Vinorelbine (VRL) has been investigated in dogs, but its use in cats has not been studied.
Vinorelbine (VRL) has been investigated in dogs, but its use in cats has not been studied.
To determine the maximal tolerated dose (MTD) and dose-limiting toxicity (DLT) of VRL in tumor-bearing cats.
Cats were included in this prospective phase I trial if they had confirmed malignancy, received ≥1 VRL treatment, and had adequate follow-up. Previous treatment was acceptable, but concurrent chemotherapy or radiotherapy was not permitted.
Using a modified phase I design, cats were enrolled in cohorts of 3 at a starting dosage of 9 mg/m2. Cats tolerating the first treatment well were eligible to receive additional VRL treatments at escalating dosages; escalations beyond the perceived MTD were permitted based on individual tolerance. Intended treatment interval was 7 days. Patient histories, physical examinations, and complete blood counts were performed weekly.
Nineteen cats were included. Sixty-one VRL treatments were administered. Median number of treatments was 2 (range, 1–9). Starting dosages were 9–12 mg/m2. Maximal dosage administered was 15.5 mg/m2. The MTD was 11.5 mg/m2. Acute DLTs were neutropenia, vomiting, and nephrotoxicity. Other notable toxicities were weight loss and anemia.
Vinorelbine is tolerated in cats at a weekly interval. Recommended starting dosage is 11.5 mg/m2. Neutropenia was transient, lasting <7 days; vomiting was self-limiting in most cases. Although VRL-associated nephrotoxicity has not been reported, potential attribution of this toxicity to VRL must not be discounted. Further investigation of the efficacy of VRL in feline malignancies is warranted.
blood urea nitrogen
complete blood count
Eastern Cooperative Oncology Group
feline leukemia virus
feline immunodeficiency virus
maximal tolerated dose
red blood cell
Response Evaluation Criteria in Solid Tumors
Veterinary Cooperative Oncology Group Common Terminology Criteria for Adverse Events
Vinorelbine (VRL) is a semisynthetic vinca alkaloid that differs from vinblastine in its modification of the catharanthine ring and its increased lipophilicity.[1, 2] It is an antimitotic drug that has exclusive affinity for mitotic tubulin and tubulin-associated protein. VRL induces its cytotoxic effects by inhibiting microtubule dynamics. Specifically, it destabilizes microtubules and inhibits their polymerization, eventually leading to destruction of the mitotic spindle, mitotic arrest, and ultimately cell death.[1, 4]
In studies in humans, VRL has shown efficacy in a variety of malignancies, including advanced breast cancer, non-small cell lung cancer, Hodgkin's and non-Hodgkin's lymphoma, and ovarian cancer.[5-7] It often is incorporated into multiagent protocols. The dose-limiting toxicity (DLT) is neutropenia, and mild emesis has been noted. As compared with vincristine, VRL is substantially less neurotoxic, likely because of its actions on mitotic microtubules rather than axonal tubules. Increased liver enzyme activities have been reported, but substantial hepatotoxicity appears to be rare. To our knowledge, nephrotoxicity has not been reported.
A phase I clinical trial investigating VRL in dogs with various malignancies demonstrated a relatively mild toxicity profile, with neutropenia as the DLT. Other notable toxicities included inappetence, vomiting, and diarrhea. Hepatic cirrhosis was noted in 1 dog, possibly attributable to VRL treatment. A starting dosage of 15 mg/m2 was recommended, and activity against bronchoalveolar carcinoma was observed.
Subsequently, the efficacy of VRL was evaluated for the treatment of cutaneous mast cell tumors in dogs. All dogs were treated at a dosage of 15 mg/m2, and neutropenia was the most common adverse event. Overall response rate was 13%.
Elucidation of tolerability, toxicities, and a safe starting dosage of VRL in cats is imperative to inclusion of this drug in the chemotherapy arsenal for cats. Furthermore, results of this prospective phase I clinical trial will provide a basis for future efficacy studies. Based on our personal experience, cats treated with VRL at dosages of 8–9 mg/m2 have not experienced toxicity. Using this information to establish a starting point, our primary endpoints were to determine the maximum tolerated dose (MTD) and DLT of VRL in a population of tumor-bearing cats, while maintaining maximal dose intensity in each individual cat.
