bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylated glutathione s-transferase 1 (mGSTP1) as a potential plasma epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer (CRPC).
Authors: Mahon Kate Lynette , Qu Wenjia , Devaney James , Paul Cheryl , Castillo Lesley , Wykes Richard , Chatfield Mark D , Boyer Michael J. , Stockler Martin R. , Marx Gavin M. , Gurney Howard , Hiriyanna Gowda Girish Mallesara , Molloy Peter , Horvath Lisa , Clark Susan J. ,   PRIMe Consortium
Published: February 2017

11

Background: GSTP1 is inactivated and displays aberrant CpG island promoter methylation in the majority of prostate cancers (PCs). The aim of this study was to assess whether changes in methylated glutathione s-transferase 1 (mGSTP1) levels are predictive of response to chemotherapy and overall survival (OS). Methods: Plasma samples were collected prospectively from a phase I exploratory cohort of 75 men with castration-resistant prostate cancer (CRPC) (40 treated with chemotherapy) and a phase II independent validation cohort (n=51). Plasma samples were collected at presentation with CRPC and pre- and post-cycle one of chemotherapy (90% Docetaxel). mGSTP1 levels were measured using a methylation-specific head-loop PCR assay from DNA isolated from either (1) immunomagnetic separation of circulating tumor cells (CTCs) or (2) free plasma DNA. The associations between plasma mGSTP1 levels, PSA response (defined by PCWG1 criteria), and OS were tested using non-parametric tests and survival analyses. Results: The ability to detect mGSTP1 was significantly higher for the plasma free DNA assay compared to DNA from CTCs (p<0.0001), so for the remainder of the study the plasma free DNA assay was used. The phase I exploratory cohort identified that detectable mGSTP1 at CRPC presentation predicted for poorer OS (HR 4.2, 95% CI 2.1-8.2; p<0.0001). In the 40 men treated with chemotherapy, a decrease in mGSTP1 levels after cycle one predicted a subsequent more than 50% decrease in PSA prior to cycle 4 (p=0.008). The phase II validation cohort demonstrated that undetectable plasma mGSTP1 after one cycle of chemotherapy predicted for a clinical benefit from treatment (PR+SD vs. PD) (p=0.007). Furthermore, an undetectable plasma mGSTP1after one cycle of chemotherapy was a better predictor of death within 12 months than change in PSA after three months (AUC 0.87, 95% CI 0.77-0.98; p=0.006). Conclusions: We have identified plasma mGSTP1 levels as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for cytotoxic chemotherapy and validated these findings in an independent phase II cohort. Prospective phase III assessment of mGSTP1 as a biomarker of therapeutic response is now warranted.
Denosumab or zoledronic acid (ZA) therapy on pain interference and cancer-specific quality of life (CSQoL) in patients with castrate-resistant prostate cancer (CRPC) and bone metastases (BM).
Authors: Patrick Donald , Cleeland Charles S. , Fallowfield Lesley , Smith Matthew Raymond , Klotz Laurence , Oudard Stephane , Marx Gavin M. , Wei Rachel , Ohrling Katarina , Qian Yi
Published: February 2017

12

Background: Patients with castration-resistant prostate cancer (CRPC) and bone metastases (BM) may experience debilitating pain that impacts daily functioning and diminishes the quality of life. Previous results from a phase III trial demonstrated superiority of denosumab to ZA in delaying or preventing skeletal-related events (pathological fracture, radiation or surgery to the bone, spinal cord compression) in CRPC patients with BM. In this ad-hoc analysis, we present the results of denosumab or ZA therapy on pain interference (PI) and cancer specific quality of life (CSQoL), focusing on the subgroup of CRPC patients with no/mild pain at baseline. Methods: Men with CRPC and BM (no prior IV bisphosphonate use) were randomized to receive either SC denosumab 120 mg+IV placebo or SC placebo+IV ZA 4mg (adjusted for creatinine clearance) every four weeks. Patients were instructed to take calcium and vitamin D supplements. The Brief Pain Inventory–Short Form (BPI-SF) was used to assess PI. The pre-specified clinically meaningful time of a greater than or equal to two point increase from baseline in PI score (overall, physical, and emotional subdomains) was determined for CRPC patients receiving denosumab or ZA therapy. Patients also completed the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline and each monthly visit to determine CSQoL scores. Declining FACT-G scores points to worsening CSQoL, where a greater than or equal to five point decrease is clinically meaningful. Results: Of the 1,901 patients enrolled (n=950, denosumab; n=951, ZA), 1,045 (55%) had no/mild pain at baseline. Compared with ZA, denosumab therapy delayed the time to a greater than or equal to two point increase from baseline in PI for the overall score (HR=0.83 [0.71, 0.98]; P=0.023), physical (HR=0.87 [0.75, 1.02]; P=0.077) and emotional (HR=0.83 [0.71, 0.97]; P=0.020) subdomains. Over a period of 18 months, more ZA-treated patients than denosumab-treated patients experienced a greater than or equal to five point decrease in FACT-G total scores (average relative difference=6.8%, range -9.4 to 14.6%) or worsening of CSQoL. Conclusions: Denosumab therapy significantly delayed the time to worsening of pain interference and maintained a higher overall CSQoL (FACT-G) compared to ZA in CRPC patients with BM. Clinical trial information: NCT00321620.
Evaluation of the Oncotype DX genomic prostate score for risk stratification in prostate cancer patients considered candidiates for active surveilance.
Authors: Kartha Ganesh K , Nyame Yaw , Klein Eric A.
Published: February 2017

