Bladder Cancer Research:
2002-2006
     
Radiother Oncol. 2006 Oct;81(1):9-17. Epub 2006 Sep 28.
Efficacy and tolerability of concurrent weekly low dose cisplatin during radiation treatment of localised muscle invasive bladder transitional cell carcinoma: A report of two sequential Phase II studies from the Trans Tasman Radiation Oncology Group.
Gogna NK, Matthews JH, Turner SL, Mameghan H, Duchesne GM, Spry N, Berry MP, Keller J, Tripcony L.
Mater Radiation Oncology Centre, Princess Alexandra Hospital, Brisbane, Qld, Australia.

BACKGROUND AND PURPOSE: To determine the feasibility, toxicity, and clinical effectiveness of concurrent weekly cisplatin chemotherapy in conjunction with definitive radiation in the treatment of localised muscle invasive bladder cancer. PATIENTS AND METHODS: In January 1997 the Trans Tasman Radiation Oncology Group embarked on a Phase II study (TROG 97.01) of weekly cisplatin (35mg/m(2)x7 doses) plus radiation to a dose of 63Gy over 7 weeks. Following an interim toxicity analysis, the dose intensity of cisplatin was reduced to 6 cycles and the radiation schedule changed to 64Gy over 6.5 weeks leading to the second study (TROG 99.06). A total of 113 patients were enrolled. RESULTS: Acute grade 3 urinary toxicity occurred in 23% of the patients. Acute grade 4 pelvic toxicity was not seen. Thirty-eight patients (33%) experienced grade 3 or 4 cisplatin related toxicities with 15 patients (12%) requiring significant dose modification. The reduced dose intensity in Study 99.06 improved tolerability. Incidence of significant late morbidity was low (6%). Seventy-nine patients (70%) achieved complete remission at the 6 month cystoscopic assessment. Local invasive recurrence was seen in 11 of the 79 patients (14%). In 18 patients (16%) isolated superficial TCC/CIS were detected (6 months and beyond).The local control rate was 45% with a functional bladder being retained in 69 of the 113 patients (61%). RFS and DSS at 5 years were 33% and 50%, respectively. CONCLUSION: Our two sequential Phase II studies have shown that concurrent chemoradiation using weekly cisplatin in the management of localised invasive bladder TCC is feasible and reasonably well tolerated. This approach is currently being investigated further in a randomised study.

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Cancer. 2006 Oct 13; [Epub ahead of print]
Standardization of pelvic lymphadenectomy performed at radical cystectomy: can we establish a minimum number of lymph nodes that should be removed?
Koppie TM, Vickers AJ, Vora K, Dalbagni G, Bochner BH.
Department of Urology, Sidney Kimmel Center for Urologic Cancer, Memorial Sloan-Kettering Cancer Center, New York, New York.

BACKGROUND.: The number of lymph nodes (LNs) removed during radical cystectomy (RC) for transitional cell carcinoma (TCC) of the bladder affects overall and disease-specific survival, but no consensus exists regarding the minimum number of LNs that should be removed. The goal of the current study was to determine if a threshold number of nodes exists, above which taking additional LNs has no clinical benefit. METHODS.: A total of 1121 patients were identified who underwent RC for clinically localized TCC of the bladder between January 1990 and April 2004. To determine the relation of LNs removal and overall survival, a Cox proportional hazards model was used with pathologic stage, age, and comorbidity as covariates. A dose-response curve, adjusted for covariates, was modeled to assess the impact of an increasing number of LNs removed on overall survival. RESULTS.: A median of 9 LNs were removed (range, 0-53 LNs). In multivariable analysis, all covariates (number of LNs removed, age, stage of disease, and comorbidity) were found to be predictive of survival. The dose-response curve for number of LNs versus survival revealed that, when adjusted for covariates, the probability of survival did not plateau but instead continued to rise as the number of LNs removed increased. CONCLUSIONS.: No evidence was found that a minimum number of LNs is sufficient for optimizing bladder cancer outcomes when a limited or extended pelvic LN dissection is performed during RC. Instead, the probability of survival continues to rise as the number of LNs removed increases. This study supports a more extended LN dissection at the time of RC, and highlights the challenges of interpreting retrospective LN dissection data. Cancer 2006. (c) 2006 American Cancer Society.

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World J Urol. 2006 Oct 10; [Epub ahead of print]
State-of-the-art management of metastatic disease at initial presentation or recurrence.
Calabro F, Sternberg CN.
Department of Medical Oncology, San Camillo/Forlanini Hospital, Nuovi Padiglioni, 4th Floor, Circonvallazione Gianicolense 87, Rome, 00152, Italy, cstern@mclink.it.

Carcinoma of the bladder is the second most prevalent genitourinay malignancy and the fifth most common solid tumor in the USA. On the basis of favorable response rates and survival data, cisplatin-based regimens can be considered the standard treatment for fit patients with metastatic urothelial cancer. Since cisplatin-containing regimens are contraindicated for patients with impaired renal function, gemcitabine plus either paclitaxel or docetaxel may be an effective and well-tolerated treatment option for these patients. Randomized trials are needed to determine the future role of these combinations in the management of advanced transitional cell carcinoma. The optimal regimens for the medically unfit patients and second-line chemotherapy remain undefined. Postchemotherapy surgical resection of residual cancer may result in a disease-free survival in highly selected patients who would otherwise die of the disease. Progresses in the understanding of the molecular biology of bladder cancer and identification of new targeted therapies will undoubtedly provide new opportunities but whether or not this approach to therapy will lead to better results must still be determined.

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Clin Genitourin Cancer. 2006 Sep;5(2):150-4.
Phase II Trial of Adjuvant Gemcitabine plus Cisplatin-Based Chemotherapy in Patients with Locally Advanced Bladder Cancer.
Jin JO, Lehmann J, Taxy J, Huo D, Stockle M, Vogelzang NJ, Steinberg G, Stadler WM.
Section of Hematology/Oncology, University of Chicago, IL.

Background: Despite the general acceptance of gemcitabine/cisplatin in metastatic bladder cancer, its role and tolerability in the adjuvant setting, in which renal insufficiency is common, is unclear. Patients and Methods: A total of 39 patients with locally advanced transitional cell carcinoma of the bladder (T2-T4, N0-N2) were treated with 4 cycles of gemcitabine/cisplatin/amifostine after radical cystectomy. All toxicities were evaluated by the National Cancer Institute Common Toxicity Criteria. Tumor samples were immunohistochemically stained for pRB, p53, and p16. Results: Thirty-five patients (90%) completed 4 cycles of chemotherapy. Eleven patients (28%) experienced grade 4 hematologic toxicity, and 14 patients (36%) experienced grade 3 nonhematologic toxicity. The median increase in creatinine was 0.3 mg/dL. With a median follow-up of 22.8 months (range, 7-70 months), 13 patients (33%) had recurrent disease, 1 patient at 6 years after completion of therapy. Twelve patients (31%) died, including 11 (28%) with recurrent disease. Thirty-three tumor blocks were evaluated for pRB, p53, and p16 alterations. In an exploratory analysis, altered expression of p53, p16, and pRB was found in 15 (45%), 22 (67%), and 30 patients (91%), respectively. No association between altered p53 and disease-free or overall survival was detected, but altered p16 and pRB expression was associated with better outcome (P </= 0.001). Conclusion: Gemcitabine/cisplatin with amifostine is tolerated in the adjuvant setting for patients with locally advanced bladder cancer. The favorable prognostic value of altered p16 and pRB raises the hypothesis of a relative beneficial effect of chemotherapy in this population but needs verification in other studies.

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Expert Rev Anticancer Ther. 2006 Sep;6(9):1301-11.
Recent improvements in the detection and treatment of nonmuscle-invasive bladder cancer.
Kausch I, Doehn C, Jocham D.
Department of Urology, University of Lubeck Medical School, Ratzeburger Allee 160, 23538 Lubeck, Germany. ingo.kausch@uk-sh.de

In total, 70-80% of newly diagnosed bladder cancers are confined to the mucosa and staged as Ta, T1 or carcinoma in situ according to the 2002 tumor, lymph nodes and metastasis classification. The standard treatment for these nonmuscle-invasive bladder cancers is transurethral tumor resection with or without adjuvant intravesical chemotherapy or intravesical immunotherapy and subsequent follow-up. Diagnosis and follow-up of nonmuscle-invasive bladder cancer offers two main problems. First, approximately 10-20% of all tumors are not seen in standard cystoscopy. Additionally, frequently repeated follow-up cystoscopies are bothersome for the patient. As an adjunct to standard cystoscopy, fluorescence-guided cystoscopy has demonstrated significantly higher tumor detection rates and optimized patient treatment in recent Phase III studies. Second, routinely performed urine cytology is characterized by high specificity but low sensitivity. Today, several urine tests are available that may increase diagnostic accuracy and potentially prolong intervals of follow-up cystocopy. Owing to rather high recurrence rates after transurethral tumor resection in most tumors and high progression rates in poorly differentiated tumors, adjuvant intravesical chemotherapy or intravesical immunotherapy has gained widespread use in patients with nonmuscle-invasive bladder cancer. Only a few further immunomodulatory drugs, such as recombinant cytokines, have shown significant clinical effectiveness. Additional approaches, such as photodynamic therapy with different photosensitizers and thermotherapy in combination with intravesical chemotherapy, have been evaluated in Phase III studies.

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Urology. 2006 Sep;68(3):543-8. Epub 2006 Sep 18.
Removal of more lymph nodes may provide better outcome, as well as more accurate pathologic findings, in patients with bladder cancer--analysis of role of pelvic lymph node dissection.
Honma I, Masumori N, Sato E, Maeda T, Hirobe M, Kitamura H, Takahashi A, Itoh N, Tamakawa M, Tsukamoto T.
Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan.

OBJECTIVES: To examine the role of pelvic lymph node dissection (PLND) in patients who underwent radical cystectomy for bladder cancer. The diagnostic and therapeutic role of PLND is still controversial in bladder cancer. The extent of PLND and the necessary number of lymph nodes to remove have not been defined. METHODS: This retrospective review included 146 patients with refractory superficial and muscle-invasive disease treated with radical cystectomy, regional PLND (internal iliac, external iliac, and obturator nodes) and urinary diversion from January 1990 to December 2002. RESULTS: Lymph node metastases were detected in 25 patients (17.1%). The average number of nodes removed in the node-positive and node-negative patients was 13.9 and 14.2, respectively. Although no difference was found in disease-specific survival in the node-negative patients when stratified by the number of nodes removed (13 or more versus less than 13), a significant survival advantage was found in the node-positive patients with 13 or more nodes removed versus less than 13 nodes removed. The patients with four or more positive nodes had a worse outcome than those with less than four positive nodes. However, even if the patients had less than four positive nodes, the survival of patients with less than 13 nodes removed was as poor as that of the patients with four or more positive nodes. CONCLUSIONS: In this series, the removal of 13 or more pelvic lymph nodes was essential for more accurate pathologic examination to predict patient outcome and contributed to an increased chance of survival.

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Nat Clin Pract Urol. 2006 Sep;3(9):485-94.
The prognostic and staging value of lymph node dissection in the treatment of invasive bladder cancer.
Sanderson KM, Skinner D, Stein JP.
Department of Urology, at the University of Southern California, Keck School of Medicine, Los Angeles, CA 90089, USA. sanderson.km@gmail.com

Regional lymph node dissection (LND) at the time of radical cystectomy is an essential component of the surgical management of invasive bladder cancer and might provide diagnostic and therapeutic benefits for both node-negative and node-positive patients. The benefits obtained in pathologically node-negative patients might result from more complete resection of undetected micrometastases or from a more meticulous surgical technique. Advanced nodal disease also seems to be amenable to thorough surgical resection in a subpopulation of patients with bladder cancer. Despite the growing body of evidence to support the role of a more extended LND, no guidelines regarding the optimal boundaries of LND have been established. An increased number of resected nodes and wider LND boundaries have been associated with improved local disease control and prolonged survival. Additionally, mapping series indicate that the common iliac and presacral nodal regions are more frequently involved with tumor metastases than previously recognized. Efforts to limit any unnecessary dissection in patients at low risk for metastases--a tailored approach--has been proposed, but remains unproven. From the available evidence, the most reliable diagnostic and therapeutic approach to LND includes the routine extended LND in all patients undergoing cystectomy with curative intent.

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J Urol. 2006 Aug;176(2):500-4.
Randomized prospective phase III trial of difluoromethylornithine vs placebo in preventing recurrence of completely resected low risk superficial bladder cancer.
Messing E, Kim KM, Sharkey F, Schultz M, Parnes H, Kim D, Saltzstein D, Wilding G.
University of Rochester, Rochester, New York 14642, USA. edward_messing@urmc.rochester.edu

PURPOSE: Ornithine decarboxylase catalyzes the rate limiting step in polyamine synthesis and its activity can be inhibited by difluoromethylornithine, which has been shown in preclinical studies, to prevent bladder cancer. MATERIALS AND METHODS: To assess the ability of difluoromethylornithine to prevent recurrence of low risk superficial bladder cancer, 454 patients with newly diagnosed (283) or occasionally recurrent (171), stage Ta (425) or T1 (29), grade 1 (263) or grade 2 (191), completely resected urothelial cancer were randomized to receive 1 gm difluoromethylornithine daily or placebo for 1 year. Patients were followed with cystoscopy every 3 months for 2 years and then semiannually for 2 years or until first recurrence. Index and recurrent tumors underwent central pathology review. RESULTS: No serious drug related toxicities were seen in either arm. Two patients died of bladder cancer at 2 and 4 years after randomization, both in the difluoromethylornithine arm. At 42 months followup, 103 patients in the difluoromethylornithine arm (46%) and 97 in the placebo arm (43%) (p = 0.30) experienced at least 1 tumor recurrence. Over 73% of recurrences occurred within 1 year in each arm. Each arm had similar responses for each stratification factor. During the 42 months of followup, 10 (4.4%) difluoromethylornithine and 9 (3.9%) placebo treated patients had progression to TIS or grade 3 disease, and 2 (0.9%) in the difluoromethylornithine arm and none in the placebo arm developed stage T2+ cancers. CONCLUSIONS: A year of difluoromethylornithine did not prevent recurrence of completely resected low risk superficial bladder cancer, when started shortly after surgery.

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Urol Oncol. 2006 Jul-Aug;24(4):349-55.
Lymphadenectomy in bladder cancer: How high is "high enough"?
Stein JP.
Department of Urology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.

PURPOSE: The role of a regional lymphadenectomy in the surgical treatment of high-grade, invasive transitional cell carcinoma of the bladder has evolved over the last several decades. Although the application of a lymphadenectomy for bladder cancer is not significantly debated, the absolute extent or level of proximal dissection of the lymphadenectomy remains a controversial issue. MATERIAL AND METHODS: A review of the literature should help elucidate the rationale and extent of an appropriate lymphadenectomy in patients undergoing radical cystectomy for bladder cancer. Various surgical issues of lymphadenectomy as well as prognostic factors in patients undergoing radical cystectomy for bladder cancer are examined. RESULTS: A growing body of evidence, spanning from early autopsy and cadaveric studies to recent retrospective series and multicenter prospective trials, suggests that an extended lymph node dissection (cephalad extent to include the common iliac arteries) may provide not only prognostic information but also provide a therapeutic benefit for both patients with lymph node-positive and lymph node-negative disease undergoing radical cystectomy for bladder cancer. Although the absolute boundaries of the lymphadenectomy remain a subject of controversy, historical reports confirmed by recent lymphatic mapping studies suggest the inclusion of the common iliac as well as possibly presacral nodes in the routine lymphadenectomy for transitional cell carcinoma of the bladder. The need to extend the dissection higher to include the distal para-aortic and paracaval lymph nodes may be important in select individuals but remains more controversial. The extent of the primary bladder tumor (p-stage), number of lymph nodes removed, the lymph node tumor burden (tumor volume), and lymph node density (number of lymph nodes involved/number of lymph nodes removed) are all important prognostic variables in patients undergoing cystectomy with pathologic evidence of lymph node metastases. Systemic adjuvant chemotherapy remains a mainstay of treatment of patients with lymph node metastases. CONCLUSIONS: Radical cystectomy with an appropriately performed lymphadenectomy provides the best survival outcomes and lowest local recurrence rates. Although the absolute limits of the lymph node dissection remain to be determined, evidence supports a more extended lymphadenectomy to include the common iliac vessels and presacral lymph nodes at cystectomy in patients who are appropriate surgical candidates. When feasible, adjuvant chemotherapy is warranted in patients with positive nodal metastasis.

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Cancer Chemother Pharmacol. 2006 Jul 4; [Epub ahead of print]
A phase I study of the safety and pharmacokinetics of edotecarin (J-107088), a novel topoisomerase I inhibitor, in patients with advanced solid tumors.
Hurwitz HI, Cohen RB, McGovren JP, Hirawat S, Petros WP, Natsumeda Y, Yoshinari T.
Division of Hematology and Oncology, Duke University Medical Center, P.O. Box 3052, Durham, NC, 27710, USA, hurwi004@mc.duke.edu.

PURPOSE : To assess the maximum tolerated dose, safety, and pharmacokinetic (PK) profile of escalating doses of the novel topoisomerase I (topo I) inhibitor edotecarin (J-107088) given as a 2-h intravenous (IV) infusion once every 21 days in patients with advanced solid tumors who had not responded to standard therapy. PATIENTS AND METHODS : Twenty-nine patients (18M:11F) received a 2-h IV infusion of edotecarin in doses of 6, 8, 11, 13, or 15 mg/m(2) every 21 days (with an additional 1-2 weeks permitted for recovery) and were evaluated for safety, PK, and tumor response. RESULTS : The most common non-hematologic toxicities were grade 1-2 nausea, fatigue, anorexia, vomiting, and fever. The most common hematologic toxicities were grade 1-2 thrombocytopenia and grade 3-4 neutropenia, leukopenia, and anemia. No grade 3-4 diarrhea was reported. Dose-limiting toxicities were observed in four patients at the 15 mg/m(2) dose and one patient at the 13 mg/m(2) dose. These toxicities included grade 3 nausea, vomiting, headache, and fatigue, as well as grade 4 neutropenia and febrile neutropenia. The maximum tolerated dose was declared at 15 mg/m(2). One patient with bladder cancer had a confirmed partial response at a dose of 13 mg/m(2). There was a trend to dose-proportional increases in edotecarin peak plasma concentrations and area under the curve values. Renal excretion of edotecarin was minimal (3-8% of the dose). CONCLUSION : The recommended Phase II dose of edotecarin is 13 mg/m(2) once every 21 days. The toxicities in this study were those typical of cytotoxic chemotherapy and less severe than those associated with other topo I inhibitors. The observed safety profile and preliminary evidence of clinical benefit warrant further investigation of this drug as monotherapy or part of combination therapy in patients with solid tumors.

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J Clin Oncol. 2006 Jul 1;24(19):3075-80.
Phase I trial of intravesical docetaxel in the management of superficial bladder cancer refractory to standard intravesical therapy.
McKiernan JM, Masson P, Murphy AM, Goetzl M, Olsson CA, Petrylak DP, Desai M, Benson MC.
Columbia University Medical Center, 161 Fort Washington Ave, 11th Floor, Department of Urology, New York, NY 10032, USA.

PURPOSE: Up to 50% of patients treated with intravesical agents for superficial bladder cancer will experience recurrence. Response rates to second-line intravesical therapies range from 20% to 40%. For these high-risk patients, novel agents are necessary to prevent recurrence. Docetaxel is a microtubule depolymerization inhibitor with unique physiochemical properties, making it an excellent candidate for investigation as an intravesical agent. PATIENTS AND METHODS: This phase I trial included patients with recurrent Ta, T1, and Tis transitional cell carcinoma who experienced treatment failure with at least one prior intravesical treatment. Docetaxel was administered as six weekly instillations at a starting dose of 5 mg, with a dose-escalation model used until a maximum tolerated dose (MTD) was achieved. Primary end points were dose-limiting toxicity (DLT) and MTD. Efficacy was evaluated by cystoscopy with biopsy, cytology, and computed tomography imaging. RESULTS: Eighteen patients (100%) completed the trial, and the distribution of stages included six patients with Tis, seven with Ta, and five with T1 disease. No grade 3 or 4 DLTs occurred in 108 infusions, and no patient had systemic absorption of docetaxel. Eight (44%) of 18 patients experienced grade 1 or 2 toxicities, with dysuria being the most common. Ten (56%) of 18 patients had no evidence of disease at their post-treatment cystoscopy and biopsy. None of the patients who experienced relapse had disease progression. CONCLUSION: Intravesical docetaxel exhibited minimal toxicity and no systemic absorption in the first human intravesical clinical trial. This suggests that docetaxel is a safe agent for further evaluation of efficacy in a phase II trial.

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Hinyokika Kiyo. 2006 Jun;52(6):445-9.
[Intra-arterial chemotherapy for invasive bladder cancer (T2-3N0M0)]
[Article in Japanese]
Maruyama T, Kondoh N, Nojima M, Yamamoto S, Mori Y, Shima H, Kamikonnya N, Hirota S, Nakao N.
The Department of Urology, Hyogo College of Medicine.

We assessed the effectiveness of intra-arterial MVAC chemotherapy or a combination of intra-arterial chemotherapy and external beam radiotherapy based on diagnostic images and histological (transurethral) examination in 15 cases with T2-3NOM0 between January 2003 and September 2005. When the clinical response was assessed one month after the treatments, a complete response (CR) was achieved in 20% (1/5) and 50% (5/10) by intra-arterial MVAC chemotherapy and a combination of intra-arterial chemotherapy and external beam radiotherapy, respectively. Total radical cystectomy was required on one patient during the follow-up period of 4-26 months. Although our result showed that the combination of external beam radiation therapy and intraarterial cisplatin effectively contributed to the preservation of the bladder with localized invasive bladder cancer, radical cystectomy is required when CR is not achieved after this treatment.

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Eur Urol. 2006 Jun 13; [Epub ahead of print]
Delay in the Surgical Treatment of Bladder Cancer and Survival: Systematic Review of the Literature.
Fahmy NM, Mahmud S, Aprikian AG.
Department of Surgery (Urology), McGill University, Montreal, Quebec, Canada.

OBJECTIVES: Eighty per cent of the newly diagnosed invasive bladder tumours are invasive from the outset. Half of these patients already have occult distant metastases reflecting the rapid nature of progression. The aim of the current study was to review the literature to determine if delay in cystectomy leads to worse prognosis and to determine if a possible cutoff point for delay exists, after which a worse outcome would be expected. METHODS: We performed a systematic review of publications indexed in Medline and other scientific databases by analyzing types and causes of delay in performing radical cystectomy. Information on the impact of such delays on tumour recurrence and survival was collected and summarized. Papers that described only delay without any outcome correlation were excluded from the study. RESULTS: A total of 13 papers published from 1965 to 2006 were included in this study. Three (23%) papers did not find any correlation between pretreatment delays and survival. Two (15%) papers reported a trend towards worse survival with delay. Eight (62%) papers documented significant association between delay and worse prognosis. Delay influenced survival as an independent variable in two (25%) of these eight papers. In the remaining six (75%) manuscripts, delay was significantly associated with a higher pathologic stage. CONCLUSIONS: Although studies on bladder cancer failed to show a linear relationship between delay and prognosis, the majority confirmed that delays are associated with worse outcome. Studies suggested a window of opportunity of less than 12 weeks from diagnosis of invasive disease to radical cystectomy.

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Eur Urol. 2006 Jun 14; [Epub ahead of print]
Laparoscopic Cystectomy with Extracorporeal-Assisted Urinary Diversion: Experience with 34 Patients.
Gerullis H, Kuemmel C, Popken G.
Department of Urology, HELIOS-Hospital, Berlin Buch, Berlin, Germany.

OBJECTIVES: Open radical cystectomy remains the gold standard for nonmetastatic muscle invasive bladder cancer. Laparoscopic cystectomy has been described as a feasible procedure and is still being evaluated. We describe our initial experience with this laparoscopic surgical approach in 34 patients. METHODS: From February 2002 to October 2004, 18 men and 16 women underwent laparoscopic cystectomy with extracorporeal-assisted urinary diversion for transitional cell carcinoma of the bladder (n=27), invasive cervical carcinoma (n=4), and atrophic bladder (n=3). We report here on specific technical details and present initial results of our series. RESULTS: The mean operating time was 244min, the mean blood loss 325ml, and the transfusion rate 5.9%. All procedures were completed laparascopically without conversion to open techniques. No major complications occurred during or after the operation. In case of urothelial malignancy (n=27), the histopathologic analysis of the removed specimen revealed organ-confined transitional cell carcinoma of the bladder in 66.7% (pT1:14.8%; pT2: 51.9%) and locally advanced disease in 33.3% (pT3: 25.9%; pT4: 7.4%). In two cases final histology proved positive surgical margins. Extended lymphadenectomy detected lymph node metastasis in two patients. CONCLUSIONS: We demonstrate that the combination of laparoscopic cystectomy and extracorporeal urinary diversion is possible and remains a safe, feasible, and repeatable surgical technique. To determine the oncologic outcome long-time follow-up will be necessary.

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J Urol. 2006 Apr;175(4):1262-7.
Cystectomy delay more than 3 months from initial bladder cancer diagnosis results in decreased disease specific and overall survival.
Lee CT, Madii R, Daignault S, Dunn RL, Zhang Y, Montie JE, Wood DP Jr.
Michigan Urology Center, University of Michigan, Ann Arbor, Michigan.

PURPOSE: Some groups hypothesize that a delay in cystectomy may result in higher pathological stage and possibly alter survival in patients with bladder cancer. The timing of this delay has been somewhat arbitrary. We evaluated the timing from T2 bladder cancer diagnosis to cystectomy, its impact on survival and potential causes of delay. MATERIALS AND METHODS: A contemporary cohort of 214 consecutive patients presented with clinical T2 bladder cancer and underwent radical cystectomy as primary therapy. Clinicopathological parameters were maintained in an institutional database. A review of time to cystectomy, pathological stage, disease specific survival and OS was performed. Variables were tested in univariate and multivariate analyses. The log rank test was used for exploratory analyses to determine meaningful delay cutoff points. RESULTS: Mean followup and time to cystectomy in the entire cohort was 40 months and 60 days, respectively. A significant disease specific survival and OS advantage was observed in patients undergoing cystectomy by 93 days or less (3.1 months) compared to greater than 93 days (p = 0.05 and 0.02, respectively). Pathological staging was similar between the groups (p = 0.15). A multivariate benefit in OS was observed in patients treated with timely cystectomy. The most common factor contributing to cystectomy delay was scheduling delay, as seen in 46% of cases. CONCLUSIONS: A cystectomy delay of 3.1 months undermines patient survival, likely through the development of micrometastases, since local stage progression is not apparent at this point. Most delays are avoidable and should be minimized. Despite the need for second opinions and the impact of busy surgical schedules clinicians must strive to schedule patients efficiently and complete surgical treatment within this time frame.

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World J Urol. 2006 Mar 4; [Epub ahead of print]
Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure.
Stein JP, Skinner DG.
Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, MS#74, 1441 Eastlake Avenue, Suite 7416, Los Angeles, CA, 90098, USA, stein@usc.edu.

Radical cystectomy with an appropriate lymphadenectomy remains the standard of therapy for high-grade invasive bladder cancer. This surgical approach provides the best survival rates with the lowest local recurrence rates and orthotopic diversion can be performed safely in most patients with an acceptable outcome and quality of life. Pathologic analysis of the bladder tumor and regional lymph nodes will help direct the need for adjuvant therapy in high-risk individuals. Equivalent long-term local control and survival are not seen with other forms of treatment including radiation therapy, chemotherapy, or a combination of the two. The rationale and clinical results of large, contemporary cystectomy series are presented, which provide a benchmark of outcomes with this form of surgical treatment.

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J Urol. 2006 Mar;175(3 Pt 1):886-9; discussion 889-90.
A critical analysis of perioperative mortality from radical cystectomy.
Quek ML, Stein JP, Daneshmand S, Miranda G, Thangathurai D, Roffey P, Skinner EC, Lieskovsky G, Skinner DG.
Keck School of Medicine at the University of Southern California, USC/Norris Comprehensive Cancer Center, Los Angeles, California, USA. mquek@lumc.edu

PURPOSE: Operative mortality from radical cystectomy has decreased as a result of improvements in surgical and anesthetic care. We reviewed the perioperative deaths from a large group of patients treated with radical cystectomy for primary bladder cancer. MATERIALS AND METHODS: All perioperative mortalities from radical cystectomy were identified from a single high volume institution. The medical records were reviewed to assess the cause of death as well as possible contributing factors. RESULTS: From August 1971 to December 2001, 1,359 patients with primary bladder cancer were treated with radical cystectomy and pelvic iliac lymphadenectomy at our institution. Of these patients, 27 (2%) died within 30 days of surgery or before discharge from hospital. Median patient age at surgery was 67 years (range 47 to 78) and males accounted for 81% of the patients. The median time to death was 28 days from cystectomy (range 0 to 80). Most deaths were cardiovascular related (including acute myocardial infarction, cerebrovascular accident, arterial thrombosis) or due to septic complications with resulting multi-organ system failure, followed by pulmonary embolism, hepatic failure and hemorrhage. Septic related mortality was most often associated with postoperative urine or bowel leak. While most deaths occurred before hospital discharge, 2 patients died at home due to a late pulmonary embolus. No association was seen between pathological stage or type of urinary diversion and mortality. CONCLUSIONS: Perioperative mortality from radical cystectomy is low in this group of patients. Most deaths are due to cardiovascular or septic complications. Careful patient selection and meticulous surgical technique may help decrease the incidence of perioperative mortality.

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Can J Urol. 2006 Feb;13 Suppl 1:81-7.
Prostate sparing radical cystectomy- not for all, but an option for some.
Pinthus JH, Nam RK, Klotz LH.
Department of Surgery, Division of Urology, McMaster University, Hamilton, Ontario, Canada.

OBJECTIVES: Prostate sparing radical cystectomy (PSRC) is a controversial surgical approach for the treatment of male bladder cancer. The objective of this review is to address some of the concerns related to the potential compromise of oncological outcome compared to radical cystoprostatectomy (RCP)-the gold standard procedure. METHODS: Review of series published in the English literature. Only studies that address PSRC for transitional cell carcinoma of the bladder were included. RESULTS: There are only a limited number of studies addressing this approach. All are retrospective, non-comparative and not uniform in terms of patient selection and technique. Long-term follow-up is lacking. The incidence of synchronous and or metachronous prostate cancer and TCC of the prostatic urethra is lower than that found in RCP due to pre-operative screening. The local recurrence rate is 5%- comparable with RCP. Stage for stage, recurrence free and overall survival are compatible. CONCLUSIONS: The experience with PSRC is too limited to allow firm conclusions as to whether the outcome with respect to disease free and disease specific survival is comparable to that achieved by RCP. However, with proper patient screening and selection the short-term results appear promising.

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Can J Urol. 2006 Feb;13 Suppl 1:77-80.
Perioperative chemotherapy for localized bladder cancer.
Winquist E.
University of Western Ontario and London Health Sciences Centre, London, Ontario, Canada.

INTRODUCTION: Survival benefits have been recently reported in meta-analyses of randomized clinical trials (RCTs) studying perioperative chemotherapy for muscle-invasive urothelial cancer. Controversy and lack of awareness of these data have diminished their impact on daily practice, and they deserve further scrutiny. MATERIALS AND METHODS: Recently published meta-analyses of RCTs studying perioperative chemotherapy for bladder cancer were narratively reviewed, along with two reports from the most recently reported RCT of neoadjuvant chemotherapy for bladder cancer. RESULTS: Two recently published individual patient data meta-analyses report that cisplatin-based combination neoadjuvant chemotherapy is associated with an absolute survival benefit of 5% at 5 years, and adjuvant chemotherapy with an absolute survival benefit of 9% at 3 years. However, the value of the adjuvant meta-analysis is limited by the available data. Positive surgical margins and fewer than 10 lymph nodes removed are associated with poorer prognosis. Pathological complete response is associated with better survival. CONCLUSIONS: Patients diagnosed with muscle-invasive urothelial cancer may benefit from perioperative chemotherapy and should be routinely referred to a medical oncologist. Surgical factors potentially have a greater impact on survival than the use of perioperative chemotherapy. RCTs studying all stages of localized muscle-invasive bladder cancer are currently enrolling patients in Canada and are a high priority.

