ORIGINAL STUDY
Association Between Cervical Screening and Prevention of Invasive Cervical Cancer in Ontario A Population-Based Case-Control Study Danielle Vicus, MD, MSc,*Þ Rinku Sutradhar, PhD,Þ Yan Lu, MSc,Þ Rachel Kupets, MD, MSc,*Þ and Lawrence Paszat, MD, PhD,Þ on behalf of the investigators of the Ontario Cancer Screening Research Network
Objective: The aim of this study was to estimate the effect of cervical screening in the prevention of invasive cervical cancer among age groups, using a population-based casecontrol study in the province of Ontario, Canada. Methods: Exposure was defined as cervical cytology history greater than 3 months before the diagnosis date of cervical cancer (index date). Cases were women who were diagnosed with cervical cancer between January 1, 1998, and December 31, 2008. Controls were women without a diagnosis of cervical cancer on, or before, December 31, 2008. Two controls were matched to each case on year of birth and income quintile, as of the index date. Conditional logistic regression was used to estimate the odds ratio for having been screened among those with cervical cancer. Results: Cervical cancer screening performed between 3 and 36 months before the index date was protective against invasive cervical cancer in women aged 40 through 69 years. In women younger than 40 years, cervical cancer screening performed 3 to 36 months before the index date was not protective. Conclusions: Cervical screening is associated with a reduced risk for invasive cervical cancer among women older than 40 years. Cervical cancer resources should be focused on maximizing the risk reduction. Key Words: Cervical cancer screening, Incidence, Prevention Received August 4, 2014, and in revised form September 12, 2014. Accepted for publication September 14, 2014. (Int J Gynecol Cancer 2015;25: 106Y111) primary goal of cervical screening is to detect and treat T hepreinvasive lesions, to prevent invasive cervical cancer
among healthy women at risk. In Canada, as in other developed
countries, invasive cervical cancer is now relatively rare accounting for approximately 2% of all new cancer cases among women.1 Negative consequences from cervical screening have
*Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Sunnybrook Health Sciences Centre; and †Institue of Clinical Evaluative Sciences, Toronto, Ontario, Canada. Address correspondence and reprint requests to Danielle Vicus, MD, MSc, Department of Gynecological Oncology, Odette Cancer Centre, T2018, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5. E-mail: [email protected]. Contributors: D.V. and L.P. devised the study concept and design, analyzed and interpreted the data, drafted the article, and are Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000305
guarantors. Y.L. performed all statistical analyses. R.S. assisted in devising study design, analyzed and interpreted the data, and critically revised the manuscript. R.K. and L.E. analyzed and interpreted the data and critically revised the manuscript for important intellectual content. Funding: The Ontario Cancer Screening Research Network is funded from endowments for cancer research held by the Board of Directors of Cancer Care Ontario. The funding party had no role in the design, conduct, or analysis of the study or in the decision to submit the manuscript for publication. The authors declare no conflicts of interest.
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Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 1, January 2015 Screening and the Prevention of Cervical Cancer
also become evident, including psychological (eg, anxiety), economical (costs to patients and to society), and medical (overdiagnosis and overtreatment) outcomes.2,3 Therefore, the challenge is to maximize the benefit while limiting the harm by implementing an optimal cervical cancer screening program. The highest incidence of cervical cancer in developed countries is in the age group between 35 and 45 years with approximately 45% of all cases diagnosed in this age group.4 It is evident that the aim should be to try and maximize the screening performed in women in this age group to have the highest impact on the incidence of cervical cancer. The challenge is how to decide the most appropriate age to start and stop screening while maximizing the benefit and minimizing any potential harm. A series of studies published by Sasieni and colleagues5Y7 have defined an optimal age group for cervical screening in England. They demonstrated limited benefit in women younger than 30 years, leading in 2004 to a change in cervical cancer screening guidelines in the United Kingdom; the new recommendation was to start screening at the age of 25 years, compared with the age of 21 years in the past. They demonstrated that the prevalence of invasive cervical cancer among women younger than 30 years is very low and calculated that among women aged 20 to 24 years to prevent 1 invasive cervical cancer, one would need to do between 12,500 and 40,000 additional screening tests and treat between 300 and 900 women, and it would be impossible to ascertain whether such a rare benefit would ever be attained.8 However, these studies were limited by the exposure definition used, which did not reflect the biennial or triennial periodicity for cervical screening, recommended in most countries.6 Cases of invasive cervical cancer were grouped into ‘‘age bands,’’ and then, cervical screening exposure was categorized into other age groups of women younger than those ‘‘age bands’’ of cancer cases. Consequently, women could have their last cytology up to 7 years before the date of diagnosis and still be included in the most recent cervical screening exposure category. The aim of our study is to estimate the preventive effect of cervical screening against invasive cervical cancer among the various age groups, currently eligible for screening in the province of Ontario, Canada.
MATERIALS AND METHODS Study Design The study was approved by the research ethics board at Sunnybrook Health Sciences Centre. We performed a populationbased case-control study at the Institute for Clinical Evaluative Sciences, which holds all electronic data bases containing records of publically funded services for all residents.
