International Urology and Nephrology 24 (4), pp. 3 6 3 - 3 6 7 (1992)
Segmental Stenosis of Ureter: A Late Complication of Intra-arterial Chemotherapy for Bladder Cancer P. K. SAHA,K. TANIGUCHI,N. MAEKAWA,H. Suzu, S. YAMASHITA, H. KANETAKE,Y. SAITO Department of Urology, Nagasaki University School of Medicine, Nagasaki, Japan (Accepted August 30, 1991) A 54-year-old Japanese male was treated with a single shot of cisplatin-phosphatidylcholine-lipiodol (CPL) suspension dut to bladder tumour (stage T~NoM0). Seven months later, a right lower ureteral stenosis developed. The possible cause of ureteral stenosis due to intra-arterial chemotherapy is discussed.
Introduction
Many studies on bladder tumour treated with intra-arterial chemotherapeutic agents have been reported. Cisplatin [1], cisplatin plus doxorubicin [2], doxorubicin only [3] and mitomycin [4] were the most common agents used. In order to ensure sustained drug action, different chemicals, like ethylcellulose [4] and methyl bisamine hydrochloride [5], have been used as adjuvants to chemotherapeutic agents and have been found more effective than when only anti-cancer drugs are used. CPL suspension was injected into the left hepatic artery of rabbits bearing transplanted VX-2 hepatic carcinoma and found prolonged residence of cisplatin within the turnout site [6]. This suspension was administered locally in 27 patients with unresectable hepatocellular carcinoma and good therapeutic effect was observed [7]. However, there is lack of evidence regarding the clinicaYu~e:of~CPL suspension for bladder tumour. In this case, we injected CPL suspension selectively into the right inferior vesical artery via a transarterial catheter for transitional cell carcinoma (T2NoM0) involving the right lateral wall and retrotrigonal region of the bladder. Although excellent therapeutic response (CR) was obtained, the patient developed right ureteral stenosis 7 months after therapy. Ischaemic necrosis and fibrosis due to complete obstruction by CPL suspension of the inferior vesical artery supplying the lower part of the ureter seemed to be responsible for the stenosis.
VSP, Utrecht Akaddmiai Kiad6, I3udapest
364
Saha et al. : S e g m e n t a l stenosis o f ureter
Case report The patient was undergoing regular follow-up at our outpatient Department for chronic prostatitis. In November, 1989, the patient first noticed gross haematuria. Cystoscopy revealed multiple papillary and non-papillary tumours in the right lateral wall and retrotrigonal region. He was admitted to our Department for further evaluation of the disease and treatment. Physical examination results were within normal limits and no abnormalities were found at routine blood and biochemical examinations. Urine cytology showed class 1V and biopsy of the tumour showed transitional cell carcinoma (TCC) grade 3. Staging diagnosis was done by bimanual palpation of the bladder, transurethral ultrasonography, CT, MRI, DIP, bone scan and pelvic angiography and these revealed T2NoM 0. On 26th December, 1989, a single shot of CPL suspension (cisplatin 100 mg, phosphatidylcholine 200 mg and lipiodol 10 ml) was injected selectively into the right inferior vesical artery (details about CPL suspension are described in [6]) and the injection time was 20 minutes. There was no major immediate side effect other than slight loss of appetite and mild leukopenia. Two weeks after therapy urine cytology showed class 1. CT showed deposition of lipiodol in the tumour region (Fig. 1). Cystoscopy revealed complete necrosis of the tumour. Bladder biopsy showed necrosis, fibrosis and inflammatory changes. Our post-treatment evaluation revealed complete remission. The patient was discharged at the beginning of February, 1990, with the advice of regular follow-up. He was doing quite well before September, 1990, when he complained of dull pain in his right lumbar region. DIP and retrograde pyelography (Figs 2a, 2b) were performed and these showed right hydronephrosis with obstruction in the lower part of the right ureter. Pelvic angiography failed to trace the right inferior vesical artery which was present before the injection of CPL suspension. However, no tumour recurrence was found by cystoscopy. The patient underwent end-to-side uretero-ureteral
Fig. 1. CT of pelvis: Deposition of lipiodol in the tumour region of the bladder International Urology and Nephrology 24, 1992
Saha et aL : Segmental stenosis o f ureter
(a)
365
(b)
Fig. 2. (a) DIP: Right hydronephrosis. (b) Retro- and ante-grade pyelography: Complete obstruction of the lower part of right ureter
Fig. 3. Histology of the resected part of right urether: Normal lining epithelium, infiltration of inflammatory ceils in the submucosa and fibrosis of muscular layer. H & E, • 40 3
International Urology and Nephrology 24, 1992
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Saha et aL ." S e g m e n t a l stenosis o f ureter
anastomosis and resection of the stenotic part. Histopathology of the resected ureter showed ischaemic necrosis and fibrosis (Fig. 3). We are following the patient and until now he is doing well without any trouble.
