bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of salvage extended lymph node dissection (LND) in patients with rising PSA and PET/CT scan detected nodal recurrence of prostate cancer.
Authors: Porres Daniel , Osmonov Daniar , Aksenov Alexey , Thissen Andrea Katharina , Kuru Timur H. , Pfister David J. K. P. , Junemann Klaus-Peter , Heidenreich Axel
Published: February 2017

242

Background: According to the risk constellation recurrence rate of prostate cancer following local therapy is up to 60%. Early salvage radiotherapy already showed a benefit in progression-free survival. We analyzed the impact of salvage extended lymph node dissection on cancer control in patients with rising PSA and nodal recurrence in PET/CT scan. Methods: Between 2003 and 2015 we performed a salvage extended lymph node dissection in 95 patients with rising PSA and nodal recurrence in PET/CT scan after previous local therapy for prostate cancer. The extent of resection field was adjusted to the pre-operative imaging. Results: We identified 95 patients with rising PSA and nodal recurrence in PET/CT scan with a mean age of 66 years (55-76 years). There were no significant intraoperative complications. Postoperatively, 12% had Clavien/Dindo grade 3 complications. Complete PSA response, defined as a postoperative PSA level < 0.2 ng/ml, was diagnosed in 36% of patients. With a median follow-up of 19 months (1-101 months) cancer-specific mortality rate was less than 1%. Median progression-free survival was 7 months (1-43 months). The interval until the initiation of systemic treatment was 12 months (1-43 months). Conclusions: Salvage LND can be performed without significant complications. Immediate complete PSA response can be achieved in one third of patients and systemic therapy can be delayed by one year. For a general treatment recommendation individual predictive markers are currently still missing.
Early assessment of PSA response in CRPC patients treated with enzalutamide (Enza) or abiraterone (Abi).
Authors: Guccione Jeffrey R. , Ledet Elisa M. , Stolten Michael D. , Steinberger Allie E. , Chow Lydia D. , Cotogno Patrick , Lewis Brian E. , Sartor A. Oliver
Published: February 2017

249

Background: Abi and Enza are used in treating metastatic CRPC. Primary resistance is well described but little data exists for early treatment responders. Further characterization of patients with early PSA declines was the goal of this study. Methods: Single institution, retrospective reviews were performed on 84 CRPC patients (pts) treated with Abi or Enza. PSAs were recorded for the duration of treatment. The primary end point was to describe receiver operating characteristics (ROC) of early PSA changes, including sensitivities and specificities, as a predictor of later treatment response (defined as ≥ 50% decrease in PSA from baseline). 12 additional clinical covariates were also evaluated as treatment response predictors. Results: 30/63 pts in the Abi treatment group and 12/44 pts in the Enza treated group had a PSA treatment response at some point. Among the “eventual” Abi responders, some achieved a response early; 16/30 at 4 weeks and 22/30 at 8 weeks. Of Enza “eventual” responders, 7/12 achieved response at 4 weeks. For early responders (either 4 or 8 weeks), Abi pts median treatment time was 336 days. Enza early responders median treatment was time 303 days. For ROC analysis of PSA changes at 4 & 8 weeks, in terms of predicting ‘eventual’ responders, the Abi group had an area under the curve (AUC) of 0.86 ± 0.07 and 0.93 ± 0.08, respectively. Enza ROC analysis of PSA change at 4 weeks had an AUC of 0.97 ± 0.03. Sensitivities and specificities were also described for various PSA change thresholds in each group. Ideal cut-off points for Abi at 4 weeks was a 37% decrease in PSA (sensitivity: 0.74, specificity: 0.97) and at 8 weeks was a 33% decrease (0.82, 0.97). For Enza ideal cut-off at 4 weeks was a 31% PSA decrease (0.82, 0.93). Covariate analysis of the Abi pts indicated that metastasis at diagnosis (P = 0.048) and prior taxanes predicted resistance to treatment (P = 0.019), as measured by < 50% decline in PSA. All covariates in the Enza pts failed to reach significance. Conclusions: Results suggest that early PSA changes for both Enza and Abi may be a reliable way for clinicians to predict long-term PSA response. This may allow for earlier modifications to be made in patient management for those not achieving an early PSA response.
Gene expression in prostate tissue according to frequency of ejaculation.
Authors: Rider Jennifer R. , Sinnott Jennifer A , Mucci Lorelei A.
Published: February 2017

25

Background: Long-term prospective data from within the Health Professionals Follow-up Study (HPFS) suggest more frequent ejaculation throughout adult life may be protective against future development of prostate cancer (PCa). Compared to men with an average monthly ejaculation frequency (EF) of 4-7 times/month during adulthood, men who ejaculated at least 21 times per month were 30% less likely to be diagnosed with PCa after adjustment for a number of potential confounders and PCa screening. We sought to explore mechanisms through which EF may influence PCa development utilizing gene expression data assessed on tumor and adjacent normal tissue. Methods: In 1992, 31,925 HPFS participants were questioned on their average monthly EF at ages 20-29, 40-49, and in the previous year; 3,839 of these men were later diagnosed with PCa. Expression of 20,254 genes was available from archival tumor tissue from 156 cases; 84 of these cases also had data from adjacent normal tissue. We regressed each gene expression value as a continuous outcome on EF, age at diagnosis, and year at diagnosis. We calculated the p value associated with the coefficient for the EF variable as a measure of the strength of the trend test. We then used t values for the coefficients to rank the genes, and ran a gene set enrichment analysis to identify pathways with genes associated with EF. Results: We observed that while there was not much signal in the tumor tissue, there was enrichment of smaller p values in the adjacent normal tissue. EF in the time period most proximal to diagnosis is most strongly associated with gene expression in normal tissue. Focusing on the association between gene expression in normal tissue and EF in the year prior to the questionnaire (1991), the top six differentially expressed genes were OR4K1, CCDC138, SERPINA9, TRMT61B, ZNF302, and ASB4. Gene set enrichment analysis revealed a substantial number of pathways differentially expressed at the FDR <0.05 threshold. Conclusions: Identifying changes in gene expression associated with EF in normal prostate tissue provides further support for a biological role of ejaculation frequency in the etiology of PCa. Notably, pathways downregulated with increasing ejaculation frequency were primarily immune related.
Comparison of abiraterone acetate (Abi) versus ketoconazole (Keto) in chemotherapy-naive patients (CN-pts) with metastatic castration resistant prostate cancer (mCRPC).
Authors: Peer Avivit , Neumann Avivit , Sella Avishay , Rosenbaum Eli , Neiman Victoria , Gottfried Maya , Kuchuk Iryna , Kovel Svetlana , Sarid David , Gez Eliahu , Mermershtain Wilmosh , Rouvinov Keren , Carducci Michael Anthony , Eisenberger Mario A. , Sinibaldi Victoria J. , Berger Raanan , Keizman Daniel
Published: February 2017

