Efficacy and Tolerability of Thermocoagulation Treatment of High-Grade Cervical Intraepithelial Neoplasia

Purpose: Cervical cancer is still one of the main causes of cancer and mortality in women, especially in low- and middle-income countries, although it is a completely preventable disease through the detection and treatment of pre-cancer lesions. We evaluated the efficacy and tolerability of thermocoagulation treatment of high-grade cervical intraepithelial neoplasia (CIN 2 and 3). Methods: We evaluated 115 women with high-grade cervical intraepithelial neoplasia, 54 with CIN 2 and 61 with CIN 3, confirmed by biopsy and without previous treatment, from January 2016 to December 2018, under-going thermocoagulation treatment at the Lower Genital Tract Pathology and Colposcopy Service of the Hospital de Clinicas de Porto Alegre , Porto Alegre, Brazil. Results: The mean age was 33.11 years (SD = 9.83) for CIN 2 and 35.28 years (SD = 7.97) for CIN 3 patients. Treatment efficacy was 90.8% in CIN 2 and 94.9% in CIN 3 cases. Pain was the main symptom


Introduction
Cervical cancer occurs mainly in less developed countries (85% of cases), being the fourth most common type of cancer among women worldwide. It is still the second most common cause of death and cancer in the female population in low-and middle-income countries [1]. It is responsible for about 311,000 deaths per year worldwide [2]. Mortality varies across different regions of the world, with rates ranging from less than 2 per 100,000 women in West Asia to 27.6/100,000 in East Africa [3].
This type of cancer is a completely preventable disease through the detection and treatment of pre-invasive lesions, cervical intraepithelial neoplasia (CIN) [4]. However, it is still a great challenge to carry out an organized screening and adequate treatment of all premalignant lesions diagnosed in the world [5].
There are several therapeutic options that can be used, depending on variables such as the possibility of access to the proposed treatment, histological degree of the lesion and its extension, professional experience, degree of cervical involvement, concomitant with other pathologies or pregnancy, age of the patient and reproductive desire. The latter should be considered in young women, since unfavorable obstetric outcomes are observed in some women after some types of treatments [6] [7].
In this context, there is a need to implement treatments that do not require super-specialized labor, as it would be of little use to offer treatments considered of technical excellence, where there are neither physical nor human resources to carry them out [8]. Simple treatments that can be implemented in regions with difficult access and easy follow-up after treatment would be preferable [9]. In the 1980s and 1990s, the use of ablative (destructive) treatment methods changed the belief that surgical procedures and histological specimens are always needed for cases of high-grade squamous intraepithelial lesions (HSIL). So much so that nowadays the World Health Organization (WHO) recommends these treatments in places with low income [10].
Destructive or excisional treatment must be individualized for each case. In both approaches, when performed properly, the success rate is around 90% [11] [12] [13]. Ablative treatment can be thermocoagulation, cryotherapy, electrocautery (thermal cautery) and chemical cauterization. The most used excisional methods are excision of the transformation zone and conization, which can be performed with a scalpel (cold knife conization), laser, electric procedures or high-frequency surgery [14]. The disadvantage of destructive methods is the ab- about the possibility of a (micro) invasion, the treatment must necessarily be excisional [7]. The risk of progression from a cervical lesion to cancer increases according to its severity, going from <1% for CIN 1 to 5% for CIN 2 [15].
The most discussed ablative treatment in recent years is thermocoagulation, also known as cold coagulation or thermoablation [16]. The method uses a simple and inexpensive device and is easy to apply, with little discomfort for the woman and with high efficiency in resolving the lesion, and is currently recommended by the WHO, mainly for low-income and middle-income countries [17].
Thermocoagulation has been used all over the world, but more frequently in the United Kingdom (UK) from the 1980s [18] [19] [20]. It is indicated for any non-pregnant woman with CIN 2/3, when the entire lesion is visible, the squamous-columnar junction is also fully visible, affecting up to 75% of the cervix and without extension to the endocervical canal [21] [22]. The procedure is quick, between 20 -60 seconds per application and reaches a depth of 4 -7 mm [23]. Temperature conduction in muscle tissue is relatively poor, therefore anesthesia is not necessary for most patients and complications and adverse effects are usually infrequent [24].
Several studies conducted recently have demonstrated the good results of thermocoagulation in the treatment of HSIL, with little need for re-treatment [25]. Efficacies range from 77% -92% for CIN 2 and 85% for CIN3 with infrequent side effects [26] [27].
The aim of this study was to evaluate the efficacy and tolerability of the ablative method of thermocoagulation with the Semm device in the treatment of women with high-grade squamous intraepithelial lesion (CIN 2/3) confirmed by biopsy, followed up for 24 months.

Methods
This study protocol was reviewed and approved by the Research Ethics Committee of the Hospital de Clinicas de Porto Alegre (IRB00000921-Project 10-0126). All study participants signed the Informed Consent Form.

Study Design and Participants
The sample evaluated consisted of 115 women aged between 25

Procedures
All women underwent thermocoagulation treatment under colposcopic vision with the Semm'sthermocoagulator device (WISAP® brand by Medical Technology, Sauerlach, Germany). The temperature was calibrated at 100˚C and the heated probe was placed over the transformation zone with CIN 2 or CIN 3 for 45 -60 seconds. Two or more applications (a maximum of 5 in total) were performed according to the size of the lesion. Participants were observed for one hour after treatment to assess any adverse events after the procedure.
Instructions about post-treatment care and symptoms that could occur, such as cramping, clear or serosanguineous watery discharge, or a little blood for up to four weeks after treatment were given to all patients. Women were advised not to undergo vaginal showers and were advised to immediately notify the research team if they developed fever (>37.8˚C) or bleeding for more than 2 days, severe abdominal pain or purulent discharge.

Outcomes
All study participants were followed up and re-evaluated at 6, 12 and 24 months after the procedure. At 12 and 24 months post-treatment, patients underwent cytopathological examination and colposcopy to assess relapse or recurrence of HSIL or even the progression of the disease. A new thermocoagulation treatment was performed if the biopsy revealed the presence of a CIN 2/3. Possible complications of the procedure, such as fibrosis, cervical canal stenosis or infection, were also evaluated.

Statistical Analysis
To

Results
All women referred to the Lower Genital Tract Pathology and Colposcopy Service of the Hospital de Clinicasde Porto Alegre with a CIN 2/3 were submitted to an assessment of socio-demographic characteristics and a new analysis with colposcopy, cytology and biopsy and were divided in separate groups, those with CIN 2 and those with CIN 3.

Analysis of CIN 2 Group before Treatment
Regarding the group with CIN 2, the mean age of women was 33.1 years (standard deviation of 9.8 years), 35.2% were married, 55.6% had an education level of five to ten years and 64.8% had an income of one to three minimum wages.
Most women (74.1%) received only one application of thermocoagulation with the SEMM device and most were asymptomatic during the procedure (51.9%).
When any symptom was present, pain was the most frequent symptom (27.8%), and its intensity was not categorized (Table 1).

Analysis of CIN 2 Group after Treatment
After treatment, cytology showed a negative result for most women at all visits, with 83.3% at 6-month follow-up, 79.6% at 12-month follow-up, and 85.1% at 24-month follow-up. Residual lesion on biopsy was observed in only five women at 12 months (9.3%), all CIN 1 and also in five women at the 24-month assessment (9.2%), with three CIN 1 (5.5%) and two with CIN 2/3 (3.7%

Analysis of CIN 3 Group before Treatment
In relation to the group with CIN 3, the mean age of women was 35.  level of five to ten years and 52.5% had an income of one to three minimum wages. Most women needed only one thermocoagulation (44.3%) or two (41%).
Pain was the most frequent symptom associated with the procedure, having been observed in 49.1%, and its intensity was not categorized (Table 3).

Analysis of CIN 3 Group after Treatment
After

Outcome 24 Months after the Treatment
In an analysis of association between the variables before treatment and the      Table 5). This same analysis in the CIN 3 group did not show a significant association in any variable analyzed in relation to the outcome at 24 months after treatment (Table 6).
To analyze the factors associated with the presence of lesion 24 months after treatment, logistic regression models were adjusted, and the selection of variables was performed using the Stepwise Method. In the multivariate analysis of factors associated with the presence of lesion 24 months after CIN 2 treatment, we observed that the older age was the greater chance of lesion 24 months after treatment, however this result was not statistically significant. The other variables did not show a significant value in the multivariate analysis and were not selected for the univariate analysis. Therefore, there was no significance of the possible factors associated with the presence of residual lesion 24 months after the treatment of CIN 2 (Table S1). When we evaluated the CIN 3 group, in relation to factors associated with the presence of residual lesion 24 months after treatment, we observed that the chance was lower for women with more than one minimum wage and that the chance was higher for women with more than ten years of education and who had had more than one application of thermocoagulation, however these results were not significant (Table S2).

