Search

Background: Neoadjuvant chemotherapy (NACT) for the treatment of muscle-invasive bladder cancer (MIBC) remains underutilized in the United States despite evidence supporting its use., Objectives: To examine the perioperative chemotherapy management of patients with MIBC by medical oncologists (MedOncs) to move toward standardization of practice, Participants and Methods: A 26-question survey was emailed to 92 MedOncs belonging to the Bladder Cancer Advocacy Network or the American Society of Clinical Oncology for completion from May to October 2011 RESULTS: A total of 83 MedOncs completed the survey: 52% were based in academic centers. Most referrals were from urologists (79%). NACT for treatment of MIBC and high-grade upper-tract urothelial carcinoma is offered by 80% and 46% of respondents, respectively. Adjuvant chemotherapy for treatment of MIBC and upper-tract urothelial carcinoma is offered by 46% and 42% of respondents, respectively. NACT was not offered by 49%, 29%, and 35% of respondents if Eastern Cooperative Oncology Group performance status was 3 or greater, if patients had T2 lesions without lymphovascular invasion, and if the glomerular filtration rate was<50ml/min, respectively. Chemotherapy regimens included gemcitabine/cisplatin (90%), methotrexate/vinblastine/adriamycin/cisplatin (30%), dose-dense methotrexate, vinblastine, adriamycin, and cisplatin (20%), and gemcitabine/carboplatin (37%)., Conclusions: Most MedOncs (79%) in this survey offer perioperative chemotherapy to all patients with MIBC. This increased use of NACT is higher than previously reported, suggesting an increase in the adoption of recommendations that follow best evidence., (Published by Elsevier Inc.)

A 78-year-old Bulgarian woman presented to the National Institutes of Health (NIH) with a diagnosis of poorly differentiated metastatic carcinoma of unknown origin. The prior month she had been seen at a hospital in Bulgaria for weight loss and a right inguinal mass. NIH pathology review confirmed a poorly differentiated carcinoma with extensive necrosis suggesting squamous cell carcinoma. She was enrolled in a treatment trial at NIH with metastatic disease invading the lungs and lymph nodes (mediastinum, abdomen, and pelvis) and a chemotherapy regimen was started of gemcitabine, carboplatin, and lenalidomide with dexamethasone as an antiemetic. The patient returned on day 8, and a rash of 2 days duration was noted. Immediately before arriving at the dermatology clinic, she developed altered mental status with aphasia and was admitted for neurologic observation. The altered mental status resolved and evaluation revealed only small-vessel ischemia. The patient was also experiencing diarrhea and was found to have elevated transaminases (4- to 7-fold over normal). Chemotherapy was held because of the transaminase abnormalities and altered mental status. The following day, the patient was seen by dermatology for a progressive asymptomatic eruption.

Purpose of Review: Greater understanding of the biology and genetics of urothelial carcinoma is helping to identify and define the role of molecules and pathways appropriate for novel-targeted therapies. Here, we review the targeted therapies that have been reported or are in ongoing urothelial carcinoma clinical trials, and highlight molecular targets characterized in preclinical and clinical studies., Recent Findings: Trials in nonmuscle-invasive bladder cancer are evaluating the role of immunotherapy and agents targeting vascular endothelial growth factor (VEGF) or fibroblast growth factor receptor-3. In muscle-invasive bladder cancer, neoadjuvant studies have focused on combining VEGF agents with chemotherapy; adjuvant studies are testing vaccines and agents targeting the human epidermal growth factor receptor 2, p53, and Hsp27. In the first-line treatment of metastatic urothelial carcinoma, tubulin, cytotoxic T-lymphocyte antigen 4, Hsp27, and p53 are novel targets in clinical trials. The majority of targeted agents studied in urothelial carcinoma are in the second-line setting; new targets include CD105, polo-like kinase-1, phosphatidylinositide 3-kinases (PI3K), transforming growth factor β receptor/activin receptor-like kinase β, estrogen receptor, and the hepatocyte growth factor receptor (HGFR or MET)., Summary: Development of targeted therapies for urothelial carcinoma is still in early stages, consequently there have been no major therapeutic advances to date. However, greater understanding of urothelial carcinoma and solid tumor biology has resulted in a proliferation of clinical trials that could lead to significant advances in treatment strategies.

