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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.

18 Years
Open (Enrolling)
Prostate Cancer

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Trial Information

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
radiotherapy) (STAD),

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.

Drug Treatment:

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.

Inclusion Criteria:

- Histological confirmation of adenocarcinoma of the prostate in the three months prior
to randomisation

- Gleason primary and secondary pattern reported. If the volume of tumour in biopsies
is too small for the pathologist to allocate a secondary pattern, the primary pattern
alone is sufficient.

- Primary tumour stage T2b - 4 (UICC 2002), or T2a providing biopsies demonstrate
Gleason score 7 or more, and presenting PSA 10 or more

- PSA value obtained within one month of randomisation

- No evidence of lymphatic or haematogenous metastases, as determined by negative chest
x-ray, CT scan of abdomen and pelvis, and bone scan in the 3 months prior to

- ECOG performance status 0 - 1

- No concurrent medical conditions likely to significantly reduce prospects of 5 year

- Patient accessible to follow up at intervals specified in protocol

- Written informed consent given (signed by both patient and investigator prior to

Exclusion Criteria:

- Previous or concurrent malignancy within previous 5 years except for non-melanomatous
skin cancer

- Prostatectomy

- Prior pelvic radiotherapy

- Prior hormone treatment for prostate cancer

- Inability to complete self administered QOL questionnaire

- Prior bisphosphonate therapy

- Serum creatinine > 2 x ULN

- Osteoporosis resulting in >30% loss in vertebral height in one or more thoraco-lumbar

- Liver disease resulting in ALT or AST levels >3 x ULN

- Prolonged continuous glucocorticoid therapy > 10 mg/day of prednisone equivalent (>6

- Current treatment with bisphosphonate

- Inability to attend for follow-up at the Investigator's clinic

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Prostate cancer-specific mortality.

Outcome Time Frame:

Two main endpoint analyses are planned when five and ten years have elapsed from treatment of the last patient registered on the trial.

Safety Issue:


Principal Investigator

Jim Denham, FRANZCR

Investigator Role:

Study Chair

Investigator Affiliation:

University of Newcastle, Australia


Australia: Department of Health and Ageing Therapeutic Goods Administration

Study ID:

TROG 03.04



Start Date:

October 2004

Completion Date:

July 2018

Related Keywords:

  • Prostate Cancer
  • Prostate Cancer
  • Androgen Deprivation
  • Hormone Therapy
  • RadiotherapyBisphosphonate
  • Prostate Specific Antigen (PSA)
  • Prostatic Neoplasms