260

Background: Abi is a standard treatment (tx) in CN-pts with mCRPC. It is a potent and selective CYP 17 inhibitor. However, in many countries where abi has not been approved yet, keto is used as an alternative CYP 17 inhibitor. Preclinical data suggests that keto is a less specific and potent inhibitor of CYP 17. Clinical data (Peer et al, Prostate 2014) suggests that in docetaxel (D) refractory mCRPC, the outcome of abi tx may be superior to keto. However, there are limited clinical data comparing both agents in CN-pts with mCRPC. We aimed to compare the clinical effectiveness of abi vs keto in CN-pts with mCRPC, who were treated after the year 2004 (approval of D for the tx of mCRPC). Methods: Records from 72 CN-pts with mCRPC treated with abi in 5 Israeli centers were reviewed retrospectively, and matched by pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012) to pts treated with keto 200 - 400 mg 3x day (international database, n = 156, from 4 centers across the US and Israel). We compared the PSA response (decrease ≥ 50% from baseline), biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. Results: The groups were matched by pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012), based on pretreatment NLR and PSA doubling time, and the prior response to a gonadotropin-releasing hormone agonist. The groups were balanced regarding age (72 abi vs 70 keto), time from primary tx to disease relapse, gleason score, pre-tx disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral), and ECOG PS. In the groups of abi vs keto, PSA response was 75% vs 47% (OR 3.8, p = 0.04), median biochemical PFS 12 vs 6 months (HR 0.62, p = 0.03), median radiological PFS 16 vs 8 months (HR 0.54, p = 0.01), median OS not reached after a median follow-up time of 18 months vs 26 months, and tx interruption d/t adverse events 10% vs 22% (0R 0.65, p = 0.05). Conclusions: In CN-pts with mCRPC, the outcome of pts treated with abi may be superior to keto.
Phase I/II study of stereotactic ablative radiotherapy including regional lymph node irradiation for patients with high-risk prostate cancer (SATURN): Early results.
Authors: Musunuru Hima Bindu , D'Alimonte Laura , Davidson Melanie , Ho Ling , Cheung Patrick , Vesprini Danny , Liu Stanley K. , Chu William , Chung Hans T. , Ravi Ananth , Deabreu Andrea , Bhounr Zeeba , Zhang Liying , Commissso Kristina , Loblaw Andrew
Published: February 2017

264

Background: Dose escalation using five-fraction stereotactic ablative radiotherapy (SABR) is gaining popularity in the treatment of prostate cancer. This has not been extensively tested in the context of pelvic radiation for high-risk groups. The objectives of study are to report early toxicity and quality of life outcomes in patients following 5-fraction prostate and pelvic radiation. Methods: A phase I/II study was performed where high-risk prostate cancer patients (T3a-3b or Gleason score ≥ 8 or PSA > 20ng/ml) received 40Gy to prostate and 25Gy to pelvis and seminal vesicles in 5 weekly fractions, on a gantry-based platform. A 3mm planning target volume margin to the prostate and a 6mm margin to the lymph nodes was applied. Image guidance was performed using gold seed fiducials and cone beam computerized tomography. Androgen deprivation therapy (ADT) was used for 12-18 months. Common Terminology Criteria for Adverse Events version 3.0 was used to assess toxicities at 3- and 6-months. Quality of life data (QOL) was captured using EPIC questionnaire. A minimally clinically important change (MCIC) definition was triggered if the EPIC QOL score decreases > 0.5 SD, where SD is the standard deviation of baseline scores. Results: Thirty patients completed the planned treatment with a median follow up of 11.9 months (IQR 8.3, 13.0). The following toxicities were observed: grade 2 genitourinary (GU): 50% at 3 months and 34.5% at 6 months; grade 2 gastrointestinal (GI): 3.3% at 3months and 6.9% at 6 months. No ≥ grade 3 toxicities were observed. Mean (95% Confidence Interval) EPIC urinary QOL scores were 86.6 (81.9-91.3), 87.1(81.4-92.6) and 86.1(80.2-92.0) at baseline, 3 months and 6 months and the bowel scores were 94.1(91.3-97.0), 93.2(89.1-97.2) and 93.2(89.5-96.8), respectively. Proportion of patients experiencing MCIC at 3 months and 6 months were 27.8% and 31.8% for urinary domain, 23.5% and 28.6% for bowel domain; respectively. Conclusions: This gantry-based novel fractionation schedule incorporating pelvic radiation for high-risk prostate cancer in combination with ADT is feasible and well tolerated in the acute setting. Clinical trial information: NCT 01953055.
Changes in T cell immunity in patients with metastatic castration resistant prostate treated with Radium-223 treatment.
Authors: Kim Joseph W. , Kang Youna , Shin Min , Deshpande Hari Anant , Hurwitz Michael E. , Roberts John D. , Cardinale Joseph G. , Narayana Ashwatha , Kang Insoo , Petrylak Daniel Peter
Published: February 2017

