Robotic versus vaginal radical trachelectomy for reproductive-aged patients with early-stage cervical carcinoma: A multi-center cohort study.

BACKGROUND: A randomized non-inferiority trial showed worse survival in women with early-stage cervical cancer treated with radical hysterectomy by minimally invasive approach compared to laparotomy; the impact of surgical approach on survival following radical trachelectomy is unknown. OBJECTIVE: To examine oncologic outcomes in women with early-stage cervical cancer who underwent robotic or vaginal radical trachelectomy at Canadian cancer centers with the highest volumes of radical trachelectomy procedures. STUDY DESIGN: Retrospective multi-centre cohort analysis which includes patients who had surgery between 2006 and 2019. Women with International FIGO 2009 stage IA-IB cervical cancer who underwent radical trachelectomy and lymph node assessment were grouped by surgical approach (vaginal versus robotic surgery). RESULTS: A total of 197 patients were included from 4 regional referral centres. 56 women underwent robotic radical trachelectomy and 141 underwent vaginal radical trachelectomy. All patients had lymph node assessment by a minimally invasive technique. Median age was 32 years, median tumor size was 12 mm, and median depth of invasion was 5 mm. Recurrence-free survival was 97% in both groups at a median follow-up of 57 months. On multivariable analysis, after adjusting for previously chosen confounders (high risk pathologic criteria, tumor size, and LVSI) there was no statistically significant difference in PFS between the 2 groups (HR 2.1, 95%CI 0.3-7.1, p = 0.5). Tumor size larger than 2 cm (HR 9.4, 95%CI 2.8-26, p = 0.003) was the only variable predictive of recurrence. CONCLUSION: Survival outcomes were excellent in both cohorts of patients undergoing robotic vs. vaginal radical trachelectomy. The surgical approach was not significantly associated with risk of recurrence after adjusting for clinically important confounders.

A parallel-group, randomized trial examining impact of colposcopy results delivery by a Nurse Liaison on patient-reported outcomes and adherence.

OBJECTIVE: Cervical cancer is on the rise in Canada. Addressing patient anxiety and improving patient understanding of colposcopy and results may improve adherence. This randomized controlled trial examined the impact of colposcopy results delivery by a nurse liaison versus the referring primary care provider (PCP) on patient anxiety, and secondary outcomes including patient satisfaction, knowledge of diagnosis, and 9-month adherence to follow-up. METHODS: Patients ≥ 18 years old presenting for initial appointment at the study colposcopy clinic were randomized 1:1 to intervention group (nurse liaison) versus control group (PCP). After receiving colposcopy results, participants completed online measures of anxiety (STAI), health care satisfaction scales (PSQ-18, HAI, VSQ-9), self-reported colposcopy diagnosis, and demographics. Chart review at 9 months assessed adherence to recommended colposcopy follow-up. Groups were compared on continuous and categorical variables, controlling for diagnosis severity and trait anxiety. RESULTS: The intervention group had significantly lower state anxiety with STAI-state mean scores 37.3 versus 40.7 in controls (P = 0.03). Intervention group participants were more likely to correctly report their diagnosis (84% vs. 66.3%, P = 0.003). Questionnaire responders were more likely to be in the intervention group and had a higher proportion of CIN2+ pathology. There were no differences in demographics, patient satisfaction, or adherence to follow-up between groups. CONCLUSION: Direct delivery of colposcopy results by a trained nurse liaison was associated with decreased patient anxiety around colposcopy results, and increased patient knowledge regarding diagnosis. This model may be considered to improve patient-centered care. OBJECTIF: Le cancer du col de l'utérus est en augmentation au Canada. Il est possible d'améliorer l'observance des patientes en se préoccupant de leur anxiété et en leur expliquant bien la colposcopie et les résultats. Cet essai clinique randomisé a examiné l'impact de la transmission des résultats de colposcopie par une infirmière de liaison ou par le médecin de première ligne (MPL) demandeur sur l'anxiété des patientes. Les critères de jugement secondaires étaient la satisfaction des patientes, la connaissance du diagnostic et l'observance du suivi à 9 mois. MéTHODES: Les patientes de 18 ans ou plus se présentant pour un premier rendez-vous à la clinique de colposcopie de l'étude ont été assignées aléatoirement, dans un ratio de 1:1, dans le groupe intervention (infirmière de liaison) ou le groupe témoin (MPL). Après avoir reçu les résultats de la colposcopie, les participantes ont rempli en ligne l'échelle d'anxiété (STAI) et les échelles de satisfaction des soins de santé (PSQ-18, HAI, VSQ-9) et donné leur diagnostic autodéclaré de la colposcopie et leurs caractéristiques démographiques. L'examen des dossiers à 9 mois a permis d'évaluer l'observance du suivi post-colposcopie recommandé. Les groupes ont été comparés en fonction de variables continues et nominales en prenant en compte la gravité du diagnostic et le trait d'anxiété. RéSULTATS: Le groupe intervention présentait un état anxiété significativement plus faible, le score moyen de l'échelle STAI étant de 37,3 comparativement à 40,7 dans le groupe témoin (P = 0,03). Les participantes du groupe intervention étaient plus susceptibles de correctement déclarer leur diagnostic (84 % p/r à 66,3 %; P = 0,003). Les personnes ayant répondu au questionnaire étaient plus susceptibles d'appartenir au groupe intervention et avaient une plus forte proportion de pathologies CIN2+. Il n'y a pas eu de différences entre les groupes en ce qui concerne les caractéristiques démographiques, la satisfaction des patientes et l'observance du suivi. CONCLUSION: La communication directe des résultats de la colposcopie par une infirmière de liaison qualifiée a été associée à une diminution de l'anxiété des patientes face aux résultats de l'examen et à une augmentation des connaissances des patientes concernant le diagnostic. Ce modèle peut être envisagé pour améliorer les soins centrés sur la patiente.

