Gy Intraoperative Radiotherapy Research Articles

Comparison of intraoperative radiotherapy as a boost vs. simultaneously integrated boosts after breast-conserving therapy for breast cancer.

Currently, there are no data from randomized trials on the use of intraoperative radiotherapy (IORT) as a tumor bed boost in women at high risk of local recurrence. The aim of this retrospective analysis was to compare the toxicity and oncological outcome of IORT or simultaneous integrated boost (SIB) with conventional external beam radiotherapy (WBI) after breast conserving surgery (BCS). Between 2009 and 2019, patients were treated with a single dose of 20 Gy IORT with 50 kV photons, followed by WBI 50 Gy in 25 or 40.05 in 15 fractions or WBI 50 Gy with SIB up to 58.80-61.60 Gy in 25-28 fractions. Toxicity was compared after propensity score matching. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. A 1:1 propensity-score matching resulted in an IORT + WBI and SIB + WBI cohort of 60 patients, respectively. The median follow-up for IORT + WBI was 43.5 vs. 32 months in the SIB + WBI cohort. Most women had a pT1c tumor: IORT group 33 (55%) vs. 31 (51.7%) SIB group (p = 0.972). The luminal-B immunophenotype was most frequently diagnosed in the IORT group 43 (71.6%) vs. 35 (58.3%) in the SIB group (p = 0.283). The most reported acute adverse event in both groups was radiodermatitis. In the IORT cohort, radiodermatitis was grade 1: 23 (38.3%), grade 2: 26 (43.3%), and grade 3: 6 (10%) vs. SIB cohort grade 1: 3 (5.1%), grade 2: 21 (35%), and grade 3: 7 (11.6%) without a meaningful difference (p = 0.309). Fatigue occurred more frequently in the IORT group (grade 1: 21.7% vs. 6.7%; p = 0.041). In addition, intramammary lymphedema grade 1 occurred significantly more often in the IORT group (11.7% vs. 1.7%; p = 0.026). Both groups showed comparable late toxicity. The 3- and 5-year local control (LC) rates were each 98% in the SIB group vs. 98% and 93% in the IORT group (LS: log rank p = 0.717). Tumor bed boost using IORT and SIB techniques after BCS shows excellent local control and comparable late toxicity, while IORT application exhibits a moderate increase in acute toxicity. These data should be validated by the expected publication of the prospective randomized TARGIT-B study.

Intraoperative Boost Radiotherapy with 50 kV X-Rays Versus External Radiotherapy in Breast Cancer: Single-Center Experiences

Background: Intraoperative radiotherapy (IORT) within breast conserving surgery (BCS) is progressively utilized to deliver the optimal dose of radiotherapy immediately after the excision of cancer during the same operation to the well-vascularized tissue and to the margin of resected cancer to damage the cancer cells, which might remain nearby the tumor just on time without no delay as radical irradiation for particular cases or as boost dose for others. Methods: This study reports 54-month single-center experiences after introduction to deliver IORT (50 kV x-ray) as a tumor bed boost in BCS for breast cancer and comparison with external beam radiation therapy (EBRT). In this retrospective study, 255 patients (stages 1 - 3) with breast cancer were treated with BCS and IORT in the Cancer Research Center, Shahid Beheshti University of Medical Sciences (April 2014-September 2018). They received 20 Gy IORT as a boost compared with 321 patients in the same stages with EBRT. Results: Within 54 months, there were 3 (1.2%) occurrences of local recurrence in IORT patients compared with 8 (2.5%) local recurrences in EBRT patients (P = 0.361) and 12 (4.7%) metastasis in the IORT group vs. 20 (6.2%) in the EBRT group (P = 0.724). The 5-year disease-free survival (DFS) was 85.1% in the IORT group compared with 86% in the EBRT group. Conclusions: IORT tumor bed boost with 50 kV x-ray during breast conserving therapy had a better outcome, but it was not significant compared with EBRT.

