bluuebunny/crossref_metadata_2025 huggingface dataset:
Testosterone replacement therapy in men with prostate cancer after proton therapy.
Authors: Bryant Curtis , Hoppe Bradford S. , Mendenhall Nancy P. , Henderson Randal H. , Nichols Romaine Charles , Morris Christopher G. , Williams Christopher R. , Su Zhong , Li Zuofeng , Mendenhall William M.
Published: February 2017

208

Background: Testosterone replacement therapy (TRT) in patients previously treated for prostate cancer is controversial. We analyzed biochemical relapse and sexual function in patients treated for prostate cancer with proton therapy (PT) at our institution who were later treated with TRT for hypogonadism. Methods: We reviewed the medical records of 27 patients with biopsy-proven, localized prostate cancer treated with definitive proton therapy (PT) at our institution between 2006 and 2012. Each patient had hypogondal symptoms and low-serum testosterone and received testosterone replacement after PT. Biochemical failure was defined by the Phoenix definition. Sexual function was reported using patient-reported data from the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Rates of sexual potency were also reported. Results: Twenty-three patients were included in the present analysis. The median follow-up duration was 38 months after PT and 14 months after initiation of TRT. After one to six months on TRT, the median serum testosterone level in this patient cohort increased from 238 to 497. No patient experienced a biochemical failure. The median prostate-specific antigen (PSA) did not significantly rise during the follow-up period. EPIC sexual summary, sexual function, and sexual bother scores all increased after initiation of TRT. The median sexual bother scores increased from 43.8 before TRT to 59.4 after 7 or more months of TRT. The median sexual summary scores improved from 50 to 61.8 and the median sexual function scores improved from 41.7 to 53 over the same time. Sexual potency also increased after TRT initiation from 50% to 68%, 7 or more months after TRT. Conclusions: For patients diagnosed with hypogonadism who were previously treated for prostate cancer, cautious use of testosterone replacement therapy does not appear to increase the risk of biochemical failure or increase PSA. Sexual function may improve to approximate pre-radiation levels in some cases. A prospective trial with long-term follow up is required to better support our findings.
IDH1 mutation in prostate cancer: R132H and beyond.
Authors: Flaherty Amber Lea , Teer Jamie , Zhang Jingsong
Published: February 2017

213

Background: Previous reports on mutations in the isocitrate dehydrogenase 1 (IDH1) gene in prostate cancer focused on the evolutionarily conserved residue R132 located in the substrate binding site of IDH1. One study reported R132 mutations in 2/75 (2.7%) prostate cancers, whereas the other study did not find R132 mutation in 4 prostate cancers. We therefore studied the IDH1 mutations in our prostate cancer targeted exon sequencing database. Methods: Targeted exon sequencing was performed on 52 treatment naïve prostate cancers as part of Moffitt Cancer Center’s Total Cancer Care initiative. The coverage was set to be at least 50 fold. 51/52 samples are primary prostate cancer obtained during radical prostatectomy and 1 sample is a brain metastasis. The 1000 Genomes and the NHLBI Exome Sequencing Project (ESP) were used to exclude likely polymorphisms. The catalogue of somatic mutations in cancer (COSMIC) was used to identify mutations seen in other sequencing projects, and Polyphen2 was used to predict the potential detrimental effect of the amino acid changes predicted from the genetic mutations. Results: 1/51 (2%) primary prostate cancers harbor the R132H mutation, which is known to generate the oncometabolite, (R)-2-hydroxylutarate. Y183C was identified in 1/51 samples. This amino acid change in exon 6 of IDH1 is seen at 1% allele frequency in 1000 Genomes and ESP-euro. It is classified as "probably_damaging" with a PolyPhen2 score of .999. Another "probably_damaging" amino acid change is T325M mutation, which is identified in a different primary prostate cancer. V178I in IDH1 was also identified and is thought to be an inherited variant, given it has an allele frequency of 4% in 1000 Genomes, 5% in ESP-european, and 8% in ESP-African-American. Among the frequent gene mutations in metastatic prostate cancer, only a missense mutation in the androgen receptor (H875Y) was identified in the treatment naïve brain metastasis. This H875Y has been linked to promiscuous androgen receptor. Conclusions: Mutations in IDH1 R132H and other “probably_damaging” amino acid changes are identified in primary prostate cancers. This holds further implications for future studies on prostate cancer, and may point to an interesting target in the disease.
A closer look at extraprostatic extension (EPE): Evaluation of PSA relapse rates following prostatectomy (RP) for pT3aN0 prostate cancer with or without margin involvement.
Authors: Watkins John Morgan , Watkins Patricia L. , Laszewski Michael , Rodacker Mark , Dufan Tarek A. , Koleilat Nadim
Published: February 2017

