Eileen W. Bradley

Radiobiological comparison of external beam irradiation and radioimmunotherapy in renal cell carcinoma xenografts.

Growth delay was measured in TK-82 renal cell carcinoma (RCC) xenografts implanted in nude mice receiving single fraction external beam irradiation (SF-XRT), multifraction external beam irradiation (MF-XRT), or radioimmunotherapy (RIT). Thermoluminescent dosimeter(s) (TLD) and autoradiography were used to ascertain the average absorbed dose delivered and the degree of heterogeneous uptake of radiolabeled antibody for the RIT irradiations. For intravenous administered activities of 100, 200, 400, and 600 microCi of I-131 labeled A6H antibody, volume doubling times (VDT) and TLD absorbed dose measurements for each administered activity were 7 days (341 cGy), 38 days (383 cGy), 85 days (886 cGy) and no regrowth (1034 cGy), respectively. For SF-XRT irradiations of 500, 1000, and 1500 cGy, VDT times were 11, 62, and 103 days, respectively. MF-XRT of 4 X 250 cGy over a 2-week period yielded a VDT of 25 days. Marked peripheral activity deposition was noted on most autoradiographs from multiple tumor samples. These data suggest that an equivalent to superior tumor growth delay is obtained for absorbed doses delivered by exponentially decaying low dose rate radioimmunotherapy RIT compared to similar doses of acute dose rate XRT as quantitated by the TLD method.

Coronary arteriosclerosis and arterosclerosis in fast neutron or photon irradiated dogs

Abstract Thirty-nine adult male beagles received either fast neutron or photon irradiation to the right thorax to obtain values for the relative biological effectiveness (RBE) of fast neutrons as assessed by quantitative parameters of lung function. Fast neutrons (15 MeV avg.) were delivered in 4 fx/wk for six weeks to total doses of 1000, 15010, 2250 or 3375 rad while the photon irradiated dogs received total doses of 3000, 4500 or 6750 rad in the same fractionation schedule. The right atrium and coronary groove of the heart were included in the irradiated field. Cholesterol levels (and triglyceride levels when obtainable) were measured prior to irradiation and every three months until death. Arteries were graded (0, negative to 5, severe) for endothelial proliferation, disruption and duplication of the elastic lamina, perivascular fibrosis and the presence of foamy macrophages. All dogs that survived 75 days post-irradiation developed arterial changes; two neutron irradiated dogs showed severe atherosclerotic plaque formation. Data suggest an RBE between 4 and 5.

Clinical observations of early and late normal tissue injury and tumor control in patients receiving fast neutron irradiation

Abstract The clinical experience of the first 211 patients treated at MANTA from October 1973 to May 1978 is described. Acute cutaneous, mucosal, gastrointestinal reactions and late effects including myelitis, damage to brain, bowel, soft tissue and mandibular necrosis are described. A review of tumor response data is also submitted.

Clinical observations of early and late normal tissue injury in patients receiving fast neutron irradiation

This communication describes early and late normal tissue effects in 177 patients treated totally or in part by 15 MeV neutrons from the Naval Research Laboratory Cyclotron in Washington, D.C. between October 1973 and December 1976. Late normal tissue reactions were found to be greater than would be expected from careful observation of the early clinical responses to neutron treatment. Neutron prescriptions must be written based on the late effect tolerance level experience which is being accumulated at several neutron therapy facilities.

Pathologic Findings in Canine Brain Irradiated with Fractionated Fast Neutrons or Photons

Thirty-seven adult male purebred beagles received total doses of 1333, 2000, 3000, or 4500 rad of fast neutrons (15 MeV av) in 4 fractions/week for 7 weeks to the entire brain. Nineteen dogs received 4000, 6000, or 9000 rad of photons (/sup 60/Co) in an identical fractionation pattern. Dogs receiving 4500, 3000, and 2000 rad of neutrons and 9000 rad of photons developed neurologic signs and died or were euthanatized when moribund followed irradiation. Cerebrospinal fluid contained excess protein and erythrocytes during and sometimes before the generally brief course. The onset of neurologic symptoms was usually followed by a moribund state in less than 48 h. The relative biological effectiveness (RBE) as measured by onset of neurologic symptoms and mortality was greater than 4.5. Gross changes included hemorrhage, edema, and malacia primarily in the white matter, especially the corona radiata, cerebellar white matter, corpus callosum, and corpus fornicis. One beagle developed a brain tumor and died 1207 days following 1333-rad neutron irradiation.

Effects of fractionated doses of fast neutrons and photons on the normal canine lung: relative biological effectiveness values obtained by radionuclide studies.

Abstract Thirty nine adult male beagles received either fast neutron or photon irradiation to the right thorax. There were 2 unirradiated control dogs. Twenty four dogs received fast neutrons with a mean energy of 15 MeV to total doses of 1000, 1500, 2250 or 3375 rad delivered in 4 fx/wk for 6 weeks. Fifteen dogs received total doses of 3000, 4500 or 6750 rad of photons ( 60 Co) in the same fractionation pattern. Radionuclide evaluations of pulmonary function were performed pre-irradiation and every three months post-irradiation for 1 year. These included: (1) radioaerosol deposition of an insoluble radiocolloid, 99m Tc-phytate; (2) 133 Xe ventilation studies; and (3) 99m Tc-macroaggregated albumin perfusion images. Values for the relative biological effectiveness (RBE) of fast neutrons in producing changes in these parameters have been obtained by plotting the changes from pre-irradiation values in the right lung as a function of the total dose. RBE values for the relative deposition of aerosol and the relative distribution of volume and perfusion have been obtained at 3, 6, 9 and 12 months post-irradiation. The relative biological effectiveness (RBE) for neutron damage to normal lung tissue was always greater than 4 in the clinical dose range of 4000–6000 rad of photons.

