S.M. Gillette

Radiation injury to the heart

For the RTOG Consensus Conference on Late Effects of Cancer Treatment we summarize the clinical manifestations of cardiac complications appearing months to years following incidental irradiation of the heart during treatment of thoracic neoplasms. The most common effects present as pericardial disease, however, it is becoming more clear that precocious or accelerated coronary artery disease is an important late effect, especially in patients treated with radiation before the age of 21 years. To the extent it is known, the pathophysiology of the various syndromes is described and the extensive literature on dose, volume, and fractionation factors is reviewed. Based upon our current understanding of late cardiac effects, a clinical grading system has been developed and is published elsewhere in this issue.

Volume effects in the irradiated canine spinal cord: do they exist when the probability of injury is low?

PURPOSE The purpose of this study was to investigate volume effects in the irradiated canine spinal cord. MATERIALS AND METHODS Eighty-nine beagle dogs were given 44-84 Gy photons in 4 Gy fractions to 4 or 20 cm lengths of thoracic spinal cord. As controls, 36 dogs were given 60-84 Gy in 2 Gy fractions to a 20 cm length of spinal cord and six dogs were unirradiated. Dogs were evaluated for clinical signs, and after euthanasia, for occurrence of gross lesions, severe lesions of massive hemorrhage, white matter necrosis and/or parenchymal atrophy and mild lesions of focal fiber loss. White matter vacuoles, meningeal thickness and dorsal root ganglia lesions were quantified. Data were analyzed to test for an effect of volume on dose-response curves. RESULTS Significant volume effects were found between 4 and 20 cm lengths of irradiated spinal cord for gross lesions, severe lesions and mild lesions (8.3-15.0 Gy difference at the ED50 level). The ED50 in 4 Gy fractions for severe lesions was 56.9 Gy (95% CI 53.1-60.6) for 20 cm and 68.8 Gy (95% CI 64.5-75.1) for 4 cm fields. Significant improvements in the fit of data to dose-response curves resulted when using models with either parallel or non-parallel curves, but in either case an appreciable difference existed between curves at low probabilities of injury. Volume effects were present for meningeal thickness and slopes of dose-response curves were different. Clinical signs correlated well with severe lesions for 20 cm (ED50 = 54.0 Gy), but not for 4 cm fields (ED50 = 77.6 Gy). CONCLUSIONS Volume effects exist for the occurrence of pathologic lesions in irradiated canine spinal cord. Clinical compensation for pathologic lesions occur at small, but not large irradiated volumes. There is insufficient data to support a decreased slope of dose-response curves with decreased volume. Volume effects estimated at the 50% level of spinal cord injury could also hold at low probabilities of injury characteristic of the clinic.

Late radiation response of canine mediastinal tissues

The mediastinal tissues which included heart, lung, trachea and esophagus of 70 adult beagle dogs were irradiated to a range of total radiation doses between 24 and 68 Gy given in 2, 3 and 4 Gy fractions. The purpose of the study was the calculation of alpha/beta ratios for morphologic and functional changes of the mediastinal tissues. Functional assays including echocardiography, electrocardiography, right heart hemodynamics and cardiac output were performed. Histomorphometric analyses of all tissues included in the field were done 2 years after treatment. Euthanasia was performed on 7 of 70 dogs prior to 2 years due to congestive heart failure and seven other dogs had signs of heart failure 2 years after treatment. Heart failure was thought to be caused by either pericardial effusions or constrictive pericarditis in these dogs. Heart failure occurred at doses of 62 and 68 Gy given in 2 Gy fractions, 60 Gy given in 3 Gy fractions and 52 Gy given in 4 Gy fractions. The ED50 values for pericardial fibrosis for 2, 3 and 4 Gy fractions were 46.1, 43.9 and 26.6 Gy, respectively. An alpha/beta ratio of 2.5 Gy was calculated by direct quantal response analysis. Small foci of myocytolytic lesions were detected in 11 dogs. Calculated ED50 values for myocytolysis were 70.4 Gy given in 2 Gy fractions and 50.8 Gy given in 4 Gy fractions. The estimated alpha/beta ratio was 3.2 Gy. Heart rates determined from physical examination and frequency of S-T segment changes increased with increasing dose. No other dose related changes were found in any of the other functional parameters. Functional changes were detected in the 14 dogs with clinical signs of heart failure. Focal consolidation and subpleural fibrosis were present in the irradiated lung volume. These late changes had no detectable physiologic effect in these dogs because of the small volume of lung irradiated. The ED50 values for lung consolidation were 54.3, 45.8 and 26.6 Gy after 2, 3 or 4 Gy fractions, respectively. The estimated alpha/beta ratio was 3.4 Gy. No dose-related changes could be detected in the trachea or esophagus at 2 years after treatment. These results demonstrate that lung and pericardium are the most responsive tissues in the mediastinum within the first 2 years after treatment. Myocardial lesions were present with high ED50 values, but were not found to be functionally significant at 2 years after irradiation. Human clinical data indicate that longer observation periods are needed for development of these lesions.(ABSTRACT TRUNCATED AT 400 WORDS)