Objectives. Level 1 evidence supports the use of neoadjuvant chemotherapy (NAC) to improve overall survival in muscle invasive bladder cancer; however utilization rates remain low. The aims of our study were to determine factors associated with NAC use, to more clearly define reasons for low utilization, and to determine the current rate of NAC use among urologic oncologists. Materials and Methods. Active members of the Society for Urologic Oncology were provided a 20-question survey. Descriptive statistical analysis was conducted for each question and univariate analysis was performed. Results. We achieved a response rate of 21%. Clinical T3/T4 disease was the most often selected reason for recommending NAC (87%). Concerns with recommending NAC were age and comorbidities (54%) followed by delay in surgery (35%). An association was identified between urologic oncologists who discussed NAC with >90% of their patients and medical oncologists "always" recommending NAC (P = 0.0009). NAC utilization rate was between 30 and 57%. Conclusions. Amongst this highly specialized group of respondents, clinical T3-T4 disease was the most common reason for implementation of NAC. Respondents who frequently discussed NAC were more likely to report their medical oncologist always recommending NAC. Reported NAC use was higher in this surveyed group (30-57%) compared with recently published rates.

The 6th Annual Bladder Cancer Think Tank brought together a multidisciplinary group of clinicians, researchers, and representatives from the National Cancer Institute and Industry in an effort to advance bladder cancer research efforts. This year's meeting comprised panel discussions and research involving 5 separate working groups, including the Survivorship, Clinical Trials, Standardization of Care, Data Mining, and Translational Science working groups. In this manuscript, the accomplishments and objectives of the working groups are summarized. Notable efforts include: (1) the development of a survivorship care plan for early and late-stage bladder cancer; (2) the development of consensus criteria for eligibility and endpoints for bladder cancer clinical trials; (3) an improved understanding of current practice patterns regarding the use of perioperative chemotherapy in an effort to standardize care; (4) creation of a comprehensive handbook to assist researchers with developing bladder cancer databases; and (5) identification of response to therapy of high-grade non muscle invasive disease through a collaborative exchange of expertise and resources., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate the success, consistency, and efficiency of a semiautomated lesion management application within a PACS in the analysis of metastatic lesions in serial CT examinations of cancer patients., Materials and Methods: Two observers using baseline and follow-up CT data independently reviewed 93 target lesions (17 lung, five liver, 71 lymph node) in 50 patients with either metastatic bladder or prostate cancer. The observers measured the longest axis (or short axis for lymph nodes) of each lesion and made Response Evaluation Criteria in Solid Tumors (RECIST) determinations using manual and lesion management application methods. The times required for examination review, RECIST calculations, and data input were recorded. The Wilcoxon signed rank test was used to assess time differences, and Bland-Altman analysis was used to assess interobserver agreement within the manual and lesion management application methods. Percentage success rates were also reported., Results: With the lesion management application, most lung and liver lesions were semiautomatically segmented. Comparison of the lesion management application and manual methods for all lesions showed a median time saving of 45% for observer 1 (p<0.05) and 28% for observer 2 (p=0.05) on follow-up scans versus 28% for observer 1 (p<0.05) and 9% for observer 2 (p=0.087) on baseline scans. Variability of measurements showed mean percentage change differences of only 8.9% for the lesion management application versus 26.4% for manual measurements., Conclusion: With the lesion management application method, most lung and liver lesions were successfully segmented semiautomatically; the results were more consistent between observers; and assessment of tumor size was faster than with the manual method.

A prognostic model that predicts overall survival (OS) for metastatic urothelial cancer (MetUC) patients treated with cisplatin-based chemotherapy was developed, validated, and compared with a commonly used Memorial Sloan-Kettering Cancer Center (MSKCC) risk-score model. Data from 7 protocols that enrolled 308 patients with MetUC were pooled. An external multi-institutional dataset was used to validate the model. The primary measurement of predictive discrimination was Harrell's c-index, computed with 95% confidence interval (CI). The final model included four pretreatment variables to predict OS: visceral metastases, albumin, performance status, and hemoglobin. The Harrell's c-index was 0.67 for the four-variable model and 0.64 for the MSKCC risk-score model, with a prediction improvement for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .002). In the validation cohort, the c-indices for the four-variable and the MSKCC risk-score models were 0.63 (95% CI = 0.56 to 0.69) and 0.58 (95% CI = 0.52 to 0.65), respectively, with superiority of the four-variable model compared with the MSKCC risk-score model for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .02).

