Small Cell Bladder Cancer Research Articles

Small Cell Bladder Cancer: Biology and Management

Small cell bladder cancer (SCBC) is a rare and aggressive form of bladder cancer. It exhibits similar biological behavior to small cell lung carcinoma. Untreated, it is associated with a very poor prognosis. Appropriate oncologic surgery remains the mainstay of treatment of this disease but is not curative alone in the majority of the cases. Adding systemic therapy to the treatment regimen has been shown to improve survival. The most common chemotherapy regimens used in published series include a platinum complex plus etoposide, although doxorubicin-based regimens and standard urothelial cancer regimens also have been associated with response. Despite robust chemotherapy responses, metastatic disease is associated with relapse and a median overall survival of 18 months or less. Better understanding of the molecular alterations driving SCBC may facilitate the development of new therapeutic strategies and improved outcomes.

Abstract 4846: Genomic analysis of high grade bladder cancer: Defining genetic subtypes and therapeutic targets

Abstract Background: Genomic instability, as manifested by copy number alteration (CNA) and mutation, is a hallmark of cancer. We sought to characterize the spectrum of CNAs in 97 high-grade bladder tumors (HGBT) using high-resolution comparative genomic hybridization (CGH). We then performed an integrated analysis of CNA and targeted mutation testing to construct a comprehensive profile of genomic alterations in these tumors and to identify any correlation with clinical outcome. Methods: Genomic DNA from 97 frozen HGBTs (tumor content>70% or greater) and commercially available normal human DNA (Roche) were labeled with cyanine-based fluorescent dyes and hybridized onto a one-million oligonucleotide microarray (Agilent) followed by scanning and image analysis. High-throughput Sanger sequencing of select genes was performed with validation of hotspot oncogene mutations using a mass spectrometry based multiplex Sequenom assay. Results: We found that 47% of HGBT samples possessed a high degree of CNA with widespread amplifications and deletions while 53% contained markedly fewer numbers of events. A non-overlapping pattern of mutations and amplifications was observed when events were grouped within the context of specific signal transduction or cell cycle pathways. Preliminary survival analysis suggests that patients in the high CNA group have a worse prognosis than those in the low CNA group: fifteen out of 46 patients (33%) in the high CNA group have died of their disease vs. 9 of 51 (18%) in the low CNA group. Highly focal amplification events were noted within HER2 (5% of samples), E2F3 (11%), and CCND1 (10%). Immunohistochemistry (IHC) confirmed 3+ overexpression of HER2 in 5 of 5 samples exhibiting genetic amplification. Deletion events were most frequent in CDKN2A (13%). A subset of 11 tumors with small-cell histologic features was included within the samples analyzed and 45% of these tumors possessed E2F3 amplification vs. only 8% within the non-small cell tumor set. Targeted sequencing of select genes revealed that the majority of mutation events occurred within the high-CNA HGBTs. Conclusions: Distinct genetic subsets exist within HGBT and can be classified based on CNA and mutational analysis. The finding of focal amplification events within genes known to drive tumorigenesis in other contexts, such as HER2, underscores the need for global genomic approaches in identifying targets for therapy in bladder cancer. Small-cell bladder cancer may possess a distinct genetic signature characterized by E2F3 amplification. The non-overlapping pattern of CNAs and mutations seen within specific mitogenic pathways suggests that focal driver lesions can be identified for targeted therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4846. doi:10.1158/1538-7445.AM2011-4846

