bluuebunny/crossref_metadata_2025 huggingface dataset:
Does abiraterone withdrawal syndrome (AWS) exist also in metastatic castration-resistant prostate cancer (mCRPC) first-line setting?
Authors: Maines Francesca , Caffo Orazio , Trentin Chiara , Veccia Antonello , Galligioni Enzo
Published: February 2017

344

Background: AWS is a recently phenomenon observed in mCRPC patients (pts) characterized by a PSA reduction with or without objective response after abiraterone acetate (AA) discontinuation. This syndrome has clinical features similar to antiandrogen withdrawal syndrome and was described in pts who treated with AA in the post-docetaxel setting. At the best of our knowledge, to date AWS was never described in chemo-naïve mCRPC pts. Methods: We retrospectively reviewed clinical records of mCRPC pts treated with first-line AA at our Institution. All pts were treated with AA 1,000 mg + prednisone (PDN) 10 mg po daily; the treatment was continued until progression disease (PD) which required an imaging confirmation too. After PD, we also discontinued the PDN administration. For each pt we recorded pre and post-AA clinical history, treatment details and outcomes. AWS was defined by PSA reduction ≥ 25% compared to the AA-end values observed in the first month after AA stop. Results: From September 2014, eight pts received first-line AA and, to date, 6 patients (75%) who discontinued the treatment due to PD are evaluable for AWS occurrence. We observed an AWS in 2/6 (33.3%). The first patient, a 76 year-old man, who experienced a PD after 12 wks AA treatment, had a 69% reduction in PSA with PSA dropping from 60 ng/mL to 19.47 ng/mL after about 30 days from the discontinuation. The second patient, 83 years old, treated with AA for 12 weeks, had a reduction in PSA from 112.2 ng/mL to 55 ng/mL at one-month (51% reduction) and to 35.36 ng/mL at two months (68.5% reduction) after AA and PDN discontinuation; after 9 wks the AWS is still ongoing. Conclusions: Notwithstanding the limits of the small sample size, our data shows for the first time that AWS can be observed also in mCRPC patients receiving AA as first-line treatment. Larger observations are needed to establish frequency and clinical role of this phenomenon. Although pathogenetic mechanisms and predictive factors are still unclear, AWS may represent a possibility to delay the second line start for mCRPC pts.
To assess the clinical effect of radium 223 (Ra223) in patients with progressive symptomatic bone metastases on a background of metastatic castrate resistant prostate cancer (mCRPC).
Authors: Hague Christina J. , Fisher Charlotte , Wylie James , Choudhury Ananya , Elliot Tony , Tran Anna , Coyle Catherine , Conroy Ruth , Logue John P.
Published: February 2017

347

Background: Ra223 is the first radiopharmaceutical shown in the ALSYMPCA trial to improve survival and achieve a tolerable safety profile in patients with symptomatic bone metastases. It remains unclear as to where Ra223 is best placed in the treatment pathway of CRPC. We assessed the effect of Ra223 in mCRPC in terms of biochemical and clinical response. Methods: Retrospective analysis of mCRPC patients treated with Ra223 via CDF between Dec 2013-May 2015. Clinical benefit assessed by pain response. Toxicities graded as per CTCAE V 4. Results: 58 patients, median follow up 11.6 (1.0-18.1) months. Median age 71 (54-84); median WHO PS 1 (0-2). 58 patients received 50kBq/kg, median number of cycles 5 (1-6). 43% and 33% completed 6 and 3 cycles respectively. Median number of previous treatments 3 (1-6). 52%, 17% and 5 % received prior Docetaxel, Bisphosphonates and Strontium respectively. Median time from radiotherapy for symptomatic bone metastases to initiation of Ra 223 was 433 days. Incidence of Grade (G) 3/ 4 events 5% ; 2% G3 anaemia, 3% G3 neutropenia and 0% G3 thrombocytopenia. No treatment related deaths. 5% developed a skeletal related event, mean time of development from completion of Ra223 was 218 days. Median PSA pre v post treatment was 225 and 418. Median ALP (Alkaline Phosphatase) pre v post treatment was 292 and 138. Median Hb (Haemoglobin) pre v post treatment was 118 and 103. 50% patients had a clinical response. Whilst no significant association was seen between clinical benefit and change in PSA (p 0.973) or ALP (p 0.455) across this cohort, a number of patients had a sharp increase in PSA and decrease in ALP with no clinical benefit and clinical benefit respectively. 36/58 (62%) are alive; 16/58 (44%) alive with progressive disease. Median PFS 7.23 months (95% c.i. 5.73, 7.93) and median OS 8.33 months ((95% c.i. 5.65-13.50). Conclusions: Ra223 is safe and effective in pre-treated mCRPC patients. PSA response is not clinically meaningful whereas ALP may be a useful adjunct in measuring response. The optimum sequence is yet to be defined but better selection and earlier use in patients with predominant bone only disease should be considered.
The impact of prostate cancer on overall cancer stage migration over time.
Authors: Ciezki Jay P. , Reddy Chandana A. , Klein Eric A.
Published: February 2017

