ADJUVANT GEMCITABINE-CISPLATIN CHEMOTHERAPY OF INVASIVE TRANSITIONAL CELL CARCINOMA OF THE UPPER URINARY TRACT

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THE JOURNAL OF UROLOGY®

334 ADJUVANT GEMCITABINE-CISPLATIN CHEMOTHERAPY OF INVASIVE TRANSITIONAL CELL CARCINOMA OF THE UPPER URINARY TRACT Yun Seob Song*, Jong Hyun Yun, Won Jae Yang, Seung Hwan Doo, Chun Kim, Hong Sup Kim, Ki Hak Song, Sun Kim, Se Joong Kim, Dong Hyun Lee, In Rae Cho, Do Hwan Seong, Jin Sun Cho, Young Sik Kim, Sang Hyun Chun, Dong Jun Kim, Kang Su Cho, Byung Ha Chung, Young Deuk Choi, Sung Joon Hong. Seoul, Republic of Korea, Daegu, Republic of Korea, Chungju, Republic of Korea, Daejeon, Republic of Korea, Suwon, Republic of Korea, Goyang, Republic of Korea, Incheon, Republic of Korea, Anyang, Republic of Korea, and Ulsan, Republic of Korea. INTRODUCTION AND OBJECTIVE: To evaluate the therapeutic benefit of adjuvant gemcitabine-cisplatin combination chemotherapy(GC) after nephroureterectomy with bladder cuff resection in patients with invasive transitional cell carcinoma(TCC) of the upper urinary tract. METHODS: From June 1998 to December 2005, 51 patients (40 men, 11 women) had invasive(Stage pT2 or pT3) TCC, not metastatic and nephroureterectomy with bladder cuff resection were performed. Of these 51 patients, 25 patients were scheduled to receive more than three courses of GC chemotherapy. The median follow-up period of all the evaluated patients was 17.8 months(range 0.77 to 40.6). RESULTS: 28 out of 51 patients (54.9%) subsequently developed recurrence with a latent period of 4 to 20 months(median 10.3 months). Recurrence of 28% in patients who underwent chemotherapy, and recurrence of 76.9% who did not, were observed, respectively (P=0.000). Disease-free and overall survival were greater in the adjuvant GC chemotherapy group than in the non-adjuvant chemotherapy group(P=0.105, P=0.001, respectively, log-rank test for trend). Univariate &R[ SURSRUWLRQDO KD]DUG PRGHO DQDO\VLV UHYHDOHG WKDW O\PSK QRGH involvement(P=0.027), performance status(P=0.025), adjuvant GC chemotherapy(P=0.001) were associated with overall survival. Multivariate &R[ SURSRUWLRQDO KD]DUG PRGHO DQDO\VLV UHYHDOHG WKDW SHUIRUPDQFH status(P=0.000), adjuvant GC chemotherapy(P=0.001) was associated with overall survival. In the adjuvant GC chemotherapy group, Grade 3 or grade 4 toxicities included anemia(8%), granulocytopenia(20%), thrombocytopenia(20%), fever(4.0%) respectively. Nonhematological toxicities were mild. CONCLUSIONS: Our results indicated that adjuvant GC FKHPRWKHUDS\FDQSURYLGHWKHUDSHXWLFEHQH¿WLQWKHWUHDWPHQWRISDWLHQWV with invasive transitional cell carcinoma of the upper urinary tract. Source of Funding: None

335 LONG-TERM EFFECTS OF BACILLUS CALMETTE-GUERIN PERFUSION THERAPY FOR UPPER URINARY TRACT UROTHELIAL CARCINOMA IN SITU Takahiro Yoneyama*, Hayato Yamamoto, Akiko Okamoto, Atsushi Imai, Ikuya Iwabuchi, Yasuhiro Hashimoto, Kazuyuki Mori, Takuya Koie, Noritaka Kamimura, Chikara Ohyama. Hirosaki, Japan. INTRODUCTION AND OBJECTIVE: Bacillus Calmette-Guerin %&*  WKHUDS\ KDV EHHQ HVWDEOLVKHG DV D WUHDWPHQW IRU VXSHU¿FLDO bladder cancer and carcinoma in situ (CIS) of the bladder. However, although there are several studies reporting the effectiveness of BCG perfusion therapy for upper urinary tract urothelial carcinoma, the clinical VLJQL¿FDQFH LV XQNQRZQ :H UHWURVSHFWLYHO\ HYDOXDWHG WKH ORQJWHUP results of BCG perfusion therapy for upper urinary tract CIS. METHODS: We observed 17 patients (14 male, 3 female) who received BCG perfusion therapy for upper urinary tract CIS (entire urinary WUDFW&,6Q ELODWHUDOQ XQLODWHUDOQ  IURP'HFHPEHU to December 2006. The average period of observation was 48.1 months (range, 5-125 months), and the average age was 71.9 years (range, 55-90 years). A double-J catheter was used for patients with synchronous bladder cancer (n = 12) and a transvesical single-J stent for those who did not have bladder cancer (n = 5). A straight ureteral catheter was used for one patient who had undergone ureterocutaneostomy. BCG WUHDWPHQWZDVJLYHQRQFHZHHNO\IRUVL[FRQVHFXWLYHZHHNVPJIRU WKH¿UVWFDVHVDQGPJIRUWKHVXEVHTXHQWODWHFDVHV8ULQH F\WRORJ\ZDVSHUIRUPHGWRDVVHVVWUHDWPHQWHI¿FDF\

