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The incidence, severity, time of onset, and clinical course of complications of treatment have been reviewed in the RTOG studies of extended field irradiation in carcinoma of the prostate. A total of 526 patients, entered between 1976 and 1980 and followed for a minimum of 18 months, comprised the study population. 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.

From 1976 to 1983 the Radiation Therapy Oncology Group conducted a study of extended field (periaortic) irradiation in carcinoma of the prostate. Eligible patients were those with clinical Stage C tumor with or without evidence of pelvic lymph node involvement and also those with Stage A-2 and B with evidence of pelvic lymph node involvement. The stratification criteria included histological grade, clinical stage, absence or presence of hormonal manipulation, and method of lymph node evaluation (lymphangiogram vs. laparotomy vs. no nodal evaluation). The patients were randomized to either receive pelvic irradiation followed by a boost to the prostate or pelvic and periaortic irradiation followed by a boost to the prostate. The prescribed daily dose was 180-200 rad to a total midplane dose to the regional lymphatics to 4000-4500 rad. The prostatic boost target volume was to receive additional 2000-2500 rad bringing the total dose to that area to a minimum of 6500 rad. A total of 523 analyzable patients have been accessioned to the protocol. Four hundred forty-eight of these are known to have received treatment per protocol. Median follow-up is 4 years and 3 months. The analyzable patients were evaluated for the incidence of distant metastases, NED survival and survival as a function of treatment arm. No statistically significant differences between the treatment arms could be documented. Similarly, no significant difference between treatment arms could be documented within a number of subpopulations such as those characterized by a particular grade, hormonal status, stage, age, acid phosphatase level, etc. The results of the study revealed no apparent benefit of elective periaortic irradiation in patients with detectable disease confined to the pelvis.

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.

A total of 285 patients with medically inoperable (RTOG Stage T1-2, N0-1) or unresectable (RTOG Stage T3, N0-1) non-small cell carcinoma of the lung were randomized by the Radiation Therapy Oncology Group (RTOG) to receive radiation therapy (6000 cGy total dose/6 weeks) plus levamisole (2.5 mg/kg twice weekly for 2 years or until tumor progression) or a placebo. One hundred twenty-nine evaluable patients were assigned to placebo and 131 to levamisole. This report is based on 260 (91%) eligible patients who started treatment and have adequate follow-up. Fifty percent of the patients in both treatment groups had Karnofsky scores of 90-100; 72% had squamous cell carcinoma, 12% adenocarcinoma, and 16% large cell undifferentiated carcinoma; 60% had RTOG Stage I or II primary tumors and 40% had Stage III (T3, N0-1) tumors. Complete regression of tumor was reported in 20% of the patients treated with levamisole and 36% of those receiving placebo. An additional 33% and 19%, respectively, had a partial response (trend test p = 0.08). Median survival was 9 months for patients treated with levamisole and 12 months for those on placebo (two-sided p less than 0.01); at 2 years, patients treated with levamisole had a 15% survival rate as compared to 24% in those receiving placebo. The cumulative proportion failing within the irradiated field with or without other sites of progression at 2 years was 30% in the levamisole group and 34% in the placebo patients. Median progression-free survival was 6 months for patients on levamisole and 7 months for those on placebo (overall two-sided p = 0.014); the estimated proportions progression-free at 2 years were 11% and 18%, respectively. The study showed no significant prolongation of survival, progression-free survival, or differences in patterns of failure in irradiated patients treated with levamisole compared with a placebo. Toxicity related to this immunoadjuvant was, in general, of moderate clinical importance. This study confirms a report by the Southeastern Cancer Study Group concluding that levamisole combined with definitive irradiation has no benefit in the treatment of unresectable non-small cell carcinoma of the lung.

The Radiation Therapy Oncology Group (RTOG) investigated the use of misonidazole as an hypoxic cell sensitizer in a Phase III prospective randomized trial employing radiotherapy, 600 cGy twice weekly to a total of 3600 cGy with and without misonidazole in the treatment of locally advanced non-metastatic squamous cell, adeno, or large cell carcinoma of the lung. Between January 1980 and July 1983, 117 patients from 21 institutions were enrolled. One-hundred eight patients were evaluable; 53 in the combined treatment arm and 55 in the radiation alone arm. Grade 3 or worse complications associated with radiation occurred in 17% of patients. Esophageal toxicity accounted for the majority of complications. Two (4%) patients in the radiotherapy plus misonidazole group experienced grade 3 peripheral neurotoxicity. Complete or partial responses were produced in 58% of the patients with radiotherapy alone and 36% of those treated with radiotherapy plus misonidazole (p = 0.08). At the time of first progression, over 50% of the patients had persistent local disease. Median survival was 7 months regardless of treatment. Misonidazole in the dose and schedule employed did not enhance the effect of radiotherapy on either local tumor control or overall survival in patients with advanced lung cancer.

