Abstract Objective Recent reviews on the sentinel lymph node (SLN) procedure in cervical cancer have shown that bilateral SLN detection and ultra staging are safe and superior options compared to a ...unilateral detection, frozen section and H&E analysis. So far, nobody identified a subgroup of patients in whom a SLN procedure may replace pelvic lymph node dissection (PLND). Methods We searched PubMed, Embase, CINAHL and Cochrane from inception up to November 26, 2014. Studies reporting SLN detection, and/or histological outcome of the SLN were included. Methodological quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies tool by two independent reviewers. Data to complete 2 × 2 contingency tables were obtained, and patient-, study- and technique characteristics were extracted. Results were pooled and plotted in forest plots. Results Forty-seven studies (4130 patients) were analyzed. Pooled data of diagnostic accuracy on ultra staging (18 studies; 1275 patients) showed a sensitivity of 94% (95% CI 80–99%) and negative predictive values ranging between 91 and 100%. After ultra staging, 19 false negative results remained. Prerequisites such as early FIGO stage (IA2, IB1, IIA primary tumor size < 40 mm), no suspicious pre-, and per-operative lymph nodes, and bilateral negative SLNs after ultra staging resulted in 1 remaining false negative result among 1257 patients (0.08%). Pooled data on a combined tracer in early stage cervical cancer patients with primary tumor size < 20 mm (6 studies; 276 patients) resulted in 87% bilateral SLN detection. Conclusions Early stage cervical cancer patients (FIGO IA2, IB1, IIA primary tumor size < 40 mm) who have no suspicious pre-, and per-operative lymph nodes, and have bilateral negative SLNs after ultra staging, have a residual risk of 0.08% (1/1257) on occult metastases. On the basis of these results we recommend not to perform a full PLND in these patients.
Abstract Objectives High attendance rates in cervical screening are essential for effective cancer prevention. Offering HPV self-sampling to non-responders increases participation rates. The ...objectives of this study were to determine why non-responders do not attend regular screening, and why they do or do not participate when offered a self-sampling device. Methods A questionnaire study was conducted in the Netherlands from October 2011 to December 2012. A total of 35,477 non-responders were invited to participate in an HPV self-sampling study; 5347 women did opt out. Finally, 30,130 women received a questionnaire and self-sampling device. Results The analysis was based on 9484 returned questionnaires (31.5%) with a self-sample specimen, and 682 (2.3%) without. Among women who returned both, the main reason for non-attendance to cervical screening was that they forgot to schedule an appointment (3068; 32.3%). The most important reason to use the self-sampling device was the opportunity to take a sample in their own time-setting (4763; 50.2%). A total of 30.9% of the women who did not use the self-sampling device preferred after all to have a cervical smear taken instead. Conclusions Organisational barriers are the main reason for non-attendance in regular cervical screening. Important reasons for non-responders to the regular screening to use a self-sampling device are convenience and self-control.
Background
Compared to the previous cytology-based program, the introduction of primary high-risk human papillomavirus (hrHPV) based screening in 2017 has led to an increased number of referrals. To ...counter this, triage of hrHPV-positive women in cervical cancer screening can potentially be optimized by taking sociodemographic and lifestyle risk factors for cervical abnormalities into account. Therefore, it is essential to gain knowledge of the views of women (30–60 years) eligible for cervical cancer screening.
Objective
The main goal of this qualitative study was to gain insight in the aspects that influence acceptability of risk-based triage in cervical cancer screening.
Design
A focus group study in which participants were recruited via four general medical practices, and purposive sampling was used to maximize heterogeneity with regards to age, education level, and cervical cancer screening experiences.
Approach
The focus group discussions were transcribed verbatim and analyzed using reflexive thematic analysis.
Participants
A total of 28 women (average age: 45.2 years) eligible for cervical cancer screening in The Netherlands participated in seven online focus group discussions. Half of the participants was higher educated, and the participants differed in previous cervical cancer screening participation and screening result.
Key results
In total, 5 main themes and 17 subthemes were identified that determine the acceptability of risk-stratified triage. The main themes are: 1) adequacy of the screening program: an evidence-based program that is able to minimize cancer incidence and reduce unnecessary referrals; 2) personal information (e.g., sensitive topics and stigma); 3) emotional impact: fear and reassurance; 4) communication (e.g., transparency); and 5) autonomy (e.g., prevention).
