Abstract
Background
The study presents cross-sectional accuracy of E6 and E7 (E6/E7) mRNA detection and p16/ki67 dual staining, alone or in combination with cytology and human papillomavirus ...(HPV)16/18 genotyping, as a triage test in HPV DNA-positive women and their impact on cervical intraepithelial neoplasia (CIN2+) overdiagnosis.
Methods
Women aged 25-64 years were recruited. HPV DNA-positive women were triaged with cytology and tested for E6/E7 mRNA and p16/ki67. Cytology positive women were referred to colposcopy, and negatives were randomly assigned to immediate colposcopy or to 1-year HPV retesting. Lesions found within 24 months since recruitment were included. All P values were 2-sided.
Results
40 509 women were recruited, and 3147 (7.8%) tested HPV DNA positive; 174 CIN2+ were found: sensitivity was 61.0% (95% confidence interval CI = 53.6 to 68.0), 94.4% (95% CI = 89.1 to 97.3), and 75.2% (95% CI = 68.1 to 81.6) for cytology, E6/E7 mRNA, and p16/ki67, respectively. Immediate referral was 25.6%, 66.8%, and 28.3%, respectively. Overall referral was 65.3%, 78.3%, and 63.3%, respectively. Cytology or p16/ki67, when combined with HPV16/18 typing, reached higher sensitivity with a small impact on referral. Among the 2306 HPV DNA-positive and cytology-negative women, relative CIN2+ detection in those randomly assigned at 1-year retesting vs immediate colposcopy suggests a -28% CIN2+ regression (95% CI = -57% to +20%); regression was higher in E6/E7 mRNA-negatives (Pinteraction = .29). HPV clearance at 1 year in E6/E7 mRNA and in p16/ki67 negative women was about 2 times higher than in positive women (Pinteraction < .001 for both).
Conclusions
p16/ki67 showed good performance as a triage test. E6/E7 mRNA showed the highest sensitivity, at the price of too high a positivity rate to be efficient for triage. However, when negative, it showed a good prognostic value for clearance and CIN2+ regression.
Objective
To assess faecal immunochemical test sensitivity for cancer in a very large population-based cohort followed up for six rounds with biennial faecal immunochemical test repetition.
Methods
...This study is based on interval colorectal cancers diagnosed in a cohort of subjects aged 50–69 undergoing repeated faecal immunochemical test screening (six rounds) from 2002 to 2015. Test sensitivity was calculated using both the Proportional Interval Cancer Rate and the Interval Cancer Proportion method.
Results
Among 441,647 faecal immunochemical tests (123,347 individuals), 150 interval colorectal cancers were detected after a negative faecal immunochemical test. Interval colorectal cancer incidence rate was 1.87 per 10,000 person-years (95%CI: 1.60–2.20), and it was higher during the second interval year (rate ratio: 1.78; 95%CI: 1.28–2.47), for proximal locations (rate ratio: 3.00; 95%CI: 1.92–4.68), and among 60–71 year old subjects (rate ratio: 2.37; 95%CI: 1.61–3.50). The Proportional Interval Cancer Rate was 13.1%, with an overall faecal immunochemical test sensitivity of 86.9% (95%CI: 84.7–89.0). Sensitivity was lowest at the first round (81.5%; 95%CI: 75.6–86.2), and increased to 91.9% (95%CI: 83.9–96.5) for subsequent rounds. Applying the Interval Cancer Proportion method, sensitivity was 83.9% (95%CI: 81.3–86.2), and it was highest at the first round (89.0%; 95%CI: 85.7–91.6), ranging between 73% and 83.1% at subsequent rounds.
Conclusions
A faecal immunochemical test sensitivity for cancer higher than 80% resulted in a low incidence of interval colorectal cancers, representing an accurate estimate of one of the major limits of screening programmes. Due to intrinsic biases, the Proportional Interval Cancer Rate and the Interval Cancer Proportion methods generated different trends in faecal immunochemical test sensitivity by screening round.
To assess detection rate and predictive factors of sessile serrated polyps (SSPs) in organised colorectal cancer (CRC) screening programmes based on the faecal immunochemical test (FIT).