Intraoperative radiation (IORT) injury to sciatic nerve in a large animal model.

Peripheral nerve appears to be a dose-limiting normal tissue in the clinical application of intraoperative radiation therapy (IORT). To assess IORT injury to peripheral nerve, three groups of five beagle dogs received doses of 12, 20 or 28 Gy to the surgically exposed and isolated right sciatic nerve in the mid-femoral region using 6 MeV electrons. The left sciatic nerve of each dog served as its own control. As a surgical control five dogs received surgical exposure of the nerve only. Monthly neurologic exams, electromyogram and nerve conduction studies were performed following treatment for 12 months. After that dogs were euthanatized and histologic studies of nerves were done to define the degree of axon and myelin loss as well as presence of fibrosis and vascular lesions for different doses of IORT. Results showed that the threshold dose most likely related to expression of severe radiation damage to the nerve in this model is between 20 and 25 Gy. Radiation injury to peripheral nerve appears to be the result of direct radiation effects on Schwann cells and nerve vasculature and secondary effects resulting from damage to regional muscle and vasculature. A theoretical mechanism of radiation injury to peripheral nerve is proposed.

Effects of intraoperative irradiation and intraoperative hyperthermia on canine sciatic nerve: Neurologic and electrophysiologic study

PURPOSE Late radiation injury to peripheral nerve may be the limiting factor in the clinical application of intraoperative radiation therapy (IORT). The combination of IORT with intraoperative hyperthermia (IOHT) raises specific concerns regarding the effects on certain normal tissues such as peripheral nerve, which might be included in the treatment field. The objective of this study was to compare the effect of IORT alone to the effect of IORT combined with IOHT on peripheral nerve in normal beagle dogs. METHODS AND MATERIALS Young adult beagle dogs were randomized into five groups of three to five dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy to 5 cm of surgically exposed right sciatic nerve using 6 MeV electrons and six groups of four to five dogs each received IORT doses of 0, 12,16, 20, 24, or 28 Gy simultaneously with 44 degrees C of IOHT for 60 min. IOHT was performed using a water circulating hyperthermia device with a multichannel thermometry system on the surgically exposed sciatic nerve. Neurologic and electrophysiologic examinations were done before and monthly after treatment for 24 months. Electrophysiologic studies included electromyographic (EMG) examinations of motor function, as well as motor nerve conduction velocities studies. RESULTS Two years after treatment, the effective dose for 50% complication (ED50) for limb paresis in dogs exposed to IORT only was 22 Gy. The ED50 for paresis in dogs exposed to IORT combined with IOHT was 15 Gy. The thermal enhancement ratio (TER) was 1.5. Electrophysiologic studies showed more prominent changes such as EMG abnormalities, decrease in conduction velocity and amplitude of the action potential, and complete conduction block in dogs that received the combination of IORT and IOHT. The latency to development of peripheral neuropathies was shorter for dogs exposed to the combined treatment. CONCLUSION The probability of developing peripheral neuropathies in a large animal model was higher for IORT combined with IOHT, than for IORT alone. The dose required to produce the same level of late radiation injury to the sciatic nerve was reduced by a factor of 1.5 (TER) if IORT was combined with 44 degrees C of IOHT for 60 min.

