Iridium-192 Interstitial Brachytherapy as Adjunctive Treatment for Canine Cutaneous Mast Cell Tumors
Eleven dogs with cutaneous mast cell tumors (MCTs) were treated with surgery and iridium-192 (192Ir) interstitial brachytherapy. Minimum tumor doses ranged from 47.2 to 63.3 Gy. Treated tumors were classified as grade II (n=7) or III (n=4). Five dogs had recurrences with a median progression-free interval of 1391 days, and six dogs had no recurrence at a median follow-up time of 942 days. Acute adverse effects were well tolerated, and late effects were mild. One dog developed a second tumor of a different cell type in the radiation treatment field.
Introduction
The efficacy of external-beam radiation therapy for local control of incompletely resected, cutaneous mast cell tumors (MCTs) in dogs has been well demonstrated.1–4 Local control rates of 94% to 97% at 1 year and 86% to 93% at 2 to 5 years have been reported for dogs with incompletely excised, intermediate-grade MCTs treated with 46.2 to 54 Gy of radiation therapy.23 Iridium-192 (192Ir) interstitial brachytherapy offers potential advantages over external-beam radiation therapy, including better localization of the radiation dose, sparing of surrounding normal tissues, delivery of a higher dose to the target volume, constant dosing, decreased total treatment duration, and fewer anesthetic episodes.5–7 Despite these potential benefits, limited use of 192Ir therapy in small animals has been reported, possibly because of difficulties in dose calculation and achieving uniform dose distribution, the requirement for isolated hospitalization of the animal, and radiation exposure to the radiation therapist and support staff.56 The purpose of this study was to describe the use of 192Ir interstitial brachytherapy as an adjunctive therapy to surgery in the management of canine cutaneous MCTs.
Materials and Methods
The University of Georgia College of Veterinary Medicine (UGA-CVM) case database was searched to identify dogs treated with 192Ir for cutaneous MCT from 1991 to 2001. The medical records of 15 dogs were retrospectively reviewed. Four dogs were excluded from the study. Reasons for exclusion included lack of follow-up information (n=2), inadequate follow-up as a consequence of early death from systemic MCT suspected to be present at the time of 192Ir implantation (n=1), and questionable histopathological diagnosis of MCT (n=1).
Pre-192Ir Evaluations and Treatment
Dogs were referred to the UGA-CVM for treatment of nonresectable, incompletely excised, or recurrent MCTs. Tumors were histopathologically graded according to the system described by Patnaik, and margins were assessed for completeness of excision.8 Histopathology slides were reviewed by a single pathologist (Howerth) for confirmation of diagnosis, grade, and to evaluate the margins. Clinical staging tests that were performed in each dog varied, based on the judgment of the attending clinician. Physical examinations, complete blood counts, and serum biochemical profiles were performed in all cases. Other staging tests performed included buffy-coat smears (n=10), abdominal ultrasonography (n=5), abdominal radiography (n=8), and/or cytological examinations of regional lymph nodes (n=8), bone marrow (n=6), spleen (n=2), and/or liver (n=2). Surgical resection was performed by the referring veterinarian or at UGA-CVM prior to 192Ir therapy. If prior excision was incomplete and adequate tissue was present to allow closure without tension, the scar and margins of surrounding normal tissue were resected by the UGA-CVM surgical service immediately prior to 192Ir implantation.