Data Sources Data were obtained from 4 sources: the Ontario Cancer Registry (OCR), Cytobase, the Ontario Health Insurance Plan (OHIP), and the Registered Persons Database. The OCR is a registry of all cases of invasive cancer diagnosed in Ontario since 1964 and has been shown to capture 95% of cases using
capture-recapture methods.8 The OCR contains a unique ID, ICD-9 diagnosis code, diagnosis date, age on date of diagnosis, vital status, date of last contact, and cause of death. Cytobase is a provincial cervical cytology database by community laboratories serving most of the Ontario population. It contains dates and results of all pap smears taken in the community setting, including doctors’ offices, as opposed to those taken in hospital colposcopy units and clinics. Cancer Care Ontario has estimated that Cytobase includes 87% of all pap smears perfomed in the province.9 The OHIP database contains all physicians’ billing records for services provided to Ontario residents. Registered Persons Database contains personal information such as sex, age, and postal code for all Ontario residents. All databases housed at the Institute for Clinical Evaluative Sciences are linkable via an encrypted version of the unique numeric 10-digit health insurance number assigned to each resident.
Cases and Controls Cases were required to have a first-time diagnosis of invasive cervix cancer in the OCR with a diagnosis date between January 1, 1998, and December 31, 2008. The date of diagnosis of a case becomes the index date for its controls. Controls were required to have no diagnosis of cervix cancer before the date of diagnosis of the case. Cases and controls were required to have continuous OHIP eligibility (reflecting continuous residence in Ontario) since January 1, 1995. Cases and controls at the index date were not required to have an identifiable primary care physician in the OHIP database but were excluded if they had an identifiable physician who was not submitting cervical cytology specimens to Cytobase community laboratories during the 36 months before the index date. Cases and controls were excluded if there was a record of hysterectomy before the index date. Two controls were matched to each case on year of birth and income quintile. Each patient was assigned the regionally adjusted median household income quintile determined from their postal code using Statistics Canada’s Postal Code Conversion File.
Exposure Exposure was defined as cervical cytology history identified through Cytobase. The most recent cytology, before the index date minus 3 months, from either source was used to define exposure. Exposure was defined as periods from the index date and categorized as (1) between greater than 3 months and 36 months before the index date, (2) 37 to 60 months before the index date, (3) 61 to 120 months before the index date, and (4) never or greater than 120 months before the index date. Cytology performed 0 to 3 months before were not considered screening and was not included. Before examining outcomes by exposure status, we categorized exposure among the study population as a whole using our method and then using the method of Sasieni et al.6 We found that the exposure status classification of Sasieni et al resulted in fewer women in the age range of exposure closest to the age range of the study population at the index date and more women without screening outside the age ranges of exposure. Accordingly, we did not use the Sasieni
* 2014 IGCS and ESGO
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et al method of classifying exposure because it does not provide an equal time interval of exposure for all women resulting in a possibile overestimation of the protective effect of cervical screening and because our method directly reflects guidelines for periodicity less than or equal to triennial for cervical screening.
Analysis Conditional logistic regression was used for each definition of exposure to estimate the odds ratio for having been screened among those with invasive cervical cancer. The estimates were calculated for each 5-year age group (eg, age of 20Y24 years) according to exposure category. The statistical software package SAS (version 9.3) was used for the analysis, and P e 0.05 was deemed statistically significant (2 sided).
RESULTS We matched 5047 individuals diagnosed with cervical cancer (cases) between January 1, 1998, and December 31, 2008, to 2 controls per case, that is, 10,094 controls. Cases and controls had a primary care physician who submitted cervical cytology to cytobase community laboratories or had no primary care physician, during the 36 months before the index date. All potential cases and controls who had a primary care physician who did not submit cervical cytology to community laboratories were excluded because of the risk for misclassification of screening exposure, due to cervical cytology performed in hospitals and not reported to Cytobase. Potential cases and controls with a history of hysterectomy were excluded. Cases were matched to controls by 5-year age group and median household income quintile on the index date. The full distribution of cases and controls in the 5-year incremental age groups is presented in Figure 1.
FIGURE 1. Age distribution of cases and controls by 5-year age increments.
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Furthermore, 79.2% of cases were diagnosed between the ages of 30 and 59 years (Table 1); 68.5% of cancers diagnosed between ages 30 and 34 years had cervical cytology between 4 and 36 months before the date of diagnosis, whereas this is true for only 38.7% of those between ages 55 and 59 years. The highest percentage of cases, with cervical cytology 4 to 36 months before diagnosis, is among the very small group of 55 women diagnosed between ages 20 and 24 years (78.6%). This percentage steadily decreases to 36.9% among the 325 women diagnosed between ages 65 and 69 years. By contrast, there is considerably less variability among control women having cervical cytology between 4 and 36 months before the index date: between ages 30 and 34 years, 60.9%, and between ages 55 and 59 years, 54.7%. The association between cervical screening and prevention of invasive cervical cancer is shown in Table 2 by 5year age groups. Among cases in the 40-to-44, 45-to-49, 50-to-54, 55-to-59, and 60-to-64 age groups, it seems that they were less likely to have had most recent cervical screening between 4 and 36 months before the index date, compared with controls. This does not seem to be true among cases in the 20-to-24, 25-to-29, 30-to-34, 35-to-39, or 65-to-69 age groups. Cases in the 40-to-44, 45-to-49, 50-to-54, and 55-to-59 age groups were somewhat less likely to have had most recent cervical screening in either the 4- to 36-month interval or the 37- to 60-month interval before the index date. There were no age groups among which the most recent cervical screening 61 to 120 months was less likely among cases compared with controls.
