Technician Update

The Use of Systemic Doxorubicin in the Treatment of Epithelioid Hemangiosarcoma

By Lisa Jolley, LVT

Improved imaging and diagnostic capabilities have increased our ability to locate and diagnose neoplasms in horses. As a result, treating cancers will be of increasing interest to the veterinary profession and to horse owners looking to improve the outcomes for their patients with malignant tumors. Although the use of intralesional and intertumoral chemotherapy with antineoplastic drugs such as 5-fluorouracil and cisplatin have become more common, the use of these treatments is limited by whether they can reach the tumor with limited effect on the surrounding healthy tissues and organs.

Radiation therapy has also been used to treat neoplasms in horses, but their use is limited by the size of the horse and the need for more frequent anesthetic episodes. The use of systemic chemotherapy in horses is rare, but with more commonly used therapies could offer a promise of remission for horses with more widespread malignancies or in areas of the body that cannot be safely or easily treated externally.

Doxorubicin, an anthracycline antitumor medication, is considered a hazardous drug and must be handled appropriately for the safety of the animal, veterinary staff and owners. This chemotherapeutic is used frequently in small animal medicine, and its use and complications in canine and feline patients have been studied more extensively than in equids. However, the choice to use this hazardous medication with more common antineoplastic therapies can produce successful outcomes.

A 15-year-old Percheron and Quarter horse cross gelding, used for mounted police patrol, presented to Texas A&M University Large Animal Teaching Hospital in November 2021 for ocular discharge and a suspected ocular mass on the medial canthus of the left eye. This was confirmed by computed tomography (CT) imaging during an appointment, on which the mass displayed mild contrast enhancement, and the adjacent bone was smoothly marginated. An incisional biopsy of the mass was performed while the patient was anesthetized for the CT scan, and histopathology of the excised mass, while originally inconclusive, was consistent with a carcinoma.

Later immunohistochemistry identified the mass as an epithelioid hemangiosarcoma.

In January 2022, the medial canthus mass was removed after which abnormal tissue deep to the mass was also palpated and then removed. Photodynamic therapy (PDT) was applied in 3 sites, with each site receiving 5 cycles of 550mW for 30 seconds for a total of 8,936 J for all 3 sites. The patient returned in March 2022 for a follow-up appointment with the ophthalmology service at Texas A&M University Large Animal Teaching Hospital, at which time it was noted that there was increased irritation and discharge from the left eye.

A flush of the nasolacrimal ducts raised a suspicion that the left nasolacrimal duct was connected to the sinus rather than the eye itself. This led to the recommendation that the patient return for a repeat CT. In August of the same year, the mass was noted to have increased and a second mass on the temporomandibular joint (TMJ) was palpated. The CT showed the periorbital component of the mass had indeed increased since the imaging performed in November 2021 and the increased size of the periocular component was now causing a mild left exophthalmos.

Punch biopsies of both the mass on the medial canthus and the TMJ were consistent with epithelioid hemangiosarcoma.

The recommendation to pursue radiotherapy followed by enucleation and finally chemotherapy with doxorubicin was agreed to by the owner. Unfortunately, due to equipment failure, TomoTherapy was not available at Texas A&M University Large Animal Veterinary Teaching Hospital, and the owners elected to take the patient to another referral hospital for a planned 5 fractions of TomoTherapy.

Scout returned to Texas A&M University in October 2022, 2 weeks after the completion of radiation therapy, and a repeat CT showed the mass size had reduced and the left-sided exophthalmos had resolved. No bone lysis nor proliferation was seen. A CBC revealed a mildly elevated fibrinogen and a red blood cell count slightly below the reference interval, but otherwise was unremarkable.

Scout was placed under general anesthesia for the enucleation of the globe and periocular tissues of the left eye. The procedure and recovery were uneventful. Pathology reported that the samples submitted from the enucleation were consistent with an incompletely excised hemangiosarcoma and the samples taken from the periocular tissues demonstrated mild inflammation, possibly from previous biopsies or radiation. The patient was discharged with the plan to return for the first doxorubicin injection in 3 weeks.

A protocol for systemic chemotherapy using doxorubicin was implemented, with the first dose given on Nov. 17, 2022, with 4 subsequent doses to be given 3 weeks apart. For each treatment, the patient was brought to Texas A&M University Large Animal Teaching Hospital 1 to 2 nights before the scheduled chemotherapy date. His weight was noted, and a CBC was sent to the clinical pathology laboratory. The venous samples were obtained for a CBC via either the saphenous vein or the transverse facial sinus to avoid damage to either jugular vein.

He was housed in an isolation stall to reduce the biohazard risk posed by urine and feces contaminated with doxorubicin post-treatment. Thirty minutes before chemotherapy started, the patient was given diphenhydramine, and topical lidocaine was placed on the future catheter sites. Immediately prior to administration of the chemotherapeutic, a 14 ga Mila long-term catheter was placed with great care shown to ensure a clean venipuncture to reduce the risk for necrosis of the tissues surrounding the jugular vein due to extravasation of doxorubicin. The catheter and its extension set were secured with tissue glue.