Human papillomavirus-based screening at extended intervals missed fewer cervical precancers than cytology in the HPV For Cervical Cancer (HPV FOCAL) trial.

While cervix screening using cytology is recommended at 2- to 3-year intervals, given the increased sensitivity of human papillomavirus (HPV)-based screening to detect precancer, HPV-based screening is recommended every 4- to 5-years. As organized cervix screening programs transition from cytology to HPV-based screening with extended intervals, there is some concern that cancers will be missed between screens. Participants in HPV FOr CervicAL Cancer (HPV FOCAL) trial received cytology (Cytology Arm) at 24-month intervals or HPV-based screening (HPV Arm) at 48-month intervals; both arms received co-testing (cytology and HPV testing) at exit. We investigated the results of the co-test to identify participants with cervical intraepithelial neoplasia grade 2 or higher (CIN2+) who would not have had their precancer detected if they had only their arm's respective primary screen. In the Cytology Arm, 25/62 (40.3%) identified CIN2+s were missed by primary screen (ie, normal cytology/positive HPV test) and all 25 had normal cytology at the prior 24-month screen. In the HPV arm, three CIN2+s (3/49, 6.1%) were missed by primary screen (ie, negative HPV test/abnormal cytology). One of these three misses had low-grade cytology findings and would also not have been referred to colposcopy outside of the trial. Multiple rounds of cytology did not detect some precancerous lesions detected with one round of HPV-based screening. In our population, cytology missed more CIN2+, even at shorter screening intervals, than HPV-based screening. This assuages concerns about missed detection postimplementation of an extended interval HPV-based screening program. We recommend that policymakers consider a shift from cytology to HPV-based cervix screening.

Declining rates of cervical intraepithelial neoplasia in British Columbia, Canada: An ecological analysis on the effects of the school-based human papillomavirus vaccination program.

Since 2008, girls in British Columbia (BC), Canada, have been offered HPV vaccination through a school-based, publicly funded immunization program. The oldest birth cohort eligible for the vaccination program was born in 1994 and uptake is on average 63%. To evaluate the impact of the HPV vaccine in BC, ecological trends in cervical intraepithelial neoplasia (CIN) rates were assessed in young women before and after the implementation of the HPV vaccination program. Information on all Pap smears and histopathological abnormalities, in calendar years 2004-2017 in women 16-28 years of age in BC were obtained from the population-based BC Cancer Cervix Screening Program database. Rates of CIN 2 and 3 were calculated as the number of cases divided by the number of cytology specimens for that period. Rate ratios (RR) were calculated by negative binomial piecewise regression. Age-centered incidence rates of CIN 2 and 3 in BC declined significantly among women 16-23 years of age after HPV vaccine introduction compared to before vaccine introduction. The overall reduction postvaccination for CIN2 and 3 in women 16-23 years was respectively 62% (95% CI 54-68%) and 65% (95% CI 58-71%). Age-specific rates for CIN2 significantly declined for those 18-22 years of age and for those 19, 20 and 23 years of age for CIN3. Among women 24-28 years of age no decline in CIN2 and 3 rate over time was observed. The observed reduction in CIN 2 and 3 rates since the introduction of the school-based HPV vaccine program might illustrate the population impact of the BC provincial school-based HPV vaccination program.

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening.

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25-65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56-1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43-1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14-65) and intervention 43 (95% CI: 25-73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1-0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.

