Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer
Brief summary
RATIONALE: Specialized radiation therapy that delivers a high-dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as leuprolide, goserelin, flutamide, or bicalutamide, may lessen the amount of androgens made by the body. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with androgen suppression and docetaxel after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well giving radiation therapy together with androgen suppression and docetaxel works in treating patients with high risk prostate cancer who have undergone radical prostatectomy.
Detailed description
OBJECTIVES: Primary * To assess whether the addition of androgen suppression therapy and docetaxel to adjuvant radiotherapy improves freedom from progression. Secondary * To assess freedom from local-regional progression, distant metastases, disease-free survival, prostate cancer specific survival, non-prostate cancer specific survival, overall survival, and time to biochemical (PSA) failure. * To evaluate treatment-related acute and late toxicity based on Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0. * To correlate genomic and proteomic biomarkers with the primary and secondary clinical endpoints utilizing archival prostatectomy tissue and pretreatment and prospectively collected serum/plasma. OUTLINE: This is a multicenter study. * Androgen suppression therapy: Patients receive a luteinizing hormone-releasing hormone (LHRH) agonist (leuprolide or goserelin) as an injection AND an oral antiandrogen (flutamide 3 times daily or bicalutamide once daily) for up to 6 months. * Radiotherapy: Beginning 8 weeks after the initiation of androgen suppression therapy, patients undergo 3-dimensional conformal radiotherapy or intensity-modulated radiotherapy once a day 5 days a week for up to approximately 8 weeks. * Chemotherapy: Beginning 3-6 weeks after the completion of radiotherapy, patients receive docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for up to 6 courses. After the completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Interventions
DRUGbicalutamide
50 mg (one tablet) daily orally for 6 months, starting within 6 months after registration
DRUGdocetaxel
75 mg/m2 IV over 1 hour on day 1 of each cycle q21 days for 6 cycles, starting 3-6 weeks after completion of radiation therapy
DRUGflutamide
250 mg (two 125-mg capsules) three times daily (total 750 mg) orally for 6 months, starting within 6 months after registration
DRUGLHRH agonist
LHRH agonist (such as leuprolide, goserelin, buserelin, or triptorelin) for 6 months, starting within 6 weeks after registration
RADIATION3-dimensional conformal radiation therapy
RADIATIONradiation therapy
66.6 Gy (1.8 Gy per fraction, 5 days per week) to the prostate bed (IMRT or 3DCRT), starting 8 weeks after start of hormones
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Pathologically proven adenocarcinoma of the prostate gland meeting one of the following criteria: * Gleason ≥ 7and post-operative PSA nadir \> 0.2 ng/ml with any pathologic tumor (pT) classification * Gleason ≥ 8, post-operative PSA nadir ≤ 0.2 ng/ml and ≥ pT3a classification * Must have undergone radical prostatectomy within the past year * PSA must be obtained within 6 weeks (42 days) prior to study registration * No lymph node or distant metastases (N0, M0), based upon the following minimum diagnostic workup: * History and physical examination within 8 weeks prior to study registration * Bone scan and CT or MRI of the pelvis and no evidence of osseous metastases on bone scan within 16 weeks prior to study registration * No pelvic lymph nodes \> 1.5 cm in greatest dimension on CT scan or MRI of the pelvis within 16 weeks prior to study registration, unless the enlarged lymph node is biopsied and negative PATIENT CHARACTERISTICS: * Zubrod performance status 0-1 * Absolute neutrophil count (ANC) ≥ 2,000/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve hemoglobin ≥ 8.0 g/dL is acceptable) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 times upper limit of normal (ULN) * Alkaline phosphatase ≤ 2.5 times ULN * Total bilirubin ≤ 1.2 times ULN * No other invasive malignancy within the past 3 years except non-melanomatous skin cancer * No active, severe co-morbidity, including any of the following: * Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months * Transmural myocardial infarction within the past 6 months * Acute bacterial or fungal infection requiring intravenous antibiotics * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy * AIDS * HIV testing is not required for study entry * No prior allergic reaction to the study drug(s) PRIOR CONCURRENT THERAPY: * No prior systemic chemotherapy for prostate cancer * More than 3 years since prior chemotherapy for a different cancer * No prior androgen deprivation for treatment of prostate cancer * Prior use of hormonal agents, such as finasteride or dutasteride, for treatment of benign prostatic hypertrophy is allowed * No prior radiotherapy to the region of the prostate that would result in overlap of radiotherapy fields
