Gregory Diorio

Sulforaphane for the chemoprevention of bladder cancer: Molecular mechanism targeted approach

The clinical course for both early and late stage Bladder Cancer (BC) continues to be characterized by significant patient burden due to numerous occurrences and recurrences requiring frequent surveillance strategies, intravesical drug therapies, and even more aggressive treatments in patients with locally advanced or metastatic disease. For these reasons, BC is also the most expensive cancer to treat. Fortunately, BC offers an excellent platform for chemoprevention interventions with potential to optimize the systemic and local exposure of promising agents to the bladder mucosa. However, other than smoking cessation, there is a paucity of research that systematically examines agents for chemoprevention of bladder cancers. Adopting a systematic, molecular-mechanism based approach, the goal of this review is to summarize epidemiological, in vitro, and preclinical studies, including data regarding the safety, bioavailability, and efficacy of agents evaluated for bladder cancer chemoprevention. Based on the available studies, phytochemicals, specifically isothiocyanates such as sulforaphane, present in Brassicaceae or “cruciferous” vegetables in the precursor form of glucoraphanin are: (a) available in standardized formulations; (b) bioavailable- both systemically and in the bladder; (c) observed to be potent inhibitors of BC carcinogenesis through multiple mechanisms; and (d) without toxicities at these doses. Based on available evidence from epidemiological, in vitro, preclinical, and early phase trials, phytochemicals, specifically isothiocyanates (ITCs) such as sulforaphane (SFN) represent a promising potential chemopreventitive agent in bladder cancer.

Management of Penile Cancer

Although rare, penile cancer carries high morbidity and mortality particularly when pertaining to the management of locally advanced or metastatic disease. The current scientific literature lacks level 1 evidence and current guidelines are based largely on retrospective studies and small single center studies. Despite these limitations, there has been paradigm shifts in the management of both local and systemic disease. Current guidelines emphasize penile sparing strategies, minimizing morbidity from surgical management of loco-regional metastasis and multimodal management of bulky inguinal lymph node metastases. The present review highlights the current state of knowledge and recommended treatment strategies of penile carcinoma.

Contemporary management of patients with penile cancer and lymph node metastasis

Penile cancer is a rare disease that causes considerable physical and psychological patient morbidity, especially at advanced stages. Patients with low-stage nodal metastasis can achieve durable survival with surgery alone, but those with extensive locoregional metastasis have overall low survival. Contemporary management strategies for lymph node involvement in penile cancer aim to minimize the morbidity associated with traditional radical inguinal lymphadenectomy through appropriate risk stratification while optimizing oncological outcomes. Modified (or superficial) inguinal lymph node dissection and dynamic sentinel lymph node biopsy are diagnostic modalities that have been recommended in patients with high-risk primary penile tumours and nonpalpable inguinal lymph nodes. In addition, advances in minimally invasive and robot-assisted lymphadenectomy techniques are being investigated in patients with penile cancer and might further decrease lymphadenectomy-related adverse effects. The management of patients with advanced disease has evolved to include multimodal treatment with systemic chemotherapy before surgical intervention and can include adjuvant chemotherapy after pelvic lymphadenectomy. The role of radiotherapy in the neoadjuvant or adjuvant setting remains largely unclear, owing to a lack of high-level evidence of possible benefits. New targeted therapies have shown efficacy in squamous cell carcinomas of other sites and might also prove effective in patients with penile cancer.

Communication on the Impact of Multidisciplinary Care in a Large Volume Robot-Assisted Radical Prostatectomy Program: A Paradoxical Stage Migration toward More Aggressive Disease