Protocol for 192Ir Treatment
Dogs were anesthetized in an approved isolation area, separate from the main hospital where the iridium seeds were implanted. A single board-certified radiologist (Roberts) implanted the 192Ir ribbonsa in all of the dogs. The ribbons were placed at 1-cm intervals using an after-loading technique [Figures 1, 2]. The ribbons contained 192Ir seeds evenly spaced at 1-cm center-to-center intervals. The activity of each seed was constant for each animal’s implant, but seed activity varied between implants. The range of seed activities was 0.45 to 0.75 milligram radium equivalent (mg Ra Eq), which is a unit used to describe the activity of radioactive isotopes. A modified Quimby system was used for dose calculation and implant characteristics.9 Manual calculations were performed for all cases. The seed activity derived from the Quimby tables for planar implants was increased by 25% to 30% to approximate tumor doses derived using the Paterson and Parker (or Manchester) system.10 Prescribed minimum tumor dosages ranged from 48.3 to 63.3 Gy, with a delivery dose rate of approximately 10 Gy per day. Duration of implantation ranged from 114 to 147.5 hours. The treatment field included the area of the surgical field or macroscopic tumor volume plus at least a 1-cm margin of normal tissue, unless limited by anatomical constraints.
Posttreatment Evaluation
An initial recheck examination at the UGA-CVM was scheduled for 2 weeks after completion of 192Ir therapy. Referring veterinarians performed the subsequent examinations. Follow-up information was obtained by telephone communication with referring veterinarians and owners. Progression-free interval (PFI) was defined as the time, in days, from removal of 192Ir implants until development of recurrent local MCT or until obvious growth of the MCT (for the two dogs with macroscopic disease). Descriptions of adverse effects associated with 192Ir brachytherapy were obtained from medical records and communications with referring veterinarians and owners. Adverse effects were retrospectively scored according to the toxicity criteria of the Veterinary Radiation Therapy Oncology Group.11
Results
Eleven dogs (10 spayed females, one intact male) were treated with 192Ir for MCT. Breeds included the golden retriever (n=3), pug (n=2), Labrador retriever (n=1), Irish wolfhound (n=1), Jack Russell terrier (n=1), and Yorkshire terrier (n=1). There were also two mixed-breed dogs. No clinically significant abnormalities were noted on complete blood counts, biochemical profiles, or urinalyses. For all dogs tested, buffy-coat smears, bone marrow cytology, splenic cytology, and hepatic cytology revealed no evidence of metastasis of the MCT. On cytology of the lymph nodes, two dogs had changes suggestive of MCT metastasis (case nos. 2, 4). However, both of these dogs survived >1 year with no further treatment and no further evidence of MCT.
Tumor location, grade, and radiation doses are presented in the Table. Three dogs had recurrent tumors. Mast cell tumors had recurred three times in case no. 8 and once in case nos. 7 and 10. Histopathology slides were reviewed for nine of the 11 dogs. For the other two dogs, histopathology reports from the medical records were reviewed. Seven dogs had grade II tumors, and four dogs had grade III tumors. Eight dogs had histopathological evidence of residual tumor at the surgical margins at the time of presentation, and one dog (case no. 10) had clean margins but was treated with 192Ir because of the location of the tumor and a history of prior recurrence. Two dogs (case nos. 2, 4) had macroscopic disease. Case no. 2 had a MCT involving much of the lower eyelid, and in case no. 4 the large size and location of the MCT precluded surgical resection and primary closure. A total of three dogs were implanted with 192Ir immediately postoperatively, including case no. 8 (which followed resection of the third recurrence of a MCT) and case nos. 3 and 7 (which followed surgical revision of the scar from a prior resection of a MCT). The remaining dogs were implanted a median of 24 days after surgery (range, 14 to 28 days). In case nos. 3 and 7, no macroscopic tumor was present, but the surgical scar and adjacent tissues were excised immediately prior to 192Ir implantation because of incomplete resection reported in the histopathological description of the prior excision of the MCT. Mast cell tumor was not subsequently identified histopathologically in the tissues resected from either of these dogs at the time of 192Ir implantation.
The median minimum tumor dose delivered was 54.5 Gy (range, 47.2 to 63.3 Gy). Case no. 4 removed the 192Ir implants 1 day before the end of the planned treatment period. Consequently, this dog received an estimated minimum tumor dose of 47.2 Gy. A tapering antiinflammatory dose of prednisone (starting at 0.5 to 1 mg/kg per day per os) was administered to four dogs for 2 to 4 weeks following 192Ir treatment for cutaneous radiation reactions. None of the dogs received any adjunctive chemotherapy for MCT.
