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Published online before print May 15, 2003, 10.1148/radiol.2281011963
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(Radiology 2003;228:139-143.)
© RSNA, 2003

Experimental Studies

Influence of Irradiated Volume on Ureteral Injury after Intraoperative Radiation Therapy: Experimental Study in Dogs1

Michael van Kampen, MD, Michael J. Eble, MD, Robert Krempien, MD, Katrin Jensen, PhD, Barbar Aydenitz, MD, Martin Metzger, PhD, Frank Hensley, PhD, Sabine Haufe, MD, Folker Amelung, MD, Diethelm Wallwiener, MD and Michael Wannenmacher, MD, DDS

1 From the Department of Radiation Oncology, Krankenhaus Nordwest, Steinbacher Hohl 2-26, D-60244 Frankfurt, Germany (M.v.K.); Department of Radiation Oncology, University of Aachen, Germany (M.J.E.); Department of Radiation Oncology (R.K., M.M., F.H., M.W.), Institute of Medical Biometry and Informatics (K.J.), and Department of Nuclear Medicine (S.H.), University of Heidelberg, Germany; Department of Gynecology, University of Tübingen, Germany (B.A., D.W.); and German Cancer Research Center, Heidelberg, Germany (F.A.). From the 2001 RSNA scientific assembly. Received November 30, 2001; revision requested February 13, 2002; final revision received October 21; accepted November 27. Supported by a grant from the Forschungskommission der medizinischen Fakultät der Universität Heidelberg. Address correspondence to M.v.K. (e-mail: m.van_kampen@khnw.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To investigate the role of irradiated volumes at intraoperative radiation therapy in the development of ureteral injury in dogs.

MATERIALS AND METHODS: Sixteen beagle dogs were randomized to receive 30 Gy of intraoperative radiation therapy in the right ureter. Lead shielding ensured that different volumes were irradiated. Six dogs received a 4 x 12-cm field, five dogs a 4 x 8-cm field, and five dogs a 4 x 4-cm field. Follow-up included magnetic resonance (MR) imaging, clinical examination, and resting sequential renography. Twelve months after irradiation, the animals were killed, and autopsy was performed. Functional outcome was defined as MR imaging and renography findings and was evaluated statistically by using the Cochran-Armitage test at a .05 significance level.

RESULTS: Twelve months after therapy, ureteral obstruction with consecutive hydronephrosis of the right kidney was observed in four of six animals that received the largest volume of irradiation. Two dogs that received the medium volume developed ureteral obstruction. None of the five dogs that received the smallest volume showed abnormal findings (P < .05). The irradiated parts of the ureters in all dogs showed abnormal histopathologic findings, such as fibrosis.

CONCLUSION: The probability of ureteral obstruction following intraoperative radiation therapy increases with the irradiated partial volume of the ureter.

© RSNA, 2003

Index terms: Animals • Experimental study • Radiations, injurious effects, 82.47 • Therapeutic radiology, experimental studies, 82.47 • Therapeutic radiology, intraoperative, 82.47 • Ureter, interventional procedures, 82.47


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
The advantage of intraoperative radiation therapy lies in the fact that the patient’s anatomy can be adjusted to the needs of radiation oncology treatment. Thus, in most situations, the surrounding organs at risk are not irradiated unnecessarily. This method is limited for certain structures, however, such as the nerves and ureters, which cannot be sufficiently mobilized within the irradiated field or which may be infiltrated by tumor and are therefore intentionally left in the field. Disadvantages of intraoperative radiation therapy are the summation of toxicity from surgery and radiation therapy; also, the high radiation dose is of biologic disadvantage. Unfortunately, the experiences from fractionated external beam radiation therapy concerning biologic effectiveness and tissue tolerance are not transferable. For that reason, in the past, several investigations were conducted to define the dose-response relationship.

