Evaluation of carbon dioxide laser ablation combined with mitoxantrone and piroxicam treatment in dogs with transitional cell carcinoma

Melinda L. Upton Oncology-Internal Medicine Referral Service, 7220 E 41st St, Tulsa, OK 74145.

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C. H. Tangner The Veterinary Surgery Center, 13551 N Indiana, Oklahoma City, OK 73120.

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Mark E. Payton Department of Statistics, Oklahoma State University, Stillwater, OK 74074.

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Abstract

Case Description—8 dogs that underwent carbon dioxide (CO2) laser ablation of transitional cell carcinoma in the bladder trigone and proximal portion of the urethra and were also treated with mitotranxone and piroxicam.

Clinical Findings—Transitional cell carcinoma of the bladder frequently involves the trigone and urethra and can be difficult to manage surgically. Dogs underwent laser ablation of the primary tumor and were treated with mitoxantrone at a dosage of 5 mg/m2 every 3 weeks for 4 treatments. Piroxicam was given at a dosage of 0.3 mg/kg (0.14 mg/lb) once daily for the remaining life of the dog.

Treatment and Outcome—Median and mean disease-free intervals were 200 and 280 days, respectively. Median and mean survival times were 299 and 411 days, respectively. Adverse treatment effects were observed in 2 dogs; signs included mild, self-limiting inappetance and lethargy. The procedure appeared to be well tolerated; all treated dogs had rapid resolution of clinical signs of disease of the lower portion of the urinary tract.

Clinical Relevance—Although survival times achieved with CO2 laser ablation and treatment with mitoxantrone and piroxicam were similar to survival times associated with chemotherapy alone, resolution of clinical signs was better with the combined treatment.

Abstract

Case Description—8 dogs that underwent carbon dioxide (CO2) laser ablation of transitional cell carcinoma in the bladder trigone and proximal portion of the urethra and were also treated with mitotranxone and piroxicam.

Clinical Findings—Transitional cell carcinoma of the bladder frequently involves the trigone and urethra and can be difficult to manage surgically. Dogs underwent laser ablation of the primary tumor and were treated with mitoxantrone at a dosage of 5 mg/m2 every 3 weeks for 4 treatments. Piroxicam was given at a dosage of 0.3 mg/kg (0.14 mg/lb) once daily for the remaining life of the dog.

Treatment and Outcome—Median and mean disease-free intervals were 200 and 280 days, respectively. Median and mean survival times were 299 and 411 days, respectively. Adverse treatment effects were observed in 2 dogs; signs included mild, self-limiting inappetance and lethargy. The procedure appeared to be well tolerated; all treated dogs had rapid resolution of clinical signs of disease of the lower portion of the urinary tract.

Clinical Relevance—Although survival times achieved with CO2 laser ablation and treatment with mitoxantrone and piroxicam were similar to survival times associated with chemotherapy alone, resolution of clinical signs was better with the combined treatment.

Transitional cell carcinoma is the most common tumor of the bladder in dogs.1 The tumor can be difficult to remove surgically because it often involves the bladder trigone and urethra.1,2 Various surgical techniques, including partial cystectomy, ureterocolonic anastomosis, vaginourethroplasty, and ileocystoplasty, have been described.3-6 Median survival times in dogs undergoing surgical excision of TCC have ranged from 86 to 125 days.1,7,8 Chemotherapy protocols that have been investigated for use in dogs with TCC include single-agent administration of cisplatin; a combination of carboplatin and piroxicam; and combinations of doxorubicin and cyclophosphamide, carboplatin and piroxicam, and cisplatin and piroxicam. Median survival times range from 130 to 181 days in dogs that receive single-agent chemotherapy to 93 to 259 days in dogs that receive combination chemotherapy.7,9-13 Results of a recent study14 of a combination of anthracenedione, mitoxantrone, and piroxicam for treatment of nonresectable TCC in dogs indicated that the combination yielded a median survival time of 350 days.

The combination of debulking procedures and chemotherapy for treatment of dogs with TCC is another area of research. Radiotherapy used to debulk TCC prior to initiation of mitoxantrone and piroxicam chemotherapy resulted in median survival times that were similar to those achieved with chemotherapy alone.15,a In another study,b dogs that underwent surgical debulking procedures had improved median survival times, compared with dogs that did not undergo debulking procedures, regardless of subsequent treatment.

Laser ablation by use of either neodymium:YAG or CO2 lasers has been used to treat neoplasia of the urinary bladder in humans for many years.16-19 An early study20 in which healthy dogs were used revealed that the entire surface area of bladder mucosa could be denuded with virtually no adverse effects. Portable CO2 lasers suitable for use in veterinary hospitals have recently become more widely available and may be useful in treatment of dogs with TCC. The purpose of the present report was to determine efficacy of CO2 laser ablation of the tumor followed by treatment with mitoxantrone and piroxicam for management of TCC of the trigone and proximal portion of the urethra in dogs.

