Chemotherapy For Advanced Bladder Cancer Research Articles

Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction.

Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa.

Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies

BackgroundSince the standard gemcitabine and cisplatin (GC) chemotherapy for advanced bladder cancer yields limited therapeutic effect due to chemoresistance, it is a clinical challenge to enhance sensitivity to GC.MethodsWe performed high-throughput screening by using a library of known chemicals and repositionable drugs. A total of 2098 compounds were administered alone or with GC to human bladder cancer cells, and chemicals that enhanced GC effects were screened.ResultsDisulfiram (DSF), an anti-alcoholism drug, was identified as a candidate showing synergistic effects with cisplatin but not with gemcitabine in multiple cell lines. Co-administration of DSF with GC affected cellular localisation of a cisplatin efflux transporter ATP7A, increased DNA–platinum adducts and promoted apoptosis. Micellar DSF nanoparticles (DSF-NP) that stabilised DSF in vivo, enhanced the inhibitory effect of cisplatin in patient-derived and cell-based xenograft models without severe adverse effects. A drug susceptibility evaluation system by using cancer tissue-originated spheroid culture showed promise in identifying cases who would benefit from DSF with cisplatin.ConclusionsThe present study highlighted the advantage of drug repurposing to enhance the efficacy of anticancer chemotherapy. Repurposing of DSF to a chemotherapy sensitiser may provide additional efficacy with less expense by using an available drug with a well-characterised safety profile.

Predictive biomarkers for drug response in bladder cancer.

Bladder cancer is a heterogeneous disease. Interpatient heterogeneity in response to a drug limits treatment options and impairs improvement of patient survival. For example, approximately half of patients do not respond to cisplatin-based combination chemotherapy, although it is the standard of care for muscle-invasive and metastatic bladder cancer. The development of robust predictive biomarkers is expected to improve outcomes by enabling clinicians to use chemotherapy only in the patients who will benefit from it. Recent advances in the molecular characterization of bladder cancer showed that the basal subtype of bladder cancer and tumors with inactivating mutations inDNA damage repair genes were associated with greater benefit from cisplatin-based chemotherapy. The present review summarizes current efforts to develop predictive biomarkers for drug response in bladder cancer, focusing on those that predict the response to cisplatin-based chemotherapy for advanced bladder cancer. We also review the current situation with regard to the identification of predictive biomarkers for response to intravesical therapy, immune checkpoint inhibitors and molecularly-targeted drugs. We also discuss the future applications of new technologies, including liquid biopsies and patient-derived organoids that will also serve as resources for the identification of biomarkers in bladder cancer.

Epidermal growth factor expression as a predictor of chemotherapeutic resistance in muscle-invasive bladder cancer

BackgroundEpidermal growth factor receptor (EGFR) overexpression is believed to be associated with bladder cancer (BC) progression and poor clinical outcomes. In vivo studies have linked EGFR subcellular trafficking and chemo-resistance to cisplatin-based chemotherapies. This has not been studied in the clinical adjuvant setting. We aimed to investigate the prognostic significance of EGFR expression in patients receiving cisplatin-based adjuvant chemotherapy following radical cystectomy for advanced BC.MethodsThe database from the Urology and Nephrology Center at Mansoura University was reviewed. BC patients who were treated with radical cystectomy and adjuvant chemotherapy for adverse pathological features or node positive disease were identified. Patients who underwent palliative cystectomy, had histological diagnoses other than pure urothelial carcinoma, or received adjuvant radiotherapy were excluded from the study. Immunohistochemical staining for EGFR expression was performed on archived bladder specimens. The following in vitro functional analyses were performed to study the relationship of EGFR expression and chemoresponse.ResultsThe study included 58 patients, among which the mean age was 57 years old. Majority of patients had node positive disease (n = 53, 91%). Mean follow up was 26.61 months. EGFR was overexpressed in 25 cystectomy specimens (43%). Kaplan-Meier analysis revealed that EGFR over-expression significantly correlated with disease recurrence (p = 0.021). Cox proportional hazard modeling identified EGFR overexpression as an independent predictor for disease recurrence (p = 0.04). Furthermore, in vitro experiments demonstrated that inhibition of EGFR may sensitize cellular responses to cisplatin.ConclusionsOur findings suggest that EGFR overexpression is associated with disease recurrence following adjuvant chemotherapy for advanced BC. This may aid in patient prognostication and selection prior to chemotherapeutic treatment for BC.

