The relative economics of screening for colorectal cancer, breast cancer and cervical cancer

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1 Critical Reviews in Oncology/Hematology 32 (1999) The relative economics of screening for colorectal cancer, breast cancer and cervical cancer Dorte Gyrd-Hansen* Institute of Public Health, Uni ersity of Southern Denmark, Odense Uni ersity, Winsløwparken 19,3, 5000 Odense C, Denmark Accepted 8 December 1998 Contents 1. Introduction Presenting the screening programmes Colorectal cancer screening Breast cancer screening Cervical cancer screening A comparison Modelling the cost-effectiveness of screening Discussion Conclusion Reviewers References Biography This paper compares the cost-effectiveness of mammography screening, colorectal cancer screening using the unhydrated Hemoccult II (H-II) test and cervical cancer screening using the Pap-smear test. Emphasis has been on shedding some light on the unique characteristics of each of these programmes. This comparative evaluation illustrates that although the breast cancer screening and cervical cancer screening programmes are more effective in detecting cancers, colorectal cancer screening using the unhydrated H-II test is overall more cost-effective. This paper suggests that in a Danish setting, it would be optimal to introduce annual colorectal cancer screening of the year olds along with biennial mammography targeted at the year olds and cervical cancer screening every 4 years for the year olds. * Tel.: ; fax: address: dgh@sam.sdu.dk (D. Gyrd-Hansen) 1. Introduction In recent decades potential methods of screening for early stage cancers diseases have surfaced. The interest in developing such screening methods has been furnaced by a wish to reduce the mortality rate of cancer diseases. Although survival rates have improved for colorectal cancer, mammae cancer and cervical cancer even when these are detected at the clinical stage, it has been shown that detecting these cancers at a yet unsymptomatic stage can reduce mortality rates further. Several randomised controlled trials have been launched in order to measure the magnitude of the effect of early detection on the mortality rates of colorectal cancer and mammae cancer. Recently, the results of two randomised trials on the early detection of colorectal cancer were published, which showed that colorectal cancer mortality was reduced by 15 18% /99/$ - see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S (99)

2 134 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) [1,2] amongst the test group. Both trials applied the unhydrated Hemoccult II test (H-II), which is one of several fecal occult blood tests (FOBT) that have been developed for potential use in population screening programmes for detection of colorectal neoplasms. The effect of mammography for the early detection of breast cancer has likewise been analysed in a series of randomised trials. A recent meta-analysis [3] based on various clinical trials shows that the relative risk for women aged offered screening mammography compared with those who do not is significantly lower than 1. The main test used to screen for cervical cancer is the Papanicolaou smear developed by Dr George Papanicolaou in the 1930s and introduced for widespread screening in the 1940s. While the Pap-smear test has never been subject to randomised trials, comparison of regions in which the test has been used with regions in which such screening has not taken place, have shown that this test has a significant impact on the mortality of cervical cancer [4]. In previous works we modelled the effects of screening for colorectal cancer, cervical cancer and mammae cancer [5 7]. In this paper we present a comparative analysis, where the work from the previous publications are presented together, in order to demonstrate the relative efficacy and costeffectiveness of the unhydrated Hemoccult II test, one-view mammography and the Pap-smear test. The cost-effectiveness of each of these screening procedures is a function of the characteristics of the tests and the natural history of the cancer diseases as well as the population incidence of the disease. The aim of this paper is to provide the reader with an intuitive understanding of the relative merits of the screening tests, and to illustrate the relative economics of such screening programmes. The discussion is largely based on a Danish setting using Danish incidence rates and, to the extent possible, test characteristics as these have been observed in Denmark. Unfortunately, Danish data were not always available, making it necessary to seek other data sources primarily data from Swedish and Dutch screening programmes. Incidence rates do however vary across countries, as do the methods of performing and analysing tests. The cost-effectiveness results presented in this paper should be interpreted with this in mind. Below, we discuss each screening procedure in turn and present parameter values used in the modelling work. This is followed by a direct comparison of the three types of screening programmes illustrating relative advantages and disadvantages. Next, we turn to the economics of each type of screening programme. This section is based on previously performed analyses, and hence focus is largely on results. Finally, we broadly outline how policy makers could distribute resources amongst programmes in order to maximise the effect of investments in these preventive interventions. 