Procedures

All dogs enrolled in the study were referred to the Oncology-Internal Medicine Referral Service from 1999 to 2001 for evaluation of recurrent hematuria. Dogs with histologically confirmed TCC that involved the urinary bladder trigone and proximal portion of the urethra but that had no evidence of metastatic disease or concurrent illness were included in the study. Tumors were staged preoperatively, and dogs were assessed by means of physical examination, thoracic radiography, abdominal ultrasonography, tumor measurements (obtained from sonographic images), CBC, serum biochemical analyses, urinalysis, and urine bacterial culture and sensitivity. Ultrasonographic imaging of the abdomen and radiographic imaging of the thorax were scheduled once monthly for 3 months after the completion of mitoxantrone treatment; at 6, 9, and 12 months after completion of treatment; and every 6 months thereafter. Ultrasonographic imaging of the abdomen was performed immediately prior to the first chemotherapy treatment to ensure that tumor could not be detected in the bladder. Ultrasonographic examinations were performed by a single veterinarian to ensure consistency of interpretation.

Surgical technique—Anesthesia was induced via mask administration of isoflurane and maintained with inhaled isoflurane after endotracheal intubation. Each dog received approximately 20 mL of balanced electrolyte solution/kg (9 mL/lb) per hour (warmed to 103°F [39.4°C]), through an IV catheter placed in a cephalic vein. Dogs received cefazolin IV at a dose of 20 mg/kg at the time of anesthetic induction.

Urethroscopy was performed on female dogs by use of a 2.7-mm rigid urethroscope to confirm that masses in the urinary tract were confined to the bladder and proximal 1 to 2 cm of the urethra. Patients with neoplastic tissue caudal to the proximal portion of the urethra were excluded from the study.

Abdominal skin was prepared for surgery by routine applications of chlorhexidine. A paramedian incision was made in male dogs and in female dogs that had undergone previous cystotomy. A ventral midline incision beginning at the level of the pubis and extending cranially was used in all other dogs. The bladder was exteriorized and isolated from the incision and peritoneal space with towels. A ventral midline cystotomy was incised in the bladder and extended to approximately 1 cm cranial and caudal to the tumor. In dogs with tumor tissue in the proximal portion of the urethra, incisions were extended into the urethra to better expose the mass. A CO2 laser (4 to 8 W) was used to ablate the entire bladder mucosa surface area, including abnormal tissue around the ureters, neck of the bladder, and proximal portion of the urethra. Efforts were made to ablate as much tumor as possible without penetrating to the serosal layer of the bladder. The cystotomy incision was closed with 3-0 polydioxanone in a simple continuous suture pattern. A soft, red rubber catheter was introduced through the urethra into the bladder lumen. The bladder was inflated with sterile electrolyte solution to test for leaks; if detected, leaks were closed with polydioxanone. The urinary catheter was secured to the skin near the urethral orifice and maintained in place for 24 to 72 hours after surgery, depending on the extent of tumor invasion of the bladder submucosa and the likelihood of urine leakage through areas of the bladder wall weakened by laser tumor ablation. Closed urine collection was performed while the urinary catheter was in place. All patients received morphine at a dosage of 1 to 2 mg/kg (0.5 to 1 mg/lb), IM, at the onset of anesthesia, then every 4 to 6 hours as needed for amelioration of signs of pain during the first 24 hours after surgery. Skin sutures were removed 10 to 14 days after surgery.

Chemotherapy protocol—Chemotherapy was initiated 10 to 14 days after surgery, at the time of suture removal. Mitoxantrone was administered IV at a dosage of 5 mg/m,2 every 3 weeks until 4 treatments had been administered. A CBC was performed immediately prior to and 7 days after each mitoxantrone treatment; dogs had to have a neutrophil count ≥ 3,000 cells/μL and a platelet count ≥ 100,000 platelets/μL before receiving the next chemotherapy treatment. Whether dogs were developing toxicosis as a result of mitoxantrone administration was determined by means of CBC results, physical examination findings, and information obtained from owners at each visit. Neutropenia and thrombocytopenia were classified according to National Cancer Institute guidelines.

Piroxicam was administered at a dosage of 0.3 mg/kg (0.14 mg/lb), PO, every 24 hours for the life of the dog. Disease-free interval was defined as the number of days from surgical excision to recurrence of tumor in the urinary bladder or urethra or development of distant metastases. Survival time was defined as the number of days from surgical excision until death. Mean, median, and SD values were calculated for each response variable.