35

Background: To define cancer stage migration according to year of diagnosis and type of cancer diagnosis. Methods: Cancer stage, site, and year of diagnosis information were retrieved from an academic radiation oncology center's database. The Jonckheere-Terpstra test was used to assess changes over time. Results: From 2005 to 2014, 12,807 newly diagnosed patients (pts) were seen. The distribution of pts by stage was 2% stage 0, 17% stage I, 33% stage II, 16% stage III, and 32% stage IV. The pattern of stage distribution significantly changed over time as seen in the table (p = 0.0016). For 4 of the 5 most commonly seen cancers, (female breast, lung, esophagus, head and neck, and prostate (CaP)) over time fewer late stage cancers were diagnosed or had no change in stage. The only exception was CaP, the largest number of pts (26.5% of total). In 2005, 10.76% of new CaP cases presented with stage IV disease, dipped to 4.6% in 2011, and rose to 8.47% in 2014 (p < 0.0001). The changes in stage I definition accounted for the increase seen in stage I disease, but could not account for the dip and subsequent increase in stage IV disease. Conclusions: The presentation of cancer by stage has changed over time, and it was predominately driven by CaP. The changes seen in stage IV CaP incidence in which it fell and then rose over the study period suggests that global practice changes may be present. An increased preference for active surveillance, recommendations against PSA screening, and increasing insurance deductibles may have favored a delay in treating/diagnosing CaP pts in the recent past. [Table: see text]
Examination of current Algoma District cancer program practices and local referral processes for patients with prostate cancer.
Authors: Febbraro Daniella , Spadafora Silvana
Published: February 2017

352

Background: The Algoma District Cancer Program (ADCP) is located in Sault Ste. Marie, ON, Canada and services the needs of the 125,000 individuals residing in the Algoma District, which has an area of approximately 49,000 square kilometres. Due to its geographic isolation in Northern Ontario, maintaining standards of care can be challenging to deliver. The objective of this project is to document any improvements in the referral process and treatment of patients with prostate cancer at the ADCP since the arrival of new medical oncologists in July 2013. Methods: Patients who had been seen by a medical oncologist at ADCP from July 2013 to July 2015 were included in this study. Patient charts were analyzed in order to gather information including date of diagnosis, stage at time of referral, date of consult with medical oncologist, previous treatments trialed, and dates of treatment. Patients were divided into two groups, diagnosed prior to 2014 and after 2014, to examine progress at ADCP. Results: From July 2013 to July 2015, there were 73 patients seen by a medical oncologist at ADCP with a diagnosis of prostate cancer. Of these patients, 54 were diagnosed prior to 2014 and 19 were diagnosed after 2014. For all patients diagnosed prior to 2014, the average number of years from diagnosis to a medical oncology consult was 5.24 years, with the longest being 19 years for two patients. In comparison, for all patients diagnosed after 2014, a medical oncologist saw them only 0.26 years on average after they were diagnosed. Since 2014, lines of therapy administered after referral to medical oncology have become greater than before 2014. Specifically for stage IV prostate cancer patients, the average number of lines of therapy ordered by a medical oncologist has increased for patients diagnosed after 2014. Conclusions: Since the arrival of new medical oncologists at ADCP in July 2013, the average number of years after diagnosis that a patient is referred to the clinic has decreased, while the average lines of therapies utilized after their consult with a medical oncologist has increased, showing an improvement in both referral processes and adherence to standard guidelines in the treatment of prostate cancer patients.
Quality of life outcomes after neobladder and ileal conduit following cystectomy for bladder cancer using a validated bladder-specific instrument: A prospective multi-institutional study.
Authors: Irani Jacques , Nicolas Gaunez , Huyghe Eric , Roupret Morgan , Briffaux Raphael , Larre Stephane , Pfister Christian , Mottet Nicolas , Neuzillet Yann
Published: February 2017

359

Background: Cystectomy followed by urinary diversion impacts significantly patients' quality of life. The aim of this study was to evaluate health-related quality of life of patients who had neobladder or ileal conduit. Methods: Eight centers participated in this prospective study that included consecutive patients. They had to complete the validated self-administered Bladder Cancer Index (BCI) and a Visual Analogic Score (VAS) preoperatively and at 6 and 12 months postoperatively. The primary outcome measure was the diversion satisfaction (VAS) at 12months. Results: Between May 2012 and November 2013 the study was proposed to 106 patients of whom 95 gave their informed consent and 71 completed their pre-operative questionnaires. No patient had neo-adjuvant chemotherapy. Patients' peri-operative characteristics by diversion procedure are reported in the table. Baseline urinary, bowel, sexual function, and body image were not different between both groups. At month 6, 58 patients completed their questionnaires (Ileal conduit 30; Neobladder 18) showing significant differences in favor of the neobladder group for body image, urinary pain (mostly because of stoma problems) and constipation, but on the other hand the ileal conduit group reported a better urinary control and less leaks (day and night). At month 12, 34 patients completed their questionnaires (Ileal conduit 19; Neobladder 15). The findings were similar to those of month 6. All patients reported a poor sexual life and the related lack of satisfaction. VAS assessing diversion overall satisfaction was not different between the groups at the 6th and the 12th month. Conclusions: Even if the results of this prospective non randomized study reflect partly the age difference between groups, they clearly show an advantage for the neobladder regarding body image and an advantage for ileal conduit regarding urinary control. In both groups, overall self-assessed satisfaction of the diversion was excellent. [Table: see text]
The risk-based STHLM3 model to improve prostate cancer testing in men 50-69 years: Further health, economic, and clinic evaluation.
Authors: Gronberg Henrik , Adolfsson Jan , Aly Markus , Nordström Tobias , Wiklund Peter , Brandberg Yvonne , Thompson James , Wiklund Fredrik , Lindberg Johan , Clements Mark , Egevad Lars , Eklund Martin
Published: February 2017

