Uptake and safety of community-based "screen-and-treat" with thermal ablation preventive therapy for cervical cancer prevention in rural Lilongwe, Malawi.

Malawi has the highest invasive cervical cancer (ICC) mortality rate worldwide, and ICC is the leading cause of cancer death among women. In 2004, Malawi adopted visual inspection with acetic acid (VIA) and ablative treatment with cryotherapy. However, screening coverage has remained low (<30%) and few women (<50%) who require ablative treatment receive it. Additional barriers include long distances to health facilities and challenges with maintaining gas supplies. Thermal ablation is a safe and effective alternative to cryotherapy. We assessed the safety and uptake of community-based ICC screening with VIA and same-day treatment using a handheld thermocoagulator (HTU) in rural Malawi. We held educational talks alongside community leaders and conducted VIA screening in nonclinic community settings to nonpregnant women aged 25 to 49 years without history of hysterectomy or genital cancer/precancer. Eligible women received same-day thermal ablation and HIV testing/counseling. We collected cervical biopsies before treatment and followed up women at Weeks 6 and 12, with repeat biopsy at Week 12. Between July and August 2017, 408 (88%) of 463 eligible women underwent VIA. Overall, 7% (n = 30) of women had a positive VIA, of whom 93% (n = 28) underwent same-day thermal ablation. Among the 30 VIA-positive women, 5 had cervical intraepithelial neoplasia (CIN) 1, 4 had CIN 2/3 and 21 had benign histologic findings. Abnormal vaginal discharge (60%) and light vaginal bleeding (52%) were the most reported adverse events. There was high uptake of the community-based ICC screening in the study population and treatment was safe in this setting. Similar strategies that minimize false-positive results are urgently needed in Malawi.

Clearance of human papillomavirus infection in patients with cervical intraepithelial neoplasia: A systemic review and meta-analysis.

BACKGROUND: There are currently no available standard drugs treating human papillomavirus (HPV) infection, especially for patients with low-grade cervical lesion. Several therapies are explored but the results are inconclusive. The objective of this study was to evaluate the efficacy of reported non-invasive treatments in patients with HPV infection and cervical lesions by meta-analysis. METHODS: A comprehensive search of prospective and randomized studies published from April 2000 to April 2020 was conducted in electronic databases. The statistical analyses of the pooled risk ratios (RRs) and the corresponding 95% confidence intervals (95% CIs) were performed using the Revman 5.2 software. RESULTS: Twelve articles including 12 randomized controlled studies and 1 prospective controlled randomized pilot study were enrolled. Therapeutic medications included biological and herbal regimen, interferon regimen and probiotics. The meta-analysis showed the experimental treatments had a statistically significant improvement in HPV clearance rate compared with the controls (RR = 0.71, 95% CI [0.63, 0.80], P < .00001); subgroup analyses stratified by regimen categories were consistent with results in the overall group. Treatment using biological and herbal regimen, interferon regimen or probiotics also resulted in a beneficial outcome in regression rate of cervical lesions compared with the controls (RR = 0.55, 95% CI [0.39, 0.79], P = .001). The trend was more favorable in the probiotics than that in the biological and herbal regimen (RR 0.48 vs 0.72). CONCLUSION: Treatment of biological and herbal regimen, interferon regimen and probiotics benefit patients who have HPV infection and cervical lesions. Both the clearance of HPV and regression of cervical lesions are significant. More studies with less heterogeneity are needed to draw a concrete conclusion.

Treatment of high risk human papillomavirus infection in low grade cervical squamous intraepithelial lesion with mild local thermotherapy: Three case reports.