1905 INCIDENCE AND SURVIVAL OF SMALL CELL BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Staging1 Apr 20111905 INCIDENCE AND SURVIVAL OF SMALL CELL BLADDER CANCER Joshua Meeks, Lee Zhao, John Cashy, and Shilajit Kundu Joshua MeeksJoshua Meeks Chicago, IL More articles by this author , Lee ZhaoLee Zhao Chicago, IL More articles by this author , John CashyJohn Cashy Chicago, IL More articles by this author , and Shilajit KunduShilajit Kundu Chicago, IL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2029AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Small cell bladder cancer (SCBC) is a rare and aggressive histologic subtype of bladder cancer thought to be derived in part from neuroendocrine cells. Given its rarity, the natural history, prognosis, and response to treatment have not been described. METHODS From the Surveillance, Epidemiology and End Results (SEER) National Cancer Registry, 498 patients with SCBC were identified between the year of 1998 and 2007. For comparison, 33624 patients with urothelial bladder cancer (UC) were identified for comparison. RESULTS The incidence of SCBC has increased over time from 0.8% to 2% of all cases of bladder cancer (p=0.0001) with an absolute increase of 14 to 77 cases per year from 1998 to 2007. The median age of diagnosis was 72 years, and 80% were male compared to 74% male of UC. The majority of patients with SCBC were white (89%). SCBC was more aggressive, with greater frequency of high grade compared to UC (42% vs. 31%), and muscle invasive disease at presentation (T2, 45% vs. 31%, p=0.001). In terms of treatment, a similar percentage of patients underwent radical cystectomy (18% with SCBC vs 19% with UC) and 19% had a lymph node dissection. Patients with SCBC were more likely to receive adjuvant radiotherapy (23% vs. 9%). Patients with SCBC had a higher rate of metastatic disease to regional lymph nodes (19% vs. 10%), with SCBC patients having higher rates of N1 (13% vs. 7%), N2 (6% vs. 3%) and N3 (0.4% vs. 0.3%) disease. Distant metastasis were present in 18% of SCBC compared to 7.5% in UC. At the time of diagnosis, 18% of patients with SCBC and only 8% of UC had evidence of metastatic disease. A significantly higher percentage of patients with SCBC died of bladder cancer compared to UC (54% vs. 32%, p=0.0001). For nearly every stage, SCBC had a higher cancer specific mortality including T1 (25% vs 14%, p=0.06), T2 (43% vs. 35%, p=0.04) and T3 (55% vs. 38%, p=0.02). Of those patients that died of bladder cancer, the mean time of survival was significantly shorter for SCBC (11 months vs. 15 months, p=0.0001). CONCLUSIONS SCBC is a rare and aggressive form of bladder cancer, with increasing incidence. Compared to standard UC, SCBC has a higher grade, stage, rate of metastasis and cancer-specific mortality. Patients with SCBC may benefit from early aggressive multi-modal therapy. Clinical Features of Patients with Small Cell Compared to Urothelial Bladder Cancer Small Cell BCa Urothelial BCa Age (years) 72 72 Gender (%male) 80 74 High Grade (%) 42 31 Muscle Invasion at Presentation (%) 45 31 Metastasis at Presentation (%) 18 8 Lymph Node Metastasis (%) 19 10 N1 13 7 N2 6 3 N3 .4 .3 Distant Metastasis 18 7.5 Overall Mortality 54 32 © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e762 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joshua Meeks Chicago, IL More articles by this author Lee Zhao Chicago, IL More articles by this author John Cashy Chicago, IL More articles by this author Shilajit Kundu Chicago, IL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Primary genitourinary small cell carcinoma: Clinicopathologic and survival outcomes from SEER database.

