How much hypofractionated IMRT is too much for localized prostate cancer?


A report to be presented at the upcoming meeting of the American Society for Radiation Oncology (ASTRO) offers 5-year outcome data from a trial comparing conventional intensity-modulated radiation therapy (IMRT) to the more recently developed hypofractionated IMRT for men with localized prostate cancer. The trial was discussed in detail at an ASTRO press briefing yesterday. A media release is available, and there is an extensive commentary on the study on the Medscape web site. The actual paper will be presented at ASTRO in October.

The trial enrolled 303 men with intermediate- and high-risk, localized prostate cancer, all of whom were treated between 2002 and 2006. It was designed to compare a total dose of 76.0 Gy delivered through conventional 2.0 Gy fractions over a period of 7.5 weeks with 70.2 Gy delivered in a hypofactionated form through 2.7 Gy fractions over a period of 5 weeks. The hypofractionated form of IMRT was estimated to be equivalent to 84.4 Gy if delivered conventionally through 2.0 Gy fractions.

The idea behind the trial was that hypofractionated IMRT would reduce the rate of biochemical failure among this group of patients compared to conventional IMRT without increasing the side effects of treatment.

We can summarize the results of the trial at 5 years of follow-up, presented yesterday by Dr. Alan Pollack, as follows:

  • Hypofractionated radiation does reduce treatment time for this group of patients by 2.5 weeks, compared with conventional radiation.
  • 41/303 men exhibited biochemical failure
    • 20 men in the conventional IMRT group
    • 21 men in the hypofractionated IMRT group
  • The 5-year cumulative incidence rates of biochemical failure were
    • 14.4 percent for men treated with conventional IMRT
    • 13.9 percent for men treated with hypofractionated IMRT
  • 6 men who had biochemical failures also exhibited local-regional failure or distant metastasis within 6.5 months of biochemical failure.
  • Rates for local-regional failure or distant metastasis were
    • 1.0 percent for men treated with conventional IMRT
    • 1.3 percent for men treated with hypofractionated IMRT
  • The cumulative incidence rates for any failure, including 4 deaths, were
    • 15.4 percent for men treated with conventional IMRT
    • 15.3 percent for men treated with hypofractionated IMRT
  • Persistent adverse urinary tract effects of grade 2 or higher occurred in
    • < 5 percent of men receiving conventional IMRT
    • < 10 percent of men receiving hypofractionated IMRT
  • Rates of genitourinary tract toxicities of grade 2 or higher were
    • 8.9 percent for men treated with conventional IMRT
    • 13.8 percent for men treated with hypofractionated IMRT
  • Rates of gastrointestinal tract toxicities of grade 2 or higher were
    • 4.1 percent for men treated with conventional IMRT
    • 5.9 percent for men treated with hypofractionated IMRT
  • Rates of bowel/rectal adverse effects and erectile dysfunction were identical for the two forms of IMRT.

Biochemical failure in this study was defined using the Phoenix criteria (nadir PSA level + 2 ng/ml).

Arguably, this trial has failed to meet either of the projected outcomes. There is no statistically significant reduction in biochemical failure rate from the use of hypofractionated IMRT and there is a small but statistically significant increase in persistent adverse urinary tract effects.

It may well be that in this trial we have exceeded the upper limit of what is an acceptable dose of radiation therapy for men with localized prostate cancer. Over the past 30+ years there has been a continuing effort to increase the dose of radiation delivered to the prostate in an attempt to optimize the chances of killing the highest possible proportion of prostate cancer cells. Sooner or later an upper limit was bound to be identified. Perhaps what we have learned from this trial is that hypofractionated IMRT does indeed offer the opportunity to reduce the number of fractions necessary to deliver a completed dose of radiation, but that the size of each fraction needs to be dialed back down a couple of notches (to the equivalent of perhaps only 80 Gy in total if delivered through conventional IMRT). We’ll leave the details to the experts.

One Response

  1. This research was evidently driven by the hypothesis that hypofractionation would increase the ratio of benefit to harm, but it appears not to do so. I have to wonder if perhaps research should be done into hyperfractionation, i.e., stretching treatment to more than the 36 sessions of the conventional group and seeing if that would increase the ratio of benefit to harm.

    Salvaging what could be salvaged, Dr. Pollack notes that there may be an advantage in terms of the convenience of a short course, a not insignificant point, but personally, I wouldn’t choose it.

    Of note, one of the distinguishing features of CyberKnife (but not the only one) is rather more extreme hypofractionation than was done here with IMRT.

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