Volume 12 • Number 5 • 2009 VA L U E I N H E A LT H
The Cost-Utility of Sequential Adjuvant Trastuzumab in Women with Her2/Neu-Positive Breast Cancer: An Analysis Based On Updated Results from the HERA Trial vhe_511
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Chris Skedgel, MDE, Daniel Rayson, MD, Tallal Younis, MBBCh, FRCP (UK) Department of Medicine, Dalhousie University, Halifax, NS, Canada
A B S T R AC T Background: The efficacy of sequential adjuvant trastuzumab (aTZ) after chemotherapy in women with early-stage human epidermal growth factor-2 (HER2/neu)-positive breast cancer reported by the updated Herceptin Adjuvant (HERA) trial appears less favorable than originally reported. Based on these updated results, we estimated the cost-utility (CU) of sequential aTZ relative to chemotherapy alone in terms of incremental cost per quality-adjusted life-year (QALY) gained. Methods: A Markov model estimated incremental costs and outcomes of 12 months of aTZ after adjuvant chemotherapy in women with HER2/ neu-positive breast cancer over a 25-year horizon. The model incorporated four broad health states (disease-free, local recurrence [LCR], distant recurrence [DCR], death), stratified with or without symptomatic cardiotoxicity. Baseline event rates and 3-year relative risk (RR = 0.75) were derived from the HERA trial. As the duration of the benefit remains
uncertain, the analysis considered 5-year and 3-year duration of benefit in two scenarios. Costs and utility weights were from the literature. The analysis took a direct payer perspective, with costs reported in 2007 Canadian dollars. Costs and QALYs were discounted by 3% annually. Results: The mean CU of sequential aTZ at a 25-year horizon was $72,292 per QALY gained in the 5-year scenario and $127,862 per QALY gained in the 3-year scenario. Results were particularly sensitive to the magnitude and duration of carryover benefit. Conclusions: The CU of sequential aTZ is primarily dependent on the magnitude and duration of benefit. Further clinical research is required to establish the optimum sequence and duration of aTZ therapy and clarify the magnitude and duration of treatment benefit. Keywords: breast cancer, cost-utility, net-benefits, relative risk, trastuzumab.
Introduction
benefit of sequential adjuvant trastuzumab may be less favorable than originally reported [8,16]. Based on these updated results, we undertook an economic evaluation to estimate the cost-utility (CU) of sequential adjuvant trastuzumab after chemotherapy for early-stage HER2/neu-positive breast cancer compared to chemotherapy alone in terms of incremental cost per qualityadjusted life-year (QALY) gained in a Canadian setting.
Human epidermal growth factor-2 (HER2/neu) protein overexpression and gene amplification is observed in 20% to 25% of women with breast cancer and is generally associated with a more aggressive disease biology and a poorer prognosis relative to cases without HER2/neu overexpression [1–3]. Trastuzumab (Herceptin®) is a recombinant humanized monoclonal antibody targeting HER2/neu receptors and has been shown to improve median progression-free and overall survival when added to chemotherapy for HER2/neu-positive breast cancer in the metastatic setting [4–7]. Initial results from clinical trials of adjuvant trastuzumab, used concurrently or sequentially to adjuvant chemotherapy, reported an approximately 50% relative improvement in diseasefree survival and 30% relative improvement in overall survival with trastuzumab for early-stage HER2/neu-positive breast cancer [8–11]. On the basis of these extraordinary results, trastuzumab was approved as adjuvant therapy for early-stage HER2/neu-positive breast cancer, despite the relatively short median follow-up reported in the trials, and the observed cardiac toxicities and considerable incremental costs associated with its use [12–15]. Although both the sequential and concurrent approaches are accepted as providing significant clinical benefit, the sequential approach appeared to offer equivalent efficacy with a lower risk of cardiotoxicity. Updated results from the HERA trial with an additional year of follow-up, however, suggest that the relative Address correspondence to: Chris Skedgel, Centre for Clinical Research, Room 207, 5790 University Ave, Halifax, NS, Canada B3H 1V7. E-mail:
[email protected] 10.1111/j.1524-4733.2009.00511.x
Methods
