Does race influence survival for esophageal cancer patients treated on the radiation and chemotherapy arm of RTOG #85-01?

PURPOSE: In reported retrospective non-randomized trials of treatment of esophageal carcinoma, blacks have a lower survival from esophageal cancer than whites. None of these studies has accounted for the extent of disease, or the methods and quality of treatment. We reviewed the data that included only patients treated on the chemoradiation arm of the RTOG-8501 esophageal carcinoma trial to see if there were differences in overall survival between black and white patients receiving the same standard of care. METHODS AND MATERIALS: One hundred-nineteen patients, 37 blacks and 82 whites were evaluated who met the criteria for receiving chemoradiation of 5000 cGy and four courses of Cisplatin (75 mg/m2) and Fluorouracil (1000 mg/m2 for 4 days). RESULTS: Blacks had squamous histology only, with 86% of blacks having weight loss of 10 lbs. or more compared to 56% of whites (p = 0.001). In addition, blacks had larger tumors and more difficulty eating (p = 0.010). Overall, there was no difference in the Kaplan-Meier median survival estimate by race (p = 0.2757). Only when we limited the analysis to the "squamous histology" subgroup, stratified according to age >70 vs. <70 years (p = 0.0002), and nodal status (p = 0.0177) in a Cox regression model analysis, did race appear to be a significant factor (p = 0.0012). However, using the entire database, the age effect was found to be a "bimodal" effect, wherein the "youngest" (< age 60 years) and "oldest" patients (age > 70 years) did poorly. Because of the dramatic differences in the age and histology distributions between blacks and whites, this issue could not be resolved in the subset of squamous only who received chemoradiation. CONCLUSIONS: The increasing incidence of adenocarcinoma among white patients without a corresponding increase of this histology in blacks reflects a difference in diet and or lifestyle compared to blacks that deserves additional study. When treated aggressively with chemoradiation, race did not appear to be a statistically significant factor for overall survival.

Androgen suppression plus radiation versus radiation alone for patients with D1 (pN+) adenocarcinoma of the prostate (results based on a national prospective randomized trial, RTOG 85-31). Radiation Therapy Oncology Group.

PURPOSE: To evaluate the effect of immediate androgen suppression in conjunction with standard external beam irradiation vs. radiation alone on a group of pathologically staged lymph node-positive patients with adenocarcinoma of the prostate. METHODS AND MATERIALS: A national prospective randomized trial (RTOG 85-31) of standard external beam irradiation plus immediate androgen suppression vs. external beam irradiation alone was initiated in 1985 for patients with locally advanced adenocarcinoma of the prostate. One hundred seventy-three of the patients in this trial had biopsy-proven pathologically involved lymph nodes. Ninety-eight of these patients received radiation plus the immediate androgen suppression (LHRH agonist), while 75 received radiation alone with hormonal manipulation instituted at the time of relapse. RESULTS: With a median followup of 4.9 years, estimated progression-free survival with PSA < 1.5 ng/ml at 5 years was 55% for the patients who received radiation plus immediate LHRH agonist vs. 11% of the patients who received radiation alone with hormonal manipulation at relapse (p = 0.0001). Because all of these patients had locally advanced disease (i.e., pathologically positive lymph nodes), stage does not explain this difference in outcome, and Gleason grade was not statistically different between the two groups. Estimated absolute survival at 5 years for the radiation and LHRH group was 73 vs. 65% for the radiation alone group who received androgen suppression at relapse. Estimated disease-specific survival at 5 years was 82% for the radiation and immediate LHRH agonist group and 77% for the radiation-alone group. CONCLUSION: Patients with adenocarcinoma of the prostate and pathologically involved pelvic lymph nodes (pN+ or clinical stage D1) should be seriously considered for external beam irradiation plus immediate hormonal manipulation over radiation alone with hormonal manipulation at the time of relapse.

Survival improvement in anaplastic astrocytoma, combining external radiation with halogenated pyrimidines: final report of RTOG 86-12, Phase I-II study.