295

Background: The bone seeking calcium mimetic, Radium223 (Ra223), emits high energy alpha particle that cause irreparable double strand DNA breaks in osseous metastases. Ra223 improves survival in patients with bone-predominant metastatic castration resistant prostate cancer (mCRPC). The effect of Ra223 on the host immune system, and T cell immunity in particular, is unknown. Methods: Eligible patients include men with mCRPC, osseous metastases and a clinical indication for Ra223 were eligible. Blood samples were collected at the following time points: prior to the first, second, and fourth treatments (tx) and 4 weeks after the sixth dose. Peripheral blood mononuclear cells (PBMCs) were purified and stained with a cocktail of antibodies to surface and effector immune molecules. Some PBMCs were stimulated and stained for intracellular cytokines (IFN-g, TNF-a, IL-13, IL-17, and IL-21). Stained cells were analyzed by flow cytometry. Results: A total seven patients completed at least two sample collections. The median number of prior lines of therapy was three. Median age was 71 (55-79). Median PSA was 78 (2-351). Effector memory (EM) CD8+ T cells were divided into two subsets expressing high and low levels of the IL-7 receptor alpha chain (IL-7Ra) with distinct cellular characteristics including perforin expression. The frequency of IL-7Rahigh and low EM CD8+ T cells expressing programmed death protein 1 (PD-1) was decreased after Ra223 treatment (pre vs. post, median (%) ± interquartile range, 14.3 ± 12.9 vs. 7.2 ± 20.9, P = 0.03; 16.7 ± 28.8 vs. 14.1 ± 37.8, P = 0.015 by Wilcoxon matched-pairs signed rank test). A similar finding was observed in the frequency of memory CD4+ T cells expressing PD-1 after the treatment (median (%) ± interquartile range, 7.2 ± 7.7 vs. 3.9 ± 3.4, P= 0.03). Conclusions: In this preliminary cohort of patients, Ra223 tx was associated with decrease in PD-1 expression by effector T cells. Further investigations of an immune mechanism of Ra223 mediated antitumor activity are warranted.
Differential gene expression in prostate tissue according to vasectomy.
Authors: Wilson Kathryn M , Gerke Travis , Ebot Ericka , Sinnott Jennifer A , Rider Jennifer R. , Mucci Lorelei A.
Published: February 2017

298

Background: We previously found that vasectomy was associated with an increased risk of prostate cancer, and particularly, risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS). However, the possible biological basis for this finding is unclear. In this study, we explored possible biological mechanisms by assessing differences in gene expression in the prostate tissue of men with and without a history of vasectomy prostate cancer diagnosis. Methods: Within the HPFS, vasectomy data and gene expression data (20,254 genes) was available from archival tumor tissue from 263 cases, 124 of whom also had data for adjacent normal tissue. To relate expression of individual genes to vasectomy we used linear regression adjusting for age and year at diagnosis. We ran gene set enrichment analysis to identify pathways of genes associated with vasectomy. Results: Among 263 cases, 67 (25%) reported a vasectomy prior to cancer diagnosis. Mean age at diagnosis was 66 years among men without and 65 years among men with vasectomy. Median time between vasectomy and prostate cancer diagnosis was 25 years. Gene expression in tumor tissue was not associated with vasectomy status. In adjacent normal tissue, three individual genes were associated with vasectomy with Bonferroni-corrected p-values of < 0.10: RAPGEF6, OR4C3, and SLC35F4. Gene set enrichment analysis found five pathways upregulated and seven pathways downregulated in men with vasectomy compared to those without in normal prostate tissue with a FDR < 0.05. Upregulated pathways included several immune-related gene sets and G-protein-coupled receptor gene sets. Conclusions: We identified significant differences in gene expression profiles in normal prostate tissue according to vasectomy status among men treated for prostate cancer. The fact that such differences existed several decades after vasectomy provides support for the idea that vasectomy may play a role in the etiology of prostate cancer.
PARPi in PCa results in decreased availability of DNA repair factors.
Authors: Schiewer Matthew Joseph , Knudsen Karen E.
Published: February 2017

301

Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions in cancer, including regulating NFkB and HIF function. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of AR function PCa, and assists in regulating AR-driven, PCa-associated phenotypes, including castrate-resistant AR function, tumor growth, and transition to CRPC. Additionally, recent clinical trial data of PARP inhibition as a single agent in advanced cancers has been promising. Given the preclinical and clinical data, pursuing a deeper understanding of the molecular underpinnings of PARP inhibitor action in PCa may yield markers of response and/or rationale for precision medicine. Methods: Hormone therapy-sensitive and CRPC models were transcriptionally profiled in response to PARP inhibition. Pathways were nominated for validation. Bioinformatics approaches were used to compare the PARP-1-sensitive transcritome with publicly available data sets. ChIP-qPCR was performed to examine the effect of PARPi on target genes of the nominated pathways. Patient specimen TMAs were utilized for PAR IHC. PARP inhibition reduced AR and E2F1 target gene expression, as well as significantly decreased expression of DNA repair genes. Both PARP enzymatic activity and the PARP-1-dependent transcriptional program are increased as a function of disease progression. Results: These data indicate that:(1) The PARPi-sensitive transcriptome holds major transcriptional regulatory events beyond AR signaling. (2) E2F1-regulated genes are sensitive to PARP-1 function. (3) The PARPi-sensitive E2F-regulated transcriptome is enriched for DNA repair factors. (4) PARP enzymatic and transcriptional functions are increased during disease progression. Conclusions: Taken together, this study demonstrates that the transcriptional roles of PARP-1 may contribute to the clinical response to PARP-1 inhibitors as single agents. This work was supported by a PCF YI award (to MJS).
The utility of serum CA9 in prognostication in prostate cancer.
Authors: Smith Alan D. , Truong Mathew , Bristow Rob , Wouters Bradley , Milosevic Michael F. , Joshua Anthony M.
Published: February 2017