DISCUSSION Among the age groups for which we found a protective association with cervical screening, it is possible that the apparent protection results from prompt treatment of highgrade cervical intraepithelial neoplasia and from differentially high participation in cervical screening by relatively low-risk middle-aged women. It is important that (1) we were able to match cases to controls on median household income quintiles as the risk for invasive cervical cancer is inversely related to income, (2) we were able to exclude potential cases and controls whose primary care physicians were not submitting cervical cytology to community laboratories, and (3) we were able to include cases and controls who had never participated in cervical screening. The frequency of cervical screening during the 4- to 36-month interval before the index date among controls between 30 and 59 years old (54.7%Y60.9%) is not optimal. The consequence of this level of screening participation is seen among the cases diagnosed between 30 and 59 years old. Moreover, 12.1% of cases diagnosed between 30 and 34 years old had never been screened during the previous 10 years, and this steadily rises to 46.2% of cases diagnosed between ages 55 and 59 years. The Centers for Disease Control and Prevention has reported an overall percentage of women screened in 2008 between ages 18 and 44 years of 81.8% and 45 and 64 years of 78.8% and older than * 2014 IGCS and ESGO
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& Volume 25, Number 1, January 2015 Screening and the Prevention of Cervical Cancer
TABLE 1. Distribution of cases and controls by age and screening exposure
TABLE 1. (Continued)
Age on Diagnosis Screening Date or Index Exposure, Date, Years Months
Age on Diagnosis Screening Date or Index Exposure, Date, Years Months
20Y24
25Y29
30Y34
35Y39
40Y44
45Y49
50Y54
55Y59
4Y36 37Y60 61Y120 9120 or never Total age, 20Y24 4Y36 37Y60 61Y120 9120 or never Total age, 25Y29 4Y36 37Y60 61Y120 9120 or never Total age, 30Y34 4Y36 37Y60 61Y120 9120 or never Total age, 35Y39 4Y36 37Y60 61Y120 9120 or never Total age, 40Y44 4Y36 37Y60 61Y120 9120 or never Total age, 45Y49 4Y36 37Y60 61Y120 9120 or never Total age, 50Y54 4Y36 37Y60 61Y120 9120 or never Total age, 55Y59
Number of Cases
Number of Controls
55 (78.6%) 8 1 6 (8.6%)
76 (54.3%) 11 6 47 (33.7%)
60Y64
70 184 (72.7%) 21 20 28 (11.1%) 253 428 (68.5%) 57 47 73 (12.1%) 605 475 (63.0%) 67 90 122 (16.2%) 754 445 (54.4%) 58 88 227 (27.8%) 818 394 (53.1%) 39 68 241 (32.5%) 742 277 (47.4%) 34 50 223 (38.2%) 584 191 (38.7%) 30 45 228 (46.2%) 494
140 319 (63.0%) 46 26 115 (22.7%) 506 737 (60.9%) 100 109 264 (21.8%) 1210 933 (61.9%) 149 141 285 (18.9%) 1508 966 (59.1%) 149 176 345 (21.1%) 1636 848 (57.1%) 161 141 334 (22.5%) 1484 698 (59.8%) 113 107 250 (21.4%) 1168 540 (54.7%) 93 102 253 (25.6%) 988
65Y69
4Y36 37Y60 61Y120 9120 or never Total age, 60Y64 4Y36 37Y60 61Y120 9120 or never Total age, 65Y69
Number of Cases 151 (37.6%) 27 36 188 (46.8%) 402 120 (36.9%) 18 30 157 (48.3%) 325
Number of Controls 401 (49.9%) 58 87 258 (32.1%) 804 275 (42.3%) 54 66 255 (39.2%) 650
64 years of 50%.10 The screening rates in the United States are considerably higher than those quoted in Ontario; nonetheless, the trend of a decrease in screening with age is consistent. The observational studies by Sasieni et al6 did not find a protective association for cervical screening among younger women. Two other observational studies have demonstrated a protective effect among younger women; however, the Australian study6 and the Swedish study12 did not account for variability in risk factors among cases and controls and did not include women who had never been screened. Diagnosis of invasive cervix cancer, and death from it, is infrequent among women younger than 30 years. At this age, cervical screening, leading to cervical excisional treatment, does not seem to reduce the diagnosis of invasive cervix cancer, which is already infrequent, or deaths from cervix cancer, which are also infrequent.11 There are likely several factors contributing to these findings among young women. Age is a risk factor for invasive cervical cancer, and the lowest risk is among the youngest. Adenocarcinoma is less likely to be prevented by cervical screening.12 The cancers diagnosed among young women are diverse but, on average, are associated with a lower risk for mortality. Cervical cancer is predominantly linked to an infection with high-risk human papilloma virus (HPV) that is transferred through sexual contact. Hence, women at a younger age with a higher number of partners are at greater risk for being exposed to and developing a high-risk HPV infection. Nonetheless, most high-risk HPV infections in younger women are transient and do not lead to the development of high-grade cervical intraepithelial neoplasia. Many reports have shown that the incidence of cervical cancer in women younger than 30 years has not decreased since the initiation of cervical cancer screening programs. In Ontario, cervical screening is opportunistic, that is, it depends on a woman and her physician or nurse practitioner