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Ann Oncol. 2006 Feb 23; [Epub ahead of print]
Neo-adjuvant chemotherapy for muscle-invasive bladder cancer: a look ahead.
Sawhney R, Bourgeois D, Chaudhary UB.
Department of Medicine, Division of Hematology/Oncology, South Carolina, USA.

Randomized clinical trials of neo-adjuvant cisplatin-based combination chemotherapy for locally advanced muscle invasive bladder cancer has shown a survival benefit over cystectomy alone. Pathologic complete response (pT0) after neo-adjuvant chemotherapy is emerging as a potentially important surrogate clinical end point. Future clinical trials incorporating targeted therapies with novel clinical end points may accelerate development of therapeutic strategies for locally advanced muscle invasive bladder cancer. Furthermore, evaluation of molecular markers may further help to stratify patients to a risk adapted approach.

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Clin Oncol (R Coll Radiol). 2006 Feb;18(1):52-9.
Radical radiotherapy for bladder cancer: retrospective analysis of a series of 459 patients treated in an Italian institution.
Tonoli S, Bertoni F, De Stefani A, Vitali E, De Tomasi D, Caraffini B, Scheda A, Bertocchi M, Somensari A, Buglione M, Magrini SM.
Radiation Oncology Department, Brescia University and Istituto del Radio 'O.Alberti', Spedali Civili, Brescia, Italy.

AIMS: To contribute to the available evidence about the efficacy of exclusive radiotherapy for bladder cancer through a retrospective analysis of a large series of patients consecutively treated in a single institution. MATERIALS AND METHODS: A total of 459 patients with UICC categories T1-T4, N0-Nx and M0 bladder cancer consecutively treated with radiotherapy alone with radical intent formed the clinical basis for this study. Many of them (and particularly the T1 cases) had poor medical conditions or were unfit for surgery. About half of the cases (54%) had a T2 tumour, and about 18% had T3-T4 disease. Eighty per cent of the cases received minimal doses in the target volume in the range 60-70 Gy; pelvic lymph nodes were treated in 34%. Simple radiotherapy techniques were used in most cases. Average follow-up for living patients was 4.4 years. Results were analysed according to number and type of relapses: overall survival, disease-specific survival, failure-free survival probability, acute and late toxicity (RTOG scale). RESULTS: Actuarial 5-year overall survival, disease-specific survival and failure-free survival rates at 5 years for the entire series were 36%, 56%, 33%, respectively. Age, T category (for all the end points) and tumour dose (only for failure-free survival) were significantly related to prognosis at multivariate survival analysis. Late enteric toxicity (6.1% of the cases) was significantly linked with the treated volumes (univariate analysis). Urinary late toxicity (23% of cases) was linked with age and T category (multivariate analysis). In both cases, toxicity was mostly Grade 1 or 2. CONCLUSIONS: The results of radiotherapy in this negatively selected series, accrued over a long period of time in patients treated with unsophisticated techniques, are reasonably good; they add to the evidence available to support the use of modern bladder-sparing programmes, including the association of chemo- and radiotherapy.

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Nat Clin Pract Urol. 2005 Jan;2(1):32-7.
Adjuvant and neoadjuvant chemotherapy for bladder cancer: management and controversies.
Garcia JA, Dreicer R.
Department of Hematology and Oncology, The Cleveland Clinic Foundation, OH 44195, USA.

Radical cystectomy remains the gold standard treatment for muscle-invasive bladder cancer. Although surgery achieves excellent local control, within 5 years almost 50% of patients relapse and subsequently progress to develop systemic disease. Transitional cell carcinoma of the bladder is sensitive to chemotherapy. Although platinum-based chemotherapy can produce relatively high overall response rates, the impact on the survival of patients with advanced disease has, at best, been limited. Randomized trials of cisplatin-based chemotherapy regimens in the neoadjuvant setting have demonstrated the potential to improve survival. By comparison, adjuvant studies have been plagued by suboptimal trial design, limited patient numbers, and lack of standardization of the chemotherapy regimens used. With the introduction of new cytotoxic drugs and novel small molecules, there is a need for well-designed studies to address the optimal utility of perioperative therapy in high-risk patients with bladder cancer.

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Surg Technol Int. 2005;14:222-6.
Endoscopic therapy of superficial bladder cancer in high-risk patients: holmium laser versus transurethral resection.
Muraro GB, Grifoni R, Spazzafumo L.
Centre of Statistic Research on Ageing Department, INRCA, Ancona, Italy.

Many lasers are widely used in urological surgery for several applications. Their use to treat the superficial bladder cancer (SBC) is safe and minimally invasive. The Holmium:YAG (Ho:YAG) laser represents the pinnacle of laser technology in Urology. The authors carried out this study on safety, efficacy, complication rates, postoperative catheterization time, and hospital stay of high-risk patients who underwent Ho:YAG vs. transurethral resection (TUR). Two groups of high-risk patients with SBC and comorbidities underwent either Ho:YAG or TUR. Different clinical aspects of the tumours and recurrences were considered. No significant difference between the two groups was noted regarding number, progression of grade and stage and place and time of recurrences. In the Ho:YAG patients, perioperative complications occurred at a lower percent than in the TUR group. Also, in 54% of patients, the catheter was removed within 24 hours; 76% had a postoperative hospital stay of 24 to 48 hours. In the TUR patients: 4% had the catheter removed within 24 hours and 6% left the hospital within 24 to 48 hours. In SBC treatment, Ho:YAG and TUR were equally as effective; the Ho:YAG laser was associated with shorter catheterization time and hospital stay. These Ho:YAG features could be advantageous from a psychological standpoint, particularly for elderly, high-risk patients and in terms of cost:benefit ratios.

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BJU Int. 2005 Dec;96(9):1286-9.
Is adjuvant chemotherapy for bladder cancer safer in patients with an ileal conduit than a neobladder?
Manoharan M, Reyes MA, Kava BR, Singal R, Kim SS, Soloway MS.
Department of Urology, University of Miami School of Medicine, Miami, FL, USA.

OBJECTIVE To assess the safety of adjuvant chemotherapy in patients with neobladder reconstruction in comparison to ileal conduit, as radical cystectomy and urinary diversion is an effective curative surgical treatment for muscle-invasive and high-risk superficial bladder cancer, and adjuvant chemotherapy is usually considered for patients with clinical stage > T2 and nodal metastasis. PATIENTS AND METHODS We analysed retrospectively patients who had had a radical cystectomy and urinary diversion between 1992 and 2004. Patients with high-risk disease who had adjuvant chemotherapy were identified and stratified based on the type of urinary diversion (ileal conduit or neobladder). The chemotherapy regimen, complications from the adjuvant chemotherapy and other relevant data were analysed. RESULTS Overall, 343 patients had radical cystectomy, 40 had adjuvant chemotherapy; 25 had an ileal conduit and 15 had a neobladder. Patient characteristics including age, stage and follow-up were similar. In all, 55% of patients had grade 1 toxicity, 23% grade 2, 18% grade 3, and 13% grade 4. No patients had serious organ toxicity and none died. There were no significant differences in the toxicity among the two groups. CONCLUSIONS Adjuvant chemotherapy appears to be safe in patients with a neobladder and equally safe in patients with an ileal conduit. Hence neobladder reconstruction should not be denied to patients with bladder cancer who are at high risk of recurrence and who might require adjuvant chemotherapy.

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J Urol. 2005 Dec;174(6):2134-7.
Restaging transurethral resection of high risk superficial bladder cancer improves the initial response to bacillus Calmette-Guerin therapy.
Herr HW.
Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. herrh@mskcc.org

PURPOSE: This study was an evaluation of whether restaging transurethral resection (TUR) of superficial bladder cancer improves the early response to bacillus Calmette-Guerin (BCG) therapy. MATERIALS AND METHODS: A total of 347 patients with high risk superficial bladder cancer (high grade Ta and T1 tumors associated with carcinoma in situ) underwent a single transurethral resection (TUR, 132 patients) or restaging TUR (215 patients) before receiving 6 weekly intravesical BCG treatments. The patients were evaluated for response (presence or absence of tumor) at first followup cystoscopy, at 6 and 12 months after treatment, and evaluated for disease stage progression within 3 years of followup. RESULTS: Of the 132 patients who underwent a single TUR before BCG therapy, 75 (57%) had residual or recurrent tumor at the first cystoscopy and 45 (34%) later had progression, compared with 62 of 215 patients (29%) who had residual or recurrent tumors and 16 (7%) who had progression after undergoing restaging TUR (p = 0.001). CONCLUSIONS: Restaging TUR of high risk superficial bladder cancer improves the initial response rate to BCG therapy, reduces the frequency of subsequent tumor recurrence and appears to delay early tumor progression.

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Oncology. 2005 Nov 24;69(5):391-398 [Epub ahead of print]
Phase II Study of Gemcitabine and Cisplatin in Patients with Advanced or Metastatic Bladder Cancer: Long-Term Follow-Up of a 3-Week Regimen.
Adamo V, Magno C, Spitaleri G, Garipoli C, Maisano C, Alafaci E, Adamo B, Rossello R, Scandurra G, Scimone A.
Department of Human Pathology, Medical Oncology and Integrated Therapies Unit, A.O. Universitaria Policlinico 'G. Martino', Messina, Italy.

Background: Bladder cancer is the fifth most common cancer among men and the seventh among women. At diagnosis, at least 25% of bladder cancer tumors are locally or systemically advanced. Systemic chemotherapy is the only current modality for advanced or metastatic transitional cell carcinoma of the bladder. Recently, a phase III randomized study has demonstrated that the regimen with gemcitabine (GMC) and cisplatin (CDDP) had a survival advantage similar to the standard M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin), with a better safety profile. Aim: It was the aim of this study to evaluate the tumor response rate, the median time to progression, the median survival and toxicity in a 21-day schedule with GMC and CDDP in patients with advanced/metastatic bladder cancer. Patients and Methods: From September 1998 to December 2000, 27 patients with advanced/metastatic transitional cell carcinoma were enrolled. All patients received 1,200 mg/m(2) GMC administered as a 30-min intravenous infusion on days 1 and 8, and 75 mg/m(2) CDDP as a 1-hour infusion on day 2. Cycles were repeated every 21 days. The patients had a median age of 59.8 years (range 39-75) and an Eastern Cooperative Oncology Group performance status of 0-2. Results: Twenty-five patients were valuable for toxic effects, length of survival and tumor response. The statistical analysis was performed in May 2004. Mean and median follow-up were 20.23 and 13.2 months (range 2-68), respectively. The overall remission rate (complete response + partial response) was 48% (95% CI 28.4-67.6%). The median time to progression was 9 months (range 2-56). The median duration of survival for all patients was 13.2 months (range 2-68+), with 1-year and 23-month survival rates of 60 and 20%, respectively. There was no grade 4 toxicity or treatment-related death. Grade 3 anemia was observed in 4 patients (16%) and grade 3 thrombocytopenia occurred in 6 patients (24%). No grade 3-4 nausea/vomiting or neutropenia was observed. Conclusion: GMC and CDDP is an active schedule with a good safety profile in a 21-day regimen. It may be a valid alternative to the standard 28-day regimen due to its high tumor response and survival with a low incidence of toxicity, especially in pretreated and metastatic patients. Copyright (c) 2005 S. Karger AG, Basel.

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Zhonghua Wai Ke Za Zhi. 2005 Nov;43(22):1457-60.
[Clinical investigation on the effect of intravesical instillation of antifibrinolytic agents with bacillus Calmette-Guerin on preventing bladder cancer recurrence.]
[Article in Chinese]
Ding GQ, Shen ZJ, Lu J, Jin XD, Chen J, Shi SF.
Department of Urology, Sir Run Run Shaw Hospital of Medical School, Zhejiang University, Hangzhou 310016, China.

OBJECTIVE: To investigate the effect of intravesical instillation of antifibrinolytic agents with bacillus Calmette-Guerin (BCG) on preventing recurrence of surperficial bladder transitional cell carcinoma (BTCC) after surgical management. METHODS: A total of 326 cases of superficial BTCC undergoing transurethral resection of bladder tumor (TURBT) or partial cystectomy were divided into 5 groups. Then the different dosage BCG with or without antifibrinolytic agents was regular instilled into bladders (once a week, then once a month after 6 times). Group A including 66 cases received intravesical instillation of 100 - 120 mg BCG plus 100 mg para-aminomethyl benzoic acid (PAMBA). Group B including 64 cases: instillation of 50 - 60 mg BCG plus 100 mg PAMBA; Group C including 65 cases: 100 - 120 mg BCG plus 2.0 g epsilon-aminocarproic acid (EACA); Group D including 64 cases: 50 - 60 mg BCG plus 2.0 g EACA; Group E (control group) including 67 cases: 100 - 120 mg BCG. All the cases had been followed up for 4 to 69 months (mean, 28.5 months). Not only was cystoscopy performed every 3 monthes, but also iopsy was carried out to identify recurrence when necessary. Side effect was recorded after instillation. RESULTS: The rate of tumor recurrence of Group A, Group B, Group C and Group D was 12%, 10%, 9%, 9% respectively, which was significantly lower than that of Group E (30%) (chi(2) = 5.699, 6.818, 7.380, 7.867, P = 0.017, 0.009, 0.007, 0.005). And there was no significant difference of tumor recurrence rate between Group A and Group B or between Group C and Group D (Group A and Group C: high dosage BCG plus antifibrinolytic agents, while Group B and Group D: low dosage BCG plus antifibrinolytic agents) (P > 0.05). But the side effects developing in Group B and Group D after BCG instillation were less than those in Group A and Group C. CONCLUSIONS: The efficacy of BCG on prevention the recurrence of surperficial BTCC can be enhanced when combined with antifibrinolytic agents. Even if the dosage of BCG was reduced by half, the efficacy didn't changed. A new approach of low dosage BCG plus antifibrinolytic agents is recommended in the prophylaxis of recurrence of bladder cancer.

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Oncologist. 2005 Nov;10(10):792-8.
The role of taxanes in the management of bladder cancer.
Galsky MD.
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY, NY 10021, USA. Galskym@mskcc.org.

Transitional cell carcinoma of the bladder is a chemo-sensitive neoplasm. Whereas the MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen was long considered the standard of care for patients with advanced disease, the evaluation of newer agents with retained activity and improved tolerability has been the focus of much investigation over the past decade. Among the most important of these newer agents are taxanes. Whereas taxane-containing regimens have not yet been shown to improve the survival of patients with transitional cell carcinoma in randomized trials, ongoing phase III trials will further define the role of these agents in both the perioperative and advanced disease settings.

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Ann Oncol. 2005 Nov 22; [Epub ahead of print]
Systemic chemotherapy in inoperable or metastatic bladder cancer.
Bamias A, Tiliakos I, Karali MD, Dimopoulos MA.
Department of Clinical Therapeutics, Medical School, University of Athens, Greece.

Urothelial cancer is a common malignancy. The management of patients with recurrent disease after cystectomy or initially metastatic or unresectable disease represents a therapeutic challenge. Systemic chemotherapy prolongs survival but long-term survival remains infrequent. During recent years there has been improvement due to the use of novel chemotherapeutic agents, mainly gemcitabine and the taxanes. The long-considered-standard MVAC has been challenged by combinations showing more favourable toxicity profiles and equal (gemcitabine-cisplatin) or even improved (dose-dense, G-CSF-supported MVAC) efficacy. Specific interest has also been generated in specific groups of patients (elderly patients, patients with renal function impairment or comorbidities), who are not fit for the standard cisplatin-based chemotherapy but can derive significant benefit from carboplatin- or taxane-based treatment. Retrospective analyses have enabled the identification of groups of patients with different prognoses, who possibly require different therapeutic approaches. Modern chemotherapy offers a chance of long-term survival in patients without visceral metastases, possibly in combination with definitive local treatment. Finally, the progress of targeted therapies in other neoplasms seems to be reflected in advanced bladder cancer by recent studies indicating that biological agents can be combined with modern chemotherapy. The true role of such therapies is currently being evaluated.

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Urol Nurs. 2005 Oct;25(5):323-6, 331-2.
Bladder cancer: current optimal intravesical treatment.
Lamm DL, McGee WR, Hale K.
BCG Oncology, PC, Phoenix, AZ, USA.

Superficial bladder cancer can be treated surgically, but patients are at high risk for recurrence. Tumors are categorized as low, intermediate, and high-risk based on grade, stage, and pattern of recurrence. Low-risk tumors are best treated with a single instillation of chemotherapy (thiotepa, doxorubicin, or mitomycin) (Lamm, 2002). Though effective, the toxicity of bacillus Calmette-Guerin immunotherapy (BCG) restricts its use to treat higher-grade tumors. Intermediate risk tumors can be treated with chemotherapy as well, but will often require immunotherapy. High-risk tumors are best treated with intravesical BCG using a 3-week maintenance schedule. Side effects of BCG immunotherapy can be decreased by logarithmic reductions in dose. Patients who fail BCG may be rescued with BCG plus interferon alfa or radical cystectomy.

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Clin Oncol (R Coll Radiol). 2005 Oct;17(7):524-38.
Novel therapies in bladder cancer.
Alonzi R, Hoskin P.
Mount Vernon Hospital, Northwood, Middlesex, UK.

The most effective non-surgical treatment for bladder cancer remains radiotherapy. The dramatic technical developments in radiotherapy have enabled greater accuracy and reliability based on three-dimensional imaging for both planning and verification. Particle therapy, in particular using protons, provides further opportunities for optimising radiation delivery and dose escalation. Novel fractionation schedules with both hyperfractionation and hypofractionation may have added benefits. Chemoradiation has been shown in one randomised-controlled trial to improve the results of radiotherapy alone, and requires further investigation. Hypoxia modification using carbogen and nicotinamide has also shown promising results in a phase II trial, and is now in phase III evaluation. Novel drug agents for bladder cancer are few, but the anti-EGFR agents and anti-angiogenic agents may have promise; the development of anti-apoptotic agents and antisense gene therapy may also become a component of the future multimodality management of this tumour.

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Clin Oncol (R Coll Radiol). 2005 Oct;17(7):514-23.
Chemotherapy for metastatic bladder cancer.
Roberts JT.
Northern Centre for Cancer Treatment, Newcastle General Hospital, Newcastle upon Tyne, UK. trevor.roberts@nuth.nhs.uk

This paper reviews the current status of systemic chemotherapy in the management of advanced and metastatic urothelial cancer. The activity of a number of single agents and combination drug regimens is discussed, and the small number of randomised-controlled studies available is also considered. Prognostic factors for response and survival, particularly long-term survival after systemic chemotherapy, are also reviewed. Special consideration is given to the role of systemic chemotherapy as a precursor to surgery (or radiotherapy) in locally advanced disease that is initially considered incurable. Therapeutic options for patients unable to tolerate cisplatin owing to renal impairment or other comorbidities are explored. Future directions are explored, including the role of molecular phenotyping in providing prognostic information, indicators of the likely success of conventional therapeutic measures and the development of specific targeted therapies.

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Clin Oncol (R Coll Radiol). 2005 Oct;17(7):503-7.
Neoadjuvant chemotherapy in transitional-cell carcinoma of the bladder.
McLaren DB.
Edinburgh Cancer Centre, Western General Hospital, Edinburgh, Scotland, UK. duncan.mclaren@luht.scot.nhs.uk

Neoadjuvant chemotherapy in transitional-cell carcinoma of the bladder (TCC) improves survival. This is one of the most important developments in the management of muscle-invasive bladder cancer in recent times. There is an improved absolute 5-year survival of at least 5% for T2-T4 disease. To achieve this benefit, a cisplatin-containing combination is required. There is no difference in survival whether radical radiotherapy or radical cystectomy is given as subsequent definitive treatment.

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Urology. 2005 Oct;66(4):726-31.
Intravesical gemcitabine therapy for superficial transitional cell carcinoma: results of a Phase II prospective multicenter study.
Bartoletti R, Cai T, Gacci M, Giubilei G, Viggiani F, Santelli G, Repetti F, Nerozzi S, Ghezzi P, Sisani M; TUR (Toscana Urologia) Group.
Department of Urology, University of Florence, Florence, Italy. bartoletti@unifi.it

OBJECTIVES: To determine the tolerability and efficacy after 1 year of weekly intravesical gemcitabine therapy in patients with intermediate-risk and high-risk superficial transitional cell carcinoma. METHODS: A total of 116 patients with intermediate-risk and high-risk bladder cancer who had undergone transurethral resection were treated with one cycle (once a week for 6 weeks) of gemcitabine 2000 mg. Local and systemic tolerability and efficacy were evaluated. RESULTS: In terms of the tolerability of gemcitabine, 14 patients (12.0%) reported urgency, 6 (5.1%) dizziness and slight fever (less than 38 degrees C), 1 (0.8%) severe abdominal pain, with ulcerative lesions of the bladder mucosa at cystoscopy, and 1 (0.8%) parosmia. The remaining 94 patients (81.3%) did not report any local side effects during the treatment period. In terms of efficacy, recurrence developed in 29 patients (25.4%) a mean of 7 months after transurethral resection; 85 patients (74.6%) were disease free after 12 months. The univariate analysis showed a greater level of efficacy in patients with a first occurrence (P = 0.0408), patients who had had no previous treatment (P = 0.0368), and patients with Stage pTa superficial transitional cell carcinoma (P = 0.0018). The multivariate analysis did not reveal any significant data. No significant differences were found between the intermediate-risk and high-risk patients in tolerability or efficacy. No recurrence developed in 18 (75%) of 24 intermediate-risk bacille Calmette-Guerin-refractory or 7 (43.7%) of 16 high-risk bacille Calmette-Guerin-refractory patients. CONCLUSIONS: The results of our study have confirmed the good tolerability and 1 year efficacy of intravesical gemcitabine. The treatment schedule proposed resulted in high patient compliance, and the results can be compared with the results of studies using other intravesical treatments.

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Urology. 2005 Sep;66(3):531-535.
Bladder cancer with obstructive uremia: Oncologic outcome after definitive surgical management.
El-Tabey NA, Osman Y, Mosbah A, Mohsen T, Abol-Enein H.
Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.

OBJECTIVES: To report the surgical and oncologic outcomes of patients with bladder cancer who present with obstructive uremia. METHODS: A total of 61 patients presented to our institute with obstructive oliguria or anuria concomitant with bladder cancer. The mean serum creatinine at presentation was 11.4 +/- 5.1 mg%. After stabilization of kidney function following nephrostomy drainage, only 38 patients were eligible for radical cystectomy. Analysis of the intraoperative findings, early postoperative course, definitive histopathologic findings, and long-term functional and oncologic outcome was performed. The mean follow-up period was 16.2 +/- 8.1 months (range 8 to 134). RESULTS: Radical cystectomy with bilateral iliac lymphadenectomy was feasible in 26 patients, palliative cystectomy in 10, and ileal conduit only without cystectomy in 2. The postoperative morbidity was minimal and treated conservatively. Bladder cancer causing uremia was invasive in 94.5%, and was pathologic Stage T4 in 30.5% of cases. At the mean follow-up, treatment failure was observed in 26 patients (68.4%), with only 12 patients living free of disease and a mean serum creatinine of 1.4 +/- 0.7 mg%. Although none of the preoperative variables proved to be predictive of the oncologic outcome, significant correlation was found between the tumor stage and grade, as well as lymph node involvement, and treatment failure. CONCLUSIONS: Although bladder cancer causing obstructive uremia is almost always muscle invasive, with a large proportion of patients presenting with locally advanced disease, an adequate number of these patients could achieve long-term disease-free survival.

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World J Surg. 2005 Sep 8; [Epub ahead of print]
Prostatic Capsule- and Nerve-sparing Cystectomy in Organ-confined Bladder Cancer: Preliminary Results.
Martis G, D'Elia G, Diana M, Ombres M, Mastrangeli B.
Department of Urology, S. Camillo Hospital, Viale Kennedy, 02100, Rieti, Italy.

We present a novel radical cystectomy technique that allows bladder cancer control while maintaining urinary continence and reducing the risk of erectile dysfunction by sparing the prostatic capsule and the neurovascular bundles. Between September 1997 and December 2002, 85 men were candidates for cystectomy; 32 were selected for a prostatic capsule- and seminal-sparing cystectomy with orthotopic urinary diversion. All patients had clinical organ-confined bladder cancer (cT1 to cT3a). One patient died of unrelated causes. Of the remaining 31 patients, two with pT4, N+ disease underwent three cycles of adjuvant chemotherapy and are free of disease at 10 and 12 months postoperatively. Twenty-nine patients with organ-confined bladder cancer are free of disease after a mean follow-up of 32 months. At 24 months, 98% of the patients are completely continent during the day and 83% during the nighttime hours. In addition, 80% of the patients are able to complete sexual intercourse without auxiliary measures at a mean of 24 months postoperatively. Prostatic capsule- and nerve-sparing cystectomy permits en bloc removal of the bladder, of the adenomatous prostatic tissue, and of the seminal vesicles, thereby achieving local cancer control and preserving erectile function and urinary continence.

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J Urol. 2005 Sep;174(3):1050-4; discussion 1054.
Quality of care: partial cystectomy for bladder cancer--a case of inappropriate use?
Hollenbeck BK, Taub DA, Dunn RL, Wei JT.
Department of Urology, University of Michigan, Ann Arbor, USA. bhollen@umich.edu

PURPOSE: Partial cystectomy is perceived to be a less morbid, less technically demanding procedure than radical cystectomy, although only select patients (approximately 6% to 10%) are appropriate candidates (solitary tumor in space/time, absence of carcinoma in situ). From a quality of care perspective, overuse of partial cystectomy may signify inappropriate delivery of health care. MATERIALS AND METHODS: Subjects who underwent extirpative treatment for bladder cancer between 1988 and 2000 were identified within the Surveillance, Epidemiology and End Results (SEER, 3,381) registry and the Nationwide Inpatient Sample (NIS, 22,088). Adjusted models were developed to identify clinical factors independently associated with the use of partial cystectomy for bladder cancer treatment within each sample. RESULTS: Among patients who underwent extirpative surgery for bladder cancer, 18% and 20% of those in SEER and NIS, respectively, underwent partial cystectomy. Significant decreases in use between early and later years were noted in both samples (SEER-22% to 13%, NIS-24% to 17%, both p <0.0001). Partial cystectomy was preferentially used in the elderly, those with stage I disease, females and black patients. Furthermore, partial cystectomy was more commonly provided in rural, nonteaching, low volume hospitals. CONCLUSIONS: Trends in national use of partial cystectomy are consistent between the NIS and SEER with 13% to 17% of patients currently being treated with partial in lieu of radical cystectomy. Partial cystectomy is disproportionately used in certain medical centers (nonteaching, rural, low volume) and patient populations (elderly, black, females, stage I disease) reflecting selective referral or overuse.

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Curr Opin Urol. 2005 Sep;15(5):315-9.
Current status of establishing standards for lymphadenectomy in the treatment of bladder cancer.
Huang WC, Bochner BH.
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, USA.

PURPOSE: Pelvic lymph node dissection at the time of radical cystectomy is a crucial component of the surgical management of invasive bladder cancer. No established therapeutic or diagnostic guidelines regarding pelvic lymph node dissection are, however, currently available. We reviewed the past and contemporary literature to clarify the current role of pelvic lymph node dissection both as a staging modality as well as potential therapeutic intervention. RECENT FINDINGS: The role of pelvic lymph node dissection has evolved over the past 60 years. Although the added benefits of radical cystectomy over simple cystectomy alone are accepted, an optimal template for pelvic lymph node dissection has not been established. Increasing evidence suggesting therapeutic and diagnostic benefits by extending the boundaries of lymphadenectomy or by increasing the number of nodes excised has been reported. Much of the recent literature, however, is based on retrospective studies, and is influenced by factors such as node count variability, inconsistencies in the quality of the surgery, and the biases in patient selection. Currently, the optimal boundaries of pelvic lymph node dissection and the minimum number of nodes to be pathologically examined remain undetermined. SUMMARY: The diagnostic and therapeutic benefits obtained by extending the limits of lymphadenectomy are compelling but inconclusive. Establishing standards for pelvic lymph node dissection will not only increase the consistency of staging and improve the design and interpretation of clinical trials in invasive bladder cancer but also help to identify and optimize the therapeutic benefits of lymphadenectomy. Prospective, randomized trials will be needed to properly establish the extent of lymphadenectomy required to obtain such benefits.

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Aktuelle Urol. 2005 Aug;36(4):337-41.
[Intravesical adjuvant chemotherapy for superficial bladder cancer - results of a survey in saxony.]
[Article in German]
Steinbach F, Schuster F.
Urologische Klinik, Stadtisches Klinikum Dresden-Friedrichstadt. Steinbach-Fr@khdf.de.

For patients with superficial bladder cancer, adjuvant intravesical chemotherapy or immunotherapy with Bacillus Calmette-Guerin (BCG) is recommended in national and international guidelines. We analyzed whether the recommended therapeutic regimens are used in daily urological practice. Questionnaires concerning the adjuvant intravesical therapy were sent to 152 urologists in the German Federal State of Saxony. Of the surveyed physicians, 134 practiced in an outpatient medical facility and 18 in a hospital. Of the questionnaires, 73 (48.02 %) were returned and evaluated. An adjuvant intravesical therapy after transurethral bladder tumor resection was performed in every second patient (median value 50.07 %). The majority of the urologists (79.4 %) treated the bladder tumors with intravesical chemotherapy or BCG depending on tumor stage and grade of malignancy. Chemotherapeutic agents or BCG was exclusively used in 13.6 % and 4.1 % of treated patients, respectively. Chemotherapeutic agents were predominantly applied up to the primary tumor stage T1 and malignancy grade G2. In cases with recurrent T1 bladder tumors of G2 or higher grade of malignancy, BCG was the main agent for intravesical treatment. In patients with recurrent T1G3 tumors, the majority of urologist (57.1 %) preferred another therapeutic regimen than intravesical instillation. Only 23.2 % of the urologists believed that intravesical BCG is superior to chemotherapeutic agents. These data demonstrate that adjuvant intravesical instillation with chemotherapeutic agents and BCG is well established in urological practice. In contrast to the recommendations of national and international guidelines, chemotherapeutic agents are more frequently used in cases with a high risk of progression.

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Hinyokika Kiyo. 2005 Jul;51(7):439-42.
[A randomized study of prophylactic intravesical instillation of pirarubicin (THP) prior to transurethral resection of
superficial bladder cancer]
[Article in Japanese]
Hashimura T, Shirahase T, Inoue T, Yamasaki T, Terada N, Ogura K, Arai Y, Hida S, Ueda T.
The Department of Urology, National Himeji Medical Center.

A prospective randomized study was conducted to evaluate the efficacy of prophylactic intravesical instillation of pirarubicin (THP) prior to transurethral resection (TUR) of superficial bladder cancer. A total of 63 patients were randomized into two groups, the THP group and the control group. In the THP group, 30 mg of THP dissolved in 50 ml saline was administered 4 times intravesically for 4 consecutive days before TUR. In the control group, no instillation was performed before TUR. The patients were followed by cystoscopy and urinary cytology every 3 months. The non-recurrence rates in the THP group and control group were 54.1% versus 37.6% at 1 year and 40.4% versus 26.8% at 2 years, respectively (P = 0.086). Time to recurrence for tumors larger than 1 cm was significantly longer in the THP group (P = 0.0137). Time to recurrence for single and grade 1+2 tumors tended to be longer in the THP group (P = 0.09, P = 0.079). No significant adverse effects were observed in any patient. Our findings suggest that intravesical THP instillation prior to TUR would be effective for patients with single, low grade lesions larger than 1 cm of superficial bladder cancer.

