Current Urology Reports

, Volume 14, Issue 3, pp 199–208 | Cite as

Proton Beam Radiation Therapy for Prostate Cancer—Is the Hype (and the Cost) Justified?

Prostate Cancer (D Parekh, Section Editor)


Although in use for over 40 years, proton beam therapy for prostate cancer has only recently come under public scrutiny, due to its increased cost compared to other forms of treatment. While the last decade has seen a rapid accumulation of evidence to suggest that proton beam therapy is both safe and effective in this disease site, a rigorous comparison to other radiotherapy techniques has not yet been completed. In this review, we provide an in-depth look at the evidence both supporting and questioning proton beam therapy’s future role in the treatment of prostate cancer, with emphasis on its history, physical properties, comparative clinical and cost effectiveness, advances in its delivery and future promise.


Prostate cancer Proton beam therapy Particle therapy IMRT Comparative effectiveness Cost 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–91.PubMedGoogle Scholar
  2. 2.
    Efstathiou JA, Trofimov AV, Zietman AL. Life, liberty, and the pursuit of protons: an evidence-based review of the role of particle therapy in the treatment of prostate cancer. Cancer J. 2009;15:312–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Gray PJ, Efstathiou JA. Prostate cancer: proton therapy-revolutionary advance or diminishing returns? Nat Rev Urol. 2013;10:128–9.Google Scholar
  4. 4.
    Shipley WU, Tepper JE, Prout Jr GR, et al. Proton radiation as boost therapy for localized prostatic carcinoma. JAMA. 1979;241:1912–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Emanuel E, Pearson S. It costs more but is it worth more? In: “The New York Times.” 2012.Google Scholar
  6. 6.
    Johnson C. Proton beams vs. radiation. In: “The Boston Globe.” 2012.Google Scholar
  7. 7.
    Bekelman JE, Mitra N, Efstathiou J, 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.PubMedCrossRefGoogle Scholar
  8. 8.
    Dinan MA, Robinson TJ, Zagar TM, et al. Changes in initial treatment for prostate cancer among Medicare beneficiaries, 1999–2007. Int J Radiat Oncol Biol Phys. 2012;82:e781–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Vargas C, Fryer A, Mahajan C, 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.PubMedCrossRefGoogle Scholar
  10. 10.
    Trofimov A, Nguyen PL, Coen JJ, 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.PubMedCrossRefGoogle Scholar
  11. 11.
    •• Gray PJ, Paly JJ, Yeap BY, et al. Patient-reported outcomes following 3D conformal, intensity-modulated or proton beam radiotherapy for localized prostate cancer. Cancer. 2013. doi:10.1002/cncr.27956. This study provided patient-reported quality of life data for three cohorts of patients treated with 3-D conformal, intensity modulated, or proton beam radiotherapy. Patients reported distinct patterns of treatment-related quality of life.
  12. 12.
    Fiorino C, Fellin G, Rancati T, et al. Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: preliminary results of a multicenter prospective study. Int J Radiat Oncol Biol Phys. 2008;70:1130–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Jackson A, Skwarchuk MW, Zelefsky MJ, et al. Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys. 2001;49:685–98.PubMedCrossRefGoogle Scholar
  14. 14.
    Karlsdottir A, Muren LP, Wentzel-Larsen T, Dahl O. Late gastrointestinal morbidity after three-dimensional conformal radiation therapy for prostate cancer fades with time in contrast to genitourinary morbidity. Int J Radiat Oncol Biol Phys. 2008;70:1478–86.PubMedCrossRefGoogle Scholar
  15. 15.
    Nguyen PL, Chen RC, Hoffman KE, et al. Rectal dose-volume histogram parameters are associated with long-term patient-reported gastrointestinal quality of life after conventional and high-dose radiation for prostate cancer: a subgroup analysis of a randomized trial. Int J Radiat Oncol Biol Phys. 2010;78:1081–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose–response. Int J Radiat Oncol Biol Phys. 2000;47:103–13.PubMedCrossRefGoogle Scholar
  17. 17.
    Tucker SL, Dong L, Michalski JM, et al. Do intermediate radiation doses contribute to late rectal toxicity? An analysis of data from radiation therapy oncology group protocol 94–06. Int J Radiat Oncol Biol Phys. 2012;84:390–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Segal RJ, Reid RD, Courneya KS, 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.PubMedCrossRefGoogle Scholar
  19. 19.
    Pickles T, Graham P. What happens to testosterone after prostate radiation monotherapy and does it matter? J Urol. 2002;167:2448–52.PubMedCrossRefGoogle Scholar
  20. 20.
