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Background Limited information exists about the design of placebo-controlled cancer trials. Through a systematic review of trials published in 2013, we describe placebo use in randomized trials testing anticancer agents and analyze strategies that increase exposure to the experimental regimen. Methods Trials were classified as add-on (placebo in combination with standard treatment) or placebo-only. Strategies to allow more than half of the participants to receive the experimental regimen were reviewed. The risk–benefit ratio of receiving the experimental agent was considered favorable if the difference in primary outcome was significant (p ≤ 0.05), neutral if there was no significant difference in the primary outcome and the experimental agent did not add substantial toxicity, and unfavorable otherwise. Results Eighty trials were included (32,694 participants). Most trials were add-on (69%). The risk–benefit outcome was favorable, neutral, and unfavorable to the experimental agent in 52%, 32%, and 16% of placebo-only trials and 25%, 53%, and 22%, respectively, of add-on trials. Four strategies increased exposure to the experimental regimen: one-way crossover (23%), uneven randomization (21%), three-arms (13%), and randomized discontinuation design (4%); these strategies were used more often in placebo-only trials. Conclusion A minority of participants received placebo alone and strategies to increase experimental exposure were used commonly. Fewer than half of the studies had favorable outcomes, thus defending the use of placebo controls, when there is no established treatment. Strategies that increase patient exposure to experimental agents rather than placebo may expose them to non-beneficial, sometimes toxic, experimental agents.

Introduction: Direct tissue autofluorescence (AF) visualization devices such as VELscope® are gaining interest to improve early detection of oral potentially malignant disorders (OPMD) and cancers. The main objective of this study was to assess inter-observer reproducibility of incandescent light (IL) and AF observations for OPMD and cancer. Materials and methods: High risk patients (exposed to alcohol or tobacco) were screened by two independent operators with a conventional oral examination (IL) followed by AF examination. The primary endpoint was the inter-observer agreement on the decision to biopsy assessed by kappa coefficients.Accuracy of IL and AF were estimated by the relative true positive rate (RTPR, increase of sensitivity), relative false positive rate (RFPR, loss of specificity) and their ratio. Results: 179 patients were included. 833 lesions were identified after IL and AF. Indication for biopsy was retrieved for 41 patients (61 lesions). Inter-observer agreement on the indications for biopsy was 93.3% after IL (Kappa coefficient 0.88 [0.80, 0.97]) and 96.1% after IL and AF (Kappa coefficient 0.78 [0.66, 0.90]). RTPR was 1.2, RFPR was 1 and their ratio was 1.2. Conclusion: IL and AF examination has shown good inter-observer reproducibility. Adjunction of AF allowed diagnosing more leukoplakia without dysplasia.

The Food and Drug Administration (FDA) recently identified the need for further safety studies of gadolinium-based contrast agents (GBCAs) due to uncertainty regarding the effects of gadolinium ret...

Purpose Patients with advanced radioactive iodine resistant differentiated (MDTC) or medullary (MMTC) thyroid cancer had an unmet need. Early data showed promising efficacy of vascular endothelial growth factor receptor inhibitors. We investigated sunitinib in this setting. Patients and methods This phase 2 trial enrolled MDTC, anaplastic (MATC) and MMTC patients in 1st line anti-angiogenic therapy with sunitinib at 50 mg/d, 4/6w. Objective response rate was the primary end-point. Secondary end-points were progression-free survival, overall survival and safety. Results Seventy-one patients were enrolled from August 2007 to October 2009, 41 MDTC/4 MATC patients and 26 MMTC patients. Patients received a median of 8 and 9 cycles, respectively. In the MDTC/MATC group, 13% of patients and 43% of cycles and in the MMTC group, 23% of the patients and 48.8% of cycles remained at 50 mg/d, respectively. The primary end-point was reached with an objective response rate of 22% (95% CI: 10.6–37.6) in MDTC patients and in 38.5% (95% CI: 22.6–56.4) in MMTC patients. No objective response was seen in MATC patients. Median progression-free survival and overall survival were 13.1 and 26.4 months in MDTC patients, 16.5 and 29.4 months in MMTC patients. The most frequent side effects were asthenia/fatigue (27.8% ≥ grade 3), mucosal (9.9% ≥ grade 3), cutaneous toxicities, hand-foot syndrome (18.3% ≥ grade 3). Of all, 14.1% had a cardiac event. Nine unexpected side effects were reported, out of which, five induced deaths. Conclusion Sunitinib is active in MDTC and MMTC patients. Side effects were more severe than with previous reports. If using sunitinib, alternative schedule/dosage should be considered.

Background: Method prespecification in study protocols is important for controlling bias in reports. The primary goal of this study was to assess potential for discordance between study protocols and publications reporting predictive or prognostic cancer biomarker research. Secondary objectives included comparing characteristics of publications with accessible protocols compared to those without. Methods: Publications reporting predictive or prognostic cancer biomarker research were identified from 15 major journals, 2012–2015. Protocols were sought online or through repeated queries of corresponding authors. The following four items were extracted: (1) biomarkers, (2) biospecimen/assays, (3) sample size, (4) endpoints. We defined “explicit discordance” as the presence of major inconsistencies on these items. Results: Of 149 eligible publications, we obtained 19 eligible protocols online (13%). Out of a random sample of 103 publications where protocols were not available online, 12 protocols (12%) were furnished by corresponding authors; 8 (8% of authors) explicitly stated the absence of a protocol. Among 24 retrospective cohort studies, no protocol could be accessed. We found explicit discordance between publications and protocols for 18 studies (58%), in particular choice of biomarkers (36%), biospecimen/assays (6%), or endpoints (29%). Conclusion: Protocols are generally not accessible or not used for cancer biomarker studies. Publications were often explicitly discordant with protocols, particularly regarding biomarkers and endpoints. Our findings point to common unaddressed risk of bias in publications of major journals reporting the relationship between cancer biomarkers and clinical endpoints.

