RADAR Trial - Randomised Androgen Deprivation and Radiotherapy

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
National Health and Medical Research Council, Australia
Hunter Medical Research Institute (HMRI)
Health Research Council, New Zealand
Abbott
Novartis Pharmaceuticals
New Zealand Cancer Society
University of Newcastle, Australia
Department of Radiation Oncology, Calvary Mater Newcastle, Australia
Information provided by (Responsible Party):
Trans-Tasman Radiation Oncology Group (TROG)
ClinicalTrials.gov Identifier:
NCT00193856
First received: September 12, 2005
Last updated: October 9, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Prostate Cancer
Drug: Leuprorelin Acetate
Drug: Zoledronic Acid
Radiation: Conventional external beam therapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by Trans-Tasman Radiation Oncology Group (TROG):

Primary Outcome Measures:
  • Prostate cancer-specific mortality. [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Cumulative incidence of PSA progression [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]
  • Cumulative incidence of local, distant and bony progression and associated patterns of clinical progression [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]
  • All-cause mortality [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]
  • Changes in bone mineral density and osteopenic fracture [ Time Frame: One endpoint analysis is planned when 4.5 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: Yes ]
  • Quality of life assessment [ Time Frame: One endpoint analysis is planned when 3 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: No ]
  • Treatment related morbidity [ Time Frame: One endpoint analysis is planned when 4 years have elapsed from randomisation of the last participant ] [ Designated as safety issue: Yes ]
  • Cumulative incidence of secondary therapeutic intervention [ Time Frame: Two main endpoint analyses are planned when 6.5 and 10 years have elapsed from randomization of the last participant ] [ Designated as safety issue: No ]

Estimated Enrollment: 1000
Study Start Date: October 2004
Estimated Study Completion Date: August 2018
Estimated Primary Completion Date: August 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: A
LH-RH analogue for 5 months prior to and during first month of radiation treatment (total 6 mths)
Drug: 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).
Radiation: 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.
Active Comparator: B
LH-RH analogue for 5 months prior to and during first month of radiation treatment (total 6 months) + bisphosphonate therapy.
Drug: 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).
Drug: 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.
Radiation: 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.
Experimental: C
LH-RH analogue as for arm A, but continued for further 12 months (total 18 months)
Drug: 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).
Radiation: 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.
Experimental: D
LH-RH analogue as for arm A, but continued for further 12 months (total 18 months) + bisphosphonate therapy.
Drug: 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).
Drug: 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.
Radiation: 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.

  Hide Detailed Description

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00193856

Locations
Australia, New South Wales
Campbelltown Hospital
Campbelltown, New South Wales, Australia, 2560
St George Hospital
Kogarah, New South Wales, Australia, 2217
Liverpool Hospital
Liverpool, New South Wales, Australia, 1871
Calvary Mater Newcastle
Newcastle, New South Wales, Australia, 2298
Nepean Cancer Care Centre
Penrith, New South Wales, Australia, 2751
Royal North Shore Hospital
Sydney, New South Wales, Australia, 2069
Riverina Cancer Care Centre
Wagga Wagga, New South Wales, Australia, 2650
Westmead Hospital
Wentworthville, New South Wales, Australia, 2145
Illawarra Cancer Care Centre
Wollongong, New South Wales, Australia
Australia, Queensland
Royal Brisbane Hospital
Herston, Queensland, Australia, 4029
Mater QRI
South Brisbane, Queensland, Australia, 4101
Premion - Tugun
Tugun, Queensland, Australia, 4224
Princess Alexandra Hospital
Woolloongabba, Queensland, Australia, 4102
Australia, Tasmania
Launceston General Hospital
Launceston, Tasmania, Australia, 7250
Australia, Victoria
Peter MacCallum Cancer Centre
East Melbourne, Victoria, Australia, 8006
Andrew Love Cancer Care Centre, Geelong Hospital
Geelong, Victoria, Australia, 3220
Australia, Western Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia, 6009
New Zealand
Auckland Hospital
Auckland, New Zealand, 1001
Christchurch Hospital
Christchurch, New Zealand, 4710
Dunedin Hospital
Dunedin, New Zealand
Waikato Hospital
Hamilton, New Zealand, 3200
Palmerston North Hospital
Palmerston North, New Zealand
Wellington Hospital
Wellington, New Zealand, 7902
Sponsors and Collaborators
Trans-Tasman Radiation Oncology Group (TROG)
National Health and Medical Research Council, Australia
Hunter Medical Research Institute (HMRI)
Health Research Council, New Zealand
Abbott
Novartis Pharmaceuticals
New Zealand Cancer Society
University of Newcastle, Australia
Department of Radiation Oncology, Calvary Mater Newcastle, Australia
Investigators
Study Chair: Jim Denham, FRANZCR University of Newcastle, Australia
  More Information

Additional Information:
Publications:
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. Radiotherapy and Oncology 90 (2009) 299-306

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Trans-Tasman Radiation Oncology Group (TROG)
ClinicalTrials.gov Identifier: NCT00193856     History of Changes
Other Study ID Numbers: TROG 03.04, ACTRN12607000097448
Study First Received: September 12, 2005
Last Updated: October 9, 2013
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Trans-Tasman Radiation Oncology Group (TROG):
Prostate Cancer
Androgen Deprivation
Hormone Therapy
RadiotherapyBisphosphonate
Prostate Specific Antigen (PSA)

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Androgens
Zoledronic acid
Leuprolide
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents
Therapeutic Uses
Antineoplastic Agents, Hormonal
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 18, 2014