Extension of cervical screening intervals with primary human papillomavirus testing: observational study of English screening pilot data.

OBJECTIVES: To provide updated evidence about the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cervical cancer after a negative human papillomavirus (HPV) test in primary cervical screening, by age group and test assay. DESIGN: Observational study. SETTING: Real world data from the English HPV screening pilot's first and second rounds (2013-16, follow-up to end of 2019). PARTICIPANTS: 1 341 584 women. INTERVENTIONS: Cervical screening with HPV testing or liquid based cytological testing (cytology or smear tests). Women screened with cytology were referred to colposcopy after high grade cytological abnormalities or after borderline or low grade abnormalities combined with a positive HPV triage test. Women screened with HPV testing who were positive were referred at baseline if their cytology triage test showed at least borderline abnormalities or after a retest (early recall) at 12 and 24 months if they had persistent abnormalities. MAIN OUTCOME MEASURES: Detection of CIN3+ and cervical cancer after a negative HPV test. RESULTS: For women younger than 50 years, second round detection of CIN3+ in this study was significantly lower after a negative HPV screen in the first round than after cytology testing (1.21/1000 v 4.52/1000 women screened, adjusted odds ratio 0.26, 95% confidence interval 0.23 to 0.30), as was the risk of interval cervical cancer (1.31/100 000 v 2.90/100 000 woman years, adjusted hazard ratio 0.44, 0.23 to 0.84). Risk of an incident CIN3+ detected at the second screening round in the pilot five years after a negative HPV test was even lower in women older than 50 years, than in three years in women younger than 50 years (0.57/1000 v 1.21/1000 women screened, adjusted odds ratio 0.46, 0.27 to 0.79). Women with negative HPV tests at early recall after a positive HPV screening test without cytological abnormalities had a higher detection rate of CIN3+ at the second routine recall than women who initially tested HPV negative (5.39/1000 v 1.21/1000 women screened, adjusted odds ratio 3.27, 95% confidence interval 2.21 to 4.84). Detection after a negative result on a clinically validated APTIMA mRNA HPV test was similar to that after clinically validated cobas and RealTime DNA tests (for CIN3+ at the second round 1.32/1000 v 1.14/1000 women screened, adjusted odds ratio 1.05, 0.73 to 1.50). CONCLUSIONS: These data support an extension of the screening intervals, regardless of the test assay used: to five years after a negative HPV test in women aged 25-49 years, and even longer for women aged 50 years and older. The screening interval for HPV positive women who have negative HPV tests at early recall should be kept at three years.

The impact of catch-up bivalent human papillomavirus vaccination on cervical screening outcomes: an observational study from the English HPV primary screening pilot.

BACKGROUND: In England, bivalent vaccination (Cervarix) against high-risk human papillomavirus (HR-HPV) genotypes 16/18 was offered in a population-based catch-up campaign in 2008-2010 to girls aged 14-17 years. These women are now entering the national cervical screening programme. We determined the impact of catch-up bivalent vaccination on their screening outcomes. METHODS: We studied the overall and genotype-specific screening outcomes in 108,138 women aged 24-25 (offered vaccination) and 26-29 years (not offered vaccination) included in the English HPV screening pilot between 2013 and 2018. RESULTS: At 24-25 years, the detection of high-grade cervical intraepithelial neoplasia (CIN2+) associated with HPV16/18 decreased from 3 to 1% (p < 0.001), with estimated vaccine effectiveness of 87% (95% CI: 82-91%). The detection of any CIN2+ halved from 6 to 3% (p < 0.001), with an estimated vaccine effectiveness of 72% (95% CI: 66-77%). The positive predictive value of a colposcopy for CIN2+ decreased for both low-grade (p < 0.001) and high-grade (p = 0.02) abnormalities on triage cytology. The decreases in screen-detected abnormalities at age 26-29 were of a substantially smaller magnitude. CONCLUSIONS: These data confirm high effectiveness of bivalent HPV vaccination delivered through a population-based catch-up campaign in England. These findings add to the rationale for extending screening intervals for vaccinated cohorts.

