DOI:10.1093/jnci/dju008 First published online March 5, 2014
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
Article
Examining the Cost-Effectiveness of Radiation Therapy Among Older Women With Favorable-Risk Breast Cancer Sounok Sen, Shi-Yi Wang, Pamela R. Soulos, Kevin D. Frick, Jessica B. Long, Kenneth B. Roberts, James B. Yu, Suzanne B. Evans, Anees B. Chagpar, Cary P. Gross Manuscript received September 19, 2013; revised December 17, 2013; accepted December 17, 2013. Correspondence to: Cary P. Gross, MD, Yale University School of Medicine, Primary Care Center, 333 Cedar St, PO Box 208025, New Haven, CT 06520 (e-mail: [email protected]).
Background
Little is known about the cost-effectiveness of external beam radiation therapy (EBRT) or newer radiation therapy (RT) modalities such as intensity modulated radiation (IMRT) or brachytherapy among older women with favorable-risk breast cancer.
Methods
Using a Markov model, we estimated the cost-effectiveness of no RT, EBRT, and IMRT over 10 years. We estimated the incremental cost-effectiveness ratio (ICER) of IMRT compared with EBRT under different scenarios to determine the necessary improvement in effectiveness for newer modalities to be cost-effective. We estimated model inputs using women in the Surveillance, Epidemiology, and End Results–Medicare database fulfilling the Cancer and Leukemia Group B C9343 trial criteria.
Results
The incremental cost of EBRT compared with no RT was $9500 with an ICER of $44 600 per quality-adjusted life year (QALY) gained. The ICERs increased with age, ranging from $38 300 (age 70–74 years) to $55 800 (age 80 to 94 years) per QALY. The ICERs increased to more than $63 800 per QALY for women aged 70 to 74 years with an expected 10-year survival of 25%. Reduction in local recurrence by IMRT compared with EBRT did not have a substantial impact on the ICER of IMRT. IMRT would have to increase the utility of baseline state by 20% to be cost-effective (70 years with tumor size ≤2 cm, estrogen receptor–positive status, and lymph node–negative disease) (9–11). Despite these guidelines, RT continues to be used in older women, raising concerns about overuse (12). It is important to consider the cost-effectiveness of RT, which has not yet been assessed among older women with early-stage breast cancer (13,14). It is also important to consider how changes in life expectancy affect the cost-effectiveness of RT, because life expectancy impacts the time at risk for recurrence and thus the effectiveness of RT in older women. In addition to evaluating the cost-effectiveness of widely used and trial-tested treatments such as EBRT, newer and costlier 1 of 8 Article | JNCI
technologies such as brachytherapy and intensity modulated RT (IMRT) are diffusing into clinical practice in the absence of comparative effectiveness data (15,16). A framework is needed to allow practitioners and policy makers to assess newer cancer treatments in the absence of substantial clinical data. To address this need, cost-effectiveness analysis can be used in a different manner, by first assessing existing trial-tested interventions (such as EBRT) and then integrating costs associated with newer modalities to determine how much more effective they would have to be to be incrementally cost-effective when compared with the standard of care. Although clinical trials comparing brachytherapy to EBRT are ongoing (5,13,15–18), brachytherapy has not demonstrated any benefit on cancer control or overall or disease-free survival and may be inferior to EBRT in subsequent mastectomy rate and risk of complications (19,20). Although IMRT has demonstrated a reduction in toxicity and improved cosmesis, it remains substantially more expensive in the United States, and it is unclear how IMRT affects patient-reported quality of life (QoL) (21,22). Vol. 106, Issue 3 | dju008 | March 12, 2014
Therefore, it is important to understand the balance between the costs and potential benefits of newer modalities. We therefore estimated the cost-effectiveness of EBRT using Medicare expenditures to estimate total cancer-related costs. Second, we used survival data of older women to estimate the costeffectiveness of EBRT across age and comorbidity groups. Finally, we explored the incremental costs for the newer RT modalities and projected how much more effective they would have to be relative to EBRT to be cost-effective.