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J Clin Oncol. 2005 Jul 20;23(21):4602-8.
Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M.
Department of Oncology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. maase@as.aaa.dk

PURPOSE: To compare long-term survival in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium treated with gemcitabine/cisplatin (GC) or methotrexate/vinblastine/doxorubicin/cisplatin (MVAC). PATIENTS AND METHODS: Efficacy data from a large randomized phase III study of GC versus MVAC were updated. Time-to-event analyses were performed on the observed distributions of overall and progression-free survival. RESULTS: A total of 405 patients were randomly assigned: 203 to the GC arm and 202 to the MVAC arm. At the time of analysis, 347 patients had died (GC arm, 176 patients; MVAC arm, 171 patients). Overall survival was similar in both arms (hazard ratio [HR], 1.09; 95% CI, 0.88 to 1.34; P = .66) with a median survival of 14.0 months for GC and 15.2 months for MVAC. The 5-year overall survival rates were 13.0% and 15.3%, respectively (P = .53). The median progression-free survival was 7.7 months for GC and 8.3 months for MVAC, with an HR of 1.09. The 5-year progression-free survival rates were 9.8% and 11.3%, respectively (P = .63). Significant prognostic factors favoring overall survival included performance score (> 70), TNM staging (M0 v M1), low/normal alkaline phosphatase level, number of disease sites (<or= three), and the absence of visceral metastases. By adjusting for these prognostic factors, the HR was 0.99 for overall survival and 1.01 for progression-free survival. The 5-year overall survival rates for patients with and without visceral metastases were 6.8% and 20.9%, respectively. CONCLUSION: Long-term overall and progression-free survival after treatment with GC or MVAC are similar. These results strengthen the role of GC as a standard of care in patients with locally advanced or metastatic TCC.

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World J Surg Oncol. 2005 Jul 15;3:43.
Extent of lymphadenectomy in radical cystectomy for bladder cancer.
Ather MH, Fatima S, Sinanoglu O.
Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan. hammad.ather@aku.edu

BACKGROUND: The benefit of pelvic lymphadenectomy in patients with cancer of the urinary bladder remains controversial. Though the inclusion of lymph node dissection in conjunction with radical cystectomy for patients with clinically negative nodes is well accepted, however, the extent of the nodal dissection remains contentious, particularly in patients with gross disease and T1G3 cancer. The extent of the primary bladder tumor, number of lymph nodes removed and the lymph node tumor burden are important prognostic variables in patients undergoing cystectomy. We analyzed the impact of the extent of lymphadenectomy during radical cystectomy on survival in the contemporary literature. METHODS: A Pubmed search was carried out for the literature published over the last 15 years using bladder cancer, radical cystectomy, survival, lymphadenectomy and complications as the key words. We have discussed the extent of lymphadenectomy on survival and its anatomical basis to determine the optimal number of lymph nodes to be removed and the concept of node density. RESULTS: Evidence from contemporary literature indicate significantly increased survival rates after cystectomy in patients with bladder cancer diagnosed with stages III or IV disease who have had relatively more lymph nodes examined, suggesting that even some patients with higher stage disease may benefit from extended pelvic lymphadenectomy at the time of cystectomy. Studies also indicate that more extensive lymphadenectomy significantly improved the prognosis of patients with bladder cancer, not only by providing prognostic information but perhaps it is also due to its inherent therapeutic value. CONCLUSION: Extended lymph node dissection improves local control and survival. However, in the absence of controlled randomized trial this remains a dubitable issue.

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BJU Int. 2005 Jun;95(9):1211-4.
Radical cystectomy in patients aged >/= 75 years: an updated review of patients treated with curative and palliative intent.
Zebic N, Weinknecht S, Kroepfl D.
Department of Urology Kliniken Essen-Mitte, Essen, Germany.

OBJECTIVE To evaluate the morbidity and mortality of radical cystectomy in a group of unselected patients aged >/= 75 years who were treated with curative and palliative intent. PATIENTS AND METHODS We retrospectively analysed 53 patients aged 75-90 years (median 78.8 years) who had radical cystectomies between May 1994 and July 2002. The patients were divided into two groups: 46 were treated with curative intent (group A) and seven with palliative intent (group B). The indications for cystectomy in group A were recurrent and otherwise therapy-resistant bladder cancer, severe irritative voiding symptoms, and recurrent macrohaematuria. The indications in group B were advanced pelvic malignancy with severe irritative voiding symptoms, severe pain, and recurrent macrohaematuria requiring blood transfusions. Patients were categorized according to the American Society of Anesthesiologists classification, with a score of II in 28 patients, III in 21 and IV in four. Complications and mortality before, during and after surgery, and the duration of hospital stay and clinical outcome, were assessed. RESULTS The early mortality rate in group A was 4% (2/46); in group B two patients died after prolonged complications. The median (range) hospital stay was 28 (6-56) days, and was significantly longer in patients with complications, at a median (range) of 36 (6-70) days. The complication rates early and late after surgery in group A were 22% and 11%, respectively, and in group B, five of seven (early). The total median survival was 2 (0.33-7) years. CONCLUSIONS Elderly people undergoing radical cystectomy have a greater risk of perioperative morbidity and mortality, especially those with very advanced pelvic malignancies who have had cystectomy with palliative intent. The incidence of early and late complications in patients treated with curative intent is acceptable, but the hospital stay is prolonged.

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BJU Int. 2005 Jun;95(9):1206-10.
A phase-1 study of sequential mitomycin C and 5-aminolaevulinic acid-mediated photodynamic therapy in recurrent superficial bladder carcinoma.
Skyrme RJ, French AJ, Datta SN, Allman R, Mason MD, Matthews PN.
Department of Urology, University Hospital of Wales, Cardiff, Wales, UK.

OBJECTIVE To report a phase-1 study of patients with recurrent superficial bladder cancer treated with photodynamic therapy (PDT) using sequential mitomycin C and 5-aminolaevulinic acid (ALA). PATIENTS AND METHODS Twenty-four patients were treated, the primary endpoint being the safety and tolerability of combined therapy at increasing doses of ALA and light. RESULTS Mitomycin C instillation was followed by ALA concentrations of 6%, 8% or 10%; there was no effect on toxicity. The light dose, at a wavelength of 635 nm, was increased from zero to 25 J/cm(2), with the upper fluences producing transient symptoms. There were no episodes of skin photosensitivity or systemic toxicity. A total fluence of 25 J/cm(2) represented the upper light dose for the tolerability of this procedure by patients. There were no persistently high urinary symptom scores or reduction in functional bladder capacity up to >/=24 months of follow-up. In this group, cumulative tumour recurrences were none at 4, two at 8, six at 12, nine at 18 and 11 at 24 months after PDT, respectively. CONCLUSION Sequential mitomycin C and ALA-PDT is a safe and well tolerated treatment, with potential for managing difficult-to-control superficial transitional cell carcinoma and carcinoma in situ of the bladder.

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Urologe A. 2005 May 4; [Epub ahead of print]
[Lymphadenectomy for bladder cancer Diagnostic and prognostic significance as well as therapeutic benefit.]
[Article in German]
Leissner J.
Klinik und Poliklinik fur Urologie, Universitatsklinikum, Bonn.

BACKGROUND: Pelvic lymphadenectomy for invasive bladder cancer is not a standardized procedure and its relevance for staging and prognoses is still under discussion. A number of retrospective studies have demonstrated a positive correlation between extent of lymphadenectomy and prognosis after radical cystectomy.MATERIALS AND METHODS: In a retrospective study, we correlated the extent of lymphadenectomy with survival after radical cystectomy. Thereafter, we conducted a prospective study to investigate the limits of pelvic lymphadenectomy and the pattern of lymphatic spread.RESULTS: Retrospectively, we found a significantly better survival for patients when 15 and more lymph nodes were removed. The individual surgeon was also evaluated as an important prognostic factor.CONCLUSIONS: Based on retrospective data, an extended and complete pelvic lymphadenectomy improves the prognosis. The cranial border should be at least at the level of the aortic bifurcation. A prospective randomized study will have to clarify the effect of lymphadenectomy on the prognosis of patients after radical cystectomy.

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Curr Oncol Rep. 2005 May;7(3):207-14.
Adjuvant chemotherapy for transitional cell carcinoma of the bladder: paradigms for the design of clinical trials.
Boyar M, Petrylak DP.
Division of Oncology, Columbia-Presbyterian Medical Center, Athcley Pavilion, Room 919, 161 Fort Washington Avenue, New York, NY 10032, USA. dpp5@columbia.edu.

Optimal treatment of high-risk, muscle-invasive bladder cancer involves local and systemic therapy. Published trials of adjuvant chemotherapy in bladder cancer are limited, but the evidence suggests that the combination of chemotherapy and surgery in high-risk patients improves survival. The identification of biologic markers with prognostic significance will allow clinicians to better determine which patients are at high risk for relapse. The development of newer, less toxic drugs with activity in bladder cancer has set the stage for the next generation of trials. Several multicenter randomized controlled trials are evaluating new chemotherapy regimens in the adjuvant setting. These new trials represent an important step forward in improving the treatment of bladder cancer.

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Eur J Surg Oncol. 2005 May;31(4):348-56. Epub 2004 Dec 16.
The management of lymph node metastasis from bladder cancer.
Simms MS, Mann G, Kockelbergh RC, Mellon JK.
Department of Urology, Leicester Hospital, Gwendolen Road, Leicester LE5 4PW, UK.

AIM: The presence of pelvic lymph node metastasis from bladder cancer has traditionally been associated with a very poor prognosis. The aim of this paper is to review the literature with regard to the management of patients with nodal disease, particularly gross nodal metastasis and suggest a strategy for management of these patients. METHODS: We performed a literature search in the PubMed database and the reference lists of relevant papers describing the management of locally advanced bladder cancer. FINDINGS: There are no randomised studies relating specifically to the management of nodal metastasis in bladder cancer. It is clear however that a significant number of patients with micrometastatic nodal disease may be cured. Few studies exist which address the management of patients with gross nodal disease and consist of series from a limited number of institutions. In patients with gross nodal disease detected pre-operatively or at the time of surgery, a multimodality approach consisting of surgery, chemotherapy and possibly radiotherapy seems appropriate. The prognosis of such patients relates to the pathological stage of the primary tumour and the degree of lymph node involvement. In addition a good response to neoadjuvant chemotherapy may identify patients who are likely to survive longer. CONCLUSIONS: The prognosis for patients with gross nodal disease from bladder cancer is poor although cure may be possible in a small number of patients. In such cases a multimodality approach is appropriate and management decisions should be made on an individual patient basis.

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Curr Opin Oncol. 2005 May;17(3):275-80.
Bladder cancer.
Borden LS Jr, Clark PE, Hall MC.
Department of Urology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

PURPOSE OF REVIEW: This article reviews the recent literature concerning important issues in the management of patients with bladder cancer. A brief overview of all aspects of bladder cancer including the etiology, diagnosis, and treatment are discussed with a focus on recent advances. RECENT FINDINGS: Bladder cancer is a significant cause of morbidity and mortality. The treatment for bladder cancer should be based on individual patient risk assessment and should include a multidisciplinary approach. In patients with superficial bladder cancer, research has focused on improving and optimizing intravesical therapy to reduce tumor recurrence and progression as well as on methods to better select the most appropriate treatment for patients with high-risk features. The important prognostic and therapeutic role of lymphadenectomy during radical cystectomy has become apparent and recent work has attempted to better define what should be considered the standard for lymph node dissection. Finally, in an attempt to improve survival, advances have been made using systemic chemotherapy in both the perioperative settings as well as for treatment of metastatic bladder cancer. SUMMARY: Research continues to improve our understanding of bladder cancer. This ongoing investigation is currently being translated to the bedside with refinements in the diagnosis and treatment of patients with bladder cancer.

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Radiother Oncol. 2005 Apr;75(1):34-43. Epub 2004 Nov 25.
A randomised trial of accelerated radiotherapy for localised invasive bladder cancer.
Horwich A, Dearnaley D, Huddart R, Graham J, Bessell E, Mason M, Bliss J.
Academic Unit of Radiotherapy and Oncology, The Royal Marsden NHS Trust and The Institute of Cancer Research, Sutton, UK.

BACKGROUND AND PURPOSE: To evaluate the efficacy and toxicity of an accelerated fractionation regimen to treat localised muscle invasive bladder cancer. PATIENTS AND METHODS: A prospective randomised trial was undertaken in 229 patients randomised between 1988 and 1998 comparing accelerated fractionation (AF) to a dose of 60.8Gy in 32 fractions over 26 days with conventional fractionation (CF) treating to 64Gy in 32 fractions over 45 days. Accelerated fractionation was delivered using two fractions per day with a 6h gap between fractions and with the first daily fraction size being 1.8Gy and the second daily fraction size being 2.0Gy. There was a 1 week treatment gap after the first 12 fractions. Conventional fractionation was one fraction per day, 5 days per week. Eligible patients had clinical stage T2 or T3, N0 or N1, M0 transitional cell carcinoma. The primary endpoint of the trial was local control and the trial was powered to detect a 20% difference (alpha 0.05, power 90%). Secondary endpoints were toxicity and survival. RESULTS: In the initial phase of the trial, randomisation was unequal such that in total 129 patients were randomised to accelerated fractionation and 100 to conventional fractionation. Acute toxicity was evaluable in 121 patients treated with AF and 96 patients treated with CF. RTOG grade 2 or 3 bowel toxicity was noted in 44% of AF patients compared to 26% of CF patients (P trend =0.001). Acute grade 2 or 3 bladder toxicity was seen in 35% of AF patients compared to 36% of CF patients (P=0.99). Late radiation toxicity was evaluated in patients surviving free from local recurrence at 2 years post treatment. Late radiation toxicity equivalent to RTOG grade 2 or more had occurred in 44% (95% CI 34-55%) of AF patients and in 38% (95% CI 26-49%) of CF patients (logrank over 5 years follow-up P=0.23). There was no significant difference in analysis of time to loss of local tumour control comparing the two treatment arms; local recurrence was recorded in 29 of the 100 patients treated with CF and in 41 of 129 patients treated with AF (logrank P=0.86). There was also no significant difference between the treatment arms comparing disease-free survival and overall survival. The overall survival figures at 3 years were for AF 54% (95% CI 45-63%) and for CF 47% (95% CI 36-57%). By 5 years the overall survival was 37% for AF and 40% for CF. There were two treatment related deaths, both on the AF arm of the trial. CONCLUSIONS: This accelerated fractionation schedule did not improve on the efficacy of conventional fractionation for patients with T2 and T3 bladder cancer and accelerated fractionation was associated with increased acute bowel reactions.

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Cochrane Database Syst Rev. 2005 Apr 18;2:CD005246.
Neoadjuvant chemotherapy for invasive bladder cancer.
Advanced Bladder Cancer Overview Collaboration.

BACKGROUND: Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials (RCTs) involving over 3000 patients. OBJECTIVES: To conduct a systematic review and meta-analysis of individual patient data to evaluate the effect of neoadjuvant chemotherapy on survival in patients with this invasive bladder cancer. SEARCH STRATEGY: MEDLINE and Cancerlit searches were supplemented with information from registers and by hand searching meeting proceedings and also by discussion with relevant trialists and organisations. These have been regularly updated until June 2003. SELECTION CRITERIA: Trials that aimed to randomise patients with biopsy proven invasive (i.e. clinical stage T2-T4a) transitional cell carcinoma of the bladder to receive local definitive treatment with or without neoadjuvant chemotherapy were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We collected, validated and re-analysed updated data on all randomised patients from all available randomised trials, including 3005 patients from 11 RCTs. For all outcomes, we obtained overall pooled hazard ratios using the fixed effects model. To explore the potential impact of trial design we pre-planned analyses that grouped trials by important aspects of their design that might influence the treatment effect. To investigate any differences in effect by pre-defined patient subgroups we used a stratified logrank analysis on the primary endpoint of survival. MAIN RESULTS: These results include data from one extra trial and so update those in the original publication ABC 2003. Platinum based combination chemotherapy showed a significant benefit on overall survival with a combined hazard ratio (HR) 0.86 (95% CI 0.77 to 0.95, p=0.003); 14% reduction in the risk of death; 5% absolute benefit at 5 years (95% CI 1 to 7%); overall survival increased from 45% to 50%. This effect was observed irrespective of the type of local treatment and did not vary between subgroups of patients. The HR for all trials, including those that used single-agent cisplatin, tended to favour neoadjuvant chemotherapy (HR= 0.89, 95% CI 0.81 to 0.98, p=0.022). Although platinum based combination chemotherapy was beneficial, there was no clear evidence to support the use of single-agent platinum, indeed there was significant difference in the effect between these groups of trials (p=0.029). AUTHORS' CONCLUSIONS: This improvement in survival encourages the use of platinum based combination chemotherapy for patients with invasive bladder cancer.

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Ai Zheng. 2005 Feb;24(2):229-31.
[Total cystectomy and neobladder for women patients with invasive bladder cancer: a report of eight cases.]
[Article in Chinese]
Wang B, Zhou FJ, Han H, Qin ZK, Liu ZW, Yu SL.
Department of Urology, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, P. R. China. zhoufaj86@263.net.

BACKGROUND & OBJECTIVE: Although total cystectomy plus neobladder is widely used, with good outcome, to treat men patients with invasive bladder cancer, the experience of treating women patients with the same therapy is limit. This study was designed to investigate the outcome of total cystectomy plus sigmoid neobladder for women patients with invasive bladder cancer. METHODS: Clinical data of 8 women with invasive bladder cancer, who underwent total cystectomy plus sigmoid neobladder from Jan. 2002 to Oct. 2003 in Cancer Center of Sun Yat-sen University, were retrospectively analyzed. RESULTS: The operations were technically successful in all cases. The mean follow-up was 18 months (ranged 6-24 months). Six patients survived disease-freely;2 developed pelvic metastasis 6 and 12 months after operation respectively. All patients could actively urinate, 4 were continent day and night, 4 were continent at daytime with mild nocturnal incontinence. Mild hydronephrosis was detected in 1 patient 3 months after operation, which disappeared spontaneously 3 months later. Renal function and serum electrolytes were normal in all cases. CONCLUSIONS: Total cystectomy plus sigmoid neobladder could manage invasive bladder cancer in women patients, and the new bladders function well. But night continence in women patients is not as good as that in men patients.

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Br J Cancer. 2005 Feb 01; [Epub ahead of print]
Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study.
Ardavanis A, Tryfonopoulos D, Alexopoulos A, Kandylis C, Lainakis G, Rigatos G.
11st Department of Medical Oncology, St Savas Anticancer Hospital, 171, Alexandras Avenue, 11522 Athens, Greece.

The purpose of the study was to investigate the toxicity and efficacy of the combination of gemcitabine and docetaxel in untreated advanced urothelial carcinoma. Patients with previously untreated, locally advanced/recurrent or metastatic urothelial carcinoma stage-IV disease were eligible. Patients with Performance status: PS ECOG >3 or age >75 years or creatinine clearance <50 ml min(-1) were excluded. Study treatment consisted of docetaxel 75 mg m(-2) (day 8) and gemcitabine 1000 mg m(-2) (days 1+8), every 21 days for a total of six to nine cycles. A total of 31 patients with urothelial bladder cancer, 25 men and six women, aged 42-74 (median 64) years were enrolled. The majority of patients had a good PS (51.6%; PS 0). In all, 15 (48.3%) patients had locally advanced or recurrent disease only and 16 (54.8%) presented with distant metastatic spread, with multiple site involvement in 22.5%. Toxicity was primarily haematologic, and the most frequent grade 3-4 toxicities were anaemia 11 (6.7%) thrombocytopenia eight (4.9%), and neutropenia 45 (27.6%), with 10 (6.1%) episodes of febrile neutropenia. No toxic deaths occurred. A number of patients had some cardiovascular morbidity (38.7%). Nonhaematological toxicities except alopecia (29 patients) were mild. Overall response rate was 51.6%, including four complete responses (12.9%) and 12 partial responses (38.7%), while a further five patients had disease stabilisation (s.d. 16.1%). The median time to progression was 8 months (95% CI 5.1-9.2 months) and the median overall survival was 15 months (95% CI 11.2-18.5 months), with 1-year survival rate of 60%. In conclusion, this schedule of gemcitabine and docetaxel is very active and well tolerated as a first-line treatment for advanced/relapsing or metastatic urothelial carcinoma. Although its relative efficacy and tolerance as compared to classic MVAC should be assessed in a phase III setting, the favourable toxicity profile of this regimen may offer an interesting alternative, particularly in patients with compromised renal function or cardiovascular disease.British Journal of Cancer advance online publication, 1 February 2005; doi:10.1038/sj.bjc.6602378.

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Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):420-5.
Phase I study of conformal radiotherapy with concurrent gemcitabine in locally advanced bladder cancer.
Sangar VK, McBain CA, Lyons J, Ramani VA, Logue JP, Wylie JP, Clarke NW, Cowan RA.
Department of Urology.

PURPOSE: A prospective phase I trial was conducted to determine the maximal tolerated dose of gemcitabine given once weekly during hypofractionated conformal radiotherapy to patients with locally advanced transitional cell carcinoma of the bladder. Eight male patients, median age 69 years, with Stage T2 (n = 4) or T3 (n = 4) N0M0, were enrolled in cohorts of 3. Treatment comprised conformal radiotherapy (52.5 Gy in 20 fractions) within 4 weeks, with concurrent gemcitabine once weekly for four cycles. The weekly gemcitabine dose was escalated from 100 mg/m(2) in increments of 50 mg/m(2) per cohort. Dose-limiting toxicity was defined as any acute Radiation Therapy Oncology Group (RTOG) toxicity Grade 3 or greater arising in >1 of 3 patients in each cohort. Tumor response was assessed cystoscopically and radiologically at 3 months. RESULTS: All 8 patients completed radiotherapy, and 6 of 8 completed chemoradiotherapy. No acute toxicity greater than RTOG Grade 1 was seen with gemcitabine at 100 mg/m(2). Dose-limiting toxicity was observed at 150 mg/m(2) with Grade 3 toxicity seen in 2 of 2 patients (one bladder, one bowel). An additional 3 patients received 100 mg/m(2) with minimal toxicity. No hematologic toxicity was encountered. A complete response was seen in 7 (87.5%) of 8 patients, all of whom were disease free at a median follow-up of 19.5 months (range, 14-23 months). No late toxicity (greater than RTOG Grade 0) has been observed. CONCLUSION: The maximal tolerated dose for gemcitabine given once weekly with concurrent hypofractionated conformal bladder radiotherapy was 150 mg/m(2), with a maximal recommended dose of 100 mg/m(2). This dose regimen has now entered Phase II clinical trials.

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Semin Radiat Oncol. 2005 Jan;15(1):10-8.
The surgical management of muscle invasive bladder cancer: A contemporary review.
Cookson MS.

Muscle-invasive bladder cancer is a potentially lethal disease with a high rate of cure if timely and effective therapy is applied while the disease is confined to the bladder or regional lymph nodes. Radical cystectomy is the gold standard to which all other local therapies including multimodality bladder-preserving strategies should be compared. Contemporary cystectomy combined with regional lymphadectomy may be performed with an acceptably low morbidity, provides unparalleled local control, and may result in durable disease-free survival even among patients with locoregional lymph node metastases. Refinements in surgical technique coupled with the expanded application of continent urinary diversion have resulted in excellent functional outcomes without compromising cancer control in properly selected patients. An increasing awareness of the importance of quality-of-life issues combined with an enhanced understanding of tumor biology have resulted in the surgical modifications which include an expanded role for lymphadectomy and preservation of uninvolved adjacent organs.

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Semin Radiat Oncol. 2005 Jan;15(1):28-35.
Organ preservation by combined modality treatment in bladder cancer: The European perspective.
Rodel C, Weiss C, Sauer R.

Combined modality therapy, including transurethral resection, radiation therapy, and systemic chemotherapy, has been shown to produce survival rates comparable to those of radical cystectomy. With these programs, cystectomy has been reserved for patients with incomplete response or local relapse after trimodality treatment. This review summarizes European series of combined modality treatment of muscle-invasive bladder cancer and reflects our emphasis on the importance of combining radiation with a transurethral resection and cisplatin-based chemotherapy. It also documents our belief that high-grade T1 disease may be effectively treated by the same approach. This represents a true distinction between the European and US strategies. We also review the role of predictive and prognostic factors in selecting patients for the respective treatment alternatives.

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Jpn J Clin Oncol. 2004 Dec;34(12):747-50.
FOLFOX-4 in Pre-treated Patients with Advanced Transitional Cell Carcinoma of the Bladder.
Di Lorenzo G, Autorino R, Giordano A, Giuliano M, D'Armiento M, Bianco AR, De Placido S.
Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita degli Studi di Napoli Federico II, Naples, Italy. giuseppedilorenzoncol@hotmail.com.

BACKGROUND: Despite recent progress in the treatment of advanced urothelial cancer, there continues to be a need to identify new active agents and their toxicity spectra. We conducted a study using FOLFOX-4 (oxaliplatin, fluorouracil, folinic acid) in pre-treated advanced bladder cancer patients. METHODS: Sixteen eligible patients with advanced disease were treated with oxaliplatin (85 mg/m(3)) on day 1 followed by fluorouracil and folinic acid (De Gramont schedule) on days 1 and 2 every 14 days until disease progression. All patients received nutritional support to increase their caloric intake. Objective responses and toxicity were evaluated. Biochemical responses (reduction of markers) and nutritional parameters (increase in body weight and albumin, and reduction in ferritin and C-reactive protein) were also considered. RESULTS: Three patients obtained an objective response (overall response rate 19%). Hematological toxicity and stomatitis were the most commonly noted side effects, but we observed only low (3-4) grade toxicity. In four patients (25%), we observed a reduction in tumoral markers (carcinoembryonic antigen and tissutal polypeptide antigen) and modified nutritional parameters. CONCLUSIONS: Using these doses and schedules of FOLFOX-4 appears to be a promising therapy in patients pre-treated with platinum compounds. More studies are required to assess the possible role of this regimen in the treatment of advanced bladder cancer.

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Int J Clin Oncol. 2004 Dec;9(6):484-90.
Chemoradiotherapy as a bladder-preservation approach for muscle-invasive bladder cancer: current status and perspectives.
Sumiyoshi Y.
Department of Urology, Shikoku Cancer Center, 13 Horinouchi, Matsuyama, Ehime, 790-0007, Japan. ysumiyos@shikoku-cc.go.jp

Radical cystectomy has been considered the gold standard for the treatment of muscle-invasive bladder cancer. However, because of disappointing results with radical surgery in terms of survival and decreased quality of life (QOL), bladder-preservation treatment has been introduced as an alternative to radical cystectomy. The primary purpose of the bladder-preservation approach has been to maximize overall cure rates, with the secondary purpose being to preserve the patient's bladder. The modalities used to ensure successful bladder preservation include radical transurethral resection (TUR), concurrent cisplatin (CDDP)-based chemotherapy, and radiotherapy. In patients who achieve a complete response (CR) after trimodality therapy, 5-year survival rates of more than 50%, the same as those of radical cystectomy, can be achieved and 70% of this group will retain an intact functional bladder. In this article, bladder-preservation studies using chemoradiotherapy are reviewed.

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Cancer Control. 2004 Nov-Dec;11(6):358-63.
Bladder preservation protocols in the treatment of muscle-invasive bladder cancer.
Torres-Roca JF.
Department of Interdisciplinary Oncology and the Radiation Oncology, Genitourinary Oncology and Experimental Therapeutics Programs, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612 USA. torresjf@moffitt.usf.edu.

BACKGROUND: Over the last 3 decades, we have seen a paradigm shift in our approach to the treatment of malignancy. During that time, organ conservation protocols have become standard in the treatment of breast cancer, laryngeal cancer, esophageal cancer, anal cancer and soft tissue sarcomas. METHODS: Data from reports of bladder preservation protocols were reviewed to evaluate organ preservation approaches in muscle-invasive bladder cancer. RESULTS: These trials have shown equivalent disease control rates when compared to radical surgery, with the advantage of organ function preservation. In spite of this, organ preservation efforts in muscle-invasive bladder cancer have lagged behind this overall trend in clinical oncology. However, efforts by several investigators over the last 2 decades have shown that for a number of selected patients with muscle-invasive bladder cancer, bladder preservation is feasible without an apparent compromise of overall survival. CONCLUSIONS: Bladder preservation therapy with a trimodality approach for a carefully selected patient population is safe and effective. Formal randomized trials comparing radical cystectomy and trimodality bladder-sparing therapy are justified.

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Strahlenther Onkol. 2004 Nov;180(11):701-709.
Current Status of Radiation Therapy and Combined-Modality Treatment for Bladder Cancer.
Rodel C.
Department of Radiation Therapy, University of Erlangen, Erlangen, Germany, claus.roedel@strahlen.med.uni-erlangen.de.

BACKGROUND:. Standard treatment for muscle-invasive bladder cancer is radical cystectomy. Combined-modality treatment (CMT), including transurethral resection (TURBT), radiation therapy (RT) and systemic chemotherapy, has been shown to produce survival rates comparable to those of radical cystectomy. With these programs, cystectomy has been reserved for patients with incomplete response or local relapse after trimodality treatment. METHODS:. This review summarizes series of radical RT with different fractionation schedules and focuses on CMT for muscle-invasive bladder cancer. Current protocols of the bladder-sparing approach will be discussed and the background of future developments, including incorporation of promising new chemotherapeutic agents as well as the role of predictive and prognostic factors in selecting patients for the respective treatment alternatives, will be given. RESULTS:. There is moderate evidence that hyperfractionated and accelerated regimens are superior to conventional RT at least in situations where no concomitant chemotherapy is applied. Several phase II studies and one phase III study indicate that concomitant radiochemotherapy is superior to RT alone. In modern series of CMT, 5-year survival rates in the range of 50-60% have been published, and about three quarters of the surviving patients maintained their own bladder. Recent data suggest that incorporation of newer chemotherapeutic agents, particularly gemcitabine and taxanes, in CMT protocols is feasible and promising. Clinical criteria helpful in determining patients for bladder preservation include such variables as early tumor stage, unifocal tumor, a visibly and microscopically complete TURBT, and absence of ureteral obstruction. CONCLUSION:. CMT for bladder cancer is a reasonable treatment option for patients who are deemed medically unfit for cystectomy and for those seeking an alternative to radical cystectomy.

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Ai Zheng. 2004 Nov;23(11 Suppl 1):1517-9.
[Initial Results of Intra-arterial Chemotherapy for Poorly Differentiated Bladder Transitional Cell Carcinoma.]
[Article in Chinese]
Liu ZW, Zhou FJ, Yu SL, Qin ZK, Han H, Wang B, Wang H, Li YH.
Department of Urology, Cancer Center, Sun Yat-sen University, Guangzhou,Guangdong,510060, P.R.China. gzlzhuowei@yahoo.com..cn.

BACKGROUND & OBJECTIVE: Bladder cancer is the most common disease among urogenital tumors, and poorly differentiated bladder transitional cell carcinoma (BTCC) tends to recur, progress, and metastasize. This paper was to report our experiences in intra-arterial chemotherapy as adjuvant and palliative therapy for poorly differentiated BTCC. METHODS: Twenty-four patients with BTCC of grade 3 were treated with intra-arterial chemotherapy of GC regimen (gemcitabine plus cisplatin). Among them, 21 had post-operative adjuvant intra-arterial chemotherapy for 3 cycles, 3 advanced cases had palliative intra-arterial chemotherapy for 6 cycles. RESULTS: All patients were followed-up for 6-20 months. The mean follow-up was 12 months for 21 patients received adjuvant treatment, 1 developed pelvic metastasis, the others survived without evidenced tumors. Of 3 advanced cases, 1 with CR survived disease-freely for 8 months; 1 with PR survived progression-freely for 6 months; 1 with PR died of tumor relapse 13 months after chemotherapy. No serious complication was observed after intra-arterial chemotherapy. CONCLUSIONS: Intra-arterial chemotherapy is effective in managing poorly differentiated BTCC.