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Free From Progression at 3 Years | From registration to 3 years. | Failure was defined as PSA ≥ 0.4 ng/mL after the end of radiation therapy confirmed by a second higher PSA, non-protocol hormones, local-regional progression, distant metastasis, or death, within 3 years after study registration. Freedom from progression (FFP) rate under null hypothesis was 50%; under alternative hypothesis ≥ 70%. Per Fleming's multiple testing procedure with 3 stages, 69 patients (76 allowing for 10% ineligible) were required for 90% power and type I error 0.025. If ≥ 44 of 69 patients had a FFP event, we would reject 50% FFP rate in favor of ≥ 70%. Analysis was out of 74 patients (not 69), so ≥ 44 was revised to ≥ 46. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Distant Metastasis (3-year Rate) | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | Time from registration to date of distant metastasis (failure), death (competing risk), or last follow-up (censored). Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. |
| Prostate Cancer Death (3-year Rate) | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | Time from registration to date of distant metastasis (failure), death (competing risk), or last follow-up (censored). Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. |
| Non-prostate Cancer Death (3-year Rate) | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | Time from registration to date of death due to other causes (failure), death due to prostate cancer (competing risk), or last follow-up (censored).Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. |
| Overall Survival (3-year Rate) | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | Time from registration to date of death (failure) or last follow-up (censored). Three-year rate and 95% confidence interval were estimated by the Kaplan-Meier method. |
| Local-regional Progression (3 Year Rate) | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | Time from registration to date of local progression (failure), death (competing risk), or last follow-up (censored). Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. |
| Number of Patients With Acute Adverse Events (Based on CTCAE, v3.0) | From start of treatment to 90 days after the planned end of treatment (21 days after last docetaxel dose). Analysis occurs at the time of the primary analysis. (Patients are followed until death or study termination whichever occurs first. | The number of patients with at least one grade 3 or higher adverse event (AE) from start of treatment to 90 days after the planned end of treatment (21 days after last docetaxel dose). Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. |
| Time to Late Grade 3+ Adverse Events (Based on CTCAE, v3.0) | From 91 to 730 days after the planned end of treatment (21 days after last docetaxel dose). Analysis occurs at the time of the primary analysis. (Patients are followed from registration to death or study termination whichever occurs first.) | Two-year rate shown (cumulative incidence method). Adverse events are graded using CTCAE v3.0. Time of first late adverse event occurrence of the Grade 3+ adverse event between 91 days and 730 days from the completion of treatment (3 weeks after the last planned docetaxel dose) calculated. Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. |
| Prognostic Value of Genomic and Proteomic Markers for the Primary and Secondary Clinical Endpoints | Analysis can occur at the same time as the primary endpoint if data is available. | — |
| Time to Biochemical (PSA) Failure (3-year Rate) | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | Failure is defined as PSA ≥ 0.4 ng/mL confirmed by a second higher PSA or initiation of non-protocol hormones. Death is considered a competing risk. Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Androgen Suppression + RT + Docetaxel LHRH agonist and oral antiandrogen (flutamide or bicalutamide), radiation therapy (RT), and docetaxel | 74 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 6 |
Baseline characteristics
| Characteristic | Androgen Suppression + RT + Docetaxel |
|---|---|
| Age, Continuous | 62 years |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 73 / 74 |
| serious Total, serious adverse events | 20 / 74 |
Outcome results
Primary
Number of Participants Free From Progression at 3 Years
Failure was defined as PSA ≥ 0.4 ng/mL after the end of radiation therapy confirmed by a second higher PSA, non-protocol hormones, local-regional progression, distant metastasis, or death, within 3 years after study registration. Freedom from progression (FFP) rate under null hypothesis was 50%; under alternative hypothesis ≥ 70%. Per Fleming's multiple testing procedure with 3 stages, 69 patients (76 allowing for 10% ineligible) were required for 90% power and type I error 0.025. If ≥ 44 of 69 patients had a FFP event, we would reject 50% FFP rate in favor of ≥ 70%. Analysis was out of 74 patients (not 69), so ≥ 44 was revised to ≥ 46.
