Tumor control in birds

Tumor Control in Birds Lucio J. Filippich, BVSc, BSc, PhD, MACVSc, GCEd

Neoplasia is common in pet birds, especially psittacines, and mainly involves the integument and urogenital system. Before treatment options are considered, a definitive diagnosis should be made and the extent of the disease determined. Treatment should initially be directed at tumor eradication and may involve using several modalities together or sequentially. Surgery, radiotherapy, and photodynamic therapy are used against localized tumors, while chemotherapy and biological response modification are also used against metastatic disease. In combination or adjunct therapy, surgery is used to excise or debulk the tumor, radiotherapy to sterilize local regional disease and chemotherapy and biological therapy to help prevent metastatic disease. The tumor control program should be rationally planned before application, rather than added on when one modality fails, as is commonly practiced. Tumor response to therapy should be regularly assessed both in the short and long term and wherever possible, assessment should be quantitated. Work place health and safety procedures for radiation and cytotoxic drugs should always be practiced. © 2004 Elsevier Inc. All rights reserved. Key words: Neoplasia; prevalence; avian; tumor control; chemotherapy; radiotherapy

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eoplasia has been more frequently reported in birds held in captivity than in free-flying wild birds. Of 109 reports of neoplasia in wild birds from 1885 to 1954, most referred to wild birds held in captivity.1 Siegfried (1982)1 found neoplasia in only 9 of 18,000 carcasses of free-flying wild birds examined over a 5-year period from 1976. Ratcliffe (1933)2 at the Philadelphia Zoological Gardens found that the incidence of neoplasia in 6898 necropsies, representing 14 orders of birds, was 1.17%. However, a subsequent survey from 1935 to 1955 found that the incidence had risen to 2.6%.3 The increase between the two Philadelphia study periods was attributed to several factors, including increased longevity, and was closer to the 3.6% reported by Hubbard and coworkers (1983)4 for 475 necrop-

sies at the San Antonio Zoo. In a survey of over 10,000 birds, which included commercial, zoological, avicultural, pet, and free-flying wild birds, submitted to a diagnostic laboratory in Australia over a 10-year period from 1977, 3.8% had neoplasia.5 In a more recent survey over a 19 yearperiod from 1984 involving over 15,000 birds representing 8 Orders submitted to a diagnostic pathology service in the United States, 6.95% were diagnosed with neoplasia, although unlike earlier studies, papilloma was the most commonly diagnosed tumor type.6 Neoplasia has been most commonly reported in Psittaciformes (3.6%), especially Budgerigars (Melopsittacus undulatus) (15.8%), followed by Galliformes (1.41%) and Anseriformes (0.89%), while Passeriformes have the lowest incidence (0.46%) of any order,2 although histological examination of tissue may reveal a higher incidence in Passeriformes.7 The lack of reports of neoplasia in an order or species does not necessarily reflect inherent tumor resistance unless large numbers are surveyed and monitored over time. Nevertheless, although Budgerigars are among the most commonly kept avian species and most studied among pet species, the incidence of neoplasia still appears high compared with other species. The overall incidence of neoplasia in Budgerigars reportedly ranges from 15.8% to 24.2%.2,9-11 However, the incidence may be over 30% if only pet birds are considered and as low as 9% if Budgerigars held by budgerigar breeders are considered, as the average age of breeders’ birds is less than for pet birds.8,9,12 A literature survey of 1539 cases of neoplasia in pet birds, which included cases diagnosed at a From the School of Veterinary Science, The University of Queensland, Queensland, Australia. Address correspondence to: Dr. Lucio J. Filippich, School of Veterinary Science, University of Queensland, Queensland 4072, Australia. © 2004 Elsevier Inc. All rights reserved. 1055-937X/04/1301-0005$30.00 doi:10.1053/S1055-937X(03)00055-0

Seminars in Avian and Exotic Pet Medicine, Vol 13, No 1 ( January), 2004: pp 25-43

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Figure 1. Lipomas are commonly reported in cockatoos, especially Rose-breasted cockatoos.

Veterinary Medical Teaching Hospital (University of California, Davis) over a 10 year period, found that the most common tumor site was the integument (31.7%), followed by the urinary system (25.1%) and the genital system (17.3%).13 However, the spectrum of tumors, such as lipomas, may depend to some extent on whether birds are presented for clinical or necropsy examination.10 Some species appear to have a higher incidence of occurrence of certain tumor types, for example, proventricular adenocarcinoma is more commonly reported in the Gray-cheeked parakeet (Brotogeris pyrrhopterus),14-17 malignant lymphoma appears more common in Canaries (Serinus canarius),2,5,9,18,19 while lipomas are generally reported in Budgerigars and cockatoos, especially Rosebreasted cockatoo (Eolophus roseicapillus) (Fig 1).13,20-23 The increased frequency of neoplasia in pet birds as compared with free flying wild birds is possibly because they are more observable, have longer life spans, may have increased exposure to contributors of carcinogenesis and may be genetically predisposed because of inbreeding.1,9,24 Neoplasia is usually diagnosed late in the course of the disease because the clinical signs are often nonspecific and slowly progressive.10,25-27 This is especially true for visceral neoplasia,17,28,29 Therefore, neoplasia should always be included in the initial differential diagnosis list, as early diagnosis of malignant neoplasia can markedly improve treatment outcomes. If neoplasia is suspected, a complete history should be taken and a thorough physical examination, especially abdominal palpation preformed before a diagnostic workup is attempted. The diagnostic workup for most tumors should include a complete blood health profile, bone marrow biopsy if anemia or blood dyscrasia is present, tumor type determina-

Lucio J. Filippich

tion, tumor measurement if applicable and imaging (survey radiographs, endoscopy), especially if the neoplasm has a tendency to metastasize. Tumor-like diseases or lesions, such as cutaneous avipoxvirus infection, mycobacteriosis, feather cysts, and infectious granuloma should be excluded. A definitive diagnosis should be made and the extent of the disease determined before treatment options are considered. Treatment for birds with neoplasia should initially be directed at tumor eradication. If this fails or is not possible, treatment should be directed at slowing down the tumor growth, reducing pain or discomfort, improving the cosmetic appearance, preserving normal function and improving the bird’s nutritional status.30,31 The treatment modules selected will depend mainly on the tumor type, tumor location, whether the tumor is localized, invasive or metastatic, local pressure effects, the bird’s general health status, and the owner’s willingness to proceed.30,32 The optimum management of a particular malignancy may involve using several modalities together or sequentially, such as surgical debulking or extirpation, radiation therapy and/or chemotherapy. It has long been recognized that using more than one treatment modality improves outcome. Furthermore, tumor free and survival times are even better, if a tumor control program using several treatment modules is rationally planned before application, rather than added on when one modality fails,33-35 as is commonly practiced. Treatment should not start without the owner being fully informed of the treatment protocol planned, the likely costs, outcomes and complications that may occur and of their involvement, such as the need for regular follow-up visits. Tumor response to therapy should be regularly assessed both in the short and long term and wherever possible assessment should be quantitated. Tumor control in avian medicine is still in its infancy. However, in the last two decades, significant advances have been made. Several treatment modalities, found useful in companion animal oncology, have been increasingly tried in avian medicine with varying outcomes. These outcomes have often been difficult to assess when tumor response was less than complete, because of the assumptions associated with extrapolating methodologies from mammals to birds and the lack of experimental and clinical avian research available. In addition, the paucity of clinical staging (extent of local and distant metastasis), and histopathological grading (degree of malignancy) of

Tumors in Birds

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treated avian tumors, length of follow-up and very small case numbers makes assessment and interpretation of various treatment outcomes difficult. Nevertheless, no longer is complete surgical excision or amputation the only method available to practitioners for tumor management in birds.