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Cancer Immunol Immunother. 2004 Nov 23; [Epub ahead of print]
Immunotherapy for superficial bladder cancer.
Schenk-Braat EA, Bangma CH.
Department of Urology, Josephine Nefkens Institute, Room Be 362, PO Box 1738, 3000, DR Rotterdam, The Netherlands.

The treatment of superficial bladder cancer requires adjuvant therapies besides transurethral resection because of a high recurrence rate after this standard treatment alone. Current adjuvant therapies involve intravesical chemotherapy for patients at low and intermediate risk for recurrence and progression, and intravesical bacillus Calmette-Guerin for patients at intermediate and high risk. However, these adjuvant therapies fail in a significant number of patients, dictating the need for new and improved adjuvant treatment modalities for superficial bladder cancer. Immunotherapy aiming at the modulation of the immune system of the patient is a promising alternative adjuvant. This review discusses the current status of the clinical development of various immunotherapy approaches for superficial bladder cancer, including passive immunotherapy, immune stimulants, immunogene therapy and cancer vaccination.

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BJU Int. 2004 Nov;94(7):1021-5.
Prostatic capsule- and seminal-sparing cystectomy for bladder carcinoma: initial results for selected patients.
Botto H, Sebe P, Molinie V, Herve JM, Yonneau L, Lebret T.
Department of Urology, Hopital Foch, Suresnes, France.

OBJECTIVE To evaluate the oncological outcome and functional results of prostate-sparing cystectomy (PSC), proposed for treating bladder cancer, used since 1999 in our institution in an attempt to preserve male sexuality and to increase continence after cystectomy. PATIENTS AND METHODS Between January 1999 and December 2001, 111 men were candidates for cystectomy; 42 were selected for a prostatic capsule- and seminal-sparing cystectomy with orthotopic urinary diversion. All patients had clinically organ-confined tumours (clinical stage </= T2, N0M0). The first stage of the procedure was a transurethral resection of the prostate to exclude the involvement of transitional cell carcinoma (TCC) in the prostate. RESULTS Eight patients were excluded from PSC because they had TCC (seven) or prostate adenocarcinoma (one). The mean age of the remaining 34 patients was 61 years and all underwent PSC. After a mean follow-up of 26 months, seven patients (21%) had a recurrence; one developed a local recurrence, there were widespread metastases in six (18%), and five had histologically confirmed organ-confined tumour (T1-2N0M0). Rates for daytime and night-time continence were 90% and 85%, and in 29 patients potency was unchanged. CONCLUSION These early results suggest that PSC is not equivalent to radical cystoprostatectomy for bladder cancer control, despite marked improvements in the functional results. Moreover, in carefully selected patients this approach appears to dramatically increase an unusually high metastasis rate. Therefore, the indications for PSC should be either clearly well defined or abandoned in these patients.

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BJU Int. 2004 Oct;94(6):793-7.
Salvage cystectomy after failure of interstitial radiotherapy and external beam radiotherapy for bladder cancer.
Nieuwenhuijzen JA, Horenblas S, Meinhardt W, van Tinteren H, Moonen LM.
Department of Urology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

OBJECTIVE: To evaluate the long-term results of salvage cystectomy after interstitial radiotherapy (IRT) and external beam radiotherapy (EBRT) for transitional cell carcinoma, and to assess the morbidity and functional results of the different urinary diversions used. PATIENTS AND METHODS: The records of 27 patients treated with salvage cystectomy in one institution between 1988 and 2003 were retrospectively analysed. RESULTS: Salvage cystectomy was used after failure of IRT in 14 or EBRT in 13 patients, with a 3- and 5-year survival probability of 46% (95% confidence interval 26-65) and 33 (11-54)%. The 5-year overall survival after cystectomy was 54% after IRT and 14% after EBRT (P = 0.12). Tumour category, response to radiation, American Society of Anesthesiology score, and complete tumour resection had a significant influence on survival. Five of seven patients with incomplete resection died because of local disease, with a median survival of 5 months. There was clinical understaging after radiotherapy in 41% of patients. Nine patients had an orthotopic neobladder, with complete day- and night-time continence in eight and four, respectively. All patients but one had good voiding function. There were early complications in two and late complications in six patients (for Bricker, seven of 14 and none; for Indiana, none of four and two of four). The duration of hospitalization was not influenced by the type of diversion. Erectile function was maintained in four of six patients after a sexuality-preserving cystectomy and neobladder. CONCLUSIONS: Salvage cystectomy can be performed with acceptable morbidity using any type of urinary diversion. Understaging after radiotherapy is common, but preoperative selection needs improving. A very significant factor for an adverse outcome and death from local tumour recurrence was incomplete resection, suggesting that salvage cystectomy should only be attempted if complete resection is probable.

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J Urol. 2004 Oct;172(4 Pt 1):1276-80.
Effective bladder sparing therapy with intra-arterial cisplatin and radiotherapy for localized bladder cancer.
Eapen L, Stewart D, Collins J, Peterson R.
Department of Radiation Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada.

PURPOSE: We evaluated the feasibility and efficacy of the organ preserving strategy of intra-arterial cisplatin and concurrent radiotherapy for localized bladder cancer. MATERIALS AND METHODS: Bladder preservation has been pursued over the decades in treatment regimens featuring radiotherapy alone or in conjunction with single or multiagent chemotherapy. The chemotherapy has consisted almost exclusively of intravenously administered drugs. There are theoretical and clinical data demonstrating a higher concentration of cisplatin within tumors following intra-arterial as opposed to intravenous delivery. This study was performed to evaluate whether this increased concentration would enhance radiosensitization and thereby increase the success of bladder preservation. RESULTS: We report on our prospectively collected experience during 15 years of treating 200 patients with localized bladder cancer using this regimen of 3 courses of intra-arterial cisplatin integrated with pelvic radiotherapy and reserving cystectomy for salvage as required. We report on the efficacy in terms of complete response rate, ultimate tumor-free bladder preservation, overall survival and patterns of failure. We detail the acute and chronic toxicity observed to date. CONCLUSIONS: This strategy has resulted in a durable high complete response rate and overall tumor-free bladder preservation rate of 75% while maintaining a survival comparable to that achieved with cystectomy. These results corroborate the hypothesis that intra-arterial administration of cisplatin enhances radiosensitization during pelvic radiotherapy.

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J R Soc Health. 2004 Sep;124(5):228-9.
Cancers of the bladder.
Sengupta N, Siddiqui E, Mumtaz FH.
Department of Urology, Chase Farm Hospital, The Ridgeway, Enfield EN2 8JL, England.

Bladder cancer is the fifth most common malignancy in Europe and the fourth most common malignancy in the United States. It affects one in 4000 people and accounts for 5% of all diagnosed cancers. The peak incidence is in the fifth and seventh decade. There is a strong association between smoking and bladder cancer. Smokers have a fourfold higher incidence of developing bladder cancer than the general population. The disease has a spectrum of clinical severity varying from superficial bladder cancer to muscle invasive or metastatic disease which carries a poor prognosis. Currently the superficial form of the disease is managed by endoscopic resection of the tumour, often followed by the instillation into the bladder of cytotoxic agents. Due to the tendency of bladder cancer to recur repeated cystoscopies and resections are often required. Because of this, one of the main thrusts of research is to find a way of preventing the progression from superficial disease to muscle invasive and metastatic bladder cancer.

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Oncology. 2004;67(1):27-32.
Single-agent gemcitabine in previously untreated elderly patients with advanced bladder carcinoma: response to treatment and correlation with the comprehensive geriatric assessment.
Castagneto B, Zai S, Marenco D, Bertetto O, Repetto L, Scaltriti L, Mencoboni M, Ferraris V, Botta M.
Department of Medical Oncology, S. Spirito Hospital, Casale Monferrato, Italy. bruno.castagneto@mbox.asl21.piemonte.it

OBJECTIVE: The study aimed at evaluating the activity and toxicity of gemcitabine monochemotherapy in a unselected series of elderly patients with advanced bladder cancer. The secondary objectives were to establish whether there is a correlation between treatment and Comprehensive Geriatric Assessment (CGA) and, in addition, to determine overall patient survival. METHODS: Treatment consisted of six courses of chemotherapy with gemcitabine at a dosage of 1,200 mg/m2 on days 1 and 8, every 21 days. CGA, as described by Gruppo Italiano di Oncologia Geriatrica, was assessed for evaluating the functional status of patients before, during, and after treatment. RESULTS: Twenty-five patients were enrolled (M/F 22/3), 22 of these were evaluable for response and 23 for toxicity. Characteristics of patients: median age 76 years (range 71-87); ECOG performance status (PS) 1 in 12 patients and 2 in 13 patients; clinical stage III in 6 patients and IV in 19 patients. At the end of the therapy the parameters of CGA improved in 4 cases (17%), remained unchanged in 17 cases (74%) and worsened only in 2 cases (9%). Two patients were not evaluable. Response evaluation showed 3 (13.5%) complete responses (CRs) and 7 (32%) partial responses (PRs), for an overall response rate of 45.5% [95% confidence interval (CI), 24.3-65.7%]. Three (13.5%) patients had stable disease (SD ) and 9 (41%) disease progression (DP). Median overall survival was 8 months and median time to progression was 5 months. Treatment was generally well tolerated, with 1 patient having grade 3 gastrointestinal toxicity and 3 having grade 4 neutropenia. CONCLUSIONS: We conclude that gemcitabine can be safely administered in monochemotherapy, is effective and does not worsen the functional status of elderly patients with advanced bladder cancer. Copyright 2004 S. Karger AG, Basel.

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J Urol. 2004 Sep;172(3):878-81.
Partial cystectomy: a contemporary review of the Memorial Sloan-Kettering Cancer Center experience and recommendations for patient selection.
Holzbeierlein JM, Lopez-Corona E, Bochner BH, Herr HW, Donat SM, Russo P, Dalbagni G, Sogani PC.
Department of Urology, Memorial Sloan-Kettering Cancer Center, 353 E. 68th Street, New York, NY 10021, USA.

PURPOSE: Partial cystectomy is a bladder sparing procedure that has been used to treat invasive bladder cancer in highly selected patients. This study analyzes the outcomes of partial cystectomy in a contemporary cohort of patients to identify appropriate selection criteria for the procedure. MATERIALS AND METHODS: Records were reviewed for 58 patients with a primary bladder tumor who had undergone partial cystectomy at Memorial Sloan-Kettering Cancer Center from 1995 to 2001. Information was collected on tumor size, histology, location, presence of carcinoma in situ (CIS), multifocality, neoadjuvant treatment, clinical stage, pathological stage and disease status. RESULTS: For the 58 patients analyzed, overall 5-year survival was 69% with a mean followup of 33 months (range 1 to 83). Of the patients 43 (74%) are alive with an intact bladder, 39 (67%) are currently disease-free with an intact bladder and 32 (55%) have been continuously disease-free with an intact bladder. Seven patients experienced a superficial recurrence and were treated successfully while 15 patients experienced an advanced recurrence. On univariate analysis CIS and multifocality were related to superficial recurrence, and lymph node involvement and positive surgical margin were related to advanced recurrence. On multivariate analysis concomitant CIS (odds ratio 7.05, p = 0.004) and lymph node involvement (odds ratio 4.38, p = 0.031) were predictors of advanced recurrence. CONCLUSIONS: In highly selected patients with invasive bladder cancer, partial cystectomy offers acceptable outcomes. Concomitant CIS and presence of metastases to regional lymph nodes predict advanced recurrence.

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Eur Urol. 2004 Sep;46(3):344-51.
Neoadjuvant chemotherapy with docetaxel and Cisplatin in patients with high-risk resectable bladder carcinoma: long term results.
Bamias A, Deliveliotis C, Karayiannis A, Varkarakis I, Zervas I, Pantazopoulos D, Gika D, Dimopoulos MA.
Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens, Greece.

Objectives: Neoadjuvant chemotherapy has been used to improve outcome after cystectomy or for selection for bladder preservation in patients with bladder cancer. We have shown encouraging results using docetaxel and cisplatin in patients with advanced urothelial cancer. We are reporting the results of a phase II study using this combination as neoadjuvant treatment in patients with muscle invasive bladder cancer. Methods: Fifty patients were treated with docetaxel and cisplatin at 75mg/m(2) every 3 weeks for 3 cycles prior to cystectomy. Median follow-up was 70.2 months. Results: Chemotherapy was well tolerated. 5-year survival and progression-free survival (PFS) were 51.92% (95% confidence intervals [CI]: 37.76-66.08) and 52.47% (95%CI: 37.99-66.95). Multivariate analysis showed that clinical stage (cT) <== 3a was associated with improved 5-year survival (86.42% vs. 40.81%, [Formula: see text] ). Forty one patients underwent cystectomy. No tumor was found in 15 cases (36.6%). 5-year survival was 60.34% (95%CI: 52.2-68.48) and PFS was 57.11% (95%CI: 41.29-72.93). Absence of residual tumor was associated with improved 5-year survival (93.33% vs. 40.72%, [Formula: see text] ). Conclusions: Neoadjuvant chemotherapy with docetaxel and cisplatin is feasible and produced high pathological complete remission rate and excellent outcome in patients with no residual tumor.

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Eur Urol. 2004 Sep;46(3):339-43.
Phase II Study to Investigate the Ablative Efficacy of Intravesical Administration of Gemcitabine in Intermediate-Risk Superficial Bladder Cancer (SBC).
Gontero P, Casetta G, Maso G, Sogni F, Pretti G, Zitella A, Frea B, Tizzani A.
Department of Medical Sciences, Urology Clinic, University of Piemonte Orientale, Via Solaroli, 17, 28100 Novara, Italy.

Objective: Phase I studies have so far demonstrated that intravesical Gemcitabine up to a 40mg/ml concentration is well tolerated and has a substantial ablative activity on high-risk BCG refractory SBC. New treatment options are needed for intermediate-risk SBC recurring after conventional intravesical treatments. The purpose of the present study was to investigate the ablative efficacy of intravesical Gemcitabine on intermediate-risk SBC. Methods: The study was designed as a two-stage phase II trial, with a sample size of 39 patients. The efficacy of intravesical Gemcitabine at a concentration of 40mg/ml (2000mg in 50ml saline solution) administered weekly for 6 weeks was assessed on a single marker tumour left in the bladder after a complete TUR of all other lesions. Patients underwent TUR or biopsy at the site of the marker lesion 2 weeks after completion of the treatment. Results: Complete response was observed in 22 out of 39 patients (56%). No progression was observed among the 17 non-responders. Neither systemic nor local side effects generally exceeded grade I toxicity. Conclusion: The ablative effect of Gemcitabine produced a higher number of responses than the minimum required by the protocol to indicate a significant probability of drug efficacy. It is worth testing the drug in phase III trials to assess for durability of response.

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Curr Opin Urol. 2004 Sep;14(5):287-93.
Novel therapeutics in the treatment of bladder cancer.
Shah JB, McKiernan JM.
Department of Urology, Columbia University Medical Center, New York, NY 10032, USA.

PURPOSE OF REVIEW: The successful treatment of bladder cancer remains a challenge for urologists and oncologists. There have been substantial changes in the therapeutic options for the management of both superficial and muscle-invasive bladder cancer in the last 5 years. Here we review the preclinical and clinical developments over the last year in bladder cancer therapeutics. RECENT FINDINGS: There is a growing trend toward the use of multimodal treatments for all bladder cancers. For superficial disease, intravesical instillation of chemotherapeutic agents after transurethral resection is quickly becoming the standard of care. Novel therapeutic modalities under investigation include DNA vaccines, magnetically targeted carriers, bio-adhesive microspheres and antisense oligodeoxynucleotides. For muscle-invasive bladder cancer, systemic perioperative chemotherapy is being used with increasing frequency and the latest preclinical research efforts are focused on the inhibition of angiogenesis and other processes predisposing to metastatic disease. SUMMARY: Treatment goals for bladder cancer of any stage are complete removal of the initial tumor, prevention of disease recurrence and effective inhibition of progression to advanced disease with the ultimate aim of reducing mortality. The myriad novel therapeutic modalities currently being explored suggest that these goals may perhaps be achievable within our lifetime.

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Curr Opin Urol. 2004 Sep;14(5):271-275.
Second-line intravesical therapy versus cystectomy for bacille Calmette-Guerin (BCG) failures.
Joudi FN, O'Donnell MA.
University of Iowa Department of Urology, Iowa City, Iowa, USA.

PURPOSE OF REVIEW: To give an update on the new modalities in treating patients with superficial bladder cancer who have failed bacille Calmette-Guerin. RECENT FINDINGS: The addition of interferon to bacille Calmette-Guerin has proven to be an effective combination therapy for bacille Calmette-Guerin failures. Electromotive intravesical mitomycin C as well as local microwave hyperthermia have been shown to improve drug delivery and increase response rates. Intravesical gemcitabine has shown some promising results in phase I studies and is being investigated in phase II trials. Photodynamic therapy is proposed as a second-line therapy for bacille Calmette-Guerin failures. SUMMARY: New treatment modalities are being introduced and existing ones improved to treat bacille Calmette-Guerin-refractory superficial bladder cancer. These agents need to be studied in large randomized trials. Until these agents prove to decrease recurrence rates and delay progression of high-risk superficial bladder cancer, cystectomy remains the standard of care for the patient who is a good surgical candidate and willing to undergo such major surgery.

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Curr Opin Urol. 2004 Sep;14(5):251-7.
Old friends, new ways: revisiting extended lymphadenectomy and neoadjuvant chemotherapy to improve outcomes.
Busby JE, Evans CP.
Department of Urology, University of California, Davis, Sacramento, CA 95817, USA.

PURPOSE OF REVIEW: Standard therapy for muscle-invasive bladder cancer is radical cystectomy and pelvic-lymph-node dissection. Because 50% of patients will die at 5 years as a result of micrometastases, improvements have been sought to increase the survival rates. Two specific approaches include administration of neoadjuvant chemotherapy or extending the boundaries of the lymph-node dissection. We reviewed the current literature to define present trends and studies that involve these adjunct treatments. RECENT FINDINGS: The benefits of extended lymphadenectomy have been demonstrated by several groups. These include mapping nodal metastatic sites and defining the requisite number of nodes removed to optimize survival. Though not universal, it is frequently concluded that increasing the number of nodes removed improves survival without worse morbidity. Neoadjuvant chemotherapy has been proposed to eliminate occult cancer cells outside the margins of resection. Results have been variable and modest, though emerging data from the Southwest Oncology Group may further support such an approach and improve organ preservation. SUMMARY: Extended lymphadenectomy has consistently shown benefit with minimal morbidity and should be considered - especially in cystectomy patients that are T3. The results from neoadjuvant chemotherapy are more modest. Further studies await further elucidation to confirm this.

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Urology. 2004 Aug;64(2):292-7.
Aggressive treatment for bladder cancer is associated with improved overall survival among patients 80 years old or older.
Hollenbeck BK, Miller DC, Taub D, Dunn RL, Underwood W 3rd, Montie JE, Wei JT.
Department of Urology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0330, USA.

OBJECTIVES: To examine the impact of various treatment modalities on survival among patients with bladder cancer who were 80 years old or older compared with younger patients. A compendium of evidence suggests that bladder cancer surgery is safe among octogenarians; however, the benefit of such treatment in a population with limited life expectancy has not been well documented. METHODS: Subjects with the primary diagnosis of bladder cancer were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registry between 1988 and 1999. Of the 13,796 patients diagnosed with bladder cancer, 24% were older than 80 years of age. Proportional hazards regression modeling was performed to determine the independent association of treatment strategy on overall and bladder cancer survival while adjusting for multiple covariates. RESULTS: Of patients 80 years old or older, bladder cancer management included watchful waiting (7%), radiotherapy alone (1%), full or partial cystectomy (12%), and transurethral resection (79%). Patients 80 years old or older were less likely to be treated with extirpative surgery than their younger counterparts (P <0.0001). Cox proportional hazards models demonstrated that, among patients 80 years old or older, radical cystectomy/partial cystectomy had the greatest risk reduction in death from bladder cancer (hazard ratio 0.3) and death from any cause (hazard ratio 0.4) among the primary treatment modalities (both P <0.0001). CONCLUSIONS: Disparities in practice patterns between younger and geriatric patients with bladder cancer exist. We provide compelling evidence that aggressive surgical management of bladder cancer in these patients may improve survival. Risk adjustment tools should be used to identify patients (young and old) who would be better served by less aggressive management.

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ANZ J Surg. 2004 Jul;74(7):569-72.
Low dose BCG as adjuvant therapy for superficial bladder cancer and literature review.
Cheng CW, Ng MT, Chan SY, Sun WH.
Department of Surgery, Alice Ho Miu Ling Nethersole Hospital, Tai Po, Hong Kong, China.

Background: Bacillus Calmette-Guerin (BCG) at low doses has long been employed as prophylactic and therapeutic treatment for superficial cancer of the urinary bladder, aiming at reducing toxicity while maintaining efficacy. A retrospective review was reported, together with a review of the literature with respect to a low dose BCG regimen. Methods: Forty-five consecutive patients with superficial bladder cancer (Ta or T1) with one or more of the appropriate criteria (grade above 1, stage above a, size >1 cm, multiple or recurrent), after complete transurethral resection, received 27 mg Connaught strain BCG weekly for 6 weeks. There was no maintenance therapy. Patients were evaluated with urine cytology and cystoscopy. Recurrence, progression and death were analysed. Results: With a median follow up of 14 (range 3-61) months, 24 (53%) of the 45 patients responded to one course of 6 weekly BCG without recurrence. A further group of 13 (29%) patients responded to a second course of BCG on recurrence. Disease progressed in one (2.2%) patient. Two (4.4%) patients died of an unrelated condition. There was no disease specific mortality. Side-effects were common but well tolerated, with only two (4.4%) cases of treatment interruption. Conclusions: Low dose BCG could be an alternative option of adjuvant therapy for superficial bladder cancer with acceptable toxicity and good compliance.

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J Clin Oncol. 2004 Jul 1;22(13):2540-5.
Combined-modality therapy with gemcitabine and radiotherapy as a bladder preservation strategy: results of a phase I trial.
Kent E, Sandler H, Montie J, Lee C, Herman J, Esper P, Fardig J, Smith DC.
Department of Internal Medicine, University of Michigan School of Medicine and Comprehensive Cancer Center, AnnArbor, 48109, USA.

PURPOSE: We conducted a phase I trial of gemcitabine given twice weekly with concurrent radiotherapy in patients with muscle-invasive bladder cancer. PATIENTS AND METHODS: Eligible patients underwent maximal transurethral resection of their bladder tumors followed by twice-weekly infusion of gemcitabine with 2 Gy/d concurrent radiotherapy to the bladder, for a total of 60 Gy over 6 weeks. The starting dose of gemcitabine was 10 mg/m(2) with subsequent dose levels of 20, 27, 30, and 33 mg/m(2). The primary end point was the determination of the maximum-tolerated dose (MTD) of twice weekly gemcitabine with concurrent radiotherapy. Secondary end points included assessment of toxicity associated with combined-modality therapy and initial assessment of the rate of bladder preservation. RESULTS: Twenty-four patients were enrolled and 23 were assessable for toxicity and response. No significant toxicity was demonstrated at the 10 or 20 mg/m(2) twice-weekly doses. Dose-limiting toxicity (DLT) occurred in two of three patients treated at 33 mg/m(2). Intermediate dose levels of 27 and 30 mg/m(2) were then evaluated. The MTD of gemcitabine was 27 mg/m(2). The DLT was systemic, manifested as an elevation in liver function tests, malaise, and edema. Fifteen of 23 patients (65%) are alive with bladders intact and no evidence of recurrent disease at a median follow-up of 43 months. CONCLUSION: Twice-weekly gemcitabine with concurrent radiotherapy at 2 Gy/d to a total dose of 60 Gy is well-tolerated. The MTD of gemcitabine is 27 mg/m(2). There is a high rate of bladder preservation in this selected group of patients.

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Urol Oncol. 2004 May-Jun;22(3):205-11.
The evolving role of pelvic lymphadenectomy in the treatment of bladder cancer.
Sanderson KM, Stein JP, Skinner DG.
Department of Urology, USC Norris Cancer Center, Los Angeles, CA, USA.

Regional lymphadenectomy is integral to the surgical management of high-grade invasive bladder cancer. A growing body of evidence suggests that a lymph node dissection may provide not only improved prognostic information, but also a clinically significant therapeutic benefit for both lymph node positive and negative patients undergoing radical cystectomy. While the inclusion of lymph node resection in conjunction with radical cystectomy for patients with clinically negative nodes is well accepted, the extent of the nodal dissection remains highly contentious. Similarly, the benefit of node dissection for patients with advanced disease and gross adenopathy or for those with superficial disease (Ta, T1 or TIS) remains a topic of heated debate. This review describes the historical evolution of lymphadenectomy in the surgical treatment of bladder cancer and provides a comprehensive review of the current literature addressing the role of lymph node dissection in the treatment of bladder cancer.

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Curr Opin Oncol. 2004 May;16(3):257-62.
Bladder cancer.
Borden LS Jr, Clark PE, Hall MC.
Department of Urology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

PURPOSE OF REVIEW: This article reviews recent advances in the diagnosis and management of bladder cancer. RECENT FINDINGS: Bladder cancer is a significant cause of morbidity and mortality. Recent research has attempted to improve the care of patients with this disease. Evidence suggests that bacillus Calmette-Guerin is the most effective intravesical therapy for the treatment of superficial bladder cancer and that maintenance therapy is superior to an induction course alone. In patients with muscle-invasive disease, nodal status and extent of lymphadenectomy have been shown to correlate with survival after radical cystectomy. The role of chemotherapy in the treatment of bladder cancer continues to evolve as well. Neoadjuvant chemotherapy has recently demonstrated a survival benefit, and trials are ongoing to define the optimal regimen of chemotherapy for urothelial carcinoma. SUMMARY: Improved understanding and advancements in the management of all stages of bladder cancer continue to improve the care of patients with this disease.

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J Urol. 2004 May;171(5):1819-22; discussion 1822.
Overall clinical outcomes after nerve and seminal sparing radical cystectomy for the treatment of organ confined bladder cancer.
Colombo R, Bertini R, Salonia A, Naspro R, Ghezzi M, Mazzoccoli B, Deho' F, Montorsi F, Rigatti P.
Department of Urology, University Vita-Salute San Raffaele, Scientific Institute H. San Raffaele, Milan, Italy. colombo.renzo@hsr.it

PURPOSE: We assessed postoperative clinical outcomes such as day and nighttime urinary continence and overall sexual function in patients who underwent nerve and seminal sparing cystectomy with ileocapsuloplasty compared with patients after standard cystoprostatectomy with similar orthotopic urinary reservoir. MATERIALS AND METHODS: A total of 27 patients (mean age 52 years, range 36 to 61) with superficial high risk or muscular invasive T2 bladder cancer underwent radical nerve and seminal sparing cystectomy with ileocapsule anastomosis. Postoperative clinical outcomes such as urinary continence, voiding patterns and urodynamic parameters were evaluated at 3, 6 and 12 months, while overall sexual function was determined at baseline and at 6 and 12-month followup. RESULTS: Nerve and seminal sparing cystectomy provides better outcomes in terms of urinary and urodynamic parameters compared to standard cystoprostatectomy. Furthermore, fully normal postoperative erectile function and satisfactory overall sexual quality of life were documented at early and delayed followup in all patients. A retrograde ejaculation with reliable sperm retrieval from urine was also documented. CONCLUSIONS: Although these findings need to be confirmed in a larger patient population, when respecting rigorous patient selection criteria and careful postoperative surveillance, nerve and seminal sparing cystectomy seems to offer satisfactory clinical and functional outcomes. From an oncological point of view, long-term followup is of paramount importance to confirm whether this surgical procedure can be proposed as a valid choice of treatment for young, fully potent and socially active patients with organ confined bladder cancer.

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Curr Oncol Rep. 2004 May;6(3):230-6.
Combined chemotherapy and external beam radiotherapy for transitional cell carcinoma of the bladder.
Ennis RD.
Department of Radiation Oncology, College of Physicians and Surgeons of Columbia University, 622 West 168th Street, BHN-Room B11, New York, NY 10032, USA. rde5@columbia.edu

A growing body of evidence supports the treatment of invasive transitional cell carcinoma of the bladder with transurethral resection, chemotherapy, and external beam radiotherapy. Randomized trials have demonstrated the superiority of chemotherapy plus radiotherapy to radiotherapy alone. Several series with 10 years of follow-up demonstrate that the success of this approach can be maintained. Preservation of the urothelium, however, results in continued risk of de novo bladder cancer development in addition to the possibility of recurrence. Thus, continued close surveillance and treatment of subsequent superficial or invasive bladder cancer is an essential component of this bladder preservation approach. Concomitant cisplatin chemotherapy and radiotherapy or initial (neoadjuvant) combination cisplatin-based chemotherapy followed by radiotherapy are the two options best supported by the literature. How these regimens compare with each other and with cystectomy-based treatment remains to be defined.

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Br J Cancer. 2004 Apr 19;90(8):1516-20.
A Phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer.
Doval DC, Sekhon JS, Gupta SK, Fuloria J, Shukla VK, Gupta S, Awasthy BS.
1Rajiv Gandhi Cancer Institute & Research Center, Delhi, India.

The primary objective of this study was to determine the response rates of the gemcitabine and cisplatin combination in unresectable gall bladder cancer patients. The secondary objectives were to evaluate the toxicity, time to progressive disease, and overall survival. Chemonaive patients with histologically proven, unresectable bidimensionally measurable gall bladder cancer were enrolled into this study. All patients were required to have a Zubrod's performance status </=2, no prior radiotherapy, and adequate major organ function. Patients received gemcitabine (1000 mg m(-2) intravenously over 30-60 min) on days 1 and 8, and cisplatin (70 mg m(-2) intravenously over 2 h) on day 1, every 21 days. Response assessment was done by a CT scan after every other cycle of chemotherapy. In all, 30 patients were eligible for efficacy and toxicity analysis. There were four (13.3%) complete responders, seven (23.3%) partial responders, and seven (23.3%) with stable disease, with four (13.2%) patients showing disease progression. The median time to progression was 18 weeks (95% confidence interval (CI) 14-24 weeks), and the median duration of response was 13.5 weeks (range 5.5-104 weeks). The median overall survival was 20 weeks (95% CI 14-31 weeks), with 1-year survival rate of 18.6%. WHO grade 3 or 4 anaemia was seen in seven (23.3%) and four (13.3%) patients, respectively. Five (16.6%) patients each experienced grade 3 or 4 neutropenia, and grade 3 or 4 thrombocytopenia was seen in three (10%) and two (6.6%) patients, respectively. The present study shows that gemcitabine/cisplatin combination is well tolerated and active in advanced unresectable gall bladder cancer.British Journal of Cancer (2004) 90, 1516-1520. doi:10.1038/sj.bjc.6601736 www.bjcancer.com Published online 16 March 2004

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Curr Opin Urol. 2004 Mar;14(2):83-7.
Laparoscopic radical cystectomy with urinary diversion.
Moinzadeh A, Gill IS.
Section of Laparoscopic and Minimally Invasive Surgery, Glickman Urological Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

PURPOSE OF REVIEW: The laparoscopic approach in urology is now an accepted option for kidney, adrenal, and prostate surgery. We review the current experience with laparoscopic radical cystectomy to identify its role in oncological bladder surgery. RECENT FINDINGS: Pure laparoscopic techniques are being employed for the extirpative portion of laparoscopic radical cystectomy at multiple institutions. Various extracorporeal and intracorporeal techniques are evolving for the reconstructive procedures necessary for urinary diversion. Worldwide experience continues to accumulate with over 150 cases already having been performed. SUMMARY: With the gradual growth and experience in laparoscopic radical cystectomy, along with continuing refinements in technique, laparoscopic radical cystectomy is now being performed at many centers worldwide. Long-term oncological and functional outcome data are necessary to determine its proper role for patients with bladder cancer.