Methods Basic Model and Model Assumptions We designed a Markov model to simulate clinical outcomes, estimate quality-adjusted life-years (QALYs) gained, and determine the incremental cost-effectiveness ratio (ICER) of various RT modalities (EBRT, IMRT, brachytherapy) from a payer perspective over a 10-year horizon in older women with early-stage breast cancer. We compared the incremental costs and health benefits of these RT modalities. Acknowledging the limited effectiveness information for the newer modalities, we estimated the ICER of the newer modalities (IMRT and brachytherapy) compared with EBRT under different scenarios, assuming the newer modalities improved recurrence-free survival and/or utility. We then estimated the necessary improvement in effectiveness over EBRT for the newer modalities to be cost-effective based on two common willingness-to-pay thresholds of $50 000 per QALY and $100 000 per QALY (23–25). Three hypothetical cohorts of women starting at ages 70, 75, and 80 years were created to determine the effect
±RT
of age. We assumed that all women are initially in a no-recurrence health state and subsequently transition to one of four health states (no recurrence, local recurrence, metastasis, or death) each year (Figure 1). We assumed that 1) survival was similar in no RT and RT groups; 2) RT reduced the risk of recurrence, according to the results derived from the Cancer and Leukemia Group B C9343 trial; and 3) the costs associated with various RT modalities were based on matched breast cancer case patients and non–breast cancer control subjects. We confined our analysis to 10 years because the efficacy measure (in terms of recurrence probability) was derived from C9343, which reported 10-year trial results. We used a payer perspective because decisions that influenced coverage and reimbursement were made by Medicare and our research question focused specifically on the costs and benefits of newer RT modalities among Medicare beneficiaries. All analyses were performed on TreeAge Pro 2012 (Williamstown, MA) and SAS version 9.2 (SAS Institute, Cary, NC). The Yale Human Investigation Committee determined that this study did not involve human subjects. Data Source and Sample Selection We determined cost and overall survival using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, which links population-based cancer registries with Medicare claims data (26). The database also includes a 5% random sample of Medicare beneficiaries without cancer who reside in the SEER areas. We identified a sample of women who met the eligibility criteria for the C9343 trial (aged ≥70 years, tumor size ≤ 2cm, estrogen receptor–positive status, lymph node–negative disease), were diagnosed in the period from 1998 to 2007, and received breast-conserving
Women with early-stage breast cancer
No recurrence
Recurrence
pRecurrence
pMetastasis
Metastasis
pMetastasis
pDeath* (metastatic cancer)
pDeath (background)
Death
pDeath (background)
Figure 1. Model overview. pDeath (background) = annual probability of death (refers to background mortality); pDeath* (metastatic cancer) = annual probability of death from metastatic breast cancer, including breast cancer specific mortality and background mortality; pMetastasis = annual probability of metastasis; pRecurrence = annual probability of recurrence; RT = radiation therapy. jnci.oxfordjournals.org
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surgery. We selected women who fulfilled C9343 criteria because the results from this trial shaped current recommendations stating that RT can be safely omitted in this population; thus our model parameters reflect characteristics of a population for whom there are distinct trial-based guidelines. We estimated 10-year survival in our SEER–Medicare sample according to age group in women who were diagnosed in the period from 1998 to 1999, for whom we had 10 years of follow-up data and determined an annual mortality rate. We used C9343 trial results to estimate probabilities for annual recurrence and metastasis. All mortality, recurrence, and metastasis rates were converted to annual transition probabilities as model inputs (Table 1). We validated our model-based estimates to the C9343 trial and SEER–Medicare in terms of a variety of outcomes (Supplementary Table 1, available online). We used C9343 data to estimate the effectiveness of RT in preventing a recurrence as well as the probability of metastatic disease. Details
of our sample selection and model validation are described in the Supplementary Materials, which include both Supplementary Methods and Supplementary Tables 1 to 5 (available online).
