Title

Interstitial Brachytherapy With or Without External-Beam Radiation Therapy in Treating Patients With Prostate Cancer
A Phase III Study Comparing Combined External Beam Radiation and Transperineal Interstitial Permanent Brachytherapy With Brachytherapy Alone for Selected Patients With Intermediate Risk Prostatic Carcinoma
  • Phase

    Phase 3
  • Study Type

    Interventional
  • Intervention/Treatment

    palladium 125-iodine ...
  • Study Participants

    588
RATIONALE: Radiation therapy uses high-energy x-rays and other sources to damage tumor cells. Interstitial brachytherapy uses radioactive material placed directly into or near a tumor to kill tumor cells. Combining interstitial brachytherapy with external-beam radiation therapy may kill more tumor cells. It is not yet known whether interstitial brachytherapy is more effective with or without external-beam radiation therapy in treating prostate cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of interstitial brachytherapy with or without external-beam radiation therapy in treating patients who have prostate cancer.
OBJECTIVES:

Compare the 5-year freedom from progression in patients with intermediate-risk prostate cancer treated with interstitial brachytherapy with or without external beam radiotherapy (EBRT).
Compare biochemical (i.e., prostate-specific antigen) failure, biochemical failure by the Phoenix definition, disease-specific survival, local progression, and distant metastases in patients treated with these regimens.
Compare morbidity and quality of life of patients treated with these regimens.
Determine the feasibility of collecting Medicare data in a large Radiation Therapy Oncology Group (RTOG) prostate cancer clinical trial for cost effectiveness and cost utility analysis of combined treatment with interstitial brachytherapy and EBRT.
Prospectively collect diagnostic biopsy samples from these patients for future biomarker analyses.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to disease stage (T1c vs T2a or T2b), Gleason score (≤ 6 vs 7), prostate-specific antigen (< 10 ng/mL vs 10-20 ng/mL), and prior neoadjuvant hormonal therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients undergo external beam radiotherapy 5 days a week for 5 weeks. Within 2-4 weeks of radiotherapy, patients undergo interstitial brachytherapy with iodine I 125 or palladium Pd 103 seeds.
Arm II: Patients undergo interstitial brachytherapy only, as in arm I. Quality of life is assessed at baseline, at 4, 12, and 24 months, and then annually for 3 years.

After completion of study treatment, patients are followed at 3-5 weeks, at 4, 6, 9, and 12 months, every 6 months for 4 years, and then annually thereafter.
Study Started
Jun 30
2003
Primary Completion
May 31
2017
Results Posted
Oct 16
2019
Last Update
Nov 05
2021

Radiation Brachytherapy (100/110)

100 Gy Palladium-103 (P-102) or 110 Gy Iodine-125 (I-125) seeds within 2-4 weeks of completion of external beam radiotherapy.

Radiation Brachytherapy (125/145)

125 Gy Palladium-103 (P-103) or 145 Gy Iodine-125 (I-125) seeds within 4 weeks of study entry.

Radiation External Beam Radiation Therapy

Total dose of 45 Gy to the prostate and seminal vesicles as a daily dose of 1.8 Gy given 5 times per week. The prescribed dose is defined at the International Commission of Radiation Units and Measurements (ICRU) reference point. Both 3D-conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT) are permitted.

  • Other names: EBRT

EBRT + Brachytherapy Experimental

External beam radiation therapy (EBRT) and transperineal interstitial permanent brachytherapy (100/110)

Brachytherapy Only Active Comparator

Transperineal interstitial permanent brachytherapy (125/145)

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed adenocarcinoma of the prostate

T1c-T2b, N0, M0

Intermediate-risk disease, as defined by 1 of the following:

Gleason score < 7 AND prostate-specific antigen (PSA) 10-20 ng/mL
Gleason score 7 AND PSA < 10 ng/mL
No evidence of distant metastases
Prostate volume ≤ 60 cc by transrectal ultrasonography
American Urological Association voiding symptom score no greater than 15 (alpha blockers allowed)

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

Zubrod 0-1

Life expectancy

Not specified

Hematopoietic

Not specified

Hepatic

Not specified

Renal

Not specified

Other

Patients must use effective contraception
No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ at any other site
No major medical or psychiatric illness that would preclude study therapy
No hip prosthesis

