Standard fractionation entails administration of 1.8 to 2.0 Gy/d to a typical dose of 74 to 80 Gy20,21; hypofractionated regimens may be as extreme as 36.25 Gy in 5 fractions.93 Unfortunately, long-term follow-up from quality level one evidence comparing fractionation regimens is lacking. In addition, a multitude of different regimens are used in the United States.
Investigators from Italy reported preliminary results from a trial (n=168) comparing 80 Gy in 40 fractions (5 fractions/wk) to 62 Gy in 20 fractions (4 fractions/wk). With a median follow-up of 32 and 35 months, respectively, biochemical control rates at 3 years were 87% and 79% (P=0.035) with no significant difference in late urinary or gastrointestinal toxicity.94 Dearnaley et al95 recently reported the results of a 3-armed randomized trial comparing 74 Gy in 37 fractions (n=153) to 60 Gy in 20 fractions (n=153) or 57 Gy in 19 fractions (n=151). With a median follow-up of 50.5 months, rates of late gastrointestinal and genitourinary toxicity were similar; tumor control outcomes were not highlighted in this publication. Investigators from Fox Chase Cancer Center compared 76 Gy in 38 fractions to 70.2 Gy in 26 fractions (2.7 Gy/fraction) in 303 patients. Slightly increased acute gastrointestinal toxicity was noted in the hypofractionated arm, but differences were mild.96 Tumor control outcomes have been presented in abstract form; 5-year biochemical failure rates were 14.4% in the conventional fractionation arm and 13.9% in the hypofractionated arm. Rates of 5-year locoregional failure/distant metastases were about 1.0% and 1.3%, respectively, suggesting the equivalence of the 2 approaches (with limited follow-up).97 Investigators at the MD Anderson Cancer Center compared 75.6 Gy in 42 fractions with 72 Gy in 30 fractions. Results are available in abstract form and show the 5-year biochemical survival rates of 92% and 96%, respectively (P-value not significant), although the hypofractionated arm displayed a trend toward higher gastrointestinal toxicity (P=0.06).98 A Lithuanian group has compared 74 Gy in 37 fractions to 57 Gy in 17 fractions (13 fractions of 3 Gy plus 4 fractions of 4.5 Gy) in 91 patients.99 The trial is currently ongoing, and data relating to survival metrics have not yet been published, although the PSA nadirs were similar in both cohorts.100
Randomized reports of more extreme hypofractionation (ie, using fraction sizes of 6 to 10 Gy) are scant. However, early results of single-arm trials seem promising. As an example, King et al101 reported outcomes in 67 patients (with a median follow-up of 2.7 y) treated with 36.25 Gy in 5 fractions. RTOG grade 3 bladder and rectal toxicity were seen in 3% and 0% of patients, respectively. The 4-year biochemical DFS rate was 94%. McBride et al102 reported on a multi-institutional cohort of 45 patients treated largely with 37.5 Gy in 5 fractions. The 3-year biochemical failure rate was 97.7%. Only 1 and 2 episodes of grade 3 genitourinary and gastrointestinal toxicity occurred, respectively, although unlike in the King and colleagues’ study, there was a significant late decline in sexual scores and a small, late decline in bowel domain scores.
Despite the theoretical benefits of hypofractionation based on the α/β ratios and the obvious benefits with regard to patient convenience, caution should be exerted before recommending hypofractionated radiation in the absence of a clinical trial. As an example, a study of 936 patients with T1-T2 prostate cancer, which randomized patients to 66 Gy in 33 fractions or 52.5 Gy in 20 fractions, found an absolute difference of 7% in the 5-year biochemical or clinical failure rates, which were worse in the hypofractionated arm (the confidence intervals for this difference did not include 0).103 Although the radiation doses used in this trial would be considered subtherapeutic by contemporary measures, these results do suggest inferior tumor control in the hypofractionated arm. However, another randomized trial using nearly the same treatment regimen (n=217), with patients randomized to 64 Gy in 32 fractions versus 55 Gy in 20 fractions, found improved biochemical control in the hypofractionated arm, with a median follow-up of 90 months.104 Ultimately, additional randomized studies of contemporary radiation schema are required before definitive conclusions can be made regarding the appropriateness of hypofractionated therapy. At this point, although hypofractionated regimens are convenient for the patient, definitive evidence of the equality or superiority of hypofractionated radiation relative to standard fractionation requires longer term follow-up.
Fortunately, prospective, randomized comparisons involving hypofractionation are being conducted. A Canadian trial is comparing 78 Gy in 39 fractions with 60 Gy in 20 fractions in a cohort of approximately 1200 men (ISRCTN 43853433), whereas a Dutch trial is comparing 78 Gy in 39 fractions to 64.6 Gy in 19 fractions in approximately 800 men (ISRCTN 85138529). With regard to extreme hypofractionation, a Scandinavian group is comparing 78 Gy in 39 fractions with 42.7 Gy in 7 fractions in approximately 600 men (ISRCTN 45905321).95 RTOG trial 09-38 is a randomized Phase II trial that has nearly completed enrollment of 174 patients comparing toxicity between 36.25 Gy in 7 fractions versus 51.6 Gy in 12 fractions. Therefore, within the following several years, additional data on the efficacy and safety of hypofractionated radiation regimens will be available.
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