Hypofractionated Radiotherapy for Localized Prostate Cancer: When and for Whom?
Purpose of Review
To summarize recent evidence concerning the use of moderately hypofractionated external beam radiotherapy, defined as 2.4–3.4 Gy per fraction, and ultrahypofractionated external beam radiotherapy (also known as stereotactic body radiotherapy [SBRT]), defined as at least 5 Gy per fraction, in men with localized prostate cancer.
Taken together, a number of recently completed randomized trials show that moderately hypofractionated radiotherapy confers similar biochemical control compared to conventionally fractionated radiotherapy without increasing late toxicity. These effects appear to extend across all baseline clinical risk groups. Several single-arm phase II studies, as well as a recently published large-scale randomized trial comparing SBRT with conventional fractionation, show very promising biochemical control and favorable acute and late treatment-related morbidity with the use of SBRT in predominantly low- and intermediate-risk prostate cancer.
As it is associated with similar prostate cancer control and toxicity while improving patient convenience and reducing cost, moderate hypofractionation is a preferred alternative to conventional fractionation in a majority of men with localized prostate cancer choosing radiotherapy as their primary treatment modality. To date, studies conducted largely in low- and intermediate-risk prostate cancer report encouraging oncologic outcomes and acceptable toxicity with SBRT. Mature results of phase III trials evaluating five-fraction SBRT regimens are eagerly awaited.
KeywordsProstate cancer Hypofractionated radiotherapy External beam radiotherapy
Compliance with Ethical Standards
Conflict of Interest
Soumyajit Roy declares no potential conflicts of interest.
Scott C. Morgan is on the advisory board and consults for Astellas, Bayer Healthcare, and Janssen.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate Cancer. N Engl J Med. 2016;375(15):1415–24. https://doi.org/10.1056/NEJMoa1606220.
- 2.Mason MD, Parulekar WR, Sydes MR, Brundage M, Kirkbride P, Gospodarowicz M, et al. Final report of the intergroup randomized study of combined androgen-deprivation therapy plus radiotherapy versus androgen-deprivation therapy alone in locally advanced prostate Cancer. J Clin Oncol. 2015;33(19):2143–50. https://doi.org/10.1200/jco.2014.57.7510.
- 3.Fossa SD, Wiklund F, Klepp O, Angelsen A, Solberg A, Damber JE, et al. Ten- and 15-yr prostate Cancer-specific mortality in patients with nonmetastatic locally advanced or aggressive intermediate prostate Cancer, randomized to lifelong endocrine treatment alone or combined with radiotherapy: final results of the Scandinavian prostate Cancer Group-7. Eur Urol. 2016;70(4):684–91. https://doi.org/10.1016/j.eururo.2016.03.021.
- 4.Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol. 2010;11(11):1066–73. https://doi.org/10.1016/s1470-2045(10)70223-0.
- 5.Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005;61(5):1285–90. https://doi.org/10.1016/j.ijrobp.2004.08.047.
- 6.Thames HD Jr, Withers HR, Peters LJ, Fletcher GH. Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships. Int J Radiat Oncol Biol Phys. 1982;8(2):219–26.Google Scholar
- 7.Proust-Lima C, Taylor JM, Secher S, Sandler H, Kestin L, Pickles T, et al. Confirmation of a low alpha/beta ratio for prostate cancer treated by external beam radiation therapy alone using a post-treatment repeated-measures model for PSA dynamics. Int J Radiat Oncol Biol Phys. 2011;79(1):195–201. https://doi.org/10.1016/j.ijrobp.2009.10.008.
- 8.Dasu A, Toma-Dasu I. Prostate alpha/beta revisited -- an analysis of clinical results from 14 168 patients. Acta Oncol. 2012;51(8):963–74. https://doi.org/10.3109/0284186x.2012.719635.
- 9.Vogelius IR, Bentzen SM. Meta-analysis of the alpha/beta ratio for prostate cancer in the presence of an overall time factor: bad news, good news, or no news? Int J Radiat Oncol Biol Phys. 2013;85(1):89–94. https://doi.org/10.1016/j.ijrobp.2012.03.004.
