Non-steroidal anti-inflammatory agents to induce regression and prevent the progression of cervical intraepithelial neoplasia

Abstract

Background: Cervical intraepithelial neoplasia (CIN) precedes the development of invasive carcinoma of the cervix. Current treatment of CIN is quite effective, but there is morbidity for the patient related to pain, bleeding, infection, cervical stenosis and premature birth in subsequent pregnancy. Effective treatment with medications, rather than surgery, would be beneficial. Objectives: To evaluate the effectiveness and safety of non-steroidal anti-inflammatory agents (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, to induce regression and prevent the progression of cervical intraepithelial neoplasia CIN. Search methods: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2013), MEDLINE (November, 2013) and EMBASE (November week 48, 2013). We also searched abstracts of scientific meetings and reference lists of included studies. Selection criteria: Randomised controlled trials (RCTs) or controlled trials of NSAIDs in the treatment of CIN. Data collection and analysis: Three review authors independently abstracted data and assessed risks of bias. Outcome data were pooled using random-effects meta-analyses. Main results: In two RCTs, 41 women over the age of 18 years, in an outpatient setting, were randomised to receive celecoxib 200 mg twice daily by mouth for six months versus placebo (one study, 25 participants) or rofecoxib 25 mg once daily by mouth for three months versus placebo (one study, 16 participants). This second study was discontinued early when rofecoxib was withdrawn from the market in 2004. The trials ran from June 2002 to October 2003, and May 2004 to October 2004. We have chosen to include the data from the rofecoxib study as outcomes may be similar when other such NSAIDs are utilised. Partial or complete regression of CIN 2 or 3 occurred in 11 out of 20 (55%) in the treatment arms and five out of 21 (23.8%) in the placebo arms (RR 2.35, 95% CI 1.03 to 5.35; P value 0.04), very low quality evidence). Complete regression of CIN 2 or 3 occurred in four of 12 (33%) of those receiving celecoxib versus two of 13 (15%) of those receiving placebo (RR 2.17, 95% CI 0.48 to 9.76; P value 0.31, very low quality evidence). Partial regression of CIN 2 or 3 occurred in five of 12 (42%) of those receiving celecoxib versus two of 13 (15%) of those receiving placebo (RR 2.71, 95% CI 0.64 to 11.43; P value 0.18), very low quality evidence). Progression to a higher grade of CIN, but not to invasive cancer, occurred in one of 12 (8%) of those receiving celecoxib and two of 13 (15%) receiving placebo (RR 0.54, 95% CI 0.05 to 5.24; P value 0.4, very low quality evidence). One study reported no cases of progression to invasive cancer within the timeframe of the study. No toxicity was reported in either study. Although the studies were well conducted and randomised, some risk of bias was detected in both studies. Furthermore, the duration of the studies was short, which may mask identifying progression to cancer. Authors' conclusions: There are currently no convincing data to support a benefit for NSAIDs in the treatment of CIN (very low quality evidence according to GRADE criteria). Results from a large on-going randomised study of celecoxib are awaited.