriptional profiling of 273 formalin fixed paraffin embedded pre-treatment endoscopic EAC biopsies was performed using the Almac Diagnostics Xcel array. All EAC patients were treated with cisplatin-based neo-adjuvant chemotherapy followed by surgical resection between 2003 and 2014 at four UK centers in the OCCAMS consortium. Further validation was performed using a publically available dataset of 270 resected gastric cancers treated with adjuvant platinum-based CT, CRT or surgery alone at the Samsung Medical Centre, Seoul, Korea. The association between the DDRD score and prognosis was assessed by Kaplan-Meier analysis and Cox Proportional Hazards regression. Results: A total of 66 EAC samples (24%) were characterized as DDRD positive with the remaining 207 samples (76%) being DDRD negative. DDRD assay positivity was associated with improved DFS (HR 0.58; 95% CI 0.36-0.93; p = 0.024) and OS (HR 0.56; 95% CI 0.34-0.92; p = 0.023) following multivariate analysis. DDRD positive patients had a higher pathological response rate (p = 0.033) and a higher rate of loco-regional versus distant relapse (30% vs 20%; p = 0.013). For GAC, 132 samples (49%) were characterized as DDRD positive with the remaining 138 (51%) being DDRD negative. DDRD positivity was associated with improved DFS (HR 0.48; 95% CI 0.25-0.96; p = 0.037) following D2 gastrectomy and adjuvant CT or CRT. DDRD status was not associated with DFS in the surgery alone cohort (HR 0.87; 95% CI 0.55-1.38; p = 0.562). Conclusions: The DDRD assay is strongly predictive of benefit from DNA damaging neo-adjuvant CT and esophagectomy in EAC and gastrectomy and CT/CRT in GAC and can be applied to routine diagnostic material.

Summary Background We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. Methods TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m 2 , 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m 2 orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2–4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. Findings The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4–12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1–8·8] vs 6·9 months [6·4–7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97–1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3–9·7], HR 1·05, 98·25% CI 0·85–1·29, p=0·64; overall log-rank of χ 2 2df =4·3; p=0·11). The commonest grade 3–4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). Interpretation Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. Funding Cancer Research UK and KAEL-GemVax.

A dose-finding study of raltitrexed (tomudex) with cisplatin and epirubicin in advanced gastro-oesophageal adenocarcinoma

Purpose The protease inhibitor bortezomib attenuates the action of NF-κB and has shown preclinical activity alone and in combination with chemotherapy. Design A Phase I dose-escalation study was performed administering bortezomib (0.7, 1.0, 1.3 and 1.6 mg m−2 on days 1 and 8 from cycle 2 onwards) in combination with Epirubicin 50 mg m−2 intravenously on day 1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg m−2 BD days 1–21 every 21 days (VECarboX regimen), in patients with advanced oesophagogastric adenocarcinoma. The primary objective was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX. Results 18 patients received bortezomib 0.7 (n = 6), 1.0 (n = 3), 1.3 (n = 6) and 1.6 mg m−2 (n = 3) and a protocol amendment reducing the capecitabine dose to 500 mg m−2 BD was enacted due to myelotoxicity. Common treatment-related non-haematological adverse events of any grade were fatigue (83.3 %), anorexia (55.6 %), constipation (55.6 %) and nausea (55.6 %). Common Grade 3/4 haematological toxicities were neutropenia (77.8 %) and thrombocytopenia (44.4 %). Objective responses were achieved in 6 patients (33.3 %) and a further 5 patients (27.8 %) had stable disease for >8 weeks. Conclusions The addition of Bortezomib to ECarboX is well tolerated and response rates are comparable with standard chemotherapy.

In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil. Here we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug. We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients. Gemcitabine and capecitabine reduced MDSCs in 42 % of patients (n = 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs. In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation. In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone. Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy. 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels. A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen.