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TABLE 2. The strength of association between cervical screening and cervical cancer by 5-year incremental age groups Age on Diagnosis Date or Index Date, Years 20Y24
25Y29
30Y34
35Y39
40Y44
45Y49
50Y54
55Y59
60Y64
65Y69
110
Screening Exposure, Months 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never
Odds Ratios (95% CI) 2.91 1.49 0.33 1.00 1.61 0.90 1.59 1.00 1.57 1.15 0.85 1.00 1.05 0.88 1.31 1.00 0.82 0.76 1.00 1.00 0.85 0.46 0.96 1.00 0.59 0.57 0.93 1.00 0.52 0.62 0.87 1.00 0.59 0.93 0.81 1.00 0.79 0.63 0.90 1.00
(1.51Y5.59) (0.58Y3.81) (0.04Y2.77) (reference) (1.15Y2.29) (0.51Y1.58) (0.87Y2.92) (Reference) (1.27Y1.94) (0.82Y1.60) (059Y1.22) (Reference) (0.88Y1.26) (0.65Y1.21) (0.99Y1.74) (Reference) (0.69Y0.97) (0.56Y1.05) (0.76Y1.31) (Reference) (0.71Y1.01) (0.32Y0.65) (0.71Y1.30) (Reference) (0.48Y0.73) (0.38Y0.85) (0.66Y1.32) (Reference) (0.48Y0.73) (0.41Y0.95) (0.6Y1.26) (Reference) (0.46Y0.76) (0.58Y1.48) (0.54Y1.22) (Reference) (0.59Y1.05) (0.36Y1.12) (0.58Y1.41) (Reference)
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to initiate and then both agree to conduct the sampling. For high-grade cytologic diagnoses, the physician must take action and refer the woman to a gynecologist who is also a colposcopist. This referral is not facilitated directly in response to the cytology. In general, sampling for cervical screening, colposcopy for diagnosis of high-grade cervical intraepithelial neoplasia, and cervical excisional treatments are available only during limited daytime office hours on weekdays; this may be a barrier for lower-income women, who unfortunately are also at higher biological risk in addition to being at risk for nonparticipation. There is no doubt that cervical cancer screening in the developed world has lowered the risk for invasive cervical cancer substantially. However, this has not come without cost. Adverse psychological (eg, anxiety, false reassurance), economical (costs to patients and to society), and medical (overdiagnosis and overtreatment) outcomes have now been well documented. Therefore, the current challenge is to maximize the benefit while limiting the harm by implementing the optimal cervical cancer screening program. The foundation of developing an optimal screening program is identifying the population at risk and aiming to maximize the screening rate in this precise population. Although younger women are at high risk for developing an HPV infection, women younger than 30 years rarely develop cervical cancer. Although women older than 60 years were previously thought to be a low-risk population, many may be at elevated risk because of the attrition in participation as well as nonparticipation in cervical screening before the age of 60 years. There is substantial data from our report and others that cervical screening among young adult women is not associated with protection against invasive cervical cancer or its mortality. The principal aim should be to maximize participation in cervical screening among women 30 to 59 years or older to maximize its protective association against invasive cervical cancer.
REFERENCES 1. Arbyn M, Raifu AO, Weiderpass E, et al. Trends of cervical cancer mortality in the member states of the European Union. Eur J Cancer. 2009;45:2640Y2648. 2. Samson SL, Bentley JR, Fahey TJ, et al. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol. 2005;105:325Y332. 3. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, et al. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet. 2006;367:489Y498. 4. Surveillance, Epidemiology and End Results Program. Percent of new cases by age group: cervix uteri cancer. SEER Stat Fact Sheets: Cervix Uteri Cancer. 2014. Available at: http://seer.cancer.gov/statfacts/html/cervix.html. 5. Sasieni P, Adams J, Cuzick J. Benefit of cervical screening at different ages: evidence from the UK audit of screening histories. Br J Cancer. 2003;89:88Y93. 6. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data. BMJ. 2009;339:b2968. 7. Sasieni P, Castanon A, Cuzick J. What is the right age for cervical cancer screening? Womens Health. 2010;6:1Y4. * 2014 IGCS and ESGO
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& Volume 25, Number 1, January 2015 Screening and the Prevention of Cervical Cancer
8. Robles SC, Marrett LD, Clarke EA, et al. An application of capture-recapture methods to the estimation of completeness of cancer registration. J Clin Epidemiol. 1988;41:495Y501. 9. Cancer Care Ontario. Ontario Cervical Screening Program: 2012 Report. Available at: www.cancercare.on.ca/cervicalreport. 10. Centers for Disease Control and Prevention. Cervical Cancer Screening Rates. Available at: http://www.cdc.gov/cancer/ cervical/statistics/screening.htm.
