Why toxicity was higher with hypofractionation in Dutch trial

Aluwini et al. have published the toxicity outcomes of a randomized clinical trial (HYPRO) designed to test whether a hypofractionated external beam (EBRT) regimen compared to conventional fractionation. They will report on the oncological outcomes at a later date.

Between 2007 and 2010, 782 intermediate and high-risk patients were treated at 4 Dutch centers. About half were treated with the hypofractionated regimen, half with conventional dosing as follows:

• ·      Hypofractionation: 19 fractions of 3.4 Gy each
• ·      Conventional fractionation: 39 fractions of 2.0 Gy each
• ·      The relative biologically effective dose is 16% higher for the hypofractionated regimen.
• ·      Both groups were treated with conformal EBRT (3D-CRT and IMRT).

After a median followup of 60 months, the 3-year late-term toxicity outcomes were as follows:

• ·      Genitourinary toxicity, grade 2 or higher: 41% among the hypofractionated group vs. 39% for conventional fractionated.

o   Hazard ratio: 1.16 (Non-inferiority threshold: 1.11)

• ·      Genitourinary toxicity, grade 3 or higher: 19% among the hypofractionated group vs. 13% for conventional fractionated.

• ·      Gastrointestinal toxicity, grade 2 or higher: 22% among the hypofractionated group vs. 18% for conventional fractionated.

o   Hazard ratio: 1.19 (Non-inferiority threshold: 1.13)

• ·      Gastrointestinal toxicity, grade 3 or higher: 3% among the hypofractionated group vs. 3% for conventional fractionated.

Because the toxicity difference slightly exceeded the pre-established thresholds, the authors conclude that the hypofractionated regimen was not non-inferior to the conventionally fractionated regimen in terms of late term toxicity.

Because the hypofractionated regimen was a higher biologically effective dose, we might expect toxicity to be somewhat higher. Several recent major trials showed that hypofractionated IMRT was non-inferior to conventional fractionation in terms of both oncological control and late-term toxicity (see this link and this one, and this one). The lesson we learn from this study is that hypofractionation carries increased risk of toxicity. To avoid that, it is important to use well-planned IMRT or SBRT regimens. 3D-CRT is probably not the optimal platform for such treatment.