Conservative Management of HSIL in Patients With Future Pregnancy Aspiration

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Brief Title

Conservative Management of HSIL in Patients With Future Pregnancy Aspiration

Official Title

Conservative Management of Patients Diagnosed With High-grade Squamous Intraepithelial Lesions (H-SIL) Who Have Pregnancy Intentions: a Prospective Observational Study

Brief Summary

      Conservative management of high-grade squamous intraepithelial lesions (HSILs) seems safe and
      justified in young women (<30 years), but evidence is insufficient on whether it is also
      advisable for older women.

      This study will be conducted to analyze spontaneous HSIL regression rates in women of
      reproductive age and establish whether conservative HSIL management could be safely
      recommended to women of childbearing potential, irrespective of age.

      This is a single-center prospective observational study that will include consecutive women
      of reproductive age, referred to a tertiary hospital due to HSIL between March 2021 and
      December 2025, who prefer conservative management rather than immediate cervical conization.

      All patients will be followed-up regularly with colposcopy, cytology, human papillomavirus
      (HPV) testing and biopsies. In case their lesions progress or HSIL persists after 24 months
      of follow-up, conization will be indicated. Rates of spontaneous regression or resolution, as
      well as progression rates, will be assessed. Furthermore, the association between potential
      predictive factors and HSIL resolution will be analyzed.
    

Detailed Description

      In most developed countries, two main strategies are currently used for cervical cancer
      prevention: primary prevention with human papillomavirus (HPV) vaccination, and systematic
      screening with periodic cytology or HPV testing. Nevertheless, a significant number of women
      are still diagnosed with high-grade squamous intraepithelial lesions (HSIL), with higher
      prevalence rates among younger women (0.6% between ages 20 and 29; 0.2% between 40 and 49).
      Since the average age at first pregnancy in Catalonia is 32.2 years, many patients have not
      yet fulfilled their reproductive intentions when they are diagnosed with HSIL.

      Most HSIL cases are treated surgically with cervical conization, although previous studies
      have indicated that this may increase the incidence of preterm labor in future pregnancies.
      Therefore, many women diagnosed with HSIL will undergo treatment that may affect their future
      reproductive life.

      In patients diagnosed with HSIL, conservative management with periodic evaluations would be
      an efficient alternative to surgery, with the expectation of spontaneous resolution. Recent
      studies have shown that 40-88% of HSIL lesions can regress spontaneously within two years,
      especially in women under 25. Furthermore, a meta-analysis of 36 studies involving 3160
      patients concluded that active surveillance of patients diagnosed with cervical
      intraepitelial neoplasia (CIN) grade 2, rather than immediate surgical treatment, is
      justified, especially in young women (<30 years). Recent clinical guidelines include active
      surveillance as a valid option for management of HSIL in fertile women, with no age
      restrictions.

      Although the biological behavior of CIN2 without surgical treatment has been described in
      numerous studies, few included lesions classified as CIN3. Since the latest anatomical and
      pathological classification of the World Health Organization does not make any distinction
      between CIN2 and CIN3, classifying both as HSIL, treatment guidelines should be uniform for
      all HSILs, without discriminating between CIN2 or CIN3.

      Furthermore, although several studies have demonstrated the safety of conservative management
      for HSIL in women younger than 25-30 years, there is insufficient information in women aged
      30-40 years. Therefore, further evidence is still needed on the rate of spontaneous
      regression of HSIL (both CIN2 and CIN3) and on the safety of active surveillance, so that
      conservative management may be considered in all women who wish to become pregnant in the
      future.

      The main goal of this study will be to analyze whether spontaneous HSIL (CIN2 and CIN3)
      regression rates in women of reproductive age are high enough to support conservative
      management without age restrictions. We aim to describe the rates of spontaneous HSIL
      regression, HSIL persistence and HSIL progression in women under conservative management.
      Furthermore, we aim to describe predictive factors associated with HSIL regression rates. If
      this study confirms the safety of conservative management of HSIL, it could be possible to
      reduce the number of cervical conizations in these patients.

      Aim This will be a prospective observational cohort study performed at a Lower Genital Tract
      (LGT) unit of a tertiary hospital (Hospital de la Santa Creu i Sant Pau, Barcelona, Spain)
      affiliated with a cytology-based cervical cancer screening program. In this center, all
      colposcopic examinations are performed by two senior colposcopists, accredited by the Spanish
      Association for Cervical Pathology and Colposcopy (AEPCC). Pathology samples are analyzed by
      specialist technicians from the Pathology department of the same hospital and reviewed by
      expert pathologists. HPV tests are performed for all patients in the same laboratory using
      Genómica's Clart Human Papillomavirus 4.

      Patients All women referred to our LGT unit with biopsy-confirmed histological diagnosis of
      HSIL (CIN2 or CIN3) are assessed with colposcopy and counseled by expert gynecologists.
      Patients considered suitable for conservative management (instead of immediate surgical
      treatment with cervical conization) are routinely informed of the potential risks and
      benefits of both cervical conization and active surveillance of HSIL. Then, a shared decision
      is made for either surveillance or immediate conization. To be considered suitable for
      conservative management, women must: be of reproductive age; have transformation zone type 1
      or 2 (fully visible squamous-columnar union) at colposcopy, with a fully visible lesion and
      no atypical glandular cells (AGC) at cytology; and commit to attend follow-up visits at
      regular intervals.

      This study will start in March 2021 and will be concluded in December 2027. Consecutive women
      of reproductive age referred to our center from March 2021 to December 2025 with a diagnosis
      of HSIL that are considered suitable for conservative management and freely chose active
      surveillance will be invited to participate in this study. Patients will be followed-up for a
      minimum of 2 years.

