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PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Background Worst-case, typical, and best-case scenarios for survival, based on simple multiples of an individual's expected survival time (EST), estimated by their oncologist, are a useful way of formulating and explaining prognosis. We aimed to determine the accuracy and prognostic significance of oncologists’ estimates of EST, and the accuracy of the resulting scenarios for survival time, in advanced gastric cancer. Materials and Methods Sixty-six oncologists estimated the EST at baseline for each of the 152 participants they enrolled in the INTEGRATE trial. We hypothesized that oncologists’ estimates of EST would be unbiased (∼50% would be longer or shorter than the observed survival time [OST]); imprecise ( Results Oncologists’ estimates of EST were unbiased (45% were shorter than the OST, 55% were longer); imprecise (29% were within 0.67–1.33 times observed); moderately discriminative (Harrell's C-statistic 0.62, p = .001); and an independently significant predictor of OS (hazard ratio, 0.89; 95% confidence interval, 0.83–0.95; p = .001) in a Cox model including performance status, number of metastatic sites, neutrophil-to-lymphocyte ratio ≥3, treatment group, age, and health-related quality of life (EORTC-QLQC30 physical function score). Scenarios for survival time derived from oncologists’ estimates were remarkably accurate: 9% of patients died within a quarter of their EST, 57% lived within half to double their EST, and 12% lived three times their EST or longer. Conclusion Oncologists’ estimates of EST were unbiased, imprecise, moderately discriminative, and independently significant predictors of OS. Simple multiples of the EST accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer. Implications for Practice Results of this study demonstrate that oncologists’ estimates of expected survival time for their patients with advanced gastric cancer were unbiased, imprecise, moderately discriminative, and independently significant predictors of overall survival. Simple multiples of the expected survival time accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer.

While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy.Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/mPreoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (≥ 1 mm) resections, 14 (48%) had R1 ( 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months.The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.

Background: Pattern of spread in patients with metastatic colorectal cancer (mCRC) is variable and may reflect different biology in subsets of patients. This is a retrospective study to explore the outcome of patients with mCRC based on their site of metastasis at diagnosis and to explore the association between tumor characteristics [KRAS/RAS, BRAF, mismatch repair (MMR) status, site of primary] and the site of metastasis. Methods: Patients from two Australian databases were divided into six groups based on site of metastasis at time of diagnosis of metastatic disease; lung-only, liver-only, lymph node-only or any patients with brain, bone or peritoneal metastases. Primary endpoint was overall survival (OS) of each cohort compared with the rest of the population. A Mantel–Haenszel chi-squared test used to explore the association between site of metastasis and selected tumor characteristics. Results: Five thousand nine hundred and sixty-seven patients were included. In a univariate analysis,median OS was significantly higher when metastases were limited to lung or liver and shorter for those with brain, bone or peritoneal metastases (p

The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy. Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015. One hundred and fifty-five patients met the inclusion criteria for which demographic, pathological and imaging data were collected, as well as the time of day patients received treatment with each fraction of radiotherapy. Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05. Of the 45 female and 110 male patients, the median age was 64. Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm. Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days, with a complete pathological response seen in 21% of patients. Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment (p < 0.01). Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response (p = 0.035) and improved nodal downstaging. There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy (p < 0.004), although no relationship was seen between response and tumour distance from the anal verge. Females were less likely to exhibit several of the above responses. Neoadjuvant radiotherapy for locally advanced rectal cancer performed later in the day coupled with a longer time period to surgical resection may improve pathological tumour response rates and nodal downstaging. A prospective study in chronomodulated radiotherapy in this disease is warranted.

