Radiation Oncology/RTOG Trials/7506

RTOG 75-06 (PROSTATE)
 * Title: Phase III Pelvic Irradiation vs Pelvic and Para-aortic Irradiation for Stage A2/B/C Adenocarcinoma of the Prostate
 * Objectives:
 * (1) Determine the value of pelvic vs. pelvic plus para-aortic nodal irradiation (when common iliac and para-aortic nodes are negative or unevaluated), and the value of pelvic plus para-aortic nodal irradiation vs. pelvic, para-aortic, mediastinal and supraclavicular irradiation (when common iliac and/or para-aortic nodes are positive) in locally advanced prostate cancer as measured by relapse-free survival and total survival.
 * (2) Determine whether radiation therapy is superior to hormonal therapy as measured by the relapse-free survival, total survival and complications and reactions.
 * (3) Determine the value of the rate of tumor clearance and post-irradiation biopsy of the prostate cancer bed in predicting long-term local control (cure).
 * Protocol:
 * Randomize patients with positive pelvic nodes and negative common iliac and para-aortic lymph nodes or with unknown nodal status or with no positive nodes to Arm I, II or III
 * Arm 1: Single-agent AST (Stilphostrol or Diethylstilbestrol). Arm terminated early
 * Arm 2: EBRT (pelvic nodes plus prostate boost)
 * Arm 3: EBRT (pelvic and para-aortic nodes)
 * Randomize patients with positive common iliac and/or para-aortic lymph nodes to Arm IV, V or VI.
 * Arm 4: Single-agent AST (Stilphostrol or DES). Arm terminated early
 * Arm 5: EBRT (prostate, pelvic and para-aortic nodes.) Arm terminated early
 * Arm 6: EBRT (prostate, pelvic, para-aortic, mediastinal and supraclavicular nodes.) Arm terminated early
 * Enrolled: 566 patients
 * Conclusion:
 * 1986 PMID 3514555 -- "Extended field (periaortic) irradiation in carcinoma of the prostate--analysis of RTOG 75-06." (Pilepich MV, Int J Radiat Oncol Biol Phys. 1986 Mar;12(3):345-51.). Median F/U 4.2 years
 * Outcome: No difference between arms for DFS, DM, OS
 * Conclusion: No benefit to elective peri-aortic irradiation
 * Publications:
 * 2003 PMID 12478146 -- "Race and survival of men treated for prostate cancer on radiation therapy oncology group phase III randomized trials." (Roach, J Urol 2003). Conclusion: As previously reported, tumor grade (Gleason score), palpation T stage, lymph node status, pretreatment PSA and treatment type are major predictors of overall and disease specific survival. We noted no evidence that race has independent prognostic significance in patients treated for prostate cancer in Radiation Therapy Oncology Group prospective randomized trials.
 * 2000 PMID 10837944 -- "Predicting long-term survival, and the need for hormonal therapy: a meta-analysis of RTOG prostate cancer trials." (Roach, IJRBOP 2000). Conclusion: Based on this meta-analysis of RTOG trials, subsets of patients can be identified who either do not appear to benefit from the use of hormonal therapy, benefit from short-term hormonal therapy, or who benefit only from long-term hormonal therapy. These observations should be confirmed by prospective randomized trials before they can be considered conclusive. In the meantime, however, these observations provide rational guidelines for deciding who should receive hormonal therapy and for how long.
 * 2000 PMID 10837943 -- "Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials." (Roach, IJRBOP 2000). Conclusion: Recognition of these four risk groups provides a basis for estimating the long-term DSS for men treated with XRT alone and should facilitate the design of future prospective randomized trials.
 * 2000 PMID 10894874 -- "Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the Radiation Therapy Oncology Group trials." (Valicenti, JCO 2000). Conclusion: These data demonstrate that higher-dose radiation therapy can significantly reduce the risk of dying from prostate cancer in men with clinically localized disease. This survival benefit is restricted to men with poorly differentiated cancers.
 * 1999 PMID 10022702 -- "Long-term survival after radiotherapy alone: radiation therapy oncology group prostate cancer trials." (Roach M, J Urol 1999). Conclusion: In the first 10 years Gleason score was the single most important predictor of death. Gleason score should be incorporated into the current clinical staging system.
