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Journal of Clinical Oncology, Vol 25, No 24 (August 20), 2007: pp. 3603-3608 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.0811 Is Proton Beam Therapy Cost Effective in the Treatment of Adenocarcinoma of the Prostate?
From the Department of Radiation Oncology, and Population Science Division, Fox Chase Cancer Center, Philadelphia, PA Address reprint requests to Andre Konski, MD, MBA, MA, Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA; e-mail: andre.konski{at}fccc.edu
Purpose: New treatments are introduced routinely into clinical practice without rigorous economic analysis. The specific aim of this study was to examine the cost effectiveness of proton beam radiation compared with current state-of-the art therapy in the treatment of patients with prostate cancer. Materials and Methods: A Markov model was informed with cost, freedom from biochemical failure (FFBF), and utility data obtained from the literature and from patient interviews to compare the cost effectiveness of 91.8 cobalt gray equivalent (CGE) delivered with proton beam versus 81 CGE delivered with intensity-modulated radiation therapy (IMRT). The length of how many years the model was run, patient's age, probability of FFBF after treatment with proton beam therapy and IMRT, utility of patients treated with salvage hormone therapy, and treatment cost were tested in sensitivity analyses. Results: Analysis at 15 years resulted in an expected mean cost of proton beam therapy and IMRT of $63,511 and $36,808, and $64,989 and $39,355 for a 70-year-old and 60-year-old man respectively, with quality-adjusted survival of 8.54 and 8.12 and 9.91 and 9.45 quality-adjusted life-years (QALY), respectively. The incremental cost effectiveness ratio was calculated to be $63,578/QALY for a 70-year-old man and $55,726/QALY for a 60-year-old man. Conclusion: Even when based on the unproven assumption that protons will permit a 10-Gy escalation of prostate dose compared with IMRT photons, proton beam therapy is not cost effective for most patients with prostate cancer using the commonly accepted standard of $50,000/QALY. Consideration should be given to limiting the number of proton facilities to allow comprehensive evaluation of this modality.
Radiation therapy delivery has evolved from orthovoltage to megavoltage; more recently, particle beam therapy has been used. Proton beam therapy has been used in the treatment of deep-seated tumors, such as base of skull chordomas and prostate cancer, because of favorable energy deposition characteristics with very little radiation dose deposition beyond the volume of interest.1-3 The specific aim of this analysis was to perform an economic analysis of proton beam therapy to treat a patient with intermediate risk adenocarcinoma of the prostate. We hypothesize that proton beam therapy is not a cost-effective treatment compared with intensity-modulated radiation therapy (IMRT).
A Markov model was constructed to evaluate a hypothetical clinical trial designed to compare treatment delivered with proton beam therapy versus IMRT in a 70-year-old male diagnosed with intermediate-risk adenocarcinoma of the prostate.
Decision Model of Prostate Cancer
The Houston definition (now named the Phoenix definition) for freedom from biochemical failure (FFBF) was used because this definition of failure closely approximates the constant yearly transition assumptions of our model.10,11 The yearly transition probability estimates for each treatment, assuming constant rates, were calculated from rates obtained from a dose-response curve generated by Fowler12 and Eade et al.13 The rationale was to pick the highest dose for which existing clinical data are found for IMRT as a starting point, which would be 81 Gy because of the experience at the Memorial Sloan-Kettering Cancer Center. This dose is at 1.8 Gy per fraction, is similar to data from Fox Chase at 2 Gy, and is not much different from the dose used in randomized trials. We then added 10 Gy, given that this would be expected to result in a meaningful difference using existing dose-response data. We believed proton therapy would not have been cost effective without the meaningful differences in outcome based on the dose-response data presented in the article.12,13 The 5-year FFBF probability was estimated to be 83% and 93% for patients treated with IMRT and proton beam therapy, respectively, based on previous work by Fowler12 and Eade et al.13 The yearly probability of a 70-year-old male dying was obtained from life tables. Limited literature exists reporting overall survival for patients with adenocarcinoma of the prostate treated with protons. Zietman et al14 did not find a difference in overall survival between patients treated with low- or high-dose radiation (97% v 96%). Only 10 deaths were reported in the low-dose arm (two related to prostate cancer) and eight deaths were reported in the high-dose arm (none were related to prostate cancer). The annual rate was calculated using the following formulas: annual rate = [–ln(1 – P)/n], were P is the probability of the occurrence such as FFBF or toxicity, and n is the number of years the rate is measured. The annual probability of the event was calculated using the following formula: annual probability = 1 – exp(–annual rate). TreeAge Pro HealthCare 2005 decision analysis software (TreeAge Software Inc, Williamstown, MA) was used to analyze the Markov model. Patient utilities and costs described in the following paragraphs were sampled from distributions once per patient and each simulation had 1,000 trials. The initial time period for the analysis was 10 stages (years).
