bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular mortality in renal cell carcinoma: A population-based study.
Authors: Alevizakos Michail , Gaitanidis Apostolos , Appleman Leonard Joseph
Published: May 2019

e16085

Background: Patients with renal cell carcinoma (RCC) often harbor risk factors for cardiovascular disease and may receive anti-VEGF agents, which are associated with cardiovascular toxicity. However, the risk for cardiovascular mortality in this patient population is currently unknown. Methods: Utilizing the SEER database, we identified patients with RCC diagnosed between 2007 (approval of sunitinib) and 2015 and selected patients aged ≥ 45 years. We calculated standardized mortality ratios (SMRs) for cardiovascular mortality (ICD-10 codes I00-I99) by comparing the number of observed deaths in the database to the number of expected deaths in age-matched groups of the US general population drawn from the CDC WONDER database. Multivariable Cox regression was used to identify risk factors for cardiovascular mortality in patients with RCC. Results: We identified 36,576 patients with RCC, of which 33,748 (92.3%) were ≥ 45 years old and among these, 1650 (4.9%) died of cardiovascular diseases. The SMR for cardiovascular mortality was 2.85 (95% CI 2.72-2.99) for all patients, 2.78 (95% CI 2.62-2.95) for males and 2.86 (95% CI 2.64-3.10) for females. Among the various age groups, the SMR was 4.75 (95% CI 3.82-5.84) for patients aged 45-54 years, 3.35 (95% CI 2.93-3.83) for patients aged 55-64 years, 2.75 (95% CI 2.49-3.04) for patients aged 65-74 years, 2.25 (95% CI 2.07-2.45) for patients aged 75-84 years, and 1.47 (95% CI 1.33-1.61) for patients aged > 85 years. In multivariate analysis, advancing age (HR 1.06, 95% CI 1.06-1.07), male sex (HR 1.18, 95% CI 1.05-1.33), black race (HR 1.48, 95% CI 1.27-1.73), stage IV disease (HR 1.21, 95% CI 1.01-1.45), and performance of surgery directed to the primary tumor (HR 0.33, 95% CI 0.29-0.38) were independently associated with cardiovascular mortality. Conclusions: Patients with RCC possess an almost 3-fold greater risk for cardiovascular mortality than the general population and this risk is even more pronounced in middle-aged patients. Aggressive management of modifiable cardiovascular risk factors in this patient population is thus warranted.
Systematic review and network meta-analysis of first-line treatments in mRCC.
Authors: Ratto Barbara Elizabeth , Chakraborty Sutirtha , Chinthapatla Harini , Kalra Manik
Published: May 2019

e16086

Background: The approval of newer agents in metastatic renal cell carcinoma (mRCC) has changed the treatment paradigm in first-line settings. The aim of this review was to compare pazopanib against current first-line treatments in RCC. Methods: A systematic review was conducted that assessed pazopanib against first-line agents in treatment naïve patients with mRCC. Relevant databases and conferences were searched to identify randomized controlled trials (RCTs) assessing treatment naïve adult patient (≥18 years). Frequentist mixed treatment comparison (MTC) method was applied for the pairwise comparisons among treatments for ITT population and favorable, intermediate, and poor risk subgroups. Results: Twenty-three RCTs met the eligibility criteria. The MTC results showed that pazopanib was comparable to sunitinib in terms of progression free survival (PFS) and overall survival (OS) in ITT population. Cabozantinib was significantly better compared to pazopanib for PFS; however, there was heterogeneity in the patient population. Pazopanib was comparable to nivolumab + ipilimumab when assessed for PFS in ITT population; although, favorable risk patients treated with pazopanib achieved significantly higher PFS compared to nivolumab + ipilimumab (HR: 0.46, 95% CI: [0.37, 0.57]). Atezolizumab + bevacizumab and avelumab + axitinib were associated with significantly higher PFS compared to pazopanib. Cabozantinib and nivolumab + ipilimumab were associated with better OS compared to pazopanib. Conclusions: The newer agents i.e. cabozantinib and nivolumab + ipilimumab are approved for intermediate/poor risk patients. The results suggests that pazopanib is still a reliable option for treatment of patients in first-line settings, especially for favorable/intermediate risk patients.[Table: see text]
Effect of gender on the outcome of patients receiving nivolumab for metastatic renal cancer: Results from a large study population.
Authors: Procopio Giuseppe , Di Cosimo Serena , De Giorgi Ugo , Cartenì Giacomo , Cortesi Enrico , Caserta Claudia , Sabbatini Roberto , Bearz Alessandra , Buti Sebastiano , Pignata Sandro , Berruti Alfredo , Ruggeri Enzo , Bengala Carmelo , Livi Lorenzo , Fagnani Daniele , Bonetti Andrea , Mitterer Manfred , Ortega Cinzia , Cognetti Francesco , Di Nicola Massimo A.
Published: May 2019