A second catheter was placed in the opposite jugular vein to administer emergency drugs during the treatment and for medicating post-treatment. Flunixin meglumine was given before treatment began via the emergency catheter on the non-chemotherapy side, and xylazine was given for sedation as needed. A 3-L bag of NaCl 0.9% was connected to the chemotherapy catheter and run at a rate of approximately 2 L over 1 hour. The first dose of doxorubicin was given over the course of 45 minutes via an Equashield closed chemotherapy system attached to the saline IV line. The patient was given a second dose of diphenhydramine 6 hours post procedure and a second dose of flunixin meglumine 12 hours after the initial dose. The patient remained in isolation for 48 hours post-chemotherapy administration to minimize caretaker contact with chemotherapy contaminated feces or urine. He was then discharged to his normal home stabling with instructions to monitor the patient for diarrhea or colic symptoms and to receive a follow-up CBC 1 week post-chemotherapy.

The first post chemotherapy CBC revealed a mild leukopenia with a white blood cell count only slightly lower than the reference intervals and was otherwise unremarkable. The next pre-chemotherapy CBC on Dec. 12, 2023 showed that the leukopenia had been rectified, but mild anemia and thrombocytopenia had developed. The decision was made to recheck the CBC and delay the scheduled chemotherapy for 24 hours. The CBC on Dec. 13, was within normal range, and the patient received doxorubicin in the left jugular using the same protocol as the chemotherapy treatment on Nov. 17. Scout’s vitals remained stable throughout the procedure; however, he exhibited tachycardia (heart rate of 92) at his 4:00 pm vitals check. A dose of diphenhydramine and flunixin meglumine was due at this time and his vital signs (heart rate was 40) were normal at 12:00 am There were no more incidents of tachycardia, and the patient returned to his normal housing after he stopped excreting doxorubicin in his urine 48 hours post chemotherapy.

The patient returned to Texas A&M University Large Animal Teaching Hospital on Jan. 5, 2023 for another dose of chemotherapy. On arrival it was noted that his coat condition had deteriorated, and he had lost a considerable amount of mane and tail, presumably due to the side effects of doxorubicin. His handlers had also noted that he was more subdued in his interactions at home. His pre-chemotherapy CBC showed moderate leukopenia. Most notably, he exhibited moderate non regenerative anemia and thrombocytopenia, most probably due to bone marrow suppression caused by doxorubicin.

The decision was made to postpone treatment for a week with the hope that the anemia and thrombocytopenia would resolve, and the patient was discharged.

On Jan. 11, 2023, the referring veterinarian submitted a CBC to ensure that the anemia had improved before returning to the hospital. While there was still moderate leukopenia and anemia, his platelet count had returned to a normal level and the decision was made to proceed with the scheduled chemotherapy.

The patient was admitted on Jan. 12, 2023, and his platelet count, while still mildly depressed, was deemed to be at an appropriate level to continue with treatment. His third course of doxorubicin was administered in the right jugular vein over the course of 45 minutes on Jan. 13, 2023 using the same pre- and post-medication protocol as the previous 2 treatments. Scout received a lower dose to reduce the non-regenerative anemia caused by doxorubicin. The patient was discharged on Jan. 16, 2023 after his urine no longer contained elevated levels of doxorubicin contamination.

In preparation for his fourth doxorubicin administration, the referring veterinarian submitted a CBC on Jan. 28, 2023. Once again, a mild leukopenia and thrombocytopenia were found as well as anemia. However, the platelet count was found to be acceptable to continue treatment, and the patient was admitted to Texas A&M University Large Animal Teaching Hospital on Jan. 30, 2023 for chest radiographs, a recheck CT scan of the head and the fourth doxorubicin administration. The CBC on admission revealed a more severe anemia than found on the CBC submitted by the referring veterinarian and a severely depressed platelet count. Radiographs of the thorax found only evidence of chronic lower airway disease but no evidence of metastatic pulmonary neoplasia.

A CT of the head with contrast was performed on Jan. 31, 2023. There was no evidence of gross neoplastic reoccurrence, although mild periosteal proliferation on the wall of the left orbit, as well as new discontinuities of its osseous components, could have indicated infiltrative neoplastic disease. However, it was more likely to be due to periostitis resulting from surgical insults from the enucleation and biopsies performed in January and November 2022. Another platelet count was performed on Jan. 31 and again on Feb. 2, still showing a thrombocytopenia too severe to continue with the administration of chemotherapeutics at that time.

