J.M. Krall

Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the radiation therapy oncology group

OBJECTIVES Androgen deprivation therapy before and during radiation therapy could, by reducing tumor volume, increase local tumor control, disease-free survival, and overall survival in patients with locally advanced adenocarcinomas of the prostate. METHODS In a randomized controlled clinical trial, patients with large T2, T3, and T4 prostate tumors, but no evidence of osseous metastasis, were randomized to receive goserelin 3.6 mg subcutaneously every 4 weeks and flutamide 250 mg orally three times daily 2 months before and during the radiation therapy course (Arm I) compared with radiation therapy alone (Arm II). Pelvic irradiation was administered with 1.8 to 2.0 Gy per day to a total dose of 45 +/- 1 Gy followed by a boost to the prostate target volume to a total dose of 65 to 70 Gy. RESULTS Of 471 randomized patients, 456 were evaluable, 226 on Arm I and 230 on Arm II. With a median potential follow-up of 4.5 years, the cumulative incidence of local progression at 5 years was 46% in Arm I and 71% in Arm II (P < 0.001). The 5-year incidence of distant metastasis on Arms I and II was 34% and 41%, respectively (P = 0.09). Progression-free survival rates including normal prostate-specific antigen (PSA) levels for 396 patients with at least one PSA recorded were 36% in Arm I and 15% in Arm II at 5 years (P < 0.001). At this time, no significant difference in overall survival could be detected (P = 0.7). CONCLUSIONS Short-term androgen deprivation with radiation therapy results in a marked increase in local control and disease-free survival compared with pelvic irradiation alone in patients with locally advanced carcinoma of the prostate. Long-term surveillance is required to assess effects on overall survival.

Combined modality program with possible organ preservation for invasive bladder carcinoma: Results of rtog protocol 85-12

PURPOSE This Phase II study was designed to test the tolerance and effectiveness of concurrent cisplatin-radiotherapy in the treatment of invasive bladder cancer. Objectives were to determine toxicity, complete response rate, bladder preservation rate, and survival. METHODS AND MATERIALS Patients with invasive bladder cancer, clinical Stages T2-4, NO-2 or NX, MO were treated with pelvic radiotherapy 40 Gy in 4 weeks and cisplatin 100 mg/m2 on days 1 and 22. Complete responders were given an additional 24 Gy bladder boost plus a third dose of cisplatin; patients with residual tumor after 40 Gy were assigned radical cystectomy. RESULTS The complete remission rate following cisplatin and 40 Gy for evaluable cases was 31/47 (66%). Acute toxicity was acceptable with only two patients not completing induction therapy. Patients with poorly differentiated tumors were more likely to achieve complete remission. Of fully evaluable patients, 28/42 (67%) achieved complete remission with induction therapy, 11 remain continuously in remission, and eight have relapsed with bladder as the only site of failure. Five of these eight cases relapsed with noninvasive tumor. Of the 14 patients who failed to achieve complete remission, only three remain disease-free. Median survival is not reached, with 17/42 (19/48) deaths reported. Actuarial survival is 64% at 3 years. CONCLUSION This combined cisplatin-radiotherapy regimen was moderately well-tolerated and associated with tumor clearance in 66% of patients treated. Isolated bladder recurrences with invasive carcinoma are infrequent. Better definition of pretreatment selection criteria is needed if combined modality treatment is to achieve disease control and organ preservation for patients with bladder cancer.

Elective pelvic irradiation in stage A2, B carcinoma of the prostate: analysis of RTOG 77-06☆

From 1978 to 1983 the Radiation Therapy Oncology Group conducted a study to evaluate the role of elective pelvic lymph node irradiation in carcinoma of the prostate. Eligible patients were those with clinical Stage A2 (occult disease with more than 3 positive chips and poorly differentiated tumor) and Stage B without clinical (lymphangiogram) or biopsy evidence of lymph node involvement. The patients were randomized to receive 6.5 weeks of either prostatic bed irradiation only 6500 cGy at 180-200 cGy per treatment or pelvic node irradiation to 4500 cGy with a boost of 2000 cGy to the prostatic bed bringing the total dose to 6500 cGy. As of February, 1988, the median follow up has been 7 years and there were 445 analyzable cases who were evaluated for local control, incidence of distant metastases, ned (no evidence of disease) survival and survival. The results of the study revealed no statistically significant benefit of elective pelvic irradiation.

