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The Financial Impact of Hypofractionated Radiation for Localized Prostate Cancer in the United States

The Financial Impact of Hypofractionated Radiation for Localized Prostate Cancer in the United... Hindawi Journal of Oncology Volume 2019, Article ID 8170428, 8 pages https://doi.org/10.1155/2019/8170428 Research Article The Financial Impact of Hypofractionated Radiation for Localized Prostate Cancer in the United States 1,2 2 3 1 1,2 Assaf Moore , Ido Stav, Robert B. Den, Noa Gordon, Michal Sarfaty, 1,2 1,2 1,4 Victoria Neiman, Eli Rosenbaum, and Daniel A. Goldstein Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Radiation Oncology, Jeeff rson University, Philadelphia, PA, USA Department of Health Policy and Management, University of North Carolina, Chapel Hill, USA Correspondence should be addressed to Daniel A. Goldstein; danielagoldstein@gmail.com Received 21 October 2018; Revised 13 November 2018; Accepted 27 November 2018; Published 2 January 2019 Academic Editor: Reza Izadpanah Copyright © 2019 Assaf Moore et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Until recently, dose intensified radiotherapy was the standard radiation method for localized prostate cancer. Multiple studies have demonstrated similar efficacy and tolerability with moderate hypofractionation. In recent years there has been an increasing focus placed on understanding the cost and value of cancer care. In this study we aimed to assess the economic impact of moderate hypofractionation for payers in the United States. Methods. We performed a population-based analysis of the total cost of external beam radiotherapy (EBRT) for localized prostate cancer in the US annually. The national annual target population of patients treated with definitive EBRT was calculated using the Surveillance, Epidemiology, and End Results (SEER) database. Treatment costs for various fractionation schemes were based on billing codes and 2018 pricing by the Centers for Medicare and Medicaid Services (CMS). Results. We estimate that 27,146 patients with localized prostate cancer are treated with EBRT annually in the US. The cost of standard fractionation in 45 or 39 fractions is US$ 26,782 and 23,625 per patient, respectively. With moderate hypofractionation in 28 or 20 fractions, the cost is US$ 17,793 and 13,402 per patient, respectively. The use of moderate hypofractionation would lead to 25-50% annual savings US$158,315,472-US$363,213,480 in the US. Conclusions. Moderate hypofractionation may have the potential to save approximately US$0.16-0.36 billion annually, likely without impacting survival or tolerability. iTh s may lead to lower personal financial toxicity. It would be reasonable for public and private payers to consider which type of radiation is most suited to reimbursement. 1. Introduction whilesomemen mayhaveamoreaggressive courseof disease, others do not. Prostate cancer is the third most common cancer diagnosed Dose escalation studies in localized prostate cancer have in the US and represents 9.6% of all new cancer cases [1, 2]. demonstrated improved outcomes compared to lower doses In 2018, the American Cancer Society estimates that 164,690 [3–7]. In light of these n fi dings, the standard of care is to use a patients will be diagnosed with prostate cancer, and 29,430 dose of 75.6-81 Gy depending on the risk stratification group will succumb to their disease [2]. Seventy-nine percent of [8]. High biologically equivalent doses can be achieved with prostate cancer patients are diagnosed with localized disease, various fractionation schemes. One such way is moderate defined as a tumor that is confined to the primary site [1, 2]. In hypofractionation. The linear quadratic model uses the 𝛼 /𝛽 general, there are three treatment options: surgical resection, ratio to describe the varying effect of fraction size on cell radiation with or without hormonal therapy, and n fi ally active survival. The higher the ratio, the more “radiosensitive” the surveillance when appropriate. The choice of these options tumor. As prostate cancer is considered to have a low𝛼 /𝛽 is largely driven by disease risk status, age, and patient ratio, higher doses per fraction could potentially improve preferences. Localized prostate cancer is heterogeneous, and prostate cancer cell killing. Several observational reports 2 Journal of Oncology Table 1: Moderate hypofractionation trials. Trial Design pts randomized Patient population (NCCN) Fractionation and Total dose 5-year FFF rate 37 X 2Gy, 74GY 88.3% CHHiP Non-inferiority 3216 73% IR 20 X 3Gy, 60Gy 90.6% 19 X 3Gy, 57Gy 85.9% 39 X 2Gy, 78Gy 79% PROFIT Non-inferiority 1206 100% IR 20 X 3Gy, 60Gy 79% 3 41 X 1.8Gy, 73.8Gy 85.3% RTOG 0415 Non-inferiority 1092 100% LR 28 X 2.5Gy, 70Gy 86.3% 4 39 X 2Gy, 78GY 77% HYPRO Superiority 804 73% HR 19 X 3.4Gy, 64.6Gy 81% 38 X 2Gy, 76Gy 85% Pollack et al. Superiority 303 64% HR 26 X 2.7GY, 70.2Gy 81% 40 X 2Gy, 80Gy 79% Arcangeli et al. Superiority 168 76% HR 20 X 3.1Gy, 62Gy 85% 42 X 1.8Gy, 75.6GY 92% Hoffman et al Superiority 204 70% IR 30 X 2.4Gy, 72Gy 96% FFF: freedom from failure. IR: intermediate risk. LR: low risk. HR: high risk. of moderate hypofractionation demonstrated an acceptable patients who decline active surveillance, to men with inter- safety prole fi [9–11]. Following these reports were a series mediate risk prostate cancer with or without