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Summary Background The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. Methods The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. Findings Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7–1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04–0·17; p=0·0003) in men and 0·06 units per year (0·01–0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21–0·25) in men and 0·14 units per year (0·12–0·15) in women (both p0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p

Background Surgery is the only curative treatment for primary cutaneous melanoma, therefore it is important to determine excision margins that minimise risk of local recurrence, distant recurrence and death. Methods MEDLINE, EMBASE and Cochrane CENTRAL were searched from 2009 to 2015. Inclusion criteria were: population/setting – patients with primary melanoma; comparison – narrow versus wide margins; outcomes – overall survival, melanoma-specific survival, recurrence-free survival, and loco-regional recurrence; design – randomized controlled trials (RCTs). Results were pooled using meta-analysis and data explored using likelihood Bayesian probability plots. Results Six RCTs with 4233 patients were included. Narrow margins were defined as 1 or 2cm of clinically normal skin around the melanoma; wide margins as 3, 4 or 5cm. Hazard ratios (HR) were as follows (HR>1 indicates wide margin better): overall survival 1.09 (95% CI 0.98–1.22; p =0.1); melanoma-specific survival 1.17 (CI 1.03–1.34; p =0.02); recurrence-free survival 1.08 (CI 0.97–1.20; p =0.2); loco-regional recurrence 1.10 (CI 0.96–1.26; p =0.2), with no evidence of heterogeneity between trials for any end point or within subgroup analyses. There was an 94% probability that overall survival was worse with a narrow margin and a 43% probability that it was more than 10% worse in proportional terms (i.e. HR>1.1). Probabilities that narrow margins were worse were 99%, 92% and 92% for melanoma-specific survival, recurrence-free survival and loco-regional recurrence respectively. Conclusions Contrary to recommendations in several national guidelines that narrow margins are safe, this systematic review and meta-analysis provides evidence that a narrow margin may lead to a worse outcome than a wide margin.

Background The purpose of this study was to determine the extent to which summary index scores from the short form Parkinson's Disease Questionnaire (PDQ-8) replicate those from the parent form (PDQ-39) in a longitudinal study. Methods Longitudinal data gained from the PD-MED trial were examined (n = 1867), to determine the extent the PDQ-8 replicates results from the PDQ-39 at baseline and follow up. The sensitivity to change of the PDQ-8 was also compared with that of the PDQ-39. Finally, results on the two measures were compared with those from the Hoehn and Yahr (HY) clinical staging scale. Results Results of the Single Index summary score gained from the PDQ-8 were found to closely replicate those gained from the PDQ-39 at each of the three time points. Furthermore at each time point the intraclass correlation coefficient between the two measures was very high (ICC range 0.93–0.96). Similarly, the two measures gave very similar accounts of change (e.g. from baseline to follow up at one year effect sizes were 0.18 for the single index calculated using the PDQ-39, and 0.09 when calculated using the PDQ-8). Similar levels of correlation were found between the two indices when correlated with the HY scale. Conclusions The PDQ-8 closely replicates results gained from the PDQ-39 when calculating single indices. In instances where a single summary score of the impact of PD on self-reported quality of life is needed, it is likely the PDQ-8 will provide reliable and accurate information.

Background There is no consensus on the association between exposure to hydrocarbons and the risk of Parkinson's disease (PD). We conducted a systematic review and meta-analysis to summarise the epidemiological evidence and included a new large case-control study. Methods Data were extracted following a predefined protocol. Risk estimates regarding the association between hydrocarbon exposure and PD were consolidated to produce a summary odds ratio (OR), 95% confidence intervals (CI), and p-value. In our case-control study, 1463 PD patients and 685 controls were recruited from clinical trials and completed a structured questionnaire describing their previous working exposure to hydrocarbons and other demographic measures. The association between exposure to hydrocarbons and risk of PD was evaluated using logistic regression. Results The systematic search identified 13 case-control studies matching the inclusion criteria. The meta-analysis included 3020 PD cases and 6494 controls. The summary OR was 1.32 (95% CI 1.08–1.62, p = 0.006) for hydrocarbon exposure (ever versus never). In the PD GEN study, occupational exposure to hydrocarbons significantly increased the risk of PD (OR = 1.61; 95% CI 1.10–2.36, p = 0.014), and risk dose-dependently increased for subjects exposed greater than 10 years compared to subjects never exposed (OR = 2.19; 95% CI 1.13–4.26, p = 0.021). The addition of PD GEN data increased the total numbers to 4483 PD cases and 7179 controls and strengthened the significant association (summary OR = 1.36; 95% CI 1.13–1.63, p = 0.001). Conclusions This systematic review supports a positive association between hydrocarbon exposure and PD. Data from prospective studies are required to reinforce the relationship between hydrocarbon exposure and PD.

