Guido Dalbagni

Defining Early Morbidity of Radical Cystectomy for Patients with Bladder Cancer Using a Standardized Reporting Methodology

BACKGROUND Reporting methodology is highly variable and nonstandardized, yet surgical outcomes are utilized in clinical trial design and evaluation of healthcare provider performance. OBJECTIVE We sought to define the type, incidence, and severity of early postoperative morbidities following radical cystectomy (RC) using a standardized reporting methodology. DESIGN, SETTING, AND PARTICIPANTS Between 1995 and 2005, 1142 consecutive RCs were entered into a prospective complication database and retrospectively reviewed for accuracy. All patients underwent RC/urinary diversion by high-volume fellowship-trained urologic oncologists. MEASUREMENTS All complications within 90 d of surgery were analyzed and graded according to the Memorial Sloan-Kettering Cancer Center complication grading system. Complications were defined and stratified into 11 specific categories. Univariate and multivariate regression models were used to define predictors of complications. RESULTS AND LIMITATIONS Sixty-four percent (735/1142) of patients experienced a complication within 90 d of surgery. Among patients experiencing a complication, 67% experienced a complication during the operative hospital admission and 58% following discharge. Overall, the highest grade of complication was grade 0 in 36% (n=407), grade 1-2 in 51% (n=582), and grade 3-5 in 13% (n=153). Gastrointestinal complications were most common (29%), followed by infectious complications (25%) and wound-related complications (15%). The 30-d mortality rate was 1.5%. CONCLUSIONS Surgical morbidity following RC is significant and, when strict reporting guidelines are incorporated, higher than previously published. Accurate reporting of postoperative complications after RC is essential for counseling patients, combined modality treatment planning, clinical trial design, and assessment of surgical success.

Epidemiology and Risk Factors of Urothelial Bladder Cancer

CONTEXT Urothelial bladder cancer (UBC) is a disease of significant morbidity and mortality. It is important to understand the risk factors of this disease. OBJECTIVE To describe the incidence, prevalence, and mortality of UBC and to review and interpret the current evidence on and impact of the related risk factors. EVIDENCE ACQUISITION A literature search in English was performed using PubMed. Relevant papers on the epidemiology of UBC were selected. EVIDENCE SYNTHESIS UBC is the 7th most common cancer worldwide in men and the 17th most common cancer worldwide in women. Approximately 75% of newly diagnosed UBCs are noninvasive. Each year, approximately 110 500 men and 70 000 women are diagnosed with new cases and 38 200 patients in the European Union and 17 000 US patients die from UBC. Smoking is the most common risk factor and accounts for approximately half of all UBCs. Occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons are other important risk factors. The impact of diet and environmental pollution is less evident. Increasing evidence suggests a significant influence of genetic predisposition on incidence. CONCLUSIONS UBC is a frequently occurring malignancy with a significant impact on public health and will remain so because of the high prevalence of smoking. The importance of primary prevention must be stressed, and smoking cessation programs need to be encouraged and supported.

Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer.

Purpose: We postulate that the number of lymph nodes examined in cystectomy specimens can have an impact on the outcome of patients with bladder cancer.Materials and Methods: We analyzed data on 322 patients with muscle invasive bladder cancer who underwent radical cystectomy and bilateral pelvic lymphadenectomy. We evaluated the associations of the number of lymph nodes identified by the pathologist in the surgical specimen with the local recurrence rate and survival outcome.Results: Patients were divided into groups by lymph node status and the distribution of the number of lymph nodes examined. In stages pN0 and pN+ cases improved survival was associated with a greater number of lymph nodes examined. We determined that at least 9 lymph nodes should be studied to define lymph node status accurately.Conclusions: These results indicate that surgical resection and pathological assessment of an adequate number of lymph nodes in cystectomy specimens increases the likelihood of proper staging and impacts pati...

Cystectomy for bladder cancer: a contemporary series.

PURPOSE To validate the current TNM staging system, we analyzed our contemporary experience with 300 cystectomies. MATERIALS AND METHODS The pathological material and medical records of 300 patients treated with cystectomy were reviewed, and the new TNM classification was adopted. RESULTS The median followup of patients with no evidence of disease was 65 months, and overall survival rate was 45% with a median survival of 50 months. In a Cox regression analysis only patient age, pT stage and neoadjuvant chemotherapy were significant factors for survival. The disease specific survival was 67% with a median survival of 94 months. In a multiple proportional hazards analysis only pT stage and previous chemotherapy were significant factors of disease specific survival. A significant difference was seen in the overall and disease specific survival between patients with organ confined and nonorgan confined tumors. We did not observe a difference in the survival rate among patients with pT4a to pT3 tumors. Significant differences were not seen in survival rates between sexes or among patients of different age groups. Transitional cell carcinoma was the predominant histological type, and no significant difference was found in patient outcome among the different histological subtypes. CONCLUSIONS Bladder cancer can be categorized into organ confined and nonorgan confined tumors. This dichotomous grouping is better suited for evaluating adjuvant clinical trials. The pT stage of the bladder and prostate should be prospectively analyzed together to better define the clinical implications of prostatic involvement. In our opinion the histological subtypes do not affect outcome.

Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer

PURPOSE Radical cystectomy and pelvic lymphadenectomy (PLND) remains the standard treatment for localized and regionally advanced invasive bladder cancers. We have constructed an international bladder cancer database from centers of excellence in the management of bladder cancer consisting of patients treated with radical cystectomy and PLND. The goal of this study was the development of a prognostic outcomes nomogram to predict the 5-year disease recurrence risk after radical cystectomy. PATIENTS AND METHODS Institutional radical cystectomy databases containing detailed information on bladder cancer patients were obtained from 12 centers of excellence worldwide. Data were collected on more than 9,000 postoperative patients and combined into a relational database formatted with patient characteristics, pathologic details of the pre- and postcystectomy specimens, and recurrence and survival status. Patients with available information for all selected study criteria were included in the formation of the final prognostic nomogram designed to predict 5-year progression-free probability. RESULTS The final nomogram included information on patient age, sex, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the constructed international nomogram (concordance index, 0.75) was significantly better than standard American Joint Committee on Cancer TNM (concordance index, 0.68; P < .001) or standard pathologic subgroupings (concordance index, 0.62; P < .001). CONCLUSION We have developed an international bladder cancer nomogram predicting recurrence risk after radical cystectomy for bladder cancer. The nomogram outperformed prognostic models that use standard pathologic subgroupings and should improve our ability to provide accurate risk assessments to patients after the surgical management of bladder cancer.

Genetic alterations in bladder cancer

To see whether genetic alterations follow a sequence of events leading to bladder cancer progression, 60 paired bladder tumours and normal tissues were analysed with polymorphic DNA markers, correlating loss of heterozygosity (LOH) at candidate tumour suppressor gene sites with pathological indices of poor clinical outcome. Distinct genotypic patterns were associated with early and late stages of bladder cancer. 9q deletions were observed in all superficial papillary tumours (Ta) and almost all tumours invading the lamina propria (T1), suggesting that this event associates with the development of superficial bladder tumours. However, 3p, 5q, and 17p deletions were absent in the Ta tumours but were identified in invasive bladder cancers. Two genetic pathways characterise the evolution of superficial bladder tumours. 9qLOH was detected in most Ta tumours, but in only 43% of muscle invasive neoplasms. Our hypothesis is that certain chromosomal abnormalities have a defined role in bladder tumour development, whereas others correlate with pathological indices of poor clinical outcome.

Phase I Trial of Intravesical Gemcitabine in Bacillus Calmette-Guérin–Refractory Transitional-Cell Carcinoma of the Bladder

PURPOSE The aim of this phase I study was to determine the safety and toxicity profile of gemcitabine administered as an intravesical agent in patients with transitional-cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS Patients with superficial bladder cancer refractory to intravesical bacillus Calmette-Guérin (BCG) therapy and refusing a cystectomy were considered eligible for the trial. Gemcitabine was given in the bladder for 1 hour twice weekly in 100 mL sodium chloride for a total of six treatments. After a 1-week break, a second course of six treatments over 3 weeks was given, followed by response assessment. Four dose levels were explored: 500 mg, 1,000 mg, 1,500 mg, and 2,000 mg. RESULTS Eighteen patients completed therapy: three at 500 mg, six at 1,000 mg, three at 1,500 mg, and six at 2,000 mg. No grade 3 or 4 toxicity was observed at 500 mg. At 1,000 mg, three patients developed hematuria and one had a skin reaction resembling grade 3 hand-foot syndrome. Three patients at 1,500 mg had no grade 3 or 4 toxicity. Of six patients at 2,000 mg, one had grade 3 thrombocytopenia and neutropenia without infection. Seven patients had a complete response (negative cytology and posttreatment biopsy), and four patients had a mixed response (negative bladder biopsy but positive cytology). CONCLUSION Gemcitabine has substantial activity as an intravesical agent in BCG-refractory TCC and warrants further investigation. Therapy given twice weekly was associated with minimal bladder irritation and tolerable myelosuppression. The recommended phase II dose for twice-weekly therapy is 2,000 mg.

Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder

Perioperative cisplatin‐based chemotherapy has shown benefit in patients with high‐risk localized urothelial bladder cancer, but it is not widely used. Renal impairment may be a major factor limiting its use. The current study was designed to determine the proportion of patients ineligible to receive adjuvant cisplatin‐based chemotherapy based on inadequate renal function alone.

Association of P53 Nuclear Overexpression and Tumor Progression in Carcinoma in situ of the Bladder

We investigated the prevalence and clinical relevance of p53 nuclear overexpression, as detected by antibody PAb1801 and immunohistochemistry, in 33 patients with carcinoma in situ of the bladder. Median followup was 124 months. Disease progressed in 16 patients (48%) during followup. The association between p53 nuclear overexpression and tumor progression was assessed by multivariate analysis, controlling for possible confounding variables, such as patient age and sex, presence of associated stage Ta bladder tumor and adjuvant bacillus Calmette-Guerin therapy. Patients were stratified into 2 groups according to the per cent of tumor cells displaying p53 nuclear overexpression: group 1-18 with less than 20% tumor cells positive and group 2-15 with 20% or more tumor cells positive. Disease progressed in 3 patients (16.7%) in group 1 and in 13 (86.7%) in group 2 (p < 0.0001). Detection of p53 nuclear overexpression in 20% or more tumor cells was the only independent marker of tumor progression in univariate and multivariate analyses (p = 0.004, adjusted relative risk 8.6, 95% confidence interval 2 to 40). Death specifically from bladder cancer was also associated with this altered pattern of p53 expression (p = 0.01, Fishers exact test). We conclude that p53 nuclear overexpression is an early event in bladder cancer, occurring in 48% of cases of carcinoma in situ of the bladder. Our results also suggest that p53 nuclear overexpression offers significant clinical information and may be a useful tool in the selection of therapy for patients with carcinoma in situ of the bladder.

Standardization of pelvic lymphadenectomy performed at radical cystectomy: can we establish a minimum number of lymph nodes that should be removed?

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.