Summary
Background
Cryotherapy is currently standard practice for treating cervical pre-cancer in see and treat programmes in low and middle income countries. Because of well documented logistic difficulties with cryotherapy (e.g. need for and costs and supply chain difficulties of refrigerant gas, equipment failure, treatment duration >10mins), a lightweight, portable, battery-operated thermal ablator has been developed. This manuscript reports the results of a pilot randomized controlled trial (RCT) aimed at comparing thermal ablation (TA) using the new device to cryotherapy.
Methods
A prospective pilot RCT of cryotherapy vs TA vs Large Loop Excision of Transformation Zone (LLETZ) was undertaken in routine ‘screen and treat’ clinics in Lusaka, Zambia providing cervical screening using visual inspection with acetic acid (VIA). 750 non-pregnant women of reproductive age and eligible for ablative therapy were randomly allocated to TA, cryotherapy or LLETZ (250 in each arm) using computer-generated allocation. The randomization was concealed though the nurses providing treatment and the participants were unblinded. Treatment success, the primary endpoint, was defined as either HPV type-specific clearance among study participants positive for the same HPV type at baseline or negative VIA test at follow up, if the baseline HPV test was negative. Per protocol analyses were done. Enrolment for the full trial is ongoing. This is not an interim analys as the final analysis of the full trial will assess non-inferiority of the arms for the primary efficacy endpoint. The study is registered with the U.S. Clinical Trial Registry (https://clinicaltrials.gov/ct2/show/NCT02956239).
Findings
Very few participants complained of moderate to severe pain in any group arms [TA- 4 (1·6%) of 250; cryotherapy- 6 (2·4%) of 250]. Treatment success was observed in 120 (60·0%) of 200, 123 (64·1%) of 192 and 134 (67.3%) of 199 for the cryotherapy, TA and LLETZ arms respectively (p-value=0·31).
Interpretation
The results of this pilot would suggest that TA has treatment success proportion similar to cryotherapy without the practical disadvantages of cryotherapy in an LMIC setting. However, the study is under-powered to establish the similarity in efficacy due to small sample size. TA was very much preferred by care providers and was quicker. There was no difference in complication or discomfort frequencies between the study arms.
Keywords: Thermal ablation, cryotherapy, Large loop excision of transformation zone, efficacy, safety, randomized controlled trial
Introduction
Systematic high coverage and quality assured population screening with treatment of precursors to cervical cancer is highly effective. This is not surprising given that the conditions for an ideal screening test1 apply very precisely to cervical cancer. The disease has a long precancerous phase, effective easy screening tests are available, treatment of precursors is highly effective and the disease is common enough to justify the expense of population screening, even in low and middle income countries (LMICs).2 Large Loop Excision of the Transformation Zone or LLETZ,3 also known as loop electrosurgical excision procedure (LEEP), has become the standard treatment in most developed countries. Ablative techniques are simpler, safer and less technically demanding than LLETZ. The currently available ablative methods are cryotherapy and thermal ablation. The techniques have been described in detail elsewhere.4 Thermal ablation (TA) was previously known as cold coagulation in order to distinguish it from radical diathermy which reaches temperatures of approximately 300°C.5 TA functions by heating the Transformation Zone (TZ) epithelium, albeit to 100°C. Cold coagulation was thus clearly a misnomer.
Screening by visual inspection with acetic acid (VIA)6 followed by immediate treatment of VIA-positive women (screen and treat approach) can reduce the number of clinic visits by women and significantly improve treatment compliance.7 Cryotherapy was previously recommended by the World Health Organization (WHO) as the ablative method of choice for screen and treat programmes in LMICs.8 The method has the advantage of not requiring electricity, being simple to perform and being relatively effective. However, the costs and difficulties in ensuring uninterrupted supply of CO2 or N2O refrigerant gas, the long treatment duration (11 minutes) as well as difficulties with equipment failure have led to frustration with the method.9,10 Thermal ablation is an alternative ablation therapy to cryotherapy. Similar effectiveness has been demonstrated in a recent pooled analysis of published observational studies.11,12 It is a much faster treatment (20 to 40 secs) and requires no gas supply. Like cryotherapy it is simple to perform and almost any level of health care provider may perform it.
Consequently, the search for a simpler, affordable and mobile ablative treatment modality to incorporate into see and treat regimes in LMICs has led to the development of a cordless, lightweight and battery operated thermal ablator. The International Agency for Research on Cancer (IARC) and the University of North Carolina of USA collaborated with Liger Medical (Utah, USA) to evaluate the new device through a project funded by the National Institute of Health, USA (Grant number 1UH2CA202721-01). This study reports the pilot phase outcomes of a three-arm randomised controlled trial of TA using the new portable device compared to cryotherapy and to LLETZ in the context of a VIA-based screen-and-treat programme in Lusaka, Zambia. The primary objective of the study was to compare the success proportion of the three treatment methods. The study also aimed to estimate the proportion of over-treatment in a VIA- screen-and-treat programme based on the post-LLETZ histopathology results in the LLETZ arm.
Methods
Study design and participants
The prospective randomized unblinded study was approved by the research ethics committee at IARC, the University of North Carolina, the University of Zambia and the National Health Research Agency of Zambia. The study is registered with the U.S. Clinical Trial Registry (). The full trial protocol may be provided on request. In the trial, eligible VIA positive women were randomized to three arms to receive treatment using either the new TA device or the standard cryotherapy or LLETZ.
The study was conducted in a primary health clinic participating in the routine ‘screen-and-treat’ programme in Lusaka, Zambia, where VIA is performed by trained nurses to screen women between 25 and 49 years of age. Like many other LMICs, the access to quality assured cytology is very limited in Lusaka and we decided to adhere to the national protocol of VIA based screening followed by treatment of the screen positive women.