2. Presenting the screening programmes The aim of this paper is to demonstrate the relative cost-effectiveness of FOBT screening for colorectal cancer, cervical cancer screening using the Pap-smear test, and mammography screening in a Danish setting. The model used for all three evaluations is a statistical model originally developed by Day and Walter [8]. Variables such as mean sojourn time, sensitivity rate and age dependent incidence rates, are inputs into a simulation process, where the number of cancers de tected per age group at each screening round are estimated for hypothetical screening programmes with varying screening intervals and target groups. Each model parameter will influence the results of the cost-effectiveness analysis. This section introduces these core parameters and presents the parameter values used in the model Colorectal cancer screening The incidence of colorectal cancer in the Danish population rises with age. Amongst year olds the incidence is 50 per , but it rises to as much as 318 per for the older age group of year olds. Consequently, the target group for screening has been the older age groups. Clinical trials have invited the +45 year olds, but since the observed detection rates amongst year olds have been minimal [1], the focus of this paper s discussion will be the year olds. One objective of fecal occult blood screening is the detection and treatment of carcinomas at the earliest possible stage, when patient prognosis is the most favourable. FOB screening, however, is also capable of detecting adenomas, or benign tumors, because these too possess a capacity to bleed. The extent to which screening programmes have an effect on mortality rates is highly dependent on the screening test s ability to detect cancers earlier. The latency period signifies the time period in which the cancer is detectable by the screening test but not yet clinically detectable. The maximum lead time obtainable is hence the latency period. This period, as well as the sensitivity rate, are characteristics of the screening test. Although often estimated independently of each other, these parameters should in principle be estimated simultaneously [8,9]. This was done in a recent article [10] using screening data from the randomised trial on Funen. The mean latency period was estimated to be 2.1 years (assuming an exponential distribution) and the sensitivity estimate

3 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) was 62.1%. These values were used to estimate the effectiveness of colorectal cancer screening. Sensitivity and specifity, along with estimates of the latency period, are vital parameters in determining the effectiveness and cost-effectiveness of screening programmes. The Hemoccult II test is characterised by a low sensitivity and a short sojourn time which renders it less (cost) effective. It does however obtain a high level of specificity which reduces monetary as well as more intangible costs of the programme. The specificity of the unhydrated Hemoccult II test is % [1,2]; an estimate of 99% was used in the analysis. In recent publications two randomised trials have shown that colorectal cancer screening using the H-II test has an effect on overall mortality [1,2]. The present economic analysis is based on the results of the Danish trial [1], since the aim is to judge the economic implications of introducing such a programme in a Danish setting. The Funen randomised population study was set up in The first screening round ended in 1986 when persons had done the test (67%). During the study period of 10 years 481 persons with colorectal cancer were found in the group allocated to screening and 483 in the control group. The main outcome of the study was a colorectal cancer mortality ratio of 0.82 (95% CI: ). The decrease in colorectal cancer deaths in the test group in Funen is a result of early detection and can be explained by a colorectal cancer mortality of 15.7% amongst patients with cancers detected by the screening test after the 10 years of followup. Within the same follow-up period the diseasespecific mortality rate amongst cancer patients in the control group is 51.5%. This indicates that 35.8% of the cancer patients, whose cancers were detected by the screening test, avoid death from colorectal cancer due to the early detection. This estimation procedure is problematic, since mortality reductions demonstrated within a relatively short observation period may constitute a postponement of death rather than the saving of a life. Hence, the excess survival rate estimated here may be exaggerated. Another problem is that not all screen detection will have had an impact on mortality within the observation period, since not all screen-detected cancers would have developed to late stage cancers (and potential deaths) within this period, had they not been screen-detected. This causes the excess survival estimate to be underestimated. Thirdly, the survival estimates are based on a randomised trial and not on observational studies. If procedures are to be handled by less experienced physicians in the case that screening is offered to the general population, similar results may not apply. A conservative estimate of 30% was applied in the model framework. The detection of adenomas is a complementary effect of screening for colorectal cancer, since especially large adenomas are likely to bleed. The effect of polypectomy and subsequent surveillance of adenomas is yet unknown, but there is a strong belief in, and evidence for, an adenoma-cancer sequence. The detection of adenomas will incur reductions in incidence and consequently mortality the question is how large this effect will be, and at what cost it will be obtained. Despite being a routine procedure polypectomy has not been evaluated in a controlled trial and is clinically unproven. However, in a retrospective review of Mayo Clinic records from a 6-year period Stryker et al. [11] identified 226 patients with colonic polyps over 10 mm in diameter. Actuarial analysis revealed that the cumulative risk of diagnosis of cancer at the polyp site at 5, 10 and 20 years was 2.5, 8 and 24%, respectively. These transition rates were used in the present analysis. According to Jørgensen et al. [12], the risk of cancer diagnosis is reduced by 43% when adenomas are detected and patients are included in a follow-up programme. This additional benefit of a colorectal cancer screening programme was included in the analysis. The cost of the unhydrated H-II test is low. The FOB test is estimated to cost US$1.50 and the overall cost per test performed including test analysis in the Danish study is estimated at US$5, whereas colonoscopy was estimated to cost US$165 [5]. All costs are in 1993 prices. These cost estimates were applied in the modelling effort presented here. Based on the data from the Danish randomised trial Bech and Kronborg [13] found that the number of hospital days for patients with cancers detected in the period were similar for the screening group and the control group. In addition, the average number of hospital days per cancer patient tended to be only slightly lower for the screening group (26.8 versus 29.9 days). This suggests that no significant treatment cost savings are to be made from early detection of colorectal cancers. Treatment cost savings are, however, incurred when adenomas are detected and cancers avoided Breast cancer screening Whereas the cost-effectiveness model on colorectal cancer screening relies largely on Danish data, such evidence is not yet available for breast cancer screening. Hence, the analysis relies on clinical effectiveness data Table 1 Sojourn time and sensitivity estimates based on screening data from the Swedish two-county trial Age Mean sojourn time ( ) ( ) ( ) ( ) 100 Sensitivity (%)