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

No prior chemotherapy

Endocrine therapy

Prior neoadjuvant hormonal therapy allowed provided the following are true:

Therapy was initiated within 2-6 months of study enrollment
Therapy was no more than 6 months in duration
Use of 5-alpha reductase inhibitors (e.g., finasteride) is discontinued before registration
No concurrent hormonal therapy

Radiotherapy

No prior pelvic radiotherapy

Surgery

No prior radical surgery for prostate cancer
No prior transurethral resection of the prostate
No prior cryosurgery

Other

No prior transurethral needle ablation of the prostate
No prior transurethral microwave thermotherapy of the prostate

Summary

EBRT + Brachytherapy

Brachytherapy Only

All Events

Event Type Organ System Event Term EBRT + Brachytherapy Brachytherapy Only

5-Year Freedom From Progression Rate

A Freedom from Progression (FFP) failure includes biochemical failure, local failure, distant failure, or death due to any cause. Patients who are failure free with less than 5 years of follow-up or who receive any secondary salvage therapy are censored. Freedom from Progression rates are estimated using the Kaplan-Meier method.

EBRT + Brachytherapy

85.5
percentage of participants
95% Confidence Interval: 81.3 to 89.7

Brachytherapy Only

83.1
percentage of participants
95% Confidence Interval: 78.7 to 87.5

Biochemical Failure Rate (Protocol Definition)

Biochemical failure is defined as having 3 consecutive rises of post-treatment PSA or starting hormones after one or more elevations in post-treatment PSA but before 3 consecutive elevations are documented. The sum of the 3 consecutive rises must exceed 1 ng/mL above the nadir. If 3 consecutive PSA rises occur during the first 24 months followed by a subsequent non-hormonal induced PSA decrease, patients will not be considered PSA failures. Three consecutive rises with any of the 3 PSA values occurring more than 24 months after the implant procedure will constitute a failure. Time to biochemical is defined as time from randomization to the date of first biochemical failure, last known follow-up (censored), or death without biochemical failure (competing risk). Biochemical failure rates are estimated using the cumulative incidence method. Five year rates are reported.

EBRT + Brachytherapy

10.5
percentage of participants
95% Confidence Interval: 7.2 to 14.4

Brachytherapy Only

10.5
percentage of participants
95% Confidence Interval: 7.3 to 14.4

Biochemical Failure (Phoenix Definition)

Biochemical Failure is defined as an increase of 2 ng/ml or more in PSA over the nadir PSA after 24 months from the start of treatment or the start of salvage hormones. Time to biochemical is defined as time from randomization to the date of first biochemical failure, last known follow-up (censored), or death without biochemical failure (competing risk). Biochemical failure rates are estimated using the cumulative incidence method. Five year rates are reported.

EBRT + Brachytherapy

8.0
percentage of participants
95% Confidence Interval: 5.2 to 11.6

Brachytherapy Only

8.1
percentage of participants
95% Confidence Interval: 5.3 to 11.7

Prostate Cancer Death

Prostate cancer death is defined as death due to prostate cancer or complications of treatment or death associated with any of the following: 1) further clinical tumor progression occurring after initiation of salvage androgen suppression therapy; 2) a rise that exceeds 1.0 ng/ml in the serum PSA level on at least two consecutive occasions that occurs during or after salvage androgen suppression therapy; and 3) disease progression in the absence of any anti-tumor therapy. Time to prostate cancer death is defined as time from randomization to the date of prostate cancer death, last known follow-up (censored), or death without prostate cancer (competing risk). Prostate cancer death rates are estimated using the cumulative incidence method. Five year rates are reported.

EBRT + Brachytherapy

0.4
percentage of participants
95% Confidence Interval: 0.0 to 1.9

Brachytherapy Only

1.1
percentage of participants
95% Confidence Interval: 0.3 to 2.9

Local Failure

Failure is defined as progression (increase in palpable abnormality) at any time, failure of regression of the palpable tumor by two years, and redevelopment of a palpable abnormality after complete disappearance of previous abnormalities. Histologic criteria for local failure are presence of prostatic carcinoma upon biopsy and positive biopsy of the palpably normal prostate more than two years after the start of treatment. Time to local failure is defined as time from randomization to the date of first local failure, last known follow-up (censored), or death without local failure (competing risk). Local failure rates are estimated using the cumulative incidence method. Five year rates are reported.

