Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy.

BackgroundEverolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety.Patients and methodsData were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately.ResultsThe rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)].ConclusionsStomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines

Disability Policies in France: Changes and Tensions between the Category-based, Universalist and Personalized Approaches

In this article, the authors show that the current French disability policy is traversed by conflicts between three different approaches to disability which came about at different periods in history. They begin by looking at the origins of disability policy in France. This policy was developed during the 20th century, from notions of repair, indemnification and compensation through rehabilitation. It became institutionalized in 1975, when two laws were passed, giving it the form of a category-based policy. Between 1970 and 2000, affected by the international situation, this policy came into conflict with a universalist policy. More recently there has been a desire to develop a personalized approach. Finally, the authors use two examples (taken from recent debates on the implementation in France of the new law of 11 February 2005) to show the tensions that have led to the coexistence of these three approaches within current disability policy

Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, is a first-line treatment for metastatic renal cell carcinoma (mRCC) in patients in ‘low’ and ‘intermediate’ Memorial Sloan Kettering Cancer Center and Heng risk groups. Disruptions of hematopoiesis, such as anemia, neutropenia, and thrombocytopenia, are typically observed during sunitinib treatment. When it comes to RBC parameters, an increase in mean cell volume (MCV) tends to occur, meeting the criteria for macrocytosis in some patients (MCV > 100 fL). We examined changes in RBC parameters of 27 mRCC patients treated with sunitinib (initial dose of 50 mg/day, 6-week treatment: 4 weeks on, 2 weeks off) and correlated them with progression-free survival time (PFS). Patients who had macrocytosis after 3 treatment cycles had significantly longer PFS than those whose MCV stayed less than 100 fL (not reached vs. 11.2 months, p < 0.001). We also found a correlation between MCV values after the first and third treatment cycles and the risk of progression: HR of 0.9 (0.81–0.99) and 0.76 (0.65–0.90) per 1 fL increase in MCV, respectively. The mechanism of MCV elevation during sunitinib treatment has not yet been fully explained. One of the probable causes is sunitinib’s inhibitory influence on c-Kit kinase, as is the case with imatinib. For mRCC patients, this phenomenon could help predict PFS, but since our sample was small, further studies are essential

Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma

BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P&lt;0.001). The objective response rate was 42% versus 27% (P&lt;0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P = 0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma

This randomised phase III trial compared standard of care Everolimus with the anti-PD1 monoclonal antibody Nivolumab in previously treated patients with locally advanced inoperable or metastatic clear cell renal cancer. 810 patients were randomised to receive either Everolimus 10 mg orally daily or 3 mg/kg of Nivolumab intravenously every two weeks. Patients were treated until unacceptable toxicity or disease progression. Patients could be treated beyond progression if the investigator believed that the patient was gaining clinical benefit. The primary endpoint was overall survival. The median survival was 25 months for Nivolumab and 19.8 months for Everolimus (p=0.002). The objective response rate was higher for Nivolumab (25 versus 5%; p=&#60;0.001).The median progression free survivals were 4.6 & 4.4 months (p=0.11). Grade 3 & 4 treatment related toxicities were observed in 19 & 37% of patients on Nivolumab or Everolimus respectively. In patients with previously treated renal cell carcinoma Nivolumab produced superior survival and more tolerable treatment than Everolimus

Impact of Reporting Bias in Network Meta-Analysis of Antidepressant Placebo-Controlled Trials

BACKGROUND: Indirect comparisons of competing treatments by network meta-analysis (NMA) are increasingly in use. Reporting bias has received little attention in this context. We aimed to assess the impact of such bias in NMAs. METHODS: We used data from 74 FDA-registered placebo-controlled trials of 12 antidepressants and their 51 matching publications. For each dataset, NMA was used to estimate the effect sizes for 66 possible pair-wise comparisons of these drugs, the probabilities of being the best drug and ranking the drugs. To assess the impact of reporting bias, we compared the NMA results for the 51 published trials and those for the 74 FDA-registered trials. To assess how reporting bias affecting only one drug may affect the ranking of all drugs, we performed 12 different NMAs for hypothetical analysis. For each of these NMAs, we used published data for one drug and FDA data for the 11 other drugs. FINDINGS: Pair-wise effect sizes for drugs derived from the NMA of published data and those from the NMA of FDA data differed in absolute value by at least 100% in 30 of 66 pair-wise comparisons (45%). Depending on the dataset used, the top 3 agents differed, in composition and order. When reporting bias hypothetically affected only one drug, the affected drug ranked first in 5 of the 12 NMAs but second (n = 2), fourth (n = 1) or eighth (n = 2) in the NMA of the complete FDA network. CONCLUSIONS: In this particular network, reporting bias biased NMA-based estimates of treatments efficacy and modified ranking. The reporting bias effect in NMAs may differ from that in classical meta-analyses in that reporting bias affecting only one drug may affect the ranking of all drugs

Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age: implications for surveillance

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome characterized by skin piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer caused by germline mutations in the fumarate hydratase (FH) gene. Previously, we proposed renal imaging for FH mutation carriers starting at the age of 20 years. However, recently an 18-year-old woman from a Dutch family with HLRCC presented with metastatic renal cancer. We describe the patient and family data, evaluate current evidence on renal cancer risk and surveillance in HLRCC and consider the advantages and disadvantages of starting surveillance for renal cancer in childhood. We also discuss the targeted therapies administered to our patient