36

Background: Prostate-specific antigen (PSA) is used to screen for prostate cancer but suffers from a high false-positive rate that translates into unnecessary prostate biopsies and over-diagnosis of low-risk prostate cancers. We aimed to develop a model for prostate cancer screening with better test characteristics than PSA. Methods: STHLM3 is a prospective, population-based, paired screen-positive diagnostic study. It investigates whether the predefined STHLM3 model, a combination of 6 plasma protein biomarkers (PSA, free-PSA, intact-PSA, HK2, MIC-1, and MSMB), genetic polymorphisms (232 SNPs), and clinical variables (age, family history, previous biopsies, DRE, and prostate volume) can substantially reduce the proportion of men biopsied while maintaining the same sensitivity to diagnose Gleason score ≥ 7 prostate cancer as PSA ≥3 ng/ml. In addition, a health economic evaluation was performed comparing the STHLM3 model with current clinical practice in Stockholm. Results: 58,818 men without prostate cancer aged 50-69, participated in the STHLM3 study, with 6,700 undergoing subsequent prostate biopsy. The STHLM3 model performed significantly better (p<0.001) than PSA for detecting GS ≥7 cancers, increasing the Area Under the Curve from 0.56 to 0.74. All variables used in the STHLM3 Model were significantly associated with Gleason score ≥7 prostate cancers (p<0.05) in a multiple logistic regression model. Using the same sensitivity as PSA ≥3 ng/ml to diagnose Gleason score ≥7 prostate cancer, the STHLM3 model reduced the number of biopsies by 32% (95% CI 24%-39%) and avoided 44% (95% CI; 35%-54%) of the negative biopsies. The number of Gleason score 6 cancers was reduced by 17% (95% CI; 7%-26%). Positive ICER for the STHLM3 model was seen in all models of the health economic analysis. Conclusions: The STHLM3 model reduces unnecessary biopsies without compromising the ability to diagnose Gleason score ≥7 prostate cancer in a cost-efficient way. This is a significant step towards personalized risk-based prostate cancer diagnostic programs. Clinical trial information: ISRCTN84445406.
Patterns of failure after radical cystectomy for pT3-4 bladder cancer: Implications for adjuvant radiation therapy.
Authors: Reddy Abhinav V. , Pariser Joseph J. , Pearce Shane M. , Weichselbaum Ralph R. , Smith Norm D. , Steinberg Gary D. , Liauw Stanley L.
Published: February 2017

370

Background: In patients with muscle-invasive bladder cancer, local-regional failure (LF) has been reported to occur in up to 20% of patients following radical cystectomy. The goals of this study were to describe patterns of LF, as well as assess factors associated with LF in a cohort of patients with pT3-4 bladder cancer. This information may have implications towards the use of adjuvant radiation therapy. Methods: Patients with pathologic T3-4 N0-1 bladder cancer were examined from an institutional radical cystectomy database. Preoperative demographics and pathologic characteristics were examined. Outcomes included overall survival and LF. Local-regional failures were defined using follow-up imaging reports and scans, and the locations of LF were characterized. Variables were tested by univariate and multivariable analysis for association with LF and overall survival. Results: 334 patients had pT3-4 and N0-1 disease after radical cystectomy and bilateral pelvic lymph node dissection. Of these, 46% received perioperative chemotherapy. The median age was 71 and median follow up was 11 months. On univariate analysis, margin status, pT stage, pN stage, and gender were all associated with LF (p < 0.05), however, on multivariable analysis, only pT and pN stage were significantly associated with LF (p < 0.01). Three strata of risk were defined, including low-risk patients with pT3N0 disease, intermediate-risk patients with pT3N1 or pT4N0 disease, and high-risk patients with pT4N1 disease, who had 2-year incidence of LF of 12%, 33%, and 72%, respectively. The most common sites of pelvic relapse included the external/internal iliac LNs and obturator LN regions. Notably, 34% of patients with LF had local-regional only disease at the time of recurrence. Conclusions: Patients with pT4 or N1 disease have a 2-year risk of LF that exceeds 30%. These patients may be the most likely to benefit from local adjuvant therapies.
Neoadjuvant gemcitabine and carboplatin followed by immediate radical cystectomy for muscle-invasive bladder cancer patients ineligible for cisplatin-based chemotherapy: A propensity score-matched analysis.
Authors: Koie Takuya , Ohyama Chikara , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro
Published: February 2017

375

Background: Standard neoadjuvant chemotherapy has not yet been established for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin (CDDP)-based chemotherapy. We conducted a propensity score analysis to evaluate the clinical significance of neoadjuvant gemcitabine and carboplatin (GCarbo) chemotherapy for CDDP-ineligible patients with MIBC. Methods: We enrolled 381 patients with MIBC, and retrospectively compared two cohorts of CDDP-ineligible patients with MIBC. The GCarbo cohort consisted of 63 patients, who received 2 courses of GCarbo consisting of 800 mg/m2 gemcitabine on days 1, 8, and 15 and carboplatin with an area under the curve of 4 on day 2, prior to RC. The RC alone cohort consisted of 56 patients receiving RC without neoadjuvant or adjuvant chemotherapy. The endpoints were overall (OS), cancer-specific (CSS), and disease-free survival (DFS). The oncological outcomes were analyzed using log-rank test and multivariate Cox regression model. Results: Propensity score-matched analysis indicated 56 matched pairs from both groups. The 3-year OS rates were 77.9% for the GCarbo cohort and 50.7% for the RC alone cohort (P = 0.002). The 3-year CSS rates were 92.8% for the GCarbo cohort and 52.6% for RC alone group (P < 0.001). The 3-year DFS rates were 80.6% for the GCarbo cohort and 48.1% for the RC alone cohort (P = 0.005). Multivariate analysis revealed that GCarbo was an extremely strong predictor of improved survival. Conclusions: Although the present study is non-randomized, neoadjuvant GCarbo chemotherapy followed by immediate RC significantly improved OS, CSS, and DFS in CDDP-ineligible MIBC patients.
Blue-light cystoscopy’s effects on management of bladder cancer when compared to traditional white-light cystoscopy.
Authors: Mount Andrew , Williams Stephen Bentley , Dinney Colin P. N. , Grossman H. Barton , Pettaway Curtis Alvin , Chapin Brian Francis , Navai Neema , Matin Surena F. , Graber William F. , Kamat Ashish M.
Published: February 2017