INTRODUCTION: Mild local hyperthermia at 44°C has been proven efficacious in the treatment of cutaneous warts induced by human papillomavirus (HPV), while its effect on cervical intraepithelial neoplasia (CIN) caused by high risk type of HPVs has not been reported. PATIENT CONCERNS: Three patients with low grade CIN and positive high risk HPV types (HPV 16, 31, 52, 56, 58) are reported in this study. DIAGNOSIS: The diagnosis was based on identification of HPV types and abnormal cytological findings. INTERVENTIONS: The 3 patients were treated with local hyperthermia from ceramic heating (surface temperature, 44°C) to cervix. The treatment was delivered once a day for 3 consecutive days, plus two similar treatments 10 ± 3 days later, with each session lasting 30 minutes. HPV and cytology test were performed 3 months thereafter. OUTCOMES: All the 3 patients recovered to normal cytological findings. Two of the patients were negative for HPV, the remaining patient with pre-treatment HPV 56 and 58 positivity changed to HPV58 positive alone. CONCLUSION: This pilot observation inspires that mild local hyperthermia be recommended as a new method in the treatment of CIN patients with persistent HPV infection, once validated by qualified RCT.

A Prospective Randomized Trial to Compare Safety, Acceptability and Efficacy of Thermal Ablation and Cryotherapy in a Screen and Treat Setting.

BACKGROUND: The prospective randomized study aimed to compare the safety, acceptability and efficacy of thermal ablation (TA) to that of cryotherapy in screen and treat setting. METHODS: The participants were recruited prospectively in a community-based screening clinic in India. Women positive on visual inspection with acetic acid (VIA) test and/or Human Papillomavirus (HPV) test were assessed for eligibility for ablative treatment. Total 286 eligible women were randomized to receive either cryotherapy (N=150) or TA (N=136) performed by health workers. Colposcopy and cervical biopsy were performed on all, prior to treatment. Post-treatment follow-up was after one year with colposcopy and biopsy. RESULTS: Both the treatment methods had high acceptability. Significantly higher proportion of women treated by cryotherapy reported pain compared to women treated by TA, though intensity was mild in vast majority of them. Approximately 30% of women in both arms had histologic abnormalities, mainly CIN 1, and among those who attended follow-up 74.1% and 81.0% didn't have any CIN after cryotherapy and TA respectively. CONCLUSION: TA is as acceptable and safe as cryotherapy in screen and treat setting. TA has the logistic advantages for the low-resourced settings as the machines are more portable, do not require costly refrigerant gas and battery-driven models are available. The cure rates for CIN 1+ lesions in our study were comparable between cryotherapy and TA.

Thermal ablation versus cryotherapy or loop excision to treat women positive for cervical precancer on visual inspection with acetic acid test: pilot phase of a randomised controlled trial.

BACKGROUND: Cryotherapy is standard practice for treating patients with cervical precancer in see-and-treat programmes in low-income and middle-income countries (LMICs). Because of logistical difficulties with cryotherapy (eg, the necessity, costs, and supply chain difficulties of refrigerant gas; equipment failure; and treatment duration >10 min), a battery-operated thermal ablator that is lightweight and portable has been developed. We aimed to compare thermal ablation using the new device with cryotherapy. METHODS: We report the pilot phase of a randomised controlled trial in routine screen-and-treat clinics providing cervical screening using visual inspection with acetic acid (VIA) in Lusaka, Zambia. We recruited non-pregnant women, aged 25 years or older, who were eligible for ablative therapy. We randomly assigned participants (1:1:1) to thermal ablation, cryotherapy, or large loop excision of the transformation zone (LLETZ), using computer-generated allocation. The randomisation was concealed but the nurses providing treatment and the participants were unmasked. Thermal ablation was achieved using the Liger thermal ablator (using 1-5 overlapping applications of the probe heated to 100°C, each application lasting for 40 s), cryotherapy was carried out using the double-freeze technique (freeze for 3 min, thaw for 5 min, and freeze again for 3 min), and LLETZ (using a large loop driven by an electro-surgical unit to excise the transformation zone) was done under local anaesthesia. The primary endpoint was treatment success, defined as either human papillomavirus (HPV) type-specific clearance among participants who were positive for the same HPV type at baseline, or a negative VIA test at 6-month follow-up, if the baseline HPV test was negative. Per protocol analyses were done. Enrolment for the full trial is ongoing. Here, we present findings from a prespecified pilot phase of the full trial. The final analysis of the full trial will assess non-inferiority of the groups for the primary efficacy endpoint. The study is registered with ClinicalTrials.gov, number NCT02956239. FINDINGS: Between Aug 2, 2017, and Jan 15, 2019, 750 participants were randomly assigned (250 per group). 206 (84%) participants in the cryotherapy group, 197 (81%) in the thermal ablation group, and 204 (84%) in the LLETZ group attended the 6-month follow-up examination. Treatment success was reported in 120 (60%) of 200 participants in the cryotherapy group, 123 (64%) of 192 in the thermal ablation group, and 134 (67%) of 199 in the LLETZ group (p=0·31). Few participants complained of moderate to severe pain in any group immediately after the procedure (six [2%] of 250 in the cryotherapy group, four [2%] of 250 in the thermal ablation group, and five [2%] of 250 in the LLETZ group) and 2 weeks after the procedure (one [<1%] of 241 in the cryotherapy group, none of 242 in the thermal ablation group, and two [<1%] of 237 in the LLETZ group). None of the participants reported any complication requiring medical consultation or admission to hospital. INTERPRETATION: Results from this pilot study preliminarily suggest that thermal ablation has similar treatment success to cryotherapy, without the practical disadvantages of providing cryotherapy in an LMIC. However, the study was not powered to establish the similarity between the techniques, and results from the ongoing randomised controlled trial are need to confirm these results. FUNDING: US National Institutes of Health.