Key Points Question How many patient study participants are needed to obtain a first US Food and Drug Administration approval for a new anticancer drug or biologic therapy? Findings In this cohort study of 120 drugs and biologic therapies, more than 12 000 patients participated in prelicense clinical trials for every new drug or biologic approved by the US Food and Drug Administration. When confined to drugs and biologic interventions with intermediate to substantial clinical impact, nearly 40 000 patients were required per approval. Meaning These results indicate that in addition to involving large private expenses, oncology drug and biologic development entails a large subsidy of altruism, time, and welfare from patients themselves., This cohort study estimates the volume of patients required to achieve a first US Food and Drug Administration (FDA) approval for a new anticancer drug or biologic therapy., Importance Several studies have estimated the financial inputs for successful drug development. Such analyses do not capture the large investment that patient study participants commit to drug development. Objective To estimate the volume of patients required to achieve a first US Food and Drug Administration (FDA) approval for a new anticancer drug or biologic therapy. Design, Setting, and Participants This cohort study included a random sample of prelicense oncology drugs and biologics with a trial site in the United States that were launched into clinical efficacy testing between January 1, 2006, and December 31, 2010. Drugs and biologics were identified using ClinicalTrials.gov registration records. Total patient enrollment was captured over an 8-year span, and each intervention was classified based on whether it received FDA approval and was deemed as having intermediate or substantial value according to the American Society of Clinical Oncology Value Framework (ASCO-VF) score. Secondarily, the association between patient numbers and intervention characteristics was tested. Data were analyzed in February 2020. Main Outcomes and Measure The prespecified primary outcome was the number of patients enrolled in prelicense trials per FDA approval. Results A total of 120 drugs and biologics were included in our study, with 84 (70.0%) targeted agents, 20 (16.7%) immunotherapies, and 71 (59.2%) novel agents. A total of 13 drugs and biologics (10.8%; 95% CI, 5.3%-16.8%) in our sample gained FDA approval within 8 years, of which 1 (7.7%) was deemed of intermediate value and 3 (23.1%) were deemed of substantial value using ASCO-VF scoring. Overall, 158 810 patients were enrolled in 1335 trials testing these drugs and biologics, 47 913 (30.2%) in trials that led to FDA approval and 110 897 (69.8%) in trials that did not. An estimated 12 217 (95% CI, 7970-22 215) patient study participants contributed to prelicense trials per FDA approval. The estimated number of patients needed to produce a single FDA-approved drug or biologic of intermediate or substantial ASCO-VF clinical value was 39 703 (95% CI, 19 391-177 991). Conclusions and Relevance The results of this cohort study make visible the substantial patient investment required for prelicense oncology drug development. Such analyses can be used to devise policies that maximize the clinical impact of research on a per-patient basis.

Phase I oncology clinical trials are designed to identify the optimal dose that will be recommended for phase II trials. In pediatric oncology, the conduct of those trials raises specific challenges, as the disease is rare with limited therapeutic options. In addition, the tolerance profile is known from adult trials. This paper provides a review of the major recent developments in the design of these trials, inspired by the need to cope with the specific challenges of dose finding in cancer pediatric oncology. We reviewed simulation studies comparing designs dedicated to address these challenges. We also reviewed the design used in published dose-finding trials in pediatric oncology over the period 2009-2014. Three main fields of innovation were identified. First, designs that were developed in order to relax the rules for more flexible inclusions. Second, methods to incorporate data emerging from adult studies. Third, designs accounting for toxicity evaluation at repeated cycles in pediatric oncology. In addition to this overview, we propose some further directions for designing pediatric dose-finding trials.

ObjectivesAfter regulatory approval, drug companies, public funding agencies and academic researchers often pursue trials aimed at extending the uses of a new drug by testing it in new non-approved indications. Patient burden and clinical impact of such research are not well understood.Design and settingWe conducted a retrospective cohort study of postapproval clinical trials launched within 5 years after the drug’s first approval, testing anticancer drugs in monotherapy in indications that were first pursued after a drug’s first Food and Drug Administration (FDA) license, for all 12 anticancer drugs approved between 2005 and 2007. FDA, Medline and Embase search date 2019 February 12.Primary and secondary outcome measuresOur primary objective was to measure burden and clinical impact for patients enrolling in these trials. Each trial was sorted into a ‘trajectory’ defined by the drug and cancer indication. The risk was operationalised by proportions of grade 3–4 severe adverse events and deaths. The clinical impact was measured by estimating the proportion of patients participating in trajectories that resulted in FDA approval, uptake into National Comprehensive Cancer Network (NCCN) clinical practice guidelines or advancement to randomised controlled trials within 8 years.ResultsOur search captured 104 published trials exploring monotherapy, including 69 unique trajectories. In total, trials in our sample enrolled 4699 patients. Grade 3–4 adverse events were experienced by 19.6% of patients; grade 5 events were experienced by 2.8% of patients. None of the trajectories launched after initial drug approval received FDA approval. Five trajectories were recommended by the NCCN within 8 years of the first trial within that trajectory. Eleven trajectories were advanced to randomised controlled testing.ConclusionsThe challenges associated with unlocking new applications for drugs that first received approval from 2005 to 2007 were similar to those for developing new drugs altogether. Our findings can help inform priority setting in research and provide a basis for calibrating expectations when considering enrolment in label-extending trials.