Ultrastructural Morphometric Analysis of Peripheral Nerves after Intraoperative Irradiation

Intraoperative irradiation (IORT) is used to enhance local tumour control by using large, single doses while removing critical structures from the treatment field. Peripheral nerve remains a dose-limiting normal tissue that often cannot be removed from the field. To assess ultrastructural changes in canine sciatic nerve after IORT, computerized morphometric analysis of plastic sections and electron micrographs of nerve cross-sections was used. Surgically exposed sciatic nerves were irradiated with 6 MeV electrons to 12, 20 or 28 Gy. Twelve months after treatment dogs were killed humanely and the nerves from three dogs per dose group, including non-irradiated controls, were analyzed. Twelve months after 28-Gy IORT a significant decrease in nerve fiber density occurred. Nerve fiber loss was particularly prominent in the central portion of the nerve predominantly among large nerve fibers. Other nerve fiber parameters including fiber and axon area, diameter and perimeter, myelin thickness, form factor (measure of roundness), and G ratio (axon diameter/fiber diameter) did not show significant, dose-related changes. An increase in microtubule and neurofilament density in irradiated nerve axons was found. These changes are suggestive of radiation-induced hypoxia (damage to microvasculature) resulting in axon damage and subsequent nerve fiber loss as a possible mechanism of late radiation injury to peripheral nerve.

Effects of intraoperative hyperthermia on peripheral nerves: Neurological and electrophysiological studies

The tolerance of peripheral nerves to heat may limit the heat dose which can be applied to tumours. This may be particularly important in intraoperative hyperthermia (IOHT) for pelvic and retroperitoneal tumours. Furthermore the effects of hyperthermia alone must be known before its effects can be assessed in combination with irradiation. In this study injury to sciatic nerves was evaluated in 30 beagle dogs for 1 year following IOHT. IOHT was performed using a water circulating hyperthermia device with multichannel thermometry system. Neurological and electrophysiological examinations were done before, during and after IOHT treatment. Electrophysiological examinations showed a significant decrease in sciatic nerve conduction velocity and potential amplitude immediately after 60 min of heating for all temperatures. The greatest decrease in conduction velocity was observed for a temperature of 45 degrees C. Full recovery of nerve conduction velocity was observed 3 weeks following hyperthermia for all dogs except for those exposed to 45 degrees C. Neurological findings correlated with electrophysiological results. All five dogs which had nerve exposed to 45 degrees C for 60 min had severe neurological changes, with recovery taking place between 3 and 11 months after treatment. Based on these results it appears that temperatures to the peripheral nerve exceeding 44 degrees C for 1 h are likely to cause significant, but not necessarily permanent, nerve injury.

Volume and dose-response effects for severe symptomatic pneumonitis after fractionated irradiation of canine lung

PURPOSE To study the dose-related incidence of severe symptomatic pneumonitis following fractionated irradiation applied to three different volumes of lung in normal beagle dogs. MATERIALS AND METHODS A three-dimensional treatment planning system was used to design mediastinal fields of increasing width to irradiate 33%, 67% or 100% of both lungs combined in 128 normal beagle dogs. Total doses, ranging from 27 to 72 Gy, were delivered in 1.5 Gy fractions over 6 weeks. RESULTS No dogs irradiated to 33% of their total lung volume developed severe symptomatic pneumonitis. In the 67% volume group, logistic fit of the data showed a dose-response curve with a 50% probability of developing severe symptomatic pneumonitis (ED50) after a total dose of 56.0 Gy (52.2-66.0 Gy, 95% confidence interval, CI). The more clinically relevant ED5 for the first 6 months after irradiation of 67% of the lung was 48.1 Gy (18.5-52.0 Gy, 95% CI). The ED50 and ED5 values after irradiation of the whole lung (100%) were 44.1 Gy (41.2-53.5Gy, 95% CI) and 39.1 Gy (8.8-41.8 Gy, 95% CI) respectively. CONCLUSION Severe symptomatic pneumonitis proved to be a very informative volume-effect endpoint, clearly demonstrating that irradiated lung volume is a critical parameter to be considered in assigning thoracic radiotherapy treatment parameters. Volume effects in lung are dependent on the compensatory capacity of the nonirradiated lung. Underlying pathophysiology of irradiated tissue, as well as decreased compensatory capacity of nonirradiated tissue may have a strong effect on the dose-volume response.Purpose : To study the dose-related incidence of severe symptomatic pneumonitis following fractionated irradiation applied to three different volumes of lung in normal beagle dogs. Materials and methods : A three-dimensional treatment planning system was used to design mediastinal fields of increasing width to irradiate 33%, 67% or 100% of both lungs combined in 128 normal beagle dogs. Total doses, ranging from 27 to 72 Gy, were delivered in 1.5Gy fractions over 6 weeks. Results : No dogs irradiated to 33% of their total lung volume developed severe symptomatic pneumonitis. In the 67% volume group, logistic fit of the data showed a dose–response curve with a 50% probability of developing severe symptomatic pneumonitis (ED50) after a total dose of 56.0 Gy (52.2–66.0 Gy, 95% confidence interval, CI). The more clinically relevant ED 5 for the first 6 months after irradiation of 67% of the lung was 48.1 Gy (18.5–52.0 Gy, 95% CI). The ED 50 and ED 5 values after irradiation of the whole lung (100%) were 44.1 Gy (41.2–53.5 Gy, 95% CI) and 39.1 Gy (8.8–41.8 Gy, 95% CI) respectively. Conclusion : Severe symptomatic pneumonitis proved to be a very informative volume-effect endpoint, clearly demonstrating that irradiated lung volume is a critical parameter to be considered in assigning thoracic radiotherapy treatment parameters. Volume effects in lung are dependent on the compensatory capacity of the nonirradiated lung. Underlying pathophysiology of irradiated tissue, as well as decreased compensatory capacity of nonirradiated tissue may have a strong effect on the dose-volume response.