Economic Model An economic model was developed in Excel (Microsoft Corporation, Redmond, WA) to estimate the long-term costs and outcomes of 12 months of adjuvant trastuzumab after adjuvant chemotherapy for HER2/neu-positive breast cancer, compared to observation alone in a hypothetical cohort of 1000 women based on HERA trial participants. A 25-year analysis horizon was used to reflect the average life expectancy in this cohort. The model took a Markov approch by defining a fixed number of possible health states and modeling the probability of transitioning from one health state to another during a specified time period, or cycle. The costs and health consequences of being in each health state were then aggregated over a defined number of cycles, or time horizon [17]. Costs and QALYs were both discounted by 3% annually. All assumptions used in the model are outlined in Table 1. The analysis used the net benefit approach to calculate the expected CU and the associated 95% confidence interval (CI). The net benefit framework calculates the hypothetical net monetary benefit (NMB) of a new program or technology by weighting incremental health outcomes (DE) by threshold willingnessto-pay (l) for a unit of health outcome (e.g., per QALY) and subtracting the incremental cost (DC) [18]:
© 2009, International Society for Pharmacoeconomics and Outcomes Research (ISPOR)
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642 Table 1 Model assumptions
NMB = ΔEλ − ΔC If, for a particular willingness-to-pay (l), NMB is greater than zero, monetized “value” is greater than cost, and the program or technology can be considered cost-effective. By setting NMB to zero, the net benefit framework can be reformulated as the conventional CU statistic:
NMB = ΔE ⋅ λ − ΔC = 0 ΔE ⋅ λ = ΔC λ=
ΔC ΔE
Unlike the conventional incremental cost-effectiveness ratio, the net benefit approach facilitates the estimation of CIs around cost-effectiveness point estimates. Ninety-five percent confidence bounds around cost-effectiveness or CU can be calculated by estimating the upper and lower 95% CIs around NMB and solving for l where NMB = 0.
Health States The model began with all patients disease-free after the completion of primary treatment (surgery, chemotherapy, and radiotherapy, if applicable). Patients in the sequential adjuvant trastuzumab arm received up to 12 months of treatment as per the HERA protocol, while the control arm received no further treatment. In each monthly cycle, patients were at risk of transitioning to LCR, well after LCR, DCR, and death (see Fig. 1). Patients in LCR were able to transition to well after LCR state; patients in the DCR state remained in that state until death. Patients developing a LCR were assumed to be at risk of a concurrent diagnosis of DCR and at increased risk of a subsequent local or DCR (see
1. The event rates reported by the HERA trial are generalizable to our hypothetical cohort. 2. Adjuvant hormonal therapy was not considered in the model. 3. There were no cancer recurrences beyond year 20 of the model. 4. The median age of the cohort at entry into the model was 49 years. [16] 5. Cost parameters were based on a log-normal distribution with a standard deviation of 0.25. 6. Patients could only develop cardiotoxicity while on active adjuvant trastuzumab therapy. 7. Patients developing cardiotoxicity while receiving adjuvant trastuzumab were excluded from further therapy. 8. Adjuvant trastuzumab patients experiencing cardiotoxicity within the first 3 months lost the benefit of therapy and reverted to the baseline risk of recurrence. Patients experiencing cardiotoxicity beyond the first 3 months maintained the benefit of therapy. 9. Symptomatic congestive heart failure (grade 3/4) was used as a proxy measure for clinically significant cardiotoxicity. 10. Median duration of cardiotoxicity was 49 months. [20] 11. Recurrent loco-regional disease and new contralateral breast cancers were combined as local recurrences (LCR). 12. Patients with LCR were treated for 4 months then entered well, treated state. 13. Twenty percent of patients with a LCR have a concurrent diagnosis of DCR in first month of LCR (“Concurrent DCR|LCR” in Table 2). These patients immediately transition to the DCR health state. 14. The risk of a subsequent local or distant recurrence is doubled after an initial LCR. (“RR[CR|LCR]” in Table 2) 15. Patients in the adjuvant trastuzumab arm experiencing a DCR less than 12 months from the end of therapy were not eligible for palliative trastuzumab. 16. Eighty percent of eligible patients with DCR received palliative trastuzumab (“Palliative Trastuzumab Eligible” in Table 2). 17. Patients could suffer two LCR. Any subsequent recurrences were distant. 18. Patients with DCR had a median survival of 21 months. [4,42] 19. Median survival of patients with DCR receiving palliative trastuzumab was extended by 4 months. [4]
Local Recurrence, No Cardiotoxicity
Well after LCR, No Cardiotoxicity
Local Recurrence, With Cardiotoxicity
Well after LCR, With Cardiotoxicity
Disease-Free, No Cardiotoxicity * Disease-Free, With Cardiotoxicity Distant Recurrence, No Cardiotoxicity Distant Recurrence, With Cardiotoxicity
Death
Figure 1 Model schematic. *Patients can receive only up to 1 year of trastuzumab therapy while in the Disease-Free, No Cardiotoxicity health state.