e16087

Background: Several studies, the majority on melanoma and lung cancer, have addressed the value of gender with respect to immune check point inhibitors outcome as compared to standard therapy, showing conflicting results. Nevertheless, few focused on gender-related clinical outcome and toxicity in renal cell carcinoma (RCC) patients. Methods: This analysis evaluated the effect of gender on overall survival and adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 in an expanded access programme of nivolumab 3 mg/kg once every 2 weeks in second-line and beyond metastatic RCC. Only patients assuming at least one dose of nivolumab were analyzed. Results: Of 389 patients analyzed, 25.2% were female. On study entry, no differences were found in women as compared to men in terms of age, on average 64 years, p = 0.91; overweight/obesity, 45 versus (vs) 49%, p = 0.47; LDH , mean U/L 391 vs 32, p = 0.17); and neutrophils/lymphocytes ratio> 3 (62 vs 63%, p = 0.87). Disease presentation was similar according to gender, although women tended to present less lung (66% vs 76%, p = 0.06) and bone metastases (42% vs 52%, p = 0.07). Notably, there was no differences in the IDMC prognostic model by gender (p = 0.94). Any drug related AEs (38 vs 30%, p 0.15), grade 3-4 (6% vs 6%) and median number of drug doses 12 (53% vs50%, p = 0.58 ) did not differ between gender. After adjusting for known prognostic variables, multivariate analysis showed that women had similar overall survival as compared to men (hazard ratio 0.81, 95% confidence interval 0.56-1.17, p = 0.26). Conclusions: Women demonstrate similar overall survival than men in metastatic RCC treated with secondal line and beyond nivolumab, with no differences observed in serious AEs and dose administered.
Nivolumab in renal cancer: French evaluation of use, current practices and medico economic approach.
Authors: Grude Francoise , Appéré Gildas , Marhuenda Fanny , Deniel Lagadec Delphine , Boughalem Elouen , Schlurmann Friederike , Travers Muriel , El Kouri Claude
Published: May 2019

e16093

Background: Since April 2016 (EMA approval), Nivolumab could be prescribed in advanced renal carcinoma after prior treatment. The Brittany and Pays de la Loire Cancer Observatory has collected data on their real-life indications, current management, safety, efficacy and medico-economics. Methods: All non opposing adult patients with renal carcinoma initiated nivolumab (3 mg/kg q2w) in 2016 and 2017 were included. Minimum follow-up for survival was 12 months. Sex, age, performans status PS ECOG, toxicities, response rate, Progression Free Survival (PFS) and Overall Survival (OS) have been studied. Results: 141 pts were treated by nivolumab in 2016 and 2017 with a median age of 68 years old [39-94] and with 26% aged at least 75 years. The median number of courses was 7 [1-47]. 68 pts (48%) had 1 to 6 courses, 16 pts (11%) 7 to 12 courses, 25 pts (18%) 13 to 24 courses and 32 pts (23%) more than 25 courses. 81 (58%) pts were treated in 2nd line, 34 (24%) in 3rd line, and 25 (18%) in further lines. All lines combined, Complete Response (CR) was observed for 3 pts (2%), Partial Response (PR) for 26 pts (18%), Stable Disease (SD) for 36 pts (26%) (disease control DC : 46%) and disease progression for 51 pts (36%). For 25 pts (18%), nivolumab treatment has been stopped before first medical imaging. PS ECOG was 0-1 for 88 pts (62%), 2 for 21pts (15%), 3-4 for 8 pts (6%) and unknown for 24 pts. Median OS and PFS were 18.2 months and 3.2 months, respectively. No difference on survival has been noticed according to gender, treatment line, age (cut-off 70 or 75 yo) and grade III/IV toxicity. However, OS and PFS were significantly influenced by general health (p < 0.0001). PFS for PS 0-1 pts was 6.5 months, for PS2 2.3 months and for PS3-4 0.8 months. OS was not reached for PS0-1 pts, 3.8 months for PS2 pts and 0.8 months for PS3-4 pts. OS for patients with DC (RC+RP+SD) has not reached and PFS was 14.9 months respectively. 17% of patients presented grade III/IV toxicities. Nivolumab courses during the 2 years costed 5.1 millions of euros (drug, hospitalisation and transportation). 80% of this costs were dedicated to pts who experienced DC. Conclusions: In real life setting, survival outcomes and toxicities with nivolumab in advanced renal carcinoma are comparable to literature’s data. ECOG PS≥2 pts presented shorter survival than PS0-1 pts. Interestingly, 80% of the cost incurred for these treatments benefited to pts with DC. Updated survival data will be available be shown at the meeting.
Time to surgery (TTS) in renal cell carcinoma (RCC): Predictors and association with overall survival (OS).
Authors: Kommalapati Anuhya , Tella Sri Harsha , Tandra Pavankumar
Published: May 2019