PURPOSE: This study evaluated the toxicity and tumor efficacy of the halopyrimidine IUdR as a chemical modifier of radiation response in patients with malignant glioma. The preliminary results published in 1993 demonstrated no real advantage in the group of patients with glioblastoma. However, a benefit appeared to be evolving in the group of patients with Anaplastic Astrocytoma (AA). We are now presenting the results on the long-term follow-up of patients with AA. METHODS AND MATERIALS: Between August 1987 and October 1991, 79 patients were entered in a prospective study with newly diagnosed malignant glioma. Twenty-one of 79 were AA. The study was designed to have a fixed dose of radiation consisting of 60.16 Gy in 32 fractions in 6.5 weeks but varying the dose schedule of IUdR, delivered in a continuous intravenous infusion of long (96 h) or short (48 and 24 h) duration, every week for the 6.5 weeks of radiation treatment. RESULTS: The last AA patient was entered in March 1991. Ninety-five percent of the AA patients were under 59 years of age and 86% had a Karnofsky score 80. Thirty-eight percent had a tumor diameter of less than 5 cm and 52% had a tumor diameter between 5-10 cm. Seventy-six percent had partial or total tumor resection. The toxicity of this treatment was acceptable and has already been published elsewhere. At the time of this report, 14 out of 21 patients with AA are dead. The median survival, calculated from the Kaplan-Meier, is 3.2 years. Thirty-three percent of the patients have survived 5 years. These results compare favorably with the best results reported in the literature with postoperative external radiation plus chemotherapy, median survival time (MST) of 3 years, and previous Radiation Therapy Oncology Group (RTOG) experience with radiation alone, MST of 2 years. CONCLUSIONS: Our findings in patients with AA corroborate the improved therapeutic results published recently when combining external radiation with "long" infusion of i.v. BUdR and indicate the need to proceed with randomized Phase III studies utilizing halogenated pyrimidines and radiation. One such study has already been activated, RTOG # 94-04.

Results of a phase II trial of external beam radiation with etanidazole (SR 2508) for the treatment of locally advanced prostate cancer (RTOG Protocol 90-20).

PURPOSE: RTOG Protocol 90-20 was designed to evaluate the effect of the hypoxic cell sensitizer Etanidazole (SR-2508) on locally advanced adenocarcinoma of the prostate treated with concurrent external beam irradiation. METHODS AND MATERIALS: Patients with biopsy-proven adenocarcinoma of the prostate with locally advanced T2b, T3, and T4 tumors were eligible for this study. No patients with disease beyond the pelvis were eligible. Serum prostate specific antigen (PSA) was mandatory. All patients received definitive external beam irradiation using standard four-field whole pelvis treatment to 45-50 Gy, followed by a cone down with a minimum total dose to the prostate of 66 Gy at 1.8-2.0 Gy/fraction over 6.5-7.5 weeks. Etanidazole was delivered 1.8 g/m2 given 3 times a week to a total of 34.2 g/m2 or 19 doses. RESULTS: Thirty-nine patients were entered onto the study. Three patients refused treatment; therefore, 36 patients were eligible for further evaluation. Median follow-up was 36.9 months from treatment end. All patients had elevated initial PSA levels, and 18 patients had PSAs of > 20 ng/ml. Tumor classification was T2, 12 patients (33.3%); T3, 22 patients (61.1%); and T4, 2 patients (5.6%). Complete clinical response, defined as PSA < 4 ng/ml and complete clinical disappearance, was attained in 17.9% of (5/28 pts) with information at 90 days and 56% of patients by 12 months following treatment. Relapse-free survival was 13% at 3 years with PSA < 4 ng/ml. There were no Grade 4 or 5 toxicities, either acute (during treatment) or in follow-up. CONCLUSIONS: Results of this trial regarding PSA response and clinical disappearance of disease are similar to historical controls and do not warrant further investigation of etanidazole as was done in this trial. Drug toxicity that, in the past, has been unacceptably high with other hypoxic cell sensitizers does not appear to be a significant problem with this drug.

A phase I/II study to evaluate the effect of fractionated hemibody irradiation in the treatment of osseous metastases--RTOG 88-22.

PURPOSE: The present study was initiated to determine the maximum tolerated total dose that can be delivered by fractionated hemibody irradiation (HBI), as defined by the acute hematological and nonhematological toxicity. Although it was designed as a dose searching trial, the influence of higher doses on occult and overt disease were considered equally important. The study was not designed to evaluate pain relief. The results were compared to Radiation Therapy Oncology Group (RTOG) 82-06, which employed single high-dose HBI, to determine if either single or fractionated HBI is more effective in controlling occult or overt disease. METHODS AND MATERIALS: A total of 144 patients were entered from September 1989 to April 1993. Only patients with a single symptomatic bone metastases from either prostate or breast cancer primaries and a KPS > or = 60 were eligible. All patients initially received 30.0 Gy in 10 fractions to the symptomatic area followed by HBI in 2.50 Gy fractions to one of five arms: I-10.0 Gy (37 patients); II-12.5 Gy (23 patients); III-15.0 Gy (18 patients); IV-17.5 Gy (40 patients), and V-20.0 Gy (26 patients). A dose limiting toxicity was defined as an observed toxicity of > or = Grade 3 lasting more than 30 days postcompletion of HBI. If three or more dose-limiting toxicities occurred at any dose level, the previous dose was considered as the maximum tolerable dose. RESULTS: Thirty-six of 142 patients experienced > or = Grade 3 hematological toxicity at some time following HBI. The distribution of dose-limiting hematological toxicity in each arm was: I-two patients; II-one patients; III-zero patients; IV-one patient; and V-three patients. The major nonhematological toxicity was gastrointestinal and occurred in 10 patients. None were dose limiting. At 12 months from the initiation of treatment, the percent of patients with new disease were: Arms I-19%; II-9%; III-17%; IV-19%; V-13%; the percent of patients requiring additional treatment in the hemibody field were: Arms I-36%; II-30%; III-33%; IV-32%; and V-19%. When compared to single high-dose HBI the estimated reduction in the failure rate was 36% after fractionated HBI which potentially represents a modest improvement. CONCLUSIONS: The maximum tolerated dose of fractionated (2.50 Gy) HBI was found to be 17.5 Gy. The major dose limiting toxicity was hematological (thromboleukopenia). There was not a significant dose response effect on occult disease (appearance of new disease) or in the requirement for additional treatment, although certain trends were noted for the higher doses. When only patients completing assigned HBI from RTOG 82-06 and 88-22 were compared, there was no difference in the time to new disease or additional treatment in the treated field. Based on the investigative parameters of this study, single high-dose HBI was as effective as fractionated HBI. The incorporation of cytokines, to ameliorate hematological toxicity, should allow for the delivery of higher doses of fractionated HBI and sequential HBI as a means of delivering systemic irradiation.

Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Group.

PURPOSE: The objectives of this randomized trial were to determine if interstitial thermoradiotherapy (ITRT) improves tumor regression/control in accessible lesions in comparison with interstitial radiotherapy (IRT) alone and to assess the skin and soft tissue complications with either modality. METHODS AND MATERIALS: From January 1986 to June 1992, 184 patients with persistent or recurrent tumors after previous radiotherapy and/or surgery, which were amenable to interstitial radiotherapy, were accessioned to a protocol developed by the Radiation Therapy Oncology Group (RTOG). One hundred seventy-three cases were analyzed (87 patients in the IRT group and 86 in the ITRT arm). The two arms were well balanced regarding stratification criteria. Most tumors were in the head and neck (40% in the IRT group and 46% in the ITRT group), and pelvis (42% and 43%, respectively). Eighty-four percent of patients in both arms had prior radiation therapy (> or = 40 Gy); 50% and 40%, respectively, had prior surgery, and 34% in each arm had prior chemotherapy. The dose of radiation therapy administered was dependent on the previous radiation dose and did not exceed a total cumulative dose of 100 Gy. Hyperthermia was delivered in one or two sessions, either before or before and after interstitial implant. The intended goal of the hyperthermia was to maintain a minimal tumor temperature of 42.5 degrees C for 30 to 60 min. RESULTS: There was no difference in any of the study end points between the two arms. Complete response (CR) was 53% and 55% in both arms. Two-year survival was 34% and 35%, respectively. Complete response rate for persistent lesions was 69% and 63% in the two treatment arms as compared with 40% and 48% for recurrent lesions. A set of minimal adequacy criteria for the delivery of hyperthermia was developed. When these criteria were applied, only one patient had an adequate hyperthermia session. Acute Grade 3 and 4 toxicities were 12% for IRT and 22 % for ITRT. Late Grade 3 and 4 toxicities were 15% for IRT and 20% for ITRT. The difference was not significant. CONCLUSIONS: Interstitial hyperthermia, as applied in this randomized study, did not show any additional beneficial effects over interstitial radiotherapy alone. Delivery of hyperthermia remains a major obstacle (since only one patient met the basic minimum adequacy criteria as defined in this study). The benefit of hyperthermia in addition to radiation therapy still remains to be proven in properly randomized prospective clinical trials after substantial technical improvements in heat delivery and dosimetry are achieved.

RTOG's first quality of life study--RTOG 90-20: a phase II trial of external beam radiation with etanidazole for locally advanced prostate cancer.