Background AGOC has a poor prognosis with limited benefits from treatments following failure of chemotherapy (CT). Regorafenib (BAY 73-4506)(REG) is an oral multi-kinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET and KIT). INTEGRATE (phase 2) demonstrated REG effectiveness in prolonging PFS in AGOC pts, with a positive OS trend and less toxicity than other REG trials at the same doses. REG was effective across all regions/subgroups, with regional differences noted in magnitude of effect. INTEGRATE II (phase 3) will explore whether REG is effective in prolonging survival in all patients, and in the Asian sub-population Methods International randomised phase III, double-blind, placebo-controlled trial with 2:1 (REG:placebo)(PBO) randomisation and stratification by tumour location, geographic region, and prior VEGF inhibitors. Histologically confirmed AGOC patients, with evaluable metastatic or locally advanced disease refractory to/relapsed following at least 2 lines of CT, will receive best supportive care plus 160mg REG or matched placebo orally on days 1-21 of each 28 day cycle until disease progression or prohibitive adverse events. Primary endpoint is OS. Secondary endpoints: PFS, response rate, quality of life, safety, identification of prognostic/predictive biomarkers for study endpoints, and REG PK across geographical regions. 350 patients (50% from Asia, with at least 50 patients to be recruited from Japan) randomized in a 2:1 ratio will provide 90% power to detect a hazard ratio (HR) for OS of 0.67 with a 2-sided α of 0.05 assuming PBO median survival is 4.5 mos. The sample size accommodates an interim analysis undertaken once 2/3 of required events have occurred. Results 27 ANZ, 8 Canadian, 15 Korean, 5 Taiwanese, and 2 Japanese sites have been activated with 106 patients enrolled. Remaining Japanese/US sites expected to activate through Q1/Q2 2019.

Aims Retrospective review of neuroendocrine tumors (NETs) treated within the Australian Capital Territory to describe the local epidemiology and assess prognostic clinicopathological factors. Methods Patients with histologically proven non-pulmonary low to intermediate grade NETs were identified from our hospital clinical database. Data were analyzed according to epidemiological, clinical and histopathological characteristics. Results Of the 107 included patients, the most common primary tumor site was jejunum/ileum (32%), followed by rectum (22%) and pancreas (11.2%). In total, 32% had distant metastases at presentation, most commonly in the liver. Most patients were symptomatic at diagnosis, while 22.4% of cases were found incidentally. Second malignancies, in particular of gastrointestinal origin, were diagnosed in 33.6%. Surgical debulking was the most common treatment (59.8%) while 18% had multimodality therapy. With a median follow-up of 25 months from diagnosis, about 78% of patients are still alive. Median time to first relapse was 15 months and the 5-year survival rate was 80% for NETs of jejunum/ileum. Univariate survival analysis revealed tumor location, high Ki67 index, raised plasma chromogranin A, and urine 5-hydroxyindoleacetic acid upon diagnosis to be associated with shorter 5-year survival. Conclusion The epidemiologic characteristics and long-term outcome in our series are comparable to other reported studies. This analysis presents some important prognostic factors which could be used for risk stratification in patients with NETs.

Purpose To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. Patients and Methods Patients with operable magnetic resonance imaging–defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. Results One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. Conclusion Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.

Purpose Epirubicin, oxaliplatin, and capecitabine (EOC) is a standard treatment in advanced esophagogastric cancer. Panitumumab (P) is a fully human, immunoglobulin G2 monoclonal antibody targeting epidermal growth factor receptor. Randomized Trial of EOC ± Panitumumab for Advanced and Locally Advanced Esophagogastric Cancer (REAL-3) will evaluate whether the addition of P to EOC improves survival in patients with advanced esophagogastric adenocarcinoma and undifferentiated carcinoma. Patients and Methods The original design of REAL-3 added P 9 mg/kg to the standard dose of EOC (dose level [DL] + 1). Due to toxicity, a dose de-escalation was made to EOC + P DL − 1 (epirubicin 50 mg/m2, oxaliplatin130 mg/m2, capecitabine 1,000 mg/m2/d + P 9 mg/kg every 3 weeks). After additional toxicity was observed, the study was amended to include two additional EOC + P dose levels. Using a 3 + 3 design, dose-limiting toxicities (DLTs) were assessed weekly during cycle 1. Patients were randomly assigned 1:1 to EOC ± P. Results Between July 2008 and October 2009, 29 patients were randomly selected for standard-dose EOC (n = 13) or EOC + P (n = 16). Five patients were treated at DL + 1, with grade 3 diarrhea in four of five patients by cycle 4. At DL − 1, one patient had grade 3 diarrhea and grade 5 infection. Three patients were treated at DL − 3, and then six were treated at DL − 2, without DLTs. Conclusion The recommended dose for EOC + P is epirubicin 50 mg/m2, oxaliplatin 100 mg/m2, capecitabine 1,000 mg/m2/d, and P 9 mg/kg every 3 weeks. This dose has been selected for the ongoing phase II/III REAL-3 study.

