Tumors of the urinary bladder of dogs are fairly uncommon, accounting for approximately 1% to 2% of all tumors in dogs.1 Transitional cell carcinoma is the most common of all urinary bladder tumors.1 Complete surgical removal of TCC is usually not possible because of the typical location within the trigone and urethra.2 Surgical treatment may be complicated by TCC recurrence within the urinary bladder or seeding to other parts of the urinary bladder, peritoneal cavity, or incision line following surgery.
Several nonlaser surgical techniques for treating TCC have been described, including partial cystectomy,3 ureterocolonic anastomosis,4 vaginourethroplasty,5 and ileocystoplasty.6 The MST for dogs undergoing surgical treatment alone has been reported to be 86 to 120 days.1,7 The MST increases to 180 days for dogs receiving single-agent chemotherapy8 and to 259 days for dogs receiving combination chemotherapy.7 A combination of mitoxantrone and piroxicam has been shown to provide an MST of 350 days.9 A regimen consisting of piroxicam, mitoxantrone, and coarse-fraction radiation was well tolerated, but the response rate and MST of 326 days were not superior to that of a regimen with mitoxantrone and piroxicam alone.10 Stent placement has been described as a rapid, safe way to provide palliative management of obstructing malignant urethral tumors in dogs, with a reported MST of 20 days.11 Placement of a permanent cystotomy catheter also has been described as a means of providing relief from trigonal and urethral obstruction, providing an MST of 106 days.12
Evidence supports surgical debulking of TCC to improve survival time, regardless of the type of subsequent treatment.a A transurethral debulking ablation of TCC by use of electrosurgery has been described previously but deemed to be unsuitable in female dogs because of a high intraoperative and postoperative complication rate.13 Recently, debulking with CO2 laser, combined with mitoxantrone and piroxicam administration, has been shown to provide an MST of 299 days.14 It has been reported that survival time was significantly shorter for dogs with tumor in the trigone and urethra than for dogs with no tumor in those locations, regardless of other treatments provided.a This is presumably because a small tumor mass within the urethra can cause fatal obstruction.
There are several reasons to investigate the diode laser as a superior option to CO2 laser for debulking TCC of the urinary tract. First, the nIR wavelength of a diode laser allows it to be more effective in a fluid-filled urinary bladder, compared with the far-infrared wavelength of a CO2 laser. This is because the absorption coefficient of water for a 980-nm diode laser is approximately 1/1,000 of that of 10,600-nm CO2 lasers,15,16 thus providing more efficient transmission of the laser beam through the fluid media to the target tissue. Likewise, the absorption coefficients of oxyhemoglobin and deoxyhemoglobin are much greater for nIR wavelengths15,16 than for the CO2 laser and, accordingly, may be differentially absorbed with higher efficacy by the largely vascular TCC tissue than the adjacent, less vascular normal urinary bladder tissue.17 Lastly, the diode laser wavelength is less absorbed by tissue water and thus penetrates more deeply into tissue, creating a wider zone of peripheral thermal coagulation of tissue than is achieved with CO2 lasers.15,16 Therefore, the purpose of the study reported here was to evaluate the efficacy of UGELAB as a repeatable and noninvasive palliative debulking treatment for relief of obstructive TCC involving the trigone, cystourethral junction, and urethra as well as nonobstructive lesions of the body or apex of the urinary bladder.
Materials and Methods
Study population—Thirty-eight privately owned dogs (36 females and 2 males) were referred to the Ridgewood Veterinary Hospital between February 2001 and April 2008 for diode laser treatment of a presumed or previously diagnosed TCC of the urinary bladder or urethra. The dogs either had obstructive lesions or had failed to respond to other treatment protocols. Most dogs were referred to the author (DJC) for endoscopic laser surgery because urinary tract obstruction provided an extremely grave prognosis, with no viable options available other than impending euthanasia. Some dogs had a tumor that was not obstructive, but because tumors tend to spread to the urethra, all of the tumors were considered potentially obstructive and thus warranted treatment before urinary tract obstruction actually occurred. Dogs were treated after the initial post-operative period with doxycycline (10 mg/kg [4.5 mg/lb], PO, q 12 h) and an NSAID, such as piroxicam (0.3 mg/kg [0.14 mg/lb], q 24 h) or carprofen (2.2 mg/kg [1 mg/lb], PO, q12h).
