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Hysteroscopic Access and Uterine Cavity Evaluation 12 Months Post-Endometrial Ablation with the Cerene® Cryotherapy Device

Published:November 24, 2021DOI:https://doi.org/10.1016/j.jmig.2021.11.016

      Abstract

      Study Objective

      To evaluate if physical access and the ability to systematically assess the post-ablation uterine cavity were preserved at 12 months after endometrial ablation with the Cerene® Cryotherapy Device (Channel Medsystems®, Emeryville, CA).

      Design

      A prospective, multi-center, single-arm study.

      Setting

      In the clinic at 8 US sites and outpatient hospital setting at 2 sites in Canada and 1 site in Mexico.

      Patients or Participants

      230 of 242 subjects post-ablation continued in the study at the Month 12 visit. 223 subjects were available for a diagnostic hysteroscopic evaluation.

      Interventions

      Subjects who had previously been treated with a 2.5-minute cryoablation of the endometrium utilizing the Cerene® Device underwent a diagnostic hysteroscopy at the Month 12 follow-up visit.

      Measurements and Main Results

      The uterine cavity was accessible in 220 of 223 subjects (98.7%) and not accessible in 3 (1.3%), due to pain (n=2) and cervical stenosis (n=1). Visualization of the uterine cavity was possible in 204 of 220 subjects (92.7%) with one or both tubal ostia identified in 89.2% (182/204) of subjects. Both tubal ostia were visible in 160 of 204 subjects (78.4%) and one ostium in 22 of 204 subjects (10.8%). The cavity was not visualized in the remaining 16 of 220 subjects (7.2%) due to intrauterine adhesions (n=14), technical difficulties (n=1), or menstruation (n=1). In 95.6% (195/204) of subjects where the cavity was visualized, the hysteroscopic view was judged adequate to evaluate the uterine cavity for pathologic change. No significant complications occurred during the hysteroscopic evaluations.

      Conclusion

      This is the largest study to date conducted to hysteroscopically evaluate the post-ablation uterine cavity. Uterine cavity assessment with in-office hysteroscopy one year after the use of the Cerene® Cryotherapy Device is attainable, enabling both diagnostic and therapeutic procedures within the endometrial cavity.

      Key Words

      Introduction

      Approximately one-half million global endometrial ablation (GEA) procedures are performed annually in the United States, which has been credited as a significant contributor to the dramatic decline in hysterectomy rates in the United States over the past 15 years (1-3). Compared with hysterectomy, GEA is less invasive, has shorter operating times, less blood loss, fewer complications, reduced financial cost, comparable short term patient satisfaction rates, allows return to normal activities within 48 hours, and may be performed in the office setting (4-9). Despite these benefits, the risk of post-ablative intracavitary scarring after GEA remains a significant disincentive, preventing both patients and physicians from choosing GEA as an option for the treatment of heavy menstrual bleeding (HMB).
      Furthermore, intracavitary scarring can lead to long term complications, such as central or cornual hematometra, post ablation tubal sterilization syndrome (PATSS), retrograde uterine bleeding potentially leading to the development of endometriosis, and the possible delay in diagnosis of an endometrial cancer (10). In particular, radiofrequency ablation (RFA), which makes up the majority of GEA (73%) performed annually in the US, has been associated with a high rate of post ablation intrauterine synechiae which may limit the ability to adequately evaluate the endometrium by biopsy or hysteroscopy to address subsequent abnormal uterine bleeding (AUB) (1, 11-14). For women who choose GEA as a treatment for HMB and develop intracavitary scarring, subsequent AUB can result in more invasive surgery such as hysterectomy for both definitive diagnosis and treatment (1, 10, 15-17). Previous publications indicate that cryoablation provides a comparatively more favorable tissue healing response resulting in preserved access to the endometrial cavity by minimizing the development of significant intrauterine adhesions (18-22). Therefore, we theorized that the Cerene® Cryotherapy Device (Channel Medsystems, Inc.) (Figure 1) would provide an endometrial ablation option where access to the endometrial cavity would be consistently preserved.
      The Cerene® device, approved by FDA in 2018, is a single use, disposable device that uses cryothermal energy to achieve ablation depths of 5 to 9mm throughout the uterine cavity. The Cerene® device is able to treat uterine cavities ranging in length between 2.5 and 6.5 cm with corresponding uterine sounding up to 10 cm. Cryothermal energy is provided by a liquid-to-gas phase change of nitrous oxide (N2O), which occurs at -86°C. During the 2½ minute treatment cycle, liquid N2O is infused into a polyurethane liner where it converts into gas. The international pivotal trial demonstrated no serious adverse device effects (SADE) (23). At month 12 post treatment, diagnostic hysteroscopy was performed to determine uterine accessibility and the ability to evaluate the post-ablation cavity.

