Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06.

PURPOSE: The recursive partitioning analysis (RPA) classes for malignant glioma patients were previously established using data on over 1500 patients entered on Radiation Therapy Oncology Group (RTOG) clinical trials. The purpose of the current analysis was to validate the RPA classes with a new dataset (RTOG 90-06), determine the predictive power of the RPA classes, and establish the usefulness of the database norms for the RPA classes. PATIENTS AND METHODS: There are six RPA classes for malignant glioma patients that comprise distinct groups of patients with significantly different survival outcome. RTOG 90-06 is a randomized Phase III study of 712 patients accrued from 1990 to 1994. The minimum potential follow-up is 18 months. The treatment arms were combined for the purpose of this analysis. There were 84, 13, 105, 240, 150, and 23 patients in the RPA Classes I-VI from RTOG 90-06, respectively. RESULTS: The median survival times (MST) and 2-year survival rates for the six RPA classes in RTOG 90-06 are compared to those previously published. The MST and 2-year survival rates for the RTOG RPA classes were within 95% confidence intervals of the 90-06 estimates for Classes I, III, IV, and V. The RPA classes explained 43% of the variation (squared error loss). By comparison, a Cox model explains 30% of the variation. The RPA classes within RTOG 90-06 are statistically distinct with all comparisons exceeding 0.0001, except those involving Class II. A survival analysis from a prior RTOG study indicated that 72.0 Gy had superior outcome to literature controls; analysis of this data by RPA classes indicates the survival results were not superior to the RTOG database norms. CONCLUSION: The validity of the model is verified by the reliability of the RPA classes to define distinct groups with respect to survival. Further evidence is given by prediction of MST and 2-year survival for all classes except Class II. The RPA classes explained a good portion of the variation in survival outcome in the data. Lack of correlation in RPA Class II between datasets may be an artifact of the small sample size or an indication that this class is not distinct. The validation of the RPA classes attests to their usefulness as historical controls for the comparison of future Phase II results.

Theoretical and practical uses of elective systemic (half-body) irradiation after 20 years of experimental designs.

This article traces the concept and different uses of systemic (Half-Body) irradiation (HBI) for the last 20 years. It presents both indirect and direct evidence of HBI effectiveness and discusses the various hypothesis that have been advanced to explain its success as a palliative and more recently as an elective therapeutic tool. The article discusses the transition from treating overt to subclinical metastatic disease and recalls the pioneer uses of elective HBI in lung and prostate cancers. Recent uses of elective HBI with a variety of unconventional fractionation schemes are discussed. These include clinical trials (51 patients with lung, esophagus, colorectal, prostate, ovary and endometrial cancers) and animal experiments (1195 C3H mice). An intriguing combination of hyper/hypo fractionated HBI proved to be the less toxic of all the schedules used in animals where mortality data, analyzed by the LQ Model, yielded an alpha/beta ratio of 8.3 Gy, a value generally associated with acutely responding tissue.

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.

Concurrent hyperfractionated irradiation and chemotherapy for unresectable nonsmall cell lung cancer. Results of Radiation Therapy Oncology Group 90-15.

