Samarium Sm 153 Lexidronam Pentasodium and 3-Dimensional Conformal Radiation Therapy or Intensity-Modulated Radiation Therapy in Treating Patients With Rising Prostate-Specific Antigen Levels After Radical Prostatectomy for Prostate Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Trial of Samarium 153 Followed by Salvage Prostatic Fossa 3D-CRT or IMRT Irradiation in High-Risk, Clinically Non-Metastatic Prostate Cancer After Radical Prostatectomy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Radiation: Radiotherapy
* Drug: Samarium 153


Participation Criteria
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Eligibility Criteria
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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) Exclusion criteria: Prior invasive malignancy (except nonmelanoma skin cancer) unless disease free for a minimum of 3 years Severe, active comorbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months Transmural myocardial infarction within the last 6 months Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects (laboratory tests for liver function and coagulation parameters, however, are not required for entry into this protocol) Renal failure (laboratory tests for renal function, however, are not required for entry into this protocol) AIDS based upon current Centers for Disease Control (CDC) definition (HIV testing is not required) PRIOR CONCURRENT THERAPY: No prior systemic chemotherapy for the study cancer Prior chemotherapy for a different cancer is permitted No hormonal therapy initiated within the last 3 months No prior radiotherapy to the pelvic region that would result in overlap of radiotherapy fields

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiotherapy + Samarium 153<br>Samarium 153 infusion followed by radiotherapy 12 weeks later | Radiation: Radiotherapy<br>* 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.<br>* Other names: Intensity-modulated radiation therapy;Drug: Samarium 153<br>* Samarium 153 lexidronam dose 2.0 mCi/kg by IV injection one time within 2 weeks (+/- 3days) after registration.<br>* Other names: Quadramet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Twelve weeks from the date of Samarium 153 infusion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 90 days from the end of radiation therapy. | 
| 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. | Twelve weeks from the date of Samarium 153 infusion. | 
| 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. | Twelve weeks from the date of Samarium 153 infusion | 
| 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. | 90 days from start of radiotherapy | 
| 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. | From randomization to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer