A Randomized, Single Blinded Trial to Evaluate the Efficacy of Imiquimod in Women With Residual/Recurrent Cervical Intraepithelial Neoplasia (CIN) After Previous Treatment

INTRODUCTION AND RATIONALE CIN Cervical dysplasia is caused by HPV and most common in women of reproductive age. Cervical dysplasia is known to be a precancerous stage of cervical cancer, where cervical cancer is the fourth most common cancer worldwide in women. Treatment of moderate to severe dysplasia is often still surgical and aimed at eliminating the affected part of the transformation zone. There are different type of surgical treatments (Large Loop excision of the transformation zone (LLETZ), knife cone biopsy, laser conisation), which have around 90% success rate. Historically moderate and severe dysplasia were treated with cold knife biopsy. Nevertheless, with deep cones hemorrhage, infection and postprocedure stenosis were reported. LLETZ seems to be a good alternative. It can be performed under local anesthesia, is cheaper, less painful and seem to have less short and long term morbidity. In outcome LETTZ has a similar risk in residual disease compared to cold knife cone. LLETZ is therefore the golden standard for treating cervical dysplasia nowadays. Still, there is uncertainty about the effects of LLETZ on short and long term in terms of recurrence, fertility and future pregnancy outcomes. Women diagnosed with CIN are usually at their reproductive age, so effects on future fertility and pregnancy are a concern. Women with a shorter time interval from LLETZ to pregnancy seem to have an increased risk for spontaneous abortion[6]. Also there is contradicting evidence on the presumed higher risk on preterm delivery and low birth weight. One study reported a 10 fold higher risk for preterm deliveries after more than one conisation procedure in women with cervical dysplasia. Furthermore, a recent study showed a higher subfertility rate with patients who underwent cervical surgery. Systematic review and meta-analysis reported on LLETZ for CIN also showed an increased rate of preterm delivery (<32wks RR 1.98, 95% CI 1.31-2.98; <28wks RR 2.33, 95% CI 1.84-2.94), premature rupture of the membranes (RR 1.88, 95% CI 1.54-2.29) and low birth weight (<2,500g RR 2.48, 95% CI 1.75-3.51) Apart from reproductive arguments there is an ongoing debate about the longterm outcome after treatment with surgical excision. Several studies show a recurrence rate of CIN 2-3 after treatment of 15-22 % within 2 years. Margin involvement seemed to be a risk factor for developing residual or recurrent cervical dysplasia Moreover, even after adequate treatment and follow up with normal smear results, patients who were treated for cervical intraepithelial dysplasia seem to have an excessive risk of cervical cancer compared to patients with normal primary smear test results. This risk is even almost 25 times higher in patients with abnormal smear test results than in patients with normal smear test results after treatment. Recent studies found that most women with residual or recurrent disease test positive for HPV after treatment. Possibly this could be a tool for risk stratification in the follow up after treatment. Also, this could raise the question if there is a need to treat HPV instead of treating the consequences of HPV (removing the transformation zone). Especially in patients with recurrent or residual disease.

Evidence for the involvement of Human Papilloma Virus in CIN Human Papilloma Virus (HPV) is the cause of pre-cancerous abnormalities of the cervix. HPV has over 100 subtypes and is present in over 95% of pre-invasive and invasive squamous carcinomas of the cervix. Some researchers state that HPV negative cervical cancer does not exist. Certain serotypes are associated with a high risk for progression to malignancy and more often found in cervical cancer. This are HPV type 16, 18, 31, 33, 35, 45, 52, and 58.

There is evidence that earlier detection of high stage CIN lesions (CIN 3) will be accomplished by screening with HPV DNA tests other than cytology alone.

Rationale Approximately 90% of the HPV is cleared after surgical treatment. Nonetheless, surgical treatment often deals more with the consequences instead of the cause of the disease. There is still a significant amount of women who will develop residual or recurrent disease. Recent publications show a higher risk of invasive cancer after treatment for cervical neoplasia grade 3 in comparison to the general population. Rebolj reported an incidence of 35,1 per 100000 years and 6,4 per 100000 years, respectively, led to an adjusted hazard ratio of 4,2 for periods after completed follow-up compared with periods after normal primary smear test results. Strander et al, showed an overall standardised incidence ratio for women with previous CIN grade 3 of 2,30 to develop invasive cervical carcinoma compared to the general population. Over time, there is a request for non-invasive treatment which treats HPV.

Young girls are vaccinated against HPV 16 and 18 nowadays. The current analysis show efficacy of almost 93% against CIN 2+associated with HPV-16/18 who had no evidence of oncogenic HPV infection on baseline. However only a 30% efficacy was seen against CIN2+ irrespective of HPV type in all women and 70% in the group who had no evidence of oncogenic HPV infection on baseline. For CIN3+ these numbers are 33% in the whole group and 87% in the HPV negative group. Vaccine efficacy against CIN2+ associated with 12 nonvaccine oncogenic types was 54%. Another problem is the vaccination uptake along young women. Since the reality is still that many women could or would not get vaccinated, primary prevention of HPV related diseases still has a long way to go.