200 Background: Small cell carcinoma of genitourinary system (SCC) is a highly aggressive and rare entity. The aim of the study is to characterize the clinicopathologic characteristics and evaluate the treatment outcomes of SCC in adult patients. Methods: Retrospective analysis of 732 patents diagnosed with small cell carcinoma of bladder from 1973 to 2007 was done via SEER database. Demographics, stage, type of treatment received and cancer-specific mortality were examined. Results: 732 patients were identified with SCC of genitourinary tract of which 341 were small cell bladder cancer, 336 were small cell prostate cancer and 55 were small cell renal cancer. Of these 644 patients were males and 88 were females. Median age of diagnosis is 73 years for bladder, 72 years for prostate and 70 years for renal cancer. Majority of the patients were Caucasians (89%) followed by African Americans (6%) and other races (4.98%). Grading of the tumor revealed that 12 patients had well differentiated tumor, 18 patients had moderately differentiated tumor, 191 patients had poorly differentiated, 292 patients had undifferentiated tumor and 219 patients had unknown grade. Pathological T-stages were as follows: T1= 34 (4.6%), T2= 102 (14%), T3= 43 (9%), T4= 41 (5.6%), 38.4% unknown T stage and 67 (9%) patients had metastatic disease. In majority of the patients the treatment received was unknown (565), 90 patients received external beam radiation, and 76 patients received surgery. Cancer-specific mortality was 54% in bladder cancer, 71% in prostate cancer and 78.6% in renal cancer. Median overall survival for all stages was 15.8 months in bladder cancer, 11.3 months in prostate cancer and 8 months in renal cancer. Conclusions: Results show that SCC is a highly aggressive tumor with poor prognosis. Clinical trials involving multiple institutes are needed to accrue enough patients so that treatment paradigms for this uncommon disease can be developed. No significant financial relationships to disclose.

Neuroendocrine Small-Cell Bladder Cancer: Our Experience

Introduction Neuroendocrine bladder cancer is extremely rare, with an estimated incidence of 0.35–0.70% of all bladder tumors. The small-cell carcinoma represents the most frequent histologic variant described. Small-cell carcinoma is an epithelial tumor associated with a more aggressive behavior and poorer prognosis than transitional cell bladder carcinoma. The overall survival rate at 5 years does not exceed 8%. At the time of presentation 59% of patients have clinical stage >T2 and 56% show metastatic disease. In 50% of the patients, fatal progression occurrs within 6 months. Local recurrence after radical surgery occurred in 50–70% of cases. Patients and Methods We report three cases of pure neuroendocrine small-cell bladder cancer. Hematuria was the most common presenting symptom. Local advanced disease was present in all the cases with stage >T2, metastatic disease in 1 case, lymph node involvement and ureteral bilateral obstruction in 2. Two patients were treated by radical cystectomy, bilateral pelvic limph node resections and urinary derivation. Platinum-based adjuvant chemotherapy was proposed but only two patients received the treatment. One patient with liver metastasis was managed only by extensive TUR and support regimen. Results In 2 patients residual or relapsed cancer reappered within 2 months after surgery. All of the three patients died of metastatic disease at 5, 7, and 13 months. Median overall survival was 7 months. The most common site of relapse and spread of disease was the peritoneum and intestinal tract, and the reason of death was uncontrolled acute hemorrhage from gastro-intestinal district. Conclusions In the absence of a prospective study, and because of the rarity of the disease, the best treatment for small-cell bladder cancer remains uncertain. Neoadjuvant chemoterapy with platinum regimen plus aggressive surgical approach will be the treatment of choice. The association of chemotherapy and radiotherapy should also be considered.

Abstract 2598: Evaluation of antitumor efficacy of Trabectedin in patient derived tumor xenografts in vitro and in vivo, and determination of a predictive gene signature

