M. van Ballegooijen

Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial.

BACKGROUND Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented. METHODS Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131. FINDINGS 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups. INTERPRETATION The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.

Screening for colorectal cancer: randomised trial comparing guaiac-based and immunochemical faecal occult blood testing and flexible sigmoidoscopy

Background: Screening for colorectal cancer (CRC) is widely accepted, but there is no consensus on the preferred strategy. We conducted a randomised trial comparing participation and detection rates (DR) per screenee of guaiac-based faecal occult blood test (gFOBT), immunochemical FOBT (FIT), and flexible sigmoidoscopy (FS) for CRC screening. Methods: A representative sample of the Dutch population (n = 15 011), aged 50–74 years, was 1:1:1 randomised prior to invitation to one of the three screening strategies. Colonoscopy was indicated for screenees with a positive gFOBT or FIT, and for those in whom FS revealed a polyp with a diameter ⩾10 mm; adenoma with ⩾25% villous component or high grade dysplasia; serrated adenoma; ⩾3 adenomas; ⩾20 hyperplastic polyps; or CRC. Results: The participation rate was 49.5% (95% confidence interval (CI) 48.1 to 50.9%) for gFOBT, 61.5% (CI, 60.1 to 62.9%) for FIT and 32.4% (CI, 31.1 to 33.7%) for FS screening. gFOBT was positive in 2.8%, FIT in 4.8% and FS in 10.2%. The DR of advanced neoplasia was significantly higher in the FIT (2.4%; OR, 2.0; CI, 1.3 to 3.1) and the FS arm (8.0%; OR, 7.0; CI, 4.6 to 10.7) than the gFOBT arm (1.1%). FS demonstrated a higher diagnostic yield of advanced neoplasia per 100 invitees (2.4; CI, 2.0 to 2.8) than gFOBT (0.6; CI, 0.4 to 0.8) or FIT (1.5; CI, 1.2 to 1.9) screening. Conclusion: This randomised population-based CRC-screening trial demonstrated superior participation and detection rates for FIT compared to gFOBT screening. FIT screening should therefore be strongly preferred over gFOBT screening. FS screening demonstrated a higher diagnostic yield per 100 invitees than both FOBTs.

PCR-based high-risk HPV test in cervical cancer screening gives objective risk assessment of women with cytomorphologically normal cervical smears

Cervical‐cancer screening programmes using cytomorphological criteria could be more efficient if the screening included objective individual risk factors for women with normal cytology, such as a test for high‐risk human papillomavirus (HPV). The value of a PCR‐based test for high‐risk HPV types was studied in a cohort of 1622 women presenting in a routine biannual population‐based screening programme. Women were included in the study when they had no previous history of cervical dysplasia; and their initial Pap smear was read as normal (Pap 1 or 2). The mean age of the women was 42 years (range 34–54 years) and mean follow‐up time was 40 months (range 5–73 months). Women were referred for colposcopically directed biopsies if they had had 2 successive cervical smears read as Pap 3a (mild to moderate dyskaryosis) or one read as ≥ Pap 3b (severe dyskaryosis). Women with histologically confirmed cervical intraepithelial neoplasia grade III (CIN III) were considered positive cases. All women were tested for 14 high‐risk HPV genotypes. Of the 86 high‐risk HPV‐positive women, 6 developed CIN III, whereas only 1 of the 1536 HPV‐negative women did. The women with normal Pap smears containing high‐risk HPV genotypes were 116 times (95% Cl, 13–990) more at risk of developing CIN III, in contrast to women without high‐risk HPV. These results support the view that the interval between successive smears in cervical‐cancer screening can be increased considerably for women with cytomorphologically normal and high‐risk HPV‐negative cervical smears as determined by PCR.

Screening for colorectal cancer: random comparison of guaiac and immunochemical faecal occult blood testing at different cut-off levels

Immunochemical faecal occult blood testing (FIT) provides quantitative test results, which allows optimisation of the cut-off value for follow-up colonoscopy. We conducted a randomised population-based trial to determine test characteristics of FIT (OC-Sensor micro, Eiken, Japan) screening at different cut-off levels and compare these with guaiac-based faecal occult blood test (gFOBT) screening in an average risk population. A representative sample of the Dutch population (n=10 011), aged 50–74 years, was 1 : 1 randomised before invitation to gFOBT and FIT screening. Colonoscopy was offered to screenees with a positive gFOBT or FIT (cut-off 50 ng haemoglobin/ml). When varying the cut-off level between 50 and 200 ng ml−1, the positivity rate of FIT ranged between 8.1% (95% CI: 7.2–9.1%) and 3.5% (95% CI: 2.9–4.2%), the detection rate of advanced neoplasia ranged between 3.2% (95% CI: 2.6–3.9%) and 2.1% (95% CI: 1.6–2.6%), and the specificity ranged between 95.5% (95% CI: 94.5–96.3%) and 98.8% (95% CI: 98.4–99.0%). At a cut-off value of 75 ng ml−1, the detection rate was two times higher than with gFOBT screening (gFOBT: 1.2%; FIT: 2.5%; P<0.001), whereas the number needed to scope (NNscope) to find one screenee with advanced neoplasia was similar (2.2 vs 1.9; P=0.69). Immunochemical faecal occult blood testing is considerably more effective than gFOBT screening within the range of tested cut-off values. From our experience, a cut-off value of 75 ng ml−1 provided an adequate positivity rate and an acceptable trade-off between detection rate and NNscope.

