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Evidence-based Practice |
1 From the Department of Radiology, Decision Analysis and Technology Assessment Group, Massachusetts General Hospital, Zero Emerson Place, Ste 2H, Boston, MA 02114 (P.M.M., J.L.B., S.G., E.F.H., J.S.L., G.S.G.); and the Department of Health Policy and Management, Harvard School of Public Health, Boston, Mass (G.S.G.). Received June 19, 2000; revision requested July 28; revision received August 21; accepted October 2. Address correspondence to G.S.G.
| ABSTRACT |
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MATERIALS AND METHODS: Standardized methods were used to calculate incremental cost-effectiveness ratios (ICERs) from published estimates of cost and effectiveness of colorectal cancer screening strategies, and the direction and magnitude of any effect on the ratio from parameter estimate adjustments based on literature values were estimated.
RESULTS: Strategies in which double-contrast barium enema examination was performed emerged as optimal from all studies included. In average-risk individuals, screening with double-contrast barium enema examination every 3 years, or every 5 years with annual fecal occult blood testing, had an ICER of less than $55,600 per life-year saved. However, double-contrast barium enema examination screening every 3 years plus annual fecal occult blood testing had an ICER of more than $100,000 per life-year saved. Colonoscopic screening had an ICER of more than $100,000 per life-year saved, was dominated by other screening strategies, and offered less benefit than did double-contrast barium enema examination screening.
CONCLUSION: Double-contrast barium enema examination can be a cost-effective component of colorectal cancer screening, but further modeling efforts are necessary.
Index terms: Cancer screening, 75.1282, 75.30 Colon neoplasms, diagnosis, 75.1282, 75.30 Colonoscopy Cost-effectiveness
| INTRODUCTION |
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There have been several cost-effectiveness analyses of screening strategies for colorectal cancer. Published estimates of cost per life-year saved span a wide range, which contributes to uncertainty about the best screening option (6). Published studies (715) include an assortment of screening strategies; the same strategies are not compared in all analyses. Also, investigators in few studies (5) followed the currently recommended methods for reporting cost-effectiveness analysis results. Investigators in earlier reviews (711) summarized published cost-effectiveness analyses of colorectal cancer screening but did not perform analyses with standardized cost-effectiveness methods. The purpose of the current analysis was twofold: to determine (a) the most cost-effective strategy costing less than some proposed (12) threshold of, for example, $100,000 per life-year saved; and (b) how the strategies available for colorectal cancer screening compare with each other.
| MATERIALS AND METHODS |
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Data Sources
We reanalyzed the results of three often-cited comprehensive studies of the cost-effectiveness of colorectal cancer screening in average-risk populations (1315). We did not have access to the original models; all analyses were conducted with published results. Glick et al (15) used the same model as Wagner at the Office of Technology Assessment (OTA) (14), but estimates of double-contrast barium enema examination specificity and fecal occult blood testing sensitivity were changed. Eddy (13) included annual fecal occult blood testing in all 11 strategies in that study, but Glick et al (15) and the OTA (14) compared 16 strategies, some of which omitted fecal occult blood testing. These three studies vary widely in their investigators assumptions with regard to model parameters. They also vary with regard to the degree of adherence to the methods recommended by the U.S. Panel on Cost-Effectiveness in Health and Medicine that were previously described (36). It is important to note that, for all strategies compared, none of the study investigators reported incremental cost-effectiveness ratios (ICERs).
Data Analysis
We first used standardized methods (5) to calculate ICERs from each studys published estimates of cost and benefit (life-years saved) for each screening strategy. Specifically, an intervention that cost more than an alternative but yielded the same or fewer life-years was referred to as dominated and was removed from the list of alternatives. To calculate each strategys ICER, the additional cost of that strategy, as compared with that of the next least-expensive alternative, was divided by the additional benefit, as compared with that of the same alternative. Strategies with lower effectiveness but with an ICER higher than that of another alternative were referred to as weakly dominated and were removed from the list of alternatives. ICERs were calculated again, and the process was repeated until all weakly dominated strategies were eliminated. The final list of alternatives was then ranked in increasing order of cost, with concurrently increasing life-year gains and therefore ICERs. Results are presented as ICERs, in dollars per life- years, for nondominated strategies from each study.