- 10.• Morgan SC, Hoffman K, Loblaw DA, Buyyounouski MK, Patton C, Barocas D, et al. Hypofractionated Radiation Therapy for Localized Prostate Cancer: Executive Summary of an ASTRO, ASCO, and AUA Evidence-Based Guideline. Pract Radiat Oncol. 2018;8(6):354–60. https://doi.org/10.1016/j.prro.2018.08.002 Recently-published clinical practice guideline on the use hypofractionated radiotherapy led by the American Society for Radiation Oncology in collaboration with the American Society of Clinical Oncology and the American Urological Association.
- 11.• Voong KR, Lal LS, Kuban DA, Pugh TJ, Swint JM, Godby J, et al. Long-term economic value of hypofractionated prostate radiation: secondary analysis of a randomized trial. Adv Radiat Oncol. 2017;2(3):249–58. https://doi.org/10.1016/j.adro.2017.07.010 . Cost-effectiveness analysis of moderate hypofractionation based on the MD Anderson Cancer Center randomized trial.
- 12.Zemplenyi AT, Kalo Z, Kovacs G, Farkas R, Beothe T, Banyai D, et al. Cost-effectiveness analysis of intensity-modulated radiation therapy with normal and hypofractionated schemes for the treatment of localised prostate cancer. Eur J Cancer Care (Engl). 2018;27(1). https://doi.org/10.1111/ecc.12430.
- 13.•• Dearnaley D, Syndikus I, Mossop H, Khoo V, Birtle A, Bloomfield D, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17(8):1047–60. https://doi.org/10.1016/s1470-2045(16)30102-4 CHHiP is, by a wide margin, the largest completed randomized controlled trial that compared moderately hypofractionated RT with conventionally fractionated RT in localized prostate cancer. It can therefore be argued that it provides the most precise effect estimates for moderate hypofractionation.
- 14.•• Widmark A, Gunnlaugsson A, Beckman L, Thellenberg-Karlsson C, Hoyer M, Lagerlund M, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019. https://doi.org/10.1016/s0140-6736(19)31131-6 HYPO-RT-PC is the only published large-scale randomized trial comparing SBRT and conventional fractionation.
- 15.• 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(20):2325–32. https://doi.org/10.1200/jco.2016.67.0448 Randomized trial of moderate hypofractionation conducted by the Radiation Therapy Oncology Group/NRG Oncology.
- 16.Pollack A, Walker G, Horwitz EM, Price R, Feigenberg S, Konski AA, et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol. 2013;31(31):3860–8. https://doi.org/10.1200/jco.2013.51.1972.
- 17.• 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(17):1884–90. https://doi.org/10.1200/jco.2016.71.7397 Randomized trial of moderate hypofractionation conducted by the Ontario Clinical Oncology Group.
- 18.• Stokes WA, Kavanagh BD, Raben D, Pugh TJ. Implementation of hypofractionated prostate radiation therapy in the United States: A National Cancer Database analysis. Pract Radiat Oncol. 2017;7(4):270–8. https://doi.org/10.1016/j.prro.2017.03.011 Observational study describing recent trends in the utilization of hypofractionated radiotherapy in the United States.
- 19.Arcangeli G, Saracino B, Arcangeli S, Gomellini S, Petrongari MG, Sanguineti G, et al. Moderate Hypofractionation in high-risk, organ-confined prostate Cancer: final results of a phase III randomized trial. J Clin Oncol. 2017;35(17):1891–7. https://doi.org/10.1200/jco.2016.70.4189.
- 20.Hoffman KE, Voong KR, Levy LB, Allen PK, Choi S, Schlembach PJ, et al. Randomized trial of Hypofractionated, dose-escalated, intensity-modulated radiation therapy (IMRT) versus conventionally fractionated IMRT for localized prostate Cancer. J Clin Oncol. 2018;36(29):2943–9. https://doi.org/10.1200/jco.2018.77.9868.
- 21.Wilkins A, Mossop H, Syndikus I, Khoo V, Bloomfield D, Parker C, et al. Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2015;16(16):1605–16. https://doi.org/10.1016/s1470-2045(15)00280-6.