radiation to the of randomized controlled trials analyzing the safety and seminal vesicles, and to men with high risk prostate cancer ecffi acy of hypofractionated radiation compared to tradi- receiving EBRT to the prostate only [21]. tionally fractionated radiation for patients with localized In recent years there has been an increasing focus placed prostate cancer. These trials varied in design as well as having on understanding the cost and value of cancer care. This differing inclusion and exclusion criteria. While most trials has led to the development of various frameworks that included mainly low and intermediate risk patients [12–16], aim to understand value [22, 23]. However, the focus has some have focused on high risk [17–19]. In essence these predominantly been placed on the value of pharmaceutical studies found an equivalent level of efficacy and safety when interventions. There are however widespread opportunities using hypofractionated radiation [12–15] (Table 1). Moderate for improving value in other fields such as surgery, radiation, hypofractionation was not found to be superior to traditional and end-of-life care. Between 2010 and 2012, radiotherapy fractionation in terms of survival, [17–19] but was found to was the primary treatment among 23% and 33-36% of be noninferior to conventional fractionation for biochemical patients under 64 and over 64 years diagnosed with prostate control with similar overall and cancer specific survival [12– cancer, respectively [1]. 14] (Table 1). The objective of this study was to assess the difference Despite concerns for an increase in late toxicity with in cost from the payers’ perspective of the USA if all higher doses per fraction, most trials have not found a sta- patients currently treated with traditional radiation received tistically significant difference [13–15, 17, 18]. One exception moderately hypofractionated radiation. is RTOG 0415, where men assigned to hypofractionation had significantly more late grade 2 GI and GU toxicity (HR 1.59, 2. Methods p=0.005 and HR 1.31, p=0.009, respectively) [12]. Another exception is the HYPRO trial that used a 3.4 Gy dose per 2.1. Methodological Overview. We performed a population- fraction in the hypofractionated arm and found that the based budget impact analysis according to the guidelines set cumulative incidence of grade 3 or worse late GU toxicity was forth by the International Society of Pharmacoeconomics significantly higher (19% versus 12.9%, p=0.021) [19]. How- and Outcomes Research [24]. We performed the analysis ever, the most relevant index regarding toxicity is patient- from the payers’ perspective in the United States. The budget reported outcomes. These were found to be equivalent as impact model was developed using Matlab version R2016b seen in the 5-year patient-reported outcomes of the CHHiP (MathWorks, Inc.). trial [13, 14]. Another report found no statistically significant difference in long-term quality of life outcomes between conventional and hypofractionated treatment [20]. 2.2. Target Population. We used the Surveillance, Epidemi- In light of these accumulating data, the recent guideline ology, and End Results (SEER) database to estimate the update by ASTRO, ASCO, and AUA has determined that population of patients treated annually with EBRT. We moderate hypofractionation should be offered to low risk performed a frequency analysis on treatment with EBRT for Journal of Oncology 3 Table 2: CPT codes and prices, fractionation options, and costs. CPT Code, Description Price per Unit Number of Units 77301, IMRT treatment planning $2033.26 77263, treatment planning complex $170.64 77338, MLC design for IMRT $527.39 77300, Basic Dose Calculation $68.76 2 ∗∗ G6015, IMRT treatment delivery $358.00 By number of fractions ∗∗ 45 fx –9; 39 fx – 8; 77336, physics consult hour $82.80 28 fx – 6; 20 fx – 4 ∗∗ 77014, cone beam CT $122.40 By number of fractions ∗∗ 45 fx –9; 39 fx – 8; 77427, weekly treatment management $191.16 28 fx – 6; 20 fx – 4 Fractionation Scheme Cost per Patient 45 fractions $26,782 39 fractions $23,625 28 fractions $17,793 20 fractions $13,402 CPT: current procedural terminology. Intensity modulated radiotherapy. MLC: multileaf collimator. Fx: fractions. The total price per code includes the professional component and technical charge when applicable. ∗∗ Number of unitsvariesby treatment duration. localized prostate cancer in the latest year summarized in the impact on cost savings. A probabilistic sensitivity analysis was SEER cancer statistics, 2014. We excluded all patients who performed using a Monte Carlo Simulation. The model was were treated with a combination of EBRT and brachytherapy, run 100,000 times, using the parameters included. patients who refused EBRT, patients for whom radiation modality was unknown, and cases in which it is unknown 3. Results whether EBRT was eventually administered. We then esti- mated the total number of patients treated in the USA by Our frequency analysis of the SEER database found that extrapolation, based on the fact that the SEER database 34,104 patients were diagnosed with localized prostate cancer covers approximately 28% of the US population. We therefore in 2014. We excluded 22,670 patients for whom EBRT status multiplied the results by 3.57. was unknown. Of patients referred for radiotherapy, we excluded 373 patients treated with adjuvant EBRT, 1549 