The pharmacological rationale for studying epirubicin in cats stems from decades of human clinical data. In metastatic breast cancer trials comparing the two drugs at equimolar doses of 50 milligrams per square metre, doxorubicin produced ten cases of congestive heart failure, an incidence of 2.6 percent, while epirubicin produced just one case, or 0.3 percent. Epirubicin achieved similar anti-tumour efficacy with a more favourable haematological and non-haematological toxicity profile, particularly with respect to cardiac harm. In veterinary practice, interest in epirubicin as an alternative to doxorubicin was initially driven by this potential for reduced cardiotoxicity, and studies in dogs confirmed its activity in lymphoma as part of multi-agent protocols and as adjunctive therapy for splenic haemangiosarcoma. In the cats of this study, epirubicin had become the standard anthracycline because doxorubicin had become cost-prohibitive at the start of the study period, creating an unplanned but valuable natural experiment in feline tolerance of the drug.

The dosing regimen followed conventions extrapolated from feline doxorubicin practice. Every cat began treatment at 1 milligram per kilogram of body weight, administered intravenously, with five patients later escalated to 25 milligrams per square metre of body surface area at the treating clinician’s discretion, accounting for 19 of the 186 treatments, or roughly 10 percent. Cats received a median of two treatments each, with a range of one to seven doses; twenty-eight cats received a single dose while twenty-seven received four or more. No dose reductions were recorded for any patient. Prophylactic anti-emetic support was common: 55 of the 186 treatments included injectable maropitant given before the epirubicin infusion, and oral maropitant was prescribed for home use in 30 treatments. Other supportive medications, most frequently corticosteroids, the acid blocker famotidine and antibiotics, accompanied 54 percent of treatments. Infusion protocols differed slightly between the two institutions, with one diluting the drug in saline and delivering it over twenty minutes and the other administering it over ten minutes through a side port of a giving set.

The headline finding is that 56 percent of cats, thirty-seven of the sixty-six, exhibited some form of possible toxicity during or after treatment, but the overwhelming majority of these events were mild. Adverse events were graded using the Veterinary Comparative Oncology Group common terminology criteria, a standardised system borrowed conceptually from human oncology that ranks side effects from grade 1, mild, to grade 5, fatal. Anorexia and neutropenia, a fall in the white blood cells that fight infection, were the most common toxicities, and nearly all were grade 1 or grade 2. Only two events in the entire study resulted in temporary hospitalisation, and just four cats, 6 percent of the cohort, had treatment withdrawn because of adverse effects. No cat died as a consequence of epirubicin treatment. The authors caution, however, that distinguishing genuine drug toxicity from clinical signs of the underlying cancer was not always possible, particularly since many patients had lymphoma or metastatic disease that itself causes lethargy and poor appetite.

The haematological data offer reassurance about one of the most feared complications of anthracycline chemotherapy. Twenty-seven percent of cats developed at least one episode of neutropenia at some stage, but the highest grades recorded were only grade 1 in thirteen cats and grade 2 in five. Across all 186 treatments there were 37 episodes of neutropenia, a rate of 20 percent, and not a single case of grade 3 or grade 4 neutropenia, febrile neutropenia, or a neutrophil count below 1 times 10 to the ninth per litre was observed. Blood counts taken seven days after treatment, the presumed nadir or lowest point of the white cell curve, were available for 43 cats, and eleven of these showed mild neutropenia. No dose delays occurred in the 38 cats that received more than one treatment. The researchers note an important caveat: because the true timing of the neutrophil nadir after epirubicin has never been established in cats, sampling at day seven may have missed the actual low point, meaning some suppression could have gone undetected.

Gastrointestinal effects were less frequent than with doxorubicin. Twenty-nine gastrointestinal events occurred across the 186 treatments, affecting 24 cats, with sixteen treatments producing hyporexia, reduced appetite, and seven producing vomiting. Constitutional signs of lethargy appeared in ten cats, accounting for fourteen events. Where timing was documented, these episodes emerged between one and twelve days after treatment and typically resolved within 24 to 48 hours. Notably, a previous study of single-agent doxorubicin in feline lymphoma reported that 47 percent of cats lost their appetite and 26 percent were severely affected, whereas only about 9 percent of treatments in this cohort produced hyporexia and just five cats vomited. The authors cannot determine whether the widespread use of the anti-emetic maropitant suppressed these signs or whether epirubicin genuinely causes less gastrointestinal harm than doxorubicin in cats. They also raise the possibility that the doses used, extrapolated from doxorubicin rather than derived from feline pharmacokinetic studies, may have been subtherapeutic.