Cost and Utility Inputs Each cancer patient was matched with a noncancer control subject based on age, race, comorbidity, region, and year of diagnosis (or year of randomly assigned index date for control subject). Total mean costs for initial treatment among no RT, EBRT, IMRT, and brachytherapy patients were calculated as all costs to Medicare (inpatient, outpatient facility, physician, home health, hospice, and Durable Medical Equipment claims) from a payer perspective in the 2 months before through 12 months after date of diagnosis/index date. Each cancer patient’s cancer-related cost was calculated as the difference between her total cost and that of her matched control
Table 1. Model input* Model assumptions Utilities, by age, treatment, and recurrence status A. Utilities according to treatment and recurrence status† Conservative surgery and radiation therapy with no recurrence Conservative surgery and radiation therapy with isolated local recurrence Conservative surgery alone with no recurrence Conservative surgery alone with isolated local recurrence Distant metastases B. Utility modifier according to age‡ 70–74 y 75–79 y 80–84 y >85 y Survival, all women† 5-year survival 70–74 y 75–79 y 80–94 y 10-year survival 70–74 y 75–79 y 80–94 y Annual recurrence probability, no RT† Relative risk of recurrence when receiving RT† Annual metastasis probability† Annual death probability from metastatic breast cancer* Cancer-related costs per patient, mean (SD)† No RT EBRT IMRT Brachytherapy Other costs Recurrence, mastectomy,† mean (SD) Metastatic care, mean Continued phase costs, mean Death, last year of life, mean (SD)† Annual discount rate, QALYs and costs
Value (range)
Source Hayman et al. (30)
0.92 (0.05–1.00) 0.82 (0.00–0.99) 0.88 (0.00–1.00) 0.81 (0.00–0.99) 0.7 (0.6–0.8) Stout et al. (32) 0.716 0.675 0.623 0.59 SEER–Medicare 91.1% 86.6% 70.3% 73.6% (70.4–76.6) 61.2% (57.4–64.8) 33.4% (29.7–37.2) 0.01 (0.007–0.016) 0.18 (0.07–0.42) 0.005 (0.003–0.009) 0.210–0.238§
CALGB C9343 (11) CALGB C9343 (11) CALGB C9343 (11) SEER (40) SEER–Medicare
$5593 (30 895) $15 396 (26 921) $23 605 (34 337) $23 628 (26 833) $6250 (4475) $37 771 $284 (2–4 y) $212 (after year 4) $44 732 (48 183) 0.03 (0–0.07)
SEER–Medicare Rao et al. (27) SEER–Medicare SEER–Medicare
* QALY= quality-adjusted life-year; RT= radiation therapy; SD = standard deviation. † Included in the probabilistic sensitivity analysis. ‡ Multiply the age-specific utility by the relevant utility in section A. For example, the utility for a woman aged 73 years receiving RT without recurrence is 0.659 (0.92 x 0.716). § Estimates had been calibrated at 1-year incremental.
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subject (Table 1; Supplementary Methods, available online). We calculated the continuing phase cost per year, as well as end-of-life costs by calculating the costs in the last year of life. Cost for distant metastasis was based on prior literature (27). Costs were adjusted for inflation and geographic price differences to 2012 US dollars (28,29). We abstracted utility weights for each health state from the literature and then age-adjusted these utilities at 5-year increments using previously reported trends (30–32). Utilities varied based on age, receipt of RT, and metastatic and recurrence status. Costs and utilities were discounted at an annual rate of 3%.
sensitivity analysis to assess uncertainty and robustness by specifying distributions for model parameters following the standard Bayesian framework (Supplementary Methods, available online). When appropriate, we used beta distributions for probability parameters and utility estimates, log-normal distributions for relative risk parameters, and normal distribution for cost parameters (34). The distributions of input parameters were drawn 100 000 times, and an acceptability curve was created.