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Cost-Utility of Sequential Adjuvant Trastuzumab Table 1). All patients were subject to age-specific background mortality rates derived from Statistics Canada life tables [19]. As patients receiving adjuvant trastuzumab were considered to be at increased risk of cardiotoxicity while they were receiving trastuzumab, the disease-free, LCR, well after LCR, and DCR health states were stratified by experience with or without cardiotoxicity. In the model, trastuzumab patients developing symptomatic cardiotoxicity were excluded from further treatment. Patients in either arm experiencing cardiotoxicity could transition to the cardiotoxicity-free strata in subsequent months, based on proportions reported by the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial in the absence of equivalent published data from the HERA trial [20]. Outcomes were measured in terms of QALYs to simultaneously incorporate both increased survival and improved quality-of-life. Utilities were assumed to be multiplicative, with relative weights applied to a baseline utility of disease-free after chemotherapy [21]. Baseline and relative quality weights were derived from the literature [22–24].
Event Rates and Relative Benefit As the model used a time-dependent state-transition approach, relative benefit was based on the 3-year relative risk (RR) of disease-free survival (i.e., cancer recurrence or death with or without recurrence) derived from the updated HERA trial of adjuvant trastuzumab after primary treatment for HER2/neupositive breast cancer, rather than the instantaneous hazard ratio (HR) reported by Smith et al. [16]. For comparability with other published evaluations of adjuvant trastuzumab, the primary analysis was based on a 5-year duration of carryover benefit. Nevertheless, because the updated HERA results suggest that the statistically significant duration of benefit may be less than 5 years, we conducted a secondary analysis using a 3-year duration of benefit. Beyond the relevant duration of benefit, the RR of a disease-free survival event with adjuvant trastuzumab compared to the observation arm was set to 1.0. The baseline risk of cancer recurrence was derived from multiple sources. The baseline risk over the first 3 years and the ratio of local or regional recurrence to DCR was derived from the HERA trial [16]. The medium-term (years 4–10) baseline risk was derived from the HER2/neu-positive subgroup of the anthracycline arm of the NSABP B-15 trial [25]. Average patient follow-up in the NSABP B-15 trial was 12.4 years, and the 2-year disease-free survival results approximated the HERA study (74.3% vs. 77.4% in HERA). For years 11 to 20, the ratio of annual recurrence between years 5 and 10 and years 10 and 15 from the Early Breast Cancer Trialists Collaborative Group review of randomized trials [26] was applied to the recurrence rates from years 5 to 10 of the NSABP B-15 trial [25]. It was assumed that there were no further recurrences after 20 years. The baseline rate and the RR of cardiac toxicity with adjuvant trastuzumab were derived from the incidence of symptomatic congestive heart failure or cardiac death from the HERA trial [16]. Because there were no cardiac deaths in the trastuzumab arm of the trial, the model assumed no additional mortality as a result of cardiotoxicity.