11. Vicus D, Sutradhar R, Lu Y, et al. The association between cervical cancer screening and mortality from cervical cancer: a population based case-control study. Gynecol Oncol. 2014;133:167Y171. 12. Zappa M, Visioli CB, Ciatto S, et al. Lower protection of cytological screening for adenocarcinomas and shorter protection for younger women: the results of a case-control study in Florence. Br J Cancer. 2004;90:1784Y1786.
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111
Association Between Cervical Screening and Prevention of Invasive Cervical Cancer in Ontario A Population-Based Case-Control Study Danielle Vicus, MD, MSc,*Þ Rinku Sutradhar, PhD,Þ Yan Lu, MSc,Þ Rachel Kupets, MD, MSc,*Þ and Lawrence Paszat, MD, PhD,Þ on behalf of the investigators of the Ontario Cancer Screening Research Network
Objective: The aim of this study was to estimate the effect of cervical screening in the prevention of invasive cervical cancer among age groups, using a population-based casecontrol study in the province of Ontario, Canada. Methods: Exposure was defined as cervical cytology history greater than 3 months before the diagnosis date of cervical cancer (index date). Cases were women who were diagnosed with cervical cancer between January 1, 1998, and December 31, 2008. Controls were women without a diagnosis of cervical cancer on, or before, December 31, 2008. Two controls were matched to each case on year of birth and income quintile, as of the index date. Conditional logistic regression was used to estimate the odds ratio for having been screened among those with cervical cancer. Results: Cervical cancer screening performed between 3 and 36 months before the index date was protective against invasive cervical cancer in women aged 40 through 69 years. In women younger than 40 years, cervical cancer screening performed 3 to 36 months before the index date was not protective. Conclusions: Cervical screening is associated with a reduced risk for invasive cervical cancer among women older than 40 years. Cervical cancer resources should be focused on maximizing the risk reduction. Key Words: Cervical cancer screening, Incidence, Prevention Received August 4, 2014, and in revised form September 12, 2014. Accepted for publication September 14, 2014. (Int J Gynecol Cancer 2015;25: 106Y111) primary goal of cervical screening is to detect and treat T hepreinvasive lesions, to prevent invasive cervical cancer
among healthy women at risk. In Canada, as in other developed
countries, invasive cervical cancer is now relatively rare accounting for approximately 2% of all new cancer cases among women.1 Negative consequences from cervical screening have
*Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Sunnybrook Health Sciences Centre; and †Institue of Clinical Evaluative Sciences, Toronto, Ontario, Canada. Address correspondence and reprint requests to Danielle Vicus, MD, MSc, Department of Gynecological Oncology, Odette Cancer Centre, T2018, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5. E-mail: [email protected]. Contributors: D.V. and L.P. devised the study concept and design, analyzed and interpreted the data, drafted the article, and are Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000305
guarantors. Y.L. performed all statistical analyses. R.S. assisted in devising study design, analyzed and interpreted the data, and critically revised the manuscript. R.K. and L.E. analyzed and interpreted the data and critically revised the manuscript for important intellectual content. Funding: The Ontario Cancer Screening Research Network is funded from endowments for cancer research held by the Board of Directors of Cancer Care Ontario. The funding party had no role in the design, conduct, or analysis of the study or in the decision to submit the manuscript for publication. The authors declare no conflicts of interest.
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Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 1, January 2015 Screening and the Prevention of Cervical Cancer
also become evident, including psychological (eg, anxiety), economical (costs to patients and to society), and medical (overdiagnosis and overtreatment) outcomes.2,3 Therefore, the challenge is to maximize the benefit while limiting the harm by implementing an optimal cervical cancer screening program. The highest incidence of cervical cancer in developed countries is in the age group between 35 and 45 years with approximately 45% of all cases diagnosed in this age group.4 It is evident that the aim should be to try and maximize the screening performed in women in this age group to have the highest impact on the incidence of cervical cancer. The challenge is how to decide the most appropriate age to start and stop screening while maximizing the benefit and minimizing any potential harm. A series of studies published by Sasieni and colleagues5Y7 have defined an optimal age group for cervical screening in England. They demonstrated limited benefit in women younger than 30 years, leading in 2004 to a change in cervical cancer screening guidelines in the United Kingdom; the new recommendation was to start screening at the age of 25 years, compared with the age of 21 years in the past. They demonstrated that the prevalence of invasive cervical cancer among women younger than 30 years is very low and calculated that among women aged 20 to 24 years to prevent 1 invasive cervical cancer, one would need to do between 12,500 and 40,000 additional screening tests and treat between 300 and 900 women, and it would be impossible to ascertain whether such a rare benefit would ever be attained.8 However, these studies were limited by the exposure definition used, which did not reflect the biennial or triennial periodicity for cervical screening, recommended in most countries.6 Cases of invasive cervical cancer were grouped into ‘‘age bands,’’ and then, cervical screening exposure was categorized into other age groups of women younger than those ‘‘age bands’’ of cancer cases. Consequently, women could have their last cytology up to 7 years before the date of diagnosis and still be included in the most recent cervical screening exposure category. The aim of our study is to estimate the preventive effect of cervical screening against invasive cervical cancer among the various age groups, currently eligible for screening in the province of Ontario, Canada.