Results

Eight dogs underwent laser ablation of the primary tumor, and 7 of 8 dogs completed the full course of chemotherapy. Median and mean ages of dogs at the time of treatment were 11.5 and 11 years, respectively (range, 9 to 13 years). Median and mean weights of the dogs were 6 and 7 kg, respectively (13 and 16 lb; range, 4 to 16 kg [8 to 35 lb]). There were 5 spayed females, 2 sexually intact females, and 1 castrated male. Two of the dogs were Maltese; 1 was of mixed breeding; and the remaining 5 dogs included 1 each of the Chihuahua, Miniature Poodle, Rat Terrier, Scottish Terrier, and West Highland White Terrier breeds.

Clinical signs at the time of evaluation included hematuria, dysuria, and stranguria. Mean and median duration of clinical signs prior to referral to the participating hospitals were 26 and 40 days, respectively (range, 14 to 129 days). All dogs had been treated with antimicrobials prior to referral, but none had received anti-inflammatory drugs.

No dog had clinical, radiographic, or ultrasonographic evidence of metastases, and all were free of concurrent illness at the time of initial examination. Ultrasonographic imaging revealed that the tumor in all dogs was confined to the urinary bladder trigone and proximal portion of the urethra with no evidence of hydronephrosis or hydroureter.

All dogs underwent laser ablation of the primary tumor and were discharged from the hospital within 72 hours of the procedure. At the time of discharge, gross hematuria had resolved in all dogs. Within 72 hours of surgery, all dogs were reportedly urinating normally with no signs of dysuria, stranguria, or incontinence.

Seven of 8 dogs completed the course of chemotherapy. One dog was killed in a motor vehicle accident after the first chemotherapy treatment, and that dog's data were excluded from statistical analysis. Of the 7 dogs that completed chemotherapy, a reduction in dose was required in 1 dog after the second mitoxantrone treatment because of subclinical post-treatment neutropenia (neutrophil count, 0.5 to 1.0 × 103 cells/μL). Adverse effects of chemotherapy were observed in 2 dogs and included mild, self-limiting anorexia and signs of lethargy.

Of the 7 dogs that completed the course of treatment, 2 developed recurrence of tumor in the bladder trigone at 127 and 159 days after surgery, 1 developed tumor in the urethra distal to the site of laser ablation at 363 days, and 1 developed tumor in the distal portion of the urethra and in the vagina at 131 days. Three dogs had no grossly apparent recurrence of tumor in the urinary tract. Three of the 7 dogs developed metastatic disease; of those, 1 dog had tumor metastasis to sublumbar lymph nodes and the L6 vertebral body 200 days after surgery, 1 had metastasis to the sublumbar lymph node 252 days after surgery, and 1 had multiple metastatic lesions in the omentum 210 days after surgery. One dog was free of disease at approximately 800 days after surgery. Median and mean disease-free intervals were 200 and 280 days, respectively (range, 127 to ≥ 700 days; SD, 215 days). Of the 6 dogs that died, 4 were euthanatized as a result of clinical signs related to recurrence of tumor in the urinary tract. One dog was euthanatized because of lumbar pain and right hind limb paresis secondary to metastasis of tumor to sublumbar lymph nodes and the vertebral body of L6. One dog was euthanatized because of signs of pain and left hind limb lameness secondary to metastatic disease in a left sublumbar lymph node; in that dog, neoplastic tissue had invaded the left femoral triangle region and affected the left femoral nerve. Median and mean postoperative survival times were 299 and 411 days, respectively (range, 200 to 801 days; SD, 246 days).

Discussion

Although several surgical techniques and various chemotherapeutic and radiotherapy protocols for treating TCC have been described,3–7,9–15,a the authors are aware of no reports of laser ablation of tumor combined with mitoxantrone treatment. Although conclusions that can be made from our study are limited by the small number of dogs treated, several conclusions can be made. The median and mean survival times of 299 and 411 days, respectively, compared favorably with survival times of 86 to 125 days achieved with traditional surgical debulking procedures and were similar to the median survival time of 350 days achieved with treatment with mitoxantrone and piroxicam alone. Median and mean survival times in this study were calculated from the day of surgery rather than from the first day of chemotherapy; survival times may thus be artificially increased, compared with those in dogs treated with mitoxantrone and piroxicam alone. Alternate median and mean survival times calculated from the time of first chemotherapy treatment were 290 and 400 days, respectively, and those values also compared favorably with survival times achieved with mitoxantrone and piroxicam alone. A randomized clinical trial in which CO2 laser ablation alone was compared with ablation and treatment with mitoxantrone and piroxicam would be necessary to establish the clinical significance of these findings. Additionally, median and mean survival times in our study were similar to the median survival time of 326 days reported in dogs treated with coarse-fraction radiotherapy, mitoxantrone and piroxicam treatment15 and to the median survival time of 350 days reported in dogs that underwent surgical debulking in addition to one of the various chemotherapy protocols.b However, both of those studies included dogs with tumors at any location in the urinary bladder, whereas our dogs had tumor growth limited to the bladder trigone and proximal portion of the urethra. In both studies, dogs with tumors in the apex or midbody portion of the bladder underwent partial cystectomy prior to radiotherapy or chemotherapy. It is possible that partial cystectomy results in more complete tumor excision, and including those dogs in statistical analyses may result in longer median survival times.

