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Comparison of calculated radiation delivery versus actual radiation delivery in military macaws (Ara militaris).

Abstract: The skin and oral cavity are common sites of neoplasia in avian species. Radiation therapy has been described for the treatment of these tumors in birds; however, its observed effectiveness has been variable. One possible explanation for this variability when radiation is used to treat the head is the unique anatomy of the avian skull, which contains an elaborate set of sinuses not found in mammalian species. To compare a calculated dose of radiation intended to be administered and the actual amount of radiation delivered to the target area of the choana in 3 adult military macaws (Ara militaris), computed tomography scans were obtained and the monitor unit was calculated to deliver 100 cGy (lGy) by using radiation planning software. The birds received 3-4 radiation treatments each from a megavoltage radiation therapy unit. A thermoluminescent dosimetry chip (TLD) placed in the choana of the birds was used to measure the amount of ionizing radiation delivered at each treatment. The TLDs were kept in place using Play-Doh as a tissue analog. The actual dose of radiation delivered was lower than the 100-cGy calculated dose, with the 95% confidence limits of predicted bias values between 2.35 and 5.39 (radiation dose from 94.61 to 97.65 cGy). A significant difference was identified between the actual amount of radiation delivered and the calculated radiation goal (P <.001). None of the TLDs received the intended dose of 100 cGy of radiation. The results revealed that the amount of radiation delivered did not reach intended levels. Because the combination of the significance of this discrepancy and the standard dose inhomogeneity could lead to greater than 10% dose inhomogeneity, future investigation is warranted for accurate dose calculation and efficacy of radiation therapy for neoplasia at the lumen of the choana in birds.

Key words: radiation therapy, thermoluminescent dosimetry chip, avian, military macaw, Ara militaris

Introduction

Soft tissue sarcoma and squamous cell carcinoma are the first and second most common tumors, respectively, of psittacine birds. (1) The most common sites of tumor location are the skin and the alimentary system. (1) Radiation therapy has been shown to have variable results for these tumors in dogs and cats. A favorable response has been reported for oral squamous cell carcinoma (2) and incompletely excised soft tissue sarcomas in dogs, (3) but a poor response has been reported for oral squamous cell carcinoma in cats receiving radiation therapy. (4) In birds, however, efficacy has been difficult to determine due to case reports demonstrating variability in the response to radiation therapy. A cutaneous squamous cell carcinoma on the foot of an American flamingo (Phoenicopterus ruber) showed no response to radiation therapy; therefore, surgical amputation of a digit was necessary for resolution. (5) A squamous cell carcinoma on the beak of a Buffon's macaw (Ara ambigua) was surgically debulked and then treated with radiation, yet the tumor showed no signs of response. (6) A malignant melanoma was treated in a thick-billed parrot (Rhynchopsitta pachyrhyncha) with radiation treatment plus oral piroxicam and cimetidine, but the bird died 11 weeks later because of metastatic disease. (7) We have also observed a poor response to radiation therapy for oral neoplasia in birds.

Various factors could influence the effectiveness of radiation therapy in birds in certain cases. Some of the described cases may not have been ideal candidates for treatment because of underlying disease or type and stage of the neoplasia. However, other species-specific factors should be considered. Birds have been reported to have an increased tolerance to radiation therapy and are considered more radioresistant when compared with other species. Chickens have the highest radiation 50% lethal dose among domestic animals. (8) Ring-necked parakeets (Psittacula krameri) exposed to external beam radiation treatment showed minimal adverse response in the mucosal and cutaneous tissue. (9) In addition to the reported radioresistance, we postulate that the anatomy of the avian skull, specifically a complex system of sinuses and air sacs, may contribute to decreased delivery of ionizing radiation.

The planning for radiation therapy is extensive and must take in to account many variables. (10,11) Slight miscalculations can result in an inadequate delivery of ionized radiation, and therefore a reduced therapeutic benefit. (12) Because of the lack of research in avian radiation therapy, treatment protocols are extrapolated from mammalian species and unique anatomic features are often not taken into account. (12) No studies in birds have reported on measuring the actual amount of radiation delivered to the target tissue versus the calculated amount as determined by radiation planning protocols. The purpose of this study was to determine if the amount of measured radiation delivered to the target tissue was the same as the calculated amount of radiation. Our hypothesis was that the actual measured radiation dose delivered to the target tissue is less than the computer-based calculated dose.

