Gy Intraoperative Radiotherapy Research Articles

Intraoperative Radiation Therapy-Induced Sarcomas in Dogs

In a canine model the tolerance of normal and surgically manipulated tissue to intraoperative radiotherapy (IORT) was investigated to provide guidelines for the clinical use of IORT in human cancer patients. A dose of 20 Gy IORT, with or without external beam radiotherapy, was generally well tolerated without significant increased treatment morbidity. Higher doses of IORT (over 30 Gy) have produced radiation-induced sarcomas in some animals followed over a long period. Therefore IORT should be used only in human cancer patients in well controlled studies, in which complications are well documented, and the possibility of radiation-induced malignancies in long-term survival should be considered.

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 ED 50 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 ED 50 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.

Bone necrosis and tumor induction following experimental intraoperative irradiation

The bone of the lumbar vertebrae of 153 dogs was examined 2 and 5 years after intraoperative irradiation (IORT), fractionated external beam irradiation (EBRT), or the combination. Groups of dogs received 15 to 55 Gy IORT only, 10 to 47.5 Gy IORT combined with 50 Gy EBRT in 2 Gy fractions or 60 to 80 Gy EBRT in 30 fractions. Six MeV electrons were used for IORT, and EBRT was done using photons from a 6 MV linear accelerator. The paraaortic region was irradiated and the ventral part of the lumbar vertebrae was in the 90% isodose level. Two years after irradiation, the dose causing significant bone necrosis as determined by at least 50% empty lacunae in the vertebral cortex was 38.2 Gy IORT alone and 32.5 Gy IORT combined with EBRT. Five years after irradiation, the dose causing 50% empty lacunae was 28.5 Gy IORT only and 14.4 Gy IORT combined with EBRT. The ED 50 for lesions of the ventral vertebral artery was 21.7 Gy IORT only and 20.1 Gy IORT combined with 50 Gy EBRT 2 years after irradiation and 27.0 Gy IORT only and 20.0 Gy IORT combined with 50 Gy EBRT 5 years after irradiation. All lesions after EBRT only were mild. Eight dogs developed osteosarcomas 4 to 5 years after irradiation, one at 47.5 Gy IORT only and the remainder at 25.0 Gy IORT and above combined with 50 Gy EBRT. In conclusion, the extent of empty lacunae, indicating bone necrosis, was more severe 5 years after irradiation than after 2 years. The effect of 50 Gy EBRT in 2 Gy fractions was equivalent to about 6 Gy IORT 2 years after irradiation and to about 14 Gy 5 years after irradiation. Based on these estimates, IORT doses of 10 to 15 Gy have an effect 5 times or greater than that amount given in 2 Gy fractions. Osteosarcomas occurred in 21% of dogs which received doses greater than 25 Gy IORT. Doses of 15 to 20 Gy IORT in combination with 50 Gy EBRT in 2 Gy fractions may be near the tolerance level for late developing bone injury.

Peripheral neuropathies following experimental intraoperative radiation therapy (IORT)

Injury to peripheral nerves in the lumbar para-aortic region was evaluated in beagle dogs 2 years following fractionated irradiation (EBRT), intraoperative irradiation (IORT), or a combination of IORT and EBRT. Time to onset of peripheral neuropathy was determined by means of serially completed neurological and electrophysiological examinations. Peripheral neuropathies were seen beginning as early as 6 months following 35 Gy (or greater) IORT only and 35 Gy plus 50 Gy EBRT. The incidence of peripheral neuropathies increased with increasing IORT doses beginning at 15 Gy. Onsets of peripheral neuropathies following IORT alone were clustered between 6 and 18 months, with onset in some dogs occurring as late as 24 months. The combination of IORT and EBRT resulted in an incidence and latency to onset of neuropathies similar to that seen with IORT alone. Neuropathies were not seen with EBRT alone at doses from 50 Gy to 80 Gy. Recovery of nerve function did not occur in affected dogs. Histological studies of nerves 2 years following irradiation demonstrated loss of axons and myelin, with a corresponding increase in endoneurial, perineurial, and epineurial connective tissue. Percentage of axon and myelin decreased to about 60% of normal at 15 Gy IORT, and additionally at higher doses. An insignificant decrease in percentage of axon and myelin was seen following EBRT alone. A significant lesion occurring in and around nerves at most IORT doses was necrosis and hyalinization of the media of small arteries and arterioles. The dose for a 50% probability for causing severe vessel lesions in the 2-year study was 19.5 Gy IORT only and 18.7 Gy when IORT was combined with EBRT. These lesions were not seen with any EBRT only dose. These studies suggest that peripheral nerve is a dose limiting normal tissue in IORT. Neuropathies appear to result from direct effects of irradiation on nerve and secondary effects to nerve resulting from damage to regional vasculature.

