CT-colonography in population-based colorectal cancer screening de Haan, M.C.

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1 UvA-DARE (Digital Academic Repository) CT-colonography in population-based colorectal cancer screening de Haan, M.C. Link to publication Citation for published version (APA): de Haan, M. C. (2012). CT-colonography in population-based colorectal cancer screening General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 20 Oct 2018

2 Chapter 10 Unit costs in population-based colorectal cancer screening using CT-colonography Margriet C. de Haan Maarten Thomeer Jaap Stoker Evelien Dekker Ernst J. Kuipers Marjolein van Ballegooijen Submitted

3 Abstract colorectal cancer screening 204 CT-colonography in population-based Objective Computed tomography colonography (CT-colonography) may equal other colorectal cancer (CRC) screening tests regarding participation and test characteristics. Previous cost-effectiveness analyses were based on cost assumptions ranging from per procedure. The aim of our study was to estimate the actual unit costs (which are unknown) associated with population-based CRC screening using primary CT-colonography based on empirical data. Materials and methods Data were collected within an invitational Dutch population-based CRC screening trial (n=2,920, age 50 to 75 years), the COCOS trial. Costs were calculated per invitation and per CT-colonography, and, based on response rates, per invitee and per participant. Sensitivity analyses were performed, and alternative assumptions on response rate were included, resulting in a best-case and worst-case scenario. Results Within the COCOS trial, 47.2% of invitees were reminded, 38.8% scheduled for an intake, 37.2% scheduled for CT-colonography, 33.6% underwent CT-colonography and 1.1% needed a re-examination. Lesions 10 mm were detected in 2.9% of invitees. Costs per invitation, reminder and intake were 4.99, 0.58, and 9.87, respectively (total 15.44). Costs per CT-colonography (appointment, procedure, evaluation, overhead, result letter) were , varying from to (best-case vs. worst-case). Extra costs of communication of positive results were For the response rates observed within the screening trial, the average costs of a screening CT-colonography were per invitee and per participant, respectively.

4 Conclusion Average costs were substantially lower compared to the cost assumptions that were used in published cost-effectiveness analyses on CTcolonography screening. This finding necessitates an update of those analyses. Chapter Unit costs of CTC screening

5 colorectal cancer screening 206 CT-colonography in population-based Introduction Computed tomography colonography (CT-colonography) is an accurate technique for the detection of advanced adenomas and colorectal cancer (CRC) 1. In several CRC screening guidelines, CT-colonography is indicated as a promising screening technique or is recommended for five-yearly screening 2-4. However, one of the main concerns is the cost-effectiveness of population-based screening. In previously published cost-effectiveness analyses, the unit costs for CT-colonography were based on the average reimbursement costs for abdominal and/or pelvic computed tomography 5,6,7,8, on the average reimbursement costs for colonoscopy 9,10 or on an unspecified assumption of the costs 11,12,13. The unit costs used in these studies ranged from 346 to 594 ($478 to $817 US dollars). The actual costs in a primary CRC screening setting using CT-colonography are unknown. In population-based CT-colonography screening, the costs might be lower than the costs of CT-colonography in daily clinical practice, due to increased efficiency and economies of scale. An increase in the number of examinations per day and the advantage of bulk discounts are expected to decrease the costs. Therefore, reimbursement fees might not reflect actual costs. The aim of this study was to estimate the unit costs of the entire procedure of CT-colonography screening (from the coordination of the invitation to the communication of the results), when used as a primary screening technique within a population-based CRC screening, based on the outcomes of the COCOS trial. Materials and methods Study population Data were collected within a Dutch population-based CRC screening trial (COCOS trial) of which the study protocol has been described in detail previously 14. Between June 2009 and August 2010, 2,920 subjects aged 50 to 75 years were randomly selected from the population registry and invited by postal mail for population-based CRC screening with CT-colonography within two Dutch regions. Ethical approval was obtained from the Dutch Health Council (2009/03WBO, The Hague, the Netherlands). All invitations (accompanied by an information leaflet) were sent by mail by a specialized screening organisation in each of the two participating