122

Background: With evidence showing over treatment, more patients are choosing active surveillance (AS) for intermediate or lower risk prostate cancer (CaP). Genomic profiling is offered to risk stratify patients to aid in management decision−making. This study reports risk discrepancies between National Comprehensive Cancer Network (NCCN) criteria and OncotypeDx Genomic Prostate Score (GPS) and how this influences decision−making in our CaP population. Methods: An inception cohort study was carried out on 56 patients with NCCN very low to intermediate risk CaP who were candidates for AS and underwent GPS testing on prostate biopsy specimens performed within 6mo of entry. GPS provided a score corresponding to a GPS-based risk stratification. Study endpoints: 1) distribution of GPS risk groups within each NCCN risk category; 2) frequency of change to lower or higher risk based on GPS; 3) effect of GPS on physician recommendations and patient choice on disease management. Results: 52/56 patients had sufficient carcinoma on biopsy for a GPS analysis. GPS reassigned risk in 23% (12/52) of patients, with 10 going from NCCN low risk to GPS very low risk and 2 assigned to a higher GPS risk profile (Table). AS was recommended in 19 patients with GPS very low risk group and 8 patients in the GPS-defined low risk group. Physicians recommended treatment to 7 patients with GPS intermediate risk. Patient choice was congruent with physician recommendation in all cases. No patients chose AS when assigned to a higher risk category. All 10 patients reassigned to a lower risk category chose AS. Conclusions: In this CaP cohort, assessment by GPS changed risk stratification in 23% of patients. Moving to a different risk category changed physician recommendation and patient choice in the corresponding direction (to surveillance or therapy) in all cases. More study and larger sample size are needed to fully assess the effect of GPS on clinical decision making. [Table: see text]
The sequential use of abiraterone and enzalutamide in metastatic castrate resistant prostate cancer patients: Experience from seven U.K. centers.
Authors: Stevenson Robert , Fackrell David Gareth , Ford Daniel , Glaholm John , El-Modir Ahmed , Porfiri Emilio , Zarkar Anjali M , Tanguay Jacob , Rackley Thomas , James Nicholas David
Published: February 2017

125

Background: Phase III studies have demonstrated survival benefits from abiraterone (Abi), and enzalutamide (Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is now available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enz has recently become available, via the UK cancer drugs fund (CDF), for progressive disease post docetaxel, prior to exposure to Abi. There has been no randomised trial on sequential usage of Enz post-Abi. We therefore, report the experience of hospitals in Coventry, Cardiff, and five centers in Birmingham. Methods: We searched the pharmacy database for patients who have received Enz as part of an early access scheme, and identified 79 patients who started treatment between the August 2012 and April 2013. A detailed notes review was carried out of these patients. Results: Median age was 74 (range of 55 to 87). All patients had received hormone androgen deprivation therapy and taxane chemotherapy (docetaxel and/or cabazitaxel) 75 patients had received previous Abi, 62 of these patients receiving Abi as the last treatment prior to Enz. The mean time to progression (TTP) for Abi in these 62 patients was 37.44 weeks (range 4 to 104). At the time of submission 55 patients had stopped Enz due to prostate-specific antigen progression with a mean TTP of 15.87 weeks and 28 patients had died. Conclusions: The AFFIRM study demonstrated TTP of 36 weeks in patients post-docetaxel. In this audit of patients receiving Enz post-Abi the TTP was only 15.87 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. Trials are underway comparing Abi alone or in combination with Enz which may improve efficacy.
Molecular characterization of circulating tumor cells (CTCs) of patients with neuroendocrine prostate cancer (NEPC).
Authors: Beltran Himisha , Louw Jessica , Kossai Myriam , Krupa Rachel , Marrinucci Dena , Mosquera Juan Miguel , Nanus David M. , Tagawa Scott T. , Dittamore Ryan , Rubin Mark A.
Published: February 2017

177

Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that commonly arises in later stages of castration resistant prostate cancer (CRPC), especially with visceral metastases in the setting of a low prostate-specific antigen (PSA). The genes AURKA and MYCNare frequently amplified. There are no reliable serum markers to identify patients that are transforming to NEPC and incidence of circulating tumor cells (CTCs) in these patients is unknown. Detection of NEPC has clinical implications as these patients are often treated with platinum chemotherapy rather than with androgen receptor (AR) targeted therapies. Methods: Ten men with metastatic NEPC underwent metastatic tumor biopsy and blood collection for CTC analysis utilizing the Epic Sciences platform. Clinical characteristics, pathologic and molecular features including exome sequencing of metastatic tumors, serum PSA and neuroendocrine (NE) markers, CTC count by CellSearch were obtained on all patients. AURKA and MYCNamplification were assessed by FISH in both tumors and Epic CTCs. Results: Sites of metastases included liver (6 out of 10), bone (9 out of 10), lymph nodes (8 out of 10), pleura (1 out of 10), and lungs (2 out of 10). Serum PSA, CellSearch CTCs, and serum NE markers were variable including 4 out of 10 patients with PSA less than 1 ng/ml (range 0.02-9.39) and 3 out of 5 evaluated patients with CTC count of zero (range 0 to 94). Four out of 7 evaluated tumors displayed amplification of AURKA and MYCN. Epic CTCs demonstrated frequent clusters, dim/low cytokeratin suggesting epithelial plasticity, and low AR expression. Patients were subsequently treated with platinum (4 out of 10), AURKAinhibitor (4 out of 10), or hormonal therapy (2 out of 10). Conclusions: PSA, serum NE markers, and CTC count by CellSearch may not be reliable in identifying patients with CRPC that have NE features. Epithelial plasticity potentially arising from epithelial-mesenchymal transition may explain lack of detection using conventional CTC assays. The Epic Sciences CTC platform is capable of detecting CTCs from patients with NEPC and CTCs are molecularly similar to metastatic biopsies. Epic CTCs may be useful in the earlier detection of NEPC and inform patient selection for therapy.
Enzalutamide after failure of docetaxel and abiraterone in metastatic castrate resistant prostate cancer (mCRPC): Results from an expanded access program.
Authors: Thomson David , Charnley Natalie , Parikh Omi
Published: February 2017

