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Background Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial. Methods DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/− CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers. Discussion DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs. Trial registration ISRCTN15837212, 31 July 2018.

IntroductionPoorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need.Methods and analysisNET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward.Ethics and disseminationThis study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register.Trial registration numbersISRCTN10996604,NCT03837977, EudraCT Number: 2017-002453-11

Background: GO2 sought to optimise chemotherapy dosing in older/frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. Methods: Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable. Two randomisation options were available: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (doses as used in the standard epirubicin/oxaliplatin/capecitabine regimen), B (0·8x A) or C (0·6x A). Non-inferiority of PFS was assessed using boundary HR=1·34, selected by a forum of patients and clinicians. Overall Treatment Utility (OTU), which combines efficacy, toxicity, QL and patient value/acceptability, was scored at nine weeks. Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, they could enter the CHEMO-BSC randomisation, comparing Level C versus best supportive care. Findings: 514 patients entered the CHEMO-INTENSITY randomisation: non-inferior PFS was confirmed for B vs A (HR=1·09 [CI=0·89-1·32]) and C vs A (HR=1·10 [0·90-1·33]). Level C produced less toxicity and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in the younger, fitter patients. 45 patients entered the CHEMO-BSC randomisation: overall survival was non-significantly longer with chemotherapy: median 6·1 vs 3·0 months, HR=0·69 [0·32-1·48], p=0·34. In multivariate analysis, baseline frailty, QL and neutrophil:lymphocyte ratio were independently associated with OTU, so can be combined in a model to estimate the probability of better or worse outcome. Interpretation: Reduced-intensity chemotherapy provided non-inferior efficacy with an improved patient experience. Baseline geriatric assessment can help predict the utility of chemotherapy. Trial Registration: [Trial registration: ISRCTN44687907] Funding Statement: Cancer Research UK [CRUK/12/022] Declaration of Interests: Dr. Grabsch reports personal fees from Merck Sharpe Dome, outside the submitted work; all other authors have nothing to declare. Ethics Approval Statement: This study was approved by the UK National Research Ethics Service and overseen by independent Trial Steering and Data Monitoring & Ethics Committees (TSC; IDMC).

Background The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. Methods The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. Discussion The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. Trial registration PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). Trial status At the time of submission, PRISM is open to recruitment and data collection is ongoing.

Importance: Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap. Objective: The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. Design, Setting, and Participants: This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty. Interventions: There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m 2on day 1, capecitabine 625 mg/m 2twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care. Main Outcomes and Measures: First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival. Results: A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P =.34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes. Conclusions and Relevance: This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment. Trial Registration: isrctn.org Identifier: ISRCTN44687907.

Background: Parkinson's disease (PD) involves motor and non-motor symptoms and loss of brain dopamine neurons. Nilotinib is a tyrosine kinase inhibitor that may alter brain dopamine metabolism. Methods: A phase II randomized, double-blind, placebo controlled trial to evaluate Nilotinib effects on safety, tolerability and clinical outcomes in PD. Seventy-five participants were randomized 1:1:1 into placebo, 150mg or 300mg Nilotinib once daily for 12 months. This study evaluated Nilotinib effects on top of the optimal standard of care in mid-stage PD (H&Y 2.5-3) at 6 and 12 months. Findings: Participants well tolerated Nilotinib and rare hematological, hepatic and other systems disorders were observed. Cardiovascular events were seen in all groups. Prior to randomization all participants were stabilized on either Levodopa and/or dopamine agonists and were tested ON time. As expected, all 3 groups were stable at 6 months, indicating the effects of PD medications. However, the placebo group declined on UPDRS II (2.39 points, p=0.007), total UPDRS I-III (4.78 points, p=0.031) and UPDRS I-IV (4.47 points, p=0.038) at 6-12 months but Nilotinib groups remained stable. Similarly, all groups were stable on PDQ39 SI and the emotional well-being subscale at 6 months but the placebo group declined (8.17 points, p=0.001 and 1.7 points, p=0.003, respectively) at 6-12 months, while Nilotinib groups remained stable. Interpretation: Nilotinib is well tolerated and appears to be safe in PD patients. Nilotinib appears to stop the decline in motor and non-motor functions up to 12 months, while the effects of optimized PD medications significantly wear off six months after treatment. Nilotinib may have a significant impact on the care and management of PD patients, leading to delay or elimination of dose adjustment of PD-medications, thus avoiding their side effects. Trial Registration: The study was conducted under FDA Investigational New Drug (IND) # 123183, and registered in ClinicalTrials.gov (NCT02954978). Funding Statement: Lasky and Barajas Family Fund and other philanthropies. Novartis Pharmaceuticals Corporation provided the study drug. Declaration of Interests: Charbel Moussa is an inventor on several US and International Georgetown University patents to use Nilotinib and other tyrosine kinase inhibitors as a treatment for neurodegenerative diseases. No other authors declare any conflict of interests with this study. Ethics Approval Statement: This study was conducted in accordance with Good Clinical Practice guidelines and was approved by the Institutional Review Board (IRB# 2016-0380) at Georgetown University Medical Center as well as by Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) scientific review board. Informed consent was obtained from all participants and study partners

