• For many years, the standard regimen for

intermediate risk and high-risk prostate cancer

treated with external beam radiotherapy has
been conventional fractionation—ie, schedules
delivered with 1.8− 2.0 Gy fractions to a typical
total dose of 74−78 Gy.
• Several reports have suggested that prostate
cancer has a high fractionation sensitivity often
expressed numerically as a low α/β ratio in the
linear-quadratic formalism.
• Hypofractionation is generally categorised as
moderate hypofractionation and ultra-
hypofractionation with fraction sizes in the
range of 2.4−3.4 Gy and at least 5 Gy,
respectively.
• The latter is also referred to as extreme
hypofractionation, stereotactic body radiation
therapy, or stereotactic ablative radiotherapy.
• Hypofractionation is generally categorised as
moderate hypofractionation and ultra-
hypofractionation with fraction sizes in the
range of 2.4−3.4 Gy and at least 5 Gy,
respectively.
• The latter is also referred to as extreme
hypofractionation, stereotactic body radiation
therapy, or stereotactic ablative radiotherapy
• pooled analysis of 1100 patients treated with
ultrahypofractionation (ie, stereotactic body
radiation therapy) in eight prospective non-
randomised phase 2 trials reported promising
results regarding both biochemical relapse-free
survival and toxicity.
• To date, however, there are no published
randomised trials that evaluate
ultrahypofractionation for localised prostate
cancer.
• To address this, the prospective Scandinavian
HYPO-RT-PC multicentre randomised phase 3 trial
was initiated.
• This trial compares the effectiveness and
tolerability of image-guided ultra-
hypofractionation and conventional fractionation
external beam radiotherapy without addition of
androgen deprivation therapy for patients with
intermediate-risk to high-risk prostate cancer
• Methods
• Study design and participants
• The HYPO-RT-PC study is an open-label,
randomised,multicentre, phase 3 trial done in
12 centres in Sweden and Denmark.
• Participants were men up to 75 years of age
with histologically verified intermediate-to-
high-risk prostate cancer and WHO
performance status between 0 and 2.
• Intermediate-to-high-risk prostate cancer was
categorised according to the TNM classification
system as T1c−T3a with no evidence of lymph
node involvement or distant metastases with one
or two of the following risk factors:
• stage T3a, Gleason score of at least 7, or prostate-
specific antigen (PSA) of at least 10 ng/mL.
• The maximum PSA allowed was 20 ng/mL and no
androgen deprivation therapy was permitted
• Randomisation and masking
• Patients were randomly assigned in a 1:1 ratio
to either conventional fractionation or ultra-
hypofractionation.
• Procedures
• Radiotherapy was delivered with image-guided
three dimensional conformal radiotherapy,
intensity-modulated radiotherapy, or volumetric
modulated arc therapy with use of fiducial
markers.
• The BeamCath technique was initially used (10%
of participants), but this technique was
subsequently replaced by implanted gold fiducial
markers.
• The clinical target volume (CTV) was defined
as the prostate only; hence, seminal vesicles
were not included in the target volume.
• The CTV delineation was done on the CT
images. T2w-MRI, co-registered to the CT
images with aid of the fiducials, was
recommended but not mandatory.
• Patients in the conventional fractionation
group received 78·0 Gy in 39 fractions (5 days
per week for 8 weeks) whereas patients in the
ultra-hypofractionation arm received 42·7 Gy
in seven fractions (3 days per week for 2.5
weeks inclusive of two weekends), prescribed
as the mean PTV dose.
• Outcomes
• The primary endpoint was PSA relapse, clinical
failure, or both.
• The primary outcome measure was failure-free
survival—ie, time from randomisation to
biochemical or clinical failure.
• PSA progression was defined according to the
Radiation Therapy Oncology Group (RTOG) and
American Society for Radiation Oncology’s
Phoenix definition as nadir plus 2.0 ng/mL
• Failure could be either local or distant
progression.
• Local progression was defined as a tumour-
induced change in urinary symptoms (frequency,
urgency, and obstructions) of such magnitude
that a change of treatment was necessary (ie,
transurethral resection of the prostate or
castration).
• Distant progression was defined as detection of
metastases by x-ray, bone scan, CT, or ultrasound
examinations.
• Physician’s evaluation of urinary and bowel
toxicity was done according to the RTOG
morbidity scale. Patient reported urinary and
bowel problems and sexual function were
evaluated with the validated PCSS questionnaire.
• This comprises questions with a response scale
from 0 (“no problem/very good function”) to 10
(“many problems/ very bad function”).
• Results
• Between July 1, 2005, and Nov 4, 2015, 1200
patients from the 12 centres were randomly
assigned to either conventional fractionation
(n=602) or ultra-hypofractionation (n=598; ).
• Ten patients withdrew their consent, eight
were found ineligible for the trial, and two
died (unrelated to prostate cancer) just before
or after radiotherapy
• After a median follow-up time of 5.0 years
(IQR 3.1–7.0),102 primary events (biochemical
or clinical failure) had occurred in the
conventional fractionation group and 100 in
the ultra-hypofractionation group.