188

Background: Abiraterone or enzalutamide are licensed for use post-docetaxel in metastatic castrate resistant prostate cancer (mCRPC). Both target the androgen receptor signalling pathway. There is little information describing their sequential use. Methods: Patients with mCRPC who had failed treatment with docetaxel and abiraterone received enzalutamide as part of an expanded access program. Patients were reviewed four weekly and post-treatment PSA used to determine efficacy. Results: Twenty three patients, median age 76 (range, 65 to 82), performance status of 1 (15/23) or 2 (8/23) with mCRPC (22/23 bone and 4/23 visceral disease) were enrolled. All had received prior docetaxel and abiraterone as well as cabazitaxel (35%), dexamethasone (30%), and stillboestrol (52%). Median biochemical progression free survival (bPFS) was 11.9 weeks. Nine (39%) patients showed sensitivity to enzalutamide, defined as a greater than 50% reduction in PSA. There was a correlation between PSA response to abiraterone and enzalutamide (R=0.45, p=0.03). In 10 out of 23 and 13 out of 23 patients who were sensitive and insensitive to abiraterone, 60% and 23% had a great than 50% reduction in PSA, respectively. There was a trend to improved bPFS in those sensitive to abiraterone (15.7 vs. 11.4 weeks, p=0.40) and in those who showed any PSA response to abiraterone (15.9 vs. 5.3 weeks, p=0.06). Conclusions: Enzalutamide has activity following failure of docetaxel and abiraterone in mCRPC. The effectiveness is more pronounced in those who have responded to abiraterone.
Biochemical response to enzalutamide therapy in patients with mCRPC following docetaxel and abiraterone treatment.
Authors: Roeder M. Andreas , Thomsen Frederik Birkebæk , Brasso Klaus , Rathenborg Per , Borre Michael , Iversen Peter
Published: February 2017

202

Background: Enzalutamide improve overall survival (OS) in patients with metastatic castrate resistant prostate cancer (mCRPC) patients following docetaxel treatment. Optimal sequencing and possible cross-resistance for novel mCRPC therapeutics is less understood. In this study we report biochemical response and OS after enzalutamide treatment in post-chemo mCRPC patients following progression on post-chemo abiraterone treatment. Methods: Twenty-four post-chemotherapy and post-abiraterone mCRPC patients with progressive disease received enzalutamide 160 mg/daily in a Danish compassionate-use program sponsored by Astellas Pharma A/S. Best PSA and alkaline phosphatase response was recorded. Fischer’s exact test, Mann-Whitney U test and linear regression model was used to test for differences in PSA response. OS was calculated from initiation of enzalutamide treatment. Results: Minimum follow-up was three months. The best median PSA response was -22% (-76% to 76%). Forty-six percent of patients had a greater than 30% decrease in PSA. The PSA response to enzalutamide did not correlate to the number of prior cancer treatments (p = 0.57), time from diagnosis to CRPC (p = 0.11), or prior response to docetaxel (p = 0.67). However, eight patients treated with second line cabazitaxel had an inferior PSA response to enzalutamide (p = 0.03), and there was a trend for the PSA response to abiraterone to correlate with the PSA response to the succeeding enzalutamide (B = 0.22, p = 0.05). The best median alkaline phosphatase response was 0.1% (-67% to 126%). Median OS was 4.8 months. Conclusions: Patients with post-chemotherapy, post-abiraterone mCRPC treated with enzalutamide showed less marked biochemical response to therapy compared to the results from the AFFIRM study where post-chemo abiraterone was not used. Whether this is an effect of cross-resistance or a result of the natural history of the disease needs further elaboration.
Phase I trial of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in combination with docetaxel (DTX) in patients (pts) with advanced solid tumors, including castration-resistant prostate cancer (CRPC).
Authors: Sarantopoulos John , Hahn Noah M. , Higano Celestia S. , Leonard E. Jane , Zhang Bin , Zhou Xiaofei , Dansky Ullmann Claudio , Graff Julie Nicole
Published: February 2017

