Current therapies in exotic animal oncology

Vet Clin Exot Anim 7 (2004) 757–781

Current therapies in exoticanimal oncology

Jennifer E. Graham, DVM, Dipl. ABVP (Avian)a,b,*,Michael S. Kent, DVM, Dipl. ACVIM (Oncology)c,

Alain Theon, DVM, PhD, Dipl. ACVR(Radiation Oncology)c

aDepartment of Comparative Medicine, School of Medicine, University of Washington,

Box 357190, Seattle, WA 98195-7190, USAbVeterinary Specialty Center, 20115 44th Avenue West, Lynnwood, WA 98036, USA

cVeterinary Medical Teaching Hospital, School of Veterinary Medicine,

University of California–Davis, One Shields Avenue, Davis, CA 95616, USA

As advances are made in exotic animal medicine, cancer and its treatmentare frequent issues that must be addressed. Information for exotic animalsregarding tumor therapy response and posttreatment survival time is limited.Many treatment protocols used in exotic animals have been extrapolatedfromdog and cat literature. Further research and data compilationwill ensurethat cancer treatment of exotic animals continues to advance. This article willdiscuss current therapies in exotic animal oncology.

Anatomic considerations

Avian

The skin of birds is thin andmore delicate thanmammal skinwith extensiveattachments to the skeleton. In feathered areas, the epidermis may be only 10cell layers thick [1]. The uropygial gland is a bilobed holocrine gland located atthe base of the tail that conditions and waterproofs the feathers, hasantibacterial properties, and produces odorous secretions in some birds [1].The uropygial gland is not present in all species, including Amazon parrots,hyacinth macaws, and palm cockatoos [2]. There is a high incidence ofneoplasia, especially squamous cell carcinoma, associated with this gland [3].

* Corresponding address: Veterinary Specialty Center, 20115 44th Avenue West,

Lynnwood, WA 98036, USA.

E-mail address: [email protected] (J.E. Graham).

1094-9194/04/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.cvex.2004.04.004

mailto:[email protected]

758 J.E. Graham et al / Vet Clin Exot Anim 7 (2004) 757–781

Vascular access ports have been used in avian species but are difficult tomaintain because of the thin skin of birds [4]. If intravenous access isnecessary, the right jugular vein is the preferred route because the left jugularvein is small or absent [5]. Columbiformes, such as pigeons and doves, havea vascular plexus rather than a distinct jugular vein [6]. The cutaneous ulnarvein and medial metatarsal vein allow vascular access but are prone tohematoma formation.

Birds are very susceptible to immunosuppression and secondary infectionfrom the use of steroids [7,8]. Great care should be taken with the use of anychemotherapeutic agents. Prophylactic antibiotics and antifungals may benecessary when chemotherapeutics are administered [9]. AfricanGray parrotsmay have complications from the use of certain antifungal medications, suchas itraconazole [10,11].

Small mammal

The thick skin of ferrets makes peripheral catheterization challenging.Making a small incision in the skin next to the vessel with a 20- or 22-gaugeneedle can prevent burring of the catheter [12]. For therapy that requiresrepeated venous access, vascular access ports are preferred [9,13]. Ferrets arevery steroid tolerant, but may develop multiple drug resistance if they arereceiving steroids for a concurrent problem such as insulinoma [9].A variety ofchemotherapeutic protocols have been used in ferrets with success [9,14–17].

Rabbits have very thin skin and care should be taken when clipping hairaway from the skin to avoid creating lacerations [18]. Auricular vessels are notideal for administration of chemotherapy because of the likelihood of necrosis[9]. Peripheral vessels can be easily catheterized. Vascular access ports havebeen used successfully in the jugular and femoral vein [9,19]. Caution shouldbe used if steroids are administered to rabbits. Steroids can cause adreno-cortical suppression, and may result in immunosuppression and secondaryinfections [20]. One of the authors (J.E.G.) has seen complications in rabbits,including suspected immunosuppression and death, resulting from the use oftopical and systemic corticosteroids. If immunosuppressive drugs are used,prophylactic antibiotic therapy may be warranted to avoid secondaryinfection, such as pasteurellosis [9].

Peripheral catheterization is more difficult in the smaller rodents such asguinea pigs, chinchillas, rats, and mice. Vascular access systems have beendescribed clinically with chinchillas [21], and are used often in researchsettings in rodents with success [22–24].

Reptile

Outward peripheral vessels are not readily visible in reptiles other thanthe jugular veins on turtles and tortoises. Cutdowns can be used to accessthe cephalic and jugular veins in lizards and allow better visualization of the

759J.E. Graham et al / Vet Clin Exot Anim 7 (2004) 757–781

jugular vein of turtles and tortoises. Vascular access ports have been used inreptiles [9,25]. The jugular vein of snakes have been successfully catheterizedand fitted with vascular access systems [21,25]. Anesthesia is often necessaryto facilitate placement of these devices, but once in position, can be usedwithout sedation [9].

Normal flora of reptiles may include Salmonella spp., Aeromonas spp.,Campylobacter spp., Citrobacter spp., Enterobacter spp., Klebsiella spp.,Proteus spp., Serratia spp., and others [26]. When immunosuppressive drugsare used in reptiles, it is possible that normal flora or pathogenic bacteria mayproliferate and cause disease [9]. Reptiles have very specific requirements forhusbandry and nutrition based on species that should be considered whentreating them.

