Hypofractionated Radiation in Prostate Cancer: Not Superior

Neil Osterweil

October 10, 2013

A regimen of hypofractionated radiation therapy for prostate cancer does not improve disease failure rates and causes significantly more urinary function problems in some patients than conventional radiotherapy, according to a new study.

The findings cast doubt on a long-standing assumption that prostate tumors are especially sensitive to radiation delivered in higher single doses over a shorter period of time, write Alan Pollack, MD, PhD, a radiation oncologist at the University of Miami Miller School of Medicine, and colleagues in their study, published online October 7 in the Journal of Clinical Oncology.

Current practice should be maintained, according to a prostate cancer specialist not involved in the study.

"Considering all of the information to date, it might not be prudent to move from the current standard of 1.8 to 2 Gy; there is simply no strong evidence that moderate hypofractionation is superior to conventional fractionation," writes W. Robert Lee, MD, MS, professor of radiation oncology at Duke University Medical Center in Durham, North Carolina, in an accompanying editorial.

Partial results from this trial were presented at the annual meeting of the American Society for Radiation Oncology (ASTRO) in 2011, as reported at that time by Medscape Medical News. The now-published final results confirm no advantage for hypofractionated radiotherapy.

In their study, Dr. Pollack and his team randomized 303 men with favorable- to high-risk prostate cancer to 1 of 2 radiation regimens. A total of 151 men were treated with hypofractionated intensity-modulated radiation therapy (IMRT) consisting of 70.2 Gy delivered in 26 fractions of 2.7 Gy, and 152 were treated with conventional IMRT consisting of 76 Gy delivered in 38 fractions of 2 Gy.

After a median follow-up of 68.4 months, the 5-year rate of biochemical and/or clinical disease failure was not significantly better with hypofractionated IMRT than with conventional IMRT (23.3% vs 21.4%).

In the hypofractionated group, patients with compromised urinary function at baseline had a significant increase in grade 2 or higher late genitourinary toxic effects, compared with patients with normal or mild urinary dysfunction. This was not the case in the conventional IMRT group.

A Question of Ratios

"Most of the enthusiasm for hypofractionation has been associated with the possibility of increasing the [alpha/beta] ratio," which is an estimate of the sensitivity of a particular cell to radiation fractions, Dr. Lee explains.

A low alpha/beta ratio indicates greater sensitivity to higher radiation doses per fraction (hypofractionation). It has been estimated that the alpha/beta ratio for prostate cancer is a relatively low 1.5 Gy. For late-responding tissues, it has been estimated to be 10 Gy or more, and for early-responding tissues, it has been estimated to be below 5 Gy (Int J Radiat Oncol Biol Phys. 1999;43:1095-1101).

The hypofractionated IMRT regimen used by Dr. Pollack's team falls in the moderate range of hypofractionation. In addition to the hypothesized therapeutic benefits, hypofractionation has the potential advantages of shorter and more convenient schedules for patients, optimizing linear accelerator use, and reducing costs in a fee-for-service environment, Dr. Lee notes.

However, the trial results indicate that hypofractionated radiation does not reduce the incidence of biochemical or clinical failure. In addition, a multivariate analysis controlling for risk, treatment, and actual length of androgen-deprivation therapy, and using the ASTRO criterion of prostate-specific antigen nadir +2, hinted that hypofractionated IMRT could be associated with an increased risk for biochemical failure. The hazard ratio for hypofractionated IMRT was a nonsignificant 1.43.

Dr. Pollack and colleagues note that the jury is still out on whether prostate cancer is as sensitive to hypofractionated radiation doses as is widely supposed.

"Although the vast majority of the evidence supports an alpha/beta ratio for prostate cancer in the 1.5 Gy range, some reports have indicated that the alpha/beta ratio is much higher. Factors that may contribute to this disparity include the heterogeneity of prostate cancer, hypoxia, use of biochemical failure as an end point without establishing local tumor control, and use of androgen-deprivation therapy as an adjunct to irradiation," Dr. Pollack and colleagues write.

Currently, 3 large noninferiority trials of moderate hypofractionation in prostate cancer are being conducted by the Radiation Oncology Therapy Group, the Ontario Clinical Oncology Group, and the UK Institute of Cancer Research.

"If, and it is a big if, the noninferiority trials suggest that moderate hypofractionation is no worse than conventional fractionation, then the burden of proof will be met and, for patient convenience and cost reasons, moderate hypofractionation should be the standard of care," Dr. Lee concludes. At present, however, there is not enough evidence to move away from conventional fractionation, he suggests.

The trial was supported by grants for the National Cancer Institute and the Florida Department of Health. Dr. Pollock reports consulting for GE Healthcare and Calypso, and receiving honoraria and/or research support from Accuray, Siemens Heatlhcare, and Varian Medical Systems. Dr. Lee has disclosed no relevant financial relationships.

J Clin Oncol. Published online October 7, 2013. Abstract, Editorial

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