MATERIALS AND METHODS Study Design The study was approved by the research ethics board at Sunnybrook Health Sciences Centre. We performed a populationbased case-control study at the Institute for Clinical Evaluative Sciences, which holds all electronic data bases containing records of publically funded services for all residents.
Data Sources Data were obtained from 4 sources: the Ontario Cancer Registry (OCR), Cytobase, the Ontario Health Insurance Plan (OHIP), and the Registered Persons Database. The OCR is a registry of all cases of invasive cancer diagnosed in Ontario since 1964 and has been shown to capture 95% of cases using
capture-recapture methods.8 The OCR contains a unique ID, ICD-9 diagnosis code, diagnosis date, age on date of diagnosis, vital status, date of last contact, and cause of death. Cytobase is a provincial cervical cytology database by community laboratories serving most of the Ontario population. It contains dates and results of all pap smears taken in the community setting, including doctors’ offices, as opposed to those taken in hospital colposcopy units and clinics. Cancer Care Ontario has estimated that Cytobase includes 87% of all pap smears perfomed in the province.9 The OHIP database contains all physicians’ billing records for services provided to Ontario residents. Registered Persons Database contains personal information such as sex, age, and postal code for all Ontario residents. All databases housed at the Institute for Clinical Evaluative Sciences are linkable via an encrypted version of the unique numeric 10-digit health insurance number assigned to each resident.
Cases and Controls Cases were required to have a first-time diagnosis of invasive cervix cancer in the OCR with a diagnosis date between January 1, 1998, and December 31, 2008. The date of diagnosis of a case becomes the index date for its controls. Controls were required to have no diagnosis of cervix cancer before the date of diagnosis of the case. Cases and controls were required to have continuous OHIP eligibility (reflecting continuous residence in Ontario) since January 1, 1995. Cases and controls at the index date were not required to have an identifiable primary care physician in the OHIP database but were excluded if they had an identifiable physician who was not submitting cervical cytology specimens to Cytobase community laboratories during the 36 months before the index date. Cases and controls were excluded if there was a record of hysterectomy before the index date. Two controls were matched to each case on year of birth and income quintile. Each patient was assigned the regionally adjusted median household income quintile determined from their postal code using Statistics Canada’s Postal Code Conversion File.
Exposure Exposure was defined as cervical cytology history identified through Cytobase. The most recent cytology, before the index date minus 3 months, from either source was used to define exposure. Exposure was defined as periods from the index date and categorized as (1) between greater than 3 months and 36 months before the index date, (2) 37 to 60 months before the index date, (3) 61 to 120 months before the index date, and (4) never or greater than 120 months before the index date. Cytology performed 0 to 3 months before were not considered screening and was not included. Before examining outcomes by exposure status, we categorized exposure among the study population as a whole using our method and then using the method of Sasieni et al.6 We found that the exposure status classification of Sasieni et al resulted in fewer women in the age range of exposure closest to the age range of the study population at the index date and more women without screening outside the age ranges of exposure. Accordingly, we did not use the Sasieni
* 2014 IGCS and ESGO
Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
107
International Journal of Gynecological Cancer
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et al method of classifying exposure because it does not provide an equal time interval of exposure for all women resulting in a possibile overestimation of the protective effect of cervical screening and because our method directly reflects guidelines for periodicity less than or equal to triennial for cervical screening.
Analysis Conditional logistic regression was used for each definition of exposure to estimate the odds ratio for having been screened among those with invasive cervical cancer. The estimates were calculated for each 5-year age group (eg, age of 20Y24 years) according to exposure category. The statistical software package SAS (version 9.3) was used for the analysis, and P e 0.05 was deemed statistically significant (2 sided).
RESULTS We matched 5047 individuals diagnosed with cervical cancer (cases) between January 1, 1998, and December 31, 2008, to 2 controls per case, that is, 10,094 controls. Cases and controls had a primary care physician who submitted cervical cytology to cytobase community laboratories or had no primary care physician, during the 36 months before the index date. All potential cases and controls who had a primary care physician who did not submit cervical cytology to community laboratories were excluded because of the risk for misclassification of screening exposure, due to cervical cytology performed in hospitals and not reported to Cytobase. Potential cases and controls with a history of hysterectomy were excluded. Cases were matched to controls by 5-year age group and median household income quintile on the index date. The full distribution of cases and controls in the 5-year incremental age groups is presented in Figure 1.
FIGURE 1. Age distribution of cases and controls by 5-year age increments.