Exocrine pancreatic function following intraoperative irradiation of the canine pancreas.

Twenty-four beagles received intraoperative irradiation (IORT) with 6 meV electrons to the pancreas and the duodenum. Intraoperative irradiation doses of 17.5 to 40 Gy were given. Billroth II gastrojejunostomy was done to bypass the irradiated duodenum. Six control dogs received only the Billroth II surgery. Two weeks postoperatively, irradiated dogs were given 50 Gy of 6 MV X radiation (external-beam radiation [EBRT]) to the pancreas and duodenum in 2 Gy fractions over a 5-week period. Dogs were monitored clinically and exocrine pancreatic function was evaluated using an N-benzoyl-l-tyrosyl-para-aminobenzoic acid (BT-PABA) test between 3 and 135 days postoperatively. Necropsies were performed on the dogs at 135 days postoperatively. The degree of gross pancreatic atrophy in the irradiated group was dose related. The mean percentage of normal acinar cells correlated with IORT doses and para-aminobenzoic acid (PABA) values (P less than 0.1). Weight loss was significantly greater in the irradiated dogs compared to the control (P less than 0.05) and the mean percentage of body weight loss correlated with the mean PABA values (P less than 0.01). In this study, the use of the BT-PABA test to evaluate progressive exocrine pancreatic function following IORT and EBRT showed an expected trend. A progressive decrease in exocrine pancreatic function in the irradiated dogs as indicated by plasma PABA levels may have been partly due to late radiation damage to acinar cells, secondary to vascular and ductular damage. At 135 days postoperatively none of the dogs showed clinical signs of exocrine pancreatic insufficiency and the plasma PABA levels were within the normal presurgical range. The progressive decrease in plasma PABA levels indicated a potential for the late development of exocrine pancreatic insufficiency. The BT-PABA test could be useful for evaluating the progressive decrease in exocrine pancreatic function and residual radiation injury to the pancreas. Because the exocrine deficiency can be managed with replacement therapy, pancreatic injury may not be a serious complication after doses of less than 30 Gy IORT with 50 Gy EBRT. Data from this study are in agreement with previous clinical and experimental reports that the duodenum is dose-limiting for IORT. Doses of 20 Gy IORT or less plus 50 Gy EBRT for treatment of carcinoma of the pancreas may not result in serious long-term complications due to radiation injury of the duodenum.

Pathologic response of the pancreas and duodenum to experimental intraoperative irradiation

The pancreas and duodenum of 24 beagle dogs were given intraoperative irradiation (IORT) with 6 MeV electrons. The dose range was 17.5 Gy to 40 Gy. Billroth II gastrojejunostomy was performed on all dogs prior to irradiation. Six control dogs received only Billroth II surgery. Starting 2 weeks after surgery, dogs in the irradiation groups were given 50 Gy 6 MV X rays external beam radiation therapy (EBRT) to the pancreas and duodenum. The total dose of 50 Gy was given in 2 Gy fractions over 5 weeks. Dogs were monitored for 135 days then necropsied. Gross and histopathologic changes in the pancreas and duodenum were evaluated and quantitative analysis of pancreatic lesions done. Duodenal ulcers were found following 32.5 Gy and 40 Gy IORT. The pancreases were atrophic in irradiated dogs and exocrine pancreatic insufficiency occurred in one dog given 25 Gy. Gross pancreatic atrophy correlated with IORT dose. Histopathologic evidence of radiation damage to the pancreas was observed in acinar cells. Islet cell lesions were not apparent. There was pancreatic fibrosis and damage to blood vessels and ducts. Dose-response relationships were observed for the index of damage to the pancreas as a whole, for pancreatic fibrosis and a decrease in normal acinar cells. Although 25 Gy IORT plus 50 Gy EBRT was tolerated by the duodenum to 135 days, these doses may cause later pancreatic injury as an expression of damage to blood vessels and ducts. Exocrine pancreatic insufficiency and diabetes mellitus may thus represent potential late complications of IORT following 25 Gy or higher doses.