4 136 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) from the Swedish two-county trial [14], whereas detailed cost data was taken from a Dutch study [15]. Tabar et al. [16] recently estimated the mean sojourn times (latency periods) of different age groups based on screening data collected from the Swedish two-county trial. A Markov chain model was used and the sojourn time was assumed exponential. The method of estimation is developed by Duffy et al. [17], but is similar to the model developed by Walter and Day [8]. Sensitivity rates were estimated simultaneously. The estimates, which have been applied in the present analysis, are given in Table 1. The relationship between incidence rates, sensitivity, sojourn time and specificity is important in the evaluation of screening programmes. If incidence rates are high, sensitivity is high and sojourn time is long, low specifity levels may be acceptable since the ratio between true positives and false positives will be low. In the case of mammography screening the specificity seems to be moderate. In the Swedish two-county trial [14] a specifity rate of 95.6% was observed in the first screening round and 96.1% was observed at subsequent rounds; these estimates were used in the analysis. Since any mortality reduction attained by introduction of a screening programme can be contributed to early detected cancers, information on participation rates and interval cancer rates in the Swedish two-county trial were used to estimate the mortality reduction per screen-detected cancer for each age group. The information was taken from Tabar et al. [14] where 58.2% of cancers observed in the test group amongst year olds were screen-detected. Corresponding proportions for age groups and were 69.1 and 59.1%. For these age groups breast cancer mortality ratios of 0.87, 0.63 and 0.79 were observed amongst those women who were invited to participate in the screening programme (average follow-up period was 10.8 years). In order to estimate the expected excess survival due to screen detection, Swedish screening data and mortality statistics for an unscreened Danish population were combined. The mortality decrease per screen-detected cancer for the age group year olds was calculated in the following manner: The relative 10-year survival for year olds following a breast cancer diagnosis is 70% [18,19]. If a 13% decrease in mortality is to be observed in this population this would entail a reduced mortality rate of 26.1%, which means that 73.9% of breast cancer patients have not died from their cancer after a follow-up period of 10 years. Assuming that this survival probability is to be obtained in the Danish population given the same participation rates and incidence interval rates as those observed in the Swedish trial, the reduction in mortality is to be achieved through the detection of screen-detected cancers which constitute only 58.2% of all observed cancers. Hence, the following equation will produce an estimate of the excess survival rate of screen-detected cancers: x+( ) 70.0=73.9 x=76.7. Thus, the excess survival rate is =6.7. This means that 6.7% of patients with screen-detected breast cancers will survive the disease due to the early detection. Similarly, excess survival rates for screen-detected cancers amongst and year olds were calculated at and 17.77, respectively. Again, these estimates suffer from the same problems as the excess survival estimate used in the evaluation of colorectal cancer screening. The high incidence rates complemented by an effective screening test as well as significant increases in survival for screen-detected cancers creates a good case for mammography screening. Nevertheless, performing a mammography is far costlier than performing a Hemoccult II test. In a recent Danish report [20] the cost of mammography was set at US$30 per mammography test. In a more detailed analysis Van der Maas et al. [15] calculate the costs of mammography (1988 currency) in Holland including cost of screening units and central units, regional joint management boards and national organisation. The cost per screen after initial set up is estimated at US$35.50, whereas the cost per test at the first and second screening round is US$86.00 and US$53.50, respectively. These estimates were applied in the cost-effectiveness analysis presented here. The follow-up procedure following a positive mammography is either magnification-view mammography and/or fineneedle aspiration cytology or open biopsy. While the former procedures are relatively inexpensive the open biopsy is costly since it requires anaesthetics. We have assumed that only 5% of false positive cases would result in open biopsy, in accordance with the Swedish experience [14] 1. The Dutch cost analysis [15] calculates the cost of an open biopsy, and reaches an estimate of US$1500 (1988 currency). Cost estimates of the magnification-view mammography/needle cytology are lacking, however. In a Danish evaluation [20] both interventions are estimated at US$62. Assuming that open biopsy is perfomed in 5% of false positive cases, the average cost of performing a diagnostic test is US$78. Whether mammography screening incurs savings in treatment costs is uncertain [21,22]. In our analysis we assumed a cost saving from early treatment. In an analysis by Van der Maas et al. [15] the average costs of treating cancers at different stages are calculated based on data from medical files in the Netherlands. Cost savings are estimated using the Miscan model to simu- 1 This is an optimistic estimate, and can only be attained if standard diagnostic procedures are of a high quality. Preliminary results from Funen County, Denmark, suggest that Danish screening programmes can be as effective at minimising the number of false positives referred to open biopsy.