Management and treatment of cervical intraepithelial neoplasia in the Netherlands after referral for colposcopy.

INTRODUCTION: The aim of this study was to describe trends in the diagnosis and treatment of women referred from the national screening program with cervical intraepithelial neoplasia (CIN) in the Netherlands, and to compare these trends with national guidelines and identify potential areas for improvement for the new primary high-risk HPV screening program. MATERIAL AND METHODS: We conducted a population-based cohort study using data from the Dutch pathology archive. Women aged 29-63 years who took part in the Dutch cervical screening program between 1 January 2005 and 31 December 2014 were selected. Three referral groups were identified: direct referrals and those referred after either one (first indirect referrals) or two (second indirect referrals) repeat cytology tests, totaling 85 239 referrals for colposcopy. The most invasive management technique and the most severe diagnosis of each screening episode was identified. Rates of management techniques were calculated separately by referral type, highest CIN diagnosis and age group. RESULTS: In all, 85.1% of CIN 3 lesions were treated with excision (either large excision or hysterectomy) and 26.4% of CIN 1 lesions were treated with large excision. Rates of overtreatment (CIN 1 or less) in see-and-treat management were higher for indirect referrals than for direct referrals and increased with age. Large excision rates increased with CIN diagnosis severity. CONCLUSIONS: Despite guideline recommendations not to treat, CIN 1 lesions were treated in just over 25% of cases and approximately 15% of CIN 3 lesions were possibly undertreated. Given the expected increase in CIN detection in the new primary high-risk HPV screening program, reduction in CIN 1 treatment and CIN 2 treatment in younger women is needed to avoid an increase in potential harm.

Organized Cervical Cancer Screening Program in Barretos, Brazil: Experience in 18 Municipalities of São Paulo State.

OBJECTIVES: The aim of this report is to demonstrate the Barretos Cancer Hospital initiative of organizational, laboratorial, and human resources training in the implementation of an organized cervical screening program in low-resource settings. METHODS: We developed a computational program to report all epidemiological, clinical, and laboratorial findings, and to trace all necessary information to recruit women for regular screening or for referral for complementary exams after liquid-based Pap test analyses. RESULTS: All Pap tests were collected in liquid medium and in 2014 more than 160,000 tests were analyzed and 2,900 colposcopy examinations were performed. From 2012 to 2015, the percentage of exams collected increased from 54.6% in 2012 to 62.4% in 2013, 68.4% in 2014, and 71% in 2015. Per 1,000 Pap tests, 0.4 cases of invasive cancer were diagnosed; for in situ carcinoma, 1.9 cases were identified. More importantly, between 2011 and 2015, 89.4% of all carcinomas were detected at clinical stage 0 or I (in situ carcinoma), and only 5% at stages III and IV. CONCLUSIONS: Since the organized system was implemented, 98% of women have attended their recall for colposcopy. So far, we have not reached the target of 70% of women for this proposal, as recommended by the international standards.