This report presents the Consolidated Standards of Reporting Trials (CONSORT) extension for the stepped wedge cluster randomised trial (SW-CRT). The SW-CRT involves randomisation of clusters to different sequences that dictate the order (or timing) at which each cluster will switch to the intervention condition. The statement was developed to allow for the unique characteristics of this increasingly used study design. The guideline was developed using a Delphi survey and consensus meeting; and is informed by the CONSORT statements for individual and cluster randomised trials. Reporting items along with explanations and examples are provided. We include a glossary of terms, and explore the key properties of the SW-CRT which require special consideration in their reporting.\ud \ud

Phase I oncology clinical trials are designed to identify the optimal dose that will be recommended for phase II trials. This dose is typically defined as the dose associated with a certain probability of severe toxicity at cycle 1, although toxicity is repeatedly measured over cycles on an ordinal scale. Recently, a proportional odds mixed-effect model for ordinal outcomes has been proposed to (i) identify the optimal dose accounting for repeated events and (ii) to provide some framework to explore time trend. We compare this approach to a method based on repeated binary variables and to a method based on an under-parameterized model of the dose-time toxicity relationship. We show that repeated binary and ordinal outcomes both improve the accuracy of dose-finding trials in the same proportion; ordinal outcomes are, however, superior to detect time trend even in the presence of nonproportional odds models. Moreover, less parameterized models led to the best operating characteristics. These approaches are illustrated on two dose-finding phase I trials. Integration of repeated measurements is appealing in phase I dose-finding trials.

Objectives: To study the diagnostic value of BCL2 rearrangement in follicle center lymphoma (FCL) presenting as primary skin lesions, evaluate its prevalence and the prognostic value in primary cutaneous FCL (PCFCL), and assess prognostic factors in PCFCL. Methods: Fifty-three patients with a cutaneous presentation of FCL without a history of nodal lymphoma were selected retrospectively. Clinical and histologic data were collected together with staging and follow-up data. A fluorescence in situ hybridization (FISH) test for BCL2 split probes was performed on skin biopsy specimens. Results: Initial staging procedures identified 47 PCFCLs and six cases of secondary skin involvement of FCL (SSIFCL). FISH detected seven cases carrying a BCL2 rearrangement: four (8.5%) of 47 PCFCLs and three (50%) of six SSIFCLs. These seven cases coexpressed BCL2 and CD10. In PCFCL, cutaneous relapse rate was 42.6%. A small/medium centrocytic cell population was associated with a higher probability of skin relapse in univariate (P = .008) and multivariate (P = .028) analysis, and BCL2 rearrangement detection was associated with secondary extracutaneous spreading (P = .05). Conclusions: We observed that BCL2 rearrangement in PCFCL is rare, associated with initial positivity of staging (diagnostic value) or with secondary extracutaneous spreading (prognostic value). In selected cases with BCL2-CD10 coexpression, FISH testing could detect patients with poor outcome and require closer monitoring.

Background Patients with advanced B-cell non-Hodgkin's lymphoma (NHL) refractory to initial chemotherapy or relapsing after autologous stem-cell transplantation have a poor prognosis. Allogeneic stem-cell transplantation after reduced-intensity conditioning (RIC) regimen can be a therapeutic option. However, the high incidence of relapse remains a challenging issue. We speculated that the incorporation of 90Y-Ibritumomab tiuxetan into a fludarabine-based RIC regimen would improve the lymphoma control without overwhelming toxicity. Our aim was to evaluate the safety of 90Y-Ibritumomab tiuxetan in association with such a regimen in a prospective multicenter phase II trial. Patients and methods Thirty-one patients with advanced lymphoma from five distinct institutions were included between February 2008 and October 2010. Thirty patients in complete or partial response after failure of a median of 3 (range, 2–4) previous chemotherapy regimens including autologous transplant in 29 were evaluable for nonrelapse mortality (NRM) at day 100 post-transplant that was the primary end point. Results With a median follow-up of 32 months (range, 29–60 months), the 2-year event-free and overall survivals of the whole study group were both 80% [95 confidence interval (CI) 60.8% to 90.5%). The 100-day and 2-year post-transplant cumulative incidences of NRM were 3.3% (95% CI 0.2% to 14.9%) and 13.3% (95% CI 5.4% to 33.2%), respectively. The 2-year cumulative incidence of relapse was 6.7% (95% CI 1.7% to 25.4%). The cumulative incidences of grade II–IV and extensive chronic graft-versus-host disease were 27% and 14%, respectively. Conclusions For chemosensitive advanced high-risk B-cell lymphoma, the addition of 90Y-Ibritumomab tiuxetan to a RIC regimen based on fludarabine, busulfan and antithymocyte globulin followed by allogeneic transplant is safe and highly effective. clinicaltrials.gov : NCT00607854.

This study aims to compare the effectiveness of education about vaccine benefits to financial incentives in increasing hepatitis B vaccine uptake and completion of three vaccine doses among African...