Background A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. Methods We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. Results ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P = 0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P

Single-agent gemcitabine was established as standard treatment for advanced pancreatic cancer after a superior clinical benefit response was demonstrated in a randomized study comparing it to 5-fluorouracil (FU). Until recently, many subsequent randomized trials of newer, often gemcitabine-based combinations have not been able to show improved survival over gemcitabine. Combination gemcitabine and capecitabine is likely to become the preferred standard treatment, at least in the UK, on the basis of the positive interim results of the UK National Cancer Research Institute (NCRI) randomized study of chemotherapy with this combination. At present, there is no standard second-line treatment for patients who have become refractory to gemcitabine, although a recently reported study has suggested that oxaliplatin with FU and leucovorin is superior to best supportive care in these patients. This article will review and discuss the clinical trials of chemotherapy for this disease, including the more recent trials, which have included the novel targeted agents.

There has been increasing interest in the use of neoadjuvant treatment for downstaging and downsizing disease in patients with initially unresectable liver metastases from colorectal cancer with a view to potentially curative surgery. This has been increasingly feasible with the more active treatment combinations presently available based on oxaliplatin or irinotecan. This article reviews the evidence supporting the use of this treatment strategy and discusses the implications of advances in treatment in other metastatic disease settings for these patients and the issues of patient selection and prognostic factors.

There are relatively few randomized studies of adjuvant chemoradiotherapy and chemotherapy in patients with resected pancreatic adenocarcinoma. The European Study Group for Pancreatic Cancer 1 (ESPAC1) trial is the largest study of adjuvant treatment to date. The results of ESPAC1 are discussed in the context of other evidence from previous randomized studies, which have also been combined in a meta-analysis. Overall, the existing data show a clear benefit for postoperative adjuvant chemotherapy, which has not been demonstrated for adjuvant chemoradiotherapy. The subgroup of patients with resection margin positive disease did seem to benefit less from adjuvant chemotherapy, and showed a trend towards improved survival with chemoradiotherapy. Adjuvant chemoradiotherapy should be evaluated further in this latter group of patients. The optimal chemotherapy regimen for use as adjuvant treatment is the subject of ongoing trials. Other strategies which should be explored include neoadjuvant treatment and the incorporation of novel targeted agents into management.

Mixed dyslipidaemia is common in people with diabetes and occurs in up to 20% of cases. Diabetes keto-acidosis can occur in patients with type 2 diabetes. Hypertriglyceridaemia is a well-recognised cause of pancreatitis. Other common causes of pancreatitis include gall stones, alcohol, drugs (azathioprine and dideoxyinosine) and post-endoscopic retrograde cholangiopancreatography (ERCP). Therapeutic options for acute and severe dyslipidaemia include insulin therapy, fibric acid derivatives, fish oils and, rarely, nicotinic acids. Hospitalisation may be required for plasmapheresis in specialised centres.

3560 Background: Although liver is the commonest site of mets in pts with CRC, pattern of spread is variable and may reflect different biology in different subsets of pts. Methods: This is a retrospective analysis to explore the outcome of pts with mCRC based on their site of mets at diagnosis and to identify tumor characteristics which could predict the site of mets. Pts from 2 Australian databases, BioGrid (BG) and South Australian Cancer Registry (SA), from 01/2006 to 12/2015 were grouped into 5 cohorts; lung only, liver only or any pts with brain, bone or peritoneal mets. Overall survival (OS) for each group was compared with the rest of the sample using Kaplan Meier analysis and the log rank test separately in each dataset. Mantel-Haenszel Chi-squared test was performed in pooled data to assess the association between KRAS, BRAF, Micro satellite instability (MSI), site of primary and site of mets. Results: 5967 pts were included. In both datasets median OS was significantly higher when mets were limited to lung or liver and shorter for those with brain, bone or peritoneal mets. BRAF, KRAS and MSI data were available for 20%, 37% and 21% of the sample. In the pooled analysis BRAF mutation was associated with brain (Relative Risk=5.2) and peritoneal mets (RR=1.8) with lower incidence of lung (RR=0.3) and liver (RR=0.7) limited mets. KRAS mutation was associated with lung only mets(RR=1.4). Left colon tumors were associated with bone (RR=1.6) and lung only mets (RR=2.3) while peritoneal spread was less frequent compared with right colon tumors(RR=0.6). Rectal cancer was strongly associated with brain, bone and lung mets (RR=1.7, 1.7, 2.0). MSI status was not associated with site of mets though liver only mets was less frequent in MSI high tumors. Conclusions: Survival duration with mCRC is related to the site of mets. OS was significantly better when mets were confined to either lung or liver. BRAF mutation and primary rectal cancer were associated with poor prognostic metastatic sites like brain and bone. [Table: see text]

