BERKELEY, CA (UroToday.com) - The improved physical sparing of normal tissues using three-dimensional (3D) or intensity modulated radiation (IMRT) techniques has resulted in a re-evaluation of the use of a few large dose fractions with a shorter treatment duration.
| "These results suggest that hypofractionation does not increase treatment-related toxic effects or decrease efficacy." |
The delivery of a reduced number of higher-dose fractions (hypofractionation) is based on the assumption that prostate cancer has a low α/β ratio. In radiobiology, the α-β ratio, defined as the dose at which killing of cells by linear (α) and quadratic (β) components is equal, is used to quantify the fractionation sensitivity of tissues and tumours. Recent analyses and reviews of tumor control in prostate cancer [1,2,3] have suggested an α/β value on the order of 1 to 3 Gy, which is somewhat lower than the value typically ascribed to the adjacent late-responding normal tissues.[4] If this is indeed the case, hypofractionation would offer a unique opportunity to optimize the therapeutic ratio taking the advantage of the potential higher sensitivity of prostate cancer to radiation dose fractions in comparison with the surrounding organs at risk (i.e. rectum, bladder, and urethra). Fewer but larger-than-conventional fractions for a lesser total dose should achieve efficacy equivalent to higher doses delivered with conventional fraction sizes. Furthermore, a RT course in a reduced number of sessions should be less distressing for elderly patients with prostate cancer, especially if living at a distance from radiotherapy centers, who might be more attracted by quicker treatments such as radical prostatectomy, or even non-definitive approaches such androgen deprivation therapy (ADT). A decrease in overall treatment time of 3-4 weeks by hypofractionation compared to conventional fractionation would have a substantial impact on quality of life and health economics.
This has prompted several trials of hypofractionation schedules with the aim of exploring the outcomes and toxicity of hypofractionation regimens. These regimens appear to be associated with excellent results and with acute and late toxicity that is similar to that observed with the conventional fractionation. However, the short follow-up and the single-arm nature of these reports do not allow for meaningful comparisons with the conventional regimens.
The first two randomised trials of hypofractionation delivered moderate radiation doses which were below the standard-of-care radiation doses of 76–80 Gy. Both trials were designed and performed before the studies suggesting a low α/β for prostate cancer (with no attempt to make the arms isoeffective) and did not provide conclusive evidence with regard to either outcomes or toxicity.[5,6]
The randomized phase III trial by our group [7] was designed to compare the effects of a conventional fractionation of 80 Gy at 2 Gy per fraction in 8 weeks versus a hypofractionation schedule of 62 Gy at 3.1 Gy per fraction in 5 weeks (4 fractions per week) to the prostate and seminal vesicles, using 3D-CRT, in patients with high risk prostate cancer who were also receiving a 9-month ADT. The two arms were hypothesized to be isoeffective with regard to tumor control, assuming a fairly low α/β ratio of 1.5-1.8 Gy. No difference was found in the incidence and severity of late gastrointestinal or genitourinary toxicity between the 2 fractionation schedules. At a median follow-up of 70 months, hypofractionation resulted only in a slightly higher, non significant, improvement in actuarial freedom from biochemical failure (FFBF) with respect to conventional fractionation, while no difference between the two fractionation schedules was detected for freedom from local (FFLF) and freedom from distant failures (FFDF). However, likely because of the better local effect of hypofractionation with respect to standard fractionation on a smaller tumor burden, as well as the achievement of local tumor control before the occurrence of metastatic spread, in the subgroup of patients with a pre-treatment prostate-specific antigen level of 20 ng/mL or less, the 5-year rates of all three endpoints, FFBF, FFLF, and FFDF resulted significantly higher in the hypofractionation than in the conventional fractionation group.
Another three randomised trials have been undertaken in the US [8,9] and UK.[10] The control doses used in these trials were between 74 Gy and 76 Gy (1·8–2 Gy per fraction) while the hypofractionated doses were between 57 Gy and 72 Gy (2·4–3.0 Gy per fraction). Both US trials [8,9] (median follow-ups of about 5 years) showed no difference in freedom from biochemical failures and grade 2 or worse gastrointestinal and genitourinary toxicity between groups. The UK trial [10] (median follow-up of about 50 months) reported only a comparable toxicity between the two schedules.
These results suggest that hypofractionation does not increase treatment-related toxic effects or decrease efficacy. However, long-term follow-up results of both efficacy and late toxic effects—especially late genitourinary toxic effects—are still needed, notably because the prostatic urethra and bladder neck still receive high fraction sizes in hypofractionation trials.
References:
- Fowler J, Chappel R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50:1021–1031.
- Brenner DJ, Martinez AA, Edmundson GK, et al. 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 2002;52:6–13.
- Williams SG, Taylor JM, Liu N, et al. 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 2007;68: 24–33.
- Steel GG. Basic Clinical Radiobiology. London: Arnold; 2003.
- Lukka H, Hayter C, Julian JA, et al. A randomized trial comparing two fractionation schedules for patients with localized prostate cancer. J Clin Oncol 2005;23:6132-6138.
- Yeoh EE, Botten RJ, Butters J, et al. Hypofractionated versus conventionally fractionated radiotherapy for prostate carcinoma: final results of phase III randomized trial. Int J Radiat Oncol Biol Phys. 2011;81:1271-1278.
- Arcangeli S, Strigari L, Gomellini S, et al. Updated results and pattern of failures in a randomized hypofractionation trial for high-risk prostate cancer. Int J Radiat Oncol. Biol Phys in press. doi: 10.1016/j.ijrobp.2012.02.049.
- Pollack AW, Buyyounouski M, Horwitz E, et al. Five year results of a randomized external beam radiotherapy hypofractionation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2011;81 (suppl): S1.
- Kuban DA, Nogueras-Gonzalez NG, 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 (suppl): S58.
- 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.
Written by:
Giorgio Arcangeli, MD and Stefano Arcangeli, MD* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
*Regina Elena National Cancer Institute, Roma, Italy
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