Advances in radiation technology have transformed treatment options for patients with localized prostate cancer. The evolution of three-dimensional conformal radiation therapy and intensity-modulated radiation therapy (IMRT) have allowed physicians to spare surrounding normal organs and reduce adverse effects. The introduction of proton beam technology and its physical advantage of depositing its energy in tissue at the end-of-range maximum may potentially spare critical organs such as the bladder and rectum in prostate cancer patients. Data thus far are limited to large, observational studies that have not yet demonstrated a definite benefit of protons over conventional treatment with IMRT. The cost of proton beam treatment adds to the controversy within the field.
We performed an extensive literature review for all proton treatment-related prostate cancer studies. We discuss the history of proton beam technology, as well as its role in the treatment of prostate cancer, associated controversies, novel technology trends, a discussion of cost-effectiveness, and an overview of the ongoing modern large prospective studies that aim to resolve the debate between protons and photons for prostate cancer.
Present data have demonstrated that proton beam therapy is safe and effective compared with the standard treatment options for prostate cancer. While dosimetric studies suggest lower whole-body radiation dose and a theoretically higher relative biological effectiveness in prostate cancer compared with photons, no studies have demonstrated a clear benefit with protons.
Evolving trends in proton treatment delivery and proton center business models are helping to reduce costs. Introduction of existing technology into proton delivery allows further control of organ motion and addressing organs-at-risk. Finally, the much-awaited contemporary studies comparing photon with proton-based treatments, with primary endpoints of patient-reported quality-of-life, will help us understand the differences between proton and photon-based treatments for prostate cancer in the modern era.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $131.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Dearnaley DP, Khoo VS, Norman AR, Meyer L, Nahum A, Tait D, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet (Lond, Engl). 1999;353:267–72.
Gray PJ, Efstathiou JA. Prostate cancer: proton therapy–revolutionary advance or diminishing returns? Nat Rev Urol. 2013;10:128–9.
Alicikus ZA, Yamada Y, Zhang Z, Pei X, Hunt M, Kollmeier M, et al. Ten-year outcomes of high-dose, intensity-modulated radiotherapy for localized prostate cancer. Cancer. 2011;117:1429–37.
Alongi F, Fiorino C, Cozzarini C, Broggi S, Perna L, Cattaneo GM, et al. IMRT significantly reduces acute toxicity of whole-pelvis irradiation in patients treated with post-operative adjuvant or salvage radiotherapy after radical prostatectomy. Radiother Oncol. 2009;93:207–12.
Kuban DA, Tucker SL, Dong L, Starkschall G, Huang EH, Cheung MR, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:67–74.
Latorzeff I, Mazurier J, Boutry C, Dudouet P, Richaud P, de Crevoisier R. [Benefit of intensity modulated and image-guided radiotherapy in prostate cancer]. Cancer Radiother: J De la Soc Fr De Radiother Oncol. 2010;14:479–87.
Gray PJ, Efstathiou JA, Bekelman JE, Lee WR. Proton therapy for prostate cancer: history, uncertainties, and opportunities. In: DeVita VT, Lawrence TS, Rosenberg SA, editors. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology, 9th edn, vol. 27. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.
Efstathiou JA, Gray PJ, Zietman AL. Proton beam therapy and localised prostate cancer: current status and controversies. Br J Cancer. 2013;108:1225–30.
Royce TJ, Efstathiou JA. Proton therapy for prostate cancer: A review of the rationale, evidence, and current state. Urol Oncol. 2018. https://doi.org/10.1016/j.urolonc.2018.11.012 [Epub ahead of print].
Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull base. Strahlentherapie und Onkologie 1999;175:57–63.
Gragoudas ES, Lane AM, Munzenrider JE, Egan KM, Li W. Long-term risk of local failure after proton therapy for choroidal/ciliary body melanoma. Trans Am Ophthalmol Soc. 2002;100:43–48.
MacDonald SM, Safai S, Trofimov A, Wolfgang J, Fullerton B, Yeap BY, et al. Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys. 2008;71:979–86.
Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–91.
Efstathiou JA, Trofimov AV, Zietman ALLife. liberty, and the pursuit of protons: an evidence-based review of the role of particle therapy in the treatment of prostate cancer. Cancer J (Sudbury, Mass). 2009;15:312–8.
