ajtcvm.org

A. Elizabeth Hershey, DVM, DACVIM (Oncology), CVA

ABSTRACT

An 8 year old, 32 kg neutered male Standard Poodle was presented for severe sterile hemorrhagic cystitis secondary to cyclophosphamide administration for small cell lymphoma. In addition to the discontinuation of cyclophosphamide, the patient was treated with a combination of a nonsteroidal anti-inflammatory drug, acupuncture, and Chinese herbal Xiao Ji Yin Zi (Cephalanoplos Decoction; Red Front Door). Clinical signs of cystitis resolved by 3 months; however the patient was euthanatized 8 months after presentation due to progressive lymphoma. This case report documents successful treatment of cyclophosphamide associated cystitis in a dog utilizing an integrated therapeutic approach.

Key words: Acupuncture, Chinese herbal therapy, TCVM, chemotherapy, cystitis An 8 year old, 32 kg neutered male Standard

Poodle was presented for clinical signs of cystitis. The patient had been diagnosed with Stage II small cell lymphoma 18 months previously. The patient also had a long history of thyroid and adrenal insufficiency which were controlled with soloxine and Desoxycorticosterone pivalate (DOCP) respectively. The patient’s lymphoma had initially been treated with a combination of chlorambucil and prednisone. At 7 months post diagnosis, the patient’s lymphoma progressed and the chemotherapy protocol changed to oral cyclophosphamide and prednisone. Cyclophosphamide was administered at 53 mg on 4 consecutive days of each week.

Twelve months post initiation of cyclophosphamide, the patient began having hematuria, pollakuria, and stranguria. Additionally, the patient developed lethargy, inappetance, and weight loss. The referring DVM reported low grade fever (103.5 F) on examination with normal pulse and respiratory rates. A complete blood cell count and biochemical profile were unremarkable. Multiple urinalyses indicated a large amount of red blood cells and protein, but no bacteria. No clinical response was seen to empirical antibiotic therapy. An abdominal ultrasound revealed marked, circumferential thickening (1.0 cm) of the bladder wall. Differentials included cystitis secondary to cyclophosphamide chemotherapy and transitional cell carcinoma. Traumatic catheterization to obtain a sample of the bladder wall for histopathology was offered but declined by the owner. Based on the history of cyclophosphamide chemotherapy and circumferential thickening of the bladder, rather than a solitary mass, cyclophosphamide-associated cystitis was felt to be most likely.

On physical examination, the patient was lethargic with enlarged submandibular lymph nodes. Urine staining was noted on the fur and the patient continually dribbled urine in the exam room. Temperature, pulse, and respiration were within normal limits. The patient exhibited discomfort on palpation of the caudal abdomen and urinary bladder.

The Traditional Chinese Veterinary Medicine (TCVM) examination revealed a patient with an Earth constitution and good Shen. His tongue was pale purple and moist with a thin white coating. Pulses were deep, fast, and choppy with the right pulse weaker than the left, especially Spleen. The patient was sensitive to palpation at BL-23. ATCVM diagnosis of Kidney and Spleen Qi deficiency with Bladder Damp Heat was made.

At the initial presentation, dry needle acupuncture was performed at BL-20 (Stomach

Back Shu associated point) BL-21 (Spleen Back Shu associated point) BL-23 (Kidney Back Shu associated point), BL-39 (special point for urinary incontinence), BL-40 (special point for caudal abdomen and urogenital system, clear heat), BL-52 (lateral Kidney Back Shu associated point) ST-36, (back 3 mile-tonify Qi), ST-40 (transform phlegm and dampness), CV-6 (tonify and regulate Qi; Kidney Front Mu point), KID-3 (tonify Kidney) LI- 10 (tonify Qi and Blood),and LI-11 (clear heat, drain damp). Cyclophosphamide was discontinued and the prednisone decreased to a physiological dose of 5 mg twice weekly. Piroxicam was initiated at 10 mg daily, except days when prednisone was administered.

On re-examination 4 weeks later, the owner reported continued urinary leakage. The urine was sticky and the patient constantly tried to ingest his urine. Urine staining was noted on the hair coat and the patient constantly dribbled urine during examination and treatment. Severe halitosis was also noted. The patient remained lethargic and inappetant. Dry needle acupuncture was performed at Bai-hui; Shen-shu (a classical acupoint transposed from horses 2 cun lateral to Bai-hui), BL-20, BL-21, BL-23, BL-52; KID-1, KID 3, LI- 10 and LI-11. Aquapuncture with Vitamin B12 (1: 3 ratio with saline; total of 1000 mcg administered) was performed at BL-40. Piroxicam was continued and the Chinese herbal formula Xiao Ji Yin Zi

(Cephalanoplos Decoction; Red Front Door a) was prescribed for Bladder Damp Heat. The formula Xiao Ji Yin Zi consists of cephalanoplos (cool blood, stop hemorrhage), rehmannia (cool blood and nourish yin), talcum (drain damp and clear heat), akebia (clear heat and drain damp), lophatherum (clear heat, drain damp, benefit urination), gardenia (clear heat, drain damp), typha (activate blood and relieve pain), angelica (activate blood and relieve pain), and glycyrrhiza (harmonize). The patient’s signs of frequent and painful urination and hemorrhagic urine are consistent with damp heat in the bladder. The goal of herbal therapy with Xiao Ji Yin Zi was to clear the heat and damp and to stop hemorrhage.

