Prostate Cancer
Conditions
Keywords
stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer
Brief summary
RATIONALE: Giving samarium Sm 153 lexidronam pentasodium and 3-dimensional (3-D) conformal radiation therapy or intensity-modulated radiation therapy may keep prostate cancer from growing in patients with rising prostate-specific antigen (PSA) levels after radical prostatectomy for prostate cancer. PURPOSE: This phase II trial is studying how well samarium Sm 153 lexidronam pentasodium and 3-D conformal radiation therapy or intensity-modulated radiation therapy work in treating patients with rising PSA levels after radical prostatectomy for prostate cancer.
Detailed description
OBJECTIVES: Primary * To assess the effectiveness of samarium Sm 153 lexidronam pentasodium (as determined by a 30% decline in the PSA level within 12 weeks) followed by either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy in patients with rising prostate-specific antigen levels (PSA) after radical prostatectomy prostate cancer. Secondary * To assess the proportion of patients completing protocol treatment. * To evaluate hematological toxicity at 12 weeks. * To evaluate samarium Sm 153 lexidronam pentasodium-related adverse events at 12 weeks. * To evaluate the acute and late radiation therapy-related events having occurred up to 24 weeks from the end of radiation therapy. * To compare the freedom from progression rate at 2 years to that predicted by the Kattan Nomograms. OUTLINE: Patients receive samarium Sm 153 lexidronam pentasodium (SM) IV on day 1. Patients are closely monitored for prostate-specific antigen (PSA) level and SM-associated toxicity for 12 weeks. After the 12 weeks, patients undergo either intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy 5 days a week for 7-8 weeks. Patients may receive hormonal therapy (after radiation therapy) at the discretion of their physician. Treatment continues in the absence of disease progression (defined as a PSA doubling time less than 3 months), severe thrombocytopenia (defined as a platelet count of 25,000 cells/mm³ or less), or unacceptable toxicity. After completion of study treatment, patients are followed up at 3 months, 6 months, and 12 months, every 6 months for 2 years, and then annually thereafter.
Interventions
RADIATIONRadiotherapy
3D-CRT or IMRT 64.8-70.2 Gy to the prostatic fossa begins 12 weeks (+/- 1 week) after Samarium 153 administration. Daily tumor doses of 1.8 - 2.0 Gy per day, 5 days per week x 7-8 weeks.
DRUGSamarium 153
Samarium 153 lexidronam dose 2.0 mCi/kg by IV injection one time within 2 weeks (+/- 3days) after registration.
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 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: Inclusion criteria: * Histologically proven diagnosis of prostate cancer progressing after prior radical prostatectomy as indicated by one of the following: * Postoperative prostate-specific antigen (PSA) rising above 1.0 ng/mL * Postoperative PSA rising above 0.2 ng/mL with a surgical tumor Gleason score of 9 or 10 * Postoperative PSA rising above 0.2 ng/ml with nodal disease * Stage II-IV disease (T2 -T4, N0-N1) * No distant metastases based on the following minimum diagnostic work up: * History or physical examination within the past 8 weeks * Bone scan negative for bone metastases within the past 4 months * Abdominal imaging negative for metastases within the past 6 months
Exclusion criteria
* Biopsy evidence of M1 disease * Presence of neuroendocrine features in any prostate cancer specimen PATIENT CHARACTERISTICS: Inclusion criteria: * Zubrod Performance Status 0-1 * Absolute neutrophil count (ANC) ≥ 1,800 cells/mm³ * Platelet count ≥ 100,000 cells/mm³ * Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is permitted)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With PSA Response (pt) Within 12 Weeks of Samarium 153 Administration | Twelve weeks from the date of Samarium 153 infusion. | A PSA response for each patient is calculated by (baseline PSA-current PSA)/baseline PSA. A decline of at least 30% is considered a response. Null hypothesis (H0): Samarium 153 is not effective (pt ≤ 0.1) vs alternative hypothesis (HA): Samarium 153 is effective (pt ≥ 0.25). The sample size of 69 analyzable patients (eligible patients receiving any protocol treatment with ≥ 12 weeks follow-up from the Samarium 153 injection) was calculated based on Fleming's Multiple Testing Procedure at a significance level of 0.019 and 91% statistical power requiring 69 patients to conclude either the null or alternative hypotheses. With only 52 analyzable patients this study had only 78% power and needed at least 11 patients with a PSA response to reject H0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Completion of Therapy | 90 days from the end of radiation therapy. | The completion of protocol treatment is defined as receiving at least 64.8 Gy radiation after the Samarium 153 injection. The null hypothesis that the proportion of the number of patients who complete the protocol treatment (the Samarium 153 and the radiation therapy) is less than or equal to 0.5 was tested using an exact test for a binomial proportion. If the true treatment completion proportion is 0.8, then the statistical power of a one-sided 0.378 level exact binomial test of proportion would be 94.1% with the sample size of 26. Therefore any number of analyzable patients greater than 26 patients provides enough power for this endpoint. |