BACKGROUND: Clinical trials of hyperfractionated radiation therapy and induction chemotherapy followed by standard radiation therapy have shown improved survival in patients with unresectable nonsmall cell lung cancer (NSCLC). Radiosensitization may improve local tumor control when chemotherapy is given concurrently with hyperfractionated radiation therapy, but also may increase toxicity. A Phase I/II trial, Radiation Therapy Oncology Group 90-15, was designed to evaluate whether this strategy could improve survival with acceptable toxicity and be part of a Phase III trial of chemoradiation sequencing. METHODS: Vinblastine (5 mg/M2 weekly x 5 weeks) and cisplatin (75 mg/M2 days 1, 29, and 50) were given during twice-daily irradiation (1.2 Gy, 6 hours apart) to 69.6 Gy in 58 fractions in 6 weeks. Eligible patients had American Joint Committee on Cancer (AJCC) Stage II (unresected) or IIIA-B NSCLC and Karnofsky performance status 70 or greater; there were no weight loss restrictions. RESULTS: Of 42 eligible patients, 76% had greater than 5% weight loss, 45% had T4 primary tumors, and 62% were Stage IIIB. All protocol treatment was completed in 53%. Acute toxicity was predominantly hematologic with 19 of 42 (45%) having Grade 4 toxicity or higher, three (7%) with septic death. Ten of 42 (24%) had Grade 3 or higher esophagitis. There were two (4.7%) patients with Grade 3 or higher (1 lung and 1 esophagus) and two (4.7%) with Grade 4 or higher (1 lung and 1 hematologic) late toxicities. Median survival time was 12.2 months, with an overall 1-year survival of 54%, an estimated 2 year survival of 28% and a 1-year progression free survival of 38%. CONCLUSIONS: For patients with unresectable nonsmall cell lung cancer, who were not selected on the basis of weight loss, concurrent hyperfractionated irradiation and chemotherapy had more intense acute toxicity than hyperfractionation alone, but late toxicity was acceptable. One and 2-year survival rates were 54 and 28%, respectively.

On the mechanism of radiation-induced emesis: the role of serotonin.

PURPOSE: The aim of this study was to determine the mechanism of action of radiation-induced emesis by determining the incidence of radiation-induced emesis following hemibody irradiation; the effects of specific antiemetics especially ondansetron, a 5-hydroxytryptamine receptor antagonist, and to determine the relationship between radiation-induced emesis and serotonin (5-hydroxytryptamine) through its active metabolite, 5-hydroxyindoleacetic acid (5-HIAA). METHODS AND MATERIALS: Forty-one patients received 53 hemibody treatments of 5-8 Gy following intravenous hydration. The patients were divided into three groups according to prehemibody irradiation treatment: Group A: no pretreatment antiemetics, 30 patients; Group B: nonondansetron antiemetics (metoclopramide, dexamethasone, prochlorperazine), ten patients; and Group C: ondansetron, 13 patients. The incidence of radiation-induced emesis was determined prehemibody irradiation or baseline and at 1 h posthemibody irradiation in 38 patients and the results expressed as the percent change in 5-HIAA (ng/ug creatinine). RESULTS: The incidence of radiation-induced emesis was 82% (14/17) following upper/mid hemibody irradiation and 15% (2/11) following lower hemibody irradiation in Group A; 50% (3/6) and 25% (1/4) following upper/mid and lower hemibody irradiation respectively, in Group B; and 0% (0/13) after upper/mid hemibody irradiation in Group C. The incidence of emesis was significantly different (p < 0.001) between the patients of Group A and C who received upper/mid hemibody irradiation. The percent change in 5-HIAA excretion following upper/mid hemibody irradiation were greatest in Group A and smallest in Group C (p < 0.002). The degree of change following lower hemibody irradiation (15% incidence of emesis) in Group A was lower than upper/mid hemibody irradiation of the same group. CONCLUSION: The higher incidence of radiation-induced emesis following upper and mid hemibody irradiation in antiemetic naive patients compared to the incidence following lower hemibody irradiation suggests that the critical organ responsible for radiation sickness is in the abdomen. The control of emesis by ondansetron, a 5-HT3 receptor antagonist, attests to the efficacy of ondansetron in radiation-induced emesis and suggests a role for serotonin in mediating radiation-induced emesis. Finally, the parallel changes in 5-HIAA and the incidence of emesis provides additional evidence for a more direct role for serotonin in radiation-induced emesis.

A prospective randomized comparison of radiation therapy plus lonidamine versus radiation therapy plus placebo as initial treatment of clinically localized but nonresectable nonsmall cell lung cancer.