Pretreatment examination and staging—All owners provided informed consent for the procedures performed. The urinary bladder and abdominal cavity were evaluated by use of ultrasonography and endoscopy to plan the laser treatment, stage the tumor according to the World Health Organization classification cancer clinical staging system for urinary bladder and urethral tumors in dogs (Appendix),18 identify tumor extent and position as well as to assess the presence of ureteral obstruction and the existence of hydronephrosis or hydroureter, and determine the proximity of tumor to the ureteral papillae. Tumor location was determined and recorded as urethral (region 1), cystourethral junction (region 2), trigonal (region 3), body (region 4), or apex (region 5). Tumors in regions 1,2, and 3 were considered inoperable by conventional partial cystectomy techniques on the basis of tumor location.
Tumors were histologically graded on the basis of findings from endoscopically obtained biopsy specimens. On microscopic examination, TCCs with a histologic grade of 1 were well differentiated and had normal cell size and normal positioning of nuclei, with minimal anisokaryosis and hyperchromicity; TCCs with a histologic grade of 2 were moderately well differentiated with moderate variation in cell volume, moderate variation in positioning of nuclei, hyperchromatic nuclei, and a single nucleolus; and TCCs with a histologic grade of 3 were anaplastic with substantial variation in cell, nuclear, and nucleolar shape and size.19
Thoracic radiographs were obtained to rule out pulmonary metastasis. A CBC and serum biochemical analysis were performed to obtain baseline data and to rule out concurrent disease. As soon as the endoscope entered the urinary bladder, prior to dilution with infused saline (0.9% NaCl) solution, urine was collected into a sterile syringe for aerobic bacterial culture and antimicrobial susceptibility analysis and urinalysis.
Preoperative protocol—Dogs were premedicated with buprenorphine (0.02 mg/kg [0.01 mg/lb], SC). Anesthesia was induced with midazolam hydrochloride (0.28 mg/kg [0.13 mg/lb], IV) and ketamine (5.5 mg/kg [2.5 mg/lb], IV) and maintained with isoflurane in oxygen after endotracheal intubation. Dogs received enrofloxacin IM at a dose of 2.5 mg/kg (1.1 mg/lb) at the time of anesthetic induction unless otherwise indicated by results of bacterial culture and antimicrobial susceptibility testing of urine. Blood pressure was supported by administration of lactated Ringer's solution (2.75 mL/kg/h [1.25 mL/lb/h], IV) starting before surgery and maintained over 24 hours and adjusted as needed. During anesthesia, heart rate, oxygen saturation as measured by pulse oximetry, blood pressure, and body temperature were monitored continuously and recorded every 15 minutes.
Epigallocatechin-3-gallate, a green tea derivative, has been shown to inhibit the growth of AY-27 transitional cells implanted in rats.20 Because of these findings, EGCG was added to the saline solution used for flushing the urinary bladder at a dose of 184 mg of EGCG/L of saline solution in 14 of 38 dogs. The EGCG solution began at the initiation of the endoscopic procedure and ended when the UGELAB procedure was terminated. Treatment of dogs with EGCG was done only after providing full disclosure to the owners about the experimental nature of the treatment and obtaining written consent. Although the safety and efficacy of EGCG use in dogs are not known, a study21 on the absorption, tissue distribution, and elimination of EGCG in Beagles revealed no adverse reactions following PO or IV administration.
Surgical procedures—In female dogs, a 2.7- or 3.5-mm 30°-offset endoscope with a 3-port sheathb was inserted into the urethra and monitored on a video screen for any abnormal tissue in the vestibule or urethra. In male dogs, a rigid endoscope was used via a perineal urethrostomy incision, as previously described.22,23 The perineal urethrostomy site was closed at the conclusion of the UGELAB procedure. Sterile saline solution was flushed through the left lateral port, and a sterile drain tube was attached to the right lateral port. The endoscope was advanced slowly, allowing the solution to alternately inflate and deflate the urethra so that abnormal tissue could be seen more accurately, and the lumen margins were determined. The urinary bladder was constantly flushed with saline solution (with or without EGCG) during the procedure, allowing continuous removal of tumor cells. Adjusting the fluid level within the urinary bladder often changed the position of the tumor, making it to some degree amenable to contact with the laser fiber. Biopsy specimens of all suspicious tissue were obtained for histologic grading prior to laser treatment.