Radiation Therapy Techniques and Treatment-Related Toxicity in the PORTEC-3 Trial: Comparison of 3-Dimensional Conformal Radiation Therapy Versus Intensity-Modulated Radiation Therapy.

PURPOSE: Radiation therapy techniques have developed from 3-dimensional conformal radiation therapy (3DCRT) to intensity modulated radiation therapy (IMRT), with better sparing of the surrounding normal tissues. The current analysis aimed to investigate whether IMRT, compared to 3DCRT, resulted in fewer adverse events (AEs) and patient-reported symptoms in the randomized PORTEC-3 trial for high-risk endometrial cancer. METHODS AND MATERIALS: Data on AEs and patient-reported quality of life (QoL) of the PORTEC-3 trial were available for analysis. Physician-reported AEs were graded using Common Terminology Criteria for Adverse Events v3.0. QoL was assessed by the European Organisation for Research and Treatment of Cancer QLQC30, CX24, and OV28 questionnaires. Data were compared between 3DCRT and IMRT. A P value of ≤ .01 was considered statistically significant due to the risk of multiple testing. For QoL, combined scores 1 to 2 ("not at all" and "a little") versus 3 to 4 ("quite a bit" and "very much") were compared between the techniques. RESULTS: Of 658 evaluable patients, 559 received 3DCRT and 99 IMRT. Median follow-up was 74.6 months. During treatment no significant differences were observed, with a trend for more grade ≥3 AEs, mostly hematologic and gastrointestinal, after 3DCRT (37.7% vs 26.3%, P = .03). During follow-up, 15.4% (vs 4%) had grade ≥2 diarrhea, and 26.1% (vs 13.1%) had grade ≥2 hematologic AEs after 3DCRT (vs IMRT) (both P < .01). Among 574 (87%) patients evaluable for QoL, 494 received 3DCRT and 80 IMRT. During treatment, 37.5% (vs 28.6%) reported diarrhea after 3DCRT (vs IMRT) (P = .125); 22.1% (versus 10.0%) bowel urgency (P = 0039), and 18.2% and 8.6% abdominal cramps (P = .058). Other QoL scores showed no differences. CONCLUSIONS: IMRT resulted in fewer grade ≥3 AEs during treatment and significantly lower rates of grade ≥2 diarrhea and hematologic AEs during follow-up. Trends toward fewer patient-reported bowel urgency and abdominal cramps were observed after IMRT compared to 3DCRT.

Age-specific outcomes from the first round of HPV screening in unvaccinated women: Observational study from the English cervical screening pilot.

OBJECTIVE: To report detailed age-specific outcomes from the first round of an English pilot studying the implementation of high-risk human papillomavirus (HR-HPV) testing in primary cervical screening. DESIGN: Observational study with screening in 2013-2016, followed by two early recalls and/or colposcopy until the end of 2019. SETTING: Six NHS laboratory sites. POPULATION: A total of 1 341 584 women undergoing screening with HR-HPV testing or liquid-based cytology (LBC). METHODS: Early recall tests and colposcopies were recommended, depending on the nature of the screening-detected abnormality. MAIN OUTCOME MEASURES: We reported standard screening process indicators, e.g. proportions with an abnormality, including high-grade cervical intraepithelial neoplasia (CIN2+) or cancer, and the positive predictive value (PPV) of colposcopy for CIN2+, by screening test and age group. RESULTS: Among unvaccinated women screened with HR-HPV testing at age 24-29 years, 26.9% had a positive test and 10.4% were directly referred to colposcopy following cytology triage, with a PPV for CIN2+ of 47%. At 50-64 years of age, these proportions were much lower: 5.3%, 1.2% and 27%, respectively. The proportions of women testing positive for HR-HPV without cytological abnormalities, whose early recall HR-HPV tests returned negative results, were similar across the age spans: 54% at 24-29 years and 55% at 50-64 years. Two-thirds of infections at any age were linked to non-16/18 genotypes. Among women with CIN2, CIN3 or cervical cancer, however, the proportion of non-16/18 infections increased with age. As expected, the detection of abnormalities was lower following screening with LBC. CONCLUSIONS: These data provide a reliable reference for future epidemiological studies, including those concerning the effectiveness of HPV vaccination. TWEETABLE ABSTRACT: Data from the English pilot study provide a comprehensive overview of abnormalities detected through HPV screening.