378

Background: Fluorescence cystoscopy (also known as blue-light cystoscopy (BL)) is an adjunct to white light cystoscopy (WL) and aids in visualization of tumors that may be missed with WL as well as allow more complete resection of tumors. Herein we present the impact of BL on subsequent patient management in a real world setting. Methods: A total of 116 consecutive patients who underwent simultaneous BL and WL from January 2013 through December 2014 were included in the study. Pathology and operative reports were reviewed to determine the grade and stage of the tumors and whether they were viewed under BL or WL. Results: Of the 116 patients, a total of 161 biopsies and/or transurethral resected specimens were analyzed. Of these, 46 (28.6%) lesions were seen only with BL, none were seen only with white light, 109 (67.7%) were seen with both, and 7 (4.4%) were identified via random biopsies. Of the 46 lesions seen only on BL, 17 (37%) were positive for cancer, while, of the 109 lesions seen with WL and BL, 84 (77%) were positive. Of the 17 (37%) true positive tumors seen only on BL, the stage and grades were; 5 (29.4%) low-grade Ta, 2 (11.8%) high-grade Ta, 1 (5.9%) high-grade T1, and 9 (52.9%) CIS. There were no instances of a tumor being found on WL that was not also visualized with BL. In this patient cohort, the false positive rates were 23% and 63% for WL and BL, respectively. The false negative rates were 0.9% and 2.1% for WL and BL, respectively. For the 46 (28.6%) lesions that were visible by BL, WL cystoscopy was not able to visualize 10 (21.7%) tumors visualized by BL. In addition, there was one patient who had multiple lesions sent for pathology by BL and WL, and the lesions identified by BL were of higher stage than the lesions visualized by WL. Conclusions: BL identified additional tumors that would have been missed with WL. Moreover, in patients who had tumors visualized only with BL, 11 (26.8%) were high-grade, including one (2.4%) patient with T1 tumor and 8 (19.5%) with CIS. Thus, BL identified a number of high-risk tumors, which had a significant impact on the subsequent management of patients with bladder cancer.
Integrated whole exome and RNA sequencing to reveal distinct genomic and transcriptomic landscape of upper tract urothelial carcinoma.
Authors: Faltas Bishoy , Bareja Rohan , Beltran Himisha , Cyrta Joanna , Rai Manoj Ponadka , Tagawa Scott T. , Nanus David M. , Mosquera Juan Miguel , Sboner Andrea , Scherr Douglas , Elemento Olivier , Robinson Brian D. , Rubin Mark A.
Published: February 2017

379

Background: Upper tract urothelial carcinoma (UTUC) represents up to 10% of all urothelial carcinoma (UC). UTUC is a lethal malignancy, with nearly one half the patients dying within 5 years. Our objective was to understand the biological differences between UTUC and bladder UC.Methods: Fresh frozen chemotherapy-naïve primary tumors from nephroureterectomy cases and corresponding germline samples underwent whole exome sequencing (WES) and RNA sequencing (RNAseq). The Cancer Genome Atlas (TCGA) WES and RNAseq raw data was reanalyzed through our in-house bioinformatic pipeline to compare the mutational and transcriptomic landscape of UTUC to bladder UC. We evaluated the expression values for a set of 40 housekeeping genes between the two different datasets to exclude batch effects. We used gene set Enrichment Analysis (GSEA) to identify differentially enriched pathways in UTUC.Results: 17 tumors underwent WES, 20 RNAseq, with 11 analyzed for both WES and RNAseq. UTUC samples harbored several recurrent mutations including PIK3CA (4/17), FGFR3 (2/17), MLL2 (4/17), MLL3 (2/17), ATM 2/17). Three KRAS mutations were discovered in two patients (G12D, G12V and Q61H), which were confirmed by targeted sequencing. Frequent copy number alterations included CDKN2A/B deletions (3/17), BG4ALT3, SEMG1 and USP6 amplifications (2/17 each). GSEA analysis revealed significant enrichment of the KRAS signaling in UTUC whereas bladder UC showed an enrichment of genes involved in mTOR and E2F signaling. There were significant differences in the expression of several key DNA damage repair (DDR) pathway genes between the two entities including TP53, RAD51 and ERCC4 despite infrequent or absent mutations in these genes (q value 0.03 for DDR gene set). MSH5, a gene associated with cisplatin-resistance was the most highly ranked DDR overexpressed gene in UTUC compared to bladder UC (enrichment score = 0.8).Conclusions: This study generates a detailed genomic and transcriptomic profile of UTUC. RNAseq demonstrated a distinct pattern of DDR pathway expression in UTUC independent of genomic alterations; these findings may have important implications for platinum-based chemotherapy.
Baseline GFR and cisplatin-induced renal toxicity in urothelial cancer patients.
Authors: Tran Adrienne , Loh Janice , Ji Lingyun , Daneshmand Siamak , Schuckman Anne K. , Groshen Susan G. , Quinn David I. , Dorff Tanya B.
Published: February 2017

