Microscopic and macroscopic tumor and parenchymal effects of liver stereotactic body radiotherapy.

PURPOSE: To describe the histologic and volumetric changes in normal liver tissue after stereotactic body radiotherapy (SBRT) for liver metastases. METHODS AND MATERIALS: Pre- and post-SBRT imaging studies were analyzed to evaluate the effect of SBRT on normal liver volume (NLV) in 15 patients treated in a prospective clinical trial. Two other patients underwent exploratory surgery after SBRT and histologic analyses of the irradiated liver were performed to characterize the pathologic effects of SBRT. RESULTS: In the 15 patients studied quantitatively, the total NLV had decreased transiently at 2-3 months after SBRT and then began to regenerate at 3-8 months after SBRT. The median NLV reduction at the maximal observed effect was 315 cm(3) (range, 125-600) or 19% (range, 13-33%). Among the several dosimetric parameters evaluated, the strongest linear correlation was noted for the NLV percentage receiving 30 Gy as a predictor of maximal NLV reduction (r(2) = 0.72). The histologic changes observed 2 and 8 months after SBRT demonstrated distinct zones of tissue injury consistent with localized veno-occlusive disease. CONCLUSION: The well-demarcated focal parenchymal changes after liver SBRT (demonstrated both radiographically and histologically) within the high-dose zone are consistent with a threshold dose-induced set of phenomena. In contrast, the more global effect of NLV reduction, which is roughly proportional to whole organ dose parameters, resembles more closely an effect determined from radiobiologically parallel architecture. These observations suggest that modeling of normal tissue effects after liver SBRT might require different governing equations for different classes of effects.

Implant volume as a prognostic variable in brachytherapy decision-making for malignant gliomas stratified by the RTOG recursive partitioning analysis.

PURPOSE: When an initial retrospective review of malignant glioma patients (MG) undergoing brachytherapy was carried out using the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) criteria, it revealed that glioblastoma multiforme (GBM) cases benefit the most from implant. In the present study, we focused exclusively on these GBM patients stratified by RPA survival class and looked at the relationship between survival and implanted target volume, to distinguish the prognostic value of volume in general and for a given GBM class. METHODS AND MATERIALS: Between 1991 and 1998, 75 MG patients were treated with surgery, external beam radiation, and stereotactic iodine-125 (I-125) implant. Of these, 53 patients (70.7%) had GBMs, with 52 (98%) having target volume (TV) data for analysis. Stratification by RPA criteria showed 12, 26, 13, and 1 patients in classes III to VI, respectively. For analysis purposes, classes V and VI were merged. There were 27 (51.9%) male and 25 (48.1%) female patients. Mean age was 57.5 years (range 14-79). Median Karnofsky performance status (KPS) was 90 (range 50-100). Median follow-up time was 11 months (range 2-79). RESULTS: At analysis, 18 GBM patients (34.6%) were alive and 34 (65.4%) were dead. Two-year and 5-year survivals were 42% and 17.5%, respectively, with a median survival time (MST) of 16 months. Two-year survivals and MSTs for the implanted GBM patients compared to the RTOG database were as follows: 74% vs. 35% and 28 months vs. 17.9 months for class III; 32% vs. 15% and 16 months vs. 11.1 months for class IV; 29% vs. 6% and 11 months vs. 8.9 months for class V/VI. Mean implanted TV was 15.5 cc (range 0.8-78), which corresponds to a spherical implant diameter of 3.1 cm. Plotting survival as a function of 5-cc TV increments suggested a trend toward poorer survival as the implanted volume increases. The impact of incremental changes in TV on survival within a given RPA class of GBMs was compared to the RTOG database. Looking at absolute differences in MSTs: for classes III and IV, there was little effect of different TVs on survival; for class V/VI, a survival benefit to implantation was still seen at the target volume cutoff (TV > 25 cc). Within a given RPA class, no significant differences were found within class III; for class IV, the most significant difference was at 10 cc (p = 0.05); and for class V/VI, at 20 cc (p = 0.06). CONCLUSION: For all GBM patients, an inverse relationship between implanted TV size and median survival is suggested by this study. However, when GBM patients are stratified using the RTOG's RPA criteria, the prognostic effect of implant volume disappears within each RPA survival class. At the critical volume of 25 cc, which approximates an implant of 5-cm diameter (upper implantation limit of many CNS brachytherapy protocols), the "poorest" prognosis GBM patients stratified by RPA still demonstrate a survival benefit with implant. We suggest that any GBM patient meeting brachytherapy recognized size criteria be considered for I-125 implant.

