A framework for developing an evidence-based, comprehensive tobacco control program

BACKGROUND: Tobacco control is an area where the translation of evidence into policy would seem to be straightforward, given the wealth of epidemiological, behavioural and other types of research available. Yet, even here challenges exist. These include information overload, concealment of key (industry-funded) evidence, contextualization, assessment of population impact, and the changing nature of the threat. METHODS: In the context of Israel's health targeting initiative, Healthy Israel 2020, we describe the steps taken to develop a comprehensive tobacco control strategy. We elaborate on the following: a) scientific issues influencing the choice of tobacco control strategies; b) organization of existing evidence of effectiveness of interventions into a manageable form, and c) consideration of relevant philosophical and political issues. We propose a framework for developing a plan and illustrate this process with a case study in Israel. RESULTS: Broad consensus exists regarding the effectiveness of most interventions, but current recommendations differ in the emphasis they place on different strategies. Scientific challenges include integration of complex and sometimes conflicting information from authoritative sources, and lack of estimates of population impact of interventions. Philosophical and political challenges include the use of evidence-based versus innovative policymaking, the importance of individual versus governmental responsibility, and whether and how interventions should be prioritized.The proposed framework includes: 1) compilation of a list of potential interventions 2) modification of that list based on local needs and political constraints; 3) streamlining the list by categorizing interventions into broad groupings of related interventions; together these groupings form the basis of a comprehensive plan; and 4) refinement of the plan by comparing it to existing comprehensive plans. CONCLUSIONS: Development of a comprehensive tobacco control plan is a complex endeavour, involving crucial decisions regarding intervention components. "Off the shelf" plans, which need to be adapted to local settings, are available from a variety of sources, and a multitude of individual recommendations are available. The proposed framework for adapting existing approaches to the local social and political climate may assist others planning for smoke-free societies. Additionally, this experience has implications for development of evidence-based health plans addressing other risk factors

Reducing Skin Toxicities from EGFR Inhibitors with Topical BRAF Inhibitor TherapyTopical BRAF Inhibitor for Anti-EGFR Toxicities

Treatment of cancer with EGFR inhibitors is limited by on-target skin toxicities induced by inhibition of the MAPK pathway. BRAF inhibitors are known to paradoxically activate the MAPK downstream of EGFR, which we confirmed using human skin keratinocytes. We then conducted a phase I clinical trial testing the hypothesis that topical therapy with the BRAF inhibitor LUT014 could improve skin toxicities induced by EGFR inhibitors. Ten patients with metastatic colorectal cancer who had developed acneiform rash while being treated with cetuximab or panitumumab were enrolled in three cohorts. LUT014 was well tolerated, and there were no dose-limiting toxicities. The acneiform rash improved in the 6 patients who started with grade 2 rash in the low and intermediate cohorts. We conclude that topical LUT014 is safe and efficacious in improving rash from EGFR inhibitors, consistent with the mechanism of action inducting paradoxical MAPK activation. SIGNIFICANCE: BRAF inhibitor topical therapy could avoid dose reductions of EGFR inhibitors, locally treating the main dose-limiting skin toxicity of this class of agents.This article is highlighted in the In This Issue feature, p. 2113

P-106 Evaluating sex as a predictive marker for response to bevacizuamb in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database

Background Previous studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma, showing a benefit in males, while the effect in females is less significant. Therefore, we evaluated response to bevacizumab according to sex. Methods Data from 3369 metastatic colorectal carcinoma patients enrolled on four first-line randomized trials testing chemotherapy with or without bevacizumab (2000-2007) were pooled. Association between sex and progression-free survival and overall survival was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut-point of 60 years to evaluate the possible role of menopausal-related effects. Results Median overall survival was not statistically different between males and females in the entire study population (18.8 vs. 17.6 months, respectively; adjusted hazard ratio=0.92, 95% CI=0.84-1.02, p=0.11). Bevacizumab was associated with an improved median overall survival in males and females, with a 2.3- and 0.6-months benefit, respectively, as well as an improved progression-free survival (2.0 and 1.9-months benefit, respectively). Stratified by age, bevacizumab resulted in improved progression-free survival and overall survival in males at both age categories. In females at or above the age of 60 (n=731), bevacizumab resulted in improved progression-free survival and overall survival. However, in females below the age of 60 (n=634), overall survival benefit did not reach statistical significance (adjusted hazard ratio=0.94, 95% CI 0.74-1.20). Conclusions Our results confirmed the median overall survival benefit from addition of bevacizumab to first-line chemotherapy in metastatic colorectal carcinoma in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no overall survival benefit