309

Background: Solid tumours are invariably less well-oxygenated than their normal tissue counterparts. Tumour hypoxia is important because it leads to resistance to radiotherapy and anticancer chemotherapy, and has been associated with prognosis in localized prostate cancer. Carbonic anhydrase IX (CA9), a member of a family of metalloenzymes that catalyze the reversible hydration of carbon dioxide, is considered to be one of the best biomarkers of cellular hypoxia. Although CA9 has been negatively correlated with survival in various cancers, no published data has demonstrated prognostic significance in prostate cancer. Methods: We retrospectively assessed CA9 in samples from 68 men with localized high-risk prostate cancer (LD) treated with radical prostatectomy (RP) or radiotherapy (RT), and twenty men with CRPC treated with docetaxel chemotherapy (DC). Samples were taken before treatment with RP and RT (in LD) or DC (in CRPC) from 2010 to 2012 at the Princess Margaret Cancer Center. Results: Of the 68 patients with LD, 57 patients underwent RP and 11 patients underwent RT. The proportion of patients with recurrence was 74% for RP and 55% for RT. Median CA9 for patients with LD and recurrence was 147 (range 60-1061) and 114 (range 48-1293) for those with no recurrence. Baseline CA9 was not associated with recurrence or PSA in these patients (p 0.79 and 0.09 respectively). Median follow-up for patients with CRPC was 14.1 months and 17 of 20 patients had confirmed death at the end of follow-up. The median CA9 level before DC was 155 pg/mL (range 38-1086). CA9 level before chemotherapy correlated with overall survival -0.41, however this did not reach statistical significance (p 0.10). There was no association between CA9 and PSA in CRPC (p 0.51). Conclusions: Absolute CA9 level negatively correlated with survival in men with CRPC, with a level that approached statistical significance in this small cohort. CA9 was not associated with recurrence of disease in men with LD, treated with either RP or RT. More data evaluating the relationship between hypoxia, CA9 and outcome in prostate cancer is needed before recommending its use as a biomarker in CRPC.
Urinary and bowel quality of life after image-guided, intensity modulated radiation therapy to the prostate bed.
Authors: Abuodeh Yazan , Naghavi Arash , Juan TzuHua , Ma Zhenjun , Wilder Richard
Published: February 2017

312

Background: Majority of patients with adverse pathological features on radical prostatectomy do not receive post-prostatectomy radiation due to concerns of negative impact on their quality of life (QOL). The purpose of this study is to evaluate QOL after post-prostatectomy intensity modulated radiation therapy (IMRT) in the “adjuvant”(ADJ) setting for positive surgical margins, extraprostatic extension, or seminal vesicle invasion with a PSA < 0.2 ng/mL and a “salvage”(SAL) setting for a PSA ≥ 0.2 ng/mL at the start of IMRT. Methods: Between 2004 and 2013, 130 patients underwent IMRT to the prostate bed. Sexual Health Inventory for Men (SHIM), International Prostate Symptom Score (IPSS), and Expanded Prostate cancer Index Composite-26 for bowel (EPIC-26-bowel) scores were recorded before radiation and at 3-month intervals after completion of treatment to assess sexual, urinary, and rectal QOL, respectively. A mixed model for repeated measurements was used to compare QOL scores over time among various subgroups. Results: ADJ and SAL radiation were delivered to 48 (37%), 82 (63%) respectively. Total radiotherapy doses were 64.8-68.4 Gy using 1.8-Gy daily in 56 (43%) patients and 70.2-72.0 Gy in 74 (57%) patients. Androgen deprivation therapy (ADT) was given to 4/48 (8%) ADJ patients and 9/82 (11%) SAL patients. Fiducials were placed in prostate bed for image guidance in 42 (32%) patients. Median follow up was 46 months. Total radiation dose did not significalntly affect QOL. SAL IMRT was associated with worse mean SHIM scores (3 points, p = 0.002) and ADJ IMRT was associated with lower mean IPSS scores (2 points, p = 0.03). Mean EPIC-26-bowel scores were lower without fiducial markers (16 points, p < 0.0001). Conclusions: SAL IMRT was associated with worse sexual QOL, possibly due to less frequent usage of phosphodiesterase-5 inhibitors. ADJ IMRT was associated with worse urinary QOL, possibly due to a shorter post-operative recovery period. Fiducial marker resulted in better rectal QOL due to greater rectal sparing. Urinary and rectal QOL with post-prostatectomy, image-guided IMRT compare favorably with previous QOL reports involving three-dimensional conformal radiation therapy.
Duration of androgen deprivation therapy for high-risk prostate cancer: Application of randomized trial data in a tertiary referral cancer center.
Authors: Muralidhar Vinayak , Regan Meredith M. , Werner Lillian , Nakabayashi Mari , Evan Carolyn , Bellmunt Joaquim , Choueiri Toni K. , Elfiky Aymen , Harshman Lauren Christine , McKay Rana R. , Pomerantz Mark , Sweeney Christopher , Taplin Mary-Ellen , Kantoff Philip W. , Nguyen Paul L.
Published: February 2017

