Siamak Daneshmand

A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer.

CONTEXT Muscle-invasive bladder cancer (MIBC) is a disease with a pattern of predominantly distant and early recurrences. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC. OBJECTIVE To review the data supporting perioperative chemotherapy and emerging regimens for MIBC. EVIDENCE ACQUISITION Medline databases were searched for original articles published before April 1, 2012, with the search terms bladder cancer, urothelial cancer, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy. Proceedings from the last 5 yr of major conferences were also searched. Novel and promising drugs that have reached clinical trial evaluation were included. EVIDENCE SYNTHESIS The major findings are addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed. CONCLUSIONS Cisplatin-based neoadjuvant combination chemotherapy is an established standard, improving overall survival in MIBC. Pathologic complete response appears to be an intermediate surrogate for survival, but this finding requires further validation. Definitive data to support adjuvant chemotherapy do not exist, and there are no data to support perioperative therapy in cisplatin-ineligible patients. Utilization of neoadjuvant cisplatin is low, attributable in part to patient/physician choice and the advanced age of patients, who often have multiple comorbidities including renal and/or cardiac dysfunction. Trials are using the neoadjuvant paradigm to detect incremental pathologic response to chemobiologic regimens and brief neoadjuvant single-agent therapy to screen for the biologic activity of agents.

Enhanced Recovery Protocol after Radical Cystectomy for Bladder Cancer

PURPOSE Enhanced recovery after surgery protocols aim to improve patient care and decrease complications and hospital stay. We evaluated our enhanced recovery after surgery protocol, focusing on length of stay, early complication and readmission rates after radical cystectomy for bladder cancer. MATERIALS AND METHODS From May 2012 to July 2013 a perioperative protocol was applied in 126 consecutive patients who underwent open radical cystectomy and urinary diversion. Nonconsenting patients (2), those with previous diversion (2) and prolonged postoperative intubation (3), and those who underwent additional surgery (9) were excluded from study. The protocol focuses on avoiding bowel preparation and nasogastric tube, early feeding, nonnarcotic pain management and the use of cholinergic and μ-opioid antagonists. Outcomes were compared to those in matched controls from our bladder cancer database. RESULTS A total of 110 patients with a median age of 69 years were included in analysis, of whom 68% underwent continent urinary diversion. Of the patients 82% had a bowel movement by postoperative day 2. Median length of stay was 4 days. The 30-day minor and major complication rates were 64% and 14%, respectively. The most common minor complication was anemia requiring transfusion in 19% of patients, urinary tract infection in 13% and dehydration in 10%. The latter 2 complications were the most common etiologies for readmission. The 30-day readmission rate was 21% (23 patients). Patients 75 years old or older had a longer length of stay (5 vs 4 days, p = 0.03) and a higher minor complication rate (72% vs 51%, p = 0.04) than younger patients. CONCLUSIONS Our enhanced recovery after surgery protocol expedites bowel function recovery and shortens hospital stay after RC and urinary diversion without an increase in the hospital readmission rates.

EphB4 Expression and Biological Significance in Prostate Cancer

Prostate cancer is the most common cancer in men. Advanced prostate cancer spreading beyond the gland is incurable. Identifying factors that regulate the spread of tumor into the regional nodes and distant sites would guide the development of novel diagnostic, prognostic, and therapeutic targets. The aim of our study was to examine the expression and biological role of EphB4 in prostate cancer. EphB4 mRNA is expressed in 64 of 72 (89%) prostate tumor tissues assessed. EphB4 protein expression is found in the majority (41 of 62, 66%) of tumors, and 3 of 20 (15%) normal prostate tissues. Little or no expression was observed in benign prostate epithelial cell line, but EphB4 was expressed in all prostate cancer cell lines to varying degrees. EphB4 protein levels are high in the PC3 prostate cancer cell line and several folds higher in a metastatic clone of PC3 (PC3M) where overexpression was accompanied by EphB4 gene amplification. EphB4 expression is induced by loss of PTEN, p53, and induced by epidermal growth factor/epidermal growth factor receptor and insulin-like growth factor-I/insulin-like growth factor-IR. Knockdown of the EphB4 protein using EphB4 short interfering RNA or antisense oligodeoxynucleotide significantly inhibits cell growth/viability, migration, and invasion, and induces apoptosis in prostate cancer cell lines. Antisense oligodeoxynucleotide targeting EphB4 in vivo showed antitumor activity in murine human tumor xenograft model. These data show a role for EphB4 in prostate cancer and provide a rationale to study EphB4 for diagnostic, prognostic, and therapeutic applications.

