Radiation Therapy With or Without Bicalutamide for Recurrent pT3N0 Prostate Cancer After Radical Prostatectomy

• ClinicalTrials.gov Identifier: NCT00002874
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Results First Posted: August 18, 2017
• Last Update Posted: June 15, 2022
• Sponsor: Radiation Therapy Oncology Group
• Collaborators: National Cancer Institute (NCI); SWOG Cancer Research Network; NRG Oncology
• Information provided by (Responsible Party): Radiation Therapy Oncology Group

Tracking Information

• First Submitted Date: November 1, 1999
• First Posted Date: January 27, 2003
• Results First Submitted Date: June 6, 2017
• Results First Posted Date: August 18, 2017
• Last Update Posted Date: June 15, 2022
• Study Start Date: February 1998
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 18, 2017)

Overall Survival (12-year Rates Reported) [ Time Frame: From date of randomization to 12 years. ]

Overall survival rates were estimated by the Kaplan-Meier method, with failure defined as death by any cause. Four-year follow-up was required of all patients, twelve-year rates are reported. Four-year follow-up was required of all patients, but twelve-year rates were reported. Patients are followed until death.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: July 18, 2017)

• Non-Prostate Cancer Death (12-year Rates Reported) [ Time Frame: From date of randomization to 12 years. ]
  Non-prostate cancer death rates were estimated by the cumulative incidence method, with failure defined as any death that does not fall into the following categories: death due to prostate cancer or complications of protocol treatment (centrally reviewed), death with known progressive metastatic disease while on salvage hormone therapy, or death with a known rising PSA while on salvage hormone therapy. All other deaths are considered competing risks. Patients alive at time of analysis were censored. Any other death was treated as a competing risk. Four-year follow-up was required of all patients, but twelve-year rates were reported. Patients are followed until death. "Non-Prostate cancer death" is a more accurate wording for the protocol endpoint of "non-disease-specific survival", and matches the protocol definition.
• Second PSA Recurrence (12-year Rates Reported) [ Time Frame: From date of randomization to 12 years. ]
  Second PSA recurrence (SPSAR) rates (i.e. first PSA failure on study) were estimated by the cumulative incidence method, with failure defined as the first occurrence of one of the following events: 1. Increase in PSA following protocol treatment according to the following criteria met during protocol treatment: If PSA dropped to undetectable level (<0.2 ng/ml) during protocol treatment (PT) then failure = increase after PT to >= 0.5 ng/ml ; If PSA decreased to a detectable level (≥ 0.2 ng/ml) during PT, then failure = increase PT of >= 0.3 ng/ml above the lowest detectable level; If PSA did not decrease during PT then failure = increase in PSA after PT of >= 0.5 ng/ml above entry PSA level. 2. The start of salvage hormone therapy. Patients alive without SPSAR at time of analysis were censored. Death without SPSAR was treated as a competing risk. Four-year follow-up was required of all patients, but twelve-year rates were reported. Patients are followed until death.
• Third PSA Recurrence (12-year Rates Reported) [ Time Frame: From start of salvage hormone therapy to 12 years. ]
  Third PSA recurrence rates (i.e. second PSA failure on study) were estimated by the cumulative incidence method, with failure defined as PSA value of 0.5ng/ml or higher or any disease progression after starting salvage hormone therapy. Patients alive without third PSA recurrence at time of analysis were censored. Death without third PSA recurrence was treated as a competing risk. Four-year follow-up was required of all patients, but twelve-year rates were reported. Patients are followed until death.
• PSA Complete Response at End of Protocol Treatment [ Time Frame: End of protocol treatment, which is planned to last for two years ]
  Complete response is defined as a drop in PSA on protocol treatment to less than 0.2 ng/ml. Note that when the study opened many institutions could not detect PSA < 05 ng/ml.
• Distant Failure (12-year Rates Reported) [ Time Frame: From date of randomization to 12 years. ]
  Distant failure rates were estimated by the cumulative incidence method, with failure defined as the first occurrence of distant failure. Patients alive without distant metastases at time of analysis were censored. Death without distant metastasis was treated as a competing risk. Four-year follow-up was required of all patients, but twelve-year rates were reported. Patients are followed until death.
• Prostate Cancer Death (12-year Rates Reported) [ Time Frame: From date of randomization to 12 years. ]
  Prostate cancer death rates were estimated by the cumulative incidence method, with failure defined as death due to prostate cancer or complications of protocol treatment (centrally reviewed), death with known progressive metastatic disease while on salvage hormone therapy, or death with a known rising PSA while on salvage hormone therapy. Patients alive at time of analysis were censored. Any other death was treated as a competing risk. Four-year follow-up was required of all patients, but twelve-year rates were reported. Patients are followed until death. "Prostate cancer death" is a more accurate wording for the protocol endpoint of "disease-specific survival", and matches the protocol definition.
• Progression-free Survival (12-year Rates Reported) [ Time Frame: From date of randomization to 12 years. ]
  Progress-free survival rates were estimated by the Kaplan-Meier method, with failure defined as the first occurrence of PSA failure, local, regional or distant failure, or death from any cause. Patients alive without progression at time of analysis were censored. Four-year follow-up was required of all patients, but twelve-year rates were reported. Patients are followed until death. "Progression-free Survival" is more accurate wording for the protocol endpoint of "Freedom from Progression", and matches the protocol definition.
• Grade 3+ Toxicity [ Time Frame: From date of randomization to four years. ]
  Adverse events are graded using the Cooperative Group Common Toxicity Criteria and the Radiation Therapy Oncology Group (RTOG) Radiation Morbidity Scoring. Grade refers to severity, assigning Grades 1 through 5 based on this general guideline: Grade 0 None, Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related toxicity. Toxicities reported to have occurred within 90 days from the start of radiotherapy are reported as "Acute Radiotherapy", all later toxicities are reported as "Hormone therapy and late radiotherapy toxicity". The highest grade toxicity event per subject is counted within each of these time periods. Four-year follow-up was required of all patients; patients are followed until death.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Radiation Therapy With or Without Bicalutamide for Recurrent pT3N0 Prostate Cancer After Radical Prostatectomy
• Official Title: A PHASE III TRIAL OF RADIATION THERAPY WITH OR WITHOUT CASODEX IN PATIENTS WITH PSA ELEVATION FOLLOWING RADICAL PROSTATECTOMY FOR pT3N0 CARCINOMA OF THE PROSTATE