Discussion
Thermocoagulation has been shown to be a good option for the treatment of with thermocoagulation, the result was similar, with an 84.2% resolution for CIN 2/3, also based on cytology, colposcopy and biopsy, when necessary [12]. In the meta-analysis by Randall et al., which included more less-developed countries, this percentage of efficacy for curing CIN 2/3 was higher, 93.8% [29].
These results are similar to those observed with excisional treatments (cold conization, with 90% -94% success rate, high frequency surgery, in 91% -98%, and laser conization with 93% -96%) [31], considered as treatment first choice for these cases of high-grade lesions, but requiring specialized training [8] [31]. For places with less infrastructure for this type of treatment, ablative treatments (thermocoagulation, cryotherapy or electrocautery) are options that should be evaluated, especially in young women without children, as they have fewer complications that can interfere with fertility, as occurs with excisional methods [8].
The device used in this study may bring advantages to the thermocoagulation procedure, as it is lightweight and portable, and runs on electricity or battery.
Cryocauterization requires a heavy cylinder and gas replacement, not always available in many low-resource locations. Electrocauterization usually requires anesthesia, as it is very uncomfortable [8] [12] [31]. The WHO classifies thermocoagulation as 1.A evidence for the treatment of CIN 2/3 lesions [30].
We had no recurrence of cytology with high-grade lesion after six months of CIN 2/3 treatment. Papoutsis et al. observed recurrence within six months in 2.8% of women with CIN 2/3 treated with thermocoagulation. In the 12-month follow-up, our recurrence was 3.3% and for this same author a little less, 1.2% [28]. In any event, this recurrence is much smaller than those reported for excisional treatments, which range from 3.5% -25% [32]. However, this difference may be a consequence of the variability of the study methodology, with different definitions of recurrence, inclusion and exclusion criteria from the study, lesion extension and evaluation with cytology or histopathology or both [33].
The number of thermocoagulation applications depends on the size of the lesion. Generally, more severe lesions tend to be more extensive than less severe ones, which is why the vast majority of CIN 2 were treated with just one application (74%), while CIN 3 required more applications, with two in 41% of the cases. The depth of the lesion is also proportional to its severity. The most frequent symptom associated with thermocoagulation was pain, especially when it was necessary to perform more than one session of the procedure, as observed in women with CIN 3, where 49% reported this discomfort, while in women with CIN 2, where the majority did only one session, pain was reported in only 28% of the cases. Most studies refer to pain as the main symptom associated with the method, ranging from 3.5% (severe pain) to 25% (mild pain) [12]. Nessa et al., evaluating women treated in Brazil and India had a higher percentage of pain during the procedure, 52% [13].
Cervical stenosis or its incompetence is the most frequent long-term effect of traditional methods of treating high-grade cervical lesions, especially with excisional methods [12]. With thermocoagulation, we did not observe any cases of stenosis, which is important for the maintenance of fertility in these women, most of whom are in menacme. Isthmus-cervical incompetence occurs in excisional methods, depending on the extent of removal of the lesion. The 2017 Cochrane Review showed an increased risk of preterm birth associated with excisional treatments (RR = 1.87; 95% CI: 1.64 -2.12) when compared to ablative methods (RR = 1.35; 95% CI: 1.20 -1.52) [34].
Our study had some limitations. Despite the small sample size, the 24-month follow-up was sufficient to robustly assess the effectiveness of thermocoagulation in the treatment of CIN 2/3. Another limitation was the non-inclusion of HPV-DNA tests as a criterion for healing the treated lesions. Currently, this test has been considered essential for the post-treatment follow-up of high-grade cervical lesions [19].
In conclusion, thermocoagulation with a Semm device showed excellent efficacy in the treatment of 2/3 CIN, with most women reporting little or no discomfort with the procedure. The method showed good tolerability, with high adherence to treatment follow-up in an observation period of up to 24 months, a time considered to be at risk for the onset of lesion recurrences.  Abbreviations: ASC-US: atypia of squamous cells of undetermined meaning; LSIL: Low-grade squamous intraepithelial lesion; HSIL: High-grade squamous intraepithelial lesion; VIA: Visual inspection after application of acetic acid 5%; VILI: Visual inspection after application of iodopovidone.