Surgical Therapy Traditionally, the most common approach to the treatment of neoplasia in birds has been surgical excision or limb amputation.30,36 Fortunately, many tumors are amenable to surgery alone, with failures being largely attributed to inadequate surgical margins or undetectable metastasis at the time of surgery,22,30,31,37-39 although the tendency for avian tumors to metastasize appears low.11,13,17,40 The use of surgery in tumor control may be definitive or palliative in nature and depends largely on the location, size and tumor involvement at presentation. The tumor’s biological behavior and the patient’s health status should also be considered. Tumors confined to the integument are more likely curative with surgery alone than tumors involving the musculoskeletal system or internal organs.26 An aseptic surgical technique should be employed, especially if adjunct chemotherapy is used, as most avian patients with neoplasia are likely to be aged, debilitated, or immunocompromised. Surgery, employing a “no touch” approach,30,31,41 should always be considered with a primary tumor that can be completely excised with adequate clean margins. Whenever possible, to minimize dissemination of malignant cells, biopsies should be excisional, the blood supply to pedunculated tumors ligated as early as possible, surgical gloves frequently changed, and flushing of the surgical site with normal saline considered.41 If complete excision is not possible, debulking may improve locomotory function, minimize secondary trauma and bleeding, reduce pain and improve immunocompetence.31 Furthermore, debulking in combination with other treatment modules, such as chemotherapy or radiotherapy, can significantly increase survival time in mammals.31,33,42,43 Tumors involving the head, especially beak tumors are generally malignant and inoperable, but some may be treated with surgery and/or electrocautary or cryosurgery (Fig 2).20,25,27,44-47 Cryosurgical techniques have limited application; however, they do provide several advantages, such as little or no systemic effects, minimal postoperative bleeding and safe repeat treatments. They can be

Figure 2. Squamous cell carcinoma involving the head may respond to treatment modalities including surgery, electrocautery, and cryosurgery.

used for small, localized lesions around the oral cavity and nares, and are helpful in treating broad-based tumors in certain areas.36,48 The most effective cytotoxic freezing effects are obtained when at least two freeze-thaw cycles are used.49 A submandibular neuroma in an ostrich (Struthio camelus) and a well encapsulated teratoma over the frontal sinus area in an African gray parrot (Psittacus erithacus) were surgically removed with no regrowth reported 12 months after surgery.50,51 Some malignant tumors, such as fibrosarcoma, on the face may be treated by careful excision or cryosurgery early in the course of the disease,36 while locally invasive mast cell tumor may not be amenable to surgery alone.52 In mammals with mast cell tumor, wide surgical margins are recommended, and if surgical excision is incomplete, a second aggressive surgery or radiotherapy should be considered.53 Benign tumors on the limbs can be surgically removed, although lack of skin in the area may make primary wound closure difficult to impossible. The application of tissue adhesive or a hydroactive dressing to the open wound for protection and to allow for granulation and eventual re-epithelialization has been suggested.54,55 However, it is imperative that the surgical incision is sufficient to ensure normal tissue margins free of disease microscopically.31,56 Furthermore, if the decision for limb amputation is based on the lack of loose skin in the area, alternate tumor control therapy should be considered, especially if leg or foot amputation is involved. For malignant limb tumors, limb amputation is recommended,30,36,57 although adjunct therapy should be considered. For example, limb amputation is recommended for fibrosarcomas because they are often too large

28 to be adequately excised,30 are locally invasive,23,48 commonly reoccur following excision,16,47 and do not readily metastasize.36 However, pulmonary metastases were found at necropsy in a Peachfaced lovebird (Agapornis roseicollis), 3 months after limb amputation for a subcutaneous fibrosarcoma on the right carpus.58 Liposarcoma is infrequently reported, may metastasize, and being locally invasive, may be difficult to completely excise.30,57,59 A liposarcoma involving the third toe of a Green-cheeked conure (Pyrrhura molinae) was treated by toe amputation, and when re-examined, 6 months later, was clear.60 Hemangiosarcomas on the limbs are generally aggressive and readily metastasize.24,61 A hemangiosarcoma in the propatagial area in a Golden pheasant (Chrysolophus pictus) returned 10 days after being surgically removed with inadequate surgical margins.39 Although squamous cell carcinoma rarely metastasize23,62 except in raptors63 and the standard therapy for accessible tumors involves surgical excision,30,36 at least 9 of 17 birds with cutaneous squamous cell carcinoma had tumor regrowth following wing amputation or aggressive surgical excision.22 However, in four raptors with cutaneous squamous cell carcinoma, surgical excision and the immediate application of topical 5-fluorouracil (Efudix, Roche Products) to any regrowths, once daily until there was no clinically evidence of neoplasia (typically 5-7 days), proved curative with no recurrences observed for over 2 years (Forbes NA, written communication 2003). Osteosarcoma and chrondrosarcoma are malignant tumors mainly seen on the long bones, particularly near the joint21 and amputation is recommended. A rose-breasted cockatoo with osteosarcoma was referred to the author because of reccurrence following limb amputation, and responded to intralesional carboplatin (Table 1). In dogs with osteosarcoma, limb amputation and adjunct chemotherapy is recommended.64,65 Lipomas are benign, fatty, single or multiple masses with a diffuse base mainly found in the subcutis on the sternum, abdomen, and inner thighs.23,54,59 Obesity, lack of exercise, advancing age, and high-energy diets appear to be predisposing factors for lipoma development.30,47 Surgical excision is recommended only after a fat-restricted diet fails or the lipoma is ulcerated, necrotic, and/or bleeding.20,47,48,54,59,66 Dietary management before surgery helps to shrink the adipose tissue mass, making surgery easier and less invasive and the tendency to hemorrhage less apparent. Although lipoma is not malignant, re-

Lucio J. Filippich

growth can occur after excision, especially if dietary restrictions are not maintained post operatively. Some lipomatous growths in Budgerigars and Rose-breasted cockatoos have reportedly responded to thyroid hormone supplementation (L-thyroxine 0.4-0.8 mg/L of drinking water),23,67 although a relationship with abnormal thyroid function is limited.36 Iodine supplementation has also been recommended.59 Occasionally, nonneoplastic xanthomatous masses develop in the skin over the lipoma and being refractive to dietary therapy need to be removed surgically,30,54 although hyperthermia and orthovoltage radiation have provided partial response when used for unresectable lesions.30 Myelolipoma is an uncommon, slow-growing, benign tumor composed of fat and hematopoietic tissue and when subcutaneously located can be surgically excised without reoccurrence, although hemostasis during surgery is essential.22,68,69 Hemangioma is a benign tumor of vascular endothelium, commonly found in the skin and following complete excision, reported survival times without tumor regrowth range from 2 to 24 months.22 Granular cell tumor has been reported, especially in Amazon parrots as a discrete mass within the dermis and complete surgical excision appears curative.70,71 Basal cell carcinoma, although rare and of low-grade malignancy, may reoccur, especially if incompletely excised23,72,73 and the use of topical 5-fluorouracil for regrowths should be considered. Thymoma is reportedly a rare, locally invasive tumor found in the subcutis along the neck of birds and may be difficult to completely excise because of its involvement with other structures in the head and neck.74 An adult Fischer’s lovebird (Agapornis personata fischeri) survived 2 years with no signs of tumor regrowth after a subcutaneous malignant lymphoma in the cervical region was surgically removed without clean borders.75 The surgical success for uropygial gland tumors largely depends on the type of neoplasia involved. Adenoma and squamous cell carcinoma respond well but adenocarcinoma in Budgerigars often metastasize. Extirpation of the uropygial gland requires careful surgical excision and hemorrhage control. Profuse bleeding will occur unless blood vessels at the cranial, middle and caudal portions of the gland are coagulated or ligated.55 The gland, including the deep fascia, is removed using blunt dissection and electrosurgery. Removal of the underlying fibrous tissue does not adversely affect the long-term mobility of the tail postoperatively. Primary closure of the