Cats with confirmed malignancy, receiving ≥1 VRL treatment, and undergoing adequate follow-up to assess toxicity, were eligible for inclusion in this prospective phase I clinical trial performed between March 2009 and September 2012. Owners were required to sign informed consent, and the protocol was approved by the Institutional Animal Care and Use Committee at the University of Georgia. Seventeen cats were treated at the University of Georgia, College of Veterinary Medicine, Athens, GA, 1 was treated at the University of Wisconsin, School of Veterinary Medicine, Madison, WI, and 1 was treated at Veterinary Medical Specialists, Concord, CA. Previous treatment was acceptable, but concurrent radiotherapy or chemotherapy was not permitted. Cats historically treated with radiotherapy, chemotherapy, or both were required to undergo a treatment washout period of ≥3 weeks before entering the study. Concurrent prednisone was allowed if indicated by the specific type of cancer, but a 72-hour washout period for nonsteroidal anti-inflammatory drugs was required before trial initiation. Required preliminary staging tests included complete blood count (CBC), serum biochemical profile, urinalysis, and histologic or cytologic confirmation of malignancy. Blood urea nitrogen (BUN) >60 mg/dL, serum creatinine concentration >3.0 mg/dL, total serum bilirubin concentration >0.5 mg/dL, debilitating concomitant disease, expected survival <4 weeks, and a modified Eastern Cooperative Oncology Group (ECOG) performance score >1 were exclusion criteria. Additional diagnostic evaluations such as imaging tests, T4, and FeLV/FIV serology were performed at the discretion of the attending clinician, but were not required as part of the study.
As defined by the study, VRL1 was diluted in 0.9% NaCl to a concentration of 1.5 mg/mL, and given IV over 5 minutes. The intended treatment interval was 7 days for up to 4 treatments. After receiving 4 weekly doses, cats were eligible to continue VRL treatment every 2 weeks at the owner's expense (Table 1).
Using a modified conventional 3 + 3 phase I trial design, patients were enrolled in cohorts of 3 per starting VRL dosage. Starting dosage cohort was defined as the cohort to which the cat was assigned at trial enrollment, independent of subsequent dosage escalations or reductions. The first cohort was treated at a starting dosage of 9 mg/m2. Dosage escalations of 1 mg/m2, up to 11 mg/m2, and 0.5 mg/m2 thereafter were permitted in the absence of DLT. If a DLT occurred within a starting dosage cohort, an additional 3 cats were enrolled in that specific cohort. The MTD was defined as the dosage at which <33% of cats experienced DLT, after treating at least 6 cats in the cohort in which toxicity occurred. Cats experiencing DLT were allowed to continue the treatment schedule once toxicity resolved, but future dosages were decreased by approximately 10%. This fixed rate of dosage reduction was 1 modification of the conventional 3 + 3 design. A 2nd modification permitted intrapatient dosage escalation according to the aforementioned schedule in the absence of DLT in that individual and if the owner was willing. Continued dosage escalation in individual cats tolerating VRL beyond the MTD also was allowable as a final modification. The latter 2 modifications were made in an attempt to maximize individual dose intensity.
Cats were eligible to receive VRL every 7 days until disease progression, withdrawal from the study, or 4 weekly doses were given. Once off-study, cats were allowed to continue VRL every 14 days or to undergo other treatments as indicated by their specific cancers.
Drug tolerability was assessed by patient history, physical examination, and laboratory results (Table 1). Patients were required to have a modified ECOG performance score of <1, a neutrophil count ≥1,500 cells/μL, and a platelet count ≥50,000 cells/μL for treatment. Toxicities were characterized according to the Veterinary Cooperative Oncology Group Common Terminology Criteria for Adverse Events (VCOG-CTCAE), and DLTs were defined as any grade 3 to 5 toxicity. Although grade 4 to 5 generally is considered dose-limiting for myelosuppression, any grade 2 to 4 neutropenia resulted in dose delay, and was thereby considered dose-limiting for this weekly protocol.