PURPOSE: To assess institutional and patient compliance with quality of life (QL) instruments in RTOG clinical trials. To assess feasibility of using the Functional Assessment Cancer Therapy (FACT), Sexual Adjustment Questionnaire (SAQ), and Changes in Urinary Function (CUF) QL instruments in a prostate clinical trial and to compare patient self-report of symptoms to medical professional ratings of the same symptoms using the RTOG acute toxicity rating scales. METHODS AND MATERIALS: Three self-assessment QL instruments, the FACT, the SAQ, and CUF, were to be administered to patients on a Phase II locally advanced prostate trial at specified time points. Specific instructions for both data managers and for patients on when, how, and why to fill out the questionnaires were included. RESULTS: Sixty-seven percent (24 out of 36) of patients accrued to RTOG 90-20 completed both the initial FACT and SAQ. Eighty-five percent completed FACT at end of RT and 73% at 3 months. Eighty-one percent completed SAQ at end of treatment, while 69% completed this form at 3 months. Compliance drops off thereafter. Seventy-five percent of patients who had their symptom of dysuria rated by a medical professional as 0 on the RTOG toxicity rating scale self-reported the same. Only 56% of patient self-reports on FACT regarding diarrhea were in agreement with the medical professional's RTOG rating of 0 toxicity. The measures were determined to be in moderate agreement when the patient evaluated a symptom as a 1 on the FACT and the medical professional rated the same symptom as a 0 on the RTOG toxicity rating scale. There was moderate agreement in 13% of patients with dysuria and 31% of patients with diarrhea. Low agreement occurred when the patient evaluated a symptom as a 2 or 3 on the FACT and the medical professional rated the same symptom as a 0 on the RTOG scale. Low agreement occurred in 13% of both patients reporting dysuria and diarrhea. Differences between how medical professionals and patients were able to rate erectile function make direct comparisons difficult, but the trend towards significant discrepancies is still noteworthy. CONCLUSIONS: Quality of life assessments are necessary and attainable in RTOG clinical trials. Compliance rates for both institutional and patient participation were acceptable at initial and 3 month follow-up. Reasons for noncompliance were predominantly institution related and not patient related. Strategies to address both institution and patient compliance have been developed and implemented within the RTOG. Serious disagreement between patient self-reports of symptoms on the FACT QL scale and medical professional ratings on the RTOG acute toxicity rating scales of the same symptoms was 13% at 3 months follow-up. This warrants continued use of QL self-assessments in clinical trials.

Iododeoxyuridine (IUdR) combined with radiation in the treatment of malignant glioma: a comparison of short versus long intravenous dose schedules (RTOG 86-12).

PURPOSE: To evaluate the toxicity and tumor efficacy of the halopyrimidine IUdR (NSC #39661, IND 22475) as a chemical modifier of radiation response when used in a high dose short time infusion versus the acceptable 4 day infusion. METHODS AND MATERIALS: In August 1987 we initiated a prospective study in patients with newly diagnosed anaplastic astrocytoma and glioblastoma. The study was designed to have a fixed dose of radiation (60.16 Gy = 1.88 Gy in 32 fractions in 6.5 weeks) but varying the dose schedule of IUdR, keeping the total dose between 21 and 24 g/m2. IUdR was delivered in a 96, 48, or 24 hr continuous intravenous infusion per week for 6.5 weeks during radiation treatment. RESULTS: The study was closed for patient accrual on October 1, 1991. Twenty-two patients were treated on the 96 hrs, 32 on the 48 hr and 25 on the 24 hr schedules. The incidence of glioblastoma ranged between 68 and 75% in the three arms. Seventy percent of the patients had a Karnofsky of 80-90% at the onset of treatment. Over 50% of the patient population were under age 55. Drug tolerance was related to the duration of the IUdR infusion. Toxicities were most pronounced in the 96 hr IUdR infusion schedule where 27.4% of the patients reported a grade 3 drug toxicity. No fatal or grade 4 toxicities were observed. More patients on the 24 and 48 hr schedule received at least 80% of the IUdR dose specified per protocol. We did not observe a trend in acute normal tissue radiation reactions in any of the three arms. The median survivals calculated from the Kaplan-Meier plot are 13.4, 10.5, and 11 months, respectively, for the 96, 48, and 24 hr infusions. The Cox Proportional Hazards model showed that any difference in survival can be attributed to histological grade, type of previous surgery and, to some extent, age of the patient. Dose schedule was not a significant predictor of survival, although statistically nonsignificant trend toward longer survival is seen in those patients with glioblastoma treated in the "long" 4 day schedule. CONCLUSION: Overall, our treatment combination, particularly for patients with glioblastoma, has not shown convincing evidence of an improvement in survival. Of interest, however, it is the 2 year survival rate of 68% for patients with anaplastic astrocytoma. In our experience, the administration of IUdR is laborious, time consuming and with bothersome acute gastrointestinal and hematological toxicities.

Cutaneous T-cell lymphoma in a patient infected with human immunodeficiency virus type 1. Use of radiation therapy.

A patient with cutaneous T-cell lymphoma (CTCL) and acquired immune deficiency syndrome (AIDS) is presented. The patient had a localized lesion on his scalp. Evaluation for systemic lymphoma was negative. A biopsy specimen showed superficial and deep dermal infiltrates of pleomorphic lymphocytes. Immunohistochemistry was consistent with T-cell lymphoma. The patient was treated successfully with local irradiation. He remained free of further systemic and cutaneous recurrences of the lymphoma until he died 8 months after treatment of pneumonia. This case is the first to our knowledge to describe a localized CTCL in a patient infected with human immunodeficiency virus type 1 (HIV-1).