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Furthermore, 79.2% of cases were diagnosed between the ages of 30 and 59 years (Table 1); 68.5% of cancers diagnosed between ages 30 and 34 years had cervical cytology between 4 and 36 months before the date of diagnosis, whereas this is true for only 38.7% of those between ages 55 and 59 years. The highest percentage of cases, with cervical cytology 4 to 36 months before diagnosis, is among the very small group of 55 women diagnosed between ages 20 and 24 years (78.6%). This percentage steadily decreases to 36.9% among the 325 women diagnosed between ages 65 and 69 years. By contrast, there is considerably less variability among control women having cervical cytology between 4 and 36 months before the index date: between ages 30 and 34 years, 60.9%, and between ages 55 and 59 years, 54.7%. The association between cervical screening and prevention of invasive cervical cancer is shown in Table 2 by 5year age groups. Among cases in the 40-to-44, 45-to-49, 50-to-54, 55-to-59, and 60-to-64 age groups, it seems that they were less likely to have had most recent cervical screening between 4 and 36 months before the index date, compared with controls. This does not seem to be true among cases in the 20-to-24, 25-to-29, 30-to-34, 35-to-39, or 65-to-69 age groups. Cases in the 40-to-44, 45-to-49, 50-to-54, and 55-to-59 age groups were somewhat less likely to have had most recent cervical screening in either the 4- to 36-month interval or the 37- to 60-month interval before the index date. There were no age groups among which the most recent cervical screening 61 to 120 months was less likely among cases compared with controls.
DISCUSSION Among the age groups for which we found a protective association with cervical screening, it is possible that the apparent protection results from prompt treatment of highgrade cervical intraepithelial neoplasia and from differentially high participation in cervical screening by relatively low-risk middle-aged women. It is important that (1) we were able to match cases to controls on median household income quintiles as the risk for invasive cervical cancer is inversely related to income, (2) we were able to exclude potential cases and controls whose primary care physicians were not submitting cervical cytology to community laboratories, and (3) we were able to include cases and controls who had never participated in cervical screening. The frequency of cervical screening during the 4- to 36-month interval before the index date among controls between 30 and 59 years old (54.7%Y60.9%) is not optimal. The consequence of this level of screening participation is seen among the cases diagnosed between 30 and 59 years old. Moreover, 12.1% of cases diagnosed between 30 and 34 years old had never been screened during the previous 10 years, and this steadily rises to 46.2% of cases diagnosed between ages 55 and 59 years. The Centers for Disease Control and Prevention has reported an overall percentage of women screened in 2008 between ages 18 and 44 years of 81.8% and 45 and 64 years of 78.8% and older than * 2014 IGCS and ESGO
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& Volume 25, Number 1, January 2015 Screening and the Prevention of Cervical Cancer
TABLE 1. Distribution of cases and controls by age and screening exposure
TABLE 1. (Continued)
Age on Diagnosis Screening Date or Index Exposure, Date, Years Months
Age on Diagnosis Screening Date or Index Exposure, Date, Years Months
20Y24
25Y29
30Y34
35Y39
40Y44
45Y49
50Y54
55Y59
4Y36 37Y60 61Y120 9120 or never Total age, 20Y24 4Y36 37Y60 61Y120 9120 or never Total age, 25Y29 4Y36 37Y60 61Y120 9120 or never Total age, 30Y34 4Y36 37Y60 61Y120 9120 or never Total age, 35Y39 4Y36 37Y60 61Y120 9120 or never Total age, 40Y44 4Y36 37Y60 61Y120 9120 or never Total age, 45Y49 4Y36 37Y60 61Y120 9120 or never Total age, 50Y54 4Y36 37Y60 61Y120 9120 or never Total age, 55Y59
Number of Cases
Number of Controls
55 (78.6%) 8 1 6 (8.6%)
76 (54.3%) 11 6 47 (33.7%)
60Y64
70 184 (72.7%) 21 20 28 (11.1%) 253 428 (68.5%) 57 47 73 (12.1%) 605 475 (63.0%) 67 90 122 (16.2%) 754 445 (54.4%) 58 88 227 (27.8%) 818 394 (53.1%) 39 68 241 (32.5%) 742 277 (47.4%) 34 50 223 (38.2%) 584 191 (38.7%) 30 45 228 (46.2%) 494
140 319 (63.0%) 46 26 115 (22.7%) 506 737 (60.9%) 100 109 264 (21.8%) 1210 933 (61.9%) 149 141 285 (18.9%) 1508 966 (59.1%) 149 176 345 (21.1%) 1636 848 (57.1%) 161 141 334 (22.5%) 1484 698 (59.8%) 113 107 250 (21.4%) 1168 540 (54.7%) 93 102 253 (25.6%) 988
65Y69
4Y36 37Y60 61Y120 9120 or never Total age, 60Y64 4Y36 37Y60 61Y120 9120 or never Total age, 65Y69
Number of Cases 151 (37.6%) 27 36 188 (46.8%) 402 120 (36.9%) 18 30 157 (48.3%) 325
Number of Controls 401 (49.9%) 58 87 258 (32.1%) 804 275 (42.3%) 54 66 255 (39.2%) 650