Data from a ...case series of colonoscopies of FIT-positive subjects were provided by 44 Italian CRC screening programmes. Data on screening history, endoscopic procedure and histology results, and additional information on the endoscopy centre and the endoscopists were collected, including the age-standardised and sex-standardised adenoma detection rate (ADR) of the individual endoscopists. The SSP detection rate (SSP-DR) was assessed for the study population. To identify SSP-predictive factors, multilevel analyses were performed according to patient/centre/endoscopist characteristics.
We analysed 72 021 colonoscopies, of which 1295 presented with at least one SSP (SSP-DR 1.8%; 95% CI 1.7% to 1.9%). At the
level, SSP-DR was associated with males (OR 1.35; 95% CI 1.17 to 1.54) and caecal intubation (OR 3.75; 95% CI 2.22 to 6.34), but not with the FIT round. The presence of at least one advanced adenoma was more frequent among subjects with SSPs than those without (OR 2.08; 95% CI 1.86 to 2.33). At the
level, SSP-DR was associated with ADR (third vs first ADR quartile: OR 1.55; 95% CI 1.03 to 2.35; fourth vs first quartile: OR 1.89; 95% CI 1.24 to 2.90).
The low prevalence of SSPs and the lack of association with the FIT round argue against SSP as a suitable target for FIT-based organised programmes. Strict association of SSP-DR with the key colonoscopy quality indicators, namely caecal intubation rate and high ADR further marginalises the need for SSP-specific quality indicators in FIT-based programmes.
To evaluate the impact of faecal immunochemical test (FIT) screening on stage distribution at diagnosis, and to estimate relative incidence rates by stage in screened at first and subsequent rounds ...vs. unscreened. We included all incident cases occurring in 2000–2008 in 50‐ to 71‐year‐olds residing in areas with an FIT‐screening programme. Multinomial logistic models were computed to estimate the relative risk ratio (RRR) of stages I and IV, compared to stage II + III, adjusting for age, sex, geographical area, and incidence year. Proportions were then used to estimate incidence rate ratios (IRR) by stage for screened subjects at the first and at subsequent rounds vs. unscreened subjects, applying the expected changes in overall incidence during screening phases. 11,663 cancers were included: 5965 in not‐invited and 5,698 in invited subjects, 3,425 of whom attendees. Compared to not‐invited, invited subjects had RRR 2.04 (95% CI: 1.84; 2.46) of stage I and RRR 0.77 (95% CI: 0.69; 0.87) of stage IV. Differences were stronger comparing attendees vs. nonattendees. Interval cancers were more frequently stage I compared to non‐invited (RRR 1.54; 95% CI: 1.15; 2.04), but there was no difference for stage IV. IRRs in screened at first round vs. unscreened were 4.6 (95% CI: 4.2; 5.1), 1.4 (95% CI: 1.3; 1.5) and 0.7 (95% CI: 0.6; 0.9) for stages I, II + III and IV, respectively; in the following rounds the IRRs of screened vs. unscreened were 1.4 (95% CI: 1.2; 1.6), 0.8 (95% CI: 0.7; 0.9) and 0.3 (95% CI: 0.1; 0.4) for stages I, II + III and IV, respectively. FIT screening reduces the incidence of metastatic cancers by about 70% after the first round.
What's new?
Screening programs are intended to reduce mortality by early diagnosis. In this study, the authors evaluated the faecal immunochemical test (FIT) for colorectal cancer. They calculated the effect of FIT screening on stage at diagnosis, and estimated the relative incidence rates by stage. Individuals who attended screening had far higher incidence of stage I cancer, and lower incidence of stage IV, than those not screened. Metastatic cancer incidence, they found, decreased by about 70% at the first round of screening.
The high volume and poor palatability of 4 L of polyethylene glycol (PEG)-based bowel cleansing preparation required before a colonoscopy represent a major obstacle for patients. The aim of this ...study was to compare two low volume PEG-based preparations with standard 4 L PEG in individuals with a positive fecal immunochemical test (FIT) within organized screening programs in Italy.