An association between the irradiated volume and the probability of side effects has been demonstrated for fractionated radiation therapy (1–4). Experimental investigations as to whether this volume-response relationship is also of clinical relevance for intraoperative radiation therapy are few. Since ureteral injury is reported to be problematic after intraoperative radiation therapy of gynecologic pelvic malignancies (5), the purpose of the present study was to investigate the role of irradiated volumes at intraoperative radiation therapy in the development of ureteral injury in dogs.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Experimental Design
The authors complied with the National Institute of Health guidelines for use of laboratory animals. This study was approved by the local animal care committee. Sixteen adult female beagle dogs were randomized to receive 30 Gy of intraoperative radiation therapy in the right retroperitoneal area with three different field sizes (Fig 1). The target volume covered the right ureter below the right kidney. To standardize the surgical procedure, a 12 x 4-cm polytetrafluoroethylene cone was placed in situ to cover the same anatomic structures in each animal. Within this cone, three differently sized stainless steel cones were placed to ensure that different volumes were irradiated. Six dogs received a 4 x 12-cm field (large volume, covering all of the maximum cone area), five dogs received a 4 x 8-cm field (medium volume, covering two-thirds of the maximum cone area), and five dogs received a 4 x 4-cm field (small volume, covering one-third of the maximum cone area). Follow-up was performed every 3 months by means of clinical examination, magnetic resonance (MR) imaging, and resting sequential renography. Twelve months after irradiation, autopsy was performed in all animals except one, in which impaired performance was observed after 3 months.



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  		Figure 1. Diagram of the experimental design. IORT = intraoperative radiation therapy.

 
Surgery
After midventral transection, the uterus was extirpated, and both ureters were dissected (D.W. or B.A., assisted by M.v.K.). The radiation field covered the right ureter, but care was taken to exclude the left ureter. After sedation with intramuscular administration of 1 mg per kilogram of body weight of azaperon, general anesthesia was administered with 1 mg/kg intravenous flunitrazepam and 5–7 mg/kg intramuscular ketamine for induction. Doses were repeated for flunitrazepam at 0.5 mg/kg/h and ketamine at 5 mg/kg/h. Oxygen and halothane (1.0–2.0 vol%) were used with a flow rate of 4.0 mL/min after endotracheal intubation. Intraoperative radiation therapy was then performed (M.v.K., assisted by M.M. or F.H.).

Irradiation
A single fraction of 30 Gy was administered intraoperatively by means of a clinical linear accelerator operating at 6 MeV. Three differently sized sterile stainless steel applicators were used for collimation. For each of these applicators, dose profiles were measured in a solid water phantom. A bolus of 0.5 cm of wet gauze was placed in the field to ensure full-dose buildup at the irradiated tissue surface, and doses were calculated at the 100% isodose line, which referred to the maximum.

Follow-up
After treatment, animals were followed regularly with clinical observation for performance score in terms of uptake of food and water, weight, and evidence of neurologic impairment of the lower legs. Performance was classified as normal or abnormal. In animals with abnormal performance, score autopsy was performed. Radiologic observation included MR imaging of the abdominal cavity every 3 months and resting sequential renography every 6 months. All MR images were acquired with a low-field-strength resistive (0.23-T) open MR system (Outlook; Marconi Medical Systems, Helsinki, Finland) by using standard radio-frequency coils. MR imaging included T2-weighted spin-echo (repetition time msec/echo time msec, 2,000/100) sequences without use of contrast media and T1-weighted spin-echo (300/24) sequences with and those without use of 0.5 mol/L gadopentetate dimeglumine at 3 mL/kg. Ureteral obstruction was diagnosed when MR images showed dilatation of the renal pelvis and calyces by more than 50% compared with the contralateral area. Hydronephrosis was diagnosed when MR images showed decline of renal parenchyma by more than 50% compared with the contralateral area. MR images were interpreted in consensus (M.v.K., R.K.).

Renal function was observed 6 and 12 months after irradiation with use of resting sequential renography with 7.4 MBq of technetium 99m mercaptoacetyltriglycine, a labeled paraaminohipporat analog. All authors also had sufficient experience with furosemide to ascertain a urine transit disturbance. Quantification of renal function was performed as described by others (6,7). According to these criteria, the findings were classified as normal, evidence of obstruction present, or intermediate. Intermediate excretion is neither timely nor diagnostic for obstruction. The resting sequential renography examinations are nondiagnostic and generally require reevaluation to determine whether the kidney is at risk, since it experiences a loss of function with time. Renograms were interpreted by one author (S.H.).