6 regions. Those invitees that did not respond within four weeks received a reminder letter. If invitees were willing to participate, they were instructed to contact the screening organisation (by reply card, telephone or ). At that occasion the co-workers of the specialized screening organisations scheduled an appointment for a prior consultation (intake) with a physician or nurse. During this intake, the benefits and risks of participation were discussed, as well as possible contra-indications. Respondents were excluded when they had had a full colonic examination in the previous five years (colonoscopy, CT-colonography or barium enema), when they had a life-expectancy of less than five years, were suffering from hyperthyroidism or when they were allergic to contrast medium. If the respondent was eligible and willing to participate, an appointment for the procedure was made, followed by a written confirmation, which was accompanied by a diet description and the bowel preparation. CT-colonography Participants received non-cathartic preparation consisting of three times 50 ml of iodinated contrast agent (Telebrix, Guerbet, Aulnay-sous-Bois, France), combined with a low-fibre diet for one day. The CT-colonography examinations were performed in two screening centres. This was done by experienced personnel using a 64-slice CT-scanner (Brilliance, Brilliance, Philips Healthcare, Best, the Netherlands; low-dose protocol with 25 ref mas; collimation 64 x mm, slice thickness 0.9 mm, reconstruction interval 0.7 mm, tube voltage 120 kv). Colonic distension was obtained with an automatic CO 2 insufflator (PROTOCO2L, Bracco, EZEM, Lake Success, USA) after intravenous administration of 1 ml hyoscine butylbromide (Buscopan, Boehringer, Ingelheim, Germany). If contra-indicated, the procedure was performed without bowel relaxants. The aim was to insufflate at least twoand-a-half to three litres within a maximum insufflation time of five minutes, before scanning. Images were obtained in both the supine and prone position. All CT-colonographies were read within two weeks after the procedure by one experienced radiologist ( 800 examinations), using primary 2D read (window setting 1500, -250 HU) with 3D problem solving using enhanced 3D visualisation software (View Forum, Philips, Best, Netherlands), followed by secondary CAD read. All detected intracolonic lesions 6 mm were reported. In addition, extracolonic structures were examined using the C-RADS classification 15. A nurse or physician informed the screenee by telephone about the final CT-colonography result. In addition, the general practitioner Chapter Unit costs of CTC screening

7 and the participant received a result letter by mail, which was sent by the screening organisation. colorectal cancer screening 208 CT-colonography in population-based Data collection During the inclusion period of the COCOS trial, we collected data on the number of respondents scheduled for intake, number of excluded respondents and drop outs after intake, number of respondents scheduled for CTcolonography, number of participants (number of respondents completing the entire screening procedure), number of re-examinations needed because of inadequate faecal tagging or bowel distension, and number of participants with lesions 6 mm and 10 mm 16. Costs at the screening organisation for the invitation, reminder, confirmation of CT-colonography appointment and communication of the results (like printing costs of the information leaflets and postal charges) were also recorded. The personnel costs and overhead costs of the screening organisation were included in the costs per invitation. We calculated the average costs per invitee by dividing the overall personnel costs and overhead costs made by the screening organisations during the screening trial, by the overall number of colonoscopy and CT-colonography invitees. In addition the nurse or physician responsible for the intake and communication of the results by telephone, the technicians responsible for the performance of the CT-colonography and the radiologists responsible for the evaluation of the CT-colonography, reported the time needed per activity per participant (using a stopwatch and by counting the number of procedures performed per dedicated working hours). Statistical analysis In the cost calculations, we discerned the following parts of the entire screening procedure: invitation (including personnel costs and overhead of the specialized screening organisations), reminder invitation, intake, scheduling and confirming CT-colonography appointment, performance of procedure, CT-colonography evaluation, communication of the results, re-examination in case of insufficient quality and overhead costs made by the screening centres (hospital). The overhead costs were calculated by multiplying the costs of the procedure and evaluation by 42% 17. In this way, we calculated the costs per invitee given a proportion of invitees that were: (1) invited, (2) reminded, (3) receiving an intake, (4) scheduled for CT-colonography (including re-examinations), and who (5) underwent CT-colonography, followed by an evaluation (including re-examinations),