Five of the 11 dogs developed local recurrences at a median of 1391 days (range, 74 to 2351 days). Six dogs had no evidence of local recurrence at a median follow-up period of 942 days (range, 261 to 2268 days). Four of the 11 dogs were alive at the completion of the study. Median follow-up for these four dogs was 960 days (range, 261 to 2268 days). Two dogs were lost to follow-up. Case no. 9 was lost to follow-up 1419 days after radiation therapy. At 1391 days posttreatment, this dog underwent resection of a histopathologically confirmed recurrent MCT and a second tumor, a confirmed soft-tissue fibrosarcoma. Both tumors were located within the radiation field. Case no. 3 was lost to follow-up at 730 days and had no evidence of MCT.
Four dogs died as a consequence of MCT at a median of 918 days (range, 124 to 2447 days). Case no. 8, treated after the third recurrence of a grade III tumor of the elbow, was euthanized 124 days after radiation therapy for multiple recurrent MCTs within and around the radiation field. Case no. 7, treated for a recurrent grade III tumor, developed a recurrence within the radiation field and at other cutaneous sites 74 days post 192Ir therapy. Case no. 7 was euthanized for progressive disease at 208 days posttreatment. This dog had the largest treatment field (100 cm2) and had MCTs at five additional sites detected during hospitalization after 192Ir brachytherapy. These additional sites were treated with surgical resection, and no further treatment was pursued. Case no. 11 was euthanized 2447 days after treatment because of a mass within the radiation field. This mass was ulcerated, hemorrhagic, and suspected to represent recurrence of MCT; however, tumor type was not confirmed cytologically or histopathologically. Case no. 10 was euthanized for a confirmed recurrence within the radiation field at 1627 days posttherapy. Case no. 4 died of unrelated causes (i.e., progressive incontinence and abnormal mentation) and had no evidence of MCT at 1153 days postradiation therapy.
None of the dogs that were implanted immediately postoperatively experienced complications in wound healing. Evidence of acute radiation toxicity during the 2 to 4 weeks after treatment was documented in seven dogs. Six of these dogs were evaluated at UGA-CVM, and one dog was examined by the referring veterinarian. Some dogs had more than one adverse effect. Erythema and inflammation (grade 1 acute skin morbidity) were seen in all seven dogs.11 Dry desquamation and scabbing (grade 1 acute skin morbidity) were seen in three dogs, and moist desquamation (grade 2 to 3 acute skin morbidity) was seen in four dogs.11 It was not possible to retrospectively determine whether moist desquamation was patchy or confluent. Descriptions of late radiation toxicity were documented in seven dogs and included alopecia (n=5), leukotrichia (n=2), and hyperpigmentation(n=2). These findings represented grade 1, late radiation morbidity according to the scoring scheme.11
Discussion
A limited number of prior reports have been published describing the use of 192Ir brachytherapy in dogs.5612–14 Two studies evaluated therapeutic 192Ir for intranasal tumors in dogs.1213 One of these studies described the clinical effects and histopathological changes in eight normal dogs after rhinotomy and 192Ir implantation.12 Acute effects included nasal discharge, glossitis, and a dorsal nasal fistula. Histopathological changes included lymphoplasmacytic rhinitis, osteonecrosis/osteolysis, submucosal fibrosis, and vacuolization and glial scarring of the brain. Lesions were more severe 6 months posttreatment than at 3 months post-treatment, which was compatible with late toxicity.12 In the other study, eight dogs with nasal tumors were treated with surgical debulking followed by 192Ir brachytherapy in doses of 70 to 100 Gy.13 Two dogs died of recurrent local disease. The three dogs treated with doses >94 Gy that survived >60 days developed radiation-induced osteonecrosis and soft-tissue necrosis, suggesting that doses >94 Gy should be avoided to prevent unacceptable toxicity.13 Another study evaluated toxicity associated with 60 Gy 192Ir interstitial brachytherapy of the head and neck in four normal dogs.14 Histopathological lesions were identified in two of three dogs euthanized 2 months postimplantation. These lesions included early osteonecrosis (n=1) and decreased mandibular hematopoietic elements (n=1), suggesting that bone might be the dose-limiting tissue for interstitial brachytherapy.
