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Tolerance doses of cutaneous and mucosal tissues in ring-necked parakeets (Psittacula krameri) for external beam megavoltage radiation.

Abstract. Currently used dosages for external-beam megavoltage radiation therapy in birds have been extrapolated from mammalian patients and often appear to provide inadequate doses of radiation for effective tumor control. To determine the tolerance doses of cutaneous and mucosal tissues of normal birds in order to provide more effective radiation treatment for tumors that have been shown to be radiation responsive in other species, ingluvial mucosa and the skin over the ingluvies of 9 ring-necked parakeets (Psittacula krameri) were irradiated in 4-Gy fractions to a total dose of either 48, 60, or 72 Gy using an isocentric cobalt-60 teletherapy unit. Minimal radiation-induced epidermal changes were present in the high-dose group histologically. Neither dose-related acute nor chronic radiation effects could be detected in any group grossly in cutaneous or mucosal tissue over a 9-month period. Radiation doses of 72 Gy in 4-Gy fractions were well tolerated in the small number of ring-necked parakeets in this initial tolerance dose study.

Key words: cobalt-60, radiation, tolerance, ingluvies, skin, avian, psittacine, birds, ring-necked parakeets, Psittacula krameri

Introduction

Neoplasia is a common problem in pet birds. In fact, neoplasms are reportedly more commonly seen in the budgerigar (Melopsittacus undulatus) than in any other domestic animal. (1) Despite this, treatment for avian patients with neoplasms has lagged far behind the technology available for other companion animals. Radiation therapy (RT) is widely used in human and veterinary medicine; approximately half of human cancer patients treated in the United States received RT. Of these, at least 50% treated with curative intent have their cancers controlled. (2) Although successful for a variety of tumors in other species, attempts in the past to use external beam RT for cutaneous neoplasms in birds have met with variable, usually poor, success. (3-6) This may be because the employed treatment regimens have been extrapolated from mammalian patients and may provide inadequate doses of radiation to provide effective tumor control in avian patients. The primary goal of RT is to administer a sufficiently high dose to the tumor to reduce the surviving fraction of clonogenic tumor cells to zero while keeping the incidence of serious damage to normal cells low. To do this, tolerance doses for the tissues of that species must first be established. Comparison between animal species is difficult and may lead to inaccurate conclusions because some remarkable variations exist with respect to clinical signs of radiation toxicities. Previous studies documenting the physiologic effects of whole body irradiation of domestic animals, including dogs, pigs, cattle, poultry, and horses, demonstrated that mortality and morbidity due to acute radiation syndromes was lowest in chickens. (7) Total doses of radiation given for therapeutic purposes in veterinary medicine have routinely been in the 40 to 50 Gy range when using a 4-Gy fractional dose. (8) Dose response, influence of fractionation, and normal tissue injury have been evaluated extensively in other companion species over the past 25 years. (8) However, there have been no controlled studies of external beam RT in avian species. An understanding of the tolerance of normal tissues included in the treatment field is essential in radiation treatment planning for any animal. The goal of this study was to determine the tolerance doses of cutaneous and mucosal tissues of a sample population of healthy psittacine birds to provide more effective treatment for neoplasms that have been shown to be radiation responsive in other species.

[FIGURE 1 OMITTED]

Materials and Methods

Subjects used in the study were 12 adult male and female Indian ring-necked parakeets (Psittacula krameri) ranging from 1 to 2 years of age. All birds were similar in size, with body weights ranging from 123 to 138 g. All procedures and methods used were approved by the University of Georgia's Animal Care and Use Committee. The birds were given a thorough examination before the start of the study and were determined to be clinically healthy. Subjects were divided into 4 randomized groups, each composed of 3 birds. One group served as control subjects and was subjected to crop and skin biopsy, but RT was not performed. The other 3 groups were irradiated to a total dose of 48, 60, and 72 Gy, respectively, with an isocentric cobalt-60 teletherapy unit. A total of 12, 15, or 18 fractions of 4 Gy each were given on a Monday, Wednesday, and Friday until the total prescribed dose was achieved. The tissue target volume extended from approximately 3 to 4 cm caudal to the mandible to the thoracic inlet over the area of the ingluvies (Fig 1). The down and covert feathers in this region were transected at skin level to allow investigators to more easily define the treatment field repeatedly and to allow for careful monitoring of the skin for evidence of radiation effects. Before the first treatment, one control bird was radiographed in order to calculate the exposure field size of 2 x 2 cm for each individual undergoing radiation. Based on this radiograph, tissues expected to be potentially included in this field included skin, esophagus/ ingluvies, trachea, thymus, vasculature, cervical vertebrae, and the cranial aspect of the pectoral girdle (sternum, clavicle, and coracoid bones). The small treatment field was achieved by using lead blocks on a clear tray between the patient and the collimater to further narrow the 4 x 4-cm field (the minimum field of the collimater) to the required 2 x 2-cm field. Output and the percentage of depth dose data for the 2 x 2 cm-treatment field were calculated by a licensed medical physicist.