Spontaneous regression of low-grade cervical intraepithelial lesions is positively improved by topical bovine colostrum preparations (GINEDIE®). A multicentre, observational, italian pilot study.

OBJECTIVES: Human papillomavirus (HPV) is the causal agent of cervical cancer. The great majority of abnormal Pap test results - almost 90% - is referrable to either atypical squamous intraepithelial lesion or CIN1. For these lesions, worldwide agreement exists concerning the high rate - ranging from 40% to 70% - of spontaneous regression over a period of 1-5 years. Host's immune response is a key point influencing the natural history of these conditions. Bovine colostrum is a natural agent positively promoting several immune activities against bacterial and viral agents. The aim of this report was to evaluate the potential positive effect of bovine colostrum-containing vaginal tablets administered to CIN1 diagnosed patients in a prospective trial in regards to spontaneous regression rate. PATIENTS AND METHODS: A series of 256 consecutive patients with histologically proven CIN1 recruited in a multicentre, observational, Italian study. Patients have been enrolled in a 24-weeks protocol of treatment and re-tested at the end of the study. Rates of regression have been recorded. RESULTS: Overall regression rate to a negative histology at the end of the 6 month follow up was 75.5%. CONCLUSIONS: Regression to normal histology was observed in a very high rate of cases in a very short period compared to the natural history of these lesions. CIN1 patients could benefit from bovine colostrum topical administration in terms of significantly shortening the regression time.

Management of abnormal cervical cytology screening in adolescent and young women in a canadian colposcopy centre: a descriptive analysis.

OBJECTIVE: To describe and analyze the management of young women referred for colposcopy at a Canadian comprehensive cancer centre for evaluation of atypical squamous intraepithelial lesion of unknown significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). METHODS: We conducted a retrospective descriptive study by searching the eCancerCare Colposcopy Database at our centre for 15- to 29-year-old females with referral cytology of ASC-US and LSIL who were seen between January 2000 and January 2009. Women in three age cohorts (15 to 19 years, 20 to 24 years, and 25 to 29 years) were reviewed for risk factors and relevant medical history, cytology and histology results, treatment, and follow-up visits. RESULTS: A total of 407 women met the entry criteria, with 36 women in the group aged 15 to 19, 173 in the group aged 20 to 24, and 198 in the group aged 25 to 29. Ten excisional procedures were performed among the 36 participants in the group aged 15 to 19, with normal histology found in two (20%), low-grade cervical intraepithelial neoplasia (CIN) in four (40%), and high-grade CIN in four (40%). An excisional procedure was performed in 52 of 173 participants in the group aged 20 to 24, with normal histology in 15%, low-grade CIN in 37%, and high-grade CIN in 48%. Among the group aged 25 to 29, 74 of 198 participants had an excisional procedure, with normal histology in 12%, low-grade CIN in 27%, high-grade CIN in 59%, and microinvasive squamous cell carcinoma in one woman (1%). CONCLUSION: Many women under the age of 25 who were referred with low-grade abnormal cervical cytology underwent treatment(s) and many did not have significant pathology. One case of microinvasive cervical cancer was identified in a patient in the group aged 25 to 29 over the nine years of our study. Our results support the safety of developing a more conservative and coordinated approach to cervical cancer screening in adolescent and young women in Canada.

Synthetic vaccine for the treatment of lesions caused by high risk human papilloma virus.

Until recently, therapeutic cancer vaccines only sporadically led to long-term clinical responses. We here report on a novel vaccine modality, characterized by the administration of long (23-45 amino acids) synthetic peptides in incomplete Freund adjuvant (mineral oil-based, Montanide ISA-51), delivered subcutaneously. Such vaccines were first demonstrated to be much more potent in preclinical T-cell response induction and tumor therapy experiments than short major histocompatibility complex class I-binding peptides that have been used extensively in the clinic. A long-peptide vaccine consisting of 13 overlapping peptides, together covering the entire length of the 2 oncogenic proteins E6 and E7 of high-risk human papilloma virus type 16 (HPV16), caused complete regression of all lesions and eradication of virus in 9 of 20 women with high-grade vulvar intraepithelial neoplasia. The nature and strength of the vaccine-induced T-cell response were significantly correlated with the clinical response. This vaccine promises to be of use, not only in patients with premalignant lesions caused by high-risk HPV16, but also in patients with malignant tumors caused by this virus, including HPV16-positive cervical cancer, anal cancer, and head and neck cancer.

