Hypofractionation and Stereotactic Treatment: Clinical Data

  • Giorgio Arcangeli
  • Stefano Arcangeli
  • Lidia Strigari
Part of the Medical Radiology book series (MEDRAD)


During the last decade, improved physical sparing of normal tissues with the most recent technologies and a better understanding of prostate cancer radiobiology has prompted a number of moderate as well as extreme hypofractionation trials using different treatment schedules with the aim of exploring the outcome and toxicity of shorter regimens. The hypofractionated regimes appear to be associated with excellent results and toxicity similar to that observed after conventional fractionation courses, in spite of the numerous variables relative to different distributions in the risk categories or androgen deprivation delivery in the trials. However, the relatively short follow-up and the single-arm nature of these reports do not permit any meaningful comparisons with the conventional regimes. Until now, six controlled randomized trials of moderate hypofractionation have been published. Notwithstanding the similar outcome and toxicity results between hypo and conventional fractionation, two of these studies used a 2D technique delivering total doses that are now considered insufficient and inconclusive for treating prostate cancer. In the most recent trial, reporting equivalent 2 year toxicity rates, the follow-up is still too short to evaluate the clinical outcome of the two schedules. The three remaining trials report similar biochemical outcomes between the short and standard regimes. Only one trial has a sufficiently long follow-up to confirm the equivalence of the two regimes in terms of biochemical, clinical local and distant failure, and overall and disease-specific survival. This trial also shows that in some subgroups of patients, i.e., those with a pretreatment PSA ≤ 20 ng/mL or with a T-stage ≥ 2c, hypofractionation may be better than conventional fractionation in terms of both local failure and disease-specific survival. These results suggest that moderate hypofractionation for prostate cancer does not increase treatment-related toxic effects or decrease efficacy, although they still need to be confirmed by trials with more patients. The premature results of extreme hypofractionation (or SBRT) studies, although associated with good treatment tolerance, excellent early biochemical outcomes and low late toxicity rates, do not lead to any firm conclusions on the clinical benefits of these regimes in comparison to escalated conventional dose fractionation. Given that a certain number of uncertainties exist in extrapolating biological effects to very large fraction size, the results of extreme hypofractionation need to be confirmed by appropriate randomized trials with a sufficiently long follow-up and accurate evaluation of long-term tolerance and toxicity.


Prostate Cancer Androgen Deprivation Therapy Stereotactic Body Radiotherapy Conventional Fractionation Late Grade 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Al-Magmani AA, Heemsbergen WD, Levendag PC, and Lebesque JV (2010) Subgroup analysis of patients with localized prostate cancer treated within the Dutch-randomized dose-escalation trial. Radiother Oncol 96:13–18Google Scholar
  2. Arcangeli G, Saracino B, Gomellini S et al (2010) A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys 78:11–18PubMedCrossRefGoogle Scholar
  3. Arcangeli G, Fowler J, Gomellini S et al (2011) 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 79:1013–1021PubMedCrossRefGoogle Scholar
  4. Arcangeli S, Strigari L, Gomellini S et al (2012) Updated results and pattern of failures in a randomized hypofractionation trial for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 84:1172–1178PubMedCrossRefGoogle Scholar
  5. Boike TP, Lotan Y, Cho LC et al (2011) Phase I dose-escalation study of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer. J Clin Oncol 29:2020–2026PubMedCentralPubMedCrossRefGoogle Scholar