Shipley WU, Tepper JE, Prout GR Jr., Verhey LJ, Mendiondo OA, Goitein M, et al. Proton radiation as boost therapy for localized prostatic carcinoma. JAMA. 1979;241:1912–5.
Benk VA, Adams JA, Shipley WU, Urie MM, McManus PL, Efird JT, et al. Late rectal bleeding following combined X-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma. Int J Radiat Oncol Biol Phys. 1993;26:551–7.
Duttenhaver JR, Shipley WU, Perrone T, Verhey LJ, Goitein M, Munzenrider JE, et al. Protons or megavoltage X-rays as boost therapy for patients irradiated for localized prostatic carcinoma. An early phase I/II comparison. Cancer. 1983;51:1599–604.
Shipley WU, Verhey LJ, Munzenrider JE, Suit HD, Urie MM, McManus PL, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys. 1995;32:3–12.
Corkum MT, Liu W, Palma DA, Bauman GS, Dinniwell RE, Warner A, et al. Online advertising and marketing claims by providers of proton beam therapy: are they guideline-based? Radiat Oncol. 2018;13:43.
Hancock J. For cancer centers, proton therapy’s promise is undercut by lagging demand. New York, NY: New York Times; 2018. Available at: https://www.nytimes.com/2018/04/27/business/proton-therapy-finances.html. Accessed Nov 2018.
Bekelman JE, Mitra N, Efstathiou J, Liao K, Sunderland R, Yeboa DN, et al. Outcomes after intensity-modulated versus conformal radiotherapy in older men with nonmetastatic prostate cancer. Int J Radiat Oncol Biol Phys. 2011;81:e325–34.
Dearnaley D, Syndikus I, Sumo G, Bidmead M, Bloomfield D, Clark C, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from the CHHiP randomised controlled trial. Lancet Oncol. 2012;13:43–54.
Catton CN, Lukka H, Gu CS, Martin JM, Supiot S, Chung PWM, et al. Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol. 2017;35:1884–90.
Lee WR, Dignam JJ, Amin MB, Bruner DW, Low D, Swanson GP, et al. Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol. 2016;34:2325–32.
Elnahal SM, Kerstiens J, Helsper RS, Zietman AL, Johnstone PA. Proton beam therapy and accountable care: the challenges ahead. Int J Radiat Oncol Biol Phys. 2013;85:e165–72.
Lievens Y, Pijls-Johannesma M. Health economic controversy and cost-effectiveness of proton therapy. Semin Radiat Oncol. 2013;23:134–41.
Ojerholm E, Bekelman JE. Finding value for protons: the case of prostate cancer? Semin Radiat Oncol. 2018;28:131–7.
Pollack A. Cancer fight goes nuclear, with heavy price tag. New York, NY: New York Times; 2007. Available at: https://www.nytimes.com/2007/12/26/health/25cnd-proton.html. Accessed Oct 2018.
Wallner PE, Steinberg ML, Konski AA. Controversies in the adoption of new healthcare technologies. Front Radiat Ther Oncol. 2011;43:60–78.
Zietman AL, Bae K, Slater JD, Shipley WU, Efstathiou JA, Coen JJ, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/american college of radiology 95-09. J Clin Oncol. 2010;28:1106–11.
Slater JD, Rossi CJ Jr., Yonemoto LT, Bush DA, Jabola BR, Levy RP, et al. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int J Radiat Oncol Biol Phys. 2004;59:348–52.
Coen JJ, Zietman AL, Rossi CJ, Grocela JA, Efstathiou JA, Yan Y, et al. Comparison of high-dose proton radiotherapy and brachytherapy in localized prostate cancer: a case-matched analysis. Int J Radiat Oncol Biol Phys. 2012;82:e25–31.
Paganetti H, Giantsoudi D. Relative biological effectiveness uncertainties and implications for beam arrangements and dose constraints in proton therapy. Semin Radiat Oncol. 2018;28:256–63.
Girdhani S, Sachs R, Hlatky L. Biological effects of proton radiation: what we know and don’t know. Radiat Res. 2013;179:257–72.
Paganetti H. Advancing (proton) radiation therapy. Int J Radiat Oncol Biol Phys. 2013;87:871–3.
Trofimov A, Nguyen PL, Coen JJ, Doppke KP, Schneider RJ, Adams JA, et al. Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison. Int J Radiat Oncol Biol Phys. 2007;69:444–53.