Laser ablation of bladder neoplasia, when performed by an experienced surgeon, can result in better hemostasis and a greater ability of the surgeon to remove extremely thin sections of mucosa, compared with sharp dissection techniques. Improved hemostasis allows for better viewing of the surgical field, particularly when debulking tumors in the bladder trigone and proximal portion of the urethra. Greater surgical precision and the ability to remove thin sections of mucosa may aid in preserving the diameter of the urethral lumen and decrease the need for ureteral transection and reimplantation into the apex of the bladder. The potential postoperative complications of urinary clot retention, ureteral or urethral obstruction, incontinence, and bladder wall perforation with extravasation of urine were not observed in any dogs. All 8 of the dogs that underwent laser ablation had clinical signs of disease in the lower portion of the urinary tract prior to surgery, and 100% of those dogs were reported by their owners to have normal urination within 72 hours of surgery. Those results compared favorably with the reported 75% of dogs that had clinical improvement with mitoxantrone and piroxicam alone14 and with the 90% of dogs that had clinical improvement after coarse-fraction radiotherapy combined with mitoxantrone and piroxicam administration.15 The rapid resolution of clinical signs associated with laser ablation may be an advantage over chemotherapy alone or radiotherapy combined with chemotherapy.

Local recurrence of the tumor in the bladder developed in 2 of the 7 dogs that completed the course of treatment. One sexually intact female and 1 castrated male dog had recurrence of the tumor in the urethra distal to the site of laser ablation. In an early study21 of complete laser denudation of the bladder mucosa in healthy dogs, regeneration of the epithelium arose from residual epithelial cells in the terminal portion of the ureters and proximal urethra, not from residual stem cells in other areas of the bladder. Given that finding, it is possible that the 2 dogs that had recurrence of neoplasia in the bladder in the present study had residual tumor cells in the distal portion of the ureters or proximal portion of the urethra, beyond areas that were ablated; however, no grossly apparent neoplasia was visible in those areas at the time of surgery. The male dog did not undergo pre-operative cystoscopy, so it is possible that a lesion distal to the primary tumor was missed. It is also possible that the original tumors in those dogs penetrated in depth to the bladder serosa. Serosal invasion was not observed in the initial biopsy specimens, but it is possible that such penetration was missed on a small biopsy specimen. Data from the previously mentioned study21 also indicated that reepithelialization in the bladders of healthy dogs proceeds rapidly after complete laser denudation. By the third postoperative week, histologic analysis of biopsy specimens revealed that the mucosal surface of the bladder was completely covered by hyperplastic transitional epithelium.21 In theory, inducing a logarithmic growth phase in residual neoplastic cells could enhance susceptibility of cells to cytotoxic effects of chemotherapy.

The treatment protocol of laser ablation and treatment with mitoxantrone and piroxicam was well tolerated in the dogs in the present study and was associated with minimal adverse effects and a high degree of owner satisfaction. The small number of patients in the study limited our ability to determine efficacy of treatment, but our findings corroborated with previous findings of survival times associated with mitoxantrone and piroxicam treatment and suggested that the addition of laser ablation to a treatment protocol may result in more rapid resolution of clinical signs in the lower portion of the urinary tract and an improved quality of life over chemotherapy alone in affected dogs. The increasing availability of portable CO2 lasers makes them an attractive alternative to surgery, and use of laser ablation in treatment of bladder neoplasia warrants further investigation.

TCC

Transitional cell carcinoma

CO2

Carbon dioxide

YAG

Yttrium-aluminum-garnet

a.

Turner AI, Hahn KA, King GK, et al. Mitoxantrone, piroxicam and external beam radiation therapy in the treatment of canine bladder tumors, 15 cases (2001–2003) (abstr), in Proceedings. 23rd Annu Conf Vet Cancer Soc 2003;20.

b.

Josel JR, Pagor CA, Glickmann MPH, et al. The role of surgical debulkment in dogs with transitional cell carcinoma of the urinary bladder: a retrospective study of 122 dogs (abstr), in Proceedings. 22nd Annu Conf Vet Cancer Soc 2002;5.

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