Life Expectancy and Comorbidity Analysis To assess the effect of age and comorbidity burden on the costeffectiveness estimates, we constructed a separate noncancer sample by randomly selecting a subset of 50 000 women aged 70 to 94 years between 1998 and 1999 to allow for 10-year follow-up. We categorized this noncancer sample by age and number of clinical comorbidities previously found to be associated with survival in noncancer patients (33). We chose to use survival data from a noncancer sample to allow for adequate sample size for each age and comorbidity combination. Using our noncancer sample, we determined the actual survival for each age and comorbidity combination (eg, patients aged 70–74 years with 1–2 comorbid conditions). Each combination of age and comorbidity was categorized into four groups based on 10-year survival (0%–25%, 25%–50%, 50%–75%, 75%–100%). We conducted a series of simulations integrating both age and mortality rate (assuming a constant mortality rate during 10 years) to estimate the range of cost-effectiveness of EBRT across these 10-year survival quartiles (ie, the range of ICERs for a predicted 10-year survival of 75%).
We included 18 340 Medicare beneficiaries who met the C9343 eligibility criteria. The 10-year survival among all C9343 eligible women for whom we had 10-year follow-up data varied between 73.6% for women aged 70 to 74 years and 33.4% for women aged 80 to 94 years (Table 1). The 10-year probability of mastectomyfree survival for women receiving no RT in our SEER–Medicare sample was 96.4%, consistent with the C9343 trial (96%). Our Markov model estimated the total costs for a 70-year old woman receiving EBRT during 10-years of follow-up to be approximately $29 500, compared with $20 077 for no RT, resulting in an incremental cost of approximately $9500 (Table 2). Using the SEER–Medicare population percentages by age as the weights, we calculated the cost-effectiveness of EBRT for all women in our sample to be $44 600 per QALY. We estimated the QALYs experienced for a 70-year old woman to be 0.25 greater for EBRT than for no RT (5.42 and 5.17, respectively), resulting in an ICER for EBRT of $38 300 per QALY. The ICERs for EBRT increased with increasing age, with an 80-year old woman experiencing 0.17 more QALYs with EBRT than no RT, corresponding to an ICER of $55 800 per QALY. The cost-effectiveness for EBRT varied by age and comorbidity status (Figure 2). Older women with more comorbidity had a decreased 10-year survival probability, which corresponded to substantially less favorable cost-effectiveness for EBRT. Specifically, the ICER for EBRT was between $36 900 per QALY and $41 800 per QALY for women with predicted 10-year survival between 75% and 99% (corresponding to women aged 70–74 years with no comorbidity). The ICER for EBRT increased to greater than $63 800 per QALY for women with a predicted 10-year survival of less than 25%.
Sensitivity Analysis We performed a series of one-way sensitivity analyses to determine the variability in the ICER as a function of the cost of RT, utility of RT, treated-recurrence probability, metastasis probability, and cost of recurrence. We conducted a two-way sensitivity analysis to investigate how much better the reduction in recurrence and improvement in age-specific QoL would need to be for the newer modalities to be cost-effective. We performed probabilistic
Results
Table 2. Cost-effectiveness estimates for women with favorable early-stage breast cancer* Model result
Age, y
No RT
EBRT
Costs, $, per woman
70–74 75–79 80–94 70–74 75–79 80–94 70–74 75–79 80–94 All
20 077 24 328 34 058 5.171 4.596 3.608 — — — —
29 500 33 774 43 569 5.418 4.814 3.778
QALY per woman
Incremental cost-effectiveness ratio, $/QALY*
Incremental changes 9423 9445 9510 0.246 0.218 0.170 38 300 43 200 55 800 44 600
IMRT† 37 710 41 983 51 778 5.524 4.909 3.852
Incremental changes, IMRT† 8209 8209 8209 0.106 0.095 0.074 77 100 86 700 110 500 89 300
* Minor discrepancies may exist because of rounding. EBRT= external beam radiation therapy; IMRT= intensity modulated radiation therapy; QALY=quality-adjusted life-year; RT= radiation therapy. † Assuming that the recurrence rate is identical in the group receiving EBRT or IMRT and IMRT increases utility by 25% of the difference between utility receiving EBRT without recurrence and utility of healthy women without breast cancer. ICERs are rounded to the nearest hundred.