      Materials and Methods

      The CLARITY Study (CLinical Study to Evaluate the Safety And Effectiveness of the CeRene DevIce to Treat HeavY Menstrual Bleeding) was a pivotal study to evaluate the safety and effectiveness of the Cerene® Device. A total of 242 subjects were treated across 11 sites. The two primary endpoints, safety and effectiveness, were measured at 12 months post endometrial ablation. These endpoints and a detailed description of the methods of the CLARITY Study have been previously reported (23).
      As a secondary endpoint to the CLARITY study, an attempt was made to schedule each subject available at the Month 12 follow-up assessment (N=230) for a diagnostic hysteroscopy in order to determine if intracavitary access and the ability to systematically assess the post-ablation uterine cavity were preserved. The characteristics of the subjects available for Month 12 hysteroscopy are listed in Tables 1 and 2. The subjects’ menstrual pattern was measured using the pictorial blood loss assessment chart (PBLAC) (24). Follicle stimulating hormone (FSH) was measured via blood laboratory test, and each subject was asked the question, “Does the subject suffer from painful cramping associated with menstruation (dysmenorrhea)?” at the Month 12 assessment. The answer choices on a 0-to-5-point scale ranged from “no symptoms” to “very severe”. Each investigator performed diagnostic hysteroscopy using his or her customary endometrial preparation, surgical technique, fluid management protocol, and clinical practice setting. The hysteroscopy setting for all of the sites in the USA, which included 175 subjects, was the office/clinic. The international sites, which included 48 subjects, performed hysteroscopy in an outpatient hospital setting. Each site investigator recorded the medications they employed for analgesia during the Month 12 hysteroscopy on a case report form. The investigator also recorded his/her ability to access (pass the hysteroscope through the internal os) the uterine cavity, visualize the uterine cavity (yes or no), and describe the type and extent of the cavity affected by intrauterine adhesions. Based upon the hysteroscopic view, investigators were asked to answer two questions: 1) Were they satisfied that the endometrium could be visualized sufficiently to evaluate for pathologic change? and 2) Could they obtain a biopsy anywhere within the cavity? These questions were not validated prior to implementation of the study.
      Table 1CLARITY Study; Demographics of Subjects Scheduled for Month 12 Hysteroscopy
      Subject Characteristics
      CharacteristicBASELINE (n= 223)
      Age, years
      Mean ± SD (median)40.0 ±5.1 (41.0)
      Range (min, max)25, 50
      Age 25-40, n (%)110 (49.3)
      Age >40-50, n (%)113 (50.7)
      Ethnicity
      Hispanic or Latino41 (18.0%)
      Not Hispanic or Latino182 (82.0)
      Race
      American Indian or Alaska Native3 (1.3%)
      Asian0 (0.0%)
      Black or African American6 (2.7%)
      Native Hawaiian or other Pacific Islander0 (0.0%)