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J Urol. 2004 Mar;171(3):1085-8.
Treatment and outcome of invasive bladder cancer in patients after renal transplantation.
Master VA, Meng MV, Grossfeld GD, Koppie TM, Hirose R, Carroll PR.
Departments of Urology and Surgery, University of California, San Francisco, California 94143, USA. vmaster@urol.ucsf.edu

PURPOSE: Optimal management and clinical outcome of bladder cancer in renal transplant recipients are not well-defined. We analyzed single institution treatment strategies and outcomes of these patients. MATERIALS AND METHODS: We retrospectively reviewed the University of California, San Francisco transplant database which contains information on 6,288 renal transplants performed between 1964 and 2002. The United Network for Organ Sharing database and Israel Penn International Transplant Tumor Registry were also queried to characterize the global nature of bladder cancer in renal transplant recipients. RESULTS: The United Network for Organ Sharing database (1986 to 2001) contained information on 31 patients who were found to have bladder cancer (0.024% prevalence) and the Israel Penn International Transplant Tumor Registry (1967 to 2001) contained information on 135 patients representing 0.84% of all reported malignancies. We identified 7 renal transplant recipients with bladder cancer at our institution. Invasive transitional cell carcinoma developed in 5 patients at a median of 2.8 years after transplant. Three patients underwent uncomplicated radical cystectomy and preservation of the renal allograft. Overall survival at 48 months was 60%. CONCLUSIONS: Bladder cancer after renal transplantation is not common. For patients who present with invasive disease, traditional extirpative surgery should be considered. Moreover, the allograft is rarely the source of transitional cell carcinoma and can be preserved. In our experience the cancer and urinary outcomes compare favorably with nontransplant patient outcomes after treatment.

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J Urol. 2004 Feb;171(2 Pt 1):870-6.
Immunotherapy for urological malignancies.
Krejci KG, Markiewicz MA, Kwon ED.
Department of Urology, Mayo Clinic, Rochester, Minnesota 55905, USA.

PURPOSE: For decades urologists have successfully used immunotherapy in the battle against cancer. Interleukin-2 in renal cell carcinoma and bacillus Calmette-Guerin in bladder cancer are standard primary and/or adjunctive therapies for these diseases. Recent advances in our understanding of mechanisms governing immune system activation have fostered a myriad of novel immunotherapeutic approaches that show great promise in vivo but have had limited success in human trials to date. This review highlights current immunotherapy strategies that may prove to be successful treatments for urological cancers. MATERIALS AND METHODS: We performed a MEDLINE literature search for articles relating to immunotherapy in bladder, prostate and renal cell carcinoma in animals and humans. We included the most promising developments in this review. RESULTS: In addition to combining existing therapies to improve their efficacy, novel approaches that attempt to exploit the immune system ability to identify, target and eradicate malignancies are now being developed. These therapies include the use of antitumoral monoclonal and bi-specific antibodies, manipulation of T-lymphocyte costimulatory molecules and the administration of newly discovered cytokines as well as the development of antitumor vaccines. CONCLUSIONS: To date the full potential of immunotherapy for the treatment of urological malignancies has not been recognized. As our knowledge of the immune system expands, so too may our ability to manipulate it to affect tumor regression. This review describes the most recent and most promising developments in immunotherapy for urological malignancies.

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Semin Oncol. 2004 Feb;31(1 Suppl 1):28-39.
Farnesyltransferase inhibitors.
Sebti SM, Adjei AA.

The farnesyltransferase inhibitors (FTIs) were designed to inhibit the post-translational processing of Ras proteins, which are mutated in 30% of all human cancers. Recent studies suggest, however, that the target of FTIs may be a protein other than Ras, and that these agents may be more appropriately used to treat tumors with activated wild-type ras signaling. Preliminary results from several phase II and phase III studies have been reported. The FTIs fail to show significant single-agent activity in non-small cell lung cancer, small cell lung cancer, pancreatic cancer, refractory colorectal cancer, and bladder cancer. Activity has been shown in hematologic malignancies (acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome), breast cancer, and glioma. Several combination studies of FTIs and standard cytotoxic agents are ongoing.

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Eur Urol. 2004 Feb;45(2):182-6.
Intravesical gemcitabine: a phase 1 and pharmacokinetic study.
Witjes JA, van der Heijden AG, Vriesema JL, Peters GJ, Laan A, Schalken JA.
Department of Urology, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. fwitjes@uro.umcn.nl

INTRODUCTION: Superficial bladder cancer can be treated by transurethral resection and additional intravesical therapy. Although agents like Mitomycin C, Epirubicin and BCG are routinely used, there is a need for more potent and/or less toxic agents. Gemcitabine is a deoxycytidine analogue, used systemically for several tumours, such as non-localised bladder cancer, where it is effective and well tolerated. We investigated the use of three dose levels of gemcitabine when given intravesically in humans for safety and pharmacokinetic research. MATERIAL AND METHODS: Patients with superficial bladder cancer, except pT1G3 or CIS were included. Six weekly instillations of 1000, 1500 or 2000 mg gemcitabine were given in 50 ml saline for one hour. Dose modifications were defined in case of dose limiting toxicities. Blood samples were taken before, and 5, 30, 60 (= evacuation) and 120 minutes after instillations 1, 3 and 6. Samples were used for blood counts and pharmacokinetics. Side effects were noted. RESULTS: 3, 4 and 3 patients were treated with 1000, 1500, and 2000 mg gemcitabine respectively, of which 2, 3 and 1 patients had highly recurrent tumours before treatment. Seven patients experienced side effects: 2 with dysuria after the first instillation, 2 after instillations 3-6 and 4-6 and in 3 patients headache, fatigue and heavy legs were experienced once. All side effects were reversible, non-limiting and WHO 1. No macroscopic hematuria was seen. Haematology showed only one case of drop in white blood cell count (lowest dose level, after the first instillation). Gemcitabine plasma levels were immeasurable or low, with peak levels between 30 and 60 minutes, decreasing after more instillations. The metabolite difluorodeoxyuridine reached levels of at most 5 microM, indicating a very low passage of the drug to the systemic circulation. CONCLUSION: Intravesical gemcitabine in the dose used has minimal and reversible side effects. Plasma evaluation indicates that its intravesical use is safe.

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Eur Urol. 2004 Feb;45(2):147-53; discussion 154.
Surgical management of infiltrating bladder cancer in elderly patients.
Peyromaure M, Guerin F, Debre B, Zerbib M.
Department of Urology, Cochin Hospital, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. michael.peyromaure@cch.ap-hop-paris.fr

OBJECTIVES: To review the surgical therapeutic options in elderly patients with infiltrating bladder cancer. METHODS: A review of the literature relevant to cystectomy and transurethral resection for infiltrating bladder cancer in elderly patients was conducted using Medline Services. RESULTS: Thanks to progress in anaesthesia, intensive care and surgery, cystectomy now forms part of the classical treatments for bladder cancer in elderly patients, with acceptable mortality and morbidity rates. The recent series of cystectomies performed in patients over 75 years old report a mortality rate associated with the procedure of less than 4.5%. The global mortality rate in the same population ranges from 10 to 50%. These rates are now similar to those reported in the general population. The mean survival after cystectomy in patients over 75 years old is more than 2 years. Global survival at 5 years is between 37 and 68%. It is acknowledged by most authors that resection alone is associated with higher relapse and progression rates than cystectomy. CONCLUSIONS: Cystectomy appears to be reasonable in elderly people who have a life expectancy of more than 2 years, provided that a rigorous pre-operative assessment and anaesthetic management are performed. Transurethral resection alone should be proposed only to patients with poor health status and/or very advanced age.

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J Urol. 2004 Feb;171(2 Pt 1):561-9.
Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis.
Winquist E, Kirchner TS, Segal R, Chin J, Lukka H; Genitourinary Cancer Disease Site Group, Cancer Care Ontario Program in Evidence-based Care Practice Guidelines Initiative.
London Regional Cancer Centre, Ontario, Canada. eric.winquist@lrcc.on.ca

PURPOSE: Despite local therapy most patients with muscle invasive transitional cell carcinoma (TCC) of the bladder die of systemic relapse, indicating a need for effective adjunctive systemic treatment. We determined whether neoadjuvant chemotherapy improved overall survival. MATERIALS AND METHODS: A systematic review and meta-analysis were performed of all known randomized controlled trials (RCTs) of neoadjuvant chemotherapy for stages II and III TCC conducted between 1984 and 2002. RESULTS: A total of 16 eligible RCTs (3,315 patients) were identified. Of these trials 11 (2,605 patients) provided data suitable for a meta-analysis of overall survival and the pooled HR was 0.90 (95% CI 0.82 to 0.99, p = 0.02). Eight trials used cisplatin based combination chemotherapy and the pooled HR was 0.87 (95% CI 0.78 to 0.96, p = 0.006), consistent with an absolute overall survival benefit of 6.5% (95% CI 2 to 11%) from 50% to 56.5%. Reported progression-free survival data were insufficient for meta-analysis but they appeared concordant with overall survival results. Mortality due to combination chemotherapy was 1.1%. A major pathological response was associated with improved overall survival in 4 trials.CONCLUSIONS Neoadjuvant cisplatin based chemotherapy improves overall survival in muscle invasive TCC. The size of the effect is modest and combination chemotherapy can be administered safely without adverse outcomes resulting in delayed local therapy. An optimal chemotherapy regimen was not identified and newer regimens have not been tested in RCTs in this setting. Further efforts to identify the patients most likely to benefit from neoadjuvant therapy are necessary to optimize its use.

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Mini Rev Med Chem. 2004 Jan;4(1):61-8.
Rhenium-188 and copper-67 radiopharmaceuticals for the treatment of bladder cancer.
Frier M.
Radiopharmacy Unit, Queens Medical Centre, Nottingham, UK. Malcolm.Frier@nottingham.ac.uk

The favourable nuclear properties of copper-67 and rhenium-188 for therapeutic application are described, together with methods for the chemical synthesis of a number of derivatives. Survival from invasive bladder cancer has changed little over the past 20 years. The intravesicular administration of Cu-67 or Re-188 radiopharmaceuticals in the treatment of bladder cancer offers some promise for improvement in this situation.

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Urology. 2004 Jan;63(1):73-7.
Concurrent chemoradiotherapy for clinical stage T2 bladder cancer: report of a single institution.
Peyromaure M, Slama J, Beuzeboc P, Ponvert D, Debre B, Zerbib M.
Department of Urology, Cochin Hospital, Paris, France.

OBJECTIVES: To report our experience with concurrent chemoradiotherapy for clinical Stage T2 bladder cancer. METHODS: From 1996 to 2002, 43 patients were treated with concurrent chemotherapy and radiotherapy for clinical Stage T2 bladder cancer. After complete bladder transurethral resection, all patients underwent chemotherapy, consisting of one daily infusion of cisplatin at a dose of 15 mg/m2 and 5-fluorouracil at a dose of 400 mg/m(2) on days 1 to 3 (first cycle) and days 15 to 17 (second cycle). Pelvic irradiation was administered at a dose of 24 Gy, using two daily fractions of 3 Gy on days 1, 3, 15, and 17. Random biopsies were performed 6 weeks after the end of the first two cycles. Patients with persistent invasive tumor underwent cystectomy; others received two additional cycles of concurrent chemoradiotherapy. RESULTS: The mean follow-up was 36.3 months (range 3 to 72). Nine patients underwent early cystectomy for nonresponse, and 2 patients underwent delayed cystectomy. The overall rate of cystectomy was 25.6%. The rate of specific survival at 3 and 5 years was 75% and 60%, respectively. The overall rate of recurrence-free survival at 3 and 5 years was 63% and 33%, respectively. Two factors correlated with patient survival: the presence of carcinoma in situ at first resection (P = 0.01) and the response after the first two cycles (half dose; P = 0.004). CONCLUSIONS: In our experience, concurrent chemoradiotherapy is less effective than primary cystectomy for clinical Stage T2 bladder cancer. This treatment may be unwarranted in patients with concomitant carcinoma in situ at the first resection.

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Arch Ital Urol Androl. 2003 Dec;75(4):202-4.
[Mitoxantrone chemoprophyaxis for multirecurrent multifocal superficial bladder tumours: results of a phase 2 controlled study]
[Article in Italian]
Bassi PF, Spinadin R, Carando R, Dal Moro F, Abatangelo G, Piazza N, Tavolini IM.
Dipartimento di Scienze Oncologiche e Chirurgiche, Sezione di Clinica Urologica, Universita di Padova, Italy. bassipf@unipd.it

Twenty-three patients with multifocal superficial bladder cancer (stage Ta - T1) unresponsive to at least 3 different intravesical agents, were enrolled in a phase II study in order to evaluate the prophylactic effects of intravesical Mitoxantrone (20 mg) after complete endoscopic resection (TUR) of any papillary tumor. The median follow-up was 6 months; 19 patients (82%) experienced superficial tumor recurrence, 1 patient (4%) progression to muscle invasion and 3 (13%) were disease-free, respectively. Six patients (26%) experienced local side-effects. The progression rate is acceptable; the side effects are at least similar to those available in the literature, but in our experience, Mitoxantrone has no prophylactic effects against superficial bladder cancer unresponsive to previous treatment.

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Arch Ital Urol Androl. 2003 Dec;75(4):199-201.
Ligasure versus sutures in bladder replacement with Montie ileal neobladder after radical cystectomy.
Manasia P, Alcaraz A, Alcover J.
Department of Urology, Hospital Clinic, University of Barcelona, Barcelona, Spain. pmanasia8@iol.it

OBJECTIVES: Electrocoagulation became an indispensable tool for surgeons. Ligasure is a computer-based, temperature-controlled bipolar electrocoagulation system designed as an alternative to suture ligatures, staplers, hemoclips and ultrasonic coagulators for legating vessels and tissue bundles. Our aim was to analyse the procedure time and intraoperative blood loss of the ileal neobladder in a series of 30 highly selected patients. PATIENTS AND METHODS: From March 1999 to May 2002, 30 patients (all men), 47 to 74 years old (mean age 57) with good performance status (American Society of Anesthesiology score 1 and 2) underwent radical cystectomy for bladder cancer and Montie ileal neobladder reconstruction, using standard surgical technique, with the exception of 15 patients that the Ligasure device was used for haemostasis. RESULTS: Procedure time was significantly less in the Ligasure arm 170 minutes (range: 150 min - 200 min ) versus 220 minutes (range: 160 min - 250 min) in the suture arm (p < 0.001). Blood loss was significantly less in the Ligasure arm an average 849 cc (range: 820 cc - 900 cc) versus 968 cc (range: 1110 cc - 897 cc) in the suture arm p < 0.02). There was no post-operative hemorrhage or return to the operating room in either arm. Two patients, one in each arm, received two units of blood for a slowly decreasing hematocrit on postoperative day 3. There was no evidence of collateral tissue injure and no injuries to the urinary or intestinal tract in either arm. CONCLUSIONS: Ligasure is a safe and effective alternative to sutures in cystectomy and bladder replacement, resulting in decreased blood loss and significant time saving.

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Vopr Onkol. 2003;49(6):734-7.
[Clinical significance of macroscopic 5-aminolevulinic acid (ALA)-inducer fluorescence in transurethral resection of non-invasive bladder cancer]
[Article in Russian]
Danil'chenko DI, Koenig F, Riedl K, Schnorr D, Waldman A, Al-Shukri S, Loening SA.

Macroscopic fluorescence which is induced with aminolevulinic acid (ALA) allows visualizing of small flat tumors, carcinoma in situ, true neoplasm margins and dysplasias of the bladder. Following ALA instillation, cystoscopy was performed under both standard and blue light illumination. In a prospective randomized multicenter study, 102 patients underwent TUR of bladder tumor(s) either with white light or ALA-fluorescence. Significant reduction in the number of residual tumours was detected in 59% (p = 0.005) after 8 weeks, 3 months--in 58% (p = 0.002) and 6 months in 38% (p = 0.01) respectively.

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Cancer Biother Radiopharm. 2003 Dec;18(6):861-77.
Radionuclide therapy with iodine-125 and other auger-electron-emitting radionuclides: experimental models and clinical applications.
Bodei L, Kassis AI, Adelstein SJ, Mariani G.
Nuclear Medicine Division, European Institute of Oncology, Milan, Italy.

Auger-electron emitters represent an attractive alternative to beta-particle emitters for cancer therapy if they can be placed intracellularly, especially in close proximity to (or within) nuclear DNA. Based on investigations in animal tumor models, including those for ovarian cancer, bladder cancer, and brain and spinal cord tumors, in which the thymidine analog 5-radioiodo-2'-deoxyuridine (*IUdR) has been shown to be therapeutically efficacious, it is hypothesized that iodine-125 and other Auger-electron-emitting radionuclides might be valuable in the treatment of certain malignant diseases, assuming that uptake of the radiopharmaceutical by tumor cells exceeds that by normal dividing cells. Preliminary patient studies have shown that this requirement can be met partially by the locoregional administration of the radiopharmaceutical and metabolic modulation of its uptake by tumor cells. Investigators continue to seek molecules that can carry Auger-electron emitters to nuclear DNA, especially those radionuclides with higher Auger-electron yields and varying half-lives.

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Can J Urol. 2003 Dec;10(6):2056-61.
Radiotherapy for muscle-invasive urinary bladder cancer in elderly patients.
Agranovich A, Czaykowski P, Hui D, Pickles T, Kwan W.
BC Cancer Agency, Fraser Valley Cancer Centre, Surrey, British Columbia, Canada.

OBJECTIVE: To review retrospectively the outcome and toxicity of Radiotherapy (RT) in the cohort of elderly patients (EP) with muscle-invasive urinary bladder carcinoma (MIUBC). METHODS: Thirty-six EP were treated with RT with radical intent. The age of the cohort ranged from 71 to 89 years with a median of 79 years. Eighty percent of the patients had Easter Cooperative Oncology Group (ECOG) 0 and 1 performance status. Conventional and accelerated fractionation RT regimens were utilized. RESULTS: With median follow up of 45.8 months, the median survival was 23.9 months. There was a trend toward better survival in patients treated with the accelerated fractionation regimen. The median survival for that group (12) has not yet been reached, where it is 9.7 months for the group (24) treated with conventional fractionation. Treatment related toxicity was low for any RT regimens. CONCLUSION: RT is well tolerated by EP with good baseline performance status. The role of accelerated fractionation should be tested by conducting randomized trials.

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Urol Oncol. 2003 Nov-Dec;21(6):468-74.
Chemotherapy and cystectomy for invasive transitional cell carcinoma of bladder.
Raghavan D.
Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. draghava@usc.edu

Invasive transitional cell bladder cancer is associated with occult metastasis. Approximately 50% of patients with clinically localized, invasive bladder cancer ultimately die of their disease. Systemic chemotherapy has been combined with radical cystectomy in an attempt to improve survival. Phase I and II trials have achieved tumor down-staging. Initial randomized trials did not show a statistically significant survival benefit from systemic single agent chemotherapy. More recently, two multi-center randomized trials have shown a significant survival benefit from neoadjuvant combination chemotherapy. Adjuvant chemotherapy trials, to date, have failed to show statistically improved survival, although most published studies have been methodologically flawed. For invasive, clinically nonmetastatic bladder cancer, neo-adjuvant chemotherapy followed by radical cystectomy is one of the new standards of care. The role of postsurgical systemic chemotherapy appears promising, but has not been proven in a randomized trial. Molecular prognostication is now being incorporated into the design of clinical trials of adjuvant chemotherapy for bladder cancer.

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Expert Rev Anticancer Ther. 2003 Dec;3(6):781-92.
Surgical management of bladder cancer in 2003.
Wade M, Seigne JD.
Department of Interdisciplinary Oncology and Surgery (Urology), H Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, University of South Florida, Tampa, FL 33612, USA.

Recent advances in molecular and cell biology have led to a greater understanding of the basic biology of bladder cancer. However, despite these advances, surgery remains a key component of modern bladder cancer treatment. Endoscopy is the mainstay of the diagnosis and treatment of superficial bladder cancer. Adjuvant intravesical therapy is recommended for patients with high-risk superficial bladder cancer (Ta/T1 high grade). Select patients with invasive bladder cancer (T2/T3) are candidates for bladder-sparing approaches, incorporating transurethral resection of bladder tumor (TURBT), radiation and chemotherapy. The results and complications of endoscopic therapy are discussed. The role of partial cystectomy, radical cystoprostatectomy, prostate-sparing cystectomy, laparoscopic radical cystectomy, lymphadenectomy and urethrectomy in invasive bladder cancer are discussed. The tumor control outcomes and complications of radical cystoprostatectomy (still the gold standard) for organ-confined and node-positive bladder cancer are reported. Surgery remains an integral part of the management of patients with bladder cancer. Improved understanding of the biology of bladder cancer, combined with better surgical techniques and safety, continues to improve the survival and quality of life of patients with bladder cancer.

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Cancer. 2003 Nov 1;98(9):1863-9.
A phase II study of gemcitabine and docetaxel therapy in patients with advanced urothelial carcinoma.
Gitlitz BJ, Baker C, Chapman Y, Allen HJ, Bosserman LD, Patel R, Sanchez JD, Shapiro RM, Figlin RA.
Division of Hematology/Oncology, University of California-Los Angeles School of Medicine, Los Angeles, California 90033, USA. gitlitz@usc.edu

BACKGROUND: The objectives of the current study were to evaluate the safety and efficacy of gemcitabine plus docetaxel in patients with unresectable (Stage T4 or >/= N1) metastatic or locally advanced transitional cell carcinoma (TCC) of the urothelial tract. METHODS: A total of 27 patients were enrolled in the current multisite study, which was performed within the University of California-Los Angeles Community Oncology Research Network. The first 10 patients in the study received 800 mg/m(2) of gemcitabine intravenously on Days 1, 8, and 15 of a 28-day treatment cycle. In addition, on Day 1, the first 10 patients received 80 mg/m(2) of docetaxel intravenously after completion of the gemcitabine infusion. Because of dose-limiting toxicity (neutropenia), the initial dose of docetaxel was reduced to 60 mg/m(2) for the remaining patients who entered the study (n = 17 patients). RESULTS: Neutropenia was the most common adverse event that occurred in patients at the Grade 3 level (in 10 of 27 patients; 37.0%) and the Grade 4 level (in 6 of 27 patients; 22.2%). There were no other adverse events at the Grade 4 toxicity level. Twenty-five of 27 patients (92.6%) completed more than 1 cycle of combination therapy and were evaluated for antitumor responses. The frequency of objective clinical responses was 33.3% (9 of 27 patients). Complete responses to therapy were observed in 2 of 27 patients (7.4%), and partial responses were observed in 7 of 27 patients (25.9%). The median duration of response was 20 weeks (range, 12+ weeks to 152 weeks). The median survival duration was 52 weeks (range, 12 weeks to 160+ weeks). Four of 27 patients (14.8%) remained alive at the time of the current data analysis. CONCLUSIONS: The results of the current study suggested that combination therapy with gemcitabine and docetaxel was an effective treatment for patients with unresectable (Stage T4 or >/= N1) metastatic or locally advanced TCC of the urothelial tract. Gemcitabine plus docetaxel appeared to be tolerated well, and treatment-related toxicities were limited to hematologic toxicities. Because cisplatin-containing regimens are contraindicated for patients with impaired renal function, the gemcitabine plus docetaxel combination may prove to be an effective and well tolerated treatment option for these patients. Copyright 2003 American Cancer Society.

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Curr Treat Options Oncol. 2003 Oct;4(5):373-83.
Laparoscopic approaches to urologic malignancies.
Matin SF.
Department of Urology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 446, Houston, TX 77030, USA. surmatin@mdanderson.org

Urologic laparoscopy has had its greatest impact on patients with genitourinary malignancies. Only pelvic lymph node dissection and the occasional nephrectomy were considered oncologically feasible early in the evolution of laparoscopic urology. Presently, multiple approaches are considered standard at centers of excellence and in the general community. Laparoscopic adrenalectomy and radical nephrectomy have gained overwhelming acceptance. Laparoscopic cytoreductive nephrectomy has been found to be feasible for select patients with metastatic renal cell carcinoma. Minimally invasive nephron-sparing approaches, such as cryoablation, radiofrequency ablation, and laparoscopic partial nephrectomy, continue to generate great interest, but follow-up remains limited. Early data with laparoscopic radical prostatectomy suggest excellent continence rates and equivalent oncologic results based on pathologic surrogates of cure. However, long-term data are still needed, in addition to validated information regarding return of erectile function and quality of life. Other novel therapies, such as laparoscopic radical cystectomy with urinary diversion and laparoscopic retroperitoneal lymph node dissection, hold great promise of benefiting patients with urologic malignancies.

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J Urol. 2003 Oct;170(4 Pt 1):1085-7.
Delaying radical cystectomy for muscle invasive bladder cancer results in worse pathological stage.
Chang SS, Hassan JM, Cookson MS, Wells N, Smith JA Jr.
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2765, USA. sam.chang@vanderbilt.edu

PURPOSE: While radical cystectomy remains the treatment of choice for invasive transitional cell carcinoma, the importance of its timing has been increasingly scrutinized. We determined whether the interval between diagnosis of muscle invasion and definitive radical cystectomy influenced pathological staging outcome. MATERIALS AND METHODS: Of the 303 patients who underwent radical cystectomy from January 1998 to December 2001, 153 were diagnosed with muscle invasive transitional cell carcinoma at transurethral resection. Charts were reviewed for pathological stage, demographics and time between diagnosis of muscle invasion and radical cystectomy. RESULTS: Mean patient age was 67.2 years (range 35 to 88) with the majority (121 of 153, 79%) being male. At the time of cystectomy, 68 of 153 (44%) patients had organ confined disease (pT2B or lower), while node positive disease was found in 58 of 153 patients (38%). Mean time from transurethral resection diagnosis of muscle invasive disease until cystectomy was 63 days (range 8 to 473). A statistically significant correlation existed between time of diagnosis and cystectomy, and final pathological stage. Specifically, those patients with an interval greater than 90 days were more likely to have pT3 or higher, nonorgan confined disease compared to those patients undergoing cystectomy before 90 days (81% versus 52%, p = 0.01). Furthermore, those patients with organ confined disease had a significantly shorter mean time between diagnosis and cystectomy of 47.5 days versus 75.1 days for nonorgan confined disease (t test p = 0.02). CONCLUSIONS: In patients with muscle invasion at diagnosis, a delay in surgery is associated with more advanced pathological stage, especially when the delay is longer than 90 days. While appropriate time should be given for consideration of options and pretreatment evaluation, undue delay may compromise cancer control.

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Dis Colon Rectum. 2003 Sep;46(9):1182-8.
Physiologic changes of the anorectum after pelvic radiotherapy for the treatment of prostate and
bladder cancer.
Kushwaha RS, Hayne D, Vaizey CJ, Wrightham E, Payne H, Boulos PB.
Department of Surgery, Royal Free and University College Medical School, and dagger Meyerstein Institute of Oncology, The Middlesex Hospital, London, United Kingdom.

INTRODUCTION: The effect of pelvic radiotherapy on anorectal function is not clearly documented and is investigated in this prospective study. METHODS: Thirty-one males (median age, 70 years) with carcinoma of the prostate (n = 28) and bladder (n = 3) completed proctitis/incontinence symptom score questionnaires and anorectal physiology studies before and six weeks after pelvic radiotherapy. At six months after completion of radiotherapy, 25 of these patients were studied again. The results were expressed as medians and ranges and compared by the Mann-Whitney U test (2-tailed). RESULTS: Six weeks and six months after treatment, respectively, the proctitis symptom scores (0 (0-4) vs. 2 (0-7) (P < 0.001) vs. 2 (0-5) (P < 0.001)) and the incontinence symptom scores (0 (0-5) vs. 4 (0-11) (P < 0.001) vs. 3 (0-14) (P < 0.001)) increased. Urgency, frequency of defecation, anorectal pain, incontinence to liquid stool and to flatus, and alteration in lifestyle were significant symptoms after treatment. The following measurements decreased: anal canal resting pressure (83 (35-137) vs. 79 (26-152) (P = NS) vs. 71 (29-97) (P < 0.01) cm H2O), the squeeze increment (152 (51-135) vs. 162 (63-321) (P = NS) vs. 108 (45-296) (P < 0.042) cm H2O), and the maximum tolerated rectal volume (245 (115-450) vs. 194 (112-344) (P < 0.05) vs. 200 (109-350) (P < 0.138) ml). The rectal electrosensory threshold increased (20 (5.4-44) vs. 22 (9-50.5) (P < 0.134) vs. 31.5 (13.6-76) (P < 0.001) mA). CONCLUSIONS: Anorectal symptoms at six weeks after pelvic radiotherapy are related to reduced rectal capacity and compounded at six months by diminished internal and external sphincter function and rectal mucosal sensitivity.

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J Urol. 2003 Sep;170(3):964-9.
Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer.
Bohle A, Brandau S.
Department of Urology, HELIOS Agnes Karll Hospital, Am Hochkamp 21, 23611 Bad Schwartau, Germany. aboehle@badschwartau.helios-kliniken.de

PURPOSE: Of all medical disciplines it is exclusively in urology in which immunotherapy for cancer has an established position today with intravesical bacillus Calmette-Guerin (BCG) against superficial bladder carcinoma recurrences. BCG is regarded as the most successful immunotherapy to date. However, the mode of action has not yet been fully elucidated. We provide a thorough overview of this complex field of research. MATERIALS AND METHODS: Rather than simply reporting all experimental data available for better understanding the involved immune mechanisms, we chose to provide comprehensively only information supported by several independent pathways of evidence. RESULTS: Major findings made during the last few years include systematic analyses of patient material, detailed in vitro studies and investigations in animal models, which have led to a substantially greater understanding of the mechanisms involved. CONCLUSIONS: The efficacy of BCG is based on a complex and long lasting local immune activation. The bladder as a confined compartment, in which high local concentrations of the immunotherapy agent and effective recruitment of immune cells can be achieved, serves as an ideal target organ for this type of immunotherapy approach.

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Eur J Cancer. 2003 Sep;39(13):1866-71
Phase II trial of pegylated-liposomal doxorubicin in the treatment of locally advanced unresectable or metastatic transitional cell carcinoma of the urothelial tract.
Winquist E, Ernst DS, Jonker D, Moore MJ, Segal R, Lockwood G, Rodgers A.
Division of Medical Oncology, Ontario N6A 4L6, London, Canada. eric.winquist@lrcc.on.ca

34 patients with advanced unresectable or metastatic urothelial carcinoma who had not received prior chemotherapy for metastatic disease were treated with pegylated-liposomal doxorubicin (PLD) 50 mg/m(2) by a 1-h intravenous infusion (i.v.) every 4 weeks in a multi-institutional phase II trial. 6 of 30 evaluable patients had a partial response to treatment (20%; 95% Confidence Interval (CI), 8-39%) and seven patients had stable disease. Toxicities were primarily non-haematological, but severe palmar-plantar erythrodysesthesia (PPE), lethargy and anorexia were infrequent. Despite a high proportion of patients with poor prognostic features, PLD had clinically significant activity in urothelial cancer in this study. The activity and unique toxicity profile of this drug make it of interest for further study in advanced urothelial cancers in combination with other active agents.