All women attending the study VIA screening clinic were counselled about the trial by a research nurse before going to the clinic room. VIA was performed as described by the IARC manual on VIA, and the VIA outcomes were categorized as negative, positive and suspected cancer.13 The examining nurses assessed the eligibility of VIA positive women for ablative treatment. These are that the TZ be a type 1 (completely ectocervical), not involving more than 75% of the ectocervix; not extending to the vagina and with no suspicion of cancer.4,14 Women who were found to be eligible for ablative treatment by the clinic nurse were invited to participate in the trial. Eligible women who agreed to take part in the study then gave written informed consent. Women fulfilling any of the following criteria were excluded:
Any reason whereby informed consent was not freely given
Not eligible for ablative treatment
Size of the lesion was such that it could not be covered by the largest cryotherapy probe
Pregnancy
Previous treatment to the cervix for any reason
Any genital tract cancer
As per routine practice in Zambia, all women undergoing VIA underwent HIV testing, unless a recent test result was available. Recently diagnosed HIV positivity required initiation of anti-retroviral therapy prior to cervical cancer screening.
Randomization and masking
Eligible participants were randomized at a 1:1:1 ratio to receive either TA or cryotherapy or LLETZ. All treatment was performed by one of four study nurses at the clinic. Request for allocation was obtained by the study nurse after checking the inclusion and exclusion criteria. Concealed allocation to a study arm was through computer-generated sealed envelopes at IARC, which were accessed by the study coordinator in the clinic. Study arm allocation was conveyed to the nurse just before performing treatment of eligible participants. Once a treatment arm had been allocated the study participant received a unique identifier number. Neither the nurse performing treatment nor the patient was blinded to the treatment allocation.
Procedures
The nurse collected a cervical sample prior to VIA using a Cervex-brush™ (Rovers Medical Devices, The Netherlands) in Preservcyt™ (Hologic INC, Marlborough, USA) medium for HPV DNA testing. If a woman was randomized to the study, her sample was sent to the University Teaching Hospital laboratory for the detection of DNA of any of the 14 high risk HPV types (along with type-specific information) by the Xpert™ HPV test (Cepheid, Sunnyvale, CA, USA). The HPV genotype information was obtained in separate channels for HPV 16, HPV 18 and/or 45, HPV 31, 33, 35, 52 and/or 58, HPV 51 and/or 59 and HPV 39, 56, 66 and/or 68. The test results were obtained later and did not alter treatment allocation and management of the eligible VIA positive women.
TA was performed using the Liger thermal ablator and as described in the IARC Colposcopy Manual.15 The portable battery-driven thermal ablator was developed by Liger Medical (Utah, USA) during 2016 and 2017 and bench tested in 2017. FDA clearance was obtained in 2017 as was the European CE mark. The device is powered by a small removable 12 volt battery incorporated into the handle, which may be recharged over two to three hours and holds enough charge to complete at least 20 treatment procedures.
Cryotherapy was carried out using the double freeze technique (freeze for 3 minutes, thaw for 5 minutes and freeze again for 3 minutes) as per routine practice in the program.4 LLETZ was performed under local anaesthesia as described by Prendiville et al3 while no anaesthesia was used for eithe ablative technique. Any treatment side-effects during and immediately after treatment were recorded by the nurse performing the treatment. Safety was assessed as any major complications leading to hospitalization and/or disability and/or death.
The nurse performing treatment counselled each participant after the procedure about possible side-effects and complications of treatment and advised her to report to the clinic or call the study coordinator for advice. Abstinence from sexual intercourse for six weeks and avoidance from douching or any vaginal medications was advised. Neither analgesics nor antibiotics were prescribed. Every participant was invited to attend a follow-up clinic appointment at six months. Before leaving the clinic, she was interviewed by the project coordinator to document her perception of pain/discomfort during and immediately after treatment and also her level of satisfaction with the overall experience. Pain and satisfaction were assessed using a visual rating scale ranging from 1 (no pain at all or was highly satisfied) to 9 (pain was so severe that the patient wanted the procedure to be stopped or was not at all satisfied).
The study coordinator called each participant 2 weeks after treatment to check if she had any complications or had visited a clinician or had been hospitalized during the intervening period. The level of pain/discomfort and the degree of satisfaction with the overall experience at that point of time was again recorded.
At the six month follow-up visit each participant was again asked about any complication, medical consultation or hospitalization. She was examined by a study nurse who first collected a cervical sample for Xpert™ HPV test and performed VIA. VIA positive participants were immediately referred for further assessment and appropriate management as per the local protocol. The participants negative on VIA but positive for HPV were advised to come for a repeat follow-up visit at 12 months. A data and safety monitoring board continues to oversee the project.
In this report, we are presenting the findings from a pre-specified pilot phase of the full trial. This pilot phase was carried out on request of the funder, a condition set before further funding for the full trial.
Outcomes
The primary outcome of interest was success of treatment at 6 months, which was defined as either a) HPV type-specific clearance at 6 months among participants positive for the same HPV type at baseline or b) negative VIA test at follow up, if the baseline HPV test was negative. The secondary outcomes were safety and acceptability of the different treatment methods. The proportion of participants undergoing LLETZ procedure and having cervical intraepithelial neoplasias (CIN) on histopathology was also assessed as a secondary outcome. The last outcome helped us to assess the over-treatment in ‘screen and treat’ setting.