Background We evaluated AMG 386, an investigational peptibody that neutralizes the interaction between angiopoietins-1 and -2 and the Tie2 receptor, combined with cisplatin/capecitabine (CX) as first-line treatment for metastatic gastro-oesophageal cancer. Patients and Methods Patients with metastatic gastric, gastro-oesophageal junction, or distal oesophageal adenocarcinoma were randomized 1:1:1 to CX (cisplatin 80 mg/m2 IV Q3W; capecitabine 1000 mg/m2 P.O. BID for 14 days Q3W) plus intravenous AMG 386 10 mg/kg QW (Arm A) or 3 mg/kg QW (Arm B), or placebo QW (Arm C). The primary end point was estimated progression-free survival (PFS). Results A total of 171 patients were enrolled. Median estimated PFS in Arms A, B, and C was 4.2, 4.9, and 5.2 months, respectively (hazard ratio for Arms A+B combined versus Arm C, 0.98; 95% CI 0.67–1.43; P = 0.92). Objective response rates were 27% (Arm A), 43% (Arm B), and 35% (Arm C). Incidence of grade ≥3 adverse events was 80% in Arm A, 84% in Arm B, and 75% in Arm C. There was no evidence of pharmacokinetic interactions. Conclusions In this study, PFS and ORR were estimated to be similar with AMG 386 plus CX and placebo plus CX treatment. Compared with placebo, toxicity of AMG 386 plus CX was greater but manageable. Previous presentation The results of this study have not been previously published or submitted for publication elsewhere. The results were presented in part at the Gastrointestinal Cancers Symposium, San Francisco, CA, January 20–22, 2011. Clinical trial registration ClinicalTrials.gov registration number: NCT00583674

The objective of this study was to compare attitudes of hospice staff towards weight loss and weight assessment in the hospice setting with those of patients with advanced malignancy in the hospital outpatient setting. Two paper-based questionnaires (one for staff and one for patients) were designed. The staff survey was circulated to all hospices in the UK and Ireland, and the patient questionnaire was given to patients attending three oncological care clinics in Belfast, Northern Ireland; Wolverhampton, England; and Auckland, New Zealand. The staff survey was posted to the medical director of each of the 215 hospices in the UK and Ireland. A total of 129 oncology outpatients with a confirmed diagnosis of malignancy and no longer receiving curative oncological interventions took part in the questionnaire. The main outcome measure was descriptive information about hospice weighing practices and attitudes of hospice staff towards weighing patients, and descriptive information was collected about patient attitudes to weighing and weight loss. We found that weighing practices vary across hospices in UK and Ireland. Patients attending the majority of hospices, 96/146 (66%), are rarely weighed. A little over half of hospice staff, 81/146 (56%) considered that weighing could cause patients to be upset. However, 124/129 (96%) of patients with advanced cancer reported that they had never found the experience of being weighed in a healthcare facility upsetting. Some 95/129 (74%) of patients weighed themselves at home and 89% would want to know if their weight was changing. While there is reluctance on the part of many hospice staff to weigh patients, most patients with advanced malignancy in the hospital setting do not report weight measurement to be upsetting.

Purpose Both gemcitabine (GEM) and fluoropyrimidines are valuable treatment for advanced pancreatic cancer. This open-label study was designed to compare the overall survival (OS) of patients randomly assigned to GEM alone or GEM plus capecitabine (GEM-CAP). Patients and Methods Patients with previously untreated histologically or cytologically proven locally advanced or metastatic carcinoma of the pancreas with a performance status ≤ 2 were recruited. Patients were randomly assigned to GEM or GEM-CAP. The primary outcome measure was survival. Meta-analysis of published studies was also conducted. Results Between May 2002 and January 2005, 533 patients were randomly assigned to GEM (n = 266) and GEM-CAP (n = 267) arms. GEM-CAP significantly improved objective response rate (19.1% v 12.4%; P = .034) and progression-free survival (hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P = .004) and was associated with a trend toward improved OS (HR, 0.86; 95% CI, 0.72 to 1.02; P = .08) compared with GEM alone. This trend for OS benefit for GEM-CAP was consistent across different prognostic subgroups according to baseline stratification factors (stage and performance status) and remained after adjusting for these stratification factors (P = .077). Moreover, the meta-analysis of two additional studies involving 935 patients showed a significant survival benefit in favor of GEM-CAP (HR, 0.86; 95% CI, 0.75 to 0.98; P = .02) with no intertrial heterogeneity. Conclusion On the basis of our trial and the meta-analysis, GEM-CAP should be considered as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.

4037 Background: AZD8931 is a novel small-molecule inhibitor which has equipotent activity against signalling by three members of the erbB family; EGFR, erbB2(HER2), and erbB3. Our hypothesis is th...