Gastric cancer is a leading cause of illness and death from cancer worldwide, with nearly a million new cases diagnosed each year and a 5-year survival rate of less than 20% among patients in most parts of the world other than Japan, where the rate is closer to 60%.1 Early dissemination of the disease through the lymphatic system, blood, and peritoneum has limited the ability of optimal surgery to cure, except in patients with relatively early tumors. The detection of early disease has remained elusive in Europe and North America, but there has been some success in the East, particularly . . .

4105Background: Nab-paclitaxel (nab-PC) and gemcitabine (GEM) are effective for metastatic PDAC. Efficacy of nab-PC and GEM as perioperative chemotherapy (CX) for resectable PDAC is unknown. The GA...

Background: Perioperative chemotherapy improves outcome in resectable colorectal liver-only metastasis (CLM). This study aimed to evaluate perioperative CAPOX (capecitabine-oxaliplatin) plus bevacizumab in patients with poor-risk CLM not selected for upfront resection. Patients and methods: Poor-risk CLM was defined as follows: more than four metastases, diameter >5 cm, R0 resection unlikely, inadequate viable liver function if undergoing upfront resection, inability to retain liver vascular supply, or synchronous colorectal primary presentation. Patients underwent baseline computed tomography, magnetic resonance imaging, and/or positron emission tomography (PET) for staging and received neoadjuvant CAPOX plus bevacizumab, with resectability assessed every four cycles. Primary end point was radiological objective response rate (ORR). Results: Forty-six patients were recruited, of which 91% underwent PET to ensure metastases confined to liver. Following neoadjuvant CAPOX plus bevacizumab, the ORR was 78% (95% confidence interval 63% to 89%). This allowed 12 of 30 (40%) patients with initial nonsynchronous unresectable CLM to be converted to resectability. In addition, 10 of 15 (67%) patients with synchronous resectable CLM underwent liver resection, with four additional patients being observed alone due to excellent response to neoadjuvant therapy. No grade 3-4 perioperative complications were seen. Conclusion: Neoadjuvant CAPOX plus bevacizumab resulted in a high response rate for patients with CLMs with poor-risk features not selected for upfront resection and converted 40% of patients to resectability.

Summary Background Patients with poor-risk rectal cancer defined by MRI can be at high risk of disease recurrence despite standard chemoradiotherapy and optimum surgery. We aimed to assess the safety and long-term efficacy of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, a treatment strategy developed to enhance the outcome of this population. Methods Between November, 2001, and August, 2005, we enrolled eligible patients with poor-risk rectal cancer defined by high-resolution MRI and without metastatic disease. The protocol was amended in January, 2004, following clinically significant cardiotoxic events (nine events in eight of 77 patients), to exclude patients with a recent history of clinically significant cardiac problems. Patients received 12 weeks of neoadjuvant capecitabine and oxaliplatin (oxaliplatin 130 mg/m 2 on day 1 with capecitabine 1000 mg/m 2 twice daily for 14 days every 3 weeks) followed by chemoradiotherapy (54 Gy over 6 weeks) with capecitabine (825 mg/m 2 twice daily), total mesorectal excision, and 12 weeks of postoperative adjuvant capecitabine (1250 mg/m 2 twice daily for 14 days every 3 weeks). The primary endpoint was pathological complete response rate. We followed up patients for a median of 55 months (IQR 47–67). Efficacy analyses were undertaken for the intention-to-treat population, unless otherwise specified. This study is registered with ClinicalTrials.gov, number NCT00220051. Findings 105 eligible patients were enrolled. Radiological response rates after neoadjuvant chemotherapy and chemoradiotherapy were 74% (78/105) and 89% (93/105), respectively. 97 patients underwent surgery, of whom 95 underwent total mesorectal excision, of whom 93 had microscopically clear resection margins and 21 had pathological complete response (21/105 [20%]). 3-year progression-free and overall survival were 68% (95% CI 59–77) and 83% (76–91), respectively. 3-year relapse-free survival for patients who had complete resection was 74% (65–83). Following the protocol amendment for cardiovascular safety, only one further thromboembolic event was reported (fatal pulmonary embolism). Interpretation Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk potentially operable rectal cancer, with acceptable safety and promising long-term outcomes. Future development of this multidisciplinary treatment strategy in randomised trials is warranted. Funding UK National Health Service, Sanofi-Aventis.

