Zdravljenje Ploščatocelične Intraepitelijske Lezije Visoke Stopnje Materničnega Vratu Z Imikvimodom

Abstract

Namen: V literaturi je malo podatkov o uspešnosti konzervativnega zdravljenja visoko tveganih ploščatih intraepitelijskih lezij materničnega vratu (PIL VS) z imikvimodom v primerjavi s standardnim zdravljenjem z električno zanko (LLETZ). Dva najpomembnejša dejavnika tveganja za nastanek predrakavih sprememb materničnega vratu in raka materničnega vratu sta obstojnost in podtip virusa humanega papiloma virusa (HPV). Razširjenost okužbe s HPV je najvišja pri ženskah, starih okoli 20 let, z naraščajočo starostjo pa upada. Zlasti pri mlajših ženskah je lahko zdravljenje z LLETZ povezano s kratkoročnimi in dolgotrajnimi stranskimi učinki, kot so krvavitve ali vnetja in kar je najpomembnejše, s prezgodnjim porodom pred 37. tednom in izjemno prezgodnjim porodom pred 28. tednom nosečnosti. Drugi, manj pogosti zapleti so poškodba materničnega vratu, bolečine v medenici in zožitev kanala materničnega vratu. Ker je prezgodnji porod eden najpomembnejših vzrokov perinatalne obolevnosti in umrljivosti, se alternativne, konzervativne metode zdravljenja PIL VS nenehno ocenjujejo. Imunomodulator imikvimod je ena najbolj raziskanih in ciljnih spojin za konzervativno zdravljenje PIL VS.

Metode: Cilj naše prospektivne randomizirane raziskave je bil oceniti učinkovitost zdravljenja z imikvimodom in jo primerjati s standardnim zdravljenjem z LLETZ. Bolnice, stare 18–40 let s histološko potrjenim PIL VS (z visokotvegano intraepitelijsko lezijo materničnega vratu, CIN2p16+ in CIN3), so bile naključno razporejene v dve skupini, v katerih je zdravljenje potekalo ali z imikvimodom ali z LLETZ. Primarni cilj raziskave je bil opredeljen kot odsotnost PIL VS po katerem koli od načinov zdravljenja. Sekundarni cilji so bili pojav stranskih učinkov. Raziskava je bila izvedena v Kolposkopski ambulanti Oddelka za ginekološko onkologijo in onkologijo dojk Klinike za ginekologijo in perinatologijo UKC Maribor in Oddelka za patologijo UKC Maribor. Vključevanje bolnic v raziskavo se je začelo novembra 2018 in zaključilo aprila 2020.

Rezultati: V vsako skupino je bilo razporejenih 52 bolnic, ki se niso razlikovale glede na osnovne značilnosti. V skupini z imikvimodom je zdravljenje zaključilo 43 (82,7 %) bolnic, zdravljenje pa je bilo uspešno pri 27 (51,9 %) bolnicah. Vse bolnice v skupini, kjer je zdravljenje potekalo z LLETZ, so zaključile zdravljenje, ki je bilo uspešno pri 48 (92,3 %) bolnicah (p < 0,001). V podskupini bolnic s CIN2p16+ je bila uspešnost zdravljenja z imikvimodom primerljiva z zdravljenjem z LLETZ (17 (73,9 %) proti 16 (84,2 %), p = 0,477). Pri nobeni od bolnic med zdravljenjem in po njem nismo opazili napredovanja v invazivno bolezen. Neželeni učinki in hudi neželeni učinki (lokalni in sistemski) so bili bolj izraziti pri zdravljenju z imikvimodom kot pri LLETZ (46 (88,5 %) proti 23 (44,2 %) (p < 0,001) in 27 (51,9 %) proti 7 (13,5 %) (p < 0,001).

Zaključek: Na splošno pri bolnicah s PIL VS LLETZ ostaja zlati standard zdravljenja. V podskupini bolnic s CIN2p16+ je bila stopnja uspešnosti med obema načinoma zdravljenja primerljiva, pomembno klinično vprašanje pa predstavlja pojavnost neželenih stranskih učinkov, zaradi katerih lahko bolnice prenehajo z zdravljenjem z imikvimodom.

Alternate abstract:

Background: There are limited data on the success of conservative treatment of high-grade cervical squamous intraepithelial lesions (HSIL) with imiquimod directly compared to standard of treatment with LLETZ. The two most important risk factors for occurrence of premalignant lesions of the cervix and cervical cancer are persistence and subtype of Human papillomavirus virus (HPV). Prevalence of HPV infection is highest among women aged around 20 years and it declines with increasing age. Especially in younger women, treatment with LLETZ can be associated with short and long-term side effects, such as bleeding or inflammation and most importantly with premature labour before 37 weeks and extremely premature labour before 28 weeks of gestation. Other, less frequent complications are uterine cervix injury, pelvic pain and stenosis of the cervical canal. Since premature delivery is one of the most important causes of perinatal morbidity and mortality, alternative, conservative methods for HSIL treatment are constantly being evaluated. The immunomodulator imiquimod is one of the main target compounds for conservative treatment of SIL.

Methods: The aim of our prospective randomized trial was to evaluate the efficacy of treatment with imiquimod and compare it to that of the standard treatment with LLETZ. Patients aged 18–40 with histological HSIL (with high-grade cervical intraepithelial neoplasia, CIN2p16+ and CIN3), were randomly assigned to treatment with imiquimod or LLETZ. The primary outcome was defined as the absence of HSIL after either treatment modality. The secondary outcomes were the occurrence of side effects. The study was performed in the Colposcopic out-patient clinic of the Department for Gynaecological and breast Oncology, Clinic for gynaecology and perinatology, University Medical Centre Maribor and the Department of pathology, University Medical Centre Maribor. Enrolment of patients started in November 2018 and closed in April 2020.

Results: 52 patients were allocated in each group and were similar regarding baseline characteristics. In the imiquimod group, 82.7% of patients completed treatment, which was successful in 51.9%. All patients in the LLETZ group completed treatment, which was successful in 92.3% (p < 0.001). In the subgroup of CIN2p16+ patients, treatment with imiquimod was not inferior to LLETZ (73.9% vs. 84.2%, p = 0.477). During and after treatment, no cases of progression to cancer were observed. Side effects and severe side effects (local and systemic) were more prevalent in the imiquimod than in the LLETZ group (88.5% vs. 44.2% (p-value < 0.001) and 51.9% vs. 13.5% (p-value < 0.001), respectively.

Conclusion: Generally, in patients with HSIL, LLETZ remains the gold standard of treatment. However, in a subgroup analysis of patients with CIN2p16+, the success rate was comparable between the two treatment modalities. Due to the prevalence of side effects, the treatment compliance with imiquimod use may, however, present a clinically important issue. Additionally, we have established collaboration with other institutions, to do further research regarding imiquimod and its effect on precancerous and cancerous lesions of uterine cervix, and our aim is to provide answers regarding (i) the need for treatment with LLETZ within two years after primary treatment with imiquimod in the experimental arm; (ii) retreatment with LLETZ two years after primary treatment with LLETZ in the control arm; (iii) the modulatory effect of imiquimod on immunoregulatory molecules, and (iv) HPV clearance after treatment with imiquimod. These results are expected to be available in three years.