      Eligibility criteria include positive high-risk (hr) HPV cytology, reproductive age and a
      wish to pursue pregnancy in the future. Women who are pregnant at diagnosis, immunosuppressed
      or diagnosed with carcinoma in situ of the cervix or cervical cancer will be excluded.

      This study was approved by the institution's ethics committee. Written informed consent will
      be obtained from all patients. All follow-up visits and clinical tests will be performed
      according to standard patient care and no tests or visits will be conditioned to
      participation in the study, nor will any additional treatment be given to patients enrolled.
      Verbal informed consent to continue conservative treatment will be reviewed at each follow-up
      visit. At any time during follow-up, patients can choose to have conization.

      Follow-up visits will be performed every 4 months, including colposcopy and cytology at each
      visit. Biopsies will not performed routinely, but on a case-by-case basis according to
      changes observed in colposcopy. The follow-up interval will be extended to 6 months if
      cytology and biopsies indicated low-grade squamous intraepithelial lesion (LSIL) or atypical
      squamous cells of undetermined significance (ASCUS) and this result is consistent with
      colposcopy. HPV will be determined every 8 12 months. This follow-up protocol will be
      continued until resolution of HSIL. Patients will be referred back to primary care when no
      HSIL is detected by cytology, colposcopy or biopsies and if HPV is negative at two
      consecutive visits.

      Conservative management will be discontinued and conization will be indicated if HSIL
      persists after 24 months of follow-up, if the patient no longer meet criteria for
      surveillance, or under the patient's request.

      All information will be retrieved from electronic patient files. Demographic data, smoking
      status, parity, use of contraceptives and colposcopy will be recorded. Information from
      pathology reports of cytology, biopsies and conization specimens will be collected, and time
      to HSIL resolution, regression or progression will be recorded.

      Patients will be classified into two groups according to the outcome of active surveillance:
      spontaneous HSIL regression or conization (women who had cervical conization for any reason
      during follow-up). Patients with spontaneous HSIL regression will be further classified into
      3 subgroups: total resolution (no colposcopic lesion, normal pathology by biopsy and
      cytology, and negative HPV for the HPV type initially detected); partial resolution
      (regression of colposcopic lesion, negative cytology and biopsies, but persistence of the
      initial hrHPV detected); and lesion regression (HSIL no longer detected, but persistent LSIL
      in either cytology, histology or colposcopy). Patients who eventually have conization will be
      further classified according to indication criteria: failure to meet criteria for
      conservative management or persistence of HSIL after 24 months of follow-up.

      Data analysis Patient characteristics will be described according to whether their lesions
      regress spontaneously or conization is indicated throughout the follow-up period. Numbers and
      percentages will be provided for categorical variables, whereas means and standard deviations
      will be used for quantitative variables.

      The association between potential predictive variables and HSIL resolution will be analyzed
      with chi-square tests (or Fisher's exact test when appropriate) for categorical variables and
      t-tests for quantitative variables. Variables assessed will include: age and ethnicity,
      smoking status, number of sexual partners within the previous 6 months, HPV type, alternative
      therapies, HPV vaccination.

      The characteristics of patients who have conization will be summarized, comparing patients
      referred to surgery because they failed to meet surveillance criteria to those referred to
      surgery due to persistence of HSIL at end of follow-up. The statistical analysis will be
      performed with SPSS version 26.0 (SPSS Inc., Chicago, IL, USA). Differences between groups
      were considered statistically significant at p < 0.05.
    


Study Type

Observational


Primary Outcome

HSIL regression


Condition

Cervical Intraepithelial Neoplasia

Intervention

Conservative management with regular follow-up

Study Arms / Comparison Groups

 Spontaneous HSIL regression
Description:  Patients that have spontaneous regression of HSIL throughout follow-up. Patients in this group will be further classified into 3 subgroups: total resolution (no colposcopic lesion, normal pathology by biopsy and cytology, and negative HPV for the HPV type initially detected); partial resolution (regression of colposcopic lesion, negative cytology and biopsies, but persistence of the initial hrHPV detected); and lesion regression (HSIL no longer detected, but persistent LSIL in either cytology, histology or colposcopy).

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

200

Start Date

March 3, 2021

Completion Date

December 31, 2027

Primary Completion Date

December 31, 2025

Eligibility Criteria

        Inclusion Criteria:

          -  Reproductive age and aspirations of future pregnancies

          -  Acceptance of conservative management

          -  Commitment to attend scheduled follow-up visits

          -  Colposcopy with transformation zone (ZT) type 1 or 2 (fully visible squamous-columnar
             union) with lesion with grade 2 changes visible in its entirety. No endocervical
             involvement

          -  Colposcopy with grade 2 changes that are not extensive: <50% of the cervical surface

        Exclusion Criteria:

          -  Pregnancy at first visit or during follow-up.

          -  Immunosuppression (either iatrogenic or due to human immunodeficiency virus (HIV))

          -  Suspected or diagnosed Atypical Glandular Cells (ACG), In Situ Adenocarcinoma (AIS) or
             Cervical Cancer (CC)
      

Gender

Female

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Cristina Vanrell Barbat, MD, +34604311873, [email protected]

Location Countries

Spain

Location Countries

Spain

Administrative Informations


NCT ID

NCT04783805

Organization ID

IIBSP-CIN-2020-126


Responsible Party

Sponsor

Study Sponsor

Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau


Study Sponsor

Cristina Vanrell Barbat, MD, Study Director, Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau


Verification Date

March 2021