Materials and Methods

Animals

Three adult military macaws (Ara militaris), 2 males and 1 female, from a local zoo were used in this study. Military macaws were selected due to their size, the similarity of their anatomic features other captive psittacine birds, and their availability. The birds were deemed to be in good health based on previous history, medical records, and reports from the zoo staff. Their diet consisted of a complete balanced diet as formulated by the zoo staff and veterinarian. Physical examination results were normal and results of blood tests performed the day of radiation administration were within reference intervals. This study was approved by the Institutional Animal Care and Use Committee at Louisiana State University.

Computed tomography planning and radiation exposure

Each bird was transported to the Louisiana State University School of Veterinary Medicine on the day of the study. They were fasted for 4 hours before transport. The bird to be transported was selected by the zoo staff and all birds received all treatments on the same day. Upon arrival at the Louisiana State University School of Veterinary Medicine, the birds received a cursory physical examination. Afterwards, they were anesthetized with 2% isoflurane delivered in 1 L/ min of oxygen via a face mask connected to a Bain circuit. Once anesthesia was achieved, the mask was removed and birds were intubated with a noncuffed endotracheal tube. A 3-mm internal-diameter tube was used in one bird and a 4-mm internal-diameter tube was used in the other 2 birds for maintenance of anesthesia. The endotracheal tube was secured to the gnathotheca with tape. Heart rate was monitored via Doppler placed over the ulnar artery of the nondependent wing. Heat was provided via an electric heating blanket, although body temperature was not monitored throughout the procedure. Approximately 1 mL of blood was obtained from the left jugular vein for a complete blood cell count and plasma biochemical analysis. The birds were then readied for computed tomography (CT) scan. The patients were placed in left lateral recumbency on a pneumatic moldable cushion (Vac-Lock Cushions, CIVCO Medical Solutions, Kalona, IA, USA) and a 1-cm bolus (Bolus, CIVCO) was affixed to the nondependent side of the head. A fiducial reference marker (Beekley spots; Beekley Corp, Bristol, CT, USA) was placed on the gnathotheca to aid in radiation therapy setup. The CT scans were performed using a 16-slice scanner (LightSpeed 16, GE Healthcare, Milwaukee, WI, USA) in 0.625-mm sections. Upon completing the CT scan, the birds were moved on a gurney to the Cancer Unit while remaining on the moldable cushion, being careful to minimize movement in order to maintain positioning. The birds were placed on the treatment table of a megavoltage linear accelerator (Clinac 600C, Varian Medical Systems, Palo Alto, CA, USA) in preparation for radiation.

[FIGURE 1 OMITTED]

The CT images were transferred to Eclipse radiation therapy planning software (Version 10, Varian Medical Systems) to develop a radiation plan (Fig 1). All radiation planning was developed by a board-certified veterinary radiation oncologist (K.S.). Contouring was performed for the body including the bolus and the planning target volume (PTV). A 0.3-cm diameter and 0.8-cm height of cylinder was contoured at the lumen of the choana and defined as the PTV since a thermoluminescent dosimetry chip (TLD) (University of Wisconsin-Madison Radiation Calibration Laboratory, Madison, WI, USA) was placed in this region. A single field was applied from the 0 degree of the gantry angle with 100-cm source-to-skin distance at the surface of 1-cm bolus. Radiation fields were set as 5 X 5 cm for all treatments. The calculation point was set at the center of the PTV in the lumen of the choana. A monitor unit was calculated to deliver 100 cGy to the calculation point by the radiation planning system. Using the CT images, the location of choana was determined in relationship to the fiducial reference marker. The table was adjusted to bring the target site (the choana) into the radiation beam. A 6-MV X-ray was used in this study because this was the only available radiation for the linear accelerator. Once alignment was achieved, a TLD was placed at the location of the choana in the buccal cavity. A 1-g piece of Play-Doh (Hasbro, Wayne, NJ, USA) flattened to a thickness of less than 1 mm was used to suspend the TLD chip within the lumen of the choana and prevent loss of the chip. Orthogonal port films were not taken for all birds because entire heads were almost within the radiation fields. A 1-cm bolus (tissue-equivalent gel) (Bolus-skinless, CIV-CO) was placed over the nondependent side of the head. Source-to-skin distance was set as 100 cm at the surface of the bolus. All radiation positioning setup was performed by the same individual (D.C.). The subjects were dosed with a single dose of 100 cGy of X-ray at a dose rate of 250 cGy/min at 0 degrees of gantry of the linear accelerator, according to the monitor unit calculations made based on the radiation planning. One bird received 3 doses of radiation and 2 birds received 4 doses of radiation. The bird that received 3 doses of radiation had the procedure discontinued early because of concerns of bradycardia during anesthesia. In each bird, TLD chips were placed and irradiated during the same anesthetic procedure. After a dose of radiation was administered, the TLD chip was removed and replaced with another chip to be irradiated immediately afterward. Forceps were used to place and remove the TLD and Play-Doh in the choana to minimize movement of the birds. Each TLD chip was irradiated only once and all other chips were outside of the radiation vault during treatment. Once all the TLD chips for that specific patient were irradiated, anesthesia was discontinued. Birds were monitored until fully recovered. For each bird, all radiation doses were delivered on the same day, in the same anesthetic event. The 3 birds were treated on separate days and the order in which they were treated was dictated only by which bird was brought by their zoo caretakers.