Summary Background Organ preservation is a concept proposed for patients with rectal cancer after a good clinical response to neoadjuvant chemotherapy, to potentially avoid morbidity and side-effects of rectal excision. The objective of this study was to compare local excision and total mesorectal excision in patients with a good response after chemoradiotherapy for lower rectal cancer. Methods We did a prospective, randomised, open-label, multicentre, phase 3 trial at 15 tertiary centres in France that were experts in the treatment of rectal cancer. Patients aged 18 years and older with stage T2T3 lower rectal carcinoma, of maximum size 4 cm, who had a good clinical response to neoadjuvant chemoradiotherapy (residual tumour ≤2 cm) were centrally randomly assigned by the surgeon before surgery to either local excision or total mesorectal excision surgery. Randomisation, which was done via the internet, was not stratified and used permuted blocks of size eight. In the local excision group, a completion total mesorectal excision was required if tumour stage was ypT2–3. The primary endpoint was a composite outcome of death, recurrence, morbidity, and side-effects at 2 years after surgery, to show superiority of local excision over total mesorectal excision in the modified intention-to-treat (ITT) population (expected proportions of patients having at least one event were 25% vs 60% for superiority). This trial was registered with ClinicalTrials.gov, number NCT00427375. Findings From March 1, 2007, to Sept 24, 2012, 186 patients received chemoradiotherapy and were enrolled in the study. 148 good clinical responders were randomly assigned to treatment, three were excluded (because they had metastatic disease, tumour >8 cm from anal verge, and withdrew consent), and 145 were analysed: 74 in the local excision group and 71 in the total mesorectal excision group. In the local excision group, 26 patients had a completion total mesorectal excision. At 2 years in the modified ITT population, one or more events from the composite primary outcome occurred in 41 (56%) of 73 patients in the local excision group and 33 (48%) of 69 in the total mesorectal excision group (odds ratio 1·33, 95% CI 0·62–2·86; p=0·43). In the modified ITT analysis, there was no difference between the groups in all components of the composite outcome, and superiority was not shown for local excision over total mesorectal excision. Interpretation We failed to show superiority of local excision over total mesorectal excision, because many patients in the local excision group received a completion total mesorectal excision that probably increased morbidity and side-effects, and compromised the potential advantages of local excision. Better patient selection to avoid unnecessary completion total mesorectal excision could improve the strategy. Funding National Cancer Institute of France, Sanofi, Roche Pharma.

Purpose Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours. Reported combination of both drugs was deemed to be too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase I study combining everolimus (EV) and AX for solid tumours was explored. Experimental design Patients (pts) with advanced cancers were enrolled in an escalation phase I study to investigate the safety of the combination. Pharmacokinetic profile and functional vascular imaging were performed. An extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored. Results 15 pts were included over three different dose levels (DLs); DL 0: AX 3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st line MRCC in the escalating phase. In the extension phase in naive MRCC treated at MTD, five pts had a PR and one pt had a prolonged stable disease. Conclusion The recommended dose for phase II is AX 5 mg BID/EV 10 mg OD.

This single-arm phase I dose-escalation study determines the optimal dose of the non-platinum treatment pegylated liposomal doxorubicin (PLD) plus cyclophosphamide (CPM) every 4 weeks in early recurrent ovarian carcinoma.Twenty-one women with ovarian carcinoma relapsing within 12 months of first-line surgery and platinum-taxane chemotherapy received escalating doses of PLD (35-45 mg/m(2)) and CPM (500-600 mg/m(2)) every 4 weeks for at least two cycles. Primary objective was assessment of maximum-tolerated dose (MTD) over the first two cycles. Secondary objectives were to assess safety over 2 cycles, efficacy evaluated every two cycles (response evaluation criteria in solid tumours criteria) and overall survival (OS).The PLD-CPM MTD was 40/600 mg/m(2) with 2/3 patients treated at 45/500 mg/m(2), showing DLTs with Grade 3/4 oesophagitis, thrombopenia/neutropenia, leucopoenia, and Grade 3 stomatitis/asthenia during the first cycle of treatment. Four severe toxicities were reported by three patients during the two first cycles, namely Grade 4 anaemia, and Grade 3 stomatitis. The most common treatment-related toxicities were anaemia (71.4 %), nausea (61.9 %), neutropenia (57.1 %), asthenia (52.4 %), leucopoenia (47.6 %), stomatitis (42.9 %), skin (28.6 %) and palmar-plantar-erythrodysesthesia (19 %). No treatment-related deaths were reported. The overall response rate (complete and partial) was 31 %, and median OS was 8.2 months [95 % CI (3.3-13.2)].The combination of PLD and CPM is feasible and may be considered particularly in cases where platinum-based treatment is not suitable. The recommended doses for a phase II trial are PLD 40 mg/m(2) plus CPM 600 mg/m(2) every 4 weeks.