Vol. 179, No. 4, Supplement, Sunday, May 18, 2008

RESULTS: Urine cytology tests became negative in 14 of the 17 patients (82.4%). Of the 14 patients for whom BCG perfusion was effective, 2 experienced recurrence in their upper urinary tract at 47 and 55 months after the treatment. The other 12 patients remained tumor free for 43.3 ± 40.5 months (mean ± SD). Of the 3 patients for whom BCG perfusion was not effective, 2 opted not to continue treatment and the third patient died of another cause. High fever and ureteral stenosis prompted cessation of therapy in three patients. Side effects were observed in 17 of the 18 patients (94.4%), the most common being bladder irritation. Severe renal tuberculosis occurred in two cases. During the observational period, two patients died from upper urinary tract urothelial cancer within one year of treatment. CONCLUSIONS: BCG perfusion therapy for the upper urinary WUDFW&,6FDQEHHIIHFWLYHKRZHYHUDVXFFHVVIXORXWFRPHLVWDPSHUHG by possible severe side effects including renal tuberculosis, prompting caution in the use of this therapeutic strategy. Source of Funding: None

336 A PHARMACOKINETICS STUDY TO OPTIMIZE INTRAVESICAL ADMINISTRATION OF GEMCITABINE Paolo Gontero*, Luigi Cattel, Giovanna Berta, Tonia C Paone, Paola Milla, Claudio Medana, Francesco Carbone, Alessandro Tizzani. Torino, Italy. INTRODUCTION AND OBJECTIVE: Phase I studies have shown that 2000 mg intravesical gemcitabine (dFdC) is an effective and well tolerated dose on non-muscle invasive bladder cancer (NMIBC). Instead drug concentration, pH and administration volume are still under discussion. So we designed a clinical and pharmacokinetic (pk) study to establish a rationale treatment schedule in which pH, concentration and duration of instillation give the best tissue penetration of the drug with the less toxic effects. METHODS: The study contemplates the enrolment of patients with NMIBC, tumor mass 1-3 cm, normal hepatic, renal and hematopoietic and the administration of 2000 mg of gemcitabine (dFdC) with different single pre-TURBT instillation’s schedules, held in the bladder for 1 hour. We divided patients (pts) in 4 arms: 3 pts pH 3.5, 40 mg/mL (A), 3 pts pH 3.5 20 mg/mL (B), 3 pts pH 5.5 40 mg/mL (C), 3 pts pH 5.5 20 mg/ mL (D). Blood samples were taken before and 30, 60, 120 minutes after drug instillation. Urinary samples were taken before drug instillation and after bladder depletion. During TUR we taken specimens from tumoral and healthy tissue. The samples were analysed with HPLC- HRMSn OLPLWRIGUXJGHWHUPLQDWLRQQJPO DQGSKDUPDFRNLQHWLFSUR¿OHRI dFdC and dFdU (inactive metabolite) were determined. RESULTS: Cmax plasma dFdC 30-60 minutes after instillation was: 0,5 µM in A, 0,8 µM in B, 1,2 µM in D. We did not perform arm C because in that condition dFdC is undissolvable and precipitates. Cmax dFdU 60 minutes after bladder depletion was: 1,2 µM in A, 7 µM in B, 2 µM in D. dFdC was recovered in urine after bladder depletion at 99,9% in pH 3,5 and 99,0% in pH 5.5 group. In tumoral tissues dFdC concentration for mg of proteins was: 300 ng A, 800 ng B, 3000 ng D. In tumoral tissues dFdU concentration for mg of proteins was: 200 ng in A, 1000 ng in B and 200 ng in D. CONCLUSIONS: Gemcitabine (dFdC) instillation schedule arm D (pH 5,5 and concentration 20 mg/mL) give the best drug penetration in tumoral tissue. By contrast acid pH (3.5) seems to better promote dFdC metabolism (conversion in dFdU), with consequent less production of the active metabolite gemcitabine triphosphate. In the future our mean goal will be to provide more data on dFdC pk both in healthy and in tumoral tissues. In particular we will be interested to study in an additional arm as by increasing the time of pre-TURBT instillation, dFdC absorption in tumour tissue would be augmented. Finally, our pk results may easily translate in a more rationale schedule and so in a EHWWHUFOLQLFDOHI¿FDF\RI10,%&WUHDWPHQWZLWKG)G& Source of Funding: None