Abstract Trabectedin is a marine derived antitumoral agent, originally isolated from Ecteinascidia turbinata. It acts by binding to the minor groove of DNA interfering with cell division, transcription, and the DNA repair machinery. Trabectedin was approved by the EMEA as second line therapy for the treatment of advanced soft tissue sarcoma and for ovarian cancer in combination with Doxil. Further Phase II trials with Trabectedin in breast and prostate cancer are underway. We characterized Trabectedin for antitumor efficacy and selectivity in patient-derived tumor xenografts to identify target tumor types for further clinical studies. The compound was tested in 67 tumor xenografts of 15 histo types using an ex vivo clonogenic assay. Pronounced concentration dependent antitumor activity (mean IC70 = 1.3 nM) and selectivity was observed, with sensitive tumor models being on average about 7-fold more sensitive than the average of all tumors tested. Trabectedin was also given to tumor-bearing nude mice at 0.2 and 0.15 mg/kg/d iv once weekly for 3 weeks and showed substantial inhibition of tumor growth at a dose level of 0.2 mg/kg/d in tumors of lung, colon, and breast. The activity data of Trabectedin against 67 tumors in the clonogenic assay were used for further bioinformatic analysis. Subsets of tumors and their corresponding data were randomly split into a training set (n=44) and an independent validation set (n=23). By matching in vitro antitumor efficacy data (IC70) of the tumors with the corresponding gene expression profiles (determined by Affymetrix HG-U133 Plus 2.0 gene chip array), a signature of 19 gene transcripts being specific for the responsiveness towards Trabectedin was determined. The classification border for activity of Trabectedin was IC70 = 0.5 nM. The signature was validated by leave-one-out-cross-validation (LOOCV) on the training set, and prediction of tumors of the independent validation set. In the LOOCV sensitivity or resistance of tumors was predicted correctly in 13/18 (72%) and 26/26 tumors (100%), in the validation set in 4/7 (57%) and 13/16 tumors (81%), respectively. In the validation set, the predicted responders showed a 4.5-fold lower median IC70 compared to the predicted non-responders (p= 0.02). Moreover, the signature was used to predict responsiveness of 173 tumors of the Oncotest xenograft collection with unknown sensitivity to Trabectedin. In this set of tumors, the signature identified sarcoma, leukemia/lymphoma, as well as ovarian, head and neck, small cell lung, mammary and bladder cancer as Trabectedin sensitive tumor types. Experimental testing of the predicted tumors so far confirmed the predictions in 11/13 cases (85%). This study shows the feasibility of combining experimental testing and virtual prediction to identify additional tumor types as candidates for further preclinical and clinical investigations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2598.

Carcinoma de célula pequeña de vejiga y adenocarcinoma de próstata sincrónico con retinopatía paraneoplásica asociada

In this paper we describe a case of a patient with synchronous small cell bladder cancer and undiferentiated carcinoma of the prostate, who also developed a paraneoplastic retinopathy. This patient received an organ-sparing treatment with chemoradiation and hormonal therapy achieving a complete remission after 8 years of follow-up.

Chromosomal imbalances in small cell carcinomas of the urinary bladder.

Small cell carcinomas (SCCs) represent a rare histological subtype of urinary bladder cancer. Little is known abut the genetic alterations in these tumours. To identify chromosomal aberrations that are typically present in SCC of the urinary bladder, ten tumours were analysed by comparative genomic hybridization (CGH). CGH allows screening for all relative DNA copy number gains and losses present in a tumour. SCCs of the bladder were characterized by a high number of genomic alterations (mean: 11.3 per tumour). Deletions were most frequent at 10q (7 of 10 tumours deleted), 4q, 5q (5/10 each), and 13q (4/10). These regions may carry tumour suppressor genes with relevance for this particular tumour type. Gains of DNA sequences were most prevalent at 8q (5/10), 5p, 6p, and 20q (4/10 each). High level amplifications were found at 1p22-32, 3q26.3, 8q24, and 12q14-21. These loci may pinpoint the localization of oncogenes with relevance for small cell bladder cancer. The analysis of one tumour having areas of both SCC and transitional cell carcinoma strongly suggests that SCC can develop from TCC through the acquisition of additional genetic alterations.

Insights into mechanisms of cisplatin resistance and potential for its clinical reversal.