e16107

Background: Guidelines recommend surgical resection of primary tumor in stages 1-3 RCC. TTS refers to the time frame from the initial diagnosis to surgical resection of primary tumor. Shorter TTS has shown OS benefit in breast, head and neck cancers whereas longer TSS was shown to be acceptable in colon cancer. However, no such data exists for RCC. Using National Cancer Data Base (NCDB), we sought to determine the factors associated with TTS and its effect on OS. Methods: Patients with RCC who underwent partial or total nephrectomy were included, excluding those received neoadjuvant therapy. Logistic regression model was utilized to evaluate relative risk of delayed TTS. OS in association with TTS was estimated using the Kaplan-Meier method and Cox multivariate analysis (MVA). Results: A total of 60,198 RCC patients met the inclusion criteria. In contrast to a prior study that showed a median TTS of 41 days our study showed a median TTS of 35 days. We dichotomized the TTS as ≤ 35 days or ≥ 36 days. On MVA, TSS ≥ 36 days had significantly better OS (HR: 0.95 [CI:0.92-0.99], p < 0.01). Factors associated with TSS ≥ 36 days were race, insurance, higher Charlson score, lower grade, and getting managed at academic facilities and Pacific region (p < 0.01) (Table). Conclusions: A longer TTS with RCC is understandably associated with greater comorbidity, and non-private insurance, but questionably so in race, ethnicity, and facility related factors. However, given that TTS ≥ 36 days was not associated with higher risk of death, it may indicate that a reasonable delay could be pursued in certain cases for more accurate preoperative evaluation. [Table: see text]
An estimate of premature deaths averted with immunotherapy in treating Brazilian patients with advanced clear cell renal cell carcinoma.
Authors: Lenz Gabriel , Peruzzo Nicolas , Arraes Cecília , Lopes Gilberto
Published: May 2019

e16114

Background: Clear cell renal cell carcinoma (RCC) accounts for 3% of all cancers in Brazil, and the majority of these patients (pts) are treated in our public health system, SUS. Sunitinib and Pazopanib were incorporated into SUS in early 2019 for use in metastatic RCC (mRCC). Although Nivolumab plus Ipilimumab (NI) is the standard first-line systemic therapy for intermediate- and poor-risk pts with mRCC, these drugs are not yet available. We aimed to estimate the number of premature deaths that could be averted with incorporation of NI for mRCC pts treated in SUS. Methods: We used incidence rates reported by GLOBOCAN to estimate the annual number of pts with mRCC due to receive first-line systemic therapy in Brazil. Privately insured patients were excluded. A review (Lalani et al., 2018) and CheckMate 214 Trial were used to estimate stage distribution at diagnosis and overall survival (OS) in 12 months, respectively. We explored differences in the number of deaths between different therapeutic strategies. Results: GLOBOCAN estimates 9,619 new cases of RCC per year in Brazil, of which 72.1% are to be treated in SUS. Twenty-five percent are de novo metastatic. Among patients with mRCC, 75% have intermediate- or poor-risk disease. That is, 1,300 pts with intermediate- or poor-risk mRCC are to be treated each year in SUS. We estimated that 9,360 pts are expected to be alive over a 10 year period with sunitinib and 10,400 pts with NI. Conclusions: In the Brazilian public health system, it can take more than a decade for novel therapies to be incorporated. Over a ten-year period, approximately 1,040 pts with mRCC will die prematurely due to the lack of access to immunotherapy (NI) in the public health system. Studies to evaluate the cost-effectiveness of NI for Brazilian pts with mRCC are urgently needed.
Objective response and prolonged stable disease in refractory adrenocortical carcinoma treated with cabozantinib: An international case series and protocols of phase II clinical trials.
Authors: Kroiss Matthias , Megerle Felix , Wendler Julia , Jimenez Camilo , Quinkler Marcus , Malzahn Uwe , Goebeler Maria-Elisabeth , Fassnacht Martin , Habra Mouhammed Amir
Published: May 2019