      White173 (77.6%)
      Other (does not identify with any category)41 (18.4%)
      BMI, kg/m2
      Mean ±SD (median)29.7 ± 6.7 (28.3)
      Range (min, max)16.7, 50.5
      BMI=body mass index; SD=standard deviation.
      Table 2CLARITY Study; Other Characteristics of Subjects Scheduled for Month 12 Hysteroscopy
      CharacteristicBASELINE (N=223)Month 12 (N =223)
      PBLAC scorePBLAC
      Mean ± SD (median)357.9 ± 340.4 (289.0)Mean ± SD (median)49.1 ± 60.6 (29.0)
      Range (min, max)150.0, 4506.5Range (min, max)0.0, 359.0
      Percent reduction
      Mean ± SD (median)84.5% ± 16.8 (89.7)
      Range (min, max)16.8, 100.0
      Point reduction
      Mean ± SD (median)309 ± 249 (335.6)
      Range (min, max50, 4454
      DysmenorrheaDysmenorrhea
      None25 (11.2%)None71 (31.8%)
      Very Mild14 (6.3%)Very Mild69 (30.9%)
      Mild21 (9.4%)Mild40 (17.9%)
      Moderate71 (31.8%)Moderate30 (13.5%)
      Severe64 (28.7%)Severe10 (4.5%)
      Very Severe28 (12.6%)Very Severe3 (1.3%)
      FSH (IU/L) Age > 40 years (N=113)FSH (IU/L) at Month 12; N=125
      6 patients with FSH > 30
      Mean ± SD (median)7.8 ± 5.5 (6.3)Mean ± SD (median)11.3 ± 14.9 (6.7)
      Range (min, max)0.2, 29.1Range (min, max)1.3, 132.4
      FSH=follicle-stimulating hormone; PBLAC=pictorial blood loss assessment chart; SD=standard deviation.
      low asterisk 6 patients with FSH > 30
      Findings were scored using a modified American Fertility Society (AFS) score for intrauterine adhesions, which has a combined range of 0 to 8 (25). The AFS score includes the extent of uterine cavity involved by adhesions (< 1/3, 1/3 to 2/3, > 2/3), the type of adhesions observed in the uterine cavity (filmy, filmy and dense, dense) and menstrual pattern (normal, hypomenorrhea, amenorrhea). This assessment tool did not include the menstrual pattern. The modified AFS scoring classification (Table 3) provided a benchmark by which clinicians could evaluate the uterine cavity. A lower score indicates less involvement of the uterine cavity by adhesions.
      Table 3Modified AFS Scoring Classification
      Extent of Cavity Involved< 1/31/3 to 2/3> 2/3
      Score124
      Type of AdhesionsFilmyFilmy & DenseDense
      Score124
      Modified AFS scores in the range of 0-2 and 3-8 were used to perform subgroup analysis to evaluate for association between uterine fibroids, dysmenorrhea (ranges 0-2 and 3-5), PBLAC score (ranges 0-75 and >75), and subject's description of her period (ranges: no period, lighter than normal period, normal period, heavy period).
      Uterine cavity access and evaluation data were tabulated. Descriptive statistical analyses were performed using SAS® software, version 9.3; and Microsoft Access version 2007.
      All required IRB approvals were obtained prior to study enrollment at each participating institution. The study protocol was registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/results?cond=&term=NCT02842736&cntry=&state=&city=&dist=), and the trial was conducted in accordance with the protocol.