The endoscope was advanced into the urinary bladder, allowing thorough endoscopic evaluation of the urinary bladder apex, body, and trigone. The ureteral orifice was inspected to ascertain any tumor involvement. The TCC was located and thoroughly evaluated by use of abdominal ultrasonography; ultrasonographic and endoscopic images were digitally recorded for evaluation of treatment and assessment of future tumor regrowth. The endoscope was advanced to within 2 to 5 mm of the tumor to allow precise viewing and control of the laser fiber. Ultrasonographic imaging of a portion of the pelvic urethra was facilitated by passive manipulation of the descending colon, with the ultrasonographer using the top of his scanning hand during angling of the ultrasound probe head toward the perineal region. In this manner, 3 to 4 cm of urethra caudal to the cystourethral junction was inspected to provide better control of the laser energy.
A 400- to 900-μm-diameter optical fiber was passed through the biopsy channel and directed toward the mass for delivery of the laser beam. The laserc was set between 16 and 25 W in continuous wave contact or noncontact mode, as indicated. In general, lower power was used when working within the urethra or within 0.5 cm of the urinary bladder wall when the 900-μm laser fiber was used and was adjusted down further when a smaller-diameter fiber was used to account for the increased power density associated with a smaller-diameter optical fiber.15,16 The laser was energized, and the optical delivery fiber was advanced into the tumor, which was viewed with a 10- or 12-MHz linear or 8-MHz microconvex ultrasound transducer. In general, the ultrasound probe was held perpendicular to the axis of the endoscope to obtain a long-axis (sagittal) view of the bladder, allowing full viewing of the depth of retrograde penetration of the endoscope and laser fiber. This view also ensured that the endoscope and laser fiber remained parallel to the urinary bladder wall. On occasion, the short-axis (transverse) view of the bladder was used when retrograde motion was of less concern and the surgeon was maneuvering to ablate the tumor from the lateral walls of the urinary bladder. Ultrasonography allowed viewing of the tumor at times when inadequate endoscopic views prevented proceeding safely and efficaciously because the tumor obstructed the endoscopic image.
As laser energy is absorbed by the tumor, the increasing tissue temperature results in protein denaturation. Laser energy vaporizes tissue in the immediate path of the laser beam when tissue temperatures exceed 100°C (212°F).15
In the present study, the tissue adjacent to the vaporization path was denatured, resulting in increased density and causing treated tissue to appear more hyperechoic on ultrasonographic images (Figure 1). This transition between hyperechoic and original echogenicity was manifested as the HTNL. Constant monitoring of the HTNL allowed optimal control of power and delivery time of laser energy to safely remove maximal tumor tissue without penetration of the urinary bladder wall. In the higher power range, the laser was used in noncontact mode to denature superficial tumor tissue not requiring surgical removal of a protruding mass. The resulting denatured, avascular tissue was usually sloughed within several days.
Sagittal (long-axis) ultrasonographic images of the dorsal aspect of the urinary bladder of a dog evaluated for midstream dysuria. A—Midportion of the urinary bladder; notice the obstructive and nonresectable nature of the TCC that is located at the cystourethral junction, caudal to the ureteral papilla (arrow). B—Ultrasound-guided endoscopic diode laser ablation of the TCC performed at 16 W. The endoscope and laser fiber are to the right. The ultrasonographer used the HTNL to monitor progression of ablation during periods when the operator was unable to see the TCC endoscopically. Notice the casting of an acoustic shadow as the tissue is denatured. C—Image of the tunnel (large arrow) created through the TCC after UGELAB, following the direct path of the diode laser energy. The endoscope and diode laser operator cannot see anything except the caudal wall of the TCC and the tunnel created. Only the ultrasonographer can assess how far the laser has penetrated the TCC and the depth of laser energy penetration as well as whether the laser angle is positioned safely (ie, parallel to the urinary bladder wall). D—Ultrasound-guided endoscopic diode laser ablation of the TCC performed at 25 W (ie, higher power) that may be used for deeper laser penetration. There is rapid laser penetration dorsally (HTNL; small arrows) in a cranial and caudal direction near the urinary bladder wall (long arrow). The surgeon cannot see this event occurring, and without ultrasonographic guidance, excessive laser penetration could lead to urinary bladder perforation. All images (A–D) were obtained with a 12-MHz linear ultrasound probe.
Citation: Journal of the American Veterinary Medical Association 240, 1; 10.2460/javma.240.1.51
Care was taken to avoid advancing the laser fiber when draining the urinary bladder to avoid penetration of the wall. At the conclusion of surgery, a Foley urinary catheter was often placed in dogs that had a TCC in regions 1, 2, and 3. The decision to catheterize was made on the basis of assessment of the extent of trauma and the likelihood of a postsurgical obstruction occurring either from cellular debris in the urinary bladder or fibrinous adhesions.
