Introduction

Inflammatory colorectal polyps (ICRP) are overrepresented in miniature dachshunds and have been proposed to be a novel form of inflammatory bowel disease (IBD).^1–3 The principal sign in the affected dogs is large bowel diarrhea including hematochezia, tenesmus, and mucoid feces, which are problematic for the canine patients and their owners as well as clinicians.⁴ ICRP are characterized by multiple, variable-sized polyps on endoscopy and proliferation of granulomatous tissue with severe infiltration of inflammatory cells (e.g., neutrophils, macrophages, lymphocytes) of the lamina propria on histology. As recently pointed out by researchers in Japan, the standard treatment for ICRP in dogs has not been established, because it is a recently recognized disease, but a combination of prednisolone and cyclosporine was shown to yield a response rate of 80% in the affected dogs, and leflunomide produced a response rate of 93% in patients who had not responded to this combination.^4,5 In terms of other strategies, endoscopic polypectomy and argon plasma coagulation were effective in a miniature dachshund with refractory ICRP.⁶

Chlorambucil (CLB)^a is a cytotoxic drug with alkylating activity and is used to treat a variety of neoplastic diseases in veterinary medicine. It is also used to decrease immune system activity. Although there is little information available on the clinical use of CLB for the treatment of canine non-neoplastic diseases, it was specifically used for dogs with protein-losing enteropathy, suggesting an effective treatment strategy.⁷ CLB generally has minimal side effects and appears to be well tolerated in dogs when given at metronomic doses of 4 mg/m² orally once daily, but a recent report showed that higher doses of CLB worsened adverse events without significantly prolonging progression-free survival as the treatment efficacy.^8–10 The major side effects are bone marrow suppression, manifesting as pancytopenia, and gastroenteritis, usually presenting as anorexia, nausea, vomiting, and/or diarrhea.¹¹

Here, we report on a series of miniature dachshunds with ICRP that had not been well controlled by previous treatments, but which was satisfactorily managed with CLB combined with firocoxib or prednisolone.

Materials and Methods

Results

The clinical characteristics of the six dogs are shown in Table 1. Three dogs (cases 1, 2, and 5) had been treated with steroid and immunosuppressive drug, two (cases 3 and 6) had been treated with surgery and immunosuppressive drug combined with nonsteroidal anti-inflammatory drug, and one (case 4) had been treated with steroid before CLB administration. The mainstay for previous treatment consisted of a combination of prednisolone^c (range: 1.0−2.7 mg/kg/day, median: 1.2 mg/kg/day) and cyclosporine^d (range: 4.6−5.8 mg/kg/day, median: 5.3 mg/kg/day) or azathioprine^e (3.0 and 1.9 mg/kg/day). Rosuvastatin^f was trialed in cases 2 and 5, because of an anecdotal report of a beneficial effect on ICRP in miniature dachshunds (M. Yuki, personal communication 2011), but no response was observed. Cases 3 and 6 underwent surgical intervention (rectal pull-through surgery) as the primary treatment for ICRP, followed by robenacoxib and prednisolone treatment to prevent recurrence, but developed new lesions in the remaining colorectal tissue within 205 and 403 days after surgery, respectively. Neither case responded to the addition of cyclosporine. In case 5, hematochezia recurred after a 50% reduction in prednisolone dosage (0.4 mg/kg/day) and, before treatment with CLB, had improved on an increased dosage (0.9 mg/kg/day). Previous treatments also included salazosulfapyridine^g tablets, piroxicam suppositories^h, salazosulfapyridine suppositoriesⁱ, and hydrocortisone/fradiomycin sulfate/dibucaine hydrochloride/esculoside suppositories^j, which did not yield a clinical advantage. Drugs other than prednisolone and immunosuppressive drugs were sequentially added. The total duration of prior therapy in each case ranged from 49 to 680 days (median: 449 days).

