S. McChesney Gillette

Response of canine soft tissue sarcomas to radiation or radiation plus hyperthermia: a randomized phase II study.

Sixty-four dogs with spontaneous soft tissue sarcomas without evidence of metastases were stratified by tumour volume and randomized to receive graded doses of radiotherapy (XRT) alone or radiotherapy plus hyperthermia (HT). An improvement in duration of local control was achieved with the addition of hyperthermia as compared with XRT alone (Wilcoxon, p = 0.040; log rank, p = 0.064). Overall frequency of late complications was not different for the two treatment arms when comparing across equivalent XRT dose groups. Frequency of distant metastases after therapy completion was not significantly different for the two treatment arms at 1 year (7.4% for XRT versus 20% for HT plus XRT) or 2 years (11.5% for XRT versus 25% for HT plus XRT) post therapy. These results suggest that a therapeutic gain was achieved for this group of tumour-bearing animals. Uni- and multivariate analyses were performed to examine the potential for various factors to influence treatment outcome. Patient related variables included tumour stage, histologic subtype and grade and tumour site. Treatment related variables included total radiation dose and 15 descriptors of temperature distributions achieved during hyperthermia. When considering patient related factors, tumour histology, grade and location were important predictors of time to minimum volume, but only tumour location influenced time to tumour regrowth. When considering treatment related factors, radiation dose was not significantly correlated with time to minimum volume or time to local regrowth, but it was correlated with probability for late normal tissue damage in the XRT alone group (p = 0.005). For the hyperthermia treatments, 13 of 15 tumour temperature distribution descriptors were correlated with time to minimum volume, but none were correlated with time to local regrowth. These results suggest that caution should be used in interpreting the value of temperature distribution descriptors in predicting for long-term local control after hyperthermia and radiotherapy, based on analysis of short-term responses.

Muscle injury following experimental intraoperative irradiation

The paraaortic region of beagle dogs was irradiated to 15 to 55 Gy intraoperative irradiation, 10 to 47.5 Gy intraoperative irradiation following 50 Gy external beam irradiation in 25 fractions, or 50 to 80 Gy external beam irradiation in 30 fractions. Six MeV electrons were used for intraoperative irradiation, and external beam irradiation was done using photons from a 6 MV linear accelerator. The psoas muscle in the irradiation field was examined histomorphometrically 2 or 5 years after irradiation. The percentage of muscle fibers and capillaries decreased, whereas the percentage of connective tissue increased with increased dose for both intraoperative irradiation only and intraoperative irradiation plus external beam irradiation. The dose causing a 50% decrease in the percentage of muscle fibers was 21.2 Gy and 33.8 Gy at 2 and 5 years, respectively, after intraoperative irradiation alone, and 22.9 Gy and 25.2 Gy at 2 and 5 years, respectively, after intraoperative irradiation combined with 50 Gy external beam irradiation. The ED50 for severe vessel lesions was 19.2 Gy and 25.8 Gy at 2 and 5 years, respectively, after intraoperative irradiation alone and 16.0 Gy and 18.0 Gy at 2 and 5 years, respectively, after intraoperative irradiation combined with 50 Gy external beam irradiation. External beam irradiation alone caused a slight decrease in percentage of muscle fibers with increased dose, and vessel lesions were infrequent or mild. Radiation-induced muscle injury was characterized by loss of muscle fibers, decreased fiber size, severe vessel lesions, hemorrhage, inflammation, coagulation necrosis, and fibrosis. These histopathologic characteristics distinguish this muscle injury from that caused by neurogenic atrophy. These data indicate that radiation-induced muscle injury most likely was caused by injury of the supporting vasculature. The lesions produced were largely a function of the single intraoperative dose rather than the external beam fractionated doses. Furthermore, it appears that 20 to 25 Gy intraoperative irradiation combined with 50 Gy external beam irradiation may be near the maximum tolerated dose by sublumbar musculature and its supporting vasculature.

Ureteral injury following experimental intraoperative radiation.

Beagle dogs were randomized to receive a range of total dose delivered in three different protocols. Sixteen dogs received external beam radiation therapy (EBRT), 32 dogs received intraoperative irradiation (IORT), and 32 dogs received combinations of external beam radiation therapy and intraoperative irradiation. A sublumbar field was irradiated which always included the left ureter. Dogs were observed for 5 years; sequential excretory urograms were done at 6 months, and 1 and 5 years. Morphometric analysis of tissues were also done. The canine ureter tolerated 17.5 Gy intraoperative irradiation with no evidence of injury and 25 Gy intraoperative irradiation with a low probability of injury. The ED50 for radiographic abnormalities was 32.9 Gy. When 50 Gy external beam radiation therapy was given prior to intraoperative irradiation, the ureter tolerated 10 Gy intraoperative irradiation with no evidence of injury and 17.5 Gy with a low probability of injury. The ED50 was 29 Gy intraoperative irradiation after EBRT. The external beam radiation therapy had little effect on the ureter when given alone or prior to intraoperative irradiation. Clinical signs of renal disease occurred only in dogs who had received bilateral ureteral irradiation intraoperatively at doses of 32.5 Gy intraoperative irradiation and 25 Gy intraoperative irradiation after external beam radiation therapy. Histologic evidence suggests that the chronic injury of the ureter expressed at 5 years is of vascular etiology. The early injury may be due to ulceration of the epithelium.