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$/QALY
Comorbidity 3
1–2
70–74
50%–75%
75–79
25%–50%
80–84
0
>75%
0 >75%
50%–75%
50%–75%
25%–50%
25%–50%
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
Article
Examining the Cost-Effectiveness of Radiation Therapy Among Older Women With Favorable-Risk Breast Cancer Sounok Sen, Shi-Yi Wang, Pamela R. Soulos, Kevin D. Frick, Jessica B. Long, Kenneth B. Roberts, James B. Yu, Suzanne B. Evans, Anees B. Chagpar, Cary P. Gross Manuscript received September 19, 2013; revised December 17, 2013; accepted December 17, 2013. Correspondence to: Cary P. Gross, MD, Yale University School of Medicine, Primary Care Center, 333 Cedar St, PO Box 208025, New Haven, CT 06520 (e-mail: [email protected]).
Background
Little is known about the cost-effectiveness of external beam radiation therapy (EBRT) or newer radiation therapy (RT) modalities such as intensity modulated radiation (IMRT) or brachytherapy among older women with favorable-risk breast cancer.
Methods
Using a Markov model, we estimated the cost-effectiveness of no RT, EBRT, and IMRT over 10 years. We estimated the incremental cost-effectiveness ratio (ICER) of IMRT compared with EBRT under different scenarios to determine the necessary improvement in effectiveness for newer modalities to be cost-effective. We estimated model inputs using women in the Surveillance, Epidemiology, and End Results–Medicare database fulfilling the Cancer and Leukemia Group B C9343 trial criteria.
Results
The incremental cost of EBRT compared with no RT was $9500 with an ICER of $44 600 per quality-adjusted life year (QALY) gained. The ICERs increased with age, ranging from $38 300 (age 70–74 years) to $55 800 (age 80 to 94 years) per QALY. The ICERs increased to more than $63 800 per QALY for women aged 70 to 74 years with an expected 10-year survival of 25%. Reduction in local recurrence by IMRT compared with EBRT did not have a substantial impact on the ICER of IMRT. IMRT would have to increase the utility of baseline state by 20% to be cost-effective (70 years with tumor size ≤2 cm, estrogen receptor–positive status, and lymph node–negative disease) (9–11). Despite these guidelines, RT continues to be used in older women, raising concerns about overuse (12). It is important to consider the cost-effectiveness of RT, which has not yet been assessed among older women with early-stage breast cancer (13,14). It is also important to consider how changes in life expectancy affect the cost-effectiveness of RT, because life expectancy impacts the time at risk for recurrence and thus the effectiveness of RT in older women. In addition to evaluating the cost-effectiveness of widely used and trial-tested treatments such as EBRT, newer and costlier 1 of 8 Article | JNCI
technologies such as brachytherapy and intensity modulated RT (IMRT) are diffusing into clinical practice in the absence of comparative effectiveness data (15,16). A framework is needed to allow practitioners and policy makers to assess newer cancer treatments in the absence of substantial clinical data. To address this need, cost-effectiveness analysis can be used in a different manner, by first assessing existing trial-tested interventions (such as EBRT) and then integrating costs associated with newer modalities to determine how much more effective they would have to be to be incrementally cost-effective when compared with the standard of care. Although clinical trials comparing brachytherapy to EBRT are ongoing (5,13,15–18), brachytherapy has not demonstrated any benefit on cancer control or overall or disease-free survival and may be inferior to EBRT in subsequent mastectomy rate and risk of complications (19,20). Although IMRT has demonstrated a reduction in toxicity and improved cosmesis, it remains substantially more expensive in the United States, and it is unclear how IMRT affects patient-reported quality of life (QoL) (21,22). Vol. 106, Issue 3 | dju008 | March 12, 2014
Therefore, it is important to understand the balance between the costs and potential benefits of newer modalities. We therefore estimated the cost-effectiveness of EBRT using Medicare expenditures to estimate total cancer-related costs. Second, we used survival data of older women to estimate the costeffectiveness of EBRT across age and comorbidity groups. Finally, we explored the incremental costs for the newer RT modalities and projected how much more effective they would have to be relative to EBRT to be cost-effective.