Economic Assumptions
Utilities Utilities or patient preference were used to calculate quality-adjusted life-years (QALY). Utilities for a patient treated with IMRT were obtained from 85 patients with intermediate-risk prostate cancer undergoing IMRT (without hormone therapy) randomly assigned to a Fox Chase Cancer Center (Philadelphia, PA) in-house phase III clinical trial using the EuroQol (EQ-5D) instrument before and 6 months after completion of radiation.19 We have, in addition, identified 40 patients who were  70 years old and measured the utilities in these patients. The mean utilities for patients age 70 years was similar at 0.90 (range, 0.186 to 1). The EQ-5D questionnaire consists of five descriptive items (mobility, self-care, daily activities, pain/discomfort, and anxiety/depression) rated on a three-point scale (no, some, or extreme problems). The 6-month value was used in the model. Although patients treated with proton beam therapy received a higher radiation dose, it was assumed that patients treated with IMRT and proton beam therapy had the same utility value. It was also assumed that proton therapy could be used to escalate the dose while maintaining a similar toxicity to that in patients treated with IMRT. This assumption will be tested in a sensitivity analysis. This assumption could bias the outcome in favor of proton therapy if proton therapy had worse toxicity than IMRT. There is some evidence to suggest that the 5-year grade 2 toxicity may be slightly higher with proton therapy compared with IMRT.14,20,21
Table 1 lists the utility values for men treated with IMRT, hormone therapy, and chemotherapy. Utility values for patients receiving hormone therapy and chemotherapy were obtained from the literature. A utility value of 0.83 was used for patients receiving hormone therapy.22 This value was obtained from a cohort of men age
Sensitivity Analysis
The ICER for a patient 70 years old is $63,578/QALY at 15 years. The ICER improves the longer the analysis, but is marginally cost effective at 15 years, with an ICER greater than $50,000/QALY. Proton beam therapy has only an approximate 49% probability of being cost effective at 15-years as determined by the cost-effectiveness acceptability curve (Fig 2). The probability of cost effectiveness increases from 21% for a trial ending at 5 years to 31% at 10 years, and finally to the 49% depicted in Figure 2. Sensitivity analysis found proton beam therapy would have a higher NMB compared with IMRT if the cost of IMRT was more than $45,000, or the cost of the protons was less than $39,000 or if the utility of the IMRT was less than 0.85. Sensitivity analysis also found that the cost-effective acceptability would only be 23.7% if the probability of control for protons were equal to the probability to control of IMRT.
The ICER for a patient 60 years old improves to $55,726/QALY for a trial ending after 15 years. Proton beam therapy has only an approximate 54% probability of cost effectiveness at 15 years compared with IMRT at a willingness to pay of $50,000/QALY (Fig 3). The probability of cost effectiveness is only 22% for a trial ending at 5 years, but increases to 36% at 10 years and then finally to 54% at 15 years. Sensitivity analysis found proton beam therapy to have a higher NMB if the cost of IMRT was more than $43,000 when the cost of proton beam therapy was less than $41,000, or if the utility of patients receiving IMRT was less than 0.86. That is, for proton beam therapy to have a higher NMB and be the preferred treatment, patients receiving IMRT would have to have a utility of less than 0.86. This would mean that they would then have a higher quality-adjusted survival if they lived an equal amount of time, given that QALY is equal to the utility spent in a time period multiplied by the time period.