Introduction: With the widespread use of robot-assisted radical prostatectomy (RARP), a stage migration to less aggressive prostate cancer (CaP) may be expected in pathological specimens due to over-treatment of low risk disease. It is unclear whether implementation of a multidisciplinary clinic (MDC) model would offset this phenomenon. We sought to analyze our database for possible stage migration in prostatectomy specimens in the setting of MDC. Methods: A total of 262 patients who underwent open prostatectomy (OP) from 2004 to 2006 and 757 patients who underwent RARP from 2007 to 2011 were identified from our prospective database. The implementation of MDC occurred concurrently at the time of RARP initiation. Demographic data, pathology, positive margin rates along with standard CaP reporting data were recorded. The two groups were com- pared with regards to percentage of cases stratified by Gleason grade. Results: The number of CaP cases managed at our institution increased considerably after the introduction of robotics and MDC. There was a significant decrease in the patients with Gleason 6 CaP undergoing RARP as compared with OP (p = 0.001). Additionally, RARP was performed on a significantly greater percentage of Gleason 7 disease (p < 0.001). When comparing pathological stage, there was a significant increase in the incidence of pT3 disease following RARP (p < 0.0001). Conclusions: The introduction of a MDC and minimally invasive radical prostatectomy did not result in an increased application of surgery for the treatment of low risk prostate cancer. This highlights the impor- tance of MDC in a large volume RARP program. * Corresponding author.

Neoadjuvant Chemotherapy in Elderly Patients With Bladder Cancer: Oncologic Outcomes From a Single Institution Experience

Introduction We conducted this study to determine if, in appropriately selected elderly patients receiving neoadjuvant chemotherapy (NAC), clinical outcomes including pathologic complete response/downstaging and overall survival were similar to a younger cohort. Methods Chart review was performed on patients receiving NAC for urothelial carcinoma of the bladder (UCB) from 2004 to 2013. A total of 116 patients were identified that underwent NAC from 2004 to 2013 for ≥ cT2N0M0 UCB. Patients were excluded who received 2 cycles or less of chemotherapy (N = 18; 11 patients in the younger cohort, 7 in the elderly group; P = .74). Data was analyzed, and Kaplan‐Meir analysis curves were used for survival and recurrence. Results Forty‐six elderly patients (age ≥ 70 years) (67% cisplatin‐based regimen) were identified and compared with 70 (93% cisplatin‐based regimen) younger patients. The estimated glomerular filtration rate, performance status, preoperative hemoglobin, and body mass index were significantly worse in elderly patients. Dose reduction and pathologic downstaging to non–muscle‐invasive disease was not statistically different between older and younger patients Complete pathologic response in older patients (16%) and in the younger cohort (17%) were similar (P = .146). There was no significant difference in follow‐up, recurrence, or in median overall survival between patient groups (28 months elderly vs. 35 months younger; P = .78). Age was not an independent predictor of pathologic downstaging, complete response, overall survival, or recurrence‐free survival. Conclusions NAC in elderly patients (≥ 70 years old) demonstrated equivalent toxicity and oncologic outcomes in our single‐institution cohort. Although older patients had significantly poorer performance status and renal function, there were no differences in survival or response to NAC. Micro‐Abstract This study evaluated elderly patients with urothelial carcinoma of the bladder receiving neoadjuvant chemotherapy (NAC). Compared with a younger cohort of patients, NAC demonstrated equivalent toxicity and oncologic outcomes in our single‐institution cohort. Although older patients had significantly poorer performance status and renal function, there were no differences in survival or response to NAC.

Surgical and Oncological Outcomes in Patients After Vascularised Flap Reconstruction for Locoregionally Advanced Penile Cancer