Combination of perioperative chemotherapy and intraoperative radiotherapy for the treatment of resectable pancreatic head cancer

Introduction: A new treatment method involving neoadjuvant chemoembolization of tumor vessels 5 days prior to surgery combined with intraoperative radiotherapy (IORT) followed by adjuvant chemotherapy was established for patients with resectable pancreatic cancer. The aim of the present study was to assess the safety and efficacy of this treatment scheme. Method: Records of 161 patients with resectable PDAC treated in Botkin Hospital between 2013–2017 were reviewed. In 49 cases was used perioperative chemoradiotherapy (PeriCRT). IORT was performed using Carl Zeiss Intrabeam PRS 500 system. After resection stage, a single dose of 20 Gy IORT boost was delivered using 50-kV x-rays to a depth of 1 mm from the applicator surface. Afterward a histological examination and electron microscopy of irradiated resection margin were performed. Results: All 161 patients with PDAC underwent gross total resection (R0) with lymphadenectomy D2. The estimated median survival was 338, 358, 372 and 337 days. Long-term survival was 70,2% (NACE), 75,1% (IORT), 80,7% (PeriCRT), 61,3% (control) for 3-year survival, respectively (p < 0,05, 95% Cl). All treatment methods were well tolerated by all patients, with few adverse effects and no serious complications. There was no association between outcomes, variations in tumor characteristics, marker concentrations and therapeutic response. Conclusions: Good 3-year OS for resected PDAC was achieved by using novel PeriCRT treatment method.

Intraoperative radiotherapy in malignant HPB diseases combine treatment

Introduction: Insufficient results after pancreatic cancer and colorectal liver metastasis surgical treatment require additional treatment methods. Methods: 18 patients with colorectal liver metastasis (CRM) and 23 patients with pancreatic head cancer were treated by intraoperative radiotherapy (IORT) in Botkin Moscow Municipal Hospital. IORT was performed using Carl Zeiss Intrabeam PRS 500 system. After resection stage a single dose of 10–15 Gy IORT boost was delivered using 50-kV X-rays to surgery surface from the applicator. Applicators were used from the size 2.5 to 5 cm. Then was made an electron microscopy study of irradiated surgery margin. Results: All of 18 patients with CRM underwent liver resection (R0) with IORT and 23 patients underwent Whipple procedure with IORT.The median dose of IORT was 12 Gy. After electron microscopy examination it was observed fat cells and endothelium destruction. The median follow-up period was 30 months. At the time of the analysis, 7 (39%) patients from CRM IORT group had disease recurrence (new liver metastasis in the same and others liver segments). The 2-year local control (LC) and overall survival (OS) rates were 61% and 74%. As for pancreatic cancer group, 8(35%) had disease recurrence (liver metastasis). The 2-year local control (LC) and overall survival (OS) rates were 82% and 64%. Conclusion: Effective influence by Carl Zeiss Intrabeam PRS 500 system on local reccurence, overal survival and liver tissue and pancreatic head bed was confirmed.

Prospective Study of Local Control and Late Radiation Toxicity After Intraoperative Radiation Therapy Boost for Early Breast Cancer

To report the local recurrence rate and late toxicity of intraoperative radiation therapy (IORT) boost to the tumor bed using the Intrabeam System followed by external-beam whole-breast irradiation (WBI) in women with early-stage breast cancer in a prospective single-institution study. Women with breast cancer≤3 cm were recruited between February 2003 and May 2005. After breast-conserving surgery, a single dose of 5 Gy IORT boost was delivered using 50-kV x-rays to a depth of 10 mm from the applicator surface. This was followed by WBI to a total dose of 50 Gy in 25 fractions. Patients were reviewed at regular, predefined intervals. Late toxicities were recorded using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring systems. Fifty-five patients completed both IORT boost and external-beam WBI. Median follow-up was 3.3 years (range, 1.4-4.1 years). There was no reported locoregional recurrence or death. One patient developed distant metastases. Grade 2 and 3 subcutaneous fibrosis was detected in 29 (53%) and 8 patients (15%), respectively. The use of IORT as a tumor bed boost using kV x-rays in breast-conserving therapy was associated with good local control but a clinically significant rate of grade 2 and 3 subcutaneous fibrosis.