A Critical Analysis of Perioperative Mortality From Radical Cystectomy

PURPOSE Operative mortality from radical cystectomy has decreased as a result of improvements in surgical and anesthetic care. We reviewed the perioperative deaths from a large group of patients treated with radical cystectomy for primary bladder cancer. MATERIALS AND METHODS All perioperative mortalities from radical cystectomy were identified from a single high volume institution. The medical records were reviewed to assess the cause of death as well as possible contributing factors. RESULTS From August 1971 to December 2001, 1,359 patients with primary bladder cancer were treated with radical cystectomy and pelvic iliac lymphadenectomy at our institution. Of these patients, 27 (2%) died within 30 days of surgery or before discharge from hospital. Median patient age at surgery was 67 years (range 47 to 78) and males accounted for 81% of the patients. The median time to death was 28 days from cystectomy (range 0 to 80). Most deaths were cardiovascular related (including acute myocardial infarction, cerebrovascular accident, arterial thrombosis) or due to septic complications with resulting multi-organ system failure, followed by pulmonary embolism, hepatic failure and hemorrhage. Septic related mortality was most often associated with postoperative urine or bowel leak. While most deaths occurred before hospital discharge, 2 patients died at home due to a late pulmonary embolus. No association was seen between pathological stage or type of urinary diversion and mortality. CONCLUSIONS Perioperative mortality from radical cystectomy is low in this group of patients. Most deaths are due to cardiovascular or septic complications. Careful patient selection and meticulous surgical technique may help decrease the incidence of perioperative mortality.

Patterns of Relapse in Patients With Clinical Stage I Testicular Cancer Managed With Active Surveillance

PURPOSE To evaluate the performance of active surveillance as a management strategy in broad populations and to inform the development of surveillance schedules by individual patient data regarding timing and type of relapse. METHODS Retrospective study including data from 2,483 clinical stage I (CSI) patients, 1,139 CSI nonseminoma and 1,344 CSI seminoma managed with active surveillance, with the majority treated between 1998 and 2010. Clinical outcomes including relapse and death, time distribution, extent of relapse and method of relapse detection observed on active surveillance were recorded. RESULTS Relapse occurred in 221 (19%) CSI-nonseminoma and 173 (13%) CSI-seminoma patients. Median time to relapse was 4 months (range, 2-61 months), 8 months (range, 2-77 months) and 14 months (range, 2-84 months) for lymphovascular invasion-positive CSI nonseminoma, lymphovascular invasion-negative CSI nonseminoma and CSI seminoma. Most relapses were observed within the first 2 years/3 years after orchiectomy for CSI nonseminoma (90%)/CSI seminoma (92%). Relapses were detected by computed tomography scan/tumor-markers in 87%/3% of seminoma recurrences, in 48%/38% of lymphovascular invasion-negative and 41%/61% of lymphovascular invasion-positive patients, respectively. 90% of CSI-nonseminoma and 99% of CSI-seminoma relapses exhibited International Germ Cell Collaborative Group good-risk features. Three patients with CSI nonseminoma died of disease (0.3%). One patient with CSI seminoma and two patients with CSI nonseminoma died because of treatment-related events. Overall, advanced disease was seen in both early- and late-relapse patients. All late recurrences were cured with standard therapy. Five-year disease-specific survival was 99.7% (95% CI, 99.24% to 99.93%). CONCLUSION Active surveillance for CSI testis cancer leads to excellent outcomes. The vast majority of relapses occur within 2 years of orchiectomy for CSI nonseminoma and within 3 years for CSI seminoma. Late and advanced stage relapse are rarely seen. These data may inform further refinement of rationally designed surveillance schedules.

Critical Analysis of Bladder Sparing with Trimodal Therapy in Muscle-invasive Bladder Cancer: A Systematic Review

CONTEXT Aims of bladder preservation in muscle-invasive bladder cancer (MIBC) are to offer a quality-of-life advantage and avoid potential morbidity or mortality of radical cystectomy (RC) without compromising oncologic outcomes. Because of the lack of a completed randomised controlled trial, oncologic equivalence of bladder preservation modality treatments compared with RC remains unknown. OBJECTIVE This systematic review sought to assess the modern bladder-preservation treatment modalities, focusing on trimodal therapy (TMT) in MIBC. EVIDENCE ACQUISITION A systematic literature search in the PubMed and Cochrane databases was performed from 1980 to July 2013. EVIDENCE SYNTHESIS Optimal bladder-preservation treatment includes a safe transurethral resection of the bladder tumour as complete as possible followed by radiation therapy (RT) with concurrent radiosensitising chemotherapy. A standard radiation schedule includes external-beam RT to the bladder and limited pelvic lymph nodes to an initial dose of 40 Gy, with a boost to the whole bladder to 54 Gy and a further tumour boost to a total dose of 64-65 Gy. Radiosensitising chemotherapy with phase 3 trial evidence in support exists for cisplatin and mitomycin C plus 5-fluorouracil. A cystoscopic assessment with systematic rebiopsy should be performed at TMT completion or early after TMT induction. Thus, nonresponders are identified early to promptly offer salvage RC. The 5-yr cancer-specific survival and overall survival rates range from 50% to 82% and from 36% to 74%, respectively, with salvage cystectomy rates of 25-30%. There are no definitive data to support the benefit of using of neoadjuvant or adjuvant chemotherapy. Critical to good outcomes is proper patient selection. The best cancers eligible for bladder preservation are those with low-volume T2 disease without hydronephrosis or extensive carcinoma in situ. CONCLUSIONS A growing body of accumulated data suggests that bladder preservation with TMT leads to acceptable outcomes and therefore may be considered a reasonable treatment option in well-selected patients. PATIENT SUMMARY Treatment based on a combination of resection, chemotherapy, and radiotherapy as bladder-sparing strategies may be considered as a reasonable treatment option in properly selected patients.