The TLD chips were mailed to the University of Wisconsin-Madison Radiation Calibration Laboratory according to the laboratory recommendations for shipping and handling.

Statistical analysis

Statistical analyses were performed with SAS 9.4 (SAS Institute, Cary, NC, USA). A MIXED procedure was performed to evaluate the actual radiation delivery. The bias (the difference between the calculated and actual radiation delivery values) was used as the dependent variable and bird was included as a random effect in the model. The homogeneity of variance among birds and the normality of the model residues were examined with Bartlett's and Shapiro-Wilk tests. The 95% confidence limits for the predicted values were used to assess the significance of this experiment (P [less than or equal to] .05).

Results

The computer-based calculated dose within entire PTV ranged from 99.7 to 101.6 cGy, and the dose inhomogeneity was 1.9% within the PTV. A total of 11 TLD chips were irradiated with 100 cGy in 3 birds with 100% isodose line. Radiation received by a single chip ranged from 91.4 to 98.8 cGy (Fig 2). No TLD chips reached the calculated dose of 100 cGy (Fig 2). The distribution of the bias (the difference between the computer-based calculated dose and actual measured radiation dose) among 3 birds is shown in Figure 3. The homogeneity of variance among birds was tested with Bartlett's test (P =.52). The experimental results are described with a linear mixed model using birds as a random factor. The predicted values and bias are shown in the Table 1. The model residues were examined with a Shapiro-Wilk test with a probability of 0.3123. The actual dose of radiation delivered was lower than the 100-cGy calculated dose. The 95% confidence limits of predicted values were between 2.35 and 5.39 (radiation dosage from 94.61 to 97.65 cGy). A significant difference was identified between the actual radiation delivered and the calculated radiation goal (P <.001).

Discussion

This study revealed that the actual amount of radiation delivered to the choana in avian patients may be less than the calculated amount of radiation. The results also revealed the potential for variability between treatments. The reason for this discrepancy and the effect on therapeutic response remains unknown. Avian species have unique anatomic features that may interfere with accurate delivery of radiation. The infraorbital sinus is a triangular air-filled soft-tissue sac connected to the nasal concha and cavity. This sinus lies beneath the skin rostroventral to the eye on the rhinotheca. The infraorbital sinus occupies the space directly between the choana and the radiation source. (13) Gas-filled spaces do not allow ionizing radiation to reach electronic equilibrium efficiently. (14) These spaces have the potential of altering the point at which the maximum dose is located. Dose accuracy between measured dose by TLD and computer-based calculated doses also might affect outcomes. In general, 5% inaccuracy would be acceptable for comparing planned to measured TLD doses for patient-specific quality assurance. (15) The TLDs are typically set on the skin surface to measure radiation dose, but in this study, the TLD was placed in the lumen of the choana. The error bars of the dose may be even larger depending on the location of the TLD.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Another anatomic feature that could have influenced our results is the thickness of cutaneous and subcutaneous structures of birds compared with those of mammals. One theory is that if the tumor target is located close to the skin, the thinner cutaneous tissues in birds may also affect the ability to achieve electronic equilibrium and could also reduce amount of backscatters, which would make it difficult to deliver ionizing radiation precisely. (12) Radiation planning software may not be able to calculate the thinner cutaneous tissues and air sinuses of birds, which would in turn affect the accuracy of the calculation.