Response was not a primary endpoint, but cats with measurable disease were evaluated for response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Tumor measurements and imaging were performed at each visit and every 4–12 weeks, respectively, for the duration of VRL treatment. For patients off-study, follow-up information was obtained by phone communication with the owner or referring veterinarian. For cats dying while on study or within 1 month of going off study, dates and causes of euthanasia were recorded. Postmortem examination was offered, but not required as part of the study.
Nineteen cats were included in this study. Patient characteristics are summarized in Table 2. The number of cats enrolled per starting dosage cohort and total treatments given per dosage are summarized in Tables 3, 4, respectively. Starting VRL dosages were 9–12 mg/m2. Maximal dosage administered was 15.5 mg/m2. The MTD was 11.5 mg/m2. Dosages were de-escalated twice in 2 cats because of recurring episodes of neutropenia and once in 2 cats because of persistent vomiting.
|Median age (years)||13 (range, 5–18)|
|Median body weight at enrollment (kg)||4.25 (range, 1.92–7.24)|
|Malignant cutaneous melanoma||1|
|Salivary gland CA||1|
|Intestinal MCT + dermal HSA||1|
|Starting Dosage Cohort||Number of Cats Treated|
|Dosage||Total Number of Doses Given|
The DLTs included neutropenia, vomiting, and acute renal injury. None of the cats experienced more than 1 DLT. Three cats experienced dose-limiting neutropenia at 12 mg/m2. One developed grade 2 neutropenia at 12 mg/m² and was withdrawn from the study at the owner's request. One developed grade 3 neutropenia after the 1st treatment, resulting in dose delay. This cat's neutrophil count normalized within 7 days, and the cat was de-escalated to 10.8 mg/m2. Interestingly, grade 4 neutropenia was noted 7 days after treatment at the de-escalated dosage, and again resolved. The VRL dosage again was de-escalated by 10% to 9.25 mg/m2. This cat received 2 treatments at this dosage at weekly intervals and only grade 1 neutropenia was noted. The 3rd cat developed fever and grade 4 neutropenia after its 2nd weekly treatment at 12 mg/m2 and was hospitalized. The cat improved with IV fluids and antibiotics and was discharged from the hospital. However, despite normalization of the neutrophil count and resolution of fever, the cat continued to have decreased appetite and activity. Abdominal ultrasound examination was performed, and pancreatitis was diagnosed. In retrospect, it was difficult to determine if the fever was related to the neutropenia caused by the VRL, if the VRL caused the pancreatitis, or if the pancreatitis contributed to the fever and protracted clinical recovery. This cat intermittently had clinical signs associated with pancreatitis before starting VRL, thus the pancreatitis was thought to be unrelated to treatment and the concomitant inflammatory condition presumably played a role in what was perceived to be a septic event. After this event, the cat was withdrawn from the study by the request of the owner.
A 4th cat developed grade 3 neutropenia at 15.5 mg/m2. To maximize this cat's dose intensity, dosage escalation was continued beyond the MTD until DLT was noted. This cat was treated weekly up to 13.5 mg/m2 and then every 2 weeks up to 15.5 mg/m2. Its neutrophil count normalized within 7 days of the grade 3 neutropenia event. For the next treatment, the cat was de-escalated to 15 mg/m2, a dosage that had previously been tolerated without myelosuppression. Similar to the cat in the 12 mg/m2 cohort, grade 4 neutropenia was noted 7 days after treatment at this de-escalated dosage.
One cat in the 12 mg/m2 cohort experienced grade 3 vomiting, which started 3 days after the first VRL treatment. The dosage was decreased by 10% for the second treatment, but vomiting continued. Although this cat was being treated for metastatic intestinal mast cell tumor, a disease commonly associated with vomiting, the cat had no clinical signs before starting treatment. In fact, the mast cell tumor was an incidental finding during staging for dermal hemangiosarcoma. This cat received only 2 VRL treatments and was euthanized 15 days after enrollment in the trial. With this exception, vomiting was self-limiting to non-existent.
