Abstract
Objective
Tumors in elephants present substantial therapeutic challenges because of their large size, anatomical complexity, and the risks associated with surgical intervention. Targeted electrochemotherapy (ECT) has emerged as an effective local treatment modality in both human and veterinary oncology. However, its application in exotic species has been rarely reported.
Animal
An adult female Asian elephant (Elephas maximus) housed at the El Paso Zoo in Texas.
Clinical Presentation, Progression, and Procedures
The elephant was diagnosed with a large solid tumor considered unsuitable for conventional surgical management. The animal underwent 6 cycles of ECT consisting of intratumoral bleomycin administration followed by the delivery of electric pulses according to established veterinary ECT protocols.
Treatment and Outcome
Treatment was well tolerated, with no clinically apparent adverse effects. Effective tumor reduction was observed in response to the first 3 ECT treatments, resulting in sustained local tumor control for more than 1 year. Electrochemotherapy was feasible, safe, and clinically effective in achieving prolonged local tumor control in an Asian elephant with mammary adenocarcinoma.
Clinical Relevance
To the authors’ knowledge, this is the first report describing the use of ECT in an elephant for the treatment of a large solid tumor. The favorable clinical outcome and absence of significant adverse effects support the feasibility and potential utility of ECT as a minimally invasive treatment option for neoplastic diseases in elephants and other exotic species. Furthermore, this case exemplifies a reverse translational approach in which therapeutic strategies established in human oncology are successfully adapted to veterinary medicine.
Keywords: targeted electrochemotherapy; oncology; adenocarcinoma; exotic; elephant
Cancer represents an important cause of morbidity and mortality in both domestic and exotic animal species, often requiring multimodal therapeutic approaches to achieve optimal disease control. Although surgery remains the primary treatment for many localized neoplasms, its application in exotic species can be limited by anatomical, physiological, and logistical constraints, as well as by the risks associated with anesthesia and postoperative management. Alternative local treatment modalities are therefore of particular interest in zoological medicine and wildlife oncology.
Electrochemotherapy (ECT) is a local antitumor treatment that combines the administration of cytotoxic drugs, most commonly bleomycin or cisplatin, with the application of short, high-voltage electric pulses that transiently increase cell membrane permeability through reversible electroporation. This process enhances intracellular drug uptake, thereby increasing cytotoxic efficacy while limiting systemic exposure. Over the last 2 decades, ECT has become an established treatment modality for cutaneous and subcutaneous tumors in human oncology and has demonstrated high objective response rates with minimal adverse effects.1–3
In veterinary medicine, ECT has been successfully applied to a variety of spontaneous tumors in dogs, cats, horses, and other species, including soft tissue sarcomas, mast cell tumors, squamous cell carcinomas, melanomas, and mammary tumors.4–7 The technique has gained increasing acceptance because of its minimally invasive nature, favorable safety profile, and demonstrated efficacy in achieving durable local tumor control, particularly in patients for whom surgery or radiation therapy is either not feasible or would be expected to result in substantial treatment-related morbidity.8
Mammary gland tumors are among the most common neoplasms in women and represent a major focus of clinical research in human oncology. In recent years, ECT has emerged as a valuable treatment option for primary and recurrent breast cancer lesions, particularly in patients who are poor surgical or radiation therapy candidates or have exhausted conventional treatment options. Clinical studies3,9,10 have demonstrated effective local tumor control, symptom palliation, and preservation of tissue function with limited toxicity.
Neoplasia appears to occur less frequently in elephants than would be expected based on their body size and longevity, a phenomenon often cited as an example of the Peto paradox. This is based on the idea that if every cell has some chance of becoming cancerous, large, long-lived organisms should have an increased risk of developing cancer compared with small, short-lived organisms. The paradox consists in the lack of correlation between body size and cancer risk. Studies suggest that elephants possess multiple copies of the tumor suppressor gene TP53, which may contribute to enhanced cancer resistance mechanisms.11 Nevertheless, neoplastic diseases do occur in both African (Loxodonta africana) and Asian (Elephas maximus) elephants and can present substantial therapeutic challenges because of the animals’ large body size, anatomical characteristics, and the risks associated with anesthesia and surgical intervention.
The management of tumors in elephants is particularly complex when lesions are large, poorly accessible, or located near critical anatomical structures. Surgical excision may be associated with significant perioperative risks, including anesthetic complications, hemorrhage, prolonged recovery, and wound-healing difficulties. Consequently, minimally invasive treatment alternatives capable of providing local tumor control are highly desirable in this species.
This clinical report describes the use of ECT in a 53-year-old female Asian elephant (E maximus) with a large cutaneous tumor that was considered unsuitable for surgical management because of its size and location. To the authors’ knowledge, this is the first published report documenting the successful application of ECT in an elephant, demonstrating the feasibility, safety, and potential clinical utility of this technique in the management of large neoplastic lesions in megavertebrate species.
