Project approved by the Fondo de investigaciones Socio Sanitarias (FISS). Resolution dated June 8, Official State Gazette: June 17, 2004.

Transcription

1 Edition No. 01 Phase III randomized and multicenter trial of adjuvant androgen deprivation combined with high-dose 3-dimensional conformal radiotherapy in intermediate- or high-risk localized prostate cancer Sponsor: Dr Almudena Zapatero Servicio de Oncología Radioterápica Hospital Universitario de la Princesa Diego de León Madrid Coordinating investigator Dr Almudena Zapatero Servicio de Oncología Radioterápica Hospital Universitario de la Princesa Project approved by the Fondo de investigaciones Socio Sanitarias (FISS). Resolution dated June 8, Official State Gazette: June 17,

2 OBJECTIVES Primary objective 1. To compare the efficacy of 2 treatment schedules in terms of biochemical disease control (biochemical disease free survival) at 5 years in patients with intermediate- and high-risk prostate cancer. The schedules were high-dose (76-82 Gy) 3D conformal radiotherapy (3D-CRT) combined with hormone therapy for 4 months (2 months previous and 2 months during radiotherapy) and the same treatment followed by adjuvant hormone therapy for 2 years. Secondary objectives 1. To compare both treatment schedules in terms of biochemical disease control (biochemical disease free survival) at 3 years and in terms of disease-free survival, metastasis-free survival, overall survival, and cause-specific survival at 5 years. 2. To determine the acute and late morbidity associated with both schedules 3. To analyze potential prognostic variables with an impact on survival and morbidity TRIAL DESIGN The trial is an open-label, prospective, randomized controlled trial with an intention-to-treat analysis. It is designed to compare the benefit of therapy with 3D-CRT combined with 4 months of hormone therapy (2 months previous and 2 months concomitant) with the same regimen followed by 2 years of androgen deprivation in patients with intermediate- and high-risk localized prostate cancer. The control arm will comprise patients undergoing neoadjuvant and concomitant androgen deprivation plus high-dose 3D-CRT (76-82 Gy to the ICRU [International Commission on Radiation Units & Measurements] reference point, fractionation of 2 Gy/session, 5 sessions/week). The experimental arm comprises neoadjuvant and concomitant androgen deprivation plus 3D-CRT (76-82 Gy to the ICRU reference point, fractionation 2 Gy/session, 5 sessions/week), followed by adjuvant androgen deprivation for 2 years. Patients with localized prostate cancer will be stratified according to risk in line with prognostic variables: Intermediate risk: T1-T2 with a Gleason score of 7 and/or PSA ng/ml High risk: T3, and/or Gleason score of 8-10, and/or PSA > 20 Patients who fulfill the inclusion criteria will be randomized in each risk group to one of the 2 treatment schedules at a ratio of 1:1. 2

3 TRIAL POPULATION Selection of the trial population Patients with a histologic diagnosis of clinical stage T1c-T3b N0 M0 prostate adenocarcinoma (AJCC 2002) Inclusion criteria 1. Written informed consent to participate in the clinical trial 2. Men aged 18 years or older with a histologic diagnosis of prostate adenocarcinoma in patients who have not previously received radiotherapy or surgery (radical prostatectomy) or cryotherapy 3. Clinical stage T1c-T3b N0 M0 in patients with intermediate- and high-risk disease (see above for definitions of risk) 4. Karnofsky performance status 70% 5. Life expectancy more than 5 years 6. No evidence of distant metastasis or other primary synchronous tumor. Patients with a previous history of tumor controlled for 5 years and patients with cutaneous basal cell or squamous cell carcinoma will not be excluded. 7. PSA < 100 ng/ml Exclusion criteria 1. Clinical stage T4 2. Presence of distant metastasis and/or N1 3. Previous surgical treatment (radical prostatectomy) or cryosurgery 4. Neoadjuvant hormone treatment lasting more than 3 months 5. Previous pelvic radiotherapy 6. Contraindications for radiotherapy 7. PSA 100 ng/ml 8. Simultaneous chemotherapy 9. Medical or psychiatric contraindications that can hamper both treatment and follow-up 10. Karnofsky performance status < 70% 3