MR imaging and sequential renographic findings were defined as functional outcome.

Autopsy and Histologic Evaluation
Twelve months after irradiation, surgical exploration of both kidneys and both ureters was performed after administration of general anesthesia. During the preparation process, retroperitoneal tissue was classified as normal or fibrotic. The ureter was palpated, and the length of stenotic parts was compared with the length of the irradiated field. Irradiated and nonirradiated parts of the right ureter were marked. The renal cortex was measured. Animals were sacrificed by using a lethal injection of potassium chloride. Tissue samples were fixed in neutral buffered formalin, embedded in paraffin, sectioned, mounted, and stained with hematoxylin-eosin. Additionally, a Masson-Goldner stain was used to demonstrate fibrosis. A descriptive depiction of functional parameters, such as reduction of pleating of the mucosa and loss of the muscles of the ureter, was performed.

Statistical Evaluation
To decide whether the number of animals with ureteral injury increases with an increased volume of irradiation, the two-sided exact Cochran-Armitage trend test was used at a .05 significance level (8). At 12 months, all animals that had developed a stenosis that was visible at functional imaging were accounted for in the statistical analysis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Clinical Follow-up
One animal showed impairment of performance status 3 months after irradiation. This animal was sacrificed, and autopsy was performed. All other animals showed a normal performance score up until the end of the study.

Progression of MR Imaging Findings
Three months after irradiation, all animals underwent MR imaging. At this time, three of six dogs from the group that received the large volume showed signs of ureteral obstruction with a dilated renal pelvis. One of these animals was sacrificed 1 day after MR imaging because of reduced performance status, and autopsy was performed. None of the animals from the groups that received the medium and small volumes showed abnormal findings on MR images.

Six months after irradiation, the same MR imaging findings were observed. The ratio of ureteral obstruction in the large volume group was three (two living animals and one that was sacrificed) of six. No animals in the medium and small volume groups showed abnormal findings on MR images.

Nine months after irradiation, two other animals developed dilatation of the renal pelvis. One of these dogs was from the large volume group. In this group, the ratio of ureteral obstruction was four of six animals at this time. One animal from the medium volume group developed ureteral obstruction 9 months after irradiation. The ratio of ureteral obstruction at this time was one of five in this group. None of the animals in the small volume group showed abnormal findings on MR images.

Twelve months after irradiation, the ratio of ureteral obstruction in the large volume group was four of six animals.

One more animal from the medium volume group developed ureteral obstruction 12 months after irradiation. The ratio of ureteral obstruction at this time was two of five in this group. None of the animals in the small volume group showed abnormal findings on MR images (Figs 2–4).



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  		Figure 2. Bar graph shows MR imaging findings: progression of the small-volume group. Vertical axis is number of animals. Gray bars indicate the number of animals without ureteral obstruction. IORT = intraoperative radiation therapy.

 


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  		Figure 3. Bar graph shows MR imaging findings: progression of the medium-volume group. Vertical axis is number of animals. Gray bars indicate the number of animals without ureteral obstruction, and black bars indicate the number of animals with ureteral obstruction. IORT = intraoperative radiation therapy.

 


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  		Figure 4. Bar graph shows MR imaging findings: progression of the large-volume group. Vertical axis is number of animals. Gray bars indicate the number of animals without ureteral obstruction, and black bars indicate the number of animals with ureteral obstruction. IORT = intraoperative radiation therapy.

 
Progression of Resting Sequential Renography Findings
Fifteen animals were studied 6 months after irradiation, 11 of which had normal renographic findings. One dog in the large volume group had a nonfunctioning kidney. Two other dogs had balanced renal function, with an associated excretory disturbance of the intermediate type. This finding was also seen in an animal in the medium volume group. None of the dogs in the small volume group had evidence of obstruction (Fig 5).