The Efficacy of the Quadrivalent Human Papillomavirus Vaccine in Girls and Women Living With Human Immunodeficiency Virus.

BACKGROUND: Human papillomavirus (HPV) vaccination is safe and efficacious in women without human immunodeficiency virus (HIV). Although good immunogenicity has been observed in women living with HIV (WLWH), efficacy data in this population are needed. METHODS: We enrolled 420 females aged ≥9 years (range, 9-65) living with HIV. Participants were to receive 3 doses of qHPV vaccine (0/2/6 months). The main endpoint was vaccine failure (ie, incident persistent qHPV infection, cervical intraepithelial neoplasia of grade 2 or higher [CIN2+], or genital warts). We compared these rates to published rates in vaccinated and unvaccinated women without HIV as well as unvaccinated WLWH. RESULTS: Among 279 eligible women, median follow-up was 2 years. In the intention-to-treat population, the incidence rate (IR) of persistent qHPV (HPV6/11/16/18) was 2.3 per 100 person-years (/100PY) (95% confidence interval [CI], 1.1-4.1), and IR of genital warts was 2.3/100PY (95% CI, 1.2-4.1). In the per-protocol efficacy population, IR of persistent qHPV was 1.0/100PY (95% CI, 0.3-2.6) and of genital warts was 1.0/100PY (95% CI, 0.3-2.5). No cases of CIN2+ occurred. Reported rates of qHPV-related infection and disease within vaccinated women without HIV, unvaccinated women without HIV, and vaccinated WLWH: 0.1 (95% CI, 0.02-0.03), 1.5 (95% CI, 1.1-2.0), and 1.2 (95% CI, 0.2-3.4) /100PY, respectively. The rate of persistent qHPV among vaccinated WLWH was lower than among unvaccinated WLWH (2.3 vs 6.0/100PY). CONCLUSIONS: Vaccinated WLWH may be at higher risk for vaccine failure than vaccinated women without HIV. However, overall rates of vaccine failure were low, and rates of persistent qHPV were lower than in unvaccinated WLWH.

Cervical Cancer Screening in Immunocompromised Women.

In the context of changing recommendations for cervical cancer screening, differing recommendations in each province, and a lack of guidance for cervical screening of immunocompromised women, this article provides specific recommendations for cervical cancer screening of immunocompromised women in Canada.

Screening for Anal Cancer in Women With a History of Vulvar High-Grade Squamous Intraepithelial Lesions.

OBJECTIVES: The primary obkective was to determine the prevalence of (a) a positive anal cancer screen and (b) histological anal high-grade squamous intraepithelial lesion (HSIL) in women undergoing surveillance for previously diagnosed and treated human papillomavirus (HPV)-associated vulvar HSIL. The secondary objective was to determine the patients' acceptability of the screen. MATERIALS AND METHODS: This is a single-institution, cross-sectional pilot study. Women, aged 30 to 80 years, with a history of biopsy-proven vulvar HSIL were invited to undergo screening for anal cancer. Positive screen characterized by abnormalities in any of the following: anal high-risk HPV (HR-HPV); anal cytology; and digital anorectal examination. All women with an abnormal screen were referred for high-resolution anoscopy. All women completed a postscreen questionnaire. RESULTS: Fifty-seven patients were recruited. The median (interquartile range) age was 61.5 (51.0-68.0) years. The prevalence of a positive screen was 56.1% (95% CI = 43.3%-68.2%). Of the 32 screen-positive patients, 12 had both abnormal cytology and HR-HPV, 3 had positive HR-HPV alone, and 17 had abnormal cytology alone. Of the 29 patients with a positive screen who went on to anoscopy, the prevalence of anal HSIL was 33.3% (95% CI = 19.2%-51.2%). The prevalence of anal HSIL among all of those who had screening (N = 57) was 18.2% (95% CI = 10.2%-30.3%). The examination was well tolerated with 100% of patients, indicating that they would have the screening again. CONCLUSIONS: Women with vulvar HSIL have an increased risk of developing anal HSIL. Larger studies are needed to define optimal screening protocols as well as algorithms for management in high-risk populations.

Identifying Barriers to Treatment for Women With Cervical Dysplasia in Rural Northern British Columbia.