- 22.• Incrocci L, Wortel RC, Alemayehu WG, Aluwini S, Schimmel E, Krol S, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17(8):1061–9. https://doi.org/10.1016/s1470-2045(16)30070-5 The only large-scale randomized trial evaluting moderate hypofractionation with a superiority design.
- 23.Aluwini S, Pos F, Schimmel E, van Lin E, Krol S, van der Toorn PP, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial. Lancet Oncol. 2015;16(3):274–83. https://doi.org/10.1016/s1470-2045(14)70482-6.
- 24.Aluwini S, Pos F, Schimmel E, Krol S, van der Toorn PP, de Jager H, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial. Lancet Oncol. 2016;17(4):464–74. https://doi.org/10.1016/s1470-2045(15)00567-7.
- 25.Shaikh T, Li T, Handorf EA, Johnson ME, Wang LS, Hallman MA, et al. Long-term patient-reported outcomes from a phase 3 randomized prospective trial of conventional versus Hypofractionated radiation therapy for localized prostate Cancer. Int J Radiat Oncol Biol Phys. 2017;97(4):722–31. https://doi.org/10.1016/j.ijrobp.2016.12.034.
- 26.Arcangeli G, Saracino B, Gomellini S, Petrongari MG, Arcangeli S, Sentinelli S, et al. A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2010;78(1):11–8. https://doi.org/10.1016/j.ijrobp.2009.07.1691.
- 27.Arcangeli G, Fowler J, Gomellini S, Arcangeli S, Saracino B, Petrongari MG, et al. Acute and late toxicity in a randomized trial of conventional versus hypofractionated three-dimensional conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2011;79(4):1013–21. https://doi.org/10.1016/j.ijrobp.2009.12.045.
- 28.Arcangeli S, Strigari L, Gomellini S, Saracino B, Petrongari MG, Pinnaro P, 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(5):1172–8. https://doi.org/10.1016/j.ijrobp.2012.02.049.
- 29.Hoffman KE, Voong KR, Pugh TJ, Skinner H, Levy LB, Takiar V, et al. Risk of late toxicity in men receiving dose-escalated hypofractionated intensity modulated prostate radiation therapy: results from a randomized trial. Int J Radiat Oncol Biol Phys. 2014;88(5):1074–84. https://doi.org/10.1016/j.ijrobp.2014.01.015.
- 30.Wilson JM, Dearnaley DP, Syndikus I, Khoo V, Birtle A, Bloomfield D, et al. The efficacy and safety of conventional and Hypofractionated high-dose radiation therapy for prostate Cancer in an elderly population: asubgroup analysis of the CHHiP trial. Int J Radiat Oncol Biol Phys. 2018;100(5):1179–89. https://doi.org/10.1016/j.ijrobp.2018.01.016.
- 31.Thor M, Deasy JO, Paulus R, Robert Lee W, Amin MB, Bruner DW, et al. Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG oncology/RTOG 0415. Radiother Oncol. 2019;135:19–24. https://doi.org/10.1016/j.radonc.2019.02.014.
- 32.Staffurth J, Haviland J, Wilkins A, Syndikus I, Khoo V, Bloomfield D, et al. Impact of prostate Cancer Hypofractionation on patient reported outcomes: baseline to 5 years change in the CHHIP trial. Int J Radiat Oncol. 2018;102:S1–2.Google Scholar
- 33.Lieng H, Pintilie M, Bayley A, Berlin A, Bristow R, Chung P, et al. Long-term outcomes of a phase II trial of moderate hypofractionated image-guided intensity modulated radiotherapy (IG-IMRT) for localized prostate cancer. Radiother Oncol. 2017;122(1):93–8. https://doi.org/10.1016/j.radonc.2016.10.017.
- 34.Sanda MG, Cadeddu JA, Kirkby E, Chen RC, Crispino T, Fontanarosa J, et al. Clinically localized prostate Cancer: AUA/ASTRO/SUO guideline. Part II: recommended approaches and details of specific care options. J Urol. 2018;199(4):990–7. https://doi.org/10.1016/j.juro.2018.01.002.
- 35.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(5):976–85. https://doi.org/10.1016/j.ijrobp.2016.12.024.