Effects of intraoperative hyperthermia on canine sciatic nerve: histopathologic and morphometric studies

Failure to achieve local control in the treatment of pelvic and retroperitoneal tumours results in a high rate of recurrences. The objective of intraoperative hyperthermia (IOHT) is to enhance the effect of intraoperative radiation therapy and to increase local tumour control. The tolerance of peripheral nerves to heat may limit the heat dose that can be applied to tumours. Histopathologic and histomorphometric changes of canine sciatic nerve after 60-min IOHT were studied in three groups of five dogs each for temperatures of 43, 44 and 45 degrees C. IOHT was performed using a water-circulating hyperthermia device with a multichannel thermometry system on surgically exposed sciatic nerve. Histopathologic and histomorphometric studies were done immediately, 3 weeks and 12 months after IOHT. Histologic changes observed immediately after treatment were minimal but at 3 weeks following 60-min 45 degrees C IOHT both axon and myelin loss and an increase in endoneurial fibrous tissue were observed. Twelve months after treatment a statistically significant decrease in axon, myelin and small vessel percentages as well as an increase in endoneurial and epineural connective tissue were observed for dog treated to 45 degrees C. Dog treated to 44 degrees C for 60 min had similar statistically significant but less severe changes. Twelve months after 43 degrees C IOHT for 60 min, nerve fibres appeared normal and endoneurial connective tissue was only increased mildly around small and medium-sized vessels. These results suggest that temperatures to the peripheral nerve > 44 degrees C for 60 min are likely to cause significant histopathologic changes that can be found 12 months after treatment. A hypothesis of the mechanism of heat injury to peripheral nerves was developed.

Radiation-induced ocular injury in the dog: A histological study

Radiation-induced ocular injury secondary to treatment of nasal cancer occurs in humans and animals. Dogs with nasal carcinomas were randomized to receive 36 to 67.5 Gy in fractionated doses given in 4 weeks using a 6 MV linear accelerator. Ophthalmic examinations were performed according to a predetermined protocol and eyes were removed for histologic examination when dogs were euthanatized. The eye in the radiation field exhibited greater injury than the contralateral eye with nasal areas of the globe having more severe lesions than temporal areas. Lesions occurred in all dogs and at all doses. At 1 month or less postirradiation treatment, all dogs had blepharitis, keratoconjunctivitis and corneal epithelial atrophy. Surface lesions persisted in all eyes, becoming less severe and more chronic with time. At 3-6 months postirradiation treatment, degenerative angiopathy of retinal vessels appeared with multifocal retinal hemorrhage and mild diffuse retinal degeneration which affected outer layers first and progressed inwardly with time. At 6 months postirradiation treatment, there were cataracts, fibrosis of retinal vessel walls with loss of vascular smooth muscle, retinal hemorrhage, and mild to moderate retinal degeneration. At 1 year postirradiation treatment, retinal vessels remained sclerotic, retinal hemorrhage was less frequent, and there was moderate retinal degeneration with swelling and loss of ganglion cells. By 2 years or more postirradiation treatment, optic nerve axonal degeneration secondary to retinal changes had appeared. Tapetal and choroidal atrophy were inconsistently seen. Thus, ocular lesions at the doses received developed along a relatively predictable time course and recovery was not seen. Structures of the canine eye appear sufficiently sensitive that even relatively low total doses given in small doses per fraction cause significant long-term injury.

Whole-body hyperthermia combined with hyperfractionated irradiation of the thorax in dog: Acute physiological response

Whole-body hyperthermia has potential as an adjuvant treatment with chemotherapy and radiation therapy for diseases such as lung cancer which require both local and systemic control. The acute toxicity of whole-body hyperthermia combined with whole-thorax irradiation was studied in dogs. Twenty-eight dogs received three 2-h whole-body hyperthermia (WBH) treatments at 42.0 degrees C deep rectal temperature. Twenty-four of these dogs were also randomized to receive radiation doses of 18, 22.5, 27, 31.5, 40.5 or 45 Gy. Irradiation was given in 1.5 Gy fractions over 6 weeks. Three WBH treatments were given to 28 dogs with all dogs surviving treatment. WBH was given on days 1, 22 and 40 of the 6-week interval. Thirty-one dogs received radiation doses of 18-49.5 Gy without WBH. Deep rectal temperature was maintained at 41.9 +/- 0.3 degrees C over 2 h with an average of 20 min outside the chamber for irradiation. Two dogs required intervention with emergency medications during WBH treatment. One of the two dogs developed permanent neurological injury. Continuous physiological monitoring was necessary for successful WBH. WBH plus thoracic irradiation was well tolerated. All dogs survived all treatments. A significant but transient increase in peripheral blood leucocytes and a decrease in platelet counts occurred after each WBH treatment. The addition of thoracic irradiation up to 45 Gy in 1.5 Gy fractions did not appear to alter the acute toxicity of WBH with the exception of an increase in the protein content of lung lavage fluids. In conclusion, multiple WBH treatments of 2 h at a target temperature of 42 degrees C in addition to thoracic irradiation up to 45 Gy in 1.5 Gy fractions was administered with only mild acute toxicities occurring. Core temperature could be maintained for up to 20 min outside of the WBH chamber which allowed irradiation to be given concurrently with hyperthermia at a core temperature of 42 degrees C +/- 0.1 degree C.

Muscle Injury in Experimental Intraoperative Irradiation

Complications reported for intraoperative radiation therapy (IORT) in humans include fibrosis (Calvo et al. 1989a; Sindelar et al. 1986; Tepper et al. 1984), hemorrhage (Tepper et al. 1984), peripheral neuropathies (Calvo et al. 1989a; Kinsella et al. 1985), bone necrosis (Hoekstra et al. 1988), and pelvic pain (Tepper et al. 1984). Most patients were followed for a relatively short period of time, with few patients observed more than 2 years after irradiation.