Early initiation of external beam radiotherapy (EBRT) may increase the risk of long-term toxicity in patients undergoing intraoperative radiotherapy (IORT) as a boost for breast cancer

Background Intraoperative radiotherapy (IORT) during breast-conserving surgery is increasingly used. We analyzed the influence of the interval between an IORT boost and external beam radiotherapy (EBRT) on late toxicity. Methods Forty-eight patients received 20 Gy IORT (50 kV X-rays (Intrabeam, Carl Zeiss, Oberkochen, Germany) followed by 46–50 Gy EBRT with a median interval of 36 days (14-197). Late toxicity was assessed with the modified LENT SOMA score after a median of 36 months. Results Twelve patients developed a higher grade fibrosis (°II–III), three teleangiectases, one a breast edema grade °II, six retractions, four hyperpigmentations and five pain (°II–III). The median interval between IORT and EBRT was significantly shorter in these patients ( n = 18) compared to the 30 patients without higher grade toxicity (29.5 days vs. 39.5 days, p = 0.023, Mann–Whitney U-test). Conclusion Starting EBRT about 5–6 weeks after IORT appears to be associated with a decreased risk of chronic late toxicity compared with a shorter interval. The impact on local recurrence of prolonged gaps between IORT and EBRT is not known.

Long-term toxicity of an intraoperative radiotherapy boost using low energy X-rays during breast-conserving surgery

Intraoperative radiotherapy (IORT) as a boost for breast cancer delivers a high single dose of radiation to a late-reacting tissue; therefore late toxicity is of particular interest, and long-term follow-up is warranted. To date there are only limited data available on breast cancer patients treated with IORT using low energy X-rays. We analyzed toxicity and cosmesis after IORT as a boost with a minimum follow-up of 18 months. A total of 73 patients treated with IORT (20 Gy/50 kV X-rays; INTRABEAM [Carl Zeiss Surgical, Oberkochen, Germany]) to the tumor bed during breast-conserving surgery as a boost followed by whole-breast radiotherapy (WBRT, 46 Gy) underwent a prospective, predefined follow-up (median, 25 months; range 18-44 months), including clinical examination and breast ultrasound at 6-months and mammographies at 1-year intervals. Toxicities were documented using the common toxicity criteria (CTC)/European Organization for Research and Treatment of Cancer and the LENT-SOMA score. Cosmesis was evaluated with a score from 1 to 4. The IORT in combination with WBRT was well tolerated, with no Grade 3 or 4 skin toxicities and no telangiectasias. Fibrosis of the entire breast was observed in 5% of the patients. A circumscribed fibrosis around the tumor bed was palpable in up to 27% with a peak around 18 months after therapy and a decline thereafter. The observed toxicitiy rates were not influenced by age, tumor stage, or systemic therapy. The cosmetic outcome was good to excellent in>or=90% of cases. After IORT of the breast using low-energy X-rays, no unexpected toxicity rates were observed during long-term-follow-up.

12 Years’ Experience with Intraoperative Radiotherapy (IORT) of Malignant Gliomas

Even after surgery and radiotherapy, malignant gliomas still have a poor prognosis. The authors report on their experience with IORT in 71 patients. From May 1992 to February 2004, 71 patients with malignant gliomas were treated with IORT. 26 patients suffered from grade III gliomas, 45 patients from glioblastomas (GBM). IORT was carried out using a standard electron tube and 9- to 18-MeV electrons. 52/71 patients who were primarily treated received 20 Gy IORT + 60 Gy postoperative radiotherapy, 19/71 patients with recurrences only received IORT (20-25 Gy). The complication rates were 1.4% for wound infections and 5.6% for hemorrhage. Median disease-specific survival amounted to 14.9 months (gliomas III) and 14.2 months (GBM). The 2-year survival rates amounted to 26.9% (gliomas III) and 6.8% (GBM; p = 0.0296). Total versus subtotal resection had no significant influence on survival (p = 0.0741), nor had age, sex, tumor site, performance status, size, primary versus recurrence, and radiation dose. A comparison to a conventionally treated patient group did not show a significant survival improvement. 3 months after treatment, initial symptoms had improved in 59% (hemiparesis), 50% (aphasia), 50% (hemianopsia), and 60% (convulsions). IORT has been shown to be feasible; perioperative complication rates were not increased. Survival was generally not improved compared to a historical control group. Recurrences achieved the same survival as primary tumors, and GBM also had a slightly increased survival, thus being possible indications for IORT.

