bluuebunny/crossref_metadata_2025 huggingface dataset:
Adiponectin-AdipoR1 axis in renal cell carcinoma plays a pivotal role in tumor progression and drug resistance.
Authors: Sun Guangxi
Published: March 2019

634

Background: It is well established that renal cell carcinoma (RCC) is an obesity-associated cancer. Adiponectin, a major adipocyte-secreted adipokine, plays anti-tumor properties in many malignancies, but exerted paradoxical actions on RCC. Herein, we investigated the effects of adiponectin on RCC progression and resistance to sunitinib, and to exploit this molecular mechanism. Methods: Tissues were collected from 126 patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitor (TKI) therapy. Tumor Adiponectine receptor 1 (AdipoR1) and Adiponectine receptor 2 (AdipoR2) were detected by immunohistochemistry. Assays with RCC cell lines were used to examine the signal transduction pathways of adiponectin in RCC. Results: AdipoR2 was generally lower expressed than AdipoR1 in mRCC tumor (15.6% vs 89.1%, p < 0.001). AdipoR1 expression, but not AdipoR2, was a significant independent predictor of favorable responding to TKI and good survival outcomes. In cultured RCC cells adiponectin inhibited migration and invasion of RCC cells and sensitized cells to killing by sunitinib. Mechanistic investigations of ligand–receptor interactions revealed that AdipoR1 could hinder migration and invasion of RCC cells by blocking GSK3β and β-Catenin pathway and increase cells sensitivity to sunitinib through inhibiting AKT and NF-κB pathway. However, AdipoR2 was not associated with the tumor-limiting properties of adiponectin. Conclusions: These results show that AdipoR1 is a potential prognostic marker for favorable outcomes of mRCC patients. Adiponectin-AdipoR1 axis could be a plausible target to impede tumor progression and sensitize tumors to TKI therapy.
Does increasing time to surgery affect survival in stage I renal cell carcinoma? Analysis of the national cancer database.
Authors: Cotta Brittney , Ryan Stephen , Eldefrawy Ahmed , Sarkar Reith , Bradshaw Aaron , Meagher Margaret Frances , Hamilton Zachary , Murphy James Don , Derweesh Ithaar
Published: March 2019

635

Background: Optimal timing for surgical treatment of localized renal cell carcinoma (RCC) remains undefined. We sought to determine the survival impact of time to definitive surgical treatment for Stage 1 RCC and elucidate factors associated with a delay in surgical care utilizing the National Cancer Database (NCDB). Methods: The NCDB was queried for Stage 1 RCC cases (cT1N0M0) from 2004-2013 treated with partial or radical nephrectomy. Quartiles were formed from the range of time to surgery of the entire cohort in days: early defined as the first two quartiles and delayed as the fourth. Descriptive analyses were conducted between early and delayed groups. Overall survival (OS) between early and delayed groups was calculated with Kaplan-Meier analysis. Multivariable analysis was performed to determine factors associated with delay in surgical care. Results: 38,859 patients were analyzed. Median time to treatment was 40 days (IQR 22-68). Early (≤40 days, n = 23,712) and delayed ( > 68 days, n = 15,147) groups had a median follow-up of 44.8 and 41 months, respectively (p < 0.001). Delayed surgery was more frequent with African-Americans (14.8% vs. 9.1%, p < 0.001), patients with government or no insurance (53.7% vs. 45.1%, p < 0.001), males (60.7% vs. 58.3%, p = 0.001), and Charlson Comorbidity Index (CCI) ≥2 (9.7% vs. 6.7%, p < 0.001). Kaplan-Meier analysis demonstrated survival benefit to the earlier treatment group, with 5 year OS of 85.5% and 80.9% (p < 0.001; Figure). On multivariable analysis, increasing age (OR = 1.001, p = 0.015), African-American race (OR = 1.5, p < 0.001), increasing distance from treatment center (OR = 1.005, p = 0.001), residence in areas with low high school graduation rates (OR = 1.42, p < 0.001), residence in an area of > 1 million population (OR = 1.6, p < 0.001), and CCI ≥2 (OR = 1.4, p < 0.001) were independently associated with increasing time to surgery. Conclusions: Surgery of T1 RCC carried out beyond 9 weeks after diagnosis is associated with reduced overall survival compared to patients treated within 6 weeks. Time to definitive surgical treatment should be a quality of care metric, with special attention given to populations most at risk for delays in care.
Prevalence, disease-free (DFS) and overall (OS) survival of contemporary high-risk renal cell carcinoma (RCC) patients eligible for adjuvant checkpoint inhibitor trials: A RECUR database analysis.
Authors: Dabestani Saeed , Beisland Christian , Stewart Grant , Capitanio Umberto , Jarvinen Petrus , Nisen Harry , Bensalah Karim , Guðmundsson Eirikur , Lam Thomas B , Marconi Lorenzo , Fernandèz-Pello Sergio , Monagas Serenella , Powles Thomas , Meijer Richard Paul , Volpe Alessandro , Staehler Michael D. , Ljungberg Borje , Bex Axel
Published: March 2019