Pathologic effects of fractionated fast neutrons or photons on the pancreas, pylorus and duodenum of dogs

Thirty-nine adult male Beagles received either fast neutron or photon irradiation to the right thorax to determine the relative biological effectiveness (RBE) of fast neutrons on normal pulmonary tissue. The right anterior abdomen was included in the field of radiation. Twenty-four dogs (six/group) received fast neutrons with an average energy of 15 MeV to total doses of 1000, 1500, 2250 or 3375 rad in four fractions per week for six weeks. Fifteen dogs received 3000, 4500 or 6750 rad of photons (five/group) in an identical fractionation pattern. All neutron irradiated dogs receiving 3375 and 2250 rad and one receiving 1500 rad developed clinical signs of pancreatic, hepatic and gastrointestinal disturbances. The liver enzymes of these dogs became elevated and they died or were euthanatized in extremis 47-367 days after irradiation. Only one 6750 rad photon dog developed similar signs and died 708 days post-irradiation. Five neutron and 10 photon exposed dogs died of other causes. Neutron-induced lesions in the stomach and duodenum included hemorrhages, erosions, ulcerations and fibrosis. Ulcers perforated the GI tract of five dogs. Pancreatic lesions included degranulation and necrosis of acinar cells, fibrosis ans atrophy. Islet cells were not obviously damaged. All lesions were associated with degenerative and occlusive vascular changes. The RBE of fast neutrons, assessed by clinical signs, gross and microscopic pathology, is approximately 3-4.5 for pancreas and about 4.5 for pylorus and duodenum.

Radionuclide Evaluation of Pulmonary Function Following Hemithorax Irradiation of Normal Dogs with 60Co or Fast Neutrons

To assess the effects of therapeutic doses of radiation on regional pulmonary function, 28 dogs had serial chest radiographs and quantitative ventilation, perfusion, and aerosol studies at three-, six-, nine-, and twelve-month intervals after hemithorax irradiation with 60-Co-gamma photons or 15-MeV fast neutrons. Findings showed marked reductions in perfusion and aerosol deposition in the irradiated lungs of dogs in the high-dose photon and neutron groups and in the medium-dose neutron group. The effects of large photon and small neutron doses were similar (neutron RBE = 4.5). Radionuclide studies were found to be useful for detecting these alterations.

The effects of fractionated doses of fast neutrons or photons on the canine brain: Evaluation by computerized tomography and evoked response recording

Abstract The use of fast neutrons in the treatment of cancer necessitates a knowledge of the normal tissue responses. This study was designed to compare the late effects of fractionated doses of fast neutrons with fractionated doses of photons on canine brains by evoked response recording and viewing computerized tomograms (CT). Adult male beagles were irradiated to the entire brain (four fractions per week) with fast neutrons to total doses of 13.33 Gy (1333 rad), 20 Gy (2000 rad), 30 Gy (3000 rad) or 45 Gy (4500 rad) or with photons (four fractions per week) to total doses of 40 Gy (4000 rad), 60 Gy (6000 rad) or 90 Gy (9000 rad). A relative biological effectiveness (RBE) of 4 was obtained for normal brain tissue assessed by mortality and onset of neurologic symptoms. Every three months post-irradiation, visual and sensory evoked responses were recorded. Changes over time appeared to be minimal; however, computerized tomographs showed marked brain shrinkage. A method of quantitating cerebrospinal fluid and parenchyma) volumes from scans is described and future use of these CT ratios to generate dose response curves and RBE values is postulated.

The Effects of Fractionated Doses of Fast Neutrons or Photons on the Canine Cervical Spinal Cord

The cervical spinal cords of 36 young adult male beagles were irradiated with fast neutrons with a mean energy of 15 MeV in four fractions/week/5 weeks to total doses of 1167, 1750, 2625, or 3938 rad. Nineteen beagles received 3500, 5250, or 7875 rad of photons in like manner. Sensory evoked responses recorded before and periodically after irradiations remained stable on 22 test and 6 control dogs. The cerebrospinal fluid contained excess protein and erythrocytes often before and always after the onset of neurological symptons. All dogs in the 3938-rad neutron, 6/9 dogs in the 2625-rad neutron, and 4/6 dogs in the 7875-rad photon groups developed cervical muscular spasms, incoordination, and progressive paralysis and were euthanatized. The relative biological effectiveness of fast neutrons as measured by the onset of neurological signs is approximately 3 (7875 photons/ 2625 neutrons) and is less than 4.5 (7875 photons/1750 neutrons). Gross pathological findings included hemorrhages, softening, and poliomyelomalacia, especially of the dorsal horns. Two dogs developed neoplasms in the irradiated field 1065 and 1470 days following neutron irradiation.