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Re: Neoadjuvant and Adjuvant Chemotherapy for Locally Advanced Bladder Carcinoma: Development of Novel Bladder Preservation Approach, Osaka Medical College Regimen
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BLADDER, PENIS AND URETHRAL CANCER, AND BASIC PRINCIPLES OF ONCOLOGY
metastatic renal cell carcinoma (RCC). Patients and Methods: In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 patients who demonstrated ⱖ 25% tumor shrinkage continued to take tivozanib, and 118 patients with less than 25% tumor change were randomly assigned to receive tivozanib or a placebo in a double-blind manner; patients with ⱖ 25% tumor growth were discontinued. Primary end points included safety, the objective response rate (ORR) at 16 weeks, and the percentage of randomly assigned patients who remained progression free after 12 weeks of doubleblind treatment; secondary end points included progression-free survival (PFS). Results: Of 272 patients enrolled onto the study, 83% of patients had clear-cell histology, 73% of patients had undergone nephrectomy, and 54% of patients were treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 14% to 23%). Of the 118 randomized patients, significantly more patients who were randomly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo (49% V 21%; P ⫽ .001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study population. The most common grade 3 and 4 treatment-related adverse event was hypertension (12%). Conclusion: Tivozanib was active and well tolerated in patients with advanced RCC. These data support additional development of tivozanib in advanced RCC. Editorial Comment: In a phase II trial of this novel vascular endothelial growth factor receptor inhibitor the drug activity is demonstrated among patients who are treatment naïve and those who are cytokine refractory. A unique attribute of this trial is the use of randomization of those patients who did not initially demonstrate objective response (more than 25% tumor reduction) or initially progress to continue to receive tivozanib or placebo. Among this group of minor responders and/or those with stable disease continuation of tivozanib resulted in a delay in time to disease progression. The importance of this finding applies when monitoring patients on chronic VEGF directed therapy. In those without evidence of clear disease progression drug continuation is likely of benefit. Samir S. Taneja, M.D.
Bladder, Penis and Urethral Cancer, and Basic Principles of Oncology Re: Neoadjuvant and Adjuvant Chemotherapy for Locally Advanced Bladder Carcinoma: Development of Novel Bladder Preservation Approach, Osaka Medical College Regimen H. Azuma, T. Inamoto, K. Takahara, N. Ibuki, H. Nomi, K. Yamamoto, Y. Narumi and T. Ubai Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan Int J Urol 2012; 19: 26 –38.
Cisplatin-based chemotherapy has been widely used in a neoadjuvant as well as adjuvant setting. Furthermore, trimodal approaches including complete transurethral resection of the bladder tumor followed by combined chemotherapy and radiation have generally been performed as bladder preservation therapy. However, none of the protocols have achieved a 5-year survival rate of more than 70%. Additionally, the toxicity of chemotherapy and/or a decreased quality of life due to urinary diversion cannot be ignored, as most patients with bladder cancer are elderly. We therefore newly developed the novel trimodal approach of combined therapy using balloon-occluded arterial infusion of anticancer agent and hemodialysis with concurrent radiation, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects (“Osaka Medical College regimen” referred
BLADDER, PENIS AND URETHRAL CANCER, AND BASIC PRINCIPLES OF ONCOLOGY
to as the OMC regimen). We initially applied the OMC regimen as neoadjuvant chemotherapy for locally advanced bladder cancer. However, since more than 85% of patients with histologically-proven urothelial cancer achieved complete response with no evidence of recurrence after a mean follow-up of 170 (range 21– 814) weeks, we have been applying the OMC-regimen as a new approach for bladder sparing therapy. We summarize the advantage and/or disadvantage of chemotherapy in neoadjuvant as well as adjuvant settings, and show the details of our newly developed bladder sparing approach OMC regimen in this review. Editorial Comment: Intra-arterial neoadjuvant chemotherapy for advanced urothelial cancer of the bladder was originally evaluated in the 1980s and not considered superior to intravenous neoadjuvant chemotherapy. This regimen adds hemodialysis to remove cisplatin from the venous circulation, thus decreasing side effects and allowing higher doses of drug to be delivered to the tumor. The results seem quite good but difficult to compare with other bladder sparing regimens. David P. Wood, M.D.
Re: Radiotherapy With or Without Chemotherapy in Muscle-Invasive Bladder Cancer N. D. James, S. A. Hussain, E. Hall, P. Jenkins, J. Tremlett, C. Rawlings, M. Crundwell, B. Sizer, T. Sreenivasan, C. Hendron, R. Lewis, R. Waters and R. A. Huddart; BC2001 Investigators School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom N Engl J Med 2012; 366: 1477–1488.
Background: Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone. Methods: In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. Results: At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P ⫽ 0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P ⫽ 0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P ⫽ 0.07) but not during follow-up (8.3% vs. 15.7%, P ⫽ 0.07). Conclusions: Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. Editorial Comment: This phase III trial shows that chemotherapy plus local bladder radiation is superior in locoregional control but not in overall survival. This finding may be due to the fact that the drugs studied (5-fluorouracil and mitomycin C) were radiation sensitizers rather than effective systemic chemotherapy. David P. Wood, M.D.