Editorial comment on “long-term adverse effects of radiation inhibition of restenosis”

Appearing in this issue is an article entitled “Long-term adverse effects of radiation inhibition of restenosis: radiation injury to the aorta and branch arteries in a canine model,” by B. E. Powers, H. D. Thames, and E. L. Gillette. This is an interesting article, both for its intrinsic merit, and for its history. From the historical perspective, the authors present data from an experiment which began nearly 15 years ago, for purposes far removed from restenosis. Their original investigations (1, 2) were focused on the nature of long-term injury to the aorta following intraoperative radiation therapy (IORT). In those original articles, they reported an ED50 for severe aortic thrombi and aneurysm of 35 Gy IORT at 5-year follow-up (i.e., necropsy). Also of note was the fact that far fewer such injuries were observed at 2-year follow-up. In the new paper, the authors have reanalyzed their 15-year old data with special emphasis on questions of particular interest vis a vis restenosis. They now report on findings such as radiation-induced intimal proliferation, adventitial fibrosis, media thickening, and radiation effects on smaller diameter arteries of 1–3-mm diameter. In light of the recent explosion of interest in endovascular brachytherapy, this reanalysis, with special attention to histomorphic factors of particular relevance to restenosis, is of special interest. Their data at 5-year follow-up is, to my knowledge, unique. Many of the results presented, both here and in the original papers, may be rather sobering, particularly for people who believe that 6-month, or even 2-year follow-up data tell the whole story. Findings such as adventitial areas 6 times normal at 5 years postirradiation for 40-Gy single fraction dose, or intimal proliferation at doses , 15–20 Gy or . 50 Gy, or adventitial fibrosis, will hopefully whet the reader’s appetite for examining this paper in greater detail. Such findings, even if translatable to humans, may ultimately be considered a small price to pay in exchange for successful prevention of restenosis, but we would certainly be remiss to ignore such warnings. These warnings could not have come at a more appropriate time. Endovascular brachytherapy as a prophylactic treatment for prevention of restenosis in coronary arteries is arguably one of the more promising radiation bandwagons today. We have many reasons to be excited about the future of this relatively new therapy. Over 500,000 patients per year undergo coronary angioplasty in the United States, with a comparable number receiving such treatments internationally. Second only to bypass surgery, it is the most common and successful treatment modality for coronary artery disease. Yet, approximately 30–50% of patients fail treatment within 6 months. In the 25 years since Andreas Gruentzig introduced the coronary balloon catheter (3), cardiologists have searched (although unsuccessfully) for an adjuvant and/or concomitant therapy that could counteract the major negative side effect of angioplasty—namely restenosis. The increased use of permanently implanted stents over the past 5–10 years has reduced restenosis rates to approximately 20–40%; however, even with stents, the annual cost burden of coronary artery restenosis exceeds $1 billion annually in the United States alone. Thus, early animal studies (first reported in 1994) which showed a 70% reduction in restenosis rates with endovascular brachytherapy (4) were received with great interest, spawned many additional new studies, and culminated in the initiation of human clinical trials. The first doubleblinded, randomized human clinical trial was started in early 1995 at the Scripps Institute (5). This blinded, randomized trial of 55 patients confirmed, in humans, that endovascular radiation could indeed reduce the rate of restenosis by approximately 70%. Until very recently, all endovascular brachytherapy studies, both in humans and in animals, have had at least two significant characteristics in common:

Tumors in dogs exposed to experimental intraoperative radiotherapy

The frequency of radiation-induced neoplasms was determined in dogs enrolled in the National Cancer Institute canine trials of intraoperative radiotherapy (IORT). Twelve protocols assessing normal tissue response to IORT involved 238 dogs in a 15-year trial. Eighty-one dogs were followed for > 24 months postoperatively and were assessed for tumor development; 59 of these animals received IORT. Twelve tumors occurred in the 59 dogs receiving IORT. Nine were in the IORT portals and were considered to be radiation induced. No tumors occurred in 13 sham animals or in 9 animals treated with external beam radiotherapy alone. The frequency of radiation-induced malignancies in dogs receiving IORT was 15%, and was 25% in animals receiving > or = 25 Gy IORT. Frequency of all tumors, including spontaneous lesions, was 20%. Intraoperative radiotherapy contributed to a high frequency of sarcoma induction in these dogs. Unknown to date in humans involved in clinical trials of IORT, this potential complication should be looked for as long-term survivors are followed.

Clinical toxicity of peripheral nerve to intraoperative radiotherapy in a canine model

The clinical late effects of intraoperative radiotherapy (IORT) on peripheral nerve were investigated in a foxhound model. Between 1982 and 1987, 40 animals underwent laparotomy with intraoperative radiotherapy of doses from 0-75 Gy administered to the right lumbosacral plexus. Subsequently, all animals were monitored closely and sacrificed to assess clinical effects to peripheral nerve. This analysis reports final clinical results of all animals, with follow-up to 5 years. All animals treated with > or = 25 Gy developed ipsilateral neuropathy. An inverse relationship was noted between intraoperative radiotherapy dose and time to neuropathy, with an effective dose for 50% paralysis (ED50) of 17.2 Gy. One of the animals treated with 15 Gy IORT developed paralysis, after a much longer latency than the other animals. Doses of 15 Gy delivered intraoperatively may be accompanied by peripheral neuropathy with long-term follow-up. This threshold is less than that reported with shorter follow-up. The value of ED50 determined here is in keeping with data from other animal trials, and from clinical trials in humans.

Intraoperative radiation therapy (IORT) for head and neck cancer

Purpose : To determine the efficacy of intraoperative radiation therapy (IORT) for patients with advanced or recurrent head and neck cancer. Methods and Materials : Intraoperative radiation therapy was given at 30 sites in 25 patients using a 6–18 MeV electron beam with or without conventional external beam irradiation. A single dose of 10–30 Gy was delivered after surgical resection. Sites treated with IORT were classified into three types after surgical resection: gross residual disease (GR, n = 7), microscopic residual disease (MR, n = 12), and close margin (CM, n = 11). Local control rate, patterns of recurrence, survival rate, and complications were analyzed. Results : The 2-year cumulative local control rate within the IORT port was 54.1% for all cases, 0% for GR, 54.5% for MR, and 81.8% for CM. There were significant differences between GR and MR ( p < 0.05), and GR and CM ( p < 0.01). The majority of the failures inside the IORT port were associated with recurrence outside the port. Distant metastases occurred in five patients. Four of these had GR. The 2-year cumulative survival rate was 45.1 % for all, 0% for GR, 33.0% for MR, and 70.0% for CM. Five patients (22%) experienced late complications. The 2-year cumulative complication rate was 32.8%. Four sites developed osteoradionecrosis and three developed carotid artery blowout. Incidence of complications increased when patients received over 20 Gy with a single dose of IORT. Conclusions : Considering both therapeutic ratio and patterns of failure, it is not suitable to treat patients with gross residual disease with IORT. We could not firmly determine the therapeutic value of IORT for patients with microscopic residual disease and close margin. For this subset, further study of moderate dose (less than 20 Gy) IORT combined with adequate postoperative irradiation is needed.