Costs The analysis took a direct payer perspective, considering direct costs to the health-care system and the patient. The costs of incorporating trastuzumab in the adjuvant setting, including HER2/neu screening, acquisition costs, drug administration, supportive medications, and patient management were taken from
earlier cost studies conducted by members of the study team [27,28]. The costs of palliative trastuzumab were based on a local study of trastuzumab utilization in the palliative setting [29]. In this study, patients received a median of 10 cycles over 7.2 months for an average cost of $28,495. Because local utilization may not reflect wider practice patterns, the cost impact of longer or shorter palliative trastuzumab therapy was tested in a one-way sensitivity analysis. Management costs for local and distant cancer recurrences were derived from a study based on the Population Health Model developed by Statistics Canada [30]. The costs of managing cardiotoxicity were taken from a Canadian cost-effectiveness study [31]. Because none of the cost studies reported the variance of their mean cost estimates, the probabilistic modeling assumed a log normal distribution with a standard deviation of 0.25 for all cost parameters. All costs were adjusted to 2007 Canadian dollars (CDN$1.00 = US$0.94 [32]) based on the Statistics Canada consumer price index, health and personal care component [33].
Sensitivity Analysis and Validation Multivariate sensitivity analysis was conducted using probabilistic modeling to generate 95% CIs around point estimates and a cost-effectiveness acceptability curve that illustrates the probability of trastuzumab being cost-effective over a range of possible willingness-to-pay thresholds. Probabilistic modeling assigns each input parameter a probability distribution and uses Monte Carlo simulation to repeatedly sample values from that distribution [34]. Input parameters and their distribution, mean and standard deviation are shown in Table 2. The modeling was conducted using @Risk (Palisade Software, Newfield, NY) with 10,000 iterations. One-way sensitivity analysis was conducted to test the sensitivity of results to the discounting of costs and benefits, and to the cost of palliative trastuzumab after DCR. Threshold analysis was also conducted to identify the threhold values of key parameters necessary to meet a $50,000 and a $100,000 per QALY gained cost-effectiveness threshold, holding all other parameters constant. Finally, because the model is a synthesis of a number of data sources, the short-term disease-free survival estimates were compared with disease-free survival results reported by the HERA trial to assess the internal validity of the model.
Results In the primary analysis, based on a 5-year duration of benefit and a 25-year analysis horizon, the cost-utility of sequential adjuvant trastuzumab was $70,292 per QALY gained, shown in Figure 2a by the point at which the expected NMB line crosses the horizontal axis (i.e., NMB = 0). The upper and lower 95% confidence bounds of the CU estimate are shown by the points where the dashed lines representing the upper and lower 95% confidence bounds for the NMB statistic cross the horizontal axis (95% CI: $28,602–139,657 per QALY gained). Undiscounted life expectancy was 18.9 years (95% CI: 15.7–22.9) in the adjuvant trastuzumab arm and 17.2 years (95% CI: 14.5–20.6) in the chemotherapy-only arm. In the secondary analysis (Fig. 2b), based on a 3-year duration of benefit, the CU results were considerably less favorable, with an incremental cost-utility of $127,862 (95% CI: $56,912–247,926). Complete incremental results for both scenarios are presented in Table 3. Cost-effectiveness acceptability curves for both scenarios, shown in Figure 3, present the likelihood of sequential adjuvant trastuzumab being cost-effective (i.e., NMB ⱖ 0) over a range of willingness-to-pay thresholds. For the primary analysis with a