Figure 4 is a FFBF plot showing the results of patients treated with IMRT and proton beam therapy from our model. The 8-year FFBF rate was 74% for patients treated to 81 Gy with IMRT in our model, which compares favorably to the 8-year FFBF rate of 78% recently reported by Zelefsky et al25 for intermediate-risk patients treated with IMRT to a dose of 81 Gy; exactly the same as the IMRT dose in our model.25
There currently are five active proton beam therapy centers in the United States, with two new sites, M.D. Anderson Cancer Center (Houston, TX) and University of Florida (Jacksonville, FL), becoming operational in the last year. Proton beam therapy also has the advantage of less radiation dose scattered to normal tissue, making it ideal for treatment of pediatric malignancies, potentially reducing the incidence of second malignant tumors.26-28
Is this new technology superior to IMRT and worth the increased cost in the treatment of men with prostate cancer? We have found that IMRT has a 54% probability of cost effectiveness compared with three-dimensional (3D) conformal radiation in a 70-year-old man with intermediate-risk prostate cancer.9 The longer the potential survival, the greater the probability of IMRT cost effectiveness became. Lundkvist et al29 examined the cost effectiveness of proton therapy in the treatment of four different malignancies. The model they used differed from our model and costs were calculated from a Swedish societal perspective. The standard patients were 65-year-old men with prostate cancer. A 20% reduction in cancer recurrence was assumed with proton therapy, whereas we assumed only a 10% improvement of FFBF at 5 years for patients treated with protons. They reported a cost/QALY of Zietman et al14 reported an 80.4% 5-year FFBF rate for men receiving high-dose radiation (a combination of photons and protons). In addition, Slater et al29a reported results of patients treated with a combination of photons and proton beam therapy, with a 5-year FFBF of 84% for patients with an initial PSA of 4.1 to 10.0 ng/mL and a 5-year FFBF of 65% for patients with an initial PSA of 10.2 to 20.0 ng/mL. These FFBF figures do not significantly differ from those for patients receiving 3D conformal radiation or IMRT. We have reported previously the 5-year FFBF probabilities of 86% and 73% for favorable- and intermediate-risk prostate cancer treated with 3D conformal radiation.8,9 Given the similar 5-year FFBF rates, higher total radiation doses probably will need to be administered for improved FFBF rates, which is one of the reasons we selected the proton therapy dose in our model. Certain assumptions were made in informing the model. Estimates of FFBF have been derived from dose-response curves from patients treated at Fox Chase Cancer Center that are similar to FFBF estimates of Fowler.12 The potential benefits of proton beam therapy stem not from an inherent preferential cell killing ability but from the ability to escalate radiation dose with the potential for less toxicity to normal tissue. The premise for the parameters used was that proton therapy would allow for higher doses without increasing toxicity. Although the 91.8 cobalt gray equivalent dose seems arbitrary, it is based on prior studies showing that a 10-Gy difference would be meaningful in terms of seeing an FFBF dose-response from 81 Gy, the dose at which the most data currently exist.12,25 The design of this analysis was predicated on the assumption that an approximate 10-Gy increase from 81 to 91 Gy could be achieved with protons without increased toxicity. This is an assumption that may not be achievable, but isolates efficacy in the model. In other words, if protons under ideal conditions could be used to deliver 91 Gy without increase risk, then protons would be cost effective under these ideal conditions. The resulting improved FFBF would then result in reduced cost because fewer patients would need to undergo salvage therapy. It seems from the results of our model that unless these higher doses of radiation are incorporated by proton beam therapy, proton beam therapy would not be cost effective. Cost estimates were developed using the APC payment rate for protons. We estimated proton beam therapy to be 2.3 times more expensive than IMRT, similar to an estimate of Goitein and Jermann,30 who estimated proton beam therapy to be 2.4 times more than the cost of IMRT. This ratio may increase as the reimbursement of IMRT decreases with time, or may stay the same as the reimbursement for both decreases. Proton therapy was found to be cost effective given that the cost to the payer of this treatment decreased.
We also assumed that although patients treated with proton beam therapy received a higher radiation dose, the utilities would remain the same as a result of the potential for proton beams to reduce normal tissue radiation exposure and therefore minimize toxicity to normal structures. Published utility data do not exist for patients treated with proton beam radiation and only limited data are available on utilities for patients treated with IMRT. The 5-year Radiation Therapy Oncology Group grade There are some who argue that the ICER should be greater than $50,000/QALY.31 Proton therapy would be considered cost effective if the ICER was closer to a revised threshold of $200,000/QALY, as Ubel et al31 have proposed. This model calculated the cost effectiveness based on a third-party payer, Medicare, and did not include the tremendous up-front construction costs or yearly operational costs. However, there is research investigating more economical methods of producing protons.32-34 This analysis showed that proton beam therapy becomes cost effective, under the conditions used to inform the model, the longer the time frame (15 years or greater) for the analysis. The conditions used to inform this model include a higher total radiation dose. Proton beam therapy would not be cost effective unless this higher radiation dose is incorporated into future clinical studies. The major question remains whether the US healthcare system can afford more proton beam facilities. The current and planned facilities are located to allow patients easy access to this technology, allowing adequate evaluation in clinical trials. This technology, however, may not be appropriate or provide additional benefit for all patients. This was also concluded by Lundkvist et al.29 Our data suggest only a small population of men with intermediate-risk prostate cancer will benefit in terms of cost effectiveness using the current definition of cost effectiveness. This benefit may be restricted to younger men with longer life expectancies, who have a longer time horizon to experience a recurrence and therefore undergo salvage treatment. Younger men may also benefit from the use of protons because of the potential decreased risk from second malignancies from IMRT; however, the appearance of second malignant tumors after IMRT is theoretical and controversial.35 Men with favorable-risk prostate cancer, who have a low recurrence potential, would not benefit from the potentially higher doses of radiation that protons could deliver. They would not benefit because of the relatively high FFBF rate that can be obtained with currently available technology, obviating the need for salvage therapy. Zelefsky et al8 recently reported an 8-year FFBF rate of 89% for favorable-risk patients undergoing IMRT at doses similar to those used in our model. At this juncture, given the increased cost of proton facilities, consideration should be given to limit the construction of proton facilities so properly designed clinical trials can be performed to identify the role of proton therapy in the management of different malignancies before wide-scale adoption of this technology.
