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Trial registered on ANZCTR

Registration number

ACTRN12607000097448

Ethics application status

Approved

Date submitted

23/12/2003

Date registered

23/12/2003

Date last updated

14/12/2015

Type of registration

Retrospectively registered

Titles & IDs

Public title

A randomised trial investigating the effect on biomedical (PSA) control and survival of different durations of adjuvant androgen deprivation in association with definite radiation treatment for localised carcinoma of the prostate (RADAR)

Scientific title

Trans Tasman Radiation Oncology Group (TROG) 03.04 - A randomised trial investigating the effect on biomedical (Prostate Specific Antigen- PSA) control and survival of different durations of adjuvant androgen (Leuprorelin acetate and zoledronic acid)deprivation in association with definite radiation treatment for localised carcinoma of the prostate (The RADAR trial)

Secondary ID [1]

National Clinical Trials Registry: NCTR491

Secondary ID [2]

ClinicalTrials.gov: NCT 00193856

Universal Trial Number (UTN)

Trial acronym

TROG 03.04 - RADAR

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Localised carcinoma of the prostate

Condition category

Condition code

Cancer

Prostate

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Androgen deprivation: artificial drugs create a depression in the production of sex hormones.
Arm A: Androgen deprivation (AD): 6 months Luteinising Hormone - Releasing Hormone (LH-RH) analogue (Leuprorelin acetate 22.5mg) depot injected every 3 months, at 0 and 3 months. Radiation begins after 5 months AD.
Arm B: Androgen deprivation: 6 months LH-RH analogue (Leuprorelin acetate 22.5mg) depot injected every 3 months, at 0 and 3 months. Radiation begins after 5 months AD. Bisphosphonate therapy (Zoledronic acid 4mg) every 3 months for 18 months by IV.
Arm C: Androgen deprivation: 18 months LH-RH analogue (Leuprorelin acetate 22.5mg) depot injected every 3 months at 0, 3, 6, 9, 12 and 15 months. Radiation treatment begins after 5 months AD.
Arm D: Andorgen deprivation: 18 months LH-RH analogue (Leuprorelin acetate 22.5mg) depot injected every 3 months at 0, 3, 6, 9, 12 and 15 months. Radiation treatment begins after 5 months AD. Bisphosphonate therapy (Zoledronic acid 4mg) every 3 months for 18 months by IV.
Radiation will be 66Gy in 33 fractions of 2gy in all cases for a period of 8 weeks.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

LH-RH analogue for 5 months prior to and during first month of radiation treatment (total 6 mths)

Control group

Active

Outcomes

Primary outcome [1]

Prostate cancer-specific mortality.

Prostate cancer specific mortality will be assessed by estimation of cumulative incidence (1). After ensuring that the hazards of prostate cancer specific mortality (PCSM) are proportional for each trial arm, the primary analysis comparing short (6 months) and intermediate (18 months) androgen deprivation with respect to PCSM will be performed using the method of Fine and Gray (cumulative incidence competing hazards estimation), adjusting for presenting PSA level (< 10, 10 - 20, > 20), Gleason score (2 - 6, 7, 8 - 10) and stage (T2, 3 - 4). If the hazard rates are not proportional then the primary analysis will be performed by comparing the cumulative incidence rates at fixed time points, namely five and ten years. These comparisons will be performed adjusting for presenting PSA level, Gleason score and stage as before. Within each stratum, the 5-year and 10-year cumulative incidences of PCSM estimates and their standard errors will be determined over the 12 strata calculated and tested for significance.

1. Fine JP, Gray R. A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association. 1999;94:496-509.

Timepoint [1]

Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.

Secondary outcome [1]

1. Cumulative incidence of PSA progression

PSA is measured at each follow-up and is measured more frequently on progression. Cumulative incidence of PSA progression will be compared between treatment arms using the method of Fine and Gray (1), adjusting for PSA level, Gleason score and stage.