5 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) Table 2 Parameter values used in the economic evaluations of mammography screening, colorectal cancer screening and cervical cancer screening Colorectal cancer Breast cancer Cervical cancer Unhydrated Hemocult II test One-view mammography Papanicolau-smear test (50 74 year olds) (50 69 year olds) (23 59 year olds) Pre-symptomatic incidence (Danish) Latency period (years) 2.1[9] [14] 16 [23] Sensitivity of screening test (%) 62.1 [9] [14] 85 [23] Excess survival rate [23] Specificity (%) 99.0 [2] 96.0 [12] 99.4 [26] Cost of screening test (incl. 5 [5] 35 (86, 53) [13] 37 [6] Analysis, US$) Cost of diagnostic test (incl. 165 [5] 62, 1500 [13,18] 165 [6] Analysis, US$) Participation rate (%) 67 [1] late the stage distribution for alternative screening programmes and applying unit costs to these predictions. The model predicts a saving in treatment costs due to early detection corresponding to US$700 per life-year saved (1988 prices) when costs and life-years are discounted by 5%. This cost estimate was applied in the present analysis Cer ical cancer screening In interpreting any evaluation based on Danish incidence data, it is important to realise that Denmark has a unique high rate of cervical cancer compared with that of other developed countries. In the period the crude incidence rate was 24.0 (a cumulative incidence of 1.9% before the age of 75), whereas in Sweden, Finland and Iceland it was much lower, in the range of [4]. In the US the crude incidence rate in the late seventies was as low as 9.4 in Washington, Seattle (14.6 in New York City) and in Holland 8.9. These numbers may be confounded by the level of screening intensity in the respective countries. However, even in the beginning of the 1960s when screening intensity was low, the incidence in Denmark was double that of many other countries. The aim of screening for cervical cancer is largely to detect precursors to the disease such as dysplasia and carcinoma in situ. These stages are, however, characterised by significant regression rates, which entails that women in some cases will be treated unnecessarily due to screening programmes. In the present analysis it is assumed that 80% of all screen-detected cases of dysplasia, and 60% of cases of carcinoma would have regressed spontaneously [23,24]. The disease is thought to pass through a series of stages before developing to symptomatic cancer. These stages are dysplasia, carcinoma in situ (CIS), microinvasive and unsymptomatic carcinoma. In order to evaluate screening programmes it is necessary to have knowledge about the duration of these phases. Several studies have estimated these progression rates [24 28]. In the present analysis estimates based on Danish screening data were applied [27]. The sojourn time of dysplasia was estimated at 3 years, CIS and microinvasive cancer had a duration of 10 years, and invasive carcinoma had an estimated latency period of 3 years. The total sojourn time was hence estimated at 16 years, while the derived sensitivity estimate was 85%. The value of screening was examined by Soost et al. [29], whose extrapolations showed a specificity of 99.4% for cytologic screening for cervical cancer, which is the estimate applied in the model. There has been performed no randomised controlled trial of screening for cervical cancer using the Pap-smear test. Hence, the evidence of effectiveness is based on the effect screening interventions have had on incidence and mortality of cervical cancer. In the Nordic countries this effect is large [30,31]. Naturally, such historic comparisons are problematic since the underlying incidence trends are unknown. Hence, in modelling applications assumptions are made on the efficacy of early detection. In the present analysis 99% of those persons who are treated for dysplasia or CIS are assumed to survive, based on the opinion of an expert panel of physicians. In contrast, only about 58% of those who are treated for invasive cervical cancer will survive according to disease specific 10-year relative survival data [19]. The cost of performing a Pap-smear test was estimated at US$37, including pathological evaluation [6]. The cost of a coloscopy is assumed to cost US$165. The costs were estimated based on Danish tariffs charged in Since cervical cancer screening most often detects early precancerous stages and treatments of these stages is considerably less costly than treating invasive cancers, screening will entail savings in treatment costs. The costs of treating precancerous stages lie in the

6 138 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) range US$ while cancerous stages on average cost between US$1130 and US$ depending on the necessary treatment [6]. The Danish estimates are based on tariff charges and estimated average bed day costs (1992 currency). Saving in treatment costs were calculated on the basis of expected stage distributions in a screening scenario A comparison In the previous sections the core parameter values were presented for the three screening modes. These values are listed in a more compact form in Table 2. We now turn to the question: what effect does each of the attributes listed herein have on cost-effectiveness? A higher incidence in the target population will lower the cost-effectiveness ratio (cost per life-year gained), since the effect of screening will be correspondingly higher. The latency period as well as the sensitivity rate is in reality a two-dimensional measure of the effectiveness of the screening test. Both figures have very important implications for cost-effectiveness. A long latency period will entail a high pick-up rate at each screening round and hence a lower CE ratio, since a high number of prevalent cancers will exist at any time. Thus, a long latency period may call for less frequent screening and compensate for a low incidence, if accompanied by a high sensitivity rate. When the sojourn time is long and