Cost of cervical cancer treatment: implications for providing coverage to low-income women under the Medicaid expansion for cancer care.

BACKGROUND: To date, no study has reported on the cost of treating cervical cancer among Medicaid beneficiaries younger than 65 years of age. This information is essential for assessing the cost effectiveness of screening interventions for low-income women and the funding required for treatment programs established by the Breast and Cervical Cancer Prevention and Treatment Act of 2000. METHODS: Administrative data from the North Carolina Medicaid program linked with cancer registry data were used to analyze total Medicaid costs for these patients and the incremental costs of cervical cancer care at 6 and 12 months from diagnosis. We compared 207 beneficiaries diagnosed with cancer during the years 2002 to 2004 with 414 controls. FINDINGS: Total Medicaid costs at 6 months after diagnosis were $3,807, $23,187, $35,853, and $45,028 for in situ, local, regional, and distant cancers, respectively. The incremental cost of cancer treatment for local and regional cancers was $13,935 and $26,174 and by 12 months increased to $15,868 and $30,917, respectively. CONCLUSION: Medicaid coverage may be required for many months after diagnosis to ensure the provision of comprehensive care, especially for women with late-stage cancers. Given the great differences in cost of early versus late-stage cancers, interventions aimed at increasing screening among low-income women are likely to be cost effective.

An alternative treatment for cervical intraepithelial neoplasia II, III.

BACKGROUND: This report describes a case of a woman with progressive and recurrent cervical dysplasia 4 years after cervical conization for severe dysplasia. PATIENT AND METHODS: A 20-year-old female was referred for colposcopy and biopsy following results of moderate to severe atypia of cervical cells on her Papanicolaou (Pap) test. Her colposcopy was satisfactory and her biopsy revealed cervical intraepithelial neoplasia (CIN) II, III. She refused the conventional recommendation of loop electrosurgical excision procedure (LEEP) and, as an alternative, elected to receive escharotic treatment at a frequency of 2 treatments per week for 5 weeks. In addition to the escharotic treatment she followed an oral vitamin and botanical protocol. She was followed for 5 years. RESULTS: The patient's 4-month and 10-month follow-up Pap smears revealed negative cervical cytology for intraepithelial lesion or malignancy. Her 10-month colposcopy was satisfactory and no lesions were noted on the colposcopic exam. Liquid based Pap results continued to remain normal for 5 years after the initiation of treatment. DISCUSSION: Escharotic treatment of high-grade cervical neoplasias with satisfactory colposcopy holds promise as an effective and low-risk alternative therapy to LEEP and other excisional procedures.

Effectiveness, safety, and acceptability of cryotherapy by midwives for cervical intraepithelial neoplasia in Maharashtra, India.

OBJECTIVE: To evaluate the effectiveness, safety, and acceptability of cryotherapy for cervical intraepithelial neoplasia (CIN) when provided by trained midwives in rural India. METHOD: Women with colposcopic findings of CIN lesions suitable for ablative treatment received cryotherapy from trained midwives before the biopsy results were known. Cure rates, adverse effects, and complications were assessed and factors influencing cure rates were evaluated by chi(2) tests. Cure was defined as no clinical or histologic evidence of CIN lesions 6 or more months after treatment. RESULTS: Of 1068 women treated with cryotherapy, 728 had histologically proven CIN in their pretreatment biopsy specimens; of the 574 reporting for follow-up, 538 (93.7%) were cured (95% confidence interval [CI], 92.1%-96.3%). Cure rates were 96.4% (95% CI, 94.6%-98.1%) for CIN 1 and 82.1% (95% CI, 74.7%-89.4%) for CIN 2 and CIN 3 lesions combined. Minor adverse effects were documented in 5.2% of the women. CONCLUSION: Cryotherapy provided by midwives was found to be safe, effective, and acceptable by the women.