Background During on-pump cardiac surgery, hemorrhagic complications occur frequently. Fresh-frozen plasma (FFP) is widely transfused to provide coagulation factors. Yet, no randomized clinical trial has demonstrated its benefits on mortality. We assessed the relationship between therapeutic transfusion of FFP and 30-day mortality in cardiac surgery patients suffering from excessive bleeding in a prospective cohort study. Study Design and Methods Adult patients who underwent on-pump cardiac surgery and experienced excessive bleeding during the 48-hour perioperative period were recruited from 15 French centers between February 2004 and January 2006. Patients who received a preventive FFP transfusion were excluded. The association between FFP transfusion and all cause 30-day mortality was estimated using a Cox proportional hazards model, adjusted for confounding. A propensity score (PS) sensitivity analysis was also performed. Results Among 967 patients included in this study, 58.1% received FFP. The median dose was 11.3 mL/kg (interquartile range, 7.6-19.5). The cumulative 30-day mortality rate was 11.3% (95% confidence interval [CI], 9.5-13.5). FFP transfusion was associated with a higher 30-day mortality (hazard ratio [HR], 3.2; 95% CI, 1.7-6.1) in univariate analysis; however, after adjusting for prognostic factors, there was no longer any association (HR, 1.5; 95% CI, 0.8-3.0, p = 0.20). The results of the PS analysis were consistent with the adjusted analysis. Conclusion Among on-pump cardiac surgery patients experiencing excessive perioperative bleeding, there is no evidence of a beneficial impact of FFP transfusion on mortality.

PURPOSE:The MNA (Mini Nutritional Assessment) is known as a prognosis factor in older population. We analyzed the prognostic value for one-year mortality of MNA items in older patients with cancer treated with chemotherapy as the basis of a simplified prognostic score. METHODS:The prospective derivation cohort included 606 patients older than 70 years with an indication of chemotherapy for cancers. The endpoint to predict was one-year mortality. The 18 items of the Full MNA, age, gender, weight loss, cancer origin, TNM, performance status and lymphocyte count were considered to construct the prognostic model. MNA items were analyzed with a backward step-by-step multivariate logistic regression and other items were added in a forward step-by-step regression. External validation was performed on an independent cohort of 229 patients. RESULTS:At one year 266 deaths had occurred. Decreased dietary intake (p = 0.0002), decreased protein-rich food intake (p = 0.025), 3 or more prescribed drugs (p = 0.023), calf circumference

Summary Background Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-β signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes. Objectives We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis. Methods We performed a phase II double-blinded trial on patients with scleroderma with either morphoea involving > 20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) ≥ 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention. Results Twenty-eight patients were included in the study with a mean age of 48·9 years (range 30–71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0·10 in imatinib group vs. −0·16 in placebo group, P = 0·098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups. Conclusions This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements.

Objective Usual dose-finding methods in oncology are sequential. Accrual is suspended after each group of patients to assess toxicity before increasing the dose. An adapted Continual Reassessment Method (CRM) and Rolling 6 (R6) method, designed to avoid this suspension of accrual in pediatric oncology, are compared with the traditional 3 + 3 design. Study design and setting The competing performances were evaluated in a simulation study integrating the temporal dimension, and a phase I trial was reanalyzed. We compared methods for various interpatient arrival times and dose-toxicity relations, in terms of distribution of final recommendations, number of skipped children and duration of trials. Results R6 and CRM can be safely implemented to limit trial suspensions, especially when mean interpatient arrival time is short. CRM was found to be more efficient than algorithm-based methods (44% of good recommendations vs. 38%) but moderately increased the risk of overtreatment. The R6 design included more patients at suboptimal doses. The design with the shortest study duration depended on the number of dose to escalate before the target. Conclusion These new methods can reduce the number of skipped patients, but only provide limited gain in terms of ability to select the right dose. New designs are needed.

Background: Cancer in older patient favours the development of frailty: feeling of exhaustion, loss of weight, decreased muscle strength, slow gait speed, and low physical activity. Objectives: To evaluate the efficacy of adapted physical activity phone advices in limiting the cancer-induced loss of autonomy and frailty phenotype development. Design: Multicenter randomized controlled trial. Setting: Patients (>70y) undergoing curative treatment for cancer (n=400) will be recruited from 12 centres. Intervention: The intervention consists in phoned personalized physical activity advices related to strength, aerobic, balance, proprioception, and flexibility. The contacts are performed twice a month during six months and then monthly until 1 year. The intervention complements the PNNS booklet advices (National Nutritional Health Program). The trial compares "individualized phone advices + PNNS" to "usual care + PNNS". Measurements: Functional, cognitive, clinical and self-reported data are assessed before treatment and at 3, 6, 12, 18, and 24 month follow-up. The primary outcome is the proportion of subjects with a one-year decreased SPPB (Short Physical Performance Battery) score of one point or more, as compared to baseline. The secondary outcomes include quality of life items, rate of hospitalizations, institutionalizations, mortality, Fried phenotype at 1 and 2 years, and the SPPB score at 2 years. Discussion: This large trial will provide clinical data of the effects of an exercise advices intervention in older patients during cancer therapy on function and cognition evolution, and quality of life. The possibilities of minimizing the development of frailty phenotype due to these advices will be explored.

Ethical concerns about randomising persons to a no-treatment arm in the context of Ebola epidemic led to consideration of alternative designs. The stepped wedge (SW) design, in which participants or clusters are randomised to receive an intervention at different time points, gained popularity. Common arguments in favour of using this design are (1) when an intervention is likely to do more good than harm, (2) all participants should receive the experimental intervention at some time point during the study and (3) the design might be preferable for practical reasons. We examine these assumptions when considering Ebola vaccine research. First, based on the claim that a stepped wedge design is indicated when it is likely that the intervention will do more good than harm, we reviewed published and ongoing SW trials to explore previous use of this design to test experimental drugs or vaccines, and found that SW design has never been used for trials of experimental drugs or vaccines. Given that Ebola vaccines were all experimental with no prior efficacy data, the use of a stepped wedge design would have been unprecedented. Second, we show that it is rarely true that all participants receive the intervention in SW studies, but rather, depending on certain design features, all clusters receive the intervention. Third, we explore whether the SW design is appealing for feasibility reasons and point out that there is significant complexity. In the setting of the Ebola epidemic, spatiotemporal variation may have posed problematic challenges to a stepped wedge design for vaccine research. Finally, we propose a set of points to consider for scientific reviewers and ethics committees regarding proposals for SW designs.