Benign retroperitoneal schwannoma: a case series and review of the literature.

OBJECTIVES To present our experience with four retroperitoneal schwannomas treated by surgical excision and review the current literature. Retroperitoneal schwannomas are rare, benign tumors and infrequently present to the urologist. METHODS From 1997 through 2002, the charts of 164 patients with a diagnosis of benign retroperitoneal soft tissue mass were reviewed. Of those, four had a pathologic diagnosis of retroperitoneal schwannoma. RESULTS Three of the 4 patients were women, with a median age of 54 years (range 46 to 80). The average tumor size was 13.7 cm (range 8.8 to 20). All patients underwent magnetic resonance imaging, computed tomography, or ultrasonography, and 3 of the 4 patients underwent a computed tomography-guided fine needle aspiration biopsy (all were either inaccurate or inconclusive). All patients underwent complete tumor excision with free margins of resection and tolerated surgery without any complications. None of the patients have had any evidence of recurrence at a mean follow-up of 26 months (range 10 to 48). CONCLUSIONS Retroperitoneal schwannomas are difficult to diagnose preoperatively. Computed tomography-guided fine needle aspiration biopsy does not appear to provide an accurate preoperative diagnosis. The surgical approach should focus on complete excision of the mass. Patients undergoing complete surgical resection tend to do well without evidence of early recurrence.

Robotic Intracorporeal Orthotopic Ileal Neobladder: Replicating Open Surgical Principles

BACKGROUND Robotic radical cystectomy (RC) for cancer is beginning to gain wider acceptance. Yet, the concomitant urinary diversion is typically performed extracorporeally at most centers, primarily because intracorporeal diversion is perceived as technically complex and arduous. Previous reports on robotic, intracorporeal, orthotopic neobladder may not have fully replicated established open principles of reservoir configuration, leading to concerns about long-term functional outcomes. OBJECTIVE To illustrate step-by-step our technique for robotic, intracorporeal, orthotopic, ileal neobladder, urinary diversion with strict adherence to open surgical tenets. DESIGN, SETTING, AND PARTICIPANTS From July 2010 to May 2012, 24 patients underwent robotic intracorporeal neobladder at a single tertiary cancer center. This report presents data on patients with a minimum of 3-mo follow-up (n=8). SURGICAL PROCEDURE We performed robotic RC, extended lymphadenectomy to the inferior mesenteric artery, and complete intracorporeal diversion. Our surgical technique is demonstrated in the accompanying video. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Baseline demographics, pathology data, 90-d complications, and functional outcomes were assessed and compared with patients undergoing intracorporeal ileal conduit diversion (n=7). RESULTS AND LIMITATIONS Robotic intracorporeal urinary diversion was successfully performed in 15 patients (neobladder: 8 patients, ileal conduit: 7 patients) with a minimum 90-d follow-up. Median age and body mass index were 68 yr and 27 kg/m2, respectively. In the neobladder cohort, median estimated blood loss was 225 ml (range: 100-700 ml), median time to regular diet was 5 d (range: 4-10 d), median hospital stay was 8 d (range: 5-27 d), and 30- and 90-d complications were Clavien grade 1-2 (n=5 and 0), Clavien grade 3-5 (n=2 and 1), respectively. This study is limited by small sample size and short follow-up period. CONCLUSIONS An intracorporeal technique of robot-assisted orthotopic neobladder and ileal conduit is presented, wherein established open principles are diligently preserved. This step-wise approach is demonstrated to help shorten the learning curve of other surgeons contemplating robotic intracorporeal urinary diversion.

Urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes

The urinary reconstructive options available after radical cystectomy (RC) for bladder cancer are discussed, as are the criteria for selection of the most appropriate diversion, and the outcomes and complications associated with different diversion options.

Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy

PURPOSE We evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy. MATERIALS AND METHODS We identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection. We evaluated survival (disease specific, progression-free and overall) and rate of pathological up staging. An independent cohort of patients from another institution was used to confirm our findings. RESULTS We identified 98 high risk and 199 low risk patients eligible for analysis. High risk patients exhibited decreased 5-year overall survival (47.0% vs 64.8%) and decreased disease specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival probabilities compared to low risk patients (p <0.001). Survival outcomes were confirmed in the validation subset. On final pathology 49.2% of low risk patients had disease up staged. CONCLUSIONS The 5-year disease specific survival of low risk patients was greater than 80%, supporting the distinction of high risk and low risk muscle invasive bladder cancer. The presence of high risk features identifies patients with a poor prognosis who are most likely to benefit from neoadjuvant chemotherapy, while many of those with low risk disease can undergo surgery up front with good expectations and avoid chemotherapy associated toxicity.