Comprehensive analysis of microRNA-messenger RNA regulatory network in gemcitabine-resistant bladder cancer cells.

Chemotherapy is still a standard treatment of unresectable bladder cancer or distant metastases. The chemotherapy resistance always occurs after a period of treatment indicating poor prognosis. The current study aimed to explore the molecular mechanism of chemoresistance in bladder cancer cells. The gene expression profiles of GSE77883, including three untreated T24 cells samples and three gemcitabine-resistant T24 cells samples, was downloaded from Gene Expression Omnibus database. The screening of differentially expressed genes (DEGs), gene function analysis, and interaction prediction between microRNAs (miRNAs) and DEGs were performed by R software. The protein-protein interaction (PPI) and miRNA-DEGs networks were constructed and visualized by Cytoscape software. Then, the small molecules, with potential synergistic or antagonistic effects to gemcitabine resistance, were identified using the Connectivity Mapdatabase. Finally, gemcitabine-resistant T24 cell line was established and key genes were validated by quantitative real-time polymerase chain reaction (qRT-PCR). In total, 536 upregulated and 513 downregulated genes were screened and mainly enriched in oxidative stress response and signaling pathways related to extracellular matrix-receptor interaction and focal adhesion. PPI network showed interleukin 6, tumor necrosis factor, kinesin family member 11, and BUB1 mitotic checkpoint serine/threonine kinase B were key genes. The miRNA-DEGs regulatory networks included 18 miRNAs and 185 DEGs, including miR-182-5p, miR-590-3p, miR-320a and serum- and glucocorticoid-regulated kinase 1 (SGK1). Then, the related key genes and miRNAs were confirmed by qRT-PCR. Furthermore, 81 small molecules with antagonistic or synergistic effect to GEM were screened. We have investigated the molecular mechanisms driving GEM-resistance in bladder cancer cells that would contribute to the development of chemotherapy for advanced bladder cancer.

Palliative Chemotherapy for Bladder Cancer: Treatment Delivery and Outcomes in the General Population.

Palliative chemotherapy for advanced bladder cancer is recommended in clinical practice guidelines because of the results achieved in clinical trials. However, real-world treatment and outcomes have not been well described. We report the treatment delivery and survival associated with palliative chemotherapy in routine clinical practice. The population-based Ontario Cancer Registry was linked to electronic records of treatment to identify all patients with bladder cancer treated with palliative chemotherapy in Ontario during 1994 to 2008. Treatment regimens were identified for those cases treated at regional cancer centers. Overall survival (OS) and cancer-specific survival (CSS) were determined from the start of palliative chemotherapy. A Cox proportional hazards model was used to identify the factors associated with OS and CSS. The palliative chemotherapy regimen was identified for 710 patients with bladder cancer in Ontario during 1994 to 2008. Gemcitabine-cisplatin (Gem-Cis) was delivered to 37% (261 of 710), gemcitabine-carboplatin (Gem-Carbo) to 14% (96 of 710), and MVAC (methotrexate, vinblastine, Adriamycin, and cisplatin) to 8% (56 of 710). Other regimens were delivered to 42% of cases. The proportion of cases treated with Gem-Cis increased during the study period: 3% in 1994 to 1999, 32% in 2000 to 2003, and 52% in 2004 to 2008 (P< .001). The median survival and 5-year OS by regimen was 10 months and 16% for Gem-Cis, 7 months and 6% for Gem-Carbo, and 10 months and 13% for MVAC, respectively. Multivariate analysis controlling for age and comorbidity demonstrated improved survival for Gem-Cis and MVAC compared with Gem-Carbo (hazard ratio, 1.53; 95% confidence interval, 1.19-1.98). The median survival associated with palliative chemotherapy for bladder cancer in routine practice is slightly inferior to the outcomes reported in clinical trials. However, consistent with the clinical trial results, a proportion of patients treated with palliative chemotherapy will achieve long-term survival. Gem-Carbo is associated with inferior survival compared with Gem-Cis and MVAC in routine practice.