TABLE 1 Clinical Information of ICRP Dogs Before CLB Administration

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Of the six dogs treated with CLB, five (cases 1−5) responded and had a median response time of 19 (range: 7–56) days. The initial dose of CLB was 1.5–3.1 mg/m²/day (median: 1.8 mg/m²/day); firocoxib^k therapy in three dogs (cases 1, 3, and 6) and prednisolone therapy in two dogs (cases 4 and 5; 2.1 and 0.47 mg/kg/day, respectively) were initiated simultaneously with CLB and, in case 2, CLB was introduced as a single agent at first (Table 2). In cases 4 and 5, prednisolone was then tapered and discontinued, after which firocoxib was used adjunctively with CLB. In case 1, on the other hand, prednisolone (1.0 mg/kg/day) was added instead of firocoxib halfway through treatment with CLB, when the owner reported blood mixed with stool and endoscopic lesions were seen to have worsened (day 106). The dose was decreased gradually, with improvement in clinical signs documented within 1 mo. Case 5, in which it was judged difficult to taper prednisolone as the condition of the animal worsened after a 50% dose reduction (0.5 mg/kg/day) during previous treatment, responded to combination CLB and 0.47 mg/kg/day prednisolone treatment. Case 6 did not respond to a combined treatment with CLB (for 3 mo) and firocoxib (for 14 wk) and was then lost to follow-up. In this study, a median starting dose and duration of administration of firocoxib were 6.15 mg/kg (range: 5.0−8.8 mg/kg) and 16 mo (range: 0.5−23 mo), respectively. Other medications used concurrently with CLB included salazosulfapyridine (case 4).

TABLE 2 Clinical Information of ICRP Dogs after CLB Administration

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Five responders had a follow-up period of >17 mo (median: 20 mo, range: 17–43 mo; Table 2) The median maintenance dose of CLB at the time of the last follow-up evaluation or before cessation of administration (case 2) was 1.4 (range: 0.46–2.0) mg/m²/day, at which time, concurrently, one dog (case 1) was treated with low-dose prednisolone (0.24 mg/kg, every 7 days), and four dogs were given firocoxib (three dogs, once daily; case 5, every 4 days). The total duration of CLB treatment ranged from 17 to 25 months (median: 20 months). No dietary changes were made for any of the dogs.

In the most recent follow-up endoscopic evaluation, gross lesions of ICRP completely resolved in two dogs (cases 2 and 5; Figures 1A, B) and remained decreased in size in the other three dogs (Figures 1C, D). At the last visit during the study period, furthermore, all responders remained stable; cases 2 and 5 had normal or nearly normal stools and the remaining three dogs had relatively normal or soft stool, sometimes with a small amount of blood, with decreased doses of CLB.

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Adverse events (Table 2) were observed in three dogs during long-term treatment with CLB: case 2 had thrombocytopenia (Veterinary Cooperative Oncology Group grade 1) and anemia (grade 2), case 3 had anorexia (grade 2), and case 5 had anorexia (grade 3), vomiting (grade 1), hyperpigmentation (grade 1), and alopecia (grade 1) of the bridge of the nose and pinna. Thrombocytopenia (162,000/μL) and anemia (packed cell volume 23.4%) in case 2 were revealed by blood work after 6 and 23 mo of treatment with CLB, respectively. Mild thrombocytopenia was managed with reducing dosage frequency of CLB from once daily to every other day and, in 133 days, returned to normal. Anemia was suspected to be a nonregenerative immune-mediated anemia on the basis of cytological findings from bone marrow aspiration, but hematological and biochemical values 3 mo prior to the time of diagnosis with anemia were within the reference interval (packed cell volume 48.7%) except for alkaline phosphatase (525 U/L). Despite cessation of CLB and firocoxib, the anemia continued to progress gradually over 18 mo. The blood erythropoietin concentration was not measured. This dog was treated for the progressive anemia with immunosuppressive drugs and multiple blood transfusions. In case 3, decreased appetite was observed at the last visit during the study period (day 583). The dose of CLB was first decreased; however, comorbidities, especially the progression of heart disease, may have been responsible for this adverse event. The anorexia in case 5 (day 114), which was treated with antibiotics and subcutaneous fluids, improved in 53 days and the dog recovered appetite within 89 days.