EBRT + Brachytherapy

1.5
percentage of participants
95% Confidence Interval: 0.5 to 3.5

Brachytherapy Only

1.1
percentage of participants
95% Confidence Interval: 0.3 to 2.9

Distant Metastases

Failure is defined as the appearance of any distant metastases. Time to distant metastases is defined as time from randomization to the date of first distant metastases, last known follow-up (censored), or death without distant metastases (competing risk). Distant metastases rates are estimated using the cumulative incidence method. Five year rates are reported.

EBRT + Brachytherapy

2.9
percentage of participants
95% Confidence Interval: 1.4 to 5.4

Brachytherapy Only

2.1
percentage of participants
95% Confidence Interval: 0.9 to 4.4

Percentage of Patients With Acute Grade 2+ and Grade 3+ Toxicities [Genitourinary (GU), Gastrointestinal (GI), and Overall]

Acute toxicities are scored according to NCI Common Toxicity Criteria (CTC) version 2.0 and will be defined as the worst severity of the toxicity occurring ≤ 180 days from start of radiation. The CTC v 2.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to based.

EBRT + Brachytherapy

Grade 2+ GU/GI

24.1
percentage of participants
95% Confidence Interval: 19.5 to 29.4

Grade 2+ Overall

27.7
percentage of participants
95% Confidence Interval: 22.8 to 33.2

Grade 3+ GU/GI

6.0
percentage of participants
95% Confidence Interval: 3.7 to 9.5

Grade 3+ Overall

7.8
percentage of participants
95% Confidence Interval: 5.2 to 11.6

Brachytherapy Only

Grade 2+ GU/GI

21.9
percentage of participants
95% Confidence Interval: 17.5 to 27.0

Grade 2+ Overall

26.4
percentage of participants
95% Confidence Interval: 21.6 to 31.8

Grade 3+ GU/GI

5.6
percentage of participants
95% Confidence Interval: 3.4 to 8.9

Grade 3+ Overall

8.3
percentage of participants
95% Confidence Interval: 5.6 to 12.2

Time to Late Grade 3+ Toxicities [Genitourinary (GU), Gastrointestinal (GI), and Overall]

Late toxicities are scored according to the Radiation Therapy Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer (EORTC) Late Radiation Morbidity Scoring Scheme and will be defined as the worst severity of the toxicity occurring > 180 days from radiation start. Grade 3+ GU/GI and overall were analyzed. RTOG/EORTC Late Radiation Morbidity Scoring Scheme assigns Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to toxicity. Time to late grade 3+ toxicity is defined as time from randomization to the date of first late grade 3+ toxicity, last known follow-up (censored), or death without late grade 3+ toxicity (competing risk). Late grade 3+ toxicity rates are estimated using the cumulative incidence method. Five year rates are reported.

EBRT + Brachytherapy

Grade 3+ GU/GI

7.9
percentage of participants
95% Confidence Interval: 5.1 to 11.4

Grade 3+ Overall

10.4
percentage of participants
95% Confidence Interval: 7.2 to 14.3

Brachytherapy Only

Grade 3+ GU/GI

3.8
percentage of participants
95% Confidence Interval: 2.0 to 6.5

Grade 3+ Overall

6.6
percentage of participants
95% Confidence Interval: 4.1 to 9.9

Change in Health-related Quality of Life From Baseline to 4-Months as Measured by Expanded Prostate Cancer Index Composite (EPIC)

The EPIC form is a 50-item, validated tool to assess disease-specific aspects of prostate cancer and its therapies and comprises of four summary domains (bowel, urinary, sexual, and hormonal function). The urinary domain summary score can be separated into 2 distinct subscales: urinary incontinence and urinary irritative. Hormonal domain was excluded as concurrent use of hormones was exclusionary and prior neoadjuvant hormone use was low. Response options for each EPIC item form a Likert scale and multi-item scale scores are transformed linearly to a 0-100 scale, with higher scores representing better health related quality of life. The change score was calculated as the value at 4 months minus the value at baseline. A negative change reflects a decline at 4 months and a positive change reflects an improvement at 4 months.