215

Background: EPE is an established risk factor for PSA failure following RP; however, often this is identified in the context of other high-risk feature(s). The objective of the current investigation study is to describe the PSA relapse rate for patients with confirmed EPE and identify associated factors for risk stratification. Methods: Retrospective analysis of patient- and tumor-specific factors. Eligible patients underwent RP for biopsy-proven prostate adenocarcinoma and pathologic finding of EPE. Patients with PSA >30 at diagnosis, involved seminal vesicles or lymph nodes at RP, or who received adjuvant therapy (hormone or radiation) were excluded. Results: Between 2002 and 2010, 644 patients underwent RP, of whom 95 had EPE and were eligible per above. The median age at diagnosis was 64 years (range 44-74), and pre-RP PSA 6.1 (1.8-25.4). At a median PSA follow-up of 64 months (range 13.3-136.5), 38 patients had experienced PSA relapse at a median of 18 months post-RP (1.2-129.8), of whom 28 had involved surgical margins. For the entire population, PSA relapse at 5 years was 39.2% (95% CI, 38.1-40.3%). Factors associated with PSA relapse included pre- and post-RP PSA and Gleason score (GS), and margin status. Subset evaluation by RP Gleason score and margin status is demonstrated in the table. Conclusions: Within the present study, all patients with EPE appear to have elevated rates of PSA relapse within 5 years of RP. Longer follow-up is necessary to determine whether the low-risk group may be safely observed following margin-negative RP. Low-grade EPE cases with involved margin and/or higher-risk Gleason score patients with any EPE/margin involvement have high rates of early PSA relapse, and should be recommended early post-operative (adjuvant) therapy in order to optimize PSA control. [Table: see text]
Preclinical efficacy of growth hormone-releasing hormone antagonist MIA-602 for androgen-dependent and castration-resistant human prostate cancer.
Authors: Rick Ferenc G. , Fahrenholtz Cale D. , Garcia Maria I. , Block Norman L. , Schally Andrew V. , Burnstein Kerry L.
Published: February 2017

221

Background: Advanced hormone-sensitive prostate cancer (PCa) responds to androgen deprivation therapy (ADT). However, therapeutic options for castration-resistant disease are limited. As growth hormone-releasing hormone receptor (GHRH-R) and ligand GHRH are regulated in an autocrine fashion in PCa, GHRH-R inhibition represents a novel approach to PCa treatment. We investigated the effects of a new, highly potent GHRH antagonist, MIA-602, on growth of androgen-dependent and castration-resistant PCa cells in vitro/in vivo. Methods: All three cell lines used in this study expressed androgen receptors (ARs). 22Rv1 cells are castration-resistant and also express clinically relevant AR splice variants. LNCaP and VCaP lines are androgen dependent models that progress to castration resistance following ADT. Protein and mRNA levels of GHRH-R and its biologically active splice variant, SV1, were evaluated in cell lines and tumors by immunoblot and real-time RT-PCR. The influence of MIA-602 on cell proliferation and tumor formation was examined. Results: GHRH-R and SV1 were present in 22Rv1, LNCaP, and VCaP. LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared to 22Rv1. However, 22Rv1 expressed higher levels of SV1. Inhibition of GHRH-R using MIA-602 decreased cell proliferation in vitro of 22Rv1, LNCaP, and VCaP PCa cell lines respectively by 70.4%, 60.7% and 20.3% (P<0.05 for all). MIA-602 decreased 22Rv1 xenograft volumes in mice by 63% after 3 weeks of treatment. VCaP showed a substantial inhibition of xenograft growth following therapy with MIA-602 in vivo. MIA-602 effectively inhibited VCaP xenografts as a single agent or in combination with ADT by surgical castration. Conclusions: The effectiveness of the novel Miami class GHRH antagonist, MIA-602, in inhibiting growth of androgen-dependent and castration-resistant PCa models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists appear to be due to effects exerted through GHRH receptors on cancer cells and/or possibly by indirect mechanisms. Further investigations of GHRH antagonists for PCa treatment are warranted.
Patient risk factors and pegfilgrastim use in cabazitaxel-treated prostate cancer pateints in an academic setting.
Authors: Kaymakcalan Marina Dusevic , Stuver Sherri , Sweeney Christopher , Choueiri Toni K. , Elfiky Aymen
Published: February 2017

224

Background: Cabazitaxel can offer a survival advantage in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). Febrile neutropenia (FN) has emerged as a serious complication, with a rate of 8% in the TROPIC trial (de Bono, Lancet 2010). Prophylaxis with pegfilgrastim (P) can decrease the risk of FN, although predictors of FN continue to evolve. We performed an analysis on the effect of prophylactic P use on FN and the impact of certain risk factors on FN rates. Methods: We conducted a retrospective analysis of mCRPC patients treated with cabazitaxel from June 2010 to August 2013 at Dana-Farber Cancer Institute. Patient clinical and treatment variables were extracted. Fisher’s exact test was used to evaluate the association between potential risk factors and FN. Results: A total of 89 patients were treated at our institution and included in this analysis. All patients received at least one dose of cabazitaxel and received a mean of four cycles. Five pts (5.6%) developed FN; 3 out of 70 (4.3%) receiving P and 2 out of 19 (10.5%) not receiving P (p=0.3). Of the 24 patients that started cabazitaxel at a reduced dose, none developed FN. No toxic death was reported. Among several risk factors including P use, age older than 65, pre-existing neutropenia, prior chemotherapy, pre-existing infection, poor performance status, liver and renal dysfunction, and recent surgery, only a prior history of palliative radiation had a significant association with FN (p=.002). Conclusions: The rate of FN in a large academic practice is similar to what was reported in the TROPIC trial. Prior radiation may be a risk factor for FN in cabazitaxel-treated mCRPC patients. Other factors that may help better predict the risk of FN in different groups of patients receiving cabazitaxel must be identified.
Prospective evaluation of low-dose ketoconazole plus hydrocortisone (HC) in chemotherapy-pretreated castration-resistant prostate cancer (CRPC) patients.
Authors: Lo Ernest N. , Beckett Laurel A. , Pan Chong-xian , Robles Daniel , Suga Jennifer Marie , Sands Jacob , Lara Primo
Published: February 2017