Statistical analysis
This pilot study, which is part of a larger randomized trial, recruited 250 participants in each arm and followed each participant for six months. The sample size used for the assessment of the preliminary safety and efficacy was empirically decided. Recruitment for the larger RCT is ongoing and is expected to complete recruitment and follow up over two years. The following data were presented as proportions and compared between the three treatment modalities using a two-tailed Fisher’s exact test: baseline socio-demographic, reproductive and clinical characteristics; side-effects, pain scores and satisfaction after treatment; proportion of women with complications after treatment; and proportion of women clearing the cervical disease at 6-month proportions. The interval between treatment and follow-up was compared using the Kruskal-Wallis equality-of-populations rank test. Statistical significance was set at the 5% level. Treated participants who had not yet reported for their 6-month follow-up (including those not yet eligible or those eligible but did not turn up) were deened not assessable in the analysis of the primary endpoint. Statistical analyses were carried out using the STATA software, version 14.0 (StataCorp, College Station, Texas, US) and R software, version 3.6.0 (The R Foundation for Statistical Computing Platform).
The study is registered with the U.S. Clinical Trial Registry (https://clinicaltrials.gov/ct2/show/NCT02956239).
Role of the funding source
The study was funded by the National Institute of Health, USA through Grant number 1UH2CA202721-01 to the International Agency for Research on Cancer (IARC). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The raw data was accessed by RM (study statistician), PB, EL and WP. The corresponding author (PB) had full access to all of the data and the final responsibility to submit for publication.
Results
The pilot phase RCT stopped further recruitment after 250 participants were included in each arm. Recruitement for this pilot phase was started on August 02, 2017 and ended January 15, 2019. Table 1 provides details of the baseline socio-demographic, reproductive and clinical characteristics between the three treatment groups. There was no significant difference in the distribution of any of these variables. There were slightly fewer HIV positive participants in the TA group than the cryotherapy and LLETZ groups at baseline assessment [123 (49·2%) of 250 vs 134 (53·6%) of 250 and 135 (54·0%) of 250, respectively], though the difference was not statistically significant (p-value=0.71). The HPV positivity on Xpert™ test was 150 (60·0%) of 250), 136 (54·6%) of 250) and 145 (58·0%) of 250) in the cryotherapy, TA and LLETZ arms respectively (p-value=0.48).
Table 1:
Baseline socio demographic, reproductive health and clinical characteristics
| Randomization arm |
||||||
|---|---|---|---|---|---|---|
| Cryotherapy | Thermal ablation | LLETZ | ||||
| n (%) | n (%) | n (%) | ||||
| Participants recruited | 250 | 250 | 250 | |||
| Age (years) | ||||||
| 25–29 | 92 | (36·8) | 89 | (35·6) | 84 | (33·6) |
| 30–34 | 54 | (21·6) | 65 | (26·0) | 64 | (25·6) |
| 35–39 | 44 | (17·6) | 37 | (14·8) | 47 | (18·8) |
| 40–44 | 35 | (14·0) | 31 | (12·4) | 37 | (14·8) |
| 45–49 | 15 | (6·0) | 17 | (6·8) | 11 | (4·4) |
| 50–54 | 9 | (3·6) | 8 | (3·2) | 6 | (2·4) |
| 55–60 | 1 | (0·4) | 3 | (1·2) | 1 | (0·4) |
| Participant education | ||||||
| None | 9 | (3·6) | 7 | (2·8) | 10 | (4·0) |
| Primary | 88 | (35·2) | 75 | (30·0) | 74 | (29·6) |
| Secondary | 101 | (40·4) | 128 | (51·2) | 123 | (49·2) |
| College/university | 50 | (20·0) | 40 | (16·0) | 41 | (16·4) |
| Unknown | 2 | (0·8) | 0 | (0·0) | 2 | (0·8) |
| Occupation | ||||||
| Housewife | 62 | (24·8) | 68 | (27·2) | 57 | (22·8) |
| Manual | 26 | (10·4) | 23 | (9·2) | 29 | (11·6) |
| Professional | 43 | (17·2) | 44 | (17·6) | 37 | (14·8) |
| Business | 92 | (36·8) | 81 | (32·4) | 86 | (34·4) |
| Other | 16 | (6·4) | 29 | (11·6) | 31 | (12·4) |
| Unknown | 11 | (4·4) | 5 | (2·0) | 10 | (4·0) |
| Marital status | ||||||
| Unmarried | 34 | (13·6) | 32 | (12·8) | 35 | (14·0) |
| Married/cohabiting | 168 | (67·2) | 171 | (68·4) | 157 | (62·8) |
| Widowed | 19 | (7·6) | 17 | (6·8) | 24 | (9·6) |
| Separated | 28 | (11·2) | 30 | (12·0) | 34 | (13·6) |
| Residence area | ||||||
| Urban | 146 | (58·4) | 152 | (60·8) | 149 | (59·6) |
| Semi-urban | 92 | (36·8) | 90 | (36·0) | 94 | (37·6) |
| Rural | 11 | (4·4) | 7 | (2·8) | 7 | (2·8) |
| Unknown | 1 | (0·4) | 1 | (0·4) | 0 | (0·0) |
| Total pregnancies | ||||||
| None | 21 | (8·4) | 14 | (5·6) | 20 | (8·0) |
| 1–2 | 74 | (29·6) | 88 | (35·2) | 102 | (40·8) |
| 3–4 | 93 | (37·2) | 90 | (36·0) | 79 | (31·6) |
| 5+ | 62 | (24·8) | 58 | (23·2) | 49 | (19·6) |
| Total number of live births | ||||||
| None | 28 | (11·2) | 22 | (8·8) | 29 | (11·6) |
| 1–2 | 97 | (38·8) | 109 | (43·6) | 120 | (48·0) |
| 3–4 | 87 | (34·8) | 85 | (34·0) | 71 | (28·4) |
| 5+ | 38 | (15·2) | 34 | (13·6) | 30 | (12·0) |
| Last menstruation | ||||||
| <=30 days | 217 | (86·8) | 213 | (85·2) | 215 | (86·0) |