the sensitivity is high, the incremental cost per life-year of reducing the screening interval is likely to be considerable, since only few additional cancers will be detected when screening is intensified. If, however, sensitivity is low, it may be cost-effective to screen more frequently, thereby detecting the cancers that were previously overlooked. If the latency period is short and the sensitivity is low, cost-effectiveness will, all other things equal, worsen considerably. However, in such a scenario frequent screening will not produce fast-rising incremental costs per life-year, since additional screening rounds are likely to provide a significant increase in number of screen-detected cancers. The excess survival rate of early detected cancers, represents the added probability of surviving due to early detection, and is crucial for the effectiveness of screening programmes. Screen-detecting cancers is the means to the goal of saving lives. Only if we can actually reduce mortality by early detection have we reached this goal. The cost-effectiveness ratio is conversely proportional to the excess survival rate. A high specificity is important in order to contain costs. If the specificity is low, this will entail a high number of unnecessary diagnostic tests incurring high costs, if the diagnostic test is costly. Hence, if specificity is low inexpensive diagnostic procedures are warranted along with infrequent screening. The combination of a low specificity and a very comprehensive diagnostic test may warrant a screening programme inoperational due to the magnitude of the tangible costs as well as the intangible costs (anxiety, inconvenience etc) involved. Finally, the cost of the screening test is very important, since this is the cost that is incurred by all participants. It is important to note that, in contrast, all other costs of a screening programme are only incurred by the small proportion of the target population who have a positive screening test. Hence, small increases in the cost of the screening test will have a significant influence on the CE ratio. Looking again at Table 2, we can see that no screening programme is obviously superior. Each type of screening programme has its own merits and disadvantages. Colorectal cancer has a short latency period and a short sojourn time, a combination which calls for frequent screening if there is to be a reasonable effect of introducing such a screening programme. Although the test is not impressive at detecting colorectal neoplasms, patients whose cancers are detected by the screening test have significantly improved prospects of survival. Moreover, frequent screening will not incur unsurmountable costs, since the cost of the screening test is very low and the specificity is high. Breast cancer screening has other characteristics. Mammography is not an inexpensive test and the specificity is only moderately high. Hence, mammography screening is likely to be a costly affair. However, the high incidence rate of mammae cancer is accompanied by an effective screening test which may render this type of screening cost-effective. Cervical cancer screening clearly has its merits in the performance of the Pap-smear test which provides good protection for participants. The very long sojourn time combined with a reasonable sensitivity does however signal the importance of infrequent screening. An additional advantage is the great improvement in survival if the cancer is detected prior to the invasive stage. Cervical cancer screening is however characterised by not having a narrow high risk group, and the overall incidence for this type of cancer is considerably lower than for mammae cancer and colorectal cancer. Having introduced the parameter values of the model and hopefully given the reader a good understanding of the relative merits of the programmes, we now turn to the modelling results and focus on the relative cost-effectiveness of the three types of programmes. 3. Modelling the cost-effectiveness of screening In previous works we modelled the effect of screening for colorectal cancer, cervical cancer and mammae cancer [5 7]. The model used for all three evaluations is a statistical model originally developed by Day and

7 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) Table 3 Screening the year olds every 2 years by mammography a Life-years (undiscounted) Cost (US$) (undiscounted) Life-years (5% p.a.) Cost (US$) (5% p.a.) First round Second round Third round Overall a The programme is simulated over a period of 36 years. Walter [8]. Variables such as mean sojourn time, sensitivity rate and age dependent incidence rates, are inputs into a simulation process, where the number of cancers detected per age group at each screening round are estimated for hypothetical screening programmes with varying screening intervals and target groups. Number of cancers detected are converted to lives saved by multiplying the number of cancers detected by the estimated excess survival rate 2. Life-years gained are estimated by identifying how many lives are saved in each 5-year age group and multiplying these by their average life expectancy (adjusted for mean lead time). Gained life-years are not quality adjusted since it has been shown that for colorectal cancer and mammae cancer recovery entails close to perfect health [32,33]. To this author s knowledge no quality of life studies have been made for cervical cancer patients post-treatment, but since early detection most commonly entails easy treatment with no side-effects, perfect health subsequent to disease is the most frequent outcome of cervical cancer screening. Number of gained life-years were estimated assuming that a population corresponding approximately in size and age-distribition to the population of Funen County, Denmark was invited to participate in the screening programmes. Each invitation initiated mailing costs, and for each participant the cost of the screening test was