A ten year follow-up of 682 patients treated for prostate cancer with radiation therapy in the United States

This report extends the follow-up of patients studied in the Patterns of Care Survey of Prostate Cancer treated in the United States between 1973 and 1975 from a maximum of 5 years to a maximum of 10 years. Survival for 60 Stage A patients was the same as expected for their age distribution (83% at 5 years and 62% at 10 years). Survival for 312 Stage B patients was 73% at 5 years and 46% at 10 years and for 296 Stage C patients was 58% at 5 years and 38% at 10 years. Infield recurrence was determined by clinical means, at 5 years 97% of Stage A patients, 86% of Stage B patients, and 74% of Stage C patients were free of local recurrence. At 10 years 97% of Stage A patients, 74% of Stage B patients, and 69% of Stage C patients remained free of local recurrence. Patients with Stage B and C cancer who developed their first failure infield show a long-term survivorship after recurrence of 40% and 20% respectively. This is in contrast to Stage B and C patients who develop a first recurrence at a metastatic site where the rate of progress to death was slower in Stage B patients than for those with Stage C disease (mean survival 32 months versus 19 months), but eventually all are dead by 7 years after recurrence. Complications were infrequent, actuarial analysis shows 93% of patients free of serious complications at 5 years and 89% free at 10 years. There were 14 patients (2%) whose complications required surgical correction and 2 of the 682 patients died of complications.

Patterns of care studies: dose-response observations for local control of adenocarcinoma of the prostate

Five hundred seventy-four patients with prostate cancer treated by external beam radiation therapy in the United States in 1973 to 1975 have been analyzed comparing radiation dose with in-field recurrence. Dose-response effects are observed for all cases (p = less than .05) and T-2 and T-3 tumors, but not for T-0, T-1 and T-4 tumors. For doses calculated at the center of the prostate, these observations suggest optimal control is obtained at no more than 6000 rad for T-0 and T-1 tumors; 6000-6500 rad for T-2 tumors; 6500-7000 rad for T-3 tumors; and that greater than 7000 rad is required only for T-4 tumors. The paraprostatic dose calculated at a point 4 cm lateral to the center of the prostate also shows a correlation of dose with infield failure for all cases (p = .01). Observations in individual T states suggest optimal control is obtained at no more than 6000 rad for T-0, T-1 and T-2 tumors, 6500-6999 rad for T-3 and greater than or equal to 7000 rad for T-4. These data suggest that for T-2 and T-3 cancers, extension in the periprostatic region must be treated. A comparison of central dose vs. stage indicates institutional policy rather than cancer volume determines the radiation dose used in treating prostate cancer. A change in institutional policies to treat with optimal doses as indicated by this study would result in an overall increase in local control and a decrease in complications.

Prognostic factors in carcinoma of the prostate— analysis of rtog study 75-06

A total of 566 evaluable patients were accessioned to a phase III RTOG study of extended field irradiation in carcinoma of the prostate from 1976 to 1983. Eligible patients were those with locally advanced disease, either clinical Stage C or clinical Stage A2 or B with pelvic lymph node involvement. The treatment consisted of irradiation of the regional lymphatics followed by a boost to the prostate. The data have been analyzed extensively to identify variables of potential prognostic significance. The assessed factors include tumor size, clinical stage, the degree of histological differentiation, nodal status, serum acid phosphatase status, hormonal management status, age, and race. These factors have been assessed as to their interdependence and correlation with the clinical course (study endpoints) using univariate analyses and Coxs Regression model. Significant interdependence of tumor size and Gleason score and tumor size and acid phosphatase was identified. The population receiving hormonal management either prior to or during radiotherapy had a significantly higher proportion of high grade tumors. 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. Age proved a useful predictor of local control (younger patients failed at a significantly higher rate), as did tumor size. Elevation of serum acid phosphatase correlated well with the incidence of metastatic disease but was not a useful predictor of survival. Tumor size and hormonal management status correlated well with the incidence of metastatic disease but only when analyzed separately from other factors. Their prognostic value was absent when Cox regression analysis was applied. Nodal status did not correlate well with any of the study endpoints, indicating then that in patients with clinical Stage C disease, treated with definitive radiotherapy to the prostate and regional lymphatics, this parameter may have limited prognostic usefulness. Although patients who received concomitant hormonal management had a significantly higher proportion of high grade lesions, their clinical course fared favorably in comparison with the population not receiving concomitant hormonal management. This may indicate a beneficial effect of adjuvant hormonal treatment which needs to be tested in a prospective study.