Discussion
Wallace et al. reported that intra-arterial cisplatin can be highly effective for localized transitional cell carcinoma of the urinary bladder [8]. Stewart et al. [9] treated 5 patients having locally invasive bladder cancer with cisplatin; all of them responded and 3 achieved complete remission. Use of various chemicals as adjuvants to chemotherapeutic agents was also reported in the literature. Kato et al. [4] used mitomycin ethylcellulose microcapsule to ensure sustained release of mitomycin into tumour tissue. Although there is lack of information on CPL suspension and its clinical use in the treatment of bladder cancer, a study by Nakashima et al. [6] on rabbit liver bearing VX-2 hepatic carcinoma demonstrated that phosphatidylcholine (lecithin) prolonged the residence time of cisplatin within the tumour site. A clinical trial also was done by Aoki et al. [7] in patients suffering from unresectable hepatocellular carcinoma. They found that local administration of CPL suspension might be effective in the treatment of liver cancer and did not observe any major side effect. In this case, we injected CPL suspension selectively into the inferior vesical artery and achieved complete response. However, the patient developed stenosis of the right ureter 7 months after therapy. The complications of intra-arterial administration of cisplatin may be systemic such as nausea, vomiting, mild to severe leukopenia, nephrotoxicity, ototoxicity and peripheral neuropathy, or local such as gluteal pain, ecchymotic discoloration of buttocks, cellulitis and gluteal ulcer. Local vascular occlusion always may occur after intra-arterial treatment [8]. Pelvic angiography performed after development of complications failed to trace the inferior vesical artery which indicated that CPL suspension caused complete occlusion of the artery. Complete occlusion of the inferior vesical artery may cause major impairment of blood supply in the lower part of the ureter, because constant blood supply comes from the inferior vesical artery, while supply from other sources is inconstant [10]. Sometimes the anastomotic vessels in the lower part of the ureter are minute and danger of ischaemic necrosis is increased in that case. It seems that CPL suspension causes obstruction of the inferior vesical artery, resulting in ischaemic necrosis and fibrosis and ultimately stenosis in the lower part of the ureter. So, as a complication of the selective administration of an intra-arterial chemotherapeutic agent (especially CPL), the possibility of ischaemic necrosis of the lower part of the ureter should be considered.