217

Background: Overexpression of AAK, a key regulator of mitosis, is seen in various solid tumors, including prostate cancer. This open-label, Phase 1 trial investigated the safety/tolerability of MLN8237, an oral selective AAK inhibitor, combined with DTX in pts with advanced solid tumors, including CRPC. Methods: Previously treated pts aged ≥18 y who were candidates for DTX received 21-day cycles of MLN8237 10–50 mg BID on days 1–7, escalated in 3+3 dosing cohorts, plus DTX 60 or 75 mg/m2 on day 1. To manage toxicity, a 5-day MLN8237 regimen was later evaluated with DTX 60 or 75 mg/m2+ G-CSF support. Primary endpoints were safety/tolerability and recommended phase II dose/schedule (RP2D). Pharmacokinetics (PK) and antitumor activity (RECIST 1.1/PSA) were also assessed. Results: 35 pts (median age 63 y [25–87]; 71% male; 17 CRPC) recruited into 8 cohorts received a median of 3 (1–33) cycles; 15 pts (11 CRPC) had ≥6 cycles. 14 DLTs were seen in 11 pts (5 CRPC) in Cycle 1: G4 neutropenia >7 days (n=3), G3/4 febrile neutropenia (FN; n=7), G3 stomatitis (n=3), and G3 urinary tract infection (n=1). The RP2D was MLN8237 20 mg BID on Days 1–7 + DTX 75 mg/m2 in 21-day cycles without G-CSF. Common G≥3 drug-related AEs included neutropenia (86%), leukopenia (31%), FN (23%) and stomatitis (14%). 20 (57%) pts reported SAEs, most commonly FN (n=8). 2 pts withdrew due to AEs, inc. 1 death (G3 FN; G3 mucositis); 4 pts continue on study. On-study deaths (n=2; disease progression) were not considered drug-related. Steady-state MLN8237 exposure (AUCss) increased approximately dose-proportionally over 10–30 mg BID when combined with DTX (n=16). Analysis of the effect of MLN8237 on DTX PK at RP2D is ongoing. Among 11 evaluable CRPC pts, 6 had PR (4 had PSA50) and 6 had SD (4 with PSA50). 2 other pts (bladder cancer and angiosarcoma) also had PR. Conclusions: The RP2D was MLN8237 20 mg BID on days 1–7 + DTX 75 mg/m2 on day 1. Despite myelosuppression, the combination of MLN8237 and DTX had a generally manageable toxicity profile in pts with advanced solid tumors. Further clinical study of this combination, particularly in CRPC pts, is warranted. Clinical trial information: NCT01094288.
Quality improvement opportunities in prostatectomy care in a regional hospital-based urologic quality collaborative.
Authors: Gore John L. , Porter Michael P , Corman John M. , Sutherland Douglas Edward , Schmidt Zeila , Flum David R ,   SCOAP-CERTAIN Collaborative
Published: February 2017

234

Background: Prostate cancer care is susceptible to regional variation in treatment and outcomes. Recent national recommendations have highlighted the harms of prostate cancer treatment including urinary incontinence and impotence. We prospectively evaluated radical prostatectomy (RP) outcomes at participating Washington-state hospitals to identify quality improvement opportunities in RP care. Methods: A local clinician advisory group developed a chart abstraction tool that captures potential quality concerns in RP care. The abstraction tool was implemented at nine regional hospitals with data consolidated for review quarterly. The research team and clinician advisory group were blinded to hospital identities in feedback reports. Data were analyzed as aggregate rates and hospital-specific rates without risk adjustment using descriptive statistics. Results: We identified 461 patients undergoing RP at nine area hospitals from 2011 to 2013. The majority (74%) were robot-assisted minimally invasive RPs, Participating hospitals report as many as 97% or as few as 12% robot-assisted procedures. 26.3% of cases were pathologic non-organ-confined prostate cancer (pT3 or higher); pathologic stage was not further classified beyond "T2" or "T3" in 31% of RPs. Surgical margins were positive in 18% of cases overall; hospital-specific positive margin rates ranged from 12 to 25% among organ-confined cases and 0 to 75% among stage pT3 or higher prostate cancer. Length of stay exceeded three days post-prostatectomy in more than 10% of cases at 4 hospitals including one hospital where 36% of cases had prolonged lengths of stay. Conclusions: We identified several quality improvement opportunities that may improve health outcomes among men undergoing RP for prostate cancer. Positive margin rates were excessive at some hospitals and may represent uncertainty in the surgical approach to higher risk cases. Variation in lengths of stay may represent provider variability in post-prostatectomy clinical care algorithms. Survey of provider practices may inform development of quality improvement initiatives such as clinical pathways that may address the variations in RP care identified.
Enzalutamide in men with prostate cancer resistant to docetaxel and abiraterone.
Authors: Scholz Mark Creamer , Lam Richard Y. , Turner Jeffrey S. , Chau Khang N. , Becker Lauren K. , Felarca Clifford U.
Published: February 2017

247

Background: Since FDA approval in 2011, abiraterone (Zytiga) has supplanted docetaxel as preferred first-line treatment for metastatic castrate-resistant prostate cancer. In August 2012 enzalutamide (Xtandi) was FDA-approved for the treatment of castrate-resistant prostate cancer after docetaxel (Taxotere). We performed a retrospective chart review at a large medical oncology clinic specializing in prostate cancer to determine the PSA response rates of enzalutamide administered to men who had previously progressed on both abiraterone and docetaxel. This report includes some patients who participated in the Astellas/Medivation-sponsored Early Access Program; however, it represents the author’s independent clinical experience. Methods: Enzalutamide was administered at a dose of 160 mg daily. Patients were subsequently followed with monthly physical examination, PSA and routine blood tests. No hepatotoxicity or seizures occurred. Men were considered evaluable for PSA response if they received enzalutamide for twelve weeks. A PSA decline of 30% from baseline after 12 weeks was defined as a response. A PSA increase of 30% from baseline within 12 weeks was defined as disease progression. Men with neither a 30% increase nor a 30% decline were classified as having stable disease. Results: 66 men were treated and 63 were evaluable for PSA response. Median age was 67. Median baseline PSA was 68.5. All participants had disease that had progressed on abiraterone. 55 men received previous docetaxel. 38 had received previous Provenge. Two men stopped before 12 weeks because of intolerable fatigue. One man died of progressive disease before 12 weeks. After a median follow up of 12.5 weeks, 18(29%) men met criteria for PSA response. 13(21%) men had stable disease and 32(51%) men had PSA progression. Conclusions: Enzalutamide has activity in a heavily pretreated population of men resistant to abiraterone and docetaxel.
Premature termination of genitourinary cancer clinical trials.
Authors: Stensland Kristian D. , McBride Russell , Wisnivesky Juan P. , Latif Asma , Hendricks Ryan , Roper Nitin , Boffetta Paolo , Hall Simon J , Oh William K. , Galsky Matt D.
Published: February 2017