2.3. Radiation Treatment Cost Estimates. In order to estimate patients treated with radioactive implants, 1094 patients treatment costs for various fractionation schemes we used treated with a combination of EBRT and radioactive implants, th billing codes by the Current Procedural Terminology, 4 79 patients for whom the radiation method was unknown, Edition (CPT) 2018 pricing by the Centers for Medicare and 148 patients who refused treatment, and 537 patients who Medicaid Services (CMS). The reimbursement rates specified were recommended to receive radiation therapy but it is are by National Payment Amount, and not by specific locality. unknown whether it was administered. The final analysis We performed multiple analyses to assess the payers cost included 7,604 patients treated with definitive EBRT as a when different fractionation regimens are used nationwide. single modality (Figure 1). As the SEER database covers 28% The billing codes included and price of various fractionation of the population, we multiplied 7,604 by 3.57 in order to schemes are presented in Table 2. We regarded all patients estimate that approximately 27,146 patients would be treated treated annually with EBRT as if all were treated with the annually with radiation in the USA. same fractionation scheme. We then calculated the total The cost of various fractionation schemes is summarized annual cost of treatment and then the annual saving for in Table 1 and ranges between US$ 26,782 for 45 fractions various moderate hypofractionation schedules. As most trials and US$ 13,402 for 20 fractions. The saving per patient reported equal tolerability, we included EBRT associated cost ranges between 25% (when comparing a 39- and 28-fraction only with no consideration of adverse event management. schedule) and up to 50% (when comparing 45 and 20 fractions). 2.4. Sensitivity Analysis. A 10% range was applied for all In our analysis, the annual cost of standard fractionated parameters of the model. We performed a univariate sensi- EBRT is US$727,024,172 and US$641,324,250 for 45 and 39 tivity analysis to assess which parameters had the greatest fractions, respectively. With moderate hypofractionation, the 4 Journal of Oncology Patients Diagnosed with Localized Prostate Cancer in 2014 (n = 34,104) Excluded: - Unknown whether referred for RT (n=22,670) - Treated with radioactive implants (n=1,549) - Treated with radioisotopes (n=50) - Treated with combination EBRT + implants (n=1,094) - RT method unspecified (n=79) - Refused treatment with RT (n=148) - RT recommended, unknown if administered (n=537) Included: EBRT (n=7,977) Figure 1: Target Population. Data extraction from the Surveillance, Epidemiology, and End Results (SEER) database. annual cost is US$483,008,778 and US$363,810,692 for 28 tumors and clinical scenarios. One study has assessed that and 20 fractions, respectively (Figure 2). Adopting moderate over one decade the number of patients receiving radiation hypofractionation as a new standard of care could lead to therapy during their initial treatment course is expected to a national annual saving of approximately US$158,315,472- increase by 22% [25]. As the numbers of linear accelerators US$363,213,480. and radiation oncologists are finite, it is clear that cutting The univariate sensitivity analysis (Figure 3) demon- treatment duration from 8-9 weeks to 4-6 weeks could relieve strates that the model variables with the greatest potential some of the burden on the healthcare system. From the impact on the differences in annual cost of each fractionation patients’ perspective, a shorter treatment course would be more convenient and require a shorter absence from work. scheme are the target population size and the cost of IMRT treatment delivery (i.e., the number of fractions). The results There are multiple limitations of our study. Firstly, esti- of the probabilistic sensitivity analyses are presented in mating the target population of patients receiving radia- Figure 4. They demonstrate different probabilities of different tion is extremely difficult. We used data from 2014, but levels of budget impact based on the inputs to our model. multiple trends may cause this estimation to be inaccurate. The US Preventive Services Task Force (USPSTF) advised against PSA screening in 2011 [26], leading to a reduction 4. Discussion in screening and thus treatments. However these guidelines were updated in the 2017 dra,ft and while recommending We performed an estimation of the impact of moderate hypofractionation on the annual cost of radiation therapy against screening in men aged 70 or older, they recommended for localized prostate cancer. We found that the annual cost individual patient decisions for screening in men aged 55-69 [27]. It is expected that PSA screening and thus treatment could be decreased by 25-50%. This reduction is mostly attributed to fewer fractions per treatment course. The rele- will therefore increase. In addition, however, there has been vance of this analysis is dependent on the clinical equivalency a growing trend towards using active surveillance for low between standard fractionation and moderate hypofractiona- risk disease [28]. In order to perform comparisons, we tion, which has been proven in several randomized trials [12– regarded all patients treated with EBRT in 2014 as if they were treated with conventional fractionation, when in reality, 15]. In