Boxing Bladder Cancer with COX-2–specific Inhibition

Abstract

Preventing recurrence of non-muscle-invasive bladder cancer (NMIBC) is important for improving patient well-being and reducing the health economic burden of this disease. To date, no oral agent has shown sufficient benefit to be adopted in clinical practice, where current strategies rely on topical (intravesical) administration of chemotherapy and immunotherapy. In this issue of the journal (beginning on page 1580), Sabichi and colleagues report the first phase II randomized controlled trial of the COX-2 inhibitor celecoxib in bladder cancer. The trial set out to measure an overly ambitious effect size but nevertheless showed encouraging signs of celecoxib activity. It lends support to COX-2 inhibition in NMIBC, which is being tested in several subsequent trials, and to the need for conclusive evidence. Cancer Prev Res; 4(10); 1534-5. Ó2011 AACR.The body of evidence pointing to the COX-2 pathway playing an important role in the development of bladder neoplasia is compelling and supported by several epidemiologic studies (1). Paralleling early development in colorectal cancer prevention, where the COX-2-specific inhibitor celecoxib [a nonsteroidal anti-inflammatory drug (NSAID)] is clinically effective, preclinical studies confirm that celecoxib can prevent neoplastic transformation of urothelium and reduce urothelial tumor burden in vivo as a single agent or in combination with the immunomodulator Bacillus Calmette-Guerin (BCG; refs. 2, 3), which is standard adjuvant treatment for preventing recurrence of non-muscle-invasive bladder cancer (NMIBC). It is therefore not surprising that celecoxib is being tested in clinical trials in patients with NMIBC.Sabichi and colleagues report the results of such a trial in this issue of the journal (4), but do the trial's results paint a clear picture of the role of COX-2 inhibition in the setting of bladder cancer prevention? They conducted a phase IIb randomized placebo-controlled trial of celecoxib (200 mg twice a day) for a minimum of 12 months to prevent recurrence in 146 patients following transurethral resection of established NMIBC and adjuvant BCG. Time to recurrence was the primary endpoint, and the statistical design powered the trial to detect a 53% relative reduction in the risk of recurrence at 12 months. The trial was initiated in an era when an effect of celecoxib may have seemed assured, but designing a trial to detect a halving of the recurrence rate in a heavily pretreated population was overly optimistic. It is not surprising that the primary endpoint did not reach statistical significance-the results are based on just 48 events and it is important to keep in mind that the estimated treatment effect was overly ambitious. Nevertheless, the results do support the possibility of a clinically beneficial effect of celecoxib. The adjusted HR was 0.69 [95% confidence interval (CI), 0.37-1.29)], and the absolute 12-month recurrence-free rates were 88% (95% CI, 81%-96%) in the celecoxib group and 78% (95% CI, 69%-89%) in the placebo group (log-rank test: P...

Enhanced inhibition of urinary bladder cancer growth and muscle invasion by allyl isothiocyanate and celecoxib in combination

“…Celecoxib, a well-known selective Cox-2 inhibitor, was chosen to test our hypothesis. Celecoxib has been evaluated in bladder cancer patients in clinical trials, but its efficacy as a single agent for bladder cancer prevention or treatment remains uncertain (21)(22)(23). Our present study shows that the combination of AITC with celecoxib at low dose levels causes strong inhibition of bladder cancer and is more effective than each agent used alone.…”

Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation

“…NSAIDs also have potent anti-inflammatory actions and have been utilized clinically in inflammatory disorders including osteoarthritis, rheumatoid arthritis, inflammatory arthropathies, and acute gout [100-103]. COX-2 inhibitors have also been utilized as anti-oncogenic agents in breast, colon, bladder, and prostate cancers, among others [104-107]. COX inhibitors have also shown promise in combating infection and sepsis [108, 109].…”