288

Background: The GU oncology literature is inundated with clinical trials that terminated prematurely, particularly in bladder cancer. Such trials require substantial resource expenditure and entail the time, trust, and commitment of patients, yet contribute minimally to the scientific knowledgebase and divert resources from answering critical questions. We sought to determine the scope of this problem within the clinical trials enterprise. Methods: ClinicalTrials.gov was queried to identify all phase II-III interventional adult cancer clinical trials registered between 9/11/05 and 11/11/11. Prematurely terminated trials were “stopped early” as defined by the registry. Kaplan-Meier methods and Cox regression were used to determine risk of premature trial termination. Results: We identified 7,776 trials, including 491 prostate (PCa), 142 kidney, 75 bladder, and 34 testis cancer trials. The risk of premature termination due to any cause for all cancers was 25% (95% CI 19-31%) and the risk due to poor accrual was 10% (95% CI 9-12%). Poor accrual was the most common reason for premature termination (Table). Risk was not significantly different for kidney, bladder or testis cancers compared to other cancer types with the exception of PCa (HR 1.35 [1.03-1.78]). Industry-funded trials were more likely to terminate prematurely (HR 2.26 [1.83-2.80]). Trials with sites outside of the USA (HR 0.63 [0.54-0.74]) or both within and outside of the USA (HR 0.68 [0.54-0.74]) were less likely to terminate prematurely as were trials with multiple sites (HR 0.56 [0.48-0.64]). Conclusions: In this large cohort of clinical trials, ~1 in 4 trials terminated prematurely (1 in 10 due to poor accrual). GU cancer trials were at similar risk of termination compared to other cancer clinical trials with the exception of PCa. Novel approaches are needed to improve the efficiency of the clinical cancer research enterprise. [Table: see text]
Prerandomization factors and utilization of neoadjuvant chemotherapy in a clinical trial of extended versus standard pelvic lymphadenectomy at the time of radical cystectomy for bladder cancer.
Authors: Lerner Seth P. , Li Hongli , Svatek Robert Scott , Koppie Theresa M. , Alva Ajjai Shivaram , La Rosa Francisco G. , Bangs Rick , Pal Sumanta Kumar , Daneshmand Siamak , Kibel Adam S. , Canter Daniel J. , Tangen Catherine M. , Thompson Ian Murchie
Published: February 2017

295

Background: Despite level I evidence supporting the use of cisplatin-based NAC, this practice has not been widely adopted. We assessed contemporary utilization of NAC within the context of an ongoing prospective clinical trial (SWOG S-1011; NCT01224665) in order to identify clinical and/or demographic factors that are associated with receipt of NAC. Methods: S1011 tests the hypothesis that an extended pelvic lymphadenectomy (PLND) is associated with a 10-12% improvement in recurrence-free survival compared to a standard PLND among patients with clinical stage T2-4aN0-2M0 urothelial cell carcinoma of the bladder. Patients are registered prior to RC and are randomized intra-operatively to extended vs. standard PLND. Receipt of NAC, including type and duration are is a stratification factor and prospectively recorded at registration. We evaluated the association of pre-randomization factors, including age, gender, clinical stage, performance status, and institution with the receipt of NAC. Results: 243 patients have been registered as of 9/18/2013 and 229 randomized. Among randomized patients, 119 (52%) received NAC, including 97 (82%) treated with cisplatin-based NAC. The most common NAC regimens, Gem-Cis (gemcitabine-cisplatin) and MVAC (methotrexate, vinblastine, adriamycin, and cisplatin), were administered to 58 and 35 patients, respectively. 63% (40/64) of patients with cT3-4a disease received NAC vs. 48% (79/165) with cT2. There was no association of age, gender, race, ethnicity or PS with receipt of NAC. Among 8 institutions with at least 10 patients registered, the range of utilization of neoadjuvant chemotherapy received was 7% to 83%. Reason for not giving NAC is recorded at time of registration and a detailed analysis will be presented. Conclusions: Interim analysis of S1011, a prospective surgical trial, reveals the highest rate of integration of NAC with RC to date and reflects a considerable change in evidence based practice patterns. The institutional variation in utilization of NAC warrants further exploration of factors influencing delivery of care. Clinical trial information: NCT01224665.
Molecular profiling of infiltrating urothelial carcinoma of the bladder.
Authors: Millis Sherri Z. , Bryant David , Basu Gargi Dan , Bender Ryan , Vranic Semir , Gatalica Zoran , Vogelzang Nicholas J.
Published: February 2017