Swallowing function and weight change observed in a phase I/II study of external-beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 9207).

BACKGROUND: A multi-institutional, prospective study was designed to determine the feasibility and tolerance of combined-modality chemotherapy, external-beam irradiation, and esophageal brachytherapy in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. Swallowing function and weight were assessed before and after treatment. MATERIALS AND METHODS: Planned treatment was with 50 Gy of external-beam irradiation (25 fractions/5 weeks) followed 2 weeks later by esophageal brachytherapy (either a high dose rate of 5 Gy at weeks 8, 9, and 10 for a total of 15 Gy or a low dose rate of 20 Gy at week 8). Chemotherapy was given weeks 1, 5, 8, and 11 with cisplatinum, 75 mg/m2, and 5-fluorouracil, 1,000 mg/m2/24 hours in a 96-hour infusion. Swallowing was graded from 0 (no dysphagia) to 4 (complete obstruction for solids and liquids). Weight "loss" or weight gain was defined as a change in 3-month post- to pretherapy weight of < or = 5% or > 5%, respectively. RESULTS: The estimated survival rate at 1 and 2 years was 49% and 31%, respectively, and the estimated median survival was 11 months. Swallowing before treatment was graded as grade 1 in 14 patients, grade 2 in 22 patients, grade 3 in nine patients, and grade 4 in four patients. Swallowing grade after treatment was reported as improved in 29 patients (59%), unchanged in 12 patients (24.5%), and worse in eight patients (16.5%). The bestimproved dysphagia score after treatment in the 29 patients reporting improvement was grade 0 in 19 patients, grade 1 in five patients, grade 2 in four patients, and grade 3 in one patient. A posttreatment weight in 42 evaluable patients was categorized as a loss in 29 patients (69%), a gain in four patients (9.5%), and stable in nine patients (21.5%). Weight loss was significantly correlated with high swallowing grade, low performance status, and absence of a feeding tube. CONCLUSIONS: Swallowing function after brachytherapy and concurrent chemoradiation therapy is satisfactory in most surviving patients. Ninety-two percent of patients were able to swallow at least liquids at some point after therapy. Future plans are to compare this with other cooperative group studies that utilized chemoradiation or surgery, without brachytherapy.

Pulmonary sequelae after electron spinal irradiation.

We measured pulmonary function in 21 patients, after craniospinal irradiation with a posterior spinal electron beam. The median age at treatment was 7.5 years. Nine patients (43%) demonstrated abnormal pulmonary function tests, five with restrictive changes, one with isolated diminished diffusion capacity, and three with obstructive disease. These changes were mild and predominantly asymptomatic.

Optimizing chemoradiation therapy approaches to unresectable stage III non--small cell lung cancer.

There have been important recent advances in the management of inoperable non--small cell lung cancer. Concurrent cisplatinum-or carboplatin-based chemotherapy and 60 to 64 Gy of thoracic radiation therapy has replaced sequential therapy as the new standard therapy for good-risk patients. New agents such as docetaxel, gemcitabine, and irinotecan are being tested to replace the standard chemotherapy given during thoracic radiation. Phase II studies of induction or consolidation chemotherapy have also shown promise but these agents have not yet been proven to improve outcome in a prospective randomized study. New strategies for optimizing thoracic radiation, primarily by dose escalation with three-dimensional conformal technique, have also led to an improved therapeutic ratio. Alternative strategies may be required for poor-risk, elderly patients.

Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) previously developed three prognostic classes for brain metastases using recursive partitioning analysis (RPA) of a large database. These classes were based on Karnofsky performance status (KPS), primary tumor status, presence of extracranial system metastases, and age. An analysis of RTOG 91-04, a randomized study comparing two dose-fractionation schemes with a comparison to the established RTOG database, was considered important to validate the RPA classes. METHODS AND MATERIALS: A total of 445 patients were randomized on RTOG 91-04, a Phase III study of accelerated hyperfractionation versus accelerated fractionation. No difference was observed between the two treatment arms with respect to survival. Four hundred thirty-two patients were included in this analysis. The majority of the patients were under age 65, had KPS 70-80, primary tumor controlled, and brain-only metastases. The initial RPA had three classes, but only patients in RPA Classes I and II were eligible for RTOG 91-04. RESULTS: For RPA Class I, the median survival time was 6. 2 months and 7.1 months for 91-04 and the database, respectively. The 1-year survival was 29% for 91-04 versus 32% for the database. There was no significant difference in the two survival distributions (p = 0.72). For RPA Class II, the median survival time was 3.8 months for 91-04 versus 4.2 months for the database. The 1-year survival was 12% and 16% for 91-04 and the database, respectively (p = 0.22). CONCLUSION: This analysis indicates that the RPA classes are valid and reliable for historical comparisons. Both the RTOG and other clinical trial organizers should currently utilize this RPA classification as a stratification factor for clinical trials.

A phase I/II study of external beam radiation, brachytherapy, and concurrent chemotherapy for patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group Study 9207): final report.

BACKGROUND: A multiinstitutional, prospective study of the Radiation Therapy Oncology Group (RTOG) was designed to determine the feasibility and toxicity of chemotherapy, external beam radiation, and esophageal brachytherapy (EB) in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. A preliminary analysis indicated a 17% 1-year actuarial risk of treatment-related fistulas. A final analysis of this study was considered important to determine the median survival time, local control, and late toxicity associated with this treatment regimen. METHODS: Planned treatment was 50 grays (Gy) of external beam radiation (25 fractions given over 5 weeks) followed 2 weeks later by EB (either high-dose-rate 5 Gy during Weeks 8, 9, and 10, for a total of 15 Gy, or low-dose-rate 20 Gy during Week 8). Chemotherapy was given during Weeks 1, 5, 8, and 11, with cisplatin 75 mg/m(2) and 5-fluorouracil 1000 mg/m(2)/24 hours in a 96-hour infusion. RESULTS: Of the 49 eligible patients, 45 (92%) had squamous histology and 4 (6%) had adenocarcinoma. Forty-seven patients (96%) completed external beam radiation plus at least 2 courses of chemotherapy, whereas 34 patients (69%) were able to complete external beam radiation, EB, and at least 2 courses of chemotherapy. The estimated survival rate at 12 months was 49%, with an estimated median survival of 11 months. Life-threatening toxicity or treatment-related death occurred in 12 (24%) and 5 (10%) cases, respectively. Treatment-related esophageal fistulas occurred in 6 cases (12% overall, 14% of patients starting EB) at 0.5-6.2 months from the first day of brachytherapy, leading to death in 3 cases. CONCLUSIONS: In this study, severe toxicity, including treatment-related fistulas, occurred within 7 months of brachytherapy. Based on the 12% incidence of fistulas, the authors continue to urge caution in employing EB, particularly when used in conjunction with chemotherapy.

Phase I trial of concurrent thoracic radiation and continuous infusion cisplatin and etoposide in stage III non-small cell lung cancer.