227

Background: Ketoconazole (keto), a known CYP17 inhibitor, is a traditional systemic treatment for CRPC. However, most of the published data has been in the pre-chemo setting; its efficacy in the post-chemo setting has not been as widely reported. Chemo-naive patients treated with attenuated doses of keto (200-300 mg TID) had prostate specific antigen (PSA) response rate (> 50% decline) ranges from 21%-62% and treatment was well tolerated. We hypothesized that low dose keto would likewise possess efficacy and tolerability in the CRPC post-chemo state. Methods: CRPC patients with ECOG PS 0-3, adequate end organ function, who had received at least one chemo were treated with low-dose keto (200 mg PO TID) and HC (20 mg PO q AM and 10 mg PO q PM) until progression, as defined by either RECIST or PSA rise > 50% from nadir or baseline. Primary endpoint was PSA response rate (> 50% reduction from baseline). A Simon minimax design was used. PSA response of > 25% was to be considered promising for further study (versus null rate of < 5%); 25 patients were required. Secondary endpoints included PSA response > 30%, progression-free survival (PFS), duration of stable disease, and evaluation of adverse events (AE). Results: 29 patients were accrued: median age was 71 (range 55-86) and median pretreatment PSA was 76 ng/mL (range 7-11,420 ng/ml); all had prior docetaxel-based chemotherapy. 28 patients were evaluable for response; all were evaluable for toxicity. PSA response of >50% was seen in 48% of patients and 59% of patients had a PSA response of > 30%. Median PFS was 138 days; median duration of stable disease was 123 days. 12 patients had grade 3 or 4 toxicity on treatment. Of the 17 grade 3 AEs, only 3 were considered ‘probably’ or ‘possibly’ related to treatment, while none of the 2 grade 4 AEs were considered related to treatment. Conclusions: In docetaxel pre-treated CRPC patients, low-dose keto + HC is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response with low-dose keto appears comparable to that of abiraterone in this patient context. A prospective randomized study of available post-chemo options is needed to assess comparative efficacy. Clinical trial information: NCT00895310.
Transurethral (TURP) biopsy of suspected anterior prostate cancers identified by MRI: Pilot study of a novel technique.
Authors: Dason Shawn , Allard Christopher Brian , Barrett Keith , Wright Ian , Shayegan Bobby
Published: February 2017

230

Background: Prostatic MRI allows for identification of cancerous lesions in patients with a prior negative TRUS biopsy. Although in-gantry and MR-ultrasound fusion technologies have been reported, access to these technologies is limited. Here we present a novel technique to sample anterior lesions suspicious for prostate cancer (PCa) identified by MRI with transurethral (TURP) biopsy. Methods: MRI studies ordered by a single uro-oncologist at a tertiary center from 2007 to 2013 were reviewed. Patients were included if their studies met the following criteria: prostate MRI (n=148), indication for MRI was prior negative TRUS biopsy (n=48), PCa considered likely by reading radiologist (n=25) and anterior tumor location (n=7). Anterior tumors were those 17mm or more from the posterior prostate margin. Medical records were thoroughly reviewed. Additionally, regional medical databases were searched for 30 day readmission, emergency room (ER) visit, or positive bacterial culture result. Biopsy patients were treated with the standard monopolar TURP clinical pathway at our center. TURP sampling was directed by pre-procedural review of MRI images and report by the surgeon. MRI imaging was read by a single radiologist and obtained with a 3-T MRI with no endorectal coil employing T1, T2, DWI, and DCE sequences. Results: All seven patients identified with anterior tumors received TURP biopsy. Patients had a mean age of 63.6, Prostate-specific antigen of 13.3 ng/mL and a mean of 2.3 prior negative TRUS biopsies. There were no immediate complications reported. In 30 day follow-up data, no patients had a postoperative infection, although one patient was assessed in the ER for self-resolving hematuria and one patient was admitted for hematuria. Mean specimen weight was 4g and all but one patient had Gleason 7 or higher PCa on biopsy. This study demonstrated that MRI followed by TURP biopsy for anterior PCa had an 85.7% cancer detection rate for clinically significant anterior cancers. Conclusions: This pilot study demonstrates that cognitively directed TURP biopsy for MRI-identified anterior prostate lesions is feasible, has an excellent pickup rate for clinically significant cancer, and does not require access to limited technology.
What is the optimal management of Gleason score 7 (GS7) prostate cancer (PC) at biopsy? A comparison of disease control for prostatectomy (RP) versus radiation therapy (RT).
Authors: Watkins John Morgan , Watkins Patricia L. , Dufan Tarek A. , Koleilat Nadim
Published: February 2017

250

Background: Optimal therapy for Gleason score 7 (GS7) prostate cancer (PC) remains to be defined, with consensus guidelines identifying both prostatectomy (RP) and radiation therapy (RT) as acceptable. The present investigation seeks to compare outcomes between these treatment approaches. Methods: Patients were retrospectively identified for inclusion by clinically localized disease, GS7, and a prostate-specific antigen (PSA) less than 30 at diagnosis. Comparison of demographic, tumor, staging, and outcome variables was performed. Disease recurrence was defined as per contemporary society guidelines. Kaplan-Meier method employed for disease control estimates. Results: Between 2003 and 2010, 267 patients were diagnosed with GS7 prostate cancer, of whom 207 were eligible for the current analysis (120 RP/87 RT). Excepting older age for RT patients (median age 73 vs. 62), the groups were well-balanced. For RP patients, 82 patients (60%) had at least one high-risk feature, of whom only four (5%) received adjuvant RT. For RT patients, 71 of patients (82%) received hormone therapy (median duration 6 months), and 48% (42) underwent external beam RT alone, 41% (36) brachytherapy (BT) alone, and 10% (9) external beam RT plus BT boost. At a median follow-up of 62.2 months (range, 13.1-136.6; with no difference between treatment groups), 64 patients had PSA relapse (51 RP/13 RT) and 15 had died (five of or with disease). Five-year disease-free and disease-specific survivals for RP versus RT were 55.4% versus 82.6% (p<0.0001) and 97.6% versus 98.8% (p=NS), respectively. Conclusions: For GS7 prostate cancer patients, RT is associated with superior disease-free survival at 5 years when compared with RP alone. Whether this difference remains in the setting of appropriately employed adjuvant RT remains to be determined. No difference in survival endpoints was detected, though there were few events at 5 years.
A sector-based postimplant dosimetric comparison of sagittal and axial ultrasound-guided source placement during I-125 permanent prostate brachytherapy.
Authors: Mohamed Yoosuf Ahamed Badusha , Mitchell Darren M. , Byrne Monica M. , Flynn Margaret A. , Napier Eoin , Jain Suneil , Workman Geraldine
Published: February 2017