In spite of advances made in the management of the other more common cancers of the gastrointestinal tract, significant progress in the treatment of pancreatic cancer remains elusive, more so with the recent negative results of several much anticipated randomized trials. Gemcitabine has been a standard treatment for advanced pancreatic cancer since it was shown a decade ago to result in a superior clinical benefit response and survival compared with bolus 5-fluorouracil (5-FU). Since then, clinical trials have explored the pharmacokinetic modulation of gemcitabine by fixed dose administration and the combination of gemcitabine with other cytotoxics or the biological 'targeted' agents. Against a background of numerous negative randomized trials of gemcitabine-based combination treatment, two trials have recently reported modest survival improvements with the use of combination treatment: the United Kingdom National Cancer Research GEMCAP trial of gemcitabine with the orally administered precursor of 5-FU-capecitabine and the National Cancer Institute of Canada Clinical Trials Group PA.3 trial in which the tyrosine kinase inhibitor erlotinib was used with gemcitabine. This review will summarize the results of several recent randomized trials of combination treatment in advanced pancreatic cancer and discuss their implications for clinical practice and for future research in this disease.

The human epidermal growth factor receptor (HER1/EGFR/ErbB1) signaling is aberrant and overexpressed in many solid malignancies making it an appealing target for biologic agents. Among the classes of drugs targeting EGFR are monoclonal antibodies and EGFR tyrosine kinase inhibitors, which have been shown effective and generally well tolerated in different clinical settings. The majority of patients treated with EGFR inhibitors (EGFRIs) develop specific dose-dependent skin toxicity. This side effect may lead to physical and psychosocial discomfort which can result in dose reduction or treatment interruption. The relationship between rash and clinical outcome has stimulated interest in this particular toxicity as a possible surrogate marker of efficacy in patients treated with targeted agents against EGFR. This review aims to summarize and update the current knowledge of the clinical presentation, predictive and prognostic value, and the management of EGFRI-related skin toxicity.

Gastric cancer is the seventh and oesophageal cancer the ninth most common cancer in the UK, and >50% of patients present with locally advanced or metastatic disease. The incidence of oesophageal and oesophagogastric junctional tumours is increasing, making these important disease entities to understand and research. Despite improvements in surgical and peri-operative supportive care, 3-year overall survival with surgery alone for resectable disease is still poor. Outcomes in localised oesophageal cancer are improved with pre-operative chemotherapy, and in gastric cancer with peri-operative treatment or post-operative chemoradiotherapy. Oesophageal squamous cell carcinoma can be treated with definitive chemoradiotherapy as an alternative to surgery. While survival in patients presenting with metastatic disease is improved with the addition of systemic chemotherapy, median survival remains

The management of locally advanced rectal cancer remains a challenge because of relatively high local recurrence rates, even with optimal surgery. This chapter reviews the evidence from clinical trials for the use of various perioperative strategies based on radiotherapy, chemotherapy, or both in these patients, as well as discusses how these results may inform clinical practice. In particular, two treatment strategies that have been shown to be beneficial and that are standard treatment options for patients with locally advanced disease are short-course preoperative radiotherapy and long-course preoperative chemoradiotherapy. In clinical trials in which these treatments were used in addition to surgery, improvements in local recurrence rates have been observed, although overall survival has less frequently been prolonged. These patients should also receive postoperative adjuvant chemotherapy.

Colorectal cancer (CRC) is one of the most common cancers in the Western world, with > 500,000 new cases diagnosed each year. One of the strongest risk factors for colon cancer is age. The incidence rates rise from 10 in 100,000 at age 40–45 years to 300 in 100,000 at age 75–80 years, with the median age at diagnosis of CRC being 71 years. With the general demographic shift toward an aging population, the number of people aged > 65 years is expected to increase. This article reviews the development of treatment for elderly patients with metastatic CRC, from single-agent fluoropyrimidines to combination therapies.