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644 Table 2 Input parameters Input parameter Age at entry Average annual mortality rate RR, trastuzumab Cancer recurrence Baseline annual rate, years 1–5 Baseline annual rate, years 6–10 Baseline annual rate, years 11–20 Proportion local recurrence Concurrent DCR|LCR RR (CR|LCR) Palliative trastuzumab eligible Median DCR survival (months) Additional survival | herceptin Total treatment cost Adjuvant trastuzumab Palliative trastuzumab Symptomatic CHF Local cancer recurrence Distant cancer recurrence Utility weights Well, off treatment Well, on adjuvant trastuzumab Cardiotoxicity 1st local cancer recurrence 2nd local cancer recurrence Well after LCR DCR Cardiotoxicity 1-year baseline, symptomatic CHF RR, symptomatic CHF | aTZ Median time with CHF (months)
Distribution
Mean
SD
Triangle Beta Beta/beta
49 0.009 0.754
4.1 0.004 0.059
Beta Beta Beta Beta Beta Normal Beta Poisson Poisson
0.094 0.067 0.046 0.251 0.200 2.001 0.800 20.895 4.018
0.005 0.015 0.010 0.019 0.018 0.249 0.040 4.576 2.006
Log Log Log Log Log
normal normal normal normal normal
Beta Beta Beta Beta Beta Beta Beta Beta Log normal Derived from beta
51,693 28,495 18,445 11,169 33,872
13,284 7,243 4,761 1,940 8,329
Source [16] [19] [16] [16] [25] [25,26] [16] Ass’m (see Table 1) Ass’m (see Table 1) Ass’m (see Table 1) [4–7] [4–7] [15,28,29] [28] [31] [30] [30]
0.900 0.922 0.835 0.700 0.500 0.900 0.600
0.009 0.008 0.012 0.015 0.016 0.009 0.015
[24] [42] [22] [24] [24] [24] [24]
0.002 14.149 49.57
0.001 9.895 4.99
[16] [16] [20]
5-year carryover benefit, there was a 25% likelihood of being cost-effective at a $50,000 per QALY gained threshold and a 76% likelihood at a $100,000 per QALY gained threshold. For the more conservative 3-year benefit scenario, the likelihood of being cost-effective was 3% and 34%, given thresholds of $50,000 and $100,000 per QALY gained, respectively.
although reducing the total cost by 50% worsened CU by 8% ($75,600/QALY gained). In the 3-year scenario, a 100% percent increase in the cumulative cost of palliative trastuzumab improved CU by 12% ($112,707/QALY gained), although reducing the total cost by 50% worsened CU by 7% ($136,367/ QALY gained).
Sensitivity Analysis
Model Validity
The key drivers of net monetary benefit in the reference scenario were, unsurprisingly, the cost and relative benefit of adjuvant trastuzumab. Results of the threshold analysis for the primary and secondary analyses are presented in Table 4, and show the critical value along with the expected value and 95% CI of key parameters in the model. The plausibility of a particular parameter meeting the critical value for a given threshold was judged against the 95% CI. For the primary analysis with a 5-year benefit scenario, threshold values were more achievable at the $100,000 than the $50,000 per QALY gained threshold. For the 3-year benefit scenario, meeting a $50,000 per QALY gained threshold was judged implausible as critical values were outside the CI for all key parameters. Meeting a $100,000 threshold was more plausible, because the critical values for adjuvant trastuzumab cost and relative benefit fell within the CIs. One-way sensitivity analyses of structural parameters in the model showed that CU results were quite sensitive to discounting (Table 5). CU was less favorable the higher the discount rate, but the results were particularly sensitive to discounting outcomes. The impact of palliative trastuzumab treatment after DCR was also tested in a one-way sensitivity analysis because, in general, the more expensive the consequences of recurrence, the more cost-effective it is to prevent that recurrence. Increasing the cumulative cost of palliative trastuzumab by 100% in the 5-year scenario improved CU by 14% ($60,561/QALY gained),
To test external validity, the model was compared with diseasefree survival end points at 3 years, as reported by the HERA trial [16]. HERA reported an absolute disease-free survival difference of 6.3%, although the model predicted a disease-free survival differential of 6.1% (95% CI: 3.0–8.9%). Much of this difference may be attributed to the use of Canadian life tables to estimate background mortality.