Tolerance of the bladder to intraoperative radiation in a canine model: A five-year follow-up

Purpose : Late effects of intraoperative radiation therapy (IORT) on bladder were investigated in a canine model. Methods and Materials : After laporatomy and cystotomy in adult female foxhounds weighing 25–35 kg, 12 MeV electrons were delivered intraoperatively to a 5 cm circular bladder field which included the trigone and both uretero-vesicle junctions. Each animal received doses of 0, 20, 25, 30, 35, or 40 Gy. All the dogs were followed 5 years postoperatively. An unoperated dog receiving no surgery or radiation treatment was followed as a control. Close clinical monitoring was performed with regular cystometrics and intravenous pyelography. Animals were killed as scheduled with complete necropsies, including histopathology, with special attention to genitourinary structures. Results : There were no acute or late bladder complications detected clinically in any animal. The dog receiving 30 Gy IORT developed rhabdomyosarcoma in the treatment field at 58 months. On follow-up testing over 5 years, there was no loss of bladder contractility on cystometry, and mild changes in the ureters on intravenous pyleography when animals receiving IORT were compared with baseline pretreatment values or with control animals. Histologically, a difference was evident between irradiated and unirradiated animals, but the changes were not clearly dose-related. Conclusion : Intraoperative radiation theraoy may by safely delivered to the canine bladder with few acute or chronic complications. It is an approach which has potential for clinical use and should continue to be explored in human clinical trials.

Late effects of intraoperative radiation therapy on retroperitoneal tissues, intestine, and bile duct in a large animal model

Purpose : The late histopathological effects of intraoperative radiotherapy (IORT) on retroperitoneal tissues, intestine, and bile duct were investigated in dogs. Methods and Materials : Fourteen adult foxhounds were subjected to laparotomy and varying doses (0–45 Gy) of IORT (11 MeV electrons) delivered to retroperitoneal tissues including the great vessels and ureters, to a loop of defunctionalized small bowel, or to the extrahepatic bile duct. One control animal received an aortic transection and reanastomosis at the time of laparotomy; another control received laparotomy alone. This paper describes the late effects of single-fraction IORT occurring 3–5 years following treatment. Results and Conclusion : Dogs receiving IORT to the retroperitoneum through a 4 × 15 cm portal showed few gross or histologic abnormalities at 20 Gy. At doses ranging from 30–45 Gy, radiation changes in normal tissues were consistently observed. Retroperitoneal fibrosis with encasement of the ureters and great vessels developed at doses ≥ 30 Gy. Radiation changes were present in the aorta and vena cava at doses ≥ 40 Gy. A 30 Gy dog developed an in-field malignant osteosarcoma at 3 years which invaded the vertebral column and compressed the spinal cord. A 40 Gy animal developed obstruction of the right ureter with fatal septic hydronephrosis at 4 years. Animals receiving IORT through a 5 cm IORT portal to an upper abdominal field which included a defunctionalized loop of small bowel, showed few gross or histologic abnormalities at a dose of 20 Gy. At 30 Gy, hyaline degeneration of the intestinal muscularis layer of the bowel occurred. At a dose of 45 Gy, internal intestinal fistulae developed. One 30 Gy animal developed right ureteral obstruction and hydronephrosis at 5 years. A dog receiving 30 Gy IORT through a 5 cm portal to the extrahepatic bile duct showed diffuse fibrosis through the gastroduodenal ligament. These canine studies contribute to the area of late tissue tolerance to IORT.

The reduced canine pancreas to study the effects of intra-operative radiotherapy.