Learning Objectives After completing this course, the reader will be able to: Understand the clinical problems associated with treating pancreatic cancer. Appreciate the role of chemotherapy in the treatment of pancreatic cancer. Appreciate the rational for the investigation of a number of novel agents in this disease. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Pancreatic carcinoma is a commonly occurring cancer that tends to present late in its course when potentially curative surgical treatment is not possible. The majority of patients are, therefore, candidates for systemic therapy. We review the patient and disease-related factors that contribute to the difficulties in the medical management of this condition and discuss new methods of assessing response to treatment, including the introduction of more clinically relevant novel end points such as clinical benefit response. We review the current trial literature examining the use of conventional cytotoxic agents in this disease, both as single agents and in combination. We also review the use of more novel targeted agents and examine their potential utility in this disease. The use of the farnesyl transferase inhibitors, matrix metalloproteinase inhibitors, epidermal growth factor receptor antagonists, and angiogenesis inhibitors is discussed.

To reduce the Hickman line-associated morbidity of continuous infusion 5-fluorouracil combined with epirubicin and cisplatin (ECF) and to investigate the need for infusional regimens, we conducted a retrospective study in patients with advanced gastro-oesophageal adenocarcinoma. Thirty-six patients, with histologically proven irresectable gastro-oesophageal adenocarcinoma were given: 60 mg/m2 cisplatin on day 1, 35 mg/m2 doxorubicin on day 1 and 500 mg/m2 5-fluorouracil on days 1 and 8 (NIACF) every 3-weeks. A median of 3 cycles was administered. The principal toxicity was myelosuppression with grade III/IV neutropenia in 47% of cycles. Neutropenic fever occurred in 5% of the cycles: non-haematological toxicity was mild and there were no treatment-related deaths. Administered dose intensity was 96.1% for doxorubicin, 93.6% for cisplatin and 90.5% for 5-fluorouracil. There were 16 partial responses and 1 complete response (overall response rate 47%, 95% confidence interval CI 31-63%); 8 patients had stable disease. Median progression-free and overall survival rates were 5 months (95% CI 4-6) and 8 months (95% CI 6-10), respectively. NIACF is a well-tolerated regimen in advanced gastro-oesophageal adenocarcinoma that precludes the need for central venous access, with activity similar to that observed with ECF.

4121 Background: The TeloVac trial randomized 1,062 patients with advanced pancreatic cancer to a control chemotherapy Arm1, using GemCap; sequential chemoimmunotherapy Arm 2, GemCap for 8 wks foll...

63 Background: Accurate prediction of outcome for neo-adjuvant therapy in early stage esophageal adenocarcinoma (EAC) is essential for clinical trial design, patient counseling and treatment decisions. The use of 18F-fluorodeoxyglucose positron emission tomography (PET) has improved the staging of EAC and can predict pathological response and survival. Our aim was to develop a pre-operative prognostic model based on metabolic imaging and clinical parameters. Methods: Between April 2004 and December 2010, 118 patients with early stage adenocarcinoma of the distal esophagus or gastro-esophageal junction were treated with platinum and fluorouracil-based combination chemotherapy prior to surgical resection. Patients were staged by endoscopic ultrasound and PET/CT was performed prior to, and upon completion of, chemotherapy. A metabolic response was defined as a >35% reduction in the maximum standard uptake variable (SUVmax). The final prognostic model was selected by multivariate Cox regression analyses and the concordance-index (c-index) was used to assess the fit of the final multivariate model. Results: In both the univariate and multivariate analysis of patient prognosis post-surgery, five pre-surgery factors were included: clinical T and N staging, PET response, neutrophil-lymphocyte ratio and albumin levels. The majority of the patients were T3 (82.1%) and N1 (73.7%) and 69.8% of patients demonstrated a PET response. In the univariate analysis PET response was the only significant prognostic factor with a median overall survival (OS) of 60.4 months for responders compared to 23.3 months for non-responders (p=0.0241). The final multivariate model of T staging and PET response had a c-index of 0.624 with T3/PET non-response resulting in a poorer prognosis compared to T3/PET response and T2/PET responder or non-responder (median OS 11.5 vs 44.5 vs undefined months; p=0.0284). We seek to validate our model in an independent patient dataset to assess its predictive capability. Conclusions: Metabolic imaging and clinical staging can be combined in a prognostic model in early stage EAC. Our model can inform patient counseling and the development of clinical trial strategies.