The study in question proposes to examine a preventative intervention for type 2 diabetes (T2D). When considering the ethical nature of a research study, we find it helpful to specify the potential...

In a prospective cohort of 82 renal transplant recipients, we evaluated the capacity of the cytomegalovirus (CMV) load in whole blood (WB) to predict the plasma CMV load, aiming to identify active CMV infections by using WB samples only and to deduce a WB threshold. Using quantitative real-time PCR, a total of 1,474 WB samples were assayed, of which 279 were positive for CMV, and 140 out of the 276 paired plasma samples tested positive. Thirty (36.6%) patients presented with at least one positive plasma PCR result, and 21 infection episodes (19 patients) required curative treatment (median follow-up time, 12 months). When the plasma CMV load was >500 copies/ml ( n = 70), more than 94% (95% confidence interval, 86.0%, 98.4%) of WB samples had >500 copies/ml. Two prediction models were built: log 10 plasma viral load (VL) was calculated as −0.3777 + 0.9342 × log 10 WB VL and as −0.3777 + 0.8563 × log 10 WB VL for patients with and without treatment, respectively. In the validation sample (578 routine samples), 77.2% of the observed and expected plasma viral loads were concordant (95% confidence intervals, 73.5 and 80.5%). According to the model, the plasma viral load was >500 copies/ml when the WB load was >3,170 or >4,000 copies/ml in patients with or without treatment, respectively. WB seems to be an appropriate candidate for routine CMV monitoring of transplant recipients by using a single assay.

Purpose/Objectives To assess feasibility and toxicity of Helical TomoTherapy® for treating anal cancer patients. Methods From 2007 to 2011, 64 patients were consecutively treated with TomoTherapy® in three centres for locally advanced squamous-cell anal carcinoma (T2 > 4 cm or N positive). Prescribed doses were 45 Gy to the pelvis including inguinal nodes and 59.4 Gy to the primary site and involved nodes with fractions of 1.8 Gy, five days a week. A positional Megavoltage Computed Tomography was performed before each treatment session. All acute and late toxicities were graded according to Common Terminology Criteria for Adverse Events version 3.0. Survival analysis was performed using the Kaplan-Meier method. Results Median follow-up was 22.9 months. Fifty-four women and 10 men were treated (median age: 62 years). Nineteen patients (29.7 %) had T2, 16 patients (25.0 %) T3, and 27 patients (42.2 %) T4 tumours. Thirty-nine patients (60.9 %) had nodal involvement. Median tumour size was 45 mm (range, 10–110 mm). Seven patients had a colostomy before treatment initiation. Fifty-seven patients received concomitant chemotherapy (5-FU/cisplatin or 5-FU/mitomycin-based therapy). Forty-seven patients (73.4 %) experienced a complete response, 13 a partial response or local recurrence, and 11 had salvage surgery; among these, six became complete responders, three experienced metastatic failure, and two local failure. At least four patients experienced metastatic recurrence (concomitant to a local failure for one patient). The two-year overall survival was 85.6 % (95 %CI [71.1 %–93.0 %]), and the one-year disease-free survival, and colostomy-free survival were 68.7 % (95 %CI [54.4 %–79.4]), and 75.5 % (95 %CI [60.7 %–85.3 %]) respectively. Overall survival, disease-free survival and colostomy free-survival were significantly better for women than men (p = 0.002, p = 0.004, and p = 0.002 respectively). Acute grade ≥3 toxicity included dermatologic (46.9 % of patients), gastrointestinal (20.3 %), and hematologic (17.2 %) toxicity. Acute grade 4 hematologic toxicity occurred in one patient. No grade 5 event was observed. Conclusions TomoTherapy® for locally advanced anal cancer is feasible. In our three centres of expertise, this technique appeared to produce few acute gastrointestinal toxicities. However, high rates of dermatologic toxicity were observed. The therapeutic efficacy was within the range of expectations and similar to previous studies in accordance with the high rates of locally advanced tumours and nodal involvement.

In phase I trials, severe and moderate toxicities occurring after the first cycle of treatment are important sources of information. Model-based approach can be used to evaluate per cycle probability of moderate or severe toxicity and cumulative probability of severe toxicity over time. It increases precision of estimates, and it enables investigating increased probability of toxicity over time. Background Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per-cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period. Patients and methods Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib + radiotherapy in brainstem gliomas with longer time on treatment) and one 3 + 3 design (T3: liposomal doxorubicin + cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM. Results Eighty-three patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 [P = 0.04; per-cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D]. At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3. Conclusions Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.

