- Email: [email protected]
Cost-effectiveness of prostate boost with high-dose-rate brachytherapy versus intensity-modulated radiation therapy in the treatment of intermediate-high risk prostate cancer
Brachytherapy
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(2018)
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Cost-effectiveness of prostate boost with high-dose-rate brachytherapy versus intensity-modulated radiation therapy in the treatment of intermediate-high risk prostate cancer Charles C. Vu1, Kevin G. Blas1, Thomas B. Lanni2, Gary S. Gustafson3, Daniel J. Krauss1,* 1
Department of Radiation Oncology, Beaumont Health, Royal Oak, MI Department of Radiation Oncology, Beaumont Health, Dearborn, MI 3 Department of Radiation Oncology, Beaumont Health, Troy, MI
2
ABSTRACT
PURPOSE: The recently published ASCENDE-RT randomized clinical trial demonstrated improved biochemical control, albeit with increased toxicity, for a prostate boost with brachytherapy versus external beam radiation therapy alone in patients with intermediate-high risk prostate cancer. In this study, we investigated the cost-effectiveness of these two modalities in the treatment of intermediate-high risk prostate cancer. METHODS AND MATERIALS: A multistate Markov model was created to model a patient with intermediate-high risk prostate cancer. The two treatment options modeled were (1) 23 fractions of intensity-modulated radiation therapy (IMRT) and two fractions of high-dose-rate prostate brachytherapy (brachytherapy boost) and (2) 44 fractions of IMRT (IMRT alone). Each patient received 1 year of hormone therapy, per the ASCENDE-RT protocol. Model assumptions, including clinical outcomes, toxicity, and utilities were derived from the medical literature. Costs of radiation therapy were estimated using Medicare reimbursement data. RESULTS: The estimated expected lifetime cost of brachytherapy boost was $68,696, compared to $114,944 for IMRT alone. Brachytherapy boost significantly lowered expected lifetime treatment costs because it decreased the incidence of metastatic castration-resistant prostate cancer, cutting the use of expensive targeted therapy for metastatic castration-resistant prostate cancer. Brachytherapy boost had an expected quality-adjusted life years of 10.8 years, compared to 9.3 years for IMRT alone. One-way sensitivity analyses of our results found brachytherapy boost to be cost-effective over a wide range of cost, utility, and cancer progression rate assumptions. CONCLUSIONS: IMRT with high-dose-rate brachytherapy boost is a cost-effective treatment for intermediate-high risk prostate cancer compared to IMRT alone. Ó 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Cost-effectiveness; Brachytherapy boost; Prostate; Radiation therapy
Introduction Evidence is mounting that patients with localized prostate cancer with aggressive features stand to benefit both
Received 1 May 2018; received in revised form 28 June 2018; accepted 3 July 2018. Conflict of interest: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. This work was presented in part as an oral presentation at ASTRO 2017 in San Diego, CA. * Corresponding author. Department of Radiation Oncology, Beaumont Health, 3577 W. 13 Mile Road, Royal Oak, MI 48073. Tel.: þ1248-551-7038; fax: þ1-248-551-0089. E-mail address: [email protected] (D.J. Krauss).
clinically and biochemically from the addition of a brachytherapy boost. Both external beam radiation therapy (EBRT) alone and EBRT in conjunction with a brachytherapy (either low-dose-rate [LDR] or high-dose-rate [HDR]) boost constitute standard treatment options for patients with intermediate-high risk prostate cancer. Publication of single-institutional analyses (1, 2) and the ASCENDE-RT randomized clinical trial (3) demonstrated improved biochemical control with a brachytherapy boost compared with an external beam radiation boost. However, brachytherapy boost has been associated with increased genitourinary toxicity, with the ASCENDE-RT trial reporting an increased incidence of late grade 3 genitourinary toxicity in the brachytherapy boost arm (4).
1538-4721/$ - see front matter Ó 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.brachy.2018.07.009
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Health care costs currently represent 17.9% of U.S. gross domestic product (5). It is estimated that the national costs of prostate cancer care in the United States will be $15e20 billion in 2020 (6). Therefore, it is important to be cognizant of the value proposition of different modes of cancer care. In this analysis, we evaluate the costeffectiveness of brachytherapy boost compared with definitive intensity-modulated radiation therapy (IMRT) for intermediate-high risk prostate cancer. Methods and materials
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metastatic hormone-resistant prostate cancer (mCRPC) state. The risk of progression on ADT was estimated from the NCIC PR.7 clinical trial (7). From the hormone-resistant metastatic prostate cancer state, the patient would be treated with systemic therapy and progress to prostate cancer death using a transition probability estimated from the expected overall survival for patients with hormone-resistant metastatic prostate cancer (8, 9). From the localized prostate cancer and recurrent prostate cancer states, patients can also progress to the dead state because of noncancer death.