Introduction Gastric antral vascular ectasia (GAVE) is a rare disorder characterised by upper GI bleeding, chronic iron-deficiency anaemia and endoscopic findings of columns of red tortuous vessels along the longitudinal folds of the antrum of the stomach. Although the pathogenesis of this condition is largely unknown, it is associated with a number of medical conditions including portal hypertension and scleroderma. There have been few studies analysing the prevalence of the associated conditions in a cohort of GAVE cases, and none in a sample size of greater than 15. Method This is a retrospective cohort study of all patients diagnosed with GAVE an Milton Keynes district general hospital between November 2007 and November 2012. Information was gathered from electronically stored patient records. Results 20 patients were identified, 50% of cases were male. Average age at diagnosis overall was 65 years. The most common symptom that lead to a diagnosis of GAVE was of iron deficiency anaemia. 45% of cases had a co-existing diagnosis of liver cirrhosis (n=9), 35% chronic renal failure, 25% (n=7) had diabetes (n=5), 20% had rheumatologic disease (n=4) and in half of these the condition was scleroderma, 11% of the cohort had thyroid function abnormalities (n=2). Patients were followed up for a mean period of 1.9 years and in this period one patient had an acute GI bleed. Argon Plasma Coagulation was performed in 5 cases and the remaining cases were treated medically. Following APC the haemoglobin increased by an average of 3.75 g/dL. Conclusion GAVE is an important differential diagnosis in the setting of iron deficiency anaemia on a background of cirrhotic liver disease or portal hypertension, especially in patients in their sixties or older. This cohort confirms the associations in previous studies but also notes that acute bleed risk is low and that APC appears an effective treatment modality.

2586 Background: Targeting poly (ADP-ribose) polymerase (PARP), an enzyme involved in DNA damage repair, may increase efficacy of DNA-damaging agents. This study evaluated the tolerability of oral rucaparib, a potent and selective PARP1/2 inhibitor, in combination with carboplatin (CP). Methods: Patients (pts) aged ≥18 with advanced solid tumors were included. Pts received lead-in doses of IV and oral rucaparib on Days -10 and -5, respectively, followed by CP on Day 1 and oral rucaparib on Days 1-14 q21 days. Treatment continued until disease progression. Pts with benefit could continue on rucaparib monotherapy once CP dosing was completed. Dose escalation was based on toxicities observed in Cycle 1 in cohorts of n=3-6. PK was assessed during Cycle 1. Results: 23 pts (median age 62 yrs [range 20 – 76]; 16 female; 9 ECOG PS=0; 6 ovarian/peritoneal cancer (OC), 5 breast cancer (BC), 2 NSCLC, 10 other tumor) were enrolled. Rucaparib doses of 80, 120, 180, 240, and 360 mg were administered with AUC3 CP, followed by 360 mg rucaparib with AUC4 CP, and currently with AUC5 CP. No DLTs have been reported. Median treatment cycles is 3 (range 1 – 15+). Treatment-related adverse events in ≥4 pts, all grades, include anemia (n=10), fatigue (n=9), nausea (n=7), thrombocytopenia (n=6), constipation (n=5), lethargy (n=5), neutropenia (n=5), and anorexia (n=4). One pt (OC, BRCAwt, AUC3 CP/180 mg rucaparib) had a PR of 5.1 mo duration. Two patients (both with OC; 1 BRCAunk, 1BRCAwt) discontinued CP (after 4 & 8 cycles) and continued on rucaparib monotherapy (additional 5 and 7+ cycles, respectively). An additional 4 pts (all BRCAunk) had stable disease (SD) >12 wks. Overall disease control rate (CR+PR+SD>12 wks) in OC pts across all dose levels was 50% (3/6). Dose-proportional increase in rucaparib exposure was observed with steady state achieved by Day 14 and mean t1/2of 15 h. Oral bioavailability was 38% and dose-independent. Rucaparib exposure was not changed by CP co-administration. Conclusions: The combination of oral rucaparib and CP is well tolerated and exhibits activity at clinically relevant doses of each agent. Further studies in platinum-sensitive and homologous recombination repair deficient populations are warranted. Clinical trial information: NCT01009190.