8 (6) received a result letter (including re-examinations), and (8) received a post-ct-colonography consultation because of a positive CT-colonography. Sensitivity analyses were performed by accounting for alternative assumptions on number of scans per hour, post-ct-colonography consultation costs (communication of the results by the general practitioner in case of positive findings, using different rates per consultation) and expected bulk discounts, which were combined into a worst-case and best-case scenario. Secondly, alternative assumptions on response rate were included in the analyses. We assumed alternative lower and higher participation rates; corresponding percentages for number of invitees that were reminded, received an intake, were scheduled for CT-colonography, underwent a CTcolonography or a re-examination, and received a result by mail and/or telephone were calculated relative to these two alternative assumptions on participation (see also Table 1). Additionally, effect on costs of alternative scenario s were calculated: offering an intake to a selection of respondents (based on possible contraindications expressed at the reply card), performing additional procedures in the evening (from Monday-Friday, 6pm-9pm) or in the weekends (Saturday, 9am-5pm), CT-colonography performed by one technician and one doctor s receptionist instead of by two technicians, CT-colonography evaluation by a technician instead of a radiologist 18 (radiologist only responsible for extracolonic findings), technician serving as a second reader next to the radiologist, and using a lower cut-off for the definition of a positive CTcolonography (lesions 6 mm vs. 10 mm). These scenarios were included in the analyses as they might result in lower costs per CT-colonography, except for the latter two, as those two scenarios would improve the diagnostic yield, at the expensive of higher costs per CT-colonography. Results Between June 2009 and August 2010, 2,920 persons were invited for CTcolonography screening (Table 1). Of these 2,920 invitees, 1,134 (38.83%) responded that they were willing to participate and underwent an intake. After the intake, 47 respondents were excluded, the remaining 1,087 (37.23%) were scheduled for CT-colonography. After making the appointment, there were 105 dropouts, leaving 982 participants (33.63%). In 44 participants the quality of the CT-colonography was insufficient. These participants were advised to have a re-examination, 33 participants underwent a reexamination (1.13% of invitees). Chapter Unit costs of CTC screening

9 colorectal cancer screening 210 CT-colonography in population-based Table 1 Inputs used for cost calculations for the base-case analysis and ranges used for the worst-case and best-case scenario Range a Source Number (base-case) Input relative to 100 invitees Respondents (%) COCOS trial (1,134/2,920*100=38.83%) Reminders (%) COCOS trial (1,377/2,920*100=47.16%) Respondents scheduled for CTC (%) COCOS trial (1,087/2,920*100=37.23%) Respondents excluded (%) COCOS trial ((1,134-1,087)/2,920*100 =1.60%) Participants (%) COCOS trial (982/2,920*100=33.63%) Re-examinations (%) COCOS trial (33/2920*100=1.13% re-examination) Participants with lesions >=6mm (%) COCOS trial (166/2,920*100=5.68% of invitees) Participants with lesions >=10 mm (%) COCOS trial (84/2,920*100=2.88% of invitees) Average number of CT-colonographies per hour per CT-colonography unit with one CT-scanner Base-case: as scheduled in COCOS trial; 20 min / participant = 3/h*8h=24/day 19-32/day; 4,750-8,000/year 24/day 6,000/year Scans per day (9am-5pm), Mo-Fr Scans per year (n * 5 days * 50 weeks) Worst case: as in daily practice; average 25 min / patient 26-44/day; 6,500-11,000/year (24+9)/day 8,250/year Scans per day (9am-5pm, 6pm-9pm), Mo-Fr Scans per year (n * 5 days * 50 weeks) Best case: as needed in COCOS trial; average of 15 min / participant 19-32/day; 5,700-9,600/year 24/day 7,200/year Scans per day (9am-5pm), Mo-Sa Scans per year (n * 6 days * 50 weeks) Variable costs in Euro of materials used per scan Telebrix 50 ml 8.28 / 50 ml 6.00 / 50 ml COCOS trial (8.28/bottle, expected discount of approximately 25%) Butylscopolamine 20mg/ml 0.86 / ampoule 0.77 / ampoule COCOS trial (0.86/ampoule, expected discount of 10%) CO 2 insufflation tube / tube 8.51 / tube COCOS trial (17.02/tube, expected discount 50%)