Model construction A multistate Markov transition model was formulated for the treatment of intermediate-high risk prostate cancer (Fig. 1). All patients begin in the localized prostate cancer state and receive one of two treatment modalities: (1) Forty-four fractions of IMRT (IMRT alone), or (2) Twenty-three fractions of IMRT and two fractions of HDR prostate brachytherapy delivered in two implants (brachytherapy boost) according to our current institutional standard. Each patient received 1 year of hormone therapy, as per the ASCENDE-RT protocol (3). Following localized prostate cancer treatment, the patient then progresses through the Markov model. During each time step (1 year), the patient could stay in the localized prostate cancer state, or progress to the recurrent cancer state. The transition probability between the localized and recurrent cancer state was estimated from the 9-year biochemical progressionfree survival rate reported in the ASCENDE-RT trial for each radiation treatment modality (3). In the recurrent prostate cancer state, the patient will receive continuous androgen deprivation therapy (ADT) until progression. For this analysis, the patient is treated with ADT and not salvage treatment modalities. If the patient progresses on ADT, they will progress to the
Data sources Table 1 summarizes the key model assumptions in our Markov model. Outcomes and toxicity data for the brachytherapy boost and IMRT alone treatment approaches were derived from the ASCENDE-RT randomized clinical trial (3, 4). These results are concordant with our institution’s retrospective matched-pair analysis of patients receiving a prostate HDR brachytherapy boost versus IMRT (14), as well as a single-institution randomized controlled trial of an HDR brachytherapy boost versus EBRT (2). Using randomized clinical trials, we estimated the annual hazard rates to be used in the model. The risk of noncancer death was estimated from the overall survival and prostate cancer death rates in the ASCENDE-RT and NCIC PR.7 trials (3, 7). Costs of local treatment (IMRT, HDR brachytherapy), hormone therapy, and additional salvage systemic therapies were included in the analysis. For the radiation treatment modalities, radiation costs were estimated from the Healthcare Common Procedure Coding System codes along with Medicare reimbursements for those procedures. For brachytherapy procedures, only radiation oncology and hospital facility reimbursement were included in this analysis; payments for other services (e.g., urology, anesthesia) were unavailable. The associated costs of managing side effects of
Fig. 1. Multistate Markov decision model.
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Table 1 Key model assumptions Transition probabilities (annual)
Base case
Alt. case #1
Alt. case #2
Recurrence after IMRT alone (3) Recurrence after brachytherapy boost (3) Progression after hormones (7) Death from metastatic prostate cancer (8, 9) Noncancer death with localized disease (3) Noncancer death with recurrent disease (7) Toxicity (4) IMRT alone Erectile dysfunction Rectal Urinary Brachy boost Erectile dysfunction Rectal Urinary Utilities (10) Localized prostate cancer Recurrent prostate cancer Metastatic prostate cancer Erectile dysfunction Rectal toxicity Urinary toxicity Costs IMRT alone (Medicare) Brachytherapy boost (Medicare) Rectal toxicity (11) Urinary toxicity (11) Erectile dysfunction (11) Androgen deprivation therapy (12) Systemic treatment for metastatic hormone-resistant prostate cancer (13)
5.0% 2.0% 6.9% 21.2% 2.0% 4.0%
5.0% 3.5% 6.9% 21.2% 2.0% 4.0%
5.0% 1.0% 6.9% 21.2% 2.0% 4.0%
62.9% 3.2% 5.2%
62.9% 3.2% 5.2%
62.9% 3.2% 5.2%
55.0% 8.1% 18.4%
70.0% 12% 25%
45.0% 3% 10%
81% 67% 25% 89% 71% 88%
81% 67% 25% 89% 71% 88%
81% 67% 25% 89% 71% 88%
$ $ $ $ $ $ $
$20,000 $40,000 $ 2,627 $ 1,068 $ 2,366 $ 4,995 $ 58,428
$30,000 $15,000 $ 2,627 $ 1,068 $ 2,366 $ 4,995 $ 58,428
31,747 21,090 2,627 1,068 2,366 4,995 58,428
Alt 5 alternative; IMRT 5 intensity-modulated radiation therapy.
local therapy are included in the model (11). The costs of systemic treatment for metastatic disease were derived from the expected annual cost of abiraterone (13). Utilities for the various treatment states (localized prostate cancer, recurrent prostate cancer, hormone-resistant prostate cancer) were defined from Stewart et al. (10). In addition, toxicity (sexual, rectal, or urinary) was modeled, with the utility at a given state defined as Utilitystate 5 Utilitytoxicity Utilitycancerstatus. Although the onset of side effects, with its associated costs, can occur years after the original radiation, all costs and decreases in utility were assumed to occur at the time of treatment for model simplicity. Statistical analysis First, the quality-adjusted life-years (QALYs) and expected lifetime costs of treatment were calculated for the two treatment options under the base case assumptions. We also calculated QALYs and expected lifetime costs of treatment under two alternative sets of assumptions (Table 1). One-way sensitivity analyses were performed for all variables (assumptions for the one-way sensitivity analyses are included in Supplementary Table 1). A tornado diagram was created to visualize the net monetary benefit
(NMB) of brachytherapy boost compared to IMRT for the one-way sensitivity analyses, assuming a threshold value for cost-effectiveness of $50,000/QALY. The cost-effectiveness analyses were performed using TreeAge Pro Healthcare version 17.1 (Williamstown, MA). The total number of cycles in the Markov model was 40. A discount rate of 3% was applied to both costs and utilities.
Results Cost-effectiveness analysis: base case The estimated expected lifetime cost of brachytherapy boost was $68,696, compared to $114,944 for IMRT alone. Brachytherapy boost significantly reduced expected lifetime costs because it decreased the incidence of recurrent prostate cancer and mCRPC, reducing the use of expensive targeted therapy for mCRPC. Brachytherapy boost had an expected QALY of 10.8 years, compared to 9.3 years for IMRT alone (Fig. 2). Because brachytherapy boost had lower expected lifetime costs and a higher expected number of QALYs, it is a dominant treatment strategy over IMRT alone in the base case.
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Fig. 2. Cost-effectiveness analysis comparing brachytherapy boost and IMRT alone: base case. IMRT 5 intensity-modulated radiation therapy; QALY 5 quality-adjusted life-year.
Cost-effectiveness analysis: alternative case assumptions In alternative case #1, we used a set of assumptions, when compared to the base case, that were designed to favor IMRT. The annual probability of disease progression of brachytherapy boost was increased from 2% to 3.5% (compared with 5% for IMRT), the toxicity of brachytherapy boost was increased above those reported in the ASCENDE-RT trial, and brachytherapy boost was assumed to be double the cost of IMRT. In this conservative scenario, brachytherapy boost was still a cost-effective approach over IMRT. The estimated expected lifetime cost of brachytherapy boost was $106,143 compared to $102,238 for IMRT alone, while brachytherapy boost had an expected QALY of 9.49 years compared to 9.30 years for IMRT alone. The incremental cost-effectiveness ratio (ICER) was $19,851/QALY, lower than the generally accepted ICER threshold of $50,000/QALY. In alternative case #2, we used a set of assumptions designed to favor brachytherapy boost. The annual probability of disease progression of brachytherapy boost was lowered from 2% to 1% (compared with 5% for IMRT), the toxicity of brachytherapy boost was decreased, and IMRT was assumed to be double the cost of brachytherapy boost. The benefits of brachytherapy boost increased in this case scenario. The estimated expected lifetime cost of brachytherapy boost was $42,817 compared to $111,738 for IMRT alone, while brachytherapy boost had an expected QALY of 12.07 years compared to 9.30 years for IMRT alone. One-way sensitivity analysis On one-way sensitivity analysis, the only parameters that would make IMRT a cost-effective strategy over
brachytherapy boost would be the probability of recurrence after IMRT (NMB $28,361 to $181,401) or brachytherapy boost (NMB $60,605 to $151,789). Figure 3 shows the tornado diagram of one-way sensitivity analyses for our model. Using a threshold analysis and an ICER threshold of $50,000/QALY, the annual probability of progression with IMRT would have to be 2% or less (compared with 2% for brachytherapy boost), or the annual probability of progression with brachytherapy boost would have to be greater than 5% (compared with 5% for IMRT) for IMRT to be cost-effective. Other than the probabilities of progression after local treatment, the variables that are most sensitive in the model were the localized cancer utility after brachytherapy boost (NMB $72,576 to $203,533), the probability of noncancer death from localized cancer (NMB $36,119 to $149,025), and the localized cancer utility after IMRT (NMB $73,514 to $165,048). For all of these variables, brachytherapy boost was a cost-effective treatment strategy even using the most conservative assumptions.
Discussion In this study, we demonstrated that HDR brachytherapy boost is a cost-effective treatment strategy compared to external beam boost in patients with intermediate-high risk prostate cancer. This conclusion was robust, with one-way sensitivity analyses showing brachytherapy boost to be cost-effective over a wide range of assumptions. Even with the assumption of it being a more toxic treatment, brachytherapy boost gives patients higher QALYs at a lower lifetime cost than external beam boost because it reduces the risk of recurrence. With fewer recurrences, patients are able
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Fig. 3. Tornado diagram of one-way sensitivity analyses. ADT 5 androgen deprivation therapy; BB 5 brachytherapy boost; IMRT 5 intensity-modulated radiation therapy; mCRPC 5 metastatic castrate-resistant prostate cancer.
to live more of their lives without recurrent or metastatic disease, which have lower utilities than the localized disease state. Furthermore, patients who received brachytherapy boost were less likely to pay the costs of long-term hormonal treatment or expensive systemic treatment for metastatic prostate cancer because of the decreased risk of progression. Based on the results of currently available clinical trials, including the ASCENDE-RT trial, a joint guideline from the American Society of Clinical Oncology and Cancer Care Ontario was published in 2017 stating that brachytherapy boost should be offered to eligible patients with highrisk prostate cancer (15). Long-term data are not yet available from the ASCENDE-RT trial; the median followup on the ASCENDE-RT was 6.5 years. It is possible that a brachytherapy boost provides a biochemical control benefit but not an overall survival benefit. However, it is cost-effective to give brachytherapy boost in eligible intermediate-high risk patients because it reduces recurrences and its high subsequent salvage treatment costs. There are examples in other disease sites where local treatments are cost-effective although they have not been shown to provide a survival benefit. Sen et al. studied the costeffectiveness of adjuvant whole-breast radiation therapy in favorable early-stage breast cancer patients who would also be candidates for observation (16). In these patients, adjuvant whole-breast radiation therapy was found to be cost-effective, particularly in patients with longer life expectancies.
