RADAR Trial - Randomised Androgen Deprivation and Radiotherapy
NCT ID: NCT00193856
Last Updated: 2017-10-12
Study Results
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Basic Information
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COMPLETED
PHASE3
1071 participants
INTERVENTIONAL
2003-10-31
2017-08-31
Brief Summary
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Detailed Description
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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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
FACTORIAL
TREATMENT
NONE
Study Groups
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A
LH-RH analogue for 5 months prior to and during first month of radiation treatment (total 6 mths)
Leuprorelin Acetate
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).
Conventional external beam therapy
The prescribed dose will be 66 Gy in 33 fractions of 2 Gy to the ICRU 50 point utilising a minimum of three fields with \>= 6 MV photons.
B
LH-RH analogue for 5 months prior to and during first month of radiation treatment (total 6 months) + bisphosphonate therapy.
Leuprorelin Acetate
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
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 bisphosphonate therapy.
Conventional external beam therapy
The prescribed dose will be 66 Gy in 33 fractions of 2 Gy to the ICRU 50 point utilising a minimum of three fields with \>= 6 MV photons.
C
LH-RH analogue as for arm A, but continued for further 12 months (total 18 months)
Leuprorelin Acetate
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).
Conventional external beam therapy
The prescribed dose will be 66 Gy in 33 fractions of 2 Gy to the ICRU 50 point utilising a minimum of three fields with \>= 6 MV photons.
D
LH-RH analogue as for arm A, but continued for further 12 months (total 18 months) + bisphosphonate therapy.
Leuprorelin Acetate
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
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 bisphosphonate therapy.
Conventional external beam therapy
The prescribed dose will be 66 Gy in 33 fractions of 2 Gy to the ICRU 50 point utilising a minimum of three fields with \>= 6 MV photons.
Interventions
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Leuprorelin Acetate
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
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 bisphosphonate therapy.
Conventional external beam therapy
The prescribed dose will be 66 Gy in 33 fractions of 2 Gy to the ICRU 50 point utilising a minimum of three fields with \>= 6 MV photons.
Eligibility Criteria
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Inclusion Criteria
* 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 randomisation
* ECOG performance status 0 - 1
* No concurrent medical conditions likely to significantly reduce prospects of 5 year survival
* Patient accessible to follow up at intervals specified in protocol
* Written informed consent given (signed by both patient and investigator prior to randomisation)
Exclusion Criteria
* 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 vertebrae
* Liver disease resulting in ALT or AST levels \>3 x ULN
* Prolonged continuous glucocorticoid therapy \> 10 mg/day of prednisone equivalent (\>6 months)
* Current treatment with bisphosphonate
* Inability to attend for follow-up at the Investigator's clinic
18 Years
MALE
No
Sponsors
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National Health and Medical Research Council, Australia
OTHER
Hunter Medical Research Institute (HMRI)
UNKNOWN
Health Research Council, New Zealand
OTHER
Novartis Pharmaceuticals
INDUSTRY
Cancer Society of New Zealand
UNKNOWN
University of Newcastle, Australia
OTHER
Calvary Mater Newcastle, Australia
OTHER
Maitland Cancer Appeal
UNKNOWN
Abbott
INDUSTRY
Trans Tasman Radiation Oncology Group
OTHER
Responsible Party
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Principal Investigators
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Jim Denham, FRANZCR
Role: STUDY_CHAIR
University of Newcastle, Australia