Diagnostics

Biopsies and aspirates

Diagnosing neoplasia is similar in exotics as it is for dogs and cats.Biopsies or aspirates are best taken at the junction of normal and abnormaltissue; avoid taking biopsies that contain only ulcerated or inflamed tissues[27]. In the case of bone biopsies however, biopsies should be taken at thecenter of the lesion, as otherwise it is possible to only biopsy a periostealreaction in response to the tumor. Aspirates and biopsies of abnormal tissueare characterized via cytologic or histopathologic examination. Care shouldbe taken with sampling to avoid damaging the tissue; electrocautery shouldnot be used to collect biopsies as it deforms the cellular architecture [27].Jamshidi bone biopsy instruments can be used in larger exotics; a modifiedtechnique, using needles to collect core biopsies, is used for smaller patients[9]. Spinal needles may be especially helpful for collecting bone marrowaspirates in smaller patients, as the stylette prevents a bone core fromblocking the needle during insertion and can be withdrawn before aspiration,and the smaller size of the needle is less likely to be traumatic. Rigid andflexible endoscopy are particulary useful to collect samples in birds andreptiles as insufflation is not needed due to their extensive air sac system [9].Biopsy methods include needle punch biopsy, punch biopsy, incisionalbiopsy, and excisional biopsy [27]. For more information on biopsies andaspirates, see the diagnostic section of the article on surgical oncology ofexotic animals by Mehler and Bennett in this book.

Imaging

Conventional radiography, magnification radiography, contrast radiog-raphy, ultrasonography, fluoroscopy, magnetic resonance imaging (MRI),computed tomography (CT), and bone scans are some of the imagingmodalities that are useful in exotic oncology cases [28]. All of these modalities


can be used to both assess the extent of the tumor locally and to assess thepatient for spread of the tumor. Thus, imaging is essential in the staging ofexotic animal patients with cancer. Limitations of MRI and CT include:difficulty of acquiring useful images due to small patient size; difficulty ofproviding anesthesia, particularly due to the inability to use metal anestheticmachine components in the presence ofMRI; expense; and limited availabilityof equipment in some areas [28] (see Figs. 1–4 for examples of imagingtumors).

Therapeutics

Vascular access

One of themost significant considerations for exotic animal oncology is thesmall patient size and resulting challenges of vascular access. Vascular accessports have been used on multiple exotic species, and can facilitate repeateddelivery of chemotherapeutic agents. As mentioned in this and other articles,vascular access ports have been used successfully in ferrets, birds, rabbits,rodents, and reptiles [4,9,13,19,21–25,29].

Totally implantable vascular access systems have been used for over 2decades in human patients [30,31]. These systems have been used in human

Fig. 1. Whole-body radiograph of an 8-year-old female corn snake with a partially mineralized

soft tissue mass originating from mid body determined to be a vertebral body osteosarcoma.

The vertebrae appear irregular in the area of the mass, and there is gas distension of the viscus

cranial to the lesion causing possible obstruction. (Courtesy of Dr. Anna Osofsky, UC Davis

College of Veterinary Medicine.)


and animal patients to facilitate administration of chemotherapeutics, bloodproducts, antibiotics, and parenteral nutrition [30–33]. The implantablevascular system is composed of an indwelling nonthrombogenic siliconerubber or polyethylene catheter that resides within the chosen vessel anda biocompatible polysulfone injection port implanted in the subcutaneous

Fig. 2. Image from a computed tomography (CT) scan of an 8-year-old female corn snake with

a vertebral body osteosarcoma. (Courtesy of Dr. Anna Osofsky, UC Davis College of

Veterinary Medicine.)

Fig. 3. Ultrasound image of a right femoral osteosarcoma invading the surrounding tissues of

a 20-year-old female hyacinth macaw. (Courtesy of Dr. Anna Osofsky, UC Davis College of

Veterinary Medicine.)


tissues [13]. The septum contained within the injection port can reportedly bepunctured up to 1500 times by a Huber-point needle without leaking [30].

Systemic chemotherapy

Although the use of systemic chemotherapy is still investigational in exoticanimal patients, useful information is available for some tumor types incertain exotic species. Please see the article on chemotherapy by Kent formore complete information on the use and dosing of chemotherapy in exoticanimal species.