Use of Palliative Chemotherapy for Advanced Bladder Cancer: Patterns of Care in Routine Clinical Practice.

Palliative chemotherapy for advanced bladder cancer is recommended in clinical practice guidelines. Patterns of care in routine clinical practice have not been well described. This article describes use rates of chemotherapy and referral rates to medical oncology in the last year of life among patients who have died of bladder cancer. A population-based cohort of patients with bladder cancer was identified from the Ontario Cancer Registry; the study population included patients who died of bladder cancer between 1995 and 2009. Electronic records of treatment and physician billing records were used to identify treatment patterns and referral to medical oncology. Log-binomial and modified Poisson regression were used to examine factors associated with chemotherapy use and medical oncology consultation. A total of 8,005 patients died of bladder cancer, 25% (n=1,964) of whom received chemotherapy in the last year of life. Use was independently associated with patient age, comorbidities, socioeconomic status, sex, time period, and treatment region. A total of 68% (n=5,426) of patients were seen by a medical oncologist. Referral to medical oncology was associated with age, comorbidities, year of death. Geographic variation was seen with chemotherapy use-from 18% to 30%-that persisted on adjusted analysis. The efficacy of palliative chemotherapy demonstrated in clinical trials and recommended in guidelines has not translated into widespread use in practice. Understanding the extent to which patient preferences and health system factors influence use is needed. Access to acceptable palliative systemic treatments remains an unmet need for most patients dying of bladder cancer.

Pretreatment Neutrophil-to-Lymphocyte Ratio Can Predict the Prognosis in Bladder Cancer Patients Who Receive Gemcitabine and Nedaplatin Therapy.

Introduction and Objectives. Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a simple marker of the systemic inflammatory response in critical care patients. We previously assessed the utility of NLR as a biomarker to predict tumor recurrence and cancer death in bladder cancer patients who underwent radical cystectomy. In this study, we evaluated the prognostic impact of NLR in bladder cancer patients who received gemcitabine and nedaplatin (GN) chemotherapy. Methods. A total of 23 patients who received GN chemotherapy for advanced bladder cancer were enrolled in this study. The cut-off point of NLR according to the sensitivity and specificity levels was derived from the area under receiver operator characteristics (AUROC) curve plotted for disease progression or overall mortality. Results. The NLR cut-off point was determined as 4.14 for both tumor progression and overall mortality. Median progression-free survival (PFS)/overall survival (OS) in the higher NLR group (NLR ≥ 4.14) and lower NLR group (NLR < 4.14) were 194/468 days versus 73/237 days, respectively. Kaplan-Meier analysis showed that higher NLR significantly correlated with poorer PFS (p = 0.011) and OS (p = 0.045). Conclusions. NLR may serve as a new biomarker to predict responses to GN-based chemotherapy in advanced bladder cancer patients and/or their prognosis.

Utilization of palliative chemotherapy for advanced bladder cancer: Patterns of care in routine clinical practice.

6525 Background: Although palliative chemotherapy for advanced bladder cancer is recommended in clinical practice guidelines, patterns of care in routine care is not described. Here we describe uti...

Abstract 904: EGFR expression predicts recurrence in patients undergoing adjuvant chemotherapy for advanced bladder cancer