Brief Summary

RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Androgens can stimulate the growth of prostate cancer cells. Hormone therapy using bicalutamide may fight prostate cancer by reducing the production of androgens. It is not yet known if radiation therapy is more effective with or without bicalutamide for prostate cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of radiation therapy with or without bicalutamide in treating patients who have stage II or stage III prostate cancer and elevated prostate-specific antigen (PSA) levels following radical prostatectomy.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Prostate Cancer

Intervention

• Drug: bicalutamide
  One (150 mg) tablet by mouth daily for two years beginning immediately upon, or just prior to, the initiation of irradiation.
  Other Name: Casodex
• Radiation: radiation therapy
  64.8 Gy in 36 fractions (1.8 Gy in 5 daily sessions per week) to the original prostate volume, the tumor resection bed, and the proximal membranous urethra.
• Drug: placebo
  One tablet by mouth daily for two years beginning immediately upon, or just prior to, the initiation of irradiation.

Study Arms

• Experimental: Bicalutamide
  Radiation therapy + bicalutamide
  Interventions:

  • Drug: bicalutamide
  • Radiation: radiation therapy
• Placebo Comparator: Placebo
  Radiation therapy + placebo
  Interventions:

  • Radiation: radiation therapy
  • Drug: placebo

Publications *

• Shipley WU, Seiferheld W, Lukka HR, Major PP, Heney NM, Grignon DJ, Sartor O, Patel MP, Bahary JP, Zietman AL, Pisansky TM, Zeitzer KL, Lawton CA, Feng FY, Lovett RD, Balogh AG, Souhami L, Rosenthal SA, Kerlin KJ, Dignam JJ, Pugh SL, Sandler HM; NRG Oncology RTOG. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017 Feb 2;376(5):417-428. doi: 10.1056/NEJMoa1607529.
• Modonutti D, Majdalany SE, Corsi N, Li P, Sood A, Dalela D, Jamil ML, Hwang C, Menon M, Rogers CG, Trinh QD, Novara G, Abdollah F. A novel prognostic model predicting overall survival in patients with metastatic castration-resistant prostate cancer receiving standard chemotherapy: A multi-trial cohort analysis. Prostate. 2022 Sep;82(13):1293-1303. doi: 10.1002/pros.24403. Epub 2022 Jul 5.
• Jackson WC, Tang M, Schipper MJ, Sandler HM, Zumsteg ZS, Efstathiou JA, Shipley WU, Seiferheld W, Lukka HR, Bahary JP, Zietman AL, Pisansky TM, Zeitzer KL, Hall WA, Dess RT, Lovett RD, Balogh AG, Feng FY, Spratt DE. Biochemical Failure Is Not a Surrogate End Point for Overall Survival in Recurrent Prostate Cancer: Analysis of NRG Oncology/RTOG 9601. J Clin Oncol. 2022 Sep 20;40(27):3172-3179. doi: 10.1200/JCO.21.02741. Epub 2022 Jun 23.
• Feng FY, Huang HC, Spratt DE, Zhao SG, Sandler HM, Simko JP, Davicioni E, Nguyen PL, Pollack A, Efstathiou JA, Dicker AP, Todorovic T, Margrave J, Liu YS, Dabbas B, Thompson DJS, Das R, Dignam JJ, Sweeney C, Attard G, Bahary JP, Lukka HR, Hall WA, Pisansky TM, Shah AB, Pugh SL, Shipley WU, Tran PT. Validation of a 22-Gene Genomic Classifier in Patients With Recurrent Prostate Cancer: An Ancillary Study of the NRG/RTOG 9601 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):544-552. doi: 10.1001/jamaoncol.2020.7671. Erratum In: JAMA Oncol. 2021 Apr 1;7(4):639.
• Dess RT, Sun Y, Jackson WC, Jairath NK, Kishan AU, Wallington DG, Mahal BA, Stish BJ, Zumsteg ZS, Den RB, Hall WA, Gharzai LA, Jaworski EM, Reichert ZR, Morgan TM, Mehra R, Schaeffer EM, Sartor O, Nguyen PL, Lee WR, Rosenthal SA, Michalski JM, Schipper MJ, Dignam JJ, Pisansky TM, Zietman AL, Sandler HM, Efstathiou JA, Feng FY, Shipley WU, Spratt DE. Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer. JAMA Oncol. 2020 May 1;6(5):735-743. doi: 10.1001/jamaoncol.2020.0109.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 3, 2013): 840
• Original Enrollment: Not Provided
• Actual Study Completion Date: May 20, 2022
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Conditions for Patient Eligibility:

• The patient on entry will have no clinical evidence of disease by physical exam or by imaging studies. A positive ProstaScint scan alone without a confirmatory biopsy must not be used to exclude a patient. Eligible patients will be those who have undergone a radical prostatectomy (either retropubic or perineal) and pelvic lymphadenectomy (either open or laparoscopic) for carcinoma of the prostate, pathologic stage T3N0, or pT2 pN0 with positive inked resection margin, at least 12 weeks prior to study entry.
• Pathological T2 patients without positive margins, who are also pathologic N0 with prostatic fossa/anastamosis biopsy at the time of rising PSA documenting recurrent cancer, are eligible.
• At entry, the PSA must be between 0.2 and 4.0ng/ml, inclusive.
• A post-prostatectomy radioisotopic bone scan which was done within 16 weeks prior to entry must reveal no evidence of metastatic disease.
• Patient must be evaluated by both the radiation oncologist and the urologist prior to entry and judged to be a suitable candidate for radiation and hormonal therapy.
• Patient must have Karnofsky performance status >= 80.
• Patients must have a life expectancy in excess of 10 years.
• Patients must have, within 6 weeks prior to entry, a hemoglobin (Hgb) of >=10 gm, a white blood cell (WBC) count of >= 4000 cells/ml3, a platelet count of >= 100,000 cells/ml3, a serum bilirubin <= the institutional upper limit of normal, a serum serum glutamic-oxaloacetic transaminase (SGOT) or serum glutamic-pyruvic transaminase (SGPT) of <= 2.5 times the institutional upper limit of normal, and a serum creatinine of <= 2.0 times the institutional upper limit of normal.
• A post-prostatectomy pelvic computerized tomography (CT) scan, within 16 weeks prior to randomization, must reveal no evidence of metastatic disease.
• Patients must sign a study-specific informed consent form.
• Patients with prior invasive cancers are eligible if disease free for at least 5 years; prior or concurrent basal or squamous cell skin cancer is eligible.

Conditions for Patient Ineligibility:

• Pathologic stage T2 (without positive inked resection margin) or less except as stated in Section 3.1.1.1.
• Pathologic lymph node stage of pN1 or greater.
• An entry serum PSA of > 4.0ng/ml.
• Patients with persistant urinary extravasation after prostatectomy.
• Patients who have been previously treated with any hormonal therapy after prostatectomy.
• Patients who have previously been treated with radiation therapy or biologic therapy for prostate cancer.
• Karnofsky performance status < 80.
• Treatment start > 4 weeks after randomization.
• Prior chemotherapy for any reason.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT00002874
• Other Study ID Numbers: RTOG-9601; CDR0000065158; RTOG-R9601
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Radiation Therapy Oncology Group
• Original Responsible Party: Not Provided
• Current Study Sponsor: Radiation Therapy Oncology Group
• Original Study Sponsor: Same as current

Collaborators

• National Cancer Institute (NCI)
• SWOG Cancer Research Network
• NRG Oncology

Investigators

• Principal Investigator: William U. Shipley, MD; Massachusetts General Hospital and Harvard Medical School, Boston
• Study Chair: Himanshu R Lukka, MD; Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON
• Study Chair: Pierre P Major, MD; Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON
• Study Chair: Niall M Heney, MD; Massachusetts General Hospital and Harvard Medical School, Boston
• Study Chair: David J Grignon, MD; Indiana University, Indianapolis

• PRS Account: Radiation Therapy Oncology Group
• Verification Date: May 2022