There are emerging data that some patients with relapse following radiation therapy from prostate cancer may benefit from additional systemic therapies to ADT. The first report from the STAMPEDE multiarm, multistage clinical trial showed that docetaxel plus ADT improved overall survival compared to ADT alone in metastatic prostate cancer (17). A second report from the STAMPEDE trial showed that the addition of abiraterone to standard androgen suppression provided an overall survival benefit for patients with metastatic castration-sensitive prostate cancer (18). If the use of docetaxel, abiraterone, or other systemic therapies becomes routine for patients with recurrent prostate cancer following radiotherapy, there will be an even greater importance placed on maximizing local control with initial treatment from a costeffectiveness perspective. There are several limitations of our cost-effectiveness analysis. Our model used HDR brachytherapy, while the ASCENDE-RT clinical trial used LDR brachytherapy. Our matched-pair single-institutional comparison of HDR brachytherapy boost and EBRT alone was concordant with the ASCENDE-RT trial results, finding brachytherapy boost to not only improve biochemical control but also increase toxicity (14). In addition, Hoskin et al. reported a single-institution randomized controlled trial of EBRT alone or combined with an HDR brachytherapy boost and found improved relapse-free survival, but no improvement in overall survival, from an HDR brachytherapy boost (2). Because of the relatively small difference in costs,
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we believe that our model’s conclusions are valid for brachytherapy boosts delivered by HDR or LDR. As in any cost-effectiveness analysis, individual patients will assign different utilities to the various prostate cancer disease states and toxicities of radiation treatment than those used in our base case assumptions (19). Our results showed brachytherapy boost to be cost-effective over a wide range of toxicity and utility assumptions, but a patient who strongly values minimizing toxicity over improvement in biochemical control may still prefer an external beam boost over a brachytherapy boost. Conclusions In conclusion, we found that brachytherapy boost is a cost-effective treatment compared to EBRT alone. Therefore, brachytherapy boost should be offered to all eligible patients with intermediate-high risk prostate cancer. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.brachy.2018.07.009. References [1] Shilkrut M, Merrick GS, McLaughlin PW, et al. The addition of lowdose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with doseescalated external-beam radiation therapy for high-risk prostate cancer. Cancer 2013;119:681e690. [2] Hoskin PJ, Rojas AM, Bownes PJ, et al. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012; 103:217e222. [3] Morris WJ, Tyldesley S, Rodda S, et al. Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT Trial): an analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a doseescalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol 2017;98:275e285. [4] Rodda S, Tyldesley S, Morris WJ, et al. ASCENDE-RT: an analysis of treatment-related morbidity for a randomized trial comparing a low-dose-rate brachytherapy boost with a dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol 2017;98:286e295.
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[5] Centers for Medicare and Medicaid Services. Historical. Available at: https://www.cms.gov/Research-Statistics-Data-and-Systems/StatisticsTrends-and-Reports/NationalHealthExpendData/NationalHealthAccounts Historical.html. Accessed January 11, 2018. [6] Mariotto AB, Robin Yabroff K, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010e2020. J Natl Cancer Inst 2011;103:117e128. [7] Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA Level after radiotherapy. N Engl J Med 2012;367:895e903. [8] Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015;16:152e160. [9] Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-na€ıve metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL Study. Eur Urol 2017;71:151e154. [10] Stewart ST, Lenert L, Bhatnagar V, et al. Utilities for prostate cancer health states in men aged 60 and older. Med Care 2005;43:347e355. [11] Sher DJ, Parikh RB, Mays-Jackson S, et al. Cost-effectiveness analysis of SBRT versus IMRT for low-risk prostate cancer. Am J Clin Oncol 2014;37:215e221. [12] Bayoumi AM, Brown AD, Garber AM. Cost-Effectiveness of Androgen Suppression Therapies in Advanced Prostate Cancer. J Natl Cancer Inst 2000;92:1731e1739. [13] Gong CL, Hay JW. Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer. J Natl Compr Canc Netw 2014;12:1417e1425. [14] Blas KG, Brown ME, Wallace M, et al. A Matched Comparison of High-Risk Prostate Cancer Patients Treated With Dose-Escalated, Image Guided Adaptive External Beam Radiation Therapy (EBRT) Versus Pelvic EBRT Plus High-Dose-Rate Brachytherapy Boost. Int J Radiat Oncol Biol Phys 2015;93:S121eS122. [15] Chin J, Rumble RB, Kollmeier M, et al. Brachytherapy for patients with prostate cancer: American society of clinical oncology/cancer care Ontario joint guideline update. J Clin Oncol 2017;35:1737e1743. [16] Sen S, Wang S-Y, Soulos PR, et al. Examining the cost-effectiveness of radiation therapy among older women with favorable-risk breast cancer. J Natl Cancer Inst 2014;106:dju008. [17] James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387:1163e1177. [18] James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017;377:338e351. [19] Deshmukh AA, Shirvani SM, Lal L, et al. Cost-effectiveness analysis comparing conventional, hypofractionated, and intraoperative radiotherapy for early-stage breast cancer. J Natl Cancer Inst 2017;109.