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BLADDER, PENIS AND URETHRAL CANCER, AND BASIC PRINCIPLES OF ONCOLOGY
metastatic renal cell carcinoma (RCC). Patients and Methods: In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 patients who demonstrated ⱖ 25% tumor shrinkage continued to take tivozanib, and 118 patients with less than 25% tumor change were randomly assigned to receive tivozanib or a placebo in a double-blind manner; patients with ⱖ 25% tumor growth were discontinued. Primary end points included safety, the objective response rate (ORR) at 16 weeks, and the percentage of randomly assigned patients who remained progression free after 12 weeks of doubleblind treatment; secondary end points included progression-free survival (PFS). Results: Of 272 patients enrolled onto the study, 83% of patients had clear-cell histology, 73% of patients had undergone nephrectomy, and 54% of patients were treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 14% to 23%). Of the 118 randomized patients, significantly more patients who were randomly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo (49% V 21%; P ⫽ .001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study population. The most common grade 3 and 4 treatment-related adverse event was hypertension (12%). Conclusion: Tivozanib was active and well tolerated in patients with advanced RCC. These data support additional development of tivozanib in advanced RCC. Editorial Comment: In a phase II trial of this novel vascular endothelial growth factor receptor inhibitor the drug activity is demonstrated among patients who are treatment naïve and those who are cytokine refractory. A unique attribute of this trial is the use of randomization of those patients who did not initially demonstrate objective response (more than 25% tumor reduction) or initially progress to continue to receive tivozanib or placebo. Among this group of minor responders and/or those with stable disease continuation of tivozanib resulted in a delay in time to disease progression. The importance of this finding applies when monitoring patients on chronic VEGF directed therapy. In those without evidence of clear disease progression drug continuation is likely of benefit. Samir S. Taneja, M.D.
Bladder, Penis and Urethral Cancer, and Basic Principles of Oncology Re: Neoadjuvant and Adjuvant Chemotherapy for Locally Advanced Bladder Carcinoma: Development of Novel Bladder Preservation Approach, Osaka Medical College Regimen H. Azuma, T. Inamoto, K. Takahara, N. Ibuki, H. Nomi, K. Yamamoto, Y. Narumi and T. Ubai Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan Int J Urol 2012; 19: 26 –38.
Cisplatin-based chemotherapy has been widely used in a neoadjuvant as well as adjuvant setting. Furthermore, trimodal approaches including complete transurethral resection of the bladder tumor followed by combined chemotherapy and radiation have generally been performed as bladder preservation therapy. However, none of the protocols have achieved a 5-year survival rate of more than 70%. Additionally, the toxicity of chemotherapy and/or a decreased quality of life due to urinary diversion cannot be ignored, as most patients with bladder cancer are elderly. We therefore newly developed the novel trimodal approach of combined therapy using balloon-occluded arterial infusion of anticancer agent and hemodialysis with concurrent radiation, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects (“Osaka Medical College regimen” referred
BLADDER, PENIS AND URETHRAL CANCER, AND BASIC PRINCIPLES OF ONCOLOGY
to as the OMC regimen). We initially applied the OMC regimen as neoadjuvant chemotherapy for locally advanced bladder cancer. However, since more than 85% of patients with histologically-proven urothelial cancer achieved complete response with no evidence of recurrence after a mean follow-up of 170 (range 21– 814) weeks, we have been applying the OMC-regimen as a new approach for bladder sparing therapy. We summarize the advantage and/or disadvantage of chemotherapy in neoadjuvant as well as adjuvant settings, and show the details of our newly developed bladder sparing approach OMC regimen in this review. Editorial Comment: Intra-arterial neoadjuvant chemotherapy for advanced urothelial cancer of the bladder was originally evaluated in the 1980s and not considered superior to intravenous neoadjuvant chemotherapy. This regimen adds hemodialysis to remove cisplatin from the venous circulation, thus decreasing side effects and allowing higher doses of drug to be delivered to the tumor. The results seem quite good but difficult to compare with other bladder sparing regimens. David P. Wood, M.D.
Re: Radiotherapy With or Without Chemotherapy in Muscle-Invasive Bladder Cancer N. D. James, S. A. Hussain, E. Hall, P. Jenkins, J. Tremlett, C. Rawlings, M. Crundwell, B. Sizer, T. Sreenivasan, C. Hendron, R. Lewis, R. Waters and R. A. Huddart; BC2001 Investigators School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom N Engl J Med 2012; 366: 1477–1488.
Background: Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone. Methods: In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. Results: At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P ⫽ 0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P ⫽ 0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P ⫽ 0.07) but not during follow-up (8.3% vs. 15.7%, P ⫽ 0.07). Conclusions: Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. Editorial Comment: This phase III trial shows that chemotherapy plus local bladder radiation is superior in locoregional control but not in overall survival. This finding may be due to the fact that the drugs studied (5-fluorouracil and mitomycin C) were radiation sensitizers rather than effective systemic chemotherapy. David P. Wood, M.D.
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