OBJECTIVE: Although combined modality therapy appears to be superior to radiotherapy alone for the treatment of locally advanced non-small cell lung cancer (NSCLC), the optimal treatment regimen has not been determined. We designed this trial to determine the maximal tolerated doses (MTD) of continuous intravenous infusion (CI) cisplatin and etoposide that could be administered concurrently with thoracic irradiation. METHODS: 19 patients with stage IIIA or IIIB NSCLC were treated at three different dose levels of CI cisplatin and etoposide with concurrent single daily fraction thoracic radiotherapy to 4500 cGy. This chemoradiotherapy phase of treatment was followed by a 1500-2000 cGy radiotherapy boost and three cycles of standard intermittent bolus cisplatin 80 mg/m2 i.v. on day 1 and etoposide 80 mg/m2 i.v. on days 1, 2 and 3. RESULTS: The MTD of CI chemotherapy was determined to be cisplatin 5 mg/m2/day plus etoposide 18 mg/m2/day for 5 days per week over 5 weeks along with thoracic irradiation. Overall, 37% of patients required breaks in the chemoradiotherapy course and 32% required attenuation of the planned duration of CI chemotherapy. Only 42% of patients received all three planned cycles of bolus chemotherapy and 16% received < 6000 cGy of thoracic irradiation. The major toxicities during concurrent chemoradiotherapy were grade 3-4 esophagitis (42%) and myelosuppression (47%). Subsequent chemotherapy was complicated by grade 3-4 myelosuppression in 38% of patients. An objective response was documented in 58% of patients (CR 11%, PR 47%). Median survival was 18 months with 2- and 5-year survival rates of 42 and 11%, respectively. CONCLUSIONS: These results demonstrate that CI cisplatin and etoposide can be administered safely to patients with locally advanced NSCLC, and that such potentially radiosensitizing strategies deserve further evaluation in this setting.

Use of the RTOG recursive partitioning analysis to validate the benefit of iodine-125 implants in the primary treatment of malignant gliomas.

PURPOSE: To date, numerous retrospective studies have suggested that the addition of brachytherapy to the conventional treatment of malignant gliomas (MG) (surgical resection followed by radiotherapy +/- chemotherapy) leads to improvements in survival. Two randomized trials have suggested either a positive or no survival benefit with implants. Critics of retrospective reports have suggested that the improvement in patient survival is due to selection bias. A recursive analysis by the RTOG of MG trials has stratified MG patients into 6 prognostically significant classes. We used the RTOG criteria to analyze the implant data at Wayne State University to determine the impact of selection bias. METHODS AND MATERIALS: Between July 1991 and January 1998, 75 patients were treated with a combination of surgery, radiotherapy, and stereotactic I-125 implant as primary MG management. Forty-one (54.7%) were male; 34 (45.3%) female. Median age was 52 years (range 4-79). Twenty-two (29.3%) had anaplastic astrocytoma (AA); 53 (70.7%), glioblastoma multiforme (GBM). Seventy-two patients had data making them eligible for stratification into the 6 RTOG prognostic classes (I-VI). Median Karnofsky performance status (KPS) was 90 (range 50-100). There were 14, 0, 14, 31, 12, and 1 patients in Classes I to VI, respectively. Median follow-up time for AA, GBM, and any surviving patient was 29, 12.5, and 35 months, respectively. RESULTS: At analysis, 29 (40.3%) patients were alive; 43 (59.7%), dead. For AA and GBM patients, 2-year and median survivals were: 58% and 40%; 38 and 17 months, respectively. For analysis purposes, Classes I and II, V and VI were merged. By class, the 2-year survival for implanted patients compared to the RTOG data base was: III--68% vs. I--76%; III--74% vs. 35%; IV--34% vs. 15%; V/VI--29% vs. V--6%. For implant patients, median survival by class was (in months): I/II--37; III--31; IV--16; V/VI--11. CONCLUSION: When applied to MG patients receiving permanent I-125 implant, the criteria of the RTOG recursive partitioning analysis are a valid tool to define prognostically distinct survival groups. As reflected in the RTOG study, a downward survival trend for the implant patients is seen from "best to worse" class patients. Compared to the RTOG database, median survival achieved by the addition of implant is improved most demonstrably for the poorer prognostic classes. This would suggest that selection bias alone does not account for the survival benefit seen with I-125 implant and would contradict the notion that the patients most eligible for implant are those gaining the most benefit from the treatment. In light of the contradictory results from two randomized studies and given the present results, further randomized studies with effective stratification are required since the evidence for a survival benefit with brachytherapy (as seen in retrospective studies) is substantial.

Prognostic factors and survival in patients with spinal cord gliomas after radiation therapy.