Locations
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Campbelltown Hospital
Campbelltown, New South Wales, Australia
St George Hospital
Kogarah, New South Wales, Australia
Lismore Hospital
Lismore, New South Wales, Australia
Liverpool Hospital
Liverpool, New South Wales, Australia
Calvary Mater Newcastle
Newcastle, New South Wales, Australia
Nepean Cancer Care Centre
Penrith, New South Wales, Australia
Royal North Shore Hospital
Sydney, New South Wales, Australia
Riverina Cancer Care Centre
Wagga Wagga, New South Wales, Australia
Westmead Hospital
Wentworthville, New South Wales, Australia
Illawarra Cancer Care Centre
Wollongong, New South Wales, Australia
Royal Brisbane Hospital
Herston, Queensland, Australia
Mater QRI
South Brisbane, Queensland, Australia
John Flynn Private Hospital
Tugun, Queensland, Australia
Princess Alexandra Hospital
Woolloongabba, Queensland, Australia
Launceston General Hospital
Launceston, Tasmania, Australia
Peter MacCallum Cancer Centre
East Melbourne, Victoria, Australia
Andrew Love Cancer Care Centre, Geelong Hospital
Geelong, Victoria, Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia
Auckland Hospital
Auckland, , New Zealand
Christchurch Hospital
Christchurch, , New Zealand
Dunedin Hospital
Dunedin, , New Zealand
Waikato Hospital
Hamilton, , New Zealand
Palmerston North Hospital
Palmerston North, , New Zealand
Wellington Hospital
Wellington, , New Zealand
Countries
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References
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Haworth A, Kearvell R, Greer PB, Hooton B, Denham JW, Lamb D, Duchesne G, Murray J, Joseph D. Assuring high quality treatment delivery in clinical trials - Results from the Trans-Tasman Radiation Oncology Group (TROG) study 03.04 "RADAR" set-up accuracy study. Radiother Oncol. 2009 Mar;90(3):299-306. doi: 10.1016/j.radonc.2008.10.011. Epub 2008 Nov 18.
Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial. Lancet Oncol. 2019 Feb;20(2):267-281. doi: 10.1016/S1470-2045(18)30757-5. Epub 2018 Dec 19.
Moulton CR, House MJ, Lye V, Tang CI, Krawiec M, Joseph DJ, Denham JW, Ebert MA. Prostate external beam radiotherapy combined with high-dose-rate brachytherapy: dose-volume parameters from deformably-registered plans correlate with late gastrointestinal complications. Radiat Oncol. 2016 Oct 31;11(1):144. doi: 10.1186/s13014-016-0719-2.
Denham JW, Steigler A, Joseph D, Lamb DS, Spry NA, Duchesne G, Atkinson C, Matthews J, Turner S, Kenny L, Tai KH, Gogna NK, Gill S, Tan H, Kearvell R, Murray J, Ebert M, Haworth A, Kennedy A, Delahunt B, Oldmeadow C, Holliday EG, Attia J. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial. Radiother Oncol. 2015 Jun;115(3):301-7. doi: 10.1016/j.radonc.2015.05.016. Epub 2015 Jun 10.
Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial. Lancet Oncol. 2014 Sep;15(10):1076-89. doi: 10.1016/S1470-2045(14)70328-6. Epub 2014 Aug 14.
Denham JW, Wilcox C, Joseph D, Spry NA, Lamb DS, Tai KH, Matthews J, Atkinson C, Turner S, Christie D, Gogna NK, Kenny L, Duchesne G, Delahunt B, McElduff P. Quality of life in men with locally advanced prostate cancer treated with leuprorelin and radiotherapy with or without zoledronic acid (TROG 03.04 RADAR): secondary endpoints from a randomised phase 3 factorial trial. Lancet Oncol. 2012 Dec;13(12):1260-70. doi: 10.1016/S1470-2045(12)70423-0. Epub 2012 Nov 12.
Denham JW, Wilcox C, Lamb DS, Spry NA, Duchesne G, Atkinson C, Matthews J, Turner S, Kenny L, Tai KH, Gogna NK, Ebert M, Delahunt B, McElduff P, Joseph D. Rectal and urinary dysfunction in the TROG 03.04 RADAR trial for locally advanced prostate cancer. Radiother Oncol. 2012 Nov;105(2):184-92. doi: 10.1016/j.radonc.2012.09.018. Epub 2012 Nov 3.
Related Links
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Click here for more information about this study on the TROG official website
Other Identifiers
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ACTRN12607000097448
Identifier Type: REGISTRY
Identifier Source: secondary_id
TROG 03.04
Identifier Type: -
Identifier Source: org_study_id