Methods Basic Model and Model Assumptions We designed a Markov model to simulate clinical outcomes, estimate quality-adjusted life-years (QALYs) gained, and determine the incremental cost-effectiveness ratio (ICER) of various RT modalities (EBRT, IMRT, brachytherapy) from a payer perspective over a 10-year horizon in older women with early-stage breast cancer. We compared the incremental costs and health benefits of these RT modalities. Acknowledging the limited effectiveness information for the newer modalities, we estimated the ICER of the newer modalities (IMRT and brachytherapy) compared with EBRT under different scenarios, assuming the newer modalities improved recurrence-free survival and/or utility. We then estimated the necessary improvement in effectiveness over EBRT for the newer modalities to be cost-effective based on two common willingness-to-pay thresholds of $50 000 per QALY and $100 000 per QALY (23–25). Three hypothetical cohorts of women starting at ages 70, 75, and 80 years were created to determine the effect
±RT
of age. We assumed that all women are initially in a no-recurrence health state and subsequently transition to one of four health states (no recurrence, local recurrence, metastasis, or death) each year (Figure 1). We assumed that 1) survival was similar in no RT and RT groups; 2) RT reduced the risk of recurrence, according to the results derived from the Cancer and Leukemia Group B C9343 trial; and 3) the costs associated with various RT modalities were based on matched breast cancer case patients and non–breast cancer control subjects. We confined our analysis to 10 years because the efficacy measure (in terms of recurrence probability) was derived from C9343, which reported 10-year trial results. We used a payer perspective because decisions that influenced coverage and reimbursement were made by Medicare and our research question focused specifically on the costs and benefits of newer RT modalities among Medicare beneficiaries. All analyses were performed on TreeAge Pro 2012 (Williamstown, MA) and SAS version 9.2 (SAS Institute, Cary, NC). The Yale Human Investigation Committee determined that this study did not involve human subjects. Data Source and Sample Selection We determined cost and overall survival using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, which links population-based cancer registries with Medicare claims data (26). The database also includes a 5% random sample of Medicare beneficiaries without cancer who reside in the SEER areas. We identified a sample of women who met the eligibility criteria for the C9343 trial (aged ≥70 years, tumor size ≤ 2cm, estrogen receptor–positive status, lymph node–negative disease), were diagnosed in the period from 1998 to 2007, and received breast-conserving
Women with early-stage breast cancer
No recurrence
Recurrence
pRecurrence
pMetastasis
Metastasis
pMetastasis
pDeath* (metastatic cancer)
pDeath (background)
Death
pDeath (background)
Figure 1. Model overview. pDeath (background) = annual probability of death (refers to background mortality); pDeath* (metastatic cancer) = annual probability of death from metastatic breast cancer, including breast cancer specific mortality and background mortality; pMetastasis = annual probability of metastasis; pRecurrence = annual probability of recurrence; RT = radiation therapy. jnci.oxfordjournals.org
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surgery. We selected women who fulfilled C9343 criteria because the results from this trial shaped current recommendations stating that RT can be safely omitted in this population; thus our model parameters reflect characteristics of a population for whom there are distinct trial-based guidelines. We estimated 10-year survival in our SEER–Medicare sample according to age group in women who were diagnosed in the period from 1998 to 1999, for whom we had 10 years of follow-up data and determined an annual mortality rate. We used C9343 trial results to estimate probabilities for annual recurrence and metastasis. All mortality, recurrence, and metastasis rates were converted to annual transition probabilities as model inputs (Table 1). We validated our model-based estimates to the C9343 trial and SEER–Medicare in terms of a variety of outcomes (Supplementary Table 1, available online). We used C9343 data to estimate the effectiveness of RT in preventing a recurrence as well as the probability of metastatic disease. Details
of our sample selection and model validation are described in the Supplementary Materials, which include both Supplementary Methods and Supplementary Tables 1 to 5 (available online).