OBJECTIVE: This study seeks to identify barriers to colposcopy examination faced by patients living in Northern BC to improve outcomes for women at risk of developing cervical cancer. METHODS: A retrospective chart review (n = 309) was conducted in the four colposcopy clinics in Northern BC to collect information regarding patients who were referred for colposcopy after abnormal cytology. Demographic factors associated with non-attendance were identified as barriers to accessing care. Aggregate data from the Cervical Cancer Screening Program (n = 4265) were used to calculate wait times by health region across BC. RESULTS: The odds of having missed an appointment was highest for women who were pregnant (OR 4.0) or attending site D vs. site A (OR 6.0); however, only clinic location remained significant in a multivariable model. Wait times were longer for women who had ever missed appointments, and varied among the sites, with site A and D having significantly longer wait times than the remaining sites. The Northern Health Authority had the longest overall median colposcopy wait time for high-grade cytology in the province at 41 days longer than the provincial average of 62 days. CONCLUSION: The Northern Health Authority faces unique challenges associated with geography and patient population that are associated with longer wait times for colposcopy when compared with other health authorities in the province.

Outcomes of Conservative Management of High Grade Squamous Intraepithelial Lesions in Young Women.

OBJECTIVE: The aim of the study was to determine regression rates of cervical intraepithelial neoplasia (CIN) 2 and 3 in women younger than 24 years, followed conservatively for up to 24 months. MATERIALS AND METHODS: This is a retrospective chart review of colposcopy patients in clinic database based on the following: (1) younger than 24 years at first visit; (2) first visit January 1, 2010, to May 31, 2013, and at least 1 follow-up visit after diagnosis; (3) histologic diagnosis of CIN2+; and (4) optimal conservative management (observation for up to 24 months or to 24 years, whichever occurred first). Patient information and clinical/pathologic data were extracted from charts to examine patient characteristics and treatment outcomes, CIN2+ regression rates, median times to regression for CIN2 versus CIN3 (Kaplan-Meier survival analysis), and predictors of regression (multivariate logistic regression analysis). RESULTS: A total of 154 women met criteria. The most severe histological diagnoses were CIN2 in 99 (64.3%), CIN3 in 51 (33.1%), and adenocarcinoma in situ in 4 (2.6%). Adenocarcinoma in situ was immediately treated. In follow-up, CIN2 regressed to CIN1 or negative in 74 women (74.7%)-median time to regression, 10.8 months. Cervical intraepithelial neoplasia 3 regressed in 11 women (21.6%)-median time to regression not reached (last follow-up censored at 52.7 months). Cervical intraepithelial neoplasia 2 on biopsy, low grade referral Pap, and younger age predicted regression. Overall, 49 women (31.8%) were treated. CONCLUSIONS: Conservative management should continue to be recommended to young women with CIN2. Rigorous retention mechanisms are required to ensure that these women return for follow-up.

Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial.

Importance: There is limited information about the relative effectiveness of cervical cancer screening with primary human papillomavirus (HPV) testing alone compared with cytology in North American populations. Objective: To evaluate histologically confirmed cumulative incident cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) detected up to and including 48 months by primary HPV testing alone (intervention) or liquid-based cytology (control). Design, Setting, and Participants: Randomized clinical trial conducted in an organized Cervical Cancer Screening Program in Canada. Participants were recruited through 224 collaborating clinicians from January 2008 to May 2012, with follow-up through December 2016. Women aged 25 to 65 years with no history of CIN2+ in the past 5 years, no history of invasive cervical cancer, or no history of hysterectomy; who have not received a Papanicolaou test within the past 12 months; and who were not receiving immunosuppressive therapy were eligible. Interventions: A total of 19 009 women were randomized to the intervention (n = 9552) and control (n = 9457) groups. Women in the intervention group received HPV testing; those whose results were negative returned at 48 months. Women in the control group received liquid-based cytology (LBC) testing; those whose results were negative returned at 24 months for LBC. Women in the control group who were negative at 24 months returned at 48 months. At 48-month exit, both groups received HPV and LBC co-testing. Main Outcomes and Measures: The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization. The cumulative incidence of CIN2+ was a secondary outcome. Results: Among 19 009 women who were randomized (mean age, 45 years [10th-90th percentile, 30-59]), 16 374 (8296 [86.9%] in the intervention group and 8078 [85.4%] in the control group) completed the study. At 48 months, significantly fewer CIN3+ and CIN2+ were detected in the intervention vs control group. The CIN3+ incidence rate was 2.3/1000 (95% CI, 1.5-3.5) in the intervention group and 5.5/1000 (95% CI, 4.2-7.2) in the control group. The CIN3+ risk ratio was 0.42 (95% CI, 0.25-0.69). The CIN2+ incidence rate at 48 months was 5.0/1000 (95% CI, 3.8-6.7) in the intervention group and 10.6/1000 (95% CI, 8.7-12.9) in the control group. The CIN2+ risk ratio was 0.47 (95% CI, 0.34-0.67). Baseline HPV-negative women had a significantly lower cumulative incidence of CIN3+ at 48 months than cytology-negative women (CIN3+ incidence rate, 1.4/1000 [95% CI, 0.8-2.4]; CIN3+ risk ratio, 0.25 [95% CI, 0.13-0.48]). Conclusions and Relevance: Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months. Further research is needed to understand long-term clinical outcomes as well as cost-effectiveness. Trial Registration: isrctn.org Identifier: ISRCTN79347302.

