The treatment of cervical pre-cancer (CIN) with anti-inflammatory agents to induce regression and prevent the progression to cervical cancer

Review Questions

We reviewed the evidence about the effect of non-steroidal anti-inflammatory agents (NSAIDs) to cause regression and prevent the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer. We found only two small studies.

Background

Cervical pre-cancer (cervical intraepithelial neoplasia: CIN) can progress to invasive cancer of the cervix (neck of the womb). CIN is identified by screening and can be treated with surgery to the cervix, either with destruction of the cells covering the cervix, such as with laser therapy, heating, or freezing, or removal by surgical excision. While this is effective in the majority of cases, the surgery can cause immediate unwanted effects, such as bleeding and infection, or later complications including difficulty with menses due to scarring of the cervix and early (premature) labour.

NSAIDs have been found to prevent the development of cancer of the large bowel and other organs, but with some unwanted side effects, especially on the heart and blood vessels. Although rofecoxib, used in one of these studies, was withdrawn from the market in 2004, it may shed light on the feasibility of treatment with other NSAIDs.

We wanted to discover whether the use of NSAIDs for women with CIN could promote regression or prevent progression to cervical cancer without undue risk or side effects.

Study characteristics

We identified two randomised studies, including 41 women over the age of 18 years, with moderate or severe CIN. The trials ran from June 2002 until October 2003 and between May 2004 and October 2004. One of them was discontinued before it was completed. The women were given either celecoxib or rofecoxib versus a placebo (sugar tablet) daily by mouth for a period of three to six months.

Key Results

There were far too few women involved in the trials to be able to show whether NSAIDs had a helpful effect in causing regression of CIN. No patients progressed to invasive cervical cancer, and no unwanted effects of the NSAID tablets were reported, but the number of women in the studies would have been too small to detect an adverse effect.

Quality of the evidence

While both studies appear to have been conducted well, there are some questions related to the quality of evidence in relation to concealment and women dropping out of the study before completion of assigned medications. There was insufficient information to assess accuracy of the reporting of information. It is possible that there are other incomplete and unreported studies that have not been identified.

Conclusion

There is insufficient data at this time to support the use of NSAIDs to cause regression or prevent progression of CIN to cervical 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.

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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 strategy: 

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.

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