Vargas C, Fryer A, Mahajan C, Indelicato D, Horne D, Chellini A, et al. Dose-volume comparison of proton therapy and intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:744–51.
Zhang X, Dong L, Lee AK, Cox JD, Kuban DA, Zhu RX, et al. Effect of anatomic motion on proton therapy dose distributions in prostate cancer treatment. Int J Radiat Oncol Biol Phys. 2007;67:620–9.
Pickles T, Graham P. What happens to testosterone after prostate radiation monotherapy and does it matter? J Urol. 2002;167:2448–52.
Segal RJ, Reid RD, Courneya KS, Sigal RJ, Kenny GP, Prud’Homme DG, et al. Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer. J Clin Oncol. 2009;27:344–51.
Zagars GK, Pollack A. Serum testosterone levels after external beam radiation for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 1997;39:85–89.
Davis EJ, Beebe-Dimmer JL, Yee CL, Cooney KA. Risk of second primary tumors in men diagnosed with prostate cancer: a population-based cohort study. Cancer. 2014;120:2735–41.
Murray L, Henry A, Hoskin P, Siebert FA, Venselaar J. ESTRO PgoG. Second primary cancers after radiation for prostate cancer: a systematic review of the clinical data and impact of treatment technique. Radiother Oncol. 2014;110:213–28.
Fontenot JD, Lee AK, Newhauser WD. Risk of secondary malignant neoplasms from proton therapy and intensity-modulated x-ray therapy for early-stage prostate cancer. Int J Radiat Oncol Biol Phys. 2009;74:616–22.
Rechner LA, Howell RM, Zhang R, Etzel C, Lee AK, Newhauser WD. Risk of radiogenic second cancers following volumetric modulated arc therapy and proton arc therapy for prostate cancer. Phys Med Biol. 2012;57:7117–32.
Yoon M, Ahn SH, Kim J, Shin DH, Park SY, Lee SB, et al. Radiation-induced cancers from modern radiotherapy techniques: intensity-modulated radiotherapy versus proton therapy. Int J Radiat Oncol Biol Phys. 2010;77:1477–85.
Moteabbed M, Trofimov A, Khan FH, Wang Y, Sharp GC, Zietman AL, et al. Impact of interfractional motion on hypofractionated pencil beam scanning proton therapy and VMAT delivery for prostate cancer. Med Phys. 2018; https://doi.org/10.1002/mp.13091. [Epub ahead of print].
Yu JB, Soulos PR, Herrin J, Cramer LD, Potosky AL, Roberts KB, et al. Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl Cancer Inst. 2013;105:25–32.
Rubin DB. Bias reduction using Mahalanobis-metric matching. Biometrics. 1980;36:293–8.
Kim S, Shen S, Moore DF, Shih W, Lin Y, Li H, et al. Late gastrointestinal toxicities following radiation therapy for prostate cancer. Eur Urol. 2011;60:908–16.
Sheets NC, Goldin GH, Meyer AM, Wu Y, Chang Y, Sturmer T, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA. 2012;307:1611–20.
Pan HY, Jiang J, Hoffman KE, Tang C, Choi SL, Nguyen QN, et al. Comparative toxicities and cost of intensity-modulated radiotherapy, proton radiation, and stereotactic body radiotherapy among younger men with prostate cancer. J Clin Oncol. 2018;36:1823–30.
Gray PJ, Paly JJ, Yeap BY, Sanda MG, Sandler HM, Michalski JM, et al. Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer. 2013;119:1729–35.
Fang P, Mick R, Deville C, Both S, Bekelman JE, Christodouleas JP, et al. A case-matched study of toxicity outcomes after proton therapy and intensity-modulated radiation therapy for prostate cancer. Cancer. 2015;121:1118–27.
Mendenhall NP, Li Z, Hoppe BS, Marcus RB Jr., Mendenhall WM, Nichols RC, et al. Early outcomes from three prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:213–21.
Hoppe BS, Michalski JM, Mendenhall NP, Morris CG, Henderson RH, Nichols RC, et al. Comparative effectiveness study of patient-reported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer. 2014;120:1076–82.
Hoppe BS, Nichols RC, Henderson RH, Morris CG, Williams CR, Costa J, et al. Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger. Cancer. 2012;118:4619–26.