Conclusion
The current study highlights several challenges regarding the development and implementation of risk-based triage that need attention in order to be accepted by the target group. These challenges include dealing with sensitive topics and a transparent communication strategy.
Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the ...underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease. This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (<100,000 inhabitants or greater than or equal to100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age greater than or equal to16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth. In this study, we observed a strong correlation between preterm birth and a volume of greater than or equal to0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy.
Recently, the safety of laparoscopic radical hysterectomy (LRH) has been called into question in early-stage cervical cancer. This study aimed to evaluate overall survival (OS) and disease-free ...survival (DFS) in patients treated with abdominal radical hysterectomy (ARH) and LRH for early-stage cervical cancer and to provide a literature review.
Patients diagnosed between 2010 and 2017 with International Federation of Gynaecology and Obstetrics (2009) stage IA2 with lymphovascular space invasion, IB1 and IIA1, were identified from the Netherlands Cancer Registry. Cox regression with propensity score, based on inverse probability treatment weighting, was applied to examine the effect of surgical approach on 5-year survival and calculate hazard ratios (HR) and 95% confidence intervals (CIs). Literature review included observational studies with (i) analysis on tumours ≤4 cm (ii) median follow-up ≥30 months (iii) ≥5 events per predictor parameter in multivariable analysis or a propensity score.
Of the 1109 patients, LRH was performed in 33%. Higher mortality (9.4% vs. 4.6%) and recurrence (13.1% vs. 7.3%) were observed in ARH than LRH. However, adjusted analyses showed similar DFS (89.4% vs. 90.2%), HR 0.92 95% CI: 0.52–1.60) and OS (95.2% vs. 95.5%), HR 0.94 95% CI: 0.43–2.04). Analyses on tumour size (<2/≥2 cm) also gave similar survival rates. Review of nine studies showed no distinct advantage of ARH, especially in tumours <2 cm.
After adjustment, our retrospective study showed equal oncological outcomes between ARH and LRH for early-stage cervical cancer – also in tumours <2 cm. This is in correspondence with results from our literature review.
•Oncological outcome is equal after abdominal and laparoscopic radical hysterectomy.•Disease-free survival and overall survival are equal in tumours <2 cm.•The exact role of laparoscopy should be examined in prospective randomised trials.
Human papillomavirus (HPV) testing on self-collected samples is a potential alternative to HPV testing on clinician-collected samples, but non-inferiority of its clinical accuracy remains to be ...assessed in the regular screening population. The IMPROVE study was done to evaluate the clinical accuracy of primary HPV testing on self-collected samples within an organised screening setting.
In this randomised, non-inferiority trial, women aged 29–61 years were invited to participate in the study as part of their regular screening invitation in the Netherlands. Women who provided informed consent were randomly allocated (1:1, with a block size of ten stratified by age) to one of two groups: a self-sampling group, in which women were requested to collect their own cervicovaginal sample using an Evalyn Brush (Rovers Medical Devices BV, Oss, Netherlands); or a clinician-based sampling group, in which samples were collected by a general practitioner with a Cervex-Brush (Rovers Medical Devices BV). All samples were tested for HPV using the clinically validated GP5+/6+ PCR enzyme immunoassay (Labo Biomedical Products BV, Rijswijk, Netherlands). HPV-positive women in both groups were retested with the other collection method and triaged by cytology and repeat cytology in accordance with current Dutch screening guidelines. Primary endpoints were detection of cervical intraepithelial neoplasia (CIN) of grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+). Non-inferiority of HPV testing on self-collected versus clinician-collected samples was evaluated against a margin of 90% for the relative sensitivity and 98% for the relative specificity. This study is registered at the Dutch Trial register (NTR5078) and has been completed.