| > 30 days - < 12 months | 18 | (7·2) | 21 | (8·4) | 22 | (8·8) |
| 12 months+ | 2 | (0·8) | 6 | (2·4) | 3 | (1·2) |
| Unknown | 13 | (5·2) | 10 | (4·0) | 10 | (4·0) |
| Size of the acetowhite area | ||||||
| <50% | 221 | (88·4) | 223 | (89·2) | 210 | (84·0) |
| >50% | 29 | (11·6) | 27 | (10·8) | 40 | (16·0) |
| Baseline HIV status | ||||||
| Negative | 108 | (43·2) | 119 | (47·6) | 110 | (44·0) |
| Positive | 134 | (53·6) | 123 | (49·2) | 135 | (54·0) |
| Unknown | 8 | (3·2) | 8 | (3·2) | 5 | (2·0) |
| If HIV positive, patient on ART | ||||||
| Yes | 129 | (96·3) | 117 | (95·1) | 130 | (96·3) |
| No | 4 | (3·0) | 5 | (4·1) | 1 | (0·7) |
| Unknown | 1 | (0·7) | 1 | (0·8) | 4 | (3·0) |
| HPV testing results | ||||||
| Negative | 100 | (40·0) | 113 | (45·4) | 105 | (42·0) |
| Positive | 150 | (60·0) | 136 | (54·6) | 145 | (58·0) |
| HPV type | ||||||
| HPV 16 | 38 | (15·2) | 41 | (16·5) | 51 | (20·4) |
| HPV 18 and/or 45 | 24 | (9·6) | 21 | (8·4) | 21 | (8·4) |
| HPV 31, 33, 35, 52 and/or 58 | 99 | (39·6) | 94 | (37·8) | 101 | (40·4) |
| HPV 51 and/or 59 | 20 | (8·0) | 11 | (4·4) | 12 | (4·8) |
| HPV 39, 56, 66 and/or 68 | 60 | (24·0) | 45 | (18·1) | 54 | (21·6) |
LLETZ: Large loop excision of the transformation zone; HIV: human immunodeficiency virus; ART: antiretroviral therapy; HPV: human papilloma virus
Figure 1 presents details of the 6-month follow-up for this pilot study at the time of these analyses. Of 250 women in the cryotherapy arm, 246 were eligible (as they had completed 6 months post-treatment), of whom 206 (83·7%) had attended the 6-month follow-up examination. In the TA arm and LLETZ groups, these figures were 244 and 197 (80·7%) (TA) and 245 and 204 (83·3%) (LLETZ) respectively. The overall median interval between treatment and follow-up was 6·0 months (interquartile range 6.0–6.4 months) and the mean was 6.6 months (standard deviation 1.8 months; range 4·8 – 19·6 months) with no difference between the treatment arms (p-value=0.83).
Figure 1:
Flow chart for the pilot RCT study in the evaluation of the new Liger Thermal Coagulator
Table 2 shows treatment success proportions at 6 months following treatment based on a combination of HPV test and VIA. When based on HPV type-specific clearance and VIA negative findings among participants who were HPV negative at baseline, proportion of participants treated successfullywere 120 (60·0%) of 200 in the cryotherapy arm, 123 (64·1%) of 192 in the TA arm, and 134 (67.3%) of 199 in the LLETZ arm (p-value=0·52). The clearance proportions of high-risk HPV at 6 months were similar between the cryotherapy [48 (39·7%) of 121], TA [44 (42·3%) of 104] and LLETZ [50 (47·2%) of 106] arms (p-value=0·48). The proportion of participants clearing HPV 16 [Cryotherapy – 14 (43.2%) of 32, TA – 18 (64.3%) of 28 and LLETZ – 18 (54.5%) of 33] was less compared to the proportion of participants HPV 18 and/or 45 [Cryotherapy - 16 (100.0%) of 16, TA – 11 (68.8%) of 16 and LLETZ – 14 (87.5%) of 16]. HIV positive participants had lower success proportions compared to the HIV negative women, irrespective of the treatment method and definition of cervical disease clearance. The proportions of successful treatment as reflected by VIA examination alone (data not shown in the table) were similar across the groups. The proportion of participants who had a normal VIA examination at follow up was 162 (79·4%) of 204, 162 (83·9%) of 193 and 162 (79·8%) of 203) in the cryotherapy, TA and LLETZ arms respectively (p=0.47).
Table 2:
Treatment success proportions at 6 months follow-up after treatment (treatment success based on follow-up HPV and VIA results)a
| Randomization arm |
|||||||
|---|---|---|---|---|---|---|---|
| Cryotherapy | Thermal ablation | LLETZ | Fisher’s exact | ||||
| n (%) | n (%) | n (%) | p-value | ||||
| Treatment success based on HPV and VIA results at 6 months follow-upa | |||||||
| Overall | |||||||
| Participants followed upb | 200 | 192 | 199 | ||||
| Participants with no evidence of diseasea | 120 | (60·0) | 123 | (64·1) | 134 | (67·3) | 0·52 |
| HPV positive at baseline | |||||||
| Participants followed up | 121 | 104 | 106 | ||||
| Participants with no evidence of diseasea | 48 | (39·7) | 44 | (42·3) | 50 | (47·2) | 0·48 |
| HIV negative at baseline | |||||||
| Participants followed up | 85 | 93 | 93 | ||||
| Participants with no evidence of diseasea | 68 | (80·0) | 77 | (82·8) | 76 | (81·7) | 0·72 |
| HIV positive at baseline | |||||||
| Participants followed up | 109 | 95 | 101 | ||||
| Participants with no evidence of diseasea | 50 | (45·9) | 42 | (44·2) | 55 | (54·5) | 0·36 |
LLETZ: Large loop excision of the transformation zone; HIV: human immunodeficiency virus; HPV: human papilloma virus
Treatment success was defined as either a) HPV type-specific clearance at 6 months among women positive for the same HPV type at baseline or b) negative VIA test at follow up, if the baseline HPV test was negative
HPV reports were missing in 6 participants in cryotherapy arm, 5 participants in TA arm and 5 participants in LLETZ arm. They were excluded from the analysis of treatment success proportion.