- 36.Kishan AU, Dang A, Katz AJ, Mantz CA, Collins SP, Aghdam N, et al. Long-term outcomes of stereotactic body radiotherapy for Low-risk and intermediate-risk prostate Cancer. JAMA Netw Open. 2019;2(2):e188006. https://doi.org/10.1001/jamanetworkopen.2018.8006.
- 37.Quon HC, Ong A, Cheung P, Chu W, Chung HT, Vesprini D, et al. Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): a phase 2 randomized trial. Radiother Oncol. 2018;127(2):206–12. https://doi.org/10.1016/j.radonc.2018.02.029.
- 38.Loblaw A, Pickles T, Crook J, Martin AG, Vigneault E, Souhami L, et al. Stereotactic ablative radiotherapy versus Low dose rate brachytherapy or external beam radiotherapy: propensity score matched analyses of Canadian data. Clin Oncol (R Coll Radiol). 2017;29(3):161–70. https://doi.org/10.1016/j.clon.2016.10.001.
- 39.Alayed Y, Cheung P, Pang G, Mamedov A, D'Alimonte L, Deabreu A, et al. Dose escalation for prostate stereotactic ablative radiotherapy (SABR): late outcomes from two prospective clinical trials. Radiother Oncol. 2018;127(2):213–8. https://doi.org/10.1016/j.radonc.2018.03.005.
- 40.King CR, Brooks JD, Gill H, Presti JC Jr. Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82(2):877–82. https://doi.org/10.1016/j.ijrobp.2010.11.054.
- 41.King CR, Collins S, Fuller D, Wang PC, Kupelian P, Steinberg M, et al. Health-related quality of life after stereotactic body radiation therapy for localized prostate cancer: results from a multi-institutional consortium of prospective trials. Int J Radiat Oncol Biol Phys. 2013;87(5):939–45. https://doi.org/10.1016/j.ijrobp.2013.08.019.
- 42.Bolzicco G, Favretto MS, Satariano N, Scremin E, Tambone C, Tasca A. A single-center study of 100 consecutive patients with localized prostate cancer treated with stereotactic body radiotherapy. BMC Urol. 2013;13:49. https://doi.org/10.1186/1471-2490-13-49.
- 43.Musunuru HB, Quon H, Davidson M, Cheung P, Zhang L, D'Alimonte L, et al. Dose-escalation of five-fraction SABR in prostate cancer: toxicity comparison of two prospective trials. Radiother Oncol. 2016;118(1):112–1. https://doi.org/10.1016/j.radonc.2015.12.020.
- 44.D'Agostino G, Franzese C, De Rose F, Franceschini D, Comito T, Villa E, et al. High-quality Linac-based stereotactic body radiation therapy with flattening filter free beams and volumetric modulated arc therapy for Low-intermediate risk prostate Cancer. A mono-institutional experience with 90 patients. Clin Oncol (R Coll Radiol). 2016;28(12):e173–8. https://doi.org/10.1016/j.clon.2016.06.013.
- 45.Rucinska M, Kieszkowska-Grudny A, Nawrocki S. SHARP hypofractionated stereotactic radiotherapy is well tolerated in prostate cancer : toxicity and quality of life assessment. Strahlenther Onkol. 2016;192(7):449–57. https://doi.org/10.1007/s00066-016-0971-2.
- 46.Mantz C. A phase II trial of stereotactic ablative body radiotherapy for Low-risk prostate Cancer using a non-robotic linear accelerator and real-time target tracking: report of toxicity, quality of life, and disease control outcomes with 5-year minimum follow-up. Front Oncol. 2014;4:279. https://doi.org/10.3389/fonc.2014.00279.
- 47.Zimmermann M, Taussky D, Menkarios C, Vigneault E, Beauchemin MC, Bahary JP, et al. Prospective phase II trial of once-weekly Hypofractionated radiation therapy for Low-risk adenocarcinoma of the prostate: late toxicities and outcomes. Clin Oncol (R Coll Radiol). 2016;28(6):386–92. https://doi.org/10.1016/j.clon.2015.12.024.