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Cost-effectiveness of prostate boost with high-dose-rate brachytherapy versus intensity-modulated radiation therapy in the treatment of intermediate-high risk prostate cancer Charles C. Vu1, Kevin G. Blas1, Thomas B. Lanni2, Gary S. Gustafson3, Daniel J. Krauss1,* 1
Department of Radiation Oncology, Beaumont Health, Royal Oak, MI Department of Radiation Oncology, Beaumont Health, Dearborn, MI 3 Department of Radiation Oncology, Beaumont Health, Troy, MI
2
ABSTRACT
PURPOSE: The recently published ASCENDE-RT randomized clinical trial demonstrated improved biochemical control, albeit with increased toxicity, for a prostate boost with brachytherapy versus external beam radiation therapy alone in patients with intermediate-high risk prostate cancer. In this study, we investigated the cost-effectiveness of these two modalities in the treatment of intermediate-high risk prostate cancer. METHODS AND MATERIALS: A multistate Markov model was created to model a patient with intermediate-high risk prostate cancer. The two treatment options modeled were (1) 23 fractions of intensity-modulated radiation therapy (IMRT) and two fractions of high-dose-rate prostate brachytherapy (brachytherapy boost) and (2) 44 fractions of IMRT (IMRT alone). Each patient received 1 year of hormone therapy, per the ASCENDE-RT protocol. Model assumptions, including clinical outcomes, toxicity, and utilities were derived from the medical literature. Costs of radiation therapy were estimated using Medicare reimbursement data. RESULTS: The estimated expected lifetime cost of brachytherapy boost was $68,696, compared to $114,944 for IMRT alone. Brachytherapy boost significantly lowered expected lifetime treatment costs because it decreased the incidence of metastatic castration-resistant prostate cancer, cutting the use of expensive targeted therapy for metastatic castration-resistant prostate cancer. Brachytherapy boost had an expected quality-adjusted life years of 10.8 years, compared to 9.3 years for IMRT alone. One-way sensitivity analyses of our results found brachytherapy boost to be cost-effective over a wide range of cost, utility, and cancer progression rate assumptions. CONCLUSIONS: IMRT with high-dose-rate brachytherapy boost is a cost-effective treatment for intermediate-high risk prostate cancer compared to IMRT alone. Ó 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Cost-effectiveness; Brachytherapy boost; Prostate; Radiation therapy
Introduction Evidence is mounting that patients with localized prostate cancer with aggressive features stand to benefit both
Received 1 May 2018; received in revised form 28 June 2018; accepted 3 July 2018. Conflict of interest: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. This work was presented in part as an oral presentation at ASTRO 2017 in San Diego, CA. * Corresponding author. Department of Radiation Oncology, Beaumont Health, 3577 W. 13 Mile Road, Royal Oak, MI 48073. Tel.: þ1248-551-7038; fax: þ1-248-551-0089. E-mail address: [email protected] (D.J. Krauss).
clinically and biochemically from the addition of a brachytherapy boost. Both external beam radiation therapy (EBRT) alone and EBRT in conjunction with a brachytherapy (either low-dose-rate [LDR] or high-dose-rate [HDR]) boost constitute standard treatment options for patients with intermediate-high risk prostate cancer. Publication of single-institutional analyses (1, 2) and the ASCENDE-RT randomized clinical trial (3) demonstrated improved biochemical control with a brachytherapy boost compared with an external beam radiation boost. However, brachytherapy boost has been associated with increased genitourinary toxicity, with the ASCENDE-RT trial reporting an increased incidence of late grade 3 genitourinary toxicity in the brachytherapy boost arm (4).
1538-4721/$ - see front matter Ó 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.brachy.2018.07.009
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Health care costs currently represent 17.9% of U.S. gross domestic product (5). It is estimated that the national costs of prostate cancer care in the United States will be $15e20 billion in 2020 (6). Therefore, it is important to be cognizant of the value proposition of different modes of cancer care. In this analysis, we evaluate the costeffectiveness of brachytherapy boost compared with definitive intensity-modulated radiation therapy (IMRT) for intermediate-high risk prostate cancer. Methods and materials
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(2018)
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metastatic hormone-resistant prostate cancer (mCRPC) state. The risk of progression on ADT was estimated from the NCIC PR.7 clinical trial (7). From the hormone-resistant metastatic prostate cancer state, the patient would be treated with systemic therapy and progress to prostate cancer death using a transition probability estimated from the expected overall survival for patients with hormone-resistant metastatic prostate cancer (8, 9). From the localized prostate cancer and recurrent prostate cancer states, patients can also progress to the dead state because of noncancer death.