The great majority of participants reported no, or the least level of discomfort with their treatment, either immediately after or within two weeks of treatment (table 3). Very few complained of moderate to severe pain (pain intensity score ≥4) during the procedure [cryotherapy – 6 (2·4%) of 250; TA – 4 (1·6%) of 250] and there was no statistically significant difference between the groups. When asked about the level of satisfaction with the service provided at the clinic and whether or not they would recommend the treatment to a friend, all three group scores approached 100%, both immediately and at two weeks after treatment. There were 5 deaths (3 in the cryotherapy and 1 each in the TA and LLETZ arms; due to intimate partner violence, suicide, metastatic breast cancer, renal failure of unknown cause and complications following a soft tissue tumour excision on thigh) in participants taking part in the study though none was related in any way to treatment. None of the participants reported any complication requiring medical consultation or hospitalization.
Table 3:
Intensity of pain and level of satisfaction reported immediately and two weeks after treatment
| Randomization arm |
|||||||
|---|---|---|---|---|---|---|---|
| Cryotherapy | Thermal ablation | LLETZ | Fisher’s exact | ||||
| n (%) | n (%) | n (%) | p-value | ||||
| Immediately after treatment | |||||||
| Participants assessed | 250 | 250 | 250 | ||||
| Intensity of pain or discomfort felt (score ranging from 1 to 9) | |||||||
| 1 (no pain) | 120 | (48·0) | 115 | (46·0) | 134 | (53·6) | 0·40 |
| 2–3 (least pain) | 123 | (49·2) | 129 | (51·6) | 111 | (44·4) | |
| 4–6 | 6 | (2·4) | 3 | (1·2) | 5 | (2·0) | |
| 7–9 (worst pain) | 0 | (0·0) | 1 | (0·4) | 0 | (0·0) | |
| Level of satisfaction with the services (score ranging from 1 to 9) | |||||||
| 1–3 (least satisfied) | 0 | (0·0) | 0 | (0·0) | 0 | (0·0) | 0·27 |
| 4–6 | 3 | (1·2) | 1 | (0·4) | 0 | (0·0) | |
| 7–9 (highly satisfied) | 246 | (98·4) | 248 | (99·2) | 250 | (100·0) | |
| Will recommend the screening procedure to others | |||||||
| Yes | 248 | (99·2) | 250 | (100·0) | 249 | (99·6) | 0·34 |
| No | 0 | (0·0) | 0 | (0·0) | 1 | (0·4) | |
| Cannot say | 2 | (0·8) | 0 | (0·0) | 0 | (0·0) | |
| Two weeks after treatment | |||||||
| Participants assessed | 241 | 242 | 237 | ||||
| Intensity of pain or discomfort felt (score ranging from 1 to 9) | |||||||
| 1 (no pain) | 214 | (88·8) | 227 | (93·8) | 208 | (87·8) | 0·21 |
| 2–3 (least pain) | 25 | (10·4) | 15 | (6·2) | 27 | (11·4) | |
| 4–6 | 1 | (0·4) | 0 | (0·0) | 2 | (0·8) | |
| 7–9 (worst pain) | 0 | (0·0) | 0 | (0·0) | 0 | (0·0) | |
| Level of satisfaction with the services (score ranging from 1 to 9) | |||||||
| 1–3 (least satisfied) | 0 | (0·0) | 0 | (0·0) | 0 | (0·0) | 0·55 |
| 4–6 | 1 | (0·4) | 0 | (0·0) | 0 | (0·0) | |
| 7–9 (highly satisfied) | 239 | (99·2) | 242 | (100·0) | 237 | (100·0) | |
| Will recommend the screening procedure to others | |||||||
| Yes | 239 | (99·2) | 242 | (100·0) | 237 | (100·0) | 0·34 |
| No | 0 | (0·0) | 0 | (0·0) | 0 | (0·0) | |
| Cannot say | 2 | (0·8) | 0 | (0·0) | 0 | (0·0) | |
LLETZ: Large loop excision of the transformation zone
Table 4 shows the histopathology reports of participants whose transformation zones were excised in the LLETZ arm. Overall 73 (30·7%) of 238 participants underwent LLETZ had histological evidence of CIN 2–3. More than half of VIA positive participants [124 (52·1%) of 238] had some grade of CIN and none had invasive cancer. In HIV positive participants eligible for ablation, 55 (43·0%) of 128 had CIN2–3 compared to 17 (16·0%) of 106 in participants who were HIV negative. Of the HPV positive (and VIA positive) participants who had LLETZ 64 (46·4%) of 138 had histologically proven CIN 2–3 compared to only 9 (9·0%) of 105 who were HPV negative. Taking baseline combinations of high-risk HPV and HIV status, CIN 2–3 was detected in 3 (4·5%) of 66 participants negative for both HPV and HIV, 6 (18·8%) of 32 HPV negative but HIV positive, 14 (35·0%) of 40 HPV positive but HIV negative, and 49 (51·0%) of 96 participants positive for both HPV and HIV.