Background BEACON-Neuroblastoma is a randomized phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT) or topotecan-temozolomide (TTo), with or without bevacizumab (Bev). The Bev randomization (Bev versus no-Bev) had two parts: Part 1 had a 2-stage Minimax Jung design with overall response (OR) as primary endpoint. Part 1 success criterion was ≥4 more responses in Bev arm compared to no-Bev. Protocol was amended to incorporate Part 2 (40 additional patients), including progression-free survival (PFS) as co-primary endpoint. OR was defined as complete or partial response (CR, PR) by RECIST (INRC for patients without measurable disease). OR and toxicity data for the Bev randomization is reported. Results For Part 1 (n=106), 17 of 52 pts on Bev had responses [33%] and 8 of 54 pts on no-Bev had responses [15%]. The trial success criterion for the primary endpoint of ORR was met. Including Part 2 (total n=154), 21 of 77 patients on Bev (7CR, 14PR) and 13 of 77 patients on no-Bev (1CR, 12PR) had responses. Response data was not available for 6 patients; 13 patients not assessable for response (discontinued before first assessment) were considered to be non-responders. OR rate [with 90% CI] was 27% [18-35%] for patients on Bev and 17% [10-24%] for patients on no-Bev. In subgroup analysis, there was no interaction between T, IT and TTo and treatment with/without Bev (heterogeneity test, p=0.8). 86% Bev and 58% no-Bev patients had grade ≥3 toxicities as per CTCAE v4.0; the most common grade ≥3 toxicities associated with Bev were platelet count decrease and anemia. Conclusions Bev reached the Phase II success criterion for OR within Part 1 of the trial when added to temozolomide-based chemotherapy in RR-HRNB. The toxicity profile for Bev is acceptable. Longer follow-up is needed before assessing whether it impacts PFS or overall survival. Clinical trial identification NCT02308527; EudraCT: 2012-000072-42. Legal entity responsible for the study University of Birmingham. Funding Roche. Disclosure L. Moreno: Honoraria (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Mundipharma; Licensing / Royalties, I am member of Siopen Executive Committee, Siopen receives royalties for the sales of dinutuximab beta: Eusa Pharma. D. Valteau-Couanet: Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties, Member of Siopen Executive Committee, SIOPEN receives royalties for the sales of dinutuximab beta: Eusa Pharma; Research grant / Funding (institution): Ophelia; Travel / Accommodation / Expenses: Jazz Pharma. K. Nysom: Advisory / Consultancy: Bayer. N. Gerber: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Novartis. R. Ladenstein: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Apeiron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Eusa Pharma; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. A.D. Pearson: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Genentech. All other authors have declared no conflicts of interest.

The preliminary results of the twelfth Medical Research Council acute myeloid leukemia trial show no evidence of a survival advantage for five courses of therapy compared to four courses in a randomized comparison involving 1078 patients (hazard ratio 1.09, 95% confidence interval [CI] 0.87-1.37, p=0.4). However, the data presented to the independent data monitoring and ethics committee (DMEC) at both its reviews in 1998 suggested large benefits for the additional course with hazard ratios of 0.47 and 0.55 (95% CIs 0.29-0.77 and 0.38-0.80, p=0.003 and p=0.002, respectively). Despite these highly significant findings, the DMEC did not recommend closure of the randomization, a decision vindicated by the subsequent reversion to a null result. The main reason for not closing the randomization was that the treatment effects observed in 1998 (53% and 45% reductions in the odds of death) were considered too large to be clinically plausible, despite the p-values associated with them. Investigations have not identified any clinical explanations, such as different types of patients in the early and later parts of the trial, to explain the loss of benefit as the trial progressed. Thus, the most likely current explanation for the large benefit observed early on is the play of chance. Lessons to be learned from this example are that: fixed stopping rules based on some predetermined p-value should not be used and the decision to close a randomization or not should take account of other factors such as the medical plausibility of the magnitude of the treatment effect; chance effects do occur and happen more frequently than many clinicians realize; it is important that DMEC members are experienced in the interpretation of clinical trial evidence and aware of the dangers of early stopping without wholly convincing evidence.