Abstract Epidermal growth factor receptor (EGFR) overexpression has been associated with bladder cancer progression and poor clinical outcomes. In vivo studies have linked EGFR subcellular trafficking and chemo-resistance to cisplatin-based protocols in other tumor types. This has not been studied in the clinical adjuvant setting in bladder cancer. In this study, we aimed to investigate the prognostic significance of EGFR expression in patients receiving adjuvant chemotherapy following radical cystectomy for advanced bladder cancer. Mansoura Urology and Nephrology Center database was reviewed. Patients treated with radical cystectomy and thereafter completed adjuvant chemotherapy for adverse pathological features or node positive diseases were identified. Patients who underwent palliative cystectomy, those with histological diagnosis other than pure transitional cell carcinoma and patients who received adjuvant radiotherapy were excluded. Immunohistochemical analysis for EGFR expression was performed on archived bladder specimens. The relationship of EGFR expression and clinical outcomes was assessed. In vitro studies were performed to determine whether EGFR expression associates with resistance to chemotherapeutic reagents. The study included 58 patients. Mean age was 57 years. All patients had pathologic stage T2 or greater. Majority of patients had node positive disease (n=53, 91%). Mean follow up was 26.61 months. EGFR was overexpressed in 25 cystectomy specimens (43%). Kaplan Meyer analysis revealed that EGFR over-expression significantly correlated with disease recurrence (p=0.021). Cox proportional hazard modeling identified EGFR overexpression as an independent predictor for disease recurrence (p=0.04). In vitro functional analysis demonstrated that EGFR expression level altered response to cisplatin-induced apoptosis, and that inhibition of EGFR enhanced sensitization of bladder cancer cells to cisplatin-induced apoptosis. In summary, our findings suggest that EGFR overexpression is associated with disease recurrence following adjuvant chemotherapy for advanced bladder cancer. EGFR status may help predict prognosis and select patients for adjuvant chemotherapy. Citation Format: Ahmed Mansour, Mona Abdulreheem, Mamdouh Elsherbeeny, Mohammed Sultan, Ahmed Shokeir, Ahmed Mosbah, Hassan Abol-Enein, Taeeun Park, Hyung Kim, Jayoung Kim. EGFR expression predicts recurrence in patients undergoing adjuvant chemotherapy for advanced bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 904. doi:10.1158/1538-7445.AM2014-904

Second-line chemotherapy for advanced bladder cancer: A survey of current UK practice

Objectives•To understand current practice of the treatment of advanced bladder cancer in the United Kingdom, and in particular, the use of second-line chemotherapy.•To gain insight into uro-oncologists' use of first-line chemotherapy, imaging following first-line chemotherapy, use of second-line chemotherapy, and the role of the multidisciplinary tumor board (MTB) in making decisions about second-line chemotherapy. Materials and methods•From August 2011 to September 2011 uro-oncologists from UK cancer centers were surveyed regarding treatment of advanced bladder cancer.•Delegates at the British Uro-oncology Group conference were invited to fill out an electronic survey Results•Uro-oncologists from 28 of 42 UK cancer centers (67%) participated, who treated, on average 45 patients per year with advanced bladder cancer.•Fifteen “always” reimage after first-line chemotherapy, mostly “after 2–4 cycles.” Symptomatic patients with progressive distant disease on imaging were most likely to trigger second-line chemotherapy (P = 0.004).•Twenty-one respondents would interrupt first-line chemotherapy to start second-line chemotherapy for progressive disease and 10 would never do this. Of the patients given first-line chemotherapy, 19% go on to receive second-line chemotherapy.•Seven different regimes were specified for second-line chemotherapy with no clear preference. National Institute for Health and Clinical Excellence approval, trial data, inclusion in hospital formulary, clinical trials, or commissioning guidelines, and easy access to imaging help to access second-line chemotherapy (P≤0.001). Constraints to second-line chemotherapy were lack of evidence and patient comorbidities.•MTB effectiveness did not improve access to second-line chemotherapy. Of the 33 respondents, 19 do not rediscuss patients at the MTB before starting second-line chemotherapy. Conclusion•The investigation and treatment of patients with advanced bladder cancer following first-line chemotherapy is variable.•Optimizing the modality and frequency of imaging and increasing the usefulness of the MTB process may improve care.

Tumor-Targeting Multifunctional Micelles for Imaging and Chemotherapy of Advanced Bladder Cancer

This work aimed to determine if the treatment outcomes of bladder cancer could be improved by targeting micelles that are decorated with bladder cancer-specific ligands on the surface and loaded with the chemotherapeutic drug paclitaxel. Targeting efficacy and specificity was determined with cell lines. An in vivo targeting and anti-tumor efficacy study was conducted in mice carrying patient-derived xenografts. Targeting micelles were more efficient than nontargeting micelles in delivering the drug load into bladder cancer cells both in vitro and in vivo (p < 0.05). The micelle formulation of paclitaxel was less toxic than free paclitaxel in Cremophor(®) (Sigma, MO, USA) and allowed administration of three-times the maximum tolerated dose without increasing the toxicity. Targeting micelles were more effective than the nontargeting micelles in controlling cancer growth (p = 0.0002) and prolonging overall survival (p = 0.002). Targeting micelles loaded with paclitaxel offer strong potential for clinical applications in treating bladder cancer.

