In the FLAME trial, we demonstrated that focal boosting of
intra-prostatic lesions improves biochemical disease-free survival without
increasing toxicity compared to the standard treatment. In the subsequent
hypoFLAME trial the same concept was translated to an ultra-hypofractionated
schedule of 5 fractions of 7 Gy, with an integrated boost to the
intra-prostatic lesion up to 10 Gy. Toxicity levels in this trial were in line
with those reported from studies testing ultra-hypofractionated radiotherapy
without focal boosting.
In both the FLAME and hypoFLAME trial, position verification
was based on fiducial markers, implanted in the prostate. An on-line position
verification and correction procedure was applied in all participating centers.
Although various measures could be taken to minimize intra-fraction motion,
there was no real-time monitoring or correction. PTV margins were 4-5 mm
posteriorly and 5-8 mm in other directions in both trials.
Before starting inclusion in the FLAME trial, it was
demonstrated that the impact of intra-fraction motion is quite limited in
standard fractionated radiotherapy schedules. As the direction of
intra-fraction motion is largely random, the systematic error S over 35 fractions was
found 0.6 mm. However, in ultra-hypofractionated schedules, this reasoning
doesn’t hold as the duration of each fraction is longer and less averaging
happens in 5 fractions.
In both the FLAME and hypoFLAME trials, extreme care was
taken to avoid the risk of toxicity. During treatment planning the dose
constraints to organs at risk took priority over the boost dose. In the
hypoFLAME trial in extreme cases where intra-fraction motion, observed on a
CBCT acquired at the end of the fraction, shifted the focal boost towards the
rectal wall in more than one fraction, no further boosting would be done in the
final fractions. Thus, while nominally a boost dose of 95 Gy was prescribed in
the FLAME trial, the median D98% to the GTV was only 84.7 Gy. For the hypoFLAME
trial the boost dose of 50 Gy in practice resulted in a median dose of 40.3 Gy.
Now that the benefit of focal boosting has been
demonstrated, the route towards improved outcome is clear. The challenge has
become a technical one: how to reach the high boost dose safely. The recent
improvements in radiotherapy techniques offer a solution. Here modern (MR)
image guidance and on-line adaptive treatment techniques may improve the
capacity to boost the tumor by external beam radiotherapy without increasing
the dose to the surrounding organs at risk.