The author(s) indicated no potential conflicts of interest.
Conception and design: Andre Konski, Alan Pollack Provision of study materials or patients: Andre Konski Collection and assembly of data: Andre Konski, Alan Pollack Data analysis and interpretation: Andre Konski, William Speier, Alexandra Hanlon, J. Robert Beck, Alan Pollack Manuscript writing: Andre Konski, J. Robert Beck, Alan Pollack Final approval of manuscript: Andre Konski, William Speier, J. Robert Beck, Alan Pollack
Supported in part by National Institutes of Health Grant No. 1 R01 CA101984-01 (A.P.). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Noel G, Feuvret L, Ferrand R, et al: Radiotherapeutic factors in the management of cervical-basal chordomas and chondrosarcomas. Neurosurgery 55:1252-1260, 2004; discussion 1260-1262[Medline] 2. Noël G, Feuvret L, Dhermain F, et al: Chordomas of the base of the skull and upper cervical spine: 100 patients irradiated by a 3D conformal technique combining photon and proton beams. Cancer Radiother 9:161-174, 2005[Medline] 3. Weber DC, Rutz HP, Pedroni ES, et al: Results of spot-scanning proton radiation therapy for chordoma and chondrosarcoma of the skull base: The Paul Scherrer Institut experience. Int J Radiat Oncol Biol Phys 63:401-409, 2005[CrossRef][Medline] 4. Scher HI, Kelly WM, Zhang ZF, et al: Post-therapy serum prostate-specific antigen level and survival in patients with androgen-independent prostate cancer. J Natl Cancer Inst 91:244-251, 1999 5. Oefelein MG, Agarwal PK, Resnick MI: Survival of patients with hormone refractory prostate cancer in the prostate specific antigen era. J Urol 171:1525-1528, 2004[CrossRef][Medline] 6. Fleming C, Wasson JH, Albertsen PC, et al: A decision analysis of alternative treatment strategies for clinically localized prostate cancer: Prostate Patient Outcomes Research Team. JAMA 269:2650-2658, 1993[Abstract] 7. Konski A, Sherman E, Krahn M, et al: Economic analysis of a phase III clinical trial evaluating the addition of total androgen suppression to radiation versus radiation alone for locally advanced prostate cancer (Radiation Therapy Oncology Group protocol 86-10). Int J Radiat Oncol Biol Phys 63:788-794, 2005[CrossRef][Medline] 8. Konski A, Watkins-Bruner D, Brereton H, et al: Long-term hormone therapy and radiation is cost-effective for patients with locally advanced prostate carcinoma. Cancer 106:51-57, 2006[CrossRef][Medline] 9. Konski A, Watkins-Bruner D, Feigenberg S, et al: Using decision analysis to determine the cost-effectiveness of intensity modulated radiation therapy in the treatment of intermediate risk prostate cancer. Int J Radiat Oncol Biol Phys 66:408-415, 2006[Medline] 10. Thames H, Kuben DA, Levy LB, et al: Comparison of alternating biochemical failure definitions based on clinical outcome in 4839 prostate cancer patients treated by external radiation therapy between 1986 and 1995. Int J Radiat Oncol Biol Phys 57:929-943, 2003[CrossRef][Medline] 11. Roach M III, Hanks G, Thames H Jr, et al: Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 65:965-974, 2006[CrossRef][Medline] 12. Fowler JF: What can we expect from dose escalation using proton beams? Clin Oncol (R Coll Radiol) 15:S10-S15, 2003 13. Eade T, Hanlon AL, Horwitz E, et al: What external beam radiation dose is high enough for prostate cancer? Int J Radiat Oncol Biol Phys 69:682-689, 2007 14. Zietman AL, DeSilvio ML, Slater JD, et al: Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA 294:1233-1239, 2005 15. Lipscomb J, Weinstein MC, Torrance GW: Time preference, in Gold M, Siegel, JE, Russell, LB, et al (eds): Cost-Effectiveness in Health and Medicine. New York, NY, Oxford University Press, 1996, pp 214-235 16. Piper NY, Kusada L, Lance R, et al: Adenocarcinoma of the prostate: An expensive way to die. Prostate Cancer Prostatic Dis 5:164-166, 