Variation in thickness of the skin layers has been reported in different species but little information is available about avian species. Scott et al (16) reported that human skin was thicker than that of rats (Rattus norvegicus) and marmosets (Callithrix jacchus), with marmosets having thinner skin than humans and rats. Angora and white New Zealand rabbits (Oryctolagus cuniculus) are reported to have similar thickness of the epidermis composed of 3-4 cell layers. (17) However, Angora rabbits have a higher overall skin thickness, which is attributed to a thicker dermal papillary layer. (17) Another study compared histologic thickness of the skin of various species. This study found the epidermis of pigs to be the thickest at 3.9-4.47 cell layers, while rabbits (1.22-1.5 cells) and mice (1.25-1.75 cells) had the thinnest layers. (18) The epidermis of birds is reported to consist of 2 to 3 cell layers with or without stratum granulosum, depending on the area of the skin. (19) A report in poultry describes the actual thickness of the skin to be between 2.1 and 2.2 mm in thickness. (20) Upon reviewing the data presented in some of the previously mentioned studies, it becomes clear that the number of cell layers does not correlate with the actual thickness of the epidermis. Therefore, comparing the actual thickness of the skin in millimeters is likely a better method than comparing the cell layers alone. Although reported in poultry, to our knowledge this has yet to be determined in psittacine species. Based on the currently available information, we cannot determine if the thinner skin thickness in avian species is indeed a contributing factor to the observed differences between the calculated and measured radiation.

Another possible explanation for the discrepancy in delivered versus calculated radiation and the degree of variation between treatments may be the handling and shifting of the patient. Shifting of the patient's position can occur between the CT room and radiation vault or in between radiation treatments. The risk of altering the patient's position is not only a risk in an experimental situation such as this one, but is also present in a clinical situation. Cone-beam CT images allow accurate assessment of a radiation therapy patient's position, but our linear accelerator radiation therapy device did not have this capability.

Although the results did reveal a significant difference between the calculated and delivered radiation, the clinical significance of this finding is unknown. These birds were not receiving a therapeutic dose of radiation, which is usually around 300-400 cGy for dogs and cats, but were being administered 100 cGy of radiation to minimize any potential adverse effects from the radiation. (21) In addition, a typical treatment regimen may consist of 12-19 treatments over several weeks. The difference shown in this study (2-8 cGy) may be insignificant, but this discrepancy, when carried out over a full therapeutic regime for several weeks may fail to deliver the adequate therapy for tumor treatment and control. Ninety-five percent of prescribed dose for 100% of PTV within 10% dose homogeneity is a typical standard recommendation for radiation therapy treatment in human and veterinary medicine. (11) The results of our study show that the target potentially could lose a maximum 10% of prescribed dose. The 8% dose loss from 105% of prescribed dose might not be of significant clinical impact, but it could potentially lead to a clinically significant outcome if 8% is lost from 95% of the prescribed dose.

Further investigation is needed to better understand the extent to which therapeutic radiation is being delivered to avian species and whether current planning procedures should be altered to better fit avian species. A possible strategy to be explored is increasing the dose administered because of the apparent radioresistance present. Also, further studies in radiation delivered to different anatomic sites or degree of radiation beam attenuation at different depths would be beneficial. Recent studies (9,22) show that avian species fail to develop expected adverse reactions to radiation therapy at doses reported to cause such reactions in mammals. Whether this is because of reduced delivery of radiation or radioresistance inherent to avian species remains unknown. It would be also interesting to investigate [alpha]/[beta] ratio in avian neoplasms. If the targeting tumor is consistent with a low [alpha]/[beta] ratio, a high dose/fraction treatment scheme (coarse fractionated therapy) would be more effective than a traditional fractionated scheme. If so, stereotactic radiotherapy might be more indicated in avian species. These discrepancies between mammalian and avian responses to radiation treatment may have a profound impact on response and may necessitate an alteration in treatment protocol.