The patient was discharged with instructions for the referring veterinarian to submit and repeat the CBC in 1 week with the hope that the platelet counts would return to a normal level. The patient was found to have an inadequate platelet count on the subsequent 2 CBCs performed on Feb. 7 and Feb. 14, 2023, and the decision was made to discontinue chemotherapy indefinitely. With the results of the CT scan showing evidence of the neoplasm in remission, the concern for the patient’s overall health outweighed the possible benefits to continuing with the last scheduled rounds of doxorubicin administration.

The patient’s CBC and condition continues to be monitored for signs of metastasis or reoccurrence of the neoplasm at the original site. On March 4, 2023, the CBC sent by the referring veterinarian showed a low-normal platelet count and very mild anemia, but the prior leukopenia had resolved. The patient returned to normal work, being cleared for his first patrol on March 13, 2023. His physical exams have been unremarkable as of Oct. 1, 2023.

While more research is needed on the long-term effects and efficacy of this treatment, doxorubicin offers a promising option for the veterinary community in the treatment of equid neoplasia. With careful management of the patient immediately pre- and post- doxorubicin injection, as well as monitoring for persistent myelosuppression, the obstacles that equine patients present due to their size, temperament, and physiology can be overcome to successfully return the equine patient to full work. MeV

Teaching Points
Due to the dangers posed by doxorubicin, as well as the size and nature of equine patients, special precautions were taken to ensure the patient’s safety. Extravasation of doxorubicin during IV administration can have extreme consequences, with sloughing and necrosis of the injection site leading to amputation reported in canine and feline patients. As jugular venous access is the most common site of administration for IV medications in equids, extravasation of doxorubicin has the potential to be catastrophic.

Therefore, care should be taken in the preparation of and the placement of the jugular catheter to minimize the risk for extravasation. The protocol developed for this patient included ensuring that neither jugular vein was used for venous access for over 48 hours prior to treatment, use of lidocaine cream instead of a subcutaneous infiltrative nerve block with mepivacaine to block the catheter site, as well as insisting on a clean “single stick” for the IV catheter placement.

The common side effects of doxorubicin reported in canine and feline patients include vomiting and diarrhea, neutropenia and anemia, and, occasionally, alopecia, while the major complication in the use of doxorubicin in humans is cardiotoxicity.

Although there are few comprehensive studies on the use of doxorubicin in equids, myelosuppression and hypersensitivity are the 2 commonly reported dose-limiting factors. Both contraindications were seen with this patient. As found in previous studies, hypersensitivity (symptoms to include increased heart rate and respiratory rate) was seen
4 to 6 hours post doxorubicin administration during the second treatment.

The patient also exhibited the mild reversible neutropenia discussed in previous studies, however, what was not examined in previous studies, and proved to be both dose limiting, and ultimately the deciding factor to discontinue treatment, was the persistent thrombocytopenia that began after the second dose of doxorubicin and did not resolve until 3 months after the final dose. This is a reported but rare side effect of doxorubicin in canine patients; further study is needed to evaluate the prevalence of this adverse effect of doxorubicin in equids.

About the Author
Lisa has worked in various roles in equine veterinary medicine for more than 20 years, from aesthesia at a busy multisurgeon sports medicine practice in Weatherford, Texas, to her current role as the lead Theriogenology technician at Texas A&M University’s Large Animal Teaching Hospital.

Lisa grew up competing in Dressage but transitioned to showing in reining and reined cow horses while she was attending Texas A&M University. When not working with horses, Lisa is found playing with her son and their dogs on their small farm.

For more information:
Theon, AP. “Oncology” The Equine Manual, 2nd Ed. Edited by Andrew J. Higgins and Jack R. Snyder, Elsevier Limited, 2006, pp. 1211-1225

Fullerton, E. (2017). Doxorubicin: An Overview. Today’s Veterinary Nurse, 2(3), 25-34.
https://todaysveterinarynurse.com/oncology/veterinary-doxorubicin/

Théon AP, Pusterla N, Magdesian KG, et al. A pilot phase II study of the efficacy and biosafety of doxorubicin chemotherapy in tumor-bearing equidae. J Vet Intern Med. 2013;27(6):1581-1588.
https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.12144

Théon AP, Pusterla N, Magdesian KG, et al. Phase I dose escalation of doxorubicin chemotherapy in tumor-bearing equidae. J Vet Intern Med. 2013;27(5):1209-1217. https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.12145

Henry CJ, Brewer WG Jr, Stutler SA. Early-onset leukopenia and severe thrombocytopenia following doxorubicin chemotherapy for tonsillar squamous cell carcinoma in a dog. Cornell Vet. 1993;83(2):163-8.
https://pubmed.ncbi.nlm.nih.gov/8467702/

Intile J, Gareau A. Monitoring of chemotherapy patients in general practice. Todays Veterinary Practice. 2022;13(1):66-76.
https://todaysveterinarypractice.com/wp-content/uploads/sites/4/2022/12/TVP-2023-0102_Monitoring_Oncology.pdf