33

Background: We wished to evaluate the incidence and predictors of the use of long-term (2-3 years) vs. shorter-term androgen deprivation therapy (ADT) in radiation-treated men with high-risk prostate cancer. Methods: We identified 302 patients from the Dana-Farber Cancer Institute patient registry diagnosed with high-risk prostate cancer (T3a or PSA > 20 ng/mL or Gleason score 8-10) between 1993 and 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate predictors of receiving shorter-course ADT than recommended by guidelines (< 2 years). Results: The course of ADT intended by physicians increased following the 2009 publication of trials showing the superiority of 2-3 years versus 4-6 months of ADT, with 43.5% intending ≥ 2 years before vs. 61.4% after (p=0.014). Starting in 2010, 49.4% of patients actually received less than 2 years of ADT. The most common reasons for receipt of shorter-course ADT were intolerance of ADT side effects, patient comorbidity/age, the presence of T3a on MRI only as the sole high-risk feature, or participation in a clinical trial. ACE-27 moderate to severe comorbidity (adjusted hazard ratio [AHR]=2.94), Gleason score less than 8 (AHR=5.66), and PSA < 20 ng/mL (AHR=4.19) all predicted receipt of shorter-course ADT (p<0.05 in all cases). Conclusions: In a tertiary-care setting, rates of long-course ADT for high-risk disease have increased since the 2008/2009 trials supporting its use. However, approximately half of patients continued to receive shorter-course ADT, often due to intolerance of side effects, underlying comorbidity, or physician judgment about the aggressiveness of the disease.
Causes of death in intermediate- and high-risk prostate cancer treated with radiotherapy with or without androgen deprivation therapy: Analysis from two phase III trials.
Authors: Nabid Abdenour , Carrier Nathalie , Vigneault Eric , Martin André-Guy , Souhami Luis , Duclos Marie , Bahary Jean-Paul , Nguyen-Huynh Thu-Van , Lemaire Céline , Brassard Marc-André , Vass Sylvie , Bahoric Boris , Archambault Robert , Vincent François
Published: February 2017

34

Background: The purpose of this analysis was to establish causes of death in a population of intermediate-risk (IR) and high-risk (HR) prostate cancer treated on two phase III trials. Methods: From October 2000 to September 2010, 1,230 patients were randomized: 630 with HR (ClinicalTrials.gov, #NCT00223171) and 600 with IR (#NCT00223145). HR was defined as T3-4, PSA >20 g/ml, Gleason >7 (with at least one of these 3 factors). IR was defined as T1-T2, Gleason < 6 and PSA 10-20 ng/ml or T1-T2, Gleason 7 and PSA < 20 ng/ml. Causes of death were compiled until July 2015 and were established from data sent by the different investigators and centrally reviewed. Causes of death were mainly based on data from clinical records, then by family members, obituaries, death certificates and family physicians. Results: The median follow-up for the 1,230 patients was 7.5 years (HR 8 vs. IR 6.8 years, p<0.001). 30.2% (372/1,230) patients had died: (HR 37% vs. IR 23.2%, p<0.001). A total of 8% (99/1,230) patients developed local, regional, and metastatic prostate cancer recurrences: (HR 11.6% vs. IR 4.3%, p<0.001) and 4.4% (54/1,230) died from prostate cancer: (HR 7.3% vs. IR 1.3%, p<0.001). The most frequent cause of death was a second cancer (120/1,230, 9.8%): (HR 10.6% vs. IR 8.8%, p=NS). Cardiovascular deaths occurred in 6.3% (78/1,230) (HR 7.1% vs. IR 5.5%, p=NS) with no statistical difference between the different durations of androgen deprivation therapy (ADT) 0, 6, 18, or 36 months. Other causes of death were pulmonary (3.7%), digestive (1.1%), others (3.3%), and unknown (1.7%). Majority of deaths occurred between 3 and 9 years after randomization (HR 70% and IR 73%). Prostate cancer deaths were distributed over all the follow-up period. The 5/10 year overall survival between HR and IR were 88.6%, 91.8%, and 61.6%, 69.8%, respectively with significant differences (p=0.045 and p=0.016). Conclusions: In patients with localized HR and IR prostate cancer, the first cause of death was a second cancer and prostate cancer came as the third one after cardiovascular disease. There was no statistical difference in the incidence of cardiovascular deaths in patients treated with different durations of ADT. Clinical trial information: Clinical Trials, gov. #NCT00223145 - Clinical Trials, gov. #NCT00223171.
Prognostic role of body mass index (BMI) in patients with metastatic castration resistant prostate cancer (mCRPC) receiving chemotherapy: Preliminary results from a retrospective Italian multicenter study.
Authors: Lutrino Stefania Eufemia , Fontanella Caterina , Caffo Orazio , Massari Francesco , Atzori Francesco , Maggi Claudia , Calvani Nicola , Sacco Cosimo , Veccia Antonello , Modena Alessandra , Cugudda Silvia , Verzoni Elena , Caliolo Chiara , Ermacora Paola , Maines Francesca , Tortora Giampaolo , Procopio Giuseppe , Ferrara Pasqualinda , Fasola Gianpiero , Cinieri Saverio
Published: February 2017

342

Background: Body mass index (BMI) is linked to an increased risk of cancers and a poorer prognosis. However, the evidence on the relationship between high BMI and metastatic castration resistant prostate cancer (mCRPC) is not entirely consistent and the data are conflicting. The aim of this observational, retrospective, multicenter study was to evaluate the correlation between BMI and progression-free survival (PFS) and overall survival (OS) in patients (pts) with mCRPC treated with chemotherapy. Methods: We collected mCRPC pts who received docetaxel 75 mg/m2 every 21 days as first line therapy in6 Italian Cancer Centers from 2005 to 2015. We classified BMI group according with the World Health Organization definition : normal weight BMI < 25kg/m2, overweight 25 ≤ BMI < 30kg/m2, and obese BMI ≥ 30kg/m2. Baseline characteristics and treatment information has been recorded in an anonymized excel file. Results: We collected 113 pts with a median age of 70.7 years (62 to 87) at the time of mCRPC diagnosis. In our cohort 33.6% of pts were normal weight at the HRPC diagnosis, 50.9% were overweight, and 15.5% were obese. At the baseline, 83.3% of obese pts had at least 1 co-morbidity versus 64.9% of normal/overweight pts. Moreover, 27.8% of obese pts needed a docetaxel dose reduction versus 17.5% normal/overweight pts. Only a non-significant trend for the detrimental effect of high BMI on PFS and OS has been documented. Median PFS in obese pts 6.4 months vs 7.0 months in of normal/overweight pts (p = 0.439); median OS in obese pts 38.8 months vs 43.4 months in of normal/overweight pts (p = 0.157). Conclusions: The relationship between BMI and mCRPC is extremely complex and unclear. Even if in this preliminary analysis we failed to confirm a significant association between BMI and survival, the data suggests that obesity may be associated with a lower tolerance to chemotherapy. Overall, we expected to enroll approximately 500 pts and data collection is currently ongoing.
Comparison of docetaxel and cabazitaxel efficacy on prostate cancer cells both in vitro and in vivo.
Authors: Nelius Thomas , Jarvis Courtney , Martinez-Marin Dalia , Filleur Stephanie
Published: February 2017

