Phase II study of MTX-HSA in combination with cisplatin as first line treatment in patients with advanced or metastatic transitional cell carcinoma.

PURPOSE: To assess the efficacy, tolerability and safety of MTX-HSA (methotrexate (MTX) covalently linked to human serum albumin (HSA)) combined with cisplatin as first line therapy for advanced bladder cancer. METHODS: Patients (pat) were treated with a loading dose of 110 mg/m(2) of MTX-HSA followed by a weekly dose of 40 mg/m(2) starting on day 8. Cisplatin was given on day 2 of each 28 day cycle at a dose of 75 mg/m(2). RESULTS: Tumor response evaluation was possible in 7 patients. Complete response (CR) and partial response (PR) was observed in 1 patient each (overall response rate: 29%). Key toxicities included CTC Grade (G) 3/4 stomatitis in 6 patients, vomiting G3 in 1 patient, fatigue G3 in 1 patient and thrombocytopenia G3 in 3 patients. CONCLUSION: The combination of MTX-HSA with cisplatin is feasible and shows antitumor activity against urothelial carcinomas combined with an acceptable toxicity profile.

Dual-parameter immunoflow cytometry in diagnosis and follow-up of patients with bladder cancer.

OBJECTIVES: The aim of this study was to evaluate the clinical significance of a dual-parameter immunoflow cytometry (DPI-FCM) assay in the detection of tumor cells in barbotage specimens of bladder cancer patients. METHODS: DPI-FCM is an automated method, based on the utilization of two monoclonal antibodies (mAbs) either used for a preselection of urothelial cells (mAb Due AUT 2) or the analysis of the expression of a differentiation antigen within the preselected urothelial cells (mAb Due ABC 3). The ratio of ABC 3-positive urothelial cells was used to discriminate between the normal and malignant state of the urothelium. At the time of examination 40 patients had endoscopically overt bladder tumors. Another 30 patients without endoscopically visible tumors were examined before routine rebiopsy. Thirty barbotage specimens from patients with diseases not related to bladder cancer were examined as controls. RESULTS: Overall, the sensitivity of DPI-FCM in patients with endoscopically overt and invisible residual tumors was 95 and 83%, respectively, regardless of concomitant urinary tract infection. The sensitivity of DPI-FCM for both patient groups was 86, 95 and 94% for tumor grades 1, 2 and 3, respectively. The specificity of the method in 30 patients with no history of bladder cancer was 93%. CONCLUSIONS: DPI-FCM appears to be a highly reliable method of recognizing tumor cells in bladder barbotage specimens even in patients with concomitant urinary tract infection. The procedure may be of value in monitoring bladder cancer patients for tumor recurrence.

Predictive value of molecular alterations for the prognosis of urothelial carcinoma.

Accumulation of p53 and C-Myc overexpression are frequently found in advanced urothelial carcinomas. The prevalence and predictive value of both molecular alterations was investigated in 61 patients with superficial urothelial tumors. Distinct patterns of p53 accumulation and C-Myc overexpression were observed in superficial urothelial carcinoma of different stages. For instance, 67% of carcinomata in situ displayed accumulation of p53, but only 44% showed C-Myc overexpression, whereas in pT1 tumors the corresponding percentages were 25 and 75%. Similarly, while p53 accumulation was significantly (p = 0.02) associated with tumor grade, C-Myc overexpression did not correlate with grade. In multivariate analysis, p53 accumulation was found to be an independent predictor of tumor progression (p = 0.0096), whereas C-Myc overexpression did not correlate with the course of disease. Alterations in both markers together predicted neither tumor recurrence nor tumor progression better than p53 accumulation on its own. Sufficient expression of C-Myc may be a general requirement for proliferative competence in urothelial tumors, barring its use as a predictive marker. The predictive value of p53 accumulation for tumor progression was further underlined by the finding that in a distinct group of 52 patients with progressive urothelial carcinoma 73% of the recurrent tumors displayed p53 accumulation.

Molecular biology of dissemination in bladder cancer--laboratory findings and clinical significance.

Recent molecular biology investigations have demonstrated that tumor progression and dissemination in bladder cancer is a highly complicated phenomenon, consisting of multiple distinct steps and regulated by a great number of different genes. Some of these genes involved in the specific steps of tumor progression and dissemination have been identified. Several oncogenes, e.g., the epithelial growth factor receptor (EGF-R), and tumor-suppressor genes, e.g., the p53 gene, have been found to correlate significantly with tumor progression. The decreased expression of cell-adhesion molecules such as E-cadherin appears to facilitate tumor-cell detachment in the primary tumor, whereas expression of the intercellular adhesion molecule (ICAM)-1 might be of relevance for cell attachment at the metastatic site. Tumor invasion through the basement membrane has been correlated with a decreased expression of laminin and elevated urinary levels of acidic fibroblast growth factor. Although the complex processes related to dissemination are far from being completely understood, the finding of differential expression of distinct genes appears to provide the first targets for therapeutic intervention.

[Prognostic factors for predicting the success of immunotherapy in metastatic renal cell carcinoma]. / Prognostiche Faktoren zur Vorhersage des Erfolges einer Immuntherapie beim metastasierten Nierenzellkarzinom.

Only approximately 20% of the patients with metastatic renal cell carcinoma who undergo systemic immunotherapy will respond to this form of treatment. Appropriate selection of patients could exclude many who will not benefit from immunotherapy from a toxic and expensive treatment. Several factors predicting the outcome of immunotherapy have been reported so far. These predictors can be classified into (1) patient-related factors, (2) tumour-related factors and (3) alterations of the immune system during immunotherapy. Performance status and the interval between tumour nephrectomy and metastasization are the most important patient-related factors. Liver metastases are apparently an unfavourable tumour-related prognostic factor. Various alterations of the immune system during immunotherapy are significantly linked with the outcome of the treatment. In consequence, the prospective investigation of prognostic factors within clinical trials appears to be mandatory.

Dual-parameter immunoflow cytometry--a new technique in the noninvasive diagnosis of bladder cancer.

The introduction of monoclonal antibodies into the diagnosis of transitional cell carcinoma (TCC) has been a further step toward the use of biological parameters to support conventional cytological diagnosis of this tumor entity. Several investigators have demonstrated the high sensitivity and good specificity of immunocytology. Nevertheless this technique is hampered by the inconvenient and time-consuming microscopic analysis. The purpose of this study was to combine the advantages of immunocytology with the capabilities of an automated flow-cytometric system. Since all monoclonal antibodies (mAbs) currently used for immunocytology cross-react with granulocytes a preselection of urothelial cells becomes necessary for immuno-flow cytometry (immuno-FCM). Based on earlier analyses mAb Due AUT 2, reactive against urothelium and not against granulocytes, was chosen to preselect for urothelial cells. mAb Due ABC 3 was used to discriminate between normal and malignant urothelial cells. Initial experiments including 10 barbotage specimens from patients with histologically proven TCC and concomitant urinary tract infection yielded a high sensitivity (90%) of immuno-FCM. In 10 control patients with malignancies other than bladder TCC and benign diseases ABC 3 expression was not increased. Flow-cytometric examination of irrigation specimens from 10 patients with a history of bladder cancer but without cystoscopic and cytologic evidence of tumor recurrence showed abnormal results in 6 patients. Rebiopsy and/or cystectomy confirmed tumor recurrence in 5 of these patients and in 1 patient with negative immuno-FCM. Ongoing prospective trials will further define the clinical impact of this approach in the diagnosis and follow-up of patients with bladder cancer.