Acceleration of cervical cancer diagnosis with human papillomavirus testing below age 30: Observational study.

Several international cervical screening guidelines advise against using high-risk human papillomavirus (HR-HPV) testing in women younger than 30. The rationale for this in young women, lies in the potential for additional detection of both low-grade and high-grade cervical intraepithelial neoplasia (CIN) leading to unnecessary treatments without reducing the burden of cervical cancer. We studied 56 544 women screened at 24 to 29 with HR-HPV testing and 116 858 screened with liquid-based cytology (LBC) in the English HPV screening pilot. They were compared to 528 460 women screened at the age of 30 to 49. We studied the detection of cervical cancer and CIN2/3 across two consecutive screening rounds 3 years apart. At 24 to 29, a positive HR-HPV test detected more cases of cervical cancer in the prevalence round than did a positive LBC test (1.36/1000 screened vs 0.82/1000, ORadj : 1.61, 95% CI: 1.18-2.19). In women with a negative HR-HPV test, cervical cancer was diagnosed before or at the incidence round in 0.07/1000. After a negative LBC test, cancer detection reached 0.47/1000 and 40% of these cases were diagnosed at FIGO stage IB+. HR-HPV testing increased the detection of CIN2/3 diagnoses in two consecutive rounds combined by 30% (71.9/1000 vs 55.2/1000). The patterns of detection of cervical cancer and CIN2/3 were almost identical at older ages. These data support using HR-HPV testing for screening of women younger than 30, which not only accelerates the diagnosis of cervical cancer but leads to a similar relative increase in CIN2/3 diagnosis to that found in women aged 30 to 49.

Patterns of anxiety and distress over 12 months following participation in HPV primary screening.

OBJECTIVES: Many countries are now using primary human papillomavirus (HPV) testing for cervical screening, testing for high-risk HPV and using cytology as triage. An HPV-positive result can have an adverse psychological impact, at least in the short term. In this paper, we explore the psychological impact of primary HPV screening over 12 months. METHODS: Women were surveyed soon after receiving their results (n=1133) and 6 (n=762) and 12 months (n=537) later. Primary outcomes were anxiety (Short-Form State Anxiety Inventory-6) and distress (General Health Questionnaire-12). Secondary outcomes included concern, worry about cervical cancer and reassurance. Mixed-effects regression models were used to explore differences at each time point and change over time across four groups according to their baseline result: control (HPV negative/HPV cleared/normal cytology and not tested for HPV); HPV positive with normal cytology; HPV positive with abnormal cytology; and HPV persistent (ie, second consecutive HPV-positive result). RESULTS: Women who were HPV positive with abnormal cytology had the highest anxiety scores at baseline (mean=42.2, SD: 15.0), but this had declined by 12 months (mean=37.0, SD: 11.7) and was closer to being within the 'normal' range (scores between 34 and 36 are considered 'normal'). This group also had the highest distress at baseline (mean=3.3, SD: 3.8, scores of 3+ indicate case-level distress), but the lowest distress at 12 months (mean=1.9, SD: 3.1). At 6 and 12 months, there were no between-group differences in anxiety or distress for any HPV-positive result group when compared with the control group. The control group were less concerned and more reassured about their result at 6 and 12 months than the HPV-positive with normal cytology group. CONCLUSIONS: Our findings suggest the initial adverse impact of an HPV-positive screening result on anxiety and distress diminishes over time. Specific concerns about the result may be longer lasting and efforts should be made to address them.

Long-Term Toxicity and Health-Related Quality of Life After Adjuvant Chemoradiation Therapy or Radiation Therapy Alone for High-Risk Endometrial Cancer in the Randomized PORTEC-3 Trial.

PURPOSE: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). METHODS AND MATERIALS: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. RESULTS: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. CONCLUSIONS: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC) Trial: A Feasibility Study.