incurred. Included on the cost side were also other direct health care costs such as cost of diagnostic tests and treatment as well as overhead costs such as costs of equipment, personnel and facilities. Most costs were assumed variable under the assumption that resources are adjusted to the scale of the programme in the long run. All costs and effects were discounted to present time by 5% p.a. In the evaluations were not included intangible costs such as the anxiety experienced in connection with a false positive result. Time 2 In this analysis it is assumed that the excess survival rate amongst individuals whose cancers are detected by screening is constant and independent of screening interval. This may be an unrealistic assumption, since it is probable that cancers will be detected at a later stage when the screening interval is long, and at earlier stages when the screening interval is short. For this reason, only screening intervals that did not differ significantly from the screening intervals applied in the trials, were included in the analyses. and travel costs experienced by participants were also excluded. The viewpoint of the cost-effectiveness analyses is that of the national health care sector. For a more thorough description of the respective evaluations see [5 7]. Tables 3 5 present estimated costs and effects of the first three screening rounds for each of three screening programmes. The target groups and screening intervals chosen here are not incidental. The cervical cancer screening programme corresponds to the Danish National Health Board s recommendation of screening the year olds every 3 years. The other two programmes represent programmes setups that are implemented, or are most likely to be implemented, in Denmark. After the initial three screening rounds the rate of detection will stabilise, making the results of the third screening round the most important for the overall cost-effectiveness ratio. Outcomes are listed undiscounted as well as discounted by 5%. Tables 3 and 5 depict high rates of detection at the first screening round relative to subsequent screening rounds. For cervical cancer screening this effect is most pronounced due to the very long latency period. Comparing the discounted costs and effect of the third screening round for the three programmes, cervical cancer screening attains the largest effect but at the highest cost while colorectal cancer screening incurs the fewest life-years at the lowest cost. Cervical cancer screening obtains a good effect due to the wide agespan of its target group, the long latency period and the high sensitivity. The effect is, however obtained at a high cost due to a low incidence of this cancer in the target population. Also, the effect of cervical cancer screening is reduced most markedly by discounting because the long latency period implies that lives are saved in the distant future. Focusing on the undiscounted costs and effects screening the year olds every 3 years for cervical cancer is a more cost-effective option than the mammography programme simulated here. Comparison of discounted results does however lead to a different conclusion. The average cost per life-year of a programme screening the year olds biennially for breast cancer is US$5155 which is similar to the average cost (US$5060) of screening the year olds every 3 years for cervical cancer, when costs

8 140 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) Table 4 Screening the year olds every 2 years using the unhydrated H-II test a Life-years (undiscounted) Cost (US$) (undiscounted) Life-years (5% p.a.) Cost (5% p.a.) First round Second round Third round Overall a Costs and effects simulated over a 36-year period. and life-year are discounted by 5% p.a. The least expensive option is inviting the year olds to have a Hemoccult II test every 2 years at a cost of US$3250 per life-year saved. Extending the comparison of the three screening technologies from focusing on only one programme constellation for each screening mode, we now turn to the estimated efficiency curves of each of these programmes and focus on the incremental cost profile of each of the programme types. In Fig. 1 are depicted efficiency curves for mammography, colorectal cancer screening and cervical cancer screening, respectively. For each screening mode a series of alternative screening programmes with varying target groups and screening intervals were simulated to determine the programme specific costs and effects [5 7]). Within each set of mutually exclusive programme setups, programmes were identified which for a given level of cost maximised life-years gained. Each efficiency curve constitutes this subset of dominating (efficient) programmes. Programmes on each efficiency curve are mutually exclusive, while programmes on different curves are independent and could be introduced simultaneously. Tables 6 8 list the average and incremental costs per life-year for each subset of efficient programmes. The incremental cost per life-year signifies the cost per life-year of the extra life-years that are saved due to more intensive screening., i.e. moving up the efficiency curve. Fig. 1 and Tables 6 8 illustrate the characteristics of the three types of screening programmes. The efficient colorectal cancer screening programmes are all placed in the southwest corner of the figure. The efficiency curve shows a moderate tendency to curve upwards with incremental costs per life-year ranging from US$2625 to Decreasing the screening interval has relatively little effect on cost per additional life-year because the number of cancers detected is increased considerably when the screening programme is intensified. The incremental cost range for efficient mammography screening programmes as well as cervical cancer programmes is much wider with maximum incremental costs of US$ and , respectively. The steep slope of the cervical cancer screening curve is explained by the long sojourn time and the high sensitivity of the screening test which renders it unnecessary to screen frequently. Incremental costs rise markedly if the screening interval is reduced beyond 4 years. For mammae cancer the slope is likewise steep which is also explained by the high sensitivity of mammography and the length of the average sojourn time. However, since the latency period for this type of cancer is considerably shorter than for cervical cancer, it is reasonably cost-effective to screen as often as every 2 years. More frequent screening does however increase incremental costs significantly. 