311

Background: Infiltrating urothelial carcinoma (UC) is the most common variant of urinary bladder cancer. The prognosis for muscle infiltrating or metastatic UC of the bladder is poor with no major advances made in the last 20 years. We investigated a large cohort of such patients for specific genetic/biomarker alterations and compared them to other, less common urothelial malignancies. Methods: We reviewed 602 cases; 518 cases (86%) were locally advanced or metastatic UCs of the bladder and the remaining 84 cases (14%) were non-bladder UCs. Multiple methodologies for optimal assessment of biomarker expression (Caris Molecular Intelligence, Caris Life Sciences, Phoenix, AZ) were employed: Mutation analysis (Next-generation sequencing, Sanger, pyrosequencing, qPCR, RFLP), in-situ hybridization (fluorescent and chromogenic), immunohistochemistry, and RNA fragment analysis. Results: Bladder UC showed slightly higher rates of HER2/neu gene amplification (12% in bladder vs. 6% non-bladder, p=0.32) and EGFR gene amplification (22% vs. 12%, p=0.25). HER2/neu and EGFR protein expressions were more common in the bladder than in non-bladder sites (10% vs. 1%, p=0.03, and 77% vs. 60%, p=0.5, respectively). Pathogenic mutations in HER2/neu and EGFR were rare. Although c-Kit and c-Met receptor kinases were more frequently overexpressed in bladder than in non-bladder cancers (10% vs. 6% and 25% vs. 8%, respectively), activating mutations were also rare. PIK3CA and/or PTEN mutations were more frequently observed in non-bladder (27%) than in bladder UCs (21%). Non-bladder UC harbored high FGFR3 gene mutation (33%), which was not observed in any of the UC of the bladder (p=0.02). TP53 gene mutations were frequently identified in both bladder and in non-bladder cancers (49% vs. 27%, respectively, p=0.15), while KRAS was frequently mutated in the bladder adenocarcinomas (56%, p<0.001). Other therapeutically targetable biomarkers over-expressed in bladder UC compared to non-bladder UC included androgen receptor (16% vs. 8%, p=0.07) and MGMT (63% vs. 47%). Conclusions: Comprehensive molecular profiling of urothelial carcinoma identifies a number of potentially actionable targets, which can be managed by the novel treatment modalities.
Cancer-specific survival in patients with urothelial carcinoma of the bladder with recurrence after radical cystectomy: External validation of the prognostic risk stratification model.
Authors: Nakagawa Tohru , Kume Haruki , Kanatani Atsushi , Ikeda Masaomi , Matsumoto Akihiko , Taguchi Satoru , Hiramatsu Kanae , Komemushi Yoshimitsu , Kawai Taketo , Enomoto Yutaka , Kondo Yasushi , Suzuki Motofumi , Fujimura Tetsuya , Fukuhara Hiroshi , Okaneya Toshikazu , Hirano Yoshikazu , Tomita Kyoichi , Tanaka Yoshinori , Nishimatsu Hiroaki , Homma Yukio
Published: February 2017

325

Background: Prognosis of the patients with urothelial carcinoma of the bladder (UCB) who developed recurrence after radical cystectomy (RC) is generally poor, but can be variable. We previously showed that shorter time to recurrence (TTR) after RC, presence of symptoms on recurrence, more than one metastatic sites (organs), high serum C-reactive protein (CRP) level were associated with decreased survival in those patients, and proposed a model to stratify patients into 3 separate risk groups (Nakagawa et al. J Urol. 2013; 189:1275). The aim of this study was to evaluate the prognostic value of this model in a multi-institutional cohort of patients. Methods: We identified 267 patients who experienced disease recurrence after RC for UCB from 9 academic and community hospitals. Patients were categorized into three groups based on the presence of four risk factors, TTR of <1 year, presence of symptoms on recurrence, more than one metastatic sites (organs), and CRP level of ≥0.5 mg/dl: the favourable risk group included patients with none or one of these risk factors; the intermediate risk group with 2 risk factors; and those with 3 or 4 risk factors were assigned to the poor risk group. Results: Overall, median survival time (MST) of the entire cohort was 8.3 months (95%CI, 6.4-9.1). Two hundred and nineteen patients died of their disease with a median survival of 5.9 months. In a multivariate analysis, all of the 4 risk factors were statistically significant for the cancer-specific survival. Sixty-five (27.4%), 84 (35.4%), and 88 (37.1%) patients were in the favorable, intermediate and poor risk group, respectively. Thirty patients were excluded because CRP value was not obtained. MSTs of the patients in the favorable, intermediate and poor risk group were 22.2 (95% CI 16.1-28.3), 7.6 (95% CI 6.3-9.5), and 3.6 (95% CI 2.6-4.4) months, respectively, and the difference was statistically significant (p<0.001, log-rank test). Conclusions: We confirmed the prognostic value of our previous criteria based on the four variables in patients with recurrence after RC for UCB. This criteria would help in patient counseling and clinical trial design.
Association of time delays to radical cystectomy by use of neoadjuvant chemotherapy with higher rates of progression.
Authors: Parker William P. , Nehra Avinash , Griffin Joshua , Lopez-Corona Ernesto , Holzbeierlein Jeffrey M.
Published: February 2017

345

Background: Neoadjuvant chemotherapy (NC) is utilized to improve survival for patients with muscle invasive bladder cancer. However, this results in a protracted treatment course of 3−4 chemotherapy cycles given over several months. Previous series have suggested that delays in radical cystectomy (RC) from initial diagnosis are associated with inferior survival rates. We investigated if similar trends are seen in a population of patients treated with neoadjuvant chemotherapy. Methods: A retrospective review of our RC database was performed to identify patients treated with NC over the last five years. Time interval was calculated from date of initial diagnosis of muscle invasive disease to date of surgery. Kaplan Meier and multivariate analysis methods were used to assess recurrence free and cancer specific survival based on pathologic stage, nodal status, margin status, and time to RC with estimation of hazard ratios for those variables. Results: 72 patients from 2006−2012 were identified. Mean age was 64 years and 80% were male. 79% of the cohort had 3 or more cycles of NC, with gemcitabine−cisplatin as the most common regimen (75%). Mean time from diagnosis to RC was 173 days. Pathologic stage distribution was T2−20.8%, T3−20.8%, T4− 18.1% and T0 status was obtained in 27.8%. 95% was of pure urothelial carcinoma histology. Node positive disease was found in 30%. At most recent follow up 33% of the cohort had died and 13% had recurrent disease. Higher tumor stage and positive nodal status were associated with lower recurrence free and cancer specific survival. When stratifying the cohort by time to RC (1−4 months, 5months, 6 months) there was no statistical difference in recurrence free or cancer specific survival. However, on multivariate analysis patients who had RC less than 5 months from diagnosis had lower rates of progression (OR 0.14; 95% CI .02−.08, p 0.038) compared to those with RC after 5 months (OR 4.86 95% CI 0.9−26, p 0.06). Conclusions: Time delays associated with use of NC of greater than five months correlated with lower recurrence free survival in our cohort but there did not appear to be any effect on cancer specific survival. This should be further validated with a larger multicenter analysis.
Forward and inverse-planned intensity-modulated radiotherapy (IMRT) in the CHHiP trial: A comparison of dosimetry and normal tissue toxicity.
Authors: Naismith Olivia Frances , Griffin Clare , Syndikus Isabel , Mayles Helen , Hall Emma , Dearnaley David Paul ,   CHHiP Trial Management Group
Published: February 2017

