Experimental designs for small randomised clinical trials: An algorithm for choice

Background: Small clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is ofte

Factors of interrupting chemotherapy in patients with Advanced Non-Small-Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>Little is known about prognosis of metastatic patients after receiving a first-line treatment and failure. Our group already showed in pre-treated patients enrolled in phase I clinical trials that a performance status (PS) > 2 and an LDH > 600 UI/L were independent prognostic factors. In this prospective study, which included 45 patients, we identified clinical and biological variables as outcome predictors in metastatic Non-Small Cell lung cancer after first line chemotherapy were identified.</p> <p>Findings</p> <p>Forty-five patients that were previously treated for metastatic disease from 12/2000 to 11/2005 in the comprehensive cancer centre (Centre Léon Bérard). Clinical assessment and blood parameters were recorded and considered. Patient prognostic factors for overall survival (OS) with a 0.05-significance level in univariate analysis were entered in a multivariate Cox model for further analysis.</p> <p>Patients' median age was 58.5 years (range: 37 - 76). Sixty two percent of the patients were PS = 0 or 1. After inclusion, nine patients received second-line (22.5%), and two received third-line chemotherapy (5%). Univariate analysis showed that the factors associated with reduced OS were: PS > 2, weight loss >10%, more than one line of chemotherapy treatment and abnormal blood parameters (hemoglobin (Hb), platelet and neutrophils counts). Multiple regression analysis confirmed that PS > 2 and abnormal hemoglobin were independent predictors for low overall survival. According to the presence of none (33%), 1 (37%) and 2 (30%) prognostic factors, median OS were 12, 5 and 2 months respectively.</p> <p>Conclusion</p> <p>From this prospective study, both PS and anemia were found as independent determinants of survival, we found that both PS and anemia were independent determinants of survival. The combination of poor PS and anemia is an effective strategy to predict survival in the case of patients with metastatic NSCLC receiving further treatment after the first line.</p

Permanent 125I-seed prostate brachytherapy: early prostate specific antigen value as a predictor of PSA bounce occurrence

<p>Abstract</p> <p>Purpose</p> <p>To evaluate predictive factors for PSA bounce after ¹²⁵I permanent seed prostate brachytherapy and identify criteria that distinguish between benign bounces and biochemical relapses.</p> <p>Materials and methods</p> <p>Men treated with exclusive permanent ¹²⁵I seed brachytherapy from November 1999, with at least a 36 months follow-up were included. Bounce was defined as an increase ≥ 0.2 ng/ml above the nadir, followed by a spontaneous return to the nadir. Biochemical failure (BF) was defined using the criteria of the Phoenix conference: nadir +2 ng/ml.</p> <p>Results</p> <p>198 men were included. After a median follow-up of 63.9 months, 21 patients experienced a BF, and 35.9% had at least one bounce which occurred after a median period of 17 months after implantation (4-50). Bounce amplitude was 0.6 ng/ml (0.2-5.1), and duration was 13.6 months (4.0-44.9). In 12.5%, bounce magnitude exceeded the threshold defining BF. Age at the time of treatment and high PSA level assessed at 6 weeks were significantly correlated with bounce but not with BF. Bounce patients had a higher BF free survival than the others (100% versus 92%, p = 0,007). In case of PSA increase, PSA doubling time and velocity were not significantly different between bounce and BF patients. Bounces occurred significantly earlier than relapses and than nadir + 0.2 ng/ml in BF patients (17 vs 27.8 months, p < 0.0001).</p> <p>Conclusion</p> <p>High PSA value assessed 6 weeks after brachytherapy and young age were significantly associated to a higher risk of bounces but not to BF. Long delays between brachytherapy and PSA increase are more indicative of BF.</p