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J Urol. 2003 Aug;170(2 Pt 1):433-7.
Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term
observational study.
Grimm MO, Steinhoff C, Simon X, Spiegelhalder P, Ackermann R, Vogeli TA.
Department of Urology, Heinrich-Heine University, Dusseldorf, Germany.

PURPOSE: We determined the long-term outcome in patients with superficial bladder cancer (Ta and T1) undergoing routine second transurethral bladder tumor resection (ReTURB) in regard to recurrence and progression. MATERIALS AND METHODS: We performed an inception cohort study of 124 consecutive patients with superficial bladder cancer undergoing transurethral resection and routine ReTURB (83) between November 1993 and October 1995 at a German university hospital. Immediately after transurethral resection all lesions were documented on a designed bladder map. ReTURB of the scar from initial resection and other suspicious lesions was performed at a mean of 7 weeks. Patients were followed until recurrence or death, or a minimum of 5 years. RESULTS: Residual tumor was found in 33% of all ReTURB cases, including 27% of Ta and 53% of T1 disease, and in 81% at the initial resection site. Five of the 83 patients underwent radical cystectomy due to ReTURB findings. The estimated risk of recurrence after years 1 to 3 was 18%, 29% and 32%, respectively. After 5 years 63% of the patients undergoing ReTURB were still disease-free (mean recurrence-free survival 62 months, median 87). Progression to muscle invasive disease was observed in only 2 patients (3%) after a mean observation of 61 months. CONCLUSIONS: These data suggest a favorable outcome regarding recurrence and progression in patients with superficial bladder cancer who undergo ReTURB. ReTURB is suggested at least in those at high risk when bladder preservation is intended.

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Lancet Oncol. 2003 Aug;4(8):489-97.
The systemic treatment of advanced and metastatic bladder cancer.
Hussain SA, James ND.
Cancer Research UK Institute for Cancer Studies, University Hospital Birmingham, Birmingham, UK. hussainsa@cancer.bham.ac.uk <hussainsa@cancer.bham.ac.uk>

Bladder cancer is the second most common genitourinary tumour and is a significant cause of morbidity and mortality. Trials of neoadjuvant and adjuvant chemotherapy have failed to show a survival advantage, although these studies generally had suboptimum design and an insufficient number of patients. Despite the introduction of newer agents, the median survival for metastatic disease is about 1 year; however, improvements in quality of life have been achieved. Platinum drugs should be included in studies of combination chemotherapy regimens wherever possible. There have been various studies exploring the role of taxanes, gemcitabine, ifosfamide, and platinum in double and triple combinations in different schedules to maximise dose intensity and improve effectiveness but large phase III trials are needed. The current tumour, node, and metastasis staging system is insufficient to predict outcome in patients with bladder cancer irrespective of the treatment they received. Evaluation of molecular prognostic markers should be incorporated into phase II and III trials to define their roles in clinical outcome. Future studies should stratify patients according to the number of risk factors they have to avoid imbalance in treatment groups and patients should be carefully selected.

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N Engl J Med. 2003 Aug 28;349(9):859-66.
Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer.
Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED.
M.D. Anderson Cancer Center, Houston, USA.

BACKGROUND: Despite aggressive local therapy, patients with locally advanced bladder cancer are at significant risk for metastases. We evaluated the ability of neoadjuvant chemotherapy to improve the outcome in patients with locally advanced bladder cancer who were treated with radical cystectomy. METHODS: Patients were enrolled if they had muscle-invasive bladder cancer (stage T2 to T4a) and were to be treated with radical cystectomy. They were stratified according to age (less than 65 years vs. 65 years or older) and stage (superficial muscle invasion vs. more extensive disease) and were randomly assigned to radical cystectomy alone or three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy. RESULTS: We enrolled 317 patients over an 11-year period, 10 of whom were found to be ineligible; thus, 154 were assigned to receive surgery alone and 153 to receive combination therapy. According to an intention-to-treat analysis, the median survival among patients assigned to surgery alone was 46 months, as compared with 77 months among patients assigned to combination therapy (P=0.06 by a two-sided stratified log-rank test). In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38 percent vs. 15 percent, P<0.001). CONCLUSIONS: As compared with radical cystectomy alone, the use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy increases the likelihood of eliminating residual cancer in the cystectomy specimen and is associated with improved survival among patients with locally advanced bladder cancer. Copyright 2003 Massachusetts Medical Society

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Int J Radiat Oncol Biol Phys. 2003 Jul 1;56(3):726-33.
Concurrent cisplatin, 5-fluorouracil, leucovorin, and radiotherapy for invasive bladder cancer.
Chen WC, Liaw CC, Chuang CK, Chen MF, Chen CS, Lin PY, Chang PL, Chu SH, Wu CT, Hong JH.
Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan.

PURPOSE: To investigate the tolerance and efficacy of a modified concurrent chemoradiation (CCRT) protocol for patients with invasive bladder cancer "unfit" for radical cystectomy. METHODS AND MATERIALS: Twenty-three muscle-invasive bladder cancer patients who were unfit for or unwilling to receive radical cystectomy were enrolled in this study. All patients had transitional cell carcinoma of bladder, and distribution of stage was 14 (61%), 1 (4%), and 8 (35%) for T3a, T3b, and T4, respectively. This study included a relatively old-age population, with the median age being 75 and 70% of patients over 70 years old. Patients were treated with maximal transurethral resection of the bladder tumor followed by curative CCRT. The chemotherapy (C/T) regimen was comprised of cisplatin, 50 mg/m(2) intravenously (i.v.) on Day 1; 5-fluorouracil (5-FU), 500 mg/m(2)/day by continuous i.v. infusion on Days 1-3; and leucovorin, 50 mg/day by continuous i.v. infusion on Days 1-3. Chemotherapy course was repeated at 21-day intervals. The radiation dose was 44-45 Gy to whole pelvis and 60-61.2 Gy to bladder, with a daily fraction of 1.8-2 Gy. The completeness of the CCRT protocol was defined as patients receiving at least 55 Gy of radiotherapy to the whole bladder and at least three courses C/T. RESULTS: Seventy-four percent of patients (17/23) completed the CCRT protocol. Radiation Therapy Oncology Group (RTOG) Grade 3 acute toxicities were observed in 4 patients, which included leucopenia, vomiting, genitourinary (GU) tract infection, and diarrhea. No treatment-related deaths occurred during the CCRT period. RTOG Grade 3 or more late complications were observed in 3 patients; one of them died of radiation cystitis superimposed with GU infection. Of the 18 patients whose response to CCRT was evaluated, a complete tumor response was documented in 16 patients (89%). With a median follow-up of 3 years, the 3-year overall survival (OS) and disease-free survival (DFS) for all patients was 69% and 65% respectively. Meanwhile, the 3-year overall and DFS rates for patients who completed CCRT vs. those who did not complete CCRT were 82% vs. 33% and 75% vs. 33%, respectively (p = 0.18 for OS and p = 0.04 for DFS). CONCLUSIONS: Concurrent cisplatin, 5-FU, leucovorin, and radiotherapy for treatment of invasive bladder cancer is a feasible and promising treatment even for relatively old patients. Our results are comparable to those in recent studies by using combined modality treatment or neoadjuvant chemotherapy plus radical cystectomy. Consequently, this novel protocol warrants a prospective clinical trial and may be a safe, effective alternative to radical cystectomy.

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Vopr Onkol. 2003;49(2):235-8.
[Combined therapy for patients with invasive bladder cancer]
[Article in Russian]
Startsev VIu, Karelin MI.
Central Research Institute of Roentgeno-Radiology, St. Petersburg.

Organ preservation has been investigated inmuscle-invasivebladder cancer over the past years as an alternative to standard radical cystectomy. However, the morbidity of radical cystectomy and early reports of good results of radical transuretheral resection of bladder tumors (TURBT) have stimulated interest in combined treatment for muscle-invasive bladder cancer. Organ preservation requires a trimodal schedule, including transuretheral surgery, mega voltage radical external beam radiotherapy (EBRT) and adjuvant chemotherapy (ACT). Our results point to the effectiveness of combined therapy of urinary bladder in old patients with invasive, advanced cancer (stage T2). These results demonstrate the effectness of intra-arterial ACT when used in combination with EBRT.

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Expert Opin Pharmacother. 2003 Jun;4(6):853-8.
Neoadjuvant chemotherapy for bladder cancer: current status.
Dreicer R.
Department of Hematology/Oncology, Desk R35, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. dreicer@cc.ccf.org

Muscle-invasive bladder cancer is typically an aggressive solid tumour with the propensity for early systemic dissemination. Although curative-intent local therapy with either radical cystectomy or radiotherapy remains the gold standard intervention, the high rate of systemic failure has prompted investigators to evaluate various strategies in an attempt to improve survival, including the early administration of systemic chemotherapy. Recently completed, Phase III studies of neoadjuvant chemotherapy trials demonstrated a modest, but real survival advantage for a small subset of patients. Other strategies include, attempts to both preserve the bladder using combinations of limited surgical resection, systemic chemotherapy and radiotherapy. This review focuses on the potential of neoadjuvantly-administered therapies to impact the management of muscle invasive bladder cancer.

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Hinyokika Kiyo. 2003 Jun;49(6):311-5.
[Clinical study of chemoradiotherapy using low dose cisplatinum as X-ray intensifier in patients with urothelial carcinoma]
[Article in Japanese]
Kanno T, Shibasaki N, Ito M, Yoshida H, Tsuji Y, Yoshimura K, Kawase N, Taki Y, Takeuchi H.
Department of Urology, Toyooka Public Hospital.

Chemoradiotherapy using cisplatinum (CDDP) as the X-ray intensifier was performed on patients with urothelial carcinoma. Ten lesions in 9 patients, 6 patients with postoperative relapse and 3 who received the therapy as a palliative treatment for progressive carcinoma, were evaluated. Four of the patients with postoperative relapse had undergone adjuvant chemotherapy. On the day of the treatment, the 9 patients were given continuous intravenous infusion of CDDP at the dose level of 5-12 mg/day prior to external irradiation at 50-66 Gy. The response to the therapy was categorized as complete response in 5 patients, partial response in 4, and no change in 1. The response rate was 90%, indicating achievement of a good local control. Pain relief and improvement of hydronephrosis were also observed in patients who underwent the therapy for treatment of progressive carcinoma. All adverse reactions were mild in intensity. These results suggest that the chemoradiotherapy is useful for both patient groups, those who have a postoperative relapse and those who undergo the therapy as a palliative treatment for progressive carcinoma.

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Urol Nurs. 2003 Jun;23(3):189-91, 199; quiz 192.
Intravesical Bacillus Calmette-Guerin for treating bladder cancer.
Boyd LA.
Southwest Florida Urologic Associates, Cape Coral, FL, USA.

Bladder cancer continues to be a leading cause of malignant neoplasm in men. Since 1976, Bacillus Calmette-Guerin (BCG) has been a recommended treatment for superficial bladder malignancy. BCG treatment indications, administration, side effects, patient education, and nursing implications are discussed.

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Lancet. 2003 Jun 7;361(9373):1927-34.
Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis.
Advanced Bladder Cancer Meta-analysis Collaboration.

BACKGROUND: Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease. METHODS: We analysed updated data for 2688 individual patients from ten available randomised trials. FINDINGS: Platinum-based combination chemotherapy showed a significant benefit to overall survival (combined hazard ratio [HR] 0.87 [95% CI 0.78-0.98, p=0.016]; 13% reduction in risk of death; 5% absolute benefit at 5 years [1-7]; overall survival increased from 45% to 50%). This effect was observed irrespective of the type of local treatment, and did not vary between subgroups of patients. The HR for all trials, including those using single-agent cisplatin, tended to favour neoadjuvant chemotherapy (HR=0.91, 95% CI 0.83-1.01) although this tendency was not significant (p=0.084). Although platinum based combination chemotherapy was beneficial, there was no evidence to support the use of single-agent platinum; indeed, there was a significant difference in the effect between these groups of trials (p=0.044). INTERPRETATION: This improvement in survival encourages the use of platinum-based combination chemotherapy for patients with invasive bladder cancer.

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J Urol. 2003 Jun;169(6):2113-7.
Is there a therapeutic role for post-chemotherapy retroperitoneal lymph node dissection in metastatic transitional cell carcinoma of the bladder?
Sweeney P, Millikan R, Donat M, Wood CG, Radtke AS, Pettaway CA, Grossman HB, Dinney CP, Swanson DA, Pisters LL.
Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

PURPOSE: We identified a subset of patients with bladder cancer (transitional cell carcinoma) and regional nodal metastasis to the retroperitoneal lymph nodes without detectable systemic dissemination. While the majority of these patients respond initially to chemotherapy, most have disease relapse at the same site within a year. We report the results of a phase II study exploring the potential benefit of retroperitoneal lymph node dissection in patients with transitional cell carcinoma of the bladder in whom disease has shown a significant response to chemotherapy. MATERIALS AND METHODS: A total of 11 patients with biopsy proven metastatic transitional cell carcinoma in the retroperitoneal lymph nodes and no evidence of visceral metastatic disease in whom disease showed a significant response to chemotherapy underwent complete bilateral retroperitoneal lymph node dissection. The end point of study was disease specific survival, calculated from the time of retroperitoneal lymph node dissection to death from transitional cell carcinoma of the bladder. RESULTS: Four patients underwent delayed retroperitoneal lymph node dissection. Seven patients underwent concurrent cystectomy, and pelvic and retroperitoneal lymph node dissection. There was no perioperative mortality. Nine patients had evidence of residual disease in the retroperitoneal nodes. Seven patients have recurrence outside of the original surgical field with a median time to recurrence of 7 months and 6 died at a median time to death of 8 months (range 5 to 14). One patient with retrocrural recurrence attained a complete response to salvage chemotherapy and remained disease-free 57 months after retroperitoneal lymph node dissection. For all 11 patients median disease specific and recurrence-free survival rates were 14 and 7 months, respectively. Four-year disease specific and recurrence-free survival rates were 36% and 27%, respectively. We stratified the patients based on the number of involved lymph nodes at retroperitoneal lymph node dissection and noted that viable tumor in no more than 2 lymph nodes correlated with greater disease specific and recurrence-free survival (p = 0.006 and 0.01, respectively). CONCLUSIONS: Retroperitoneal lymph node dissection can be safely performed for metastatic transitional cell carcinoma. Retroperitoneal lymph node dissection has curative potential, particularly in patients with viable tumor in no more than 2 lymph nodes after chemotherapy.

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Actas Urol Esp. 2003 Jun;27(6):438-41.
[Oral tegafur plus mitomycin versus intravesical mitomycin alone in the prevention of recurrence in stage Ta bladder tumors]
[Article in Spanish]
Server Pastor G, Rigabert Montiel M, Banon Perez V, Valdelvira Nadal P, Cao Avellaneda E, Garcia Hernandez JA, Perez Albacete M.
Servicio de Urologia, Hospital Universitario Virgen de La Arrixaca, Murcia.

OBJECTIVE: The aim of this study is to know if the use of oral Tegafur associated to intravesical mitomycin is effective in the prevention of the relapses of Ta bladder tumors. METHOD: This is a prospective study in which we compare the recurrence rate and the disease-free interval of 2 groups of 40 patients each one, the first of them treated after the TUR with oral Tegafur and intravesical mitomycin, and the second with intravesical mitomycin alone. Tolerance of Tegafur was also studied. RESULTS: The group of the Tegafur presented a descent of the relapse rate and a continuation of the time free of illness; but it was not statistically significant. The tolerance to the drug was good, without important adverse effects. CONCLUSIONS: Tegafur seems an useful drug in the prevention of the recurrence of superficial bladder tumors, although it will be necessary bigger studies to reach statistically valid conclusions.

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Cochrane Database Syst Rev. 2003;(3):CD003231.
Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer.
Shelley MD, Court JB, Kynaston H, Wilt TJ, Coles B, Mason M.
Research Laboratories, Velindre NHS Trust, Velindre Road, Whitchurch, Cardiff, Wales, UK, CF14 2TL.

BACKGROUND: Tumour recurrence following transurethral resection (TUR) for Ta and T1 bladder cancer is a major clinical problem. Intravesical administration of mitomycin C (MMC) or bacillus Calmette-Guerin (BCG) has proven prophylactic activity but both are associated with local and systemic side-effects. A systematic review was carried out to compare the efficacy of these two agents. OBJECTIVES: To undertake a systematic review and meta-analysis comparing intravesical mitomycin C and Bacillus Calmette-Guerin in terms of tumour recurrence, disease progression and overall survival in Ta and T1 bladder cancer. Treatment-related toxicities would also be evaluated. SEARCH STRATEGY: A comprehensive search of MEDLINE, EMBASE, Healthstar, Cochrane Controlled Trials Register, Cancerlit, and DARE was performed, and hand searching of relevant journals undertaken. SELECTION CRITERIA: Trials in any language were included in the meta-analysis if they were properly randomised, included medium to high risk patients with Ta or T1 bladder cancer and compared intravesical MMC versus BCG. DATA COLLECTION AND ANALYSIS: Trial eligibility, methodological quality and data extraction were assessed independently by two reviewers. Time to event analysis was evaluated using log hazard ratios, with a sensitivity analysis for subgroups according to patient's risk of recurrence. MAIN RESULTS: Twenty-five articles were identified but only seven were considered eligible. This represented 1901 evaluable patients in total, 820 randomised to MMC and 1081 to BCG. Six trials had sufficient data for meta-analysis and included 1527 patients, 693 in the mitomycin arm and 834 in the BCG arm. The weighted mean log hazard ratio (variance) for tumour recurrence for the six trials was - 0.022 (0.005). This indicated no significant difference between MMC and BCG (p = 0.76). However, the meta-analysis indicated evidence of significant heterogeneity between trials (p = 0.001). A subgroup analysis of three trials that included only high risk Ta and T1 patients indicated no heterogeneity (p = 0.25) and a log hazard ratio (variance) for recurrence of -0.371 ( 0.012). With MMC used as the control in the meta-analysis, a negative ratio is in favour of BCG and, in this case, is highly significant (p = 0.0008). The seventh trial, in abstract form only, used BCG in low doses for two arms of the trial (27 mg and 13.5mg) compared to a standard dose of mitomycin C (30mg), and reported a significantly reduced recurrent rate with BCG (27mg) compared to mitomycin C (p = 0.001). Only two trials included sufficient data to analyse disease progression and survival, representing a total of 681 patients; 338 randomised to BCG and 343 to MMC. There was no significant difference between MMC and BCG for disease progression (log hazard ratio + variance: 0.044 + 0.04, p = 0.16) or survival (-0.112 + 0.03, p = 0.50). Local toxicities (dysuria, cystitis, frequency, and haematuria) were associated with both MMC (30%) and BCG (44%). Systemic toxicities, such as chills, fever and malaise, were observed with both MMC and BCG (12% and 19%, respectively) although skin rash was more common with MMC. REVIEWER'S CONCLUSIONS: The data from the present meta-analysis indicate that tumour recurrence was significantly reduced with intravesical BCG compared to MMC only in the subgroup of patients at high risk of tumour recurrence. However, there was no difference in terms of disease progression or survival, and the decision to use either agent might be based on adverse events and cost.

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Curr Opin Oncol. 2003 May;15(3):227-33.
Bladder cancer.
Borden LS Jr, Clark PE, Hall MC.
Department of Urology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.

Bladder cancer is a significant public health problem responsible for more than 130,000 deaths annually worldwide. Disease prevalence is also remarkable, with more than 500,000 patients carrying the diagnosis in the United States alone. Significant progress has been made in understanding the underlying molecular and genetic events in bladder cancer. However, there remains a great need for the development of reliable markers that can provide clinically useful information regarding diagnosis and prognosis and to facilitate the selection of appropriate therapy in the individual patient. Ongoing and future investigation is anticipated to refine treatment of patients with high-risk superficial disease, to determine the role of neoadjuvant and adjuvant chemotherapy for high-risk invasive disease, and to improve the efficacy of chemotherapy for patients with metastatic bladder cancer.

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Semin Oncol. 2003 Apr;30(2 Suppl 5):34-41.
Gallium nitrate in the treatment of bladder cancer.
Einhorn L.
Department of Medicine, Indiana University, Indianapolis, IN 46202, USA.

For over 15 years, the MVAC regimen (methotrexate/vinblastine/doxorubicin/cisplatin) has been standard chemotherapy for patients with unresectable or metastatic bladder cancer. The taxanes and gemcitabine have provided new treatment options, but development of more effective regimens is needed. Gallium nitrate has significant activity as a single agent in the treatment of advanced bladder cancer, including activity in heavily pretreated patients and patients previously treated with MVAC or single-agent cisplatin. At a dosage of 300 mg/m(2) daily by continuous infusion for 5 to 7 days every 3 weeks, toxicity has been acceptable in the treatment of patients with refractory disease. Gallium nitrate is also active in combination regimens for advanced bladder cancer. Because it has a different mechanism of action, minimal myelosuppression, and activity in previously treated patients, gallium nitrate may be useful as a single agent in patients with advanced bladder cancer who fail front-line chemotherapy regimens. Evaluation of gallium nitrate in combination with newer agents such as the taxanes or gemcitabine may also be warranted given its activity, different mechanism of action, and non-overlapping toxicity profile. Copyright 2003 Elsevier Inc. All rights reserved.

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Actas Urol Esp. 2003 Apr;27(4):274-80.
[Mucinous adenocarcinoma of the bladder]
[Article in Spanish]
Palmero Marti JL, Queipo Zaragoza JA, Bonillo Garcia MA, Budia Alba A, Vera Sempere FJ, Jimenez Cruz JF.
Servicio de Urologia, Hospital Universitario La Fe, Valencia.

Mucinous adenocarcinoma is a rare entity within the group of primary adenocarcinoma of the bladder which represent 0.5-2% of all malignant epithelial bladder tumours. In spite of the rarity of this tumoral type; it is a poor prognosis entity mainly due to its diagnosis especially in advanced stage of the disease. There is no general agreement on the treatment of adenocarcinoma of bladder. Not withstanding surgery would be the only curative treatment, although unfortunately, it is curative in just a few cases. We report six cases with mucinous adenocarcinoma of the bladder attended in our Department in the last ten years (january 1991-december 2001). In one of them a radical cystectomy was performed, while transurethral resection with or without adjuvant treatment was practiced in the other one. Only one patient is alive today, namely, the one where the tumour not invade the muscular tissue. These findings show the discouraging results of this entity closely intertwined with the pathologic stage.

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Anticancer Res. 2003 Mar-Apr;23(2C):1903-6.
Gemcitabine and oxaliplatin in advanced transitional cell carcinoma of the urothelium: a pilot study.
Culine S, Rebillard X, Iborra F, Mottet N, Faix A, Ayuso D, Pinguet F.
Department of Medical Oncology, C.R.L.C. Val d'Aurelle, Parc Euromedecine, 34598-Montpellier, France. stculine@valdorel.fnclcc.fr

BACKGROUND: Despite the fact that new drugs have emerged from clinical research in urothelial cancer during the last decade, the prognosis of patients with advanced disease remains poor with a median survival of 12 to 14 months. We designed a feasibility study of gemcitabine and oxaliplatin (GO) in patients with advanced urothelial cancer. PATIENTS AND METHODS: Twenty patients received bimonthly cycles of gemcitabine 1500 mg/m2 and oxaliplatin 85 mg/m2. The cycles were given at 2-week intervals without G-CSF support. Thirteen patients were treated with the GO combination as first-line chemotherapy because of a poor performance status or a creatinine clearance < 1 ml/s. RESULTS: The median number of cycles of GO was 5 (1-7). The median number of days between cycles was 14 throughout the treatment. Seven (8%) out of 87 cycles had to be delayed because of neutropenia or asthenia. A 25% dose reduction in the doses of cytotoxic drugs was necessary in 2 patients. Chemotherapy was stopped before the sixth cycle because of an early death related to a myocardial infarction in 1 patient, a grade 3 neuropathy in 1 patient and a progressive disease in 9 patients. CONCLUSION: Using these doses and schedules, the GO regimen appears a safe therapy for patients with advanced urothelial cancer. Phase II studies are required to assess the possible role of this combination in advanced urothelial cancer.

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Ai Zheng. 2003 Apr;22(4):421-3.
[Intravesical instillation of pirarubicin (THP) together with polyvinylpyrrolidone (PVP) in the prevention of postoperative recurrence of superficial bladder cancer]
[Article in Chinese]
Yu ZX, Weng ZL, Chen W, Zhang FY, Zhou XS, Li CD.
Department of Urology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, PR China. yuzhix@wz163.com

BACKGROUND & OBJECTIVE: Superficial bladder transitional cell carcinoma is aggressive and tends to recurrence after operation. In order to prevent the relapse of bladder neoplasms,this study was designed to explore the effect of intravesical instillation of pirarubicin (THP) together with polyvinylpyrrolidone (PVP) on patients with superficial bladder cancer who had undergone surgical operation. METHODS: A total of 34 cases were enrolled from October 1999 to May 2002. After one week of operation, pirarubicin (20 mg) dissolved in 10 ml normal saline plus 20 ml PVP was instilled into bladder, and was retained for 60 minutes. In the following 7 weeks, intravesical instillation of pirarubicin was administered once a week. Subsequently it was done bi-monthly, finally once a month for 6 months. RESULTS: Follow-up was performed for 5-26 months (mean:17.2 months). Among the 34 cases, recurrence was found in 2 cases (5.8%),bladder irritation in 6 cases (17.6%) and hematuria in 4 cases (11.7%) as well. CONCLUSION: Intravesical instillation of THP/PVP is effective for prevention of postoperative recurrence of superficial bladder cancer with fewer side effects. Further study is needed for wide use in such way.

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Croat Med J. 2003 Apr;44(2):187-92.
Immunoprophylactic intravesical application of bacillus Calmette-Guerin after transurethral resection of superficial bladder cancer.
Librenjak D, Situm M, Eterovic D, Dogas Z, Gotovac J.
Department of Urology, Split University Hospital, Soltanska 2, 21 000 Split, Croatia. davor.librenjak@krizine.kbsplit.hr

AIM: To evaluate the effect of intravesical instillation of Bacillus Calmette-Guerin (BCG) in the prevention of recurrence and progression of the superficial bladder cancer. METHODS: Between February 1989 and May 1994, 170 patients with histologically proven superficial transitional cell carcinoma of the bladder stage Ta and T1 were assessed as eligible for 6-week + 6-month protocol of intravesical BCG instillation at the Split University Hospital. All patients underwent complete transurethral resection of the tumor, which established tumor size, histology, stage, and absence of muscle invasion. Out of 170 patients offered to receive intravesical BCG instillations, 80 agreed to undergo the treatment (BCG group), and 90 refused it (control group). The median duration of follow-up was 64 months (range, 16-128). RESULTS: The BCG group had lower incidence rates of recurrence (12 vs 26 events per 100 patient-years in controls, p<0.001) and progression (3.0 vs 6.6 events per 100 patient-years in controls, p=0.017, large-sample one-sample binomial test in both cases) than the control group, but similar mean intervals to first recurrence or progression. The 5-year recurrence-free rates were 55% in BCG patients and 31% in controls, and in case of progression, 86% and 70%, respectively. Cox regression showed that the independent predictors of recurrence were tumor size (p<0.001), absence of BCG treatment (p=0.002), and patient age (p=0.05). The single independent predictor of tumor progression was absence of BCG treatment, but only in case of tumor grade III (roughly doubling the relative risk of the event). CONCLUSION: Our data suggest that BCG intravesical instillation, using 6 week + 6 month scheme, prevents against recurrence and progression of superficial bladder tumors. This treatment should be especially advocated in patients with advanced grade tumors, but the scheme remains to be evaluated against other BCG treatment schemes.

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Cancer. 2003 Apr 15;97(8 Suppl):2115-9.
Overview of bladder cancer trials in the Radiation Therapy Oncology Group.
Shipley WU, Kaufman DS, Tester WJ, Pilepich MV, Sandler HM; Radiation Therapy Oncology Group.
Genitourinary Oncology Committee, Radiation Therapy Oncology Group, American College of Radiology, Philadelphia, Pennsylvania, USA. wshipley@partners.org

In the United States, radical cystectomy is viewed as the gold standard and, with few exceptions, is the only treatment recommended for patients with invasive bladder cancer. In many areas of cancer treatment, however, the trend in the 1990s has been toward organ conservation using combined chemotherapy and radiation with or without conservative local surgery. For patients with breast, esophageal, anal, and laryngeal cancers as well as limb sarcomas, conservative therapy often is recommended. However, invasive bladder cancer has not been viewed generally as a condition that allows for conservative management. In the past 15 years, the Radiation Therapy Oncology Group (RTOG) has completed six prospective protocols of combined-modality therapy for patients with muscle-invasive cancer who were candidates for cystectomy. Bladder preservation with intravesical surgery, chemotherapy, and radiation therapy were combined as initial treatment, with radical cystectomy recommended for incomplete responders. Five of the RTOG protocols were Phase I-II trials of concurrent chemotherapy and radiation therapy, and one protocol was a Phase III trial that tested the efficacy of adjuvant chemotherapy with methotrexate, cisplatin, and vinblastine. A total of 415 patients were entered on these trials. The 5-year overall survival rate was approximately 50%, with three-quarters of those patients achieving a cure for their bladder cancer while maintaining a functioning bladder. The current RTOG protocol and its successor are directed toward better tolerated and potentially more effective chemotherapy regimens that may result in a high protocol compliance rate and, possibly, a higher overall survival rate. The trimodality therapeutic approach used in all of these RTOG protocols was more effective compared with the radiation monotherapy offered in the 1970s and with protocols that used only chemotherapy. Trimodality therapy with selective bladder preservation is not designed to take the place of radical cystectomy; however, it may be offered as a reasonable alternative to patients with invasive bladder cancer who are not willing to undergo radical cystectomy and urinary diversion. A bladder-sparing strategy may be offered appropriately to highly selected patients with the understanding that radical cystectomy is an available option in those who fail combined radiation and chemotherapy with no diminution in survival related to the delay in cystectomy. Copyright 2003 American Cancer Society

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Cancer. 2003 Apr 15;97(8 Suppl):2120-6.
Overview of bladder cancer trials in the European Organization for Research and Treatment.
de Wit R; European Organization for Research and Treatment.
Department of Medical Oncology, Rotterdam Cancer Institute and Erasmus University Medical Center, Rotterdam, The Netherlands. wit@onch.azr.nl

In the 1990s, the European Organization for Research and Treatment of Cancer Genito-Urinary (EORTC GU) Group focused on dose-intensity concepts of the methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) regimen for patents with bladder cancer. In a randomized trial in patients with advanced urothelial cell cancer, standard MVAC was compared with 2-weekly intensified MVAC plus granulocyte-colony stimulating factor (G-CSF) support. Although the dose-intensified therapy resulted in a higher overall and complete response rates, it did not result in a better median survival. In parallel, the Spanish Oncology Genitourinary Group (SOGUG), in collaboration with the EORTC GU Group, conducted Phase I and II trials to investigate the feasibility and efficacy of the incorporation of two new active agents, gemcitabine and paclitaxel, into two-drug or three-drug cisplatin-based or carboplatin-based regimens. The EORTC GU Group currently is conducting randomized studies of combined paclitaxel, cisplatin, and gemcitabine compared with combined gemcitabine plus cisplatin in patients with good performance status and good renal function and studies of combined gemcitabine plus carboplatin compared with combined carboplatin, methotrexate, and vinblastine in patients who are unsuited for cisplatin. In the 1990s, the EORTC coordinated a large Intergroup study of neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy versus no chemotherapy before definitive treatment. That study included 976 patients and was based on a design to detect at least a 10% absolute improvement in survival. The final results showed a 5.5% survival difference at 3 years in the chemotherapy arm. The EORTC GU Group currently is coordinating an Intergroup study that was designed to detect an improvement of 7% in absolute survival in the adjuvant setting. Cancer 2003;97(8 Suppl):2120-6. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11288

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Gene Ther 2003 Jan;10(2):172-9
Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo.
Chester JD, Kennedy W, Hall GD, Selby PJ, Knowles MA.
Cancer Research UK Clinical Centre in Leeds, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.

