544 PHASE I-II STUDY WITH INTRAVENOUS PACLITAXEL AND ORAL CYCLOPHOSPHAMIDE IN PATIENTS WITH METASTATIC CARCINOMA OF THE BLADDER

541



542

Extended lymph node dissection in patients with urothelial cell carcinoma of the bladder: Can it make a difference?

Improved prediction of clinical outcomes in patients with advanced bladder cancer using a panel of four cell cycle regulators

Liedberg F.1, Bendahl P.O.2, Davidsson T.3, Gudjonsson S.3, Holmer M.3, Månsson W.3 1

Shariat S.F.1, Bolenz C2, Karakiewicz P.I.3, Fradet Y.4, Bastian P.J.5, Ashfaq R.2, Groshen S.6, Nielsen M.E.7, Rigaud J.4, Mueller S.C.5, Heukamp L.C.5, Netto G.7, Lerner S.P.8, Sagalowsky A.2, Cote R.J.6, Lotan Y.2

Introduction & Objectives: We compared extended and limited lymph node dissections performed during radical cystectomy with regard to impact on survival and time to recurrence in bladder cancer patients.

UT Southwestern, Dept. of Urology, New York, United States of America, 2UT Southwestern, Dept. of Urology, Dallas, United States of America, 3University of Montreal, Dept. of Urology, Montreal, Canada, 4 Universite Laval, Dept. of Urology, Quebec, Canada, 5University Bonn, Dept. of Urology, Bonn, Germany, 6 University of Southern California, Dept. of Urology, Los Angeles, United States of America, 7John Hopkins University, Dept. of Urology, Baltimore, United States of America, 8Baylor College of Medicine, Dept. of Urology, Houston, United States of America

Växjö County Hospital, Dept of Urology, Växjö, Sweden, 2Lund University, Dept of Oncology, Lund, Sweden, 3Lund University Hospital, Dept of Urology, Lund, Sweden

Material & Methods: We analyzed 170 patients who underwent radical cystectomy for urothelial carcinoma between January 1997 and December 2005. From 1997 to 2000, 69 of the patients were subjected to limited lymph dissection that included perivesical nodes and nodes in the obturator fossa. In 2001–2005, the remaining 101 patients underwent extended lymph dissection that included perivesical nodes, nodes in the obturator fossa, the internal, external, and common iliac nodes, and the presacral nodes. Results: Tumors penetrating the bladder wall (pT3 and pT4a) were more common in the extended than in the limited dissection group (48% and 33%, respectively). The median numbers of lymph nodes removed in the two groups were 37 and 8, respectively. Lymph node metastases were detected in 38% of the extended dissection patients but only in 17% of the limited dissection patients. There was no significant difference in survival or time to recurrence between the two groups. Subgroup analyses showed a significantly longer time to recurrence (HR 0.45, 95% CI 0.22–0.93; p = 0.032) in patients with non-organ-confined disease who underwent extended lymph node dissection. In a multivariate analysis adjusting for tumor stage, lymph node status, age, sex, and adjuvant chemotherapy there was a significantly improved survival (HR 0.47, 95% CI 0.25–0.88; p = 0.018) and time to recurrence (HR 0.42, 95% CI 0.23–0.79; p = 0.007) in the patients with extended lymph node dissections. Conclusions: Extended lymph node dissection was in multivariate analysis related to significantly improved disease-specific survival and prolonged time to recurrence in radical cystectomy patients. These results should be interpreted cautiously, since they might have been affected by stage migration and the shorter follow-up in the extended dissection group.



543

1

Introduction & Objectives: Given the complexity of the molecular abnormalities associated with advanced urothelial carcinoma of the bladder (UCB), single cell cycle regulators can not accurately differentiate tumors of similar clinico-pathologic phenotypes into distinct prognostic categories. We and other have reported that combinations of cell cycle regulators may provide more accurate prediction of outcomes compared to a single marker. The aim of the current study was to test whether the combination of four established cell cycle regulators (p53, pRB, p21, and p27) could improve our ability to predict clinical outcomes in a large multi-institutional collaboration of patients with pT3-4N0 or pTany Npositive UCB. Material & Methods: The study comprised 692 patients with pT3-4N0 or pTany Npositive UCB treated with radical cystectomy and bilateral lymphadenectomy (median follow-up: 5.3 years). Scoring was performed using advanced cell imaging and color detection software. Predictive accuracy (PA) was quantified using the concordance index and 200-bootstrap re-samples were used to reduce over-fit bias. Bootstrapadjusted PA estimates were compared using the Mantel-Haenszel test. The base model incorporated patient age, gender, pT stage, grade, lympho-vascular invasion, number of lymph nodes removed, number of lymph nodes positive, concomitant carcinoma in situ, and adjuvant chemotherapy. Results: Altered expression of biomarkers was as follows: p53 (341, 49.3%), p21 (303, 43.8%), pRB (392, 56.6%), and p27 (384, 55.5%). 161 (23.3%), 209 (30.2%), 199 (28.8%), and 61 (8.8%) exhibited alterations in 1 to 4 bio-markers, respectively. Addition of any single biomarker failed to improve the PA for disease recurrence and cancer-specific mortality. Combination of all four biomarkers into number of altered biomarkers resulted in significantly higher PA than any single biomarker (p values<0.001). Moreover, addition of number of altered biomarkers to the base model significantly improved its PA for both disease recurrence (4%, p<0.001) and cancer-specific mortality (3.7%, p<0.001). Addition of number of altered biomarkers retained its statistical significance for improving prediction of clinical outcomes in the subgroup of patients with pT3N0 (n=280), pT4N0 (n=83), pTanyNpositive (n=213) (p values<0.001). Conclusions: While the status of individual biomarkers does not add sufficient value to outcome prediction in patients with advanced UCB, combinations of biomarkers improve the PA of current models in this population. Single biomarkers are unlikely to have the desired level of accuracy and the appropriate degree of certainty to foretell the course of UCB. The future of UCB profiling will rely on the combination of a panel of biomarkers that can give accurate molecular staging, indicating the likelihood of aggressive behavior and, possibly, response to therapy.