PURPOSE: By means of a multicenter, prospective randomized, placebo-controlled study, to assess the impact of adding the radiation-enhancing agent lonidamine to standard "curative-intent" radiation therapy upon overall survival, progression-free survival, and local progression-free survival of patients with clinically localized but nonresectable nonsmall cell lung cancer. METHODS AND MATERIALS: Lonidamine, or the lonidamine-placebo, was administered at a dose of 265 mg/m2 in three divided daily doses. Drug therapy began 2 days prior to the initiation of radiation therapy and continued until progression of disease mandated a change in therapy. The radiation therapy dose was 55-60 Gy, at a daily dose of 1.8 Gy and five treatments per week. Patients with clinical Stage II or III nonsmall cell lung cancer were stratified within the treatment center, and within two histologic strata: epidermoid vs. other nonsmall cell cancers. RESULTS: A total of 310 patients were enlisted on study, 152 on the placebo arm and 158 on the lonidamine arm. The median survival durations were 326 days and 392 days for the placebo and lonidamine-treated groups respectively, p = 0.41 for a comparison of the survival curves. Median progression-free survival and median local progression-free survival durations were 197 days and 341 days for placebo + radiation therapy vs. 230 days and 300 days for lonidamine + radiation therapy; p-values for the respective curves were 0.75 and 0.42. Although there were proportionately more lonidamine-treated patients than placebo-treated patients demonstrating continued local control in excess of 12 months, the numbers of patients still at risk after 24 months were too small for meaningful statistical analysis. CONCLUSION: This multicenter Phase III study failed to demonstrate a significant advantage in the lonidamine-treated population in overally patient survival, in progression-free survival, or in the median duration of local control.

Radiation-induced emesis: effects of ondansetron.

The incidence, severity, and onset of radiation-induced emesis (RIE) are related to field size, site, and dose per fraction. Radiation-induced emesis can occur (1) within 2 to 3 weeks in approximately 50% of patients after conventional fractionated radiotherapy (200 cGy/fraction) to the upper abdomen, (2) acutely in more than 90% of patients receiving fractionated total body irradiation (TBI) for bone marrow transplantation, and (3) within 30 to 60 minutes in more than 80% of patients following single high-dose (> 500 cGy)/large field hemibody irradiation (HBI). The increased frequency of emesis associated with TBI and HBI has renewed the interest in the mechanism and treatment of RIE. A number of studies have reported a significant difference in the incidence of emesis following doses of > or = 500 cGy to the upper-mid (> 80%) and lower (20% to 40%) hemibody. The data suggested that the organ responsible for emetic response was in the upper abdomen. However, the mechanism of RIE is not well understood, although degradation products from normal tissues and tumor have been suggested. The introduction and effectiveness of the 5-hydroxytryptamine3 receptor antagonists in chemotherapy-induced emesis and the location of these receptors in the upper abdomen (possible site of the radiation-associated emetic response) suggested that this group of compounds may have a role in RIE. Lucraft and Palmer (Clin Radiol 33:621-622, 1982) reported no differences between levonantradol and chlorpromazine in preventing RIE in patients treated with single doses of more than 10 Gy to a small upper abdominal field. Priestman (Eur J Cancer Clin Oncol 25:529-533, 1989 [Suppl]) reported on a pilot and randomized study with ondansetron after single doses of 8 to 10 Gy to the upper abdomen. In the pilot study, ondansetron achieved major or complete control of vomiting in 77% to 90% of patients; subsequently, he reported a significant difference between ondansetron (97%) and metoclopramide (45%) in controlling RIE on the day of radiotherapy. Hewitt et al (Bone Marrow Transpl 7:431-433, 1991) reported a complete or major response on 93% of the days of ondansetron therapy during pretreatment therapy with cyclophosphamide and TBI for bone marrow transplantation. A preliminary analysis of 41 patients treated with HBI at the Rex Cancer Center confirms the role of ondansetron in RIE. Twenty-eight patients (upper-mid 16 patients/lower HBI 12 patients) did not receive pretreatment antiemetics (group A); seven received non-ondansetron pre-HBI (group B); and six received ondansetron (group C).(ABSTRACT TRUNCATED AT 400 WORDS)

Lonidamine in head and neck cancer: an overview.