HPV for cervical cancer screening (HPV FOCAL): Complete Round 1 results of a randomized trial comparing HPV-based primary screening to liquid-based cytology for cervical cancer.

Complete Round 1 data (baseline and 12-month follow-up) for HPV FOCAL, a randomized trial establishing the efficacy of HPV DNA testing with cytology triage as a primary screen for cervical cancer are presented. Women were randomized to one of three arms: Control arm - Baseline liquid-based cytology (LBC) with ASCUS results triaged with HPV testing; Intervention and Safety arms - Baseline HPV with LBC triage for HPV positives. Results are presented for 15,744 women allocated to the HPV (intervention and safety combined) and 9,408 to the control arms. For all age cohorts, the CIN3+ detection rate was higher in the HPV (7.5/1,000; 95%CI: 6.2, 8.9) compared to the control arm (4.6/1,000; 95%CI: 3.4, 6.2). The CIN2+ detection rates were also significantly higher in the HPV (16.5/1,000; 95%CI: 14.6, 18.6) vs. the control arm (10.1/1,000; 95%CI: 8.3, 12.4). In women ≥35 years, the overall detection rates for CIN2+ and CIN3+ were higher in the HPV vs. the control arm (CIN2+:10.0/1,000 vs. 5.2/1,000; CIN3+: 4.2/1,000 vs. 2.2/1,000 respectively, with a statistically significant difference for CIN2+). HPV testing detected significantly more CIN2+ in women 25-29 compared to LBC (63.7/1,000; 95%CI: 51.9, 78.0 vs. 32.4/1,000; 95%CI: 22.3, 46.8). HPV testing resulted in significantly higher colposcopy referral rates for all age cohorts (HPV: 58.9/1,000; 95%CI: 55.4, 62.7 vs. CONTROL: 30.9/1,000; 95%CI: 27.6, 34.6). At completion of Round 1 HPV-based cervical cancer screening in a population-based program resulted in greater CIN2+ detection of across all age cohorts compared to LBC screening.

Post-Loop Electrosurgical Excision Procedure High-Risk Human Papillomavirus Testing as a Test of Cure: The British Columbia Experience.

OBJECTIVES: To determine whether Hybrid Capture 2 High-Risk HPV DNA Test (HC2) can be used as a test of cure in women treated for cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and allow discharge from colposcopy follow-up with a return to a cytology-based screening program for HC2-negative women. MATERIALS AND METHODS: Data were analyzed for all women who underwent a loop electrosurgical excision procedure between August 1, 2008, and June 30, 2011, and had a valid HC2 result after loop electrosurgical excision procedure and follow-up histopathology result, to determine risk of persistent or recurrent CIN 2+ in HC2-positive and HC2-negative women. RESULTS: Two thousand three hundred forty women had adequate biopsies and valid HC2 results. Of 460 HC2-positive women, 118 (25.7%) were diagnosed with CIN 2+, whereas of 1,880 HC2-negative women, 35 (1.9%) had a subsequent diagnosis of CIN 2+ (p < .0002) yielding a HC2-negative predictive value of 98.1% (95% confidence interval = 97.4-98.7). Of 460 HC2-positive women, 306 initially had negative biopsies. In the subsequent 36 months, 38 of the 306 were diagnosed with CIN 2+. CONCLUSIONS: We conclude that women with a negative HC2 test can safely return to routine annual cytology screening by primary care providers while women who test HC2 positive are at higher risk and should continue to be followed by colposcopy, even if their initial biopsy is negative.

Disease detection and resource use in the safety and control arms of the HPV FOCAL cervical cancer screening trial.

BACKGROUND: The HPV FOCAL Trial is a RCT comparing human papilloma virus (HPV) with Liquid Based Cytology (LBC) screening for cervical cancer. Results are presented for the comparison of the Safety and Control arms after two rounds. METHODS: HPV FOCAL included randomisation of women aged 25-65 into the Safety arm, where they were initially screened with HPV and the Control arm, where they received entry screening with LBC, with both arms screened again with LBC at 24 months. RESULTS: There are 6203 (Safety) and 6075 (Control) women included in this analysis. For the Safety vs Control arms, Round 1 screening resulted in increased detection of cervical intraepithelial neoplasia 2 or worse (CIN2+),15.3 vs 10.4 per 1000, RR=1.48 (95%CI=1.08-2.03) and higher colposcopy referral rates, 5.6% vs 3.2%. LBC screening at 24 months resulted in similar colposcopy referral rates, 1.5% vs 1.9%, and decreased CIN2+ detection, 2.0 vs 4.7 per 1000, RR=0.43 (95%CI=0.21-0.88) in the Safety vs Control arms. CIN2+ detection and colposcopy referral rates declined with increasing age in both arms. One round of HPV screening detected similar levels of CIN2+ as two rounds of LBC screening. INTERPRETATION: CIN2+ detection at 2 years was lower in those screened by HPV, indicating an improved 2-year negative predictive value of the HPV test.