262

Background: To use sector based pre- and postimplant dosimetric analysis to evaluate the effect of changes in implant technique in a developing I-125 permanent prostate brachytherapy program (PPB). Methods: 109 men treated with PPB were divided into two groups by implant technique. The first 50 patients (group 1) had needle-by-needle seed deposition under axial ultrasound (USS) guidance and subsequent 59 patients (group 2) having needle placement row-by-row then seed deposition under sagittal USS guidance. Twelve sector dose volume analysis of pre-implant ultrasound (USpre) and postimplant CT (CTpost) study was performed in all cases. Individual sectors were created by dividing the cranio-caudal prostate into three equal lengths creating prostate base, midgland and apex. Each of these volumes was then divided into four axial sectors (right and left anterior, right and left posterior). The difference in the minimum dose delivered to 90% of prostate volume (D90) and the prostate volume receiving 100%, 150%, and 200% of the prescribed dose (V100, V150, and V200) was compared between both groups. Results: In both groups, the volume of prostate in sectors one through six (entire base and anterior midgland) were significantly larger on CTpost when compared to equivalent sectors in USpre (p < 0.001), conversely the volumes in sectors 11 and 12 (posterior apex) were significantly smaller (p =0.001). When comparing dosimetric parameters of all equivalent sectors in CTpost of both groups, it was found that D90 of sector seven and eight (posterior midgland) in Group 1 received increased dose leading to elevated dose to the rectum but was significantly reduced in Group 2 (p < 0.01), which resulted in achieving the dose as planned in USpre. Prostate implant dosimetry was significantly improved in group 2 with a trend to increased equivalent dose between CTpost and USpre to each sectors and significant decrease in V150 and V200 in majority of the sectors. Conclusions: The row-by-row technique under sagittal USS guidance significantly improved our post implant dosimetric parameters when compared to single needle source placement under axial USS guidance as assessed by 12 sector analysis.
The REQUITE project: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side effects.
Authors: Rancati Tiziana , Talbot Christopher , Azria David , Brookes Antony , Burr Tom , Chang-Claude Jenny , Davidson Susan , Ruysscher Dirk De , Dunning Alison , Elliot Rebecca M. , Gutierrez-Enríquez Sara , Lambin Philippe , Rosenstein Barry , Symonds R. Paul , Thierens Hubert , Valdagni Riccardo , Vega Ana , Wenz Frederik , Yuille Martin , West Catharine
Published: February 2017

276

Background: Recently the first replicated genetic associations for adverse reactions to radiotherapy (RT) have been reported. These will help to build predictive statistical models for optimising RT delivery or interventions to alleviate the side effects. It is now timely to start a project that aims to validate known predictors of adverse reactions and develop the statistical models to become clinically useful. REQUITE is a European Union funded FP7 project that aims to do this. Methods: REQUITE’s objectives: (1.) Perform a multi-centre, cohort study collecting: blood samples, epidemiology and treatment data, longitudinal side-effect and QOL data (before and after treatment, yrs 1 and 2). (2.) Produce a centralised biobank of DNA from 5,300 patients and a centralised data management system. (3.) Validate published biomarkers of radiosensitivity. (4.) Validate clinical predictors of RT toxicity in breast, prostate, and lung cancer and incorporate biomarker data. (5.) Design interventional trials to reduce long-term side effects. (6.) Provide a resource for dissemination and exploitation to the RT community. Results: REQUITE is funded for 60 mos and organised into 7 work packages. Overall management and scientific oversight is run by Manchester. The central activity of the project is a multi-centre, observational study. Enrolment will proceed for 2 yrs in 9 clinical centres, with 2 yrs follow-up. The primary endpoints are change in breast appearance; rectal bleeding (prostate); pneumonitis (lung). Blood samples will be collected before radiotherapy. Tracking, biobanking, DNA preparation and validation of biomarkers (genetic markers and apoptosis assays) as predictive factors will be carried out in WP3-4. Some clinical factors have suggested predictive value for RT side-effects, but there is no consensus. Validation of published models in existing cohorts will be performed, leading to replicated models that can be validated using the REQUITE cohorts. Conclusions: The predictive models will be used to design clinical interventional trials and produce protocols that seek to lower RT side-effects in those individuals at high risk of developing them without affecting tumour control. Dissemination will follow.
Relationship of bone scan index and progression-free survival after docetaxel treatment for CRPC patients with bone metastases.
Authors: Mizokami Atsushi , Izumi Kouji , Ueno Satoru , Kadono Yoshifumi , Wakabayashi Hiroshi , Nakajima Kenichi , Namiki Mikio
Published: February 2017