Interstitial 192Ir brachytherapy is an effective adjunctive therapy to surgery in humans when administered for local control of soft-tissue sarcomas.715–17 In horses, interstitial 192Ir brachytherapy has been described as effective therapy for sarcoids and periorbital squamous cell carcinoma.1819 A review of techniques for 192Ir interstitial brachytherapy revealed preliminary results of 30% tumor control at 1 year for squamous cell carcinomas and 50% tumor control at 1 year for hemangiopericytomas of the extremities, but the number of animals treated was not stated.5
The radiation responsiveness and superficial location of canine cutaneous MCTs make them attractive candidates for 192Ir brachytherapy.1–4 With the potential for increased localization of the radiation dose, it was hypothesized that 192Ir therapy might be as effective as external-beam radiotherapy in controlling incompletely excised, cutaneous MCTs. It is disappointing that five of the 11 tumors in the study reported here recurred. When the treated cases are examined more closely, however, this number may underestimate the efficacy of adjunctive 192Ir brachytherapy. Case selection in this study likely affected the recurrence rate. The two cases with early recurrence (case nos. 7, 8) may have been poor choices for 192Ir therapy, because each had advanced recurrent grade III tumors at the time of treatment. In case no. 8, the tumor had already recurred three times prior to 192Ir implantation, and case no. 7 had a large recurrent MCT and additional MCTs at other sites at the time of treatment. The remaining three dogs with recurrent MCTs experienced long PFIs, ranging from 3.8 to 6.4 years after treatment.
It is also possible that this study overestimated the efficacy of 192Ir therapy. Case nos. 3 and 7 underwent revision of the surgical scar along with 192Ir implantation. Mast cell tumor was not identified histopathologically in the resected tissue from either dog; however, case no. 7 developed a recurrence, suggesting that there was residual tumor at the site. Case no. 3 remained disease free, so interpretation of the actual effect of the 192Ir therapy versus the second surgery was difficult.
When assessing results of this study, recent studies evaluating the local recurrence rates following surgical resection of intermediate-grade, cutaneous MCTs in dogs were reviewed.20–22 In two such studies, two of 11 dogs with incompletely excised tumors and one of three dogs with incomplete or clean but close surgical margins developed recurrences during the follow-up period.2022 Based on the results of these surgical studies, it is possible that some of the tumors in the study reported here might not have recurred even if they received no adjunctive 192Ir therapy.
Technical and dosimetric considerations limit the size of an 192Ir implant in humans to maximum dimensions of about 20 to 25 cm ×10 cm.15 Because of this limitation, recurrence at the edge of the radiation field might be expected with treatment of large target volumes from either under-dosing or a geographic miss of portions of the target. The results of the study reported here did not demonstrate this phenomenon, as all recurrences were within the radiation field. Mast cell tumors recurred within two of the three largest treatment fields, and the tumor treated after its third recurrence (case no. 8) recurred both within and around the radiation field. Recurrence within the treatment field may be a consequence of tumor cell resistance, protection of tumor cells within the scar from hypoxic conditions, or inadequate dosing. In animals treated with 192Ir brachytherapy, recurrence may also be the result of inhomogeneity in dose distribution throughout the treatment volume or insufficient dosing of deep tissues because of rapid fall-off of the dosage in tissues >0.5 to 1 cm from the source. Because of dosing issues, external-beam radiation therapy would be expected to be superior for local control of larger or recurrent tumors. It is possible that computerized treatment planning would improve accuracy of dosing and potentially improve tumor control with 192Ir interstitial brachytherapy.