e16118

Background: Median overall survival (OS) in advanced adrenocortical (ACC) is only 12-15 months. Previous clinical trials with oral multi-kinase inhibitors (MKI) were negative likely due to inadvertent drug interaction with mitotane. Objective: To investigate the potential of cabozantinib (CABO) monotherapy in ACC patients. Methods: Retrospective cohort study at three referral centers for ACC (U.S. and Germany). Results: Fifteen patients (13 female) with progressive disease after mitotane (14/15 patients) and three (median; range 0-8) further systemic therapies were treated with 60 mg (20-140) CABO. Mitotane had been discontinued in all patients, in 11/15 patients mitotane was stopped > 270 days before CABO treatment or plasma concentration documented to be < 2 mg/L. Adverse events (AE) of grade 1/2 and 3 were observed in 12 and 2 patients, respectively and consistent with the known safety profile of CABO. Best response was partial response in 3, stable disease in 4 and progressive disease in 8 patients. Progression-free survival (PFS) of > 4 months (PFS4) was observed in 7 patients. Median PFS and OS was 12 and 41 weeks, respectively. Two single center phase II trials of CABO in advanced ACC in the U.S. (NCT03370718) and Germany (NCT03612232) will accrue 18 and 37 patients, respectively. Mitotane discontinuation and plasma concentrations < 2 mg/L are key inclusion criteria. The primary endpoint is PFS4. Conclusions: Cabozantinib monotherapy appears to be safe and active as a monotherapy in advanced ACC. Two parallel phase II trials will investigate CABO prospectively while controlling for drug interaction with mitotane.
Study of the clinical characteristics of scrotal mesothelioma.
Authors: Zhang Chen , Goldsztajn Harry Jack
Published: May 2019

e16122

Background: Scrotal mesothelioma (SM) is an extremely rare type of genitourinary cancer. To the best of our knowledge, no clinical trial was performed in SM. The objective of this study aims at evaluating the clinical characteristics of scrotal mesothelioma. Methods: Retrospective and comprehensive literature search was performed for SM case report/series on PUBMED/Medline. 184 articles were found through January 2019 and 81 articles were excluded due to non-English language or unavailability. A total of 124 patients in 103 articles were included. All necessary data were extracted including age, asbestos exposure history, clinical presentation, diagnostic method, tumor marker, management approach and surveillance. P < 0.05 was considered significant. Results: Out of 124 patients, the median age at diagnosis was 60 years old. 16 patients (12.9%) had a history of asbestos exposure, 58 (46.8%) without exposure and 50 (40.3%) were not mentioned. Most common initial presentation was hydrocele (n = 78, 62.9%), followed by mass (n = 38, 30.6%). 50% (n = 62) of tumors presented on the right testicle while 34.7% (n = 43) were on left side, 0.8% (n = 1) bilaterally and 14.5%(n = 18) were unclear. 40 (32.3%) patients developed metastatic disease, while 20 (16.1%) developed it at diagnosis. 102 (82.3%) patients were diagnosed by post-operative pathology, and 22 (26.7%) were diagnosed before surgery. Alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) were checked in 24 patients. AFP was uniformly negative (100%) and hCG was negative in 23 patients (95.8%). Most patients underwent surgery (n = 119, 96%), of which orchiectomy and/or hemiscrotectomy (n = 93, 78.2%) comprised the majority. For adjuvant therapy, 14 (11.3%) patients received radiotherapy and 9 (7.3%) received chemotherapy. Out of 71 patients without initial metastasis and with follow-up data, median follow-up time was 17 months, median time to recurrence was 19 months, and 5-year recurrence-free status was 11.3%. Conclusions: The most common presentation of SM is hydrocele and the most common location is the right testicle. Surgery is a common intervention, but the recurrence rate is high. Due to limited number of reports, more clinical data and further clinical studies are warranted for management guidance.
Venous thromboembolism related hospitalizations among patients with genitourinary malignancy in the United States: A nationwide analysis.
Authors: Albagoush Sara , Abushalha Kamelah , Aurit Sarah J , Baskaran Janani , Gbadamosi-Akindele Maryam
Published: May 2019