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of colorectal cancers. It is the target for a class of agents at the forefront of development for the treatment of colorectal cancer, ie, the anti-EGFR monoclonal antibodies, which include cetuximab, panitumumab, and matuzumab. At present, cetuximab is the furthest along in terms of established efficacy in the treatment of metastatic or inoperable disease and is licensed for the treatment of patients with irinotecan-refractory colorectal cancer. This article reviews the recent evidence supporting the combination of these anti-EGFR agents with the cytotoxic chemotherapeutic agent irinotecan.

387 Background: Pancreatic cancer (PC) outcomes remain poor, recent series show approximately 37% of patients achieve R0 resection (all margins ≥ 1mm) for resectable disease. Recent data in metastatic disease shows that nab-paclitaxel (nab-PC) and gemcitabine (GEM) chemotherapy (CX) is an active regimen. We aimed to determine the feasibility and R0 resection rate with peri-operative nab-PC and GEM for resectable PC. Methods: A multicentre, single arm, phase 2 trial. Patients with operable PC received 2 cycles of neo-adjuvant GEM 1000mg/m2 and nab-PC 125mg/m2CX on days 1, 8 and 15 of a 28 day cycle followed by surgical resection and then 4 cycles of post-operative CX. The primary endpoint was R0 resection with the aim to assess if a rate of 85% could be achieved. Secondary endpoints included feasibility, toxicity, pathological response (College of American Pathologists Cancer Reporting Protocol for Exocrine Pancreatic Cancer, 2009), recurrence and survival. Results: Forty-one patients were enrolled from 2012-14. Median age was 65 (range 43-79), 41% male, 49% stage I and 51% stage II. Twenty nine (71%) patients underwent resection with evaluable cancer: 1 did not have proven cancer on central pathology review; 5 did not go to surgery (2 disease progression, 2 refused surgery, 1 due to cholangitis); and in 6 patients surgery was abandoned (unresectable disease). No deaths were surgery-related. Median tumor size was 27.5mm (IQR = 25-35). Pre-operative GEM and nab-PC produced an R0 rate of 52% (15/29) (95% CI 34-69%). 15/29 (52%) of resected tumors showed grade 0-2 tumor regression grade. Twenty-nine patients (71%) experienced >1 grade 3/4 toxicities (total 52 events) during pre-operative CX, neutropenia (46%) being most frequent with 8% febrile neutropenia. 39/41 (95%) patients received 2 cycles of pre-operative CX. Conclusions: Peri-operative GEM and nab-PC CX is feasible and well tolerated. The pre-operative regimen was associated with an R0 resection rate comparable or higher than surgical series without pre-operative therapy, although the primary endpoint of 85% could not be met. The value of this regimen will also depend on longer term outcomes related to recurrence and survival. Clinical trial information: 12611000848909.

TO THE EDITOR: We read with interest the report by Rinke et al 1 of the interim analysis of a randomized, placebo-controlled trial of octreotide LAR, the long-acting somatostatin analog (SSA), in metastatic midgut neuroendocrine tumors (NETs), along with the companion editorial by Oberg. 2 These results are an important contribution to our understanding of the biology of NETs. However, although scientifically provocative and supportive of the long-held belief of many clinicians in this field that SSAs have an antiproliferative effect in this heterogeneous group of diseases, the data published thus far still leave some important issues unresolved. The study planned to enroll 162 patients, but after nearly 8 years, only 85 were randomly assigned. Despite the much-reduced accrual, Rinke et al reported a marked difference in median time to progression on the basis of WHO radiologic criteria in the intent-to-treat population of 14.3 months with octreotide LAR compared with 6.0 months with placebo (hazard ratio [HR], 0.33; 95% CI, 0.20 to 0.59;P.000072). Importantly, similar benefits were demonstrated regardless of the presence or absence of carcinoid syndrome ( 40% of patients had carcinoid syndrome). As impressive as these results seem, we have concerns about whether both study arms are comparable. Notably, there was a highlystatisticallysignificantimbalanceinthetimesincediagnosis between the study arms in favor of the octreotide LAR arm, with a medianof7.5monthscomparedwith3.3monthsfortheplaceboarm (P.0096). Given the heterogeneous natural history of these tumors and the relatively small size of the analyzed population, it is unclear how this imbalance might have influenced the overall outcome of the study. A longer duration between diagnosis and treatment suggests more indolent disease; if by chance more of these patients were in the experimental treatment arm, as seems to have been the case in this trial, a longer time to progression could have ensued, whether or not the treatment was effective. Similarly, the planned subgroup analysis suggested that the benefit of octreotide LAR was greatest in patients withlimited(0%to10%)liverinvolvement(HR,0.17;95%CI,0.08to 0.40). Conceivably, those patients with a longer time since diagnosis were also those with limited liver involvement as a result of lower biologic aggressiveness. However, the explanation for the suggestion ofreducedactivityofoctreotideLARinthosepatientswithsignificant liver involvement in this trial was not discussed. If there is a proportionate increase in the overall quantity of somatostatin receptors with tumor bulk, the dose of octreotide LAR used may have been inade