Table 4:
Histology findings at baseline in the LLETZ arm
| Women | Women with histology | Histological diagnosis at baseline |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| treated | report | Normal | CIN 1 | CIN 2 | CIN 3 | CIN 2/3 | |||||||
| n | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | |||||||
| Overall | 250 | 238 | (95·2) | 114 | (47·9) | 51 | (21·4) | 32 | (13·4) | 41 | (17·2) | 73 | (30·7) |
| Age (years) | |||||||||||||
| 25–29 | 84 | 81 | (96·4) | 46 | (56·8) | 20 | (24·7) | 7 | (8·6) | 8 | (9·9) | 15 | (18·5) |
| 30–39 | 111 | 105 | (94·6) | 42 | (40·0) | 18 | (17·1) | 21 | (20·0) | 24 | (22·9) | 45 | (42·9) |
| 40+ | 55 | 52 | (94·5) | 26 | (50·0) | 13 | (25·0) | 4 | (7·7) | 9 | (17·3) | 13 | (25·0) |
| HPV testing results | |||||||||||||
| Negative | 105 | 100 | (95·2) | 66 | (66·0) | 25 | (25·0) | 5 | (5·0) | 4 | (4·0) | 9 | (9·0) |
| Positive | 145 | 138 | (95·2) | 48 | (34·8) | 26 | (18·8) | 27 | (19·6) | 37 | (26·8) | 64 | (46·4) |
| Baseline HIV status | |||||||||||||
| Negative | 110 | 106 | (96·4) | 60 | (56·6) | 29 | (27·4) | 7 | (6·6) | 10 | (9·4) | 17 | (16·0) |
| Positive | 135 | 128 | (94·8) | 51 | (39·8) | 22 | (17·2) | 25 | (19·5) | 30 | (23·4) | 55 | (43·0) |
| Baseline HPV and HIV status combinations | |||||||||||||
| HPV negative, HIV negative | 70 | 66 | (94·3) | 44 | (66·7) | 19 | (28·8) | 2 | (3·0) | 1 | (1·5) | 3 | (4·5) |
| HPV negative, HIV positive | 33 | 32 | (97·0) | 20 | (62·5) | 6 | (18·8) | 3 | (9·4) | 3 | (9·4) | 6 | (18·8) |
| HPV positive, HIV negative | 40 | 40 | (100·0) | 16 | (40·0) | 10 | (25·0) | 5 | (12·5) | 9 | (22·5) | 14 | (35·0) |
| HPV positive, HIV positive | 102 | 96 | (94·1) | 31 | (32·3) | 16 | (16·7) | 22 | (22·9) | 27 | (28·1) | 49 | (51·0) |
LLETZ: Large loop excision of the transformation zone; CIN: cervical intraepithelial neoplasia; HIV: human immunodeficiency virus; HPV: human papilloma virus
Discussion
To our knowledge this study is the only randomized study that included acceptability, safety as well as TA efficacy, specifically using a modern battery-driven portable machine. The most important finding of the preliminary report of our study is that TA appears to be highly acceptable to women and is associated with minimal side effects. The early results of the RCT indicate similarity of efficacy between TA and cryotherapy, though the pilot study is under-powered to conclusively comment on this. The shorter treatment time, less cumbersome equipment and non-dependance on refrigerant gas are distinct advantages of TA over cryotherapy. The cost of the battery driven TA is comparable to that of standard cryotherapy equipment and a huge cost-saving is expected due to low operational costs, if cryotherapy is replaced by TA. Also, current battery operated thermal ablators are small lightweight and highly portable. Avoiding cumbersome gas tanks is a genuine practical advantage to health care providers in LMIC. The outcomes of our study are particularly significant because of the high proportion of HIV positive women among the study participants. We have demonstrated that the technique is safe in the HIV positive women as well. The preliminary results also demonstrate similar efficacy for the two ablative techniques in HIV-positive women, albeit significantly lower than that in the HIV negative women. The trial being implemented in the routine healthcare facilities in Zambia and treatment being provided by the regular in-service nursing staff, the results are highly generalizable at least in the LMIC settings.
TA has been used extensively in Scotland since Semm first introduced the technique in Germany in the 1960s, and more recently in many other parts of the world. Duncan16 in Scotland has produced the largest and longest series of patients treated with TA (1453 patients followed up for over 14 years) and the cure proportions in his case series compare favourably with other treatment methods.17 The effectiveness of TA has been evaluated in several meta-analytical reviews.11,12 In the most recent review by Randall’s group, the authors report an overall cure proportion from 16 included studies for CIN2 or worse lesions to be 93·6% (95% CI 90·8% to 96·0%). The overall cure proportions for CIN1+ were 92·9% (CI 90·4% to 95·1%) and for CIN 3 were 89% (84–95%).The only RCT included in the analysis came from Singapore.18 In that study the authors reported no difference in success proportions between cryotherapy and TA for any grades of CIN. The reported cure proportions after TA in the Singapore study were 88·4%, 84·2% and 78·6% for CIN 1, CIN 2 and CIN 3 respectively. Duan and colleagues19 have also presented the results of a randomised controlled trial of TA vs cryotherapy in a study of 149 women eligible for ablative therapy. In this study TA was as or more effective than cryotherapy at 8 months as judged by HPV and cytological assessment respectively.