an era of numerous medical and technological inno- some may have been treated with hypofractionation. Pelvic vations, treatment costs are rising. High precision radiation nodal irradiation is another subject we cannot account for. While most high risk trials have treated the pelvic lymph techniques are associated with significant expense and are now incorporated into the treatment algorithm of multiple nodes, two major trials addressing this issue specifically are Journal of Oncology 5 $800,000,000.00 $727,024,172.00 $700,000,000.00 $641,324,250.00 $600,000,000.00 $483,008,778.00 $500,000,000.00 $400,000,000.00 $363,810,692.00 $300,000,000.00 $200,000,000.00 $100,000,000.00 $0.00 45 Fx 39 Fx 28 Fx 20 Fx Figure 2: Totalannualcost by fractionation scheme. # base population cost of IMRT treatment delivery # base population cost of cone beam CT cost of IMRT treatment delivery cost of IMRT treatment planning cost of cone beam CT cost of weekly treatment management cost of IMRT treatment planning cost of physics consult hour cost of weekly treatment management cost of MLC design for IMRT cost of physics consult hour cost of treatment planning complex cost of MLC design for IMRT cost of treatment planning complex cost of basic dose calculation cost of basic dose calculation % radioisotopes % radioisotopes % RT method unspecified % RT method unspecified % refused treatment % refused treatment % adjuvant radiation % adjuvant radiation % treatment recommended, unknown if administered % treatment recommended, unknown if administered % combination EBRT + implants % combination EBRT + implants % radioactive implants % radioactive implants % status unknown % status unknown 4 6 8 10 12 468 10 8 8 ×10 ×10 (a) (b) # base population # base population cost of IMRT treatment delivery cost of IMRT treatment delivery cost of cone beam CT cost of cone beam CT cost of IMRT treatment planning cost of IMRT treatment planning cost of weekly treatment management cost of weekly treatment management cost of MLC design for IMRT cost of MLC design for IMRT cost of physics consult hour cost of physics consult hour cost of treatment planning complex cost of treatment planning complex cost of basic dose calculation cost of basic dose calculation % radioisotopes % radioisotopes % RT method unspecified % RT method unspecified % refused treatment % refused treatment % adjuvant radiation % adjuvant radiation % treatment recommended, unknown if administered % treatment recommended, unknown if administered % combination EBRT + implants % combination EBRT + implants % radioactive implants % radioactive implants % status unknown % status unknown 8 8 ×10 ×10 (c) (d) Figure 3: Univariate sensitivity analysis for various parameters’ impact on total cost of EBRT by fractionation scheme. (a) 45 fractions; (b) 39 fractions; (c) 28 fractions; (d) 20 fractions. Total Annual Cost 6 Journal of Oncology 0.025 0.03 0.025 0.02 0.02 0.015 0.015 0.01 0.01 0.005 0.005 0 0 02468 10 12 14 0 2 4 6 8 10 12 8 8 ×10 ×10 (a) (b) 0.03 0.03 0.025 0.025 0.02 0.02 0.015 0.015 0.01 0.01 0.005 0.005 8 8 ×10 ×10 (c) (d) Figure 4: A probabilistic sensitivity analysis using population and treatment parameters by fractionation scheme. (a) 45 fractions; (b) 39 fractions; (c) 28 fractions; (d) 20 fractions. controversial [29, 30]. Whether elective nodal irradiation When calculating costs, we referred to the CPT codes by improves outcomes for high risk patients would hopefully CMS. When we attempted to calculate costs based on the be determined with the results of RTOG 0924. Moderate Hospital Outpatient Prospective Payment System (OPPS), we hypofractionation trials have not targeted the pelvic nodes found that access to hospital and physician specific billing with the exception of a small subset in one trial [17] and was limited. While we realize that the CPT coding system are not recommended by the updated guidelines for high represents only one aspect of the US healthcare system, its risk patients requiring nodal irradiation [21]. It is unknown relative conformity and easy access proved more suitable for the purpose of this study. In addition, concerns have whether moderate hypofractionation could safely treat pelvic lymph nodes in case this proves to be efficacious in RTOG been raised that SEER data may underreport radiotherapy 0924. While most trials have found standard fractionation use. In a survey of breast cancer patients, 273 of 1292 and moderate hypofractionation to be equally tolerated, a few patients who reported receiving radiotherapy were coded have demonstrated a higher incidence of GI or GU toxicity as not receiving radiotherapy in SEER [31]. As such, we [12, 19]. This could have an economic and clinical impact that might be underestimating the potential saving with moder- was not considered. The recently updated ASTRO, ASCO, ate hypofractionation. Our frequency analysis of the SEER and AUA guidelines have concluded that while there is database for localized prostate cancer in 2014 found that limited follow-up, moderate hypofractionation and standard 34,104 patients were referred for EBRT. We excluded 22,670 fractionation have a similar risk of GI and GU toxicities [21]. patients for whom EBRT status was unknown. This very large Journal of Oncology 7 number could have significant implications on cost estimates References (Figure 3, “status unknown” bar). 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The Financial Impact of Hypofractionated Radiation for Localized Prostate Cancer in the United States

