Projected Impact of HPV and LBC Primary Testing on Rates of Referral for Colposcopy in a Canadian Cervical Cancer Screening Program.

OBJECTIVE: To estimate the impact of implementing primary human papilloma virus liquid-based cytology (LBC) screening on four-year rates of referral for colposcopy in the British Columbia screening program. METHODS: We used data on referral for colposcopy from an RCT (HPV FOCAL) comparing HPV testing every four years with LBC testing every two years. We also used data from population screening with conventional cytology among women aged 25 to 69. The predicted effect of adoption of either trial protocol on rates of referral for colposcopy was estimated using trial age-specific result and screening result-specific rates weighted by their screening program distribution. The cumulative age-specific rates of referral for colposcopy over four years were calculated. RESULTS: Use of HPV testing initially increased rates of referral for colposcopy in the trial, but over four years the cumulative rates of referral were similar to those for LBC except in women aged 25 to 29, in whom a substantial excess persisted. Four-year rates of referral for colposcopy declined with age in women screened with HPV testing, LBC, and conventional cytology. Extrapolating the trial results to the distribution in the provincial screening program, implementation of either HPV or LBC throughout the provincial population would approximately double the current rates of referral for colposcopy. CONCLUSION: Compared with LBC screening, primary screening for HPV increased rates of referral for colposcopy only among women aged 25 to 29. In contrast to current practice, referral for colposcopy was largely driven by the trial protocol recommendations for the management of abnormal results and not by which screening test was used.

Objectif : Estimer les effets de la mise en œuvre d'un dépistage primaire du virus du papillome humain par cytologie en milieu liquide (CML) sur les taux d'orientation en colposcopie sur quatre ans, dans le cadre du programme de dépistage de la Colombie-Britannique. Méthodes : Nous avons utilisé les données sur l'orientation en colposcopie issues d'un ECR (HPV FOCAL) comparant le dépistage du VPH tous les quatre ans au dépistage par CML tous les deux ans. Nous avons également utilisé des données issues du dépistage populationnel par cytologie conventionnelle mené auprès des femmes de 25 à 69 ans. Le taux d'orientation en colposcopie en fonction de l'âge et le taux d'orientation en colposcopie en fonction des résultats de dépistage ont été pondérés en fonction de la distribution de leurs programmes de dépistage respectifs, ce qui a permis d'estimer l'effet populationnel prévu de l'adoption de l'un ou l'autre des protocoles d'essai en question sur les taux d'orientation en colposcopie. Les taux cumulatifs (en fonction de l'âge) de l'orientation en colposcopie sur quatre ans ont été calculés. Résultats : Le recours au dépistage du VPH a initialement mené à la hausse des taux d'orientation en colposcopie dans le cadre de l'essai; toutefois, sur quatre ans, les taux cumulatifs d'orientation ont été semblables à ceux de la CML, sauf chez les femmes de 25 à 29 ans (chez lesquelles un excès substantiel a persisté). Les taux d'orientation en colposcopie sur quatre ans ont connu une baisse en fonction de l'âge chez les femmes ayant fait l'objet d'un dépistage du VPH, d'une CML et d'une cytologie conventionnelle. En extrapolant les résultats de l'essai à la distribution qui existe au sein du programme provincial de dépistage, nous avons constaté que la mise en œuvre du dépistage du VPH ou de la CML au sein de la population provinciale mènerait au doublement approximatif des taux actuels d'orientation en colposcopie. Conclusion : Par comparaison avec le dépistage par CML, le dépistage primaire du VPH n'a entraîné la hausse des taux d'orientation en colposcopie que chez les femmes de 25 à 29 ans. Contrairement à la pratique actuelle, l'orientation en colposcopie était largement motivée par les recommandations du protocole d'essai en ce qui concerne la prise en charge des résultats anormaux, et non par le test de dépistage utilisé.

Incidence of breast cancer and estimates of overdiagnosis after the initiation of a population-based mammography screening program.