Intralesional chemotherapy

The use of systemic chemotherapy in exotic animal oncology is limitedbecause of potential toxicity to target organs and lack of information onspecific tumor response. Toxicity associated with what would be consideredtherapeutic drug doses in other species when adequate supportive care isprovided has not been described. Intratumoral administration of antineo-plastic agents has been evaluated to improve drug therapeutic index in thetreatment of solid tumors. Intratumoral chemotherapy consists of injectingantineoplastic drugs directly into the tumor and adjacent tissues. It is thesimplest and most direct approach for treatment of accessible solid tumors.However, intratumoral injections using aqueous solutions of cytotoxic agentshave had only marginal success, in part because of rapid clearance of the drugfrom the tumor mass after injection, which is often accompanied by systemic

Fig. 4. CT scan of a 20-year-old female hyacinth macaw with a right femoral osteosarcoma

invading the surrounding soft tissues and causing multiple pathologic fractures. (Courtesy of

Dr. Anna Osofsky, UC Davis College of Veterinary Medicine.)


exposure in small size animals [34,35]. The pharmacokinetic advantage ofintratumoral chemotherapy may be optimized by use of slow-releaseformulations that allow prolonged local exposure of the tissue to high drugconcentrations in the rodent [34], canine [36], feline [35], equine [37], and aviantumors [38]. Collagen matrix has been used as a drug carrier in companionanimals [39] and people [40]. A water-in-sesame oil emulsion has beendeveloped as a cost-effective drug carrier for use with cisplatin [37] and otherantineoplastic drugs [41]. Cisplatin is an ideal candidate for intratumoraladministration because it is not necrotizing, it displays a steep dose–responserelationship, and it has a wide spectrum of activity against all histologic typesof solid tumors. It is the drug of choice for intratumoral chemotherapy innondomesticated species [34,42]. Intratumoral administration of cisplatin insesame oil emulsion results in a high tumor-to-plasma drug concentrationratio [38].No dose-limiting cisplatin-related toxicities, such as nephrotoxicity,nerotoxicity, or bone marrow toxicity, have been observed.

Current drug formulations of cisplatin in sesame seed oil have beendescribed [43]. Briefly, Cisplatin, cis-Platinum(II)-diammine-dichloride, isreconstituted with sterile water at a concentration of 10 mg/mL and mixedwith medical grade sesame seed oil by use of the pumping method [44].Sesame seed oil can be sterilized by gamma-irradiation or by pasteurization.An emulsifier (Sorbitan monoleate) may be added to sesame seed oil (1:20volume) to decrease the fluidity of the mixture. The mixture is formulated todeliver 3.3 mg of cisplatin per mL, with oil to water ratio of 2. The use ofa commercially available aqueous solution of cisplatin (1 mg/mL) with orwithout a drug carrier is not recommended because of decreased potency.Because antineoplastic drugs are mutagenic and carcinogenic, strict safetyrules have to be observed concerning drug preparation and administration,and handling by caretakers [44]. Only personnel properly trained in thehandling and use of antineoplastic drugs should be involved in the treatmentprocedure. Good technique is critical to maintain product sterility and avoidcontamination of the environment or personnel by accidental exposure tocytotoxic dust or aerosols. Protective garb, that is, disposable protectivegown made of low-permeability fabric, disposable high filtration efficiencyrespirator, chemical splash goggle, and chemotherapy gloves are requiredduring drug preparation and treatment.

A standard treatment protocol includes four intratumoral chemotherapytreatment sessions at 1-week intervals. Each session consists of a series ofinjections into all gross tumor and a margin of normal tissue of 1 to 2 cm(biologic margins) depending on tumor type and tumor size. Treatments areusually done while the patient is anesthetized to facilitate accurate drugplacement and to minimize patient discomfort during injections. Tumordosage is 1 mg of cisplatin/cm3 of tissue. To administer the drug mixture, theneedle (25 gauge) mounted on the syringe (luer-lock type) is inserted to thedesired length into tissue, and the drug is injected at a constant flow whilethe needle is withdrawn. Because the efficacy of treatment relies on exposure


of tumor cells to high drug concentrations, the technique and pattern ofinjection is critical to the success of the treatment. Depending on the shapeand accessibility of the lesion, parallel-row technique or field-blocktechnique of injection can be used to obtain a high and uniform dose dis-tribution in tissues [37]. Because cisplatin does not diffuse in tissues fartherthan 4 mm from the site of injection, the rows of injections should be kept at0.6 to 0.7 cm (0.25 inch) apart.

Intratumoral cisplatin chemotherapy can be used alone or in combinationwith other treatment modalities, including surgery or radiotherapy. Treat-ment is indicated for accessible and localized soft tissue tumors. Intratumoralchemotherapy with cisplatin is effective for treatment of squamous cellcarcinomas, soft tissue sarcomas, and round cell tumors. Treatment cannotbe used for bone tumors or tumors invading bone. This treatment is ideal fortumors in locations where surgery would result in a cosmetic or functionaldeficit (Fig. 5). Lesions on the face, oral cavity, base of tail, and extremitiesare treated successfully with minimal local normal tissue reactions. Fortumors \2 cm in diameter the treatment may be used alone. For largerlesions, the treatment must be used in combination with surgery or radiationtherapy. The goals of a combined approach are to improve the efficacy andreduce the morbidity of the treatment. As a rule, the treatment is used incombination with surgery for operable lesions, and with radiation therapy forinoperable lesions. The central idea in combining surgery and intratumoralcisplatin chemotherapy is that a conservative surgery and adjuvant intra-tumoral chemotherapy is as effective as a radical surgical resection. Thistreatment combination is indicated for accessible tumors that are notoperable or tumors for which radical surgery would result in unacceptablefunctional and cosmetic defects. The two treatment modalities are comple-mentary, that is, conservative surgery removes the tumor bulk and cisplatineradicates the residual disease. Treatment may be started 2 to 3 weeks aftersurgery when wound healing is complete. However, excessive delay betweenincomplete excision and chemotherapy may reduce the efficacy of thetreatment due to active tumor regrowth. For large inoperable tumors ortumors surrounded by radiosensitive normal tissues, tumor response toradiation may be maximized by use of intratumoral administration ofcisplatin. Cisplatin, in addition to its direct cytotoxic effect, enhances theeffect of radiation. Therapy includes concomitant irradiation and four weeklyintratumoral chemotherapy treatments with cisplatin. The concept has beenvalidated in dogs [36], and the treatment combination has been usedsuccessfully by one of the authors (APT) in birds [38,45].