1. Fine JP, Gray R. A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association. 1999;94:496-509.

Timepoint [1]

Measured until a death from any cause. Follow up is 3 monthly up to 30 months . Then 6 monthly for 5 years post randomisation and then annually until death.

Secondary outcome [2]

2. Cumulative incidence of local, distant and bony progression and associated patterns of clinical progression

The effect of androgen deprivation on risk of local and distant progression will be tested using competing risks methodology to compare the short term and intermediate term arms as a first event in a competing risks analysis of clinical progression data. In a separate analysis the data will be examined to see if there is an interaction between androgen deprivation arm and dose of radiotherapy (=< 70 Gy versus > 70 Gy) using Cox regression (ie to see if the effect of duration of androgen deprivation depends on the radiation dose used).

Timepoint [2]

Measured until local progression, distant progression, rising PSA, or death from any cause. Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.

Secondary outcome [3]

3. All-cause mortality (5 years)

Timepoint [3]

Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.

Secondary outcome [4]

4. Changes in bone mineral density and osteopenic Fracture

Risk of osteoporotic fracture: Any fracture occuring during follow-up is reported, each incidence will be investigated and cause attributed by the investigator. All patients will have a thoracor-lumbar x-ray at 0 and 3 years to assess vertebral fracture. The effect of bisphosphonate (BP) on the risk of osteoporotic and sporadic fractures will be tested by comparing the proportions of patients at three years with new fractures, between the arms, no BP and BP, using an exact test of proportions, stratifying for type of androgen deprivation arm (Short or intermediate term) and age (<60, 60 - 70, 70+). Patients eligible for this analysis will be those alive and who have been examined for presence of fracture by plain radiograph at baseline and at three years. The proportions of patients in each arm who have died before three years or who are otherwise not included in the comparison will be taken into account in the interpretation of the results. A test for interaction between bisphosphonate arm and androgen deprivation arm will be performed; if there is a significant interaction (ie if the effect of BP depends importantly on the AD arm) the BP arms may be tested separately within short-term AD patients and within intermediate term AD patients.

Loss of Bone mineral density: BMD will be measured in a subset of patients at 0, 2 and 4 years by DEXA scan. The primary analysis for the effect of bisphosphonate on loss of BMD will be tested using multiple linear regression analysis on the change from baseline at two years of BMD, with a further analysis at 4 years, adjusting for baseline BMD and length of androgen deprivation received. It is intended to log-transform data prior to analysis, however the pooled data will be examined prior to analysis to see whether a different transformation or the use of a nonparametric test is appropriate. Patients eligible for these analyses are those alive and who are tested for BMD by DEXA scan at baseline and at two years. The proportions of patients in each arm who have died before two years or are otherwise not included in the comparison will be taken into account in the interpretation of the results. Testing for, and interpretation of, interaction between BP and AD will be as for fracture risk.

Timepoint [4]

Measured until death. Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.

Secondary outcome [5]

5. Quality of life self-assessment

Patient reported outcomes will be measured using the EORTC QLQ C-30 and PR 25 questionnaires at baseline, 3 months, at end of RT and at 12, 18, 24, 36 and 60 months. Mean change from baseline in global and domain scores will be plotted by time and by treatment arm. The primary analysis of QOL will be a comparison between treatments of the change from baseline of the global QOL score at three years, adjusted for baseline QOL score, using multiple linear regression. Patients included in this analysis will be those who are alive at three years and who have completed both baseline and three-year questionnaires. Pooled data will be examined prior to analysis to see whether transformation or use of a nonparametric test is appropriate.

Timepoint [5]

Performed at baseline, 3 months, end of radiation therapy treatment, 12 months, 18 months, 24 months, 36 months, 60 months and then yearly.

Secondary outcome [6]

1. Treatment related morbidity

Radiation induced toxicity: Patient reported outcomes will be measured using the EORTC QLQ C-30 and PR25 questionnaires, the International Prostate Symptom Score (IPSS) for urinary function and pharmaceutical intervention (PI) questionnaire for androgen deprivation and bisphosphonate side effects at baseline, 3 months, end of RT, 12 months, 18 months, 24 months, 36 months, 60 months and then yearly.

