Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, stage I prostate cancer, stage IIA prostate cancer, stage IIB prostate cancer, stage III prostate cancer
Brief summary
RATIONALE: Androgens can cause the growth of prostate cancer cells. Androgen deprivation therapy may stop the adrenal glands from making androgens. Radiation therapy uses high-energy x-rays to kill tumor cells. PURPOSE: This randomized phase III trial studies androgen-deprivation therapy and radiation therapy in treating patients with prostate cancer.
Detailed description
OBJECTIVES: Primary * Demonstrate that prophylactic, neoadjuvant androgen-deprivation therapy (NADT) combined with whole-pelvic radiation therapy (WPRT) improves overall survival (OS) compared with NADT combined with prostate and seminal vesicle radiation therapy (RT), with both arms receiving a high-dose prostate boost delivered by intensity-modulated RT (IMRT), external-beam RT (EBRT), high-dose-rate (HDR) brachytherapy, or permanent prostate implant (PPI). Secondary * Demonstrate that prophylactic WPRT improves biochemical control. * Determine the distant metastasis (DM)-free survival. * Determine the cause-specific survival (CSS). * Compare acute and late treatment-adverse events between patients receiving NADT and WPRT versus NADT, P, and SV RT. * Determine whether health-related quality of life (HRQOL), as measured by the Expanded Prostate Cancer Index Composite (EPIC), significantly worsens with increasing aggressiveness of treatment (i.e., Arm 2, NADT + WPRT). * Determine whether more aggressive treatment (Arm 2, NADT + WPRT) is associated with a greater increase in fatigue (PROMIS Fatigue Short Form) from baseline to last week of treatment, and a greater increase in circulating inflammatory markers (IL-1, IL-1ra, IL-6, tumor necrosis factor (TNF)-alpha, and C-reactive protein). * Demonstrate an incremental gain in OS and CSS with more aggressive therapy that outweighs any detriments in the primary generic domains of HRQOL (i.e., mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). * Determine whether changes in fatigue from baseline to the next three time points (week prior to RT, last week of treatment, and 3 months after treatment) are associated with changes in circulating cytokines, mood, sleep, and daily activities across the same time points. * Collect paraffin-embedded tissue blocks, plasma, whole blood, and urine for planned and future translational research analyses. OUTLINE: This is a multicenter study. Patients are stratified according to moderate- to high-risk groups as listed in the Disease Characteristics of this abstract, type of radiotherapy boost (IMRT vs brachytherapy \[Low-dose rate (LDR) using PPI or HDR\]), and duration of androgen-deprivation therapy (short-term \[4-6 months\] vs long-term \[32 months\]). Patients are randomized to 1 of 2 treatment arms. All patients receive neoadjuvant androgen-deprivation therapy comprising bicalutamide orally (PO) once daily or flutamide PO thrice daily for 4-6 months, and luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy comprising leuprolide acetate, goserelin acetate, buserelin, triptorelin, or degarelix subcutaneously (SC) or intramuscularly (IM) every 1 to 3 months beginning 2 months prior to radiotherapy and continuing for 4-6 or 32 months. Radiotherapy begins within 8 weeks after beginning LHRH agonist/antagonist injection. Patients may undergo blood and urine sample collection for correlative studies. Primary tumor tissue samples may also be collected. Patients may complete the Expanded Prostate Cancer Index Composite (EPIC), the PROMIS-Fatigue Short Form, and the EuroQol (EQ-5D) quality-of-life (QOL) questionnaires at baseline and periodically during treatment. Patients who participate in the QOL portion of the study must also agree to periodic blood collection. After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 3 years, and then yearly thereafter.