4051 Background: Before 2000, trials comparing BSC +/- chemo for aGOAC showed overall survival (OS) benefit, but in predominantly fit patients (pts). We have revisited this question in a modern context, using low-dose chemo in a frail population, with comprehensive baseline health and frailty assessment. Methods: In the GO2 trial, elderly and/or frail aGOAC pts with a “certain” indication for chemo were randomised between 3 chemo doses. In this GO2 substudy, pts with an “uncertain” indication for chemo were instead randomised to BSC ± the lowest dose chemo. Pts were eligible if clinician and pt agreed the indication for chemo was uncertain. There was no PS threshold, but eGFR ≥30 and bili < 2xULN were required. Baseline assessment included global QL, symptom & functional scales, frailty and comorbidity. Randomisation was 1:1 to BSC alone, or with oxaliplatin 78 mg/m2 d1, capecitabine 375 mg/m2 bd d1-21 (modified if eGFR 30-50 ml/min or bili 1.5-2.0 xULN), q21d. QL was reassessed after 9 and 18 wks. The primary endpoint analysis was OS, adjusted for baseline factors. The sample size for this exploratory sub-study was not pre-set, but around 60 pts were anticipated. Results: 558 pts entered GO2 at 61 centres 2014-17, of whom only 45 pts (8%) at 21 centres entered this uncertain randomisation. This would provide 80% power at p = 0.05 (2-tailed) to detect an OS HR of 0.3. OS was shorter in pts with worse baseline PS (p0.32. QL deteriorated less with BSC+chemo than with BSC alone. Conclusions: In this frail, poor PS population, we observed a small survival benefit with chemo but this did not reach statistical significance. Clinicians should carefully consider BSC alone as a valid treatment option for aGOAC pts with poor PS and/or frailty. Clinical trial information: 44687907. [Table: see text]

TPS4158 Background: The prognosis for pts with PD-EP-NEC is poor. First-line treatment for advanced disease is etoposide/platinum-based chemotherapy, analogous to that of high grade lung NEC, with no standard second-line treatment, and is an area of unmet need. Methods: This is a multi-centre, randomised, phase II trial of nal-IRI; 80mg/m2 intravenously (IV) over 90 mins, prior to 5-FU; 2400 mg/m2 infusion over 46 hrs and folinic acid, Q14 days, or docetaxel; 75mg/m2 IV over 60 mins, Q21 days, as second-line therapy in pts with progressive PD-EP-NEC (Ki-67 > 20%), with the overall aim of selecting a treatment for continuation to a phase III trial. The standard arm is that used in high-grade lung NEC, of which docetaxel is a second-line therapy option (NCCN guidelines) and combination regimens such as Irinotecan/5-FU are a second-line therapy option currently used without trial evidence for this subset of pts. Pts must have had prior treatment with first-line platinum-based chemotherapy, have documented disease progression and have an ECOG performance status of ≤2. This study plans to recruit 102 pts from 16 UK centres (over 37 mths). Primary endpoint is 6-mth progression-free survival (PFS) rate; trial is designed to have an 80% chance of demonstrating that the one-sided 95% confidence interval of the 6 mth PFS rate excludes 15%, if the true rate is at least 30%, where 30% is the required level of efficacy, and a rate of < 15% would give grounds for rejection. If both treatment arms exceed the required level of efficacy to warrant further evaluation in a phase III trial, treatment with the higher PFS rate at 6 mths will be selected. Secondary endpoints include overall survival, objective response rate, toxicity, quality of life, serum neuron-specific enolase. Exploratory endpoints include quantification of circulating tumour cells (CTCs), circulating tumour deoxyribonucleic acid (ctDNA) and molecular profiling of CTCs, ctDNA and tumour tissue, and generation of CTC-derived xenografts. This trial is open and has enrolled 6 pts at time of submission. Clinical trial information: 10996604.