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Tumors in Birds

Table 1. Drugs Used for Neoplasia in Birds Drug Corticosteroid Prednisolone

Alkylating agents Cyclophosphamide Chlorambucil

Tubulin-binding agent Vincristine Anthracycline antibiotic Doxorubicin

L-asparaginase Platinum analogs Cisplatin

Neoplasia

Dosage

Lymphoid neoplasia Lymphoid neoplasia*

2.2 mg/kg PO18,131 2.2 mg/kg bid or 25 mg/m2 PO oid for 5 wks and than 2.5 mg/m2 every other day108,111

Lymphoid neoplasia* Lymphoid neoplasia* Pseudolymphoma

200 mg/m2 IO weekly for 4-5 wks111 2 mg/kg PO twice weekly for 17 wks140 Two courses, 12-weeks apart. Each course involved 3 oral doses of 20 mg/m2 or 2 mg/kg q14d141

Lymphoid neoplasia*

0.75 mg/m2 IO weekly for 11 wks111 0.1 mg/kg IV once or twice weekly for 17 wks140

Lymphoid neoplasia* Osteosarcoma

30 mg/m2 IO every 3 wks on 3 occasions**111 60 mg/m2, IV infusion over 30 min, q28d, on 4 occasions**46 400 IU/kg IM weekly for 6 wks**111

Lymphoid neoplasia* Normal cockatoo Fibrosarcoma

Carboplatin

Normal cockatoo Pancreatic duct adenocarcinoma Bile duct carcinoma Osteosarcoma

Squamous cell carcinoma Immunotherapy Acemannan

Alpha interferon

Fibrosarcoma

Lymphoid neoplasia

1.0 mg/kg IV over 1h, once. Hydrated with fluids 1h before and 2h after cisplatin infusion117 0.3 mg/cm3 intratumorally as a 3.3 mg/mL water/sesame oil emulsion†88 5 mg/kg IV or IO over 3 min (0.4 mg/mL in 5% dextrose), once120,156 3 doses of 5 mg/kg IO, at 4-wk intervals158 100 mg/m2 IV over 1 min followed 3-wks later with 125 mg/m2 83 15 mg/kg IO on 2 occasions, 3-wks apart and then the same dose in sesame oil/water emulsion intralesionally, for 3 injections, 3-wk apart 5 mg/kg intratumorally as a 10 mg/mL sesame oil/water emulsion after surgical debulking90 2 mg/kg intratumorally and 1 mg/kg SC weekly for 4 wks, and then interoperatively as a systemic and intratumoral injection after partial surgical debulking and then SC at 1 and 4 wks, postoperatively90 15,000 units/m2 SC on alternate days for 3 Treatments111

*Cyclic chemotherapy. †Chemoradiotherapy, using 3.3 mg of cisplatin in 0.33 mL of sterile distilled water and 0.66 mL of medical-grade sesame oil. **Premedicated with diphenhydramine (2 mg/kg IO) and dexamethasone (1 mg/kg IM).

resulting wound is usually not possible due to the lack of loose skin in the area and the size of the incision. Postoperatively, avoid handling the bird as this will often induce bleeding from the surgical wound and use an Elizabethan collar, if necessary, until granulation and re-epithelialization has occurred.

Tumor control for abdominal neoplasia usually involves an exploratory celiotomy with a view to surgically removing the tumor mass.38 Urogenital tumors are most common, especially in Budgerigars and Cockatiels (Nymphicus hollandicus).13,16,36 Renal tumors may be unilateral or bilateral and some are cystic in appearance.16,26,76,77 Renal ad-

30 enocarcinoma in Budgerigars usually involves the anterior pole of the kidney, rarely metastasizes until late in the course of the disease and usually does not disrupt kidney function.21,76,77 Testicular tumors tend to occur in older birds, are usually unilateral, and may metastasize. The most frequently reported ovarian tumor is granulosa cell tumor, followed by adenocarcinoma.36 These tumors may be solid or cystic, and except for adenocarcinoma, rarely metastasize.25,78 Oviduct tumors are less common than ovarian tumors.36 Although, surgery is suggested for several types of gonadal tumors,25 renal and gonadal tumors unless contained and pedunculated are virtually impossible to successfully remove because access to their respective arteries is restricted by the tumor and the short length of their artery to the aorta, makes ligation or forceps hemostasis difficult to impossible.66 Also, birds will often die during or shortly after ligation or physical removal of ovarian tumors from the coelomic cavity,78 unless aggressive fluid therapy is administered. Leiomyosarcoma can arise from any smooth muscle location such as the alimentary tract, oviduct, and spleen.79 Since they are locally invasive and rarely metastasize, early detection, aggressive surgical excision, and total excision of recurrences is recommended.56,79 A smooth muscle neoplasm of suspected oviductal origin in a Blue-fronted Amazon (Amazona aestiva) returned after partial surgical resection, but following salpingohysterectomy, the bird was clinically normal when examined 18 months later.79 Carcinomas, especially bile duct carcinoma, may be a sequel to internal papillomatosis in Amazon and macaw parrots, although a relationship and the etiology of internal papillomatosis is unclear.80-83 Surgical removal of a pancreatic carcinoma in a Cockatiel was unsuccessful as at necropsy, 66 days after surgery, the neoplasm had regrown and metastasized throughout the coelomic cavity.37 Incomplete surgical resection of a coprodeal papillary adenocarcinoma in a Blue-and-gold macaw (Ara ararauna) was unsuccessful.38

Radiation Therapy Radiation therapy involves the administration of ionizing radiation to tumor cells. In the process, the ensuing radiation-induced injury results in mitotic cell death or interphase death, not only in tumor cells, but also in the adjacent radiated normal cells.35,43 Therefore, the aim of radiotherapy is to use a radiation dose and irradiation tech-