Urinary and rectal function will be analysed at four cross-sectional time points: 1. At baseline prior to any treatment; 2. At the end of radiotherapy; 3. At 24 months (ie approximately 18 months post radiation); 4. At 36 months (ie 30 months post radiation). Individual function scores and composite scores will be compared between trial arms using non-parametric uni-variable and multi-variable techniques.

Hormone deprivation induced toxicity: Pre-morbidity data and serial testosterone measures will be collected; reported cardiac and other adverse events will be thoroughly reviewed and classified. Cumulative incidence (CI) of myocardial infarction or other serious adverse event will be derived by competing risk methodology and multi-variable models to determine contributing factors. Data will be analysed at 5 years post randomisation.

Timepoint [6]

Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.

Eligibility

Key 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)

Minimum age

18 Years

Maximum age

No limit

Sex

Males

Can healthy volunteers participate?

Key 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

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Central randomisation by phone / computer

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Stratified allocation. Factors: Treatment centre, presenting Prostate Specific Antigen, Gleason score, stage. Simple randomisation by computer.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Factorial

Other design features

Phase

Phase 3

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

23/10/2003

Actual

23/10/2003

Date of last participant enrolment

Anticipated

29/08/2007

Actual

29/08/2007

Date of last data collection

Anticipated

Actual

Sample size

Target

1000

Accrual to date

Final

1071

Recruitment in Australia

Recruitment state(s)

NSW,VIC,QLD,WA,TAS

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health & Medical Research Council Project Grant

Address [1]

Level 5, 20 Allara St Canberra ACT 2601

Country [1]

Australia

Funding source category [2]

Government body

Name [2]

Health Research Council New Zealand

Address [2]

PO Box 5541, Wellesley Street, Auckland

Country [2]

New Zealand

Primary sponsor type

Other Collaborative groups

Name

Trans Tasman Radiation Oncology Group (TROG)

Address

TROG Central Operations, Department of Radiation Oncology, Calvary Mater Newcastle, Locked Bag 7, Hunter Regional Mail Centre, NSW 2310

Country

Australia

Secondary sponsor category [1]

Individual

Name [1]

Professor Jim Denham

Address [1]

Prostate Cancer Trials Group, University of Newcastle, Callaghan NSW 2308

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Hunter New England Human Research Ethics Committee

Ethics committee address [1]

Locked Bag 1 
New Lambton NSW 2305
Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

17/07/2003

Ethics approval number [1]

03/06/11/3.02

Summary

Brief summary

Six months of hormone treatment improves the results of radiotherapy for men with early prostate cancer.  This trial will determine if adding another 12 months of hormone treatment after radiotherapy is even better.  Bones are often affected by prostate cancer and can also be damaged by prolong hormone treatment.  Bisphosphonates are drugs that make bones stronger.  This trial will also determine if treatment with a bisphosphonate can help prevent these bone problems.

Trial website

Trial related presentations / publications

Delahunt B, Egevad L, Srigley JR, Steigler A, Murray JD, Atkinson C, Matthews J, Duchesne G, Spry NA, Christie D, Joseph D, Attia J, Denham JW.  Validation of International Society of Urological Pathology (ISUP) grading for prostatic adenocarcinoma in thin core biopsies using TROG 03.04 ‘RADAR’ trial clinical data.  Pathology (October 2015) 47(6), pp. 520–525..

Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai K-H, 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 September;15 (10): 1076-1089.

Denham JW, Nowitz M, Joseph D, Duchesne G, Spry NA, Lamb DS, Matthews J, Turner S, Atkinson C, Tai K-H, Gogna K, Kenny L, Diamond T, Smart R, Rowan D, Moscato P, Vimieiro R, Woodfield R, Lynch K, D’Este C, McElduff P, Steigler A, Kautto A, Ball J. Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the TROG 03.04 RADAR trial for locally advanced prostate cancer. BJUI. 2014 September; 114 (3); 344-353. Doi: 10.1111/bju.12497. 