Daniel C. Cutler, DVM, Keijiro Shiomitsu, BVSc, Dipl ACVR (Radiation Oncology), ChinChi Liu, PhD, and Javier G. Nevarez, DVM, PhD, Dipl ACZM, Dipl ECZM (Herpetology)

From the Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr, Baton Rouge, LA 70803, USA. Present address (Cutler): Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, 1800 Denison Ave, Manhattan, K.S 66505, USA.

Acknowledgments: We thank Daniel Neck for his advice regarding the thermoluminescent dosimetry chips.

References

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(4.) Bregazzi VS, LaRue SM, Powers BE, et al. Response of feline oral squamous cell carcinoma to palliative radiation therapy. Vet Radiol Ultrasound. 2001; 42(1):77-79.

(5.) Abu J, Wunschmann A, Redig PT, Feeney D. Management of a cutaneous squamous cell carcinoma in an American flamingo (Phoenicopterus ruber). J Avian Med Surg. 2009;23(1):44-48.

(6.) 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.

(7.) Guthrie AL, Gonzalez-Angulo C, Wigle WL, deMaar TW. Radiation therapy of a malignant melanoma in a thick-billed parrot (Rhynchopsitta pachyrhyncha). J Avian Med Surg. 2010;24(4):299-307.

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(14.) Butson M, Cheung T, Yu Peter, Metcalfe P. Effects on skin dose from unwanted air gaps under bolus in photon beam radiotherapy. Radiat Meas. 2000;32:201-204.

(15.) Kirby TH, Hanson WF, Johnston DA. Uncertainty analysis of absorbed dose calculations from thermoluminescence dosimeters. Med Phys. 1992; 19(6): 1427-1433.

(16.) Scott RC, Corrigan MA, Smith F, Mason H. The influence of skin structure on permeability: an intersite and interspecies comparison with hydrophilic penetrants. J Invest Dermatol. 1991;96(6):921-925.

(17.) Oznurlu Y, Celik I, Sur E, et al. Comparative skin histology of the white New Zealand and Angora rabbits: histometrical and immunohistochemical evaluations. J Anim Vet Adv. 2009;8(9): 1694-1701.

(18.) Monteiro-Riviere NA, Bristol DG, Manning TO, et al. Interspecies and interregional analysis of the comparative histologic thickness and laser doppler blood flow measurements at five cutaneous sites in nine species. J Invest Dermatol. 1990;95(5):582-586.

(19.) Sawyer RH, Knapp LW, O'Guin WM. Epidermis, dermis, and appendages. In: Bereiter-Hahn J, Matoltsy AG, Richards KS, eds. Biology of the Integument 2: Vertebrates. New York, NY, Berlin and Heidelberg, Germany: Springer-Verlag; 1986:194-238.

(20.) Christensen KD, Zimmerman NG, Wyatt CL, et al. Dietary and environmental factors affecting skin strength in broiler chickens. Poult Sci. 1994;73(2):224-235.

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(22.) Wilson GH, Roberts R, Northrup NC, et al. Radiation tolerance doses of cutaneous and mucosal tissues in psittacine birds using cobalt-60 teletherapy. Proc Annu Conf Eur Assoc Avian Vet. 2005:504.
Table 1. The predicted bias values showing the
difference between the computer-calculated and actual
measured radiation dose and 95% confidence limits in 3
military macaws that received a target radiation dose of
100 cGy.

                                  95% Lower      95% Upper
               Predicted bias     confidence     confidence
                 value (cGy)     limit (cGy)    limit (cGy)

Bird 1              3.79             2.18           5.39
Bird 2              3.81             2.23           5.38
Bird 3              4.00             2.43           5.57
Overall mean        3.87             2.35           5.39
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Title Annotation:Original Study
Author:Cutler, Daniel C.; Shiomitsu, Keijiro; Liu, ChinChi; Nevarez, Javier G.
Publication:Journal of Avian Medicine and Surgery
Article Type:Report
Date:Mar 1, 2016
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