Chemotherapy in advanced bladder cancer: current status and future.

Bladder cancer occurs in the majority of cases in males. It represents the seventh most common cancer and the ninth most common cause of cancer deaths for men. Transitional cell carcinoma is the most predominant histological type. Bladder cancer is highly chemosensitive. In metastatic setting, chemotherapy based on cisplatin should be considered as standard treatment of choice for patients with good performance status (0-1) and good renal function-glomerular filtration rate (GFR) > 60 mL/min. The standard treatment is based on cisplatin chemotherapy regimens type MVAC, HD-MVAC, gemcitabine plus cisplatin (GC) or dose dense GC. In unfit patients, carboplatin based regimes; gemcitabine plus carboplatin or methotrexate plus carboplatin plus vinblastine (MCAVI) are reasonable options. The role of targeted therapies when used alone, or in combination with chemotherapy, or in maintenance, was evaluated; targeting angiogenesis seem to be very promising. The purpose of this literature review is to highlight the role of chemotherapy in the management of advanced transitional cell carcinoma of the bladder.

Which patients benefit the most from neoadjuvant chemotherapy in advanced bladder cancer?

Despite 5% advantage in 5-year overall survival, neoadjuvant chemotherapy may result in considerable overtreatment of bladder cancer patients because of the lack of response criteria. The review's purpose was to identify the criteria on which the selection of bladder cancer patients for neoadjuvant chemotherapy followed by radical cystectomy should be based. About 30-40% of patients with metastatic bladder cancer are ineligible for platinum-based neoadjuvant chemotherapy because of renal impairment. Stratification based on the clinical tumor stage is likely to be biased by inappropriate preoperative staging. Differences in the response to neoadjuvant chemotherapy seem not to be predictable by histological subtype of bladder cancer. Future developments in radiological imaging, molecular cancer staging and response prediction aim to identify patients who will profit from neoadjuvant chemotherapy. Patients considered for neoadjuvant chemotherapy should be eligible for cisplatinum-based regimens. To avoid overtreatment, preferably patients with nonorgan-confined and lymph-node disease should be treated by neoadjuvant chemotherapy. However, the possibility of staging error should be taken into account. Patients with limited metastatic disease may also profit from neoadjuvant chemotherapy followed by radical cystectomy with concomitant metastasectomy.

