Monday, August 29, 2016

Hypofractionated Radiation Therapy: Same results in less time

The largest yet randomized clinical trial comparing hypofractionated (fewer treatments or fractions) to normally fractionated IMRT has proved that oncological outcomes and late-term toxicities were the same for both treatment schedules.

The results of the CHHiP study were reported in an abstract by Dearnaly et al. delivered at the European Cancer Congress this week. There was also an interim toxicity analysis in 2012. There were 3,216 patients treated at 71 centers in the UK between 2002 and 2011. All patients were stage T1b-T3a, with <30% probability of seminal vesicle involvement. Patients were randomly assigned to one of three IMRT treatment schedules, for which I also show the relative biologically effective dose (BED) for oncological control compared to normal fractionation:
1.     74 Gy =2 Gy x 37 fractions (normal fractionation)
2.     60 Gy = 3 Gy x 20 fractions; relative BED: +4%
3.     57 Gy = 3 Gy x 19 fractions; relative BED: -1%
ADT began 3 months prior to the start of IMRT, and continued through treatment. The 2012 analysis showed that 93% of patients in each group received ADT.

Patient characteristics were as follows:
  • ·      NCCN risk groups:
o   Low risk: 15%
o   Intermediate risk: 73%
o   High risk: 12%
  • ·      Median age: 69 years
  • ·      PSA: 10.1 ng/ml
After a median follow-up of 63.2 months, the 5-year progression-free (either biochemical or clinical) survival (PFS) rates were:
  • ·      74 Gy: 88%
  • ·      60 Gy: 91%
  • ·      57 Gy: 85%

The difference in PFS for the 57 Gy vs. the 60 Gy schedule was statistically significant; the other differences were not statistically significant.

The toxicity outcomes reported as those with RTOG toxicity grades of 2 or higher were as follows:
  • ·      Acute GI toxicity was lower with normal fractionation:
o   74 Gy: 25%
o   60 Gy: 39%
o   57 Gy: 38%
  • ·      Acute GU toxicity was not significantly different among groups.
  • ·      2-year GI toxicity was lower with hypofractionation in the 57 Gy group:
o   74 Gy: 4%
o   60 Gy: 3%
o   57 Gy: 2%
  • ·      5-year GI toxicity was not significantly different among groups.
o   74 Gy: 1%
o   60 Gy: 2%
o   57 Gy: 2%
  • ·      Neither 2-year nor 5-year GU toxicities were different among groups.
It is important to note that the normal fractionation schedule used in this trial (2 Gy x 37 fractions) is low compared to the current standard of care (2 Gy x 40 fractions), but was standard when this trial began in 2002. The 60 Gy schedule comes close to the current standard of care in terms of its biologically effective dose. Given this, it is not surprising that only the 60 Gy schedule achieved 5-year progression-free survival levels over 90%. The lowest dose schedule is on the steep part of the dose/response curve where even small increases in dose achieve large increases in cancer control.

While acute GI toxicity was higher at first with hypofractionation, the effect was transient, and had disappeared by 2 years. Lasting GI toxicity was negligible, and there were no differences at any time in GU toxicity.

Based on all this, the authors state, “Modest hypofractionated RT using 60Gy/20f appears effective and safe and may be recommended as a new standard of care.”

We should be clear that this is not SBRT; it is only IMRT with an accelerated dosing schedule. There are some important differences. SBRT typically uses doses of 6-8 Gy per fraction and just 4 or 5 fractions. Because of the extreme hypofractionation, it becomes critical to track prostate motion during each fraction and not just between fractions. Treatment margins are typically narrower with SBRT and may be as low as 0 on the rectal side. These differences are what make SBRT safe. In the current study, there was no allowance made for intra-fractional prostate motion and the margins were not altered, so it is not very surprising that rectal toxicity was higher at first, but it was perhaps surprising that there were no lasting differences.

We should also note a few similar randomized comparative trials in the last year. One, at Fox-Chase (n=333), looked at 76 Gy delivered in 38 fractions of 2 Gy each (normal fractionation) compared to 70 Gy delivered in 26 fractions of 2.7 Gy each (hypofractionated) among intermediate and high-risk patients. The 5-year biochemical and/or clinical disease failure rate was the same -- 21% for normal fractionation, 23% for hypofractionation -- and there was no difference in late term toxicity, except among men with compromised urinary function.

An M.D.Anderson study (n=203) compared the late toxicity of a normally fractionated schedule (76 Gy in 1.8 Gy fractions) to a hypofractionated schedule (72 Gy in 2.4 Gy fractions). As in the UK study, there were no differences in GU toxicity. There was an increase in GI toxicity in the hypofractionated group, although it was not statistically significant. Unsurprisingly, the authors found it was related to the volume of the rectum that received high doses.

A multi-institutional study from the Netherlands among intermediate and high-risk men (n=820) reported on the acute toxicity of a normally fractionated schedule (78 Gy in 2 Gy fractions) compared to a hypofractionated schedule (65 Gy in 3.4 Gy fractions). At 3 months, there was no difference in GI or GU toxicity. At 6 months, there was no difference in GU toxicity, but GI toxicity was higher in the hypofractionated group (42% vs. 31%).

We also saw recently (see: Can salvage radiation therapy be safely and effectively completed in less time?) that a shortened treatment schedule appeared to be safe and effective for salvage IMRT. However, this UK study is more compelling because it is a randomized comparative trial of great size.

The only impediment seems to be the higher rate of acute rectal side effects. The patient will have to decide if it is worth accepting those transient symptoms in exchange for the convenience of a 4-week treatment schedule. Given the lower rate of patient-reported adverse outcomes and the high rate of oncological control with SBRT, however, it would seem that the 10-day schedule (5 fractions, every other day) is a better alternative on all counts.

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