Posttreatment care—Typically, the urinary catheter was left in place for 3 to 7 days for dogs with a tumor located in region 1 and for 1 to 2 days for dogs with a tumor located in regions 2 and 3. Following urinary catheter removal, these patients were released from the hospital after normal urination for > 12 hours. Dogs with no tumor in the urethra or cystourethral junction were released from the hospital as soon as normal urination was observed, but this interval did not last > 24 hours for any dog. Dogs received buprenorphine (0.02 mg/kg, SC, q 8 h) for pain management, starting prior to anesthesia induction and continuing through their hospital stay. Dogs were discharged from the hospital and prescribed carprofen (2.2 mg/kg, PO, q 12 h) or piroxicam (0.3 mg/kg, PO, q 24 h) for pain management.
Long-term monitoring—Because many dogs were referral patients, the types of medications administered prior to UGELAB or during long-term follow-up treatment varied. Owners were contacted by telephone every 2 to 4 weeks for the remainder of the dogs' lives to monitor the presence or absence of any clinical signs as well as owner satisfaction with UGELAB. When possible, ultrasonographic or endoscopic examination was repeated every 6 to 8 weeks to monitor tumor regrowth. The UGELAB procedure was repeated on the basis of recurrence of stranguria or either ultrasonographic or endoscopic evidence of tumor regrowth or as a preemptive attempt to retard tumor regrowth.
Statistical analysis—Time to death or censoring was the primary outcome for analysis. Nonparametric survival curves were estimated by use of the Kaplan-Meier product limit method and survival curves compared by use of the log rank test.24,25 Because of the potential correlation between survival time and the number of treatments, the relationship between survival time and the covariates location and treatment with EGCG were modeled by use of Cox proportional hazards including the number of treatments as a time-dependent covariate.25 The proportional hazards assumption for each covariate individually and globally was verified by use of the Schoenfeld residual method.26 No significant deviation from the assumption was observed. Survival data analysis was performed by use of statistical software.d Values of P < 0.05 were considered significant.
Results
Thirty-eight dogs (36 females and 2 males) were treated with UGELAB for TCC of the urinary bladder or urethra (confirmed via histologic examination), and their urinary obstructions were removed. None of the dogs had evidence of metastatic disease, and all TCCs were staged as T1 or T2, as induration of the urinary bladder wall could not always be ruled out on the basis of the depth of biopsy specimens provided by the endoscopic biopsy sampling technique (Appendix). Hence, dogs with a TCC staged as T1 were considered to potentially have a stage T2 tumor if deep biopsy specimens were not obtained. None of the dogs included in this study had TCCs that were staged as Tis, T0, or T3. All dogs had been neutered previously. The median age of the dogs was 11.7 years, with a range of 6.4 to 16 years. Median weight of dogs at initial treatment was 12.1 kg (26.6 lb), with a range of 4.3 to 77.3 kg (9.5 to 170 lb). Breeds represented included the following: mixed (n = 12), Scottish Terrier (4), Beagle (3), West Highland White Terrier (3), Shetland Sheepdog (2), pit bull-type dog (2), Bichon Frise (2), and Corgi (1), Collie (1), Shih Tzu (1), Miniature Poodle (1), Jack Russell Terrier (1), Dalmatian (1), Miniature Pinscher (1), Mastiff (1), Lhasa Apso (1), and Springer Spaniel (1).
In 2 dogs, a biopsy specimen had been collected percutaneously by the referring veterinarian, and both dogs developed needle-tract tumor implantation to the peritoneal cavity, as described previously.27 All other dogs had the biopsy specimen collected endoscopically. One dog was treated short term with mitoxantrone before UGELAB treatment, but administration of the drug was discontinued because of adverse effects. Two dogs had completed radiation and chemotherapy treatment protocols prior to UGELAB, but they still had severe urethral obstruction. None of the dogs had evidence of metastasis or any clinically important concurrent disease other than that related to the urinary tract disease.
All dogs tolerated anesthesia well. Endoscopic equipment used as described was applicable in all weight categories and did not cause excessive urethral trauma. Procedures took between 1.1 and 5 hours, with a median surgical time of 2.1 hours.