| Number of Patients With Hematologic Toxicity at 12 Weeks | Twelve weeks from the date of Samarium 153 infusion. | 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. Hematological toxicities consist of platelet grade 3-5, white blood cell grade 3-5, hemoglobin grade 3-5, and any secondary leukemia's. |
| Samarium 153-related Adverse Events at 12 Weeks (Percentage of Patients) | Twelve weeks from the date of Samarium 153 infusion | Adverse events are evaluated by the NCI Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. The treatment-related attribution includes definitely, probably or possibly related to treatment. The treatment-related adverse events are: * HEMATOLOGIC Platelet grade 3-5 White blood cell count (WBC) grade 3-5 Hemoglobin grade 3-5 Any secondary leukemia's * HEMORRHAGE/BLEEDING Hemorrhage, gastrointestinal - anus, rectum grade 3-5 Hemorrhage, genitourinary - bladder, prostate, urethra grade 3-5 * SAMARIUM 153-RELATED GRADE 5 ADVERSE EVENT PRIOR TO TREATMENT OF RADIATION. |
| Acute and Late Radiotherapy-Related Adverse Events | 90 days from start of radiotherapy | The number of patients who experienced a grade 1-5 radiation-related adverse events within 90 days of the start of radiotherapy (acute) and after 90 days (late). Adverse events are evaluated by the NCI Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. Multivariate logistic regression was used to model the association of clinical T-stage (pT2 vs. pT3 \[reference level\]), baseline PSA, Gleason score (\<8 vs. 8-10\[reference level\]), and age with the occurrence of any acute radiotherapy-related adverse event. Odds ratios and the respective 95% confidence intervals were computed for each factor. Per the protocol, late adverse events were not analyzed. |
| Freedom From Progression (FFP) Rate at 2 Years | From randomization to 2 years | Progression is defined as biochemical (PSA) failure at any time for 2 years after prostatic fossa radiation therapy (RT), initiation of systemic therapy, or clinical failure. Biochemical failure is defined as a rise of 0.2 ng/ml or more above the nadir PSA after completion of RT followed by another higher value, or a continued rise in the serum PSA despite RT. FFP rate at 2 years was to be compared to that predicted by the Kattan Nomograms. See Limitations and Caveats section. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Radiotherapy + Samarium 153 Samarium 153 infusion followed by radiotherapy 12 weeks later | 62 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 5 |
Baseline characteristics
| Characteristic | Radiotherapy + Samarium 153 |
|---|---|
| Age, Continuous | 65 years |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 55 / 60 |
| serious Total, serious adverse events | 5 / 60 |
Outcome results
Primary
Proportion of Patients With PSA Response (pt) Within 12 Weeks of Samarium 153 Administration
A PSA response for each patient is calculated by (baseline PSA-current PSA)/baseline PSA. A decline of at least 30% is considered a response. Null hypothesis (H0): Samarium 153 is not effective (pt ≤ 0.1) vs alternative hypothesis (HA): Samarium 153 is effective (pt ≥ 0.25). The sample size of 69 analyzable patients (eligible patients receiving any protocol treatment with ≥ 12 weeks follow-up from the Samarium 153 injection) was calculated based on Fleming's Multiple Testing Procedure at a significance level of 0.019 and 91% statistical power requiring 69 patients to conclude either the null or alternative hypotheses. With only 52 analyzable patients this study had only 78% power and needed at least 11 patients with a PSA response to reject H0.
Time frame: Twelve weeks from the date of Samarium 153 infusion.
Population: All eligible patients who received Samarium 153 with at least 12 weeks follow-up from the injection
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiotherapy + Samarium 153 | Proportion of Patients With PSA Response (pt) Within 12 Weeks of Samarium 153 Administration | 7 percentage of participants |
Secondary
Acute and Late Radiotherapy-Related Adverse Events
The number of patients who experienced a grade 1-5 radiation-related adverse events within 90 days of the start of radiotherapy (acute) and after 90 days (late). Adverse events are evaluated by the NCI Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. Multivariate logistic regression was used to model the association of clinical T-stage (pT2 vs. pT3 \[reference level\]), baseline PSA, Gleason score (\<8 vs. 8-10\[reference level\]), and age with the occurrence of any acute radiotherapy-related adverse event. Odds ratios and the respective 95% confidence intervals were computed for each factor. Per the protocol, late adverse events were not analyzed.