636

Background: Designing adjuvant trials is challenging because of uncertainties of prevalence and outcome of high-risk RCC despite use of validated risk scores. Methods: RECUR is a European multicenter database capturing patient and tumour characteristics, recurrence patterns and survival of all patients treated with (partial) nephrectomy for non-metastatic RCC from 2006 to 2011 at each participating center. We evaluated prevalence, DFS and OS of RCC according to eligibility criteria of adjuvant trials IMMotion 010 (NCT03024996, IM), Checkmate 914 (NCT03138512, CM), Keynote-564 (NCT03142334, KN) and RAMPART (NCT03288532, RP), which all predominantly recruited high-risk clear cell RCC patients. Results: Of 2669 relevant patients in RECUR, 424(15.9%), 681(25.5%), 579(21.7%) and 1221(45.7%) met eligibility criteria for IM, CM, KN and RP respectively (p < 0.001). Median DFS and OS estimates (Kaplan-Meier) in RECUR corresponding to each trial placebo arm were 37.5 (95%CI 30.4–44.6) and 89.6 (95%CI 76.1–103.0) months for IM, 89.4 (95%CI 66.1–112.7) and 96.2 (95%CI 79.8–112.6) months for CM, 62.6 (95% CI39.6–85.6) and 86.6 (95%CI 74.3–98.9) months for KN and finally at 144 months (DFS not reached) and 123.8 (95% CI 110.1 – 137.4) months for RP. Additionally, at pairwise analysis of evaluated trials, DFS estimates were significantly different between all trials (p < 0.001) except between CM and KN (p = 0.125), while OS estimates did not differ significantly between all trials except between RP and the other three trials (p = 0.002). Conclusions: Percentages of eligible high-risk RCC patients in RECUR were low to moderate and, together with estimated placebo arm DFS and OS, varied due to differences in trial eligibility criteria. These differences may impact on the results and interpretation of the trials.
Direct impact of clinical research in metastatic renal cell carcinoma (mRCC): A cost-effectiveness analysis of patient care outcomes and cost savings in a real-life scenario of a large public university hospital in Spain.
Authors: Garcia-Garro Silvia , Gajate Pablo , Gómez-de-Salazar Esther , Alonso Gordoa Teresa , Rodriguez-Sagrado Miguel Angel , Molina CerrilloMD Javier , Manzano Luis , Bermejo Teresa , Carrato Alfredo , Grande Enrique
Published: March 2019

637

Background: Public health sustainability is a major concern worldwide. Clinical research is considered to leverage patient care outcome but also can lead costs savings and, subsequently, to maintain public health system. Thus, we analyzed the direct impact of clinical research in terms of improvement in clinical outcomes and costs related to research in patients with mRCC in real-life setting. Methods: We retrospectively collected data related to overall survival (OS) and direct health care costs from all mRCC patients who were treated with oral anti-tumour medication and followed at the Medical Oncology Department of Ramón y Cajal University Hospital in Madrid, between January 2010 and February 2017. A statistical analysis comparing the outcomes of patients included in clinical trials versus those not included was conducted. Results: In the study period, 65 patients were newly diagnosed with mRCC and received treatment. Those patients included in clinical trials showed higher median OS (91 vs. 29 months. HR 0.389; 95% CI: 0.150: 1.000; p=0.04). Median direct cost per mRCC patient in ‘real-life’ was €67,376. Median cost for a patient enrolled in at least one clinical trial was €53,673 vs. €63,834 for those who were never recruited for a trial. Participation in clinical trials contributed to a decrease in total health expenditure by 9.02% (€362,367), mainly due to reduction in the cost of medications and diagnostic tests (91.46% vs. 8.54%, respectively). Furthermore, clinical trial participants have required less number of hospitalizations (0.08 vs. 1.75) and emergency visits (0.39 vs. 3.2) per patient. Conclusions: Under the public health system perspective, participation in clinical trials is related to an improvement in overall survival as well as direct and indirect cost savings in mRCC patients.
The association of NOX4 mediated nuclear colocalization and overall survival in renal cell carcinoma.
Authors: Kaushik Dharam , Wang Hanzhang , Ashcraft Keith A. , Nazarullah Alia , Liss Michael A. , Pruthi Deepak , Mansour Ahmed , Tye Cooper B. , Chowdhury Wasim , Bacich Dean , O’Keefe Denise , Rodriguez Ronald
Published: March 2019

639

Background: NOX4 protein are involved in cell differentiation, migration and apoptosis. We recently demonstrated that NOX4 in renal cell carcinoma (RCC) is an energetic sensor and couples energy metabolism to drug-resistance. In this study we demonstrate that enhanced nuclear localization of NOX4 is correlated with poor survival. Methods: We identified 350 RCC patients with (n = 85) and without (n = 265) venous tumor thrombus (VTT) who underwent radical nephrectomy with or without thrombectomy at our institution between 2013-2016. Fifty patients with RCC and VTT were matched 1:1 to patients with RCC and no VTT. Tissue Microarray (TMA) consisting of primary renal tumor, adjacent renal tumor and VTT were created. These matched TMA (n = 174) were stained with NOX4 antibodies; scanned using the Aperio scanning system and analyzed with the ImageScope software. The RCC nucleus was evaluated for roundness, elongation and size. NOX4 nuclear staining was categorized based on intensity as either strong positive, moderate, weak or no localization. Differential protein expression between the primary tumor, adjacent normal parenchyma and VTT was assessed using the Chi-squared test or t-test. Progression-free survival (PFS) and overall-survival (OS), stratified by NOX4 staining intensity, was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox regression model was used to investigate effect of NOX4 staining on survival in multivariate analyses. Results: NOX4 nuclear colocalization was higher in patients who had progression and death from RCC. On univariate analysis, the intensity of NOX4 protein expression in the nucleus was significantly associated with PFS (HR 1.67, 95%CI (1.08-2.57; p = 0.02) and OS (HR 2.31, 95%CI (1.26-4.24; p = 0.007). On multivariate analyses the association between NOX4 protein expression and OS remains statistical significance (HR 2.09, 95%CI (1.05-4.18, p = 0.037). Conclusions: We provide evidence that in high grade/high stage cancer, NOX4 is colocalized within the nucleus of RCC. The prognostic role of NOX4 was determined at the protein level. We provide rationale for further investigation of NOX4, which may serve as a checkpoint in RCC.
Cost implications of multi-parametric magnetic resonance imaging in prostate cancer active surveillance.
Authors: Yu Michelle , Maganty Avinash , Macleod Liam C , Yabes Jonathan G , Fam Mina M , Bandari Jathin , Furlan Alessandro , Turner Robert , Filson Christopher Paul , Davies Benjamin John , Jacobs Bruce Lee
Published: March 2019