HPV triage testing or repeat Pap smear for the management of atypical squamous cells (ASCUS) on Pap smear: is there evidence of process utility?

A two-stage standard gamble was used to evaluate women's preferences for alternative managements of atypical squamous cells of undermined significance (ASCUS) on Pap smear (repeat Pap smear compared with immediate HPV test), and to test for the evidence of process utility. Women's utilities for the health state scenarios were clustered towards the upper end of the 0-1 scale with considerable variability in women's preferences. There was evidence of process utility, with immediate human papillomavirus (HPV) testing strategies having lower valuations than repeat Pap smear, where the clinical outcome was the same. Mean (95% CI) utilities for HPV testing (negative test) followed by resolution were 0.9967 (0.9957-0.9978) compared with repeat Pap smear followed by resolution: 0.9972 (0.9964-0.9980). Mean (95% CI) utilities for immediate HPV testing (positive test), followed by colposcopy, biopsy and treatment were 0.9354 (0.8544-1.0) compared with repeat Pap smear followed by colposcopy, biopsy and treatment: 0.9656 (0.9081-1.0). Our results add to the existing evidence that the impact of healthcare interventions on well-being is not limited to the effect of the intervention on the health outcomes expected from the intervention; process of care can have quality of life implications for the individual. A modelled application of trial-based data will allow characterisation of the true population costs, benefits, risks and harms of alternative triage strategies and subsequent policy implications thereof.

Management of cervical cancer.

BACKGROUND: Australia now has one of the lowest incidence and mortality rates for cervical cancer worldwide. Women who develop the disease frequently have underutilised cervical screening opportunities and commonly present with symptoms such as abnormal vaginal bleeding. OBJECTIVE: This article reviews the management of women presenting with cervical cancer in Australia today. DISCUSSION: Although fertility sparing options of management are emerging, these options are only available for women presenting with early stage disease. For women presenting with substantial disease, radical surgery and/or chemoradiation is required. These women face the rigors of radical therapy as well as challenges to their sexual identity with loss of fertility, loss of ovarian function, and vaginal shortening and stenosis. Health care providers need to be cognitive and sensitive to these issues.

Cervical dysplasia: early intervention.

Cervical cancer is the second-most common cancer in young women and is one of the most common causes of cancer deaths among women, particularly in minorities and in impoverished countries. Cervical dysplasia, a premalignant lesion that can progress to cervical cancer, is caused primarily by a sexually transmitted infection with an oncogenic strain of the human papillomavirus (HPV). Not all women with the virus develop cervical dysplasia or cervical cancer. It has been postulated there are multiple host factors that contribute to progression of disease. Many of these factors, such as nutrient deficiencies, can be reversed, which will result in regression of dysplastic lesions. Studies have shown dietary intervention and nutrient supplementation to be effective in preventing cervical cancer. Additionally, local escharotic treatment combined with systemic treatment shows significant potential in reducing dysplasia. Recent advances in vaccination technology demonstrate the effectiveness of an HPV vaccine. The vaccine, however, may have many social and cost-prohibiting limitations, as well as health side effects.

Pre-clinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens.

Human papillomavirus (HPV) E6 and E7 oncoproteins are attractive targets for T-cell-based immunotherapy of cervical intraepithelial neoplasia (CIN) and cancer. A newly designed vaccine, comprising the HPV16 L2, E6 and E7 as a single fusion protein (TA-CIN), was shown to elicit HPV16-specific CTL, T-helper cells and antibodies in a pre-clinical mouse model. These immune responses effectively prevented outgrowth of HPV16-positive tumour cells in a prophylactic setting as well as in a minimal residual disease setting. CTL immunity was optimally induced when TA-CIN was employed in heterologous prime-boost regimens in combination with TA-HPV, a clinical grade vaccinia-based vaccine. These data provide a scientific basis for the use of TA-CIN, alone or in combination with TA-HPV in future human trials.