10 Variable costs in Euro of personnel Based on current rates of general practitioners 9.00 / consultation / consultation Communication of positive CTC results by general practitioner Mo-Fr after 8pm 22% bonus, on Saturday after 12am 38% bonus Desk clerk 29,00 / h Depending on time of the day Mo-Fr after 8pm and on Saturday after 12am 47% bonus Technician 37,00 / h Depending on time of the day Mo-Fr after 8pm 22% bonus, on Saturday after 12am 38% bonus Doctor s receptionist / h Depending on time of the day Radiologist / h Not variable Based on current rates for radiologists in breast cancer screening a We assumed alternative participation rates of 24% and 44% in the lower and higher participation pattern; corresponding percentages were calculated relative to these two alternative assumptions on participation. For example, the percentage of re-examinations as observed in trial / participation of 33.63% as observed in trial * alternative assumption on participation rate (24% and 44%, resulted in 0.81% and 1.48% of re-examinations in the alternative participation patterns). The only exception was percentage of reminders, which was calculated as % reminders as observed in the COCOS trial (47.16%) / % invitees that did not receive an intake in the COCOS trial (100%-38.83%=61.17%) * alternative % invitees that did not receive an intake (100%-27.71% in lower participation and 100%-50.80% in higher participation, respectively). CTC = CT-colonography, ml = millilitres, h = hour. Chapter Unit costs of CTC screening

11 All cost estimates are at 2011 price level. Alternative assumptions (ranges) used for the sensitivity-analysis are displayed in Table 1. colorectal cancer screening 212 CT-colonography in population-based Costs per invitation and per CT-colonography Tables 2 and 3 summarise the cost results. The costs made by the specialized screening organisations for sending an invitation letter, reminder letter and for performing the intake were 4.99, 0.58, and 9.87, respectively. This adds up to overall costs of the invitation process of The costs of scheduling and confirm a CTcolonography appointment, and of communication of negative and positive results, also made by the screening organisations, were 27.76, 1.16 and 10.16, respectively. The costs made by the screening centres (hospital) for performing the CT-colonography procedure, the CT-colonography evaluation, and overhead costs per performed CT-colonography were 69.72, 20.38, and 37.84, respectively (total ). The costs per procedure and evaluation (including overhead costs) were (77%) and (23%), respectively. This adds up to overall costs per CT-colonography of in case of a negative result and in case of a positive result. The overall costs for the total screening process in case of a negative and positive result were therefore and , respectively. Sensitivity analysis costs per CT-colonography Table 4 summarises the results of the sensitivity analyses. Worst-case: when the average performance time per CT-colonography would have been 25 minutes instead of 20 minutes and when the post- CT-colonography consultation (only applicable for positive cases) would have been more expensive, the following parts of the screening procedure would have increased in costs: performance of CT-colonography ( ), evaluation of CT-colonography (+ 0.67), overhead screening centre per CTcolonography (+ 5.91) and consultation positive results ( ). The costs per CT-colonography (in case of a positive result) would have increased from to Best-case: when the average performance time for CT-colonography would have been 15 minutes instead of 20 minutes, the post-ct-colonography consultation costs (positive results) would have been lower, the CTcolonography would have been read by a technician instead of a radiologist and by including expected bulk discount in the sensitivity analyses, the following

12 Table 2 Costs outside the in-hospital screening centre: average costs made by the screening organisation and the general practitioner per type of action, base-case Costs Source COCOS trial Costs per invitation Invitation letter ,- / 40,000 = 0.02 per invitee Information leaflet ,- / 3,300 = 0.30 per invitee Envelope ,- / 1,500 = 0.12 per invitee Postal charges grams, charge 0.88 per invitee Personnel per invitee Overhead per invitee Subtotal 4.99 Costs per reminder Reminder letter per reminder Envelope per reminder Postal charges grams, charge 0.44 per reminder Subtotal 0.58 Costs per intake Schedule appointment 1.45 Salary administrative worker 29,-/h, 20 calls/h = 1,45/call Confirmation letter per confirmation Envelope per confirmation Postal charges grams, charge 0.44 per confirmation Intake by telephone (nurse) 7.84 Salary nurse 31,37/h, 4 calls/h = 7,84/call Subtotal 9.87 Costs per scheduling and confirming an appointment for CT-colonography (including preparation) Confirmation letter per confirmation Diet description per confirmation Bowel preparation per bottle, 3 bottles Envelope per envelope ( Postal charges 2.64 Charge 2.64 per confirmation Subtotal Costs per result letter Letter to participant per letter Envelope per envelope Postal charges gr, charge 0.44 per envelope Letter to general practitioner per letter Envelope per envelope Postal charges gr, charge 0.44 per envelope Subtotal 1.16 Post-CTC consultation in case of findings >=10 mm (GP consult costs, not necessarily through screening organisation) CTC = CT-colonography, h = hour, gr = gram, GP = general practitioner. Chapter Unit costs of CTC screening