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Copyright © 2019 Assaf Moore et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Journal of Oncology Volume 2019, Article ID 8170428, 8 pages https://doi.org/10.1155/2019/8170428 Research Article The Financial Impact of Hypofractionated Radiation for Localized Prostate Cancer in the United States 1,2 2 3 1 1,2 Assaf Moore , Ido Stav, Robert B. Den, Noa Gordon, Michal Sarfaty, 1,2 1,2 1,4 Victoria Neiman, Eli Rosenbaum, and Daniel A. Goldstein Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Radiation Oncology, Jeeff rson University, Philadelphia, PA, USA Department of Health Policy and Management, University of North Carolina, Chapel Hill, USA Correspondence should be addressed to Daniel A. Goldstein; danielagoldstein@gmail.com Received 21 October 2018; Revised 13 November 2018; Accepted 27 November 2018; Published 2 January 2019 Academic Editor: Reza Izadpanah Copyright © 2019 Assaf Moore et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Until recently, dose intensified radiotherapy was the standard radiation method for localized prostate cancer. Multiple studies have demonstrated similar efficacy and tolerability with moderate hypofractionation. In recent years there has been an increasing focus placed on understanding the cost and value of cancer care. In this study we aimed to assess the economic impact of moderate hypofractionation for payers in the United States. Methods. We performed a population-based analysis of the total cost of external beam radiotherapy (EBRT) for localized prostate cancer in the US annually. The national annual target population of patients treated with definitive EBRT was calculated using the Surveillance, Epidemiology, and End Results (SEER) database. Treatment costs for various fractionation schemes were based on billing codes and 2018 pricing by the Centers for Medicare and Medicaid Services (CMS). Results. We estimate that 27,146 patients with localized prostate cancer are treated with EBRT annually in the US. The cost of standard fractionation in 45 or 39 fractions is US$ 26,782 and 23,625 per patient, respectively. With moderate hypofractionation in 28 or 20 fractions, the cost is US$ 17,793 and 13,402 per patient, respectively. The use of moderate hypofractionation would lead to 25-50% annual savings US$158,315,472-US$363,213,480 in the US. Conclusions. Moderate hypofractionation may have the potential to save approximately US$0.16-0.36 billion annually, likely without impacting survival or tolerability. iTh s may lead to lower personal financial toxicity. It would be reasonable for public and private payers to consider which type of radiation is most suited to reimbursement. 1. Introduction whilesomemen mayhaveamoreaggressive courseof disease, others do not. Prostate cancer is the third most common cancer diagnosed Dose escalation studies in localized prostate cancer have in the US and represents 9.6% of all new cancer cases [1, 2]. demonstrated improved outcomes compared to lower doses In 2018, the American Cancer Society estimates that 164,690 [3–7]. In light of these n fi dings, the standard of care is to use a patients will be diagnosed with prostate cancer, and 29,430 dose of 75.6-81 Gy depending on the risk stratification group will succumb to their disease [2]. Seventy-nine percent of [8]. High biologically equivalent doses can be achieved with prostate cancer patients are diagnosed with localized disease, various fractionation schemes. One such way is moderate defined as a tumor that is confined to the primary site [1, 2]. In hypofractionation. The linear quadratic model uses the 𝛼 /𝛽 general, there are three treatment options: surgical resection, ratio to describe the varying effect of fraction size on cell radiation with or without hormonal therapy, and n fi ally active survival. The higher the ratio, the more “radiosensitive” the surveillance when appropriate. The choice of these options tumor. As prostate cancer is considered to have a low𝛼 /𝛽 is largely driven by disease risk status, age, and patient ratio, higher doses per fraction could potentially improve preferences. Localized prostate cancer is heterogeneous, and prostate cancer cell killing. Several observational reports 2 Journal of Oncology Table 1: Moderate hypofractionation trials. Trial Design pts randomized Patient population (NCCN) Fractionation and Total dose 5-year FFF rate 37 X 2Gy, 74GY 88.3% CHHiP Non-inferiority 3216 73% IR 20 X 3Gy, 60Gy 90.6% 19 X 3Gy, 57Gy 85.9% 39 X 2Gy, 78Gy 79% PROFIT Non-inferiority 1206 100% IR 20 X 3Gy, 60Gy 79% 3 41 X 1.8Gy, 73.8Gy 85.3% RTOG 0415 Non-inferiority 1092 100% LR 28 X 2.5Gy, 70Gy 86.3% 4 39 X 2Gy, 78GY 77% HYPRO Superiority 804 73% HR 19 X 3.4Gy, 64.6Gy 81% 38 X 2Gy, 76Gy 85% Pollack et al. Superiority 303 64% HR 26 X 2.7GY, 70.2Gy 81% 40 X 2Gy, 80Gy 79% Arcangeli et al. Superiority 168 76% HR 20 X 3.1Gy, 62Gy 85% 42 X 1.8Gy, 75.6GY 92% Hoffman et al Superiority 204 70% IR 30 X 2.4Gy, 72Gy 96% FFF: freedom from failure. IR: intermediate risk. LR: low risk. HR: high risk. of moderate hypofractionation demonstrated an acceptable patients who decline active surveillance, to men with inter- safety prole fi [9–11]. Following these reports were a series mediate risk prostate cancer with or without radiation