Time frame: From registration to 3 years.
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen Suppression + RT + Docetaxel | Number of Participants Free From Progression at 3 Years | 54 participants |
Secondary
Distant Metastasis (3-year Rate)
Time from registration to date of distant metastasis (failure), death (competing risk), or last follow-up (censored). Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method.
Time frame: Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.)
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen Suppression + RT + Docetaxel | Distant Metastasis (3-year Rate) | 6.8 percentage of participants |
Secondary
Local-regional Progression (3 Year Rate)
Time from registration to date of local progression (failure), death (competing risk), or last follow-up (censored). Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method.
Time frame: Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.)
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen Suppression + RT + Docetaxel | Local-regional Progression (3 Year Rate) | 0 percentage of participants |
Secondary
Non-prostate Cancer Death (3-year Rate)
Time from registration to date of death due to other causes (failure), death due to prostate cancer (competing risk), or last follow-up (censored).Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method.
Time frame: Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.)
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen Suppression + RT + Docetaxel | Non-prostate Cancer Death (3-year Rate) | 1.4 percentage of participants |
Secondary
Number of Patients With Acute Adverse Events (Based on CTCAE, v3.0)
The number of patients with at least one grade 3 or higher adverse event (AE) from start of treatment to 90 days after the planned end of treatment (21 days after last docetaxel dose). Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time frame: From start of treatment to 90 days after the planned end of treatment (21 days after last docetaxel dose). Analysis occurs at the time of the primary analysis. (Patients are followed until death or study termination whichever occurs first.
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen Suppression + RT + Docetaxel | Number of Patients With Acute Adverse Events (Based on CTCAE, v3.0) | 57 participants |
Secondary
Overall Survival (3-year Rate)
Time from registration to date of death (failure) or last follow-up (censored). Three-year rate and 95% confidence interval were estimated by the Kaplan-Meier method.
Time frame: Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.)
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen Suppression + RT + Docetaxel | Overall Survival (3-year Rate) | 98.6 percentage of participants |
Secondary
Prognostic Value of Genomic and Proteomic Markers for the Primary and Secondary Clinical Endpoints
Time frame: Analysis can occur at the same time as the primary endpoint if data is available.
Population: The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from the NRG tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this outcome measure. Specimen use will require federal approval and funding separate from this trial.
Secondary
Prostate Cancer Death (3-year Rate)
Time from registration to date of distant metastasis (failure), death (competing risk), or last follow-up (censored). Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method.
Time frame: Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.)
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen Suppression + RT + Docetaxel | Prostate Cancer Death (3-year Rate) | 0 percentage of participants |
Secondary
Time to Biochemical (PSA) Failure (3-year Rate)
Failure is defined as PSA ≥ 0.4 ng/mL confirmed by a second higher PSA or initiation of non-protocol hormones. Death is considered a competing risk. Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method.
Time frame: Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.)
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen Suppression + RT + Docetaxel | Time to Biochemical (PSA) Failure (3-year Rate) | 25.7 percentage of participants |
Secondary
Time to Late Grade 3+ Adverse Events (Based on CTCAE, v3.0)
Two-year rate shown (cumulative incidence method). Adverse events are graded using CTCAE v3.0. Time of first late adverse event occurrence of the Grade 3+ adverse event between 91 days and 730 days from the completion of treatment (3 weeks after the last planned docetaxel dose) calculated. Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time frame: From 91 to 730 days after the planned end of treatment (21 days after last docetaxel dose). Analysis occurs at the time of the primary analysis. (Patients are followed from registration to death or study termination whichever occurs first.)
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen Suppression + RT + Docetaxel | Time to Late Grade 3+ Adverse Events (Based on CTCAE, v3.0) | 8.1 percentage of participants |