13 Table 3 Costs in-hospital screening centre: average direct and overhead costs per screening CT-colonography procedure Costs Source COCOS trial colorectal cancer screening 214 CT-colonography in population-based CT-colonography performance of procedure Desk clerk 9.06 Salary administrative worker 29,-/h * 7.5h = per day / X Two technicians Salary technician 37,-/h * 8h = 296,-/day per technician; 592,- / X Butylscopolamine 20mg/ml b per ampoule * (83.7% of CTC participants received butylscopolamine) Fill needle per needle; 83.7% of CTC participants received butylscopolamine 0.14 * ml needle per 2 ml needle; 83.7% of CTC participants received butylscopolamine 0.03 * Injection needle per needle; 83.7% of CTC participants received butylscopolamine 0.16 * Handgloves per 2 handgloves CO 2 insufflation tube per tube CO per 50 scans = 0.13/scan Depreciation insufflator a 0.14 ( / 10 years = ) / (50 weeks * 5 days * X) Hospital clothing participant per set of clothing Sheet per sheet / (0.5 * X) Pillow per pillow / (5 days * 24 scans) Towel per towel Washcloth per washcloth Technicians clothing * ((32,48 per outfit /depreciation in 250 days) + 2,- for washing) / X Depreciation a and maintenance CT scanner Subtotal Evening program b Weekend program c CT-colonography radiologic evaluation Depreciation a and maintenance viewforum (depreciation 56,000,-/year + maintenance 45,000,-/year) (50 weeks * 5 days * X) (Depreciation 7,000,-/year + maintenance 8,200,-/year) / (50 weeks * 5 days * X) Evaluation 2D by radiologist (Salary 180,- (source: Dutch breast cancer screening)/13 per hour (source: COCOS trial) = 13.85/scan) Evaluation extracolonic findings by radiologist 4.00 (Salary 180,-/45 per hour = 4,-/scan) Subtotal Evening program b Weekend program b

14 Overhead in-hospital screening centre Overhead hospital - procedure - evaluation Evening program b Weekend program b Costs material and personnel * 0.42 Total costs Total - procedure - evaluation Evening program b Weekend program b X = number of scans per day (source Table 1), h = hour, gr = gram. a Depreciation in 10 years b Costs per participant of a screening program including performance of procedures in the evening or on Saturday, were calculated using the alternative number of examinations per day (X) and by correcting the personnel costs for the time of the day, using the base-case data and corresponding ranges as provided in Table 1. parts of the screening procedure would have decreased in costs: schedule CT-colonography (- 6.84), performance of CT-colonography ( ), evaluation of CT-colonography ( ), overhead screening centre per CTcolonography ( ) and consultation positive results (- 4.44). The costs per CT-colonography (in case of a positive result) would have decreased from to Average costs per invitee and per participant Table 4 summarises the results. The average overall costs of CT-colonography screening were per invitee and per participant. These estimates were based on the response and participation rates observed in the COCOS trial. By including alternative assumptions on number of scans per hour, post-ct-colonography consultation costs and expected bulk discounts (as defined in Table 1), as well as alternative assumptions on response and participation rates, we found average costs per invitee of and in the worst-case (high costs, low participation rate) and best-case scenario (low costs, high participation), respectively. The average costs per participant were and in the two respective scenarios. Chapter Unit costs of CTC screening