e16126

Background: Cancer Patients are at high risk of developing venous thromboembolism (VTE), pulmonary embolism (PE), and deep venous thrombosis (DVT). In this study, we aim to get an estimate of the incidence of VTE as a primary admission diagnosis among patients with genitourinary malignancies. Methods: We utilized ICD-9-CM and ICD-10-CM codes to identify patients with malignant neoplasms of the prostate, bladder, kidney, and testis who are older than 18 years and admitted with a primary diagnosis of DVT, PE within the NIS database during 2007-2016. Unadjusted incidence of DVT and PE was analyzed for each cancer site with the Rao-Scott chi-square test; multivariable logistic regression was employed to adjust for age, biological sex ( not for prostate/ testicular cancer), race, insurance, year of admission, and use of chemotherapy to further examine incidence. Results: We identified 3,339,985 admissions affiliated with genitourinary malignancies of whom 0.59% experienced DVT and 0.13% experienced PE with bladder cancer patients have the highest risk of hospitalization for VTE ( 79/1000). Within bladder cancer population; insurance ( p < 0.001) and hospital location and teaching status ( p < 0.001) were associated with DVT incidence; and biological sex ( p = 0.040) and race and ethnicity ( p = 0.026) with PE incidence. For all sites combined and after adjusting for all else, it was found that every year increase in age was associated with 1.2% increased odds of DVT or PE incidence (OR 95% CI: 1.01-1.02; p < 0.001). Further, rural vs. urban teaching hospitals had 41.2% increased odds (95% CI: 1.26-1.58; p < 0.001), and urban non teaching vs. urban teaching hospitals had 35.1% increased odds (95% CI: 1.26-1.45) of DVT or PE incidence. African Americans vs. whites had 46.8% increased odds of DVT or PE incidence (95% CI: 1.35-1.60; p < 0.001). Conclusions: Within the population of genitourinary malignancies who admitted with a primary diagnosis of VTE; the incidence was higher with older age, African Americans, uninsured population, in rural and urban non teaching facilities, bladder cancer population.
Antigen (Ag) spread after sipuleucel-T and correlation with overall survival (OS): A real-world experience.
Authors: Berry William R. , Pieczonka Christopher Michael , Vogelzang Nicholas J. , Karsh Lawrence Ivan , Bailen James L. , Van Velzen Krista , Kandadi Harini , Sheikh Nadeem Anwar , Dakhil Shaker R.
Published: May 2019