 * 1999 Valicenti R, Lu JD, Grignon D, et al.: "Radiation dose-response is Gleason score dependent on the Radiation Therapy Oncology Group prostate cancer trials." [Abstract] Proceedings of the American Society of Clinical Oncology 18: A1194, 311a, 1999.
 * 1998 PMID 9531359 -- "Ten-year outcomes for pathologic node-positive patients treated in RTOG 75-06." (Hanks GE, IJRBOP 1998). Conclusion: A small fraction of node-positive patients are cured at 10-year follow-up by radiation therapy (2 of 90 with PSA +3 of 90 by clinical endpoints). Innovative treatment programs should be directed at node-positive patients in an effort to improve the fraction cured.
 * 1998 Roach M, Lu J, Pilepich M, et al.: "Long term survival in 1500 men treated for prostate cancer with radiotherapy alone (XRT): based on radiation therapy oncology group protocols 7706, 7506, 8531, and 8610." [Abstract] Proceedings of the American Urological Association 1998.
 * 1998 ASCO Abstract -- "Prognostic subgroups predict disease specific survival for men treated with radiotherapy alone on Radiation Therapy Oncology Group (RTOG) prostate cancer trials." (Roach M, ASCO 1998; Proceedings of the American Society of Clinical Oncology 17: A1201, 312a, 1998.). Conclusion: Recognition of these four prognostic subgroups should allow estimates to be made of the long term DSS of men treated with radiotherapy alone for CAP.
 * 1996 Hanks, G. E., Buzydlowski, J., Perez, C. A., Emami, B., Rubin, P., Sause, W., Earle, J., Rotman, M., Roach, M. and Russell, A.: "The Ten Year Outcome of Pathologic and Imaging Node Positive Patients Treated with Irradiation In RTOG 75-06." AUA, J Urol, 1996.
 * 1995 PMID 7591889 -- "Correlation of survival with quantitative tissue staining of prostate specific acid phosphatase in patients with prostate carcinoma by using microscopic image analysis: a preliminary report of correlative studies on RTOG protocols 75-06, 77-06, and 83-07." (Zhou R, IJRBOP 1995). Conclusion: Quantitative image analysis of the IPSAP stain predicts survival in patients treated with external beam radiotherapy with and without prior hormonal therapy
 * 1994 PMID 8270458 -- "Patterns of Care and RTOG studies in prostate cancer: long-term survival, hazard rate observations, and possibilities of cure." (Hanks GE, IJRBOP 1994). Conclusion: These data make a strong argument for the long-term cure of prostate cancer by external beam radiation, and support the continued use and study of radiation therapy as a curative modality in prostate cancer. No similar national data is available for any other method of management.
 * 1992 PMID 1587749 -- "Comparison of pathologic and clinical evaluation of lymph nodes in prostate cancer: implications of RTOG data for patient management and trial design and stratification." (Hanks GE, IJRBOP 1992). Conclusion: The clinical determination of nodal status, therefore, has no prognostic value in contrast to pathologic determination and should not be used for stratifying patients in clinical trials. The CT scans often used to evaluate nodal status are more useful if delayed until they can be done as part of the treatment planning process where the CT has value. When imaging tests suggest positive lymph nodes in prostate cancer patients, the imaging finding is confirmed by biopsy.
 * 1991 PMID 1917621 -- "The effect of overall treatment time on the outcome of definitive radiotherapy for localized prostate carcinoma: the Radiation Therapy Oncology Group 75-06 and 77-06 experience." (Lai PP, IJRBOP 1991). Conclusion: The incidence of late complications was not related to the number of elapsed treatment days. Therefore, the overall treatment time does not have an impact on the outcome of definitive radiotherapy for localized prostate carcinoma. It is hypothesized that prostate carcinoma behaves as late-reacting tissue in which there is little, if any, accelerated repopulation of clonogenic tumor cells during the later half of a protracted course of radiotherapy.
 * 1989 PMID 2463874 -- "Correlation of prostate-specific acid phosphatase and prostate-specific antigen immunocytochemistry with survival in prostate carcinoma." (Hammond ME, Cancer 1989). Conclusion: In those patients who subsequently relapsed and were subjected to hormonal manipulation, there appeared to be a higher likelihood of response to hormones with intense prostate-specific acid phosphatase staining.