Background:\ud The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel.\ud \ud Methods:\ud tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0–1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546).\ud \ud Findings:\ud Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10–10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63–68] in the gemcitabine group vs 65% [62–67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86–1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]).\ud \ud Interpretation:\ud The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup.\ud \ud Funding:\ud Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

Background Over recent years a number of novel therapies have shown promise in advanced renal cell carcinoma (RCC). Internationally the standard of care of first-line therapy is sunitinib™, after a clear survival benefit was demonstrated over interferon-α. Convention dictates that sunitinib is continued until evidence of disease progression, assuming tolerability, although there is no evidence that this approach is superior to intermittent periods of treatment. The purpose of the STAR trial is to compare the standard treatment strategy (conventional continuation strategy, CCS) with a novel drug free interval strategy (DFIS) which includes planned treatment breaks. Methods/Design The STAR trial is an NIHR HTA-funded UK pragmatic randomised phase II/III clinical trial in the first-line treatment of advanced RCC. Participants will be randomised (1:1) to either a sunitinib CCS or a DFIS. The overall aim of the trial is to determine whether a DFIS is non-inferior, in terms of 2-year overall survival (OS) and quality adjusted life years (QALY) (averaged over treatment and follow up), compared to a CCS. The QALY primary endpoint was selected to assess whether any detriment in terms of OS could be balanced with improvements in quality of life (QoL). This is a complex trial with a number of design challenges, and to address these issues a feasibility stage is incorporated into the trial design. Predetermined recruitment (stage A) and efficacy (stage B) intermediary endpoints must be met to allow continuation to the overall phase III trial (stage C). An integral qualitative patient preference and understanding study will occur alongside the feasibility stage to investigate patients’ feelings regarding participation or non-participation in the trial. Discussion The optimal duration of continuing sunitinib in advanced RCC is unknown. Novel targeted therapies do not always have the same constraints to treatment duration as standard chemotherapeutic agents and currently there are no randomised data comparing different treatment durations. Incorporating planned treatment breaks has the potential to improve QoL and cost effectiveness, hopefully without significant detriment on OS, as has been demonstrated in other cancer types with other treatments. Trial Registration Controlled-trials.com ISRCTN 06473203

The STAR trial is a UK randomized phase II/III study of first-line sunitinib in locally advanced/metastatic clear cell renal carcinoma (mRCC). It compares the utilization of a sunitinib conventional continuation strategy (CCS) with an experimental sunitinib drug-free interval strategy (DFIS). Sunitinib is approved for the first-line treatment of mRCC and convention dictates that it is continued until disease progression or unacceptable toxicity. Duration of chemotherapy is frequently determined by cumulative toxicity, but this is not necessarily the case for targeted therapies, and the default has previously been to continue these treatments for longer. A DFIS has the potential advantage of improved quality of life (QoL) and cost-effectiveness, due to longer time-periods off-treatment. The STAR trial is unique in determining whether QoL benefits from a DFIS can offset any potential detriment in overall survival (OS). Endpoints will assess both survival and QoL separately, but will also assess averaged QALY (quality of life year). Temporarily stopping a treatment, which is working, is recognized to be potentially challenging for patients, and a qualitative substudy will be performed alongside the phase II trial, to explore patient feelings regarding trial entry and stopping treatment. Results from this will inform recruitment strategies in phase III. The multi-stage design maximizes resource efficacy by facilitating a seamless transition between the phase II and III parts, assuming attainment of the phase II endpoints (recruitment rate and time to strategy failure). It also enables the QALY data from the initial phase II part of the trial to be used to inform and verify the powering of the overall phase III trial, as minimal data was available during initial trial design to power on a QALY outcome. Other novel outcome measures (time to strategy failure and summative progression free interval) have also been required, due to the intermittent nature of the DFIS reducing the utility of the standard progression free survival endpoint. With increasing use of targeted therapies and interest in DFIS due to potential QoL and cost effectiveness benefits, these novel endpoints will be increasing required in future clinical trial designs. The STAR trial will be an exemplar trial in the evaluation of optimal treatment strategies for targeted therapies in other diseases. We will discuss issues relating to the trial design and the methodology relating to the novel endpoints in this study, as well as comment on the implications for future trial design.