Lucio J. Filippich

nique that will deliver a tumoricidal dose without causing excessive injury to surrounding normal tissues. This is commonly achieved by arbitrarily dividing the total radiation dose into several smaller doses (fractions) and administering the fractions over a period of time.33,43,84,85 A total radiation dose of 40 to 48 Grays (Gy) has been commonly used in birds for most malignancies, divided into 10 to 12 fractions of 4Gy/fraction and given 3 times a week61,86-88 (1 Gy ⫽ 100 centigray [cGy] ⫽ 100 rad). Fractionating the total radiation dose enhances the therapeutic ratio, that is, it improves the efficacy of the radiation treatment while sparing normal tissue.49,85 Current recommendations are to use more frequent (daily) lower radiation doses.35 The effect of radiation on normal tissue occurs at the site of irradiation and can appear at anytime during therapy to several months or years later.35 Acute effects of radiation always accompany curative radiotherapy as they reflect, to some extent, the damage done to tumor tissue.35 Radiation effects in mammals include erythema, desquamation of the skin, pigmentary changes, necrosis, ulceration and fibrosis and if severe can be a limiting factor in radiotherapy.85,89 Erythema, feather loss delineating the radiation field, pigmentary changes and possibly edema, necrosis, radiation-induced fibrosis, and leukopenia have been reported in birds following radiotherapy.86-88 However, the lack of observed radiation injury to normal tissue in some birds27,90 may suggest that some avian species have a higher tissue tolerance to radiation than mammals or that the current total radiation dosage used is too low. Ionizing radiation has been administered to birds from an external source (teletherapy), and currently available radiation-producing equipment for veterinary use include orthovoltage x-rays, cesium-137 (137Cs), cobalt-60 (60Co), and linear accelerators.43 The ionizing radiation produced by each unit varies in its tissue penetrating ability and absorption. Orthovoltage x-rays (0.4 MeV) are a low-energy radiation with limited tissue penetration so that the maximum radiation dose is limited to the skin surface. These x-rays are also disproportionately absorbed by bone and so are best used to treat dermal and superficial soft tissue tumors not directly overlying bone.33,43 However, orthovoltage x-rays teletherapy was used to treat a periorbital malignant lymphoma involving the right nasal sinus and adjacent bone in an African gray parrot without any deleterious bone effects.86 Orthovoltage radiation (20-30 Gy) for

Tumors in Birds

unresectable xanthoma has provided partial response and control of clinical signs.30 Cesium-137 gamma emissions are intermediate in energy (0.66 MeV) and although they have deeper tissue penetration and provide more uniform dose distribution, they have limited skin sparring effect. Cesium-137 teletherapy has been used to treat hemangiosarcoma in a Budgerigar.61 Cobalt-60 gamma emissions (1.25 MeV), being in the megavoltage range (⬎1MeV) can penetrate skin so that the maximum dose delivered is below the skin surface, thus achieving a degree of skin sparring. Also, with megavoltage teletherapy, there is minimal disparity of dose distribution between soft tissue and bone. Gamma ray teletherapy can be used to treat subcutaneous tumors, soft tissue tumors and bone tumors33 and has been used in birds to treat squamous cell carcinoma and fibrosarcoma.27,88,90 Ionizing radiation administered through placement of radioactive isotopes on or in birds (brachytherapy) has apparently been investigated but small patient size may make this form of therapy impractical.30,36 Radiotherapy has been shown to be an effective treatment for many localized solid tumors in small animals.35 It should be considered for benign tumors that cannot be easily surgically extirpated with clean margins, malignant tumors that do not readily metastasize and tumors that are considered inoperable.33,61,91,92 The small size of some birds may make radiation impractical.27,36 The efficacy of radiotherapy in birds to date is difficult to assess because the optimal radiation dosage, fractionation schedule and normal tissue tolerance levels have not been determined. Nevertheless, when undertaking radiotherapy ensure that the primary tumor is completely irradiated, the tumor volume is not too large to achieve an effective tumor cell kill and unacceptable complications do not develop.27,43,84 Tumors of the hemolymphatic system are most responsive to radiotherapy, epithelial tumors (carcinoma) are moderately responsive and mesenchymal tumors (sarcoma) are least responsive.33,88 An important cause of radiotherapy failure is that the tumor cells are radioresistant. Radiosensitivity is known to decrease when neoplastic cells are quiescent or poorly oxygenated.43 Manucy and coworkers (1998)27 found no histologic evidence of tumor cell kill following irradiation of a squamous cell carcinoma on the mandible of a Buffon’s macaw (Ara ambigua) that was associated with infectious dermatitis, abscessation and osteomyelitis and attributed the poor response to several factors in-

31 cluding radioresistant tumor cells due to hypoxia. For radioresistant tumors, surgical debulking reduces tumor burden and improves the efficacy of radiation.88 Radiotherapy has been used as a primary form of treatment for malignant tumors in birds, with mixed results. A malignant lymphoma involving the periorbital area in an African gray parrot86 initially responded to irradiation but recurred 2 months later. A hemangiosarcoma on the wing of a Budgerigar resolved without complications following radiotherapy but returned 1 month later, and the bird was subsequently euthanized due to disseminated hemangiosarcoma.61 A swan with hemangiosarcoma on the beak has remained tumor-free for 6 months following radiotherapy.22 Adjunct chemotherapy should always be considered for subclinical disease where the primary malignant tumor has been effectively treated with radiotherapy. In dogs, treatment for hemangiosarcoma includes surgical excision/amputation followed by radiotherapy, chemotherapy and/or immunotherapy.61,93,94 Radiotherapy can be administered before, during, or after surgery. Preoperative irradiation has not been used in birds. However, it may be helpful in eliminating microscopic tumor growth extending beyond the visual tumor margins and lessen the likelihood of metastasis spread from tumor manipulation during surgery,33,43,85 although impaired wound healing would need to be considered. Postoperative radiotherapy, administered immediately or shortly after surgery to allow for healing, is indicated if complete surgical removal is not possible.43,91,92 However, surgery may produce distant metastases, reduce tumor radiosensitivity by promoting tissue hypoxia, and allow tumor proliferation to occur if irradiation is postponed or delayed to allow for surgical healing to occur.33,43,91 Nevertheless, surgical resection does reduce the number of tumor cells and so improves radiocurability.33,43 Radiotherapy has been used 2 to 3 weeks after surgery to treat squamous cell carcinoma in a Buffon’s macaw and in an Amazon parrot (Amazona ochrocephala oratrix) without success.27,90 Also, a facial fibrosarcoma in a Blue-and-gold macaw failed to respond after surgical debulking and 6 fractions of orthovoltage radiotherapy.87 Although surgical excision30,36 and/or radiotherapy23,92 are recommended for such accessible tumors, failure may have been due to radiation dosage or radioresistance.27 Aggressive surgical excision and postop-

32 erative megavoltage radiation has increased the survival times of dogs with fibrosarcoma.92 Radiotherapy and chemotherapy have been combined in an effort to increase antitumor activity. Cisplatin is a known radiosensitizer,95 and intratumoral cisplatin has been shown to enhance the effects of radiation in dogs while avoiding systemic toxicity.96,97 This radiochemotherapy approach has been used in birds to treat fibrosarcoma. A broad-based myxoid fibrosarcoma on the wing of a Blue-and-gold macaw was treated without evidence of reoccurrence at 15 months post treatment, using megavoltage teletherapy and cisplatin in a water/sesame oil emulsion injected into the tumor and the surrounding margin of about 1.0 cm (Table 1).88,98 The injections were given according to a parallel row pattern arranged in a single plane as described by Theon and coworkers (1993),98 10 minutes before the 1st, 3rd and 8th radiation fraction. However, a radiating pattern from a single injection site may help minimize drug leakage from the tumor during injection. The sesame oil limits drug egress from the injection site, allowing it to work locally with reduced systemic side effects.98 A collagen-matrix gel can also be used as a vehicle for intratumoral cisplatin delivery.53,97,98 In another Blue-and-gold macaw, a facial fibrosarcoma which appeared refractive to surgical debulking and orthovoltage teletherapy was held in remission for 29 months after intralesional cisplatin was injected before the 8th and 11th radiation fraction.87