37

Background: CHHiP (CRUK/06/016) is a multicentre randomised controlled trial investigating the use of hypofractionated radiotherapy dose schedules for treatment of localised prostate cancer. RT treatment employs a complex target volume treated with either a multi-segment “forward” plan or inverse-planned intensity-modulated radiotherapy (IMRT). This study compares dose-volume histogram (DVH) and toxicity data for rectum and bladder for the two planning techniques. Methods: Three hundred thirty seven patients (230 forward-planned [F]; 107 inverse-planned [I]) with prospectively collected 2 year toxicity and DVH data for rectum and bladder dose constraints were included. Patients were paired for comparison by matching on (1) rectum and prostate + seminal vesicle PTV volumes for the rectal dose comparison (53 matched pairs available); and (2) bladder and prostate-alone PTV volumes for bladder dose comparison (61 matched pairs). For the toxicity comparison patients were additionally matched on randomised dose schedule. Results: Forward-planned patients had significantly larger volumes of rectum irradiated to 50 to 70Gy and bladder at 50 to 60Gy. In contrast, inverse-planned patients had significantly larger volumes of bladder irradiated to 74 Gy. Acute bowel toxicity (G2+ toxicity within 18 weeks of start of RT) was significantly worse in forward-planned patients (27/53 [52%] F vs 11/53 [21%] I; Mann-Whitney p=0.0002). There were no significant differences in acute urinary symptoms. Late toxicity was rare in both planning groups with only two patients (0 F; 2 I) reporting RTOG G2+ bowel/bladder effects at 24 months. Considering LENTSOM data, there was a suggestion of less late bowel toxicity in the inverse group (G1+ at 18 months: 16/53 (30%) F vs. 6/53 (11%) I; p=0.008). Patient reported outcomes of bowel habits showed no consistent differences between planning methods, although there was a tendency for worse urinary function scores in the inverse group at 12 months. Conclusions: Both planning techniques were associated with low late toxicity. Significant differences were found between DVHs from forward and inverse plans. There were some associations between DVH differences and normal tissue effects; these resolved by 2 years. Clinical trial information: CRUK/06/016.
Postoperative complications of radical nephrectomy with atrial thrombectomy: A contemporary population-based analysis.
Authors: Borza Tudor , Chung Benjamin I. , Chang Steven L.
Published: February 2017

423

Background: The mainstay treatment for patients with stage T3c renal cell carcinoma is radical nephrectomy with atrial thrombectomy (RN−AT). Although this procedure is widely recognized to have substantial morbidity and mortality, little data exist on the actual rates of postoperative complications. Using a contemporary population−based cohort, we sought to determine the postoperative complication rates among patients undergoing RN−AT. Methods: We queried the Premier Perspective Database (Premier, Inc, Charlotte, NC) to identify patients that underwent nephrectomy (ICD9 55.51) between January 1, 2003 and December 31, 2010. We limited our analysis to patients who concurrently underwent cardiopulmonary bypass, determined through billing codes, as these patients were assumed to have undergone RN−AT. We captured patient and hospital data as well as determined 90−day postoperative complications defined by the Clavien System through review of ICD9 codes and disposition data. Results: Our study cohort included a weighted sample size of 1417 patients; the majority were men (63.7%) and Caucasian (61.9%) with a mean age of 58 years. One−third of patients had metastatic disease while one−quarter had significant comorbidities (i.e., Charlson Comorbidity Score (CCS) ≥2). Ninety−day major complication (Clavien grade 3−5) was present in 38% of patients with half (19%) suffering mortality (Clavien grade 5). The predictors of a major complication included age <50 years (vs >70 years, Odds Ratio [OR] 3.1, p=0.01), CCS ≥3 (vs CCS 0, OR 5.7, p<0.0001), and surgery in an urban hospital (vs rural, OR 8.5, p=0.047). Increased complication rate was not associated with gender, race, metastatic disease, teaching institution, or hospital size. Conclusions: We confirm that RN−AT is associated with significant morbidity and mortality. The mortality rate for this procedure exceeds those reported for other complex surgeries. The higher complication rate seen in younger patients is likely secondary to selection bias. This information is important for preoperative counseling for patients considering RN−AT. Future studies are needed to compare the outcomes of RN−AT versus systemic therapy.
Everolimus as second-line therapy for metastatic renal cell carcinoma (mRCC) after one previous VEGF-targeted therapy: Final results of the noninterventional change study.
Authors: Goebell Peter J. , Kube Ulrich , Staehler Michael , Doehn Christian , Steiner Thomas , Kindler Manfred , Herrmann Edwin , Janssen Jan , Weikert Steffen , Scheffler Michael Thomas , Schmitz Joerg , Overkamp Friedrich , Guderian Gernot , Albrecht Michael , Bergmann Lothar
Published: February 2017