351

Background: Despite recently approved novel agents, taxane-based chemotherapy remains the major therapeutic strategy for metastatic castration-refractory prostate cancer/mCRPC. Still mCRPC continues to be incurable. Besides, patients often experience severe side effects, prompting a re-evaluation of standard regimen. Past studies have demonstrated promise for Low-Dose Metronomic/LDM chemotherapy, defined as the frequent administration of low doses of chemotherapeutic drugs with no prolonged drug-free breaks. Yet relative activities of LDM taxanes and combinations with known anti-neoplasic agents have to be investigated. Methods: PC3, Du145 and LNCaP-derivative CL1cell lines were used to compare the effect of increasing doses of taxanes on cell proliferation, cell cycle distribution and apoptosis by crystal violet, propidium iodide and AnnexinV stainings, respectively. Autophagy was assessed by western blotting against Beclin1. In vivotumor growth was measured using CL1 control and CL1-PEDF xenografts. Phagocytosis was determined by cytotoxicity assay in CL1-macrophages co-cultures. Results: Our data showed that cabazitaxel/cbz-treated cells had a significantly lower EC50 compared to docetaxel/doc, with Du145 cells presenting the greatest differences. Both low-dose taxanes increased the sub-G0 cells population. However, the sub-G0 increase was significantly greater in cbz- than doc-treated Du145 cells, but not in PC3 and CL1. Accordingly, plasma membrane Annexin V elevation occurred in Du145 cells at lower doses of cbz than doc validating a higher efficacy due to increased apoptosis. Although Beclin1 levels remain unchanged in PC3 and CL1 cells, it was found up-regulated for all doses of cbz in Du145. In vivo, LDM cbz was significantly more efficient in curbing tumor growth than doc. This effect was markedly increased when cbz was combined with the angio-inhibitor and anti-tumor Pigment Epithelium-Derived Factor (PEDF); an effect that could be explained by increased phagocytosis. Conclusions: Our data demonstrate a higher efficacy of cbz on CRPC both in vitro and in vivo, and suggest that LDM taxane chemotherapy/PEDF combination could be used as a novel therapeutic strategy for CRPC.
Neutrophil-to-lymphocyte ratio as a prognostic biomarker in bladder cancer: A REMARK-guided secondary analysis of SWOG 8710.
Authors: Ojerholm Eric , Smith Andrew , Hwang Wei-Ting , Baumann Brian Christopher , Tucker Kai N. , Lerner Seth P. , Christodouleas John Paul
Published: February 2017

361

Background: Pre-operative risk stratification is a major challenge in bladder cancer (BC), and a biomarker is needed. Recent studies suggest baseline neutrophil-to-lymphocyte ratio (NLR) correlates with survival in BC, but these results are threatened by methodological limitations. We tested whether NLR is prognostic for overall survival (OS) in BC following principles detailed by the REMARK biomarker guidelines. Methods: SWOG 8710 was a randomized, phase III trial assessing radical cystectomy (RC) ± neoadjuvant chemotherapy (NAC). It enrolled 317 patients with T2-T4aN0 BC. Baseline NLR was calculated from prospectively-collected pre-treatment complete blood counts. We performed a secondary analysis on 230 patients with valid NLR who successfully completed RC (119 patients) or NAC + RC (111 patients). We evaluated the association of NLR with OS in univariable and multivariable Cox regression models, adjusting for pre-specified factors (age, gender, T-stage, lymphovascular invasion [LVI], and treatment received). Model assumptions of linearity and proportional hazards were checked. We estimated an 80% power to detect a hazard ratio (HR) of ≥ 1.11 for death with each unit increase in NLR at α = 0.05. We addressed missing values via multiple imputation and defined OS from date of treatment to death. Results: There were complete data for all covariates except a small portion ( < 7%) of LVI values. Median baseline NLR was 2.7 (IQR 2.0-4.1), and NLR was not significantly associated with any other covariate. During a median follow-up of 18.6 years, there were 172 deaths. On multivariable analysis, older age (HR 1.05, 95% CI [1.04-1.07], P < 0.001) and treatment with RC alone (HR 1.39, 95% CI [1.03-1.88], P = 0.03) were associated with worse OS. Baseline NLR was not associated with OS in either univariable (HR = 1.03, 95% CI [0.97 – 1.10], P = 0.30) or multivariable models (HR = 1.04, 95% CI [0.98 – 1.11], P = 0.24). Conclusions: In contrast to previous studies, this analysis of prospectively-collected trial data suggests baseline neutrophil-to-lymphocyte ratio is not prognostic for OS in patients with muscle-invasive bladder cancer.
Safety, clinical activity, and PD-L1 expression of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic urothelial carcinoma from the JAVELIN Solid Tumor phase Ib trial.
Authors: Apolo Andrea B. , Infante Jeffrey R. , Hamid Omid , Patel Manish R. , Wang Ding , Kelly Karen , Mega Anthony E. , Britten Carolyn D. , Mita Alain C. , Ravaud Alain , Cuillerot Jean-Marie , von Heydebreck Anja , Gulley James L.
Published: February 2017