The side effects of intratumoral treatment are strictly local. All acutereactions including inflammation, swelling, and focal ulceration are self-limiting and resolve quickly. Swelling frequently occurs after treatment offacial lesions and usually starts 2 to 3 days after each treatment. There are noknown contraindications, and drug-related systemic toxicity or hypersensi-tivity reactions have not been observed. Treatment of grossly infected lesions


should be postponed until the infection has resolved. Prophylactic antibiotictherapy is recommended after each treatment session. Treatment does notproduce tissue fibrosis or necrosis, and does not affect feather growth andcolor. A second course of treatment for recurrent tumor can safely be givenwithout increased local reactions.

Electrochemotherapy involves the intratumoral administration of a che-motherapeutic drug followed by delivery of electric pulses to the tumornodule. Electrochemotherapy with cisplatin has been used in dogs and catswith better response to therapy and prolongation of duration of responsewhen compared with intratumoral cisplatin alone [46]. Local hyperthermiacombined with intralesional cisplatin chemotherapy was found to be a safeand effective method for the treatment of selected localized neoplasms inspontaneous canine and feline tumors [47]. These modalities have also beenused in experimentally induced tumors in laboratory animals.

Fig. 5. (A) Five-year-old blue and gold macaw that presented with a fibrosarcoma involving

facial skin and eyelid. (B) Setting for intratumoral chemotherapy with cisplatin in sesame oil

emulsion. (C) No evidence of tumor recurrence or treatment complication 22 months after

treatment.


Radiation therapy

Radiation therapy can be a very effective method for the treatment oflocalized tumors in veterinary and human medicine. There are now manyradiation therapy facilities dedicated to the treatment of veterinary patientswith cancer. However, there is very little published literature available onthe treatment of exotic animals with radiation therapy alone. There are alsoseveral case reports on the combined use of irradiation and intralesionalchemotherapy.

The dose of radiation to be delivered is described by the unit Gray (Gy),which is defined as the absorbed dose in tissue in Joules/kg. The old unit, whichis still commonly used to describe absorbed dose, is the rad.One rad is equal to1 cGy and 100 rads is equal to 1 Gy. The total dose to be delivered is dividedintomultiple small doses to help limit possible late side effects of irradiation tonormal tissues. Each treatment is referred to as a fraction. Fractions can bedelivered in a number of different schemes. Definitive treatment is defined asa treatment designed to cure or obtain long-term control of a tumor, whilepalliative radiation therapy is designed to alleviate clinical signs and may notextend life. Commonly, definitive radiation therapy protocols deliver 12 to 16fractions on a Monday through Friday or a Monday, Wednesday, Fridaybasis. In the case of palliative radiation therapy, treatments are often doneonce weekly for 3 or 4 treatments total. One of the drawbacks of radiationtherapy is the need for anesthesia for each treatment; although with advancesin exotic animal anesthesia, this is becoming less of a problem.

Radiation therapy can either be used alone for certain tumor types or morecommonly is combined with other treatment modalities such as surgery orchemotherapy. Irradiation of a tumor can be done either in the preoperativeor postoperative setting. The optimal treatment protocol should be plannedby the surgeon, the radiation oncologist, and by the practitionermanaging theindividual case. If surgery is done first, the use of hemoclips or other metallicmarkers that can be visualized on plain radiographs are used to delineate thetumor margins and aid in treatment planning, allowing for smaller treatmentfields and decreasing the chance of a geographic miss.

There is a single case report describing the use of radiation therapy ina snake. A boa constrictor was treated with 48 Gy divided into 16 3 Gyfractions on a Monday through Friday basis using a Cobalt-60 radiationtherapy unit for a fibrosarcoma of the body wall that was previously debulkedby surgery. The mass enlarged over the course of treatment and the snakedeveloped a marked lymphopenia. Radiation was followed by intratumoraladministration of 50 mg of carboplatin. A biopsy taken at that time revealeda decrease in fibrosarcoma cells but an infection with acid-fast bacilli anda granulamatous cellulitis was identified. The snake was subsequentlyeuthanized [48].

The use of radiation therapy for the treatment of squamous cell carcinomaof themandibular beak in amacaw is described in a published case report. The


lesion was surgically debrided and treated with 48 Gy delivered in alternateday 4 Gy fractions followed by an additional 8 Gy boost. The tumor failed torespond. The bird was then treated with intralesional cisplatin at 30 mg/m2.The bird became anorexic, and eventually died 30 weeks after initialpresentation. Due to limited reports of the use of radiation therapy it is notclear if they did not give an adequate dose, if the intratreatment interval wastoo great, or if squamous cell carcinoma of the beak is resistant to irradiationsuch as squamous cell carcinoma of the oral cavity in the cat [49].

