Cervical Screening and Cervical Cancer Death in Older Women
Cervical Screening and Cervical Cancer Death in Older Women
In this study, we observed that cervical cancer screening by cytology during the DPP, estimated as the 7 years prior to symptom onset or screen-detected diagnosis, was associated with a 74% reduction in cervical cancer death among women aged 55–79 years at death. This reduction is nearly identical to the estimate by Kamineni et al. of efficacy with respect to incidence (77%) from the same 2 health plans and during a similar time period (1980–1999). The similarity between the 2 estimates suggests that cervical cytology screening in older women does not preferentially detect slow-growing and/or treatment-responsive lesions.
This study was designed to answer a direct and interpretable question of public health significance. Outcome and exposure data were drawn from valid sources: established tumor registries and medical record review, respectively. Previous research has repeatedly documented that the medical record is a more accurate source of Pap smear screening history than self-report. Unlike in prior studies addressing this research question, in this study we ascertained hysterectomy status and the presence of cervical cancer signs and/or symptoms at the time of each cytology test, and women who had any evidence of care outside the health plan were excluded in an attempt to ensure that complete exposure information could be ascertained. The results were robust; when subjects with less than 7 years of enrollment prior to the reference date were excluded, or the length of the DPP was shortened, results did not change meaningfully. Further, the observed 74% decrease in cervical cancer death associated with screening may actually be an underestimate if the DPP duration is truly longer than 7 years.
Given the small number of total cases in the main analysis, the precision of the 3 prespecified exploratory analyses was limited. First, although the efficacy among women aged 65 years or older was less than that among women under 65 years of age, the confidence intervals of these estimates preclude any strong inferences about the differential efficacy of cytology screening by age. Indeed, other cervical screening studies have observed that screening efficacy is not attenuated and may actually increase with age among older women, though the differences in risk estimates by age were not of large magnitude (nor statistically significant), and these studies examined the outcome of incidence rather than death. The 2 studies that examined cervical cancer death found comparable trends by age; Andrae et al. observed a higher cure proportion associated with screen detection among women aged 66 years or older compared with those aged 23–65 years (36%, 95% CI: 11, 80 vs. 26%, 95% CI: 15, 36, respectively), and the results of Lönnberg et al. were consistent with similar efficacy among women aged 55–69 years compared with women aged 40–54 years (OR = 0.29, 95% CI: 0.16, 0.54 vs. OR = 0.33, 95% CI: 0.20, 0.56). Second, the similarity of the odds ratios in the 2 time intervals, 1999 or earlier versus 2000 or later, supports the inference that improvements in cervical cancer treatment—primarily, the addition of chemotherapy to radiation-based treatment regimens—have not rendered screening relatively less efficacious with respect to death. Third, the somewhat higher efficacy observed for SCC cases corroborates other studies' conclusions that cytology screening is likely more efficacious at detecting SCC than adenocarcinoma.
This study did have limitations. No data were available on sexual history or HPV, the etiological agent of cervical cancer. However, neither of these variables is routinely ascertained for postmenopausal women; therefore, neither is likely to influence a clinician's decision to screen for cervical cancer. During the study period, clinical screening guidelines at Group Health and KPNW did not include ascertaining high-risk HPV status. These guidelines did consider age at sexual debut, but this influenced only age at screening initiation, not cessation. For these reasons, lack of ascertainment of sexual history and HPV status are not likely to confound the measured odds ratios. Smoking is the most plausible confounder, because it is a strong ICC risk factor. Smoking status was ascertained for all subjects. Second, the 7-year estimate of the DPP of cervical cancer screening by means of cytology may underestimate the true DPP. However, data from the United Kingdom, the United States and a worldwide analysis indicate that 1 or 2 negative Pap smears predicts low risk of disease for no more than 7 years, and sensitivity analyses in this study did not indicate that shortening the DPP duration affects the odds ratio substantially (Table 3). If cervical cancer or its precursors were detectable via Pap smear for more than 7 years prior to the index date, a greater proportion of screening Pap smears would be missed among controls than among cases (Figure 1), minimizing any difference between the comparison groups and thus attenuating the odds ratio. Finally, this study could not address the impact of recent screening as a function of the adequacy of screening earlier in life, because data on screening prior to health plan enrollment were not available. However, previous research indicates that older women experience a low incidence of cervical cancer for no more than 7 years following 1 or 2 negative Pap smears. Further, the cure proportion did not differ with prior cytology screening history among women aged 66 years or older at diagnosis. Thus, it is reasonable to infer that the results of the present study are applicable to older women regardless of prior Pap smear screening history.