Editorial Comment

The authors ought to be commended for their diligent follow-up and assessment of long-term outcomes from their original phase I study of docetaxel in patients who were refractory to most other intravesical therapies. Although it is difficult to resist the temptation to assess and report “response” from phase I studies, one has to be cautious about doing so. These data substantiate earlier observations with other chemotherapeutic agents used intravesically in the BCG refractory setting, such as valrubicin 1 Steinberg G. Bahnson R. Brosman S. et al. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder The Valrubicin Study Group. J Urol. 2000; 163: 761-767 Abstract Full Text Full Text PDF Scopus (254) Google Scholar and gemcitabine. 2 Dalbagni G. Russo P. Sheinfeld J. et al. Phase I trial of intravesical gemcitabine in bacillus Calmette–Guérin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol. 2002; 20: 3193-3198 Crossref Scopus (145) Google Scholar Initially, chemotherapy appears to yield an admirable response rate as seen with gemcitabine 3 Dalbagni G. Russo P. Bochner B. et al. Phase II trial of intravesical gemcitabine in bacilli Calmette-Guérin-refractory transitional cell carcinoma of the bladder. J Clin Oncol. 2006; 24: 2729-2734 Crossref Scopus (144) Google Scholar and with docetaxel. 4 McKiernan J.M. Masson P. Murphy A.M. et al. Phase I trial of intravesical docetaxel in the management of superficial bladder cancer refractory to standard intravesical therapy. J Clin Oncol. 2006; 24: 3075-3080 Crossref Scopus (107) Google Scholar However, the response does not appear to be durable. The relatively poor long-term success of single agent intravesical chemotherapy has a familiar ring to it. Single agent systemic chemotherapy for advanced bladder cancer has long been abandoned after it was demonstrated to be comparatively less effective than combination therapy. 5 Brinkley W.M. Torti F.M. Systemic chemotherapy of transitional cell carcinoma of the urothelium. Semin Surg Oncol. 1997; 13: 365-375 Crossref Scopus (7) Google Scholar Therefore, why do we presume it will be any different when the chemotherapy is delivered directly into the bladder? It would be reasonable to expect that a combination of intravesical agents may prove more effective than using a single agent and this indeed appears to be the case based on early reports. 6 Breyer BN, Whitson JM, Carroll PR, et al. Sequential intravesical gemcitabine and mitomycin C chemotherapy regimen in patients with non-muscle invasive bladder cancer. Urol Oncol, in press. Google Scholar We now have at least 3 chemotherapeutic agents (mitomycin, gemcitabine, and docetaxel) that have some demonstrated activity against non–muscle-invasive urothelial cancer. It may behoove us to investigate if any or all of these 3 drugs along with other, yet to be tested agents, can be used to devise a combination regimen that is more effective in these patients who are refractory to BCG or other immunotherapy. Long-term Clinical Outcomes of a Phase I Trial of Intravesical Docetaxel in the Management of Non–muscle-invasive Bladder Cancer Refractory to Standard Intravesical TherapyUrologyVol. 75Issue 1PreviewTo report the long-term clinical outcomes and durability of response after treatment with induction intravesical docetaxel. Most novel agents used to treat bacillus Calmette-Guerin refractory high-grade non–muscle-invasive (NMI) bladder cancer are evaluated only after short follow-up periods. Our previously published phase I trial demonstrated that docetaxel is a safe agent for intravesical therapy with minimal toxicity and no detectable systemic absorption. We sought to determine long-term clinical outcomes after treatment with intravesical docetaxel. Full-Text PDF

7187 Clinical effectiveness of palliative chemotherapy for advanced bladder cancer

7187 Clinical effectiveness of palliative chemotherapy for advanced bladder cancer

Drug Related Genetic Polymorphisms Affecting Adverse Reactions to Methotrexate, Vinblastine, Doxorubicin and Cisplatin in Patients With Urothelial Cancer

There is considerable interindividual diversity in the development of adverse reactions during chemotherapy for cancers. This diversity is suggested to be attributable to differences in the disposition of chemotherapeutic agents, which is modified by genetic polymorphisms. In this study we evaluated the possible association of polymorphisms of genes involved in the metabolism, detoxification and transport of the agents with adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin therapy. A total of 40 patients with urothelial cancer who received methotrexate, vinblastine, doxorubicin and cisplatin or high dose methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy between 1996 and 2005 at Akita University Medical Center were included in this study. Four genetic polymorphisms (ABCB1, GSTP1, CYP3A5 and MTHFR) and clinical parameters were included in the analysis to determine whether there was any association with the grade of adverse reactions at the first cycle and the worst grade of each adverse reaction throughout the chemotherapy period. On multivariate analysis the CYP3A5 A6986G genotype *3/*3 (OR 8.205, 95% CI 1.616-41.667, p = 0.011) and smaller number of treatment cycles (OR 0.156, 95% CI 0.037-0.659, p = 0.011) were independent factors for leukocytopenia (grade 3 or greater) throughout the period of chemotherapy. The mean white blood cell count nadir in patients with genotype *3/*3 was significantly lower than that in those with the *1 allele (1,542 +/- 903 vs 2,431 +/- 973/mm(3), p = 0.009). The A6986G polymorphism of CYP3A5, which is involved in the metabolism of vinblastine and doxorubicin, might be a genetic predictor of the severity of leukocytopenia induced by chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin.