The MISCAN-COLON simulation model for the evaluation of colorectal cancer screening

A general model for evaluation of colorectal cancer screening has been implemented in the microsimulation program MISCAN-COLON. A large number of fictitious individual life histories are simulated in each of which several colorectal lesions can emerge. Next, screening for colorectal cancer is simulated, which will change some of the life histories. The demographic characteristics, the epidemiology and natural history of the disease, and the characteristics of screening are defined in the input. All kinds of assumptions on the natural history of colorectal cancer and screening and surveillance strategies can easily be incorporated in the model. MISCAN-COLON gives detailed output of incidence, prevalence and mortality, and the results and effects of screening. It can be used to test hypotheses about the natural history of colorectal cancer, such as the duration of progressive adenomas, and screening characteristics, such as sensitivity of tests, against empirical data. In decision making about screening, the model can be used for evaluation of screening policies, and for choosing between competing policies by comparing their simulated incremental costs and effectiveness outcomes.

A systematic review of the role of human papilloma virus (HPV) testing within a cervical screening programme: summary and conclusions.

A systematic review of the available evidence on the role of HPV testing in cervical screening has been published by the Health Technology Assessment Committee of the UK Department of Health. The review summarized relevant data on testing methods, natural history, and prevalence of the virus in different disease groups. Cost-effectiveness modelling was undertaken. Ten major conclusions were reached and are reported here. The key conclusions were that HPV testing was more sensitive than cytology, but that there were concerns about specificity, especially in young women. The increased sensitivity led to a recommendation that HPV testing be introduced on a pilot basis for women with borderline and mild smears. HPV testing has great potential as a primary screening test, but large trials are needed to properly evaluate this application and to determine if its introduction can reduce invasive cancer rates. There is an urgent need to undertake a large trial of HPV testing in conjunction with other new technologies (liquid-based cytology and computer-assisted cytology reading) to determine the best way to integrate them into ongoing screening programmes. A range of issues including the age to start and stop screening, the appropriate screening interval, the role of self-sampling for HPV testing and the choice of primary test (HPV and/or cytology) require further evaluation.

Immunochemical Fecal Occult Blood Testing Is Equally Sensitive for Proximal and Distal Advanced Neoplasia

OBJECTIVE:Fecal immunochemical testing (FIT) is increasingly used for colorectal cancer (CRC) screening. We aimed to estimate its diagnostic accuracy in invitational population screening measured against colonoscopy.METHODS:Participants (50–75 years) in an invitational primary colonoscopy screening program were asked to complete one sample FIT before colonoscopy. We estimated FIT sensitivity, specificity, and predictive values in detecting CRC and advanced neoplasia (carcinomas and advanced adenomas) for cutoff levels of 50 (FIT50), 75 (FIT75), and 100 (FIT100) ng hemoglobin (Hb)/ml, corresponding with, respectively, 10, 15 and 20 μg Hb/g feces.RESULTS:A total of 1,256 participants underwent a FIT and screening colonoscopy. Advanced neoplasia was detected by colonoscopy in 119 (9%), 8 (0.6%) of them had CRC. At FIT50, 121 (10%) had a positive test result; 45 (37%) had advanced neoplasia and 7 (6%) had CRC. A total of 74 of 1,135 FIT50 negatives (7%) had advanced neoplasia including 1 (0.1%) CRC. FIT50 had a sensitivity of 38% (95% confidence interval (CI): 29–47) for advanced neoplasia and 88% (95% CI: 37–99) for CRC at a specificity of 93% (95% CI: 92–95) and 91% (95% CI: 89–92), respectively. The positive and negative predictive values for FIT50 were 6% (95% CI: 3–12) and almost 100% (95% CI: 99–100) for CRC, and 37% (95% CI: 29–46) and 93% (95% CI: 92–95) for advanced neoplasia. The sensitivity and specificity of FIT75 for advanced neoplasia were 33% (95% CI: 25–42) and 96% (95% CI: 94–97). At FIT100, 71 screenees (6%) had a positive test result. The sensitivity and specificity of FIT100 were for advanced neoplasia 31% (95% CI: 23–40) and 97% (95% CI: 96–98), and for CRC 75% (95% CI: 36–96) and 95% (95% CI: 93–96). The area under curve for detecting advanced neoplasia was 0.70 (95% CI: 0.64–0.76). FIT had a similar sensitivity for proximal and distal advanced neoplasia at cutoffs of 50 (38% vs. 37%; P=0.99), 75 (33% vs. 31%; P=0.85) and 100 (33% vs. 29%; P=0.68) ng Hb/ml.DISCUSSION:Nine out of ten screening participants with CRC and four out of ten with advanced neoplasia will be detected using one single FIT at low cutoff. Sensitivity in detecting proximal and distal advanced neoplasia is comparable.