All dogs were treated with the diode laser until all obstructions were removed or the tumor mass was reduced as far as possible without compromising the urinary bladder or urethral walls, as determined via ultrasonographic evaluation of the HTNL. Findings on postoperative ultrasonographic examination within 24 to 72 hours revealed that the HTNL was an accurate determinant of tissue denaturation on the basis of the observation that the postoperative tissue slough extended to this point and not beyond. Twenty dogs underwent 1 laser treatment, 8 had 2 treatments, 3 had 3 treatments, 1 had 4 treatments, 1 had 5 treatments, 2 had 6 treatments, 2 had 7 treatments, and 1 had 12 treatments. The 3 dogs that had 12 or 7 treatments required a greater number of treatments because scar tissue was forming a stenosis at the cystourethral junction. Incidental tumor regrowth in these dogs was also removed at this time. Twelve dogs required additional UGELAB treatments because they developed clinical signs as a result of tumor regrowth. Four dogs had multiple treatments as a preemptive measure. Sixteen female dogs were treated in which the TCC was filling approximately 33% to 100% of the length of the urethra. All of these dogs required placement of a urinary catheter for 3 to 7 days following their first laser treatment. The urinary catheters were sutured in place, and an Elizabethan collar was worn by each dog to prevent urinary catheter removal. The urinary catheter was allowed to drain continuously.
In dogs with a tumor isolated to the cystourethral junction, sufficient tumor mass was removed via a single UGELAB treatment. Complete luminal patency was obtained, as determined via postoperative endoscopy for up to 7 weeks after treatment (Figure 2). For dogs in which the obstruction was eliminated entirely and did not have urethral involvement, a urinary catheter was placed for 1 to 2 days after treatment during hospitalization. Initially, dogs were evaluated for tumor regrowth with ultrasonography or endoscopy at 1 and 3 months after treatment or sooner if signs recurred or the owner requested an earlier reevaluation.
Endoscopic images of the cystourethral region in a dog with a TCC. A—The TCC is obstructing approximately 90% of the urethral lumen. B—Patent cystourethral junction immediately following laser treatment of the same tumor. The lumen is now patent, and the devitalized tumor is expected to slough within days. C—Appearance of the cystourethral junction, as seen in A and B, 7 weeks after UGELAB treatment.
Citation: Journal of the American Veterinary Medical Association 240, 1; 10.2460/javma.240.1.51
On initial examination, 2 of the dogs were found to have hydronephrosis and hydroureter caused by TCC of the urinary bladder, which was relieved by use of the UGELAB procedure. In these dogs, ultrasonography was necessary to determine when enough laser energy had been applied to relieve the hydronephrotic condition without perforating the urinary bladder wall.
All dogs in this study had relief from urethral obstruction following the UGELAB procedure. After treatment, dogs were either free of urethral obstruction by having a urethral catheter placed and then remained unobstructed after catheter removal or were immediately free of urethral obstruction (ie, without the need for urethral catheter placement).
Complications—Although dogs no longer had urethral obstruction caused by TCC, some dogs continued to strain to urinate for several days after UGELAB treatment, presumably from the irritation caused by the procedure. Within 24 hours after urinary catheter removal, all dogs were observed or reported to be urinating without clinically important stranguria, dysuria, or incontinence.
Based on gross examination of the urine, approximately a third (13/38) of the dogs had mild hematuria for approximately 1 to 2 weeks but had no signs of discomfort during urination and subjectively had a normal stream of urine. Two female dogs developed stranguria approximately 6 weeks after initial surgery and required subsequent laser treatments to remove stenotic lesions in the cystourethral region that were determined via histologic examination to be primarily fibrous tissue with minimal involvement of TCC.
Only 1 female developed urethral involvement after earlier treatment of a tumor within the urinary bladder body, and 1 male developed TCC at the site of the perineal urethrostomy used to insert the endoscope. One female dog developed a urethral perforation requiring euthanasia. The cause of the urethral perforation was deemed to be the result of operator inexperience with evaluating the ultrasonographic appearance of laser tissue interaction as related to the HTNL as a measure of laser penetration depth. Postoperative bacterial cystitis developed in 19 of 38 dogs; bacterial isolates from 7 dogs were resistant to multiple antimicrobials.
Survival time—Thirty-four dogs were euthanized for the following reasons: recurrent TCC had metastasized or invaded locally, making the dogs unsuitable candidates for further treatment with UGELAB (n = 13), owner declined additional laser treatments (11), tumors or other illnesses unrelated to the TCC (9), and complications of urethral perforation at 11 days after UGELAB treatment (1). Four dogs were still alive at the end of this study. The multivariate hazard ratios and corresponding 95% confidence intervals were computed by use of the Cox proportional hazard model with time-dependent covariates (Table 1); when considered together, none of the 4 factors included in the model (tumor location, histologic grade, EGCC treatment, or number of treatments) were significant predictors of time to death.
