Standard moderately hypofractionated radiotherapy vs. ultra-hypofractionated focal lesion ablative microboost in prostate cancer, Hypo-FLAME 3.0

External beam radiotherapy (EBRT) is one of the standard treatment options for
patients with localized prostate cancer (PCA). Based on the outcome of
randomized trials, moderately hypofractionated radiotherapy (19-25 fractions of
2.5-3.4 Gy) is considered equivalent to conventional fractionated schemes with
35-39 fractions of 2 Gy. A schedule of 20 fractions to a dose of 60-62 Gy is
adopted as standard of care for all risk-groups [1]. Driven by the success of
moderate hypofractionation, there is a strong trend towards extreme
hypofractionation, also called stereotactic body radiotherapy (SBRT), reducing
the number of fractions even further. The schedule mostly used is 5 fractions
of 7-7.25 Gy. Its effectiveness, equivalence to standard EBRT schedules, has
been demonstrated for low and favourable intermediate risk (IM) patients [2]
[3].
For unfavourable IM (here defined as IM with ISUP grade 3) and high-risk (HR)
PCA the outcome of EBRT can be further improved by dose escalation. Because of
dose-limiting toxicity, the maximal dose of EBRT for conventionally
fractionated schemes was approximately 80 Gy. Initially hypofractionation was
considered as a potential way to escalate the biologically effective dose (BED)
above 80 Gy, however, this proved not to be the case. With hypofractionation, a
saturation in dose effect seems to be present at a BED of 80 Gy [4]. Recently,
the multi-centre phase III FLAME trial broke the *80 Gy barrier* and showed
that in mainly HR PCA patients, treated with a conventional fractionation
schedule, focal boosting of the intraprostatic lesion to a total dose of 95 Gy
improves biochemical disease-free survival (bDFS) [5]. However, given the
advantages of hypofractionation in terms of patient comfort and costs, the
FLAME schedule is not ideal as the standard treatment.
For unfavourable IM and HR PCA patients the value of SBRT has not yet been
established [1] [2]. The FLAME trial showed that higher than standard BED is a
prerequisite for optimal bDFS [5]. Furthermore, post SBRT biopsies results
suggest a dose response relationship with better outcome of dose levels above
40 Gy [6] [7]. Therefore, probably a higher than standard dose SBRT is
necessary for these patients. A recent meta-analysis suggests diminishing
results from increased fraction sizes in SBRT [8]. So, the question remains
whether dose escalation in SBRT will indeed improve treatment outcome.
With standard SBRT to the whole prostate, dose escalation is limited to 40 Gy
because of unacceptable toxicity [9][10]. In line with FLAME, we conducted the
Hypo-FLAME trial investigating focal dose escalation in SBRT. In the phase II
Hypo-FLAME trial, 100 patients with IM or HR PCA were treated with SBRT 35 Gy
in 5 weekly fractions to the whole prostate with a focal boost up to 50 Gy. The
acute toxicity rates, the primary endpoint, were low and similar to standard
SBRT indicating this schedule can be safely applied [11]. Given this was a
phase II trial, no conclusions on oncological outcome can be drawn.
Shortening of the overall treatment time (OTT) has been suggested to play a
role in SBRT efficacy and 5 fractions delivered every other day this is
internationally accepted as standard [9]. We therefore initiated the phase II
Hypo-FLAME 2.0 trial, investigating the feasibility of a reduction in the OTT
of the Hypo-FLAME schedule from 29 to 15 days with acute toxicity as primary
endpoint. The accrual of this trial is completed and a first analysis of the
primary endpoint shows low toxicity figures, well in the range of what was
expected. We expect to submit the analysis for publication by the end of 2022.
At present, it is unknown what the oncological efficacy of the Hypo-FLAME
schedule is compared to the standard of care in unfavourable IM and HR prostate
cancer. Therefore, we will conduct a Phase III multi-centre randomized trial,
in which 484 patients with unfavourable IM or HR PCA will be randomized between:
1. Standard treatment; moderately hypofractionated radiotherapy 62 Gy in 20
fractions of 3.1 Gy
2. Experimental treatment; SBRT 5x7Gy with an iso-toxic integrated focal boost
up to 50 Gy (Hypo-FLAME).

To demonstrate superiority of whole gland SBRT with a simultaneous integrated
focal boost 35/50 Gy in 5 fractions (Hypo-FLAME) regarding 5-year bDFS compared
to the current standard moderately hypofractionated schedule of 62 Gy in 20
fractions of 3.1 Gy. bDFS will be assessed, using the Phoenix consensus
definition [12].

A Phase III multi-centre randomized trial, in which 484 patients with
unfavourable IM or HR PCA who meet the selection criteria will be randomized
(1:1) to one of the following arms:
1. Standard treatment; moderately hypofractionated radiotherapy 62 Gy in 20
fractions of 3.1 Gy
2. Experimental treatment; SBRT 5x7Gy with an iso-toxic integrated focal boost
up to 50 Gy (Hypo-FLAME) in 15 days (2 fractions per week).

Radiotherapy

Theoretically the Hypo-FLAME schedule could be less effective and/or more toxic
than the current standard treatment. Given the favourable results reported in
the literature and scientific conferences so far, the favourable results within
the Hypo-FLAME and Hypo-FLAME 2.0 trials and the quality assurance and
accreditation program that is part of Hypo-FLAME 3.0 the risk is considered
minor and acceptable.

A possible benefit of participation is that half of the patients will be
treated with only 5 instead of 20 treatments.