to the of randomized controlled trials analyzing the safety and seminal vesicles, and to men with high risk prostate cancer ecffi acy of hypofractionated radiation compared to tradi- receiving EBRT to the prostate only [21]. tionally fractionated radiation for patients with localized In recent years there has been an increasing focus placed prostate cancer. These trials varied in design as well as having on understanding the cost and value of cancer care. This differing inclusion and exclusion criteria. While most trials has led to the development of various frameworks that included mainly low and intermediate risk patients [12–16], aim to understand value [22, 23]. However, the focus has some have focused on high risk [17–19]. In essence these predominantly been placed on the value of pharmaceutical studies found an equivalent level of efficacy and safety when interventions. There are however widespread opportunities using hypofractionated radiation [12–15] (Table 1). Moderate for improving value in other fields such as surgery, radiation, hypofractionation was not found to be superior to traditional and end-of-life care. Between 2010 and 2012, radiotherapy fractionation in terms of survival, [17–19] but was found to was the primary treatment among 23% and 33-36% of be noninferior to conventional fractionation for biochemical patients under 64 and over 64 years diagnosed with prostate control with similar overall and cancer specific survival [12– cancer, respectively [1]. 14] (Table 1). The objective of this study was to assess the difference Despite concerns for an increase in late toxicity with in cost from the payers’ perspective of the USA if all higher doses per fraction, most trials have not found a sta- patients currently treated with traditional radiation received tistically significant difference [13–15, 17, 18]. One exception moderately hypofractionated radiation. is RTOG 0415, where men assigned to hypofractionation had significantly more late grade 2 GI and GU toxicity (HR 1.59, 2. Methods p=0.005 and HR 1.31, p=0.009, respectively) [12]. Another exception is the HYPRO trial that used a 3.4 Gy dose per 2.1. Methodological Overview. We performed a population- fraction in the hypofractionated arm and found that the based budget impact analysis according to the guidelines set cumulative incidence of grade 3 or worse late GU toxicity was forth by the International Society of Pharmacoeconomics significantly higher (19% versus 12.9%, p=0.021) [19]. How- and Outcomes Research [24]. We performed the analysis ever, the most relevant index regarding toxicity is patient- from the payers’ perspective in the United States. The budget reported outcomes. These were found to be equivalent as impact model was developed using Matlab version R2016b seen in the 5-year patient-reported outcomes of the CHHiP (MathWorks, Inc.). trial [13, 14]. Another report found no statistically significant difference in long-term quality of life outcomes between conventional and hypofractionated treatment [20]. 2.2. Target Population. We used the Surveillance, Epidemi- In light of these accumulating data, the recent guideline ology, and End Results (SEER) database to estimate the update by ASTRO, ASCO, and AUA has determined that population of patients treated annually with EBRT. We moderate hypofractionation should be offered to low risk performed a frequency analysis on treatment with EBRT for Journal of Oncology 3 Table 2: CPT codes and prices, fractionation options, and costs. CPT Code, Description Price per Unit Number of Units 77301, IMRT treatment planning $2033.26 77263, treatment planning complex $170.64 77338, MLC design for IMRT $527.39 77300, Basic Dose Calculation $68.76 2 ∗∗ G6015, IMRT treatment delivery $358.00 By number of fractions ∗∗ 45 fx –9; 39 fx – 8; 77336, physics consult hour $82.80 28 fx – 6; 20 fx – 4 ∗∗ 77014, cone beam CT $122.40 By number of fractions ∗∗ 45 fx –9; 39 fx – 8; 77427, weekly treatment management $191.16 28 fx – 6; 20 fx – 4 Fractionation Scheme Cost per Patient 45 fractions $26,782 39 fractions $23,625 28 fractions $17,793 20 fractions $13,402 CPT: current procedural terminology. Intensity modulated radiotherapy. MLC: multileaf collimator. Fx: fractions. The total price per code includes the professional component and technical charge when applicable. ∗∗ Number of unitsvariesby treatment duration. localized prostate cancer in the latest year summarized in the impact on cost savings. A probabilistic sensitivity analysis was SEER cancer statistics, 2014. We excluded all patients who performed using a Monte Carlo Simulation. The model was were treated with a combination of EBRT and brachytherapy, run 100,000 times, using the parameters included. patients who refused EBRT, patients for whom radiation modality was unknown, and cases in which it is unknown 3. Results whether EBRT was eventually administered. We then esti- mated the total number of patients treated in the USA by Our frequency analysis of the SEER database found that extrapolation, based on the fact that the SEER database 34,104 patients were diagnosed with localized prostate cancer covers approximately 28% of the US population. We therefore in 2014. We excluded 22,670 patients for whom EBRT status multiplied the results by 3.57. was unknown. Of patients referred for radiotherapy, we excluded 373 patients treated with adjuvant EBRT, 1549 2.3. Radiation