Effects of intraoperative irradiation (IORT) and intraoperative hyperthermia (IOHT) on canine sciatic nerve: histopathological and morphometric studies

PURPOSE/OBJECTIVE Peripheral neuropathies have emerged as the major dose-limiting complication reported after intraoperative radiation therapy (IORT). The combination of IORT with hyperthermia may further increase the risk of peripheral nerve injury. The objective of this study was to evaluate histopathological and histomorphometric changes in the sciatic nerve of dogs, after IORT with or without hyperthermia treatment. METHODS AND MATERIALS Young adult beagle dogs were randomized into five groups of 3-5 dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy. Six groups of 4-5 dogs each received IORT doses of 12, 16, 20, 24, or 28 Gy simultaneously with 44 degrees C of intraoperative hyperthermia (IOHT) for 60 min. One group of dogs acted as hyperthermia-alone controls. Two years after the treatment, dogs were euthanized, and histopathological and morphometric analyses were performed. RESULTS Qualitative histological analysis showed prominent changes such as focal necrosis, mineralization, fibrosis, and severe fiber loss in dogs which received combined treatment. Histomorphometric results showed a significantly higher decrease in axon and myelin and small blood vessels, with a corresponding increase in connective tissue in dogs receiving IORT plus hyperthermia treatment. The effective dose for 50% of nerve fiber loss (ED50) in dogs exposed to IORT only was 25.3 Gy. The ED50 for nerve fiber loss in dogs exposed to IORT combined with IOHT was 14.8 Gy. The thermal enhancement ratio (TER) was 1.7. CONCLUSION The probability of developing peripheral neuropathies in a large animal model is higher when IORT is combined with IOHT, when compared to IORT application alone. To minimize the risk of peripheral neuropathy, clinical treatment protocols for the combination of IORT and hyperthermia should not assume a thermal enhancement ratio (TER) to be lower than 1.5.

Effects of Volume Irradiated on the Function of the Canine Ureter

This study was designed to investigate the influence of the volume irradiated on the probability of ureteral complications and to provide data for volume modeling. One hundred thirty-four purpose-bred beagle dogs received single intraoperative doses of 6 MeV electrons ranging from 12 to 54 Gy to three lengths of ureter: 2, 4 or 8 cm. The response was evaluated by excretory urography. The ED50 was 21.9 Gy (95% CI 13.3-30 Gy) for 8 cm 3 years after treatment. The estimated ED50s were greater than 43 Gy for 4 cm and 85 Gy for 2 cm. Reducing the length of ureter irradiated from 8 cm to 4 cm increased the ED50 for ureteral dilation by at least a factor of 2, while reduction from 8 cm to 2 cm increased the ED50 by at least a factor of 4. The ED50 for renal injury secondary to stenosis was 30.5 Gy (95% CI 17.2-232 Gy) when an 8-cm field was irradiated. There was a significant effect of volume irradiated on the frequency of ureteral stenosis. Reducing the length of ureter included in the treatment field should allow delivery of higher doses to tumors without increased complications.