Next, we estimated the magnitude and direction of any changes to the derived ICERs that were caused by adjustments to parameter estimates. This was in following the practice of Brown and Fintor (16), who described a method for comparing existing cost-effectiveness analyses of breast cancer screening.
Several adjustments of Eddys (13) results were made. First, we reduced the charge-based cost estimates used by Eddy by multiplying all costs by a cost-to-charge ratio of 0.57:1. This ratio was derived from Medicare reimbursement data (Appendix). Second, Eddy (13) required that fecal occult blood testing involve rehydration, an optional process in which water is added to the fecal occult blood testing card at the time of processing. However, Eddy (13) used a sensitivity estimate (0.60) lower than the estimate of 92% for fecal occult blood testing with rehydration that was given in a recent meta-analysis (17) and a specificity estimate (98%) higher than would be expected, since rehydration increases sensitivity at the expense of specificity (18,19). Finally, the estimated dwell time was increased from 7 to 10 years (20) to equal the Glick et al (15) and OTA (14) value.
The Glick et al (15) and OTA (14) results were adjusted. First, investigators in both studies estimated that 70% of cancers arise from polyps; we adjusted this to 93% (equal to that used in Eddys study [13]) because the general consensus is that most, if not all, colorectal cancers arise from benign adenomatous polyps (2022) because of the accumulation of mutations in oncogenes and tumor suppressor genes (2325). It was not clear how to adjust for Glick et als (15) fecal occult blood testing sensitivity estimate of 60%, which was intermediately between estimates for unhydrated and rehydrated tests from a recent meta-analysis (17). The OTA (14) estimate of 40% for "mostly unhydrated" fecal occult blood testing sensitivity is consistent with the meta-analysis results and requires no adjustment (14). A fecal occult blood testing specificity estimate of 96% (26) may be more accurate than the 90% estimates used in the studies by Glick et al (15) and the OTA (14). Investigators in all three studies used discount rates of 5%, which is higher than the 3% rate now recommended for a reference case analysis (5).
Finally, we determined whether concordant estimates emerged for the relative cost-effectiveness of common screening strategies.
All costs presented in this article were adjusted to 1999 U.S. dollars by using the medical care component of the U.S. Consumer Price Index (27).
| RESULTS |
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The cost per life-year saved for the strategy of double-contrast barium enema examination every 3 years plus annual fecal occult blood testing (see end of paragraph and Table 2) was further adjusted to reconcile differences in parameter estimates between the original studies. These adjustments decreased the estimated ICERs for the strategy of double-contrast barium enema examination every 3 years plus annual fecal occult blood testing, although it is unlikely that the estimates would be less than $100,000 per life-year.
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Increasing the estimated percentage of cancers that were derived from polyps in the Glick et al (15) and OTA (14) studies would yield more screening-detected cancers and lower ICER estimates. Adjustments to the Glick ICER for fecal occult blood testing characteristics counteracted each other to some extent and had no clear net effect. The OTA ICER estimate (14) could likely be decreased, since a higher specificity results in fewer false-positive results. Again, as previously described, it is possible that a higher specificity would decrease overall effectiveness, although in a high-cost inefficient way.
At a lower discount rate, the up-front screening costs would not increase as much as the net present value of the future benefits, so the ratios should decrease.
After the previously described adjustments were made, the ICERs for screening with double-contrast barium enema examination every 3 years plus annual fecal occult blood testing that were derived from all three cost-effectiveness analyses were likely equal to or greater than $100,000 per life-year.
There was less agreement on the estimated cost-effectiveness of colonoscopy as a screening examination. Strategies of colonoscopy alone or with annual fecal occult blood testing were greater than the threshold or dominated in the studies by the OTA (14) and Eddy (13), but colonoscopy every 10 years was among the optimal strategies in the study by Glick et al (15) (Table 1).
A possible explanation for the differences in the inclusion or exclusion of screening colonoscopy is that Glick et al (15) assumed low values for both specificity and sensitivity of double-contrast barium enema examination; this assumption may have reduced the effectiveness of the double-contrast barium enema examination strategies enough to prevent their domination of colonoscopy. Glick et als (15) estimate of specificity (90%), although within reported ranges (2931), was low, as compared with values of more than 96% in the other two models. Glick et al (15) also used an estimate of 70% for double-contrast barium enema examination sensitivity, which is outside the reported ranges for the sensitivity of double-contrast barium enema examination for cancer (85%100%) and large polyps (81%100%) (30,32,33). Lower sensitivities (50% 80%) have been reported for 0.50.9-cm polyps (33), although only about 1% of polyps smaller than 1 cm harbor malignancy (21).