Treatment Cost Estimates. In order to estimate patients treated with radioactive implants, 1094 patients treatment costs for various fractionation schemes we used treated with a combination of EBRT and radioactive implants, th billing codes by the Current Procedural Terminology, 4 79 patients for whom the radiation method was unknown, Edition (CPT) 2018 pricing by the Centers for Medicare and 148 patients who refused treatment, and 537 patients who Medicaid Services (CMS). The reimbursement rates specified were recommended to receive radiation therapy but it is are by National Payment Amount, and not by specific locality. unknown whether it was administered. The final analysis We performed multiple analyses to assess the payers cost included 7,604 patients treated with definitive EBRT as a when different fractionation regimens are used nationwide. single modality (Figure 1). As the SEER database covers 28% The billing codes included and price of various fractionation of the population, we multiplied 7,604 by 3.57 in order to schemes are presented in Table 2. We regarded all patients estimate that approximately 27,146 patients would be treated treated annually with EBRT as if all were treated with the annually with radiation in the USA. same fractionation scheme. We then calculated the total The cost of various fractionation schemes is summarized annual cost of treatment and then the annual saving for in Table 1 and ranges between US$ 26,782 for 45 fractions various moderate hypofractionation schedules. As most trials and US$ 13,402 for 20 fractions. The saving per patient reported equal tolerability, we included EBRT associated cost ranges between 25% (when comparing a 39- and 28-fraction only with no consideration of adverse event management. schedule) and up to 50% (when comparing 45 and 20 fractions). 2.4. Sensitivity Analysis. A 10% range was applied for all In our analysis, the annual cost of standard fractionated parameters of the model. We performed a univariate sensi- EBRT is US$727,024,172 and US$641,324,250 for 45 and 39 tivity analysis to assess which parameters had the greatest fractions, respectively. With moderate hypofractionation, the 4 Journal of Oncology Patients Diagnosed with Localized Prostate Cancer in 2014 (n = 34,104) Excluded: - Unknown whether referred for RT (n=22,670) - Treated with radioactive implants (n=1,549) - Treated with radioisotopes (n=50) - Treated with combination EBRT + implants (n=1,094) - RT method unspecified (n=79) - Refused treatment with RT (n=148) - RT recommended, unknown if administered (n=537) Included: EBRT (n=7,977) Figure 1: Target Population. Data extraction from the Surveillance, Epidemiology, and End Results (SEER) database. annual cost is US$483,008,778 and US$363,810,692 for 28 tumors and clinical scenarios. One study has assessed that and 20 fractions, respectively (Figure 2). Adopting moderate over one decade the number of patients receiving radiation hypofractionation as a new standard of care could lead to therapy during their initial treatment course is expected to a national annual saving of approximately US$158,315,472- increase by 22% [25]. As the numbers of linear accelerators US$363,213,480. and radiation oncologists are finite, it is clear that cutting The univariate sensitivity analysis (Figure 3) demon- treatment duration from 8-9 weeks to 4-6 weeks could relieve strates that the model variables with the greatest potential some of the burden on the healthcare system. From the impact on the differences in annual cost of each fractionation patients’ perspective, a shorter treatment course would be more convenient and require a shorter absence from work. scheme are the target population size and the cost of IMRT treatment delivery (i.e., the number of fractions). The results There are multiple limitations of our study. Firstly, esti- of the probabilistic sensitivity analyses are presented in mating the target population of patients receiving radia- Figure 4. They demonstrate different probabilities of different tion is extremely difficult. We used data from 2014, but levels of budget impact based on the inputs to our model. multiple trends may cause this estimation to be inaccurate. The US Preventive Services Task Force (USPSTF) advised against PSA screening in 2011 [26], leading to a reduction 4. Discussion in screening and thus treatments. However these guidelines were updated in the 2017 dra,ft and while recommending We performed an estimation of the impact of moderate hypofractionation on the annual cost of radiation therapy against screening in men aged 70 or older, they recommended for localized prostate cancer. We found that the annual cost individual patient decisions for screening in men aged 55-69 [27]. It is expected that PSA screening and thus treatment could be decreased by 25-50%. This reduction is mostly attributed to fewer fractions per treatment course. The rele- will therefore increase. In addition, however, there has been vance of this analysis is dependent on the clinical equivalency a growing trend towards using active surveillance for low between standard fractionation and moderate hypofractiona- risk disease [28]. In order to perform comparisons, we tion, which has been proven in several randomized trials [12– regarded all patients treated with EBRT in 2014 as if they were treated with conventional fractionation, when in reality, 15]. In an era of