Renal and hepatic laboratory changes were scrutinised closely because nephrotoxicity is a known hazard of doxorubicin in cats. Among 52 cats with before-and-after measurements, eleven, or 21 percent, showed elevated or worsening blood urea nitrogen, though ten of these were grade 1 and seven cats with pre-existing elevation actually had stable or improved values afterwards. Only three cats, 6 percent, had increases in creatinine, all grade 1 and all less than 10 percent above baseline in animals that already had mild pre-treatment elevations. Urine specific gravity was not recorded, so pre-renal dehydration cannot be excluded as a contributor. On the liver side, seven of 42 cats, 17 percent, developed raised alanine aminotransferase, including two grade 3 and three grade 4 elevations, but the authors considered most of these unlikely to be caused by epirubicin. One grade 4 case resolved with antibiotics for a urinary tract infection, another occurred in a cat with chronic pancreatitis, cholangiohepatitis and hyperthyroidism, and a third involved a myeloma patient whose liver was infiltrated by plasma cells. No cat stopped treatment because of liver enzyme changes.

One clinically instructive case involved a hypersensitivity reaction during a cat’s second epirubicin infusion, with retching, vomiting, dullness, stridor and pharyngeal oedema appearing acutely. Treatment with oxygen, the antihistamine chlorphenamine, dexamethasone and maropitant resolved all signs within ten minutes, and the cat went on to receive two further uneventful treatments after prophylactic pre-medication. The timing after the second dose suggests a possible antibody-mediated mechanism, and the faster infusion rate used at one institution may have been a contributing factor, although two of three acute ptyalism events occurred during slower infusions at the other site. The authors also acknowledge a blind spot regarding the heart: no cat in the study developed signs of cardiotoxicity, but patients did not routinely undergo cardiac auscultation by a cardiologist, biomarker testing, electrocardiography or echocardiography, so cardiac harm may have been underestimated, particularly given that few cats received high cumulative doses or survived long enough for late effects to emerge.

The study’s limitations are those inherent to retrospective design: medical records vary in how faithfully adverse events are captured, clinician interpretation introduces observer bias, concurrent chemotherapy drugs and radiotherapy may have contributed to perceived toxicity, and owner reporting depends on their ability to recognise side effects at home. Severe events are considered unlikely to have been missed, since owners typically contacted the referral hospitals directly when problems arose. Nevertheless, the authors conclude that epirubicin at the doses used appears generally well tolerated in cats, with mainly mild and self-limiting adverse effects, and they argue that the low rates of gastrointestinal toxicity and neutropenia suggest dose escalation could be worth exploring. Before that happens, however, they strongly recommend a phase 1 clinical trial to establish the maximum tolerated dose, characterise feline pharmacokinetics, standardise infusion rates, which are known to influence doxorubicin pharmacology in cats, and define the drug’s optimal spectrum of activity. Proper evaluation of systemic toxicity, they emphasise, remains essential before epirubicin can be adopted as a routine substitute for doxorubicin in feline cancer patients.

Subject of Research: Toxicity of epirubicin chemotherapy in cats with cancer

Article Title: Retrospective assessment of toxicity associated with epirubicin chemotherapy in 66 tumour-bearing cats

Article References: Retrospective assessment of toxicity associated with epirubicin chemotherapy in 66 tumour-bearing cats. (n.d.). https://doi.org/10.1186/s44356-025-00029-0

Image Credits: AI Generated

DOI: 10.1186/s44356-025-00029-0

Keywords: epirubicin, doxorubicin, chemotherapy, feline oncology, veterinary oncology, toxicity, neutropenia, cardiotoxicity, lymphoma, cats, anthracyclines, adverse events