BACKGROUND: There has been growing interest in the overdiagnosis of breast cancer as a result of mammography screening. We report incidence rates in British Columbia before and after the initiation of population screening and provide estimates of overdiagnosis. METHODS: We obtained the numbers of breast cancer diagnoses from the BC Cancer Registry and screening histories from the Screening Mammography Program of BC for women aged 30-89 years between 1970 and 2009. We calculated age-specific rates of invasive breast cancer and ductal carcinoma in situ. We compared these rates by age, calendar period and screening participation. We obtained 2 estimates of overdiagnosis from cumulative cancer rates among women between the ages of 40 and 89 years: the first estimate compared participants with nonparticipants; the second estimate compared observed and predicted population rates. RESULTS: We calculated participation-based estimates of overdiagnosis to be 5.4% for invasive disease alone and 17.3% when ductal carcinoma in situ was included. The corresponding population-based estimates were -0.7% and 6.7%. Participants had higher rates of invasive cancer and ductal carcinoma in situ than nonparticipants but lower rates after screening stopped. Population incidence rates for invasive cancer increased after 1980; by 2009, they had returned to levels similar to those of the 1970s among women under 60 years of age but remained elevated among women 60-79 years old. Rates of ductal carcinoma in situ increased in all age groups. INTERPRETATION: The extent of overdiagnosis of invasive cancer in our study population was modest and primarily occurred among women over the age of 60 years. However, overdiagnosis of ductal carcinoma in situ was elevated for all age groups. The estimation of overdiagnosis from observational data is complex and subject to many influences. The use of mammography screening in older women has an increased risk of overdiagnosis, which should be considered in screening decisions.

Cancer risk in multiple sclerosis: findings from British Columbia, Canada.

Findings regarding cancer risk in people with multiple sclerosis have been inconsistent and few studies have explored the possibility of diagnostic neglect. The influence of a relapsing-onset versus primary progressive course on cancer risk is unknown. We examined cancer risk and tumour size at diagnosis in a cohort of patients with multiple sclerosis compared to the general population and we explored the influence of disease course. Clinical data of patients with multiple sclerosis residing in British Columbia, Canada who visited a British Columbia multiple sclerosis clinic from 1980 to 2004 were linked to provincial cancer registry, vital statistics and health registration data. Patients were followed for incident cancers between onset of multiple sclerosis, and the earlier of emigration, death or study end (31 December 2007). Cancer incidence was compared with that in the age-, sex- and calendar year-matched population of British Columbia. Tumour size at diagnosis of breast, prostate, colorectal and lung cancers were compared with population controls, matched for cancer site, sex, age and calendar year at cancer diagnosis, using the stratified Wilcoxon test. There were 6820 patients included, with 110 666 person-years of follow-up. The standardized incidence ratio for all cancers was 0.86 (95% confidence interval: 0.78-0.94). Colorectal cancer risk was also significantly reduced (standardized incidence ratio: 0.56; 95% confidence interval: 0.37-0.81). Risk reductions were similar by sex and for relapsing-onset and primary progressive multiple sclerosis. Tumour size was larger than expected in the cohort (P = 0.04). Overall cancer risk was lower in patients with multiple sclerosis than in the age-, sex- and calendar year matched general population. The larger tumour sizes at cancer diagnosis suggested diagnostic neglect; this could have major implications for the health, well-being and longevity of people with multiple sclerosis.

Population studies of the effectiveness of mammographic screening.

OBJECTIVE: To examine population data to see whether survival from breast cancer has improved differentially in screened and unscreened women and examine published studies on mammographic screening to determine whether there is evidence that screening is no longer effective. METHODS: Data was reviewed on trends in breast cancer specific survival among women participating and not participating in the British Columbia Breast Screening Program. Population studies of mammographic screening published between 2000 and 2010 with breast cancer mortality as the outcome were also reviewed. RESULTS: Breast cancer specific survival in British Columbia improved more in screening participants than non-participants, HR=0.74 (0.58,0.93) between the periods 1990-4 and 2000-4. Among the published studies of mortality between 2000 and 2010 selected from different jurisdictions all had found a reduction in breast cancer mortality although this was not always statistically different from zero. Studies had used a range of designs and evaluative methods which may have contributed to the magnitude of the effect reported. CONCLUSION: No evidence was found in the British Columbia data and the published studies reviewed, that treatment or other changes, had caused mammographic screening to become ineffective.

Comparison of nonbreast cancer incidence, survival and mortality between breast screening program participants and nonparticipants.