A total of 3660 patients with a positive FIT result were randomized to receive, in a split-dose regimen, 4 L PEG or 2 L PEG plus ascorbate (PEG-A) or 2 L PEG with citrate and simethicone plus bisacodyl (PEG-CS). The noninferiority of the low volume preparations vs. 4 L PEG was tested through the difference in proportions of adequate cleansing.
A total of 2802 patients were included in the study. Adequate bowel cleansing was achieved in 868 of 926 cases (93.7 %) in the 4 L PEG group, in 872 out of 911 cases in the PEG-A group (95.7 %, difference in proportions + 1.9 %, 95 % confidence interval CI - 0.1 to 3.9), and in 862 out of 921 cases in the PEG-CS group (93.6 %, difference in proportions - 0.2 %, 95 %CI - 2.4 to 2.0). Bowel cleansing was adequate in 95.5 % of cases when the preparation-to-colonoscopy interval was between 120 and 239 minutes, whereas it dropped to 83.3 % with longer intervals. Better cleansing was observed in patients with regular bowel movements (95.6 %) compared with those with diarrhea (92.4 %) or constipation (90.8 %).
Low volume PEG-based preparations administered in a split-dose regimen guarantee noninferior bowel cleansing compared with 4 L PEG. Constipated patients require a personalized preparation.
EudraCT 2012 - 003958 - 82.
To assess the appropriateness of recommendations for endoscopic surveillance in organised colorectal cancer (CRC) screening programmes based on the faecal immunochemical test (FIT).
74 Italian CRC ...screening programmes provided aggregated data on the recommendations given after FIT-positive colonoscopies in 2011 and 2013. Index colonoscopies were divided into negative/no adenoma and low- risk, intermediate-risk and high-risk adenomas. Postcolonoscopy recommendations included a return to screening (FIT after 2 years or 5 years), an endoscopic surveillance after 6 months or after 1 year, 3 years or 5 years, surgery or other. We assessed the deviation from the postcolonoscopy recommendations of the European Guidelines in 2011 and 2013 and the correlation between overuse of endoscopic surveillance in 2011 and the process indicators associated with the endoscopic workload in 2013.
49 704 postcolonoscopy recommendations were analysed. High-risk, intermediate-risk and low-risk adenomas, and no adenomas were reported in 5.9%, 19.3%, 15.3% and 51.5% of the cases, respectively. Endoscopic surveillance was inappropriately recommended in 67.4% and 7%, respectively, of cases with low-risk and no adenoma. Overall, 37% of all endoscopic surveillance recommendations were inappropriate (6696/17 860). Overuse of endoscopic surveillance was positively correlated with the extension of invitations (correlation coefficient (cc) 0.29; p value 0.03) and with compliance with post-FIT+ colonoscopy (cc 0.25; p value 0.05), while it was negatively correlated with total colonoscopy waiting times longer than 60 days (cc -0.26; p value 0.05).
In organised screening programmes, a high rate of inappropriate recommendations for patients with low risk or no adenomas occurs, affecting the demand for endoscopic surveillance by a third.
Each high-risk HPV genotype has different oncogenic potential, and the risk of CIN3+ varies according to genotype. We evaluated the performance of different strategies of HPV-positivity triage ...combining cytology, p16/ki67 dual staining (DS), and extended genotyping.
Samples from 3180 consecutive women from the NTCC2 study (NCT01837693) positive for HPV DNA at primary screening, were retrospectively analyzed by the BD Onclarity HPV Assay, which allows extended genotyping. Genotypes were divided into three groups based on the risk of CIN3+. HPV DNA-positive women were followed up for 24 months or to clearance.
Combining the three groups of genotypes with cytology or DS results we identify a group of women who need immediate colposcopy (PPV for CIN3+ from 7.8 to 20.1%), a group that can be referred to 1-year HPV retesting (PPV in those HPV-positive at retesting from 2.2 to 3.8), and a group with a very low 24-month CIN3+ risk, i.e. 0.4%, composed by women cytology or DS negative and positive for HPV 56/59/66 or 35/39/68 or negative with the Onclarity test, who can be referred to 3-year retesting.
Among the baseline HPV DNA positive/cytology or DS negative women, the extended genotyping allows to stratify for risk of CIN3+, and to identify a group of women with a risk of CIN3+ so low in the next 24 months that they could be referred to a new screening round after 3 years.