Time frame: 90 days from start of radiotherapy
Population: Eligible patients with adverse event data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Radiotherapy + Samarium 153 | Acute and Late Radiotherapy-Related Adverse Events | Acute | 35 participants |
| Radiotherapy + Samarium 153 | Acute and Late Radiotherapy-Related Adverse Events | Late | 27 participants |
Comparison: Modeling the association of age with the occurrence of any acute radiotherapy-related adverse event, adjusting for clinical T-stage (pT2 vs. pT3 \[reference level\]), baseline PSA, and Gleason score (\<8 vs. 8-10\[reference level\]).95% CI: [0.91, 1.063]
Comparison: Modeling the association of baseline PSA with the occurrence of any acute radiotherapy-related adverse event, adjusting for clinical T-stage (pT2 vs. pT3 \[reference level\]), Gleason score (\<8 vs. 8-10\[reference level\]), and age.95% CI: [0.89, 1.169]
Comparison: Modeling the association of clinical T-stage (pT2 vs. pT3 \[reference level\]) with the occurrence of any acute radiotherapy-related adverse event, adjusting for baseline PSA, Gleason score (\<8 vs. 8-10\[reference level\]), and age.95% CI: [0.364, 4.697]
Comparison: Modeling the association of Gleason score (\<8 vs. 8-10\[reference level\]) with the occurrence of any acute radiotherapy-related adverse event, adjusting for clinical T-stage (pT2 vs. pT3 \[reference level\]), baseline PSA, and age.95% CI: [0.217, 2.006]
Secondary
Completion of Therapy
The completion of protocol treatment is defined as receiving at least 64.8 Gy radiation after the Samarium 153 injection. The null hypothesis that the proportion of the number of patients who complete the protocol treatment (the Samarium 153 and the radiation therapy) is less than or equal to 0.5 was tested using an exact test for a binomial proportion. If the true treatment completion proportion is 0.8, then the statistical power of a one-sided 0.378 level exact binomial test of proportion would be 94.1% with the sample size of 26. Therefore any number of analyzable patients greater than 26 patients provides enough power for this endpoint.
Time frame: 90 days from the end of radiation therapy.
Population: All eligible patients who started treatment and did not withdraw consent prior to 90 days from the end of radiation therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiotherapy + Samarium 153 | Completion of Therapy | 93.3 percentage of participants |
p-value: <0.001binomial proportion
Secondary
Freedom From Progression (FFP) Rate at 2 Years
Progression is defined as biochemical (PSA) failure at any time for 2 years after prostatic fossa radiation therapy (RT), initiation of systemic therapy, or clinical failure. Biochemical failure is defined as a rise of 0.2 ng/ml or more above the nadir PSA after completion of RT followed by another higher value, or a continued rise in the serum PSA despite RT. FFP rate at 2 years was to be compared to that predicted by the Kattan Nomograms. See Limitations and Caveats section.
Time frame: From randomization to 2 years
Population: Eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiotherapy + Samarium 153 | Freedom From Progression (FFP) Rate at 2 Years | 25.50 percentage of participants |
Secondary
Number of Patients With Hematologic Toxicity at 12 Weeks
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. Hematological toxicities consist of platelet grade 3-5, white blood cell grade 3-5, hemoglobin grade 3-5, and any secondary leukemia's.
Time frame: Twelve weeks from the date of Samarium 153 infusion.
Population: Eligible patients who started study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radiotherapy + Samarium 153 | Number of Patients With Hematologic Toxicity at 12 Weeks | 15 Participants |
Secondary
Samarium 153-related Adverse Events at 12 Weeks (Percentage of Patients)
Adverse events are evaluated by the NCI Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. The treatment-related attribution includes definitely, probably or possibly related to treatment. The treatment-related adverse events are: * HEMATOLOGIC Platelet grade 3-5 White blood cell count (WBC) grade 3-5 Hemoglobin grade 3-5 Any secondary leukemia's * HEMORRHAGE/BLEEDING Hemorrhage, gastrointestinal - anus, rectum grade 3-5 Hemorrhage, genitourinary - bladder, prostate, urethra grade 3-5 * SAMARIUM 153-RELATED GRADE 5 ADVERSE EVENT PRIOR TO TREATMENT OF RADIATION.
Time frame: Twelve weeks from the date of Samarium 153 infusion
Population: Eligible patients with adverse event data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiotherapy + Samarium 153 | Samarium 153-related Adverse Events at 12 Weeks (Percentage of Patients) | 16 percentage of participants |