Irrespective of the study's strengths and the robustness of its results, some may consider its research question obsolete. Cytological screening will most likely decline in favor of HPV-based screening because of its superiority over cytology in the 2 characteristics that influence test efficacy; HPV DNA testing can detect ICC risk for a longer period than cytology, and its sensitivity is an absolute 40% higher than that of cytology. Thus, the relationship between these screening modalities' efficacies is knowable—the efficacy of HPV-based screening is expected to exceed that of cytology, all things being equal. Analysis of extant data on cytology screening, therefore, may offer a minimum estimate of HPV-based screening efficacy among older women. However, screening by cytology alone remains acceptable under all current guidelines, and Pap smears continue to be widely used. Further, a study to evaluate the efficacy of HPV DNA testing among older women will not be possible for years after an HPV DNA–based screening program is implemented, until a sufficient number of deaths have occurred to make meaningful comparisons on the basis of prior HPV DNA screening history. Until such data are available, this study's results may shed light on the potential efficacy of an HPV-based screening program to prevent cervical cancer death among older women. In effect, the present study provides insight into whether to screen older women, not the best modality to do so.
In the meantime, cancer screening guideline groups acknowledge that lack of evidence hampers their ability to make evidence-based recommendations for cervical cancer screening in older women. The present study addresses this research gap. On the basis of this study's odds ratios and the screening prevalence among the cases, and assuming the observed association is causal, 36.2% of cervical cancer deaths among women aged 55–79 years in the United States, or approximately 630 deaths per year, could have been averted by screening in the 7 years prior to symptom onset or screen-detected diagnosis. It is likely that a larger number of deaths could be averted with an HPV-based screening strategy.
The results of this study, in conjunction with those from previous analyses, suggest a potential benefit of extending screening guidelines to include women older than 65 years. Cervical cytology screening is not without harms, such as invasive diagnostic procedures, short-term psychological distress, and overdiagnosis. If, after quantification of the potential harms of screening older women, they are deemed to be outweighed by the potential benefits, national guideline groups could consider an expansion of the age group for which cervical cancer screening is currently recommended.
Discussion
In this study, we observed that cervical cancer screening by cytology during the DPP, estimated as the 7 years prior to symptom onset or screen-detected diagnosis, was associated with a 74% reduction in cervical cancer death among women aged 55–79 years at death. This reduction is nearly identical to the estimate by Kamineni et al. of efficacy with respect to incidence (77%) from the same 2 health plans and during a similar time period (1980–1999). The similarity between the 2 estimates suggests that cervical cytology screening in older women does not preferentially detect slow-growing and/or treatment-responsive lesions.
This study was designed to answer a direct and interpretable question of public health significance. Outcome and exposure data were drawn from valid sources: established tumor registries and medical record review, respectively. Previous research has repeatedly documented that the medical record is a more accurate source of Pap smear screening history than self-report. Unlike in prior studies addressing this research question, in this study we ascertained hysterectomy status and the presence of cervical cancer signs and/or symptoms at the time of each cytology test, and women who had any evidence of care outside the health plan were excluded in an attempt to ensure that complete exposure information could be ascertained. The results were robust; when subjects with less than 7 years of enrollment prior to the reference date were excluded, or the length of the DPP was shortened, results did not change meaningfully. Further, the observed 74% decrease in cervical cancer death associated with screening may actually be an underestimate if the DPP duration is truly longer than 7 years.
Given the small number of total cases in the main analysis, the precision of the 3 prespecified exploratory analyses was limited. First, although the efficacy among women aged 65 years or older was less than that among women under 65 years of age, the confidence intervals of these estimates preclude any strong inferences about the differential efficacy of cytology screening by age. Indeed, other cervical screening studies have observed that screening efficacy is not attenuated and may actually increase with age among older women, though the differences in risk estimates by age were not of large magnitude (nor statistically significant), and these studies examined the outcome of incidence rather than death. The 2 studies that examined cervical cancer death found comparable trends by age; Andrae et al. observed a higher cure proportion associated with screen detection among women aged 66 years or older compared with those aged 23–65 years (36%, 95% CI: 11, 80 vs. 26%, 95% CI: 15, 36, respectively), and the results of Lönnberg et al. were consistent with similar efficacy among women aged 55–69 years compared with women aged 40–54 years (OR = 0.29, 95% CI: 0.16, 0.54 vs. OR = 0.33, 95% CI: 0.20, 0.56). Second, the similarity of the odds ratios in the 2 time intervals, 1999 or earlier versus 2000 or later, supports the inference that improvements in cervical cancer treatment—primarily, the addition of chemotherapy to radiation-based treatment regimens—have not rendered screening relatively less efficacious with respect to death. Third, the somewhat higher efficacy observed for SCC cases corroborates other studies' conclusions that cytology screening is likely more efficacious at detecting SCC than adenocarcinoma.