228 Background: GEM-based treatment is a standard treatment for metastatic pancreas cancer. Monotherapy efficacy is only modest, and outcomes are improved by combination treatment or the non-GEM FOLFIRINOX triplet. There is a need for biomarkers to select between these divergent options. hENT1 is a potential predictive marker of benefit from GEM, but conflicting results have been observed in studies that have evaluated resected and metastatic pancreatic cancer. This principal objective of this study was to evaluate hENT1 prospectively as a predictive marker in GEM and non-GEM treated patients. Methods: Patients with previously untreated metastatic pancreatic adenocarcinoma and tumour tissue available for hENT1 testing were randomized between GEM (1,000 mg/m2 D1, 8, 15 Q4w) or FOLFOX (oxaliplatin 85 mg/m2, 5-fluorouracil (5FU) 400 mg/m2, leucovorin 400 mg/m2 D1 and 5FU 2,400 mg/m2over 46 hours D1-3) until disease progression or unacceptable toxicity. Tumor samples were tested prospectively for hENT1 by immunohistochemistry. The primary endpoint was progression-free survival (PFS). Results: The study was open from July 2011 to February 2013, but closed after 16 of the planned 80 patients were enrolled. 1 patient who died before treatment was excluded from the outcome analysis. 7/16 patients were hENT1 high (43.8%, 95%CI 23.1-66.8%). In the GEM arm (n=7), the 4 who were hENT1 high had longer PFS and overall survivals (OS) than those who were hENT1 low (median PFS 5.7 vs. 1.8 months; median OS 13.9 vs. 3.5 months), whereas outcomes were similar with FOLFOX for both hENT1 groups. There were no unexpected adverse events. Conclusions: This prospective study showed a longer survival in those patients with high hENT1 treated with GEM. There was no difference in survival according to hENT1 expression in patients treated with FOLFOX. Given the small sample size this may be due to chance, but supports the need for further research into the predictive value of hENT1. Clinical trial information: ACTRN12610001047088.[Table: see text]

TPS4137 Background: Biomarker-based selection of cancer treatments has already entered routine clinical practice in some cancer types. Recent retrospective data suggests the human equilibrative nucleoside transporter 1 (hENT1) to be promising predictive marker for benefit from gemcitabine in pancreatic cancer, at least in resected disease. Methods: 80 patients will be randomised to receive either gemcitabine or FOLFOX chemotherapy (folinic acid (FOL) fluorouracil (F) and oxalipatin (OX)) with stratification based on hENT1 status. All patients will be required to have tumour samples tested for hENT1 prior to randomisation, with both hENT1 positive and negative patients eligible for inclusion. Patients will continue their assigned treatment until progression, or unacceptable toxicity. Primary endpoint: Progression free survival in each chemotherapy arm (FOLFOX/gemcitabine). Secondary endpoints: efficacy/activity of gemcitabine and FOLFOX as assessed by OS (overall survival), TTP (time to progression), RR (response rate according to RECIST v1.1), CA19.9 response; Percentage of eligible patients able to be randomised within 14 days of screening; PFS in each biomarker-selected cohort (hENT1 positive/negative); Treatment related toxicity in each chemotherapy group (CTCAE v4.0) and in biomarker cohorts (hENT1 positive/negative); establishment of a tissue bank from patients treated with and without gemcitabine for further biomarker studies. Eligibility: Adult patients with radiologically and histologically confirmed metastatic pancreatic adenocarcinoma who have not previously received treatment for metastatic disease, and who have tumour tissue available for hENT1 testing are eligible for the study. Patients who do not have tumour tissue available will be required to undergo core biopsy to obtain tissue for hENT1 testing. Status: Opened to accrual July 2011.

