COMPARATIVE EFFICACY, SAFETY AND COST EFFECTIVENESS OF CHEMOPREVENTIVE AGENTS FOR COLORECTAL CANCER

Abstract

Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide. Given the limitations of current population based screening methods, chemoprevention approaches have been considerably gaining credibility and interest as effective additional measures for CRC prevention during the last few decades. The aim of this dissertation was to assess the benefits of such approaches in a population whose constituents had different risks of developing CRC. The dissertation outcomes can be used to make evidence based decisions about the administration of chemopreventive agents (CPAs) for optimised prevention of CRC in Malaysia. The study addressed three distinctive analyses; however, the three were related in significant respects. First, comparative efficacy and safety of CPAs for the prevention of CRC were evaluated using network meta analysis techniques based on a systematic review of randomised controlled trials that compared at least one CPA (aspirin at different doses, any nonsteroidal anti inflammatory drugs, any antioxidants, folic acid, vitamin B6, vitamin B12, calcium, vitamin D, alone or in combination) to placebo or other CPA. Second, the balance between benefits and harms of those CPAs with evidence of efficacy was assessed using either net clinical benefit or risk benefit integrated analysis. Third, both long term clinical and economic outcomes of using CPA in the Malaysian setting were evaluated by cost effectiveness analysis. The assessment of CPAs in average risk individuals for CRC (that is, no personal history of CRC) suggested that aspirin at the dose range of 75--325 mg/day could be a safe and effective primary prevention for long--term CRC with potential dose--dependent effects. None of the other interventions were found to be effective in this population. Net clinical benefit analysis combining mortality from CRC, cardiovascular (CV) disease and bleeding suggested that low--dose aspirin (>100--325 mg/day; ASA--LD) provided the highest net survival gain but data were too limited to make a definitive conclusion. The assessment of CPAs in increased risk individuals for CRC due to a personal history of colorectal adenomas suggested that celecoxib (400--800 mg/day) and very--low--dose aspirin (≤100 mg/day; ASA--VLD) were the most effective agents for the prevention of recurrent advanced colorectal adenomas. However, the risk--benefit profile potentially favours the use of ASAV--LD especially in those with a history of advanced colorectal adenomas. Therefore, a Markov model was developed to assess the cost--effectiveness of ASA--VLD for the secondary prevention of CRC in a population with a personal history of advanced colorectal adenomas in Malaysia. It suggested that combining ASA--VLD with routine 3--year surveillance colonoscopy offered the best value for money when compared to ASA--VLD alone or routine 3--year surveillance colonoscopy. It also suggested that for those individuals who were compliant to ASA--VLD and willing to take this treatment for a longer period, an extension of surveillance colonoscopy intervals to 5 years could be considered in those countries with limited resources. Overall, this dissertation concludes that the addition of ASA--VLD as recommended for the CV disease prevention in Malaysia with routine surveillance colonoscopy in individuals with a previous history of advanced colorectal adenomas is a simple and effective means of reducing morbidity and mortality, and results in overall cost--saving.