Obesity is the major etiologic driver for endometrial cancer. The levonorgestrel intrauterine system (LNG-IUS) reduces the risk of endometrial cancer and its precursor, atypical hyperplasia. We assessed feasibility and uptake of the LNG-IUS for primary prevention of endometrial cancer in high-risk women and its impact on endometrial tissue biomarkers. Women with class-III obesity [body mass index (BMI) > 40 kg/m2] and histologically normal endometrium were invited to participate in a clinical trial of the LNG-IUS for endometrial protection. Recruitment, successful LNG-IUS insertion, and adherence to trial procedures were recorded. We measured impact of the LNG-IUS on circulating biomarkers of endometrial cancer risk, endometrial proliferation (Ki-67, pAKT, PTEN), endometrial hormone receptor status [estrogen receptor and progesterone receptor (PR)], mental wellbeing, and menstrual function. At 6 months, women chose to keep their LNG-IUS or have it removed. In total, 103 women were approached, 54 were offered a participant information sheet, 35 agreed to participate, and 25 received a LNG-IUS. Their median age and BMI were 54 years [interquartile range (IQR) 52-57] and 47 kg/m2 (IQR 44-51), respectively. Three women (3/35, 9%) were ineligible due to atypical hyperplasia/endometrial cancer on their baseline biopsy. The LNG-IUS was well tolerated and had a positive overall effect on bleeding patterns and mental wellbeing. The LNG-IUS was associated with endometrial morphologic change, reduced Ki-67, and PR expression, but circulating biomarkers of endometrial cancer risk were unchanged. All but one woman (96%) kept her LNG-IUS. The LNG-IUS appears to be acceptable to some women with class-III obesity for primary prevention of endometrial cancer, which could provide a strategy for a prevention trial.Prevention Relevance: Novel strategies are urgently needed to prevent the rise in endometrial cancer diagnoses predicted by escalating obesity rates. Here, we show that women with class III obesity are willing to engage in risk reduction with a levonorgestrel intrauterine system, which could provide a strategy for an endometrial cancer prevention trial.

Attendance at early recall and colposcopy in routine cervical screening with human papillomavirus testing.

Attendance at early recall and colposcopy is crucial to attaining the benefits of primary high-risk human papillomavirus (HR-HPV)-based screening. Within the English HPV pilot, we analysed deprivation- and age-related patterns of attendance at colposcopy and 12- and 24-month early recall of HR-HPV positive women screened in 2013 to 2015 (N = 36 466). We fitted logistic regression models for adjusted odds ratios (OR). Despite high overall attendance, area deprivation had a small but significant impact at both early recalls, for example, attendance at 24 months was 86.3% and 83.0% in less vs more deprived areas, respectively (ORadj : 0.76; 95% CI: 0.67-0.87). Older women (≥30 years) were more likely to attend early recall than younger women (<30 years), for example, attendance at 24 months was 86.1% vs 82.3%, respectively (ORadj : 1.32, 95% CI: 1.16-1.51). Most women attended colposcopy following a baseline referral, with 96.9% attendance among more deprived and 97.8% among less deprived areas (ORadj : 0.70; 95% CI: 0.55-0.88). Differences in colposcopy attendance by deprivation level at 12 and 24 months were of approximately the same magnitude. In conclusion, attendance at early recall and colposcopy was reassuringly high. Although there were statistically significant differences by deprivation and age group, these were small in absolute terms.

Information needs among women taking part in primary HPV screening in England: a content analysis.

OBJECTIVES: Introducing primary human papillomavirus (HPV) testing to cervical screening programmes means changes to the results women receive. We explored additional information needs among women undergoing HPV primary screening. DESIGN: Women were sent a postal questionnaire shortly after receiving their results and 6 and 12 months later. Each questionnaire asked if women had any unanswered questions about cervical screening or HPV testing. Free-text responses constituted the data. Themes were identified using content analysis. SETTING: National Health Service (NHS) Cervical Screening Programme, England. PARTICIPANTS: 381 women who recorded one or more free-text responses. RESULTS: The most common theme represented women's emotional responses and attempts to understand their results. This theme was raised by 45% of women overall, but was as high as 59% in the HPV cleared group. General questions about the cause and epidemiology of HPV were raised by 38% of women and were more common among those testing HPV positive with normal cytology (52%). Questions about the purpose and procedure for HPV testing were most common among HPV-negative women (40%, compared with 16%-24% of the other results groups). Questions about future implications of test results were raised by 19% of women, and this theme was most common among those with persistent HPV. CONCLUSIONS: Despite provision of information alongside screening invitations, women can still have unanswered questions following receipt of their results. Details about the epidemiology of HPV and why cervical screening procedures are changing should be included with screening invitations. Some results groups may benefit from additional tailored information with their results letter.

Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy.

PURPOSE: The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. METHODS: Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated (POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis. RESULTS: Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC (P < .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (P = .019); 100% versus 97% for patients with POLEmut EC (P = .637); 68% versus 76% (P = .428) for MMRd EC; and 80% versus 68% (P = .243) for NSMP EC. CONCLUSION: Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.

Preferences for interventions designed to increase cervical screening uptake in non-attending young women: How findings from a discrete choice experiment compare with observed behaviours in a trial.

BACKGROUND: Young women's attendance at cervical screening in the UK is continuing to fall, and the incidence of invasive cervical cancer is rising. OBJECTIVES: We assessed the preferences of non-attending young women for alternative ways of delivering cervical screening. DESIGN: Postal discrete choice experiment (DCE) conducted during the STRATEGIC study of interventions for increasing cervical screening uptake. Attributes included action required to arrange a test, location of the test, availability of a nurse navigator and cost to the National Health Service. SETTING AND PARTICIPANTS: Non-attending young women in two UK regions. MAIN OUTCOME MEASURES: Responses were analysed using a mixed multinomial logit model. A predictive analysis identified the most preferable strategy compared to current screening. Preferences from the DCE were compared with observed behaviours during the STRATEGIC trial. RESULTS: The DCE response rate was 5.5% (222/4000), and 94% of respondents agreed screening is important. Preference heterogeneity existed around attributes with strong evidence for test location. Relative to current screening, unsolicited self-sampling kits for home use appeared most preferable. The STRATEGIC trial showed this same intervention to be most effective although many women who received it and were screened, attended for conventional cytology instead. CONCLUSIONS: The DCE and trial identified the unsolicited self-sampling kit as the most preferred/effective intervention. The DCE suggested that the decision of some women receiving the kit in the trial to attend for conventional cytology may be due to anxieties around home testing coupled with a knowledge that ignoring the kit could potentially have life-changing consequences.

Anxiety and distress following receipt of results from routine HPV primary testing in cervical screening: The psychological impact of primary screening (PIPS) study.

We used a cross-sectional survey to examine short-term anxiety and distress in women receiving different results following routine human papillomavirus (HPV) primary testing at cervical screening. Participants were women aged 24-65 (n = 1,127) who had attended screening at one of five sites piloting HPV primary screening in England, including a control group with normal cytology who were not tested for HPV. Women completed a postal questionnaire ~2 weeks after receiving their screening result. Unadjusted mean anxiety scores ranged from 32.9 (standard deviation [SD] = 12.2) in HPV-negative women to 42.1 (SD = 14.9) in women who were HPV-positive with abnormal cytology. In adjusted analyses, anxiety was significantly higher in women testing HPV-positive with either normal cytology (mean difference [MD] = 3.5, CI: 0.6-6.4) or abnormal cytology (MD = 7.2, CI: 3.7-10.6), than the control group. Distress was slightly higher in women who tested HPV-positive with abnormal cytology (MD = 0.9, CI: 0.02-1.8), than the control group. We also found increased odds of very high anxiety in women who tested HPV-positive with normal or abnormal cytology compared to the control group. This pattern of results was only observed among women receiving their first HPV-positive result, not among women found to have persistent HPV at 12-month follow-up. Testing HPV-positive with normal cytology for the first time, is associated with elevated anxiety despite carrying very low immediate cervical cancer risk. However, receiving the same test result at 12-month early recall does not appear to be associated with higher anxiety, suggesting anxiety may normalise with repeated exposure and/or over time.

16/18 genotyping in triage of persistent human papillomavirus infections with negative cytology in the English cervical screening pilot.