  6. Brenner DJ, Martinez AA, Edmundson GK et al (2002) Direct evidence that prostate tumors shows high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 52:6–13PubMedCrossRefGoogle Scholar
  7. Cowan RA, Mitchel DM, Bottomley IC et al (2007) Hypofractionated conformal radiotherapy for good prognosis carcinoma of the prostate: seven year outcome analysis. J Radiat Oncol Biol Phys 69:S339CrossRefGoogle Scholar
  8. Dearnaley DP, Sydes MR, Graham JD et al (2007) Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from MRC RT01 randomised controlled trial. Lancet Oncol 8:475–487PubMedCrossRefGoogle Scholar
  9. Dearnaley D, Syndicus I, Sumo G et al (2012) Conventional versus hypofractionated high dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from CHHiP randomized controlled trial. Lancet Oncol 13:4354CrossRefGoogle Scholar
  10. Faria S, Dal Pra A, Cury F et al (2011) Treating intermediate-risk prostate cancer with hypofractionated external beam radiotherapy alone. Radiother Oncol 101:486–489PubMedCrossRefGoogle Scholar
  11. Ferlay J, Parkin DM, Steliarova-Foucher E (2012) Estimates of cancer incidence and mortality in Europe in 2008. Radiother Oncol 46:765–781Google Scholar
  12. Fonteyne V, Soete G, Arcangeli S et al (2012) Hypofractionated high-dose radiation therapy for prostate cancer: long term results of a multi-institutional phase II trial. Int J Radiat Oncol Biol Phys 84:e483–e490PubMedCrossRefGoogle Scholar
  13. Fowler JF (2005) The radiobiology of prostate cancer including new aspects of fractionated radiotherapy. Acta Oncol 44(3):265–276PubMedCrossRefGoogle Scholar
  14. Fowler J, Chappel R, Ritter M (2001) Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 50:1021–1031PubMedCrossRefGoogle Scholar
  15. Freeman DE, King CR (2011) Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes. Radiat Oncol 6:3PubMedCentralPubMedCrossRefGoogle Scholar
  16. Fuller DB, Shirazi R, Naitoh J et al (2011) Virtual HDR SBRT for localized prostatic carcinoma: efficacy and quality of life assessment. Int J Radiat Oncol Biol Phys 81:S423–S424CrossRefGoogle Scholar
  17. Higgins GS, McLaren DB, Kerr GR et al (2006) Outcome analysis of 300 prostate cancer patients treated with neoadjuvant androgen deprivation and hypofractionated radiotherapy. Int J Radiat Oncol Biol Phys 65:982–989PubMedCrossRefGoogle Scholar
  18. Kang JK, Cho CK, Choi CW et al (2011) Image-guided stereotactic body radiation therapy for localized prostate cancer. Tumori 97:43–48PubMedGoogle Scholar
  19. Katz AJ, Santoro M, Ashley R et al (2010) Stereotactic body radiotherapy for organ-confined prostate cancer. BMC Urol 10:1PubMedCentralPubMedCrossRefGoogle Scholar
  20. Katz AJ, Santoro M, Di Blasio F et al (2011) Stereotactic body radiation therapy for low, intermediate and high-risk prostate cancer: disease control and quality of life. Int J Radiat Oncol Biol Phys 81:S100 (abstract)Google Scholar
  21. King CR, Brooks JD, Gill H et al (2012) Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys 82(2):877–882PubMedCrossRefGoogle Scholar
  22. Kuban D, Pollack A, Huang E et al (2003) Hazard of dose escalation in prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys 57:1260–1268Google Scholar
  23. Kuban D, Tucker S, Dong L et al (2008) Long-term results of the M.D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol. Biol Phys 70:67–74Google Scholar
  24. Kuban DA, Nogueras-Gonzalez NG, Hamblin L et al (2010) Preliminary report of a randomized dose escalation trial for prostate cancer using hypofractionation. Int J Radiat Oncol Biol Phys 78(suppl):S58CrossRefGoogle Scholar
  25. Kupelian P, Willoughby TR, Reddy CA et al (2007) Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland clinic experience. Int J Radiat Oncol Bio Phys 68:1424–1430Google Scholar
  26. Leborgne F, Fowler J (2009) Late outcomes following hypofractionated conformal radiotherapy vs. standard fractionation for localized prostate cancer: a non randomized contemporary comparison. Int J Radiat Oncol Biol Phys 74(1441):1446Google Scholar