 * 1987 PMID 3318090 -- "Prognostic significance of nodal involvement in locally advanced (stage C) carcinoma of prostate--RTOG experience." (Pilepich MV, Urology 1987).
 * 1987 PMID 3546223 -- "Correlation of pre-treatment transurethral resection and prognosis in patients with stage C carcinoma of the prostate treated with definitive radiotherapy--RTOG experience." (Pilepich MV, IJRBOP 1987). Conclusion: The TUR population fared significantly worse for all four end-points (rate of locoregional failure, incidence of distant metastases, disease-free survival, and survival).
 * 1987 PMID 3558026 -- "Prognostic factors in carcinoma of the prostate--analysis of RTOG study 75-06." (Pilepich MV, IJRBOP 1987). Conclusion: Correlation of the assessed variables and the study endpoints (local control, incidence of distant metastases, NED survival, survival) singled out the degree of histological differentiation as the most powerful prognostic factor for all the endpoints.
 * 1987 PMID 3494005 -- "Correlation of radiotherapeutic parameters and treatment related morbidity in carcinoma of the prostate--analysis of RTOG study 75-06." (Pilepich MV, IJRBOP 1987). Conclusion: The study design entailed randomization to either pelvic irradiation followed by a prostate boost or pelvic and periaortic irradiation followed by a prostate boost. Periaortic irradiation was not associated with a significantly increased incidence of bowel injuries manifested by diarrhea. No correlation between the total dose to the regional lymphatics (ranging from 4400 to 5100 cGy) and the incidence of bowel and bladder injuries could be established. Doses to the prostate in excess of 7000 cGy have not resulted in a significantly increased incidence of bladder injuries, but have been associated with a significant increase in the incidence of bowel injuries manifested by diarrhea. The techniques of pelvic irradiation did not seem to significantly influence the incidence of bowel or bladder complications. The technique of delivery of the prostatic boost did seem to influence the incidence of bowel injuries. This refers to the lateral boost technique and the perineal boost technique which have been associated with a higher incidence of diarrhea.
 * 1986 PMID 3514555 -- "Extended field (periaortic) irradiation in carcinoma of the prostate--analysis of RTOG 75-06." (Pilepich MV, IJRBOP 1986). Conclusion: The results of the study revealed no apparent benefit of elective periaortic irradiation in patients with detectable disease confined to the pelvis.
 * 1984 PMID 6483687 -- "Surgical staging in carcinoma of the prostate: the RTOG experience. Radiation Therapy Oncology Group." (Pilepich, Prostate 1984). Conclusion: The incidence of postirradiation lymphedema was found to be strongly dependent upon the extent of dissection.
 * 1984 PMID 6386761 -- "Treatment-related morbidity in phase III RTOG studies of extended-field irradiation for carcinoma of the prostate." (Pilepich, IJROBP 1984). Conclusion: In most instances of treatment-related morbidity, the symptoms were recorded during the first several months to 1 year following completion of treatment. Late occurrences, however, were not uncommon in certain types of radiation-produced injuries, such as proctitis, hematuria, and urethral strictures. Resolution of symptoms has been observed in a large proportion of patients including those with late occurrences of treatment-related morbidity, although the probability and the pattern of resolution differed considerably from one type of morbidity to another. Symptoms of cystitis are more likely to abate than those of proctitis. In patients who develop symptoms of proctitis the probability of persistence of symptoms beyond the second year following occurrence has been estimated at 20%-30%. Hematuria and symptoms secondary to urethral strictures seem to be even more likely to recur or persist, while genital and leg edema remain chronic in the majority of patients.
 * 1983 PMID 6346857 -- "Preliminary report on phase III RTOG studies of extended-field irradiation in carcinoma of the prostate." (Pilepich, Am J Clin Oncol 1983). Conclusion: The use of paraaortic fields in RTOG 75-06 and pelvic fields in RTOG 77-06 have not resulted in a significant increase of GI or GU morbidity at this time. The only statistically significant trend was the incidence of postirradiation genital and lower extremity edema which strongly correlated with the extent of staging lymphadenectomy.
 * 1982 PMID 7155987 -- "Some questions raised by histologic study of RTOG protocols 75-06 and 77-06 as illustrated by selected samples." (Terry, Prostate 1982).