Of the 187 473 women invited to participate, 8212 were randomly allocated to the self-sampling group and 8198 to the clinician-based sampling group. After exclusion of women who met the exclusion criteria or who did not return their sample, 7643 women were included in the self-sampling group and 6282 in the clinician-based sampling group. 569 (7·4%) self-collected samples and 451 (7·2%) clinician-collected samples tested positive for HPV (relative risk 1·04 95% CI 0·92–1·17). Median follow-up duration for HPV-positive women was 20 months (IQR 17–22). The CIN2+ sensitivity and specificity of HPV testing did not differ between self-sampling and clinician-based sampling (relative sensitivity 0·96 0·90–1·03; relative specificity 1·00 0·99–1·01). For the CIN3+ endpoint, relative sensitivity was 0·99 (0·91–1·08) and relative specificity was 1·00 (0·99–1·01).
HPV testing done with a clinically validated PCR-based assay had similar accuracy on self-collected and clinician-collected samples in terms of the detection of CIN2+ or CIN3+ lesions. These findings suggest that HPV self-sampling could be used as a primary screening method in routine screening.
Ministry of Health, Welfare, and Sport (Netherlands), and the European Commission.
The aims of this study were to evaluate the safety and impact of pretreatment surgical para-aortic lymph node staging (PALNS) in advanced cervical cancer (International Federation of Gynecology and ...Obstetrics stage IB2-IVA) and to evaluate the preoperative imaging of PALNs.
We searched in PubMed and the Cochrane Library to identify data investigating the role of surgical PALNS. Selection criteria included English-language and advanced-stage cervical cancer (International Federation of Gynecology and Obstetrics stage IB2-IVA) articles.
Twenty-two articles were included. Para-aortic lymph node metastases were present in 18% (range, 8%-42%) of all patients with cervical cancer stage IB to IVA. The proportions of positive para-aortic nodes on histological analysis with suspicious para-aortic nodes on imaging (positive predictive value) were 20% to 66%, 0% to 27%, 86% to 100%, and 50% to 75% for computed tomographic (CT) scan, magnetic resonance imaging (MRI) scan, positron emission tomography (PET), and PET-CT, respectively. The negative predictive values of the imaging techniques were 53% to 92% for CT scan, 75% to 91% for MRI, 87% to 94% for PET, and 83% to 92% for PET-CT. The proportions of histologically proven PALN metastasis with normal findings on imaging were 9% to 35% for CT scan and MRI, 4% to 11% for PET, and 6% to 15% for PET-CT. The mean complication rate of PALNS is 9%, with a range of 4% to 24%, with lymphocysts being the most common complication.
Pretreatment surgical PALN dissection or sampling is feasible, with low complication rates and short delay in starting treatment. Pretreatment PET or PET-CT is the most accurate imaging method in detecting PALN metastases but has limitations detecting microscopic tumor volumes. Even with normal findings on PET-CT, PALN metastases are present in 4% to 15% of patients. Positive PALNs in stage IB2 to IVA cervical cancer will lead to modification of treatment and may lead to better overall and disease-free survival.
Summary Background Cytology is a widely used method of triaging women who test positive for human papillomavirus (HPV). However, self-sampled specimens, which can substantially increase participation ...in screening programmes, are not suitable for accurate cytological assessment. We investigated whether direct DNA methylation-based molecular triage on self-sampled cervicovaginal specimens was non-inferior to cytology triage on additional physician-collected cervical samples in the detection of cervical intraepithelial neoplasia grade 2 (CIN2) or worse in women who did not attend cervical screening programmes. Methods In this randomised controlled non-inferiority trial, we invited women (aged 33–63 years) registered as non-attendees of cervical screening in the Netherlands in 2007 to submit a self-collected cervicovaginal sample for HPV testing. Using a computer-generated sequence, we randomly allocated women who tested positive for high-risk hrHPV on a self-sample to either triage by cytology on an additional physician-taken smear or direct triage on the self-sample by methylation analysis of MAL and miR-124-2 genes (1:1; stratified by age and region, with block sizes by age group). Triage-positive women in either group were referred for colposcopy. The primary endpoint was detection of CIN2 or worse, analysed by intention to treat. The non-inferiority margin was 0·80. This study is registered in the Primary Trial Register of the Netherlands, number NTR6026. Findings We invited 46 001 women to participate, 12 819 of whom returned self-sampled material; 1038 samples tested positive for high-risk HPV. Between Nov 1, 2010, and Dec 31, 2011, after exclusion of women who were ineligible, we enrolled and randomly allocated 515 women to methylation triage and 509 to cytology triage. The detection of CIN2 or worse with methylation triage was non-inferior to that with cytology triage (90 17% of 515 women vs 75 15% of 509 women; relative risk 1·19, 95% CI 0·90–1·57). Referral for colposcopy was more common in the molecular group (284 55% women) than in the cytology group (149 29% women; p<0·0001). Mean time to CIN2 or worse diagnosis was shorter in the molecular triage group (96 days, range 44–101) than in the cytology triage group (158 days, 71–222; p=0·00084). Interpretation DNA methylation analysis of MAL and miR-124-2 genes on HPV-test-positive self-samples is non-inferior to cytology triage in the detection of CIN2 or worse, opening the way to full molecular screening. Funding Midden-West and Oost Screening Organisations and Stichting Achmea Gezondheidszorg.