Phase I oncology clinical trials are designed to identify the optimal dose that will be recommended for phase II trials. This dose is typically defined as the dose associated with a certain probability of severe toxicity at cycle 1, although toxicity is repeatedly measured over cycles on an ordinal scale. Recently, a proportional odds mixed-effect model for ordinal outcomes has been proposed to (i) identify the optimal dose accounting for repeated events and (ii) to provide some framework to explore time trend. We compare this approach to a method based on repeated binary variables and to a method based on an under-parameterized model of the dose-time toxicity relationship. We show that repeated binary and ordinal outcomes both improve the accuracy of dose-finding trials in the same proportion; ordinal outcomes are, however, superior to detect time trend even in the presence of nonproportional odds models. Moreover, less parameterized models led to the best operating characteristics. These approaches are illustrated on two dose-finding phase I trials. Integration of repeated measurements is appealing in phase I dose-finding trials.

International audience; BACKGROUND: Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic. METHODS: We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial. RESULTS: We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled

International audience; OBJECTIVE: We tested the effect of dietary advice dedicated to increase intake in older patients at risk for malnutrition during chemotherapy, versus usual care, on one-year mortality. METHOD: We conducted a multicentre, open-label interventional, stratified (centre), parallel randomised controlled trial, with a 1ratio1 ratio, with two-year follow-up. Patients were aged 70 years or older treated with chemotherapy for solid tumour and at risk of malnutrition (MNA, Mini Nutritional Assessment 17-23.5). Intervention consisted of diet counselling with the aim of achieving an energy intake of 30 kCal/kg body weight/d and 1.2 g protein/kg/d, by face-to-face discussion targeting the main nutritional symptoms, compared to usual care. Interviews were performed 6 times during the chemotherapy sessions for 3 to 6 months. The primary endpoint was 1-year mortality and secondary endpoints were 2-year mortality, toxicities and chemotherapy outcomes. RESULTS: Between April 2007 and March 2010 we randomised 341 patients and 336 were analysed: mean (standard deviation) age of 78.0 y (4.9), 51.2% male, mean MNA 20.2 (2.1). Distribution of cancer types was similar in the two groups; the most frequent were colon (22.4%), lymphoma (14.9%), lung (10.4%), and pancreas (17.0%). Both groups increased their dietary intake, but to a larger extent with intervention (p\textless0.01). At the second visit, the energy target was achieved in 57 (40.4%) patients and the protein target in 66 (46.8%) with the intervention compared respectively to 13 (13.5%) and 20 (20.8%) in the controls. Death occurred during the first year in 143 patients (42.56%), without difference according to the intervention (p = 0.79). No difference in nutritional status changes was found. Response to chemotherapy was also similar between the groups. CONCLUSION: Early dietary counselling was efficient in increasing intake but had no beneficial effect on mortality or secondary outcomes. Cancer cachexia antianabolism may explain this lack of effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT00459589.

Phase I oncology clinical trials are designed to identify the optimal dose that will be recommended for phase II trials. This dose is typically defined as the dose associated with a certain probability of dose limiting toxicity (DLT) during the first cycle of treatment, although toxicity is repeatedly measured over cycles on an ordinal scale. We present the main dose finding methods developed in the era of cytotoxic agents. We illustrate their properties and limitations in different scenarios. We also explore different implementations of these methods that have been proposed in a Bayesian or likelihood framework or that can rely on several dose-toxicity models. We highlight the fact that the binary nature of the primary outcome (DLT or no DLT) drastically limits the performances of any methods. We then present adaptive dose-finding designs that use toxicity measurements at all cycles of treatment and not only the first one; some authors have proposed to consider the DLT as a time to event variable while others have analyzed the longitudinal measurements of toxic side events. This however raises the delicate issue of the definition of the optimal dose. These approaches are illustrated on two dose finding phase I trials; data are reanalysed and results are compared and discussed. Integration of richer information appears appealing in phase I dose-finding trials, as it gives more accurate estimates of the risk of toxicity and increases the ability of selecting the correct dose. Use of longitudinal data in addition allows for detecting cumulative or delayed effects of strong magnitude. Model-based methods give a flexible framework for using more complete data.

International audience; Phase I oncology clinical trials are designed to identify the optimal dose that will be recommended for phase II trials. This dose is typically defined as the dose associated with a certain probability of severe toxicity during the first cycle of treatment, although toxicity is repeatedly measured over cycles on an ordinal scale. We propose a new adaptive dose-finding design using longitudinal measurements of ordinal toxic adverse events, with proportional odds mixed-effect models. Likelihood-based inference is implemented. The optimal dose is then the dose producing a target rate of severe toxicity per cycle. This model can also be used to identify cumulative or late toxicities. The performances of this approach were compared with those of the continual reassessment method in a simulation study. Operating characteristics were evaluated in terms of correct identification of the target dose, distribution of the doses allocated and power to detect trends in the risk of toxicities over time. This approach was also used to reanalyse data from a phase I oncology trial. Use of a proportional odds mixed-effect model appears to be feasible in phase I dose-finding trials, increases the ability of selecting the correct dose and provides a tool to detect cumulative effects.