Finally, 1 cat experienced grade 4 acute renal injury at 12 mg/m². Two days after treatment, the cat was presented for weakness, decreased appetite, and polydipsia. It was clinically dehydrated and hypotensive (50 mmHg). BUN concentration was >100 mg/dL (reference range, 7.5–30 mg/dL) and serum creatinine concentration was 4.3 mg/dL (reference range, 0.6–1.2 mg/dL). These values had been 49 mg/dL and 1.5 mg/dL, respectively, with a urine specific gravity of 1.017 before VRL treatment. This cat was hospitalized and treated with IV fluids and gastroprotectants. Twelve and 36 hours after presentation, serum creatinine concentration was 4.6 mg/dL and 7.3 mg/dL, respectively. Because of the worsening azotemia, the cat was euthanized. At necropsy, widespread severe acute renal tubular necrosis, multifocal mild to moderate chronic tubulointerstitial nephritis and glomerulopathy were noted. This was the cat's 2nd VRL dose, and it tolerated the 1st treatment at 11.5 mg/m² well, experiencing only grade 1 anemia.
Another clinically relevant toxicity was weight loss. One cat in the 11 mg/m2 cohort and 2 in the 12 mg/m2 cohort experienced weight loss of approximately 10–14%. Weight loss generally was progressive over the 1st 3 weeks of treatment, but cats' body weights eventually stabilized. As defined by VCOG-CTCAE criteria for constitutional signs, weight loss of 10–14% is considered a grade 2 AE, and by definition of our protocol was not considered dose-limiting. In contrast, under the heading of anorexia, weight loss ≥10% is considered a grade 3 AE and therefore would be dose-limiting. None of the owners reported anorexia, vomiting, or diarrhea to explain the weight loss, and admittedly 1 cat concurrently was receiving amoxicillin/clavulanic acid2 for a urinary tract infection, which may have contributed to weight loss in this cat. We ultimately deemed this AE as non–dose-limiting. Nevertheless, close monitoring of body weight during VRL therapy is warranted.
Other toxicities including grade 1 neutropenia, grade 1 to 2 vomiting, and grade 1 anorexia were uncommon and self-limiting when observed. Of note, however, was grade 1 to 2 anemia seen in 6 cats. Baseline hematocrit was within the reference range for all cats included in the study, and no particular dosage was correlated with the onset of anemia. Three cats received only 1 dose of VRL. The remaining cats received >1 dose, and anemia was noted after 3, 4, and 6 doses, respectively. Anemia resolved or improved in all cats with VRL delay or discontinuation.
Ten cats received VRL at dosages above the MTD, in part because intrapatient dosage escalation was allowed to maintain individual dose intensity. Five of these 10 cats experienced DLT at 12 mg/m2, and of these, 3 were in the 12 mg/m2 starting dosage cohort. Two cats continued treatment at 12 mg/m2 without further dosage escalation at the owners' request despite the fact that they did not experience DLT. Only 3 were escalated beyond 12 mg/m2. One of these 3 developed grade 4 thrombocytopenia at 13 mg/m2. One was escalated to 12.5 mg/m2, experienced no toxicity, but received no additional VRL treatments because this was the cat's 4th weekly dose. The 3rd cat was treated weekly up to 13.5 mg/m2 and then every 2 weeks up to 15.5 mg/m2. Grade 2 anemia (at dosages of >13.5 mg/m²) and the aforementioned grade 3 and 4 neutropenia (at 15.5 mg/m2 and 15.5 mg/m2, respectively) were the only toxicities this cat experienced.
Although 10 cats received <4 VRL doses, the majority were withdrawn from the trial for reasons other than toxicity. Three cats were withdrawn because of overt disease progression. Three cats were withdrawn to pursue other treatments for their individual cancers. One cat, treated elsewhere, was lost to follow-up 2 weeks after the first VRL treatment. One week after VRL treatment, the cat was examined by the attending oncologist and a CBC was performed. No adverse events were reported. Three cats were withdrawn from the trial because of toxicity, and of these, 2 ultimately were euthanized in part because of toxicity. Although the 3rd cat was withdrawn at the owner's request after experiencing grade 2 neutropenia, no other adverse events were noted. At last follow-up, 5 months after VRL discontinuation, this cat was still alive.