Comparisons of cancer mortality between users and nonusers of screening are potentially biased because of the effects of self-selection. Previous studies of breast screening have found that individuals likely to participate have lower breast cancer mortality than those unlikely to participate. This study compares the incidence, survival and mortality for all cancer types other than breast between participants and nonparticipants in a service screening mammography program. British Columbian females having their first mammogram between the ages of 40 and 79 and the years 1988 and 2004 were identified as a cohort of "participants". Person-years of follow-up of participants were aggregated by age and year. Nonparticipant person-years were obtained by subtraction from the total female population. Cancer diagnoses other than breast were identified for participants and nonparticipants. Age, calendar year, and income adjusted relative risks of cancer incidence were estimated from generalized additive models with Poisson errors. Hazard ratios were estimated by Cox regression. Observed cancer mortality in participants was compared with expected mortality generated from nonparticipant incidence and survival rates. Incidence rates of cancer showed a mixed relationship with some elevated, some decreased and others similar to nonparticipant rates. Cancer survival was higher among participants for most cancer types, with an overall hazard ratio of 0.76 (0.73-0.79). Observed mortality in participants was less than expected for most cancers, with an overall mortality ratio of 0.60 (0.58-0.62). The general cancer experience of screening program participants is different from that of the general population.

Impact of changing from annual to biennial mammographic screening on breast cancer outcomes in women aged 50-79 in British Columbia.

OBJECTIVES: The objective of this study was to compare breast cancer outcomes among women subject to different policies on mammography screening frequency. SETTING: Data were obtained for women participating in the Screening Mammography Programme of British Columbia (SMPBC) for 1988--2005. The SMPBC changed its policy for women aged 50-79 years from annual to biennial mammography in 1997, but retained an annual recommendation for women aged 40-49 years. METHODS: Breast cancer outcomes were compared for women participating in the programme before and after 1997 for two groups: ages 40-49 and 50-79 years. RESULTS: There were data on 658,151 women. Comparing pre-1997 and post-1997, the median interscreen interval increased by 11.1 months in women 50-79 but by only 0.3 months in women aged 40-49. Excluding those detected at initial screen, 6291 breast cancers were identified. Comparing pre-1997 and post-1997: the relative rates (RR) of screen detected cancer increased in women aged 40-49 (RR = 1.32) and the rate of invasive cancers > or =20 mm at diagnosis decreased (RR = 0.83); the rate of cancers with axillary node involvement increased in women aged 50-79 (RR = 1.23). Cancer survival improved after 1997 for women diagnosed at ages 40-49 (hazard ratio = 0.62), but was unchanged for women aged 50-79. Breast cancer mortality rates did not change between the periods in either age group. CONCLUSION: The proximal cancer outcomes considered (staging and survival) improved in women aged 40-49 but this was offset in women aged 50-79 associated with the change in screen frequency. These changes did not result in alterations in breast cancer mortality rates in either age group.

Risk of invasive cervical cancer after Pap smears: the protective effect of multiple negatives.

OBJECTIVE: To determine the relationship between the number of initial negative Pap smears and risk of subsequent cervical cancer. DESIGN: A cohort study was conducted using data from the British Columbia Cervical Cancer Screening Program and British Columbia Cancer Registry. The analysis used a random sample (1%) of women aged 20-69 with Pap smears and all cases of invasive cervical cancer diagnosed between 1994 and 1999. Each negative screen defined the beginning of a screening interval and intervals longer than five years were truncated. The following variables were created for each interval: age at the beginning of the interval, interval length, previous cytological abnormality, previous cervical procedure and number of preceding consecutive negative screens. The relationship between these variables and risk of squamous cervical cancer was determined using survival analysis methods. RESULTS: A total of 388 cases of invasive cervical cancer (252 squamous) were included in the study from a study population of over 3.3 million Pap smears. The risk of invasive squamous cancer increased with time since the last negative screen, history of cytological abnormality and history of cervical therapeutic procedure. Risk was not significantly related to age (P=0.2) but was highest in women aged 30-49. Multiple consecutive negative pap smears were associated with reduced risk in women with a history of moderate atypia (P<0.0001), but not in women without a history (P=0.4). CONCLUSIONS: Multiple consecutive negative cytology was not associated with reduced risk of invasive cervical cancer in women with no history of cytological abnormality.