Correlation of radiotherapeutic parameters and treatment related morbidity ― analysis of RTOG study 77-06

The current report is an updated and detailed analysis of treatment related morbidity in RTOG 77-06, a Phase III randomized study comparing prostatic irradiation versus pelvic irradiation followed by a prostatic boost, in patients with Stage A2 and B carcinoma of the prostate without evidence of nodal involvement. A total of 453 analyzable cases were accrued from 1978 to 1983, when the study was closed. All cases of treatment related morbidity were classified as to severity (using a clinical severity grading system). The data were then correlated with a number of radiotherapeutic parameters including treatment volumes (fields), doses, and techniques. Overall, pelvic irradiation, compared to prostate irradiation only, was not associated with a significantly increased incidence of treatment related morbidity. Within the range of pelvic doses used in this study a significant dose effect could not be detected. Total doses to the prostate of more than 7000 cGy were associated with an increased risk of rectal bleeding. Certain treatment techniques, (AP/PA irradiation of the pelvic lymphatics) were associated with an increased incidence of bowel complications.

Correlation of radiotherapeutic parameters and treatment related morbidity in carcinoma of the prostate--analysis of RTOG study 75-06.

Treatment related morbidity, recorded in patients entered onto a RTOG phase III study (testing the value of periaortic irradiation in locally advanced carcinoma of the prostate), has been correlated with radiotherapeutic parameters to identify and quantify the relationship with treatment volumes, doses, and techniques. Between 1976 and 1983 a total of 526 analyzable cases were entered onto the study. 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. All of the conclusions based on this analysis are applicable only to treatment volumes and dose ranges used in this study and to conventional fractionation of 180 to 200 cGy per day.

Patterns of care and rtog studies in prostate cancer: Long-term survival, hazard rate observations, and possibilities of cure☆

PURPOSE This study was undertaken to show the long-term survival and probability of cure of prostate cancer patients treated with external beam radiation in USA national surveys and in the prospective clinical trials of the RTOG. METHODS AND MATERIALS Two national patterns of care surveys of patients treated in 1973 and 1978 are reported along with two RTOG prospective trials (7506 and 7706). Hazard rates represent the risk of death and are compared to the rate expected for a normal population. RESULTS For patients with Stage A cancers, the survival is not different from the expected survival for any of the reported surveys. The hazard rate for death does not significantly exceed the expected hazard rate out to 15 years. For patients with Stage B cancer, there is a decrease in survival below expected and hazard rates show a continuing excess mortality as long as 15 years after treatment. For patients with Stage C cancers, there is a more rapid decrease in survival that then becomes parallel to the expected survival. Hazard rates indicate there has been a return to expected mortality at 15 years. 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.

Outcome for lymph node dissection negative T-1b, T-2 (A-2,B) prostate cancer treated with external beam radiation therapy in RTOG 77-06

One hundred four patients with stage T-1b, T-2 N-O M-O prostate cancer were treated with external beam irradiation as part of RTOG 77-06. Lymph nodes were negative by lymph node dissection in 16 patients with T-1b and 88 patients with T-2 cancers. Survival exceeds age matched expected survival for the 10 years of observation (63% vs 59% at 10 years). Patterns of failure at 10 years show 87% of patients were free of isolated local recurrence, 79% free of metastatic failure, 67% free of any failure, and cause specific survival shows 86% free of cancer death at 10 years. The outcome of this group is equal or superior to reports of radical prostatectomy in similar stage patients.