Methods
Histopathologic examination
Formalin-fixed, paraffin-embedded tissue sections (4 μm) were stained with hematoxylin and eosin for routine histopathologic examination. It was performed according to the protocol previously described by our group for canine transitional cell carcinomas.12 Briefly, sections were incubated with a polyclonal anti-human epidermal growth factor receptor 2 (HER2/neu) antibody (Dako) at a dilution of 1:250 in Tris-buffered saline for 1 hour at room temperature. At the completion of the immunohistochemical analysis, the tumor showed no detectable HER2/neu immunoreactivity, indicating the absence of HER2 overexpression.
Anesthesia
All ECT procedures were performed under general anesthesia under the supervision of the El Paso Zoo veterinary team. Because the elephant was a geriatric, approximately 8,000-lb (3,600-kg), 53-year-old Asian elephant (E maximus), minimizing anesthetic risk was a major consideration in treatment planning. Consequently, the duration of anesthetic episodes was limited, and treatment intervals were adapted to balance oncologic benefit with patient safety. Although the total number of episodes was unusual for an elephant and not anticipated at the outset of treatment, the elephant’s stability during and recovery following each procedure allowed consideration of additional sessions in response to tumor behavior.
Before each procedure, the elephant voluntarily entered a custom-designed elephant restraint chute as part of her routine husbandry training. A sedative dose of 200 mg azaperone was administered IM by hand injection. Anesthesia was induced with 9 mg etorphine IM by hand injection. The hydraulic restraint system gradually secured the animal in a standing position during anesthetic induction and subsequently tilted to allow controlled transition into lateral recumbency, minimizing the risk of injury associated with uncontrolled collapse. This approach facilitated safe positioning and access to the mammary mass while reducing stress for the animal and personnel.
General anesthesia was maintained for approximately 90 minutes during each treatment session. Etorphine was supplemented as needed by 0.5- to 1-mg IV boluses for induction or etorphine continuous rate infusion for maintenance. The elephant was intubated with a 35-mm inner-diameter endotracheal tube and ventilated using a megavertebrate demand ventilator. An IV catheter was placed in a caudal ear vein for medication administration. Throughout anesthesia, parameters including temperature, oscillometric blood pressure, end-tidal CO2, pulse oximetry, ECG, and venous and arterial blood gases were monitored by veterinarians experienced in elephant medicine, and supportive care was provided until recovery. Following completion of the ECT procedure, anesthesia was reversed with naltrexone at 500 mg IV and 500 mg IM. The elephant recovered with positional support within the restraint system before safely returning to an unsupported standing position. No anesthesia-related complications were observed during any of the treatment sessions.
The large body size of the patient and the risks associated with repeated general anesthesia influenced the treatment schedule. Unlike the short treatment intervals commonly adopted for companion animals undergoing ECT, sessions were intentionally spaced over longer periods to minimize cumulative anesthetic risk while maintaining local tumor control.
Electrochemotherapy
Electrochemotherapy was performed using a Cliniporator Vite pulse generator (IGEA). Bleomycin sulfate was administered by intratumoral injection to achieve homogeneous distribution throughout the lesion. Approximately 1 minute after drug administration, electric pulses were delivered using single stainless-steel needle electrodes (diameter, 1.2 mm; IGEA) inserted directly into the tumor tissue. Four electrodes were positioned according to a predefined treatment grid to ensure adequate electric field distribution throughout the tumor volume and surrounding margins. Electrode repositioning was performed repeatedly to treat overlapping regions until the entire gross tumor volume and clinically identifiable margins had been covered.
The Cliniporator Vitae system automatically recorded all treatment parameters, including electrode configuration, interelectrode distance, applied voltage, pulse duration, pulse number, and delivered current for each application. Treatment data were reviewed after each procedure to verify appropriate pulse delivery and tissue electrical conductivity. Following completion of ECT, the treated area was visually inspected for evidence of hemorrhage or immediate complications before recovery from anesthesia. Clinical follow-up consisted of serial physical examinations and photographic documentation to evaluate changes in tumor dimensions, tissue appearance, and local treatment-related adverse events.
Euthanasia
For euthanasia, the El Paso Zoo Veterinary team follows strict protocols outlined by AVMA to ensure a peaceful, pain-free transition. Because a sudden fall can cause massive trauma or dangerous distress, the process was carefully staged into 2 distinct phases: the elephant was first anesthetized as previously described. A large-bore catheter was carefully placed into a prominent vein in the animal’s ear. Then, the terminal agents (300 mg azaperone and 12 mg etorphine in 177 mL of solution) were administered.
Results
Histopathologic diagnosis
In October 2016, a 53-year-old female Asian elephant (E maximus) was diagnosed with a malignant mammary gland neoplasm involving the right mammary region. Histopathologic examination of biopsy specimens revealed a densely cellular epithelial neoplasm composed of tubulopapillary structures, solid sheets, and acinar arrangements supported by scant fibrovascular stroma and surrounded by minimal collagenous connective tissue (Figure 1).
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