280

Background: A computer-aided diagnosis system for bone scintigraphy using semiquantitative index [Bone Scan Index (BSI)] has been used to measure the tumor burden of bone metastases. We examined relationships of BSI, bone turnover marker, and prostate-specific antigen (PSA)-progression free survival (PFS) after docetaxel-treatment for castration resistant prostate cancer (CRPC) with bone metastasis. Methods: Sixteen CRPC patients with bone metastases (median age 72, range 52 to 82) were treated with docetaxel. We evaluated bone metastasis by bone scintigraphy before or around six months after docetaxel-treatment retrospectively. BSI was automatically calculated by BONENAVI software version 1 (FUJIFILM RI Pharma, Co. Ltd., Tokyo, Japan; Exini Bone, Exini Diagnostics, Sweden). Serum PSA, bone alkaline phosphatase (BAP), carboxyterminal telopeptide of type I collagen (I-CTP) were examined every months. PSA-PFS was evaluated after docetaxel-treatment and compared with baseline of BSI, BAP, I-CTP, and change of these value after treatment. Overall survival (OS) was also evaluated by these markers. The rate of patients with PFS and OS was estimated by the Kaplan-Meier method. Results: Baseline of BSI, the serum BAP, and I-CTP before docetaxel-treatment did not affect PFS. The change of BAP and I-CTP by the docetaxel-treatment also did not affect PFS. Only the change of BSI affected PFS and the median PFS of CRPC patients with increased BSI and decreased BSI was 5.5 months and 10 months, respectively (p=0.026). Although OS showed a longer tendency in CRPC patients with decreased BSI than with increased BSI, there was not the significant difference (p=0.12). Conclusions: The change of BSI affected PFS in CRPC patients with bone metastases. Bone scan and its evaluation with BONENAVI was effective to monitor the clinical course during chemotherapy.
Long-term outcomes among patients who achieve complete or near-complete responses after the induction phase of bladder-preserving combined modality therapy for muscle-invasive bladder cancer: A pooled analysis of RTOG 9906 and 0233.
Authors: Mitin Timur , George Asha , Zietman Anthony L. , Kaufman Donald S. , Uzzo Robert G. , Dreicer Robert , Heney Niall M. , Wallace H. James , Souhami Luis , Dobelbower M. Chris , Sandler Howard Mark , Shipley William U.
Published: February 2017

284

Background: Bladder preserving combined-modality therapy for muscle-invasive bladder cancer (MIBC) includes transurethral resection and concurrent chemo-RT given in two phases. After the induction phase with chemo-RT to 40 Gy the tumor response is assessed by cystoscopic biopsies and urine cytology. Early salvage cystectomy is promptly offered in case of persistent disease, otherwise patients proceed to consolidation chemo-RT to 64 Gy. The two most recent RTOG protocols 9906 and 0233 allowed patients with near-complete response (Ta or Tis) after the induction phase to proceed to consolidation. Methods: We performed a pooled analysis of 119 eligible patients with MIBC enrolled on RTOG trials 9906 and 0233, who were classified as having a complete (T0) or near-complete (Ta or Tis) response after induction chemo-RT and completed consolidation with a total RT dose of at least 60 Gy. We estimated bladder recurrence, salvage cystectomy rates and disease-specific survival by the cumulative incidence method and bladder-intact and overall survivals by the Kaplan-Meier method. Results: Among 119 eligible patients, 101 (85%) achieved T0 and 18 (15%) achieved Ta or Tis after induction chemo-RT and proceeded to consolidation. After a median follow-up of 5.9 years, 36/101 (36%) T0 patients vs. 5/18 (28%) Ta or Tis patients experienced bladder recurrence (p=0.52). Fourteen patients among complete responders eventually required late salvage cystectomy for tumor recurrence, in comparison to one patient among near-complete responders (p=0.47). Disease-specific, bladder-intact, and overall survivals were not significantly different. Conclusions: There is no apparent difference in the bladder recurrence and salvage cystectomy rates between complete and near-complete responders as judged at the time of cystoscopic evaluation after induction phase of bladder preserving CMT. It is appropriate to recommend that patients with Ta or Tis after induction chemo-RT continue with bladder-sparing therapy. This project was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the NCI.
Population-based analysis of a novel prognostic model for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with abiraterone acetate (AA).
Authors: Azad Arun , Lester Renee , Leibowitz-Amit Raya , Joshua Anthony Michael , Heng Daniel Yick Chin , Eigl Bernhard J. , Chi Kim N.
Published: February 2017

29

Background: Using data from the COU-AA-301 trial, a novel prognostic model was recently developed for predicting overall survival (OS) in post-chemotherapy mCRPC pts treated with AA (J Clin Oncol 31, 2013 (suppl; abstr 5013)). The model is comprised of six pre-treatment risk-factors (RF) associated with poor outcome: ECOG performance status (PS) ≥ 2, presence of visceral metastases, time from start of LHRH agonists to start of AA ≤ 36 months, low albumin, high ALP and high LDH. The aim of this study was to evaluate this model in an unselected population-based cohort. Methods: Cancer registries at three Canadian centers were used to identify mCRPC pts treated with AA. OS was estimated using the Kaplan-Meier method. Multivariate Cox proportional hazard regression was used to determine independent prognostic factors for OS. Results: A total of 415 pts received AA – 286 were post-docetaxel and 129 were chemotherapy-naïve. In post-docetaxel pts, 21%, 50% and 28% were classified into good (0-1 RF), intermediate (2-3 RF) and poor (4-6 RF) prognosis (prog) groups respectively based on the COU-AA-301 model. Median OS in the post-docetaxel cohort was significantly longer for pts with good prog disease (23.9 months) compared to intermediate (17.6 months) and poor prog pts (8.4 months) (Table). ECOG PS (p<0.001), LDH (p=0.025), albumin (p=0.007) and visceral metastases (p<0.001) were confirmed as independent prognostic factors. Although the number of events in chemotherapy-naïve pts was low, median OS was significantly longer in good prog pts (not reached) compared to both intermediate (22.9 months; p=0.011, log-rank) and poor prog pts (10.3 months; p<0.001, log-rank). Conclusions: In a population-based setting, our data validate the COU-AA-301 model as a tool for prognostic stratification of mCRPC pts treated with AA after docetaxel. Prospective evaluation of this prognostic model in post-docetaxel and docetaxel-naive pts commencing AA is warranted. [Table: see text]
BASE47 gene set predictor as an identifier of “basal-like” subtype of urothelial carcinoma of the bladder in African Americans.
Authors: Chism David D. , Damrauer Jeffrey S. , Miller Andrew S. , Milowsky Matthew I. , Kim William Y.
Published: February 2017