      Results

      Two hundred and thirty (230) subjects were available for their Month 12 follow-up visit and attempts were made to schedule and complete the diagnostic hysteroscopy. Two hundred twenty-three subjects (223) were ultimately scheduled for hysteroscopy, and the remaining seven subjects encountered scheduling conflicts or illness precluding their Month 12 hysteroscopy (Figure 2). The demographics for the study subjects that were scheduled for hysteroscopy are listed in Table 1. Additional characteristics for the study subjects provided in Table 2 include menstrual bleeding status, dysmenorrhea symptoms, and FSH value.
      Overall, the 223 subjects who had an attempted hysteroscopy tolerated the hysteroscopy very well. Fifty-eight (26%) patients did not require any analgesia or paracervical block (PCB); 79 (35.4%) received a PCB alone and 42 (18.8%) only received oral medication such as a nonsteroidal anti-inflammatory drug (NSAID) and/or anxiolytic and/or narcotic (Table 4). No significant complications occurred during the hysteroscopic evaluations.
      Table 4Medications Administered prior to Month 12 Hysteroscopy
      Anesthesia/Medications Used During Treatment (N=223)N%
      No medication required5826.0%
      Paracervical block (PCB) only7935.4%
      NSAID and/or Anxiolytic and/or Narcotic only (No PCB)4218.8%
      PCB with NSAIDs62.7%
      PCB with Narcotics and/or Anxiolytics3415.3%
      PCB with IV Sedation41.8%
      General anesthesia requiring airway management00%
      The uterine cavity was visualized in 204 of 223 (91.5%) subjects. It was not visualized in 16 (7.2%) due to intrauterine adhesions (n=14), technical difficulties (n=1), or menstruation (n=1). Uterine cavity access was not possible in 3 (1.3%) subjects due to pain intolerance (n=2) and cervical stenosis (n=1).
      Investigators were asked to answer two questions after performing hysteroscopy: 1) Were they satisfied that the endometrium could be visualized sufficiently to evaluate for pathologic change? and 2) Could they obtain a biopsy anywhere within the cavity? Investigators reported satisfaction with endometrial evaluation for pathologic change in 95.6% (195/204) of subjects where the uterine cavity was visualized. Additionally, investigators reported that the entire cavity was accessible for endometrial biopsy in 87.3% (178/204) of these subjects (Table 5). Both ostia were visualized in 160/204 (78.4%) of subjects, and the majority of cavities (127/204, 62.2%) had either no or filmy intrauterine adhesions.
      Table 5Investigator Evaluation of the Uterine Cavity
      Assessment (N=204)
      Uterine cavities that could be visualized
      Yes Responses (%)
      Overall, was the Investigator satisfied that he/she was able to adequately visualize the endometrium to evaluate the uterine cavity for pathologic change?195 (95.6%)
      Would the Investigator be able to direct a biopsy anywhere within the uterine cavity?178 (87.3%)
      low asterisk Uterine cavities that could be visualized
      Among the 204 subjects where the cavity could be visualized, 148 (72.5%) had a modified AFS score of 3 or less, 121 (59.3%) had a combined modified score of 2 or less, and 80 (39.2%) subjects had a modified score of 0 (Table 6). Among the 14 subjects where the cavity could not be visualized due to adhesions the average modified AFS score was 6.6. Analysis of selected subgroups did not demonstrate any association between the modified AFS score and the presence of a uterine fibroid(s) (n=37), dysmenorrhea, PBLAC score, and subject's description of her period.
      Table 6Modified AFS Scores (N=204)
      Modified AFS ScoreN
      080 (39.2%)
      10 (0%)
      241 (20.1)
      327 (13.2)
      423 (11.3)
      510 (4.9%)
      617 (8.3%)
      70 (0%)
      86 (2.9%)
      Among subjects where the cavity was visualized, unless at least two-thirds of the cavity was involved with adhesions, there was no association between the type of intrauterine adhesions and the extent of cavity involvement. When involved to this extent, at least 50% of the adhesions were dense (Table 7).
      Table 7Type of Uterine Adhesions Present and Extent of Uterine Cavity Involvement Using Modified AFS Classification
      Uterine Adhesion Type (N=204)Uterine Cavity Involvement
      None<1/31/3 to 2/3>2/3Total
      No adhesions8000080 (39.2%)
      Filmy0416047 (23.0%)
      Filmy and Dense02123650 (24.5%)
      Dense01011627 (13.2%)
      TOTAL80724012204 (100%)