Evidence of Decreased Long-term Risk of Cervical Precancer after Negative Primary HPV Screens Compared with Negative Cytology Screens in a Longitudinal Cohort Study.

BACKGROUND: The growing use of primary human papillomavirus (HPV) cervical cancer screening requires determining appropriate screening intervals to avoid overtreatment of transient disease. This study examined the long-term risk of cervical precancer after HPV screening to inform screening interval recommendations. METHODS: This longitudinal cohort study (British Columbia, Canada, 2008 to 2022) recruited women and individuals with a cervix who received 1 to 2 negative HPV screens (HPV1 cohort, N = 5,546; HPV2 cohort, N = 6,624) during a randomized trial and women and individuals with a cervix with 1 to 2 normal cytology results (BCS1 cohort, N = 782,297; BCS2 cohort, N = 673,778) extracted from the provincial screening registry. All participants were followed through the registry for 14 years. Long-term risk of cervical precancer or worse [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)] was compared between HPV and cytology cohorts. RESULTS: Cumulative risks of CIN2+ were 3.2/1,000 [95% confidence interval (CI), 1.6-4.7] in HPV1 and 2.7/1,000 (95% CI, 1.2-4.2) in HPV2 after 8 years. This was comparable with the risk in the cytology cohorts after 3 years [BCS1: 3.3/1,000 (95% CI, 3.1-3.4); BCS2: 2.5/1,000 (95% CI, 2.4-2.6)]. The cumulative risk of CIN2+ after 10 years was low in the HPV cohorts [HPV1: 4.7/1,000 (95% CI, 2.6-6.7); HPV2: 3.9 (95% CI, 1.1-6.6)]. CONCLUSIONS: Risk of CIN2+ 8 years after a negative screen in the HPV cohorts was comparable with risk after 3 years in the cytology cohorts (the benchmark for acceptable risk). IMPACT: These findings suggest that primary HPV screening intervals could be extended beyond the current 5-year recommendation, potentially reducing barriers to screening.

Preoperative radiotherapy for inoperable stage II endometrial cancer: insights into improving treatment and outcomes.

OBJECTIVE: To review recurrence patterns and survival outcomes of women receiving preoperative radiotherapy for clinical stage II endometrial cancer in British Columbia. METHODS: We performed a retrospective population-based cohort study of all patients with clinical stage II endometrial cancer who were referred to the British Columbia Cancer Agency from 2000 to 2008, deemed ineligible for primary surgery, and therefore offered preoperative radiotherapy followed by surgery. Patient demographics, uterine risk factors, timing and details of treatments, and timing and sites of recurrence were obtained from patient records. Primary outcome measures were the sites and rates of recurrence and recurrence-free survival. RESULTS: We identified 29 patients with a mean age of 61 years (range 41 to 83) and median follow-up of 3.1 years (range 0.3 to 5.3). Three-year overall survival was 79%, and median recurrence-free survival was 2.5 years. Eight patients had recurrence of disease (27.6%), with a median time to recurrence of 1.3 years, (range 0.4 to 2.7). Six of these eight women had two or more high-risk uterine factors (deep myometrial invasion, grade 3 tumour), ovarian involvement, or adverse histological type (carcinosarcoma), compared with only one of 21 patients without recurrence. Seven of eight women had recurrence outside the radiated volume of tissue. Median survival after recurrence was 1.0 years (range 0.4 to 2.2). CONCLUSIONS: Women with clinical stage II endometrial cancer had a significant risk of recurrence when treated with preoperative radiotherapy followed by surgery. They were more likely to have distant recurrences, implying the need for an alternate treatment paradigm.