Lonidamine (LNM) has been employed in the treatment of advanced head and neck cancer (H & N) primarily with radiotherapy. It has been proposed that LNM potentiates the effects of radiation by inhibiting repair of potentially lethal damage by interfering with the mitochondrial associated repair processes. In addition, LNM appears to be more effective with fractionated doses of radiotherapy, which in light of the current emphasis on hyper/accelerated fractionation schemes may make it more efficacious. Initial H & N studies comparing LNM treated patients to historical controls report a complete response (CR) rate of 65% versus 45% respectively. All major H & N sites were included. Subsequent nonrandomized Phase II studies, although containing small numbers of patients, showed LNM to be ineffective as a single agent in patients previously treated with chemotherapy and not significantly different when radiotherapy was given with conventional dose rates. In a randomized Phase III study in which patients received an accelerated radiotherapy schedule (150 cGy bid) with either lonidamine or placebo, the CR rate was not significantly different, however, the local regional control rate was 48% versus 25% in favor of the LNM group. In addition, the 3 and 5 year duration of resonse (44% and 42% versus 26% and 17%) was improved in the LNM group. However, the 3-year actuarial survival rate was not different (49% v 43%). In summary the role of LNM as a radiopotentiator in advanced head and neck cancer appears to improve the local control rate, although survival was not significantly changed. However, future studies employing hyperfractionation schemes may show that the improved local control rate will translate into improved survival.

Overlap of nuclear diameters in lung cancer cells.

The nuclear diameters (NDs) of randomly selected malignant cells from 35 cases of small-cell lung cancer (SCLC; 4,370 nuclei) and 31 cases of non-SCLC (NSCLC; 1,280 nuclei) were measured on the pretreatment tissue sections by ocular micrometry. The mean ND (+/- standard deviation) of malignant cells for SCLC patients was 8.1 +/- 1.5 microns; these cases included 23 oat-cell carcinomas and 12 intermediate-cell carcinomas. The ND of malignant cells for NSCLC patients was 12.8 +/- 2.2 microns; these cases included 17 squamous-cell carcinomas, 12 adenocarcinomas and 2 large-cell carcinomas. The differences of ND between SCLC and NSCLC and between intermediate-cell cancer and NSCLC were highly significant (P = 0.001). However, the malignant cells of 36 (54.5%) of the 66 lung cancer patients had NDs that overlapped in the range of 8 microns to 13 microns. For the 12 intermediate-cell patients, the NDs of the malignant cells overlapped with those of 8 (66.7%) of the 12 adenocarcinomas and 10 (58.8%) of the 17 squamous carcinomas. In contrast, the NDs of only 5 (21.7%) of the oat-cell patients overlapped with those of 5 (41.7%) of the 12 intermediate-cell cases and showed no overlap with NSCLC cases. Since there is overlapping of the nuclear diameters of malignant cells between SCLC and NSCLC patients, nuclear parameters other than the diameter are necessary to differentiate these two major histologic types of lung cancers.

Implications of nuclear diameter in small cell lung carcinoma.

The nuclear diameter of 5,117 malignant cells from 42 small cell lung carcinoma (SCLC) patients was assessed either on pretreatment tissue sections (35 cases) or cytologic smears (7 cases) by ocular micrometry. The SCLCs were subtyped as 30 oat cell carcinomas and 12 intermediate cell carcinomas according to the World Health Organization classification, based on the predominant histology of the tumor. The median number of nuclei measured from each patient was 110. All patients were treated identically by sequential hemibody and local irradiation combined with chemotherapy and had a median follow-up time of 310 days. The mean nuclear diameter (+/- standard error) obtained from tissue sections was 8.2 +/- 0.03 microns (median = 8.0), including 7.3 +/- 0.03 microns (median = 7.0) for oat cell cases and 9.5 +/- 0.06 microns (median = 9.0) for intermediate cell cases (P less than .001). In 28.6% of these patients, the nuclear diameter overlapped in the range of 8 microns to 9 microns between both subtypes. Comparisons between the nuclear diameter of primary and metastatic SCLC cells revealed no statistically significant differences. The nuclear diameter of malignant cells correlated with the mitotic index and stage of disease, but did not correlate with the other nuclear morphologic variables or with survival. The only identified prognostic factor was the stage of disease; these results indicate that the nuclear diameter of malignant cells should not be considered a prognosticator or a guide for therapy in SCLC patients.