There is growing enthusiasm for robotic-assisted laparoscopic operations across many surgical specialities, including colorectal surgery, often not supported by robust clinical or cost-effectiveness data. A proper assessment of this new technology is required, prior to widespread recommendation or implementation.The ROLARR trial is a pan-world, prospective, randomised, controlled, unblinded, superiority trial of robotic-assisted versus standard laparoscopic surgery for the curative treatment of rectal cancer. It will investigate differences in terms of the rate of conversion to open operation, rate of pathological involvement of circumferential resection margin, 3-year local recurrence, disease-free and overall survival rates and also operative morbidity and mortality, quality of life and cost-effectiveness. The primary outcome measure is the rate of conversion to open operation. For 80% power at the 5% (two-sided) significance level, to identify a relative 50% reduction in open conversion rate (25% to 12.5%), 336 patients will be required. The target recruitment is 400 patients overall to allow loss to follow-up. Patients will be followed up at 30 days and 6 months post-operatively and then annually until 3 years after the last patient has been randomised.In many centres, robotic-assisted surgery is being implemented on the basis of theoretical advantages, which have yet to be confirmed in practice. Robotic surgery is an expensive health care provision and merits robust evaluation. The ROLARR trial is a pragmatic trial aiming to provide a comprehensive evaluation of both robotic-assisted and standard laparoscopic surgery for the curative resection of rectal cancer.

Multispectral and hyperspectral imaging are efficient methods of measuring spectral reflectance at high spatial resolution. This non-invasive technique has been applied to the imaging of paintings over the last 20 years. PRISMS (Portable Remote Imaging System for Multispectral Scanning) was designed specifically for imaging wall paintings. Optical Coherence Tomography (OCT) is a low coherence interferometric technique capable of fast non-invasive imaging of subsurface microstructure. This paper shows the first application of in situ OCT imaging of a wall painting. The combination of PRISMS and OCT gives information on the varnish and paint layer structure, pigment identification, the state of degradation of the paint and varnish layers and informing curators on the painting schemes and techniques.

This article considers the need to support women's choices, by referring to a Case Study in which a woman required donor breast milk. Diagnosed with breast cancer whilst pregnant, the lady still wanted her baby to receive breast milk until she was able to breastfeed herself, once the chemotherapy medication was out of her system. As Infant Feeding Coordinator, I wanted to explore all the options available to support her choice.

Background: Past studies have linked lenalidomide to an increased risk of second primary malignancy (SPM) and in-particular a higher incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Such studies in which oral melphalan was used in combination with lenalidomide resulted in haematological SPM incidence of between 3.0-11.4% at 5 years. More recently, meta-analysis has suggested that lenalidomide in combination with other agents such as cyclophosphamide and dexamethasone does not result in an increased rate of SPM development. Here we report the incidence of SPM in Myeloma XI, the largest randomised trial to date in-which lenalidomide is used as both an induction and maintenance treatment option. Methods: Myeloma XI is a phase III, randomised, multi-centre, parallel group design, open-label trial comparing thalidomide, lenalidomide and bortezomib combinations and lenalidomide as maintenance treatment in newly diagnosed symptomatic myeloma patients. The trial has both transplant eligible (TE) and transplant non-eligible (TNE) pathways. NDMM patients are entered into the TE pathway if they are deemed fit/young enough to tolerate high dose therapy. Those who enter the TNE pathway receive attenuated doses of chemotherapy agents. Patients in the TE pathway will receive high dose melphalan supported by autologous stem cell transplantation if they achieve a very good partial response or better following induction or, if appropriate following pre-transplant consolidation. Pre-transplant consolidation with bortezomib is protocol treatment for patients with refractory disease or no change post-induction whereas for patients with a sub-optimal response (MR/PR) randomisation to bortezomib versus observation alone is compared. Both pathways include maintenance with lenalidomide, lenalidomide and vorinostat or monitoring only. Since May 2010, 2745 patients have been recruited with over 950 patients enrolled for more than 2 years since initial induction randomisation. A total of 1225 patients have entered maintenance with 720 receiving lenalidomide maintenance either as a single agent or in combination with vorinostat. Results: Thirty three patients (1.2% of entrants) have developed a second primary malignancy since enrolment. One patient developed a haematological SPM (CML) whilst on the trial (0.04%). This occurred in a patient being treated on the TE pathway who had received lenalidomide containing induction and had undergone 24 months of lenalidomide maintenance. The remaining 32 SPM cases were solid or non-invasive skin cancers with an incidence of 1.16%. Cumulative incidence of all SPMs is 0.53%,1.00% and 1.70% at one, two and three years respectively. Median overall time to SPM development from induction is 15.4 months (range 1.6 – 38.4). Approximately half the patients who developed an SPM (54.5%, n=18) received lenalidomide induction therapy with a median time to SPM development of 10.2 months (2.1 – 26.5) in the TE group (n=8) and 19.9 months (1.6 - 37.6) in the TNE group (n=10). Fifteen patients (45.5%) received thalidomide induction with a median time to SPM development in the TE group (n=2) of 10.1 months (7.7-12.4) and 21.3 months (3.7 – 38.4) in the TNE group (n=13). Over two thirds of SPM patients (70%) were being treated on the TNE pathway. The average age at the time of SPM development was 76.7 and 65.9 for the TNE and TE pathways respectively. The majority of SPMs were observed during maintenance (52%, n=17) with 94% (n=16) of these patients receiving lenalidomide. Of the remaining patients, 27% developed an SPM during induction (n=9), 12% (n=4) following bortezomib and 9% (n=3) following induction but prior to maintenance randomisation. Conclusions: The Myeloma XI trial has so far reported very low overall SPM incidence. Concerns of an increased incidence of haematological malignancy in earlier trials containing lenalidomide in combination with oral melphalan have not been reproduced here. The findings support recent meta-analysis that suggests lenalidomide in combination with cyclophosphamide or dexamethasone is not associated with an increased haematological SPM risk. It is however noted that the majority of patients who developed an SPM during maintenance were on lenalidomide and thus this will need to be monitored closely as the trial continues. On behalf of the NCRI Haemato-oncology subgroup Disclosures Jones: Celgene: Research Funding, Unrestricted educational grant Other. Off Label Use: Vorinostat and Lenalidomide as maintenance treatment for myeloma. . Pawlyn:Celgene: Honoraria, Unrestricted educational grant Other. Brioli:Celgene: Honoraria, Unrestricted educational grant Other. Cairns:Celgene: Unrestricted educational grant Other. Quartillo:Celgene: unrestricted educational grant Other. Sigsworth:Celgene: Unrestricted travel grant Other. Howard:Celgene: Unrestricted educational grant Other. Collett:Celgene: Unrestricted travel grant Other. Ouzman:Celgene: Unrestricted educational grant Other. Gregory:Celgene: Unrestricted educational grant Other. Russell:Celgene: unrestricted travel grant Other. Jackson:Celgene: Honoraria, Unrestricted travel grant Other. Davies:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Unrestricted educational grant Other. Morgan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Unrestricted educational grant Other.