There are two case reports of the use of radiation therapy combined withintralesional chemotherapy in birds. One case reports describes the treatmentof intratumoral cisplatin and orthovoltage radiation therapy for thetreatment of a fibrosarcoma in a Macaw, resulting in a remission of 29months duration. The bird was treated with 44 Gy of radiation therapy;unfortunately, the dose of cisplatin used was not reported limiting theusefulness of this case report [45]. Another case report describes the treatmentof amyxoid fibrosarcoma in the wing of a blue and goldmacaw. It was treatedwith 40 Gy of radiation on an alternate day schedule of 4 Gy per fraction andthree weekly treatments of intratumoral cisplatin at 0.3 mg per cm3 of tumor.A complete response was noted at 2 months postcompletion of therapy, andno tumor recurrence was noted when the bird died of unrelated causes 15months later. No systemic toxicity was noted with cisplatin administration.Acute local tissue complications included edema and necrosis of the skin, andwere self-limiting. Decreased range of motion of the carpal joint was notedand thought to be secondary to the radiation therapy [38].

Interestingly, chickens are among the least radiosensitive species withregard to total body irradiation when compared with other domestic animals,such as sheep, cattle, and swine [50,51].When death is defined as the endpoint,radiosensitivity varies among species and can expressed as LD50/60, or thewhole body radiation dose that results in death of half of the animals within 60days [52]. The LD50/60 for chickens is estimated at 9 Gy for whole-bodyirradiation, compared with 4 Gy for sheep, 5 Gy for cattle, and 6.4 Gy forswine [53].

Consultation with a board-certified veterinary radiation oncologist shouldbe sought when planning to include radiation therapy as part or all ofa patient’s treatment protocol.

Cryosurgery, hyperthermia, and photodynamic therapy

Cryogens such as nitrous oxide (N2O) and liquid nitrogen (N2) can be usedto induce freezing of tissue in the treatment of certain neoplasms, resulting incell rupture and death [54]. Nitrous oxide is suitable for smaller (\1 cm)lesions, but drawbacks include its high temperature, slow speed of freezing,shallow depth of penetration, and lack of effective spray capabilities whencompared with liquid nitrogen [54]. Liquid nitrogen applicators may be smalland portable, and N2 can be applied with probes or with a fine mist or spray


[54]. Lesions of the eyelid, perianal region, oral cavity, and skin, may beespecially suitable for treatment with cryosurgery [54]. Cryosurgery has beendescribed in treating ferrets with adrenal gland disease [55].

Hyperthermia is a modality that has been used in human medicine forthousands of years. Although cautery was originally used, radiofrequencyelectrocautery is the approach being considered today [56]. Hyperthermiacombined with radiation therapy or chemotherapy may be advantageouswhen compared with radiation or chemotherapy alone [47,57–61]. Tumors incanine and feline patients treated with hyperthermia combination therapiesinclude osteosarcomas, malignant melanomas, mast cell tumors, soft tissuesarcomas, and squamous cell carcinomas [56]. Although not reported asa routine treatment with spontaneous tumors in exotic animals, there aremany reports of experimentally induced neoplasms in rat and mice modelstreated with hyperthermia combined with radiation or chemotherapy [62–65].Despite some promising research studies, hyperthermia is not likely to bea mainstay in animal cancer management due to its high cost and difficulty ofdependably heating and measuring temperatures within tumors [56].

Photodynamic therapy (PDT) is a newmodality that has shown promisingresults in treating a variety of human and veterinary patients [66]. With thistherapy, a photosensitizer preferentially accumulates in neoplastic tissue andis activated by light, and destroys tumor tissue but spares normal surroundingtissue [66]. PDT has been used to treat a variety of tumors in dogs, cats, andreptiles [67,68]. Squamous cell carcinomas have been treated most frequentlywith PDT in companion animals [66]. Remission rates have been reportedfrom 50% to 100%, but toxic reactions from the photosensitizer have beena problem [66]. Porfrimer sodium (Photofrin) was used to treat squamous cellcarcinoma (SCC) in a cockatiel with minimal side effects; lack of ownercompliance was considered as a factor preventing complete resolution of thelesion [69]. Photochlor (HPPH) has also been used against SCC in birds andseems to be an effective method to kill avian SCC cells [67]. The optimal timeto postinjection treatment seems to be shorter in birds than in dogs and cats[67]. Disadvantages of PDT include its expensive equipment requirements,limited tissue light penetration, expense of the photosensitizing agents,inability to determine tumor margins, and inability to effectively treat deeptumors [66]. Following treatment with a photosensitizer, animals may besensitive to light exposure for several weeks, as some photosensitizers areretained in the skin for weeks [66]. As newer photosensitizers with lesscutaneous toxicity and more readily available light delivery systems are used,PDT is becoming more affordable, available, and has applications for deepertumors [66].

