J.W. Hopewell

Fluoroscopically guided interventional procedures: a review of radiation effects on patients' skin and hair.

Most advice currently available with regard to fluoroscopic skin reactions is based on a table published in 1994. Many caveats in that report were not included in later reproductions, and subsequent research has yielded additional insights. This review is a consensus report of current scientific data. Expected skin reactions for an average patient are presented in tabular form as a function of peak skin dose and time after irradiation. The text and table indicate the variability of reactions in different patients. Images of injuries to skin and underlying tissues in patients and animals are provided and are categorized according to the National Cancer Institute skin toxicity scale, offering a basis for describing cutaneous radiation reactions in interventional fluoroscopy and quantifying their clinical severity. For a single procedure performed in most individuals, noticeable skin changes are observed approximately 1 month after a peak skin dose exceeding several grays. The degree of injury to skin and subcutaneous tissue increases with dose. Specialized wound care may be needed when irradiation exceeds 10 Gy. Residual effects from radiation therapy and from previous procedures influence the response of skin and subcutaneous tissues to subsequent procedures. Skin irradiated to a dose higher than 3-5 Gy often looks normal but reacts abnormally when irradiation is repeated. If the same area of skin is likely to be exposed to levels higher than a few grays, the effects of previous irradiation should be included when estimating the expected tissue reaction from the additional procedure.

Radiation-therapy effects on bone density.

Only limited data are available on the effects of radiation-therapy on the mineral content of the bone of children treated for malignancy. The incidence of osteopenia varies between 8 and 23%, but confounding factors were the use of chemotherapy and the effects of prophylactic cranial irradiation. The factors influencing bone atrophy are no more clearly defined in adults treated for cancer by high dose local radiation-therapy. Pathological observed in patient tissues, indicates a clear role for vascular changes in the development of osteopenia, although there remains some uncertainty as to the effects of osteoblast cell loss. Reduced blood flow in bone is clearly dose-related in experimental animal studies and after single doses of >20 Gy changes in bone mineral content have been found. However, this was only at late times (≥30 weeks) after irradiation. The relationship between these changes and bone strength remains unproven because of the limited nature of many of the animal studies. Radiation dose fractionation data for rib-fracture in breast cancer patients suggests an α/β ratio is in the range 1.8–2.8 Gy, comparable to values obtained for other late responding normal human tissues. Med Pediatr Oncol 2003;41:208–211.

Late effects of radiation on the central nervous system: role of vascular endothelial damage and glial stem cell survival.

Abstract Coderre, J. A., Morris, G. M., Micca, P. L., Hopewell, J. W., Verhagen, I., Kleiboer, B. J. and van der Kogel, A. J. Late Effects of Radiation on the Central Nervous System: Role of Vascular Endothelial Damage and Glial Stem Cell Survival. Radiat. Res. 166, 495–503 (2006). Selective irradiation of the vasculature of the rat spinal cord was used in this study, which was designed specifically to address the question as to whether it is the endothelial cell or the glial progenitor cell that is the target responsible for late white matter necrosis in the CNS. Selective irradiation of the vascular endothelium was achieved by the intraperitoneal (ip) administration of a boron compound known as BSH (Na2B12H11SH), followed by local irradiation with thermal neutrons. The blood-brain barrier is known to exclude BSH from the CNS parenchyma. Thirty minutes after the ip injection of BSH, the boron concentration in blood was 100 μg 10B/ g, while that in the CNS parenchyma was below the detection limit of the boron analysis system, <1 μg 10B/g. An ex vivo clonogenic assay of the O2A (oligodendrocyte-type 2 astrocyte) glial progenitor cell survival was performed 1 week after irradiation and at various times during the latent period before white matter necrosis in the spinal cord resulted in myelopathy. One week after 4.5 Gy of thermal neutron irradiation alone (approximately one-third of the dose required to produce a 50% incidence of radiation myelopathy), the average glial progenitor cell surviving fraction was 0.03. The surviving fraction of glial progenitor cells after a thermal neutron irradiation with BSH for a comparable effect was 0.46. The high level of glial progenitor cell survival after irradiation in the presence of BSH clearly reflects the lower dose delivered to the parenchyma due to the complete exclusion of BSH by the blood-brain barrier. The intermediate response of glial progenitor cells after irradiation with thermal neutrons in the presence of a boron compound known as BPA (p-dihydroxyboryl-phenylalanine), again for a dose that represents one-third the ED50 for radiation-induced myelopathy, reflects the differential partition of boron-10 between blood and CNS parenchyma for this compound, which crosses the blood-brain barrier, at the time of irradiation. The large differences in glial progenitor survival seen 1 week after irradiation were also maintained during the 4–5-month latent period before the development of radiation myelopathy, due to selective white matter necrosis, after irradiation with doses that would produce a high incidence of radiation myelopathy. Glial progenitor survival was similar to control values at 100 days after irradiation with a dose of thermal neutrons in the presence of BSH, significantly greater than the ED100, shortly before the normal time of onset of myelopathy. In contrast, glial progenitor survival was less than 1% of control levels after irradiation with 15 Gy of thermal neutrons alone. This dose of thermal neutrons represents the approximate ED90–100 for myelopathy. The response to irradiation with an equivalent dose of X rays (ED90: 23 Gy) was intermediate between these extremes as it was to thermal neutrons in the presence of BPA at a slightly lower dose equivalent to the approximate ED60 for radiation myelopathy. The conclusions from these studies, performed at dose levels approximately iso-effective for radiation-induced myelopathy as a consequence of white matter necrosis, were that the large differences observed in glial progenitor survival were directly related to the dose distribution in the parenchyma. These observations clearly indicate the relative importance of the dose to the vascular endothelium as the primary event leading to white matter necrosis.