Model construction A multistate Markov transition model was formulated for the treatment of intermediate-high risk prostate cancer (Fig. 1). All patients begin in the localized prostate cancer state and receive one of two treatment modalities: (1) Forty-four fractions of IMRT (IMRT alone), or (2) Twenty-three fractions of IMRT and two fractions of HDR prostate brachytherapy delivered in two implants (brachytherapy boost) according to our current institutional standard. Each patient received 1 year of hormone therapy, as per the ASCENDE-RT protocol (3). Following localized prostate cancer treatment, the patient then progresses through the Markov model. During each time step (1 year), the patient could stay in the localized prostate cancer state, or progress to the recurrent cancer state. The transition probability between the localized and recurrent cancer state was estimated from the 9-year biochemical progressionfree survival rate reported in the ASCENDE-RT trial for each radiation treatment modality (3). In the recurrent prostate cancer state, the patient will receive continuous androgen deprivation therapy (ADT) until progression. For this analysis, the patient is treated with ADT and not salvage treatment modalities. If the patient progresses on ADT, they will progress to the
Data sources Table 1 summarizes the key model assumptions in our Markov model. Outcomes and toxicity data for the brachytherapy boost and IMRT alone treatment approaches were derived from the ASCENDE-RT randomized clinical trial (3, 4). These results are concordant with our institution’s retrospective matched-pair analysis of patients receiving a prostate HDR brachytherapy boost versus IMRT (14), as well as a single-institution randomized controlled trial of an HDR brachytherapy boost versus EBRT (2). Using randomized clinical trials, we estimated the annual hazard rates to be used in the model. The risk of noncancer death was estimated from the overall survival and prostate cancer death rates in the ASCENDE-RT and NCIC PR.7 trials (3, 7). Costs of local treatment (IMRT, HDR brachytherapy), hormone therapy, and additional salvage systemic therapies were included in the analysis. For the radiation treatment modalities, radiation costs were estimated from the Healthcare Common Procedure Coding System codes along with Medicare reimbursements for those procedures. For brachytherapy procedures, only radiation oncology and hospital facility reimbursement were included in this analysis; payments for other services (e.g., urology, anesthesia) were unavailable. The associated costs of managing side effects of
Fig. 1. Multistate Markov decision model.
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Table 1 Key model assumptions Transition probabilities (annual)
Base case
Alt. case #1
Alt. case #2
Recurrence after IMRT alone (3) Recurrence after brachytherapy boost (3) Progression after hormones (7) Death from metastatic prostate cancer (8, 9) Noncancer death with localized disease (3) Noncancer death with recurrent disease (7) Toxicity (4) IMRT alone Erectile dysfunction Rectal Urinary Brachy boost Erectile dysfunction Rectal Urinary Utilities (10) Localized prostate cancer Recurrent prostate cancer Metastatic prostate cancer Erectile dysfunction Rectal toxicity Urinary toxicity Costs IMRT alone (Medicare) Brachytherapy boost (Medicare) Rectal toxicity (11) Urinary toxicity (11) Erectile dysfunction (11) Androgen deprivation therapy (12) Systemic treatment for metastatic hormone-resistant prostate cancer (13)
5.0% 2.0% 6.9% 21.2% 2.0% 4.0%
5.0% 3.5% 6.9% 21.2% 2.0% 4.0%
5.0% 1.0% 6.9% 21.2% 2.0% 4.0%
62.9% 3.2% 5.2%
62.9% 3.2% 5.2%
62.9% 3.2% 5.2%
55.0% 8.1% 18.4%
70.0% 12% 25%
45.0% 3% 10%
81% 67% 25% 89% 71% 88%
81% 67% 25% 89% 71% 88%
81% 67% 25% 89% 71% 88%
$ $ $ $ $ $ $
$20,000 $40,000 $ 2,627 $ 1,068 $ 2,366 $ 4,995 $ 58,428
$30,000 $15,000 $ 2,627 $ 1,068 $ 2,366 $ 4,995 $ 58,428
31,747 21,090 2,627 1,068 2,366 4,995 58,428
Alt 5 alternative; IMRT 5 intensity-modulated radiation therapy.
local therapy are included in the model (11). The costs of systemic treatment for metastatic disease were derived from the expected annual cost of abiraterone (13). Utilities for the various treatment states (localized prostate cancer, recurrent prostate cancer, hormone-resistant prostate cancer) were defined from Stewart et al. (10). In addition, toxicity (sexual, rectal, or urinary) was modeled, with the utility at a given state defined as Utilitystate 5 Utilitytoxicity Utilitycancerstatus. Although the onset of side effects, with its associated costs, can occur years after the original radiation, all costs and decreases in utility were assumed to occur at the time of treatment for model simplicity. Statistical analysis First, the quality-adjusted life-years (QALYs) and expected lifetime costs of treatment were calculated for the two treatment options under the base case assumptions. We also calculated QALYs and expected lifetime costs of treatment under two alternative sets of assumptions (Table 1). One-way sensitivity analyses were performed for all variables (assumptions for the one-way sensitivity analyses are included in Supplementary Table 1). A tornado diagram was created to visualize the net monetary benefit
(NMB) of brachytherapy boost compared to IMRT for the one-way sensitivity analyses, assuming a threshold value for cost-effectiveness of $50,000/QALY. The cost-effectiveness analyses were performed using TreeAge Pro Healthcare version 17.1 (Williamstown, MA). The total number of cycles in the Markov model was 40. A discount rate of 3% was applied to both costs and utilities.