65

Background: Multi-parametric resonance imaging (mpMRI) has emerged to improve disease risk-stratification and decrease number of repeat biopsies in men on prostate cancer active surveillance (AS). However, the impact of mpMRI on cost of AS has not been established. We thus characterize the impact mpMRI on cost of AS in the Medicare population. Methods: Using SEER-Medicare files we identified men ≥66 years old with localized grade group I-II prostate cancer diagnosed 2008-2013. With an established algorithm, we classified men into active surveillance with and without mpMRI. We then determined cost of surveillance in each group using inflation-adjusted Medicare payments for surveillance-related procedures and their sequalae (i.e. PSA tests, prostate biopsies, post-biopsy complications and mpMRIs). Multivariable median regression compared cost and procedural-intensity for men who received mpMRI and those who did not. Results: We identified 9,081 men on AS with median follow up 45 months (IQR 29-64 months). 7,856 (87%) men did not receive mpMRI and 1,225 (13%) did. On multivariable median regression, receipt of mpMRI was associated with an additional $449 (95%CI $391-$507) in Medicare payments per year. Younger age, treatment in the west or northeast, greater population density and treatment later in the study period were associated with increased cost of AS. Conclusions: Among Medicare beneficiaries on AS, mpMRI is associated with additional annual cost to Medicare. MpMRI may be a marker of more stringent AS, which is likely more costly than watchful waiting. Future studies are needed to determine optimal use of mpMRI during AS to maximize value.
Sunitinib for metastatic renal cell carcinoma: A systematic review and meta-analysis of real world and clinical trials data.
Authors: Moran Michael , Nickens Dana J. , Adcock Katherine , Desscan Arial , Bennetts Meg , Charnley Natalie , Fife Kate
Published: March 2019

650

Background: Randomized controlled trials (RCTs) are the basis of approval for medical interventions, but may not fully reflect populations seen in clinical practice. Sunitinib is a widely used 1st-line treatment for patients (pts) with metastatic renal cell carcinoma (mRCC). This is the first large-scale meta-analysis to evaluate the efficacy of sunitinib using the novel approach of combining RCTs and real-world data (RWD). Methods: PubMed, Ovid, MEDLINE and EMBASE were searched from 2000-2017 for RCTs and RWD studies of sunitinib as 1st-line treatment in pts with mRCC. Eligible studies contained a cohort of ≥50 adult pts per study arm. The meta-analysis combined RWD and RCT study arms, adjusting for data type (RCT or RWD). Recorded outcomes were: median progression-free survival (mPFS), median overall survival (mOS) and objective response rate (ORR). A random effects model to account for study heterogeneity was applied to each endpoint. Sensitivity analyses evaluated the robustness of the overall estimate. Results: Of the studies that met eligibility criteria, mPFS, mOS and ORR were reported by 18, 19 and 15 studies, respectively. Combined RWD and RCT analyses are presented in the Table. Reported mPFS (RWD, 7.5–11.0; RCTs, 5.6–15.1 months) and ORR data (RWD, 14.0–34.6%; RCTs, 18.8–46.9%) were consistent with the overall estimates. Reported mOS showed greater variation in RWD (6.8–33.2 months) compared with RCTs (21.8–31.5 months). Sensitivity analyses showed no evidence of lack of robustness for mPFS, mOS or ORR. Interpretation of these results is limited by differences in trial design and cohort characteristics. Conclusions: This novel, large-scale meta-analysis validates sunitinib as an effective 1st-line treatment for pts with mRCC in both RCTs and everyday clinical practice. [Table: see text]
Leveraging a robust patient-derived xenograft platform to characterize predictors for engraftment and oncologic outcomes in renal cell carcinoma patients.
Authors: Singla Nirmish , Woolford Layton , Stevens Christina , Tcheuyap Vanina , Onabolu Oreoluwa , Xie Zhiqun , McKay Renee , Wang Tao , Christie Alana , Gahan Jeffrey , Bagrodia Aditya , Raj Ganesh , Sagalowsky Arthur I. , Lotan Yair , Cadeddu Jeffrey A , Margulis Vitaly , Kapur Payal , Brugarolas James
Published: March 2019

651

Background: Patient-derived xenograft (PDX) models of renal cell carcinoma (RCC) preserve the biological features of patient tumors, providing a platform for biomarker identification and preclinical drug testing. We sought to identify predictors of successful tumor engraftment and evaluate the prognostic value of engraftment in patients with RCC using a robust murine PDX platform. Methods: 1,200 specimens derived from nephrectomy, thrombectomy, metastasectomy, or biopsy were orthotopically (renally) implanted into NOD/SCID mice between 2008-2018. Non-RCC pathology was excluded. Stable engraftment was defined by successful passage of tumor tissue at least twice with histologic confirmation. Clinicopathologic characteristics were stratified by engraftment status, and multivariate (MVA) logistic regression was used to identify predictors of engraftment. Kaplan-Meier and Cox regression analyses were used to assess the prognostic value of engraftment on patient overall (OS) and disease-free (DFS) survival. Results: 1,003 independent PDX lines derived from 770 RCC patients were included. 157 (15.6%) lines successfully engrafted and exhibited higher tumor grade, stage, size, and presence of sarcomatoid or rhabdoid components. Whole exome sequencing was performed on 230 PDX lines. On MVA, sarcomatoid (OR 5.71, p < 0.001), rhabdoid (OR 2.79, p = 0.046), and advanced stage (OR 1.72, p = 0.049) were significant predictors for engraftment, while high grade and metastatic tumor source were significant only on UVA. Engraftment was associated with poor OS (HR 2.11, p < 0.001) and DFS (HR 1.85, p = 0.020) in patients after controlling for sarcomatoid, rhabdoid, grade, stage, and age on MVA. Conclusions: Aggressive RCC biology correlates with successful engraftment in PDX models. Engraftment remains independently predictive of OS and DFS even after controlling for adverse pathologic features. Engraftment in mice may illuminate aspects of tumor biology not captured by clinicopathologic variables and provide insight into novel determinants of tumor aggressiveness and metastasis. Efforts are underway to elucidate genomic drivers of engraftment.
Safety and efficacy of restarting immune checkpoint inhibitors (CPI) after immune-related adverse events (irAEs) in metastatic renal cell carcinoma (mRCC).
Authors: Abou Alaiwi Sarah , Martini Dylan J , Xie Wanling , Nassar Amin , Bakouny Ziad , Steinharter John A. , Nuzzo Pier Vitale , Flippot Ronan , Chanza Nieves M. , Wei Xiao X. , McGregor Bradley Alexander , Bilen Mehmet Asim , Choueiri Toni K. , Harshman Lauren Christine
Published: March 2019