Background Combination chemotherapy is the treatment of choice for patients with advanced oesophago-gastric cancer and efforts to incorporate novel agents into chemotherapy regimens have been problematic. Bortezomib (Velcade®) attenuates the action of the transcription factor NF-κB, and has shown preclinical activity alone and in combination with chemotherapy in oesophago-gastric cell lines. Design A Phase I dose-escalation study using a 3 + 3 design was performed with Bortezomib (Velcade®) in combination with Epirubicin 50 mg/m2 day1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg/m2 BD days 1-21 every 21 days, in advanced or metastatic gastro-oesophageal adenocarcinoma. Bortezomib was administered at four dose levels of 0.7, 1.0, 1.3 and 1.6 mg/m2 on days 1 + 8. Due to myelotoxicity the dose of capecitabine was reduced to 500 mg/m2 after the first patient cohort. The primary end point was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX with secondary end points of radiological response rate (RR) and toxicity. Results 20 patients, 18 evaluable for response, were enrolled (6 gastric, 9 GOJ and 3 oesophageal), 2 were Stage III and 16 Stage IV. The overall RR was 33.3% with 6 patients achieving a partial response. An additional 7 patients had stable disease for an overall Disease Control Rate (DCR) of 61.1%. Common grade 3/4 adverse events included nausea, fatigue, anaemia, neutropenia and thrombocytopenia. The first 3 patients developed grade 4 neutropenia and pyrexia resulting in a protocol amendment reducing the Capecitabine dose to 500 mg/m2 BD. Bortezomib-induced pulmonary infiltrates occurred in one patient treated at dose level 2, requiring discontinuation of Bortezomib and withdrawal from the study. Recruitment is ongoing at dose level 4 and the MTD is yet to be defined. Conclusions The addition of Bortezomib to amended combination chemotherapy for locally advanced or metastatic gastro-oesophageal adenocarcinoma has not been previously investigated and is well tolerated. Response rates are comparable with standard chemotherapy and updated data will be presented. Disclosure All authors have declared no conflicts of interest.

66 Background: AMG 386, a first-in-class investigational peptide-Fc fusion protein (peptibody), blocks angiogenesis via inhibiting the interaction between angiopoietins-1 and -2 and the Tie2 receptor. We evaluated the efficacy and tolerability of AMG 386 or placebo plus CX in the first-line treatment of metastatic gastroesophageal adenocarcinoma. Methods: Pts with confirmed metastatic adenocarcinoma of the stomach, gastroesophageal junction or distal esophagus were randomized 1:1:1 to receive CX (cisplatin, 80 mg/m2 IV Q3W; capecitabine, 1,000 mg/m2 orally BID for 14 days Q3W) plus AMG 386 10 mg/kg (Arm A), 3 mg/kg (Arm B), or placebo (Arm C) IV QW. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR; in pts with measurable disease), adverse events (AEs), and pharmacokinetics (PK). Results: 171 pts were randomized (Arm A/B/C, n = 56/59/56). Efficacy results are summarized in the table. The incidence of grade ≥ 3 AEs in Arms A/B/C was 80/84/75%. Serious AEs occurred in 73/60/47% and serious AEs grade ≥ 3 in 66/60/43% of pts. AEs in Arms A/B/C included abdominal pain (30/40/17%; grade ≥ 3, 18/3/4%), peripheral edema (13/29/6%; grade ≥ 3, 0/2/0%), venous thromboembolic events (20/22/19%; grade ≥ 3, 20/19/17%), and pulmonary embolism (9/3/15%; grade ≥ 3, 9/2/13%). Median AMG 386 Cmax and Cmin values at steady state after CX coadministration were dose-proportional. Coadministration with CX did not markedly affect AMG 386 exposure. Conclusions: In this study, AMG 386 plus CX did not significantly improve PFS or ORR over placebo plus CX in this patient population. The toxicity of the combination of AMG 386 plus CX, compared with placebo, was greater but manageable. No unexpected AEs occurred. [Table: see text] [Table: see text]

e14571 Background: Combined positron emission tomography with computed tomography(PETCT) using [18F] 2-fluoro-2-deoxy-D-glucose (FDG) is an important modality for staging oesophageal cancer and may also predict pathological response to chemotherapy. We therefore conducted this retrospective review to assess the relationship between metabolic response measured by FDG-PETCT imaging following neoadjuvant chemotherapy in oesophageal cancer and survival. Methods: Oesophageal cancer patients presenting to Northern Ireland Cancer Centre between January 2003 to December 2008, who had FDG-PETCT assessment for staging and also following neoadjuvant chemotherapy before surgery were included. Routine FDG-PETCT findings were collated and metabolic response (≥ 35% reduction in the tumour standard uptake values[SUV]), evaluated. Pathologic response was assessed and stratified into five histological tumour regression grades (TRG1-5). TRG 1 and 2 groups were classified as pathological responders. Overall survival and even...