Clinical trial NCT00193856: RADAR Trial - Randomised Androgen Deprivation and Radiotherapy
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prostate Cancer
Keywords: Prostate Cancer
Androgen Deprivation
Hormone Therapy
RadiotherapyBisphosphonate
Prostate Specific Antigen (PSA)
Lead sponsor: Trans Tasman Radiation Oncology Group
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Australia
name: Hunter Medical Research Institute (HMRI)
name: Health Research Council, New Zealand
name: Novartis Pharmaceuticals
name: Cancer Society of New Zealand
name: University of Newcastle, Australia
name: Calvary Mater Newcastle, Australia
name: Maitland Cancer Appeal
name: Abbott
First posted: 2005-09-19
Enrollment: 1071
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The principal objectives of the RADAR trial is to address the hypotheses; 1) that 18 months androgen deprivation in conjunction with radiotherapy is superior to 6 months androgen deprivation prior to and during radiotherapy; 2) that 18 months Bisphosphonate therapy will prevent bone loss caused by androgen deprivation therapy and further reduce relapse risk by impeding the development of bony metastases.

Detailed description: 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.

Eligibility criteria: 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 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:

* 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 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

Primary outcomes:
measure: Prostate cancer-specific mortality.
timeFrame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant
Secondary outcomes:
measure: Cumulative incidence of PSA progression
timeFrame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant
measure: Cumulative incidence of local, distant and bony progression and associated patterns of clinical progression
timeFrame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant
measure: All-cause mortality
timeFrame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant
measure: Changes in bone mineral density and osteopenic fracture
timeFrame: One endpoint analysis is planned when 4.5 years have elapsed from randomisation of the last participant
measure: Quality of life assessment
timeFrame: One endpoint analysis is planned when 3 years have elapsed from randomisation of the last participant
measure: Treatment related morbidity
timeFrame: One endpoint analysis is planned when 4 years have elapsed from randomisation of the last participant
measure: Cumulative incidence of secondary therapeutic intervention
timeFrame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomization of the last participant
Other outcomes:
Locations:
city: Campbelltown
country: Australia
facility: Campbelltown Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Lismore
country: Australia
facility: Lismore Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Penrith
country: Australia
facility: Nepean Cancer Care Centre
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Wagga Wagga
country: Australia
facility: Riverina Cancer Care Centre
state: New South Wales
city: Wentworthville
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Illawarra Cancer Care Centre
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater QRI
state: Queensland
city: Tugun
country: Australia
facility: John Flynn Private Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Launceston
country: Australia
facility: Launceston General Hospital
state: Tasmania
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Geelong
country: Australia
facility: Andrew Love Cancer Care Centre, Geelong Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Auckland
country: New Zealand
facility: Auckland Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Palmerston North
country: New Zealand
facility: Palmerston North Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
Study officials:
affiliation: University of Newcastle, Australia
name: Jim Denham, FRANZCR
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.