300

Background: African-Americans [AAs] have a higher cancer-specific mortality when compared to whites with urothelial carcinoma (UC) of the bladder. Recent gene expression studies identified two intrinsic, molecular subsets of high-grade bladder cancer: “luminal” and “basal-like”, which can be accurately classified using the BASE47 gene set predictor. We applied the BASE47 gene set predictor to AA tumors and assessed enrichment for basal-like bladder tumors. Methods: Gene expression data from 179 high-grade, muscle invasive bladder tumors—9 AAs and 170 non-AAs (whites, Asians, and race not defined) from the TCGA was analyzed. Prediction analysis of microarrays (PAM) was used to derive the Bladder cancer Analysis of Subtypes by Expression (BASE47) gene set predictor and validated with 2 independent datasets. Comparisons of gene expressions patterns between bladder and breast intrinsic subtypes were peformed. Results: The BASE47 subtype classifier was highly concordant with Consensus Cluster subtype calls on 2 independent datasets. Based on the BASE47 gene classifier, a significant fraction of the tumors from AA (7/9) were classified as “basal-like” (P=0.07 Two tail). Basal-like bladder tumors trended strongly towards a worse prognosis (P=0.09 TCGA, 0.0194 MSKCC). Gene expressions patterns for“basal-like” and luminal bladder cancer correlated highly with basal-like breast and luminal A/B subtypes respectively. In addition, a subset of “basal-like” bladder cancer was found to be a claudin-low subtype. Conclusions: We have identified two molecular subtypes of high-grade bladder cancer that highly reflect the intrinsic subtypes of breast cancer. The BASE47 is a robust subtype classifier that can reliably distinguish basal and luminal bladder cancers. African-Americans have enrichment in the “basal-like” subtype of bladder cancer. These results will be validated in an independent set of samples as well as on FFPE tumors.
PECULIAR study: Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer.
Authors: Lee Jae-Lyun , Lee Se-Hoon , Choi Yoon Ji , Ahn Jin-Hee , Song Cheryn , Hong Bum-Sik , Hong Jun Hyuk , Kim Choung-Soo , Ahn Hanjong
Published: February 2017

301

Background: Pemetrexed has demonstrated a favorable response with minimal toxicity when used as single agent as first-line and second-line treatment for advanced urothelial carcinoma. The safety and tolerability of pemetrexed plus cisplatin combination has been widely recognized in malignant mesothelioma. This trial was performed to evaluate the efficacy and safety of pemetrexed plus cisplatin in advanced urothelial carcinoma. Methods: Eligible criteria included chemotherapy-naïve advanced urothelial carcinoma, ECOG PS 0-2 and measurable disease. Pemetrexed 500mg/m2 on day 1 with cisplatin 70 mg/m2on day 1 were administered every 3 weeks til disease progression or a maximal of 8 cycles. Primary endpoint was response rate (RR), and secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicities. Response was evaluated every 6 weeks according to the RECIST criteria v.1.0 and toxicities were assessed with NCI CTCAE v.3.0. Results: A total of 42 patients were enrolled and 2 patients were excluded because of different histology and concomitant malignancy. At the time of this analysis, 36 patients (median age 66 years, ECOG 0-1 100%, visceral metastasis 50.0%, recurrent disease 61.1%) were evaluable; 6 patients were too early to assess. Twenty four partial responses for an overall response rate of 66.7% [95% confidence interval (CI) 50.3-79.9%] were documented. Six patients had stable disease. The median PFS was estimated to be 6.9 months [95% CI 6.2-7.7 months]. The median OS was 16.3 months [95% CI 12.9-19.7 months]. The most common grade 3 or 4 toxicities were neutropenia in 33.3% of patients. No one experienced febrile neutropenia. Other grade 3 or 4 hematological and non-hematological toxicities were rarely observed (thrombocytopenia 6%, anemia 6%, transaminitis 6%, nausea 3%, anorexia 3%, edema 3%, dyspnea 3%). Conclusions: The combination of pemetrexed and cisplatin is very active, with an overall response rate of 66.7% and well tolerated in patients with advanced urothelial cancer. The final mature results will be presented in the meeting. Clinical trial information: NCT01490437.
Neoadjuvant gemcitabine-cisplatin (GC) for muscle-invasive bladder cancer (MIBC): Does midway CT staging predict for pathologic complete response (pCR)?
Authors: Seah Jo-An , Leibowitz-Amit Raya , Atenafu Eshetu G. , Alimohamed Nimira , Joshua Anthony Michael , Knox Jennifer J. , Tannock Ian , Sridhar Srikala S.
Published: February 2017