Discussion The long-term CU of sequential adjuvant trastuzumab after chemotherapy is primarily dependent on the magnitude and duration of clinical benefit. In our analyses, CU was particularly sensitive to the duration of carryover benefit for trastuzumab beyond the 3-year efficacy results reported by the updated HERA trial. The CU for sequential adjuvant trastuzumab, based on the updated HERA results, was $72,292 and $127,862 per QALY gained for the 5- and 3-year benefit scenarios, respectively. Moreover, sequential adjuvant trastuzumab had a 76%—compared to 34%—likelihood of meeting a $100,000 per QALY threshold for the 5- and 3-year scenarios, respectively. Under a more stringent $50,000 threshold, the likelihood fell to 25% and 3%, respectively. It is important to note our estimates of long-term CU are based on the recent update to the HERA trial [16] that reported
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Cost-Utility of Sequential Adjuvant Trastuzumab a
$80,000
$60,000
Net Moneraty Benefit
$40,000
$20,000
$0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
80,000
90,000
100,000
70,000
80,000
90,000
100,000
-$20,000
-$40,000
-$60,000
-$80,000
b
Threshold Willingness-to-Pay per QALY
$40,000
$20,000
Net Moneraty Benefit
$0
10,000
20,000
30,000
40,000
50,000
60,000
-$20,000
-$40,000
-$60,000
-$80,000
Threshold Willingness-to-Pay per QALY
Figure 2 (a) Net monetary benefit adjuvant trastuzumab vs. primary treatment alone: 12-m treatment, 5-year benefit, 25-year Horizon. (b) Net monetary benefit adjuvant trastuzumab vs. primary treatment alone: 12-m treatment, 3-year benefit, 25-year horizon.
a less favorable relative disease-free survival advantage than originally reported in the interim HERA analysis [8]. The HERA update suggested that the hazard rates in the treatment and control arms were converging at less than 5 years, but the true duration of benefit remained uncertain. The difference in CU results between the 5- and 3-year benefit scenarios in our analysis highlights the need for longer follow-up in clinical trials to define the true duration of adjuvant trastuzumab benefit. Our measure of relative benefit was also based on the RR rather than the HR of a disease-free survival event and was based on reported disease-free survival end points at 3 years. Although the RR was
considerably less favorable than the reported HR (RR 0.75 vs. HR 0.64), the instantaneous HR, derived from a Cox proportional hazard survival model, does not specify how the risk of an event changes over time, and consequently, “. . . its use to inform time-dependency in Markov models is limited” [34]. Because our model specifically incorporated time-dependent rates of recurrence and mortality, RR was felt to be the more appropriate measure of relative clinical benefit. Previous CU estimates for sequential adjuvant trastuzumab have been more favorable than our results, based on the 2-year updated results. Nevertheless, these analyses were based on the
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646 Table 3 CU results
Analysis horizon Treatment benefit Incremental cost 95% CI Unadjusted life-years gained 95% CI QALYs gained per patient 95% CI CU at 25 years 95% CI Net monetary benefit @ $50,000 per QALY 95% CI Net monetary benefit @ $100,000 per QALY 95% CI
Scenario 1
Scenario 2
25 years 5 years $41,533 $20,838–$71,410 0.77 0.37–1.19 0.59 0.51–0.76 $70,292 $28,602–$139,657 -$11,990
25 years 3 years $43,094 $22,656–$72,906 0.51 0.25–0.78 0.34 0.29–0.40 $127,862 $56,912–$247,926 -$26,242
-$50,134 to $19,872 $17,553
-$61,006 to -$190 -$9,390
-$37,893 to $67,652
-$54,694 to $27,787
more the favorable interim results [8], used more favorable HRs as the measure of relative benefit, and assumed a longer duration of benefit. Many also consider the results over a longer analysis horizon than used in our evaluation. A National Institute for Clinical Excellence (NICE) guidance [35] reported a CU estimate of £18,000 per QALY gained, based on a disease-free survival HR of 0.54 and an assumption of a 5-year duration of benefit. The authors of the NICE report recently commented that the updated HERA results is expected to increase (i.e., worsen) the cost-effectiveness ratio associated with sequential trastuzumab [36]. Millar and Millward also incorporated HRs from the interim HERA analysis in a cost-effectiveness evaluation of sequential adjuvant trastuzumab [37]. Assuming an 8-year benefit, they reported a CU of $22,793 per QALY gained (2005 Australian dollars) over a 51-year horizon. Finally, a Swiss study, based on the interim HERA analysis and assuming a carryover benefit of 5-years, reported a cost-effectiveness of €19,673 per quality-unadjusted life-year gained at 15 years, although a sensitivity analysis reducing the carryover benefit from 5 to 3 years nearly doubled the cost-effectiveness estimate to €37,630 per life-year gained [38].