The purpose of this study was to determine the impact of various prognostic factors on survival in spinal cord gliomas treated with radiation. Fifty-three patients with spinal cord gliomas irradiated at three major institutions were studied. Fifty-one patients were classified as having ependymoma, astrocytoma, or both. Two patients were classified as having gliomas (otherwise unspecified). Eleven patients had complete resection of their tumor. Biopsy or partial resection was done in the remaining patients. All patients received external beam radiation. Information on these patients was placed in a central database file and analyzed for the effect of several prognostic factors on survival. Overall survival of the entire group was 76.9% and 61.5% at 5 and 10 years, respectively. Pathologic status significantly affected survival (p = 0.03). Patients with ependymomas had a 5-year survival of 93.8% and a 10-year survival of 67.5%. Patients with astrocytoma had a 5-year survival of 64.2% and a 10-year survival of 54%. Univariate analysis showed pathology and the presence of cysts (p = 0.038) to significantly affect survival. Age, sex, location of the primary, extent of surgery radiation dose, and number of involved segments did not affect survival. On multivariate analysis, astrocytic pathology, involvement of more than five segments, male sex, and the absence of cysts (in or adjacent to the tumor) were associated with a significantly inferior survival. This study confirms the importance of pathology and number of segments involved in determining outcome or survival. The presence of cysts adjacent to or within the tumor was found to be associated with an improvement in survival.

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.

Lung cancer in patients < 50 years of age: the experience of an academic multidisciplinary program.

OBJECTIVE: To determine if the clinicopathologic features and survival of lung cancer patients < 50 years of age differ from those of older patients. DESIGN: Retrospective review of patients with primary bronchogenic carcinoma diagnosed at a single, multidisciplinary cancer center. SETTING: A National Cancer Institute-designated comprehensive cancer center in urban Detroit, MI. PATIENTS: All patients with primary bronchogenic carcinoma evaluated in the Multidisciplinary Lung Cancer Clinic at the Barbara Ann Karmanos Cancer Institute between 1990 and 1993. RESULTS: Of 1,012 patients with lung cancer, 126 (12.5%) were < 50 years old at diagnosis, with a median age of 44 years. The median age of the 886 patients > or = 50 years of age was 65 years. The gender (p = 0.08) and racial (p = 0.12) characteristics of the younger and older patient groups were not significantly different. More than 90% of patients in both groups were smokers. The incidence of adenocarcinoma was significantly higher in younger patients (48.4% vs 36.0%, p < 0.001), and early-stage disease was less frequently diagnosed in younger patients (4.8% vs 19.7%, p < 0.001). Younger patients were more likely than older patients to undergo treatment, including surgery and combined-modality therapy (p < 0.001). Median survival was 13 months in younger and 9 months in older patients, while overall survival was similar in younger and older patients (p = 0.13). CONCLUSIONS: Although younger patients with lung cancer present with more advanced-stage disease, their overall survival is similar to that of older patients, suggesting that lung cancer is not an inherently more aggressive disease in patients < 50 years of age.

Permanent 125iodine implants for recurrent malignant gliomas.

PURPOSE: To determine the efficacy and toxicity of permanent 125iodine implants for recurrent malignant gliomas. METHODS AND MATERIALS: Between January 1989 and January:, 59 patients with histologically confirmed recurrent malignant gliomas (22 nonglioblastoma malignant gliomas, 37 glioblastoma multiforme at the time of implant) received a permanent 125iodine implant. Patients ranged in age from 13-74 years. The median ages for the overall group, nonglioblastoma (nonGBM), and glioblastoma (GBM) groups was 47 years, 39 years, and 53 years, respectively. RESULTS: With a median follow-up of 40 months, the median survival for the 59 total patients is 1.34 years; nonGBM 2.04 years, GBM 0.9 years. Factors predictive for poor prognosis were GBM histology, age 60 years or more, target volume 17 cc or more, and/or tumor location within the corpus callosum or thalamus. Reoperations have been performed in 24 (40%) patients; 15 (25%) for tumor progression; 3 (5%) for radiation necrosis; 2 (3%) for skull necrosis/infection, and 4 (7%) for other reasons (Ommaya reservoir insertion, catheter removal, hematoma evacuation). CONCLUSION: Permanent 125iodine implants in selected patients with recurrent malignant gliomas are associated with reasonable long-term survival and a low risk of complications. Given the low incidence of radiation necrosis, future plans are to increase dose rate and/or total dose delivered with the permanent implant.