15 colorectal cancer screening 216 CT-colonography in population-based Table 4 Costs in Euro per action (base-case), sensitivity analyses (worst-case vs. best-case scenario) and average costs per invitee and per participant Invitation process CT-colonography Overall costs Total positive CTC Total negative CTC Reminder Consultation positive results (9) Result letter Overhead hospital Evaluation of CTC Performance of CTC Schedule CTC Intake Invitation (1) (2) (3) (4) (5) (6) (7) (8) (4-8) (4-9) 1 Base-case Bc Bc (-5.61) (-0.63) Univariate sensitivity analyses a 15 min/scan (4/h) Bc b Bc Bc Bc instead of 20 min (-12.72) Bc Bc (+5.91) (+0.67) Bc Bc Bc Bc (+13.42) b 25 min/scan (2.4/h) instead of 20 min Bc Bc Bc (-3.64) (-8.67) c Bulk discount Bc Bc Bc (-6.84) Bc Bc Bc Bc Bc Bc Bc Bc 4.56 (-4.44) d Lower costs post-ctc consultation by GP Bc Bc Bc Bc Bc Bc Bc Bc (+20.28) e Higher costs post-ctc consultation by GP (+20.28) (+5.91) (+0.67) Multivariate sensitivity analyses 2 Worst-case = combined b and e (+13.42) (-4.44) (-9.25) (-0.63) (-21.39) (-6.84) 3 Best-case = combined a and c and d

16 Participation pattern (% of invitees) 2.88% n.a. n.a % d (+1.13%) 33.63% d (+1.13%) 33.63% d (+1.13%) 33.63% d (+1.13%) A As observed in trial 100% 47.16% 38.83% 37.23% d (+1.13%) 2.05% n.a. n.a % d (+0.81%) 44.00% d (+1.48%) 24.00% d (+0.81%) 44.00% d (+1.48%) 24.00% d (+0.81%) 44.00% d (+1.48%) 24.00% d (+0.81%) 44.00% d (+1.48%) B Lower participation c 100% 55.70% 27.71% 26.57% d (+0.81%) 3.76% n.a. n.a. C Higher participation c 100% 37.91% 50.80% 48.71% d (+1.48%) Costs per invitee n.a. n.a. 1*A Base-case costs with observed participation n.a. n.a. 2*B Worst-case costs with lower participation n.a. n.a. 3*C Best-case costs with higher participation Costs per participant n.a. n.a. 1*A/33.63% f Base-case costs with observed participation n.a. n.a n.a. n.a. 2*B/24.00% f Worst-case costs with lower participation 3*C/44.00% f Best-case costs with higher participation CTC = CT-colonography, h = hour, min = minutes, GP = general practitioner. a Costs of the entire screening procedure of a participants with a positive result, without invitation, reminder and intake. b b.c. = as in base-case. c Percentages related to alternative assumptions on participation pattern are derived from Table 1. d Corrected for fraction of re-examinations needed. e n.a. = not applicable. f Corrected for number of participants. Chapter Unit costs of CTC screening

17 colorectal cancer screening 218 CT-colonography in population-based Alternative scenarios Next to different assumptions on response rate and number of scans per hour, several different scenarios can be considered. The intake could be offered to only a selection of the respondents (based on possible contra-indications, expressed at a reply card). This strategy would result in an increase in costs of the invitation of 0.14 (costs of reply card), but would also lead to an unknown decrease in number of intakes. Several alternative scenarios could lead to a decrease in costs per scan. By performing additional procedures in the evening (from Monday- Friday, 6pm-9pm) or in the weekends (Saturday, 9am-5pm), the costs per scan would decrease with 5.45 and 2.82, respectively, due to a decrease in depreciation costs per CT-colonography of the insufflator machine, CT scanner, and workstation used for evaluation. The CT-colonography could be performed by one technician and one doctor s receptionist instead of two technicians. This would result in a decrease of the costs per scan of Finally, if the evaluation of scans concerning intracolonic findings would be performed by a technician instead of a radiologist, a decrease in costs of per scan could be achieved. On the other hand, when the technician would be serving as a second reader next to the radiologist, the diagnostic yield of CT-colonography screening might increase but this would result in an increase in costs per scan of The diagnostic yield could also be increased by lowering the cut-off value for a positive CT-colonography to lesions 6 mm. This latter strategy would result in a positive CT-colonography in 5.68% of invitees instead of 2.74% of invitees (and an increase in number of invitees needing a post-ct-colonography consultation by the general practitioner resulting in an 9.00 cost increase in the additional 2.94% of invitees with a positive CTcolonography). Discussion Based on the participation rate, time measurements and costs made during the COCOS trial, the average unit costs of CT-colonography screening within a population-based CRC screening program were determined at per invitee and per participant. The overall costs for the screening procedure, from scheduling the CT-colonography until communication of the results were in case of a participant with a positive result. In the base-case and worst-case analyses, the unit costs were predominantly influenced by anticipated higher costs