Outcome of recurrent and metastatic small cell carcinoma of the bladder

<p>Abstract</p> <p>Background</p> <p>Bladder small cell carcinoma is an uncommon tumour. Through a retrospective study we will present the evolution of recurrent and metastatic disease and outcome of patients treated at Léon-Bérard Cancer Centre.</p> <p>Methods</p> <p>Only 15 patients having recurrent or metastatic bladder small cell carcinoma were treated at Léon-Bérard Cancer Centre between 1996 and 2007. The patients were divided in two groups: a mixed small cell carcinoma group (9 patients) and a pure small cell carcinoma group (6 patients). All the records and informations related to treatment and outcome of the 15 patients were retrospectively analyzed. Various characteristics of small cell carcinoma were investigated.</p> <p>Results</p> <p>The median age of the 15 patients having recurrent or metastatic bladder small cell carcinoma and treated at Léon-Bérard Cancer Centre was 63 years and the disease was at stage IV for all cases. Nine patients were treated by chemotherapy. Four patients were treated by local radiotherapy (3 with radiotherapy without previous surgery and 1 with surgery followed by radiotherapy) and chemotherapy. One patient was treated by whole brain radiotherapy. And one patient died before treatment. After 52.4 months median follow up, 12 patients died. Median overall survival was 7.6 months. Survival probability at 1 year was 33%. Median overall survival was 9.9 months in the mixed small cell carcinoma group, and was only 4.6 months in the pure small cell carcinoma group. Survival probability at 1 year in the mixed small cell carcinoma group was 44% as compared to 17% in the pure small cell carcinoma group (Log-rank test: p = 0.228).</p> <p>Conclusion</p> <p>Recurrent and metastatic bladder small cell carcinoma is associated with very poor prognosis. The pure bladder small cell carcinoma appears to have poorer outcome than the mixed bladder small cell carcinoma. Chemotherapy using platinum drugs is a mainstay treatment.</p

A methodological framework for drug development in rare diseases

International audienceDeveloping orphan drugs is challenging because of their severity and the requisite for effectivedrugs. The small number of patients does not allow conducting adequately powered randomized controlled trials(RCTs). There is a need to develop high quality, ethically investigated, and appropriately authorized medicines,without subjecting patients to unnecessary trials

Validation of prognostic scores for survival in cancer patients beyond first-line therapy

Abstract Background We aimed to validate prognostic scores for survival in patients undergoing chemotherapy for advanced or metastatic cancer after first-line treatment. Methods We previously described two models with good prognostic value based on a combination of Performance Status (PS) and either lactate dehydrogenase (LDH) level or lymphocyte count. These factors were evaluated for their ability to predict overall survival (OS) in a prospective cohort of 299 patients. Clinical and blood parameters were prospectively recorded. Candidate prognostic factors for OS with 0.05 significance level in univariate analysis were included in a multivariate Cox model. Results Median age was 59 years (range: 26-85). Primary tumor sites were breast (45%), lung (15%), ovaries (11%) and others (29%). The number of metastatic sites was 1 (29%), 2 (48%), >2 (23%). Median follow-up and median OS were 12 and 6 months, respectively. Multiple regression analysis confirmed that PS >1, lymphocyte count ≤700/μL and LDH >600 UI/L were independent predictors of short OS, as well as interleukin 6 (IL-6) level, serum albumin concentration and platelet count. Conclusions Prognostic scores using PS plus LDH level or PS plus lymphocyte count were validated for predicting survival in metastatic cancer patients in relapse beyond first-line treatment. A score combining PS, LDH, lymphocyte and platelet count, serum albumin and IL-6 level was superior in determining patients' prognosis.</p

Bevacizumab plus microtubule targeting agents in heavily pre-treated ovarian cancer patients: a retrospective study.

International audienceOBJECTIVES. As vascular endothelial growth factor (VEGF) is expressed in ovarian cancer, we assessed the efficacy and safety of bevacizumab (a monoclonal antibody targeting VEGF) plus microtubule targeting agents for heavily pre-treated ovarian carcinoma patients. METHODS. We retrospectively reviewed 43 patients with recurrent epithelial ovarian carcinoma. Combined treatment included bevacizumab with paclitaxel in 32 (74%), docetaxel in 10 (23%), and vinorelbine in one (2.3%) patients, respectively. RESULTS. The median number of combined treatment was six cycles (range 1-29). On RECIST criteria, the objective response rate (ORR) was 40% (16% CR and 24% PR). Clinical benefit (complete response [CR] plus partial response [PR] and stable disease [SD] lasting ≥ 3 months) was 74% (CI95%: 46.7-77%). Median duration of treatment and overall survival were 3.9 months (range 0.2-14.4 months) and 20.1 months (CI95%: 13.8-20.1) respectively. No toxic death was reported. Grade 3-4 toxicity occurred in 30% of patients. Gastrointestinal perforations and fistula occurred in 3 (7%) and 6 (14%) patients, respectively. CONCLUSION. Although being active in terms of ORR, bevacizumab plus microtubule targeting agents - mainly taxanes - leads to a high rate of gastro-intestinal perforations and fistula in heavily pre-treated ovarian carcinoma patients