Purpose: Although gemcitabine and carboplatin (GCa) is a standard option for patients with advanced urothelial cancer (UC) who are ineligible for cisplatin, outcomes remain poor. This trial evaluated the efficacy and safety of bevacizumab with GCa in advanced UC., Patients and Methods: Patients with Karnofsky performance status of 60% to 70%, creatinine clearance less than 60 mL/min, visceral metastasis, or solitary kidney were eligible and received a lead-in dose of bevacizumab 10 mg/kg followed 2 weeks later by gemcitabine 1,000 mg/m(2) on days 1 and 8 and carboplatin at area under the [concentration-time] curve (AUC) 5.0 or 4.5 and bevacizumab 15 mg/kg on day 1 every 21 days for six cycles. Patients achieving at least stable disease (SD) continued bevacizumab 15 mg/kg every 21 days for 18 additional cycles. The study was powered to detect a 50% improvement in median progression-free survival (PFS) over a historical control., Results: Fifty-one patients, median age 67 years (range, 42 to 83 years), were enrolled onto the study and were evaluable for toxicity. Twenty (39%) experienced grade 3 to 4 toxicity, and 10 (20%) had thromboembolic events (deep venous thrombosis or pulmonary embolism). Four received one or fewer cycles leaving 47 evaluable for outcomes. Twenty-three (49%) achieved response (three complete; 20 partial), and 11 had SD. Median PFS was 6.5 months (95% CI, 4.7 to 7.8 months); PFS was greater in the carboplatin AUC 5.0 group (P = .04). Median overall survival (OS) was 13.9 months., Conclusion: The 95% one-sided lower confidence bound of 4.77 months for median PFS did not meet the predesignated PFS of more than 4.8 months considered sufficient for further study. Median OS was greater than expected. An ongoing phase III trial in patients who are eligible for therapy with cisplatin will define the role of bevacizumab in UC.

A monoclonal antibody against prostate stem cell antigen (PSCA) has emerged as a novel cancer therapy currently being tested in clinical trials for prostate and pancreatic cancers, but this treatment is likely to be efficient only in patients with PSCA-expressing tumors. The present study demonstrates that a genetic variant (rs2294008) discovered by bladder cancer genome-wide association studies is a strong predictor of PSCA protein expression in bladder tumors, as measured by two-sided multivariable linear regression (P = 6.46×10(-11); n = 278). The association pattern is similar in non-muscle-invasive tumors, stages Ta (P = 3.10×10(-5); n = 173) and T1 (P = 2.64×10(-5); n = 60), and muscle-invasive tumors, stages T2 (P =.01; n = 23) and T3/4 (P =.03; n = 22). The study suggests that anti-PSCA immunotherapy might be beneficial for bladder cancer patients with high tumor PSCA expression, which is statistically significantly associated with the presence of CT and TT genotypes of a common genetic variant, rs2294008. Future clinical studies will be needed to validate PSCA as a therapeutic target for bladder cancer.

Advances in tumor biology and cancer genetics have led to the development of effective targeted therapies in oncology over the past decade. However, targeted drug development for urothelial carcinoma has been slower than for some other malignancies. The path forward in drug development is through a better understanding of the aberrant pathways driving urothelial tumor development. Steady progress has been made in the characterization of genomic alterations in urothelial carcinoma. The Cancer Genome Atlas (TCGA) project is well underway in the analysis of a large set of urothelial cancer specimens using multiple approaches and technologies. In addition, there are already many well-established mutations and genetic alterations in urothelial carcinoma that likely contribute in an important way to tumor development. In addition, urothelial cancer genome-wide association studies have identified common variants associated with urothelial cancer risk and protein expression that can potentially be therapeutically targeted. Furthermore, the MET pathway has emerged as an exciting target in multiple tumors, including urothelial carcinoma. Our knowledge of how to clinically target many emerging molecular aberrations in urothelial cancer is still in the early stages of development. However, there is much promise in the ongoing research being conducted in urothelial cancer molecular pathogenesis.