Immunotherapy

Acemannan, an immunustimulating polysaccharide, has been used totreat tumors in a variety of species with varying response [70]. It is believed


to exert its antitumor activity through macrophage activation and therelease of tumor necrosis factor, interleukin-1, and interferon [70]. Ace-mannan was used intratumorally and systemically, in combination withincomplete surgical debulking, in an umbrella cockatoo (Cacatua alba) witha suspected fibrosarcoma. There was no evidence of tumor regrowth 6months postoperatively; the patient was lost to follow-up evaluation afterthis period [71].

Interferons (IFN) are naturally occurring glycoproteins with a variety ofbiologic effects [72]. Interferons have been researched to determine efficacyagainst many types of neoplasms and IFNa, specifically IFNa-2a and IFNa-2b, derived from leukocytes, shows the most promise with antitumor effect[73]. In veterinary medicine, IFN therapy is primarily used with feline viraldiseases [72]. Retinoids act by activating or inhibiting gene transcription, andhave an antineoplastic effect. Interferons and retinoids have been used incombination, as their synergestic effect may be useful in treating a variety ofneoplasms [73]. Cutaneous T-cell Lymphoma (CTLT), also known asMycosis Fungoides, is an epitheliotrophic neoplasm of T-cell lymphocytesthat has been reported in exotic mammals such as rabbits and ferrets (Fig. 6)[74–76]. Although not curative, retinoids have been useful for the palliativetreatment of CTLT in a ferret [74].

Liposome-encapsulated muramyl tripeptide (L-MTP) nonspecificallyactivates monocytes and macraophages [77]. A lipophilic derivative ofMycobacterium cell walls, L-MTP has been shown to be tumoricidal inrodents and humans [77,78]. L-MTP has been shown to have antitumoractivity in human metastatic osteosarcoma, hemangiosarcoma, melanoma,and renal cell carcinoma [79]. Additionally, the drug has been found to havevariable success against canine osteosarcoma, hemangiosarcoma, melanoma,and feline mammary adenocarcinoma [72]. L-MTP is not available commer-cially; thus, its usefulness is limited.

Fig. 6. Appearance of cutaneous T-cell lymphoma (CTLT), or mycosis fungoides, in a ferret.


Cimetidine, a histamine-2 receptor antagonist, has an immunomodulatingeffect, and has been used to treat dermal, oral, and conjunctival papilloma-tosis in humans with mixed results [80]. Studies have also shown thatcimetidine has a synergistic effect with interferon in treating melanoma, acutemyeloid leukemia, and myelodysplastic syndrome [81]. In horses, cimetidinehas been reported to cause regression of cutaneous melanoma [82]. Variableresults have been obtained with the use of cimetidine and experimentallyinduced tumors in rats. Further research involving clinical trials is needed todetermine its effectiveness as a therapeutic immunomodulator [72].

Interleukin-2 (IL-2), an immunomodulating cytokine, has been studied forits potential antitumor effect [72]. Rodent models have shown promisingresults with IL-2 immunotherapy, but response rates in humans have beenaround 10% to 20% with prolonged remission [83,84]. Human recombinantIL-2 has been used in veterinary medicine with some promising results as animmunomodulator [72]. IL-2 has been used as a liposome encapsulated agentto nebulize dogs with pulmonary metastasis, and resulted in regression for 12to 20 months [85]. Local or intratumoral IL-2 can induce antitumor activityand mice with metastasized lymphoma were treated with local IL-2 injectionssuccessfully [86]. Additionally, IL-2 intratumorally caused tumor regressionin cows with squamous cell carcinoma [87]. IL-12 is another interleukin thathas been shown to have antitumor effects [72]. Further research is needed todetermine if interleukins can be useful with exotic animal oncology; differentproducts may have widely variable results, and optimal dose, route, andschedule for IL-2 has not yet been determined in any species [72].

Other types of immunologic treatments, such as monoclonal antibodies,tumor vaccines, gene therapy, bacterial vectors, superantigens, antiangio-genic therapy, bone marrow transplantation, and others have not beenevaluated thoroughly for exotic animal oncology. The majority of biologictherapeutics are human products adapted for veterinary usage [72]. Rodentsare typically used as models for developing therapies in human medicine,and this should be kept in mind when exploring treatment options for exoticanimal patients.

Nonsteroidal therapy

Many nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin,indomethacine, sulindac, and piroxicam, have antitumor activity [88].Cyclooxygenase inhibition, inhibiting formation of direct carcinogens,antiangiogenic effects, and prevention of metastasis via inhibition of plateletaggregation are potential mechanisms of activity [89]. Piroxicam’s antitumoractivity has been demonstrated against several canine tumors, most notablytransitional cell carcinoma [90]. A large amount of research is currentlyunderway to further examine the effects of NSAIDs on various types oftumors inmultiple species. It is likely that there will be application forNSAIDtherapy in exotic animal oncology in the future.


Complementary and alternative therapy

Complementary and alternative medicine (CAM) therapies are pursuedby up to 50% of human patients with cancer [91,92]. Interestingly, in 1997,CAM was reported at 42%, with more visits made to alternative medicinepractitioners than to all US primary care physicians [93]. It follows thatowners are often interested in pursuing complementary and alternativeveterinary medicine (CAVM) for their animals with cancer [94].