Response was not an endpoint of this study, and not all cats were evaluable for response. However, 1 cat with metastatic intestinal mast cell tumor experienced a durable partial response to VRL. In addition, 1 cat with metastatic pulmonary carcinoma experienced resolution of 2 lung nodules after 4 treatments of VRL.
Results of this prospective phase I trial demonstrate that VRL is tolerated at a weekly interval in tumor-bearing cats, with an MTD of 11.5 mg/m2. Dose-limiting toxicities were transient neutropenia, vomiting, and acute renal injury. Weight loss also was clinically relevant, and mild anemia was noted but not deemed dose-limiting. A small subset of cats tolerated incremental dosage escalations above the MTD. However, 2 cats were euthanized after treatment above the MTD. Although both cats had advanced cancers that may have contributed to their progressive clinical signs, we cannot entirely discount the possible role of VRL in the outcome of these cats. However, we believe its favorable toxicity profile at the MTD makes VRL a reasonable therapeutic option in cats with cancer.
All cases of neutropenia resolved before the next scheduled treatment, but 2 cats experienced worsening grades of neutropenia at de-escalated dosages. One possible explanation was that the neutropenia was a consequence of cumulative dosing and detrimental effects on the bone marrow. However, it was noted after the 1st 2 VRL doses in 1 cat. Alternatively, a double neutrophil nadir may have occurred. A double nadir previously has been reported in cats treated with CCNU, and although not reported in the literature, we have seen the same effect in animals treated with carboplatin. The cause of this repeated neutropenia remains unclear, but it warrants further investigation because it was noted in more than 1 cat.
The acute renal injury was the most concerning AE. It was unclear if the clinical signs of dehydration and hypotension occurred first, possibly because of VRL treatment, and subsequently caused the acute renal injury, if the acute renal injury was a direct result of VRL nephrotoxicity, or if the event was completely unrelated. Unfortunately, necropsy did not answer this question because histologic changes were nonspecific and suggestive of severe acute tubular necrosis. Infiltrative disease, specifically renal metastasis was not noted. Although we were unable to find reports of VRL causing nephrotoxicity in humans or dogs, we could not exclude the possibility of its direct contribution to this AE.
Nephrotoxicity unique to cats has been noted with other chemotherapeutic agents. Both doxorubicin and liposome-encapsulated doxorubicin have been shown to cause subclinical to clinical nephrotoxicosis with histologic evidence of renal tubular injury in cats.[16, 17] Furthermore, renal injury associated with doxorubicin administration is thought to be a cumulative dosing effect. VRL may have a similar effect on feline kidneys and, if so, may only become clinically apparent in a subset of patients. Nephrotoxicity caused by other vinca alkaloids commonly used in cats has not been reported to our knowledge.
The weight loss noted was difficult to explain and its relationship to VRL was unclear. Associated gastrointestinal signs were not observed by owners, and none of the cats was known to have concomitant disease (eg, hyperthyroidism or clinically relevant renal failure) to explain the weight loss. Cancer cachexia was a consideration, but none of the cats experiencing weight loss had clinically relevant measurable disease. Although body weight eventually stabilized in each cat, none regained lost weight while receiving VRL.
Variations in interpatient drug tolerability were noted, and some cats experienced toxicity in the lower dosage cohorts, whereas others tolerated dosages above the apparent MTD. This was also observed in a phase I trial of VRL in dogs, and it has been reported with other chemotherapeutics used in cats. In a phase I study of carboplatin, Kisseberth et al reported prolonged neutropenia and thrombocytopenia in some cats treated at dosages well-tolerated by other cats. Henry reported substantial variability in the timing of neutrophil nadirs in healthy cats treated with the combination of mitoxantrone and cyclophosphamide. Prolonged neutropenia, inconsistencies in the timing of neutrophil nadirs, and variability in interpatient tolerance all have been reported in cats treated with lomustine.[15, 20, 21] A plausible explanation for this variability in drug tolerance is differences in individual patient organ function and therefore drug metabolism and elimination. VRL is metabolized by the liver and excreted in the bile, and renal insufficiency thus is unlikely to play a role in altered VRL elimination. Furthermore, in this study, no clear correlation between hepatic function and drug variability could be made. Finally, most cats experienced DLTs at 12 mg/m2. Regardless, more cats will need to be treated with VRL to answer this question.