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  		Figure 5. Graph shows resting sequential renographic findings 6 months after irradiation: number of animals and degree of ureteral injury. Vertical axis is number of animals. White bars indicate the number of animals without ureteral obstruction, gray bars indicate the number of animals with intermediate excretion disturbance, and black bars indicate the number of animals with ureteral obstruction.

 
At the follow-up examination 12 months after irradiation, a urinary transport disturbance was identified in three animals in the large volume group. Two of these animals had an obstruction, and one animal had intermediate excretion disturbance. Two other animals in this large volume group had normal urinary excretion. The medium volume group included one animal with relevant obstruction, one animal with intermediate excretory disturbance, and three animals with timely excretion. None of the animals in the small volume group had evidence of obstruction (Fig 6).



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  		Figure 6. Graph shows resting sequential renographic findings 12 months after irradiation: number of animals and degree of ureteral injury. Vertical axis is number of animals. White bars indicate the number of animals without ureteral obstruction, gray bars indicate the number of animals with intermediate excretion disturbance, and black bars indicate the number of animals with ureteral obstruction.

 
Functional Outcome 12 Months after Irradiation
Figure 7 summarizes MR imaging and sequential renography findings at 12 months. The Cochran-Armitage test was used for this endpoint (ratio of ureteral injury 12 months after irradiation). At that time, none of the five animals in the small volume group showed abnormal findings. Two of the five animals in the medium volume group and four of the six animals in the large volume group showed ureteral injury. The dependence of ureteral injury on increasing volume was statistically significant (P = .034).



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  		Figure 7. Number of animals with (black bars) and number without (gray bars) ureteral injury at MR imaging and sequential renography 12 months after irradiation. Vertical axis is number of animals. The progression of the number of animals with ureteral injury independence from the irradiated volume is statistically significant (P = .034, Cochran-Armitage test).

 
Autopsy Results
Autopsy showed a stenosis of the right ureter in four of six animals in the large volume group. One of these animals was sacrificed 3 months after irradiation because of reduced performance score. Autopsy showed fibrosis of the right ureter and an obstruction of the left ureter due to scar tissue, which resulted in bilateral hydronephrosis. Three of five animals in the medium volume group and no animals in the small volume group had a stenosis. The length of the stenoses, which were visible and palpable, was identical to the length of the radiation field. These animals showed a decrease in width of the right renal cortex of more than 50% compared with that of the left kidney. Retroperitoneal fibrosis was observed in four animals in the large volume group, three animals in the medium volume group, and one animal in the small volume group.

Histopathologic Findings
Fibrosis of the right ureter was seen in 14 of 16 animals. There was no significant difference in the degree of fibrosis between ureters with and those without macroscopically visible stenosis. In all cases, the ureter was not totally obstructed, and there was a residual lumen. As a sign of functional loss, the pleating of the mucosa was reduced, and a loss of muscle was observed.

Hydronephrosis of the right kidney was observed in four of six animals in the large volume group and in three of five animals in the medium volume group. One of these animals had mild signs and had no corresponding findings at diagnostic imaging. None of the five animals in the small volume group showed signs of hydronephrosis.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Ureteral obstruction with hydronephrosis has been reported to occur in up to 63% of patients with pelvic malignancies who receive intraoperative irradiation (5). The purpose of the present study was to investigate the role of the irradiated volume in the development of ureteral injury.

To keep the number of irradiated animals as low as possible, a constant dose of radiation was given. The dose-response relationship of intraoperatively irradiated ureters in beagle dogs is well known. An effective dose of 32.9 Gy delivered intraoperatively with a field size of 8 x 5 cm was reported to cause abnormal findings at diagnostic imaging in 50% of dogs (9). In that study (9), the effective dose that caused abnormal histopathologic findings in 50% of dogs was 29.3 Gy. On the basis of these data, the intraoperatively delivered dose in our study was 30 Gy. Since radiation-induced sequels are late effects, the observation time was a critical issue in our study. An increase in abnormal histopathologic findings was reported (10) within the 1st year after irradiation of retroperitoneal structures. After this time, no significant changes were reported. As a result of these published data, we chose an observation time of 12 months in our study.