In 1994 the first heat shock protein 90 (Hsp90) inhibitor was identified and Hsp90 was reported to be a target for anticancer therapeutics. In the past 18 years there have been 17 distinct Hsp90 inhibitors entered into clinical trial, and the small molecule Hsp90 inhibitors have been highly valuable as probes of the role of Hsp90 and its client proteins in cancer. Although no Hsp90 inhibitor has achieved regulatory approval, recently there has been significant progress in Hsp90 inhibitor clinical development, and in the past year RECIST responses have been documented in HER2-positive breast cancer and EML4-ALK-positive non-small cell lung cancer. All of the clinical Hsp90 inhibitors studied to date are specific in their target, i.e. they bind exclusively to Hsp90 and two related heat shock proteins. However, Hsp90 inhibitors are markedly pleiotropic, causing degradation of over 200 client proteins and impacting critical multiprotein complexes. Furthermore, it has only recently been appreciated that Hsp90 inhibitors can, paradoxically, cause transient activation of the protein kinase clients they are chaperoning, resulting in initiation of signal transduction and significant physiological events in both tumor and tumor microenvironment. An additional area of recent progress in Hsp90 research is in studies of the posttranslational modifications of Hsp90 itself and Hsp90 co-chaperone proteins. Together, a picture is emerging in which the impact of Hsp90 inhibitors is shaped by the tumor intracellular and extracellular milieu, and in which Hsp90 inhibitors impact tumor and host on a microenvironmental and systems level. Here we review the tumor intrinsic and extrinsic factors that impact the efficacy of small molecules engaging the Hsp90 chaperone machine.

At the 11th annual meeting of the Society of Urologic Oncology, an expert panel was convened to discuss the practical use of perioperative chemotherapy for muscle-invasive bladder cancer. The discussion was structured as a case-based debate among the panelists. The topics included: neoadjuvant chemotherapy with a focus on T2 disease, pros and cons, survival data, tolerability of cisplatin-based therapy, can we avoid radical cystectomy in complete responders, limitations and alternatives to cisplatin-based therapy, management of 'suboptimal' chemotherapy, residual disease after neoadjuvant chemotherapy, adjuvant chemotherapy, and key aspects of radical cystectomy and lymph-node dissection in multimodal therapy. The presentations were derived from published literature. The panelists agreed that patients with muscle-invasive bladder cancer should be managed with a multidisciplinary team, including urologist and medical oncologist. Cisplatin-based neoadjuvant chemotherapy has demonstrated improved survival and should be incorporated into the management of all eligible patients with muscle-invasive bladder cancer. However, in some centers, neoadjuvant chemotherapy is reserved for patients with >T2 disease or high-risk features. There are no data for the administration of non-cisplatin-based neoadjuvant chemotherapy, such as carboplatin-combinations. Cisplatin-ineligible patients should proceed directly to surgical extirpation with adjuvant cisplatin-based chemotherapy considered based on pathologic findings. However, the data for adjuvant chemotherapy is less compelling. As our refinement of the selection process continues, we may be able to better identify subsets of patients who may be spared chemotherapy, but much work remains to be done in this arena. The current standard for muscle-invasive bladder cancer patients is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy and pelvic lymph-node dissection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Unlabelled: We evaluated the kinetics of (18)F-sodium fluoride (NaF) and reassessed the recommended dose, optimal uptake period, and reproducibility using a current-generation PET/CT scanner., Methods: In this prospective study, 73 patients (31 patients with multiple myeloma or myeloma precursor disease and 42 with prostate cancer) were injected with a mean administered dose of 141 MBq of (18)F-NaF. Sixty patients underwent 3 sequential sessions of 3-dimensional PET/CT of the torso beginning approximately 15 min after (18)F-NaF injection, followed by whole-body 3-dimensional PET/CT at 2 h. The remaining 13 prostate cancer patients were imaged only at 2 and 3 h after injection. Twenty-one prostate cancer patients underwent repeated baseline studies (mean interval, 5.9 d) to evaluate reproducibility., Results: The measured effective dose was 0.017 mSv/MBq, with the urinary bladder, osteogenic cells, and red marrow receiving the highest doses at 0.080, 0.077, and 0.028 mGy/MBq, respectively. Visual analysis showed that uptake in both normal and abnormal bone increased with time; however, the rate of increase decreased with time. A semiautomated workflow provided objective uptake parameters, including the mean standardized uptake value of all pixels within bone with SUVs greater than 10 and the average of the mean SUV of all malignant lesions identified by the algorithm. The values of these parameters for the images beginning at approximately 15 min and approximately 35 min were significantly different (0.3% change per minute). Differences between the later imaging time points were not significant (P < 0.01). Repeated baseline studies showed high intraclass correlations (>0.9) and relatively low critical percentage change (the value above which a change can be considered real) for these parameters. The tumor-to-normal bone ratio, based on the maximum SUV of identified malignant lesions, decreased with time; however, this difference was small, estimated at approximately 0.16%/min in the first hour., Conclusion: (18)F-NaF PET/CT images obtained with modest radiation exposures can result in highly reproducible imaging parameters. Although the tumor-to-normal bone ratio decreases slightly with time, the high temporal dependence during uptake periods less than 30 min may limit accurate quantitation. An uptake period of 60 ± 30 min has limited temporal dependence while maintaining a high tumor-to-normal bone ratio.