Cost and Utility Inputs Each cancer patient was matched with a noncancer control subject based on age, race, comorbidity, region, and year of diagnosis (or year of randomly assigned index date for control subject). Total mean costs for initial treatment among no RT, EBRT, IMRT, and brachytherapy patients were calculated as all costs to Medicare (inpatient, outpatient facility, physician, home health, hospice, and Durable Medical Equipment claims) from a payer perspective in the 2 months before through 12 months after date of diagnosis/index date. Each cancer patient’s cancer-related cost was calculated as the difference between her total cost and that of her matched control
Table 1. Model input* Model assumptions Utilities, by age, treatment, and recurrence status A. Utilities according to treatment and recurrence status† Conservative surgery and radiation therapy with no recurrence Conservative surgery and radiation therapy with isolated local recurrence Conservative surgery alone with no recurrence Conservative surgery alone with isolated local recurrence Distant metastases B. Utility modifier according to age‡ 70–74 y 75–79 y 80–84 y >85 y Survival, all women† 5-year survival 70–74 y 75–79 y 80–94 y 10-year survival 70–74 y 75–79 y 80–94 y Annual recurrence probability, no RT† Relative risk of recurrence when receiving RT† Annual metastasis probability† Annual death probability from metastatic breast cancer* Cancer-related costs per patient, mean (SD)† No RT EBRT IMRT Brachytherapy Other costs Recurrence, mastectomy,† mean (SD) Metastatic care, mean Continued phase costs, mean Death, last year of life, mean (SD)† Annual discount rate, QALYs and costs
Value (range)
Source Hayman et al. (30)
0.92 (0.05–1.00) 0.82 (0.00–0.99) 0.88 (0.00–1.00) 0.81 (0.00–0.99) 0.7 (0.6–0.8) Stout et al. (32) 0.716 0.675 0.623 0.59 SEER–Medicare 91.1% 86.6% 70.3% 73.6% (70.4–76.6) 61.2% (57.4–64.8) 33.4% (29.7–37.2) 0.01 (0.007–0.016) 0.18 (0.07–0.42) 0.005 (0.003–0.009) 0.210–0.238§
CALGB C9343 (11) CALGB C9343 (11) CALGB C9343 (11) SEER (40) SEER–Medicare
$5593 (30 895) $15 396 (26 921) $23 605 (34 337) $23 628 (26 833) $6250 (4475) $37 771 $284 (2–4 y) $212 (after year 4) $44 732 (48 183) 0.03 (0–0.07)
SEER–Medicare Rao et al. (27) SEER–Medicare SEER–Medicare
* QALY= quality-adjusted life-year; RT= radiation therapy; SD = standard deviation. † Included in the probabilistic sensitivity analysis. ‡ Multiply the age-specific utility by the relevant utility in section A. For example, the utility for a woman aged 73 years receiving RT without recurrence is 0.659 (0.92 x 0.716). § Estimates had been calibrated at 1-year incremental.
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subject (Table 1; Supplementary Methods, available online). We calculated the continuing phase cost per year, as well as end-of-life costs by calculating the costs in the last year of life. Cost for distant metastasis was based on prior literature (27). Costs were adjusted for inflation and geographic price differences to 2012 US dollars (28,29). We abstracted utility weights for each health state from the literature and then age-adjusted these utilities at 5-year increments using previously reported trends (30–32). Utilities varied based on age, receipt of RT, and metastatic and recurrence status. Costs and utilities were discounted at an annual rate of 3%.
sensitivity analysis to assess uncertainty and robustness by specifying distributions for model parameters following the standard Bayesian framework (Supplementary Methods, available online). When appropriate, we used beta distributions for probability parameters and utility estimates, log-normal distributions for relative risk parameters, and normal distribution for cost parameters (34). The distributions of input parameters were drawn 100 000 times, and an acceptability curve was created.