Summary results from Cox proportional hazards model of correlations between survival time and various covariates in 38 dogs with TCC that underwent UGELAB as a palliative treatment.
| Covariate | Hazard ratio | 95% confidence interval | P value |
|---|---|---|---|
| Location* | |||
| Bladder body or apex | Reference | ||
| Trigonal only | 1.48 | 0.32–6.89 | 0.615 |
| Urethral and trigonal | 1.43 | 0.47–4.34 | 0.522 |
| Urethral only | 0.84 | 0.13–5.37 | 0.852 |
| Histologic grade | |||
| 1 or 2 | Reference | ||
| 3 | 1.12 | 0.40–3.10 | 0.834 |
| EGCG treatment | |||
| No | Reference | ||
| Yes | 0.54 | 0.19–1.51 | 0.243 |
| Treatments (No.)† | 1.13 | 0.94–1.37 | 0.198 |
Omnibus test for location (P = 0.818).
Modeled as a time-dependent covariate.
The estimated MST by location and treatment characteristics was determined. The MST for all dogs that underwent UGELAB as a means of palliative treatment was 380 days (Figure 3), with a range of 11 to 1,906 days. The MST was 380 days for tumors localized only to the urethra, 390 days for tumors in the urethra and trigone, 230 days for trigonal tumors with no urethral involvement, and 473 days for tumors in the body or apex of the urinary bladder with no involvement of the trigone or urethra. There were no significant (P = 0.826) differences noted in survival time on the basis of these tumor locations (Figure 4). The 2 tumor locations most dissimilar with regard to the expected likelihood of causing death due to obstruction were the urethral-only location (MST, 380 days) and the urinary bladder body or apex (MST, 473 days). When the survival curves were compared, there was no significant (P = 0.321) difference with regard to these 2 tumor locations in dogs following UGELAB treatment (Figure 5). Dogs with TCCs of the urethra only had an MST of 380 days (range, 11 to 910 days), and dogs with a nonresectable tumor in the trigone only had an MST of 230 days (range, 80 to 1,586 days). When the survival curves were compared, there was no significant (P = 0.922) difference with regard to these 2 tumor locations (ie, urethral only vs trigonal only) in dogs following UGELAB treatment (Figure 6).
Kaplan-Meier survival curve for 38 dogs with TCC that underwent UGELAB as a palliative treatment. The MST for all dogs was 380 days.
Citation: Journal of the American Veterinary Medical Association 240, 1; 10.2460/javma.240.1.51
Kaplan-Meier survival curves of the same dogs as in Figure 3. The MSTs were estimated and compared among dogs on the basis of tumor location as follows: urethra only (10 dogs; MST, 380 days), urethra and trigone (12; MST, 390 days), trigone only (6; MST, 230 days), and urinary bladder body or apex (10; MST, 473 days). There was no significant (P = 0.826) difference in MST among dogs grouped on the basis of tumor location.
Citation: Journal of the American Veterinary Medical Association 240, 1; 10.2460/javma.240.1.51
Kaplan-Meier survival curves of 20 of the same dogs as in Figure 4. The MSTs were estimated and compared between dogs on the basis of tumor location as follows: urethra only (10 dogs; MST, 380 days) versus the urinary bladder body or apex (10; MST, 473 days). There was no signifcant (P = 0.321) difference in MST between dogs with these tumor locations.
Citation: Journal of the American Veterinary Medical Association 240, 1; 10.2460/javma.240.1.51
Kaplan-Meier survival curves of 16 of the same dogs as in Figure 4. The MSTs were estimated and compared between dogs on the basis of tumor location as follows: urethra only (10 dogs; MST, 380 days) versus the trigone only (6; MST, 230 days). There was no significant (P = 0.922) difference in MST between dogs with these tumor locations.