Interventions
RADIATIONthree-dimensional conformal radiotherapy
Daily fractions
RADIATIONintensity modulated radiotherapy
Daily fractions
RADIATIONBrachytherapy
Implant
DRUGAnti-androgen
Tablet
DRUGluteinizing hormone-releasing hormone (LHRH) agonist or antagonist
Injection
Sponsors
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
NRG Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: Pathologically (histologically or cytologically) proven diagnosis of prostatic adenocarcinoma within 180 days of registration at moderate to high risk for recurrence as determined by one of the following combinations: * Gleason score 7-10 + T1c-T2b (palpation) + PSA \< 50 ng/ml (includes intermediate and high risk patients); * Gleason score 6 + T2c-T4 (palpation) + PSA \< 50 ng/ml -ORGleason score 6 + ≥ 50% (positive) biopsies + PSA \< 50 ng/ml; * Gleason score 6 + T1c-T2b (palpation) + PSA \> 20 ng/ml. Patients previously diagnosed with low risk prostate cancer undergoing active surveillance who are re-biopsied and found to have unfavorable intermediate risk disease or favorable high risk disease according to the protocol criteria are eligible for enrollment within 180 days of the repeat biopsy procedure. * History/physical examination (to include at a minimum digital rectal examination of the prostate and examination of the skeletal system and abdomen) within 90 days prior to registration. * Clinically negative lymph nodes as established by imaging (pelvic ± abdominal CT or MR), (but not by nodal sampling, or dissection) within 90 days prior to registration. * Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are ≤ 1.5 cm. \*No evidence of bone metastases (M0) on bone scan within 120 days prior to registration (Na F PET/CT is an acceptable substitute). * Equivocal bone scan findings are allowed if plain films (or CT or MRI) are negative for metastasis. \*Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott, Hybritech) within 120 days prior to registration. * Study entry PSA should not be obtained during the following time frames: (1) 10- day period following prostate biopsy; (2) following initiation of hormonal therapy; (3) within 30 days after discontinuation of finasteride; (4) within 90 days after discontinuation of dutasteride. * Zubrod Performance Status 0-1(unless otherwise specified); * Age ≥ 18; * CBC/differential obtained within 60 days prior to registration on study, with adequate bone marrow function defined as follows: * Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; * Platelets ≥ 100,000 cells/mm3; * Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.); * Patient must be able to provide study specific informed consent prior to study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Alive (Overall Survival) | From randomization to death or last follow-up. Median follow-up at time of analysis was 6.8 years. Five- and ten-year estimates are reported. | Survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants by Highest Grade Acute Adverse Event Reported | From protocol treatment start date to 30 days from completion of radiation therapy. RT begins approximately weeks 8-10 after starting protocol therapy and ends approximately weeks 19-22, depending on boost technique. | Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Acute adverse events are defined as those occurring within 30 days after the completion of radiation therapy. RT begins approximately weeks 8-10 after starting protocol therapy and ends approximately weeks 19-22, depending on boost technique. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. |
| Number of Participants by Highest Grade Late Adverse Event Reported | From 30 days after completion of radiation therapy (approximately weeks 19-22, depending on boost technique) to highest grade late adverse event. Median follow-up at time of analysis was 6.7 years. | Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Late adverse events are defined as occurring ≥ 30 days after end of RT (approximately weeks 19-22, depending on boost technique). Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. |
| EPIC-26 Urinary Bowel Domain Score Change From Baseline at 6 Months | Baseline and 6 months after the end of RT, approximately 19-22 weeks, depending on boost technique. | The Expanded Prostate Cancer Index Composite-26 (EPIC-26) measures health-related quality of life in men with prostate cancer across urinary incontinence, urinary irritative/obstructive, bowel, sexual, and hormonal domains. Possible scores range from 0 to 100, with higher scores indicating better quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline. |