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Background: The mTOR inhibitor everolimus is approved for the treatment of mRCC following failure of VEGF-targeted therapy. To evaluate the effectiveness and tolerability of everolimus following the first VEGF-targeted therapy in routine clinical practice, we conducted the prospective, noninterventional CHANGE study in Germany. Methods: Patients (pts) with mRCC (any histology) were registered at the time of everolimus initiation, or within 90 days thereof, following treatment with either VEGFR-TKI or bevacizumab. Other previous systemic therapies (e.g., cytokines) were permitted. Pts received everolimus 10 mg/d according to the summary product characteristics until disease progression or intolerable toxicity. Study objectives included assessing treatment duration, time to progression (TTP), progression-free survival (PFS), Karnofsky performance status (KPS), and safety. Results: 334 pts were documented at 116 German sites between August 2009 and January 2012 (median age, 68 years; 75% male; median KPS, 80%; 88% clear cell histology). At the start of first-line therapy, MSKCC risk status was favorable in 35%, intermediate in 56%, and poor in 9%. Effectiveness results are shown in the table. In the safety population (n=318), median time to ≥10% deterioration in KPS was 8.4 months (95% CI, 6.1-10.1 months); the most common AEs (any grade) were dyspnea (17%), anemia (14%), and fatigue (12%). Treatment adherence was high, with <2% of patients per visit showing <50% intake of the expected doses. Conclusions: The CHANGE study demonstrates favorable effectiveness and tolerability for everolimus when given in routine clinical practice to pts with mRCC. Our data confirm the use of everolimus as a standard second-line therapy following VEGF-targeted treatment. [Table: see text]
MRC SORCE trial: Analysis of patients' presenting characteristics, tumor staging, and surgical approach.
Authors: Ritchie Alastair W. S. , Meade Angela M. , Choo Louise , Smith Ben , Welland Andrew , Gregory Adam , Kaplan Richard S. , Eisen Tim ,   SORCE Trial Management Group
Published: February 2017

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Background: SORCE is a randomised double blind trial of sorafenib, given for one or three years, versus placebo for patients at moderate or high risk of disease recurrence after surgical excision of primary renal cell carcinoma (RCC). Methods: Between July 2007 and April 2013, 1,711 patients were recruited from the UK (78%), Australia, France, Belgium, Denmark, The Netherlands and Spain. We describe the presenting characteristics, staging and surgical details of the randomised population. The surgical approach was at the surgeon’s discretion. Results: Baseline information is available for 1,681 patients (98%). Median age was 59 years (range 19 to 86): 1,195 (71%) were male. Histology was conventional/clear cell in 86%. T category was pT1a (<1%), pT1b (11%), pT2 (23%), pT3a-4 (65%). 47% were at high risk of recurrence with Leibovich scores of ≥6. Surgical data are available for 1,528 patients (89%). Total (radical) nephrectomy was performed for 97% of patients with 44% having laparoscopic surgery, of which 60% had a transperitoneal approach and 10% required conversion to open surgery. Some form of lymph node dissection was performed in 25% of patients (33% of open procedures and 15% of lap. procedures). The ipsi-lateral adrenal was removed in 47% and 11% had simultaneous resection of other structures/organs. Excision of venous extension was required in 19%. Laparoscopic procedures were performed for 58% of patients with maximum tumour diameter (MTD) <10cm and 17% of those with MTD ≥ 10 cm. Intra-operative complications were reported in 6% and post-operative complications reported in 12%. Hospital stay was median (IQR) 4 days (3-5) for patients having laparoscopic procedures and 7 days (5-8) for open surgery. Hospital stay was median (IQR) 8 days (6-11) for those having post-operative complications compared to 5 days (4-7) for uncomplicated recovery. Conclusions: These data reveal the varied surgical approaches to excision of primary RCC and will inform future adjuvant trials. The use of lymph node dissection appears arbitrary and evidence of benefit from randomised controlled trials is required. Analysis of the effect of sorafenib on disease free survival is likely to be performed in 2016. Clinical trial information: ISRCTN38934710.
Renal nephrometry score and predictors of complications in partial nephrectomies.
Authors: Pruthi Deepak K. , Drachenberg Darrel E , McGregor Thomas B
Published: February 2017

512

Background: Feasibility of partial nephrectomy for small renal masses extends beyond standard clinical tumor size. We analyze patient characteristics and anatomic tumor factors to determine variables associated with surgical complications after partial nephrectomy. Methods: Retrospective review of all patients who underwent partial nephrectomy at our institution between January 1, 2012 and Aug 31, 2013. Follow-up extended to 8 week post-operative outpatient clinic visit. The R.E.N.AL. Nephrometry score is a tumor descriptive (the maximum radius, exophytic/endophytic, nearness to collecting system/sinus, anterior/posterior position, location relative to polar line) that was applied to each pre-operative scan. Standardized grading systems and statistical analysis were applied. Results: Of the 83 patients who underwent partial nephrectomy 72 had a laparoscopic approach. Seventeen (20%) patients had complications and seven were Clavien-Dindo grade 3 to 4. Two patients had laparoscopic partial nephrectomies converted intra-operatively to radical nephrectomies; two other laparoscopic partial nephrectomies were converted to open partial nephrectomies. Forty-three (52%) of operated patients were either obese, morbidly obese, or super obese. Fifteen (18%) of patients had pathologic oncocytomas or angiomyelipomas. In univariate analysis Charlson comorbidity score (>6 p=0.0027), diabetes (42% p=0.0195), age (>70 p=0.02034), and total R.E.N.A.L. Nephrometry score (10-12, 67%, p=0.0254) were associated with complications. Nephrometry score also correlated with warm ischemic time (WIT) in laparoscopic cases (low 26 min [SD +/- 11.71], intermediate 31 min [SD +/- 7], high 34 min [SD +/- 14]). Conclusions: Categorizing renal masses according to the R.E.N.A.L. Nephrometry score may help us council patients towards expected WITs, complication rates, and predicted renal function outcomes. This is increasingly important as the majority of our patients are either obese, elderly, or have significant comorbidities; all of which have been shown to be associated with increased complication rates.