A Randomised Trial Investigating the Effect on Biochemical (PSA) Control and Survival of Different Durations of Adjuvant Androgen Deprivation in Association With Definitive Radiation Treatment for Localised Carcinoma of the Prostate.
Traditionally androgen deprivation (by orchidectomy, or more recently by medication) has
been reserved for the palliative treatment of men with advanced, incurable prostate cancer.
However, evidence from large scale trials is beginning to suggest that androgen deprivation
(AD) may be helpful in preventing relapse in patients with more localised disease who are
treated surgically or by radiotherapy. Of the 8000 patients per annum who are treated with
curative intent, one half (4000) have cancers where 'adjuvant' AD may be prescribed
according to interpretation of the registered indications. There are, however, enormous
variations in prescribing practices which reflect uncertainty as to the appropriate
indications. An important issue is osteopenia.
The increasing use of AD in men with earlier stages of cancer, whose life expectancies
exceed 3 years, has exposed many unwanted metabolic sequelae of prolonged AD, the most
important being osteopenia. In 1996, with the funding support of the NHMRC and the
pharmaceutical industry, TROG therefore launched a large randomised three-arm trial. Two of
the arms repeated the two arms of the US Radiation Therapy Oncology Group (RTOG) 86.01 trial
which, at the time, was showing early indications of benefit for the addition of two months
maximal androgen deprivation (MAD), using Goserelin (Zoladex) and Flutamide, before
radiation therapy and one month during. Since work from Canada had indicated that continued
AD for periods longer than three months produced additional shrinkage of the prostatic
tumour, the TROG 96.01 trial incorporated a third arm: six months MAD prior to and during
radiotherapy. The trial completed its recruitment target of 800 eligible patients in early
2000. Although in August 2001 the median follow up time was still very short, a preliminary
analysis indicated that significant increases in time to biochemical relapse had been
produced by AD. In fact, the benefits of AD were independent of stage, tumour grade and
initial PSA value which were confirmed also to predict time to biochemical failure. The
hazard of relapse reduced to 0.75 (0.55 - 0.97, 95% confidence intervals) with 3 months AD,
and still further to 0.6 (0.45 - 0.82) with six months AD.
Subsequent international developments in this area of research encouraged the design of a
'follow on' trial. A European Organisation for Research and Treatment of Cancer (EORTC)
trial reported that 3 years of adjuvant ('post hoc') AD (using Goserelin alone),
administered after radiotherapy, reduced relapse and improved survival in patients with
locally advanced prostate cancer. The US Radiation Therapy Oncology Group (RTOG) 85.31 trial
indicated that indefinite Goserelin administration after radiotherapy reduced treatment
failure rates at all sites when compared with radiotherapy alone. The RTOG 92.02 trial
showed that 24 months of adjuvant Goserelin also reduced failure rates in patients treated
with 4 months of MAD prior to and during radiotherapy. Subset analyses of the RTOG trials,
suggested that patients who gain most from prolonged AD in terms of survival are those with
high grade cancers.
It was therefore logical for TROG to propose a second trial with the intention of finding
out whether an additional 12 months of AD administered after radiotherapy (aka 'intermediate
term' AD [ITAD]) would reduce relapse and mortality in patients treated with six months of
AD prior to and during radiotherapy (aka 'short term' AD [STAD]) as in the 'best' arm of its
first (96.01) trial. The availability of the potent bisphosphonate, zoledronic acid, also
made it possible to find out whether or not osteopenia induced in the two arms of the
proposed second trial would be prevented by a second random assignment to 18 months'
bisphosphonate therapy (BP).
This is a randomised phase III multicentre clinical trial.
After informed consent is given and eligibility is checked patients will be randomised to
one of four trial arms:
1. 6 months of androgen blockade with an LH-RH analogue (5 months before start of
2. 18 months of androgen blockade with an LH-RH analogue (starting 5 months before start
of radiotherapy) (ITAD),
3. 18 months of therapy with zoledronic acid 4 mg by intravenous infusion every 3 months
for 18 months beginning concurrently with STAD
4. 18 months of therapy with zoledronic acid beginning concurrently with ITAD.
Stratification will be according to the following criteria:
T2 / T3, 4 Gleason score 2 - 6 / 7+ Presenting PSA <10 / 10 - 20 / >20 Treatment centre
Radiation Treatment will be delivered using a conventional technique, unless the treatment
centre of the participating clinician demonstrates an ability to deliver the treatment using
a CRT, IMRT, or HDRB technique verified by the trial TACT.
LH-RH analogue (LH-RHa) (Leuprorelin acetate 22.5 mg) will be delivered as a depot injection
every 3 months. This will be administered as an Intramuscular injection (IMI).
Zoledronic acid 4 mg will be delivered as an intravenous infusion over 15 minutes once every
3 months for 18 months, in patients randomised to this therapy. No placebo therapy will be
given to patients randomised to 'no bisphosphonate therapy' treatment arm.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
Prostate cancer-specific mortality.
Two main endpoint analyses are planned when five and ten years have elapsed from treatment of the last patient registered on the trial.
Jim Denham, FRANZCR
University of Newcastle, Australia
Australia: Department of Health and Ageing Therapeutic Goods Administration