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Evaluation of two alternative ablation treatments for cervical pre-cancer against standard gas-based cryotherapy: a randomized non-inferiority study
  1. Miriam Cremer1,2,3,
  2. Karla Alfaro2,
  3. Jillian Garai3,
  4. Manuel Salinas4,
  5. Mauricio Maza2,
  6. Alberto Zevallos5,
  7. Luis Taxa5,
  8. Ana C Diaz4,
  9. Philip Castle6,
  10. Todd A Alonzo7,
  11. Rachel Masch3,
  12. Montserrat Soler1,3,
  13. Gabriel Conzuelo-Rodriguez3,
  14. Julia C Gage8 and
  15. Juan C Felix9
  1. 1 OB/GYN and Women's Health Institute, Cleveland Clinic, Cleveland, Ohio, USA
  2. 2 Basic Health International, San Salvador, El Salvador
  3. 3 Basic Health International, New York City, New York, USA
  4. 4 Instituto Salvadoreño del Seguro Social, San Salvador, El Salvador
  5. 5 Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
  6. 6 Yeshiva University Albert Einstein College of Medicine, Bronx, New York, USA
  7. 7 University of Southern California, Los Angeles, California, USA
  8. 8 National Cancer Institute, Bethesda, Maryland, USA
  9. 9 Medical College of Wisconsin, Milwaukee, Wisconsin, USA
  1. Correspondence to Dr Montserrat Soler, OB/GYN and Women's Health Institute, Cleveland Clinic, Cleveland, OH 44195, USA; solerm{at}ccf.org

Abstract

Introduction Gas-based cryotherapy is the conventional ablative treatment for cervical pre-cancer in low-income settings, but the use of gas poses significant challenges. We compared the depth of necrosis induced by gas-based cryotherapy with two gas-free alternatives: cryotherapy using CryoPen,and thermoablation.

Methods We conducted a five-arm randomized non-inferiority trial: double-freeze carbon dioxide (CO2) cryotherapy (referent), single-freeze CO2 cryotherapy, double-freeze CryoPen, single-freeze CryoPen, and thermoablation. Subjects were 130 women scheduled for hysterectomy for indications other than cervical pathology, and thus with healthy cervical tissue available for histological evaluation of depth of necrosis post-surgery. The null hypothesis was rejected (ie, conclude non-inferiority) if the upper bound of the 90% confidence interval (90% CI) for the difference in mean depth of necrosis (referent minus each experimental method) was <1.14 mm. Patient pain during treatment was reported on a scale of 0 (no pain) to 10 (worst pain).

Results A total of 133 patients were enrolled in the study. The slides from three women were deemed unreadable. One patient was excluded because her hysterectomy was postponed for reasons unrelated to the study, and two patients were excluded because treatment application did not follow the established protocol. For the remaining 127 women, mean depth of necrosis for double-freeze CO2 (referent) was 6.0±1.6 mm. Differences between this and other methods were: single-freeze CO2 = 0.4 mm (90% CI −0.4 to 1.2 mm), double-freeze CryoPen= 0.7 mm (90% CI 0.04 to 1.4 mm), single-freeze CryoPen= 0.5 mm (90% CI −0.2 to 1.2 mm), and thermoablation = 2.6 mm (90% CI 2.0 to 3.1 mm). Mean pain levels were 2.2±1.0 (double-freeze CO2 cryotherapy), 1.8±0.8 (single-freeze CO2 cryotherapy), 2.5±1.4 (double-freeze CryoPen), 2.6±1.4 (single-freeze CryoPen), and 4.1±2.3 (thermoablation).

Discussion Compared with the referent, non-inferiority could not be concluded for other methods. Mean pain scores were low for all treatments. Depth of necrosis is a surrogate for treatment efficacy, but a randomized clinical trial is necessary to establish true cure rates.

  • cervix uteri
  • genitalia, female
  • gynecology
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Footnotes

  • Contributors All authors contributed significantly to the connection and design of the trial, or the analysis, interpretation, and drafting of the manuscript.

  • Funding Study funded by NIH/NCI Award UH2CA189833 to Miriam Cremer (NCT02914448).

  • Competing interests MC is president/founder of Basic Health International, a trainer for Nexplanon, and a speaker for Merck. PEC has received cervical screening tests and diagnostics at a reduced or no cost for research from Roche, BD, Cepheid, and Arbor Vita Corporation. JCG declares that the National Cancer Institute has received cervical cytology and HPV testing results for independent NCI-directed studies at reduced or no cost from Roche and Becton Dickinson. MS is a former employee of Basic Health International.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Data availability statement Data are available upon reasonable request.

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