Implication of nuclear morphological characteristics in small cell lung cancer.

We report the pretreatment quantitative nuclear morphological findings of malignant cells from 42 patients with small cell lung cancer (SCLC) to evaluate their impact on the stage of disease, therapeutic response and survival as well as their interrelationships. The variables analysed were nuclear configuration, distinction of nuclear membrane, chromatin and its distribution, mitotic index and nucleolar index. All patients were treated uniformly with chemotherapy and hemibody irradiation. The series consisted of 30 OAT cell cancers and 12 intermediate cell cancers, according to the World Health Organization histological subclassification of SCLC. The morphological analysis used histological (n = 35) and cytological (n = 7) slides from either primary (n = 30) or metastatic (n = 12) tumors. A total of 5117 cancer nuclei (median = 110 per patient) were assessed. The SCLC subtype was significantly associated with a specific nuclear chromatin pattern, mitotic index and stage of disease. However, none of the evaluated nuclear morphological variables or the SCLC subtypes had therapeutic or survival impact. The stage of disease was the only factor which significantly correlated with the survival of SCLC patients.

Concurrent chemotherapy and single high-dose plus whole abdominopelvic radiation for persistent ovarian carcinoma.

Twenty-two patients were treated with concurrent single high-dose and standard fractionated abdominopelvic radiation and chemotherapy (cisplatin or hexamethylmelamine). Those who had prior cisplatin received hexamethylmelamine and radiation (16 patients) while those without prior cisplatin received cisplatin and radiation (6 patients). The primary aim of the study was to assess the tolerance and effectiveness of concurrent radiation and chemotherapy in patients who had failed prior chemotherapy. All patients experienced mild to moderate nausea, vomiting, and diarrhea. Hematologic adverse effects were minimal. Three patients requiring laparotomy for radiation induced small bowel obstruction had confirmed complete responses but 2 died acutely of treatment-related complications without evidence of tumor. In the 15 patients with suboptimal disease (greater than 1 cm residual disease) prior to the study, only 1 had a complete response while 2 of 7 optimal patients (less than or equal to 1 cm residual disease) had a complete response. All 3 complete responders received cisplatin and 2 had 1 cm or less of residual disease prior to the study. In the hexamethylmelamine group 3 of 16 patients had a partial response. Concurrent single high-dose whole abdominopelvic radiation and cisplatin may be effective in patients with minimal disease (less than or equal to 1 cm); however, radiation-associated bowel complications were severe.

Morphometric and morphologic evaluations in stage III non-small cell lung cancers. Prognostic significance of quantitative assessment of infiltrating lymphoid cells.

This study evaluated data from 30 non-small cell lung cancer (NSCLC) patients to determine whether demographic, clinical, and morphologic and morphometric data that were obtained prior to treatment, could be used to predict survival. All patients had Stage III disease, and all subsequently were treated identically with concurrent radiotherapy, cisplatin, and 5-fluorouracil. The series consisted of 18 squamous carcinomas, eight adenocarcinomas, and four large cell carcinomas. Morphometric measurements of randomized selected cancer cells per case included diameter of cytoplasm, nuclei, and nucleoli. Morphologic parameters evaluated were mitotic index, histologic differentiation, and pattern of nuclear chromatin of cancer cells, and the degree of necrosis and fibrosis of tumor tissue. The lymphoid and neutrophil index defined as the ratio of lymphoid cells and neutrophils to cancer cells from randomized microscopic fields (median = 25) at 400 x magnification were also determined. Our study indicated that the peritumor lymphoid index was the only factor significantly associated with the length of survival. The correlation coefficient (Pearson r) of these two factors was 0.5 (P less than 0.005). The median survival time of patients with peritumor lymphoid index less than 3 and greater than or equal to 3 was 95 days and 376 days, respectively (Kaplan-Meier estimation). The peritumor lymphoid index was an independent prognosticator of clinical outcome of Stage III NSCLC patients, and did not correlate with any of the other parameters analyzed.