e16504

Background: Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In IMPACT (NCT00065442), a phase 3 trial, sipuleucel-T-induced immune responses against target Ag prostatic acid phosphatase (PAP) or PA2024, a recombinant protein consisting of PAP and granulocyte macrophage colony stimulating factor, correlated with OS (Sheikh 2013). Additionally, sipuleucel-T-induced immunoglobulin G (IgG) responses against secondary, non-target Ag (i.e. Ag spread) and the breadth of Ag spread also correlated with improved OS (GuhaThakurta 2015). Here we assessed Ag spread and OS in real-world patients from PRIME (NCT01727154), an immune monitoring sub-study of sipuleucel-T trials Methods: IgG levels in pre and wk 6 (2 wk post sipuleucel-T completion) sera from PRIME (n = 100) were quantified using Luminex xMAP. IgG responses to secondary Ag (LGALS3, PSA, KLK2, LGALS8, K-Ras, E-Ras) were defined as ≥ 1.5-fold increase over baseline. OS associations with individual Ag responses and total number of Ag per patient were assessed using the Kaplan-Meier method. Hazard ratios (HR) were estimated using a Cox Proportional Hazard Model. Results: IgG responses to ≥1 secondary Ag were observed in ≥72% of patients. Individual IgG responses to LGALS3, K-Ras, and LGALS8 at wk 6 were significantly associated with OS. Furthermore, breadth of Ag spread positively correlated with OS (Table); as the total number of Ag responses per patient increased, OS improved compared to patients with no secondary IgG responses. Conclusions: The results presented are consistent with findings from the prior phase 3 trial IMPACT. Secondary Ag responses were generated in real-world patients treated with sipuleucel-T, and these responses correlated with OS. Furthermore, breadth of Ag spread also correlated with improved OS. Clinical trial information: NCT01727154. [Table: see text]
Targeting differential response using molecular guided biopsies in bone-metastatic prostate cancer.
Authors: Roth Alison , Tomlins Scott A. , Tuite Michael , Liu Glenn , Jeraj Robert
Published: May 2019

e16516

Background: Methods for molecular image-guided biopsies have been limited to targeting lesions with high radiotracer uptake. The purpose of this study is to determine the value of using molecular imaging response to select lesions for biopsy. Methods: 7 metastatic prostate cancer patients received 18F-NaF PET/CT scans at baseline and after 12 weeks of enzalutamide therapy. Lesion uptake was quantified semi-automatically. Lesions were classified as partially responding (PR, significantly decreased uptake), stable disease (SD, no significant change), and progressing disease (PD, significantly increased uptake) using test-retest limits of agreement for the relative change in SUVtotal. In the case that response was stable by SUVtotal, the relative change of SUVmax (and corresponding limits of agreement) were used to reclassify response. 3 candidate lesions from each response category (PR, PD) were selected, including SD lesions if needed. Interventional radiologists biopsied two lesions from different response categories per patient within 7 days of the week 12 scan. Up to 3 needle cores and aspirate were taken per biopsy. Core and aspirate samples were subjected to multiplexed PCR using custom Ampliseq panels targeted to common mutations (DNA) and alterations (RNA) in prostate cancer. The presence of androgen receptor splice variant 7 (AR-V7) was determined for each sample. Results: 8/13 lesions biopsied contained tumor, but one patient’s samples were not tracked (one lesion contained tumor). 7/11 tracked lesions contained tumor including 2/3 PR lesions, 1/4 SD lesions, and 4/4 PD lesions. The average tumor content in successful needle passes was 30.0% for PR (3/6 passes), 20.0% for SD (1/8 passes), and 35.7% for PD lesions (7/8 passes). Aspirate samples were acquired for 1 PR and 3 PD lesions; all 4 contained tumor. AR-V7 was identified in 0/2 PR, 0/1 SD, and 3/4 PD lesions. 3/7 patients had two biopsy lesions that contained tumor. Two patients had PR and PD biopsies and one patient had SD and PD biopsies). AR-V7 was identified in the PD lesions of one of the PR/PD patients and the SD/PD patient. Conclusions: Molecular imaging response has the potential to increase the success of difficult biopsy scenarios. Additional information about developing therapy resistance can be gathered by preferentially sampling PD lesions. Clinical trial information: NCT02677376.
Adherence enhancing program for patients with metastatic, castration-resistant prostate carcinoma treated with abiraterone acetate plus prednisone: A cluster randomized trial.
Authors: Suttmann Henrik , Feyerabend Susan , Gleissner Jochen , Hübner Andreas , Mathes Tim , Baurecht Werner , Krützfeldt Katrin , Sweiti Hussein
Published: May 2019