Sharpley CF, Birsika V, Denham JW. Factors associated with feelings of loss of masculinity in men with prostate cancer in the RADAR trial. Psycho-Oncology 2014 May; 23(5): 524-30. 

Galvao DA, Spry N, Denham J, Taaffe DR, Cormie P, Joseph D, Lamb D, Chambers S, Newton R. A Multicentre Year-long Randomised Controlled Trial of Exercise Training Targeting Physical Functioning in Men with Prostate Cancer Previously Treated with Androgen Suppression and Radiation from TROG 03.04 RADAR. Eur Urol. 2014 May; 65 (5): 856- 864. 

Ebert MA, Bulsara M, Haworth A, et al. Technical quality assurance during the TROG 03.04 RADAR prostate radiotherapy trial: Are the results reflected in observed toxicity rates? J Med Imaging Radiat Oncol 2014.

Ebert MA, Foo K, Haworth A, et al. Derivation and representation of dose-volume response from large clinical trial data sets: an example from the RADAR prostate radiotherapy trial. J Physics 2014; Conference Series 489(1)(012090).

Kearvell R, Haworth A, Ebert MA, Murray J, Hooton B, Richardson S, et al. Quality improvements in prostate radiotherapy: Outcomes and impact of comprehensive quality assurance during the TROG 03.04 'RADAR' trial. J Med Imaging Radiat Oncol. 2013; 57: 247-57.

Denham JW, Wilcox C, Joseph D, Spry NA, Lamb DS, Tai KH, et al. 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; 13(12): 1260-70.

Denham JW, Wilcox C, Lamb DS, Spry NA, Duchesne G, Atkinson C, et al. Rectal and urinary dysfunction in the TROG 03.04 RADAR trial for locally advanced prostate cancer. Radiother Oncol. 2012; 105(2): 184-92.

Ebert MA, Harrison KM, Howlett SJ, Cornes D, Bulsara M, Hamilton CS, et al. Dosimetric intercomparison for multicentre clinical trials using a patient-based anatomic pelvic phantom. Med Phys. 2011; 38(9): 5167-75.

Delahunt B, Lamb DS, Srigley JR, Murray JD, Wilcox C, Samaratunga H, et al. Gleason scoring: a comparison of classical and modified (International Society of Urological Pathology) criteria using nadir PSA as a clinical end point. Pathology. 2010; 42(4): 339-43.

Galvao DA, Spry N, Taaffe DR, Denham J, Joseph D, Lamb DS, et al. A randomized controlled trial of an exercise intervention targeting cardiovascular and metabolic risk factors for prostate cancer patients from the RADAR trial. BMC Cancer. 2009; 9: 419.

Haworth A, Kearvell R, Greer PB, Hooton B, Denham JW, Lamb D, et al. 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; 90(3): 299-306.

Ebert MA, Harrison KM, Cornes D, Howlett SJ, Joseph DJ, Kron T, et al. Comprehensive Australasian multicentre dosimetric intercomparison: issues, logistics and recommendations. J Med Imaging Radiat Oncol. 2009; 53(1): 119-31.

Public notes

Contacts

Principal investigator

Name

Prof Jim Denham

Address

Prostate Cancer Trials Group, University of Newcastle, Callaghan NSW 2308

Country

Australia

Phone

+61 2 4985 4017

Fax

jim.denham@newcastle.edu.au

Contact person for public queries

Name

Allison Steigler

Address

Prostate Cancer Trials Group, University of Newcastle, Callaghan NSW 2308

Country

Australia

Phone

+61 2 4985 4019

Fax

N/A

allison.steigler@newcastle.edu.au

Contact person for scientific queries

Name

Jim Denham

Address

Prostate Cancer Trials Group, University of Newcastle, Callaghan NSW 2308

Country

Australia

Phone

+61 2 4985 4018

Fax

N/A

Jim.Denham@newcastle.edu.au

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