Subjects were fasted for 4 hours before each treatment session, which was administered with the subject under general anesthesia. Isoflurane was administered by face mask induction at 5% and maintained by using 1%-3% isoflurane and oxygen adjusted to individual patient requirements. The birds were placed in right lateral recumbency with the wings held in extension out of the beam of radiation. Equally weighted, parallel-opposed, lateral treatment portals were used for each treatment. This position was chosen to maximize radiation to the skin and ingluvial mucosa, while minimizing spinal exposure. A water-soaked 4 x 4-in gauze square, folded over twice to a thickness of 5 mm, was used to ensure that the bolus dose of radiation reached the skin.

[FIGURE 2 OMITTED]

The birds were examined daily during the study for evidence of radiation-associated lesions, including esophagitis, ingluvitis, tracheitis, and erythema or desquamation of cutaneous tissues. Lesions were graded according to the Veterinary Radiation Therapy Oncology Group acute and chronic radiation morbidity scoring criteria. (9) Body weights were monitored weekly during the treatment period. To monitor closely for radiation effects, subjects were maintained in a research facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care for the 4-, 5-, or 6-week period of radiation plus an additional 2 weeks after cessation of therapy. They were offered water and a commercial seed mix ad libitum. Biopsy samples of skin and ingluvial mucosa (3-4 mm) for histologic analysis were obtained at the end of each group's treatment period or, in the case of the control group, at week 6. The biopsy specimens were fixed in 10% neutral-buffered formalin solution, processed routinely, embedded in paraffin wax, and sectioned at 4 [micro]m. The same pathologist read all tissue sections and was blinded as to group. Routine tissue sections were stained with hematoxylin and eosin. Special stains were used as needed for additional microscopic evaluation of any unusual lesions.

Isoflurane inhalant anesthesia was used to immobilize the subjects during RT and biopsy procedures. Ketoprofen (2 mg/kg IM) was used postoperatively after biopsy. (10) Once the biopsy incision was healed, the parakeets were adopted into a private home where they were maintained as a group in a large outdoor flight enclosure and rechecked at 6 and 9 months.

Results

Physical examinations

Grossly, all birds received a score of 0 (no change compared to baseline), on the Veterinary Radiation Therapy Oncology Group radiation scoring scheme at the end of radiation treatment. Recheck examinations at 6 and 9 months were also within normal limits. Body weights remained stable throughout the study, as did appetite and attitude. The same veterinarian examined all birds at all points in the study.

Histopathologic examination

There was no histologic evidence of radiation-induced tissue alterations in either the low-dose (48 Gy) or the medium-dose group (60 Gy). In these birds, the histologic findings were similar to that of the control group. However, all 3 birds in the high-dose group (72 Gy) had minimal radiation-induced epidermal changes. One bird in this group had mild, multifocal, anisokaryosis of keratinocytes in the epidermis (Fig 2A). The other 2 birds had mild to moderate multifocal, nonheterophilic, perivascular dermatitis and folliculitis (Fig 2B).

Discussion

An understanding of the tolerance of normal tissues included in the treatment field is essential for the design of a course of RT and the initial decision as to whether radiation should be used for cancer treatment. This study documents some important findings as tolerance doses for avian tissues have never before been established. The results of this study suggest that doses of 72 Gy given in 4-Gy fractions may be used safely, with no clinically significant dose-related acute or chronic radiation effects, on cutaneous or mucosal tissue in Indian ring-necked parakeets. As a note of interest, this dose of radiation was provided with good results to 3 psittacine patients of varying age and species with integumentary neoplasms of different types at the University of Georgia College of Veterinary Medicine in the 6 months that followed this study.

Although a few reports have been published advocating the use of RT to treat avian neoplasms, results in previous clinical cases we have treated have suggested that birds are more resistant than mammals to megavoltage irradiation. In 2 birds that were treated at the University of Georgia College of Veterinary Medicine with cobalt-60 radiation for tumors of the head and neck, doses that would be considered high in other species had no discernable effect on either the neoplasms or the normal surrounding tissues. (3,5)

The lack of data in treatment for avian neoplasia may, in part, be because of concerns in treating such small patients. Ring-necked parakeets were chosen for this study because of their small size and our conviction that relatively small treatment fields, in this case 2 x 2 cm, can be achieved.