    Zagars GK, Pollack A. Serum testosterone levels after external beam radiation for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 1997;39:85–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Nichols Jr RC, Morris CG, Hoppe BS, 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.PubMedCrossRefGoogle Scholar
  22. 22.
    Rechner LA, Howell RM, Zhang R, et al. Risk of radiogenic second cancers following volumetric modulated arc therapy and proton arc therapy for prostate cancer. Phys Med Biol. 2012;57:7117–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Yoon M, Ahn SH, Kim J, 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.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar
  25. 25.
    Goitein M. Magical protons? Int J Radiat Oncol Biol Phys. 2008;70:654–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Clasie B, Wroe A, Kooy H, et al. Assessment of out-of-field absorbed dose and equivalent dose in proton fields. Med Phys. 2010;37:311–21.PubMedCrossRefGoogle Scholar
  27. 27.
    Trofimov A, Nguyen PL, Efstathiou JA, 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.PubMedCrossRefGoogle Scholar
  28. 28.
    Yoon M, Shin D, Kwak J, 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Wang Y, Efstathiou JA, Sharp GC, et al. Evaluation of the dosimetric impact of interfractional anatomical variations on prostate proton therapy using daily in-room CT images. Med Phys. 2011;38:4623–33.PubMedCrossRefGoogle Scholar
  30. 30.
    Athar BS, Bednarz B, Seco J, et al. 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.PubMedCrossRefGoogle Scholar
  31. 31.
    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.PubMedCrossRefGoogle Scholar
  32. 32.
    Robertson JB, Williams JR, Schmidt RA, et al. Radiobiological studies of a high-energy modulated proton beam utilizing cultured mammalian cells. Cancer. 1975;35:1664–77.PubMedCrossRefGoogle Scholar
  33. 33.
    Shipley WU, Verhey LJ, Munzenrider JE, 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.PubMedCrossRefGoogle Scholar
  34. 34.
    Slater JD, Rossi Jr CJ, Yonemoto LT, et al. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int J Radiat Oncol Biol Phys. 2004;59:348–52.PubMedCrossRefGoogle Scholar
  35. 35.
    Johansson S, Astrom L, Sandin F, et al. Hypofractionated proton boost combined with external beam radiotherapy for treatment of localized prostate cancer. Prostate Cancer. 2012;2012:654861.PubMedCrossRefGoogle Scholar
  36. 36.
    Mendenhall NP, Li Z, Hoppe BS, 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.PubMedCrossRefGoogle Scholar
  37. 37.
    • Coen JJ, Bae K, Zietman AL, et al. Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology Phase II study 03–12. Int J Radiat Oncol Biol Phys. 2011;81:1005–9. This study of dose escalation to 82 Gy (RBE) using proton beam monotherapy for prostate cancer highlights the concern that a dose ceiling in terms of toxicity may exist with current delivery techniques.PubMedCrossRefGoogle Scholar
  38. 38.
    Nihei K, Ogino T, Onozawa M, et al. Multi-institutional phase II study of proton beam therapy for organ-confined prostate cancer focusing on the incidence of late rectal toxicities. Int J Radiat Oncol Biol Phys. 2011;81:390–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Zietman AL, Bae K, Slater JD, 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.PubMedCrossRefGoogle Scholar
  40. 40.
    Mayahara H, Murakami M, Kagawa K, et al. Acute morbidity of proton therapy for prostate cancer: the Hyogo Ion Beam Medical Center experience. Int J Radiat Oncol Biol Phys. 2007;69:434–43.PubMedCrossRefGoogle Scholar
  41. 41.
    Nihei K, Ogino T, Ishikura S, et al. Phase II feasibility study of high-dose radiotherapy for prostate cancer using proton boost therapy: first clinical trial of proton beam therapy for prostate cancer in Japan. Jpn J Clin Oncol. 2005;35:745–52.PubMedCrossRefGoogle Scholar
  42. 42.
    Talcott JA, Rossi C, Shipley WU, et al. Patient-reported long-term outcomes after conventional and high-dose combined proton and photon radiation for early prostate cancer. JAMA. 2010;303:1046–53.PubMedCrossRefGoogle Scholar
  43. 43.
    McGee L, Mendenhall NP, Henderson RH et al. Outcomes in men with large prostates (>/= 60 cm(3)) treated with definitive proton therapy for prostate cancer. Acta Oncol. 2012.Google Scholar
  44. 44.
    Hoppe BS, Nichols RC, Henderson RH, 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.PubMedCrossRefGoogle Scholar
  45. 45.
    Coen JJ, Paly JJ, Niemierko A, et al. Long-term quality of life outcome after proton beam monotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:e201–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Coen JJ, Zietman AL, Rossi CJ, 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.PubMedCrossRefGoogle Scholar
  47. 47.