Objectif : Passer en revue les profils de récurrence et les issues en matière de survie, en ce qui concerne les femmes qui reçoivent une radiothérapie préopératoire en raison de la présence d'un cancer de l'endomètre de stade clinique II en Colombie-Britannique. Méthodes : Nous avons mené une étude de cohorte rétrospective en population générale qui portait sur toutes les patientes présentant un cancer de l'endomètre de stade clinique II qui ont été orientées vers la British Columbia Cancer Agency entre 2000 et 2008, qui étaient estimées comme étant inadmissibles à la chirurgie primaire et qui, donc, se sont vu offrir une radiothérapie préopératoire suivie d'une chirurgie. Les caractéristiques démographiques des patientes, les facteurs de risque utérins, la chronologie et les détails des traitements, et la chronologie et les sites des récurrences ont été tirés des dossiers des patientes. La survie sans récurrence et les sites et les taux de récurrence constituaient les critères d'évaluation primaires. Résultats : Nous avons identifié 29 patientes dont l'âge moyen était de 61 ans (plage de 41 à 83) et dont le suivi médian était de 3,1 ans (plage de 0,3 à 5,3). Le taux global de survie à trois ans était de 79 % et la survie médiane sans récurrence était de 2,5 ans. Huit patientes ont connu une récurrence de la maladie (27,6 %), le délai médian avant l'apparition de la récurrence étant de 1,3 an (plage de 0,4 à 2,7). Six de ces huit femmes présentaient deux facteurs de risque utérins élevés ou plus (envahissement myométrial profond, tumeur de grade 3), un envahissement ovarien ou un type histologique indésirable (carcinosarcome), par comparaison avec seulement une des 21 patientes n'ayant pas connu de récurrence. Sept des huit femmes ont connu une récurrence au-delà du volume de tissu irradié. La survie médiane à la suite de la récurrence était de 1,0 an (plage de 0,4 à 2,2). Conclusions : Les femmes présentant un cancer de l'endomètre de stade clinique II étaient exposées à un risque significatif de récurrence lorsqu'elles ont été traitées au moyen d'une radiothérapie préopératoire suivie d'une chirurgie. Elles étaient plus susceptibles de présenter des récurrences distantes, ce qui sous-entend la nécessité de formuler un autre paradigme de traitement.

Age-Specific Trends of Invasive Cervical Cancer Incidence in British Columbia, Canada, 1971-2017.

This study examined invasive cervical cancer (ICC) incidence trends in British Columbia (BC) by age and stage-at-diagnosis relative to World Health Organization ICC elimination targets (4 per 100,000 persons). Incident ICC cases (1971-2017) were obtained from the BC Cancer Registry. Annual age-standardized incidence rates (ASIRs) per 100,000 persons were generated using the direct method. ASIRs were examined among all ages 15+ years and eight age groups using Joinpoint Regression with the Canadian 2011 standard population. Standardized rate ratios (SRRs) compared stage II-IV (late) versus stage I (early) ASIRs by age (2010-2017). ICC ASIRs did not reach the elimination target. ASIRs declined from 18.88 to 7.08 per 100,000 persons (1971-2017). Stronger declines were observed among ages 45+ years, with the largest decline among ages 70-79 years (AAPC = -3.2%, 95% CI = -3.9% to -2.6%). Among ages 25-69 years, varying levels of attenuation in declining trends and stabilization were observed since the 1980s. SRRs indicated higher rates of late-stage ICC among ages 55+ years (SRR-55-69 years = 1.34, 95% CI = 1.08-1.71). Overall, ICC incidence declined in BC since 1971 but did not reach the elimination target. The pace of decline varied across age groups and increased with age. Continued efforts are needed to progress cervical cancer elimination among all age groups.

HSV-2 infection and HPV incidence, persistence, and precancerous lesions in a cohort of HPV-vaccinated women living with HIV.

BACKGROUND: Several co-factors for HPV oncogenesis have been proposed, including co-infection with HSV-2. We assessed the relationship between HSV-2 infection and HPV-related outcomes in quadrivalent HPV-vaccinated (qHPV) women living with HIV (WLWH). METHODS: In this multi-site study of immunogenicity and efficacy of the qHPV vaccine in WLWH, visits took place at months -3, 0, 2, 6, 12, 18, 24, and annually thereafter. Participants provided clinical data and cervico-vaginal swabs for HPV DNA detection; baseline serum was tested for HSV-2 type-specific antibodies. We used non-parametric statistics to compare HPV-related outcomes by HSV-2 serostatus and use of anti-HSV medication. RESULTS: 151 baseline serum samples underwent HSV-2 testing. At baseline, median age was 39 years, median CD4 count was 500 cells/mm3, and 70% had an HIV viral load of <50 copies/mL. Baseline HSV-2 seroprevalence was 76.2%. HSV-2 seropositivity was associated with increased age (p = 0.006). Controlling for age and median CD4 count, HSV-2 seropositivity was not associated with HPV incidence, persistence, and precancerous lesions. The use of anti-HSV medications was associated with higher odds of HSIL cytology (OR = 3.35, 95% CI = 1.03,11.26) and a greater number of HPV types detected (OR = 1.18, 95% CI = 1.00,1.39). Results were similar in sensitivity analyses using an index value of 3.5. The presence of HSV lesions during the study was not associated with HPV outcomes. CONCLUSIONS: HSV-2 seropositivity was common in this cohort of WLWH in Canada but was not associated with multiple measures of HPV incidence, persistence, and precancerous lesions. However, the use of anti-HSV medications was associated with HSIL cytology and number of HPV types detected.