A canine model is described to study the tolerance of the pancreas to intra-operative radiotherapy (IORT). The canine pancreas is a horseshoe-shaped organ. To create a homogeneous delivery of IORT to the whole pancreas surgical manipulation is necessary which may induce pancreatitis. A resection of the left and right lobes of the pancreas facilitates the delivery of IORT, reduces the risk of pancreatitis and will demonstrate, eventually, minimal functional changes in the exocrine and endocrine pancreas at an earlier stage. Sixteen beagles were used. Investigations before and after the reduction procedure were intravenous glucose tolerance tests, serum insulin levels, faecal fat excretion, blood chemistry tests and body weight. Eight weeks after the pancreas reduction 15 dogs underwent an IORT procedure in which 25, 30 or 35 Gy IORT was delivered to the pancreatic remnant. We conclude that the pancreas reduction technique used to study the effects of IORT to the canine pancreas is feasible without mortality or morbidity. Endocrine and exocrine pancreatic function remained normal with a minimal follow-up of 3 months.

Long term tolerance of thoracic organs to intraoperative radiotherapy

The tolerance of mediastinal structures to intraoperative radiotherapy (IORT) was investigated in 3 separate animal trials using 49 adult foxhounds and one limited Phase I trial in 4 patients with Stage II or III non-small cell lung cancer (NSCLC). The 1- to 2-year results of these trials have been previously reported with significant toxicity found at dose levels over 20 Gy. We now report the results of five dogs reserved for long term studies and one Stage II NSCLC patient alive at 5 years. Two dogs received 20 Gy IORT and one received 30 Gy IORT to the esophagus, all three to a single 6 cm field with 9 MeV electrons. One control dog underwent surgery without irradiation. One dog received 20 Gy IORT to a single 5 cm mediastinal field with 13 MeV electrons following left pneumonectomy. At 5 years, all five dogs reserved for a long term evaluation were alive and evaluable with minimal endoscopic and radiographic abnormalities. The one patient alive at 5 years for evaluation received 25 Gy IORT to two matched 6 cm fields with 13 MeV electrons. She has stable dyspnea on exertion and there is no evidence of cancer by endoscopy. We conclude, based on these limited data, that IORT in the mediastinum may be safe at dose levels that do not exceed 20 Gy, and further careful evaluation at these lower treatment doses is warranted to determine efficacy.

Intraoperative radiotherapy with localized radioprotection: Diminished duodenal toxicity with intraluminal WR2721

The radiosensitive duodenum must be treated during IORT of human pancreatic head tumors, leading to an approximately 25% incidence of late bleeding. This study aimed to decrease the toxicity by administering WR2721 directly into the duodenal lumen. Duodenal toxicity in the canine was evaluated after intraoperative radiotherapy (IORT) with and without the intraluminal radioprotector WR2721. Eight adult dogs were divided into two groups. All underwent IORT using a 5.7 cm cone that covered the duodenum and pancreas. 30.0 Gy IORT was given with 6 MeV electrons. Cholecystojejunostomy and gastrojejunostomy were performed. Four dogs served as IORT only controls; one was unevaluable. Four dogs received WR2721, intraluminally at 720 mg/M 2, in 16–18 ml Ringer's. Atraumatic clamps were placed on proximal and distal duodenum, without vascular compromise. WR2721 was injected into the duodenal lumen 30 minutes prior to IORT. Immediate post-operative recovery of the dogs receiving WR2721 was faster than controls. Necropsies were performed at 6 months. Grossly increased adhesions were noted in controls. Histopathologically, mucosal atrophy was greater in control dogs. Duodenal ulceration was noted in all controls, but in only one of four WR2721 dogs. Masson's trichrome and Verhoff Van Gieson stains demonstrated increased perivascular fibrosis, intimal proliferation, and fibrinoid medial necrosis of vessels in all controls, and one WR2721 dog. The other three WR2721 dogs had only mild perivascular fibrosis. Radioprotection, evaluated by the presence or absence of pancreatic atrophy, appeared to stop just beyond the bowel wall. In summary, WR2721 provided duodenal radioprotection in most dogs. The intraluminal administration of WR2721 allows decreased systemic side effects, and may eliminate tumor absorption. The study indicates that the intraluminal use of radioprotectors has broad potential application.