Several caveats apply to our study findings. The numbers reported here are small and the efficacy estimates should be interpreted with caution. The study continues to recruit eligible women and will do so until a sufficient sample size has been gained. According to our estimate, an additional 1,000 participants need to be recruited in each arm to give sufficient power to detect non-inferiority of TA as a treatment method for VIA-positive women compared to cryotherapy or LLETZ. A second caveat is that follow-up assessment at 6 months is probably too early to assess cure of disease, but we do not anticipate any difference arising between the study groups, which are well-balanced due to randomization. A major criticism of the study is the lack of histopathology verification either at baseline or at follow-up. Ablative techniques are likely to be used widely in ‘screen-and-treat’ settings and we have followed the ‘standard of care’ (i.e. VIA) to detect abnormalities pre- or post-treatment. It is well known that VIA is not a perfect screening test with low to moderate sensitivity and low specificity.6 It is still recommended by the WHO for LMICs that can not afford an HPV detection test for population screening. The National Cancer Control Strategic Plan (2016–2021) by the Zambian Ministry of Health also stipulates the use of VIA as the screening test of choice followed by immediate cryotherapy/TA of all the VIA positive women eligible for ablation.20 We implemented a pragmatic study and followed the existing protocol for VIA screen and treat. In VIA screen and treat program, negative VIA result alone is considered as the test of cure. To increase the validity of our study, in addition to VIA we have used the most frequently used and powerful ‘test of cure’, which is a validated high-risk HPV test. This allowed us to learn about the relationship between HPV and VIA status and also to have a more valid end-point than VIA alone. Addition of HPV testing didn’t interfere with the local screen and treat decision algorithm. The low proportions of ‘treatment success’ as reflected in HPV status may reflect both the early follow-up appointment timing at 6 months but also the possibility of recurrent infection, particularly in the context of relatively high prevalence of HIV in recruited women. There is a possibility that the follow up VIA might have missed some of the lesions in the HPV negative women due to the low sensitivity of the test. However, similar success proportions observed between the ablative and excisional treatment arms using the stringent criteria of disease clearance gives us confidence in our study outcomes.
Duration of treatment is still an unresolved issue with TA. Randall’s meta-analysis found that the cure proportion did not vary significantly according to the duration of treatment. Patients treated for 20 seconds duration had a cure proportion of 92·9%, those treated for 30 seconds 95·1% and those treated for 45 seconds 85%. The largest body of data with the longest duration of follow-up comes from Ian Duncan’s case series where 20-second applications were used but with the important caveat that where the probe tip did not cover the entire TZ, overlapping applications were made.16 The variables of probe tip size and the number of applications are, as yet, open questions. So far in our study we used 45 seconds duration and multiple overlapping applications using a 20 mm probe. Our DSMB has recommended that we reduce the treatment time to 30 seconds in the larger RCT because the members couldn’t find evidence in the published literature for an advantage to a treatment duration of greater than 30 seconds.
It is reassuring that very low frequency of discomfort during and after treatment were reported in all three study groups. The frequencies reported in the procedure room during and immediately after treatment were slightly lower in the TA arm and this may be explained by the very much shorter treatment duration associated with TA when compared to cryotherapy (45 seconds vs 11 minutes). The relatively low reporting of pain or cramps during LLETZ may be explained by the fact that local infiltration was routinely used for LLETZ but not for ablative treatment of either kind. Also, similarly low discomfort levels were reported by women after they had left the procedure room and by telephone two weeks later.
All participants in our study were advised to avoid penetrative sex for six weeks to reduce the risk of post-treatment bleeding and infection. Though an important concern in the HIV infected women, it is now well-established that virus shedding does not increase after ablative treatment, if women are already on anti-retroviral therapy (ART).21,22 All our HIV positive participants were on ART at the time of VIA screening. Earlier studies have demonstrated that 5% - 31% of women treated with cryotherapy fail to comply with the advice for abstinence and the proportion of compliance increases with better counseling.23 Though we ensured appropriate counseling of each participant, it is possible that some of them were non-compliant and suffered from the consequences. However, we found it difficult to document the compliance proportion due to the cultural sensitivities around questions related to the sexual practices.
One of the reasons that we included a third study arm (excision by LLETZ) was to discover the histological diagnosis in VIA positive women eligible for cryotherapy and thereby to better assess the test characteristics of visual inspection in its ability to discriminate between high grade and low grade or normal transformation zones, hence describe the proportion of over-treatment specifically in the context of a screen-and-treat approach. The trial participants require a type I LLETZ, which has been demonstrated to be quite safe in our study and due approval was taken from the ethics and regulatory agencies. Only 31% of women with a positive VIA and who were eligible for an ablative therapy had histologically proven high grade CIN 2 or worse. This positive predictive value (PPV) is higher for women in their 30s (43%) and for those who are HIV positive (43%). Much lower proportions (~5%) have been reported from studies that were implemented in regions with a low prevalence of cervical cancer.24 The meta-analysis of 26 cross-sectional studies by Sauvaget et al observed that the average PPV of VIA to detect CIN 2 or worse disease was 10%.6 The PPV in our study population was much higher due to the high prevalence of HIV infection. Most of the earlier studies used punch biopsy as the gold standard to define disease status. Our study provides a more valid estimate of PPV by subjecting the entire transformation zone to histopathologic evaluation. Even then, the low PPV and resulting over-treatment (nearly half of the women treated had no CIN) in a ‘VIA - screen and treat’ programme is a matter of concern. This also underscores the need for a safe treatment method that causes minimal discomfort to patients.
It is reassuring to know that no invasive cancer was inadvertently treated at least in the LLETZ arm.
