A Nonselective Cyclooxygenase Inhibitor Enhances the Activity of Vinblastine in a Naturally-Occurring Canine Model of Invasive Urothelial Carcinoma

Abstract

Background: Chemotherapy is expected to remain an important part of invasive urothelial carcinoma (UC) treatment. Strategies to enhance chemotherapy efficacy are needed.Objective: To determine the chemotherapy-enhancing effects of a nonselective cyclooxygenase (COX) inhibitor on vinblastine in a naturally-occurring canine model of invasive UC.Methods: With IACUC approval, privately-owned dogs with naturally-occurring histologically-diagnosed invasive UC, expected survival ≥6 weeks, and informed owner consent were randomly allocated to receive vinblastine (2.5 mg/m2 intravenously every 2 weeks) plus piroxicam (0.3 mg/kg daily per os) or vinblastine alone (same dose) with the option to receive piroxicam alone when vinblastine failed. Scheduled evaluations included physical exam, standard laboratory analyses, thoracic radiography, abdominal ultrasonography, and standardized measurement of urinary tract tumors.Results: Dogs receiving vinblastine alone (n = 27) and vinblastine-piroxicam (n = 24) were similar in age, sex, breed, tumor stage, and grade. Remission occurred more frequently (P < 0.02) with vinblastine-piroxicam (58.3%) than with vinblastine alone (22.2%). The median progression free interval was 143 days with vinblastine alone and 199 days with the combination. Interestingly, the overall median survival time was significantly longer (P < 0.03) in dogs receiving vinblastine alone followed by piroxicam alone (n = 20, 531 days) than in dogs receiving the combination (299 days). Treatment was well tolerated in both arms.Conclusions: Piroxicam significantly enhanced the activity of vinblastine in dogs with UC where the cancer closely mimics the human condition, clearly justifying further study. The study suggest the potential importance of tracking COX inhibitor use in patients in clinical trials as COX inhibitors could affect treatment response.

Survival analysis in dogs with urinary transitional cell carcinoma that underwent whole‐body computed tomography at diagnosis

“…A similar result was also obtained in the analysis that was conducted using female dogs alone to avoid the influence of prostate involvement, which was reported to be a negative prognostic factor in male dogs, thus, indicating urethral TCC itself might be a negative prognostic factor regardless of prostate involvement. Previous studies have reported that metastasis rates to the lung and bone at diagnosis were 6% to 29% and 8% to 10%, respectively . Our data showed that 35.4% and 24.6% of dogs had metastasis to the lung and bone, respectively.…”

“…This retrospective study was designed to evaluate factors associated with ST and to compare characteristics between tumour localizations in dogs with urinary TCC that underwent whole‐body CT at diagnosis. Because bladder TCC involves the urethra in 56% to 58.8% of dogs and the prostate in 29% to 54.5% of male dogs, few studies have distinguished the characteristics of urethral TCC from that of bladder TCC . Our results revealed two major findings about the clinical behaviour and outcome of urethral TCC and new factors associated with ST. First, dogs with urethral TCC had higher metastasis rates at diagnosis and shorter ST than did dogs with bladder TCC.…”

“…First, although primary TCCs of the bladder and/or urethra in each dog were re‐evaluated by a single observer and classified into three groups on the basis of both ultrasonography and CT findings, definite identification of the tumour development region was occasionally difficult because of the retrospective nature of the study, particularly in cases in which the tumour existed at the boundary between the bladder and urethra. To reduce the variability in primary tumour findings, TCC localization across dogs should be interpreted under constant conditions when using imaging modalities, such as body position, imaging plane and degree of bladder distension …”

The selective cyclooxygenase‐2 inhibitor mavacoxib (Trocoxil) exerts anti‐tumour effects in vitro independent of cyclooxygenase‐2 expression levels

“…In canine prostatic carcinoma, both piroxicam and carprofen (a preferential COX‐2 inhibitor; this class of drugs affects both COX‐1 and COX‐2 but is more selective towards COX‐2) significantly increased survival time as single agents when compared to untreated dogs in both early stage and metastatic disease . As part of dual modality treatment and metronomic chemotherapy, piroxicam significantly increased survival time and incidences of complete or partial remission compared to the same treatments without piroxicam in a range of cancer types including invasive urothelial carcinoma and primary lung carcinoma . A recent review on canine mammary carcinoma concludes that including NSAIDs in treatment significantly improves survival, especially in inflammatory mammary carcinomas when NSAIDs are used alone as palliative treatment or in combination with chemotherapy .…”

“…Interestingly, Knapp et al (2016) noted that when vinblastine treatment was followed by piroxicam as two single agents there was a significant increase in overall survival time compared to dogs receiving the same agents simultaneously. It is suggested that this could be the consequence of drug resistance developing separately for each drug over time rather than concurrently, which raises the interesting possibility that chemotherapy may sensitize the tumour to the action of COX inhibitors . After chemotherapy treatment, resistant cells can go on to repopulate the tumour, a process that has been shown to involve the COX‐2 pathway .…”