Overview of important cervical cancer screening process values in European Union (EU) countries, and tentative predictions of the corresponding effectiveness and cost-effectiveness

The objective was the evaluation of the (cost-)effectiveness of cervical cancer screening in the European Union (EU) countries. Data were collected on recommended screening age ranges and intervals, coverage, proportion of non-negative smears and smear use. Estimates reported by representatives of each participating Member State were compared, and used as input for model based on (using the MISCAN simulation model for cancer screening) effectiveness and cost-effectiveness calculations. Differences in coverage from below 50 to 82% resulted in more or less proportional differences in expected percentage life-years lost reduction, almost regardless of differences in 7-50+ smears recommended in a lifetime. Differences in screening intensity (resulting from the recommended number of smears per lifetime and the number of excess smears on top of these recommendations) resulted in more than 2-fold difference in the expected number of smears per percentage life-years lost reduction. (Cost-)effectiveness predictions would have greatly improved if estimates of long-term coverage had also been available. To conclude, estimates for a restricted set of well defined parameters - a few for short and long-term coverage and one for the total number of smears - are quite useful for country-specific (cost-)effectiveness evaluations. The main, and to some extent, unsolvable problem for further improvement of the analysis is the lack of reliable country-specific estimates for the background risk of cervical cancer in women eligible for screening in the near future.

The NordICC Study: rationale and design of a randomized trial on colonoscopy screening for colorectal cancer.

BACKGROUND AND STUDY AIM While colonoscopy screening is widely used in several European countries and the United States, there are no randomized trials to quantify its benefits. The Nordic-European Initiative on Colorectal Cancer (NordICC) is a multinational, randomized controlled trial aiming at investigating the effect of colonoscopy screening on colorectal cancer (CRC) incidence and mortality. This paper describes the rationale and design of the NordICC trial. STUDY DESIGN Men and women aged 55 to 64 years are drawn from the population registries in the participating countries and randomly assigned to either once-only colonoscopy screening with removal of all detected lesions, or no screening (standard of care in the trial regions). All individuals are followed for 15 years after inclusion using dedicated national registries. The primary end points of the trial are cumulative CRC-specific death and CRC incidence during 15 years of follow-up. POWER ANALYSIS: We hypothesize a 50 % CRC mortality-reducing efficacy of the colonoscopy intervention and predict 50 % compliance, yielding a 25 % mortality reduction among those invited to screening. For 90 % power and a two-sided alpha level of 0.05, using a 2:1 randomization, 45 600 individuals will be randomized to control, and 22 800 individuals to the colonoscopy group. Interim analyses of the effect of colonoscopy on CRC incidence and mortality will be performed at 10-year follow-up. CONCLUSIONS The aim of the NordICC trial is to quantify the effectiveness of population-based colonoscopy screening. This will allow development of evidence-based guidelines for CRC screening in the general population.

Colorectal cancer risk in adenoma patients: A nation‐wide study

Colorectal cancer incidence after adenoma removal has been studied in selected populations of adenoma patients. Our study estimates the trend in colorectal cancer incidence after adenoma removal in actual clinical practice. From PALGA, a nationwide network and registry of histo‐ and cytopathology in the Netherlands, we extracted data of all patients diagnosed with colorectal adenomas between 1 January 1988 and 1 October 1998. The data were used to calculate population‐based colorectal cancer incidence rates after adenoma removal. A total of 78,473 adenoma patients were followed for a mean of 4.5 years after the first adenoma removal. The colorectal cancer incidence ratio compared with the general population matched by age and gender was 38.4 (37.3–39.5) in the first year after adenoma removal and 1.5 (95% confidence interval (CI): 1.4–1.6) after Year 1. The incidence ratio decreased from 2.8 (2.5–3.1) in Year 2 to 0.9 (0.6–1.2) in Years 9–11. This time trend is the opposite of the upward time trend that was expected after adenoma removal. Adenoma patients in the Netherlands are at increased risk for colorectal cancer compared to the general population. The high cancer incidence in Years 1–5 after polypectomy can be explained by a colonoscopic sensitivity for cancer of approximately 90%.