- 48.Hannan R, Tumati V, Xie XJ, Cho LC, Kavanagh BD, Brindle J, et al. Stereotactic body radiation therapy for low and intermediate risk prostate cancer-results from a multi-institutional clinical trial. Eur J Cancer. 2016;59:142–51. https://doi.org/10.1016/j.ejca.2016.02.014.
- 49.Meier RM, Bloch DA, Cotrutz C, Beckman AC, Henning GT, Woodhouse SA, et al. Multicenter trial of stereotactic body radiation therapy for Low- and intermediate-risk prostate Cancer: survival and toxicity endpoints. Int J Radiat Oncol Biol Phys. 2018;102(2):296–303. https://doi.org/10.1016/j.ijrobp.2018.05.040.
- 50.Fuller DB, Naitoh J, Mardirossian G. Virtual HDR CyberKnife SBRT for localized prostatic carcinoma: 5-year disease-free survival and toxicity observations. Front Oncol. 2014;4:321. https://doi.org/10.3389/fonc.2014.00321.
- 51.Fuller DB, Falchook AD, Crabtree T, Kane BL, Medbery CA, Underhill K, et al. Phase 2 multicenter trial of heterogeneous-dosing stereotactic body radiotherapy for Low- and intermediate-risk prostate Cancer: 5-year outcomes. Eur Urol Oncol. 2018;1(6):540–7. https://doi.org/10.1016/j.euo.2018.06.013.
- 52.Kataria S, Koneru H, Guleria S, Danner M, Ayoob M, Yung T, et al. Prostate-specific antigen 5 years following stereotactic body radiation therapy for Low- and intermediate-risk prostate Cancer: an ablative procedure? Front Oncol. 2017;7:157. https://doi.org/10.3389/fonc.2017.00157.
- 53.• Jackson WC, Silva J, Hartman HE, Dess RT, Kishan AU, Beeler WH, et al. Stereotactic body radiation therapy for localized prostate Cancer: asystematic review and meta-analysis of over 6,000 patients treated on prospective studies. Int J Radiat Oncol Biol Phys. 2019;104(4):778–89. https://doi.org/10.1016/j.ijrobp.2019.03.051 Large pooled analysis of prospective, predominantly single-arm, studies of SBRT.
- 54.Alayed Y, Cheung P, Vesprini D, Liu S, Chu W, Chung H, et al. SABR in high-risk prostate Cancer: outcomes from 2 prospective clinical trials with and without elective nodal irradiation. Int J Radiat Oncol Biol Phys. 2019;104(1):36–41. https://doi.org/10.1016/j.ijrobp.2018.11.011.
- 55.• Van As N, Brand D, Tree A, Ostler P, Chu W, Loblaw A PACE: analysis of acute toxicity in PACE-B, an international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) to conventionally fractionated or moderately hypofractionated external beam radiotherapy (CFMHRT) for localized prostate cancer (LPCa). J Clin Oncol. 2019;37:1. https://doi.org/10.1200/JCO.2019.37.7_suppl.1. This abstract reports early toxicity data from the PACE randomized trial comparing SBRT with either moderate hypofractionation or conventional fractionation. These are the only results reported to date from a randomized trial of a 5-fraction SBRT regimen similar to those used in North America.
- 56.Quon HC, Musunuru HB, Cheung P, Pang G, Mamedov A, D'Alimonte L, et al. Dose-escalated stereotactic body radiation therapy for prostate Cancer: quality-of-life comparison of two prospective trials. Front Oncol. 2016;6:185. https://doi.org/10.3389/fonc.2016.00185.
- 57.Kim DW, Cho LC, Straka C, Christie A, Lotan Y, Pistenmaa D, et al. Predictors of rectal tolerance observed in a dose-escalated phase 1-2 trial of stereotactic body radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014;89(3):509–17. https://doi.org/10.1016/j.ijrobp.2014.03.012.
- 58.Sharieff W, Greenspoon JN, Dayes I, Chow T, Wright J, Lukka H. The technique, resources and costs of stereotactic body radiotherapy of prostate Cancer: acomparison of dose regimens and delivery systems. Technol Cancer Res Treat. 2016;15(1):171–8. https://doi.org/10.7785/tcrt.2012.500431.