Italian Ministry of Health (grant number RF-2009-1536040). Hologic-Genprobe, Roche Diagnostics, and Becton & Dickinson provided financial and non-financial support.
Objective
To compare the results from an initial negative human papillomavirus (HPV) test with re‐screening after 3 years in women attending two HPV‐based screening programmes.
Design
...Population‐based cohort study.
Setting
Two cervical service screening programmes in Italy.
Population
Women aged 25–64 years invited to screening from April 2009 to October 2015.
Methods
Eligible women were invited to undergo an HPV test. Those with a negative HPV test went on to the next screening round 3 years later. Cytology triage was performed for HPV+ (HPV by Hybrid Capture 2) samples, with immediate colposcopy (if abnormal) and HPV re‐testing 1 year later (if negative).
Main outcome measures
Participation rate, positivity at HPV and at triage, referral rate to colposcopy, positive predictive value for cervical intraepithelial neoplasia grade 2+ (CIN2+) at colposcopy, and detection rate for CIN2+.
Results
We present the results from 48 751 women at the first screening and 22 000 women at re‐screening 3 years later. The response rate was slightly higher at the second screening (74.5 versus 72.1% at the first screening; referral rate, RR 1.11; 95% confidence interval, 95% CI, 1.07–1.14). Compared with the first screening, we observed a significant reduction at the second screening in terms of HPV positivity (RR 0.55, 95% CI 0.51–0.60), referral rate to colposcopy (RR 0.47, 95% CI 0.41–0.53), CIN2+ detection rate (RR 0.24, 95% CI 0.13–0.39), and positive predictive value (PPV) for CIN2+ at colposcopy (RR 0.51, 95% CI 0.29–0.87).
Conclusions
The very low frequency of disease and inadequate PPV at colposcopy indicate that a 3‐year interval after a negative HPV test is too short.
Tweetable
Three years after a negative HPV the frequency of cervical disease is so low that re‐screening is inefficient.
Tweetable
After a negative HPV test the frequency of cervical disease is so low at 3 years that re‐screening is inefficient.
Background
The objective of this study was to describe the determinants of adequacy and positivity of the p16/Ki‐67 assay in a human papillomavirus (HPV)‐positive screening population enrolled within ...the New Technologies for Cervical Cancer 2 (NTCC2) study.
Methods
ThinPrep slides were immunostained for p16/Ki‐67; each slide had 3 reports from different laboratories. The authors included population‐related, sampling‐related/staining‐related, and interpretation‐related variables in the analyses. Adequacy and positivity proportions were stratified by variables of interest. Univariate and multivariate logistic models were used to identify determinants of adequacy and positivity.
Results
In total, 3100 consecutive HPV‐positive cases were analyzed. Because every slide was interpreted by 3 centers, 9300 reports were obtained, including 905 (9.7%) that were inadequate and 2632 (28.3%) that were positive. The percentage of cases in which all 3 reports were inadequate increased with increasing age of the women and with inadequate cytology. The highest percentage of adequacy in all 3 reports and of cases with all 3 reports positive was observed in specimens from women who had grade ≥2 cervical intraepithelial neoplasia (CIN2+), atypical squamous cells of undetermined significance or more severe (ASC‐US+) cytology, or mRNA positivity. The number of inadequate reports was significantly associated with increasing age, inadequate cytology, mRNA negativity, and scant cellularity. A positive p16/Ki‐67 report was associated with an ASC‐US+ result and with a positive mRNA result in cases both with and without CIN2+ but was associated with an HPV type 16 and/or 18 infection only in CIN2+ cases. The presence of CIN2+ was strongly associated with dual staining positivity.
Conclusions
The interpretation of p16/Ki‐67 results may be influenced by several different variables, all of which are part of the steps in the procedure, and by the characteristics of the screened population.
The determinants of adequacy and positivity of the p16/Ki‐67 assay are described in a human papillomavirus‐positive screening population. Even using the same assay and reporting the results according to the same criteria, the findings suggest that many variables linked to the characteristics of the population under study, the laboratory that performs the immunostaining, and/or the laboratory that interprets the slides should be taken into consideration.
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