• Across both treatment groups, PSA relapse was
detected in 193 patients, local recurrences in six
patients, and distant metastases in three patients
as a first primary event,with each event equally
distributed between the groups.
• Failure-free survival at 5 years was 84% (95% CI
80−87) in the ultra-hypofractionation group and
84% (80−87) in the conventional fractionation
group (log-rank p=0・99;).
• There was no significant difference in overall
survival at 5 years between the treatment
arms (94% [95% CI 92–96] in the ultra-
hypofractionation group vs 96% [95–98] in the
conventional fractionation group;
• weak evidence of a higher frequency of acute
grade 2 or worse urinary toxicity in the
ultrahypofractionation group at end of
radiotherapy compared with the conventional
fractionation group (158 [28%] of 569 patients
vs 132 [23%] of 578 patients;).
• There were no significant differences in grade 2 or
worse urinary or bowel toxicity between the two
treatment groups at any point after radiotherapy,
except for an increase in urinary toxicity at 1-year
follow-up in the ultra-hypofractionation group
compared with the conventionalfractionation group
(32 [6%] of 528 patients vs 13 [2%] of 529 patients;).
• The frequency at 5-year follow-up of grade 2 or worse
urinary toxicity was 5% (11/243) for ultra-
hypofractionation and 5% (12/249) for conventional
fractionation
• The estimated physician-recorded cumulative
late urinary grade 2 or worse toxicity was 13%
(95% CI 11−16) for ultra-hypofractionation
and 9% (7−12) for conventional fractionation
at 2-year follow-up and 18% (15−22) and 17%
(14−20) at 5-year follow-up, respectively.
• Patients in the ultra-hypofractionation group
reported significantly higher levels of acute
urinary and bowel symptoms (ie, at end of
radiotherapy;
• No significant increases in late symptoms were
found,except for increased urinary problems at 1-
year follow up in the ultra-hypofractionation
group (mean score 2.06, 95% CI 1.82−2.30)
compared with the conventional fractionation
arm (1.58, 1.37–1.78), in line with the physician-
evaluated toxicity.
• Discussion
• To our knowledge, the present study is the first randomised
trial to report on the efficacy and side-effects of ultra-
hypofractionation compared with conventional
fractionation for prostate cancer.
• In this adequately powered clinical trial, we found that the
ultra-hypofractionation radiotherapy schedule of 42·7 Gy in
seven fractions (3 days per week for 2.5 weeks inclusive of
two weekends) was non-inferior (4% margin in failure free
survival at 5 years) to a standard regimen of 78·0 Gy in 39
fractions (5 days per week for 8 weeks) in regards to failure-
free survival for intermediate-to-high risk prostate cancer
• Four published randomised trials, comprising three
non-inferiority studies (CHHiP,8 NRG Oncology RTOG
0415,10 and PROFIT11) and one superiority study
(HYPRO9), have compared conventional fractionation
and moderate hypofractionation radiotherapy for
prostate cancer.
• Overall, they show that moderate hypofractionation is
safe and results in disease control that is comparable to
that achieved with conventional fractionation
radiotherapy; these studies have changed clinical
practice in many American and European centres
• The 5-year failure-free survival of this trial,
which was comprised of 89% intermediate-risk
patients and 11% high-risk patients, was
almost identical in the treatment groups (84%
in both groups; adjusted HR 1·002,95% CI 0・
758−1・325; log-rank p=0・99) and was
comparable to the outcome of the moderate
hypofractionation trials.
• In conclusion, this is the first randomised trial
comparing ultra-hypofractionation to conventional
fractionation in men with intermediate-to-high-risk
prostate cancer. With a median follow-up of 5 years,
we found that ultra-hypofractionation is non-inferior to
conventional fractionation radiotherapy regarding
failure-free survival.
• As expected, acute side-effects were more pronounced
with ultra-hypofractionation while these results show
that both physician-recorded and patient-reported
bowel and urinary treatment-related late side-effects
of ultra-hypofractionation are similar to those of
conventional fractionation.
• The results are specifically relevant for patients
with intermediate risk disease as there were few
high-risk patients in the trial and no androgen
deprivation therapy was used.
• Introduction of ultra-hypofractionation with
image guided radiotherapy techniques would
offer added patient convenience and significantly
reduced radiotherapy department workloads.
• HYPOFRACTIONATION
• Moderate hypofractionation is 2.4–4 Gy/fx.
• Randomized studies of moderate
hypofractionation report similar PFS to
conventional fractionation (1.8–2 Gy/fx),but
often with small increased toxicity risks.
• Extreme hypofractionation is 6.5–10 Gy/fx for
4–7 fractions,typically using SBRT with intra-
fraction motion management
• Early data for extreme hypofractionation is
promising,but long-term follow-up data is
limited.