380

Background: Cisplatin eligibility for clinical trials has been defined as calculated GFR > 60 mL/min due to risk of nephrotoxicity in patients (pts) with renal impairment. For urothelial cancer (UCa), substitution of cisplatin compromises outcomes. We evaluated change in GFR in pts treated with cisplatin despite baseline GFR < 60 to determine risk of nephrotoxicity. Methods: 150 USC pts were identified who received systemic therapy for UCa from 2009 to 2014. Creatinine and weight values closest to treatment start and finish were used for calculation of GFR using the Cockcroft-Gault formula. Wilcoxon rank-sum tests and analyses of variance (ANOVA) were used to compare GFR percent change by age ( < 75 vs > 75 years), pre-treatment GFR ( < 60 vs > 60), therapy setting (neoadjuvant, adjuvant, or metastatic), primary disease site, and comorbidities (diabetes, hypertension, hyperlipidemia). Log-rank tests and Cox regression models were used to examine the association between overall survival (OS) and age or GFR. Results: 114 received cisplatin-based therapy at least once; 26 in the neo-adjuvant setting, 27 adjuvant, and 61 for metastatic disease. GFR could be calculated pre- and post-treatment for 81 pts; lowest GFR in pt receiving cisplatin was 25.5 mL/min. Median GFR change was -1.6% (range: -50% ~ 49%) for pts with pre-treatment GFR < 60 compared to -10.9% (range -72%, 135%) for pts with pre-treatment GFR > 60 (p = 0.17). Treatment setting (neo-adjuvant, adjuvant, or metastatic) had significant association with GFR change (p = 0.027). Median (range) of GFR change for the neo-adjuvant setting, adjuvant setting and metastatic setting was 4.6% (95% CI -32%, 90%), -5.8% (95% CI-39%, 20%), -11.9% (95% CI -72%, 135%), respectively. Age, primary disease site, diabetes, hypertension and hyperlipidemia were not associated with GFR change. Univariate analysis showed an association between GFR > 60 at stop of treatment with worse OS (p = 0.087) in metastatic pts. Conclusions: Our data support the hypothesis that UCa pts with GFR < 60 do not experience a greater decline in renal function after cisplatin treatment compared to patients with GFR > 60. If validated, this may extend the option of cisplatin-based therapy to previously ineligible pts.
A phase 2 study of the Aurora A kinase (AAK) tyrosine kinase inhibitor (TKI) alisertib (MLN8237) in patients (pts) with pretreated urothelial cancer (UC).
Authors: Necchi Andrea , Raggi Daniele , Lo Vullo Salvatore , Mariani Luigi , Giannatempo Patrizia , Calareso Giuseppina , Togliardi Elena , Nicolai Nicola , Perrone Federica , Pelosi Giuseppe , Salvioni Roberto , De Braud Filippo G.
Published: February 2017

382

Background: Progress in developing effective salvage therapies for UC is warranted. AAK overexpression has been described in UC and spindle checkpoint (SC) dysregulation is a common feature. Alisertib is an orally available, selective TKI of AAK. Methods: A single-group, Ph2 trial was conducted with Alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT01653028). The primary endpoint was RECIST 1.1 objective response-rate (ORR), and ≥ 3/20 responses were required (H0 ≤ 5%, H1 ≥ 20%, α = 5%/β = 20%) to move to a randomized trial of paclitaxel plus either Alisertib or placebo. Eligibility included failure of ≤ 2 platinum-based regimens. Cox regression analyses were done. Targeted sequencing of pts is being performed through the Ion AmpliSeq Comprehensive Cancer Panel (Life Technologies). Results: From 10/2014 to 04/2015, 22 pts were enrolled (20 evaluable for response), 8 (36.4%) in 2nd line and 14 (63.6%) > 2ndline. 8 (36.4%) had an ECOG-PS 1-2, 3 (13.6%) had Hb < 10mg/dl, 9 (40.9%) had liver metastases. 2 PR (ORR: 10%), 7 stable disease (SD) and 11 PD were recorded. Median FUP was 6.3 mos (IQR: 4.5-8.0). 6m-PFS was 18.2% (95%CI: 7.5-44.1), including 2 pts with 9.7 and 9.5 mos FUP (still ongoing, both > 2nd line). Median PFS was 1.8 mos (IQR: 1.3-3.4), but median OS was not reached (6m-OS: 63.6%, 95%CI: 46.4-87.3). Hb < 10gr/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). AAK-IHC expression did not correlate with outcome. Tissue of pt with 9.7 month SD harbored a missense mutation of mTOR (E1813D*) and the nonsense mutation Q527STOP* of TSC1, together with HER3 and TAF1Lmissense mutations. Grade 3-4 adverse events (AE) were: 54.5% alopecia, 41% mucositis, 36.4% fatigue, 18% neutropenia (14% febrile neutropenia). There were 2 treatment-related deaths (septic shock). Conclusions: Preliminary data suggest the possibility for sustained disease control in about 20% of pts, including very long term PR/SD. Hb ≥ 10 and mutations of TSC1/mTOR (TAF1L?) might be the clinical and biological markers for patient enrichment design with SC inhibitors like Alisertib, although the incidence of AE is a major concern. Clinical trial information: NCT01653028.
Impact of prior platinum on patients receiving salvage systemic therapy for advanced urothelial carcinoma (UC).
Authors: Sonpavde Guru , Pond Gregory Russell , di Lorenzo Giuseppe , Buonerba Carlo , Rozzi Antonio , Lanzetta Gaetano , Necchi Andrea , Giannatempo Patrizia , Raggi Daniele , Matsumoto Kazumasa , Choueiri Toni K. , Mullane Stephanie A. , Niegisch Guenter , Albers Peter , Lee Jae-Lyun , Kitamura Hiroshi , Kume Haruki , Bellmunt Joaquim
Published: February 2017