Results Cost-effectiveness analysis: base case The estimated expected lifetime cost of brachytherapy boost was $68,696, compared to $114,944 for IMRT alone. Brachytherapy boost significantly reduced expected lifetime costs because it decreased the incidence of recurrent prostate cancer and mCRPC, reducing the use of expensive targeted therapy for mCRPC. Brachytherapy boost had an expected QALY of 10.8 years, compared to 9.3 years for IMRT alone (Fig. 2). Because brachytherapy boost had lower expected lifetime costs and a higher expected number of QALYs, it is a dominant treatment strategy over IMRT alone in the base case.
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Fig. 2. Cost-effectiveness analysis comparing brachytherapy boost and IMRT alone: base case. IMRT 5 intensity-modulated radiation therapy; QALY 5 quality-adjusted life-year.
Cost-effectiveness analysis: alternative case assumptions In alternative case #1, we used a set of assumptions, when compared to the base case, that were designed to favor IMRT. The annual probability of disease progression of brachytherapy boost was increased from 2% to 3.5% (compared with 5% for IMRT), the toxicity of brachytherapy boost was increased above those reported in the ASCENDE-RT trial, and brachytherapy boost was assumed to be double the cost of IMRT. In this conservative scenario, brachytherapy boost was still a cost-effective approach over IMRT. The estimated expected lifetime cost of brachytherapy boost was $106,143 compared to $102,238 for IMRT alone, while brachytherapy boost had an expected QALY of 9.49 years compared to 9.30 years for IMRT alone. The incremental cost-effectiveness ratio (ICER) was $19,851/QALY, lower than the generally accepted ICER threshold of $50,000/QALY. In alternative case #2, we used a set of assumptions designed to favor brachytherapy boost. The annual probability of disease progression of brachytherapy boost was lowered from 2% to 1% (compared with 5% for IMRT), the toxicity of brachytherapy boost was decreased, and IMRT was assumed to be double the cost of brachytherapy boost. The benefits of brachytherapy boost increased in this case scenario. The estimated expected lifetime cost of brachytherapy boost was $42,817 compared to $111,738 for IMRT alone, while brachytherapy boost had an expected QALY of 12.07 years compared to 9.30 years for IMRT alone. One-way sensitivity analysis On one-way sensitivity analysis, the only parameters that would make IMRT a cost-effective strategy over
brachytherapy boost would be the probability of recurrence after IMRT (NMB $28,361 to $181,401) or brachytherapy boost (NMB $60,605 to $151,789). Figure 3 shows the tornado diagram of one-way sensitivity analyses for our model. Using a threshold analysis and an ICER threshold of $50,000/QALY, the annual probability of progression with IMRT would have to be 2% or less (compared with 2% for brachytherapy boost), or the annual probability of progression with brachytherapy boost would have to be greater than 5% (compared with 5% for IMRT) for IMRT to be cost-effective. Other than the probabilities of progression after local treatment, the variables that are most sensitive in the model were the localized cancer utility after brachytherapy boost (NMB $72,576 to $203,533), the probability of noncancer death from localized cancer (NMB $36,119 to $149,025), and the localized cancer utility after IMRT (NMB $73,514 to $165,048). For all of these variables, brachytherapy boost was a cost-effective treatment strategy even using the most conservative assumptions.
Discussion In this study, we demonstrated that HDR brachytherapy boost is a cost-effective treatment strategy compared to external beam boost in patients with intermediate-high risk prostate cancer. This conclusion was robust, with one-way sensitivity analyses showing brachytherapy boost to be cost-effective over a wide range of assumptions. Even with the assumption of it being a more toxic treatment, brachytherapy boost gives patients higher QALYs at a lower lifetime cost than external beam boost because it reduces the risk of recurrence. With fewer recurrences, patients are able
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Fig. 3. Tornado diagram of one-way sensitivity analyses. ADT 5 androgen deprivation therapy; BB 5 brachytherapy boost; IMRT 5 intensity-modulated radiation therapy; mCRPC 5 metastatic castrate-resistant prostate cancer.
to live more of their lives without recurrent or metastatic disease, which have lower utilities than the localized disease state. Furthermore, patients who received brachytherapy boost were less likely to pay the costs of long-term hormonal treatment or expensive systemic treatment for metastatic prostate cancer because of the decreased risk of progression. Based on the results of currently available clinical trials, including the ASCENDE-RT trial, a joint guideline from the American Society of Clinical Oncology and Cancer Care Ontario was published in 2017 stating that brachytherapy boost should be offered to eligible patients with highrisk prostate cancer (15). Long-term data are not yet available from the ASCENDE-RT trial; the median followup on the ASCENDE-RT was 6.5 years. It is possible that a brachytherapy boost provides a biochemical control benefit but not an overall survival benefit. However, it is cost-effective to give brachytherapy boost in eligible intermediate-high risk patients because it reduces recurrences and its high subsequent salvage treatment costs. There are examples in other disease sites where local treatments are cost-effective although they have not been shown to provide a survival benefit. Sen et al. studied the costeffectiveness of adjuvant whole-breast radiation therapy in favorable early-stage breast cancer patients who would also be candidates for observation (16). In these patients, adjuvant whole-breast radiation therapy was found to be cost-effective, particularly in patients with longer life expectancies.