Severe Hemolytic Uremic Syndrome Associated with Cisplatin-based Chemotherapy for Advanced Bladder Cancer

Hemolytic uremic syndrome (HUS) is a heterogeneous disorder characterized by hemolytic anemia, thrombocytopenia and renal failure that occurs predominantly in infants and young children. However, HUS in adults has also been described as a complication of various chemotherapy regimens with a relatively poor prognosis. Since cisplatin is now widely used for treatment of solid cancers, it is necessary to take into account the possibility of cisplatin-induced hemolytic uremic syndrome as a rare but potentially fatal side- effect. Herein, we describe our experience with a 67-year old woman being treated for a urothelial carcinoma of the bladder who suffered chemotherapy-induced HUS after a cisplatin-based regimen. Plasmapheresis was carried out five times; however, her serum platelets remained depressed, and she subsequently died. We conclude that there is a high risk potential for HUS in patients undergoing intensive chemotherapy for advanced-stage bladder cancer.

Results of the phase II EORTC 22971 trial evaluating combined accelerated external radiation and chemotherapy with 5FU and cisplatin in patients with muscle invasive transitional cell carcinoma of the bladder

Introduction. We prospectively evaluated concomitant radiotherapy and chemotherapy for advanced bladder cancer in a phase II EORTC trial to test whether it could be further studied as a potential treatment of bladder cancer. Patients and methods. Patients up to 75 years of age with invasive transitional-cell carcinoma of the bladder up to 5 cm, stage pT2 to pT3b, N0M0, without residual macroscopical tumour after transurethral excision were eligible. Radiotherapy consisted of 2 fractions of 1.2 Gy daily up to 60 Gy delivered in a period of 5 weeks. During the first and the last week, cisplatin 20 mg/m2/day and 5 FU 375 mg/m2/day were given concomitantly. Results. The study was interrupted early due to poor recruitment. Nine patients of the originally 43 planned were treated. Mean age was 63 years. Five patients had tumour stage pT2, 1 stage pT3a and 3 stage pT3b. All patients completed radiotherapy and chemotherapy as scheduled. Only one grade 3 and no grade 4 toxicity was seen. All patients were evaluated 3 months after treatment: eight patients had no detectable tumour and one had para-aortic lymph nodes. During further follow-up, a second patient got lymph node metastases and two patients developed distant metastases (lung in the patient with enlarged lymph nodes at the first evaluation and abdominal in one other). Those three patients died at respectively 19, 14, and 18 months after registration. Late toxicity was limited and often temporary. After 26 to 57 months of follow-up, no local recurrences were seen. Six patients remained alive without disease. Discussion. Despite the small cohort, this combination of concomitant chemotherapy and accelerated hyperfractionated radiotherapy for invasive bladder cancer seemed to be well tolerated and to result in satisfactory local control with limited early and late toxicity. It could therefore be considered for study in further clinical trials.

Oncological and Functional Outcome of Radical Cystectomy in Patients With Bladder Cancer and Obstructive Uropathy

We present our experience with the perioperative, functional and oncological outcomes of radical cystectomy in patients with bladder cancer and obstructive uremia. From 1998 to June 2006, 58 patients with bladder cancer, and concomitant obstructive uropathy and azotemia presented to our institution. Mean +/- SD serum creatinine at presentation was 9.2 +/- 4.5 mg% (range 2.4 to 16.5). Radical cystectomy, bilateral pelvic lymphadenectomy and urinary diversion were performed after stabilizing renal function with and without percutaneous nephrostomy in 28 and 8 patients, respectively. Various preoperative variables were evaluated for predicting long-term treatment failure and renal deterioration. Mean followup was 34 months. Mean serum creatinine at surgery was 1.85 mg%. An ileal conduit was used in 32 patients and cutaneous ureterostomy was used in 4. One patient died of chest infection in the perioperative period. All patients had muscle invasive disease, while 15 had positive lymph nodes. At the mean followup 15 patients (41.6%) were free of disease and 21 had treatment failure. Of the factors evaluated pathological tumor stage, grade and lymph node involvement predicted the long-term oncological outcome, while serum creatinine greater than 2.5 mg% at surgery and ileal conduit diversion predicted long-term renal deterioration. Patients with bladder cancer who have obstructive uremia usually present with locally advanced disease. Radical cystectomy is not associated with additional morbidity, provided that patients are adequately prepared before surgery by optimizing renal function. An adequate number of these patients achieve long-term disease-free survival after radical cystectomy. As the urinary diversion of choice, an ileal conduit appears to be safe in patients with serum creatinine less than 2.5 mg% at surgery.