    Kim S, Shen S, Moore DF, et al. Late gastrointestinal toxicities following radiation therapy for prostate cancer. Eur Urol. 2011;60:908–16.PubMedCrossRefGoogle Scholar
  48. 48.
    •• Sheets NC, Goldin GH, Meyer AM, 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. This study highlights the differences in gastrointestinal (GI) and genitourinary toxicity in prostate cancer patients treated with 3-D conformal radiotherapy, IMRT, and proton beam using the linked SEER–Medicare database. Using propensity score matching, IMRT was associated with less late GI toxicity, as compared with 3-D conformal or proton therapy; however, data on radiation dose and treatment volume were not available.PubMedCrossRefGoogle Scholar
  49. 49.
    •• 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. 2013;105:25–32. This study investigated differences in 6- and 12-month toxicity for prostate cancer patients treated with IMRT or proton beam and also investigated the median cost of the two therapies, using a Medicare database. They found that proton beam therapy had a higher median cost but was associated with a time-limited benefit in genitourinary toxicity.PubMedCrossRefGoogle Scholar
  50. 50.
    • Shah A, Efstathiou JA, Paly JJ, et al. Prospective preference assessment of patients' willingness to participate in a randomized controlled trial of intensity-modulated radiotherapy versus proton therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012;83:e13–9. This study prospectively assessed patient willingness to participate in a randomized controlled trial of IMRT versus PBT for localized prostate cancer. Nearly 60 % of eligible patients stated that they were likely to enroll in such a trial.PubMedCrossRefGoogle Scholar
  51. 51.
    Jarosek S, Elliott S, Virnig BA. Proton beam radiotherapy in the U.S. Medicare population: growth in use between 2006 and 2009: data points # 10. 2011.Google Scholar
  52. 52.
    Konski A, Speier W, Hanlon A, et al. Is proton beam therapy cost effective in the treatment of adenocarcinoma of the prostate? J Clin Oncol. 2007;25:3603–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Elnahal SM, Kerstiens J, Helsper RS, et al. Proton beam therapy and accountable care: the challenges ahead. Int J Radiat Oncol Biol Phys. 2013;85:e165–72.Google Scholar
  54. 54.
    Herman JM. Proton therapy in an era of cost containment. J Natl Compr Cancer Netw. 2011;9:821–5.Google Scholar
  55. 55.
    Arcangeli S, Strigari L, Gomellini S, et al. Updated results and patterns of failure in a randomized hypofractionation trial for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2012;84:1172–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Boike TP, Lotan Y, Cho LC, et al. Phase I dose-escalation study of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer. J Clin Oncol. 2011;29:2020–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Dearnaley D, Syndikus I, Sumo G, 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.PubMedCrossRefGoogle Scholar
  58. 58.
    Kupelian PA, Willoughby TR, Reddy CA, et al. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland clinic experience. Int J Radiat Oncol Biol Phys. 2007;68:1424–30.PubMedCrossRefGoogle Scholar
  59. 59.
    Kase Y, Yamashita H, Fuji H, et al. A treatment planning comparison of passive-scattering and intensity-modulated proton therapy for typical tumor sites. J Radiat Res. 2012;53:272–80.PubMedCrossRefGoogle Scholar
  60. 60.
    Widesott L, Pierelli A, Fiorino C, et al. Helical tomotherapy vs. intensity-modulated proton therapy for whole pelvis irradiation in high-risk prostate cancer patients: dosimetric, normal tissue complication probability, and generalized equivalent uniform dose analysis. Int J Radiat Oncol Biol Phys. 2011;80:1589–600.PubMedCrossRefGoogle Scholar
  61. 61.
    Weber DC, Wang H, Cozzi L, et al. RapidArc, intensity modulated photon and proton techniques for recurrent prostate cancer in previously irradiated patients: a treatment planning comparison study. Radiat Oncol. 2009;4:34.PubMedCrossRefGoogle Scholar
  62. 62.
    Lomax AJ, Pedroni E, Rutz H, Goitein G. The clinical potential of intensity modulated proton therapy. Z Med Phys. 2004;14:147–52.PubMedGoogle Scholar
  63. 63.
    Tang S, Both S, Bentefour H, et al. Improvement of prostate treatment by anterior proton fields. Int J Radiat Oncol Biol Phys. 2012;83:408–18.PubMedCrossRefGoogle Scholar
  64. 64.
    Shah A, Paly JJ, Efstathiou JA, Bekelman JE. Physician evaluation of internet health information on proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2013;85:e173-7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Harvard Radiation Oncology ProgramBostonUSA
  2. 2.Department of Radiation OncologyMassachusetts General HospitalBostonUSA

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