Discussion

Of six miniature dachshunds with ICRP that had been difficult to control with previous treatments, five demonstrated improvement, and long-term control of ICRP was achieved with administration of CLB combined with firocoxib or prednisolone. However, ICRP is not a simple inflammatory condition, thus many months of treatment with CLB were required along with careful monitoring for toxicity.

CLB in combination with firocoxib or an anti-inflammatory dose prednisolone can be effective in dogs with refractory ICRP, resulting in satisfactory quality of life for patients and their owners. Because there are typically multiple polyps, as seen in the cases in our study, and as some recur after surgical excision (cases 3 and 6), oral systemic therapy could provide the most benefit to dogs with ICRP. CLB is an anticancer alkylating drug with additional immunosuppressive activity, which may account for its ability to suppress T and B lymphocytes, and has been reported to be effective in treating canine protein-losing enteropathy.^7,13–15 ICRP in miniature dachshunds are suspected, based on pathology and treatment response to immunosuppressive drugs, to be a novel type of canine IBD. Additionally, more recently, the epithelial cells in ICRP were found to express higher levels of cyclooxygenase-2 than did those of other colorectal proliferative lesions.¹⁶ Therefore, a synergistic effect might be obtained by combining two drugs with similar effects but different modes of action. In fact, it was interesting that case 1, in which the disease could not be well controlled with prednisolone and cyclosporine, responded to anti-inflammatory doses of prednisolone added to CLB and was maintained on CLB and low-dose prednisolone (every 7 days). Moreover, case 5 had been treated with CLB and firocoxib every 4 days. In this study, unfortunately, the impact of CLB or firocoxib as a single agent on ICRP was not clarified. Therefore, it merits further research, including an assessment of the use of firocoxib as a single agent or in combination with other immunosuppressive drugs.

In one dog, nonregenerative anemia was noted 23 mo after the start of treatment with CLB. A causal relationship remains unclear; however, it is possible that the dog developed anemia due to continued treatment with CLB, given that this drug can cause severe bone marrow depression, which may take months to years to resolve, and inhibits production of erythropoietin.^11,17 However, toxicities attributable to CLB are generally considered to be relatively mild and reversible. The drug was well tolerated by four responders during long-term administration, for at least 15 mo. Moreover, no late malignancies had been observed in any of the dogs at the time of writing. Our findings are in agreement with previous reports of metronomic administration of CLB in dogs with cancer.^8–10 Nevertheless, care should be taken when using CLB in dogs over an extended period, considering that the risk of malignancy and pulmonary fibrosis are considered to be related to the total cumulative dose and duration of treatment in human medicine.^18–21 Further research is warranted to reach consensus on the most practical CLB treatment protocol for ICRP, with due consideration of the risk of long-term use.

This report has some limitations. The doses of cyclosporine, concentrations of which were not measured in blood samples, and prednisolone might have been insufficient in some of the dogs in our series. On the other hand, although the effectiveness of leflunomide in dogs with refractory ICRP has been reported (response rate, 93%; median response time for improvement in clinical signs: 35 days), we could not conclude that leflunomide is superior to CLB in this regard because of the small number of cases studied and the differences in patient characteristics between our series and that in the previous report.⁵ Other major limitations included historical inaccuracy associated with the retrospective nature of this study and variation in the treatment protocols used. Thus, case accumulation in a longitudinal study that compares CLB with leflunomide, especially in dogs with refractory ICRP, is needed to demonstrate the usefulness of CLB.

Conclusion

CLB was relatively well tolerated by all dogs in this series. Despite the limitations of this research, CLB in combination with firocoxib or prednisolone may be considered in dogs with ICRP that did not respond well to traditional therapies. Prospective controlled trials are warranted to compare CLB-based protocol with the presently available treatments for dogs with ICRP.