Ho CK, Bryant CM, Mendenhall NP, Henderson RH, Mendenhall WM, Nichols RC, et al. Long-term outcomes following proton therapy for prostate cancer in young men with a focus on sexual health. Acta Oncol. 2018;57:582–8.
Nichols RC Jr., Morris CG, Hoppe BS, Henderson RH, Marcus RB Jr., Mendenhall WM, et al. Proton radiotherapy for prostate cancer is not associated with post-treatment testosterone suppression. Int J Radiat Oncol Biol Phys. 2012;82:1222–6.
Henderson RH, Hoppe BS, Marcus RB Jr., Mendenhall WM, Nichols RC, Li Z, et al. Urinary functional outcomes and toxicity five years after proton therapy for low- and intermediate-risk prostate cancer: results of two prospective trials. Acta Oncol. 2013;52:463–9.
Iwata H, Ishikawa H, Takagi M, et al. Long-term outcomes of proton therapy for prostate cancer in Japan: a multi-institutional survey of the Japanese Radiation Oncology Study Group. Cancer Med. 2018;7:677–89.
Massett M. Protons for prostate cancer: Bragging points, trials, and treatment optimization. Appl Rad. Oncol. 2017;6:24–7.
Cuaron JJ, Harris AA, Chon B, Tsai H, Larson G, Hartsell WF, et al. Anterior-oriented proton beams for prostate cancer: a multi-institutional experience. Acta Oncol. 2015;54:868–74.
Trofimov A, Nguyen PL, Efstathiou JA, Wang Y, Lu HM, Engelsman M, et al. Interfractional variations in the setup of pelvic bony anatomy and soft tissue, and their implications on the delivery of proton therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2011;80:928–37.
Yoon M, Shin D, Kwak J, Park S, Lim YK, Kim D, et al. Characteristics of movement-induced dose reduction in target volume: a comparison between photon and proton beam treatment. Med Dosim. 2009;34:191–201.
Athar BS, Bednarz B, Seco J, Hancox C, Paganetti H. Comparison of out-of-field photon doses in 6 MV IMRT and neutron doses in proton therapy for adult and pediatric patients. Phys Med Biol. 2010;55:2879–91.
Brenner DJ, Elliston CD, Hall EJ, Paganetti H. Reduction of the secondary neutron dose in passively scattered proton radiotherapy, using an optimized pre-collimator/collimator. Phys Med Biol. 2009;54:6065–78.
Robertson JB, Williams JR, Schmidt RA, Little JB, Flynn DF, Suit HD. Radiobiological studies of a high-energy modulated proton beam utilizing cultured mammalian cells. Cancer. 1975;35:1664–77.
Moteabbed M, Trofimov A, Sharp GC, Wang Y, Zietman AL, Efstathiou JA, et al. A prospective comparison of the effects of interfractional variations on proton therapy and intensity modulated radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2016;95:444–53.
Moteabbed M, Sharp GC, Wang Y, Trofimov A, Efstathiou JA, Lu HM. Validation of a deformable image registration technique for cone beam CT-based dose verification. Med Phys. 2015;42:196–205.
Hamstra DA, Mariados N, Sylvester J, Shah D, Karsh L, Hudes R, et al. Continued benefit to rectal separation for prostate radiation therapy: final results of a phase III trial. Int J Radiat Oncol Biol Phys. 2017;97:976–85.
Underwood TS, Voog JC, Moteabbed M, Tang S, Soffen E, Cahlon O, et al. Hydrogel rectum-prostate spacers mitigate the uncertainties in proton relative biological effectiveness associated with anterior-oblique beams. Acta Oncol. 2017;56:575–81.
Thompson IM, Valicenti RK, Albertsen P, Davis BJ, Goldenberg SL, Hahn C, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013;190:441–9.
Swisher-McClure S, Yin L, Rosen M, Batra S, Berman AT, Both S, et al. Prospective MRI-based imaging study to assess feasibility of proton therapy for post-prostatectomy radiation. Acta Oncol. 2016;55:828–33.
Deville C, Jr., Jain A, Hwang WT, Woodhouse KD, Both S, Wang S, et al. Initial report of the genitourinary and gastrointestinal toxicity of post-prostatectomy proton therapy for prostate cancer patients undergoing adjuvant or salvage radiotherapy. Acta Oncol. 2018;57:1–9.