EBRT + Brachytherapy

Bowel

-10.4
units on a scale (Mean)
Standard Deviation: 13.6

Sexual

-13.7
units on a scale (Mean)
Standard Deviation: 22.3

Urinary

-20.1
units on a scale (Mean)
Standard Deviation: 15.4

Urinary-Incontinence

-10.3
units on a scale (Mean)
Standard Deviation: 17.7

Urinary-Irritative

-23.6
units on a scale (Mean)
Standard Deviation: 18.1

Brachytherapy Only

Bowel

-6.3
units on a scale (Mean)
Standard Deviation: 12.7

Sexual

-11.2
units on a scale (Mean)
Standard Deviation: 21.0

Urinary

-14.1
units on a scale (Mean)
Standard Deviation: 14.8

Urinary-Incontinence

-8.7
units on a scale (Mean)
Standard Deviation: 17.7

Urinary-Irritative

-15.9
units on a scale (Mean)
Standard Deviation: 17.3

Change in Health-Related Quality of Life From Baseline to 24-Months as Measured by EPIC

The EPIC form is a 50-item, validated tool to assess disease-specific aspects of prostate cancer and its therapies and comprises of four summary domains (bowel, urinary, sexual, and hormonal function). The urinary domain summary score can be separated into 2 distinct subscales: urinary incontinence and urinary irritative. Hormonal domain was excluded as concurrent use of hormones was exclusionary and prior neoadjuvant hormone use was low. Response options for each EPIC item form a Likert scale and multi-item scale scores are transformed linearly to a 0-100 scale, with higher scores representing better health related quality of life. The change score was calculated as the value at 24 months minus the value at baseline. A negative change reflects a decline at 24 months and a positive change reflects an improvement at 24 months.

EBRT + Brachytherapy

Bowel

-7.1
units on a scale (Mean)
Standard Deviation: 12.6

Sexual

-16.7
units on a scale (Mean)
Standard Deviation: 23.4

Urinary

-11.2
units on a scale (Mean)
Standard Deviation: 15.7

Urinary- Incontinence

-7.6
units on a scale (Mean)
Standard Deviation: 17.7

Urinary-Irritative

-11.9
units on a scale (Mean)
Standard Deviation: 17.4

Brachytherapy Only

Bowel

-2.4
units on a scale (Mean)
Standard Deviation: 9.9

Sexual

-10.6
units on a scale (Mean)
Standard Deviation: 21.0

Urinary

-5.6
units on a scale (Mean)
Standard Deviation: 13.6

Urinary- Incontinence

-6.3
units on a scale (Mean)
Standard Deviation: 15.5

Urinary-Irritative

-4.8
units on a scale (Mean)
Standard Deviation: 14.3

Change in Health-related Quality of Life From Baseline to 4-Months as Measured by EQ-5D (European Quality of Life-5 Domains) and AUA-SI (American Urological Association-Symptom Index)

Outcome Measure Data Not Reported

Change in Health-Related Quality of Life From Baseline to 24-Months as Measured by EQ-5D and AUA-SI

Outcome Measure Data Not Reported

Overall Survival

Failure is defined as death due to any cause. Overall survival time is defined as time from randomization to the date of death or last known follow-up (censored). Survival rates are estimated using the Kaplan-Meier method. Five year rates are reported.

EBRT + Brachytherapy

95.3
percentage of participants
95% Confidence Interval: 92.8 to 97.8

Brachytherapy Only

93.2
percentage of participants
95% Confidence Interval: 90.3 to 96.2

Feasibility of Collecting Medicare Data in a Large RTOG Prostate Cancer Clinical Trial for Cost Effectiveness and Cost Utility Analysis of Combined Treatment With Interstitial Brachytherapy and External Beam Radiotherapy

EBRT + Brachytherapy

Brachytherapy Only

Total

579
Participants

Age, Customized

Baseline Prostate Specific Antigen (PSA)

Combined Gleason Score (GS)

Ethnicity (NIH/OMB)

Gleason Score & PSA

Neoadjuvant Hormone Therapy

Race (NIH/OMB)

Sex: Female, Male

T Stage

Zubrod Performance Status

Overall Study

EBRT + Brachytherapy

Brachytherapy Only

Drop/Withdrawal Reasons

EBRT + Brachytherapy

Brachytherapy Only