64 years of 50%.10 The screening rates in the United States are considerably higher than those quoted in Ontario; nonetheless, the trend of a decrease in screening with age is consistent. The observational studies by Sasieni et al6 did not find a protective association for cervical screening among younger women. Two other observational studies have demonstrated a protective effect among younger women; however, the Australian study6 and the Swedish study12 did not account for variability in risk factors among cases and controls and did not include women who had never been screened. Diagnosis of invasive cervix cancer, and death from it, is infrequent among women younger than 30 years. At this age, cervical screening, leading to cervical excisional treatment, does not seem to reduce the diagnosis of invasive cervix cancer, which is already infrequent, or deaths from cervix cancer, which are also infrequent.11 There are likely several factors contributing to these findings among young women. Age is a risk factor for invasive cervical cancer, and the lowest risk is among the youngest. Adenocarcinoma is less likely to be prevented by cervical screening.12 The cancers diagnosed among young women are diverse but, on average, are associated with a lower risk for mortality. Cervical cancer is predominantly linked to an infection with high-risk human papilloma virus (HPV) that is transferred through sexual contact. Hence, women at a younger age with a higher number of partners are at greater risk for being exposed to and developing a high-risk HPV infection. Nonetheless, most high-risk HPV infections in younger women are transient and do not lead to the development of high-grade cervical intraepithelial neoplasia. Many reports have shown that the incidence of cervical cancer in women younger than 30 years has not decreased since the initiation of cervical cancer screening programs. In Ontario, cervical screening is opportunistic, that is, it depends on a woman and her physician or nurse practitioner
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TABLE 2. The strength of association between cervical screening and cervical cancer by 5-year incremental age groups Age on Diagnosis Date or Index Date, Years 20Y24
25Y29
30Y34
35Y39
40Y44
45Y49
50Y54
55Y59
60Y64
65Y69
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Screening Exposure, Months 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never 4Y36 37Y60 61Y120 9120 or never
Odds Ratios (95% CI) 2.91 1.49 0.33 1.00 1.61 0.90 1.59 1.00 1.57 1.15 0.85 1.00 1.05 0.88 1.31 1.00 0.82 0.76 1.00 1.00 0.85 0.46 0.96 1.00 0.59 0.57 0.93 1.00 0.52 0.62 0.87 1.00 0.59 0.93 0.81 1.00 0.79 0.63 0.90 1.00
(1.51Y5.59) (0.58Y3.81) (0.04Y2.77) (reference) (1.15Y2.29) (0.51Y1.58) (0.87Y2.92) (Reference) (1.27Y1.94) (0.82Y1.60) (059Y1.22) (Reference) (0.88Y1.26) (0.65Y1.21) (0.99Y1.74) (Reference) (0.69Y0.97) (0.56Y1.05) (0.76Y1.31) (Reference) (0.71Y1.01) (0.32Y0.65) (0.71Y1.30) (Reference) (0.48Y0.73) (0.38Y0.85) (0.66Y1.32) (Reference) (0.48Y0.73) (0.41Y0.95) (0.6Y1.26) (Reference) (0.46Y0.76) (0.58Y1.48) (0.54Y1.22) (Reference) (0.59Y1.05) (0.36Y1.12) (0.58Y1.41) (Reference)
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to initiate and then both agree to conduct the sampling. For high-grade cytologic diagnoses, the physician must take action and refer the woman to a gynecologist who is also a colposcopist. This referral is not facilitated directly in response to the cytology. In general, sampling for cervical screening, colposcopy for diagnosis of high-grade cervical intraepithelial neoplasia, and cervical excisional treatments are available only during limited daytime office hours on weekdays; this may be a barrier for lower-income women, who unfortunately are also at higher biological risk in addition to being at risk for nonparticipation. There is no doubt that cervical cancer screening in the developed world has lowered the risk for invasive cervical cancer substantially. However, this has not come without cost. Adverse psychological (eg, anxiety, false reassurance), economical (costs to patients and to society), and medical (overdiagnosis and overtreatment) outcomes have now been well documented. Therefore, the current challenge is to maximize the benefit while limiting the harm by implementing the optimal cervical cancer screening program. The foundation of developing an optimal screening program is identifying the population at risk and aiming to maximize the screening rate in this precise population. Although younger women are at high risk for developing an HPV infection, women younger than 30 years rarely develop cervical cancer. Although women older than 60 years were previously thought to be a low-risk population, many may be at elevated risk because of the attrition in participation as well as nonparticipation in cervical screening before the age of 60 years. There is substantial data from our report and others that cervical screening among young adult women is not associated with protection against invasive cervical cancer or its mortality. The principal aim should be to maximize participation in cervical screening among women 30 to 59 years or older to maximize its protective association against invasive cervical cancer.
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8. Robles SC, Marrett LD, Clarke EA, et al. An application of capture-recapture methods to the estimation of completeness of cancer registration. J Clin Epidemiol. 1988;41:495Y501. 9. Cancer Care Ontario. Ontario Cervical Screening Program: 2012 Report. Available at: www.cancercare.on.ca/cervicalreport. 10. Centers for Disease Control and Prevention. Cervical Cancer Screening Rates. Available at: http://www.cdc.gov/cancer/ cervical/statistics/screening.htm.
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