Microvasculature and Radiation Damage

The association between late damage in irradiated tissues and the vasculature was reported shortly after the discovery of X-rays. Gross blood vessel abnormalities were a consistent finding in radiation-damaged tissues (Gassmann 1899; Muhsam 1904). Since then there have been numerous pathology reports emphasizing the significance of vascular damage in association with late radiation effects. This led to a hypothesis, to a major degree conceived by Rubin and Casarett (1968), that the vascular system was the main target for late radiation damage in normal tissues, the effects seen being related to vascular insufficiency. Although the validity of this hypothesis has been correctly challenged (Withers et al. 1980), there is still sufficient evidence to implicate the slowly dividing cells in the walls of blood vessels as the target cell populations in the pathogenesis of late radiation effects. Most recently, research related to radiation effects on the vasculature has focused on radiation-induced modifications in endothelial cell clonogenic survival and time-related changes in endothelial cell number. In addition, within the last decade, modifications in endothelial cell function have become more fully understood. Some of the most recent findings have raised the possibility of treating the endothelial-cell-mediated effects, leading to the amelioration of late radiation damage in normal tissues.

Late behavioural and neuropathological effects of local brain irradiation in the rat

The delayed consequences of radiation damage on learning and memory in rats were assessed over a period of 44 weeks, commencing 26 weeks after local irradiation of the brain with single doses of X-rays. Doses were set at levels known to produce vascular changes alone (20 Gy) or vascular changes followed by necrosis (25 Gy). Following T-maze training, 29 weeks after irradiation, irradiated and sham control groups performed equally well on the forced choice alternation task. When tested 35 weeks after irradiation, treated rats achieved a much lower percentage of correct choices than controls in T-maze alternation, with no difference between the two irradiated groups. At 38-40 weeks after irradiation, rats receiving both doses showed marked deficits in water maze place learning compared with age-matched controls; performance was more adversely affected by the higher dose. The extent of impairment was equivalent in the two groups of rats irradiated with 25 Gy, those trained or not previously trained in the T-maze, suggesting that water maze acquisition deficits were not influenced by prior experience in a different spatial task. In contrast to water maze acquisition, rats irradiated with 20 Gy showed no deficits in working memory assessed in the water maze 44 weeks after irradiation, whereas rats receiving 25 Gy showed substantial impairment. Rats receiving 25 Gy irradiation showed marked necrosis of the fimbria and degeneration of the corpus callosum, damage to the callosum occurring in animals examined histologically 46 weeks after irradiation, but in only a third of the animals examined at 41 weeks. However, there was no evidence of white matter necrosis in rats irradiated with 20 Gy, examined 46 weeks after irradiation. These findings demonstrated that local cranial irradiation with single doses of 20 and 25 Gy of X-rays produced delayed impairment of spatial learning and working memory in the rat. The extent of these deficits appears to be task- and dose-related, since rats treated with 25 Gy showed marked impairments in all measures, whereas rats treated with the lower dose showed less impairment in water maze learning and no deficits water maze working memory, despite significant disruption of working memory in the T-maze. The findings further suggest that although high dose irradiation-induced white matter necrosis is associated with substantial impairment, cognitive deficits may also be detected after a lower dose, not associated with the development of necrosis.