4. Discussion From the list of efficient programmes in Tables 6 8, it is evident that while biennial mammography screening of year olds is amongst the efficient subset of programmes, offering Pap-smear screening to the years olds every 3 years and screening the year olds biennially for colorectal cancer are not efficient options. For example, screening the year olds every 3 years for cervical cancer gains 4257 lifeyears at an average cost of US$5060. This programme is dominated by an alternative cervical cancer programme, which invites the year olds every 4 years. This programme gains 4346 life-years at an average cost of US$4760. These cost-effectiveness analyses suggest that colorectal cancer screening is a cost-effective health care intervention irrespective of screening interval. The older age groups should have first priority when setting the target group, since the increasing risk by age clearly offsets the decreasing life-expectancy. Hence, it is optimal to reduce the screening interval to 1 year before inviting the year olds. The results presented here rely on the assumptions made on parameter values. It should, however, be noted that a cost-effectiveness analysis based on the evidence from the H-II trial in Nottingham, UK [34], produces very similar unit cost estimates and almost identical cost-effectiveness results. Nevertheless, if the cost of FOBT were to rise to US$3 (rather than

9 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) Table 5 Screening the year olds every 3 years using the Pap-smear test a Life-years (undiscounted) Cost (US$) (undiscounted) Life-years (5% p.a.) Cost (US$) (5% p.a.) First round Second round Third round Overall a Costs and effects are estimated over a 36-year period. US$1.50), the incremental cost ratios would lie in the range US$ across the list of efficient programmes. If the cost of colonoscopy were as much as US$460, incremental cost per life-year would rise to US$9140 for a programme that invites the year olds annually. If no cancers are avoided by adenoma detection and follow-up the incremental cost per lifeyear will lie in the range US$ The results of the evaluation of mammography indicate that it is reasonably cost-effective to implement breast cancer screening programmes if the screening programmes are not extended beyond screening the years olds every 2 years. Screening this age group more frequently will increase incremental costs considerably. Moreover, it is not cost-effective to screen the year olds. Screening the year olds biennially was estimated to incur incremental costs of US$9060 per life-year or an average cost of US$5155 per life-year. If the cost per mammography for the third and subsequent screening rounds were to differ from the present estimate (US$35.50) by US$8.00, this would alter the incremental cost ratio for this programme by US$1586 per life-year. The incremental cost per life-year did however vary depending on frequency of open biopsy. If 25% of false positives were to undergo open biopsy, the incremental cost ratio would increase by US$1035 for the least intensive programme, and by as much as US$ for the most intensive programme, i.e. screening the years olds annually. Hence, in planning a breast cancer screening programme it is not only important to decide on screening interval and target group. It is also important to decide on a policy regarding assessment procedures following a positive mammography. In the cost-effectiveness analysis of cervical cancer screening the incremental cost per life-year gained was estimated to lie in the area of US$ if the screening interval was not shorter than every 3 years [6]. The conclusions are that it is not cost-effective to screen women under the age of 20 or above the age of 69. Moreover, cost ratios rise markedly if screening programmes are intensified beyond screening the year olds every 4 years. Participation rates have very little effect on cost-effectiveness in the above evaluations, the reason being that most overhead costs are assumed variable in the long run. Moreover, for colorectal cancer screening where an invitation entails cost of H-II test in addition to the costs of a standard invitation, the model assumes that persons who have denied previous invitations are not re-invited 3. This corresponds to the protocol of the Funen trial, and entails that the likelihood of sending the H-II test to people who decline to participate is minimised. This is not to say that resources should not be spent on enhancing participation. The reason being that an increase in participation rates will incur additional life-years at a lower cost than if programmes were to be intensified by expanding the target group and/or decreasing the screening interval. Early detection of colorectal cancers is unlikely to produce any significant savings in treatment costs [13]. Detection of adenomas produces savings, since cancer treatment is avoided, but analysis has shown that the magnitude of such savings in present values is negligible, since these savings will be incurred years from the present time [5]. Although evidence is not Fig. 1. Efficiency curves for colorectal cancer screening, breast cancer screening and cervical cancer screening. 3 It is common practice in Denmark not to re-invite individuals who deny previous invitations. At present this system is practised in several population screening programmes.