e14088 Background: The EXPERT-C trial randomised 165 patients into neoadjuvant CAPOX and CRT ± cetuximab and demonstrated a significant increase in radiological response (RR) and overall survival (OS) with cetuximab in KRAS/BRAF wild type (WT) rectal cancer (Dewdney et al JCO in press). TP53 mutation has been associated with worse CRT response and survival in rectal cancer and could lead to stimulation of PI3K signalling pathway, thus potential resistance to cetuximab. This analysis evaluates the impact of TP53 mutation in the EXPERT-C trial. Methods: FFPE tissue from biopsy (n=102) and resection specimens (n=99) were analysed for TP53 mutations (exons 5-8) using a multiplex PCR method followed by direct sequencing. If discordant results were encountered on paired biopsy and resection samples, analyses were repeated. Results: 53/102 (52%) biopsy and 24/99 (24%) resection samples harboured TP53 mutation, most commonly missense in exons 5 and 7. The vast majority had single TP53 mutations, only 4/53 biopsy and 1/24 resection samples had 2 mutations. 21/55 (38%) paired samples demonstrated discordant TP53 mutation status. In both all-treated and KRAS WT populations, presence of TP53 mutation had no impact on RR to neoadjuvant chemotherapy or CRT, regardless of treatment arm. A trend towards worse progression-free (PFS) (HR: 2.68; 95% CI: 0.85 - 8.43; p=0.08) and OS (HR: 4.04; 95% CI: 0.86 - 19.11; p=0.056) was observed in patients with TP53 mutation when treated with cetuximab, independent of the KRAS status. Conclusions: TP53 mutations were common in high-risk rectal cancer patients, the lower mutation rate in the resection samples was potentially due to lower tumour volume post CRT. The presence of a TP53 mutation at baseline had no impact on RR to treatment, however a trend towards worse PFS and OS was observed with the addition of cetuximab, consistent with the perceived biology.

3513 Background: This trial evaluates the addition of C to our previously described treatment strategy of neoadjuvant chemotherapy before CRT and TME in patients with MRI selected high-risk operabl...

4024 Background: Consideration of metastasectomy is now standard practice in the management of selected patients (pts) with stage IV MCRC. As a result, modification to the current staging system has been suggested to more clearly define subgroups of stage IV pts. As yet, there are no prospective data comparing the outcomes of pts according to resectability status. This phase II study evaluates the outcomes of pts according to baseline resectability status, and examines the utility of CapOx chemotherapy as a neoadjuvant treatment strategy. Methods: Eligible pts had received no prior chemotherapy for MCRC. At study entry imaging review was undertaken and pts stratified into 3 groups according to resectability status; non-resectable (group 1), potentially resectable liver disease (group 2), resectable liver disease (group 3). All pts received identical chemotherapy; capecitabine 2,000mg/m2 d1–14 and oxaliplatin 130mg/m2 d 1 repeated every 3 weeks. Repeat imaging was undertaken every 4 cycles. For pts in groups 2 & 3, all imaging was reviewed by a specialist hepatic MDT, where feasible metastasectomy was undertaken following 4 or 8 cycles of chemotherapy. Planned enrolment was 130 pts, with study endpoints including; response rate, PFS & OS. Results: 129 pts are enrolled. Median age 62 (range 29–78). Median number of cycles delivered 8 (range 1–12). Grade III/IV toxicities; diarrhoea 14%, neutropenia 7.8%, peripheral neuropathy 2%. 60 day all cause mortality 3.1%. There have been no post operative deaths following liver resection. Median follow up is 19.3 months. Outcome data for each group is summarised below. Conclusion: CapOx chemotherapy is safe and well tolerated when used as a neoadjuvant treatment strategy. This prospective study clearly demonstrates the wide variation in outcomes according to baseline resectability status, and highlights the need for modification to the staging system to account for these patient subgroups in future studies. [Table: see text] [Table: see text]

3559 Background: Based on the positive results of adjuvant fluoropyrimidine chemotherapy in Dukes B colorectal cancer in the QUASAR trial it is expected that more patients with this stage of diseas...