BACKGROUND: In the English pilot of primary cervical screening with high-risk human papillomavirus (HR-HPV), we exploited natural viral clearance over 24 months to minimise unnecessary referral of HR-HPV+ women with negative cytology. Three laboratories were permitted to use 16/18 genotyping to select women for referral at 12-month recall. We estimated the clinical impact of this early genotyping referral. METHODS: The observed numbers of women referred to colposcopy and with detected high-grade cervical intraepithelial neoplasia (CIN2+), and of women who did not attend early recall in the three laboratories were compared with those estimated to represent a situation without an early genotyping referral. The 95% confidence intervals (CI) for the differences between the protocols were calculated by using a parametric bootstrap. RESULTS: Amongst 127,238 screened women, 16,097 (13%) had HR-HPV infections. The genotyping protocol required 5.9% (95% CI: 4.4-7.7) additional colposcopies and led to a detection of 1.2% additional CIN2+ (95% CI: 0.6-2.0), while 2.3% (95% CI: 2.1-2.5) fewer HR-HPV+/cytology- women did not attend the early recall compared with the non-genotyping protocol. CONCLUSIONS: In a screening programme with high quality of triage cytology and high adherence to early recall,16/18 genotyping of persistent HPV infections does not substantially increase CIN2+ detection.

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.

BACKGROUND: The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis. METHODS: In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. FINDINGS: Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported. INTERPRETATION: This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

HPV testing compared with routine cytology in cervical screening: long-term follow-up of ARTISTIC RCT.

BACKGROUND: The National Screening Committee (NSC) based its recommendation that human papillomavirus (HPV) testing should replace cytology in primary cervical screening largely on the 2009 follow-up results of the ARTISTIC trial (A Randomised Trial In Screening To Improve Cytology). The NSC must now decide on screening intervals and triage policy. Options include extending the screening interval up to 10 years for human papillomavirus-negative (HPV-) women, delaying recall for human papillomavirus-positive (HPV+) women with normal cytology (as their infections are usually transient), and basing triage on full HPV typing. METHODS: In ARTISTIC, 24,510 women were recruited who were attending routine cervical cytology in Greater Manchester in 2001-3. The women were randomly allocated between revealing and concealing their HPV test results and were recalled every 3 years. After 2009, the women returned to routine cytological screening with recall every 3 years for those aged < 50 years, and every 5 years for those aged 50-64 years. We have followed the cohort to 2015 through national cancer registration for CIN3 (cervical intraepithelial neoplasia grade 3) and cancer, and through linkage to the cervical screening call-recall system to obtain lifetime cytology records. RESULTS: The analysis comprised 24,496 women at round 1 and 13,591 women at round 2 (which was 30-48 months later). Follow-up via local histology laboratories and national cancer registration identified 505 cases of cervical intraepithelial neoplasia grade 3 or cervical cancer (CIN3+) (including 22 invasive cervical cancers). The cumulative CIN3+ risk 10 years after a negative HPV test [0.31%, 95% confidence interval (CI) 0.18% to 0.49%, in the revealed arm] was similar to that 3 years after negative cytology (0.30%, 95% CI 0.23% to 0.41%, in the concealed arm) and fell sharply with age, from 1.1% (95% CI 0.7% to 1.8%) in those women aged < 25 years to 0.08% (95% CI 0.03% to 0.20%) in those women aged > 50 years. The 10-year cumulative CIN3+ risk following a new HPV infection at round 2 was 3.4% (95% CI 2.1% to 5.4%). The highest risks were associated with type-specific persistent infections that, overall, resulted in a 10-year cumulative CIN3+ risk of 20.4% (95% CI 15.6% to 26.4%). CONCLUSIONS: We found a similar level of protection 10 years after a negative HPV test and 3 years after negative cytology. These data support a considerably longer screening interval after a negative HPV test than after a negative cytology test. About three-quarters of women with HPV infection and normal cytology clear their infections within about 3 years. Their risk of CIN3+ within this time frame is low (1.5%), suggesting that the current policy of annual repeat testing and referral after 2 years may be unnecessarily cautious. Approximately 40% of women who remained HPV+ had cleared their initial infection and acquired a new HPV type. The cumulative CIN3+ risks in women with type-specific persistent infections are about six times higher than in women with new infections. Triage strategies based on HPV persistence would, therefore, reduce unnecessary referral of women with new (and largely transient) infections. HPV assays that identify HPV types 31, 33, 45, 52 and 58 in addition to 16 and 18 could be useful in triage as well as in primary HPV testing. Similar results in recent routine HPV screening suggest that our results are generalisable despite changes in cytology and HPV assay methods. We are continuing to follow the ARTISTIC cohort into the new era of primary HPV screening. Future work will focus on the implications of more sensitive HPV testing for primary HPV screening policy and triage of HPV-positive women. Our results suggest that a more sensitive test is needed to detect occult CIN3 at high risk of progression to cancer, but this would substantially increase the overall HPV detection rate. Tests such as DNA (deoxyribonucleic acid) methylation for distinguishing HPV infection from neoplasia will be evaluated on stored samples and on further samples now being collected from women in the cohort who are still being screened. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 28. See the NIHR Journals Library website for further project information.