10 142 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) Table 6 Incremental costs for efficient colorectal cancer screening programmes Programme Life-years Cost (US$) Average cost per life-year Incremental cost per life-year a,b a,b a,b a,c a,d a,d a Units=years. b I=2 years. c I=1.5 years. d I=1 year. Table 7 Incremental costs for efficient cervical cancer screening programmes Programme Life-years Cost (US$) Average cost per life-year Incremental cost per life-year a,b a,b a,b a,c a,c a,c a,c a,d a,e a,e a,e a Units=years. b I=5 years. c I=4 years. d I=3 years. e I=2 years. based on randomised trials, cervical cancer screening is likely to produce substantial savings since most screendetected neoplasms are precancerous and easily treated. However, the present value of these savings is significantly reduced due to the long latency period of this cancer disease. For mammae cancer the situation is less clear. There seems to be no published evidence based on randomised trials, and those studies that are published do not agree on the importance of these potential savings [21,22]. In the present evaluation we have assumed that for every life saved a saving of approximately US$7550 will incur. If it should turn out that breast cancer screening, like colorectal cancer screening, does not produce savings, the conclusions of this paper still hold. If treatment costs remain constant after introduction of a breast cancer screening programme, cost per life-year would decrease by as little as US$ and would not influence the list of efficient breast cancer programmes. Overall, one can conclude that treatment cost saving has no significant impact on the cost-effectiveness ratio of the three screening programmes analysed here. Let us assume that risk reduction is valued similarly whether it is derived from a reduction in deaths from colorectal cancer, mammae cancer or cervical cancer. Let us moreover assume that inclusion of time and travel costs as well as intangibles involved in participating in each of these programmes would not substantially alter the relative economics of these screening modes. Under these assumptions we can now compare incremental cost values and suggest that independent programmes be implemented such that incremental costs are kept approximately equal across all three screening programmes. Any large discrepancy in incremental costs across programmes would entail an inoptimal distribution of resources and redistribution could potentially improve effectiveness. Implementing the following three programmes in Danish counties: biennial mammography screening targeted at the year olds, cervical cancer screening every 4 years for the year olds and annual H-II testing of the year olds would entail a

11 D. Coyle et al. / Critical Re iews in Oncology/Hematology 32 (1999) Table 8 Incremental costs for efficient breast cancer screening programmes Programme Life-years Cost (US$) Average cost per life-year Incremental cost per life-year a,b a,b a,c a,c a,d a,e a,c a,d a,e maximum cost per life-year of US$9060. The total life-year gain based on a Funen population would be and the total cost US$44 million in present values. Such a programme constellation would represent an optimal distribution of resources. Alternatively, offering the year olds mammography at 3-year intervals or possibly screening the year olds biennially for breast cancer would likewise represent good use of resources. The former alternative would lower the overall maximum cost per life-year to an estimate of US$6570, whereas screening the year olds for breast cancer every 2 years would increase the maximum cost per life-year across all programmes to US$ This can be verified from conferring with Tables 6 8. Various efficient programme constellations exist. A combination of programmes should be chosen such that incremental costs are near-equivalent subject to the budget constraint. If a budget is not predetermined, the policy maker should consider how much he at maximum is prepared to pay per life-year and let this be a guide to planning future programmes setups. To illustrate the importance of an appropriate resource allocation, let us assume that Funen county were to introduce annual mammography screening of the year olds while simultaneously offering cervical cancer screening to the year olds every 3 years. Let us also assume that Funen county decided not to introduce colorectal cancer screening. The total cost would be US$59 million and the programmes would produce a gain in life-years of only This example shows how vital it is to distribute resources appropriately so that a maximum effect is obtained down to the last dollar invested. 5. Conclusion This paper seeks to compare the cost-effectiveness of mammography screening, colorectal cancer screening by FOBT and cervical cancer screening (Pap-smear). This comparative evaluation has shown that although breast cancer screening and cervical cancer screening programmes are more effective in detecting cancers, colorectal cancer screening, using the unhydrated H-II test, is overall more cost-effective overall. This paper suggests that in a Danish setting, it would be optimal to introduce annual colorectal cancer screening of the year olds along with biennial mammography targeted at the year olds and cervical cancer screening every 4 years for the year olds. Other optimal programme constellations can be identified depending on the relevant budget level and the implicit threshold for marginal cost-effectiveness, but any large discrepancy in incremental costs across programmes would entail an inoptimal distribution of resources and redistribution could potentially improve effectiveness. 6. Reviewers This paper was reviewed by Dr Rob Boer and Dr Willem-Jan Meerding, Department of Public Health imgz, Erasmus University of Rotterdam, P.O. Box 1738, NL 3000 DR Rotterdam, The Netherlands. References [1] Kronborg O, Fenger C, Olsen J, Jøgensen OD, Søndergaard O. A randomised study of screening for colorectal cancer with fecal occult blood test at Funen in Denmark. Lancet 1996;348: [2] Hardcastle JD, Chamberlain OJ, Robinson MHE, et al. Randomised controlled trial of faecal-occult blood screening for colorectal cancer. Lancet 1996;348: [3] Kerlikowski K, Grady D, Rubin SM, Sandrock C, Ernster VL. Efficacy of screening mammography. A meta-analysis. J Am Med Assoc 1995;273: [4] IARC. Cancer Incidence in five continents. Vol. V. Oxford Press, [5] Gyrd-Hansen D, Søgaard J, Kronborg O. Colorectal cancer screening: efficiency and cost effectiveness. Health Econ 1998;7:9 20. [6] Gyrd-Hansen D, Hølund B, Andersen P. A cost effectiveness analysis of screening of cervical cancer screening.: health policy implications. Health Policy 1995;34: [7] Gyrd-Hansen D. Breast cancer screening. A sensitivity analysis. CHS Working Paper 1997, Odense University.