8537 Background: Treatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) has dramatically increased response rates and survival for myeloma patients over the last decade. Tri...

In the care home sector, we have been aware for some time that involving people in making decisions about their lives is very beneficial. Recent policy documents from the Department of Health (DH) tell us that the involvement of patients, carers and the public in decision making about health care is at the heart of the modernization of the NHS. This article explains how this policy decision is being implemented in England and its significance to you and your residents.

The standard operation for an aortic root dissection is an aortic root replacement with direct re-implantation of the coronary arteries. In some cases, such as acute dissection and redo surgery, this approach can be difŽ cult. The Cabrol technique was developed to overcome this and involves the use of a Dacron interposition graft to connect both coronary oriŽ ces to the aortic graft. This was found to carry the risk of right coronary artery thrombosis. The subsequent modiŽ ed Cabrol’s technique involves the direct re-implantation of the right coronary artery and the re-implantation of the left coronary artery by the utilization of a Dacron graft anastomosed to the left coronary artery ostium. This is then passed posterior to the ascending aortic graft and anastomosed to the right side of the aortic graft. This 74-year-oldmale recently had redo aortic root surgery with a composite carbosealprosthesis.He originally had an aortic valve replacement and presented 19 years later with chronic aortic dissection. In this case, because of the scarring caused by previous surgery, the left coronary artery could not be adequatelymobilized and was attached using the modiŽ ed Cabrol’s technique described. A 6-month postoperative contrast-enhanced computed axial tomography (CAT) scan at the level of the ascending aorta reported a small residual dissection  ap. The large Dacron interposition graft (arrow) lies at the right postero-lateral aspect of the root replacement. The appearances strongly resemble an aortic dissection (Panels A and B). The incidence of aortic dissection after aortic root surgery is 0.7% . CAT scans are highly sensitive and speciŽ c for aortic dissection. The appearance of two lumens separated by an intimal  ap is speciŽ c for aortic dissection, but care must be taken not to misdiagnose an extra-aortic structure as a false lumen. The left innominate vein, the superior vena cava, the left superior intercostal vein, the left superior pulmonary vein and the superior pericardial recesses can mimic a false channel as can adjacent pleural or pericardial thickening and adjacent atelectasis of the lung. This CAT Ž nding highlights a less considered differential diagnosis of an aortic intimal  ap.

