Is Proton Beam Therapy Ready for Prime Time?
By: Brian Chun, MD; Adam C. Olson, MD; Benjamin J. Davies, MD; Bruce L. Jacobs, MD, MPH | Posted on: 01 Jul 2022
This year, an estimated 60,000 men will receive radiation therapy for prostate cancer in the United States, of whom the vast majority will receive intensity-modulated radiation therapy (IMRT). A small proportion of patients will receive proton beam therapy, which has grown in popularity in the last 2 decades, with claims to provide more accurate dosing while reducing treatment-related toxicities.1
Proton beam therapy is not a novel form of radiation therapy. Its clinical use in radiation oncology dates to the 1950s, where it found a niche in the treatment of pediatric and complex head/neck tumors. The primary benefit of proton beam therapy lies in the physical properties of the energy source itself—the proton. While traditional radiation therapies utilize photons that transmit energy to all tissues within their directed path, a proton is roughly 1,800 times heavier and carries an elemental charge. This imparts momentum to the proton, which decelerates as it penetrates tissue, eventually releasing most of its energy at a specific depth with little dose deposition in front of and beyond the target through a phenomenon known as the “Bragg peak.” This rapid dose falloff at depth can decrease radiation exposure to adjacent normal tissue by a factor of 2 to 3.2 In the 1990s, proton therapy was explored for use in prostate cancer with the hopes of reducing treatment morbidity to the rectum and bladder.1,3
Proton beam therapy appears to have similar oncologic outcomes compared to IMRT based on many single-institution experiences. A contemporary study found 5-year freedom from biochemical progression rates to be 99%, 94% and 74% for low-, intermediate- and high-risk prostate cancer, respectively.4 However, whether proton therapy’s theoretical toxicity benefit translates to a meaningful clinical improvement is less clear. A case-matched study of patients receiving proton beam treatment and IMRT between 2009 and 2012 found no differences in late genitourinary and gastrointestinal toxicities 90 days after treatment, despite proton therapy showing an 8.5- and 6-fold reduction in radiation dose to the bladder and rectum, respectively.5 A population-based study using SEER (Surveillance, Epidemiology, and End Results)-Medicare linked data demonstrated that IMRT was associated with less gastrointestinal morbidity compared to proton therapy.6 A separate Medicare analysis of 27,000 men who received proton beam treatment showed an association with lower genitourinary toxicities at 6 months compared to IMRT, but found no differences in genitourinary or gastrointestinal toxicities at 12 months.7
In the late 2000s, proton beam therapy gained momentum in prostate cancer treatment as direct-to-patient marketing fueled demand and cancer centers engaged in a “radiation arms race” to offer the latest therapies.3 As a result, the number of proton treatment centers exploded from 5 in 2009 to 39 in 2021 (see Figure).8 Proton treatment centers are expensive, and construction costs can range from $40–$250 million. Once operational, its profitability favors simple prostate cancer treatments over more complex or pediatric tumors, which take longer and are more technically demanding.9 Indeed, cost analyses of proton facilities show that a single gantry center treating only complex or pediatric patients would need to fill 85% of its treatment slots to cover debt costs, but could recoup the same amount in 4 hours of prostate cancer treatments.9 This economic model appears to have driven practice patterns toward high throughput prostate cancer treatment. Even still, operating margins for proton treatment centers are volatile and have been undermined by insurers’ growing reluctance to reimburse. According to The New York Times, in 2018 nearly a third of all centers in the U.S. were losing money, had defaulted on their debt or had to overhaul their finances.10
Given the available evidence, proton beam therapy appears to have similar cancer control and toxicity rates compared to IMRT, but at significantly higher cost, with estimates showing it to be between 1.5 and 2 times more expensive.3 Median Medicare reimbursement for proton therapy in 2008 and 2009 was $32,428, which was 75% more expensive than IMRT ($18,575).7 Additionally, stereotactic body radiation therapy—which typically delivers 5 fractions of radiation over 2.5 weeks instead of the standard 40 fractions over 8 weeks—is an alternative treatment that is gaining momentum and emerging as an attractive option due to its short duration and cost-effectiveness.3 In an era when value has become an important factor in quality care, proton therapy has been justifiably scrutinized for overzealous commercial development and expense that has outpaced the clinical evidence. However, proponents of proton beam therapy argue that the technology has not reached its full potential and that improvements in treatment delivery make comparisons from decade-old studies obsolete. Proton treatment is also expected to become more affordable with a trend toward smaller treatment centers that are less expensive. Moreover, shortening treatment durations using hypofractionation protocols is another opportunity for cost savings.1,3
Several randomized controlled trials comparing IMRT to proton beam therapy are currently underway with primary completion dates anticipated within the next few years. The Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL; NCT01617161) trial will involve 12 treatment centers with a planned sample size of 400 patients. Patients will receive IMRT or proton therapy in either standard or hypofractionation protocols with the primary outcome comparing gastrointestinal quality of life scores 24 months after treatment. Additionally, the study will compare disease-specific quality of life, cost-effectiveness, dosimetry, biomarker identification, and disease-specific and long-term survival. Another large, prospective, pragmatic controlled comparison trial (Prospective Comparative Study of Outcomes With Proton and Photon Radiation in Prostate Cancer [COMPPARE]; NCT03561220) started recruitment in 2018 and will assess quality of life measures, toxicity rates and freedom from biochemical progression in 3,000 men receiving either photon or proton therapy. These studies will provide the first high-quality data directly comparing proton beam therapy to IMRT for prostate cancer and are likely to influence its future as a sustainable treatment option. Until then, we should view proton beam therapy as an expensive option with mixed toxicity benefits.
- Zietman A: Proton beam and prostate cancer: an evolving debate. Rep Pract Oncol Radiother 2013; 18: 338.
- De Laney TF and Kooy HM: Proton and Charged Particle Radiotherapy. Philadelphia: Lippincott Williams & Wilkins 2008.
- Royce TJ and Efstathiou JA: Proton therapy for prostate cancer: a review of the rationale, evidence, and current state. Urol Oncol 2019; 37: 628.
- Bryant C, Smith TL, Henderson RH et al: Five-year biochemical results, toxicity, and patient-reported quality of life after delivery of dose-escalated image guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2016; 95: 422.
- Fang P, Mick R, Deville C et al: A case-matched study of toxicity outcomes after proton therapy and intensity-modulated radiation therapy for prostate cancer. Cancer 2015; 121: 1118.
- Sheets NC, Goldin GH, Meyer A-M et al: Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA 2012; 307: 1611.
- Yu JB, Soulos PR, Herrin J et al: Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl Cancer Inst 2012; 105: 25.
- National Association for Proton Therapy: Map of Proton Therapy Centers in the US, 2022. Available at https://www.proton-therapy.org/map/.
- Johnstone PAS, Kerstiens J and Richard H: Proton facility economics: the importance of “simple” treatments. J Am Coll Radiol 2012; 9: 560.
- Hancock J: For cancer centers, proton therapy’s promise is undercut by lagging demand. New York Times, April 27, 2018.