652

Background: CPI can induce a range of irAEs with various degrees of severity. Clinical experience with retreatment following clinically significant irAEs is growing. Methods: We retrospectively reviewed mRCC patients treated with CPI-based regimens who had >1 week therapy delay for irAEs at Dana Farber and Emory to characterize the safety and outcomes of retreatment. Toxicity was graded by CTCAEv5. Patients were divided into retreatment (R) and discontinuation (D) cohorts. Patient characteristics were compared by Fisher’s exact test or Wilcoxon’s rank sum test. ORR, OS and PFS were assessed descriptively. Results: Of 339 treated with CPI, 53 (16%) had irAEs warranting treatment interruption: 24 (45%) in R and 29 (55%) in D. Median (med) time to drug interruption was 2.0 (<0.1-74) months (mos) in D and 3.2 (<0.1-21) mos in R (p=0.89). Prior to irAE onset, 8 (28%) of cohort D and 5 (21%) of cohort R experienced partial responses (PR). While type of irAEs were balanced across D and R, initial irAEs were less severe in R vs D (all p<0.05) with fewer grade (gr) 3-4 events (29% vs 66%), less hospitalizations (25% vs 69%), and lower steroid requirements (>40 mg: 29% vs 79%). The most common irAEs in R were transaminitis, pancreatitis and dermatitis with 7 gr 3/4 events (pancreatitis, colitis, adrenal insufficiency and dermatitis). Median drug break before retreatment was 1.2 (0.3-4.8) mo. Subsequent irAEs occurred in 42% (n=10) after restarting (8 new, 2 recurrent) with 2 discontinuations; 6/10 were gr 3 with no gr 4/5 events. Median interval to irAE recurrence after retreatment was 2.1 (0.5-3.3) mos. Retreatment resulted in 4 (17%) PRs in patients whose disease had not responded prior to irAE (med time to PR from R = 2 mos). Conclusions: Despite a significant rate of irAE recurrence, most patients with prior clinically significant irAEs can be safely retreated. Retreatment can induce responses in an appreciable proportion of patients with no response prior to irAE. Larger studies are warranted to confirm these findings. [Table: see text]
Management of isolated local failures following stereotactic body radiation therapy for low to intermediate risk prostate cancer.
Authors: Drescher Nicolette , Aghdam Nima , Danner Malika , Ayoob Marilyn , Yung Thomas M. , Lei Siyuan , Collins Brian Timothy , Lischalk Jonathan , Dritschilo Anatoly , Suy Simeng , Kumar Deepak , Lynch John J. , Collins Sean P.
Published: March 2019

66

Background: SBRT is a safe and effective treatment option for patients with low to intermediate risk prostate cancer (PCa). SBRT delivers high biologically effective doses resulting in very low PSA nadirs. Strategies to diagnose and confirm salvageable isolated local failures (ILF) are needed. This study aims to examine the incidence and approach to management of ILF after SBRT in a large single institution cohort. Methods: All patients with low or intermediate risk PCa treated with SBRT at our institution were eligible for this study. Treatment was delivered using the robotic SBRT with doses of 35-36.25 Gy in five fractions. ILF were diagnosed using mpMRI and/or biopsy prompted by PSA rise after achieving long-term nadir. Choice of salvage therapy and post-salvage PSA were ascertained on follow up. Results: Between December, 2008 to August, 2018, 998 men with low to intermediate risk prostate cancer were eligible for analysis. Twenty patients (low risk, n = 4; intermediate risk, n = 16) were found to have ILF on either MRI (n = 15) and/or biopsy (n = 17). Three patients with MRI-identified ILF elected active surveillance in lieu of biopsy. Median pre-treatment PSA was 7.5 ng/ml. Median time to diagnosis of ILF was 72 months (37-96 months) with median PSA at the time of ILF of 2.3 ng/ml (1.1-10 ng/ml). Median PSA doubling time was 17 months (5-22 months). Thirteen patients with biopsy proven ILF proceeded with salvage therapy (cryotherapy n = 12, HIFU n = 1). Of 12 patients who underwent cryotherapy, 8 had a post-treatment PSA of < 0.1ng/ml, two patient’s results were unavailable, one patient had a PSA nadir of 0.7 ng/ml and one patient had yet to undergo post-salvage PSA test at the time of this report. Conclusions: The incidence of ILF is rare in our series. Diagnosis and management of ILF post-SBRT continues to evolve in the era of successful salvage therapy. Our report suggests an important role for early utilization of MRI and confirmatory biopsy at relatively low PSA levels and long PSA doubling time. Additionally, undetectable PSA post-salvage therapy supports early treatment after identifying ILF. Larger trials are needed for refinement of patient selection and most appropriate salvage modality.
Role of magnetic resonance imaging-transrectal ultrasound fusion targeted biopsy in the detection of prostate cancer in biopsy-naïve men: A literature based meta-analysis of randomized trials.
Authors: Tu Xiang , Liu Zhenhua , Qiu Shi , Xu He , Li Jiakun , Liao Xinyang , Jin Kun , Bao Yige , Yang Lu , Wei Qiang
Published: March 2019