Human papillomavirus (HPV) causes cervical cancer. The latest scientific evidence shows that screening for HPV is better than screening for abnormal cytology with a 'smear' test, so HPV testing is being rolled out nationally. The main disadvantage is that more women will test positive and be referred for further tests. Most infections are harmless and clear without treatment, and balance must be achieved so that women who progress to CIN3 (pre-cancer) are identified but that unnecessary referral and anxiety for women is minimised. A Randomised Trial In Screening To Improve Cytology (ARTISTIC) recruited 24,510 women attending for cervical screening in Greater Manchester in 2001­3. Cervical samples taken at recruitment and again at screening 3 and 6 years later were tested for HPV. The women then returned to routine screening. We have followed them through national screening records and cancer registration until the end of 2015. By comparing the HPV results taken at entry with those collected 3 years later, we can categorise HPV infections into new and persistent. We have found that the CIN3 risk in women with persistent infections is about six times higher than in women with new infections, which in turn is about 30 times higher than in women with no infection. About three-quarters of women with HPV infection but no abnormal cells clear their infections within 3 years. Their risk of pre-cancer within 3 years is low (1.5%) and so intensive follow-up is unnecessary. Moreover, 40% of those who remain human papillomavirus positive (HPV+) have cleared their initial infection and acquired a new infection, meaning that they are also at much lower risk of disease than those with a persistent infection. The current practice in the national pilot study of annual repeat testing and referral of anyone who is still HPV+ after 2 years may, therefore, be too conservative. We have also shown that the CIN3 risk after 10 years in women testing negative for HPV is similar to the risk after about 3 years in women testing negative for cytology. This means that screening intervals could be extended for women testing negative for HPV.

Cross-sectional study of HPV testing in self-sampled urine and comparison with matched vaginal and cervical samples in women attending colposcopy for the management of abnormal cervical screening.

OBJECTIVES: Human papillomavirus (HPV) testing in cervical screening offers the potential for self-sampling to improve uptake among non-attenders. High-risk (HR) HPV detection in urine shows promise, but few studies have examined its sensitivity for cervical intraepithelial neoplasia (CIN2+) detection compared with standard cervical samples. The aims of this cross-sectional study were to optimise conditions for urine testing for HPV detection; to determine concordance for HR-HPV detection in matched urine, vaginal and cervical samples; to compare the sensitivity of HR-HPV testing for the detection of CIN2+ in matched samples; and to determine the acceptability of urine testing for cervical screening. DESIGN: Cross-sectional study. SETTING: Secondary care colposcopy clinic in North West England. PARTICIPANTS: Women aged 25 years of age or older, attending colposcopy clinic for management of abnormal cervical screening results or a suspicious-looking cervix. In total, 104 women took part in the study. Triple matched samples were available for 79 and 66 women using Abbott RealTime (ART) and Roche Cobas 4800 (RC), respectively. INTERVENTION: Self-collected urine and vaginal samples and practitioner-obtained cervical samples were tested for HR-HPV by ART and RC assays, including comparison of neat and preservative-fixed urine. Colposcopic opinion was recorded and directed cervical biopsies taken if clinically indicated. The acceptability of self-testing was evaluated by questionnaire. PRIMARY OUTCOME MEASURE: The sensitivity of urine to detect underlying CIN2+. SECONDARY OUTCOME MEASURES: The comparative sensitivity of vaginal and cervical samples to detect CIN2+; the acceptability of urine sampling. RESULTS: Preservative-fixed, but not neat urine, showed good concordance with vaginal samples for the detection of HR-HPV. The sensitivity for detecting CIN2+ was 15/18 (83%) for urine and 16/18 (89%) for cervical and vaginal samples by ART, and 15/17 (88%) for all samples by RC. Urine-based testing was broadly acceptable to women. CONCLUSIONS: Urinary HR-HPV detection offers an alternative strategy of cervical screening. Larger studies to determine its clinical utility are warranted.