| EPIC-26 Urinary Irritative/Obstructive Subscore Change From Baseline at 6 Months | Baseline and 6 months after the end of RT, approximately 19-22 weeks, depending on boost technique. | The Expanded Prostate Cancer Index Composite-26 (EPIC-26) measures health-related quality of life in men with prostate cancer across urinary incontinence, urinary irritative/obstructive, bowel, sexual, and hormonal domains. Possible scores range from 0 to 100, with higher scores indicating better quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline. |
| Quality Adjusted Life Years (QALYs) | Baseline; the week prior to radiation therapy (RT); the last week of RT; 6 months, 1 year, and 5 years after RT. RT begins about weeks 8-10 after starting protocol therapy and ends about weeks 19-22, depending on boost technique. | Quality adjusted life years is calculated as the weighted sum of the number of years spent in different health states. The weight value is a utility score between 0 (worst health state) and 1 (best health state) derived from the EQ-5D questionnaire, designed to describe and value health based on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. |
| PROMIS Fatigue Score Change From Baseline Line at Last Week of Radiation Treatment | Baseline and last week of radiation treatment, approximately 19-22 weeks, depending on boost technique. | The Patient-Reported Outcome Measurement Information System (PROMIS) fatigue score measures self-reported fatigue symptoms over the past 7 days. Possible raw scores range from 29.4 to 83.2 (higher raw score indicating greater fatigue) and are converted into standardized T-scores (mean=50, standard deviation=10) with higher scores also indicating greater fatigue. Change score is calculated by subtracting baseline T-score from later T-score, with a positive change score indicating increased fatigue. |
| Percent of Participants Who Died Due to Prostate Cancer | From randomization to death due to prostate cancer or last follow-up. Median follow-up at time of analysis was 6.8 years. Five- and ten-year estimates are reported. | Prostate cancer death rates were estimated using the cumulative incidence method, treating death due to other causes as a competing risk, and otherwise censoring participants alive at time of analysis. |
| Percentage of Participants With Biochemical Failure | From date of randomization to the date of biochemical failure, death, or last follow-up, whichever occurs first. Median follow-up at time of analysis was 6.8 years. Five- and ten-year estimates are reported. | Biochemical failure is defined as a rise in prostate-specific antigen (PSA) of ≥2.0 ng/mL above the post-treatment PSA nadir following radiation therapy for prostate cancer (Phoenix definition). Biochemical failure rates were estimated using the cumulative incidence method, treating death as a competing risk, and otherwise censoring participants alive without biochemical failure at time of analysis. |
| Percentage of Participants With Distant Metastasis | From date of randomization to distant metastasis, death, or last follow-up, whichever occurs first. Median follow-up at time of analysis was 6.8 years. Five- and ten-year estimates are reported. | Distant metastasis rates were estimated using the cumulative incidence method, treating death as a competing risk, and otherwise censoring participants alive without distant metastasis at time of analysis. |
Countries
Canada, Hong Kong, Israel, Singapore, Switzerland, United States
Contacts
PRINCIPAL_INVESTIGATORMack Roach, MD
University of California, San Francisco
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 69 years |
| Duration of androgen deprivation therapy (ADT) (per stratification) 32 months (long term) | 387 Participants |
| Duration of androgen deprivation therapy (ADT) (per stratification) 4 months (short term) | 123 Participants |
| Duration of androgen deprivation therapy (ADT) (per stratification) 6 months (short term) | 720 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 53 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1163 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 33 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants |
| Race (NIH/OMB) Asian | 33 Participants |
| Race (NIH/OMB) Black or African American | 225 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 35 Participants |
| Race (NIH/OMB) White | 940 Participants |
| Risk group (per stratification) Gleason 6+T1c-T2b+PSA>20 | 16 Participants |
| Risk group (per stratification) Gleason 6+T2c-T4+PSA<50 | 33 Participants |
| Risk group (per stratification) Gleason 7-10+T1c-T2b+PSA<50 | 1214 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1245 Participants |
| Type of radiation boost (per stratification) Brachytherapy (low or high dose rate) | 257 Participants |
| Type of radiation boost (per stratification) intensity modulated radiotherapy (IMRT) | 1951 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 257 / 1,228 | 257 / 1,245 |
| other Total, other adverse events | 1,081 / 1,231 | 1,093 / 1,239 |
| serious Total, serious adverse events | 114 / 1,231 | 107 / 1,239 |
Outcome results
None listed