Caroline L. P. Muntinga

Improving imiquimod use in cervical high‐grade squamous intraepithelial lesions: A qualitative study

AbstractIntroductionTo investigate patient experiences and satisfaction with imiquimod for cervical high‐grade squamous intraepithelial lesions and its side effects, possibly influencing the (dis)continuation of treatment. Secondary objectives include evaluating patient counseling and guidance before and during imiquimod treatment for cervical high‐grade squamous intraepithelial lesions by gynecologists and nurse practitioners to improve patient guidance.Material and MethodsSemi‐structured interviews were conducted with patients treated with imiquimod for cervical high‐grade squamous intraepithelial lesions and with healthcare professionals from hospitals in the Netherlands. Interviews were transcribed and transcripts were analyzed using thematic analysis.ResultsA total of 15 patients, 11 of whom finished imiquimod treatment and four who discontinued imiquimod treatment, and six healthcare professionals were interviewed. Three main themes were identified: counseling and side effects, use of imiquimod, and contact moments during treatment. Many patients believed that sharing patient experiences would help in making treatment decisions. Patients discontinued treatment early due to side effects and the mode of application. Detailed information on application methods and side effect severity during counseling is desirable. Healthcare professionals agreed on the factors that need to be addressed during counseling but held different opinions on imiquimod's side effect severity and application methods.ConclusionsAdequate patient counseling on imiquimod treatment, including the possible application methods and potential side effects, along with optimal guidance during treatment, contributes to a better patient experience and reduces the likelihood of early discontinuation of treatment.

Topical imiquimod treatment of residual or recurrent cervical intraepithelial neoplasia lesions (TOPIC‐2): A randomised controlled trial

AbstractObjectiveTo investigate the efficacy of imiquimod in women with residual or recurrent cervical intraepithelial neoplasia (rrCIN), compared with large loop excision of the transformation zone (LLETZ).DesignRandomised controlled non‐inferiority trial.SettingOne academic and one regional hospital in the Netherlands.PopulationThirty‐five women with rrCIN were included in the study between May 2016 and May 2021.MethodsWomen were randomised to receive treatment with 5% imiquimod cream (12.5 mg) intravaginally (three times a week for a duration of 16 weeks) or a LLETZ procedure (standard treatment).Main outcome measuresThe primary outcome was reduction to normal cytology at 6 months after starting treatment. Secondary outcomes were clearance of high‐risk human papilloma virus (hr‐HPV) in both groups and reduction to ≤CIN1 in the imiquimod group. Side effects were monitored.ResultsTreatment success was 33% (6/18) in the imiquimod group versus 100% (16/16) in the LLETZ group (P < 0.001), whereas HPV clearance was 22% (4/18) in the imiquimod group versus 88% (14/16) in the LLETZ group (P < 0.001). After the randomisation of 35 women, the futility of treatment with imiquimod was proven and the trial was prematurely finished. In the follow‐up period, three patients remained without additional treatment, whereas all other patients underwent LLETZ, conisation or hysterectomy. In the LLETZ group none of the patients received additional treatment during 2 years of follow‐up.ConclusionsThis is the first randomised controlled trial to show that topical imiquimod has a significantly lower success rate in terms of reduction to normal cytology and hr‐HPV clearance, compared with LLETZ, in women with rrCIN. Additionally, imiquimod has numerous side effects and after using imiquimod most women with rrCIN still required additional surgical treatment.

Real-world performance of the Assessment of Different NEoplasias in the adneXa (ADNEX) model for the pre-operative classification of ovarian tumors.

To predict the risk of malignancy in ovarian tumors, the multi-class risk prediction Assessment of Different NEoplasias in the adneXa (ADNEX) model of the International Ovarian Tumor Analysis group is used internationally. This study aimed to perform an external validation of this model in a real-world clinical setting in the Netherlands. A multi-center, retrospective diagnostic accuracy study was performed. Women aged ≥18 years who attended the outpatient clinic between May 2020 and December 2021 and had a first ultrasound assessment for an ovarian tumor with application of the International Ovarian Tumor Analysis ADNEX model were included. The reference standard was the pathology result in case of surgery or follow-up with ultrasound according to the current Dutch guideline in case of conservative management. Of the 363 women included, 286 (78.8%) had benign, 24 (6.6%) had borderline, and 53 (14.6%) had malignant pathology. Most (62.5%) of the included patients underwent surgery. The area under the receiver operating characteristic (ROC) curve was 0.92 (95% CI 0.89 to 0.96) if borderline tumors were considered malignant and 0.93 (95% CI 0.89 to 0.96) if borderline tumors were considered benign. Cutoff values between 7% and 14% yielded the highest Youden index. The model was moderately able to differentiate between malignant histologic sub-types. The ADNEX model showed excellent diagnostic performance in daily clinical practice and retained its value in a population in which a proportion of patients were treated with conservative management.

Risk factors for recurrence of vulvar high-grade squamous intra-epithelial lesions: long-term follow-up of the PITVIN Study (primary imiquimod vs surgery for vulvar intra-epithelial neoplasia).

To assess risk factors for long-term recurrence of vulvar high-grade squamous intra-epithelial lesions (vulvar HSIL) and other high-risk human papillomavirus-related genital dysplasia after primary treatment with imiquimod or surgery. This was a long-term follow-up of the PITVIN trial (Clinicaltrials.gov identifier: NCT01861535), a multi-center, randomized, phase 3 non-inferiority clinical study of topical imiquimod versus surgery for vulvar HSIL. Number of recurrent vulvar HSIL or other HSIL and related treatment types were assessed. The relationship between initial study treatment, patient characteristics, primary response (quick versus slow) to imiquimod, and pre-treatment immune infiltrates in recurrent and non-recurrent HSIL were analyzed. Long-term clinical data was available for 87 patients (42 imiquimod, 45 surgery) of the 107 patients included in the original intention-to-treat analysis. Mean follow-up time was 70 months (standard deviation ±24). Among the 80 patients with per-protocol treatment in the initial study, recurrent vulvar HSIL was diagnosed in 33% (12/36) after imiquimod and in 20% (9/44) after surgery (p =.20). Baseline recurrence status, age, and smoking were not associated with vulvar HSIL recurrence. Within the imiquimod study group, patients with an initial slow or partial response to imiquimod experienced recurrent HSIL lesions in 54% (7/13), and patients with an initial quick response in 22% (5/23) of cases (p =.05). Recurrent vulvar HSILs showed significantly higher initial intra-epithelial infiltration of cluster of differentiation 33+ immature monocytes compared with non-recurrent lesions (p =.04), suggesting tumor-mediated immunosuppression. In the intention-to-treat population, 21% (18/87) developed cervical HSIL (n = 9), vaginal HSIL (n = 3), anal HSIL (n = 3), cervical cancer (n = 1), anal cancer (n = 1) and vulvar cancer (n = 1) during long-term follow-up. Topical imiquimod and surgical treatment of vulvar HSIL are effective in long-term follow-up, with recurrences occurring in 20% to 33% of patients within 5 years. Initial slow or partial treatment response to imiquimod and the composition of pre-treatment immune infiltrates may be predictors of an increased long-term recurrence risk.