Photodynamic Therapy Photodynamic therapy (PDT) involves irradiating neoplastic tissue with tissue-penetrating light, 24 to 48 hours after a patient has been given, usually systemically, an intravenous, tumor-localizing, photosensitizing agent.99 The wavelengths of light used depend on the photosensitizing agent and the reported response with various neoplasms.99,100 When the photosensitizing agent is activated by light of a particular wavelength, cytotoxic oxygen radicals are generated photochemically that presumably disrupt cell membranes, resulting in cell death.101 However, since the tumor tissue preferentially retains the photosensitizing agent, selective tumor destruction occurs. However, in vivo studies indicate that the major target is not the tumor cell itself but the vascular connective tissue that supports it,101 so that following light exposure, destruction of the microcirculation leads to tumor death and some degree of

Lucio J. Filippich

necrosis of the surrounding normal tissue margin. Photosensitizing agents, such as porfimer sodium (wavelength of 630 nm) and hexylether pyropheophorbide (wavelength of 665 nm) have been given to birds without any evidence of adverse drug reaction.100,102 Agents that are activated by light between 650 and 690 nm wavelength are preferred because tissue penetration is greater than for light at lower wavelengths.99 PDT has been shown to be an effective treatment modality for surface-oriented neoplasms of the skin, respiratory, gastrointestinal and urogenital system99,101,103,104 and has been used successfully in cats with squamous cell carcinoma.99,105,106 Despite a lack of avian information regarding therapeutic frequency of treatment or laser settings, PDT has been used as a treatment module for squamous cell carcinoma in birds. Squamous cell carcinoma in the casque of a Great hornbill (Buceros bicornis) was treated with PDT on two occasions, 8 weeks apart.100 The bird was anesthetized on each occasion, after being given Hexylether pyropheophorbide (0.3 mg/kg IV) the previous day, and the area surgically debrided before being irradiated with 665-nm light (tissue dose [energy density] delivered was 100 J/cm2 and light maintained [power density] at 100 mW/cm2). Each 3-cm focal spot was irradiated for 16.8 minutes, and after 3.5 hours, the therapy was complete. After each therapy session, histological evidence of tumor tissue necrosis was observed, but regrowth resumed shortly afterward even after aggressive surgical debulking was performed at the second therapy session. Aggressive surgery alone failed to control a carcinoma in the casque of another hornbill.45 However, early intervention and small lesions in cats with squamous cell carcinoma improved the efficacy of PDT, presumably reflecting full light penetration.99 A squamous cell carcinoma on the left flank in a cockatiel that had been previously surgically debulked on a number of occasions, was given several PDT sessions using porfimer sodium.102 Each time the neoplastic tissue shrunk in size but eventually returned to pretreatment size. Skin edema over the hocks occurred several weeks after PDT and was attributed to sun exposure. Skin photosensitization can occur with porfimer sodium and patients should avoid sun exposure for several weeks following therapy, although its occurrence with newer photosensitizing agents is less.99,101,104,105 Other potential side effects reported with PDT include anorexia, pulmonary edema, pleural effusions and hepatotoxicity in cats,104,106 shock in

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Tumors in Birds

rodents107 and vasoconstrictive effects.99-101 The size of the PDT treatment area, compared with the animals total body surface area, may determine the clinical significance of these side effects.107 Nevertheless, debulking before PDT improves tumor exposure to light. Cats treated with PDT are generally given pain relief for the vasoconstrictive effects of therapy and corticosteroids for local edema.104 Butorphanol tartrate (3 mg/kg IM q24 hour) and Carprofen (1.0 mg/kg orally q12 hour) have been used in birds given PDT.100,102 Despite the limited response in a very small number of birds, PDT has several advantages over other standard treatment modalities such as ease of application, minimal side effects, lack of toxicity to normal cells and little posttreatment care. Furthermore, PDT may eradicate certain lesions with one or two treatment sessions, thereby reducing overall treatment duration as well as number of revisits and anesthetic episodes required for patient management.99,104,106 Even if complete response is not achievable, PDT may have a palliative role to play in the management of advanced nonresectable tumors.99

Immunotherapy Immunotherapy as a tumor control measure involves stimulating or moderating a bird’s immune system against tumor cells.31 Tumors are known to cause immunosuppression and the stage and size of the tumor burden correlates with the degree of immunosuppression.31,42 Concurrent infection has been reported in birds with neoplasia.19,29,108 Surgery itself is a form of immunotherapy, as it can effectively reduce the size of the tumor mass and potentially reverse the immunosuppression.31 Tumor-specific immunotherapy, based on the host recognizing tumor cell antigen, has been used in birds in the form of autogenous vaccines.109 In general, efficacy of autogenous vaccines is usually restricted to those tumors caused by viruses.30 Nonspecific immunotherapy involves the use of various biological or chemical agents to nonspecifically stimulate the immune system against tumor tissue. Acemannan (Acemannan Immunostimulant, Carrington Labs Inc, Irving TX), an immunostimulant drug derived from the aloe vera plant, has shown promise as an adjunct to surgery and radiation therapy in dogs and cats with fibrosarcoma.110 A nonresectable fibrosarcoma on the face and neck of an Umbrella cockatoo (Cacatua alba) was successfully treated with acemannan and surgical debulking (Table 1).90

Alpha interferon was used in a Moluccan cockatoo (Cacatua moluccensis) with lymphoid neoplasia (Table 1).111 A monocyte/macrophage activator, liposome-encapsulated muramyl tripeptide phosphatidylethanolamine has shown significant antimetastatic activity in mammals with malignant neoplasia93 and its use in birds should be considered.

Hyperthermia Hyperthermia has tumor-killing potential,84,112 and therapy involves heating tumor tissue to temperatures above 42°C.49 Although hyperthermia usually has a transitory effect on tumors,112 it can increase tumor responsiveness when used with radiotherapy and chemotherapy.49,84,112,113 Whole-body hyperthermia has been shown to increase cisplatin-induced toxicity in mammals,114-116 and the difference in body temperature between mammals (37°C) and birds (40-42°C) may have contributed to cisplatin toxicity reported in cockatoos.117 Hyperthermia has been suggested as an alternative to surgery for nonresectable xanthoma in birds.30 However, appropriate heating devices need to be developed for birds and because birds are normally hyperthermic compared with mammals, therapeutic temperature ranges, heating times and treatment cycles need to be determined before this form of tumor therapy can be applied clinically to birds.

