Treatment of cervical intraepithelial lesions

Precancerous cervical lesions precede the development of invasive cervical cancer by 10–20 years, making cervical cancer preventable if these lesions are detected and effectively treated. Treatment has evolved in the last few decades and now includes ablative options that can be performed in lower‐resource settings where surgical excision is not feasible or routinely available. Gas‐based cryotherapy, which freezes cervical tissue to induce localized necrosis, is the most commonly used ablative treatment. However, its implementation in low‐resource settings is difficult because the refrigerant gas can be difficult to procure and transport, and is expensive. New cryotherapy devices that do not require an external supply of gas appear promising. Thermal coagulation, which burns cervical tissue to induce necrosis, has become more widely available in the last few years owing to its portability and the feasibility of using battery‐powered devices. These two ablative treatments successfully eradicate 75%–85% of high‐grade cervical lesions and have minor adverse effects.


| INTRODUCTION
Although cervical cancer is preventable, more than half a million women around the world develop this disease every year, and around 270 000 die. 1 The main reasons for these unnecessary deaths are the lack of screening, management, and treatment for women at the target age for secondary prevention in many low-and middle-income countries (LMICs). In high-income countries, effective screening programs based on cervical cytology (Pap smear) resulted in a dramatic decrease in cases of cervical cancer, but these have not been established in low-resource areas because of inadequate infrastructure and insufficient numbers of skilled providers. Currently, there are several newer screening options for detecting precancerous lesions of the cervix. 2 However, there will be no impact on the burden of disease if screen-positive women do not receive care, including effective treatment for precancerous cervical lesions. 3 Today there is a better understanding of the natural history of human papillomavirus (HPV) infection and cervical cancer. Virtually all cases of cervical cancer are associated with chronic infection by carcinogenic HPV genotypes, which leads to the development of precancer in the epithelium of the cervix. 4 Lesions designated as cervical intraepithelial neoplasia (CIN) grade 3 (CIN 3) (formerly termed carcinoma in situ) and adenocarcinoma in situ (AIS) precede the development of invasive cervical cancer by 10-20 years and are the best proxies for cancer risk.  Table 1). It is unclear whether these differences are real, or are due to differences in screening methods, size of the lesions, or differences/errors in mea- surements. An analysis of these reports indicates that in order to eliminate close to 100% of CIN 3 lesions, the treatment should destroy or remove the epithelium up to 5 mm or 6 mm in depth. The depth of CIN 3 lesions, and therefore the depth of necrosis that should be achieved by treatment, is much greater than the thickness of the epithelium itself owing to involutions forming the cervical glands. Treatment for CIN 3 may be excisional or ablative. Excisional treatments remove all or part of the cervix; pathologists can evaluate the excised tissue and render final histological diagnosis. Ablative procedures do not remove the tissue, but instead destroy it in situ; therefore, no histological specimen is available for definitive diagnosis nor to reveal a cancer that needs additional follow-up and care.

| EVOLUTION IN THE TREATMENT OF PRECANCEROUS LESIONS
Treatment options for CIN 3 have changed over the last several decades, but some in the medical community have been unwilling to alter their practices and adopt the more conservative approach that ablative techniques provide. Hysterectomy was the treatment recommended for most CIN 3 lesions until the 1970s. This surgery requires general anesthesia and hospitalization for several days and is associated with significant morbidity. Cold-knife conization (CKC) is the surgical removal of the transformation zone of the cervix-the site of most precancerous lesions. Originally, this procedure was used for diagnosis prior to hysterectomy, but later was accepted as a definitive treatment if histological analysis of the specimen showed complete excision of the CIN 3 lesions. 7 Later, large loop excision of the transformation zone (LLETZ or loop electrosurgical excision procedure [LEEP] in the USA) was introduced for performing cone excision of the cervix, and it was rapidly adopted because it can be done using local anesthesia in outpatient clinics. 10 Both CKC and LEEP/LLETZ procedures provide tissue specimens for histological evaluation.
In the 1980s and 1990s, use of ablative treatments changed the prevailing belief that a surgical specimen and pathology evaluation were always required for appropriate care. It is now generally accepted that only a small percentage of women with precancerous lesions of the cervix need excisional procedures and the associated specimen for diagnosis, as reflected in WHO recommendations for ablation as the first option for treatment. 2 In the 1990s, the ablative technique of cryotherapy was introduced in a number of LMICs. This treatment uses a refrigerant gas (nitrous oxide or carbon dioxide) to cool a probe to very cold temperatures (−90°C). The cold probe is applied to the cervical tissue, freezing the cervical epithelium and inducing necrosis of the cells, thereby destroying the abnormal (HPV-infected) cells.
Another ablative technique, cold coagulation-now termed thermal coagulation-has been used for several decades in the UK but has not gained wide acceptance elsewhere, presumably because of the predominance of cryotherapy in low-resource settings. This treatment uses a heated probe applied in a manner similar to the cold probe used for cryotherapy, but instead burning the cervical epithelium to induce tissue necrosis. 11