18 for post-ct-colonography consultation costs by the general practitioner ( ), closely followed by the effect of changes in average number of scans per hour. The more scans per hour, the lower the costs for depreciation of the scanner per CT-colonography and vice versa (performance of a CTcolonography within 15 minutes instead of 20, would lead to a decrease in costs of per scan). Additionally, our study showed that a substantial decrease in costs can be realized by including expected bulk discounts in the model, for example a discount of 8.67 for the insufflation tube and of 6.84 per scan for the tagging agent. The unit costs per invitee ranged from to (worst-case scenario vs. best-case scenario), while the unit costs per participant ranged from to (best-case scenario vs. worst-case scenario). These unit costs were calculated by multiplying the costs per action of the basecase, worst-case and best-case by the participation rate in the COCOS trial, and anticipated low and high participation rates in the worst-case and best-case scenario, respectively. The lower costs per invitee in the worstcase scenario compared to the costs per invitee in the best-case scenario can be explained by the fact that the lower participation rate used in the worst-case scenario results in less examinations per 100 invitees. So, even though the costs per examination in the worst case are higher than in the best-case scenario, the average costs per invitee are lower due to the lower participation. The average costs per participant were not strongly influenced by alternative assumptions on participation rate, because they were dominated by the costs of the CT-colonography. The effect of additional scan programs in the evening and in the weekends also was relatively small (decrease in costs per scan of 5.45 and 2.82, respectively). This is explained by the fact that personnel costs increase (higher remuneration per hour), which compensates for the decrease in depreciation costs per scan. Of course, the benefits of offering evening or weekend scans could be a higher participation rate. These findings indicate that for the costs it is important to decrease the costs per procedure e.g. by increasing the number of scans per hour and by organizing bulk discount. To our knowledge no previous studies addressed the costs of population-based CRC screening using primary CT-colonography based on time measurements and costs made in a primary CT-screening pilot. The unit cost assumptions used in previous cost-effectiveness analysis varied from 346 to 594, and were based on reimbursement costs for colonoscopy, abdominal or pelvic CT, or unspecified cost estimates Our study shows that Chapter Unit costs of CTC screening

19 colorectal cancer screening 220 CT-colonography in population-based these assumptions were too high - at least not representative for the Dutch situation -, and thus the estimated cost-effectiveness of CT-colonography screening was presented too unfavourable. In some of these cost-effectiveness analyses, threshold analyses were performed to evaluate what CT-colonography might cost relative to colonoscopy to be cost-effective. Vijan et al 6 showed that CT-colonography unit costs should not exceed 61% and 48% of a negative and positive colonoscopy, respectively, to be cost-effective. Several other cost-effectiveness analyses also indicated that the unit costs for CT-colonography screening should be less than 60% 9 or 72% 12 of the average unit costs for colonoscopy to make it the most cost-effective strategy. Knudsen et al 5 showed that CT-colonography screening with equal adherence rates of colonoscopy and CT-colonography screening - might be cost-effective at per scan, assuming that the average costs for a negative and positive colonoscopy (including biopsies, etc) were and 470, respectively. However, if the relative adherence to CT-colonography screening was 25% higher than in colonoscopy screening, it could be cost-effective at Lansdorp-Vogelaar et al indicated 10 that CT-colonography threshold costs could be 71% ( 341) of the average unit costs for colonoscopy screening ( 662), when assuming a 25% higher adherence in CT-colonography screening. In this study we found substantial lower unit costs for CT-colonography screening ( per participant) compared to the rates that were determined in previous cost-effectiveness analyses. When we assume that the unit costs for colonoscopy screening as determined in previous costeffectiveness analyses were representative, than CT-colonography would be a cost-effective alternative for colonoscopy screening. On the other hand, assumptions on the unit costs of colonoscopy in a population-based screening setting, either as a primary tests or as a diagnostic colonoscopy after a positive primary screening CT-colonography (or FOBT or sigmoidoscopy), in the literature so far suffer the same problem as for CT-colonography: they were based on reimbursement rates that have been set in a more or less clinical setting. In addition, the cost-effectiveness seems to be strongly depended on differences in adherence rate. In the COCOS trial, a 55% higher adherence rate was found within CT-colonography screening, relative to colonoscopy screening 16. A more final judgment therefore requires a screening colonoscopy cost study, followed by a new cost-effectiveness analyses in which the actual unit costs and adherence rates of colonoscopy and CT-colonography screening are included.