70

Background: Magnetic Resonance Imaging-Transrectal Ultrasound (MRI/TRUS) fusion targeted biopsy (TB) has been demonstrated to increase detection rates (DRs) of prostate cancer (PCa) in repeat-biopsy setting. However, its role in biopsy-naïve men remains controversial. We performed a meta-analysis based on well-designed randomized controlled trials (RCTs) to compare the diagnostic accuracy of MRI/TRUS fusion TB and systematic biopsy (SB) in the detection of PCa in biopsy-naïve men. Methods: A systematic review of PubMed (Medline), Embase, Ovid and the Cochrane Library up to 1st October, 2018 was conducted. The statistical analyses were performed with Revman 5.3. We compared the diagnostic accuracy between the intervention group (assisted with fusion TB) and the control group (SB only) by calculating the risk ratio (RR) with 95% confidence intervals (CIs) of overall PCa and clinically significant PCa (csPCa) DRs. Subgroup analysis was performed to highlight the independent role of MRI/TRUS fusion TB alone or combining fusion TB and SB together in the detection of PCa. Results: Six RCTs with 2187 participants were evaluated for the DRs of overall PCa. Pooled analysis revealed slight higher DRs of 62.7% (687/1095) in the intervention group compared with that of 41.3% (451/1092) in the control group (RR 1.40, 95% CI: 1.00-1.95). Four studies with 962 participants were evaluated for the DRs of csPCa. There is a trend favoring the intervention group which detected more csPCa (42.8%, 206/481) compared with SB in the control group (31.6%, 152/481) but with no significant difference (RR 1.36, 95% CI: 0.95-1.95). Subgroup analysis revealed fusion TB alone with less biopsy cores may equal the DRs of csPCa compared with SB alone (RR 1.24, 95% CI: 0.79-1.93). However, the DRs of overall PCa when combining MRI/TRUS fusion TB and SB was comparable to that applying SB alone (RR 1.48, 95% CI: 0.99-2.22). Conclusions: MRI/TRUS fusion TB may obtain similar csPCa DRs with less biopsy cores. But currently there was no enough evidence showing fusion TB can help significantly improve overall PCa or csPCa DRs compared with SB alone in biopsy-naïve men.
Racial disparities in survivorship care adherence among Medicare beneficiaries with prostate cancer.
Authors: Parikh Ravi Bharat , Chhatre Sumedha , Malkowicz S. Bruce , Li Bingnan , Jayadevappa Ravishankar
Published: March 2019

72

Background: African-American men with prostate cancer have higher cancer-related and all-cause mortality than their Caucasian counterparts. Differences in adherence to guideline-based survivorship care may contribute to these disparities. Methods: Using the SEER-Medicare database, we conducted a retrospective cohort study of men ≥66 years old treated for localized prostate cancer between 2008 and 2011 who had at least two visits with a specialist or primary care physician after diagnosis. Patients were followed until 2013. We calculated rates of bone mineral density screening (among men treated with androgen deprivation therapy) and colorectal cancer screening after diagnosis, stratified by race and provider seen. We analyzed the association between continuity of care (CoC) and adherence to colorectal cancer screening after calculating a CoC index. Results: Among 107262 men with localized prostate cancer, adherence to colorectal cancer and bone mineral density screening was higher for Non-Hispanic White and Hispanic men compared to African-American men (Table). Adherence to screening was slightly higher for men who followed with primary care physicians compared to specialists. After adjusting for relevant covariates and number of providers, higher CoC with primary care physicians was associated with improved adherence to colorectal screening among Non-Hispanic Whites (OR = 1.25, 95% CI = 1.11-1.40), African-Americans (OR = 1.39, CI = 1.05-1.84) and Hispanics (OR = 2.74, CI = 1.27-5.90). However, higher CoC with specialists was significantly associated with colon cancer screening only among African Americans (OR 1.59, 95% CI 1.25-2.04). Conclusions: Among a large cohort of men with localized prostate cancer, the association between CoC and guideline-based survivorship care varied by type of provider and by racial and ethnic group. [Table: see text]
Plasma citrulline levels as a biomarker for bowel toxicity in prostate stereotactic radiotherapy with or without pelvic nodal radiation.
Authors: Fairmichael Ciaran , Redmond Kelly M. , Lyons Ciara , Stevenson Sarah R. , Osman Sarah O. , McGarry Conor K. , Irvine Denise M. , Mitchell Darren M. , King Raymond B. , Hounsell Alan R. , O'Sullivan Joe M. , Waugh David J. , Jain Suneil
Published: March 2019