numerous medical and technological inno- some may have been treated with hypofractionation. Pelvic vations, treatment costs are rising. High precision radiation nodal irradiation is another subject we cannot account for. While most high risk trials have treated the pelvic lymph techniques are associated with significant expense and are now incorporated into the treatment algorithm of multiple nodes, two major trials addressing this issue specifically are Journal of Oncology 5 $800,000,000.00 $727,024,172.00 $700,000,000.00 $641,324,250.00 $600,000,000.00 $483,008,778.00 $500,000,000.00 $400,000,000.00 $363,810,692.00 $300,000,000.00 $200,000,000.00 $100,000,000.00 $0.00 45 Fx 39 Fx 28 Fx 20 Fx Figure 2: Totalannualcost by fractionation scheme. # base population cost of IMRT treatment delivery # base population cost of cone beam CT cost of IMRT treatment delivery cost of IMRT treatment planning cost of cone beam CT cost of weekly treatment management cost of IMRT treatment planning cost of physics consult hour cost of weekly treatment management cost of MLC design for IMRT cost of physics consult hour cost of treatment planning complex cost of MLC design for IMRT cost of treatment planning complex cost of basic dose calculation cost of basic dose calculation % radioisotopes % radioisotopes % RT method unspecified % RT method unspecified % refused treatment % refused treatment % adjuvant radiation % adjuvant radiation % treatment recommended, unknown if administered % treatment recommended, unknown if administered % combination EBRT + implants % combination EBRT + implants % radioactive implants % radioactive implants % status unknown % status unknown 4 6 8 10 12 468 10 8 8 ×10 ×10 (a) (b) # base population # base population cost of IMRT treatment delivery cost of IMRT treatment delivery cost of cone beam CT cost of cone beam CT cost of IMRT treatment planning cost of IMRT treatment planning cost of weekly treatment management cost of weekly treatment management cost of MLC design for IMRT cost of MLC design for IMRT cost of physics consult hour cost of physics consult hour cost of treatment planning complex cost of treatment planning complex cost of basic dose calculation cost of basic dose calculation % radioisotopes % radioisotopes % RT method unspecified % RT method unspecified % refused treatment % refused treatment % adjuvant radiation % adjuvant radiation % treatment recommended, unknown if administered % treatment recommended, unknown if administered % combination EBRT + implants % combination EBRT + implants % radioactive implants % radioactive implants % status unknown % status unknown 8 8 ×10 ×10 (c) (d) Figure 3: Univariate sensitivity analysis for various parameters’ impact on total cost of EBRT by fractionation scheme. (a) 45 fractions; (b) 39 fractions; (c) 28 fractions; (d) 20 fractions. Total Annual Cost 6 Journal of Oncology 0.025 0.03 0.025 0.02 0.02 0.015 0.015 0.01 0.01 0.005 0.005 0 0 02468 10 12 14 0 2 4 6 8 10 12 8 8 ×10 ×10 (a) (b) 0.03 0.03 0.025 0.025 0.02 0.02 0.015 0.015 0.01 0.01 0.005 0.005 8 8 ×10 ×10 (c) (d) Figure 4: A probabilistic sensitivity analysis using population and treatment parameters by fractionation scheme. (a) 45 fractions; (b) 39 fractions; (c) 28 fractions; (d) 20 fractions. controversial [29, 30]. Whether elective nodal irradiation When calculating costs, we referred to the CPT codes by improves outcomes for high risk patients would hopefully CMS. When we attempted to calculate costs based on the be determined with the results of RTOG 0924. Moderate Hospital Outpatient Prospective Payment System (OPPS), we hypofractionation trials have not targeted the pelvic nodes found that access to hospital and physician specific billing with the exception of a small subset in one trial [17] and was limited. While we realize that the CPT coding system are not recommended by the updated guidelines for high represents only one aspect of the US healthcare system, its risk patients requiring nodal irradiation [21]. It is unknown relative conformity and easy access proved more suitable for the purpose of this study. In addition, concerns have whether moderate hypofractionation could safely treat pelvic lymph nodes in case this proves to be efficacious in RTOG been raised that SEER data may underreport radiotherapy 0924. While most trials have found standard fractionation use. In a survey of breast cancer patients, 273 of 1292 and moderate hypofractionation to be equally tolerated, a few patients who reported receiving radiotherapy were coded have demonstrated a higher incidence of GI or GU toxicity as not receiving radiotherapy in SEER [31]. As such, we [12, 19]. This could have an economic and clinical impact that might be underestimating the potential saving with moder- was not considered. The recently updated ASTRO, ASCO, ate hypofractionation. Our frequency analysis of the SEER and AUA guidelines have concluded that while there is database for localized prostate cancer in 2014 found that limited follow-up, moderate hypofractionation and standard 34,104 patients were referred for EBRT. We excluded 22,670 fractionation have a similar risk of GI and GU toxicities [21]. patients for whom EBRT status was unknown. This very large Journal of Oncology 7 number could have significant implications on cost estimates References (Figure 3, “status unknown” bar). 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