20 One of the advantages of our study is that we collected data on the estimated unit costs for CT-colonography screening in a population-based CRC screening trial. Costs for CT-colonography in a high risk population would probably have overestimated the procedural costs as these patients are (most of the times) symptomatic, as well as weaker and older relative to screening invitees, leading to increased performance times and increased costs per scan. In the design of the logistics of this study, we aimed to perform the invitation procedure and procedure itself as efficiently as possible. Costs per invitation (letter, information leaflet, and envelope) were based on the actual costs made for the study. Time needed per intake, per scan, and per CTcolonography evaluation were noted for all participants, and number of scans performed per dedicated time slot were recorded. These measurements led to data representative for daily practice. Additionally, we collected data on number of participants, number of re-examinations needed and average number of positive results per 100 invitees for example. In this way, we were able to calculate the actual average costs per participant, which is relevant, as for each participant in the study we had to invite approximately three individuals (with subsequent costs). Unfortunately, we were not able to specify the personnel costs and overhead costs that were made by the screening organisations. During the study their average costs were 3.67 per invitee. On the one hand the costs made per non-participant were probably lower than the costs per participant, on the other hand these costs are small and thus also the possible effects on these costs. Secondly, we calculated the overhead costs made by the screening centres (hospital) by multiplying the costs of the procedure and evaluation by 42% 17. This was the best possible but a rough approach to estimate the overhead costs. Thirdly, the expected discounts that were used in the sensitivity analyses were not originating from the companies, as they were not willing to provide us these data out of commercial point of view. Finally, it is questionable whether our results are generalizable to other hospitals and other countries. Our data were derived in an academic hospital, which might lead to an overestimation of the costs compared to a setting in smaller hospitals. For example, the overhead in smaller, non academic institutions presumably is lower. In this perspective another option might be mobile CT-colonography units - similar to mobile breast cancer screening units that are currently used in the Netherlands - with possibly reduced costs and increased participation. Further, the costs were based on Dutch rates for scanners, personnel costs, and material costs and the organisation of the Chapter Unit costs of CTC screening

21 colorectal cancer screening 222 CT-colonography in population-based Dutch healthcare system; this may differ from other countries. However, by providing details of the screening procedure, the costs of performing similar CT-colonography screening in different settings can be estimated. As far as age is concerned, the costs for the individual parts of the examination (like sending an invitation or reminder letter, or the material costs per procedure) will not change relative to the age of the invitees and/ or participants. Older participants might have more often a positive result, which might lead to higher radiologic evaluation costs. On the other hand, participation is lower in older age groups 16. The costs for the follow-up of (both intra- and extracolonic) findings were not included in our cost-estimates. In the Netherlands, the current estimate for the costs per follow-up colonoscopy is 325 (based on the Dutch rates for a clinical colonoscopy). The estimated average costs per participant for follow-up of extracolonic findings has been published previously, and are estimated to be around per participant These costs strongly depend on the cut-off for follow-up (i.e. should participants with 6-9 mm lesions be offered a surveillance CT-colonography or should they be referred for colonoscopy? Which follow up procedures are recommended by type and seriousness of extracolonic findings?). Therefore it makes sense to include costs of follow-up only in a more complete cost(-benefit) analysis in which also the health effects and the savings from prevented advanced disease are included. In summary, we found that the actual unit costs per CT-colonography when used as a primary screening technique in population-based CRC screening were substantially lower (within the Netherlands) compared to the estimated unit costs that were used in previous cost-effectiveness analyses. This warrants the need for a new cost-effectiveness analysis.

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