Optimising future cervical screening strategies.

The switch from primary cytology to primary high risk papillomavirus (HR-HPV) testing for cervical screening is now being implemented in a number of countries. The advantages of this are to increase screening sensitivity which will save lives, and at the same time to extend screening intervals. The challenge with HR-HPV testing is its relatively poor specificity which means identifying a large number of women who are HR-HPV positive with negative cytology. One way of tackling this is to use early recall, in order to select referral to colposcopy to those women who do not clear the virus over a period of 1-2 years, as done in the recently published English Pilot Study. Another challenge in optimising screening is to recognise that wide coverage with prophylactic vaccination will require fewer screens over the lifetime of vaccinated women to maintain cost-effectiveness. HR-HPV testing allows self sampling which could both encourage more women to be screened and be more convenient for those who do wish to be screened. Cervical cancer prevention which combines vaccination and screening now offers a future in which cervical cancer could become a rarity, but efficient strategies need to be implemented.

The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome.

PURPOSE: There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients. METHODS: Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice. RESULTS: Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer. CONCLUSION: This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

Primary cervical screening with high risk human papillomavirus testing: observational study.

OBJECTIVE: To provide the first report on the main outcomes from the prevalence and incidence rounds of a large pilot of routine primary high risk human papillomavirus (hrHPV) testing in England, compared with contemporaneous primary liquid based cytology screening. DESIGN: Observational study. SETTING: The English Cervical Screening Programme. PARTICIPANTS: 578 547 women undergoing cervical screening in primary care between May 2013 and December 2014, with follow-up until May 2017; 183 970 (32%) were screened with hrHPV testing. INTERVENTIONS: Routine cervical screening with hrHPV testing with liquid based cytology triage and two early recalls for women who were hrHPV positive and cytology negative, following the national screening age and interval recommendations. MAIN OUTCOME MEASURES: Frequency of referral for a colposcopy; adherence to early recall; and relative detection of cervical intraepithelial neoplasia grade 2 or worse from hrHPV testing compared with liquid based cytology in two consecutive screening rounds. RESULTS: Baseline hrHPV testing and early recall required approximately 80% more colposcopies, (adjusted odds ratio 1.77, 95% confidence interval 1.73 to 1.82), but detected substantially more cervical intraepithelial neoplasia than liquid based cytology (1.49 for cervical intraepithelial neoplasia grade 2 or worse, 1.43 to 1.55; 1.44 for cervical intraepithelial neoplasia grade 3 or worse, 1.36 to 1.51) and for cervical cancer (1.27, 0.99 to 1.63). Attendance at early recall and colposcopy referral were 80% and 95%, respectively. At the incidence screen, the 33 506 women screened with hrHPV testing had substantially less cervical intraepithelial neoplasia grade 3 or worse than the 77 017 women screened with liquid based cytology (0.14, 0.09 to 0.23). CONCLUSIONS: In England, routine primary hrHPV screening increased the detection of cervical intraepithelial neoplasia grade 3 or worse and cervical cancer by approximately 40% and 30%, respectively, compared with liquid based cytology. The very low incidence of cervical intraepithelial neoplasia grade 3 or worse after three years supports extending the screening interval.