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Background: Plasma levels of citrulline, an amino acid, are derived mainly from small bowel enterocytes. Decreased levels occur in a range of bowel conditions and citrulline has been proposed as a biomarker of bowel toxicity in pelvic radiotherapy. In a prospective study, we identify no correlation between plasma citrulline and toxicity in men receiving prostate stereotactic radiotherapy randomized to receive either pelvic nodal irradiation or not. Furthermore, citrulline levels were not significantly different between these two groups. Methods: As part of an approved clinical trial, men with intermediate to high risk prostate cancer were randomised 1:1 to prostate only or prostate + pelvic nodal radiotherapy, delivered with a rectal spacer gel in situ. The prostate and proximal seminal vesicles received 40 Gy in 5 fractions. Those randomised to the pelvic nodal arm also received 25 Gy in 5 fractions to pelvic nodes. Citrulline was measured at 10 points during treatment – consent, before fraction 1, 1 and 24 hours following fraction 1, prior to each fraction 2 – 5 and at 6 weeks’ and 3 months’ follow up. Bowel toxicity was measured by EPIC patient reported scores. Results: 16 men with follow up of at least 3 months (median 9, maximum 18 months) were analysed. Reported toxicity was significantly higher in the prostate and pelvis arm: 5 of 9 men showed a decrease in EPIC bowel domain summary score of 10 points or more compared to 0 of 7 in the prostate-only arm (p = 0.0337, two tailed Fisher’s exact test). No significant correlation between toxicity and citrulline levels was seen, nor did citrulline vary significantly between arms or fall as treatment progressed. Data analysis for a further 8 men already recruited to the study is ongoing. Conclusions: Toxicity was more commonly reported by men randomised to receive pelvic radiotherapy, suggesting that the small bowel irradiated in pelvic fields plays a role in bowel toxicity experienced during stereotactic radiotherapy. Citrulline levels showed no significant correlation with toxicity or radiation dose to small bowel. We propose that citrulline is not a useful biomarker of small bowel toxicity in this setting. Clinical trial information: NCT03253978.
Four-year outcomes of hypofractionated proton therapy for localized prostate cancer.
Authors: Grewal Amardeep S. , Schonewolf Caitlin , Both Stefan , Lam Sarah , Mazzoni Susan , Bekelman Justin E. , Christodouleas John Paul , Vapiwala Neha
Published: March 2019

80

Background: Hypofractionated radiation therapy (HFRT) is an effective treatment for localized prostate cancer (LPC). This study was performed to determine the toxicity profile and biochemical-clinical failure (BCF) rates for patients with LPC treated with hypofractionated proton therapy (HFPT). Methods: Between 2010 and 2017, 184 men were enrolled on a trial of 70Gy in 28 fractions of HFPT for low to intermediate-risk LPC. Androgen suppression (AS) was allowed. Acute and late toxicity was evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. Urinary and erectile quality of life changes were captured using the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF-5) Questionnaire, respectively. Results: Median follow-up was 49.2 months. Enrolled patients had low-risk [LR] (n = 18), favorable intermediate-risk [FIR] (n = 78), and unfavorable intermediate-risk [UIR] (n = 88) disease. Twenty-six percent of patients received neoadjuvant and concurrent AS, with a median duration of 6 months. Four-year rates of BCF free survival were 95.7%, 94.4%, 98.7%, and 93.2% in the overall group and the LR, FIR, and UIR cohorts, respectively (p = .21). Overall survival at 4 years was 97.3%. No deaths were attributable to prostate cancer. Median IPSS before and 1 year post-HFPT were 6 and 7 for LR patients, 6 and 6 for FIR patients, and 8 and 7 for UIR patients. Median IIEF-5 before and 1 year post-HFPT were 21 and 18 for LR patients, 18 and 16.5 for FIR patients, and 15 and 10.5 for UIR patients. The incidence of acute grade 2 or higher gastrointestinal (GI) and urologic (GU) toxicities were 3.8% and 12.5%, respectively. One acute grade 3 GI toxicity was reported. The 4-year incidence of late grade 2 or higher GU and GI toxicity was 7.6% and 13.6%, respectively. One late grade 3 GI toxicity was reported. The predominant late grade 2 GI and GU toxicities were rectal bleeding and urinary frequency, respectively, accounting for 79% and 57% events. All late toxicities were transient. Conclusions: HFPT is associated with low rates of toxicity in the treatment of prostate cancer. Further analyses are warranted to assess long term toxicity and understand differences between proton and photon HFRT. Clinical trial information: NCT01352429.
Health literacy is a barrier to shared decision making in early prostate cancer (PCA) among African American (AA) men.
Authors: Martin-Doyle William , Filson Christopher Paul , Regan Susan , Trinh Quoc-Dien , Williams Sierra , Master Viraj A. , Kilbridge Kerry L.
Published: March 2019

84

Background: ASCO, AUA, ASTRO and SUO endorse shared decision making for men with localized PCa. We explored treatment decisions among providers and their AA patients (pts) in a prospective cohort study at Grady Memorial Hospital and the Atlanta Veterans Administration Hospital. Methods: Following their visit, 18 providers documented the PCa treatment options they had discussed with 124 newly diagnosed, early-stage, African American PCa pts. At a subsequent visit, prior to choosing their cancer treatment, pts were asked to name the options they had discussed with their provider. Demographics were collected. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM). Numeracy, comprehension of common PCa terms, and anatomic knowledge were assessed using published methods (Kilbridge K, et al. J Clin Oncol 27:2015-2021, 2009). Chi-square, t-tests and multivariate logistic regression were used to identify variables associated with correct understanding of treatment choices. Results: Just 23.4% of pts correctly understood their treatment options. In univariate analysis, only health literacy was statistically significantly associated with comprehension of PCa treatment options (p < 0.05). In a multivariate logistic model adjusting for age, education, income, numeracy, comprehension of common PCa terms, and anatomic knowledge; health literacy remained the only significant predictor of pts’ comprehension of their treatment choices (OR 3.8, 95% CI 1.2-11.9, p = 0.021). Even among the 49 pts with the highest level of health literacy, only 34.7% correctly understood their cancer treatment options (compared to 16.0% among low literacy patients). Conclusions: Successful shared decision making requires pts to understand their treatment choices. Information presented by healthcare providers may be overwhelming for newly diagnosed pts, particularly those with lower health literacy. Our study suggests that even pts with the highest level of health literacy may need additional support to understand their PCa treatment options.
Clinical and genetic determinants of toxicity and quality-of-life (QOL) outcomes for SBRT in Asian prostate cancer.
Authors: Tan Janice Ser Huey , Tan Sheena Xue Fei , Li Youquan , Tuan Jeffrey Kit Loong , Tan Terence Wee Kiat , Wang Michael Lian Chek , Tay Kae Jack , Lee Lui Shiong , Teh Jonathan Yi Hui , Chua Melvin Lee Kiang
Published: March 2019