Purpose: Fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been approved for imaging in many malignancies but not for bladder cancer. This study investigated the value of FDG-PET/CT imaging in the management of patients with advanced bladder cancer., Patients and Methods: Between May 2006 and February 2008, 57 patients with bladder cancer at our center underwent FDG-PET/CT after CT (n = 52) or magnetic resonance imaging (MRI; n = 5). The accuracy of FDG-PET/CT was assessed using both organ-based and patient-based analyses. FDG-PET/CT findings were validated by either biopsy or serial CT/MRI. Clinician questionnaires performed before and after FDG-PET/CT assessed whether those scan results affected management., Results: One hundred thirty-five individual lesions were evaluable in 47 patients for the organ-based analysis. Overall sensitivity and specificity were 87% (95% CI, 76% to 94%) and 88% (95% CI, 78% to 95%), respectively. In the patient-based analysis, malignant disease was correctly diagnosed in 25 of 31 patients, resulting in a sensitivity of 81% (95% CI, 63% to 93%). FDG-PET/CT was negative in 15 of 16 patients without malignant lesions for a specificity of 94% (95% CI, 71% to 100%). Pre- and post-PET surveys revealed that FDG-PET/CT detected more malignant disease than conventional CT/MRI in 40% of patients. Post-PET surveys showed that clinicians changed their planned management in 68% of patients based on the FDG-PET/CT results., Conclusion: FDG-PET/CT has excellent sensitivity and specificity in the detection of metastatic bladder cancer and provides additional diagnostic information that enhances clinical management more than CT/MRI alone. FDG-PET/CT scans may provide better accuracy in clinical information for directing therapy.

Bladder cancer is a significant healthcare problem in the USA, with a high recurrence rate, the need for expensive continuous surveillance and limited treatment options for patients with advanced disease. Research has contributed to an understanding of the molecular pathways involved in the development and progression of bladder cancer, and that understanding has led to the discovery of potentially diagnostic, predictive and prognostic biomarkers. In this review, a clinical states model of bladder cancer is introduced and integrated into a paradigm for biomarker development. Biomarkers are systematically incorporated with predefined end points to aid in clinical management.

There are presently no accurate methods of imaging prostate cancer metastases to bone. An unprecedented number of novel imaging agents, based on the biology of the disease, are now available for testing. We reviewed contemporary molecular imaging modalities that have been tested in humans with metastatic prostate cancer, with consideration of the studies' adherence to current prostate cancer clinical trial designs. Articles from the years 2002 to 2008 on PET using (18)F-FDG, (11)C-choline, (18)F-choline, (18)F-flouride, (11)C-acetate, (11)C-methionine, and (18)F-fluoro-5alpha-dihydrotestosterone in patients with metastatic prostate cancer were reviewed. Although these studies are encouraging, most focus on the rising population with prostate-specific antigen, and many involve small numbers of patients and do not adhere to consensus criteria for clinical trial designs in prostate cancer. Hence, although many promising agents are available for testing, such studies would benefit from closer collaboration between those in the fields of medical oncology and nuclear medicine.