PSMA-PET guided hypofractionated salvage prostate bed radiotherapy of biochemical failure after radical prostatectomy for prostate cancer

Prostate cancer (PCa) is the most common malignancy in men and a major cause of
cancer deaths. Most of the cases are diagnosed as organ-confined diseases,
where radical prostatectomy is one of the primary treatment options. After
radical prostatectomy approximately 15-40% of men develop a biochemical
recurrence (BR) within 5 years.
The standard treatment of post-prostatectomy BR is salvage external beam
radiation therapy (sEBRT). sEBRT can provide long-term disease control; with 5
year biochemical progression-free survival (bPFS) up to 60% and with most
treatment failures in the first 2 years after sEBRT.

We hypothesize two potential causes for failure of the treatment.
First, the second BR may result from the possible presence of (occult)
oligometastases, for which local sEBRT is inappropriate. For most patients, the
only evidence of recurrent disease after radical prostatectomy is an increased
serum prostate-specific -antigen (PSA) level - a marker also used for
metastatic diseases - because radiographic detection of recurrent disease has
historically been difficult. Consequently, discriminating between local
recurrence and metastasis is impossible, leading to unnecessary local treatment
in patients with metastatic disease.
The identification of oligometastases can be improved by using PSMA-PET/CT or
PSMA-PET/MRI, which has improved the detection of recurrent PCa at low PSA
levels. Patients with oligometastases can thus be detected at an early stage
and excluded from local salvage radiotherapy to avoid unnecessary toxicity.

Secondly, the currently applied radiation dose for local sEBRT may be low and
insufficient. Like in primary PCa, also in post-operative sEBRT, a dose-effect
relationship has been reported, indicating a 2.0% improvement in bPFS for each
additional Gy. This may offer an opportunity to lower BR by increasing the
radiotherapy dose. Therefore, in non-metastatic patients, dose escalation to
the prostate bed may improve the bPFS. Recent studies have shown that the α/β-
ratio for PCa cells may be lower than that of surrounding normal tissues,
perhaps as low as 1.5 Gy. This means that PCa cells are more sensitive to
fraction dose than the surrounding normal tissues, leading to the rationale for
increasing the dose-per-fraction (hypofractionation) instead of the total dose.
In doing so, the biological dose to the tumour cells, but not to the
surrounding normal tissues, will increase.
Besides an increase in therapeutic gain by reducing the biochemical recurrence
rate, hypofractionated schedules for prostate cancer could lead to economic and
logistic advantages.

We will perform a prospective open phase III randomized trial to compare the
5-year progression-free survival in patients receiving sEBRT of 35 x 2Gy and
patients receiving hypofractionated sEBRT of 20 x 3Gy.

The main goal of this project is to investigate whether the oncologic outcome
in patients with post-prostatectomy recurrent PCa can be improved, by
increasing the biological effective radiation dose using a hypofractionated
schedule of 20 x 3 = 60 Gy.

The study is designed as a prospective open phase III randomized multicenter
trial.

All eligible patients will be randomized to one of the following two treatment
arms:
Arm 1 = Conventional sEBRT to apply a total dose of 70 Gy in 35 daily fractions
of 2 Gy during 7 weeks.
Arm 2 = Hypofractionated sEBRT to apply a total dose of 60 Gy in 20 fractions
of 3 Gy during 4 weeks.

Patients will be randomised into two groups. Patients participating in the
conventional arm will follow the standard treatment regimen of 35 fractions,
the experimental treatment will be delivered in 20 fractions. Patients
participating in the experimental arm of the study will visit the hospital less
frequently during the treatment phase (20 times), compared to the standard
treatment (35 times). Unlike non-study patients, all patients participating in
the study will complete side effect and QoL questionnaires at baseline, at the
end of the treatment and the follow-up. The follow up is the same in both
treatment arms.
The expected toxicity profile of postoperative RT in both arms consists of
acute and late urinary (urge, frequency, nocturia and possibly incontinence)
and gastrointestinal complaints (urge, frequency, rectal bleeding, loss of
mucous and possibly incontinence), fatigue, and erectile dysfunction (if
preserved after prostatectomy). Given the difference in α/β-ratios between PCa
and late responding normal tissue, the use of hypofractionation will increase
the biological effective dose to prostate cancer but not to the organs at risk
(bladder and rectum). Calculating the biologically equivalent dose assuming an
α/β of 4Gy for bladder and
rectum, the use of 20 x 3Gy equals an EQD2 of 70Gy, which is equal to the 70Gy
of the standard arm. Nevertheless, a slight increase in the acute toxicity in
the experimental arm might be expected due to the short overall treatment time.