Citation: Journal of the American Veterinary Medical Association 240, 1; 10.2460/javma.240.1.51
The MST was compared on the basis of the number of treatments provided to each patient. Patients that received 1, 2, and ≥ 3 UGELAB treatments had an MST of 279, 245, and 515 days, respectively. Comparison of the Kaplan-Meier survival curves did not reveal any significant (P = 0.411) difference among dogs with a varying number of treatments (Figure 7). There was no significant (P = 0.321) difference in MST between dogs that were treated intraoperatively with EGCG (14 dogs; MST, 380 days) and dogs that did not receive EGCG (24; MST, 340 days; Figure 8). The MST was compared on the basis of the histologic grade of the tumor. Patients that had grade 1 or 2 tumors had an MST of 375 days, compared with dogs with grade 3 tumors, which had an MST of 380 days. Comparison of the Kaplan-Meier survival curves did not reveal any significant (P = 0.877) difference between dogs with histologic grade 1 or 2 tumors versus grade 3 tumors (Figure 9).
Kaplan-Meier survival curves of the same dogs as in Figure 4. The MSTs were estimated and compared among dogs on the basis of number of treatments as follows: 1 treatment (20 dogs; MST, 279 days), 2 treatments (8; MST, 245 days), or ≥3 treatments (10; MST, 515 days). There was no significant (P = 0.411) difference in MST among dogs grouped on the basis of number of treatments.
Citation: Journal of the American Veterinary Medical Association 240, 1; 10.2460/javma.240.1.51
Kaplan-Meier survival curves of the same dogs as in Figure 4. The MSTs were estimated and compared between dogs on the basis of whether they received intravesicular treatment with EGCG as follows: yes (14 dogs; MST, 380 days) versus no (24; MST, 340 days). There was no significant (P = 0.321) difference in MST between dogs that were or were not treated with EGCG.
Citation: Journal of the American Veterinary Medical Association 240, 1; 10.2460/javma.240.1.51
Kaplan-Meier survival curves of the same dogs as in Figure 4. The MSTs were estimated and compared between dogs on the basis of histologic tumor grades as follows: grade 1 or 2 (23 dogs; MST, 375 days) versus grade 3 (15; MST 380 days). There was no significant (P = 0.877) difference in MST between dogs with histologic grade 1 or 2 versus grade 3 tumors.
Citation: Journal of the American Veterinary Medical Association 240, 1; 10.2460/javma.240.1.51
Discussion
Conventional surgical treatment of TCC has been associated with significantly shorter survival time than the combined use of mitoxantrone and piroxicam, and patients are subject to all of the negative aspects of laparotomy and cystotomy.1,7,9 Although the MSTs achieved with CO2 laser ablation were similar to those achieved with chemotherapy alone, CO2 laser treatment in combination with chemothera2py provided better resolution of clinical signs14; however, CO2 laser treatment has limitations and disadvantages, compared with UGELAB treatment.
The CO2 laser procedure requires a laparotomy incision, providing the opportunity for neoplastic cells to spread within the abdominal cavity or to incision sites. It also requires placement of a urinary catheter for 24 to 72 hours with hospitalization and for 10 to 14 days before suture removal.14 A major limitation of the CO2 laser technique as previously described14 is that only the cranial aspects of the trigone can be treated easily, and there is a limited ability to treat the urethra. In the absence of a fluid-filled urinary bladder, ultrasonographic guidance is not practically available to evaluate the depth of laser energy penetration and tissue interaction when the CO2 laser technique was used.
Compared with CO2 laser techniques, the nIR diode laser penetrates to deeper layers of the tumor, as demonstrated in the present study with close observation of the HTNL via transabdominal ultrasonography (Figure 1). The nIR diode laser energy can be delivered through an endoscope; thus, an abdominal incision is not required. In addition, the procedure is easily repeated in females and can treat the entire lower urinary tract, including the urethra and vestibule. Visibility of the tumor is enhanced by distension with saline solution and ultrasonographic guidance, allowing controlled endoscopic laser irradiation. Near-infrared diode lasers are readily available in the veterinary market and have a distinct advantage over CO2 laser when working in a water environment, when endoscopes are required for a minimally invasive approach, and when attempting to target pigmented tissues such as melanin or hemoglobin (blood vessels).17 With the UGELAB procedure, the combined use of endoscopy and ultrasonography, in short- (transverse) and long-axis (sagittal) views, provided a 3-D perception of the tumor location, decreasing the likelihood the surgeon would penetrate the urinary bladder wall or urethra.