386

Background: Trials of salvage therapy for advanced UC have required prior platinum-based therapy. This practice requires scrutiny since non-platinum-based first-line therapy may be offered to cisplatin-ineligible patients (pts). We examined the impact of prior exposure to first-line platinum vs. non-platinum based chemotherapy on overall survival (OS) with salvage systemic chemotherapy. Methods: Data of pts receiving salvage systemic chemotherapy were collected retrospectively or from trials. Data on prior first-line platinum exposure were required in addition to the known prognostic factors: treatment free interval, hemoglobin, performance status, albumin and liver metastasis status. Cox proportional hazards regression was used to evaluate their association with OS after accounting for salvage therapy with single agent chemotherapy or combination chemotherapy. Results: Data was obtained from 455 pts exposed to prior platinum and 37 pts not exposed to prior platinum. In the group exposed to prior platinum, salvage therapy consisted of a single agent taxane (n = 184) and taxane containing combination chemotherapy (n = 271). In the group not exposed to prior platinum, salvage therapy consisted of single agent taxane or vinflunine (n = 20), single agent 5-fluorouracil (n = 1), taxane containing combination chemotherapy (n = 12), carboplatin-based combinations (n = 2) and cisplatin-based combinations (n = 2). The median OS for the prior platinum group was 7.8 (95% CI: 7.0, 8.1) months (mo), and for the prior non-platinum group was 9.0 (6.0, 11.0) mo (p = 0.50). In a multivariable analysis including major prognostic factors and after controlling for single agent or combination salvage chemotherapy, prior platinum vs. no prior platinum exposure conferred no independent impact on OS (HR 1.10 [0.75, 1.64], p = 0.62). Conclusions: Prior platinum vs. non-platinum based chemotherapy did not confer a prognostic impact on OS after accounting for major prognostic factors in pts receiving salvage systemic chemotherapy for advanced UC. Lack of exposure to prior platinum should not disqualify pts from inclusion in trials of salvage therapy after accounting for the 5 known prognostic factors.
Impact of tumor location on local recurrence after nephroureterectomy for upper tract urothelial carcinoma: Implications for adjuvant radiotherapy.
Authors: Yoo Sangjun , You Dalsan , Jeong In Gab , Song Cheryn , Hong Bumsik , Hong Jun Hyuk , Ahn Hanjong , Kim Choung-Soo
Published: February 2017

390

Background: To date, risk factors for local recurrence after complete removal of upper tract urothelial carcinoma (UTUC) have not been clearly identified. We evaluated the impact of tumor location on local recurrence in UTUC patients underwent radical nephroureterectomy. Methods: Among UTUC patients who underwent radical nephroureterectomy between 1998 and 2012, 192 (54.4%) patients with renal pelvic tumor and 161 (45.6%) patients with ureter tumor were included. Local recurrence was divided into regional lymph node recurrence (LNR) and surgical bed recurrence (SBR). The significance of tumor location and other variables on local recurrence were evaluated. Results: Lymphovascular invasion (p = 0.003), carcinoma in situ (p = 0.006) and high grade tumor (p < 0.001) were more common in ureter tumor. During median follow-up period of 73 months, local recurrence was occurred in 33 (9.3%) patients. Among subtype of local recurrence, SBR (8.1 vs. 2.1%, p = 0.011) were more common in patients with ureter tumor compared to renal pelvic tumor although the probability of regional LNR was not significantly different according to tumor location (7.5% vs. 3.1%, p = 0.088). 5-year local recurrence-free survival (80.5% vs. 94.2%, p = 0.002), LNR-free survival (89.8 vs. 96.5%, p = 0.046) and SBR-free survival (88.3% vs. 97.6%, p = 0.005) were inferior in ureter tumor compared to renal pelvic tumor. Ureter tumor (HR; 2.552, p = 0.017), high grade tumor (HR; 3.064, p = 0.016) and advanced tumor stage (≥T3) (HR; 3.236, p = 0.002) were associated with local recurrence. Ureter tumor (HR; 4.704, p = 0.002) and advanced tumor stage (HR; 4.840, p = 0.006) were risk factors for SBR. However, tumor location was not associated with LNR although lymphovascular invasion (HR; 5.451, p < 0.001) and high grade tumor (HR; 4.191, p = 0.012) were related with LNR. Conclusions: Ureter located tumor was associated with local recurrence which comes from the SBR. Adjuvant radiotherapy or surgical technique for reducing the risk of SBR should be considered in patients with ureter tumor.
Metastatic bladder neoplasms treated with stereotactic body radiosurgery.
Authors: Lederman Ariel Joseph , Loksen Mordecha , Lowinger Thomas , Izon Daniel , Lederman Gilbert S.
Published: February 2017

397

Background: Stereotactic Body Radiosurgery (SBR) as treatment for metastatic bladder cancer delivers high dose radiation precisely to the site of cancer. In our prospective data analysis, 20 sites of extravesical bladder cancer treated with SBR were analyzed. Methods: Twenty metastatic bladder neoplasms were treated in 15 patients. Sixteen were transitional cell carcinoma, 2 adenocarcinoma, 1 squamous cell carcinoma, and 1 rhabdomyosarcoma. Ages ranged from 39 to 82 years (mean 64) with 4 females and 11 males. Tumor volumes ranged from 10.2 to 563 cc (mean 129.8 cc). Patients were treated with 500-900 cGy (median 800) in 5-8 fractions (median 5) for a total dose of 3000-4500 cGy (median 4000). Cancers were radiographically evaluated with contrast CT and/or MRI studies and reviewed independently by radiologists. Disease control is defined as cessation of growth, shrinkage or disappearance of the tumor after treatment. Results: Follow-up ranged from 1 to 20 months (mean 8 months). The overall control rate was 90%. Both patients who did not respond to treatment were males with transitional cell carcinoma. By dose, volume, age, sex and prior treatment, there was no statistically significant difference in outcome among the 20 patients treated. Conclusions: SBR for metastatic bladder cancer offers a well-tolerated, non-invasive technique with a high rate of tumor control. Patients continue to be evaluated for longer follow up, possible benefits of local control and potential survival advantage. SBR remains an option for those whom standard approaches have not produced desired results or in patients seeking an alternative to surgical or chemotherapeutic treatment.
NBI-assisted cystoscopy to improve follow-up of patients with transitional cell carcinoma of the bladder.
Authors: Eisenhardt Andreas , Hirner Lucas , Ruebben Herbert
Published: February 2017