367

Background: Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in multiple clinical trials. We report safety and clinical activity of avelumab as a second-line therapy in patients (pts) with metastatic urothelial carcinoma (mUC) based on level of PD-L1 expression (NCT01772004). Methods: Pts with mUC unselected for PD-L1 expression received avelumab at 10 mg/kg Q2W by IV infusion until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumors were assessed every 6 wks (RECIST 1.1). Best overall response rate (ORR) and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression was assessed by immunohistochemistry. Results: As of 19 Mar 2015, 44 pts (30 men, 14 women) with mUC were treated with avelumab (median 13 wks [range 2-28]) and followed for a median of 3.5 mo (range 3.0-5.0). Median age was 68y (range 30-84), ECOG performance status was 0 (43.2%) or 1 (56.8%), and pts had received a median of 2 prior therapies (range 1- ≥ 4). Treatment-related treatment-emergent AEs (TR-TEAEs) of any grade occurred in 26 pts (59.1%); those occurring ≥ 10% were grade 1/2 infusion-related reactions (8 [18.2%]) and fatigue (7 [15.9%]). One pt had grade 3 asthenia. There were no treatment-related deaths. ORR was 15.9% (7 pts; 95% CI: 6.6, 30.1) with 1 CR and 6 PRs; 6 responses were ongoing at data cutoff. Stable disease (SD) was observed in 19 pts (42.3%) and disease-control rate (CR+PR+SD) was 59.1%. PD-L1 expression was evaluable in 32 pts. Using a ≥ 5% cutoff (10/32 [31.3%] were PD-L1+), ORR was 40.0% in PD-L1+ pts (4/10) vs 9.1% in PD-L1– pts (2/22; p= 0.060). PFS rate at 12 wks was 70.0% (95% CI: 32.9, 89.2) in PD-L1+ pts vs 45.5% (95% CI 22.7, 65.8) in PD-L1− pts. Conclusions: Avelumabshowed an acceptable safety profile and had clinical activity in pts with mUC. There was a trend towards higher ORR and prolonged PFS rate at 12 wks in pts with PD-L1+ mUC. Further analyses of PD-L1 expression and clinical activity of avelumab in UC are ongoing. *Proposed INN. Clinical trial information: NCT01772004.
Variant isoforms of CD44 expression as predictive markers for mortality in surgically treated patients with locally advanced upper tract urothelial carcinoma.
Authors: Kikuchi Eiji , Hagiwara Masayuki , Hayakawa Nozomi , Mizuno Ryuichi , Kosaka Takeo , Mikami Shuji , Miyajima Akira , Saya Hideyuki , Oya Mototsugu
Published: February 2017

388

Background: The variant isoforms of CD44 (CD44v), which are some of the new cell surface markers for cancer stem cells, have been associated with tumor growth, treatment resistance, and cancer death in several cancers. We investigated the role of CD44v8-10, which is a CD44v, on the clinical outcome of patients with advanced upper tract urothelial cancer (UTUC). Methods: The protein expression of CD44v8-10 was immunohistochemically evaluated using CD44v9 antibody, which detects immunogen of CD44v8-10, and investigated the association with clinical characteristics and outcome in surgical specimens obtained from 110 patients who had been treated with radical nephroureterectomy for ≥pT2 UTUC. The mean percentage of positive cancer cells stained with CD44v9 antibody in each tumor was estimated. Results: The median percentage of CD44v9 positivity was 5.50±7.74%. Patients were subsequently stratified into a CD44v9-positive group (n = 82) and a CD44v9-negative group (n = 28) based on a cut-off level of 5%. During the mean follow-up of 4.8 years, disease recurrence was observed in 49 patients (59.8%) in the CD44v9-positive group and in 8 patients (28.6%) in the CD44v9-negative group. The 5-year recurrence-free survival rates were 47.6% in the CD44v9-positive group and 66.6% in the CD44v9-negative group (p= 0.038). Multivariate analysis showed that tumor grade G3 (p= 0.005, HR = 3.77), the presence of lymphovascular invasion (p= 0.041, HR = 1.84), and CD44v8-10 expression (p= 0.028, HR = 2.33) were independent risk factors for disease recurrence. In this series, 37 patients in the CD44v9-positive group (45.1%) and 5 (17.9%) in the CD44v9-negative group died of the disease. The 5-year cancer-specific survival rates were 57.8% in the CD44v9-positive group and 80.4% in the CD44v9-negative group (p= 0.032). The CD44v9 expression (p= 0.040, HR = 2.67) in addition to tumor grade G3 (p= 0.003, HR = 8.35) were independently associated with cancer death. Conclusions: The expression ofCD44v8-10 may be a new biomarker of malignant potential in locally advanced UTUC and could provide additional prognostic information in patients with UTUC.
A phase I study of chemoradiation with weekly panitumumab following neoadjuvant chemotherapy and pelvic lymph node dissection as an organ preserving treatment of invasive bladder cancer.
Authors: Fransen van de Putte Elisabeth E. , Pos Floris J. , Doodeman Barry , van Rhijn Bas W.G. , van der Laan Elsbeth , Van Der Heijden Michiel Simon , Kerst Jan M. , Horenblas Simon , Bergman Andre M.
Published: February 2017