97 Background: The median age of death from gastroesophageal (GO) cancer is 77 years. Palliative chemotherapy can improve survival and quality of life. Current standard combination regimens have been developed in trials involving patients of median age under 65 years with predominantly good performance status (PS). In light of audit and survey evidence of widespread use of arbitrarily modified chemotherapy schedules in frail and elderly patients, better evidence is needed to guide treatment. Based on our experience with the MRC FOCUS trial in colorectal cancer, 321GO aimed to test the feasibility of a randomised trial comparing chemotherapy in frail and elderly patients with advanced GO cancer. Methods: Patients with advanced GO cancer considered unfit for full-dose 3-drug chemotherapy, were randomly allocated (1:1:1) to 3, 2 or 1 drug chemotherapy at 80% dose of standard regimens with EOX: epirubicin 40mg/m2 d1, oxaliplatin 104mg/m2 d1, capecitabine 500mg/m2 bd x21d, OX: oxaliplatin 104mg/m2 d1, capecitabine 500mg/m2 bd x21d or X: capecitabine 1000mg/m2 bd d1-14, then 7 day rest. The primary endpoint for feasibility required 45 patients to be recruited over 18 months. Secondary endpoints included tolerability, treatment benefit and compliance with detailed health and quality of life (QoL) assessment. Results: 55 patients were recruited over an average of 18 months for each of the six recruiting centres; 17 to EOX, 19 to OX and 18 to X. The median age was 75. 37 (66%) patients were of WHO PS 0 or 1 and 18 (33%) were of PS 2. After 6-weeks, 12 (71%), 9 (47%) and 9 (50%) patients in the EOX, OX and X arms had experienced a treatment delay, dose reduction, grade 3 toxicity or stopped treatment. Treatment benefit (no radiological progression or clinical deterioration) at 12 weeks was seen in 8 (47%), 11 (58%) and 3 (16%) patients for EOX, OX and X respectively. Compliance with baseline health and QoL assessment was 98% at baseline and 69% at 12 weeks. Conclusions: A phase III trial randomising frail or elderly patients with advanced GO cancer to alternative chemotherapy regimens is feasible. EOX was associated with greater toxicity compared with OX; X offered no improvement in tolerability over OX.

506 Background: After gem showed encouraging activity in advanced BC and pre-clinical evidence of a favorable interaction with paclitaxel, tAnGo was designed to evaluate, for the first time, its potential role in anthracycline and taxane containing adjuvant CT for EBC. Methods: tAnGo, an international phase III trial, compared EC-GT (4 cycles of epirubicin 90mg/m2 IV and cyclophosphamide 600mg/m2 IV day1 every (q) 3 weeks, followed by 4 cycles of paclitaxel 175mg/m2/3hour infusion day1 and gem 1,250mg/m2 IV days1 and 8 q3 weeks) with EC-T, in respect of disease-free survival (DFS) in women with invasive higher risk EBC, with definite indication for adjuvant CT. Stratification was by country, age, radiotherapy, and nodal, estrogen (ER) & HER2 status. Toxicity, dose delivery and QoL, presented at ASCO'04 and SABCS'06, showed both regimens to be safe, feasible and tolerable. We anticipated 550 DFS events at the preplanned primary endpoint efficacy analysis at 30 months (m) minimum follow-up (FU). Results: Be...

821 Background: tAnGo is an ongoing 3000-patient (pt) randomized trial evaluating for the first time the role of G in adjuvant CT for breast cancer. We present the results of a preliminary prospective safety study designed to assess the incidence of any treatment (trt)-related clinical or sub-clinical disturbances of pulmonary, cardiac, or hepatic fn in the first 135 pts randomised. Methods: Pulmonary (Hb-adjusted TLCO, FEV1, FVC, CXR), cardiac (LVEF, ECG), and hepatic (AST/ALT) fn tests were conducted in 135 pts (66 EC+T, 69 EC+GT) at baseline, mid-CT, post-CT/pre-RT, and 6 months post-CT. Results: Pulmonary fn tests: majority normal at all time points, with no differences between trts or changes over time in FEV1 (p>0.3 and 0.9 resp) or FVC (p=0.95 and 0.5 resp). TLCO dropped marginally during trt (p 0.25) and no changes over time (p=0.14). Cardiac fn tests: 95% of all Echo/MUGA scans and 90% of all...