A statistically significant increase in frequency of functional ureteral injury depending on the volume irradiated was observed in the present study. Twelve months after irradiation, none of five animals with a 4 x 4-cm irradiated field showed abnormal findings at diagnostic imaging. Two of the five animals with a 4 x 8-cm irradiated field showed ureteral injury, and four of the six animals with a 4 x 12-cm irradiated field showed ureteral injury.

On the other hand, abnormal histologic findings in the irradiated ureter, such as fibrosis, did not reflect a strong volume-dependent relationship. In the literature, this experience was reported for external-beam therapy (11). After irradiation of two different lung volumes in pigs, no significant differences between the dose-response relationships of structural damage were observed. In contrast, an increased breathing rate as an expression of functional morbidity that depends on the amount of irradiated volume was found. This is in accordance with the findings of other authors who investigated the volume effect of percutaneous irradiation of the rectum and ureters in mice (12,13). Even if conclusions have to be drawn cautiously for the small number of intraoperatively irradiated animals in our study, our findings indicate that for the evaluation of volume effects in intraoperative radiation therapy, functional endpoints must be chosen. The same degree of a structural isoeffect may be well tolerated in a small volume but may cause functional breakdown if a large volume of an organ is irradiated. Since tumors of the lower pelvis require treatment with radiation therapy more often than do other regions, in clinical situations, the lower part of the ureter is of more interest. Therefore, in the present study, the inferior part of the ureter was selectively irradiated. Since the histologic findings showed that there was no total obstruction, it could be assumed that the peristaltic power of the unirradiated ureter was able to overcome a short fibrotic part. A longer fibrotic part of the ureter seemed to cause a functional breakdown. It would be interesting to study whether selective irradiation of the upper part of the ureter would fail to show a volume effect, since the renal pelvis is not able to produce significant pressure.

Preliminary data have been published in another experimental study (14) that addresses the same questions. The purpose of that study was to describe an increase in the effective dose (that caused effects in 50% of dogs) with regard to incidence of ureteral injury for three irradiated volumes of the ureter in beagle dogs. A dose of 21.9 Gy for an irradiated length of 8 cm of the ureter was given. A dose of 43 Gy for an irradiated length of 4 cm and a dose of 85 Gy for an irradiated length of 2 cm were also reported. Unfortunately, no radiation was applied in this dose range; therefore, these data are calculated values (14). The reported effects were abnormal findings at diagnostic imaging; histologic verification was not performed.

The data in our study and the extrapolated results of the previous study (14) support the hypothesis that a volume-response relationship exists for intraoperative radiation therapy. Furthermore, even the time course of ureteral injury seems to follow this relationship. In the large volume group, not only a higher number of animals with ureteral injury was reached at an earlier time than in the medium volume group, but also the degree of abnormal findings showed a higher level at an earlier time. Data concerning the time course of abnormal findings within the 1st year after intraoperative radiation therapy are not reported in the previous study (14).

Practical applications: Our data suggest a volume-response relationship for intraoperative radiation therapy. Further clinical investigations might involve identification of a threshold volume at a certain dose level at which irradiation of parts of the ureter would be possible without taking a great risk for functional impairment. A clinical study has been published that identify such a threshold volume for soft-tissue fibrosis (15).


   FOOTNOTES
 
Author contributions: Guarantors of integrity of entire study, M.v.K., M.W., D.W.; study concepts, M.v.K., M.J.E., M.W., D.W.; study design, all authors; literature research, M.v.K., R.K., S.H.; experimental studies, all authors; data acquisition, M.v.K., M.J.E., R.K., K.J., B.A., M.M., F.H., S.H., F.A.; data analysis/interpretation, M.v.K., K.J.; statistical analysis, K.J.; manuscript preparation, M.v.K., R.K., K.J., S.H.; manuscript definition of intellectual content, all authors; manuscript editing, M.v.K.; manuscript revision/review and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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  11. Herrmann T, Baumann M, Voigtmann L, Knorr A. Effect of irradiated volume on lung damage in pigs. Radiother Oncol 1997; 44:35-40.[CrossRef][Medline]
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