International Urclogy and Nephrology 24, 1992
Saha et al.." Segmental stenosis of ureter
367
References I. Jacobs, S. C., Manashe, D. S., Mewissen, M. W., Lipchik, E. O.: Intra-arterial cisplatin infusion in the management of transitional cell carcinoma of the bladder. Cancer, 64, 388 (1989). 2. Maatman, T. J., Montie, J. E., Bukowski, R. M., Risins, B., Geisinger, M.: Intra-arterial chemotherapy as an adjuvant to surgery in transitional cell carcinoma of the bladder. J. UroL, 135, 256 (1986). 3. Nakazono, M., Iwata, S.: Preoperative intra-arterial chemotherapy for bladder cancer. UroL Res., 9, 289 (1981). 4. Kato, T., Nemoto, R., Mori, H., Takahashi, M., Tamakawa, Y., Harada, M.: Arterial chemoembolization and mierocapsulated anticancer drug. J A M A , 245, 1123 (1981). 5. Klopp, C. T., Alford, T. C., Bateman, J., Berry, C. N., Winship, T. : Fractionated intraarterial cancer chemotherapy with methyl bisamine hydrochloride; a preliminary report. Ann. Surg., 132, 811 (1950). 6. Nakashima, M., Nakano, M., Ishii, Y., Matsuyama, K., Ichikawa, M., Sasaki, H., Nakamura, J., Shibasaki, J. : Tissue distribution of eisplatin-lipiodol suspension containing phosphatidylcholine to rabbits carrying VX-2 hepatic carcinoma. Pharmacol Res., 6, 342 (1989). 7. Aoki, Y., Hirai, K., Yamashita, K., Noguchi, H., Sakai, T., Majima, Y., Tanikawa, K., Inoue, H., Okano, Y., Hitoshi, T. : Chemotherapy with eisplatin-phosphatidylcholinelipiodol (CPL) suspension for unresectable hepatocellular carcinoma. Jpn. J. Cancer Chemother., 16, 3066 (1989). 8. Wallace, S., Chuang, V. P., Samuels, M., Johnson, D.: Transcatheter intra-arterial infusion of chemotherapy of advanced bladder cancer. Cancer, 49, 640 (1982). 9. Stewart, D. J., Futter, N., Maroun, J. A., Murphy, P., Mekay, D., Rasuli, P. : Intra-arterial cisplatin treatment of unresectable or medically inoperable invasive carcinoma of the bladder. J. UroL, 131, 258 (1984). 10. Williams, P. L., Warwick, R.: Gray's Anatomy. ChurchilI-Livingstone, Edinburgh 1980.
3*
International Urology and Nephrology 24, 1992
Segmental Stenosis of Ureter: A Late Complication of Intra-arterial Chemotherapy for Bladder Cancer P. K. SAHA,K. TANIGUCHI,N. MAEKAWA,H. Suzu, S. YAMASHITA, H. KANETAKE,Y. SAITO Department of Urology, Nagasaki University School of Medicine, Nagasaki, Japan (Accepted August 30, 1991) A 54-year-old Japanese male was treated with a single shot of cisplatin-phosphatidylcholine-lipiodol (CPL) suspension dut to bladder tumour (stage T~NoM0). Seven months later, a right lower ureteral stenosis developed. The possible cause of ureteral stenosis due to intra-arterial chemotherapy is discussed.
Introduction
Many studies on bladder tumour treated with intra-arterial chemotherapeutic agents have been reported. Cisplatin [1], cisplatin plus doxorubicin [2], doxorubicin only [3] and mitomycin [4] were the most common agents used. In order to ensure sustained drug action, different chemicals, like ethylcellulose [4] and methyl bisamine hydrochloride [5], have been used as adjuvants to chemotherapeutic agents and have been found more effective than when only anti-cancer drugs are used. CPL suspension was injected into the left hepatic artery of rabbits bearing transplanted VX-2 hepatic carcinoma and found prolonged residence of cisplatin within the turnout site [6]. This suspension was administered locally in 27 patients with unresectable hepatocellular carcinoma and good therapeutic effect was observed [7]. However, there is lack of evidence regarding the clinicaYu~e:of~CPL suspension for bladder tumour. In this case, we injected CPL suspension selectively into the right inferior vesical artery via a transarterial catheter for transitional cell carcinoma (T2NoM0) involving the right lateral wall and retrotrigonal region of the bladder. Although excellent therapeutic response (CR) was obtained, the patient developed right ureteral stenosis 7 months after therapy. Ischaemic necrosis and fibrosis due to complete obstruction by CPL suspension of the inferior vesical artery supplying the lower part of the ureter seemed to be responsible for the stenosis.
