al trial data that have emerged since the launch of STAMPEDE have been equivocal as to the value of COX-2 inhibitors in prostate27,28 and colorectal29,30 cancers. So far, published trials have not supported the use of COX-2 Maraviroc inhibitors unequivocally in any established cancer type; our trial adds further evidence of their limited clinical utility in established tumours. We do note Panel: SNX-5422 HSP-90 inhibitor Research in context Systematic review At the time of trial design, there was substantial epidemiological, laboratory, and clinical evidence that COX-2 has a role in development and progression of a range of cancers, including prostate cancer. Celecoxib was chosen for assessment in hormone-sensitive prostate cancer based on in-vitro evidence of activity and data in other cancers, particularly familial polyposis coli, where it has a role in prevention of progression from polyp to cancer.
We assessed a range Luteolin 491-70-3 of drugs with COX-2-inhibitory properties and selected celecoxib based on the data in familial polyposis coli and its safety profile in large-scale trials of other diseases. Data from trials of celecoxib in established cancers have been tracked through the registers, and lead investigators have been contacted for information each time reviews are updated but registers do not include recent data. Interpretation At the second preplanned intermediate analysis, we have shown that celecoxib given attwice daily for 1 year is insufficiently active in high-risk, hormone-sensitive prostate cancer to signifi cantly affect failure-free survival.
Other trials in prostate cancer have not supported the use of COX-2 inhibitors unequivocally in any setting, and our trial adds further evidence buy Diosmin of the limited clinical utility of these drugs in established, advanced cancer. We do not recommend their use in these patients. positive findings for chemoprevention of non-melanoma skin cancer in patients with actinic keratoses.31 Several trials of celecoxib in other types of established tumours continue to recruit patients, including large trials in We cannot identify at this stage why a drug with a sound pretrial rationale would show no evidence of activity in a large-scale trial, but there are several possibilities to consider. First, there could be lack of expression of the target molecule COX-2, which we could retrospectively assess by collecting tissue blocks and studying COX-2 expression.
Second, there might be a lack of on-target activity; celecoxib was chosen because of documented activity in the setting of familial polyposis coli,20 thus it seems reasonable to assume that the drug dose and delivery are within the necessary therapeutic range. Third, the dose or duration of exposure of celecoxib, or both, may have occupation been inadequate. The initial planned duration of therapy was 2 years, but in view of the excess cardiovascular problems reported with rofecoxib just before accrual to STAMPEDE, a shorter duration was selected. Even if the duration was too short for optimum effect, we would still expect some effect, particularly with a median time to progression of around 2 years. A key strength of STAMPEDE is that several therapeutic combinations are tested synchronously, thereby shortening the time to assess efficacy and toxicity in new drug combinations in hormone-naive patients undergoing hormone therapy. A further strength is that recruitment is broadly based, incorporating more than 100 centres in two countries. The entry criteria were intended to define a population.