Aizer AA, Yu JB, McKeon AM, Decker RH, Colberg JW, Peschel RE. Whole pelvic radiotherapy versus prostate only radiotherapy in the management of locally advanced or aggressive prostate adenocarcinoma. Int J Radiat Oncol Biol Phys. 2009;75:1344–9.
Vees H, Dipasquale G, Nouet P, Zilli T, Cozzi L, Miralbell R. Pelvic lymph node irradiation including pararectal sentinel nodes for prostate cancer patients: treatment optimization comparing intensity modulated X-rays, volumetric modulated arc therapy, and intensity modulated proton therapy. Technol Cancer Res Treat. 2015;14:181–9.
Chera BS, Vargas C, Morris CG, Louis D, Flampouri S, Yeung D, et al. Dosimetric study of pelvic proton radiotherapy for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2009;75:994–1002.
Morgan SC, Hoffman K, Loblaw D, Buyyounouski MK, Patton C, Barocas D, et al. Hypofractionated radiation therapy for localized prostate cancer: An ASTRO, ASCO, and AUA evidence-based guideline. J Clin Oncol. 2018; JCO1801097, https://doi.org/10.1200/JCO.18.01097. [Epub ahead of print].
Goddard LC, Brodin NP, Bodner WR, Garg MK, Tome WA. Comparing photon and proton-based hypofractionated SBRT for prostate cancer accounting for robustness and realistic treatment deliverability. Br J Radiol. 2018;91:20180010.
Kole TP, Nichols RC, Lei S, Wu B, Huh SN, Morris CG, et al. A dosimetric comparison of ultra-hypofractionated passively scattered proton radiotherapy and stereotactic body radiotherapy (SBRT) in the definitive treatment of localized prostate cancer. Acta Oncol. 2015;54:825–31.
Stapinski, H. The high-tech, big-footprint Cancer center. New York, NY: New York Times; 2017. Available at: https://www.nytimes.com/2017/12/26/nyregion/the-high-tech-big-footprint-cancer-center.html. Accessed Oct. 2018.
Konski A. Cost effectiveness of prostate cancer radiotherapy. Transl Androl Urol. 2018;7:371–7.
Konski A, Speier W, Hanlon A, Beck JR, Pollack A. Is proton beam therapy cost effective in the treatment of adenocarcinoma of the prostate? J Clin Oncol. 2007;25:3603–8.
Thaker NG, Ali TN, Porter ME, Feeley TW, Kaplan RS, Frank SJ. Communicating value in health care using radar charts: a case study of prostate cancer. J Oncol Pract. 2016;12:813–20.
Yu JB, Efstathiou JA, Bekelman JE. Proton radiotherapy for prostate cancer: how did we get here, and where do we go from here? Oncology 2013;27:1293–4.
Shah A, Ricci KI, Efstathiou JA. Beyond a moonshot: insurance coverage for proton therapy. Lancet Oncol. 2016;17:559–61.
Bekelman JE, Denicoff A, Buchsbaum J. Randomized trials of proton therapy: why they are at risk, proposed solutions, and implications for evaluating advanced technologies to diagnose and treat cancer. J Clin Oncol. 2018;36:2461–4.
ASTRO model policies: Proton beam therapy, 2017. Available at: https://www.astro.org/uploadedFiles/_MAIN_SITE/Daily_Practice/Reimbursement/Model_Policies/Content_Pieces/ASTROPBTModelPolicy.pdf. Accessed Nov 2018.
Oklahoma Insurance Department - Legislative Changes, 2015. Available at: https://www.ok.gov/oid/documents/100215_2015%20OID%20Legislative%20Update-reducedsize.pdf. Accessed Oct 2018.
Bortfeld TR, Loeffler JS. Three ways to make proton therapy affordable. Nature. 2017;549:451–3.
Bekelman JE, Hahn SM. Reference pricing with evidence development: a way forward for proton therapy. J Clin Oncol. 2014;32:1540–2.
We thank Maryam Moteabbed, PhD, for her assistance with the Figures. JAE serves as the principal investigator of the PARTIQoL multi-center randomized phase 3 clinical trial of proton therapy versus intensity-modulated radiotherapy for localized prostate cancer and acknowledges funding support from the Federal Share of program income earned by Massachusetts General Hospital (grant C06 CA059267) and the Prostate Cancer Foundation.