Threshold dose for peripheral neuropathy following intraoperative radiotherapy (IORT) in a large animal model

Radiation injury to peripheral nerve is a dose-limiting toxicity in the clinical application of intraoperative radiotherapy, particularly for pelvic and retroperitoneal tumors. Intraoperative radiotherapy-related peripheral neuropathy in humans receiving doses of 20–25 Gy is manifested as a mixed motor-sensory deficit beginning 6–9 months following treatment. In a previous experimental study of intraoperative radiotherapy-related neuropathy of the lumbro-sacral plexus, an approximate inverse linear relationship was reported between the intraoperative dose (20–75 Gy range) and the time to onset of hind limb paresis (1–12 mos following intraoperative radiotherapy). The principal histological lesion in irradiated nerve was loss of large nerve fibers and perineural fibrosis without significant vascular injury. Similar histological changes in irradiated nerves were found in humans. To assess peripheral nerve injury to lower doses of intraoperative radiotherapy in this same large animal model, groups of four adult American Foxhounds (wt 20–25 kg) received doses of 10, 15, or 20 Gy to the right lumbro-sacral plexus and sciatic nerve using 9 MeV electrons. The left lumbro-sacral plexus and sciatic nerve were excluded from the intraoperative field to allow each animal to serve as its own control. Following treatment, a complete neurological exam, electromyogram, and nerve conduction studies were performed monthly for 1 year. Monthly neurological exams were performed in years 2 and 3 whereas electromyogram and nerve conduction studies were performed every 3 months during this follow-up period. With follow-up of >42 months, no dog receiving 10 or 15 Gy IORT shows any clinical or laboratory evidence of peripheral nerve injury. However, all four dogs receiving 20 Gy developed right hind limb paresis at 8, 9, 9, and 12 mos following intraoperative radiotherapy. These experimental data suggest that intraoperative doses of <20 Gy may not result in clinically significant peripheral nerve injury with follow-up of 3.5 years. Longer (5 yrs) followup up with planned sacrifice of the remaining dogs is scheduled to assess any late peripheral nerve damage.

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 ED 50 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.

Response of aorta and branch arteries to experimental intraoperative irradiation

Injury to the aorta was evaluated in dogs 2 and 5 years after fractionated irradiation (EBRT), intraoperative irradiation (IORT) or a combination. Doses greater than 20 Gy IORT combined with 50 Gy EBRT given in 2 Gy fractions or 30 Gy IORT alone were accompanied by a significant risk of aneurysms or large thrombi as determined at necropsy 4 to 5 years following irradiation. Narrowing of the aorta as detected by aortography occurred at 5 years but was not detected earlier. The ED50 for aortic narrowing was 38.8 Gy IORT and 31 Gy IORT plus 50 Gy EBRT. The ED 50 for branch artery injury was 24.8 Gy IORT alone and 19.4 Gy IORT plus 50 Gy EBRT. The difference in ED 50s for IORT alone and IORT plus EBRT indicates that the contribution of the EBRT dose in terms of an IORT dose for aortic narrowing was 7.8 Gy and for branch artery injury was 5.4 Gy. The ED 50 for incidence of small thrombi in the aorta was about 29 Gy for IORT alone and 23.5 Gy for IORT combined with EBRT. Fibrous thickening of the adventitia was measured and the effect of the 50 Gy EBRT component of a combination of EBRT and IORT was determined to be equivalent to 10 to 12 Gy IORT. Based on the various estimates, IORT doses of 10–15 Gy have an effect of 5 times or greater the amount given in 2 Gy fractions. At all EBRT doses and at lower IORT doses the intima was greatly thickened. At IORT doses of 20 Gy or above there was a dose related decrease in intimal thickness to near normal values. This was probably due to cell killing or inhibition of intimal proliferation that predominated at higher doses. Although the risk of serious vascular complications appears low following IORT of humans, this may be due to short observation times and the fact that IORT doses currently used are usually 20 Gy or less; this may be near the tolerance for late response of larger arteries. Only one dog in this study had complete rupture of the aorta causing death. Five other dogs at high IORT doses had near ruptures of the aorta but were clinically normal.