392

Background: Radical Cystectomy (RC) is the standard treatment of Invasive Bladder Cancer (IBC). Although organ sparing, external beam Radiation Treatment (RT) alone is considered inferior to RC. Since the Epidermal Growth Factor receptor (EGFr) is frequently overexpressed in IBC, combined EGFr inhibition by Panitumumab (P) and RT might improve treatment outcome. In this study, the safety and efficacy of concurrent RT and P (RT/P) following Neoadjuvant Chemotherapy (NAC) and Pelvic Lymph Node Dissection (PLND) was evaluated. Methods: cT2-4N0-2M0 or cT1N1-2M0 bladder cancer patients were enrolled in the study. NAC consisted of a maximum of 4 cycles platinum-based chemotherapy. cN0 patients received NAC after PLND, while cN+ patients (confirmed by fine needle aspiration) received NAC prior to PLND. RT/P consisted of concurrent P (7 weekly doses of 2.5 mg/kg) and bladder RT (66Gy in 33 fractions). Primary end-points were treatment-related toxicity and complete clinical response (CR) assessed by Computed Tomography and cystoscopy 3 months after therapy completion. Partial response (PR) was defined as cT < 2N0. Results: A total of 31 patients were included (mean age: 60±10 years), 3/31 patients were cN1-2. Three patients discontinued NAC after 3 cycles due to toxicity. After NAC (24 cisplatin-based and 7 gemcitabine/carboplatin) 13 (41.9%) patients had remaining visible disease. All patients completed RT, while 4/31 patients terminated P prematurely (2-6 doses) due to toxicity. Preliminary response results after RT/P were available for 29/31 patients. Twenty-six/29 (89.7%) patients had a CR, 3 patients PR (10.3%) of which 2 were treated with transurethral resection and intravesical treatment (TaG1-2) and 1 patient underwent immediate cystectomy after histologic confirmation of T1G3. Conclusions: These preliminary results suggest that concurrent P and RT following NAC and PLND is an organ-preserving option for IBC. Toxicity, EGFr expression, mutational status and long-term oncologic outcomes have to be awaited. Clinical trial information: NL31148.031.10.
Effect of chemotherapy and/or TURBT on pathologic response in patients receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer.
Authors: Brant Aaron , Kates Max , Chappidi Meera , Patel Hiten D. , Sopko Nikolai A. , Bivalacqua Trinity J.
Published: February 2017

395

Background: Neoadjuvant chemotherapy (NAC) for muscle−invasive bladder cancer (MIBC) has been associated with a survival benefit in patients who achieve pathologic response. However, a smaller but significant group of patients who receive transurethral resection of bladder tumor (TURBT) without NAC will also be down−staged. We estimated the prevalence of pathologic response to TURBT in patients who receive NAC. Methods: Of 737 serial patients who received radical cystectomy (RC) at Johns Hopkins Medical Center from 2005–2014, 328 with cT2 urothelial carcinoma were identified. 172 patients received NAC and TURBT, while 156 received only TURBT prior to RC. Demographic, clinical, and pathologic information was compared between groups using Wilcoxon−Mann−Whitney for continuous and chi−squared for categorical variables. Pathologic response was defined as < pT2 at RC. A Poisson regression model with robust error variance was used to determine relative risk (RR) of pathologic response in NAC vs. non−NAC patients, adjusting for age, body mass index (BMI), race, gender, Charlson score, smoking status, days from MIBC diagnosis to surgery, and history of prior non−MIBC (NMIBC). Results: Pathologic response was higher in NAC patients compared to non−NAC patients (62% vs. 21%, RR = 3.00). NAC patients were significantly younger than non−NAC patients (64.8 vs. 71.2 years, p < 0.01), with higher BMI (28.1 vs. 26.7 kg/m2, p < 0.01), lower frequency of Charlson score ≥ 3 (13.4% vs. 26.7%, p < 0.01), and lower frequency of prior NMIBC (9.4% vs. 22.4%, p < 0.01). Adjustment resulted in a RR of pathologic response in NAC vs. non−NAC patients of 2.50 (95% CI: 1.69−3.69, p < 0.01). Assuming no interaction between NAC and TURBT, this adjusted model suggests that in a cohort of patients who receive NAC, 40% (95% CI: 27–59%) of pathologic response can be attributed to TURBT. Conclusions: An adjusted model suggests that in a cohort of patients who receive NAC and TURBT prior to RC, 40% of pathologic response can be attributed to TURBT. An understanding of which patients are true responders to chemotherapy and which receive a therapeutic TURBT is needed to select optimal candidates for NAC.
Diagnostic and therapeutic workup of patients with hematuria: Analysis of 1048 consective patients in a German outpatient service.
Authors: Eisenhardt Andreas , Heinemann Daniel , Niedworok Christian , RÃƒÂ¼bben Hebert
Published: February 2017

399

Background: The diagnostic workup of patients with hematuria especially microhematuria is discussed controversially. For this reason the diagnostic and therapeutic procedures of 1049 patients with hematuria referred to our urological outpatient service in the years 2011-2012 were analysed. Methods: A number of 1049 consecutive patients with hematuria referred to the outpatient service Praxisklinik Urologie Rhein-Ruhr in the years 2011-2012 were retrospectively included into the analysis. The following parameters were measured: demographic data, concomittant diseases, clinical symptoms regarding the urinary tract, history of cancer or radiation of the pelvis, diagnostic and therapeutic procedures. Results: The median age was 58 years and the study group comprised 479 men and 570 women. A number of 160 patients had a urinary tract infection within 4 weeks of presentation and 89 individuals presented with macrohematuria. Symptoms of urolithiasis occured in 148 patients. All patients had ultrasound of the genitourinary tract and 731 were examined by excretion urogram, 111 patients via CT-scan of the abdomen and 888 individuals via urethrocystoscopy. Further workup revealed 77 stones via radiological examination and a total of 11 renal cell cancers, 57 papillary urothelial tumors of the bladder, 1 tumor of the ureter and 6 muscle-invasive bladder tumors were detected. Conclusions: Our data presented here reassures invasive diagnostic workup of patients with hematuria due to the fact that cancer of the genitourinary tract is detected in more than 5 percent of patients.