Reduced cardiotoxicity of doxorubicin given in the form ofN-(2-hydroxypropyl) methacrylamide conjugates: an experimental study in the rat

SummaryA rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of threeN-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg;P<0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of ≈30% in function beginning at the 4th week after drug administration. The heart rate in these animals was ≈12% lower than that measured in age-matched control rats (P<0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P<0.05). In addition, no significant histological change was observed in the hearts of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P<0.01). This study demonstrates that covalent binding of DOX to HPMA copolymer conjugates via both stable and biodegradable peptidyl linkages considerably reduces both the general acute toxicity and the late cardiotoxicity of DOX in the rat and could offer the potential for improving the therapeutic index in the clinical application of DOX.

Excess late subcutaneous fibrosis after irradiation of pig skin, consequent upon the application of the NSD formula

Abstract The development of subcutaneous fibrosis after X irradiation in courses of 1, 6 or 30 fractions has been studied quantitatively in the domestic pig. The NSD formula fails to predict the correct variation in dose for changes in the number of fractions so as to produce comparable levels of connective tissue damage even over the clinically used range from 6f./18d. to 3Of./39d.; the error in the prediction may amount to an excess dose of circa 30 per cent. The slope the iso-effect curve between 6 and 30 fractions is 0·46, compared with the combined fractionation and time factors of 0·33 in the NSD formula. The degree of late fibrosis did not correlate with the severity of the early skin reaction. The results suggest that the NSD formula is not suitable for use when planning new treatment schedules in which the number of dose fractions is reduced.

Volume effects in radiobiology as applied to radiotherapy

PURPOSE To explore the radiobiological evidence for a dependence of normal tissue complication probability on irradiated normal tissue volume. MATERIALS AND METHODS Data from experimental studies on the volume effect in different organs, using different criteria of structural or functional organ damage and in different animals, were evaluated to investigate the volume effects for structural radiation damage as opposed to functional radiation damage, and the importance of organ anatomy and dose distribution within the organ on the development of chronic radiation damage in the respective organ. RESULTS There is little or no volume effect for structural radiation damage, however, some very pronounced volume effects have been reported for functional damage. Volume, as such, is not the relevant criterion, since critical, radiosensitive structures are not homogeneously distributed within organs. CONCLUSION Volume effects in patients and experimental animals are more related to organ anatomy and organ physiology than to cellular radiobiology.

10 GY TOTAL BODY IRRADIATION INCREASES RISK OF CORONARY SCLEROSIS, DEGENERATION OF HEART STRUCTURE AND FUNCTION IN A RAT MODEL

Purpose: To determine the impact of 10 Gy total body irradiation (TBI) or local thorax irradiation, a dose relevant to a radiological terrorist threat, on lipid and liver profile, coronary microvasculature and ventricular function. Materials and methods: WAG/RijCmcr rats received 10 Gy TBI followed by bone marrow transplantation, or 10 Gy local thorax irradiation. Age-matched, non-irradiated rats served as controls. The lipid profile and liver enzymes, coronary vessel morphology, nitric oxide synthase (NOS) isoforms, protease activated receptor (PAR)-1 expression and fibrinogen levels were compared. Two-dimensional strain echocardiography assessed global radial and circumferential strain on the heart. Results: TBI resulted in a sustained increase in total and low density lipoprotein (LDL) cholesterol (190 ± 8 vs. 58 ± 6; 82 ± 8 vs. 13 ± 3 mg/dl, respectively). The density of small coronary arterioles was decreased by 32%. Histology revealed complete blockage of some vessels while cardiomyocytes remained normal. TBI resulted in cellular peri-arterial fibrosis whereas control hearts had symmetrical penetrating vessels with less collagen and fibroblasts. TBI resulted in a 32 ± 4% and 28 ± 3% decrease in endothelial NOS and inducible NOS protein, respectively, and a 21 ± 4% and 35 ± 5% increase in fibrinogen and PAR-1 protein respectively, after 120 days. TBI reduced radial strain (19 ± 8 vs. 46 ± 7%) and circumferential strain (−8 ± 3 vs. −15 ± 3%) compared to controls. Thorax-only irradiation produced no changes over the same time frame. Conclusions: TBI with 10 Gy, a dose relevant to radiological terrorist threats, worsened lipid profile, injured coronary microvasculature, altered endothelial physiology and myocardial mechanics. These changes were not manifest with local thorax irradiation. Non-thoracic circulating factors may be promoting radiation-induced injury to the heart.

Changes in the microcirculation of normal tissues after irradiation

Abstract We have suggested an hypothesis supported by experimental observations for the initial development of vascular damage following radiation. This initial vascular injury may impair the functional vascularity, and in normal tissues such as the central nervous system and skin, treated with radiation doses close to tolerance, this impairment may be transient. The subsequent improvement may be due to an active vascular response or parenchymal atrophy.