100% 90% 80% Scenario 1 (5yr Benefit) 70%
Pr(CE)
60% 50% 40% Scenario 2 (3yr Benefit) 30% 20% 10% 0% 0
10000
20000
30000
40000
50000
60000
70000
80000
90000
100000
Threshold Value per QALY
Figure 3 Cost-effectiveness acceptability curve adjuvant trastuzumab vs. primary treatment alone scenario 1 and scenario 2.
Table 4 Threshold analysis Parameter Scenario 1 (5-year benefit) Analysis horizon Adjuvant trastuzumab treatment cost RR DFS event | adjuvant trastuzumab Absolute rate of cardiotoxicity | adjuvant trastuzumab Scenario 2 (3-year benefit) Analysis horizon Adjuvant trastuzumab treatment cost RR DFS event | adjuvant trastuzumab Absolute rate of cardiotoxicity | adjuvant trastuzumab Cells in bold indicate threshold values falling within 95% CI of model parameter.
Threshold value ⱕ$50,000/QALY
Threshold value ⱕ$100,000/QALY
Baseline value in model (95% CI)
>60 years ⱕ$40,369 ⱕ0.698 Not found
ⱖ14.7 years ⱕ$72,634 ⱕ0.822 ⱕ7.1%
25 years $51,693 ($31,014–83,421) 0.754 (0.645–0.878) 2.5% (0.3–8.8%)
>60 years ⱕ$25,676 ⱕ0.526 Not found
ⱖ33.8 years ⱕ$44,713 ⱕ0.729 ⱕ1.0%
25 years $51,693 ($31,014–83,421) 0.754 (0.645–0.878) 2.5% (0.3–8.8%)
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Cost-Utility of Sequential Adjuvant Trastuzumab Table 5 Structural parameter scenarios Duration of adjuvant trastuzumab benefit Discount rate 0% 3% 5% 0% 5%
costs; 0% costs; 3% costs; 5% costs; 5% costs; 0%
outcomes outcomes outcomes outcomes outcomes
5 years
3 years
$46,595 $70,292 $92,163 $90,395 $70,865
$83,768 $127,862 $170,895 $168,701 $128,533
Each cell (except for the reference scenario) was simulated with 1000 iterations.
CU estimates for sequential adjuvant trastuzumab based on the updated HERA results with a median 2-year follow-up, including our study, have been less favorable. A recent evaluation by Lidgren et al. applied efficacy estimates from the updated HERA study to a baseline breast recurrence risk derived from a Swedish cohort [39]. Assuming a lifetime duration of benefit, they reported a CU of €36,000 per QALY gained with sequential adjuvant trastuzumab after HER2/neu testing compared to conventional treatment. Nevertheless, in a sensitivity analysis, applying a more conventional assumption of a 5-year duration of benefit, they found the CU to be in the range of €66,800 per QALY gained. A Japanese study estimated the cost per qualityunadjusted life-year gained over a 50-year horizon to be €40,000 and €17,000 for 2- and 5-year carryover benefit scenarios, respectively [40]. This analysis was based on net treatment costs of approximately €24,000 to €22,000, reflecting lower average body weight (50–60 kg) and lower drug acquisition costs of trastuzumab in Japan. A sensitivity analysis adjusting for weight (60–75 kg) increased cost-effectiveness to €49,000 and €22,000 per life-year gained for the 2- and 5-year carryover scenarios. Adjusting for international differences in acquisition costs would further inflate these estimates of cost-effectiveness. Finally, costs per unadjusted life-year gained reported in the Swiss and Japanese studies are expected to be more favorable than the costs per QALY gained reported in our evaluation. Overall, CU estimates based on the updated HERA results suggests that the true costeffectiveness of sequential adjuvant trastuzumab may be less favorable than earlier estimates. CU analyses of concurrent adjuvant trastuzumab, based on the joint analysis of the NSABP-B31 and NTCTG-N9831 studies [9], appear more favorable. Liberato et al. reported CU estimates of €14,861 per QALY gained from the perspective of the Italian health-care system and US$18,970 per QALY gained from a US health-care perspective, both over a 15-year analysis horizon [41]. Kurian et al. reported a CU estimate of US$39,982 per QALY gained over a lifetime horizon [42]. Finally, Garrison et al. reported a CU of US$26,417 over a lifetime horizon and US$34,201 over a 20-year horizon [43]. Because the costs, health states, and assumptions included in our model were specific to the sequential approach studied in the HERA trial, these results cannot be generalized to