  27. Livsay JE, Cowan RA, Wylie J et al (2003) Hypofractionated conformal radiotherapy in carcinoma of the prostate: five-year outcome analysis. Int J Radiat Oncol Biol Phys 1254–1259Google Scholar
  28. Lukka HR (2012) A randomized phase II trial of hypofractionated radiotherapy for favorable risk prostate cancer-RTOG CCOP study, 201125, Katz AJ Personal communication ASTRO 2012Google Scholar
  29. Lukka H, Hayter C, Julian JA et al (2005) A randomized trial comparing two fractionation schedules for patients with localized prostate cancer. J Clin Oncol 23:6132–6138PubMedCrossRefGoogle Scholar
  30. Madsen BL, Hsi RA, Pham HT et al (2007) Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results. Int J Radiat Oncol Biol Phys 67:1099–1105PubMedCrossRefGoogle Scholar
  31. Martin JM, Rosewall T, Bayley A et al (2007) Phase II trial of hypofractionated image-guided intensity-modulated radiotherapy for localized prostate adenocarcinoma. Int J Radiat Oncol Biol Phys 69:1084–1089PubMedCrossRefGoogle Scholar
  32. McBride SM, Wong DS, Dombrowski JJ et al (2011) Hypofractionated stereotactic body radiotherapy in low-risk prostate adenocarcinoma: Preliminary results of a multi-institutional phase 1 feasibility trial. Cancer 118:3681–3690Google Scholar
  33. Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO (2010) Radiation dose-volume effects in radiation-induced rectal injury. Int J Radiat Oncol Biol Phys 76:S20–S27Google Scholar
  34. Miralbel R, Roberts SA, Zubizarreta E et al (2012) Dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5,969 patients in seven international institutional datasets: α/β = 1.4 (0.9–2.2) Gy. Int J Radiat Oncol Biol Phys 82:e17–e24CrossRefGoogle Scholar
  35. Pollack AW, Buyounouski M, Horwitz E et al (2011) Five year results of a randomized external beam radiotherapy hypofractionation trial for prostate cancer. Int J Radiat Oncol Biol Phys 81(suppl):S1CrossRefGoogle Scholar
  36. Rene N, Faria S, Cury F et al (2010) Hypofractionated radiotherapy for favorable risk prostate cancer. Int J Radiat Oncol Biol Phys 77:805–810PubMedCrossRefGoogle Scholar
  37. Ritter MA, Forman JD, Kupelian P et al (2001) Five-year efficacy and toxicity outcomes from phase I/II trial of increasingly hypofractionated radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 81(S2):S99Google Scholar
  38. Steel GG (2003) Basic clinical radiobiology. Arnold, LondonGoogle Scholar
  39. Strigari L, Arcangeli G, Arcangeli S, Benassi M (2009) Mathematical model for evaluating incidence of acute rectal toxicity during conventional or hypofractionated radiotherapy courses for prostate cancer. Int J Radiat Oncol Biol Phys 73(5):1454–1460PubMedCrossRefGoogle Scholar
  40. Thomson D, Merrick S, Swindell R et al (2012) Dose-escalated hypofractionated intensity-modulated radiotherapy in high-risk carcinoma of the prostate: outcome and late toxicity. Prostate Cancer. doi: 10.1155/2012/450246 PubMedCentralPubMedGoogle Scholar
  41. Williams SG, Taylor JM, Liu N et al (2007) Use of individual fraction size data from 3756 patients to directly determine the alpha/beta ratio of prostate cancer. Int J Radiat Oncol Biol Phys 68:24–33PubMedCrossRefGoogle Scholar
  42. Yeoh EE, Botten RJ, Butters J et al (2011) Hypofractionated versus conventionally fractionated radiotherapy for prostate carcinoma: final results of phase III randomized trial. Int J Radiat Oncol Biol Phys 81:1271–1278PubMedCrossRefGoogle Scholar
  43. Zelefsky MJ, Yamada Y, Fuks Z et al (2008) Long-term results of conformal radiotherapy for prostate cancer: impact of dose escalation on biochemical tumor control and distant metastasis-free survival. Int J Radiat Oncol Biol Phys 71:1028–1033PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Giorgio Arcangeli
    • 1
  • Stefano Arcangeli
    • 1
  • Lidia Strigari
    • 1
  1. 1.Regina Elena National Cancer InstituteRomeItaly

Personalised recommendations