2002[CrossRef][Medline] 17. Doubilet P, Begg CB, Weinstein MC: Probabilistic sensitivity analysis using Monte Carlo simulation: A practical approach. Med Decis Making 5:157-177, 1985 18. Pass T, Goldstein LP: A computerized aid for medical cost-effective analysis. Med Decis Making 1:465, 1981 (abstr) 19. EuroQol: A new facility for the measurement of health-related quality of life—The EuroQol Group. Health Policy 16:199-208, 1990[CrossRef][Medline] 20. Zelefsky MJ, Fuks Z, Hunt M, et al: High-dose intensity modulated radiation therapy for prostate cancer: Early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 53:1111-1116, 2002[CrossRef][Medline] 21. Gardner BG, Zietman AL, Shipley WU, et al: Late normal tissue sequelae in the second decade after high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer. J Urol 167:123-126, 2002[CrossRef][Medline] 22. Stewart ST, Lenert L, Bhatnagar V, et al: Utilities for prostate cancer health states in men aged 60 and older. Med Care 43:347-355, 2005[CrossRef][Medline] 23. Bayoumi AM, Brown AD, Garber AM: Cost-effectiveness of androgen suppression therapies in advanced prostate cancer. J Natl Cancer Inst 92:1731-1739, 2000 24. Briggs A: Handling uncertainty in economic evaluation and presenting the results, in Drummond MM (ed): Economic Evaluation in Health Care. Oxford, United Kingdom, Oxford University Press, 2001, pp 173-214 25. Zelefsky MJ, Chan H, Hunt M, et al: Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J Urol 176:1415-1419, 2006[CrossRef][Medline] 26. Horwitz EM, Vicini FA, Ziaja EL, et al: The correlation between the ASTRO Consensus Panel definition of biochemical failure and clinical outcome for patients with prostate cancer treated with external beam irradiation: American Society of Therapeutic Radiology and Oncology. Int J Radiat Oncol Biol Phys 41:267-272, 1998[CrossRef][Medline] 27. Wilson VC, McDonough J, Tochner Z: Proton beam irradiation in pediatric oncology: An overview. J Pediatr Hematol Oncol 27:444-448, 2005[CrossRef][Medline] 28. Yuh GE, Loredo LN, Yonemoto LT, et al: Reducing toxicity from craniospinal irradiation: Using proton beams to treat medulloblastoma in young children. Cancer J 10:386-390, 2004[Medline] 29. Lundkvist J, Ekman M, Ericsson SR, et al: Proton therapy of cancer: Potential clinical advantages and cost-effectiveness. Acta Oncol 44:850-861, 2005[CrossRef][Medline] 29. Slater JD, Rossi CJ, Yonemoto LT, et al: Proton therapy of prostate cancer: The initial Loma Linda University experience. Int J Radiat Oncol Biol Phys 59:348-352, 2004[CrossRef][Medline] 30. Goitein M, Jermann M: The relative costs of proton and X-ray radiation therapy. Clin Oncol (R Coll Radiol) 15:S37-S50, 2003 30. Kupelian PA, Thakkar UU, Khuntia D, et al: Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 hyperfraction) for localized prostate cancer: Long-term outcomes. Int J Radiat Oncol Biol Phys 63:1463-1468, 2005[CrossRef][Medline] 31. Ubel PA, Hirth RA, Chernew ME, et al: What is the price of life and why doesn't it increase at the rate of inflation? Arch Intern Med 163:1637-1641, 2003 32. Fourkal E, Li JS, Ding M, et al: Particle selection for laser-accelerated proton therapy feasibility study. Med Phys 30:1660-1670, 2003[CrossRef][Medline] 33. Li JS, Shahine B, Fourkal E, et al: A particle track-repeating algorithm for proton beam dose calculation. Phys Med Biol 50:1001-1010, 2005[CrossRef][Medline] 34. Luo W, Fourkal E, Li J, et al: Particle selection and beam collimation system for laser-accelerated proton beam therapy. Med Phys 32:794-806, 2005[CrossRef][Medline] 35. Hall EJ: Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 65:1-7, 2006[CrossRef][Medline] Submitted September 5, 2006; accepted March 20, 2007. Related Editorial
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
26,776 for proton therapy for the standard case result. 