Herbal remedies are used to treat cancer or alleviate the side effects fromtraditional cancer therapy, but clients and many professionals often do notunderstand benefits, risks, and potential interactions [95,96]. Medicinal herbsare not required to demonstrate safety or efficacy before marketing and arenot regulated for quality [95]. Additionally, herbs may be misidentified,contaminated, or contain unlisted ingredient; however, there have been fewreports of consumer harm [95,97]. Aloe vera, ashwagandha, astragalus,garlic, ginger, green tea, milk thistle, mushroom, and many others arebotanical compounds thatmay be beneficial for cancer patients [97]. Formorecomplete descriptions of herbal remedy options, alternative therapy veteri-nary texts are available. Nutraceuticals such as vitamin E, glutathione, andcoenzyme Q10 have been used in the treatment of cancer as well, although theefficacy of such agents has yet to be demonstrated [97].

Acupuncture is a relatively safe therapy because side effects are rare [97].Cancer-related ailments in humans such as nausea, malignant pain, post-operative ileus, and phantom limb pain of amputees have been alleviated byacupuncture [97]. Massage and manipulative therapy have been used forpain and stress relief, immune enhancement, and alleviation of lymphedemain humans [97].

Homeopathy involvesCAMusingdilutionsofnatural substances tosimulatean individual’s natural healing response [97]. Homeopathy is not considereda self-care option for cancer patients, because no single remedy exists fortreating cancer with homeopathy [98]. Although remedies may be used to treatside effects of conventional cancer treatment, cancer is not directly addressed[99]. Homeopathic remedies suggested for supportive care with cancer patientsinclude such dilutions as gelsemium, cantharis, ipecac, and nux vomica [97].

It is important that individuals offering CAVM be appropriately trainedto provide this type of care [97]. Currently, certification for veterinarians inCAVM is offered by privately run courses, creating potential bias [97]. Asmore universities offer training courses in CAVM, methodical and in-depthstudy will provide clinical data on safety and efficacy of CAVM modalitiesin veterinary cancer patients [97].

Nutrition

One of the most common paraneoplastic syndromes seen in veterinarypatients is cancer cachexia [100]. Cachexia in cancer patients results from


altered metabolism of proteins, carbohydrates, and lipids that leads toanorexia, impaired immune function, fatigue, and weight loss despiteadequate nutritional intake [101]. It is significant to note that the metabolicalterations seen in animals with cancer occur before clinical signs are evident[101]. Thus, nutritional intervention should begin early in treatment ofpatients with cancer andmaintained diligently throughout their care [101]. Asin other species, nutrition is a vital component of treatment for exotic animalpatients with cancer.

When considering appropriate nutrition for exotic animal patients withcancer, there is a wide variation in dietary requirements between species.Clearly, the clinician must ensure that an appropriate diet is fed to avoidcausing further complications. For information on the requirements ofindividual exotic species, please consult exotic animal veterinary texts. Thefollowing is a generalized discussion of nutritional information for cancerpatients. In general, avoiding diets high in simple carbohydrates is preferablebecause certain types of cancers may use simple carbohydrates as a preferredenergy source [100]. In studies in rats, sucrose-rich diets have carcinogenicactions in the colon and liver and cause a genotoxic response by increasing themutation frequency in rat colon in a dose-dependent manner [102]. Withregard to protein intake for carnivores and omnivores, diets with moderateamounts of highly bioavailable protein may be of value, with certain aminoacids such as glutamine, cystine, and arginine being beneficial [103,104]. x-3fatty acids, especially eicosapentaenoic and docosahexaenoic acid, found infish oil, in moderate amounts appear to benefit the cancer patient [100].Soluble and insoluble fibers are important to prevent cancer and to enhancebowel function [100]. In addition to treating disorders of the gastrointestinaltract, adequate fiber can also prevent concurrent diseases such as clostridialcolitis [100]. Data demonstrates that antioxidants, minerals, proteases, garlic,enzymes, and tea have the potential for reducing the risk of cancer or thegrowth and metastases of established malignant diseases, although muchwork needs to be done in this area before specific recommendations can bemade [100].

Clearly, further research is needed to fully understand the role of nutritionconcerning exotic animal oncology treatment. Much of the available dataconcerning diet and cancer is based on work with humans, canine, and felinepatients, and experimentally induced tumors in laboratory animals. Extrap-olation from the available literature is a starting point for managing exoticanimal cases and for future research.

Enteral nutrition

Whenever possible, enteral feeding should be considered before paren-teral feeding is attempted. A variety of methods can be used to encouragefood consumption such as warming foods when applicable, providinga selection of foods, and reducing environmental stress [100]. Chemical


stimulants, such as benzodiazepine derivatives and antiserotinin agents, areused in canine and feline patients [100]. One of the authors (J.E.G.) has hadvariable success using drugs such as midazolam and cyproheptadine asappetite stimulants in exotic animal patients. Metoclopramide may be usefulto reduce nausea associated with chemotherapy or surgery [100]. When theabove techniques fail, enteral nutrition support with force feeding as needed,nasogastric, pharyngostomy, esophagostomy, gastronomy, or jejunostomytube feeding can be considered [100].