4 TREATMENT UNDER STUDY: DOSE, PHARMACEUTICAL PRESENTATION, ROUTE OF ADMINISTRATION, THERAPEUTIC GROUP. Radiotherapy: control arm and experimental arm Radiotherapy technique: 3D conformal radiotherapy with dose intensification. Definition of volumes and irradiation doses: CTV: prostate with or without seminal vesicles (according to risk factors established using nomograms or formulas: Partin and Roach) No prophylactic nodal irradiation in intermediate-risk patients; decision to be based on local criteria for high-risk patients, with subsequent stratification in the statistical analysis Dose to prostate: minimum 76 Gy (range Gy); fractionation 2 Gy/session, 5 sessions/week Dose to seminal vesicles: Gy Specification of radiotherapy dose: - The dose specification point ICRU reference point is defined as the center of mass of the PTV, which should generally coincide with the isocenter for the treatment of that PTV. - The 2 classic prescription approaches for radiotherapy in patients with prostate cancer are as follows: - Dose to the ICRU reference point. PTV coverage: 95%-105% of the ICRU reference dose - Minimum dose to the PTV (minimum dose that covers 99% of the PTV). The maximum dose should not exceed the prescribed dose by more than 10%. Hormone therapy: Control arm: Neoadjuvant therapy: During the 2 months before radiotherapy, the patient will receive goserelin acetate plus bicalutamide (50 mg/day, starting 10 days before goserelin acetate). During the following 2 months, the patient will receive goserelin acetate alone. Experimental arm: Neoadjuvant therapy: As in the control arm. Maintenance-adjuvant therapy: goserelin acetate administered every 3 months for 2 years starting at the end of radiotherapy. 4

5 ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS DATA MANAGEMENT All patients preselected for the study will have a patient code. This number is the only type of patient identification and will be used to identify the patient in the CRF. All patients will be assigned a code during the selection period, irrespective of whether they are subsequently randomized to receive the trial medication. Eligibility will be established before assignment to treatment. Patients will be randomized in a strictly sequential manner once it is determined that they are eligible for inclusion/randomization. If a patient withdraws from the trial, his code will not be re-used and the patient will not be subsequently included in the study. The treatment assigned to each patient will be determined by means of a computerized randomization schedule. Randomization will be stratified by risk groups and participating centers. The trial data will be collected using an electronic CRF. PROCEDURES FOR BLINDING AND UNBLINDING (NOT APPLICABLE) ENDPOINTS Main endpoint Main evaluation criterion Biochemical disease free survival at 5 years Secondary evaluation criteria Biochemical disease free survival at 3 years Disease-free survival at 5 years Metastasis-free survival at 5 years Overall survival and cause-specific survival at 5 years Prognostic variables with an impact on survival and morbidity Safety: Late acute genitourinary and rectal morbidity associated with both treatments Nature, incidence, and severity of adverse events 5

6 WORKING HYPOTHESIS DETERMINATION OF SAMPLE SIZE Considering that high-dose 3D-CRT (76-82 Gy) combined with short-term neoadjuvant hormone therapy (4 months) has an expected probability of 60%-70% of maintaining biochemical control at 5 years, depending on the risk (high vs. intermediate), our hypothesis is that with the experimental treatment, the biochemical control would improve to 75%-80% at 5 years, depending on the risk (high vs. intermediate). Assuming that the risks between the groups are proportional and accepting a 2-tailed alpha risk of 0.05 with a 1 beta = 0.80, we calculate that a sample of 307 patients would be sufficient (using the method proposed by Primar M. and Machin D in Survival Analysis, Wiley Ed. 1995). If we use the tables proposed by Bailey A., Crook A. and Machin D. (Blood Reviews 1994; 8: ), the proposed sample size is 312. In both cases, the sample is evenly distributed between the 2 subsamples. Assuming losses of 15%, the sample size would increase to approximately 350 patients. STATISTICAL ANALYSIS: GENERAL ASPECTS All patients who are included and receive the trial medication will be considered the intention-totreat population. All hypotheses will be tested using 2-tailed approaches. Statistical significance will be set at <0.05. All events will be determined from the date of randomization to relapse-progression, death from any cause, or the last follow-up visit. Events corresponding to overall survival, disease-free survival, and biochemical disease free survival will be evaluated using the Kaplan-Meier actuarial method. Survival curves will be compared using the log-rank test. 29 Prognostic factors will be analyzed using a Cox multivariate analysis. Safety data will be analyzed using descriptive statistics, and a qualitative analysis will be performed. 6

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