Glick et al (15) and the OTA (14) also reported the costs and benefits of screening by assuming a shorter dwell time of 5 years. We calculated ICERs for the 5-year dwell time scenario (data not presented); in both studies, the investigators concur that double-contrast barium enema examination every 3 years is cost-effective but differ on the incremental costs and benefits of adding annual fecal occult blood testing. These studies differed in the assumptions of sensitivity of the fecal occult blood test, as described previously; this difference could account for the differences in conclusions. It is not clear that this analysis is relevant, since dwell time is generally agreed to be longer than 5 years (20).
| DISCUSSION |
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The use of average ratios is not meaningful in situations in which multiple alternatives are available, as in colorectal cancer screening, since the fundamental goal of a cost-effectiveness analysis is to compare the relative values of alternative interventions (5). By ranking nondominated programs in increasing order of ICER and implementing the most effective alternative after the societal willingness to pay (revealed by specific programs already funded), resource allocation can be optimized. Proposed benchmarks or cutoffs range from $20,000 to $100,000 per quality-adjusted life-year (12,35). However, strict definitions of "cost-effective" or thresholds for funding that are based solely on cost-effectiveness ratios are oversimplifications.
A concordant strategy for mean risk populations emerged from studies (1315) in which investigators compared colorectal cancer screening strategies with those including fecal occult blood testing, flexible sigmoidoscopy, double-contrast barium enema examination, and colonoscopy when the published results of these studies were corrected for methodologic deficiencies. Thus, across a range of assumptions and costing methods, on the basis of analyses conducted by different investigators, strategies involving double-contrast barium enema examination (either double-contrast barium enema examination alone every 3 years, or every 5 years with annual fecal occult blood testing) appear most cost-effective. These findings support screening guidelines from the American Cancer Society (36) and the American Gastroenterological Association and the Agency for Healthcare Policy and Research (37), which recommend double-contrast barium enema examination every 510 years for average-risk individuals.
The popular press and media often promote colonoscopy as the reference standard screening examination (3840), but even large lesions can be overlooked at colonoscopy (4145). In our analysis, colonoscopy as a screening examination was dominated, surpassed in efficacy, or not cost-effective relative to other screening options, as defined by an ICER greater than $100,000 per life-year saved. Colonoscopy is often regarded as too expensive for screening (34); Medicare reimbursement for screening colonoscopy is roughly double that for double-contrast barium enema examination. Colonoscopy has higher risks of perforation and mortality than do other screening options. An additional risk of colonoscopy and sigmoidoscopy is that of disease transmission (46), a risk not considered in modeling efforts that we were aware of at the time this article was written but one that the average person might strongly wish to avoid.
Investigators in recent cost-effectiveness analyses have examined virtual colonoscopy, or computed tomographic (CT) or magnetic resonance colonography (47), and flexible sigmoidoscopic screening examinations every 5 years (48). Both analyses were incomplete, however, since only two strategies were compared in each. Furthermore, incremental analysis of the results in the study in reference 45 shows that CT colonography is dominated by standard colonoscopy. Although flexible sigmoidoscopic screening every 5 years was shown to be cost-saving (48), a recent trial of colonoscopy as a screening examination (49) demonstrated the limitations of sigmoidoscopy. Investigators in this trial (49) reported no cost data and included no other screening examinations.
In the year 2000, nearly 56,300 Americans died of colorectal cancer (36), and most Americans do not undergo screening for this disease (6,50). Although higher compliance will save more lives and thus should be promoted, it is not necessarily true that poor compliance will make a program less cost-effective or unworthy of funding. Increases in compliance increase both costs and benefits and may have little effect on the cost-effectiveness ratio. (For a more detailed discussion of compliance, see reference 51.) However, there is an interaction between the optimal age to begin screening and declining rates of compliance (52); if compliance declines each screening period (18,53), a later starting age will be favored.
In conducting this study, we did not rely on the construction or use of decision-analysis models or perform sensitivity analyses. Influences on cost-effectiveness estimates from variables such as discount rates are difficult to adjust for without modeling and should be examined in future research. Glick et al (15) and the OTA (14) used the same model but different estimates of double-contrast barium enema examination specificity and fecal occult blood testing sensitivity. In the current study, we did not intend to analyze specific tests but reconcile the findings of previously published studies. However, it is obvious that the cost-effectiveness of any screening strategy depends on the quality of the examination and its interpretation.
To our knowledge, no trial of colorectal cancer screening has shown a decrease in overall mortality. However, colorectal cancer deaths have decreased in recent decades because of some combination of improvements in screening, prevention, or treatment (54), and the findings of colorectal cancer screening trials have demonstrated decreases in colorectal cancer mortality (18,55,56).
None of the investigators in the studies reviewed in this analysis (1315) compared all relevant alternative screening strategies; this results in incomplete incremental analyses (5). Future research into the cost-effectiveness of colorectal cancer screening should model the entire sequence of screening, which includes the administrative costs of the screening program (57), follow-up, treatment, and surveillance, to establish the list of the most effective and cost-effective strategies. All relevant screening strategies, including one-time screening and colonoscopy, should be compared simultaneously. Uncertainty surrounding many parameters leads to wide variations in estimates across studies. It is clear that the effectiveness of the follow-up regimen and the surveillance schedule will influence the observed effectiveness of any screening program and should therefore be explicitly stated in the model variables. In a similar way, compliance and target ages for screening should be examined in detail. Recent data on treatment costs for colorectal cancer are available (10,58).
Future models should also include measurement of outcomes in terms of quality-adjusted life-years, which include both mortality and morbidity effects. Each year is assigned a weight of zero (dead) to one (perfect health) that corresponds to the health-related quality of life. This will allow comparisons with other studies in which the reference case method was used. Recent data on preference-based quality-of-life weights in colorectal cancer (59) are available.
The current lack of consensus among screening guidelines (6) is partially due to methodologic inconsistencies of published cost-effectiveness analyses. Investigators in published cost-effectiveness analyses of colorectal cancer screening have failed to report incremental cost-effectiveness ratios. When standardized methods are used to reevaluate published studies, a concordant strategy emerges from disparate studies.
In average-risk individuals, our analysis findings suggest that screening with double-contrast barium enema examination every 3 years or every 5 years with annual fecal occult blood testing has an incremental cost-effectiveness ratio of less than $55,600 per life-year saved. However, further research and modeling efforts are necessary.
| APPENDIX |
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Fecal occult blood testing is an inexpensive and noninvasive but indirect test for cancer or polyps. Blood in the stool may signal the presence of cancer or precancerous polyps, which bleed more than normal mucosa. Fecal occult blood testing is much more sensitive for cancer than for polyps. Investigators in several large trials (18,55, 56,61) have shown that annual or biennial screening in asymptomatic populations can reduce colorectal cancer mortality by 15%33%.
Several varieties of fecal occult blood tests are available; the Hemoccult (guaiac-based) is the most common. Sigmoidoscopy can be performed with either a rigid or flexible sigmoidoscope and allows direct visualization of the distal colon. Investigators in case-control studies (60,62) demonstrated that persons who underwent screening with sigmoidoscopy at least once in the past decade had 21%30% of control subjects risk of fatal colorectal cancer. Double-contrast barium enema examination provides a radiographic depiction of the entire colon in 90%98% of examinations (30,31,63,64). Double-contrast barium enema examination can depict the entire colon and has high sensitivity for large polyps and cancers (32,65). Patient acceptance of double-contrast barium enema examination has been reported as higher than that of flexible sigmoidoscopy or colonoscopy (66,67). Colonoscopy allows direct visualization of the entire colon in 80%98% of cases (30,6870) and offers the added benefit of removal of cancers and premalignant lesions but has higher complication and mortality rates than the other screening options (6973).
The cost-to-charge ratio was derived from data available as part of the Medicare Ambulatory Surgical Center Payment Rate Survey of 1994 (74). We averaged the cost-to-charge ratios provided for Current Procedural Terminology, or CPT, codes 4000049999 to derive the 0.57 value used in the text; however, values for other CPT ranges were similar (0.55 and 0.52 for codes 50000 and 60000, respectively).
| FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, P.M.M., G.S.G.; study concepts and design, P.M.M., G.S.G.; literature research, P.M.M.; data acquisition, P.M.M.; data analysis/interpretation, all authors; manuscript preparation and definition of intellectual content, P.M.M., G.S.G.; manuscript editing, revision/review, and final version approval, all authors.
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