Philip Castle

Safety and Acceptability of Three Ablation Treatments for High-Grade Cervical Precancer: Early Data From a Randomized Noninferiority Clinical Trial

PURPOSE This ongoing trial is comparing the efficacy and safety of three ablation treatments for cervical intraepithelial neoplasia grade 2 or higher. Here, we present early data regarding pain, side effects, and acceptability of CO2 gas-based cryotherapy (CO2), nongas cryotherapy, and thermal ablation (TA). Efficacy results are expected to become available in late 2023. MATERIALS AND METHODS This noninferiority randomized trial is taking place in El Salvador, China, and Colombia. Patients are 1,152 eligible women with biopsy-confirmed cervical intraepithelial neoplasia grade 2 or higher who will receive one of three ablation treatments. Pain is measured before, during, and after treatment with a visual analog scale (1-10). Side effects and acceptability are assessed at 6 weeks. RESULTS To date, 1,024 of 1,152 (89%) women were randomly assigned to treatment. The median pain level was higher during TA (4, IQR = 4) than CO2 (2, IQR = 4) or nongas cryotherapy (2, IQR = 4) ( P < .01, range: 0-10). The most common post-treatment symptom was watery discharge, reported by 97.9% of women, and it lasted longer in the CO2 group than the other two treatments (in days, median [IQR]: CO2 = 20[20], nongas cryotherapy = 15[10], TA = 18[15], P < .01). Bleeding was reported more frequently in women treated with TA (27.6%) than CO2 (17.5) or nongas cryotherapy (18.7%) ( P < .01). The majority of patients reported being very satisfied with the treatment they received at 6 weeks (91%) and again at 12 months post-treatment (97%). CONCLUSION Despite differences in pain and side effects across ablation treatments, all were safe and highly acceptable to patients. In addition to efficacy, considerations such as cost and portability may be more significant in choosing a treatment method.

Racial and Ethnic Disparities in Cervical Cancer Incidence, Survival, and Mortality by Histologic Subtype

PURPOSE We conducted an integrated population-based analysis of histologic subtype–specific cervical cancer incidence, survival, and incidence-based mortality by race and ethnicity, with correction for hysterectomy prevalence. METHODS Using the SEER 21 and 18 registries, we selected primary cases of malignant cervical cancer diagnosed among women ≥ 15 years. We evaluated age-adjusted incidence rates among cases diagnosed between 2000 and 2018 (SEER21) and incidence-based mortality rates among deaths from 2005 to 2018 (SEER18), per 100,000 person-years. Rates were stratified by histologic subtype and race/ethnicity (incidence and mortality), and stage, age at diagnosis, and county-level measures of social determinants of health (incidence only). Incidence and mortality rates were corrected for hysterectomy using data from the Behavioral Risk Factor Surveillance System. We estimated 5-year relative survival by histologic subtype and stratified by stage at diagnosis. RESULTS Incidence rates of cervical squamous cell carcinoma were highest in Black and Hispanic women, while incidence rates of cervical adenocarcinoma (ADC) were highest among Hispanic and White women, particularly for localized ADC. County-level income and education variables were inversely associated with squamous cell carcinoma incidence rates in all racial and ethnic groups but had less influence on ADC incidence rates. Black women had the highest overall mortality rates and lowest 5-year relative survival, irrespective of subtype and stage. Disparities in survival were particularly pronounced for Black women with regional and distant ADC, compared with other racial/ethnic groups. CONCLUSION Although Black women are less likely to be diagnosed with ADC compared with all other racial/ethnic groups, they experience the highest mortality rates for this subtype, likely attributed to the poor survival observed for Black women with regional and distant ADC.

Clarifying the Equivocal Diagnosis of Cervical Intraepithelial Neoplasia 2: Still a Work in Progress

Expanding Cervical Cancer Screening in Mozambique: Challenges Associated With Diagnosing and Treating Cervical Cancer

PURPOSE Mozambique has one of the highest burdens of cervical cancer globally. Treatment options are few as most women present with advanced disease, and there are limited trained health professionals and health care resources. The objective of this study was to describe the outcomes of women diagnosed with invasive cancer as part of the Mozambican women undergoing cervical cancer screening with human papillomavirus (HPV) testing in conjunction with family planning services (MULHER) study. MATERIALS AND METHODS Women age 30-49 years were prospectively enrolled in the MULHER study and offered screening with primary HPV testing followed by treatment of screen-positive women with thermal ablation or excision as appropriate. Women with cervical examination findings suspicious for cancer were referred to one of the three gynecologic oncologists in the country. RESULTS Between January 2020 and January 2023, 9,014 women underwent cervical cancer screening and 30 women were diagnosed with cervical cancer. In this cohort, four patients (13.3%) had early-stage disease, 18 (60.0%) had locally advanced disease, one (3.3%) had distant metastatic disease, and seven (23.3%) did not have staging information available. Five patients (16.6%) died without receiving oncologic treatment, and seven patients (23.3%) are still awaiting treatment. Of the remaining 18 patients, three (17.6%) underwent surgery and four (23.5%) received radiotherapy. Eleven (36.7%) patients received only chemotherapy. CONCLUSION As cervical screening programs are implemented in low-resource settings, there will likely be an increase in the number of women diagnosed with invasive cervical cancer. Our results in Mozambique demonstrate the need to increase access to advanced surgery, radiation, and palliative care services.