High-risk surgically resected primary or loco-regional cutaneous malignant melanoma, although uncommon, can be associated with less than 50% 5-year survival; adjuvant therapy of proven efficacy is therefore appropriate. Since immunological control mechanisms seem to be important in the natural history of melanoma, biological agents have been the subject of many adjuvant studies. Most popular has been recombinant interferon. Well over 4000 patients have been entered into randomized studies. Results suggest that there may be a clinical benefit, most clearly in relapse-free but also perhaps in overall survival. More precise estimates of the magnitude of any benefits are needed. The doses, schedules and cost-benefits have yet to be fully evaluated. Interferon cannot yet be recommended as standard adjuvant therapy in high-risk malignant melanoma.

Background Three strategies are used to prevent relapse in patients with acute myeloid leukaemia in first remission. Most of those with suitable donors are offered allogeneic haemopoietic-stem-cell transplant. Other patients may receive intensive chemotherapy or autologous transplantation; we undertook this randomised prospective trial to assess which is the better option. Methods After three courses of intensive chemotherapy, bone marrow was harvested from patients (

The effects on long-term outcome in childhood acute lymphoblastic leukaemia (ALL) of the duration and the intensity of maintenance chemotherapy need to be assessed reliably. With this objective the Childhood ALL Collaborative Group coordinated a worldwide overview of all randomised trials that began before 1987.Individual patient data were sought for about 3900 children in trials of longer vs shorter maintenance (eg, 3 vs 2 years), 3700 in trials of intensive "reinduction" chemotherapy during maintenance, and 4400 in trials of various other questions, including 1300 in trials of pulses of vincristine and prednisone (VP) during maintenance. Analyses were of survival in first remission, overall survival, and cause-specific mortality.Deaths during remission were increased by longer maintenance (2.7 percent vs 1.2 percent), VP pulses (4.0 vs 3.2 percent), and intensive reinduction (4.8 percent vs 3.3 percent), but these increases were counterbalanced by reductions in relapses. Total events (relapse or death) were significantly reduced by longer maintenance (23.3 percent vs 27.6 percent), VP pulses (31.2 percent vs 40.4 percent) and intensive reinduction (27.8 percent vs 35.8 percent) (each 2p0.001). Many of those who relapsed were successfully re-treated, however, and only for intensive reinduction was overall survival significantly improved (18.5 percent vs 22.3 percent; 2p=0.01).Intensive reinduction chemotherapy in these trials produced an absolute improvement of about 4 percent in long-term survival; if the extra deaths in remission had been avoided, this would have been a 5 percent benefit. Further improvements in survival seem more likely to be obtained with intensive treatment than with longer low-level maintenance.

To minimise bias, clinical trials must be randomised, and all patients analysed by allocated treatment. With several separate randomisations, patients should be analysed only within the randomisation they entered, and not compared against patients in different randomisations. Some people worry that randomised trials result in many patients receiving an inferior treatment. Accordingly, several suggestions have been made, including a combined control arm for many trials, and performing several randomisations at the same up-front time point. These approaches fundamentally contradict the above statistical principles, and can lead to wrong conclusions. We explore these problems, with reference to one such recent proposal.