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 Cox's 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.

The Radiation Therapy Oncology Group conducted a Phase III single blind trial to evaluate the addition of Levamisole to post-operative thoracic irradiation (200 cGy five times weekly to a total of 5000 cGy plus 1000 cGy boost) in patients with resected RTOG Stage II-III non-small cell lung cancer with positive nodes. Between February 1980 and February 1983, 74 patients from 18 RTOG institutions were randomized; accrual to this study was prematurely terminated due to poor accrual and the inferior survival observed in the levamisole-treated patients on another RTOG trial. Sixty-four patients were evaluable; 32 assigned to levamisole and 32 were assigned to placebo. Over 95% of the patients have been followed for a minimum of 4 years or to death. Two patients on placebo and 5 on levamisole experienced Grade 3 pneumonitis or esophagitis; 1 patient on placebo and 2 on levamisole experienced Grade 3 pulmonary fibrosis. Three patients on levamisole experienced other Grade 3 or 4 toxicity: 1 case of intractable nausea and vomiting and 2 with Grade 4 neutropenia (less than 500 per mm3). There were no fatal complications. Median disease-free survival was 13 months in the placebo group and 9 months for the levamisole group. Median time to distant metastases was 18 and 12 months, and median survival was 20 and 13 months, respectively. We concluded that this study failed to demonstrate an advantage for levamisole.

Patients with localized unresectable non-oat cell carcinoma of the lung were treated by supervoltage radiation therapy to the primary tumor, mediastinum and supraclavicular lymph nodes with 50.4 Gy, 42 fractions of 1.2 Gy, twice daily, 4 to 6 hours apart, 5 times a week. Small field treatment to the known involved areas of primary and lymph nodes was given from 9.6 to 24 Gy, also with 1.2 Gy, twice daily. One hundred twenty-five patients were entered, three of whom were cancelled and two were ineligible. Of the remaining 120 eligible patients, 10 patients received a dose of 50.4 Gy, 20 received 60.0 Gy, 79 received 69.6 Gy and 11 patients received 74.4 Gy. Of these, nine patients were unable to complete hyperfractionated radiation therapy for various reasons. Treatment was discontinued or stopped in 14 patients because of early death or deterioration of the patient's condition. Four additional patients were found to have unacceptable doses to tumor or normal tissues, for a total of 27 patients with protocol violations. Complete regression occurred in 19% of T1-T3, N0-N2 patients with 9% among T3.3b, T4 or N3 patients. Partial regression was 29 and 41%, respectively. There were six cases of severe and two of life-threatening toxicity, but there were no fatalities attributable to the treatment. Toxicity consisted mainly of pneumonitis and pulmonary fibrosis as well as esophagitis. Median survival of the entire group was 7.2 months, which is consistent with previous experience with the treatment of localized inoperable non-oat cell carcinoma of the lung by radiation therapy. Further study of this method of treatment is warranted.

Four hundred and ninety-four patients with clinical Stage C carcinoma of the prostate, who were entered onto a phase III RTOG study, have been analyzed as to the potential effect of the pre-treatment transurethral resection (TUR) of the tumor. Treatment consisted of definitive irradiation to the prostate (6500-7000 cGy) and regional lymphatics (4500-5000 cGy). A total of 202 patients underwent pre-treatment TUR. This population was compared with the remaining 292 patients as to the rate of locoregional failure, incidence of distant metastases, disease-free survival, and survival. The TUR population fared significantly worse for all four end-points. To account for uneven distribution of recognized prognostic factors the results were then adjusted using stratified Mantel-Haenszel tests. The stratification process resulted in a reduced level of significance in the differences between the two populations. However, a trend toward a higher incidence of distant metastases could be observed within most strata. The trend was most pronounced in subpopulations characterized by Gleason score 6-7 and normal serum acid phosphatase (SAP). For the population characterized by Gleason score 6-10 and normal SAP, the differences in the incidence of distant metastases retained statistical significance. Whether these findings are secondary to tumor dissemination during TUR or are due to incompletely identified selection biases remains to be demonstrated in future (prospective) studies.