Colposcopy referral rates post-introduction of primary screening with human papillomavirus testing: evidence from a large British Columbia cohort study.

Background: Shifting from cytology to human papillomavirus (HPV)-based cervical cancer screening will initially increase colposcopy referrals. The anticipated impact on health systems has been raised as a concern for implementation. It is unclear if the higher rate of colposcopy referrals is sustained after initial HPV-based screens or reverts to new lower baselines due to earlier detection and treatment of precancer. This study aimed to investigate long-term rates of colposcopy referrals after participation in HPV-based screening. Methods: Participants of HPV for Cervical Cancer Screening trial (HPV FOCAL) received one (HPV1, N = 6204) or two (HPV2, N = 9540) HPV-based screens. After exit, they returned to British Columbia's (BC) cytology screening program. A comparison cohort from the BC screening population (BCS, N = 1,140,745) was identified, mirroring trial inclusion criteria. All participants were followed for 10-14 years through the provincial screening registry. Colposcopy referral rates per 1000 screens were calculated for each group. Trial colposcopy referrals for HPV1 and HPV2 were calculated under two referral scenarios: (1) all HPV positive referred to colposcopy; (2) cytology triage with ASCUS or greater referred to colposcopy. Colposcopy referrals from post-trial screens in HPV1 an HPV2 and all screens in BCS were based on actual recommendations from the screening program. A multivariable flexible survival regression model compared hazard ratios (HR) throughout follow-up. Findings: Scenario 2 referral rates were higher during initial HPV screen(s) vs cytology screen (HPV1: 28 per 1000 screens (95% CI: 24, 33), HPV2: 32 per 1000 screens (95% CI: 29, 36), BCS: 8 per 1000 screens (95% CI: 8.9)). However, post-trial rates in HPV1 and HPV2 were significantly lower than in BCS. Cumulative rates in HPV1 and HPV2 approached the cumulative rate in BCS 11-12 years after HPV-based screening (HPV1: 11 per 1000 screens (95% CI: 10, 12), HPV2: 16 per 1000 screens (95% CI: 15-17), BCS: 11 per 1000 screens (95% CI: 10, 11)). Adjusted models demonstrated reductions in referral rates in HPV1 (HR = 0.6, 95% CI: 0.5, 0.7) and HPV2 (HR = 0.7, 95% CI: 0.6, 0.8) relative to BCS by 54 and 72 months post-final HPV screen respectively. Interpretation: Reduced colposcopy referral rates were observed after initial rounds of HPV-based screening. After initial HPV screening, referral rates to colposcopy after cytology triage were below the current rates seen in a centralized cytology program after approximately four years. Any expected increase in referrals at initiation of HPV-based screening could be countered by staged program implementation. Funding: This work was supported by the National Institutes of Health (R01 CA221918), Michael Smith Health Research BC (RT-2021-1595), and the Canadian Institutes of Health Research (MCT82072).

The role of the fallopian tube in ovarian cancer.

High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer. Research over the past decade has strongly suggested that "ovarian" HGSC arises in the epithelium of the distal fallopian tube, with serous tubal intraepithelial carcinomas (STICs) being detected in 5-10% of BRCA1/2 mutation carriers undergoing risk-reducing surgery and up to 60% of unselected women with pelvic HGSC. The natural history, clinical significance, and prevalence of STICs in the general population (ie, women without cancer and not at an increased genetic risk) are incompletely understood, but anecdotal evidence suggests that these lesions have the ability to shed cells with metastatic potential into the peritoneal cavity very early on. Removal of the fallopian tube (salpingectomy) in both the average and high-risk populations could therefore prevent HGSC, by eliminating the site of initiation and interrupting spread of potentially cancerous cells to the ovarian/peritoneal surfaces. Salpingectomy may also reduce the incidence of the 2 next most common subtypes, endometrioid and clear cell carcinoma, by blocking the passageway linking the lower genital tract to the peritoneal cavity that enables ascension of endometrium and factors that induce local inflammation. The implementation of salpingectomy therefore promises to significantly impact ovarian cancer incidence and outcomes.