Nasogastric tubes may be useful in exotic animals such as ferrets andrabbits (Fig. 7). Themajor disadvantage of nasogastric tubes in rabbits is theirsmall diameter, limiting the size of fiber that can pass through the tube [105]. Astudy evaluating pharyngostomy tubes for chronic aspirin dosing in rabbitsreported complications that included accidental severing of the carotid arteryor jugular vein in three of over 40 rabbits resulting in death and insertion siteabscesses in two rabbits [106]. Pharyngostomy and gastrostomy tubes havebeen used in ferrets [107–109]. Esophagostomy tubes are preferable topharyngostomy tubes in dogs and cats because of decreased risk ofcomplications such as damage to neurovascular structures, potential forairway obstruction and aspiration pneumonia, and problemswith swallowing[110]. Percutaneously placed gastrostomy tubes have been examined in therabbit but had a high incidence of complications including necrosis andabscessation around the tube, peritonitis, tube removal by the patient, gastricretention of the catheter tip following removal, catheter balloon rupture,intraabdominal hematoma, and death [111,112]. A variety of enteral feedingmethods, including gastostomy tubes, have been described in rodentlaboratory animals. A technique has been described to provide duodenalalimentation in pigeons via needle catheter duodenostomy [113]. Thisprocedure may be an option for providing nutrition to avian species when

Fig. 7. Nasogastric tube in an obese adult male Flemish Giant rabbit.


bypassing the upper gastrointestinal tract is required. In comparison tonasogastric, pharyngostomy, gastrostomy, and jejunostomy tubes, esoph-agostomy tubes are considered to be more reliable and have fewercomplications [114]. One of the authors (J.E.G.) has used esophagostomytubes in a variety of exotic animals, including rabbits, reptiles, and birds, withgood results (Fig. 8). Potential complications that can occur with esoph-agostomy tubes include infection at the tube entrance site, vomiting,scratching, and inadvertent removal of the tube, and kinking of the tubeduring placement [110,114,115]. Additionally, because most reptiles do noteat daily, care should be taken to avoid overfeeding adults [9].

Parenteral nutrition

Parenteral nutrition techniques have been reported in many exotic animalspecies. Although parenteral feeding has not been completely researched inrabbits, one study showed hepatocellular degeneration and portal tractinflammation in rabbits receiving total parenteral nutrition (TPN) [116]. Ina study comparing TPN with enteral feeding through gastrostomy tube,enteral feeding was superior to TPN during early posttraumatic woundhealing in Sprague-Dawley rats [117]. TPN was administered through thejugular vein in pigeons four times daily for 5 days [118]. Complications in theTPN pigeon study included 8.7% weight loss during the 5-day trial,hyperglycemia for up to 90 minutes after infusion, and glucosuria afterinfusion [118]. The study determined that while intermittent TPN in pigeons ispossible, further research is needed to develop better techniques of admin-istration and caloric and nutritional needs of birds under stress receiving TPN

Fig. 8. Esophagostomy tube in an adult rabbit following hemimandibulectomy surgery. (Photo

courtesy of G. Heather Wilson, University of Georgia, College of Veterinary Medicine.)


[118]. TPN has been used in ferrets, rabbits, and rodents in a clinical settingwith minimal complications [119,120].

Pain management

Pain management is a vital part of exotic animal medicine in general, andmay be especially helpful concerning oncology cases. Cancer pain is generallyacute, chronic, or intermittent, and is related to the disease itself or to thetreatment [121]. Although mild to moderate pain may be alleviated witha nonopiod such as an NSAID, opiods may be needed for more severe pain[121]. NSAIDs such as aspirin, carprofen, ketoprofen, celecoxib, andmeloxicam have been used with exotic animal patients successfully. Potentialside effects of using NSAIDs include the risk of gastrointestinal ulceration,nephrotoxicity, hepatotoxicity, and hemorrhage [122].Mild to moderate painfrom intrathoracic and intraabdominal masses and bone metastases can berelieved with NSAIDs [121]. If opiods must be added, NSAIDs have anopiod-sparing effect so lower doses of opiods can be used [121]. Opiods, suchas buprenorphine and butorphanol, are often used with exotic animals.

Studies in pigeons show that they have more kappa opiod receptors thanmu opiod receptors [123]. Because of this, birds do not respond to muagonists like morphine, buprenorphine, and fentanyl as do mammals [124].Research suggests that butorphanol is a more efficacious analgesic thanbuprenorphine in African gray parrots [125]. In contrast, butorphanol maynot provide effective analgesia in some reptiles, as butorphanol was notfound to have an isoflurane-sparing effect in green iguanas [126].

Summary

This article is a review of current therapies in exotic animal oncology. Themajority of research and data on oncology therapies has been reported inhumans, canine, and feline patients, and laboratory animals with experimen-tally induced tumors. There are many species of exotic pets and anatomicconsiderations as well as husbandry and nutritional requirements must betaken into account when treating these patients. A variety of techniques in-cluding radiation therapy, intralesional chemotherapy, photodynamic ther-apy, and others have been used in exotic animal patients with success. Asmoreandmore exotic pets are viewed as familymembers, veterinarians should striveto provide the highest quality of care for their exotic animal patients, includingthe latest diagnostic and treatment options for cancer therapy.

Acknowledgment

The authors would like to thank Dr. Anna Osofsky for assistance withacquisition of images used in this manuscript.


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Current therapies in exotic animal oncology