Single high dose-large field irradiation in drug resistant non-Hodgkin's lymphoma.

Single high dose-large field irradiation (SHD-LFI), also described as half-body irradiation (HBI), has previously been reported as an effective modality for the palliation of symptoms in a number of solid tumors. This report concerns the ability of SHD-LFI to produce palliation of symptoms and/or objective response in patients with drug resistant non-Hodgkin's lymphoma (NHL). From 1981 to 1984, 34 patients with advanced drug resistant NHL were treated with SHD-LFI either to the whole abdomen (24 patients) or to the upper half body (10 patients). Overall, 19 of 23 patients achieved symptomatic improvement, while objective response was noted in 23 of 30 patients. We noted subjective and objective response in all histologies, and duration of response was not significantly different. Our results suggest a beneficial role for the early and judicious use of SHD-LFI in NHL.

Sequential hemibody irradiation integrated into a chemotherapy-local radiotherapy program for limited disease small cell lung cancer.

Twenty-four patients with limited disease small cell lung cancer (SCLC) were treated with sequential hemibody irradiation (SHB) integrated into a conventional chemotherapy-local radiotherapy (LRT) program. Among 23 evaluable patients, 12 (52%) attained a complete response (CR) and 8 (35%) attained a partial response for an overall major response rate of 87%. The median time since study entry is 29 months. Durations of response are 9.9 months for all patients and 16.5 months for patients who achieved a CR. The primary site was the predominant area of recurrence. The median survival is 13.2 months for all patients and 23.2 months for the 12 patients who attained a CR. Myelosuppression, especially thrombocytopenia, was the major toxicity. Acute radiation toxicities and subacute pneumonitis previously associated with hemibody radiotherapy were well controlled or prevented using the current dose, premedication, and shielding techniques. This integrated program of systemic therapies with SHB and combination chemotherapy plus LRT is feasible for limited disease SCLC; it may prolong survival in patients who attain a CR but compared to similar programs without hemibody irradiation, there was no improvement in overall response rate, response duration, or survival.

Residual adriamycin (AdR)-induced hematopoietic damage: a consideration for subsequent radiotherapy.

The long-term effect of adriamycin (AdR) on the radiation response of hematopoietic marrow was studied at 16 weeks after treatment with a MTD (10 mg/kg) for the BDF1 mouse. The radiation response was monitored in both the "stem cell" (CFUs-8) and myeloid (CFU-gm, granulocyte, WBC) compartments, as well as the erythroid (BFUe, CFUe, HcT) compartments of the marrow for 14 days following a whole body dose (TBI) of 4.5 Gy X ray. At the time of irradiation, animal and spleen weight of AdR treated animals were reduced while HcT and WBC remained at control levels. At the same time the granulocyte and CFUs-8d compartments were depressed, while the BFUe compartment was expanded. The CFUe and CFU-gm compartments remained at control levels. For all marrow compartments, treatment with AdR 16 weeks prior to 4.5 Gy resulted in a radiation response deficit determined from the temporal recovery curves. The data suggest that manifestation of long-term AdR injury, at least through 16 weeks following treatment, is dependent on a subsequent stress of sufficient magnitude to enhance the proliferative activity associated with hematopoietic cell production and differentiation. A comparison is made between these observations and previously reported long-term drug-induced hematopoietic injury.