Data on health-related quality of life (HRQoL) is paramount for shared and evidence based decision-making. Since an overview of cervical cancer HRQoL tools and their validity appears to be lacking, ...we performed a systematic review on usage of disease specific HRQoL instruments in cervical cancer patients and their psychometric properties to identify the most suitable cervical cancer specific HRQoL tool.
We searched Pubmed, EMBASE and PsycINFO from inception up to 18 October 2016 for studies on quality of life in cervical cancer patients. Data extraction and HRQoL identification was performed by two independent reviewers. Validation studies of the identified cervical cancer specific HRQoL tools were retrieved and assessed on psychometric properties using the COSMIN checklist. All used cervical cancer specific HRQoL instruments were scored and ranked according to their psychometric properties.
We included 156 studies (20,690 patients) and identified 31 HRQoL tools. The EORTC QLQ-CX24 (35 studies; 5,556 patients) and FACT-Cx (22 studies; 4,224 patients) were the only cervical cancer specific tools. The EORTC QLQ-CX24 had 4 out of 9 positive rated psychometric properties; internal consistency, content and construct validity, and agreement. Criterion validity, reliability, and interpretability scored doubtful. Responsiveness and floor- and ceiling effects were not reported. The FACT-Cx had 2 out of 9 positive rated psychometric properties; internal consistency and agreement. Content validity, reliability, and interpretability scored doubtful while criterion and construct validity scored negative. Responsiveness and floor- and ceiling effects were not reported.
The validity of the often used EORTC QLQ-CX24 questionnaire for cervical cancer patients remains uncertain as 5 out of 9 psychometric properties were doubtful or not reported in current literature. Cervical cancer specific HRQoL tools should therefore always be used in conjunction with validated generic cancer HRQoL tools until proper validity has been proven, or a more valid tool has been developed.
Offering self-sampling of cervico-vaginal material for high-risk human papillomavirus (hrHPV) testing is an effective method to increase the coverage in cervical screening programs. Molecular triage ...directly on hrHPV-positive self-samples for colposcopy referral opens the way to full molecular cervical screening. Here, we set out to identify a DNA methylation classifier for detection of cervical precancer (CIN3) and cancer, applicable to lavage and brush self-samples.
We determined genome-wide DNA methylation profiles of 72 hrHPV-positive self-samples, using the Infinium Methylation 450K Array. The selected DNA methylation markers were evaluated by multiplex quantitative methylation-specific PCR (qMSP) in both hrHPV-positive lavage (
= 245) and brush (
= 246) self-samples from screening cohorts. Subsequently, logistic regression analysis was performed to build a DNA methylation classifier for CIN3 detection applicable to self-samples of both devices. For validation, an independent set of hrHPV-positive lavage (
= 199) and brush (
= 287) self-samples was analyzed.
Genome-wide DNA methylation profiling revealed 12 DNA methylation markers for CIN3 detection. Multiplex qMSP analysis of these markers in large series of lavage and brush self-samples yielded a 3-gene methylation classifier (
and
). This classifier showed a very good clinical performance for CIN3 detection in both lavage (AUC = 0.88; sensitivity = 74%; specificity = 79%) and brush (AUC = 0.90; sensitivity = 88%; specificity = 81%) self-samples in the validation set. Importantly, all self-samples from women with cervical cancer scored DNA methylation-positive.
By genome-wide DNA methylation profiling on self-samples, we identified a highly effective 3-gene methylation classifier for direct triage on hrHPV-positive self-samples, which is superior to currently available methods.
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