This study did have limitations. No data were available on sexual history or HPV, the etiological agent of cervical cancer. However, neither of these variables is routinely ascertained for postmenopausal women; therefore, neither is likely to influence a clinician's decision to screen for cervical cancer. During the study period, clinical screening guidelines at Group Health and KPNW did not include ascertaining high-risk HPV status. These guidelines did consider age at sexual debut, but this influenced only age at screening initiation, not cessation. For these reasons, lack of ascertainment of sexual history and HPV status are not likely to confound the measured odds ratios. Smoking is the most plausible confounder, because it is a strong ICC risk factor. Smoking status was ascertained for all subjects. Second, the 7-year estimate of the DPP of cervical cancer screening by means of cytology may underestimate the true DPP. However, data from the United Kingdom, the United States and a worldwide analysis indicate that 1 or 2 negative Pap smears predicts low risk of disease for no more than 7 years, and sensitivity analyses in this study did not indicate that shortening the DPP duration affects the odds ratio substantially (Table 3). If cervical cancer or its precursors were detectable via Pap smear for more than 7 years prior to the index date, a greater proportion of screening Pap smears would be missed among controls than among cases (Figure 1), minimizing any difference between the comparison groups and thus attenuating the odds ratio. Finally, this study could not address the impact of recent screening as a function of the adequacy of screening earlier in life, because data on screening prior to health plan enrollment were not available. However, previous research indicates that older women experience a low incidence of cervical cancer for no more than 7 years following 1 or 2 negative Pap smears. Further, the cure proportion did not differ with prior cytology screening history among women aged 66 years or older at diagnosis. Thus, it is reasonable to infer that the results of the present study are applicable to older women regardless of prior Pap smear screening history.
Irrespective of the study's strengths and the robustness of its results, some may consider its research question obsolete. Cytological screening will most likely decline in favor of HPV-based screening because of its superiority over cytology in the 2 characteristics that influence test efficacy; HPV DNA testing can detect ICC risk for a longer period than cytology, and its sensitivity is an absolute 40% higher than that of cytology. Thus, the relationship between these screening modalities' efficacies is knowable—the efficacy of HPV-based screening is expected to exceed that of cytology, all things being equal. Analysis of extant data on cytology screening, therefore, may offer a minimum estimate of HPV-based screening efficacy among older women. However, screening by cytology alone remains acceptable under all current guidelines, and Pap smears continue to be widely used. Further, a study to evaluate the efficacy of HPV DNA testing among older women will not be possible for years after an HPV DNA–based screening program is implemented, until a sufficient number of deaths have occurred to make meaningful comparisons on the basis of prior HPV DNA screening history. Until such data are available, this study's results may shed light on the potential efficacy of an HPV-based screening program to prevent cervical cancer death among older women. In effect, the present study provides insight into whether to screen older women, not the best modality to do so.
In the meantime, cancer screening guideline groups acknowledge that lack of evidence hampers their ability to make evidence-based recommendations for cervical cancer screening in older women. The present study addresses this research gap. On the basis of this study's odds ratios and the screening prevalence among the cases, and assuming the observed association is causal, 36.2% of cervical cancer deaths among women aged 55–79 years in the United States, or approximately 630 deaths per year, could have been averted by screening in the 7 years prior to symptom onset or screen-detected diagnosis. It is likely that a larger number of deaths could be averted with an HPV-based screening strategy.
The results of this study, in conjunction with those from previous analyses, suggest a potential benefit of extending screening guidelines to include women older than 65 years. Cervical cytology screening is not without harms, such as invasive diagnostic procedures, short-term psychological distress, and overdiagnosis. If, after quantification of the potential harms of screening older women, they are deemed to be outweighed by the potential benefits, national guideline groups could consider an expansion of the age group for which cervical cancer screening is currently recommended.