400

Background: Narrow Band Imaging (NBI) is a new technique of urethrocystoscopy, in which only a certain bandwidths of illumination (415 (blue) and 540nm (green)) of the spectrum is used to detect urothelial carcinoma. The aim of the investigation was to analyse the potential benefit of NBI in the follow up of patients with transitional cell carcinoma of the bladder. Methods: In the time between August 2013 until August 2014, patients with history of transitional cell carcinoma of the bladder, who presented for follow-up cystoscopy , were either examined via flexible white light endoscopy [WLE] plus second look WLE (n = 317, controls) or second look NBI-cystoscopy alone (n = 308) in the same session. Results: Rates of recurrences were similiar in both groups (NBI 95 (25%); WLE 85 (26.8%)). NBI after WLE identified more tumours in 21 patients (6.1 vs. 3.81). In 9 patients NBI showed no vascularization in suspicious areas. In the control arm, in 9 cases more tumours (4,67 vs. 3.33) were identified in the second WLE. After macroscopical identification of a recurrence, the time since the last resection was measured (WLE 10,67 months, NBI 16,85 months). Conclusions: While the number of patients with recurrent bladder cancer is not influenced by the use of NBI, the additional use of NBI in the follow-up cystoscopy of patients after transurethral resection of superficial bladder cancer (TUR) leads to an increased number of detected tumors. A part of the additionally detected tumors can be explained by the double examination. In addition NBI appears to provide a hint in individual cases whether a TUR is necessary at all.
Development and validation of contouring guidelines for post-cystectomy adjuvant radiation of bladder cancer.
Authors: Baumann Brian C. , Bosch Walter , Bahl Amit , Birtle Alison J. , Breau Rodney H. , Challapalli Amarnath , Chang Albert , Choudhury Ananya , Daneshmand Siamak , Feldman Adam S. , Guzzo Thomas J. , Hilman Serena , Jani Ashesh B. , Malkowicz S. Bruce , Master Viraj A. , Mitra Anita , Porten Sima P. , Efstathiou Jason A. , Eapen Libni , Christodouleas John Paul
Published: February 2017

409

Background: Several organizations are developing clinical trials to evaluate adjuvant radiotherapy (RT) for bladder cancer patients at elevated risk of locoregional failure (LF). However, the clinical target volumes (CTVs) & organs at risk (OARs) for this treatment have not been defined in detail. Our purpose was to define multi-institutional consensus CTVs & OARs for male & female bladder cancer patients undergoing adjuvant RT in clinical trials. Methods: We convened a multi-disciplinary group of bladder cancer specialists from 9 centers in 3 countries. 5 radiation oncologists (ROs) & 7 urologists participated in the development of the proposed contours. The group proposed initial language for the CTVs & OARs and contoured them on CT scans of a male & female cystectomy patient with input from ≥ 1 urologist at each center. Using the binomial maximum-likelihood estimates method, we generated 95% level initial contours. We evaluated the contours for level of agreement using the Landis & Koch interpretation of the K statistic. Based on the initial contouring, the group updated its descriptions of the CTVs & OARs. To determine if the revised language produced consistent contours, the cystectomy bed (CB) contour was redrawn on the CT sets by an additional 5 ROs. Results: The group proposed that patients at elevated risk for LF with R0 resections should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac & presacral) whereas patients with ≥ R1 resections should be treated to the pelvic nodes & CB. The group proposed the rectum, bowel space, bone marrow & urinary diversion as OARs. The level of agreement for the initial CTVs & OARs from the group varied substantially (Table). Consensus language to describe CTV & OAR structures where the initial contours varied was successfully developed. Contours & feedback from the validation group are being analyzed. Conclusions: Initial descriptions of CTVs & OARs have been successfully developed. External validation & feedback are pending. The results will be applicable to clinical trials of adjuvant RT in bladder cancer. [Table: see text]
Safety and efficacy of combination therapy with low-dose gemcitabine, paclitaxel, and sorafenib in patients with cisplatin-resistant urothelial cancer.
Authors: Miyata Yasuyoshi , Ohba Kojiro , Matsuo Tomohiro , Sakai Hideki
Published: February 2017