VSP, Utrecht Akaddmiai Kiad6, I3udapest
364
Saha et al. : S e g m e n t a l stenosis o f ureter
Case report The patient was undergoing regular follow-up at our outpatient Department for chronic prostatitis. In November, 1989, the patient first noticed gross haematuria. Cystoscopy revealed multiple papillary and non-papillary tumours in the right lateral wall and retrotrigonal region. He was admitted to our Department for further evaluation of the disease and treatment. Physical examination results were within normal limits and no abnormalities were found at routine blood and biochemical examinations. Urine cytology showed class 1V and biopsy of the tumour showed transitional cell carcinoma (TCC) grade 3. Staging diagnosis was done by bimanual palpation of the bladder, transurethral ultrasonography, CT, MRI, DIP, bone scan and pelvic angiography and these revealed T2NoM 0. On 26th December, 1989, a single shot of CPL suspension (cisplatin 100 mg, phosphatidylcholine 200 mg and lipiodol 10 ml) was injected selectively into the right inferior vesical artery (details about CPL suspension are described in [6]) and the injection time was 20 minutes. There was no major immediate side effect other than slight loss of appetite and mild leukopenia. Two weeks after therapy urine cytology showed class 1. CT showed deposition of lipiodol in the tumour region (Fig. 1). Cystoscopy revealed complete necrosis of the tumour. Bladder biopsy showed necrosis, fibrosis and inflammatory changes. Our post-treatment evaluation revealed complete remission. The patient was discharged at the beginning of February, 1990, with the advice of regular follow-up. He was doing quite well before September, 1990, when he complained of dull pain in his right lumbar region. DIP and retrograde pyelography (Figs 2a, 2b) were performed and these showed right hydronephrosis with obstruction in the lower part of the right ureter. Pelvic angiography failed to trace the right inferior vesical artery which was present before the injection of CPL suspension. However, no tumour recurrence was found by cystoscopy. The patient underwent end-to-side uretero-ureteral
Fig. 1. CT of pelvis: Deposition of lipiodol in the tumour region of the bladder International Urology and Nephrology 24, 1992
Saha et aL : Segmental stenosis o f ureter
(a)
365
(b)
Fig. 2. (a) DIP: Right hydronephrosis. (b) Retro- and ante-grade pyelography: Complete obstruction of the lower part of right ureter
Fig. 3. Histology of the resected part of right urether: Normal lining epithelium, infiltration of inflammatory ceils in the submucosa and fibrosis of muscular layer. H & E, • 40 3
International Urology and Nephrology 24, 1992
366
Saha et aL ." S e g m e n t a l stenosis o f ureter
anastomosis and resection of the stenotic part. Histopathology of the resected ureter showed ischaemic necrosis and fibrosis (Fig. 3). We are following the patient and until now he is doing well without any trouble.