Conclusions
The World Health Organisation (WHO) has recently updated its clinical guidelines for the treatment of cervical precancer (to be published soon) and now endorses the use of TA for ablative treatment. The low complication proportions for either intervention, objectively documented and reported by our study, specially in a large number of HIV positive women was a valuable evidence for the WHO to develop the new guidelines. An RCT to compare thermal ablation to cryotherapy (using standard cryotherapy or cryopen) to treat histopathologically proved CIN 2 or CIN 3 is ongoing in Colombia, El Salvadore and Peru. (ClinicalTrials.gov identifier: ) If our early findings on similarity of efficacy between the two ablative techniques are confirmed by our ongoing large RCT and other studies, then health care workers caring for screen positive women in ‘screen-and-treat’ programmes in LMICs may choose modern cordless lightweight and battery operated TA devices over cryotherapy instruments because of the practical disadvantages of cryotherapy. In view of the relatively low proportion of histologically proven CIN2+ in VIA screen positive women it is perhaps time to reconsider the optimal screening test for low and middle-income regions. Hopefully both much less expensive and laboratory independent HPV tests will become available in the near future or alternative techniques, for example artificial intelligence image recognition systems, will emerge.
Data Sharing Plan
Final research data will be shared with the wider scientific community. This will be achieved through the following mechanisms:
Publication of research data and results in open access peer reviewed journals, subject to approval of publication by co-investigators.
Presentation of research data and results at scientific conferences, subject to approval of the presentation by co-investigators.
External researchers may make written requests for sharing of data prior to publication or presentation. Requests will be evaluated on a case-by-case basis in consultation with lead and co-investigators. A brief analysis plan and data request will be required and reviewed by the investigators for approval of data sharing. When requests are approved, data will be sent electronically in password protected files.
All data sharing will abide by rules and/or policies defined by the sponsor, relevant IRBs, local, state, and Federal laws and regulations. Data sharing mechanisms will ensure that the rights and privacy of individuals participating in NIH sponsored research will be protected at all times.
Research in context
It is well-known that the see-and-treat approach, in reducing the number of clinic visits, improves treatment compliance in a screening programme in the limited resourced settings. Screening cervical cancer by visual inspection with acetic acid (VIA) followed by immediate ablative procedure was the most common approach used in low- and middle-income countries (LMIC). Currently, the World Health Organization (WHO) recommends cryotherapy as the ablative method of choice for screen-and-treat programmes. Thermal ablation (TA) is an alternative ablative procedure. The WHO has endorsed cryotherapy as the standard method of treatment for cervical pre-cancer in LMICs for over a decade. Although cold coagulation (now known as thermal ablation) has been in use for many years in the UK and elsewhere and despite evidence from large and long term follow up studies in Scotland the method has not achieved penetration in LMICs, perhaps largely because of the WHO endorsement of cryotherapy. We searched PubMed with no language or date restrictions using the keywords “cervical intraepithelial neoplasia OR CIN OR cervical precancerous lesions” and “ablative treatment” and “LMICs” on Sept 7, 2018, for articles describing this ablative procedure in low resource settings. We also checked the reference list of the selected articles. A recent meta-analysis of the available published evidence revealed similarity in effectiveness between cryotherapy and thermal ablation. There was only one small randomised-controlled trial in the studies included.
Added value of this study
The results of the pilot phase of our study reveals similarity in efficacy between thermal ablation and cryotherapy, though the pilot study does not have adequate power due to small sample size. TA was very much preferred by care providers and was quicker (45 seconds vs 11 minutes). There was no difference in complication or discomfort levels between the study arms. The excisional arm revealed that only 25% of participants deemed to be screen positive and eligible for ablation had high grade squamous lesions (HSIL).
Implications of all the available evidence
The study will continue until sufficient power has been achieved to establish equivalent efficacy between TA and cryotherapy. The results of this pilot would suggest that TA as a method of treating cervical precancers is as safe as cryotherapy and is highly acceptable to the patients and the providers. If the early results of the pilot study regarding similarity of treatment efficacy between TA and cryotherapy are established by our ongoing RCT, TA without the practical disadvantages of cryotherapy will certainly be the ablative treatment of choice in a LMIC setting.
Acknowledgements
The study is fully funded by the National Institute of Health, USA (Grant number 1UH2CA202721-01). Leeya Pinder was funded by University of North Carolina at Chapel Hill T32 Fellowship (Grant No. 5T32HD075731-05) and University of Washington T32 Fellowship (grant No. 5T32CA009515-34). The authors would like to give particular thanks to the women who participated in the study. The authors are grateful to Wm. Dean Wallace, LIGER/Cure Medical LLC. for being the technical partner. The authors would also like to thank the following UH2 staff: Anne Njobvu, Besnart Ngandu, Susan Banda, Gift Kaputula, Beatrice Zulu and Barbra Nakasote. The authors thank Mrs Krittika Guinot, IARC for her help in the preparation of this manuscript.
Funding: The study is funded by the National Institute of Health, USA (Grant number 1UH2CA202721-01).
Footnotes
Declaration of interests
Walter Prendiville worked closely with LIGER Medical to provide technical inputs in the design and development of the battery-operated thermal ablator over the last several years. He has not received any financial reward from the company. Other authors declare that they have no competing interest.
Disclaimer
Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.
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Contributor Information
Leeya F Pinder, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington; Honorary Lecturer, University of Zambia, Lusaka, Zambia.
Groesbeck P Parham, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill; Honorary Lecturer/Consultant, University of Zambia.
Partha Basu, Screening Group, Early Detection and Prevention Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
Richard Muwonge, Screening Group, Early Detection and Prevention Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
Eric Lucas, Screening Group, Early Detection and Prevention Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
Namakau Nyambe, UNC Global Project- Zambia, Lusaka, Zambia.
Catherine Sauvaget, Screening Group, Early Detection and Prevention Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
Mulindi H Mwanahamuntu, Department of Obstetrics and Gynecology, Women and Newborn Hospital, University of Zambia, Lusaka, Zambia.
Rengaswamy Sankaranarayanan, Research Triangle Institute, International-India, Commercial Tower, Pullman Hotel Aerocity, New Delhi, India.
Walter Prendiville, Screening Group, Early Detection and Prevention Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
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