Evaluation of two alternative ablation treatments for cervical pre-cancer against standard gas-based cryotherapy: a randomized non-inferiority study

Abstract

IntroductionGas-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.MethodsWe 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).ResultsA 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).DiscussionCompared 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.

Comparison of the tissue interaction between thermal ablation and cryotherapy as treatment for cervical precancerous lesions in an ex-vivo model

“…Our findings are in line with the results of a clinical study conducted in Peru and El Salvador where patients planned for hysterectomy for benign indication were treated with cryotherapy or thermal ablation one day in advance [19]. This study evaluated the tissue necrosis depth 24 to 48 h after initial treatment.…”

Efficacy, acceptability and safety of ablative versus excisional procedure in the treatment of histologically confirmed CIN2/3: A systematic review

“…On the other hand, ablative methods destroy the TZ by freezing the epithelium down to −80°C (cryotherapy) or by heating the epithelium to 100°C (thermal ablation), causing tissue necrosis. Tissue necrosis following cold or heat injury is expected to ensure the treatment of high‐grade lesions extending to the crypts, although some studies have questioned the adequacy of the depth of treatment achieved following thermal ablation 30,31 . An inability to identify the squamocolumnar junction correctly, and hence a failure to select appropriate cases for ablation, may be another reason for the variability in treatment outcomes after ablation.…”

Locoregional Thermal and Chemical Tumor Ablation: Review of Clinical Applications and Potential Opportunities for Use in Low- and Middle-Income Countries

“…Some studies reported that superficial CO 2 cryotherapy achieved an average necrotic depth of 3.4 mm 24 hours after ablation, 90 , 91 while others reported depths of 6 mm 48 hours after ablation. 92 Although CIN1 and 2 can be adequately treated with shallower depths (2-4 mm), CIN3 and CIN extending into the endocervical canal require deeper depths (≥4.8 mm). 90 , 91 Because of the conflicting evidence, 93 it remains unclear if superficial cryotherapy can adequately treat more advanced CIN.…”