INTRODUCTION AND OBJECTIVES: The aim of bio-banking is to allow further use of tissue samples in research. Surgeons and pathologists have to satisfy many precautions in order to ensure the samples quality. We wanted to assess the quality of our frozen kidney tissue bio-collection, so on validate our routine surgical procedures and find out predictive factors of sample degradation. METHODS: Kidney cancer and matched normal kidney tissues were prospectively collected from 160 patients who underwent Surgery for Renal Cancer and immediately cryopreserved. RNA extraction was performed on 302 frozen samples using QIAGEN RNeasy mini Kit ©. Both quantitative (RNA concentration) and qualitative (RNA Quality Score RQS) assessement was done. Clinical and histopathological data, the characteristics of surgical (surgical approach, operative time) and cryopreservation procedures were recorded for each patient and we looked for predictive factors of RNA impairment in univariate and multivariate analysis. RESULTS: Tissue samples were collected from 116 Radical Nephrectomies (RN) (72%) and 44 Partial Nephrectomies (PN) (28%). The rate of laparoscopic procedures was 51%. Mean tumor size was 7,07 / 6,95 cm. Median time to cryopreservation was 30 minutes (5-100). Mean RNA concentration for tumor and normal kidney samples were respectively 142,43 ( 114,62) ng/ L and 115,06 ( 114,62) ng/ L. Mean RQS value was 7,52 ( 1,43) and 70% of the extracted RNAs scored higher than 7, that is generally considered suitable for further gene expression studies. Quantity and quality of paired samples were finally considered good enough in 133 patients (83%). In univariate analysis, high extraction efficiency was associated with year of surgery (p 0,001), general symptoms at diagnosis (p 0,012), sarcomatoid component (p 0,011), necrosis (p 0,021) and high Fuhrman grade (p 0,001). Year of surgery (p 0,001) and Fuhrman grade (p 0,01) only, remained independent predictive factors of extraction efficiency. Healthy tissue and a pre-operative arterial embolisation were associated in univariate and multivariate analysis, with a significant RQS decrease : RQS 1.69 (p 0.001) and 1,44 (p 0,001), respectively. CONCLUSIONS: This study validates our biobanking procedures in routine surgical practice with 83% of paired frozen samples suitable for molecular biology experiments. In multivariate analysis, Fuhrman grade and Year of surgery were associated with extraction efficiency; Tissue type (tumor or healthy tissue) and pre-operative arterial embolization significantly impacted RNA quality.

Background The treatment of stage I Merkel cell carcinoma (MCC) usually includes wide local excision (WLE) combined with irradiation of the tumor bed (ITB). No randomized study has ever been conducted in MCC. The purpose of this study was to assess the efficacy and safety of prophylactic adjuvant radiotherapy on the regional nodes. Patients and methods In this randomized open controlled study, patients for a stage I MCC treated by WLE and ITB were randomly assigned to regional adjuvant radiotherapy versus observation. Overall survival (OS) and probability of regional recurrence (PRR) were primary end points. Progression-free survival (PFS) and tolerance of irradiation were secondary end points. Results Eighty-three patients were included before premature interruption of the trial, due to a drop in the recruitment mainly due to the introduction of the sentinel node dissection in the management of MCC. No significant improvement in OS (P = 0.989) or PFS (P = 0.4) could be demonstrated after regional irradiation, which, however, significantly reduced the PRR (P = 0.007) with 16.7% regional recurrence rate in the observation arm versus 0% in the treatment arm. The treatment was well tolerated. Conclusion The adjuvant regional irradiation significantly decreased the PRR in MCC, but benefit in survival could not be demonstrated.

Introduction The purpose of this study was to investigate the relationship among Pseudomonas aeruginosa acquisition on the intensive care unit (ICU), environmental contamination and antibiotic selective pressure against P. aeruginosa. Methods An open, prospective cohort study was carried out in a 16-bed medical ICU where P. aeruginosa was endemic. Over a six-month period, all patients without P. aeruginosa on admission and with a length of stay >72 h were included. Throat, nasal, rectal, sputum and urine samples were taken on admission and at weekly intervals and screened for P. aeruginosa. All antibiotic treatments were recorded daily. Environmental analysis included weekly tap water specimen culture and the presence of other patients colonized with P. aeruginosa. Results A total of 126 patients were included, comprising 1,345 patient-days. Antibiotics were given to 106 patients (antibiotic selective pressure for P. aeruginosa in 39). P. aeruginosa was acquired by 20 patients (16%) and was isolated from 164/536 environmental samples (31%). Two conditions were independently associated with P. aeruginosa acquisition by multivariate analysis: (i) patients receiving ≥3 days of antibiotic selective pressure together with at least one colonized patient on the same ward on the previous day (odds ratio (OR) = 10.3 ((% confidence interval (CI): 1.8 to 57.4); P = 0.01); and (ii) presence of an invasive device (OR = 7.7 (95% CI: 2.3 to 25.7); P = 0.001). Conclusions Specific interaction between both patient colonization pressure and selective antibiotic pressure is the most relevant factor for P. aeruginosa acquisition on an ICU. This suggests that combined efforts are needed against both factors to decrease colonization with P. aeruginosa.

and were similar among older and younger adults (all p N 0.05). The subscales with the greatest improvement were social function and role function. Although 2MWT improved by 64% and 68% among younger and older patients (p = 0.69), improvements in grip strength and timed chair stands were much smaller (24% and 39% in younger adults, 15% and 18% in older adults, respectively). Patterns of recovery in physical performance were similar among older and younger adults (all p N 0.05). Results were similar when missing data were imputed. Conclusion: Survivors of AML after successful intensive chemotherapy achieve significant improvements in QOL, fatigue, and physical function by one year after diagnosis. The course of recovery is remarkably similar in younger and older AML patients, although significant attrition in older adults is a noteworthy limitation and fatigue improved less in older adults than younger adults. These data suggest that appropriately selected older patients generally recover as well as younger adults following IC for AML.