Discussion
Wallace et al. reported that intra-arterial cisplatin can be highly effective for localized transitional cell carcinoma of the urinary bladder [8]. Stewart et al. [9] treated 5 patients having locally invasive bladder cancer with cisplatin; all of them responded and 3 achieved complete remission. Use of various chemicals as adjuvants to chemotherapeutic agents was also reported in the literature. Kato et al. [4] used mitomycin ethylcellulose microcapsule to ensure sustained release of mitomycin into tumour tissue. Although there is lack of information on CPL suspension and its clinical use in the treatment of bladder cancer, a study by Nakashima et al. [6] on rabbit liver bearing VX-2 hepatic carcinoma demonstrated that phosphatidylcholine (lecithin) prolonged the residence time of cisplatin within the tumour site. A clinical trial also was done by Aoki et al. [7] in patients suffering from unresectable hepatocellular carcinoma. They found that local administration of CPL suspension might be effective in the treatment of liver cancer and did not observe any major side effect. In this case, we injected CPL suspension selectively into the inferior vesical artery and achieved complete response. However, the patient developed stenosis of the right ureter 7 months after therapy. The complications of intra-arterial administration of cisplatin may be systemic such as nausea, vomiting, mild to severe leukopenia, nephrotoxicity, ototoxicity and peripheral neuropathy, or local such as gluteal pain, ecchymotic discoloration of buttocks, cellulitis and gluteal ulcer. Local vascular occlusion always may occur after intra-arterial treatment [8]. Pelvic angiography performed after development of complications failed to trace the inferior vesical artery which indicated that CPL suspension caused complete occlusion of the artery. Complete occlusion of the inferior vesical artery may cause major impairment of blood supply in the lower part of the ureter, because constant blood supply comes from the inferior vesical artery, while supply from other sources is inconstant [10]. Sometimes the anastomotic vessels in the lower part of the ureter are minute and danger of ischaemic necrosis is increased in that case. It seems that CPL suspension causes obstruction of the inferior vesical artery, resulting in ischaemic necrosis and fibrosis and ultimately stenosis in the lower part of the ureter. So, as a complication of the selective administration of an intra-arterial chemotherapeutic agent (especially CPL), the possibility of ischaemic necrosis of the lower part of the ureter should be considered.
International Urclogy and Nephrology 24, 1992
Saha et al.." Segmental stenosis of ureter
367
References I. Jacobs, S. C., Manashe, D. S., Mewissen, M. W., Lipchik, E. O.: Intra-arterial cisplatin infusion in the management of transitional cell carcinoma of the bladder. Cancer, 64, 388 (1989). 2. Maatman, T. J., Montie, J. E., Bukowski, R. M., Risins, B., Geisinger, M.: Intra-arterial chemotherapy as an adjuvant to surgery in transitional cell carcinoma of the bladder. J. UroL, 135, 256 (1986). 3. Nakazono, M., Iwata, S.: Preoperative intra-arterial chemotherapy for bladder cancer. UroL Res., 9, 289 (1981). 4. Kato, T., Nemoto, R., Mori, H., Takahashi, M., Tamakawa, Y., Harada, M.: Arterial chemoembolization and mierocapsulated anticancer drug. J A M A , 245, 1123 (1981). 5. Klopp, C. T., Alford, T. C., Bateman, J., Berry, C. N., Winship, T. : Fractionated intraarterial cancer chemotherapy with methyl bisamine hydrochloride; a preliminary report. Ann. Surg., 132, 811 (1950). 6. Nakashima, M., Nakano, M., Ishii, Y., Matsuyama, K., Ichikawa, M., Sasaki, H., Nakamura, J., Shibasaki, J. : Tissue distribution of eisplatin-lipiodol suspension containing phosphatidylcholine to rabbits carrying VX-2 hepatic carcinoma. Pharmacol Res., 6, 342 (1989). 7. Aoki, Y., Hirai, K., Yamashita, K., Noguchi, H., Sakai, T., Majima, Y., Tanikawa, K., Inoue, H., Okano, Y., Hitoshi, T. : Chemotherapy with eisplatin-phosphatidylcholinelipiodol (CPL) suspension for unresectable hepatocellular carcinoma. Jpn. J. Cancer Chemother., 16, 3066 (1989). 8. Wallace, S., Chuang, V. P., Samuels, M., Johnson, D.: Transcatheter intra-arterial infusion of chemotherapy of advanced bladder cancer. Cancer, 49, 640 (1982). 9. Stewart, D. J., Futter, N., Maroun, J. A., Murphy, P., Mekay, D., Rasuli, P. : Intra-arterial cisplatin treatment of unresectable or medically inoperable invasive carcinoma of the bladder. J. UroL, 131, 258 (1984). 10. Williams, P. L., Warwick, R.: Gray's Anatomy. ChurchilI-Livingstone, Edinburgh 1980.
3*
International Urology and Nephrology 24, 1992