Long-Term Prospective Cohort Study of Cervical Cancer Screening Using Triage of Women Who Are Human Papillomavirus–Positive With Dual Stain and Human Papillomavirus Genotyping

PURPOSE Primary human papillomavirus (HPV) testing has the best tradeoff of benefits and harms for cervical screening but requires triage to determine management among HPV positives. We conducted a prospective observational study to evaluate triage of women who are HPV-positive using dual stain (DS) and HPV genotyping. MATERIALS AND METHODS We included 9,645 consecutive women who are HPV-positive undergoing cervical screening in two periods between 2015 and 2017 in the organized cervical screening program at Kaiser Permanente Northern California. Absolute risk and clinical performance of DS and cytology for detection of cervical intraepithelial neoplasia grade 3 and greater (CIN3+) were estimated overall and by HPV genotype and by age. Cumulative absolute risk of CIN3+ was modeled over 5 years using a prevalence-incidence mixture model, which allows estimating risk accounting for differences in disease ascertainment, surveillance intervals, and compliance. RESULTS The baseline risk of CIN3+ was 9.4% and 0.8% for women testing positive and negative for DS, respectively, and 6.9% and 2.0% for women testing positive and negative for cytology, respectively. Sensitivity, specificity, and predictive values for CIN3+ detection were better for DS compared with cytology over 5 years ( P < .001 for all comparisons). Risk in women with HPV16-positive/negative for intraepithelial lesion or malignancy was substantially higher than the risk in women with HPV16-positive/DS-negative (7.5% v 2.9%, P < .001). DS had better triage performance compared with cytology in all age groups and in women positive for HPV types other than HPV16 or HPV18. CONCLUSION Long-term reassurance of low risk among DS negatives suggests that DS detects molecular changes earlier in the carcinogenic pathway than cytology. DS has better risk stratification than cytology overall, within HPV risk strata, and across all screening age groups and is a better option for triage of vaccinated populations.

Whole‐genome sequencing of 1,083 HPV45 cases and controls identifies genetic variants associated with glandular cervical lesions

AbstractHuman papillomavirus type 45 (HPV45) causes ~6% of all cervical cancers and an even greater proportion of adenocarcinomas, the latter of which are challenging to detect using current cervical cancer screening. Little is known about how HPV45 genetic variation is related to the risk of cervical precancer/cancer. To investigate this, we whole‐genome sequenced a total of 1,083 HPV45‐positive samples from two large studies. We evaluated associations of HPV45 genetic variation (sublineages, subclades, and SNPs) with histology‐specific precancer/cancer risk using logistic regression and evaluated risk modification by self‐reported race/ethnicity. Compared to the common A1 sublineage, A2 and B1 were associated with increased precancer/cancer (A2, OR = 3.9, 95% CI = 1.9–8.5; B1, OR = 2.7, 95% CI = 1.3–5.8; B2, OR = 3.3, 95% CI = 1.6–7.3), and most strongly with the glandular precancers/cancers (AIS/ADC; A2, OR = 6.9, 95% CI = 1.0–184; B1, OR = 6.2, 95% CI = 1.1–159). The A2 sublineage was most prevalent in women in East Asia and women who self‐reported as Asian/Pacific Islander (PI) in the U.S.; East Asian and Asian/PI women had the greatest precancer/cancer risk associated with A2 infections (OR = 5.8, 95% CI = 1.3–37.4) compared to all other sublineages among these women. We further evaluated precancer/cancer risk associations for 262 individual HPV45 SNPs and identified four SNPs significantly associated with only glandular precancers/cancers after correction for multiple tests (ORs ranged 7.8–20.7). One of these SNPs was a nonsynonymous variant in both overlapping viral E2/E4 ORFs. In summary, we show that HPV45 genetic variation influences the risk of precancer/cancer, specifically glandular precancer/cancer. Further studies of these genetic variants may improve our understanding of glandular lesions.