544

BRCA1 mRNA expression in patients with bladder cancer treated with neoadjuvant cisplatin-based chemotherapy

Phase I-II study with intravenous paclitaxel and oral cyclophosphamide in patients with metastatic carcinoma of the bladder

Gago Ramos J.L.1, Font Pous A.2, Ibarz Servio L.1, Taron M.2, Boix Orri R.1, Celiz P.2, Carrato C.3, Saladié Roig J.M.1, Rosell R.2

Verze P.1, Di Lorenzo G.2, Imbimbo C.1, Creta M.1, Arcaniolo D.1, Forchia F.1, Mirone V.1

Hugtip, Dept. of Urology, Badalona, Spain, 2Hugtip, Dept. of Oncology, Badalona, Spain, Hugtip, Dept. of Pathology, Badalona, Spain

1 University Federico, Dept. of Urology, Naples, Italy, 2University Federico, Dept. of Oncology, Naples, Italy

1 3

Introduction & Objectives: In patients (p) with muscle invasive bladder cancer, neoadjuvant cisplatin-based chemotherapy followed by cystectomy improves survival compared to surgery alone, especially in p attaining a pathological response (pT0-1N0M0). However, at present no clinical markers are available to predict response to chemotherapy in bladder cancer. BRCA1 mRNA expression has been associated with chemosensitivity and survival in lung and ovarian cancer p (Taron et al. 2004; Quinn et al. 2007) and could be a useful predictive marker in bladder cancer as well. Material & Methods: We analyzed BRCA1 mRNA expression by quantitative PCR in tumour biopsies obtained by transurethral resection from 57 p with locally-advanced bladder cancer. 47 p were clinically staged as cT3-4N0M0, 8 p had regional lymph nodes (cTxN+), and 2 p had distant lymph nodes. 36 p received cisplatin, methotrexate plus vinblastine; 21 p were treated with gemcitabine plus cisplatin. Results: After a median of 3 cycles of chemotherapy, cystectomy was performed in 53 p (93%). A significant pathological response (pT0 or T1) was attained in 28 p (52%). A close correlation was found between BRCA1 levels and pathological response. 24 p (66%) with low BRCA1 levels but only 4 p (23%) with high BRCA levels obtained a pathological response (P=0.01). Median survival was 168 months (m) in 39 p with low BRCA1 levels (≤26.77) and only 41 m in 18 p with high BRCA1(>26.77) levels (P=0.009). In the multivariate analysis of survival, only BRCA1 levels and lymphovascular invasion emerged as independent prognostic markers (table). Conclusions: BRCA1 expression is associated with better pathological response and survival in bladder cancer p treated with neoadjuvant cisplatin-based chemotherapy. Based on these results, in p with low mRNA BRCA1 expression, neoadjuvant chemotherapy should be recommended. BRCA1 can be used to customize multimodality treatment in patients with muscle-invasive bladder cancer. Hazard Ratio

95% CI

P

BRCA1 mRNA levels

Low High

1(ref.) 2.3

1.1-4.9

0.03

Lymphovascular invasion

Yes No

6.1 1(ref.)

2.3-15.7

<0.0001

Eur Urol Suppl 2009;8(4):256

Introduction & Objectives: Taxane-based chemotherapy is actually the most utilized second line treatment in patients affected by metastatic bladder carcinoma. To date, no data exists on the association between paclitaxel and cyclophosphamide. We conducted a phase I-II study with intravenous paclitaxel in combination with oral cyclophosphamide as a rescue therapy for patients with advanced bladder cancer previously treated with gemcitabine/cisplatin as a first line treatment. Material & Methods: Thirty-six patients were enrolled in the study. The treatment cycle included the use of intravenous paclitaxel (175 mg/mq) for three hours a day every three weeks. Two dose levels of cyclophosphamide in association with paclitaxel were evaluated: level 1 dose (oral cyclophosphamide 50 mg for 7 consecutive days every three weeks) and level 2 dose (oral cyclophosphamide 50 mg for 14 consecutive days every three weeks). Patients were divided into twelve homogeneous cohorts composed of three units. Toxicity tests were performed in all groups. Dose-limiting toxicity (DLT) was defined as a WHO grade 3/4 nonhematologic toxicity. If no DLT was reported in two or more patients within each cohort with a level 1 dose, then a level 2 dose was administered. The primary end-point was to determine the DLT, while the secondary end point was to assess the efficacy and the response duration associated with this combination. Results: 32 patients were treated with a level 1 dose and 3 with a level 2 dose. The DLT was 50 mg of cyclophosphamide for 14 days. Toxicity (grades 1-2): vomiting, peripheral neuropathy and neutropenia were present in 11 patients (31.5%), 8 patients (23%) and 8 patients (23%), respectively. Two patients receiving the level 2 dose suffered from grade 4 neutropenia and continued at a level 1 dose. Partial responses were observed in 11 patients (31.5%). Mean progression free survival (PFS) was 3.4 months (95% with a 1-7 month interval). Conclusions: Paclitaxel in combination with cyclophosphamide at a level 1 dose is well tolerated and shows promising efficacy. Further trials are needed to confirm our preliminary data.