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Background: Neoadjuvant cisplatin-based chemotherapy (NC) improves overall survival in MIBC, with pCR post radical cystectomy (RC) linked to better outcomes. NC is underutilized in part due to concerns over disease progression during NC. Midway radiological CT (post 2 NC cycles) may identify patients (pts) progressing on NC who should proceed to definitive therapy (DT). Methods: We reviewed 39 MIBC pts planned to receive 4 cycles of NC (GC) between Jan2005-April2013. Most pts (70%) had midway CT staging. A radiological response was defined as clear improvement in tumour +/- nodal status on CT compared to baseline, taking into account prior trans-urethral resection of bladder tumour; any other result was considered no response. DT consisted of RC, concurrent chemoradiation (CCR), or radiation alone (R). Descriptive statistics and Fisher’s exact test examined associations between disease characteristics and outcomes. Results: Overall, 28 pts (72%) completed planned NC; 7 pts (18%) stopped early due to no response on midway CT; 4 (10%) discontinued due to death (1), sepsis (2), and fatigue (1). Twenty-six pts (67%) had RC, 3 (8%) had CCR, 6 (15 %) had R and 4 (10%) did not receive DT. Of the 26 RC pts – 6 (23%) had a pCR. There were no pCRs among pts who had no radiological response at midway CT. At time of last follow up, 8 pts (21%) had died, 13 (33%) had recurrence/ metastases, and the remainder are being actively followed. Of pts with pCR, there were no recurrences (median follow up 12.2 mo (range 6.3-20.9 mos). The rate of venothromboembolism (VTE) was 26%, and nearly half occurred during NC, but did not affect treatment. Conclusions: Lack of response on midway CT was associated with a lack of pCR at RC, suggesting midway staging may be of value in MIBC receiving NC. The rates of pCR were consistent with reported literature, but rates of VTE appear higher than expected and requires further investigation. [Table: see text]
Targeted sequencing of upper tract urothelial carcinoma.
Authors: Sfakianos John P. , Kim Philip H. , Iyer Gopa , Cha Eugene K. , Zabor Emily C. , Hakimi A. Ari , Scott Sasinya N. , Ramirez Ricardo , Hanrahan Aphrothiti , Rosenberg Jonathan E. , Al-Ahmadie Hikmat , Dalbagni Guido , Bajorin Dean F. , Berger Michael F. , Bochner Bernard H. , Solit David B. , Coleman Jonathan A.
Published: February 2017

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Background: Regardless of the anatomic location (renal pelvis or ureter (upper tract), bladder or urethra) urothelial carcinoma is considered a single entity. Outcomes differ depending on site of initial diagnosis. Moreover, little is known about the comparative biology across primary sites. To define the genomic profile of urothelial carcinoma arising from the upper tract, we used a next generation sequencing technology to analyze 26 sporadic high-grade urothelial tumors of the renal pelvis. Methods: Frozen tumor samples and matched germline blood or normal kidney DNA from 26 nephroureterectomy specimens were obtained under an IRB-approved protocol. DNA was analyzed using a next generation, targeted sequencing assay. We compared these tumors to a set of 108 bladder tumors. Fisher’s exact test analyzed associations with pathological stage and Cox regression with log-rank p-values examined associations with bladder recurrence and disease-free survival. Fisher’s exact test was used to compare mutation frequencies between upper tract and bladder tumors. P-values were adjusted for multiple comparisons using the Benjamini-Hochberg method. Results: Surgical pathology was Ta, T1, T2 and T3 in 7 (26.9%), 5 (19.2%), 4 (15.4%) and 10 (38.5%) patients, respectively. High-grade disease was found in 24 (92.3%) patients with 6 (27.3%) patients having node positive disease. The most frequently altered genes included FGFR3 (42.3%), KDM6A (38.5%), MLL2 (26.9%), TSC1 (26.9%), CREBBP (23.1%), CDKN2A (19.2%) and HRAS (19.2%). No significant differences in tumor and patient characteristics were found between the bladder and upper tract cohorts. A significant difference in the frequency of alterations between the upper tract and bladder cohorts was found in HRAS (19.2% vs 2.8%, p=0.032), TP53 (7.7% vs 57.4%, p<0.001) and TSC1(26.9% vs 5.6%, p=0.024). Conclusions: We identified unique patterns of genomic alterations within upper tract urothelial carcinoma compared to bladder cancers. Upper tract tumors are characterized by a higher frequency of activating FGFR3 and HRAS mutations, TSC1 nonsense mutations, and a lower frequency of TP53 alterations. These findings may have future implications on the utility of targeted therapies in this disease subtype.
Changes in health-related quality of life (HRQL) after bladder cancer (BC) diagnosis (DX): A longitudinal population-based study.
Authors: Fung Chunkit , Pandya Chintan , Guancial Elizabeth A. , Noel Shri , Noyes Katia , Sahasrabudhe Deepak M. , Messing Edward M. , Scosyrev Emelian , Mohile Supriya Gupta
Published: February 2017