Life Expectancy and Comorbidity Analysis To assess the effect of age and comorbidity burden on the costeffectiveness estimates, we constructed a separate noncancer sample by randomly selecting a subset of 50 000 women aged 70 to 94 years between 1998 and 1999 to allow for 10-year follow-up. We categorized this noncancer sample by age and number of clinical comorbidities previously found to be associated with survival in noncancer patients (33). We chose to use survival data from a noncancer sample to allow for adequate sample size for each age and comorbidity combination. Using our noncancer sample, we determined the actual survival for each age and comorbidity combination (eg, patients aged 70–74 years with 1–2 comorbid conditions). Each combination of age and comorbidity was categorized into four groups based on 10-year survival (0%–25%, 25%–50%, 50%–75%, 75%–100%). We conducted a series of simulations integrating both age and mortality rate (assuming a constant mortality rate during 10 years) to estimate the range of cost-effectiveness of EBRT across these 10-year survival quartiles (ie, the range of ICERs for a predicted 10-year survival of 75%).
We included 18 340 Medicare beneficiaries who met the C9343 eligibility criteria. The 10-year survival among all C9343 eligible women for whom we had 10-year follow-up data varied between 73.6% for women aged 70 to 74 years and 33.4% for women aged 80 to 94 years (Table 1). The 10-year probability of mastectomyfree survival for women receiving no RT in our SEER–Medicare sample was 96.4%, consistent with the C9343 trial (96%). Our Markov model estimated the total costs for a 70-year old woman receiving EBRT during 10-years of follow-up to be approximately $29 500, compared with $20 077 for no RT, resulting in an incremental cost of approximately $9500 (Table 2). Using the SEER–Medicare population percentages by age as the weights, we calculated the cost-effectiveness of EBRT for all women in our sample to be $44 600 per QALY. We estimated the QALYs experienced for a 70-year old woman to be 0.25 greater for EBRT than for no RT (5.42 and 5.17, respectively), resulting in an ICER for EBRT of $38 300 per QALY. The ICERs for EBRT increased with increasing age, with an 80-year old woman experiencing 0.17 more QALYs with EBRT than no RT, corresponding to an ICER of $55 800 per QALY. The cost-effectiveness for EBRT varied by age and comorbidity status (Figure 2). Older women with more comorbidity had a decreased 10-year survival probability, which corresponded to substantially less favorable cost-effectiveness for EBRT. Specifically, the ICER for EBRT was between $36 900 per QALY and $41 800 per QALY for women with predicted 10-year survival between 75% and 99% (corresponding to women aged 70–74 years with no comorbidity). The ICER for EBRT increased to greater than $63 800 per QALY for women with a predicted 10-year survival of less than 25%.
Sensitivity Analysis We performed a series of one-way sensitivity analyses to determine the variability in the ICER as a function of the cost of RT, utility of RT, treated-recurrence probability, metastasis probability, and cost of recurrence. We conducted a two-way sensitivity analysis to investigate how much better the reduction in recurrence and improvement in age-specific QoL would need to be for the newer modalities to be cost-effective. We performed probabilistic
Results
Table 2. Cost-effectiveness estimates for women with favorable early-stage breast cancer* Model result
Age, y
No RT
EBRT
Costs, $, per woman
70–74 75–79 80–94 70–74 75–79 80–94 70–74 75–79 80–94 All
20 077 24 328 34 058 5.171 4.596 3.608 — — — —
29 500 33 774 43 569 5.418 4.814 3.778
QALY per woman
Incremental cost-effectiveness ratio, $/QALY*
Incremental changes 9423 9445 9510 0.246 0.218 0.170 38 300 43 200 55 800 44 600
IMRT† 37 710 41 983 51 778 5.524 4.909 3.852
Incremental changes, IMRT† 8209 8209 8209 0.106 0.095 0.074 77 100 86 700 110 500 89 300
* Minor discrepancies may exist because of rounding. EBRT= external beam radiation therapy; IMRT= intensity modulated radiation therapy; QALY=quality-adjusted life-year; RT= radiation therapy. † Assuming that the recurrence rate is identical in the group receiving EBRT or IMRT and IMRT increases utility by 25% of the difference between utility receiving EBRT without recurrence and utility of healthy women without breast cancer. ICERs are rounded to the nearest hundred.
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$/QALY
Comorbidity 3
1–2
70–74
50%–75%
75–79
25%–50%
80–84
0
>75%
0 >75%
50%–75%
50%–75%
25%–50%
25%–50%