The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984-2000.

BACKGROUND AND PURPOSE: To describe the risk of second malignancy following a diagnosis of prostate cancer, in British Columbia (BC), Canada. To ascertain whether that risk changed with the use of radiation therapy. METHODS AND MATERIALS: All invasive cases of prostate cancer diagnosed from 1984 through to 2000 were retrieved from the BC Tumor Registry. Standardized incidence ratios (SIRs) were calculated from observed and expected numbers as a percentage. Patients were divided into those who received high-dose radiation therapy (>/=45 Gy, RT group) and those not treated with radiation (non-RT group). RESULTS: Overall there was no significant difference between observed and expected second cancer rates, SIR=100 (RT group, N=101; non-RT group, N=98, P=n.s.). Individual tumour sites at significantly increased risk (P<0.01) included bladder (non-RT group, SIR=132), colo-rectal (RT group, SIR=121), pleura (RT group, SIR=228). Other sites of possible significance (P<0.05) include sarcoma (RT group, SIR=170) and testis (non-RT group, SIR=282). CONCLUSIONS: Increased rates of bladder and testis cancers in the non-RT group are likely to be due to increased urologist surveillance and the use of therapeutic orchiectomy. Increased rates of colorectal cancer in those treated with radiation may be either due to surveillance or treatment. Increases in sarcomas in the RT group are probably treatment-related. Overall the increased second cancer risk for those undergoing radiation therapy was 1 in 220.

The changing face of prostate cancer in British Columbia 1988-2000.

OBJECTIVE: To evaluate changes of prostate cancer incidence, referrals, stage, treatment and outcomes delivered in British Columbia since the 1980's. MATERIALS AND METHODS: Examination of the BC Provincial Tumour Registry, BC Cancer Agency (BCCA) and BC Medical Services Plan databases. RESULTS: The number of incident cases increased linearly from 1980 through 1990. Between 1991 and 1995 a harvesting effect was seen due to unofficial PSA screening, balanced by a post-harvest effect between 1995 and 1998. Since 1999 the incidence has resumed the linear trend extrapolated from the 1980's. The age-standardised incidence rate has recently risen in younger (<65yrs) men. The incidence of metastatic cancer has dropped from 14% of cases referred to the BCCA in 1988 to 3.5% in 2000. A steady proportionate increase in T1 and T2 referrals has occurred since 1988. PSA levels at referral are lower (mean PSA 10 nmol/L in 2000 versus 15 nmol/L in 1990. Gleason scores are higher, likely reflecting changes of interpretation of pathological grade. The number of men receiving any curative therapy has increased from 43% in 1990 to 53% by 1999, and the proportion treated with surgery has increased from 30% in 1990 to 50% by 2000. Mortality rates have been falling since 1991, and BC has the lowest mortality rate in Canada. CONCLUSIONS: Predictions of incidence have been beset by unanticipated external factors, and have underestimated actual incidence. Stage migration towards better prognosis tumours occurring in younger men has led to the increased use of surgery and brachytherapy and decreased use of external radiation.

Pan-Canadian study of mammography screening and mortality from breast cancer.

BACKGROUND: Screening with mammography has been shown by randomized controlled trials to reduce breast cancer mortality in women aged 40 to 74 years. Estimates from observational studies following screening implementation in different countries have produced varyied findings. We report findings for seven Canadian breast screening programs. METHODS: Canadian breast screening programs were invited to participate in a study aimed at comparing breast cancer mortality in participants and nonparticipants. Seven of 12 programs, representing 85% of the Canadian population, participated in the study. Data were obtained from the screening programs and corresponding cancer registries on screening mammograms and breast cancer diagnoses and deaths for the period between 1990 and 2009. Standardized mortality ratios were calculated comparing observed mortality in participants to that expected based upon nonparticipant rates. A substudy using data from British Columbia women aged 35 to 44 years was conducted to assess the potential effect of self-selection participation bias. All statistical tests were two-sided. RESULTS: Data were obtained on 2796472 screening participants. The average breast cancer mortality among participants was 40% (95% confidence interval [CI] = 33% to 48%) lower than expected, with a range across provinces of 27% to 59%. Age at entry into screening did not greatly affect the magnitude of the average reduction in mortality, which varied between 35% and 44% overall. The substudy found no evidence that self-selection biased the reported mortality results, although the confidence intervals of this assessment were wide. CONCLUSION: Participation in mammography screening programs in Canada was associated with substantially reduced breast cancer mortality.