Cisplatin in combination with other cytotoxic agents is the backbone for a potential cure of testicular germ cell neoplasms and is a critical factor in the substantial activity observed in the treatment of small cell lung cancer, bladder cancer, and ovarian germ cell tumors. Resistance to cisplatin at the onset of treatment or at relapse limits its curative potential, however. Laboratory studies using both cells selected for cisplatin resistance by exposure to sublethal concentrations and biopsy specimens from patients' tumors provide insights for the potential mechanisms of resistance. The mechanisms identified in vitro include a complex and wide array of related and unrelated pathways such as alterations in cellular drug transport, enhanced DNA repair dependent and independent of signal transduction pathways, and enhanced intracellular detoxification such as glutathione and metallothionein systems. Studies of these mechanisms have identified a number of agents with known potential for administration to humans and that reverse cisplatin resistance in vitro; for example, reversal of cellular accumulation defects by dipyridamole; inhibition of DNA repair by hydroxyurea, pentoxifylline, and novobiocin; inhibition of the glutathione system by ethacrynic acid and buthionine sulfoximine; and inhibition of signal transduction pathways by cyclosporine, tamoxifen, and calcium channel-blocking agents. Current phase I clinical trials are focusing on the most effective doses and schedules to administer these agents in combination with cisplatin. Initial uncontrolled trials in limited numbers of patients suggest that the addition of modulators of cisplatin has the potential to reverse resistance in patients previously failing therapy. Another promising avenue for circumventing cisplatin resistance is the development of noncross-resistant platinum analogs.

Experimental radioimmunotherapy.

Radiolabeled monoclonal antibodies have been used for radioimmunotherapy studies with human tumor spheroids and murine and human tumor xenografts in experimental animals. This paper reviews the work that has been performed in these models with different types of cancer, and highlights those papers that have presented dosimetry estimates and attempts to correlate the findings. Radioimmunotherapy studies in multicell spheroids, as a model for micrometastases, have been performed in human neuroblastoma, colon cancer, and melanoma cell lines using 131I-, 125I-, 186Re-, and 212Bi-labeled antibodies. The uniform geometry of the spheroid has allowed radiation dose estimates to be made. Up to three logs of cell kill have been achieved with 131I- and 186Re-specific antibody with minimal toxicity from labeled nonspecific antibody, but 212Bi-antibody had little effect because of its short half-life as shown by Langmuir. It appears that the two most important factors for therapeutic efficacy in this model are good penetration of the radiolabeled antibody and an adequate radionuclide half-life to allow penetration of the immunoconjugate prior to significant radionuclide decay. Radioimmunotherapy studies in animals bearing transplants of colon cancer, leukemia, lymphoma, hepatoma, renal cell carcinoma, neuroblastoma, glioma, mammary carcinoma, small cell lung carcinoma, cervical carcinoma, ovarian carcinoma, and bladder cancer have been performed with 131I, 90Y, 186Re, 153Sm, and 177Lu beta emitting, and 212Bi alpha emitting radionuclides conjugated to monoclonal antibodies. A few studies compared different radionuclides in the same model system. The approaches that have been used in these studies to estimate tumor dosimetry include the MIRD approach, thermoluminescent dosimetry, autoradiography, and comparison to external irradiation. The majority of investigators have estimated the dose to tumor and normal organs using MIRD-based calculations (time-activity curve and equilibrium dose constant method). The range of tumor doses has been between 17 and 11 171 mGy/MBq of administered radioactivity. The effectiveness of radiolabeled monoclonal antibody therapy depends on a number of factors relating to the antibody such as specificity, affinity, and immunoreactivity. The density, location, and heterogeneity of expression of tumor-associated antigen within tumors will affect the localization and therapeutic efficacy of radiolabeled antibodies, as will physiological factors such as the tumor vascularity, blood flow, and permeability. These factors are discussed and examples are presented.(ABSTRACT TRUNCATED AT 400 WORDS)

The podophyllotoxin derivatives VP16-213 and VM26.

VP16-213 and VM26 are compounds with definite anticancer activity in specific tumor types. Despite 10 years of clinical development the full impact of these compounds in current cancer therapy requires further study. There is no conclusive evidence that one compound is superior to the other in any specific tumor type. The composite activities suggest possible differences in certain cancers such as small cell anaplastic lung cancer, lymphoma, leukemia, bladder and ovarian cancer, but sufficiently adequate studies to determine this have not been reported for any tumor. Understanding the basic pharmacology of these compounds should also be considered of high priority since it is obvious that there is much to learn in this area and further clarification should allow improved clinical utilization. It is hoped that the presentations and discussions of the First International Symposium will generate a new wave of interest in future podophyllotoxin research and development.