Phase I dosage escalation trials are used to determine MTD, toxicities, and safe starting dosages of novel therapeutics. A traditional 3 + 3 design often employs a modified Fibonacci sequence in which the dosage escalation increment decreases as the total dosage increases and the suspected MTD is approached. This design was developed based on the assumption that toxicity and efficacy increase as the dosage increases, and it therefore preserves patient safety while minimizing the number of patients treated at subtherapeutic dosages. An inevitable consequence of this design is that numerous dosage escalations generally are required before reaching the MTD.[12, 22] As a result, it is likely that a substantial number of patients is treated at subtherapeutic dosages.[12, 23] To overcome this consequence, this study employed several modifications to the traditional 3 + 3 cohort design.
One modification allowed for intrapatient dosage escalation. An advantage of intrapatient escalation is reduction in the number of patients ultimately treated at subtherapeutic dosages. Although some patients may start the trial at subtherapeutic dosages, they eventually escalate to more effective dosages. Another advantage is more rapid data accrual with fewer patients enrolled in the trial. This advantage is especially attractive in veterinary studies, which are often conducted with limited funding. On the other hand, a disadvantage of intrapatient dosage escalation is that it potentially limits the ability to detect certain toxicities and the dosages at which they occur. Furthermore, it becomes difficult to distinguish cumulative toxicities from delayed toxicities.
A 2nd modification allowed for continued dosage escalation in individual cats tolerating VRL beyond the MTD. The approach was employed in attempt to maintain individual dose intensity. We recognized from the outset that some cats would tolerate VRL better than the overall population in general. We made this modification to avoid use of presumably subtherapeutic dosages in these individuals.
A final modification was use of a standard 10% dosage reduction rate for cats experiencing DLT as compared to de-escalation to the dosing cohort immediately below the cohort in which the DLT occurred (as employed in conventional phase I trials). In our lower dosage cohorts (9–11 mg/m2), the 10% reduction approximated the conventional approach, as a cat with DLT at 11 mg/m2 was de-escalated by 10% to 9.9 mg/m2. However, as we approached the anticipated MTD and were escalating cohorts by only 0.5 mg/m2, we were concerned that such a modest dosage reduction would not substantially decrease the risk of repeated DLT. Although it remains unclear if this concern was valid, we observed repeated DLTs at de-escalated dosages in 3 cats (2 with neutropenia and 1 with vomiting) while using the 10% reduction rate.
Drug efficacy was not considered a primary endpoint of the study, but responses were seen in 1 of each of metastatic intestinal mast cell tumor and metastatic pulmonary carcinoma. Responses were based on imaging at baseline compared to imaging after 4 weekly VRL treatments using RECIST criteria. Although these cancers are rare in cats, the data support phase II investigation of VRL for these cancers.
In conclusion, VRL appears well-tolerated in cats with cancer at a weekly interval and an MTD of 11.5 mg/m2. VRL should be considered part of the treatment repertoire for cats with cancer. With careful monitoring of clinical signs and hematologic variables, some cats may tolerate incremental dosage escalations beyond the apparent MTD.
The authors acknowledge Drs Cecilia Robat (University of Wisconsin) and Michael Kiselow (Veterinary Medical Specialists) for case contribution.
Funding for this study was provided by the University of Georgia Clinical Research committee.
Conflict of Interest Declaration: Authors disclose no conflict of interest.
Navelbine; Sagent Pharmaceuticals, Schaumburg, IL
Clavamox; Pfizer, New York, NY