Unexpected Neurotoxicity in Dogs Receiving a Cyclophosphamide, Dactinomycin, and 5‐Fluorouracil Chemotherapy Protocol

Abstract

An inexpensive combination chemotherapy protocol containing cyclophosphamide, dactinomycin, and 5-fluorouracil was evaluated in dogs with carcinomas. Fifteen dogs were entered in this study, and there were 1 complete response and 2 partial responses among 1 2 evaluable dogs.However, 6 of 1 5 dogs (40%) developed neurotoxicity. The neurotoxicity of this protocol was compared with a previactinomycin (actinomycin D; Cosmegen, Merck, D Sharp and Dohme Research Laboratories), a potent inhibitor of protein and RNA synthesis, has recently been shown to have a broad spectrum of antineoplastic activity against spontaneous tumors in dogs.' Dactinomycin is inexpensive when compared with other commonly used antineoplastic agents (eg, doxorubicin, mitoxantrone, cisplatin, bleomycin), and this is a desirable factor in a veterinary oncology practice. Therefore, we designed an inexpensive chemotherapy protocol using cyclophosphamide (Cytoxan; Mead Johnson and Company, Evansville, IN), dactinomycin (Cosmegen; Merck, Sharp and Dohme, West Point, PA), and 5-fluorouracil (Fluorouracil; Roche Laboratories, Nutley, NJ) (CDF) for dogs with carcinomas or adenocarcinomas.In addition to being efficacious and inexpensive, chemotherapy protocols designed for widespread use in veterinary medicine must be relatively safe and nontoxic. Use of dactinomycin has resulted primarily in gastrointestinal toxicity in approximately 30% of the dogs treated; myelosuppression was rare.' Cyclophosphamide may cause myelosuppression, nausea and vomiting, hemorrhagic cystitis, and, at high doses, cardiac toxicity.'" 5-Fluorouracil(5-FTJ) has been associated with neurotoxicity, mucositis, and myelosuppression.'-IO The CDF protocol was evaluated for toxicity and compared with a similar 5-FLJ-containing protocol previously used at the Veterinary Teaching Hospital-Ohio State University (VTH-OSU). Materials and Methods Eligibility CriteriaDogs with biopsy-proven carcinomas or adenocarcinomas were eligible for this study. Criteria for entry included an expected survival greater than 3 weeks, a packed cell volume (PCV) greater than 18%, a neutrophil count greater than 2,000 cells/pL, and a platelet count greater than 50,000 cells/pL. In addition, the dogs could not have received any chemotherapy for the previous 2 weeks, nor could they have received prior dactinomycin chemotherapy. Chemotherapy ProtocolThe tumors were staged according to the Worth Health Organization-TNM system," and the dogs were treated as outlined in Table 1. A total of 10 cycles or 3 cycles beyond a complete response were to be given. Withdrawal from the study was based on prcgressive disease, unacceptable toxicity, or the owner's request. Toxicity Monitoring and Response CriteriaComplete blood counts (CBC) were evaluated weekly; hematclogical, gastrointestinal, and neurological toxicity were graded according to Table 2. Tumor responses were evaluated every 3 weeks and recorded as complete response (CR), disappearance of all clinically detectable disease; partial response (PR), >50% decrease ...

Postsurgical intra‐incisional 5‐fluorouracil in dogs with incompletely resected, extremity malignant spindle cell tumours: a pilot study

“…5‐FU can be administered intravenously, topically and intraperitoneally 18,58,59 to treat a variety of sarcomas and carcinomas 20–24 . Reported side‐effects in the canine species include neurotoxicity and bone marrow suppression 25–28 . Overall, treatment was well tolerated in this study, with no dogs experiencing systemic adverse events and only one dog having one episode of local cutaneous hyperpigmentation, which completely and spontaneously resolved.…”

“…While fatal in the feline species, 19 5‐FU has been used as single agent or in combination regimens to treat a variety of canine cancers, including malignant mammary tumours, 20 gastrointestinal adenocarcinoma, 21 anal sac adenocarcinoma, 22 nasal adenocarcinoma 23 and sun‐induced squamous cell carcinoma 24 . 5‐FU is generally well tolerated; side‐effects are rare and include neurotoxicity and bone marrow suppression 25–28 . Goals of this study were to document the safety and efficacy of intra‐incisional 5‐FU in the management of incompletely resected malignant spindle cell tumours on canine extremities, as an alternative to amputation, radiation therapy and systemic chemotherapy.…”

Concurrent 5‐fluorouracil and carboplatin for the treatment of canine carcinomas

“…As previously stated, fewer than 25% of dogs and cats had uracil:dihydrouracil concentrations greater than a value associated with decreased DPD in humans . In the present study, dogs were administered 150 mg/m 2 5‐FU intravenously, a dosage comparable to the toxic levels ingested by those dogs that experienced neurotoxicity, and comparable to previous reports in which dogs developed neurotoxicity . However, our dosing interval was different than previously cited studies.…”

“…While 5‐FUs potential for neurotoxicity has likely prevented its widespread use in veterinary oncology, it has been evaluated in a small set of canine anal sac adenocarcinoma patients . Additionally, 5‐FU was used in a combination protocol with dactinomycin and cyclophosphamide in canine carcinomas . 5‐FU was repeated twice within 1 week (on Day 8 and 15) and 40% of dogs developed neurotoxicity.…”

Treatment-related toxicities in tumor-bearing cats treated with temozolomide alone or in combination with doxorubicin: a pilot assessment

“…The use of 5-fluorouracil results in lethal neurotoxicosis in cats treated by common routes of administration, 4 whilst neurotoxicosis occurs only at higher doses in dogs 5 or with certain drug combinations. 6 Some drugs appear to be less toxic in cats than in dogs. For example, the recommended dose for ifosfamide in cats is almost three times the recommended dose in dogs, 7,8 although this may be a result of inefficient activation of the prodrug to the active form in the feline species.…”