On re-examination 3 weeks later, the patient continued to dribble almost constantly, but ceased having large accidents in the house. The patient’s appetite and energy had improved. Acupuncture was repeated as above and piroxicam and Xiao Ji Yin Zi herbal continued. Four weeks later, the patient’s overall condition, including appetite and energy had continued to improve. He was not leaking as much urine and there was less urine staining of the fur. Acupuncture was repeated and piroxicam and Xiao Ji Yin Zi continued.

By 3 months post initiation of therapy the patient’s urinary incontinence had resolved. His appetite and energy levels had returned to normal. Gross hematuria had resolved, although hematuria remained microscopically based on urine dipstick testing. Piroxicam and Xiao Ji Yin Zi were continued and the patient maintained on monthly acupuncture treatments. A repeat abdominal ultrasound 7 months post diagnosis of cystitis revealed a normal bladder wall at 0.4 cm thickness. The patient was ultimately euthanatized 8 months post diagnosis of cystitis due to progression of lymphoma. No clinical signs of cystitis were present.

Cyclophosphamide is an alkylating agent commonly used in multi-agent chemotherapy protocols for the treatment of lymphoma, sarcomas, and immune-mediated diseases. Cyclophosphamide is broken down by hepatic microenzymes to the metabolites phosphoramide mustard and acrolein.1-3 Toxicosis to the urinary bladder may occur in some patients receiving cyclophosphamide and is attributable to the action of acrolein on the urinary bladder mucosa2. Acrolein causes submucosal edema, necrosis, hemorrhage, and fibrosis.2, 4 Cyclophosphamide has been reported to cause sterile hemorrhagic cystitis (SHC) in 9-24% of treated dogs.5, 6 Concurrent use of furosemide with cyclophosphamide may decrease the incidence of SHC in dogs. 5

Clinically SHC results in hematuria, stranguria, and dysuria. In mild cases, signs resolve within days to weeks after discontinuation of the cyclophosphamide treatment and symptomatic treatment with anti-inflammatories and antispasmodics. However, in severe cases, fibrosis and calcification of the urinary bladder wall may result in persistent hematuria and urinary incontinence. Treatment of severe cystitis may require more aggressive measures such as partial cystectomy, or intravesicular administration of DMSO or formalin.7, 8

This case represents a severe case of cyclophosphamide associated cystitis treated successfully with a combination of a non-steroidal anti-inflammatory drug along with dry needle acupuncture and Chinese herbal therapy. The use of this integrated therapeutic resolved clinical symptoms of cystitis and improved quality of life, thus avoiding a more aggressive, invasive intervention for cystitis. The patient’s quality of life was greatly improved for 8 months until progression of lymphoma occurred and the patient was euthanatized.

^{a .}   Available from Jing Tang herbal; www.tcvmherbal.com

REFERENCES

1. Stanton ME, Legendre AM. Effects of cyclophosphamide in dogs and cats. J AM Vet Med Assoc 1986; 188:1319-1322.

2. Dhaliwal RS, Kitchell BE. Cyclophosphamide. Compend Contin Educ Vet Pract 1999; 21: 1059- 1063.

3. Plumb DC. Veterinary drug handbook, 4th ed. White Bear Lake, Minn: PharmVet Publishing 1995; pp

4. Peterson JL, Couto CG, Hammer AS et al. Acute sterile hemorrhagic after single administration of cyclophosphamide in 3 dogs. J Am Vet Med Assoc 1992; 201: 1572-1574.

5. Charney SC, Bergman PJ, Hohenhaus AE, et al. Risk factors for sterile hemorrhagic cystitis in dogs with lymphoma receiving cyclophosphamide with or without concurrent administration of furosemide: 216 cases (1990-1996). J Am Vet Med Assoc 2003; 222: 1388-1393.

6. Henness AM. Treatment of cyclophosphamide induced cystitis. J Am Vet Med Assoc 1985; 187:4-5.

7. Laing EJ, Miller CW, Cochrane SM. Treatment of cyclophosphamide-induced hemorrhagic cystitis in five dogs. J Am Vet Med Assoc 1988; 193: 233- 236.

8. Henrikson TD, Moore L, Biller DS, et al. Intravesical instillation of dilute formalin for the treatment of severe hemorrhagic emphysematous cystitis in a diabetic dog. J Am Anim Hosp Assoc 2004;40: 64-68.

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