BACKGROUND Treatment of locoregionally advanced penile squamous cell carcinoma (LAPSCC) is challenging. The exact role (in terms of oncological benefit) of extensive surgery is not well established. Moreover, surgery invariably leads to large defects requiring reconstructive surgery. Rectus abdominis myocutaneous (RAM) and abdominal advancement flaps have an independent and constant blood supply, are easily harvested, and provide substantial skin coverage and soft tissue. OBJECTIVE To determine the surgical and oncological outcomes in patients with LAPSCC undergoing surgical resection with RAM flaps. DESIGN, SETTING, AND PARTICIPANTS From 2002 to 2016, a multi-institutional database identified 15 LAPSCC patients undergoing flap reconstructions. INTERVENTION Local surgical resection with RAM or abdominal advancement flap reconstruction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Perioperative and pathologic data were collected. Postoperative complications were identified using the Clavien-Dindo classification for surgical complications. RESULTS AND LIMITATIONS Fifteen patients (median age 61 yr) were treated, ten with curative intent. Thirteen patients received induction chemotherapy. Thirteen of the 15 patients (87%) experienced wound complications, including five Clavien-Dindo grade III complications. In 11/15 patients (73%), the disease recurred (median recurrence-free interval 106 d). The majority of recurrences (91%) were locoregional, and in four cases the patient also had lesions in distant organs. Ten of the 15 patients (67%) died of their disease. The overall median follow-up interval was 10.5 mo. The study was limited by its retrospective design, the absence of quality-of-life measurements, and the cohort size. CONCLUSIONS The results of this study show that surgical resection with reconstruction is associated with a risk of perioperative complications, including high-grade Clavien-Dindo complications. With a cure rate of 27%, surgery must be carefully considered and there is a need for alternative treatments. Lack of robust quality-of-life-data is also a serious shortcoming in the decision process for this patient category. PATIENT SUMMARY Surgery in locoregionally advanced penile cancer has a low cure rate. Reconstruction of defects is surgically feasible, albeit with a high risk of complications. Furthermore, decision-making lacks robust data on quality of life after surgery.

PD49-01 ADJUVANT PELVIC RADIATION IS ASSOCIATED WITH IMPROVED SURVIVAL AND DECREASED DISEASE RECURRENCE IN PELVIC NODE-POSITIVE PENILE CANCER AFTER LYMPH NODE DISSECTION: A MULTI-INSTITUTIONAL STUDY

INTRODUCTION AND OBJECTIVES: Few studies have examined the role of adjuvant radiation therapy (AXRT) in advanced penile squamous cell carcinoma. We sought to evaluate the association of pelvic AXRT with survival and recurrence for patients with penile cancer and positive pelvic lymph nodes (PLN) after lymph node dissection. METHODS: Data were collected retrospectively across 4 international centers of patients with penile squamous cell carcinoma (PeCa) undergoing lymph node dissections from 1980 to 2013. 92 patients with positive PLN were analyzed. Variables recorded included age, stage, histological grade, PLN status, pelvic extranodal extension (ENE), chemotherapy status, disease-specific survival, overall survival, and recurrence. RESULTS: 43% (n1⁄440) patients received AXRT after a positive PLN dissection. Median follow up was 9.3 months (IQR 5.2-19.8). The median number of positive PLN was 2 (IQR 1-3). Patients receiving AXRT had an improved median overall survival (OS) of 12.2 months versus 8 months in those who did not receive radiation (p1⁄40.0447). Median disease-specific survival (DSS) was 14.4 months versus 8 months in the AXRT and non-AXRT group respectively (p1⁄40.0232). Patients not receiving AXRT was associated with worse OS (HR: 1.9; 95% CI: 1.11-3.26; p1⁄40.0195) and DSS (HR: 2.08; 95% CI: 1.18-3.66; p1⁄40.0112) on multivariable analysis. Median time to recurrence was 7.7 months versus 5.3 months in the radiation and non-radiation arm respectively (p1⁄40.0425). Patients not receiving AXRT was also independently associated with higher overall recurrence on multivariable analysis (HR: 1.98; 95% CI: 1.15-3.42; p1⁄40.0131). CONCLUSIONS: AXRT is associated with improved OS and DSS, and decreased recurrence in this population of PeCa patients with positive PLN. Further studies with a prospective design and larger data sets are required to validate this finding. Source of Funding: none

Comprehensive characterization of the perioperative morbidity of cytoreductive nephrectomy

The authors report a single institution retrospective analysis of the reported complications and delay to initiation of systemic therapy in a cohort of 294 patients with metastatic renal cell carcinoma (1). This is the largest series evaluating this novel study question. There is presently no randomized controlled data in the era of targeted therapy demonstrating a survival benefit of upfront cytoreductive nephrectomy (CN). Despite this, CN is commonly utilized in well selected patients utilizing extrapolated data from the immunotherapy era. There is some evidence from the National Cancer Database, that adoption of CN from 2005–2008 (era of targeted therapy) actually has been decreasing with improvement in the effectiveness and enhanced reported toxicity profile of targeted therapy (2). Questions remain regarding which patients derive optimal benefit from CN.