the concurrent strategy. Direct clinical and economic comparisons between the sequential and concurrent approaches, however, should only be conducted after the mature results of the NCCTG-N9831 study become available. There remains considerable uncertainty around the optimal schedule and duration of adjuvant trastuzumab treatment. Reflecting trial protocols and current international practice, our analysis and all those mentioned previously modeled 1 year of adjuvant trastuzumab therapy, either sequential or concurrent to adjuvant chemotherapy. The FinHer study, however, suggests that a similar relative benefit may be possible with just 9 weeks of adjuvant trastuzumab therapy [11]. If confirmed by a larger
trial, the CU of adjuvant trastuzumab would be considerably more favorable than current estimates. There were several limitations to our analysis. First, our analysis was based on estimates of efficacy under controlled conditions rather than effectiveness in actual clinical practice. It is likely that the observed clinical benefit of adjuvant trastuzumab in routine clinical practice—and hence the CU—will be less favorable than that observed in strictly monitored clinical trials. Second, the HERA trial allowed patients in the control arm to switch to the trastuzumab arm after the first interim report suggested the clinical benefit of aTZ. Although this unplanned crossover reflects ethical research practice, it could potentially bias the updated HERA results. Nevertheless, it is impossible to predict the net effect of the crossover, and the authors report that the intent-to-treat and censored HRs in the updated HERA analysis were essentially the same (0.64 vs. 0.63, respectively) [16]. Third, the model relied on symptomatic congestive heart failure as a proxy measure of clinically significant cardiotoxicity, and adapted long-term recovery data from the NSABP B-31 trial of concurrent adjuvant trastuzumab [20]. Future research should aim to clarify the incidence and consequences of cardiotoxicity associated with trastuzumab therapy in routine practice. Fourth, the probabilistic analysis was forced to rely on assumptions regarding the variance of the cost parameters. Although this weakens the empirical basis of the input distributions, we feel that it represents an improvement over a strictly deterministic approach. Fifth, we took a direct payer rather than a societal cost perspective that would include costs such as lost productivity and caregiver time. A direct payer perspective was felt to be most relevant to health-care payers, considering coverage decisions around breast cancer treatments, and to be most comparable with previous economic evaluations of adjuvant trastuzumab. Including indirect costs would likely improve the relative cost-effectiveness of adjuvant trastuzumab. Finally, in the absence of an accepted cost-effectiveness threshold, we judged the favorability of our CU estimates relative to the common yet ultimately arbitrary thresholds of $50,000 and $100,000 per QALY gained. Further research is required to identify an appropriate and meaningful cost-effectiveness threshold [44]. In summary, the CU of sequential adjuvant trastuzumab after chemotherapy relative to chemotherapy alone is dependent on the cost of trastuzumab therapy and the magnitude and duration of benefit achieved. Based on the updated HERA results, we estimated the CU of adjuvant sequential trastuzumab to be $72,292 per QALY gained based on a 5-year duration of benefit, and $127,862 per QALY with a 3-year duration of benefit over a 25-year analysis horizon. The sensitivity of these results to the relative benefit observed in the updated 3-year results versus the interim 2-year results and to assumptions around the duration of carryover benefit highlights the need for further clinical research to determine the true magnitude and duration of clinical benefit and the associated CU of sequential adjuvant trastuzumab in HER2/neu-positive breast cancer. Source of financial support: Department of Medicine, Dalhousie University.
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