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Late tissue changes after low dose rate total body irradiation

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  • Proceedings of the 1st Annual ASTRO Meeting




    E. L. Travis, J. McNei12, C. Karolis3, and L.J. Peters

    Division of Radiotherapy,3M.D. Anderson Hospital, Houston, TX 77030; Australian Atomic Energy Commission, Lucas Heights, New South Wales; Department of Physics, Prince of Wales Hospital, Randwick, New South Wales.

    Pulmonary complications are generally accepted to be dose-limiting in the treatment of malignant and nonmalignant hemopoietic diseases with total body irradiation (TBI). However, other factors such as prior chemotherapy or graft vs. host disease may contribute to the incidence of radiation pneumonitis. In a study to determine the effect of dose rate on late nonhemopoietic deaths after TBI of mice, complete necropsies were performed on all long term survivors (I yr.), as well as on any animals dying during the study to determine if histological signs of damage were evident in tissues other than the lung. A range of total doses was given to the whole body of mice at dose rates ranging from I to 25 rads/min. Bone marrow was reconstituted to avoid deaths from bone marrow syndrome. No histological changes were observed in the stomach, large or small intestine, rectum, or brain. However, lung, kidney, and liver all showed histological signs of injury. There were a wide range of changes observed in the lung including fatal scarring, nodular lymphocytic infiltrate, and emphysematous-like bullae. Tubule depletion and degeneration characterized the changes in the kidney with no evidence of glomerular damage. Mitotic figures in the liver of irradiated mice indicated a regenerative response. Dose response curves were obtained for the lung and kidney by scoring the proportion of mice with any of the histological changes and plotting these as a function of dose for each dose rate. These curves showed that sparing of damage continued down to dose rates of I rad/min. in both tissues. In addition, it was clear that the kidney was not spared more than the lung after any given dose rate. These data suggest, then, that in addition to the lung, which is dose-limiting after TBI, other normal tissues such as liver and kidney may also be dose-limiting.

    These studies were supported in part by grant CA-06294, awarded by the NCI.


    Bruce F. Kimler, P.G. Shankar Giri, Uma P. Giri, and Gail G. Cox.


    Radiation Biology Laboratory, Department of Radiation Therapy, University of Kansas Medical Center, Kansas City, KS.

    One problem with the use of combined modality therapy (radiation therapy and chemotherapy) for the treatment of neoplastic disease in the chest is that of delayed pulmonary toxicity. Damage to the lungs can be quite severe when a chemotherapy combination that itself produces pulmonary toxicity is combined with thoracic irradiation. In an attempt to document the potential complications that might accrue from the use of radiation therapy and cancer chemotherapy, we have utilized the rat lung damage model to investuate a number of chemotherapeutic agents that have been implicated as contributing to the development of pulmonary problems and/or as promoting the development of radiation-induced pneumonitis or fibrosis. The drug6 that were studied were BCNU, Cyclophosphamide (CTX), Mitomycin-C (MC), cis-Platinum (cis-Pt), and Vincristine (VCR). Male CFl rats were irradiated with single doses of 12, 15. or 18 Gy to the thoracic cavity using a Cesium-137 source irradiator at a dose rate of 10 Gy/min. Rats were immobilized without the use of anesthesia during irradiation by a restraint device that permitted irradiation of a 4 cm field that encompassed the entire thorax but spared the abdomen. The following drug doses were given as single treatments or were combined with 12 Gy thoracic irradiation: BCNU, 15 mg/kg; CTX, 25 mg/kg; MC, 1.0 mg/kg; cis-Pt. 2.0 nlgtkg; and VCR, 0.5 z&g. Assessment of normal tissue damage included survival, physiological, histological, and morphological changes. At day 365 after initiation of treatment, survival levels in all groups (other that the 18 Gy group where survival was 16%) were equal to or greater than 70%. However, histolugical examination of lung tissues as early as 100 days after treatment revealed an enhancement of damage in several drug combination treatment groups (BCNU, MC, CTX) compared to the drug only groups, the 12 Gy, or the 15 Gy groups. We conclude that, in the rat lung model, a number of chemotherapy agents in combination with a thoracic dose of 12 Gy produce no more acute lethality than does 12 Gy alone. However, histological effects as evidenced by deposition of collagen and development of fibrosis are significantly increased by the addition of BCNU. Mitomycin-C, and Cytoxan. Thus. these cancer chemotherapeutic agents have the ability to potentiate radiation-induced lung damage at the tissue level and this fact should be considered when designing combined modality treatment regimens where radiation therapy encompasses the chest.

    Supported in part by grant number CA 29017 from NIH, DHHS.


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