Case selection and postradiation management may have affected the survival times of the dogs in this study. Four dogs died as a consequence of recurrence of their MCTs. None of the dogs in this study received adjunctive chemotherapy or prolonged prednisone therapy. Mast cell tumors have been shown to be responsive to chemotherapeutic agents.23–26 Systemic chemotherapy may have improved local control and decreased the risk of systemic spread for some dogs, particularly those with grade III tumors or grade II tumors with negative prognostic indicators, such as large tumor size or recurrent tumor.
Overall, 192Ir brachytherapy was well tolerated. The only complication observed during 192Ir treatment was the premature removal of implanted ribbons by one dog. None of the dogs that were implanted immediately postoperatively experienced complications in healing. It is possible that complications in wound healing were not detected because of the small number of cases in this study. In a study of human patients with soft-tissue sarcomas, wound complications were seen in 48% of cases implanted immediately postoperatively, while delaying the implantation until >5 days after surgery reduced the rate of wound complications to a level similar to that experienced with surgery alone.27
The ability of this study to detect adverse effects associated with interstitial brachytherapy was hindered by the small number of dogs treated and incomplete documentation of toxicity. Only seven of the dogs were examined for acute toxicity, and these were examined only at one point in time (2 to 4 weeks after implantation). For two dogs examined 4 weeks after 192Ir treatment, it was possible that adverse lesions were already healing, and their severity was underestimated. Based on the limited information available, acute morbidity was most severe 2 to 4 weeks after treatment, involved only the skin, and was self-limiting. Late-occurring side effects were mild and mainly cosmetic in nature.
Case no. 9 developed a second type of tumor in the radiation field. This dog was diagnosed with both a MCT and a fibrosarcoma within the radiation field 3.8 years after 192Ir treatment. The fibrosarcoma might have represented radiation-induced tumor formation, or it may have been coincidental.2829
The potential benefits of 192Ir interstitial brachytherapy include shorter overall treatment time, fewer anesthetic episodes, increased dose delivered to the tumor, and sparing of surrounding tissues.5–7 This therapy may be useful in animals where a high anesthetic risk precludes the multiple anesthetic episodes required for fractionated teletherapy. Also, for facilities without access to electron-beam radiation therapy, 192Ir may be a useful alternative for cutaneous tumors in areas where sparing of underlying tissues is desirable (e.g., thoracic wall, abdominal wall, and periocular tissues). Iridium brachytherapy is probably most applicable to superficial, localized tumors that can be effectively treated with field sizes of 10 ×10 cm or smaller.
Conclusion
This study provides preliminary data on the efficacy and toxicity associated with 192Ir interstitial brachytherapy. Conclusions based on this study are limited, because the study involved a small number of dogs treated over many years, during which a better understanding of the biological behavior of canine MCTs and improved treatment options were developed. Case selection and posttreatment management likely contributed to some of the treatment failures. As a retrospective study, this study is limited by incomplete staging procedures, incomplete observations in medical records, and limited follow-up information. Despite these limitations, this report introduces the use of 192Ir interstitial brachytherapy for cutaneous MCTs and supports further evaluation of this treatment modality for cutaneous tumors in dogs.
Iridium-192 seeds; Best Medical International, Inc., Springville, VA
Acknowledgment
The authors thank Dr. Kenneth Rassnick of the Comparative Cancer Program, College of Veterinary Medicine, Cornell University, for his assistance with manuscript preparation.
Citation: Journal of the American Animal Hospital Association 40, 4; 10.5326/0400309
Citation: Journal of the American Animal Hospital Association 40, 4; 10.5326/0400309
Photograph of 192Ir implantation in case no. 2, a 5-year-old golden retriever with a grade II mast cell tumor of the lower eyelid. The guide catheters are in place, and nylon ribbons containing 192Ir seeds are pulled through the catheters.