Chemotherapy Chemotherapy involves the use of cytotoxic drugs to treat neoplastic disease. These drugs are generally administered at a dose that gives maximum tumorcidal effect with minimal normal tissue toxicity. To achieve this, several biological and pharmacological principles need to be considered when using these drugs. Most chemotherapeutic drugs will only affect cells during the active growing phase (cell-cycle-specific). Therefore, the proportion of tumor cells actively replicating (growth fraction) at the time of treatment is important because only those active cells will be affected. Small tumors are more likely to have a greater number of actively growing cells (high growth fraction) compared with large tumors and so are more likely to respond favorable to chemotherapy. Indeed, the smaller the tumor, the higher the probability of a good response to chemotherapy. In addition, since these drugs generally have a steep dose-response curve, they are administered

34 at the highest dose possible to achieve maximum cell kill. This dose (maximally tolerated dose) can result in mild to moderate but sublethal toxicity in a significant percentage of patients, or serious toxicity to approximately 5% of normal animals of that species.118 Thus, toxicity is the major doselimiting factor when using these drugs, although intratumoral injection or implantation of slowreleasing formulations is one way of achieving high drug concentrations in the tumor with low systemic exposure and minimal side effects.98,119 Finally, since only a limited number of cells are killed with any single drug exposure, the interval between dosing needs to be such that regrowth between dosing does not exceed cell death during dosing. Thus, although toxicity often dictates the dosing interval, cytotoxic drugs should be used at the shortest interval possible to avoid significant tumor cell repopulation. Toxicity often occurs to varying degrees, and if severe, may require a delay, reduction or discontinuation of subsequent drug doses. Toxicity most commonly involves organs containing rapidly dividing cells, such as the bone marrow and the alimentary tract. Hematologic toxicity (leukopenia, thrombocytopenia) is usually detected within 7 to 14 days postdosing. Alimentary tract signs (inappetence/anorexia, vomiting, and weight loss) can occur and have been observed in birds following cyclophosphamide, doxorubicin, L-asparaginase, cisplatin and carboplatin administration.111,117,120 They are usually mild, transient, and generally do not warrant dose modifications. Some drugs also have drug-specific or speciesspecific toxicities, such as cisplatin-induced nephrotoxicity and doxorubicin-induced cardiotoxicity. Cytotoxic drugs may also impair fertility (chlorambucil, cyclophosphamide) and affect wound healing. Preexisting organ dysfunction involving drug metabolism or excretion pathways (liver, kidney) may require drug dose adjustment. Also some drugs, such as doxorubicin and vincristine, can cause tissue necrosis, if extravasated. Extravasation can be avoided by ensuring that the bird is adequately restrained, preferably anesthetized during drug administration, an intravenous catheter is used and its patency tested before drug administration, the injection site is carefully monitored during infusion and the catheter is flushed with normal saline after cessation of drug administration. If extravasation does occur, several remedies are advocated, depending on the drug in question.34,121,122 In addition, acute tumor lysis syndrome following chemotherapy has been re-

Lucio J. Filippich

ported in veterinary medicine and should be distinguished from drug toxicity. Most drugs are eliminated by processes that are dependent on metabolic rate. Since birds have a higher metabolic rate than mammals, drug dosage and frequency may need to be increased in birds to match this higher metabolism. The dose rate for many cytotoxic drugs is calculated according to body surface area in square meters (m2) rather than bodyweight (kg). This is because in a given species the relationship between the dosage and the animal’s ability to metabolize the drug is more closely related to body surface area than bodyweight. As an animal’s body mass decreases, its surface area and metabolic rate do not proportionally decrease with the bodyweight so that a greater mg/kg dosage would be needed in a small animal having a proportionally greater metabolic rate compared with a large animal. However, the meter-squared calculation for doxorubicin123 and cisplatin124 has been shown to overdose small dogs less than 10kg. When extrapolating drug-dosing regimes from one animal group to another, for example from mammals to birds, scaling formulae have been advocated to correct for metabolic differences between species.125 These formulae relate metabolic rate to bodyweight and so attempt to express the dosage required as a function of metabolic energy instead of bodyweight. They assume that the dose needed to achieve therapeutic levels is correlated to metabolic rate and that the absorption, distribution, metabolism and excretion of the drug are the same or achieve the same end result for both animal groups. However, the differences in the anatomy and function of the alimentary tract of mammals and birds can potentially alter oral drug absorption.126 Also, since most drugs are eliminated by hepatic or renal excretion, with or without hepatic biotransformation, differences between mammals and birds in respect to renal anatomy and function,76,127,128 hepatic cytochrome P450 levels and plasma protein levels can potentially negate direct extrapolation of drug dosages between these two animal groups.129 Indeed, the allometrically scaled mammalian cisplatin dose (70 mg/m2) was found to be nephrotoxic in cockatoos.117 Also, within an avian group (psittacines), the pharmacokinetic profiles of certain drugs (chloramphenicol, doxycycline) vary and could lead to toxicity unless the dose is appropriately adjusted for the species.130 Drugs that are eliminated by processes that are independent of metabolic rate are not affected by scaling formulae. Resistance to chemotherapy is a major barrier to successful treatment of malignancy. Drug resis-

Tumors in Birds

tance may be intrinsic or acquired during treatment and can be kinetic, biochemical or pharmacological in origin. Kinetic resistance occurs when the tumor growth fraction is small and so few cells are sensitive as commonly occurs with large tumors and may be overcome by reducing tumor bulk (surgery, radiotherapy), by using drugs that are effective against cells in the resting phase or by scheduling drugs to synchronize cell populations and increase cell kill. Indeed, chemotherapy is more effective against residual microfoci because they often have a richer blood supply and a more rapid rate of cell turnover than the primary tumor.31,42 Biochemical resistance is due to several cellular mechanisms that result in altered drug targets, decreased drug accumulation, altered drug metabolism or increased nucleic acid repair capacity. Pharmacological resistance may be due to drug interactions or from altered drug absorption, metabolism or excretion. Some forms of pharmacological and biochemical resistance may be minimized by increasing the drug dosage, if possible. Since chemotherapeutic drugs have their own pattern of sensitive and resistant tumor types, combining them may be beneficial. The recommended guidelines when using several drugs sequentially or in combination are that the drugs should be active against the malignancy when used alone, they should have different mechanisms of action, resistance profiles and side effect profiles, if possible.34 Combination therapy has been used in the treatment of lymphoid neoplasia in a Moluccan cockatoo111 and in a Pekin duck (Anas platyrhynchos domesticus).108 Currently in veterinary medicine, chemotherapy is a valuable method of tumor control and its side effects are usually predictable, transient and manageable. In avian medicine, chemotherapy is increasingly being tried although its use is limited because of the lack of experimental and clinical studies in birds and workplace health and safety issues. Chemotherapy is indicated for the treatment of chemosensitive tumors for curative or palliative intent, as adjuvant therapy directed against systemically disseminated tumor cells after removal of the primary tumor or as neoadjuvant therapy to reduce the size of the primary tumor, so as to facilitate its surgical removal.118 Since metastatic disease is the major cause of death in animals with neoplasia, chemotherapy can play an important role in controlling distant spread of the disease and thus extend survival times.34 Corticosteroids can play an important role in tumor control, especially for malignant lym-