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Background: Few studies have examined longitudinal changes in HRQL among BC patients. To our knowledge, this is the largest prospective population-based study to quantify HRQL changes from before to after BC DX and to compare their HRQL with a non-cancer cohort. Methods: Our sample included 179 BC patients (≥ age 65) and 376,986 non-cancer subjects within the SEER-Medicare Health Outcomes Survey database (1998-2007). We assessed HRQL as measured by physical (PCS) and mental (MCS) component summary scores of the veterans RAND 12-item health survey. An analysis of covariance model was used to estimate changes in HRQL scores for patients after BC DX relative to control subjects with adjustment for baseline HRQL scores and covariates. Results: 84.4% (N=151) of BC patients had non-muscle invasive BC (NMIBC) and 15.6% (N=28) had muscle invasive BC (MIBC). 49.2% and 39.1% of BC patients had ≥2 comorbid conditions and ≥1 activities of daily living (ADL) deficit, respectively. Compared to the control subjects, more BC patients were men (67.0% vs 38.5%; P<0.01), current or former smokers (58.7% vs 37.3%; P<0.01), and had income ≥ $50,000(15.1% vs 8.8%; P=0.02). Other baseline demographic and socioeconomic characteristics were similar (P>0.05). After DX, BC patients reported a significant decline in PCS (1.9; 95% CI 0.1, 3.7) score compared to non-cancer controls whereas the decrease in MCS score (1.4; 95% CI -0.1, 3.0) was not statistically significant. For those with NMIBC, HRQL was not significantly different than that of the non-cancer cohort (P>0.05) after DX. However, the PCS and MCS scores of MIBC patients decreased by 5.3 (95% CI 0.9, 9.8) and 3.8 points (95% CI -0.1, 7.7) after DX, respectively. Older age at BC DX, lower educational and income levels, smoking history, and higher numbers of comorbid conditions and ADL deficits were significantly associated with inferior PCS and MCS scores after BC DX (P<0.01). Conclusions: Treatment-related side effects and/or symptoms due to BC adversely affect HRQL of BC patients, especially in those with MIBC, and should be consistently assessed by health care providers. Future research that examines interventions to improve HRQL is critical to improve BC care.
Outcome of patients with clinically node-positive bladder cancer who undergo consolidative surgery after preoperative chemotherapy: MD Anderson Cancer Center experience.
Authors: Ho Philip Levy , Willis Daniel Levi , Patil Jeevitha , Tart Karen , Parikh Sahil , Shah Jay Bakul , Delacroix Scott Edward , Siefker-Radtke Arlene O. , Dinney Colin P. N. , Pisters Louis L. , Kamat Ashish M.
Published: February 2017

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Background: We previously reported results of our phase II study in patients with retroperitoneal lymph node (RPLN) metastasis from bladder cancer (BC) undergoing consolidative surgery after preoperative chemotherapy. Here we present an expanded cohort of patients who underwent consolidative surgery after chemotherapy for clinically node-positive BC. Methods: We reviewed results of patients from our IRB approved protocol including those with clinical evidence of nodal metastasis in the pelvis or retroperitoneum (M1), without visceral metastasis, from 1995-2010. Endpoint of the study was cancer-specific survival (CSS) calculated from time of surgery. Results: 55 patients with either clinical pelvic lymph node (PLN) metastasis (n=29) or PLN and RPLN metastasis (n=26) were identified. Median CSS was 19 months for all patients; 21 for PLN alone and 16 for PLN and RPLN disease. Kaplan-Meier estimate of 5-year CSS was 31% with no difference between PLN alone and PLN with RPLN disease. Clinical nodal stage was N1: 16, N2: 5, N3: 8, and M1 (RPLN): 26. Majority (94%) of patients received cisplatinum-based chemotherapy. At cystectomy, all patients underwent a PLN dissection with 12 patients (all clinical M1 RPLN) undergoing concurrent RPLN dissection (RPLND). In all, 30 of 55 (55%) patients were pN0 at the time of surgical extirpation while 26% (5 of 19) were pN+ despite radiologic complete response after chemotherapy. 5-year CSS was 57% for pN0 and 9% for pN+ disease (p<0.0001). Median survival in patients with residual tumor in PLN (n=17) was 10.5 months vs. 7 months for RPLN (n=8) (median survival not reached in pN0 patients, p< 0.001). 17 patients developed recurrences outside the surgical field after a median of 8 months. While no recurrences occurred within the lymphadenectomy template, 14% of patients with clinical M1 RPLN disease who did not undergo RPLND had recurrences in RPLN basin. Conclusions: Post-chemotherapy consolidative surgical resection may result in 5-year disease-free survival in patients with clinical evidence of node-positive disease, including those with RPLN positive disease, who have major response to chemotherapy.
Post-prostatectomy persisting PSA: Correlation with disease progression and survival in pT3 prostate cancer patients of the ARO 96-02 randomized phase III clinical trial—10 years' follow-up.
Authors: Wiegel Thomas , Bartkowiak Detlef , Bottke Dirk , Hinke Axel , Stöckle Michael , Wirth Manfred , Semjonow Axel , Miller Kurt
Published: February 2017

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Background: In the ARO 96-02 trial, patients with pT3 prostate cancer were randomly assigned before achieving an undetectable prostate-specific antigen (PSA) after radical prostatectomy (RP) to receive a wait and see policy (arm A) or adjuvant radiotherapy (RT) (arm B). If the undetectable PSA level was not achieved, patients were excluded by protocol and received RT with 66 Gy (arm C). Methods: Three hundred eighty eight patients with pT3-4 pN0 prostate cancer with positive or negative surgical margins were recruited; 78 retained a detectable PSA (median 0.6 ng/mL, range 0.05-5.6 ng/mL) after RP; 74 of them were irradiated with 66 Gy to the prostatic fossa. Radiotherapy was applied in median 86 days post-RP. Results: Compared to patients in arm A and B, the patients with persisting PSA after RP had higher preoperative PSA values (p<0.0001), higher tumor stages (p=0.0057), higher grades (more G3 tumors), higher Gleason scores (p=0.0013) and more positive surgical margins (p=0.033). For the 74 patients, the 10 years clinical relapse-free survival rate was 63%. Forty three men had hormonal therapy, 12 developed distant metastases; 23 patients died. Compared to patients who did achieve an undetectable PSA (arms A+B), arm-C patients fared significantly worse with a 10 year overall survival of 68% versus 84% (p=0.0019). The rate of developing distant metastases within 10 year post-RP was 2.5 fold higher (14.6 vs. 5.8%) for men with a persisting PSA compared with the patients in arm A (p=0.0079). Metastasis-free survival after 10 years was 67% in arm C versus 81% in arm B (p=0.01). Conclusions: A persisting PSA after prostatectomy seems to be an important prognosticator of clinical progression for pT3 tumors which should then prompt aggressive treatment. It correlates with a higher rate of distant metastases and with worse overall survival. The results underline the significance of achieving an undetectable PSA after radical prostatectomy.