There are emerging data that some patients with relapse following radiation therapy from prostate cancer may benefit from additional systemic therapies to ADT. The first report from the STAMPEDE multiarm, multistage clinical trial showed that docetaxel plus ADT improved overall survival compared to ADT alone in metastatic prostate cancer (17). A second report from the STAMPEDE trial showed that the addition of abiraterone to standard androgen suppression provided an overall survival benefit for patients with metastatic castration-sensitive prostate cancer (18). If the use of docetaxel, abiraterone, or other systemic therapies becomes routine for patients with recurrent prostate cancer following radiotherapy, there will be an even greater importance placed on maximizing local control with initial treatment from a costeffectiveness perspective. There are several limitations of our cost-effectiveness analysis. Our model used HDR brachytherapy, while the ASCENDE-RT clinical trial used LDR brachytherapy. Our matched-pair single-institutional comparison of HDR brachytherapy boost and EBRT alone was concordant with the ASCENDE-RT trial results, finding brachytherapy boost to not only improve biochemical control but also increase toxicity (14). In addition, Hoskin et al. reported a single-institution randomized controlled trial of EBRT alone or combined with an HDR brachytherapy boost and found improved relapse-free survival, but no improvement in overall survival, from an HDR brachytherapy boost (2). Because of the relatively small difference in costs,
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we believe that our model’s conclusions are valid for brachytherapy boosts delivered by HDR or LDR. As in any cost-effectiveness analysis, individual patients will assign different utilities to the various prostate cancer disease states and toxicities of radiation treatment than those used in our base case assumptions (19). Our results showed brachytherapy boost to be cost-effective over a wide range of toxicity and utility assumptions, but a patient who strongly values minimizing toxicity over improvement in biochemical control may still prefer an external beam boost over a brachytherapy boost. Conclusions In conclusion, we found that brachytherapy boost is a cost-effective treatment compared to EBRT alone. Therefore, brachytherapy boost should be offered to all eligible patients with intermediate-high risk prostate cancer. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.brachy.2018.07.009. References [1] Shilkrut M, Merrick GS, McLaughlin PW, et al. The addition of lowdose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with doseescalated external-beam radiation therapy for high-risk prostate cancer. Cancer 2013;119:681e690. [2] Hoskin PJ, Rojas AM, Bownes PJ, et al. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012; 103:217e222. [3] Morris WJ, Tyldesley S, Rodda S, et al. Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT Trial): an analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a doseescalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol 2017;98:275e285. [4] Rodda S, Tyldesley S, Morris WJ, et al. ASCENDE-RT: an analysis of treatment-related morbidity for a randomized trial comparing a low-dose-rate brachytherapy boost with a dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol 2017;98:286e295.
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[5] Centers for Medicare and Medicaid Services. Historical. Available at: https://www.cms.gov/Research-Statistics-Data-and-Systems/StatisticsTrends-and-Reports/NationalHealthExpendData/NationalHealthAccounts Historical.html. Accessed January 11, 2018. [6] Mariotto AB, Robin Yabroff K, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010e2020. J Natl Cancer Inst 2011;103:117e128. [7] Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA Level after radiotherapy. N Engl J Med 2012;367:895e903. [8] Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015;16:152e160. [9] Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-na€ıve metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL Study. Eur Urol 2017;71:151e154. [10] Stewart ST, Lenert L, Bhatnagar V, et al. Utilities for prostate cancer health states in men aged 60 and older. Med Care 2005;43:347e355. [11] Sher DJ, Parikh RB, Mays-Jackson S, et al. Cost-effectiveness analysis of SBRT versus IMRT for low-risk prostate cancer. Am J Clin Oncol 2014;37:215e221. [12] Bayoumi AM, Brown AD, Garber AM. Cost-Effectiveness of Androgen Suppression Therapies in Advanced Prostate Cancer. J Natl Cancer Inst 2000;92:1731e1739. [13] Gong CL, Hay JW. Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer. J Natl Compr Canc Netw 2014;12:1417e1425. [14] Blas KG, Brown ME, Wallace M, et al. A Matched Comparison of High-Risk Prostate Cancer Patients Treated With Dose-Escalated, Image Guided Adaptive External Beam Radiation Therapy (EBRT) Versus Pelvic EBRT Plus High-Dose-Rate Brachytherapy Boost. Int J Radiat Oncol Biol Phys 2015;93:S121eS122. [15] Chin J, Rumble RB, Kollmeier M, et al. Brachytherapy for patients with prostate cancer: American society of clinical oncology/cancer care Ontario joint guideline update. J Clin Oncol 2017;35:1737e1743. [16] Sen S, Wang S-Y, Soulos PR, et al. Examining the cost-effectiveness of radiation therapy among older women with favorable-risk breast cancer. J Natl Cancer Inst 2014;106:dju008. [17] James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387:1163e1177. [18] James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017;377:338e351. [19] Deshmukh AA, Shirvani SM, Lal L, et al. Cost-effectiveness analysis comparing conventional, hypofractionated, and intraoperative radiotherapy for early-stage breast cancer. J Natl Cancer Inst 2017;109.