False-positive screening mammograms and biopsies among women participating in a Canadian provincial breast screening program.

BACKGROUND: Mammography screening results in false positives that cause anxiety and utilize scarce medical resources for their resolution. Determination of screening recommendations requires knowledge of the population risk of false positives. METHODS: Data were extracted from the Screening Mammography Program of British Columbia and analyzed to determine the influence of personal factors including age, ethnic group and screening history, and the centre where screening was performed, on the likelihood a new screen would result in a false positive and whether a biopsy was required. The resulting probabilities were combined to provide values for lifetime screening algorithms. RESULTS: Age, screen sequence number, history of previous abnormal screens and centre where screening was performed were significantly related to the likelihood a new screen would be a false positive. British Columbia women screened biennially between the ages of 50 and 69 have a projected 41% chance of a false-positive screen and a 5.6% risk of a related biopsy, with the best performing centres having rates of 26% and 3%, respectively. INTERPRETATION: Model projections for BC overall are comparable to other North American estimates. Estimates varied depending upon screening centre attended.

40-year trends in skin cancer in British Columbia, Canada, 1973 to 2003.

BACKGROUND: Skin cancer is common in North America. Incidence rate trends are potentially important in the assessment of the effects of measures to increase sun awareness in the population as well as measures to reduce sun damage. OBJECTIVE: To determine the incidence of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and cutaneous malignant melanoma (CMM) in a geographically defined Canadian population over a 40-year period. METHODS: Data were obtained from the BC Cancer Registry for the calendar years 1973, 1983, 1993, and 2003. RESULTS: Age-standardized incidence rates increased significantly from 1973 to 2003 for BCC, SCC, and CMM. LIMITATIONS: The ethnic makeup of British Columbia has changed over time, and a novel method of accounting for the effect of this on skin cancer rates is presented. CONCLUSION: The incidence rate for skin cancers continued to rise in British Columbia, but there appears to have been a decline in the incidence of CMM and BCC in the youngest cohorts.

A retrospective study of the effect of participation in screening mammography on the use of chemotherapy and breast conserving surgery.

A population sample was obtained from the British Columbia (BC) Cancer Registry of all women diagnosed with a first breast cancer in 2002 who were resident in Greater Vancouver or Greater Victoria, BC. Information on treatment and prognostic factors were obtained from source records. The study group was linked to the records of the Screening Mammography Program of BC to identify screening histories on women prior to diagnosis. Logistic regression was used to determine the relationship between screening participation and treatment and to predict treatment use from prognostic factors. Fifteen hundred and eighty-nine women with breast cancer were included in the study and 1,071 (67%) had participated in screening prior to diagnosis: 786 (49%) had been screened within the 30 months prior to their diagnosis (regular participants). Breast conserving surgery (BCS) rates were higher (OR = 2.3, p < 0.001) and chemotherapy use lower (OR = 0.53, p < 0.001) among regular participants compared with nonparticipants after adjustment for age. A predictive model based on the distribution of prognostic factors between participants provided estimates of OR = 1.47 and OR = 0.54 for BCS and chemotherapy, respectively, and adjustment for self-selection changed the predicted values to OR = 1.16 and OR = 0.67, respectively. Participation in screening produced a considerable change in the use of chemotherapy but less on BCS use.

Breast cancer mortality after screening mammography in British Columbia women.