Existing local therapies for superficial transitional cell carcinoma (TCC) of the bladder have limited success in preventing progression to life-threatening, muscle-invasive disease, and novel therapies are needed. Recent studies have raised doubts concerning the feasibility of adenovirus-mediated gene therapy for bladder cancer. We have therefore investigated adenoviral transduction of normal and malignant human urothelial cells, both as primary cultures and in intact epithelium.All 15 primary normal human urothelial cell lines tested were transduced in vitro by Adv-cmv-beta-gal at high efficiency, and better than most human TCC cell lines. Eight primary human TCC explants were also successfully transduced. In contrast, in intact normal urothelium, transduction efficiency was lower, and occurred only in superficial epithelial layers. Expression of the hCAR adenovirus receptor, however, occurred throughout the full thickness of urothelium. Transduction of human TCC biopsy specimens was at least as efficient as intact normal urothelium.We demonstrate for the first time that adenoviral transduction of both normal and malignant human urothelial cells is feasible. A physical barrier, rather than hCAR status, may be the main determinant of transduction of intact epithelium. Clinical trials of adenovirus-mediated gene therapy for superficial bladder cancer are warranted.

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Cancer 2003 Jan 1;97(1):71-8
Epirubicin and meglumine gamma-linolenic acid: a logical choice of combination therapy for patients with superficial bladder carcinoma.
Harris NM, Anderson WR, Lwaleed BA, Cooper AJ, Birch BR, Solomon LZ.
Solent Department of Urology, St. Mary's Hospital, Portsmouth, Hampshire, United Kingdom. neilandjane@supanet.com

BACKGROUND: Anthracyclines have been established as first-line drugs for intravesical use in the treatment of patients with superficial bladder carcinoma, although they result only in a modest reduction in tumor recurrence rates. The essential fatty acid gamma-linolenic acid (GLA) also is an effective cytotoxic agent against superficial bladder carcinoma when it is applied topically. The objective of this study was to assess the efficacy of combined epirubicin and GLA with the purpose of developing a suitable model for modification of existing intravesical regimens. METHODS: The human urothelial carcinoma cell lines MGH-U1 and RT112 were used in standard cytotoxicity assays and were exposed to meglumine GLA (MeGLA) and epirubicin in two-dimensional concentration matrices. A thiozolyl blue (methyl-thiazoldiphenyl tetrazolium) assay was used to determine residual cell biomass. Drug interaction was quantified by median-effect analysis software (CalcuSyn), and the evaluation of drug uptake utilized fluorescence confocal microscopy (FCM) and flow cytometry. RESULTS: MeGLA caused a significant enhancement of anthracycline uptake, viewed by FCM, from 92 fluorescence units to 222 fluorescence units (P < 0.001). Flow cytometry confirmed the increased drug uptake and showed that the mean epirubicin content per cell increased from 23 to 57 units and from 8 to 24 units for MGH-U1 and RT112 cells, respectively (99% confidence interval < 0.3). This resulted in improved cytotoxicity, and it was shown that the drugs acted synergistically with all but the highest MeGLA concentrations. CONCLUSIONS: The efficacy of epirubicin was enhanced significantly when it was used in combination with most concentrations of MeGLA (< 300 microg/mL), and the two agents acted synergistically. There was a corresponding increase in epirubicin uptake by cells under these conditions. At high MeGLA concentrations, however, anthracycline solubility was compromised, and drug synergy was lost. Copyright 2003 American Cancer Society.

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J Clin Oncol 2003 Feb 15;21(4):690-6
Radical cystectomy for bladder cancer today—a homogeneous series without neoadjuvant therapy.
Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, Studer UE.
Department of Urology, University of Bern, Anna-Seiler Haus, CH-3010 Bern, Switzerland. madersbacher@hotmail.com

PURPOSE: To investigate the effect of pelvic lymph node dissection and radical cystectomy for transitional cell cancer of the bladder on recurrence-free and overall survival, pelvic recurrences, and metastatic patterns in a homogeneous group. PATIENTS AND METHODS: A consecutive series of patients undergoing pelvic lymphadenectomy and radical cystectomy between 1985 and 2000 was analyzed. All patients were staged N0, M0 preoperatively, and no patient received neoadjuvant radio/chemotherapy. Pathologic characteristics based on the 1997 tumor-node-metastasis system, recurrence-free/overall survival, and metastatic patterns were determined. RESULTS: Five hundred seven patients (age 66 +/- 12 years) with a mean follow-up time of 45 months (range, 0.1 to 176 months) were analyzed. Five-year recurrence-free and overall survival were, respectively, 73% and 62% for patients with organ-confined, lymph node-negative tumors (n = 217; < or = pT2, pN0) and 56% and 49% for non-organ-confined, lymph node-negative tumors (n = 166; > pT2, pN0). Positive lymph nodes were found in 124 (24%) patients who had a 5-year recurrence-free (33%) or overall (26%) survival. Isolated local recurrences were observed in 3% of patients with organ-confined tumors (< or = pT2, pN0), 11% with non-organ-confined tumors (> pT2, pN0), and 13% with positive lymph nodes (any pT, pN+). Distant metastases developed in 25% of patients with organ-confined tumors, 37% with non-organ-confined tumors, and 51% with positive lymph nodes. CONCLUSION: Despite negative preoperative staging, pelvic lymphadenectomy and cystectomy for bladder cancer reveal a high percentage of unsuspected nodal metastases (24%) that have a 25% chance for long-term survival. This procedure also ensures a low pelvic recurrence rate even in lymph node-positive patients, and patients with locally advanced cancer have a 56% probability of 5-year recurrence-free survival.

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J Clin Oncol 2003 Feb 15;21(4):697-703
Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the bladder: a phase I and pharmacokinetic study.
Laufer M, Ramalingam S, Schoenberg MP, Haisfield-Wolf ME, Zuhowski EG, Trueheart IN, Eisenberger MA, Nativ O, Egorin MJ.
Department of Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA.

PURPOSE: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer. PATIENTS AND METHODS: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 2'2'-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy. RESULTS: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 weeks. Low concentrations of gemcitabine (< or = 1 microg/mL) were present transiently in plasma of all patients receiving 2,000 mg in 50 mL. Gemcitabine was undetectable in plasma of other patients. dFdU was undetectable in plasma of patients receiving less than 1,500 mg. At doses > or = 1,500 mg, dFdU concentrations increased until 90 to 120 minutes and then declined little, if any. Plasma dFdU concentrations implied absorption of 0.5% to 5.5% of instilled dose. Between 61% and 100% of the gemcitabine dose was accounted for in voided urine. No dFdU was measured in voided urine. CONCLUSION: Intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising efficacy in treatment of superficial bladder cancer.

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J Urol 2003 Mar;169(3):955-60
Prognostic significance of vascular and perineural invasion in urothelial bladder cancer treated with
radical cystectomy.
Leissner J, Koeppen C, Wolf HK.
Department of Urology, Otto-von-Guericke-University, Magdeburg, Germany.

PURPOSE: Data on the prognostic significance of tumor invading lymphatic and blood vessels in bladder cancer are controversial, while little is known about perineural invasion in this tumor. We determined the prognostic value of these parameters in radical cystectomy specimens. MATERIALS AND METHODS: Slides of 283 radical cystectomy specimens obtained from 1986 to 1997 were examined retrospectively with respect to tumor invasion in lymphatic and blood vessels, and perineural spaces. This review was performed while blinded to lymph node tumor involvement or the postoperative disease course. The Kaplan-Meier probability analysis of tumor-free survival and the log rank test were used to determine the prognostic effects of vascular and perineural invasion. Multivariate analysis using the Cox proportional hazards model was also performed. RESULTS: Lymphatic, blood vessel and perineural tumor invasion were present in 54.1%, 13.1% and 47.7% of specimens, respectively. Tumor progressed in 46.3% of patients. On univariate analysis all 3 factors showed strong prognostic significance. However, on multivariate analysis only blood vessel invasion, invasion depth and regional lymph node status were independent prognostic factors (p <0.05). CONCLUSIONS: Lymph node metastases, pT classification and blood vessel invasion are independent prognostic parameters of tumor-free survival that should be used to guide patient treatment after radical cystectomy. Invasion of the blood and lymphatic vessels should be commented on separately in the pathology report.

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Cancer Res 2003 Feb 15;63(4):760-5
Adenoviral-mediated retinoblastoma 94 produces rapid telomere erosion, chromosomal crisis, and caspase-dependent apoptosis in bladder cancer and immortalized human urothelial cells but not in normal urothelial cells.
Zhang X, Multani AS, Zhou JH, Shay JW, McConkey D, Dong L, Kim CS, Rosser CJ, Pathak S, Benedict WF.
Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

Retinoblastoma (RB)94, which lacks the NH(2)-terminal 112 amino acid residues of the full-length RB protein (RB110), is a more potent tumor and growth suppressor than RB110. In this study, Ad-RB94, but not Ad-RB110, produced marked growth inhibition, cytotoxicity, caspase-dependent apoptosis, and G(2)-M block in the human RB-negative, telomerase-positive bladder cancer cell line UM-UC14. This effect was completely inhibited by pretreatment with caspase inhibitors (P < 0.0001). Similar results were seen in RB-positive and other RB-negative bladder cancer cell lines. Ad-RB94 produced rapid telomere length shortening and loss of telomere signal, which was associated with polyploidy and chromosomal aberrations (P < 0.001). Ad-RB94, however, showed no cytotoxicity to telomerase-negative human normal urothelium cells but was highly cytotoxic to telomerase-positive human E6 and E7 immortalized urothelial cells (P < 0.0001). In addition, telomerase-negative cells, which maintain their telomere length through an alternative lengthening of telomeres DNA recombination pathway, showed no cytotoxicity to RB94. These results suggest that the induction of rapid telomere erosion and chromosomal crisis by RB94 in telomerase-positive cancer and in telomerase-expressing immortalized human cells is a major factor in its selective and potent tumor suppression and cytotoxic activity. The lack of cytotoxicity to normal cells should also provide a high therapeutic index when used in gene therapy protocols for the treatment of bladder and other cancers.

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J Urol 2003 Mar;169(3):946-50
Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: analysis of data from the Surveillance, Epidemiology and End Results Program data base.
Konety BR, Joslyn SA, O'Donnell MA.
Department of Urology, University of Iowa, Iowa City, USA.

PURPOSE: The benefit of pelvic lymphadenectomy in patients with bladder cancer remains controversial. We analyzed the impact of lymphadenectomy on disease specific survival in a population based sample of patients with bladder cancer who underwent radical cystectomy. MATERIALS AND METHODS: Analysis included data on 1,923 patients who underwent radical cystectomy for bladder cancer between 1988 and 1996 obtained from the Surveillance, Epidemiology and End Results program cancer registry. We analyzed the impact of the number of lymph nodes examined, number of positive lymph nodes and ratio of positive-to-total number of lymph nodes resected on disease specific and overall survival independent of patient age, gender, stage, race, radiation and chemotherapy. RESULTS: Median followup in cystectomy cases was 63.5 months (range 0 to 131). Patients with 0 to 3 lymph nodes examined were at significantly higher risk of death from bladder cancer than those with greater than 3 (HR 1 to 1.2 versus 0.41 to 0.58). Patients with stages I/in situ, III and IV disease benefited from more extensive lymphadenectomy. In stage IV cases, while the total number of positive lymph nodes removed did not correlate with increased survival, the proportion of excised lymph nodes positive for metastatic bladder cancer tended to correlate with the risk of death from the disease. CONCLUSIONS: These results indicate significantly increased survival rates after cystectomy in patients with bladder cancer diagnosed with stages III or IV disease who have relatively more lymph nodes examined, suggesting that even some with higher stage disease may benefit from extended pelvic lymphadenectomy at cystectomy.

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J Urol 2003 Mar;169(3):943-5
Superiority of ratio based lymph node staging for bladder cancer.
Herr HW.
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

PURPOSE: The current study evaluated lymph node staging and the outcome in patients with lymph node positive bladder cancer after radical cystectomy. MATERIALS AND METHODS: A total of 162 patients with lymph node positive bladder cancer were followed a median of 7.5 years after radical cystectomy and pelvic lymph node dissection for survival and local recurrence. Lymph node disease was stratified by pN stage, the number of positive lymph nodes and the number of positive lymph nodes in relation to the number removed (ratio based pN stage). RESULTS: A median of 13 lymph nodes (range 2 to 32) was examined, showing an average of 3.3 positive lymph nodes per specimen. An increased number of lymph nodes correlated with the identification of lymph node positive cases. The ratio of the number of positive-to-total number of lymph nodes removed better defined surgical outcome than conventional lymph node staging. CONCLUSIONS: Ratio based lymph node staging, which reflects the number of lymph nodes examined and the quality of lymph node dissection, was a significant prognostic variable for survival and local control in patients with lymph node positive bladder cancer after radical cystectomy.

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J Urol 2003 Mar;169(3):931-4; discussion 934-5
Comment in: J Urol. 2003 Mar;169(3):936-7.
T2a transitional cell carcinoma of the bladder: long-term experience with intravesical immunoprophylaxis with bacillus Calmette-Guerin.
Volkmer BG, Gschwend JE, Maier SH, Seidl-Schlick EM, Bach D, Romics I.
Deparment of Urology, University of Ulm, Germany.

PURPOSE: In this prospective study we evaluate the effect of combined transurethral resection of early muscle invasive bladder cancer and immunotherapy with bacillus Calmette-Guerin (BCG) in patients unfit for radical cystectomy or refusing more aggressive therapies. MATERIALS AND METHODS: A total of 22 patients with a mean age 73.6 years were included in the study. Inclusion criteria were histologically proven muscle invasive transitional cell carcinoma of the bladder with a tumor-free second resection and negative staging examinations in patients unfit for radical cystectomy or refusing more aggressive therapies. All patients received 6 weekly instillations of 120 mg. BCG starting 14 to 21 days after the last transurethral resection of the tumor. Followup at 3 months included cystoscopy, urinary cytology, ultrasound of the abdomen and chest x-ray. Every 6 months computerized tomography of the abdomen and bone scans were performed. RESULTS: The overall 5-year survival rate was 69.1%, while the disease specific 5-year survival rate was 94%. One muscle invasive recurrence was noted at 69 months, which was again treated with the same regimen but ultimately led to radical cystectomy 21 months later. One patient died of progressive recurrence in the upper urinary tract. The 5-year recurrence-free survival rate was 46.5%. The only severe complication was BCG pneumonitis. CONCLUSIONS: The data show encouraging results for transurethral resection of bladder tumor with intravesical BCG therapy in select patients with T2a bladder cancer who are not candidates for radical cystectomy.

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Semin Oncol 2002 Dec;29(6 Suppl 18):69-75
Pemetrexed in bladder, head and neck, and cervical cancers.
Paz-Ares L, Ciruelos E, Garcia-Carbonero R, Castellano D, Lopez-Martin A, Cortes-Funes H.
Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain.

Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in a wide range of solid tumors, including cervix, head and neck, and bladder carcinomas, which are the focus of this review. Toxicity, particularly hematologic, is higher in patients with these tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B(12) appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies. Copyright 2002, Elsevier Science (USA). All rights reserved.

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Medicina (Kaunas) 2002;38 Suppl 1:79-83
[Treatment of superficial transitional cell bladder carcinoma. Long-term results of trial comparing transurethral resection alone and adjuvant chemotherapy with Doxorubicin]
[Article in Lithuanian]
Milonas D, Mickevicius J, Mickevicius R, Motiejunas A, Sukys D, Gudinaviciene I.
Urology Clinic of Kaunas Medical University, Lithuania.

OBJECTIVE: We compared the efficacy of transurethral resection alone or transurethral resection followed by bladder instillations of Doxorubicin for 1 year in patients with superficial bladder carcinoma, and followed them long term for the incidence of recurrence and progression to muscle invasion. MATERIALS AND METHODS: Between December 1998 and December 2000 a total of 69 patients with superficial transitional cell carcinoma of bladder participated in this prospective study. Final analysis of treatment results included 64 patients. Doxorubicin was administered to 25 patients, 39 patients were treated only by TUR. Patients were followed by control cystoscopy. RESULTS: The mean follow-up was 22.95 months; SD 7.79. Mean time to first recurrence in Doxorubicin group was 14.14 months; SD 7.84, in TUR alone group - 7.61 months; SD 4.4; p>0.05. Disease free survival was significantly prolonged in Doxorubicin group; p<0.05. There are no significant difference to comparison recurrence rate and progression rate between two groups. CONCLUSIONS: In regard to time of first recurrence and disease free survival this study indicates that adjuvant chemotherapy with Doxorubicin is superior to transurethral resection alone. However, progression in stage or recurrence rate was not influenced by the treatment regimen.

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Anticancer Res 2002 Nov-Dec;22(6C):4073-80
Ex vivo chemosensitivity to mitomycin C in bladder cancer and its relationship with P-glycoprotein and apoptotic factors.
Gontero P, Sargent JM, Hopster DJ, Lewandowic GM, Taylor CG, Elgie AW, Williamson CJ, Sriprasad SI, Muir GH.
Clinica Urologica, Dipartmento di Scienze Mediche, Universita del Piemonto Orientale, Novara, Italy. paolo.gontero@med.unipmn.it

BACKGROUND: Intravesical treatment with mitomycin C (MMC) leads to a complete response rate of around 40% in superficial bladder cancer (TCC). In order to determine in advance which patients will fail to respond, we describe a study assessing the feasibility of applying the ATP assay to test the chemosensitivity of samples from patients with this disease. MATERIALS AND METHODS: TURBT or biopsy samples were received from 27 patients, 23 of which were suitable for the ATP assay (16 primary tumours and 7 recurrences). RESULTS: The success rate of the assay was 91%. There was a marked variation in the effect of MMC between patients with a > 50-fold range in LC50 values (drug concentration required to kill 50% of cells) from 2.99- > 150 microM with a median value of 22.4 microM. We were unable to determine any overall correlation between chemosensitivity and tumour stage or grade or the treatment status of the patient in this small data set. P-glycoprotein status and caspase-3 levels were assessed on these samples using immunohistochemistry but there did not appear to be any relationship between either of these parameters and MMC resistance. Apoptotic counts and mitotic counts were also measured but, whilst these appeared to correlate with grade (p < 0.01), there was no overall significant relationship established with MMC chemosensitivity. CONCLUSION: This study suggests that it is possible to use the ATP assay for chemosensitivity testing in TCCs. Despite a lack of overall correlation between ex vivo MMC resistance and the conventional prognostic factors tested, further studies are warranted in a larger data set to test the ability of this technique to predict clinical outcome in this disease.

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J Urol 2003 Feb;169(2):721-3
Over expression of metallothionein predicts resistance of transitional cell carcinoma of bladder to intravesical mitomycin therapy.
Lynn NN, Howe MC, Hale RJ, Collins GN, O'Reilly PH.
Department of Urology, Stepping Hill Hospital, Stockport, United Kingdom.

PURPOSE: Metallothionein, a low molecular weight intracellular protein, binds mitomycin with high affinity protecting the tumor DNA. We prospectively studied the relationship of metallothionein expression in bladder transitional cell carcinoma and resistance to intravesical mitomycin. MATERIALS AND METHODS: A series of 45 consecutive patients with superficial transitional cell carcinoma treated with intravesical mitomycin were studied. Resected tumor tissues were stained with metallothionein monoclonal antibody E9. Two pathologists scored staining intensity and distribution. All patients were followed with regular flexible cystoscopy. RESULTS: Median patient age was 73 years (range 44 to 89). Tumor grade was 1 to 3 in 6, 33 and 6 cases, respectively. In 20 patients (44.44%) tumor recurred after mitomycin therapy. Median cytoplasmic staining scores for recurrent and nonrecurrent tumors were 5 (range 0 to 61) and 0 (0 to 14), respectively. Median nuclear staining scores for recurrent and nonrecurrent tumors were 3 (range 0 to 56) and 0 (0 to 11), respectively. Median followup of patients without recurrence was 18 months (range 12 to 36). Nuclear and cytoplasmic staining scores were significantly higher in recurrent than in nonrecurrent tumors. There was no significant relationship of metallothionein expression with tumor grade. CONCLUSIONS: Over expression of metallothionein predicts the resistance of bladder transitional cell carcinoma to intravesical mitomycin therapy.

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Anticancer Res 2002 Sep-Oct;22(5):2981-4
Gemcitabine plus Epi-doxorubicin as first-line chemotherapy for bladder cancer in advanced or
metastatic stage: a phase II.
Neri B, Doni L, Fulignati C, Gemelli MT, Turrini M, Di Cello V, Dominici A, Mottola A, Raugei A, Ponchietti R, Cini G.
Department of Internal Medicine, Oncological Day Hospital, Viale Pieraccini 18, 50139 Florence, Italy. brunoneri@unifi.it

Combination chemotherapy with newer, more active drugs in patients with advanced and/or metastatic bladder cancer might show improved response rate and survival. Gemcitabine (GEM) and Epidoxorubicin (EPI) have demonstrated activity in this disease. In addition, experimental studies in vitro have shown that the two agents have additive-synergistic effects when used in combination. Our prior phase I dose-finding study in previously untreated patients with advanced or metastatic bladder cancer defined recommended doses for further trials of GEM 1000 mg/m2 and EPI 25 mg/m2 on days 1, 8 and 15 every 28 days. A phase II trial at this dose level was initiated in previously untreated patients to assess efficacy and toxicity. Eligible patients had measurable disease; Karnofsky performance status (PS) of > 40; no prior chemotherapy; and adequate bone marrow reserve, cardiac, hepatic and renal function. Thirty- one patients (22 males, 9 females) with median age of 64 (range 44-75) and median PS of 80 were accrued, and all were eligible. Twelve patients had T4N1-2 M0, 8 had lymph node only metastases, while 11 had visceral metastases (liver, bone, lung). A total of 181 cycles was administered (range 3-7 per patient). Major toxicities (WHO grade > or = 3) were: neutropenia in 5 patients, thrombocytopenia in 2 patients, and anemia in 2 patients. Three patients had febrile neutropenic episodes and only 3 patients required dose reduction. Grade 1-2 non-hematological toxicities included nausea/vomiting, stomatitis and alopecia. No cardiac toxicity was observed. Of the 30 response evaluable patients, 17 (57%) demonstrated a major response (3 complete and 14 partial) (95% CI: 39%-75%), 7 had stable disease (23%) and 6 progressed (20%). These preliminary results confirm the phase I observation that the combination of GEM--EPI is highly active in the treatment of advanced and metastatic bladder cancer with a favourable toxicity profile.

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Anticancer Res 2002 Sep-Oct;22(5):2971-6
Does P-glycoprotein-170 expression predict for chemoresistance in transitional cell carcinoma
of the bladder?
Sanguedolce R, Calascibetta A, Porcasi R, Melloni D, Pavone C, Tomasino RM, Pavone-Macaluso M.
Dipartimento di Scienze Farmacologiche, Policlinico via del Vespro N. 127, 90100 Palermo, Italia. sanguedolce@unipa.it

INTRODUCTION: The glycoprotein P-170, causing drug efflux from the cells, may represent at least one cause of resistance to most drugs used in intravesical chemotherapy of superficial bladder cancer. MATERIALS AND METHODS: GP-170 was retrospectively assessed in 60 patients affected by superficial transitional cell tumours of the bladder. It was assessed by immunohistochemistry in a semiquantitative way by the intensity of staining and by the percentage of positive cells. Correlation of GP-170 expression with G-grade, T-category, multiplicity, recurrence rate and treatment was investigated. In 44 patients recurrence was analysed in relation to GP-170 basal expression and to its variations. The monoclonal antibody JSB1 (DBA) at 1:20 dilution was employed for the GP-170 assay. RESULTS: GP-170 expression increases with grade but was lower in multiple tumours. No difference between Ta and T1 categories was detected. GP-170 immunohistochemistry from different portions of the same tumour showed a very marked variability in 35.7% of patients. Seven patients (11.6%) were totally negative for GP-170. No statistically significant correlation was found between recurrence, progression and GP-170 basal expression. Similarly no correlation emerged between grade and stage variations at recurrence and modifications in GP-170 expression. One third of the tumours recurring after chemotherapy were negative for GP-170 in spite of an increase in recurrence rate and other risk factors. CONCLUSION: At the present stage of our experience, we have been unable to show that GP-170 is a useful marker for monitoring chemoresistance to intravesical chemotherapy in superficial bladder cancer. Furthermore, GP-170 determination has shown several technical difficulties.

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Nippon Hinyokika Gakkai Zasshi 2002 Nov;93(7):727-35
[Combination chemotherapy with ifosfamide, 5-fuluorouracil, etoposide and cisplatin for advanced urothelial cancer: the treatment results and significance of tumor marker evaluation in response assessment of chemotherapy]
[Article in Japanese]
Maezawa T, Yonese J, Tsukamoto T, Ishii N, Fukui I.
Department of Urology, Cancer Institute Hospital, Tokyo, Japan.

PURPOSE: We investigated treatment results of IFEPchemotherapy in patients with advanced urothelial cancer (N2-3, M1) and the usefulness of measuring serum CEA, CA19-9 and SCC to evaluate the treatment response of chemotherapy. PATIENTS AND METHODS: From March 1994 to May 2000, we treated 41 patients with IFEP therapy consisting of ifosfamide (2 g/m2), 5-fluorouracil (750 mg/m2), etoposide (100 mg/m2) and cisplatin (20 mg/m2), all of which were given daily for 3 consecutive days every 3 weeks. Before initiating the chemotherapy, serum CEA, CA19-9 and SCC were measured. And in patients with high pretreatment serum concentration, they were serially evaluated and compared with the tumor response assessed by imaging studies and the patients' clinical course. RESULTS: The response rate of the chemotherapy was 53.7% (CR + PR), with a median survival period being 10.8 months and a median duration of response for the 22 responders being 7.5 months. One and three-year survival rates of all the patients were 59.3% and 16.5%. Response rates of primary tumors and metastatic lesions to the lymph node, bone, lung and liver were in 54% and 57%, 56%, 50% and 40%, respectively. Bone marrow toxicity was significant with 1 drug-related death. Before chemotherapy, tumor marker was elevated in 19 patients: CEA in 7, CA19-9 in 13 and SCC in 10. Serum levels of the tumor markers were related neither to the primary and metastatic tumor sites nor to patient's survival time. However, decline of serum tumor markers after chemotherapy was well related to response of the tumor assessed by imaging studies. CONCLUSION: IFEP chemotherapy appears to be active in the treatment of advanced urothelial tumor and serial measurement of serum CEA, CA19-9 and SCC may be useful in judgement of tumor response to the chemotherapy.

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Chin Med J (Engl) 2002 Oct;115(10):1548-51
Combined modality therapy following bladder conservation surgery for bladder cancers.
Sun X, Hu J, Yang Q.
Department of Radiation Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China. sunxiaonan@hotmail.com

OBJECTIVE: To analyze the efficacy of recurrence prophylaxis using radiation and chemotherapy following bladder conservation surgery for muscle invasive bladder cancer. METHODS: 23 patients with muscle invasive bladder cancer were treated with radiotherapy combined with bladder mitomycin infusion after bladder conservation surgery (study group). Radiotherapy was given using an external beam at an average dose of 5148 +/- 462 cGy with conventional fractionation. For comparison, 29 similar patients treated with postoperative bladder mitomycin infusion without radiation served as control (control group). All patients were followed up for more than 3 years, an average of 41.6 months (36 - 60 months). RESULTS: The 3-year pelvic recurrent rate of muscle invasive bladder cancer was 17.4% in the study group and 44.8% (P = 0.036) in the control group. The 3-year distant metastasis rates were 17.4% and 24.1%, respectively (P = 0.554). The 3-year overall survival rates were 81.8% and 86.2%, respectively (P = 0.670). Two patients from the study group had their treatment interrupted, one for 3 days and the other for one week due to acute cystitis, while the rest of the patients were able to complete the treatment according to schedule. CONCLUSION: Radiotherapy plus chemotherapy after bladder conservation surgery for muscle invasive bladder cancer can decrease the rate of pelvic recurrence effectively and be used as a realistic adjuvant treatment.

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Scand J Urol Nephrol 2002;36(5):339-43
An organ-sparing treatment using combined intra-arterial chemotherapy and radiotherapy for muscle-invading bladder carcinoma.
Tsukamoto S, Ishikawa S, Tsutsumi M, Nakajima K, Sugahara S.
Department of Urology, Hitachi General Hospital, Ibaraki, Japan. s-tsuka@md.tsukuba.ac.jp

OBJECTIVE: We describe the results of an organ-sparing approach for the treatment of non-metastatic, invasive bladder carcinoma. MATERIAL AND METHODS: Twenty-three patients (mean age 71 years; age range 47-87 years) with bladder carcinoma of clinical stage T2-T3N0M0 and histologically proven muscle invasion were examined between 1992 and 1998. The median duration of follow-up was 30 months. The treatment protocol for intra-arterial chemotherapy consisted of methotrexate 30 mg/m(2) and cisplatin 50 mg/m(2) in 7 patients and cisplatin 50 mg/m(2) in 16 patients, administered in three cycles via catheters inserted in the internal iliac arteries. Concomitantly, 41.4 Gy of radiotherapy was given to the lesser pelvis. Transurethral biopsy and urine cytology were performed after the completion of treatment; patients were followed observationally if residual tumor was absent, and underwent radical cystectomy if it was present. RESULTS: At the end of treatment, 18 patients (78%) showed a complete response (CR) and the bladder was spared in all cases. Radical cystectomy was performed for 4 non-CR cases, with the result that 2 cases had residual superficial cancer and the other 2 had muscle-invading cancer histologically. Among the patients with a CR, 2 experienced intravesical recurrence. Overall, 2 patients died of cancer, 5 died of other causes and 2 died during treatment. The 5-year disease-specific survival rate was 70.3% and the overall survival rate 46.4%. CONCLUSIONS: A bladder-sparing approach for the treatment of muscle-invading bladder carcinoma which utilizes combined intra-arterial chemotherapy and radiotherapy may arrest the decline in quality of life induced by urinary diversion and yield equivalent therapeutic benefit to that of radical cystectomy.

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Tumori 2002 Sep-Oct;88(5):390-4
Muscle-invasive bladder cancer in elderly-unfit patients with concomitant illness: can a curative radiation therapy be delivered?
Santacaterina A, Settineri N, De Renzis C, Frosina P, Brancati A, Delia P, Palazzolo C, Romeo A, Sansotta G, Pergolizzi S.
Department of Radiological Sciences, University of Messina, Italy.

AIMS AND BACKGROUND: There is no standard treatment for elderly-unfit patients with muscle-invasive bladder cancer. Pelvic irradiation alone is an usual approach in this instance, and some reports have demonstrated that curative radiotherapy is feasible in elderly patients. To our knowledge, no data exist about the feasibility of a curative treatment in elderly patients with concomitant illness and a Charlson Comorbidity Index (an index of comorbidity that includes age) greater than 2. The main purpose of the present study was to establish the feasibility of irradiation in a cohort of elderly patients in poor general condition. METHODS: The records of 45 elderly-unfit patients (median age, 75 years; range, 70-85), with a comorbid Charlson score >2, treated with curative dose, planned continuous-course, external beam radiotherapy for muscle-invasive bladder cancer were reviewed. The patients were treated to a median total dose of 60 Gy (range, 56-64), with an average fractional dose of 190 +/- 10 cGy using megavoltage (6-15 MV). All patients were treated with radiation fields encompassing the bladder and grossly involved lymph nodes with a radiographic margin of at least 1.5 cm. RESULTS: No treatment-related mortality and clinically insignificant acute morbidity was recorded. No patient was hospitalized during or after the irradiation because of gastrointestinal or urogenital side effects. In one patient a week rest from therapy was necessary due a febrile status. Median survival was 21.5 months; overall 3- and 5-year survival was 36% and 19.5%, respectively. CONCLUSIONS: Elderly-unfit patients with comorbidities and >70 years of age can be submitted to radical pelvic irradiation. The results observed in this retrospective analysis have encouraged us to use non-palliative radiotherapy doses in these patients with muscle-invasive bladder cancer.