Addition of chemotherapy to radiation therapy alters failure patterns by cell type within non-small cell carcinoma of lung (NSCCL): analysis of radiation therapy oncology group (RTOG) trials.

PURPOSE: To evaluate the influence of cell type within non-small cell carcinoma of lung (NSCCL) on failure patterns when chemotherapy (CT) is combined with radiation therapy (RT). METHODS AND MATERIALS: Data from 4 RTOG studies including 1415 patients treated with RT alone, and 5 RTOG studies including 350 patients also treated with chemotherapy (RT + CT) were analyzed. Patterns of progression were evaluated for squamous cell carcinoma (SQ) (n = 946), adenocarcinoma (AD) (n = 532) and large cell carcinoma (LC) (n = 287). RESULTS: When treated with RT alone, SQ was more likely to progress at the primary site than LC (26% vs. 20%, p = 0.05). AD and LC were more likely to progress in the brain than SQ (20% and 18% vs. 11%, p = 0.0001 and 0.011, respectively). No differences were found in intrathoracic and distant metastasis by cell type. When treated with RT + CT, AD was less likely to progress at the primary than either SQ or LC (23% vs. 34% and 40%, respectively; p = 0.057 and 0.035). AD was more likely than SQ to metastasize to the brain (16% vs. 8%, p = 0.03), and other distant sites (26% vs. 14%,p = 0.019). No differences were found in intrathoracic metastasis. LC progressed at the primary site more often with RT + CT than with RT alone (40% vs. 20%, p = 0.036). Death with no clinical progression was more likely with SQ than AD or LC for RT alone and RT + CT (p < 0.01). Brain metastasis was altered little by the addition of CT, but other distant metastases were significantly decreased (p < 0.001) in all cell types by the addition of CT. CONCLUSION: CT, although effective in reducing distant metastasis in all types of NSCCL, has different effects on the primary tumor by cell type, and has no effect on brain metastasis or death with no progression. Different treatment strategies should be considered for the different cell types to advance progress with RT + CT in NSCCL.

Failure patterns by prognostic group determined by recursive partitioning analysis (RPA) of 1547 patients on four radiation therapy oncology group (RTOG) studies in inoperable nonsmall-cell lung cancer (NSCLC).

PURPOSE: To identify groups of patients who might benefit from more aggressive systemic or local treatment, based on failure patterns when unresectable NSCLC was treated by radiation therapy (RT) alone. METHODS: From 4 RTOG trials, 1547 patients treated by RT alone were analyzed for patterns of first failure by RPA class defined by prognostic factors, including KPS, weight loss, nodal stage, pleural effusion, age and radiation therapy dose. All patients had NSCLC AJCC Stage II, IIIA, or IIIB, KPS > 50, with no previous RT or chemotherapy. Progressions in the primary (within irradiated fields), thorax (outside irradiated area, but within thorax), brain and distant metastasis other than brain were compared (2-sided) for each failure category by RPA. RESULTS: The RPA classes were 4 distinct subgroups that had significantly different median survivals of 12.6, 8.3, 6.3 and 3.3 months for Classes I, II, III and IV, respectively, (all groups, p = 0.0002). There were 583, 667, 249 and 48 patients in Classes I, II, III and IV, respectively. Primary failure was seen in 27%, 25%, 21% and 10% for Classes I, II, III, and IV, respectively (I vs. IV, p = 0.014; II vs. IV, p = 0.022). Distant metastasis, including brain metastasis, occurred at significantly higher rates among Classes I and II (58% and 54%) than in Classes III and IV (42% and 27%). A higher rate (58%) of death without an identifiable site of failure was found in Class IV than in Classes I, II and III (27%, 28% and 36%, respectively). CONCLUSIONS: The data suggest that physiologic compromise from the intrathoracic disease in Class IV patients is sufficient to cause death before specific sites of failure became evident. Clinical investigations using treatments directed at specific sites of failure could lead to improved outcome for Class I, II and, possibly, Class III patients. Inclusion of Class IV patients in clinical trials may obscure outcomes.