95

Background: There is limited data on clinical and patient-reported quality of life (PRO-QOL) outcomes after stereotactic body radiotherapy (SBRT) in Asian men with localised prostate cancer. Demographic differences with regard to PRO-QOL outcomes may be due to variation in germline genetics. We therefore conduct a single-institution prospective phase II trial of prostate SBRT in Asian men with intermediate-risk prostate cancers (IR-PCa). Additionally, we investigated association of dosimetric and genetic factors with outcomes. Methods: Patients with biopsy-proven NCCN-defined IR-PCa were recruited. SBRT was delivered at 36.25 Gy/5fr using a Linac-based RapidArc technique. Adverse events (AEs) were assessed with CTCAEv4.0 and IPSS; PRO-QOL assessed using the EPIC instrument at baseline, 1 and 2-year post-SBRT. Germline genetics were profiled by whole exome sequencing (30X). Results: 65 patients were recruited over the period of 2014-2016 (median follow-up = 30 mo). We observed 4 acute ≥G2 gastrointestinal (GI) events (3 fecal urgency, 1 diarrhea). Longitudinal assessment of acute genitourinary (GU) events by IPSS showed worsened symptoms that peaked at 1 wk post-SBRT (44.6% vs 6.2% at 1 mo for men reporting scale upgrade). There was no significant association between acute GU effects (by IPSS) and dosimetric parameters of the irradiated urethra and bladder. PRO-QOL scores demonstrated minimal change over time across all domains; however, sexual bother in the top 50th percentile subgroup at baseline indicated ≥20% worsening of scores for 10/32 (31%) at 12 mo and 5/12 (42%) at 24 mo; which was not associated with Dosemax to the penile bulb (P = 0.1). We observed a high frequency of germline mutations in DNA repair genes (N = 10; 15.4%), including two BRCA2 stop-gain and frameshift mutations. In particular, BRCA2 mutations were detected in 2 of 4 cases with ≥G2 GI effects, independent of rectal dose. Conclusions: While prostate SBRT is well tolerated in our Asian cohort, there appears to be demographic differences in sexual bother compared to Caucasian cohorts. Interestingly, we observed a higher than expected prevalence for germline mutations in DNA repair genes, which may predict treatment response. Clinical trial information: NCT02313298.
A 17-gene genomic prostate score as a predictor of adverse pathology for men on active surveillance.
Authors: Kornberg Zachary , Cooperberg Matthew R. , Cowan Janet E. , Simko Jeffry , Chan June M. , Tenggara Imelda , Carroll Peter
Published: March 2019

97

Background: The OncotypeDX Genomic Prostate Score (GPS) test is a RNA expression assay that can be performed on needle-core biopsies from men with prostate cancer (PCa). GPS has previously been validated as a predictor of adverse pathology in men with low-risk prostate cancer who undergo primary radical prostatectomy (RP). We sought to determine whether GPS was associated with increased risk of adverse pathology for men enrolled on active surveillance (AS) who undergo delayed RP. Methods: Of 1,662 men enrolled on AS at the University of California San Francisco (UCSF) who consented for prospective data collection, we evaluated 215 men on AS with Gleason score (GS) 3+3 and GS 3+4 PCa who underwent GPS testing at diagnostic or confirmatory biopsy (ie. within 1 year). Patients had at least 6 biopsy cores sampled and ≤ 33% positive cores, stage T1 or T2 disease, PSA < 20, and clinical Cancer of the Prostate Risk Assessment (CAPRA) score < 6. The primary outcome was adverse pathology at delayed RP, defined as GS ≥ 4+3, stage ≥ pT3a or pN1. We performed Cox proportional hazards regression, and inverse probability censored weights (IPCW) models to evaluate association between GPS and adverse pathology, adjusting for CAPRA score. Results: 72 percent (N=154) of the cohort had GS 3+3, and 28 percent (N=61) had GS 3+4. 83 percent of men (N=179) were low risk, and 17 percent of men (N=36) were intermediate risk by CAPRA scoring. Median GPS was 26.4 (interquartile range [IQR]: 18.8, 34.6). Median time from diagnosis to RP was 23 months (IQR: 15, 40). 121 men had adverse pathology on delayed RP at a median time of 27 months (IQR 16, 43) to prostatectomy. In a Cox-proportional hazards regression adjusted for CAPRA, GPS was associated with increased risk of adverse pathology at delayed RP (Hazard Ratio [HR] per 5 units: 1.12, 95 Confidence Interval [CI]: 1.05, 1.20, p < 0.01). CAPRA score was not associated with adverse pathology (p=0.09). IPCW model findings were very similar to Cox results. Conclusions: In patients who undergo RP after a relatively short period of AS, a higher GPS is associated with increased risk for adverse pathology on delayed RP.
Impact of testosterone replacement therapy after radiation therapy on prostate cancer outcomes.
Authors: Sarkar Reith , Parsons J Kellogg , Einck John Paul , Mundt Arno James , Kader A. Karim , Kane Christopher J. , Riviere Paul , McKay Rana R. , Murphy James Don , Rose Brent Shane
Published: March 2019