35 phoma, by reducing peritumor inflammation and edema.34 Prednisolone has been used alone in birds as palliative therapy for lymphoid neoplasia,18,131 thymoma74 and in combination chemotherapy (Table 1).108,111 Methylprednisolone has also been used or recommended in birds at about 10 mg/kg as a palliative therapy for several neoplasias,18,36,132 although higher doses have been used.21,76 Corticosteroids should be used with caution in birds and may predispose to fungal infections.36,54,76 Several nonsteroidal antiinflammatory drugs (NSAID), such as piroxicam, aspirin, celecoxib, meloxicam, and ibuprofen, have been shown to have chemopreventive and antitumor activity in mammals and rodents.133-136 Since NSAID drugs have been studied and are used in birds,137-139 their role in tumor control should be investigated. Alkylating agents (cyclophosphamide, chlorambucil, lomustine) react chemically with DNA by substituting alkyl radicals for hydrogen on the guanine or cytosine bases, resulting in breaks in the DNA molecule or cross-linking of the two DNA strands. Cross-linking interferes with DNA replication and RNA transcription. They are cell-cycle-nonspecific, and so are active against slow growing as well as rapidly growing tumors. Cyclophosphamide, being a prodrug, needs to be metabolized by the liver to its active metabolite and is mainly used in mammals in combination chemotherapy for lymphoid neoplasia, various soft tissue sarcomas (fibrosarcoma, hemangiosarcoma) and carcinomas. Myelosuppression and alimentary tract toxicity are dose limiting. When used in a Moluccan cockatoo with malignant lymphoma at a conventional mammalian dose, depression and regurgitation that occurred for about 24 hours after dosing was attributed to it (Table 1).111 Chlorambucil is also used as a component of maintenance therapy for malignant lymphoma and as a substitute for cyclophosphamide in animals showing cyclophosphamide–induced myelosuppression.34 In mammals, chlorambucil is well absorbed from the gastrointestinal tract and mainly metabolized by the liver. Although it may cause myelosuppression or augment the myelosuppressive effects of other drugs, alimentary tract toxicity is uncommon and generally mild. Chlorambucil has been used in combination chemotherapy for lymphoid neoplasia in an Umbrella cockatoo (Table 1),140 and in a Pekin duck.108 Chlorambucil has also been used in a Blue-and-gold macaw with cutaneous pseudolymphoma (lymphocytoma) (Table 1).141 No adverse effects were observed except for an increase in serum alanine aminotransferase activity. Hepatopathy

36 in humans has been reported following chlorambucil administration. Lomustine (chloroethylcyclohexyl-nitrosourea, CCNU) has been shown to be an effective single agent for treating canine malignant lymphoma and its dose-limiting toxicity is neutropenia.142 Its use in birds with lymphoid neoplasia should be investigated.90 Vincristine binds to the microtubular protein tubulin and blocks mitosis by interfering with chromosomal separation, resulting in metaphase arrest.34 It is cell-cycle-specific, and in mammals, it is mainly metabolized by the liver and excreted in the bile. Toxicity generally appears as alimentary tract signs (anorexia, vomiting) and its dose-limiting toxicities include peripheral neuropathy, lymphoid hypoplasia and constipation.34 Vincristine has mainly been used in combination chemotherapy and has been used in birds with lymphoid neoplasia,108,111,140 although when given intraosseously, it may cause edema and skin lesions at the injection site, as it is tissue necrotizing if extravasated (Table 1). Doxorubicin is an anthracycline antibiotic that forms stable complexes with DNA, thereby inhibiting DNA and RNA synthesis. However, its antineoplastic activity is believed to result from induction of free radical formation and from topoisomerase II-dependent DNA cleavage.108 Doxorubicin is cell-cycle-nonspecific and has a broad spectrum of antineoplastic activity. In mammals, it has been used alone or in combination in the treatment of solid sarcomas (malignant lymphoma, hemangiosarcoma).34 It is metabolized by the liver and excreted in the bile. Myelosuppression is dose limiting, especially with multidrug therapy. Other potential side effects and toxicity include gastrointestinal toxicity (vomiting, diarrhea, anorexia), acute or chronic cardiac toxicity, and hypersensitivity reactions. The hypersensitivity reactions (facial swelling, head shaking, pruritis, urticaria, erythema and vomit) can be minimized by pretreating with diphenhydramine or glucocorticoids. Since doxorubicin toxicity in mammals is related to its peak concentration, it is administered by infusion in 0.9% sodium chloride over 30 to 60 minutes and to avoid the development of cardiomyopathy, the total cumulative dosage should not exceed 240 mg/m2. Doxorubicin at a conventional mammalian dose was given intraosseously in combination chemotherapy for malignant lymphoma in a Moluccan cockatoo (Table 1).111 The bird was on prednisone, and was given diphenhydramine and dexamethasone before each doxorubicin treatment. Although prolonged anes-

Lucio J. Filippich

thetic recovery, depression and anorexia occurred on the second and one-week after the third doxorubicin treatment, its involvement in the toxicity is unclear. However, the edema and skin lesions that developed at the intraosseous site distally along the leg may have been due to doxorubicin, as it can cause tissue necrosis, if extravasated. No cardiac toxicity was reported. Doxorubicin alone at twice the mammalian dose was also used for a facial osteosarcoma in a Blue-front amazon after surgical excision and radiosurgical coagulation (Table 1).46 This bird was also premedicated with diphenhydramine, 30-minutes before each administration. No clinical or blood abnormalities were detected and the tumor was still in remission 20 months later. L-asparaginase, a cell-cycle-specific drug, depletes tumor cells of L-asparagine, which results in inhibition of protein synthesis. It is used in multidrug protocols and has been effective in canine lymphoid neoplasia.34 L-asparaginase at a conventional mammalian dose was used to treat malignant lymphoma in a Moluccan cockatoo and gastrointestinal toxicity (anorexia, regurgitation) was attributed to it (Table 1).111 Lymphoid neoplasia is the most common form of hemolymphatic neoplasia in birds143 and may originate from either the peripheral lymphoid tissue (malignant lymphoma or lymphosarcoma), the bone marrow (lymphoid leukemia) or thymus (thymoma).24 Although lymphoid neoplasia is relatively uncommon in pet birds,59,143 malignant lymphoma is most common and often involves the abdominal viscera, especially the liver, spleen and kidneys.22,144 In small animals, the treatment of lymphoid neoplasia has been well-documented145,146 and specific protocols, based on the tumor stage and histomorphologic grade of the tumor at the time of diagnosis, have been developed that lengthen survival time and improves the quality of life. Although a cure remains elusive, most modern chemotherapy protocols for lymphoid neoplasia involve combination chemotherapy (polychemotherapy) using prednisolone, doxorubicin, cyclophosphamide, vincristine and L-asparaginase.147 Currently, there is no treatment protocol for lymphoid neoplasia in birds, mainly because staging and grading schemes for neoplasia have not been developed and the pharmacokinetic and pharmacodynamic profiles of most of these cytotoxic drugs in birds are unknown. Nevertheless, combination chemotherapy has been tried for a mammalian equivalent of stage 5A lymphosarcoma with limited success.111 Prednisolone alone or in combination with vincristine may reduce