      Discussion

      The Cerene® Device provides consistent access to the endometrial cavity one year after performance of endometrial cryoablation. Preservation and accessibility of the endometrial cavity should aid in evaluation and treatment of women who experience abnormal uterine bleeding or new pelvic pain after an ablation procedure, addressing the challenges frequently observed after endometrial ablation using heat-generating electrosurgical methods (23). Another endometrial ablation device using water vapor to ablate the endometrium showed similar hysteroscopic findings within the post-ablation uterine cavity in 70 subjects (26). Our study is the largest cohort of subjects to date having undergone hysteroscopic evaluation of the uterine cavity post-endometrial ablation. Overall, there is a paucity of peer reviewed literature concerning access of the uterine cavity after endometrial ablation and the ability to perform a directed endometrial biopsy. Several studies consistently report that hysteroscopic evaluation of the uterine cavity could not be performed due to contracture and wide spread adhesions and/or that endometrial biopsy could not or could only be performed with limited success (11-14). For many presently marketed GEA technologies, hysteroscopy, and therefore directed endometrial sampling for accurate diagnosis of endometrial histopathology, may not be feasible after endometrial ablation (27-30). Additionally, if hysteroscopy can be performed, it can be painful and complex in post-ablation cavities. In some of these women, hysterectomy is the only reasonable alternative for the inability to adequately sample the endometrium (29). In the study of the Cerene® Device, investigators reported that, in 95.6% of subjects where the cavity could be visualized, the ability to systematically assess the uterine cavity was preserved at the time of the Month 12 hysteroscopic evaluation. Subjects also tolerated the hysteroscopic assessment of the cavity well, requiring very limited management for pain control. Thus, when women undergo treatment with the Cerene® device, it should be possible in most cases to adequately and comfortably evaluate the endometrial cavity in order to diagnose and treat intrauterine conditions.
      Furthermore, a number of publications recognize the complications arising from the formation of intrauterine adhesions following heat-based endometrial ablation, often resulting in the need for additional surgical interventions such as hysterectomy (2, 13, 15-17). Of the 230 subjects available for a Month 12 follow-up visit, 97 subjects had undergone a tubal ligation prior to cryoablation. None reported symptoms of PATSS or hematometra. These conditions often arise 6-10 months post-treatment and can lead to more invasive surgical procedures (13). This is another important surrogate marker reflecting the uncommon occurrence of extensive dense adhesions after Cerene® cryothermal endometrial ablation, particularly in the lower uterine segment, that cause hematometra and subsequent PATSS.
      Cryoablation creates a different tissue effect with data supporting evidence of a decreased risk of adhesion formation. Tissue repair begins quickly after thawing and there is an immediate infiltration of inflammatory cells (lymphocytes and macrophages) into the necrotic tissue. Over the following weeks to months, the necrotic tissue is slowly debrided and replaced by a fibrous scar of collagen. The preservation of the collagen matrix architecture of the tissue during freezing provides a distinct asset to tissue repair and healing. Cryoablation contrasts with heating in which a similar response is noted in the periphery, but without clear demarcation as with freezing. The interior of the heated target zone is characterized by charring, boiling, and even popping. Thermal denaturation results in the complete loss of the tissue architecture that interferes with wound repair and tissue remodeling (31).
      The authors acknowledge several limitations of this study including the lack of precisely identified anatomical locales of the intrauterine adhesions. The modified American Fertility Society score is a descriptive methodology for objectively evaluating the uterine cavity for adhesions and has not been formally validated as a tool related to clinical outcomes. Also, we are not aware of a standardized criteria for complete or partial hysteroscopic visualization of the uterine cavity. Investigators determined if the cavity was “visualized” according to their judgement without other set criteria required. This potentially results in a bias toward a too liberal or too conservative assessment of cavity access depending on the investigators perspective. However, all investigators were expert in the performance of hysteroscopy and the answers to the questions reported in Table 5 give further clinical relevance to what could be evaluated when the cavity was “visualized.” Moreover, the investigators’ uterine cavity assessments were not evaluated by an external expert. We were unable to include the menstrual pattern variable from the AFS score for intrauterine adhesions because the PBLAC scores that correspond to the AFS classifications of normal and hypomenorrhea menstrual patterns have either not been validated or the validation has not been published to our knowledge. Additionally, the AFS menstrual pattern classification does not include a heavy menstrual bleeding pattern. Any association between the modified AFS score and the presence of a uterine fibroid(s) could not be established due to the small number of subjects with myomas. We acknowledge that 19 of the 242 (7.8%) subjects who underwent endometrial ablation were unavailable for the month 12 hysteroscopy and that further comment on hysteroscopic evaluation of their uterine cavities would be speculative.
      The strengths of this study are that it included all subjects available at the Month 12 follow-up visit (N=230) along with the utilization of the modified AFS classification for a standardized assessment of intrauterine adhesions. Of these, 89% (223) returned for their hysteroscopy, resulting in a robust dataset. In addition, when evaluating the association between menstrual bleeding and uterine cavity adhesions, the menstrual diary score (PBLAC) provided a more objective measure of menstrual bleeding at Month 12 than the woman's description of her last menstrual period. Finally, the study demonstrates that office hysteroscopy after endometrial ablation with the Cerene® device can be performed in a widely generalizable patient population.

      Conclusion

      For the vast majority of patients who undergo endometrial ablation with the Cerene® device, the ability to systematically assess the uterine cavity is preserved one year after treatment. After Cerene® treatment, most patients who require evaluation of the endometrial cavity via hysteroscopy, to diagnose and treat intrauterine conditions, can tolerate this procedure in the office setting.

      Acknowledgements

      a. Channel Medsystems Inc. for sponsoring the study and coordinating statistical support from Gordon and Associates, Inc. b. Site Primary Investigators (PI): Bruce Allan, MD PhD, Claude Fortin, MD, Scott Schade, MD, Cindy Basinski, MD, Todd Rumsey, MD, Gerard Reilly, MD, Randall Kahan, MD, Eric Hawes, MD, and Amy Brenner, MD.

      Declarations of Interest

      None.

      Funding Source

      Channel Medsystems, Inc., Emeryville, CA.

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