| EFFECTIVENESS OF TREATMENTS FOR CIN 3
The main determinant for cure of CIN 3 is complete excision or destruction of the lesion. The mean depth of CIN 3 is between 1.2 and 1.4 mm, 8,9 but as noted above, the treatment should destroy tissue approximately 5-6 mm deep to eradicate these lesions. However, there could be other factors at work in the successful treatment of the CIN 3, such as the lateral size of the lesion that influences whether the margins of the lesion are clear (negative). 12,13 A randomized study in the USA reported a success rate of 84% when lesions were excised using LEEP, compared with 76% if the tissue was destroyed with cryotherapy. 14 The severity of the lesion (CIN 1-3) was not the main factor for a successful treatment; rather, the proper selection of treatment based on the size of the lesion appeared to be the key determinant. A study from a population-based program in a low-resource setting found a cure rate of 70% for CIN 3 lesions treated with cryotherapy at 1-year follow-up. 15 CIN 3 cases were selected for cryotherapy based on the size and location of the lesions, and large lesions were referred for excision with LEEP. A recent meta-analysis reported that cryotherapy cures 85%-92% of CIN 2 or CIN 3 (CIN 2-3) lesions. 16 A recent meta-analysis reported that thermal coagulation cures 85%-95% of CIN 2-3 lesions. 17 The studies in the meta-analysis  prospective follow-up of just 1-2 years, the information available shows that thermal coagulation is a very promising treatment. Thermal coagulation appears to cure most CIN 3 cases, and the time needed for the treatment is a fraction of that required for cryotherapy. The remainder of this review focuses on cryotherapy and thermal coagulation, whose features are presented in Table 2 and discussed below.

| EXPERIENCE WITH CRYOTHERAPY
Cryotherapy has several advantages that make it attractive in areas

| EXPERIENCE WITH THERMAL COAGULATION
Thermal coagulation has been in use for treating CIN 3 for the last 3-4 decades but, as noted above, most of the experience has been in the UK. 17,23 However, in the last 5 years, several LMICs have reported promising results with this method. Nessa et al. 24 implemented thermal coagulation in a study in Bangladesh for treatment of CIN 1-2 T A B L E 2 Comparison of features of cryotherapy and thermal coagulation as ablative treatments for precancer of the cervix.

Cryotherapy Thermal coagulation
Meta-analysis level evidence of efficacy: 85%-92% cure rates for CIN 2-3 lesions 16 Meta-analysis level evidence of efficacy: 85%-95% cure rates for CIN 2-3 lesions 17 Treatment requires 3-min freeze, 5-min thaw, 3-min freeze cycle or a single 5-min application Treatment requires single 30-45-s application Cleaning and sterilizing procedures are straightforward Cleaning and sterilizing procedures are straightforward Appropriate for nonphysician provider (ongoing continuing professional development and competency assessment should be built into VIA "screen and treat" program) Appropriate for nonphysician provider (ongoing continuing professional development and competency assessment should be built into VIA "screen and treat" programs) Weight of full gas cylinder 15-20 kg Weight of thermo-coagulator 3.6 kg (first generation) Requires regular purchase of compressed gas, supply of which is expensive and often erratic in many LMICs Initial cost outlay for machine plus probes but ongoing maintenance costs are low (in one Malawian setting, cost savings compared with cryotherapy were realized after 50 treatments) Electricity is not required Requires electricity (grid or battery-powered) Few reports of adverse events 16 Few reports of adverse events 17 lesions, but most cases treated with ablation were CIN 1, and LEEP was offered to most women with high-grade lesions. The authors reported that 95% of patients treated with either LEEP or thermal coagulation cleared the virus and were without evidence of CIN during follow-up.
Naud et al. 25 reported that in a group of 52 women, 84% with CIN 2-3 lesions were cured using thermal coagulation, and no serious adverse effects or complications were observed. Patients were selected for thermal coagulation if the WHO criteria for cryotherapy treatment were met. 19 Most women reported only mild pain. A study in Cameroon aimed to determine the percentage of screen-positive patients who met the criteria to undergo thermal coagulation, but did not evaluate cure rate. Among 121 screen-positive women, 91% were eligible for this treatment, and 99% received their treatment 1 month after screening. 26  when thermal coagulation is used in population-based programs in such settings and the treatment is delivered by trained healthcare workers. Next, there are some reports of pain from women receiving treatment, but detailed quantification is required to determine if local anesthesia should be recommended for some or all women. It is also important to evaluate cultural differences in the reporting of pain.

| VISUALIZING LESIONS FOR ABLATIVE TREATMENT
For the successful use of ablative techniques, the cervix must be visualized to determine which lesions can be successfully treated by ablation and which need LEEP/LLETZ or cancer management. 19 The

5.
Is the pain/discomfort from thermal coagulation greater than from cryotherapy? If so, can a local anesthetic be cheaply and effectively applied prior to treatment? One clinical trial addressed the question of using anesthesia prior to thermal coagulation and reported a significant reduction in pain. 35 However, the practicality (cost, procurement, and logistics) of using such an approach, especially in an LMIC setting, should be evaluated and may vary by location. Thermal coagulation has been used successfully for several decades in the UK, but experiences outside of high-income regions, especially in LMICs, are needed. Thermal coagulation is an attractive option because it requires minimal supplies, and because there are very low rates of complications. While it appears that sufficient evidence is available to deploy thermal coagulation for treatment, especially in LMIC settings with limited alternative therapeutic options, it will be important to conduct concurrent research studies and gather additional information on its effectiveness, safety, and acceptability, and on causes of treatment failures. Finally, even if the newer ablative treatments are available, many countries and health workers will not incorporate these options into their practices until recommendations are issued by international agencies-a process that is already underway-and national guidelines are updated.

AUTHOR CONTRIBUTIONS
All authors contributed to the development, drafting, and editing of this manuscript.