PracticeUpdate: Haematology & Oncology | Vol 1.No.3 - 2016

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JOURNAL SCAN
Conventional vs hypofractionated high-dose intensity-modulated
radiotherapy for prostate cancer
The Lancet Oncology
Take-home message
• This phase 3 noninferiority study enrolled 3216 men with localised prostate cancer who were randomised 1:1:1 to
receive conventional radiotherapy (74 Gy in 37 fractions over 7.4 weeks) or one of two hypofractionated schedules
(60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3.8 weeks). At 5 years, the proportion of patients
who were clinically or biochemically failure-free were comparable between patients receiving 60 Gy and the
conventional 74 Gy (90.6% and 88.3%, respectively), and the two schedules were noninferior; however, 57 Gy
(85.9 % of patients failure-free) was not noninferior to 74 Gy. Side effects were similar between conventional and
hypofractionated treatment groups based on clinician- and patient-reported outcomes.
• The authors recommend hypofractionated radiotherapy at 60 Gy over 20 fractions as a new standard of care for
radiotherapy in patients with localised prostate cancer given that it is noninferior to the conventional 74 Gy in 37
fractions.
Abstract
BACKGROUND Prostate cancer might
have high radiation-fraction sensitivity
that would give a therapeutic advan-
tage to hypofractionated treatment.
We present a pre-planned analysis of
the efficacy and side-effects of a ran-
domised trial comparing conventional
and hypofractionated radiotherapy after
5 years follow-up.
METHODS CHHiP is a randomised, phase
3, non-inferiority trial that recruited men
with localised prostate cancer (pT1b-
T3aN0M0). Patients were randomly
assigned (1:1:1) to conventional (74 Gy
delivered in 37 fractions over 7.4 weeks)
or one of two hypofractionated sched-
ules (60 Gy in 20 fractions over 4 weeks
or 57 Gy in 19 fractions over 3·8 weeks)
all delivered with intensity-modulated
techniques. Most patients were given
radiotherapy with 3–6 months of neo-
adjuvant and concurrent androgen
suppression. Randomisation was by
computer-generated random permuted
blocks, stratified by National Compre-
hensive Cancer Network (NCCN) risk
group and radiotherapy treatment
centre, and treatment allocation was
not masked. The primary endpoint was
time to biochemical or clinical failure;
the critical hazard ratio (HR) for non-
inferiority was 1.208. Analysis was by
intention to treat. Long-term follow-up
continues.
FINDINGS Between Oct 18, 2002, and
June 17, 2011, 3216 men were enrolled
from 71 centres and randomly assigned
(74 Gy group, 1065 patients; 60 Gy
group, 1074 patients; 57 Gy group, 1077
patients). Median follow-up was 62.4
months (IQR 53.9–77.0). The propor-
tion of patients who were biochemical
or clinical failure free at 5 years was
88.3% (95% CI 86.0–90.2) in the 74 Gy
group, 90.6% (88.5–92.3) in the 60 Gy
group, and 85.9% (83.4–88.0) in the
57 Gy group. 60 Gy was non-inferior
to 74 Gy (HR 0.84 [90% CI 0.68–1.03],
pNI=0.0018) but non-inferiority could
not be claimed for 57 Gy compared with
74 Gy (HR 1.20 [0.99–1.46], pNI=0.48).
Long-term side-effects were similar in
the hypofractionated groups compared
with the conventional group. There
were no significant differences in either
the proportion or cumulative incidence
of side-effects 5 years after treatment
using three clinician-reported as well
as patient-reported outcome measures.
The estimated cumulative 5 year inci-
dence of Radiation Therapy Oncology
Group (RTOG) grade 2 or worse bowel
and bladder adverse events was 13.7%
(111 events) and 9.1% (66 events) in the 74
Gy group, 11.9% (105 events) and 11.7%
(88 events) in the 60 Gy group, 11.3% (95
events) and 6.6% (57 events) in the 57
Gy group, respectively. No treatment-
related deaths were reported.
INTERPRETATION Hypofractionated radio-
therapy using 60 Gy in 20 fractions is
non-inferior to conventional fractiona-
tion using 74 Gy in 37 fractions and is
recommended as a new standard of
care for external-beam radiotherapy of
localised prostate cancer.
Conventional versus hypofraction-
ated high-dose intensity-modulated
radiotherapy for prostate cancer:
5-year outcomes of the randomised,
non-inferiority, phase 3 CHHiP trial.
Lancet Oncol 2016;17:1047–1060,
Dearnaley D, Syndikus I, Mossop H,
et al.
Dr Sonpavde, Associate Professor of Medicine, UAB School of Medicine in Alabama, discusses
the novel proteasome inhibitors and where this class of drug would fit in the spectrum of
treatment for advanced prostate cancer.
Dr Haffizulla: I know that you are the
principal investigator for an upcom-
ing clinical trial, and probably the
date will mature in the next couple
of years or months. The trial concerns
proteasome inhibitors, especially
carfilzomib and its place in the spec-
trum of treatment in prostate cancer.
Can you tell me a little bit more
about this particular class of drugs?
Dr Sonpavde: This is a novel class of
compounds to be looked at in ad-
vanced castrate-resistant prostate
cancer. Proteasome inhibitors, of
course, are widely used in multiple
myeloma, or haematologic malig-
nancy. There is rationale to look at
them in advanced prostate cancer.
More than a decade ago, bortezomib
was the first in class proteasome in-
hibitor also approve in myeloma. It
was looked at in a phase 1 trial that
included solid tumours, and there
was deep activity in a small subset
of patients with advanced castrate-
resistant prostate cancer. That
included tumour tissue responses,
regressions, and PSA declines. That
was a small subset, but the responses
were deep. So we believe that there
might be even better activity with
carfilzomib, which is a more potent
irreversible proteasome inhibitor, in
patients with this disease. We have a
phase 2 trial ongoing looking at this.
Dr Haffizulla: Where do you think
that would fit into the spectrum
of treatment for advanced prostate
cancer, specifically castrate-resistant
prostate cancer?
Dr Sonpavde: One of the things that
we are still learning is that, despite
all of the agents that are out now,
including enzalutamide and abira-
terone, which are novel androgen
pathway-inhibiting drugs, they’re
active, but there is a ton of cross-re-
sistance. The patients who progress
on abiraterone, or enzalutamide,
when switched to the other drug,
don’t have a huge response rate.
The response rate is in the 20% to
30% range. So we need new classes
of agents for these patients who are
progressing after these novel agents,
because of the cross-resistance.
There could be a big draw for a new
class of agents in these patients
who progress after abiraterone, or
enzalutamide, or both.
EDITORIAL
Managing Editor
Anne Neilson
Editor
Carolyn Ng
Designer
Jana Sokolovskaja
Medical Advisor
Dr Barry M Dale
Consultant Haematologist,
Medical Oncologist
SALES
Commercial Manager
Fleur Gill
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EMON091601
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PHARMACEUTICAL BENEFITS
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Biotech Australia – Ovarian stimulation,
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There could be a big draw
for a new class of agents
in these patients who
progress after
abiraterone, or
enzalutamide, or both.
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EXPERT OPINION
Proteosome inhibitors in advanced
castrate-resistant prostate cancer
Interview with
Guru Sonpavde, MD
View the full
interview with
Dr Guru Sonpavde
PROSTATE
VOL. 1 • No. 3 • 2016
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