Tumors in Birds

tumor volume or induced partial remission.111,131 Vincristine, chlorambucil combination may resolve malignant lymphoma nodules,140 while the addition of prednisolone may initially reduce hepatomegaly and resolve abdominal effusion.108 However, cyclophosphamide when added to a prednisone, vincristine combination did not result in a further reduction in tumor size.111 A combination protocol involving prednisone, vincristine, cyclophosphamide, doxorubicin, L-asparaginase, and alpha interferon at conventional mammalian doses may result in some partial response to treatment with local and systemic toxicities similar to those observed in mammals.111 However, irrespective of the protocols used to date, lymphoid neoplasia in birds is progressive and peripheral lymphocytosis persists. Although chlorambucil alone successfully treated pseudolymphoma (lymphocytoma) in a Blue-and-gold macaw,141 its efficacy is questionable as pseudolymphoma, a benign nonneoplastic but lymphoproliferative process which mimics malignant lymphoma, may regress spontaneously.148 Cisplatin and carboplatin are water-soluble, platinum-containing compounds that can inhibit DNA synthesis and have some alkylating activity. They are cell-cycle-nonspecific, and the free platinum (nonprotein-bound fraction) is responsible for their tumorcidal activity and toxicity.149 In veterinary medicine, cisplatin has been mainly used to treat canine solid tumors64,65,150 but its toxicity profile (nephrotoxicity, gastrointestinal toxicity, neurotoxicity) has limited its use.149 Moreover, to minimize toxicity it needs to be given by infusion and patients require intensive saline diuresis before and for several hours after cisplatin administration.65,117,151 Carboplatin, an analog of cisplatin, has largely replaced cisplatin because it has a similar mechanism of action and efficacy, but with reduced toxicity.149,152-154 Furthermore, carboplatin can be given slowly as a bolus dose and hydration is not required. The pharmacokinetic profile of cisplatin and carboplatin has been determined in Sulfur-crested cockatoos (Cacatua galerita) and is similar to those previously reported in mammals.120,155 Cisplatin can be safely given intravenously at 1.0 mg/kg, but if given at the allometrically scaled canine dose of 70 mg/m2 (6.4 mg/kg), nephrotoxicity can occur (Table 1).117 Carboplatin has been given parenterally to cockatoos (Table 1)120,156 at a dose derived from published platinum pharmacokinetic data in cockatoos155 and by allometrically adjusting the carboplatin dose commonly used in dogs (300 mg/m2).125,152 Plasma platinum

37 levels were found to be similar whether carboplatin was given intravenously or intraosseously and the free plasma platinum levels persisted longer than for cisplatin.156 Also, platinum tissue distribution was found to be similar to that reported for cisplatin with the kidneys having the highest accumulation, followed by the liver.120 Gastrointestinal signs, such as inappetence and vomiting, were mild, transient and did not warrant the use of antiemetics. Although myelosuppression is dose-limiting in mammals following carboplatin therapy with the nadir for white blood cell and platelet count occurring between 14 days and 28 days,149,152 significant myelosuppression has not been reported in avian studies to date,90,120 although there was some evidence of hepatopathy.90 The current recommendation in dogs is to administer carboplatin at 3-weekly intervals.157 Preliminary studies by the author suggest that carboplatin at three times the 5 mg/kg dose, intraosseously can be given to parrots on two occasions at 3-weekly intervals without causing myelosuppression. Carboplatin was successfully used to treat pancreatic duct adenocarcinoma in a Greenwinged macaw (Ara chloroptera) (Table 1)158 and markedly reduced the abdominal swelling and hepatomegaly due to bile duct carcinoma in a Yellow-naped Amazon (Table 1).83 However, it was unsuccessful in a male Budgerigar with renal adenocarcinoma, although improvement was initially observed during treatment.159 Platinum analogs have also been given intratumorally as a function of tumor volume,88 tumor size,113 bodyweight90 or body surface area.27 Unlike tumor volume, the dose administered as a function of tumor size is determined by the volume of drug (for example 3.3 mg/mL cisplatin) that can be injected into the tumor until its extruded from the treatment area.113 Intratumoral chemotherapy is a way of maximizing cytotoxic drug concentrations in tumor tissue while minimizing normal tissue exposure and has a place for primary tumors confined to single organs or regions of the body. The cytotoxicity of neoplastic drugs is enhanced if the drug exposure time and effective drug concentration in the tumor are increased.160 Intratumoral cisplatin as a function of tumor volume in combination with radiotherapy, was successful in treating a fibrosarcoma on the wing of a Blue-and-gold macaw (Table 1)88 while in another Blue-and-gold macaw, where it was presumably given as a function of tumor size, the fibrosarcoma was held in remission for 29

38

Lucio J. Filippich

Table 2. Guidelines for the Use of Cytotoxic Drugs ● ● ● ● ● ● ● ●

Use cytotoxic reconstitution services, whenever possible When making up cytotoxic preparations, a biological safety cabinet should be used Wear personal protective clothing (goggles, mask, gloves, gown) Administer drugs in an area only used for cytotoxic drugs that is off limit to the general public and untrained staff Ensure all patients are well restrained during administration Ensure that a procedure is in place for managing spills and biological waste Use designated cytotoxic waste disposal facilities Clinicians should inform owners and caretakers of the potential risks of contact with the treated patient and of the procedures they should adopt to avoid exposure when administering drugs or disposing of excreta and unused drugs.

months.87 Since potentiation of radiation by cisplatin is dose dependent,161 it is advisable that dosage based on tumor volume is used to avoid adverse radiation-drug interaction. Intratumoral carboplatin when used alone, presumably as a function of tumor size, was unsuccessful in treating cutaneous xanthomatous masses in a Greylag goose (Anser anser).162 Intratumoral carboplatin as a function of bodyweight was effective when used with surgical debulking to treat squamous cell carcinoma in an Amazon parrot (Amazona ochrocephala oratrix) that failed to respond to surgical excision and megavoltage teletherapy (Table 1).90 However, it failed to prevent regrow of squamous cell carcinoma following incomplete uropygial gland removal,22 although the dose and frequency used were not stated. Nevertheless, radiochemotherapy with a platinum analog may be the optimum treatment for cutaneous squamous cell carcinoma.90 A Rose-breasted cockatoo with recurrent stump osteosarcoma following limb amputation appeared not to respond when the author used carboplatin intraosseously (Table 1). However, when the same dose in sesame oil was given intratumorally, no evidence of neoplasia was observed 3 weeks after the first intratumoral injection. Mild myelosuppression was observed after the fourth carboplatin dose. 5-Fluorouracil, an antimetabolite to uracil, ultimately inhibits DNA and RNA synthesis. It is cell-cycle-specific and has been used topically in dogs for the treatment of superficial malignancies. It has been recommended for squamous cell carcinoma regrowths following surgical excision in raptors (Forbes NA, written communication 2003). Traditional herbal remedies as an adjunct to chemotherapy have also been suggested21 and a chrondrosarcoma involving the tarsus of a Yellowcollared macaw (Ara auricollis) reportedly re-

sponded to the homeopathic preparation, Hecla lava.163

Safety Issues The guidelines for the proper handling and disposal of radioactive and cytotoxic material have been developed122,164,165 and the legislative requirements covering these procedures vary in different countries. Current information can be accessed from several www cites including US Department of Labor (osha.gov/SLTC/hazardousdrugs/index.html) and Veterinary Practice Consultants -Chemotherapy (v-p-c.com/phil/osha/chemo.htm). Clinicians should be familiar with workplace health and safety requirements for the use of cytotoxic substances as many are carcinogenic with no known risk-free dose and many may cause local toxicity or allergic reactions. Exposure through the skin or mucous membrane, inhalation, ingestion or needle-stick injury can occur during the preparation, administration or disposal of agents or from contact with the patient’s excretions. For oncology nurses, a strong link exists between safe work practices and reduced drug exposure, as indicated by urinary excretion of cytotoxic agents.118 Clinicians should consider the recommendations outlined in Table 2, when using cytotoxic drugs.

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