Acute Myeloid Leukaemia is a rare disease in children but is a significant cause of childhood cancer mortality. This makes running effective clinical trials in the area very difficult. This trial will test strategies in both induction and consolidation for their value in improving survival by evaluating treatments in four randomised comparisons. The embedded dose finding study (EDFS) aims to identify the optimum dose of Gemtuzumab ozogamicin that can be safely combined with induction chemotherapy, which will then form part of the induction randomised comparisons. A rolling design is applied to the EDFS to reduce the need to pause recruitment between cohorts. Patient’s treatment pathways will be determined by their cytogenetics, molecular characteristics and morphological response. 700 patients will be randomised over 6 years. While randomisations 2 and 4 are based on conventional hypothesis testing, randomisation 1 and 3 will use a probability based approach to assess event free survival and relapse free survival. This involves plotting bayesian posterior probability distributions using non-informative priors and observed data to infer the probability that one treatment is better than the other. 280 events are anticipated in randomisation 1, if the observed hazard ratio was 0.89 or better in favour of a particular treatment we could be > 80% sure that this is the more effective treatment. Each randomisation will be analysed in their own right and where appropriate be stratified by previous randomisations. No interaction between treatments is anticipated. This design will allow effective evaluation of multiple randomised comparisons in small patient populations.

Aim: We aimed to assess whether RFS is a valid surrogate for OS for high risk stage I-III melanoma through a meta-analysis of randomized controlled trials. Methods: All trials with available IPD on RFS (time until recurrence/death) and OS were collected from high risk stage I-III pts enrolled in 11 randomized adjuvant trials (N = 5826) comparing interferon (IFN) to observation: EORTC (18871, 18952, 18991), ECOG (1684, 1690), MRC (AIMHIGH), WHO-16, NCCTG (83-7052), DKG 80-1, DeCOG and Scottish group. In addition IPD from ECOG 1694 trial, IFN vs GMK vaccine (N = 842), and ECOG 2696, IFN administered concomitantly/sequentially with GMK vaccine vs GMK vaccine (N = 107) were added. We applied a two-level modeling approach assessing Spearman's individual-level correlation of RFS and OS (rho) and the trial-level coefficient of determination (R2) of the treatment effect on RFS and on OS. Results: At a 7-yr median follow-up, a consistent advantage of IFN vs No IFN was observed for RFS and OS (see table). R2 could not reliably be estimated when all trials were considered. A proper R2 estimate was obtained after exclusion of ECOG 2696 trial, which was an outlier [HR(RFS) = 0.72 vs HR(OS) = 1.11]. As a sensitivity analysis, the model was also fitted after excluding the other vaccine comparator trial (ECOG 1694). In these two analyses, RFS and OS were strongly correlated and the surrogate threshold effect (STE) was estimated to be a HR of 0.774 and 0.786, respectively. The leave-one-out cross-validation showed consistently good model accuracy. All pts (N = 6815) All but ECOG2696(N = 6708) No vaccine trials (N = 5826) No IFN IFN HR * No IFN IFN HR * No IFN IFN HR * 5-yr RFS 35.2% 38.8% .87 35.2% 38.8% .88 34.0% 38.0% .88 5-yr OS 47.2% 50.3% .91 47.0% 50.2% .91 45.4% 49.0% .91 rho* * .887 .887 .887 R2* * - .906 .924 STE* * - .774 .786 * Forest plots; **Plackett copula. Conclusions: We found that both individual-level and trial-level correlations are close to 1, suggesting a valid surrogacy of RFS for OS. If, in a future trial, the treatment effect HR on RFS were less than 0.774, one would expect this trial to also show a treatment effect on OS. Disclosure: A.M.M. Eggermont: Member of advisory board: AMGEN, BMS, GSK, MedImmune, MSD; P. Lorigan: Advisory board member: BMS, Celgene, GSK, Merck, Novartis, Roche. Other supportive relationships: Support for travel BMS, Merck, Roche; J. Kirkwood: Consultancy: BMS, Celgene, MSD, Prometheus, Vical, Ziopharma; C. Garbe: Member of advisory board: BMS, GSK, MSD, Novartis, Philogen, Roche Corporate sponsore research: BMS, GSK, Roche; D. Cameron: Member of advisory board (compensated to employer): Roche Corporate sponsored research (paid to another institution): Roche; S. Kotapati: Stock ownership: BMS Corporate sponsored research: BMS; C. Konto: Stock ownership: BMS Corporate sponsored research: BMS Other: employee of BMS; T. Chen: Stock ownership: BMS Corporate sponsored research: BMS; M. Buyse: Stock ownership: IDDI. All other authors have declared no conflicts of interest.