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J Urol 2003 Jan;169(1):357-60
A phase I study of intravesical suramin for the treatment of superficial transitional cell carcinoma
of the bladder.
Uchio EM, Linehan WM, Figg WD, Walther MM.
Urologic Oncology Therapeutic Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD, USA.

PURPOSE: Suramin is a polysulfonated naphthylurea that inhibits proliferation and DNA synthesis of transitional cell carcinoma cell lines. Its large molecular size and negative charge inhibit bladder absorption, making suramin an excellent candidate for intravesical chemotherapy. Intravesical suramin was evaluated in a phase I study to define dose limiting toxicity and systemic absorption, determine a starting dose and regimen for phase II studies and provide a preliminary assessment of in vivo antitumor activity. MATERIALS AND METHODS: Intravesical suramin treatment was administered in 9 patients with histologically identified transitional cell carcinoma (Tcis, Ta or T1) in whom at least 1 course of standard intravesical chemotherapy (bacillus Calmette-Guerin, thiotepa or mitomycin C) had failed. Suramin was administered once weekly for 6 weeks. Patients were treated in groups of 3 using a 60 cc volume and intrapatient dose escalation schedule. Suramin doses of 0.3 to 614.4 mg./ml. were administered intravesically. The last group was treated with the same weekly dose for 6 weeks. RESULTS: The 9 patients underwent 54 treatments with suramin. Plasma suramin concentration after treatment was 1.9 to 38.0 microg./ml. and was not related to treatment dose. The dose escalation phase was limited by the solubility of suramin in solution. Complications included self-limited bladder spasms (less than 24 hours) in 4 of 54 treatments (7%) and new or worsening vesicoureteral reflux in 3 ureters (17%). Another patient who was treated after the Foley balloon was inflated in the urethra experienced bladder spasms, skin flushing and fever (39C). Mean bladder capacity before and after treatment was 600 and 540 ml., respectively. At followup 7 patients had stage Ta tumors and 2 had carcinoma in situ. CONCLUSIONS: An intravesical suramin dose of 153 mg./ml was defined as a safe treatment parameter with acceptable plasma concentrations and minimal side effects. Phase II studies are needed to assess the antitumor activity of suramin in patients with transitional cell carcinoma of the bladder.

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J Urol 2003 Jan;169(1):177-81
Orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence.
Yossepowitch O, Dalbagni G, Golijanin D, Donat SM, Bochner BH, Herr HW, Fair WR, Russo P.
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

PURPOSE: The impact of orthotopic urinary diversion on the quality of cystectomy and ensuing cancer control has not been adequately studied. We analyzed our experience with this clinical problem. MATERIALS AND METHODS: The records of 214 patients who underwent cystectomy and orthotopic diversion for bladder cancer were retrospectively evaluated and compared with those of 269 treated with an ileal conduit. Analyzed end points included overall and cancer specific survival. We specifically assessed the patterns of relapse and their association with pathological findings at cystectomy in the neobladder group. RESULTS: No cancer specific survival difference was identified in the neobladder and ileal conduit cohorts when adjusting for pathological stage. Patterns of relapse in 62 of the 214 patients with a neobladder (29%) included local recurrence in 23 (11%), distant recurrence in 19 (9%), and combined local and distant recurrence in 18 (8%). Urethral recurrence was rare (2%). Of 10 patients (4.6%) diagnosed with upper tract recurrence 6 and 4 initially had relapse in the ureteroenteric anastomosis and renal pelvis, respectively. Five of the 6 patients with anastomotic relapse had evidence of disease in the intramural or juxtavesical ureter that was removed en bloc with the cystectomy specimen. Only 1 patient required neobladder takedown after such anastomotic recurrence. CONCLUSIONS: These results indicate that neobladders do not compromise the quality of preceding cystectomy or interfere with management in the presence of local or distant disease relapse. Our data suggest that involvement of the intramural or juxtavesical ureteral segment at cystectomy irrespective of surgical margin status may identify patients at higher risk for anastomotic recurrence, which is associated with an ominous prognosis.

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J Urol 2003 Jan;169(1):110-5; discussion 115
Comment in: J Urol. 2003 Jan;169(1):116-7.
An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma.
Sanchez-Ortiz RF, Huang WC, Mick R, Van Arsdalen KN, Wein AJ, Malkowicz SB.
Division of Urology, Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, PA, USA.

PURPOSE: The standard of care for muscle invasive transitional cell carcinoma of the bladder is radical cystectomy. Definitive therapy may often be delayed for various reasons. We assessed whether pathological stage and survival correlated with the length of time between diagnosis of muscle invasion and cystectomy. MATERIALS AND METHODS: The records of 290 consecutive patients who underwent radical cystectomy between February 1987 and July 2000 were reviewed. Of 265 (91.4%) cystectomies performed for transitional cell carcinoma data were available for 247 (85.2%) and 189 (65.2%) patients were identified who underwent surgery for muscle invasive disease (T2 or greater). The interval between diagnosis of muscle invasion and cystectomy was calculated for each patient. Patients were divided into groups based on time to surgery as group 1-less than 4 weeks, 2-4 to 6 weeks, 3-7 to 9 weeks, 4-10 to 12 weeks, 5-13 to 16 weeks, and 6-greater than 16 weeks. Exploratory univariate and multivariate analyses were performed to test the association of time lag with clinical features and postoperative survival. RESULTS: Mean patient age was 66 years (range 37 to 84) and overall 3-year Kaplan-Meier estimated survival was 59.1% +/- 4% (median followup 36 months). For all patients mean interval from diagnosis to cystectomy was 7.9 weeks (range 1 to 40). Extravesical disease (P3a or greater) or positive nodes were identified in 84% (16 of 19) of patients when the delay was longer than 12 weeks, compared with 48.2% (82 of 170) in those with a time lag of 12 weeks or less (p < 0.01). Similarly 3-year estimated survival was lower (34.9% +/- 13.5%) for patients with a surgery delay longer than 12 weeks compared to those with a shorter interval 62.1% +/- 4.5% (hazards ratio 2.51, 95% CI 1.30-4.83, p = 0.006). When adjusted for nodal status, and clinical and pathological stages the interval was still statistically significant (adjusted hazards ratio 1.93, 95% CI 0.99-3.76, p = 0.05). CONCLUSIONS: In patients undergoing radical cystectomy a delay in surgery of greater than 12 weeks was associated with advanced pathological stage and decreased survival. Although this relationship persisted after adjusting for nodal status, and clinical and pathological stages, the presence of lymph node metastasis remained the strongest predictor of patient outcome.

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J Urol 2003 Jan;169(1):105-9
Comment in: J Urol. 2003 Jan;169(1):116-7.
The impact of co-morbid disease on cancer control and survival following radical cystectomy.
Miller DC, Taub DA, Dunn RL, Montie JE, Wei JT.
Department of Urology, University of Michigan, Ann Arbor, MI, USA.

PURPOSE: We clarified the impact of concurrent medical disease on tumor control and survival following radical cystectomy. MATERIALS AND METHODS: A total of 106 consecutive patients with clinically localized (cT2 or less) disease underwent radical cystectomy at the University of Michigan between 1997 and 1998. The Charlson Index, a validated risk adjustment index, was used to assess preoperative co-morbidity. The 3 primary end points were pathological stage, disease specific survival and overall survival. Logistic regression models were used to determine the relationship between Charlson Index and pathological stage, while Cox regression models were used for the 2 survival end points. RESULTS: Of our study population 24% had a Charlson Index score of 2 or greater. Myocardial infarction, nonurothelial solid malignancies and cerebrovascular disease were the most common co-morbid conditions at 14%, 12% and 10%, respectively. On bivariate analysis the Charlson Index was significantly associated with decreased disease specific (p = 0.049) and overall (p = 0.016) survival. In a multivariate model the index was independently associated with decreased cancer specific survival (p = 0.049) and increased risk of extravesical disease (p = 0.033). CONCLUSIONS: We demonstrated an association between co-morbid illness and adverse pathological and survival outcome following radical cystectomy. This finding underscores the value of assessing overall health before recommending and proceeding with surgery. Moreover, our results emphasize the need to adjust for co-morbidity when comparing outcomes following radical cystectomy.

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J Urol 2003 Jan;169(1):101-4
Comment in: J Urol. 2003 Jan;169(1):116-7.
Complications of radical cystectomy for nonmuscle invasive disease: comparison with muscle
invasive disease.
Cookson MS, Chang SS, Wells N, Parekh DJ, Smith JA Jr.
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

PURPOSE: Radical cystectomy is gold standard treatment for muscle invasive bladder cancer and is an option for many patients with nonmuscle invasive disease at high risk for disease progression. We assessed the early complications of radical cystectomy among patients with nonmuscle invasive compared to those with muscle invasive disease. MATERIALS AND METHODS: We reviewed the records of 304 consecutive patients who underwent radical cystectomy from December 1995 to July 2000. We evaluated complications that occurred within 30 days of the procedure. Cases were stratified into nonmuscle invasive (PO, Pa, P1 and PIS, N0) or muscle invasive (P2-4, N0-3) tumors based on final specimen pathology. The 2 groups were then compared with respect to age, gender, race, American Society of Anesthesiologists score, type of urinary diversion, estimated blood loss, operative time and length of stay, and major and minor complications. RESULTS: Of the 293 available patients 105 (36.8%) had nonmuscle invasive specimen pathology. Overall major and minor complications occurred in 4.9% and 30.4% of cases, respectively. Independent t test revealed no significant difference between groups in terms of age (p = 0.85), gender (p = 0.77), race (p = 1.0), American Society of Anesthesiologists (p = 0.32), type of urinary diversion (p = 0.33), estimated blood loss (p = 0.31), operative time (p = 0.41), length of stay (p = 0.75), or presence of major (p = 0.78) or minor (p = 0.79) complications. CONCLUSIONS: The early morbidity associated with radical cystectomy for nonmuscle invasive disease is similar to but not less than that associated with muscle invasive tumors. These acceptable risks as well as the potential benefits should be discussed with patients with nonmuscle invasive bladder cancer at high risk for disease progression.

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J Urol 2003 Jan;169(1):96-100; discussion 100
A retrospective analysis of 153 patients treated with or without intravesical bacillus Calmette-Guerin for primary stage T1 grade 3 bladder cancer: recurrence, progression and survival.
Shahin O, Thalmann GN, Rentsch C, Mazzucchelli L, Studer UE.
Department of Urology, Institute of Pathology, University of Bern, Inselspital, Bern, Switzerland.

PURPOSE: We retrospectively evaluated the long-term outcome in patients with newly diagnosed stage T1 grade 3 bladder cancer treated with transurethral resection with or without intravesical bacillus Calmette-Guerin (BCG). MATERIALS AND METHODS: Of 153 patients with a median age of 67 years (range 36 to 88) and a male-to-female ratio of 4:1 we treated 92 with transurethral bladder resection and additional BCG, and 61 with transurethral bladder resection alone. BCG was administered intravesically as 120 mg. BCG Pasteur F dissolved in 50 ml. saline, retained for up to 2 hours weekly for 6 weeks and repeated as necessary. RESULTS: Median followup was 5.3 years (range 0.4 to 18.2). Disease recurred in 70% of the patients treated with BCG and in 75% treated with transurethral resection alone. Median time to recurrence was 38 and 22 months for BCG and resection alone (p = 0.19). Tumor progressed in 33% of patients with BCG and in 36% with resection alone. Deferred cystectomy was performed in 29% of the patients with BCG and in 31% with resection alone. Overall and disease specific survival did not differ significantly. CONCLUSIONS: Our results suggest that intravesical BCG therapy after transurethral bladder resection for stage T1 grade 3 bladder cancer may delay the time to recurrence and cystectomy but it does not substantially alter the final outcome. Our findings reflect the rule of 30% for stage T1 grade 3 cancer, namely approximately 30% of patients never have recurrence, 30% ultimately die of metastatic disease and 30% require deferred cystectomy.

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J Urol 2003 Jan;169(1):90-5
Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity.
Bohle A, Jocham D, Bock PR.
Department of Urology, Medical University of Lubeck, Lubeck, Germany.

PURPOSE: We compare the therapeutic efficacy and toxicity of intravesical bacillus Calmette-Guerin (BCG) with mitomycin C on recurrence of stages Ta and T1 bladder carcinoma. MATERIALS AND METHODS: Combined published and unpublished data from comparative studies on BCG versus mitomycin C for superficial bladder carcinoma considering possible confounding factors were analyzed. Odds ratio (OR) and its 95% CI were used as primary effect size estimate. Toxicity data were evaluated descriptively. RESULTS: In 11 eligible clinical trials 1,421 patients were treated with BCG and 1,328 were treated with mitomycin C. Within the overall median followup time of 26 months 38.6% of the patients in the BCG group and 46.4% of those in the mitomycin C group had tumor recurrence. In 7 of 11 studies BCG was significantly superior to mitomycin C, in 3 studies no significant difference was found, while in 1 study mitomycin C was significantly superior to BCG. An overall statistically significant superiority of BCG versus mitomycin C efficacy in reducing tumor recurrence was detected (OR 0.56, 95% CI 0.38 to 0.84, p = 0.005). In the subgroup treated with BCG maintenance all 6 individual studies showed a significant superiority of BCG over mitomycin C (OR 0.43, 95% CI 0.35 to 0.53, p <0.001). In 4 of the 5 studies with reported data on toxicity BCG associated cystitis was significantly more frequent than in the mitomycin C group (53.8% versus 39.2%). The combined cystitis OR was 1.81 (95% CI 1.48 to 2.23, p <0.001). The OR for cystitis in the BCG maintenance group did not significantly differ from that in the nonmaintenance therapy group. CONCLUSIONS: The results suggest superiority of BCG over mitomycin C for prevention of tumor recurrences in the combined data and particularly in the BCG maintenance treatment subgroup, irrespective of the actual (intermediate or high) tumor risk status. The toxicity with BCG is higher but does not differ between BCG maintenance and nonmaintenance groups.

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Urology 2002 Dec;60(6):1025-8
Do patients profit from 5-aminolevulinic acid-induced fluorescence diagnosis in transurethral resection of bladder carcinoma?
Filbeck T, Pichlmeier U, Knuechel R, Wieland WF, Roessler W.
Department of Urology, St. Joseph's Hospital, Regensburg, Germany.

OBJECTIVES: To evaluate in a prospective study the influence of fluorescence diagnosis (FD) controlled transurethral resection of bladder tumors on therapeutic consequences. The aim was to determine in how many patients FD led to a change in treatment strategy compared with conventional white light (WL) cystoscopy. METHODS: A total of 279 patients with suspected bladder tumors underwent transurethral resection using FD in addition to WL cystoscopy. The number of additional tumor-positive patients, staging change, number of multilocular tumors exclusively detected by FD, and resulting therapeutic consequences compared with the results after WL cystoscopy were investigated. In addition a biopsy-based evaluation was performed. RESULTS: Tumor or dysplasia II degrees (moderate dysplasia) was detected in 177 patients. In 168 patients, tumor was detected by WL cystoscopy, and in 9 (5.1%) of the patients, tumor was completely overlooked by WL cystoscopy and diagnosed exclusively by FD (n = 3 TaG1-G2, n = 2 carcinoma in situ, n = 1 greater than T1, and n = 3 dysplasia II degrees ). Multilocular tumor involvement was detected in 10 cases using FD, and a change in the stage by detection of coexisting dysplasia II degrees and carcinoma in situ occurred in 8 patients. In 27 patients (15.3%), additional information was obtained by exclusive detection of tumors by FD. This resulted in a change in the treatment strategy for 16 patients (9%). CONCLUSIONS: FD leads to an improvement in the diagnosis of bladder carcinoma. It allows the early selection of the best treatment option and thus has a potentially positive effect on the prognosis of the affected patients.

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Lancet Oncol 2002 Dec;3(12):738-47
The role of systemic chemotherapy in the management of muscle-invasive bladder cancer.
Juffs HG, Moore MJ, Tannock IF.
Princess Margaret Hospital, Ontario, Toronto, Canada.

Patients with localised but muscle-invasive transitional-cell carcinoma (TCC) of the bladder are at high risk of relapse and death from metastatic disease after local treatment by cystectomy, radiation, or both. Despite improvements in treatment, patients with metastatic TCC have a median survival of about a year. TCC is quite sensitive to chemotherapy, and patients are able to tolerate newer regimens such as gemcitabine plus cisplatin better than older regimens such as methotrexate, vinblastine, doxorubicin, and cisplatin. However, the role of chemotherapy in the management of locally advanced muscle-invasive TCC remains uncertain. Most trials of neoadjuvant or adjuvant chemotherapy have shown no significant improvement in survival, but many of these studies had suboptimum design, evaluated chemotherapy that was less effective than regimens in current use, and had sample sizes that were too small for important changes in survival to be detected or ruled out. Recent trials show trends in the direction of improved survival when optimum chemotherapy is used. Large trials that recruit more than 1000 patients are required to assess the effectiveness of adjunctive chemotherapy, and a large intergroup trial is in progress. Other trials should address the role of molecular markers in selecting patients for chemotherapy. Whenever possible, chemotherapy for locally advanced muscle-invasive TCC should be given in the context of a well-designed clinical trial.

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Lancet Oncol 2002 Dec;3(12):728-37
ARCON: a novel biology-based approach in radiotherapy.
Kaanders JH, Bussink J, van der Kogel AJ.
Department of Radiation Ocology of the University Medical Centre Nijmegen, Nijmegen, Netherlands. j.kaanders@rther.umcn.nl

Two mechanisms of radiotherapy resistance which are of major importance in various tumour types are tumour-cell repopulation and hypoxia. ARCON (accelerated radiotherapy with carbogen and nicotinamide) is a new therapeutic strategy that combines radiation treatment modifications, with the aim of counteracting these resistance mechanisms. To limit clonogenic repopulation during therapy, the overall duration of the radiotherapy is reduced, generally by delivering several fractions per day. This accelerated radiotherapy is combined with inhalation of hyperoxic gas to decrease diffusion-limited hypoxia, and nicotinamide, a vasoactive agent, to decrease perfusion-limited hypoxia. Preclinical studies have been done to test the enhancing effects of these three components of ARCON, individually and in combination, in several experimentally induced tumours and normal tissues. In a mouse mammary carcinoma, the tumour-control rate obtained with ARCON was the same as that with conventional treatment, but with a radiation dose almost 50% lower. Phase 1 and 2 clinical trials have shown the feasibility and tolerability of ARCON, and have produced promising results in terms of tumour control. In particular in cancers of the head and neck and bladder, the local tumour-control rates are higher than in other studies, and phase 3 trials for these tumour types are underway. In conjunction with these trials, hypoxia markers detectable by immunohistochemistry are being tested for their potential use in predictive assays to select patients for ARCON and other hypoxia-modifying therapies.

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Ter Arkh 2002;74(10):70-2
[Features of BCG-therapy in treating patients with superficial bladder cancer]
[Article in Russian]
Chepurov AK, Murshudli ECh, Mazo EB.

AIM: To specify features of BCG-therapy which may predict effectiveness of the treatment and optimize the treatment regimen. MATERIAL AND METHODS: Intravesical immunotherapy with imuron (a 6-week course) was conducted in 62 patients with superficial cancer of the urinary bladder who had undergone surgical treatment and were prognostically poor. 51 patients of group 1 received maintenance therapy as 3 weekly instillations each 3 months for the first year followed by once in 6 months. 11 patients of group 2 received single monthly instillations. All the patients registered their complaints, measured body temperature with fixation of maximal value. The diagnosis of the recurrence was made with control cystoscopy carried out each 3 months in the first postoperative year and later once in 6 months. RESULTS: Recurrent tumors were observed in 25 (49%) and 7 (63.6%) patients of groups 1 and 2, respectively. Side effects (high body temperature, dysuria and macrohematuria) were reported in group 1 during basic treatment. Side effects occurred also in maintenance. They were more pronounced than in group 2. CONCLUSION: Intravesical BCG-therapy causes cystitis considered a normal reaction to treatment. Fever indicates an inflammatory reaction which is rather a positive sign of immune reaction and may serve a prognostic factor.

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BJU Int 2002 Dec;90(9):957-64
Intravesical pH: a potentially important variable affecting efficacy and the further development of anthracycline chemotherapy for superficial bladder cancer.
Harris NM, Duffy PM, Crook TJ, Anderson WR, Sharpe P, Hayes MC, Cooper AJ, Solomon LZ.
Solent Department of Urology, St. Mary's Hospital, Portsmouth, UK. neilandjane@supanet.com

OBJECTIVE: To assess, using epirubicin-sensitive and multidrug resistant (MDR) derivatives of human bladder cancer cell lines in vitro, the probable effect of intravesical pH changes, with and without the MDR antagonist verapamil, on the uptake, intracellular distribution and cytotoxicity of epirubicin during intravesical chemotherapy. MATERIALS AND METHODS: Incubations for cytotoxicity testing were carried out in buffered medium containing epirubicin, at pH values of 6.0-8.5, with verapamil where appropriate. The cytotoxicity of epirubicin, with and without verapamil, was determined using the tetrazolium cytotoxicity assay. Intracellular epirubicin fluorescence was assessed using flow cytometry and confocal microscopy. Flow cytometric total intracellular epirubicin fluorescence was measured at pH 6.0, 6.4, 6.8, 7.2, and 7.6, and confocal microscopy was carried out at pH 6.0 and 8.0. The MDR-reversing agent verapamil was added at 100 micro g/mL to some incubations. RESULTS: Epirubicin cytotoxicity in resistant cell lines appears considerably enhanced by adding verapamil and further improved, especially in MDR cells, by alkalinization of the drug solution to pH 8.0. Flow cytometry results showed striking and consistent differences in epirubicin handling with pH. Sensitive cells can be induced to absorb considerably more drug at alkaline pH, whilst resistant cells show no such behaviour. Nuclear drug fluorescence was greater in sensitive cells at alkaline pH, but cytoplasmic drug fluorescence in the resistant cells was little changed by pH. Adding verapamil to resistant cells restored the sensitive phenotype of drug handling. CONCLUSION: Buffering epirubicin to an alkaline pH before intravesical application should increase its intrinsic cytotoxicity. The potential for synergy at certain drug combinations will be enhanced by applying these findings. MDR reversal and fatty acid augmentation of drug uptake are discussed as examples.

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J Urol 2003 Jan;169(1):357-60
A phase I study of intravesical suramin for the treatment of superficial transitional cell
carcinoma of the bladder.
Uchio EM, Linehan WM, Figg WD, Walther MM.
Urologic Oncology Therapeutic Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD, USA.

PURPOSE: Suramin is a polysulfonated naphthylurea that inhibits proliferation and DNA synthesis of transitional cell carcinoma cell lines. Its large molecular size and negative charge inhibit bladder absorption, making suramin an excellent candidate for intravesical chemotherapy. Intravesical suramin was evaluated in a phase I study to define dose limiting toxicity and systemic absorption, determine a starting dose and regimen for phase II studies and provide a preliminary assessment of in vivo antitumor activity. MATERIALS AND METHODS: Intravesical suramin treatment was administered in 9 patients with histologically identified transitional cell carcinoma (Tcis, Ta or T1) in whom at least 1 course of standard intravesical chemotherapy (bacillus Calmette-Guerin, thiotepa or mitomycin C) had failed. Suramin was administered once weekly for 6 weeks. Patients were treated in groups of 3 using a 60 cc volume and intrapatient dose escalation schedule. Suramin doses of 0.3 to 614.4 mg./ml. were administered intravesically. The last group was treated with the same weekly dose for 6 weeks. RESULTS: The 9 patients underwent 54 treatments with suramin. Plasma suramin concentration after treatment was 1.9 to 38.0 microg./ml. and was not related to treatment dose. The dose escalation phase was limited by the solubility of suramin in solution. Complications included self-limited bladder spasms (less than 24 hours) in 4 of 54 treatments (7%) and new or worsening vesicoureteral reflux in 3 ureters (17%). Another patient who was treated after the Foley balloon was inflated in the urethra experienced bladder spasms, skin flushing and fever (39C). Mean bladder capacity before and after treatment was 600 and 540 ml., respectively. At followup 7 patients had stage Ta tumors and 2 had carcinoma in situ. CONCLUSIONS: An intravesical suramin dose of 153 mg./ml was defined as a safe treatment parameter with acceptable plasma concentrations and minimal side effects. Phase II studies are needed to assess the antitumor activity of suramin in patients with transitional cell carcinoma of the bladder.

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J Urol 2003 Jan;169(1):177-81
Orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence.
Yossepowitch O, Dalbagni G, Golijanin D, Donat SM, Bochner BH, Herr HW, Fair WR, Russo P.
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

PURPOSE: The impact of orthotopic urinary diversion on the quality of cystectomy and ensuing cancer control has not been adequately studied. We analyzed our experience with this clinical problem. MATERIALS AND METHODS: The records of 214 patients who underwent cystectomy and orthotopic diversion for bladder cancer were retrospectively evaluated and compared with those of 269 treated with an ileal conduit. Analyzed end points included overall and cancer specific survival. We specifically assessed the patterns of relapse and their association with pathological findings at cystectomy in the neobladder group. RESULTS: No cancer specific survival difference was identified in the neobladder and ileal conduit cohorts when adjusting for pathological stage. Patterns of relapse in 62 of the 214 patients with a neobladder (29%) included local recurrence in 23 (11%), distant recurrence in 19 (9%), and combined local and distant recurrence in 18 (8%). Urethral recurrence was rare (2%). Of 10 patients (4.6%) diagnosed with upper tract recurrence 6 and 4 initially had relapse in the ureteroenteric anastomosis and renal pelvis, respectively. Five of the 6 patients with anastomotic relapse had evidence of disease in the intramural or juxtavesical ureter that was removed en bloc with the cystectomy specimen. Only 1 patient required neobladder takedown after such anastomotic recurrence. CONCLUSIONS: These results indicate that neobladders do not compromise the quality of preceding cystectomy or interfere with management in the presence of local or distant disease relapse. Our data suggest that involvement of the intramural or juxtavesical ureteral segment at cystectomy irrespective of surgical margin status may identify patients at higher risk for anastomotic recurrence, which is associated with an ominous prognosis.

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Acta Oncol 2002;41(5):447-56
Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive
bladder tumours.
Sengelov L, von der Maase H, Lundbeck F, Barlebo H, Colstrup H, Engelholm SA, Krarup T, Madsen EL, Meyhoff HH, Mommsen S, Nielsen OS, Pedersen D, Steven K, Sorensen B.
Department of Oncology, University Hospital Herlev, Copenhagen, Denmark. lisa.sengelov@dadlnet.dk

This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma of the bladder. In the first trial, local treatment consisted of cystectomy (DAVECA 8901) and in the other trial the treatment was radiotherapy (DAVECA 8902); 153 eligible patients were randomized. The majority of the patients (89%) completed the protocol. The overall time to progression for all 153 patients was 12.9 months. Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy. The actuarial 5-year overall survival rate for all 153 patients was 29%, and 29% for both treatment groups. Multivariate analyses showed that T-stage, tumour size and serum creatinine were independent prognostic factors for survival. The cystectomy trial included 33 patients. Median survival was 78.9 months, 82.5 months with chemotherapy and 45.8 months without chemotherapy (p = 0.76). The radiotherapy trial included 120 patients. The median survival was 17.6 months. Median survival was 19.2 months in the group receiving chemotherapy and 16.3 in the group not receiving chemotherapy. The 5-year survival rate was 19% in the group receiving chemotherapy and 24% in the groups not receiving chemotherapy (p = 0.98). Late toxicity grade 3 or 4 of the bladder was recorded in 25% of the patients (actuarial rate). Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 randomized patients with invasive bladder cancer.

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J Urol 2002 Dec;168(6):2373-6
Adoptive immunotherapy for superficial bladder cancer with autologous macrophage activated killer cells.
Thiounn N, Pages F, Mejean A, Descotes JL, Fridman WH, Romet-Lemonne JL.
Service d'Urologie, Hopital Cochin, France.

PURPOSE: We assessed the efficacy and safety of adoptive immunotherapy administered to 17 patients with TaGIII or recurrent TaGII superficial bladder cancer following transurethral tumor resection. MATERIALS AND METHODS: Macrophage activated killer (MAK) cells were obtained from autologous mononuclear cells harvested by apheresis, after in vitro culture for 7 days and activation with interferon-gamma on the last day of culture. The patients received 6 weekly intravesical infusions of approximately 2 x 10(8) cells each. Additionally, 5 patients received 2 or 3 more infusions at 3-month intervals. Each patient was followed for 1 year or until tumor recurrence, whichever came first. RESULTS: A total of 112 intravesical infusions were performed. During the 12-month followup period 8 patients experienced 11 common toxicity criteria grade 1 or grade 2 adverse events considered possibly related to protocol. No clinically relevant grade 1 or 2 laboratory test results were reported while the patients received treatment. In 17 patients 8 tumors recurred compared to 34 recurrences during the year before the first MAK cell infusion. This difference was highly significant (p </=0.0005). CONCLUSIONS: The promising efficacy and safety results of this study and the fact that the MAK cell treatment regimen proved feasible should encourage initiation of further large scale studies to confirm these data.

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Urology 2002 Nov;60(5):822-4; discussion 824-5
Impact of a second transurethral resection on the staging of T1 bladder cancer.
Dalbagni G, Herr HW, Reuter VE.
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

OBJECTIVES: To evaluate the impact of a second transurethral resection (TUR) on the pathologic stage in a unique patient population with T1 tumors. METHODS: Seventy-one patients with Stage T1 transitional cell carcinoma of the bladder were prospectively enrolled and underwent restaging TUR. Fifteen patients underwent immediate cystectomy and 56 patients were treated endoscopically. The patients who underwent immediate cystectomy were the subjects of this report. RESULTS: Fifteen patients underwent immediate cystectomy. At restaging TUR, 13 patients had persistent T1, 1 patient had Tis, and 1 patient had no residual disease. The pathologic stage at cystectomy revealed the presence of residual disease in 12 of 15 patients, and 3 patients had pT0. Of the 12 patients with residual disease, 3 had residual pT1, 2 had pT1 with pTis, 5 had pTis alone, and 2 had muscle-invasive tumors. Thirteen percent of the patients who underwent immediate cystectomy after restaging TUR had a pathologic stage greater than pT1. CONCLUSIONS: Understaging for T1 disease is negligible after restaging TUR.

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Urologe A 2002 Sep;41(5):470-4
[Prospective study of effectiveness. Reoperation (re-TUR) in superficial bladder carcinoma]
[Article in German]
Vogeli TA, Grimm MO, Simon X, Ackermann R.
Urologische Klinik, Heinrich-Heine-Universitat, Moorenstrasse 5, 40225 Dusseldorf.

To assess the rate of residual cancer after transurethral resection (TUR) of superficial bladder cancer, a prospective study was carried out. All patients with transitional cell cancer (TCC) stage pTa-pT1 underwent a repeat TUR (ReTUR) within 6-8 weeks. Sites and rates of tumors found during ReTUR were documented as well as the morbidity of the ReTUR. Of a total of 192 TUR, superficial TCC was found in 124 cases; 83 underwent ReTUR according to the study protocol. Residual tumor was detected in 27% of pTa and 53% of pT1 tumors. Worsening of grading or T stage was found in 8%. Of the tumors detected by ReTUR, 81% were localized at the site of the first TUR. In this prospective study, residual tumor formation was detected in a high percentage. Routine ReTUR is therefore recommended in superficial bladder cancer except solitary pTaGI lesions.

   

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