Mammographic screening is a proven method for the early detection of breast cancer. The authors analyzed the impact of service mammographic screening on breast cancer mortality among British Columbia women who volunteered to be screened by the Screening Mammography Program of British Columbia. A cohort of women having at least one mammographic screen by Screening Mammography Program of British Columbia between the ages of 40 and 79 in the period 1988-2003 was identified. All cases and deaths from breast cancer occurring in British Columbia were identified from the British Columbia Cancer Registry and linked to the screening cohort. Expected deaths from breast cancer in the cohort were calculated using incidence and survival rates for British Columbia women not in the cohort. Adjustment was made for age and socioeconomic status of their area of residence at time of diagnosis. The breast cancer mortality ratio was calculated by dividing observed by expected breast cancer deaths. The mortality ratio (95% confidence interval) was 0.60 (0.55, 0.65) for all ages combined (p < 0.0001). The mortality ratio in women aged 40-49 at first screening was 0.61 (0.52, 0.71), similar to that in women over 50 (p = 0.90). Exclusion of mortality associated with breast cancers diagnosed after age 50 in women starting screening in their 40s increased the mortality ratio to 0.63 (0.52, 0.77), but it remained statistically significant. Correction for self-selection bias using estimates from the literature increased the mortality ratio for all ages to 0.76. Mammographic screening at all ages between 40 and 79 reduced subsequent mortality rates from breast cancer.

Risk of a second malignant neoplasm among 5-year survivors of cancer in childhood and adolescence in British Columbia, Canada.

BACKGROUND: We examined second malignancies, a recognized late effect of therapy among survivors of childhood and adolescent cancer, among a recent, population-based cohort of 2,322 5-year survivors diagnosed before 20 years of age in British Columbia (BC), Canada between 1970 and 1995. PROCEDURE: Survivors and second malignancies were identified from the BC Cancer Registry. Risk of second malignancy was evaluated using standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative risk. The effect of demographic, temporal, and disease-related characteristics on risk was assessed. RESULTS: Fifty-five second malignancies were observed after 26,071 person-years of follow-up. Relative rate of developing a second malignancy among survivors was 5 times higher than expected (SIR = 5.0, 95% CI, 3.8-6.5), and absolute excess risk was 1.7 deaths per 1,000 person-years. Cumulative incidence of a second malignancy was 5.1% at 25 years after diagnosis of the first cancer. SIRs and absolute excess risk of subsequent cancer was higher among females (SIR = 5.9, 95% CI, 4.5-8.3 and AER = 2.66). While relative risk of second cancer was higher for those diagnosed before 10 years of age (SIR = 10.6, 95% CI, 7.1-16.0), absolute excess risk was slightly higher for those diagnosed after 10 years of age. SIRs were significantly elevated for all follow-up periods, but absolute excess risk of a second cancer was highest among patients surviving more than 15 years. CONCLUSIONS: Increased risk of a subsequent neoplasm is evident among childhood cancer survivors diagnosed in more recent periods than has been previously reported, continues years after diagnosis, and varies according to several risk factors. Continued surveillance is essential to quantify and characterize long-term and changing risks for appropriate follow-up.

Organized breast screening programs in Canada: effect of radiologist reading volumes on outcomes.

PURPOSE: To examine retrospectively the relationship between radiologist screening program reading volumes and interpretation results. MATERIALS AND METHODS: This research project was reviewed by the University of British Columbia Research Ethics Board. Informed patient consent was not required. Data were requested from Canadian provincial screening programs for the period 1988-2000. Cancer detection rates, abnormal interpretation rates, and positive predictive values (PPVs) were calculated for individual radiologists in those programs. Multivariate Poisson mixed regression models were used to examine the effect of patient age, screening examination sequence (first or subsequent screening examination), province, radiologist reading volume, and interradiologist differences on cancer detection rate, abnormal interpretation rate, and PPV. RESULTS: The results of the interpretation of 1406678 screening mammograms by 304 radiologists from seven provincial programs were analyzed. Cancer detection rate, abnormal interpretation rate, and PPV all varied according to age of woman screened and screening sequence and across the sample of radiologists. None of the rates varied by province. Neither the cancer detection rate nor the abnormal interpretation rate varied by reading volume, but the average PPV was increased by 34% for volumes over 2000 mammograms versus volumes of 480-699 mammograms per year. There was no evidence that the magnitude of variability around the average, for radiologists reading the same volume of mammograms, varied across different volume groups for any of the outcome measures. CONCLUSION: Cancer detection did not vary with reading volume. The average PPV for individual radiologists increased as reading volume rose up to 2000 mammograms per year; it stabilized at higher volumes.