Hypofractionated Radiotherapy for Prostate Cancer: Has the Time Come?

OncologyONCOLOGY Vol 26 No 6
Volume 26
Issue 6

This review by Aneja et al provides an excellent discussion of prostate external beam hypofractionated radiation therapy and its potential benefits and pitfalls.

This review by Aneja et al provides an excellent discussion of prostate external beam hypofractionated radiation therapy and its potential benefits and pitfalls. As has been highlighted by the data presented, there are multiple theoretical benefits to applying hypofractionated radiation therapy techniques to the treatment of prostate cancer. These benefits include improved convenience, decreased cost, increased patient access to treatment, and possibly improved clinical outcomes due to the biologic response of prostate cancer relative to the nearby normal tissues. However, there are significant unknowns with the available data from the modern era of prostate-specific antigen (PSA) monitoring and use of intensity-modulated radiotherapy (IMRT) or stereotactic radiotherapy. The data suffer from relatively short follow-up, low patient numbers, and a lack of level 1 evidence. Furthermore, it has been difficult to isolate the effects of hypofractionation from those of androgen deprivation-with regard to biochemical failure, overall survival, and toxicity.

There is a biologic rationale for using hypofractionation to treat prostate cancer; it is based on the variable response and sensitivity of prostate cancer vs the surrounding normal structures. If prostate cancer cells are more sensitive to larger fractions than the surrounding normal tissues, utilizing a hypofractionated approach should increase the therapeutic window. Administering biologically higher doses of radiation should yield higher local control rates, with toxicity equal to that seen with standard fractionation. Likewise, giving doses that are biologically equivalent to standard doses should reduce toxicity.

As the authors describe, there is general agreement that the α/β ratio for prostate cancer is low; however, not every study confirms this.[1-4] The methods used to calculate the α/β ratio are problematic, being based on a number of questionable assumptions, and confounded by the use of biochemical failure as an endpoint and by the frequent combination of androgen deprivation therapy with hypofractionated radiotherapy.

Single-institution and phase II studies of extended hypofractionation (between 2.2 and 5 Gy per fraction) in the treatment of prostate cancer have shown reasonable results based on low α/β ratio calculations. The most extensive experience has been described by Kupelian et al[5]; these investigators noted that IMRT in 2.5-Gy fractions to 70 Gy resulted in 5-year biochemical failure-free survival rates of 95%, 85%, and 68% for low-, intermediate-, and high-risk patients, respectively. Late grade 2 or greater rectal toxicity was 4.5%. These results compare favorably with those from the dose-escalated randomized studies of 74 Gy to 80 Gy of standard fractionated three-dimensional (3D) conformal radiation.[6-8] The results are also comparable to published data for standard fractionated IMRT.[9,10]

However, retrospective studies, single-institution experiences, and small phase II studies have inherent selection biases and limitations, and their results should be viewed with some skepticism. The clear logic of α/β ratio modeling and the promising results from the initial clinical experiences have not translated into clear benefits in the phase III randomized studies of hypofractionation. Of the three randomized studies that have evaluated this question in the modern era, one published by Arcangeli et al[11] suggested an α/β ratio < 3. Two others, one presented at the 2011 meeting of the American Society for Radiation Oncology (ASTRO) by Pollack et al[12] in which a postulated benefit in biochemical failure was not realized, and the other with a similar aim from Kuban et al,[13] suggest α/β ratios > 3. These assessments would not have been possible without the completion of well-designed phase III clinical trials.

We have now moved into the realm of extreme hypofractionation (> 5 Gy per fraction), or stereotactic radiotherapy. There has been a rapidly growing acceptance of this technology based on the publication of single-institution experiences and small phase II clinical studies. As with more protracted hypofractionation, initial clinical results look very promising, with excellent early biochemical failure results and limited late toxicity. However, follow-up remains short, and toxicity, particularly genitourinary, may continue to increase over time. Given past experience and the absence of level 1 evidence, a true assessment of the efficacy and toxicity of these techniques is not possible at this point. A determination of cost-effectiveness remains elusive. Thus, caution is advised in adopting these techniques as standard practice.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.



1. Fowler J, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys. 2001;50:1021-31.

2. Valdagni R, Italia C, Montanaro P, et al. Is the alpha-beta ratio of prostate cancer really low? A prospective, nonrandomized trial comparing standard and hyperfractionated conformal radiation therapy. Radiother Oncol. 2005;75:74-82.

3. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys. 1999;43:1095-101.

4. King CR, Fowler JF. A simple analytic derivation suggests that prostate cancer alpha/beta ratio is low. Int J Radiat Oncol Biol Phys. 2001;51:213-4.

5. 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.

6. Peeters ST, Heemsbergen WD, van Putten WL, et al. Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys. 2005;61:1019-34.

7. Kuban DA, Tucker SL, Dong L, 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.

8. Zietman A, DeSilvio M, Slater JD, et al. A randomized trial comparing conventional dose (70.2 GyE) and high dose (79.2 GYE) conformal radiation in early stage adenocarcinoma of the prostate: results of an interim analysis of PROG 95-09. Int J Radiat Oncol Biol Phys. 2004;60(Suppl):S131-32.

9. Zelefsky MJ, Chan H, Hunt M, et al. Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J Urol. 2006;176:1415-9.

10. Eade TN, Horwitz EM, Ruth K, et al. A comparison of acute and chronic toxicity for men with low-risk prostate cancer treated with intensity-modulated radiation therapy or (125)I permanent implant. Int J Radiat Oncol Biol Phys. 2008;71:338-45.

11. Arcangeli G, Saracino B, Gomellini 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;78:11-8.

12. Pollack A, Walker G, Buyyounouski M, et al. Five year results of a randomized external beam radiotherapy hypofractionation trial for prostate cancer. Int J Radiat Oncol Biol Phys. 2011;81:S1.

13. Kuban DA, Nogueras-Gonzalez GM, Hamblin L, et al. Preliminary report of a randomized dose escalation trial for prostate cancer using hypofractionation. Int J Radiat Oncol Biol Phys. 2010;78:S58-S59.

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