In the present study, UGELAB provided relief from urethral obstruction usually with only 1 to 2 treatments (28/38). One treatment would provide additional time to respond with concurrent chemotherapy and, at least, postpone the need for euthanasia and provide improved quality of life for the patient. Patients with no tumor in the urethra were able to go home on the day of surgery, and most dogs had immediate relief from signs of stranguria, meaningful gross hematuria, and dysuria as reported by hospital caretakers and owners. In dogs, tumors isolated to the cystourethral junction, although obstructive in nature, are among the easiest to treat and require short hospital stays. Tumors in the cystourethral junction were those that occluded the point at which the urethra attached to the urinary bladder but did not extend > 1 cm caudally into the urethra or contact the ureteral papillae cranially. Obstructive tumors at this location were considered a distinct group that cause neither obstruction of the ureters nor the challenges of removing TCC from the entire urethra and were thus particularly amenable to UGELAB.
Physical obstruction of the urinary outflow track accounts for the observation that dogs with tumors of the trigone and urethra have a significantly shorter survival time than do those with tumors elsewhere in the urinary bladder.a Urethral tumors present a challenge because of the restrictions imposed when working within this small space and the potential limitations of ultrasonography in this region, although with proper manipulation of the ultrasound transducer, the intrapelvic urethra 3 to 4 cm distal to the cystourethral junction can be viewed.
The UGELAB technique is applicable to male and female dogs, although the number of females (n = 36) treated in the present study far exceeded the number of males (2). The nIR diode laser energy is delivered transurethrally though an endoscope, and application of laser energy is guided with ultrasonography in terms of laser fiber placement and depth of tissue removal and coagulation during laser treatment. This technique can be used to treat tumors of the urinary bladder and urethra and, as in 2 affected dogs of the present study, can be used to relieve hydronephrosis and hydroureter caused by TCC of the urinary bladder. In mild cases of ureteral obstruction by TCC, UGELAB may provide temporary relief from ureteral obstruction; however, for more advanced cases of ureteral obstruction, stent placement likely will be required.
Most of the dogs in the present study were treated after the initial postoperative period with an NSAID (eg, piroxicam or carprofen) and doxycycline. Doxycycline has antiangiogenic properties and may inhibit tumor growth.28 The use of EGCG in the present study resulted in no significant increase in MST. Each of these items were added to the procedure as it developed, so not all dogs in the present study were treated identically.
In the present study, dogs that had obstructive lesions of the urethra treated with UGELAB did not have a significantly shorter MST, compared with dogs that had lesions at other locations. In a previous study,a survival time was significantly shorter for dogs with tumors in the trigone and urethra than for dogs with no tumors in those locations, regardless of other treatments provided. This difference in survival time depending on location is thought to be based on the fact that a small volume of tumor mass within the urethra can cause fatal urinary tract obstruction, whereas the same mass volume within the apex, body, or trigone without ureteral involvement does not cause obstruction. Treatment with UGELAB adequately removes these obstructive lesions and thus effectively avoids death as a direct result of obstruction. Future studies of the UGELAB technique need to be done on a larger number of dogs to better evaluate whether the TCC location and extent and number of treatments affected overall survival time, whether EGCG or postoperative treatments affect survival time, and whether early detection and proactive UGELAB intervention affects survival time.
ABBREVIATIONS
| EGCG | Epigallocatechin-3-gallate |
| HTNL | Hyperechoic tissue line of necrosis |
| MST | Median survival time |
| nIR | Near-infrared |
| TCC | Transitional cell carcinoma |
| UGELAB | Ultrasound-guided endoscopic diode laser ablation |
Josel JR, Pagor Ca, Glickman 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.
HopkinsII 30° rigid telescope, 2.7 mm × 18 cm or 3.5 × 36.5 cm, and Operating Sheath, Karl Storz Veterinary Endoscopy, Goleta, Calif.
CeralasD15, 980-nm diode laser, CeramOptec Industries Inc (subdivision of BioLitec), East Longmeadow, Mass.
Stata, version 11, Stata Corp, College Station, Tex.
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Appendix
World Health Organization clinical TNM staging of urinary bladder and urethral tumors in dogs.18
| Category | Description |
|---|---|
| T | |
| Tis | Carcinoma in situ |
| T0 | No evidence of primary tumor |
| T1 | Superficial papillary tumor |
| T2 | Tumor invading urinary bladder wall with induration |
| T3 | Tumor invading neighboring organs |
| N | |
| N0 | No regional lymph node involvement |
| N1 | Regional lymph node involved |
| N2 | Regional and juxtaregional lymph node involved |
| M | |
| M0 | No evidence of metastasis |
| M1 | Distant metastasis |
M = Distant metastasis. N = Regional lymph node (internal or external iliac lymph nodes). T = Primary tumor.