418

Background: Various chemotherapeutic regimens have been examined. However, there is no effective regimen, and some studies have been stopped because of severe adverse events. Therefore, maintenance of quality of life is also important. This study examine the anti-cancer effects, changes in the quality of life (QoL), and safety of combined therapy of low dose gemcitabine, paclitaxel, and sorafenib in these patients. Methods: Twenty patients were treated with gemcitabine (700 mg/m2 on day 1), paclitaxel (70 mg/m2 on day 1), and sorafenib (400 mg/day on days 8–22). QoL and pain relief were evaluated using the short-form survey (SF)-36 and the visual analogue scale (VAS). Data on QoL and pain were collected on the day before the first cycle was started and 8 weeks after starting the therapy. A total of 124 cycles were administered and the median (IQR) number of treatment cycles per patient was 5 (3–8) cycles. Results: Among 20 patients, 12 and 8 patients were received as 2nd- and 3rd-line therapy, respectively. In 2nd-line therapy, median / interquartile range of VAS scores after therapy (2 / 2–3) significantly decreased (p = 0.012) compared to their pretreatment levels (3 / 2–5). Likewise, a significant decrease was also found in 3rd-line therapy (5/ 4–6 to 3/ 2–3, p = 0.028). Similar findings were confirmed by the bodily pain score from the SF-36 survey. A decrease in analgesic consumption was seen in three patients (17.6%), and 2 patients (11.8%) was improved the pain without increasing the dose. Complete responses, partial responses, and stable disease were found in 0 (0.0%), 1 (5.0%), and 13 patients (65%), respectively. The period of overall survival after starting of this therapy was 7 (5–11) months. Three patients (15.0%) stopped therapy because of grade 3 fatigue and hand-foot reactions. Conclusions: Combined therapy of low dose gemcitabine, paclitaxel, and sorafenib was well tolerated. QoL was maintained and improvements in their pain levels were found after treatment. We suggest that this treatment regimen is worthy of consideration as 2nd- and 3rd-line therapy for patients with CDDP-resistant UC. Clinical trial information: 000010957.
Treatment of urinary bladder cancers by growth hormone-releasing hormone antagonists: A preclinical report.
Authors: Rick Ferenc G. , Popovics Petra , Block Norman L. , He Jinlin , Zhang Xian Yang , Vidaurre Irving , Szepeshazi Karoly , Schally Andrew V.
Published: February 2017

433

Background: Urinary bladder cancer is the fifth most frequent cancer diagnosed and among the most expensive cancers to treat in the United States. The management of muscle-invasive tumors presents a clinical challenge because of the toxicity and limitations in efficacy and durability of current therapeutic modalities. Novel therapeutic strategies for this disease are of paramount importance. Growth hormone-releasing hormone (GHRH) receptors and its splice variant were detected in a series of urothelial malignancies and GHRH has been shown to influence the growth of these tumors. Herein we evaluated the effect of GHRH antagonists on the growth of various experimental human urinary bladder cancers in vitro and in vivo in nude mice. Methods: We investigated the effects of several GHRH antagonists MIA 602, MIA 606 and MIA 690 on growth of urothelial HT-1376, J82, and RT-4 tumors xenografted into nude mice. The presence of GHRH receptors was validated by Western blotting. Results: The receptors for GHRH and their main splice variant, SV1, were detected in tumor samples of all 3 human bladder cancer models. In the HT-1376 tumors, the GHRH antagonists caused a 30-60% reduction in volume and 52-70% decrease in tumor weights (p < 0.05). All three antagonists strongly inhibited growth of J82 cancers as shown by a 62-75% reduction in tumor volume and 54-66% decrease in tumor weights (p < 0.05). Treatment with MIA-602 and MIA-606 resulted in a similar marked inhibition of growth of RT-4 cancers; tumor volume and weights were reduced by about 51-71% in the treated groups (p < 0.05). The mice tolerated this therapy well; body and organ weights were not significantly changed by the treatments. No toxicity from the GHRH antagonists was noted. Conclusions: We demonstrated the efficacy of potent GHRH antagonists and their lack of toxicity in inhibiting the growth of experimental models of bladder cancer in vivo. The expression of GHRH receptors was detected in all 3 models of human primary urothelial bladder carcinomas. Our findings warrant further development of GHRH antagonists for clinical therapy of bladder cancer alone or in combination with current chemotherapeutic agents and Exploration of their mechanism of action.
The clinical impact of routine bladder biopsy after BCG treatment of high grade non muscle invasive bladder cancer.
Authors: De Jong Igle J. , Jonker Leonie Theresa , Weerink Maud Anne Sien , Cornel Erik Bastiaan , Luijendijk Daphne , Leliveld Anna Maria
Published: February 2017

438

Background: The need for invasive and costly routine bladder biopsies after an induction course of intravesical Bacillus Calmette-Guérin (BCG) in patients with high-grade non-muscle invasive bladder cancer is being questioned. Previous studies focused on differences in tumor detection between cystoscopic, cytologic and histologic results, whereas the clinical impact was disregarded. The aim of this study is to determine the impact of routine bladder biopsies on treatment. Methods: This retrospective multicenter trial included 348 patients from four hospitals in the Netherlands, who had had their BCG therapy evaluated by routine bladder biopsies between 2005 and 2014. The results of urethrocystoscopy (UCS) and/or cytology were compared to pathology outcomes. The influence of malignancies missed by UCS and/or cytology on further treatment was analyzed in 348 patients and in subgroups of patients with and without carcinoma in situ (CIS). A number needed to test was calculated. Secondary outcomes were costs and complications. Results: In patients with a normal UCS, malignancies were detected in 27/228 (11,8%), 19/136 (14%) and 8/92 (8,7%) in respectively all patients, patients with CIS and patients without CIS. This resulted in a radical cystectomy in only six (2,6%) patients, of which five (3,7%) with and one (1,1%) without CIS. Thirty-eight patients with a normal UCS have to undergo routine biopsies to effect therapeutic treatment in one (Number needed to test, NNT = 38). Estimated costs of one change of treatment are $81.300 USD(€72.818). Twenty-three of 348 (6,6%) transurethral biopsies were complicated. Conclusions: Considering the small clinical impact and high costs, routine bladder biopsies to evaluate BCG-induction are not recommended. The decision to perform bladder biopsies should be based on cystoscopic and cytologic results.