99

Background: Currently there is little data to guide the use of testosterone replacement therapy in prostate cancer patients who have received radiation therapy (RT). We sought to evaluate the impact of post-RT testosterone replacement on prostate cancer outcomes in a large national cohort. Methods: We conducted a population-based cohort study using the Veterans Affairs Informatics and Computing Infrastructure. We identified node-negative and non-metastatic prostate cancer patients diagnosed between 2001-2015 treated with RT. We excluded patients for missing covariate and follow-up data. Receipt of testosterone was coded as a time-dependent covariate. Other covariates included: age, Charlson Comorbidity index, diagnosis year, body mass index, race, PSA, clinical T/N/M stage, Gleason score, and receipt of hormone therapy. We evaluated prostate cancer-specific survival, overall survival, and biochemical recurrence free survival using multivariable Cox regression. Results: Our cohort included 41,544 patients, of whom 544 (1.3%) received testosterone replacement after RT. There were no differences in Charlson comorbidity, clinical T stage, median pre-treatment PSA or Gleason score between treatment groups. Testosterone patients were more likely to be of younger age, non-black, have a lower median post-treatment PSA nadir (0.1 vs. 0.2; p < 0.001), have higher BMI, and have used hormone therapy (46.7% vs 40.3%; p = 0.003). Median duration of ADT usage was equivalent between treatment groups (testosterone: 185 days vs. non-testosterone: 186 days, p = 0.77). The median time from RT to TRT was 3.52 years. After controlling for differences in covariates between treatment groups, we found no difference in prostate cancer specific mortality (HR 1.02; 95% CI 0.62-1.67; p = 0.95), overall survival (HR 1.02; 95% CI 0.84-1.24; p = 0.86), non-cancer mortality (HR 1.02; 95% CI 0.82-1.27; p = 0.86) biochemical recurrence free survival (HR 1.07; 95% CI 0.90-1.28; p = 0.45). Conclusions: Our results suggest that testosterone replacement is safe in prostate cancer patients who have received RT. Prospective data are required to confirm the safety of post-RT testosterone replacement.
Randomized phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning [PSMA-SRT].
Authors: Calais Jeremie , Czernin Johannes , Fendler Wolfgang P , Elashoff David , Nickols Nicholas George
Published: March 2019

TPS136

Background: Salvage radiotherapy (SRT) for prostate cancer (PCa) biochemical recurrence (BCR) after radical prostatectomy (RP) is commonly initiated in patients with PSA < 1 ng/mL, a threshold at which standard-of-care imaging is insensitive for detecting recurrence. The purpose of this randomized phase 3 trial is to evaluate the success rate of SRT for PCa BCR after RP with and without planning based on 68Ga-PSMA-11 PET/CT (PSMA). Here we present the study protocol. Methods: This is an interventional phase 3 randomized prospective open label clinical trial with parallel assignment designed for superiority. Patients who are planned to undergo SRT for PCa BCR with PSA > 0.1 ng/ml are eligible. The choice of treating the prostate bed with/without pelvic lymph nodes, with/without androgen deprivation therapy, is left to the discretion of the treating radiation oncologist (RO). RO may or may not change the RT plan depending on the PSMA findings. Any other imaging is allowed for SRT planning if done per routine care. The primary endpoint is the success rate of SRT measured as biochemical progression-free survival (PFS) after initiation of SRT. Biochemical progression is defined by PSA≥0.2 ng/mL and rising. Based on literature data we hypothesized that 1) the incorporation of PSMA to SRT planning will improve 5-year PFS by 20%, 2) the 5-year PFS will be 60% in standard Arm 1 and 80% in interventional Arm 2, and 3) 13% of subjects randomized to Arm 2 will have extra-pelvic metastasis detected by PSMA and will not be included in analysis of the primary endpoint. We will randomize 193 patients (1:1.13 ratio) to proceed with standard SRT (n = 90) or undergo PSMA scan (free of charge for patients) prior SRT planning (n = 103). Patients will be followed for 5 years after the date of initiation of SRT. Discussion: Main pitfalls in study design include 1) drop-out of patients randomized to the control arm and 2) potential FDA approval of PSMA PET imaging probes in the near future (no randomization to standard arm would be then acceptable). This is the first prospective randomized phase 3 trial designed to determine whether PET/CT can improve outcome of SRT in patients with BCR. Clinical trial information: NCT03582774.
The “ProPSMA Study” clinical trial protocol: A prospective randomized multi-center study of the impact of Ga-68 PSMA PET/CT imaging for staging high-risk prostate cancer prior to curative-intent surgery or radiotherapy.
Authors: Hofman Michael , Murphy Declan G. , Williams Scott , Nzenza Tatenda , Herschtal Alan , Matera Anetta , Marusic Petra , De Abreu Lourenco Richard , Bailey Dale L , Iravani Amir , Hicks Rodney J , Francis Roslyn J , Lawrentschuk Nathan
Published: March 2019

TPS138

Background: Disease persistence or relapse following curative-intent surgery or radiotherapy of high-risk prostate cancer is not uncommon. This is attributable, in part, to a failure of accurate staging with diagnostic imaging being insensitive for detection of small volume metastatic disease. Prostate-specific-membrane-antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is a new whole body scanning technique that enables visualisation of prostate cancer with high sensitivity. The hypotheses of this study are that PSMA-PET/CT (a) has improved diagnostic accuracy compared to conventional imaging, (b) should be used as a first-line diagnostic test for staging, (c) the improved diagnostic accuracy will result in significant management impact and (d) provides economic benefits when incorporated into the management algorithm. Methods: This is a 300 patient phase III multi-centre randomized study of patients with untreated high-risk prostate cancer defined by Gleason grade group 3-5, PSA ≥ 20ng/ml or clinical stage ≥ T3. Patients are randomized to Gallium-68-PSMA11 PET/CT or conventional imaging, consisting of computer tomography of the abdomen/pelvis and bone scintigraphy with SPECT/CT. Patients with negative, equivocal or oligometastatic disease cross-over to receive the other imaging arm. The primary objective is to compare the accuracy of PSMA-PET/CT to conventional imaging for detecting nodal or distant metastatic disease. Accuracy is defined by a pre-defined “ground truth” scoring system incorporating histopathologic, imaging and clinical follow-up at six months post randomisation. Secondary objectives include comparing management impact, the number of equivocal studies, the incremental value of second-line imaging in patients who cross-over, health economics, radiation exposure, inter-observer agreement and safety of PSMA-PET/CT. Longer term follow-up will also assess the prognostic value of a negative PSMA-PET/CT. 294 of 300 (98%) patients randomised at time of abstract submission. Clinical trial information: 12617000005358.