As the population of companion birds has increased and as many pet birds are aging, neoplasia will undoubtedly be seen more commonly. (6,11,12) More companion animal owners are requesting radiation oncology services for their pets. (8) By determining the appropriate course of RT, clinicians involved in the management of avian neoplasia will be able to offer a more informed treatment plan.

In other species, it has been shown that lower doses of radiation given more frequently allow a higher total dose to be given. This study did not address the influence of fractionation of the dosage of radiation in birds. However, the general principle providing the rationale of RT should always be practiced. That principle is to maximize the radiation dose to the tumor and tumor-harboring tissues while minimizing radiation exposure to surrounding healthy tissues.

The relatively young age of the study birds, as compared with the typically more aged avian cancer patient, should be considered. An additional limitation of this study was the small sample size. However, based on the results of this study and subsequent clinical experiences, it is our opinion that lower doses of radiation may be insufficient to provide effective tumor control in psittacine birds.

Acknowledgements." We thank the students, especially Megan Murphy, and the staff of the University of Georgia, College of Veterinary Medicine for their assistance. Mr Kip Carter of Education Resources kindly provided illustration for Figure 1.

References

(1.) Bauck LD. A clinical approach to neoplastic disease in the pet bird. Semin Avian Exotic Pet Med. 1992;1(2):65-72.

(2.) Gillette EL. Principles of radiation therapy. In: Theilen GH, Madewell BR, eds. Veterinary Cancer Medicine. 2nd ed. Philadelphia, PA: Lea and Febiger; 1987:137-143.

(3.) Manucy TK, Bennett RA, Greenacre CB, et al. Squamous cell carcinoma of the mandibular beak in a Buffon's macaw (Ara ambigua). J Avian Med Surg. 1998; 12(3): 158-166.

(4.) Freeman KP, Hahn KA, Admas WH, et al. Radiation therapy for hemangiosarcoma in a budgerigar. J Avian Med Surg. 1999;13(1):40-44.

(5.) Wilson GH, Graham J, Roberts RE, et al. Integumentary neoplasms in psittacine birds: treatment strategies. Proc An Conf Assoc Avian Vet. 2000:211-214.

(6.) Schmidt RE, Quesenberry K. Neoplasia. In: Altman RB, Clubb SL, Dorrestein GM, Quesenberry K, eds. Avian Med Surg. Philadelphia, PA: WB Saunders; 1997:590-600.

(7.) yon Zallinger CV, Tempel K. The physiologic response of domestic animals to ionizing radiation: a review. Vet Avian Medicine and Surgery Ultrasound. 1998;39(6):495-503.

(8.) Gillette EL, LaRue SM, Gillette SM. Normal tissue tolerance and management of radiation injury. Semin Vet Med Surg. 1995;10(3):209-213.

(9.) LaDue T, Klein MK. Toxicity criteria of the veterinary radiation therapy oncology group. Vet Radiol Ultrasound. 2001;42(5):475-476.

(10.) Carpenter JW, Mashima TY, Rupiper DJ. Exotic Animal Formulary. 2nd ed. Philadelphia, PA: WB Saunders; 2001.

(11.) Schmidt RE. Morphologic diagnosis of avian neoplasms. Semin Avian Exotic Pet Med. 1992;1(2):73-79.

(12.) Leach MW. A survey of neoplasia in pet birds. Semin Avian Exotic Pet Med. 1992;1(2):52-64.

Heather W. Barron, DVM, Dipl ABVP (Avian), Royce E. Roberts, DVM, MS, Dipl ACVR, Kenneth S. Latimer, DVM, PhD, Dipl ACVP, Stephen Hernandez-Divers, BVetMed, DZooMed, Dipl ACZM, and Nicole C. Northrup, DVM, Dipl ACVIM (Oncology)

From the School of Veterinary Medicine, St Matthew's University, PO Box 32330, Grand Cayman, KYI-1209, Cayman Islands, British West Indies (Barron); the Departments of Anatomy and Radiology (Roberts), and Small Animal Medicine (Hernandez-Divers and Northrup), College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA; and Covance Laboratories, Inc, 9200 Leesburg Pike, Vienna, VA 22027, USA (Latimer).
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Title Annotation:Research Brief
Author:Barron, Heather W.; Roberts, Royce E.; Latimer, Kenneth S.; Hernandez-Divers, Stephen; Northrup, Nic
Publication:Journal of Avian Medicine and Surgery
Article Type:Report
Geographic Code:1USA
Date:Mar 1, 2009
Words:2322
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