A first step towards ultra-hypofractionation for unfavourable intermediate and high-risk prostate cancer: a prospective safety and feasibility study in patients with metastatic prostate cancer

One of the key treatment modalities for prostate cancer is external beam
radiation therapy. Considering the relatively low alpha/beta ratio of prostate
cancer, increasing the dose per fraction could yield higher tumour control
rates with acceptable toxicity in a reduced number of treatment fractions
(hypofractionation). Ultrahypofractionation (fraction dose > 5 Gy) has shown
promising results for low- and intermediate risk prostate cancer.
Ultrahypofractionation for high-risk prostate cancer however is challenging
as the seminal vesicles (SV) are included in the target volume, which is not
the case for intermediate and low-risk prostate cancer patient. These SV belong
to the male reproduction system and their exact shape and size can differ
substantially. The SV are attached bilaterally to the prostate and, similarly
to the prostate, their motion is caused by changes in bladder and rectal
filling status. However, although the cause of motion is similar for both the
prostate and the SV, multiple studies report that the inter- and intra-fraction
motion of the SV remain significant and largely uncorrelated to the prostate
motion.
Considering the SV must be included in the target volume, the significant
SV motion has to be accounted for during treatment. A solution is to use safety
margins to extend the clinical target volume (CTV) to the planning target
volume (PTV). Due to their substantial inter- and intra-fraction motion, the SV
require a relatively large PTV-margin of 8 mm, which causes the bladder and
rectum to receive more dose per fraction, which in combination with a higher
fraction dose could result in unacceptable genitourinary and gastrointestinal
toxicity rates.
This means that to safely introduce ultra-hypofractionation for high-risk
prostate cancer patients, strategies to minimize PTV-margins around the SV are
required. To account for the inter-fraction motion of the SV, adaptive
radiotherapy (ART) in the form of online re-planning could be the solution.
Online re-planning is a workflow in which a new treatment plan is generated for
each fraction, optimized on the anatomy of the day. ART accounting for the
intra-fraction motion of the prostate has been studied well, for example by
tracking the intra-prostatic markers with the CyberKnife system. Using the
in-room CT-scan of our institution*s CyberKnife, it is feasible to combine
online re-planning with intra-fraction fiducial tracking.
A few papers have recently been published regarding the feasibility of
ultra-hypofractionation when including the SV in the target volume, using
different methods than we are proposing here. And while they showed feasibility
in principle, the overall conclusions were that further research is needed.
To summarize, this study aims to make a first step towards
ultra-hypofractionation for high-risk prostate cancer by proving the technical
feasibility of margin reduction of the SV by combining the intra-fraction
fiducial tracking with an online re-planning workflow for each fraction to
account for the inter-fraction SV motion.

to take a first step towards ultrahypofractionation for high-risk prostate
cancer by showing the technical feasibility of PTV-margin reduction around the
SV using adaptive radiotherapy.
Primary: To assess the feasibility of reducing the PTV-margins around the SV
using online adaptive re-planning.
Secondary:
• To assess treatment tolerance using a standardized questionnaire.
• To assess possibilities for further treatment optimisation, regarding organs
at risk dose, for patients without clinical or radiological SV involvement

Non-randomized single arm prospective phase II Study.

Patients will be treated according to current clinical practice and following
the procedures and protocols derived from the STAMPEDE trial. Six weekly
fractions of 6 Gy will be given and before and after each fraction a CT-scan
will be made.
The target volume will be defined according to our standard current practice,
i.e. the whole prostate and the basis of or the whole SV. For these patients a
treatment plan will be generated using the pre-fraction CT-scan and online
re-planning to account for differences in daily anatomy, hence justifying
treatment with reduced SV PTV-margins. By means of a post-fraction CT-scan dose
volume histograms (DVH) parameters will be extracted to estimate the achieved
intra-fraction coverage of the SV.
In patients without SV involvement on imaging and no clinical need for
including the SV, they will be excluded from the target volume. This group of
patients will receive an unadapted
treatment plan based on the original planning CT. A pre- and post-treatment CT
scan will be made, to simulate offline SV target coverage
and gather data for potential Organ at risk (OAR) sparing.

The additional burden for the patients consists of a longer treatment fraction
duration, filling out questionnaires at regular intervals and one additional
follow-up telephonic consultation one year after radiotherapy. The additional
risks associated with partaking in this study are, firstly, the added radiation
dose associated with the extra CT-scans at the start and end of each fraction
(175mGy). Secondly, the possible underdosage of the target volume in the SV.
However, considering the SV were not included in the target volume for the
STAMPEDE trial, the effect of this underdosage on the efficacy of the treatment
is expected to be minimal. The benefits are (1) a significant reduction from 20
to 6 treatment fractions, and thus fewer hospital appointments for a palliative
group of patients. (2) A smaller margin for prostate and SV, which we expect to
correspond to less toxicity.