e16520

Background: Abiraterone acetate plus prednisone (AA+P) is an effective treatment for patients (pts) with metastatic, castration-resistant prostate carcinoma (mCRPC). Adherence is an important factor for the success of AA+P treatment. Research has shown that adherence in pts taking oral anti-cancer agents is often lower than required. The objective of this cluster randomized trial (CRT) was to assess the influence of an adherence enhancing program (AP) for AA+P in pts with mCRPC. Methods: This was a pragmatic parallel CRT of pts with mCRPC performed under real-world conditions. The study sites were randomly assigned to AP or no-AP (1:1) using a computer generated random schedule. The AP consisted of an educational video and reminder telephone calls. The primary endpoint was “rate of therapy discontinuation after 3 months for reasons other than disease progression or start of a new cancer therapy” (discontinuation). A secondary outcome was medication adherence (Morisky Scale; MMAS-4). Results: In the final intention-to-treat analysis, 47 sites comprising 360 men were allocated to AP and 40 sites comprising 315 men to no-AP. Baseline characteristics and results for each group are presented in the table. The odds ratio (OR) for discontinuation, adjusted for baseline adherence was 1.16 (95%CI: 0.63 to 2.11) and 1.21 (95%CI: 0.74 to 1.97) for 3 and 6 months, respectively. The OR for medium/low medication adherence, adjusted for baseline adherence, was 0.56 (95%CI: 0.26 to 1.21) and 0.84 (95%CI: 0.36 to 1.97) for 3 and 6 months, respectively. Conclusions: The rate of treatment discontinuation in the first 3 and 6 months was low and similar in both study arms. Medication adherence at baseline was generally high, but with some difference between both arms. The adjusted OR for medication adherence at 3 and 6 months revealed a trend towards a slower drop in medication adherence for the AP arm, compared to the no-AP arm, but with a wide confidence interval. Table Clinical trial information: 284. [Table: see text]
Safety and clinical outcomes of GT0918 (Proxalutamide), a potent androgen receptor (AR) blocker, in patients with mCRPC progressing on standard (SoC) and experimental therapies: Phase I/II trial.
Authors: Vogelzang Nicholas J. , Levin Richard , Chu David , Gabrail Nashat Y. , Nordquist Luke T. , Stein Mark N. , Dave Harish P. , Zhang Phoebe , Zhou Karl
Published: May 2019

e16527

Background: GT0918 is a new chemical entity of AR blocker. A phase I dose escalation study was planned for 6 dose cohorts in pts with mCRPC who have progressed on SoC and experimental therapies. No DLT or major toxicity was found in planned doses, therefore a cohort of 600 mg daily was added in December 2018. Methods: Patients (pts) with histologically confirmed mCRPC who progressed on enzalutamide +/- abiraterone and docetaxel were eligible. GT0918 was administered once daily orally for 28 consecutive days for DLT assessment. Pts could continue on GT0918 until they experienced intolerable toxicity, disease progression or withdrew consent. All pts consented for exploratory biomarker studies of CTC and cf-DNA/RNA. Results: 40 pts were treated with GT0918 in 7 cohorts. Pts had metastatic disease to bone only (44%), and lymph node +/-visceral +/- bone (56%), who progressed on multiple lines of therapies including but not limited to abiraterone, enzalutamide, docetaxel, cabazitaxel. GT0918 related adverse events (AEs) were grade 1 or 2 as per CTCAE v4.03. including fatigue, anemia, nausea, loss of appetite, hot flushing, depression, etc. The most common TEAE is fatigue and all pts at 500 mg dose reported having fatigue and one pt required dose reduction. Toxicity at the 600mg is still being analyzed but at least 2 pts had tremor. Treatment duration showed more pts in the treatment of 400 mg and 500 mg with SD in this heavily pretreated group (see Table). Exploratory biomarkers of CTCs also suggested higher dose of GT0918 resulted in better clinical outcomes. Conclusions: GT0918 administrated orally once daily was well tolerated. Better clinical outcomes were shown in dose cohorts of 400 mg and 500 mg without major toxicities. Thus these 2 doses were selected for dose expansion. Table. Clinical outcomes of GT0918 in heavily pretreated mCRPC pts Clinical trial information: NCT02826772. [Table: see text]
Prediction of metastatic castrate-resistant prostate cancer response to abiraterone or enzalutamide by a baseline blood-based CTC gene expression signature.
Authors: Lariviere Michael Joseph , Haas Naomi B. , Cherkas Yauheniya , Nielsen Karl , Foulk Brad , Patel Jaymala , Smirnov Denis , Vaughn David J. , Amaravadi Ravi K. , Savitch Samantha L. , Majmundar Krishna , Buckingham Thomas H. , Yee Stephanie S. , Jones Jeremy , Pal Sumanta K. , Carpenter Erica L.
Published: May 2019

e16529

Background: Prostate cancer is the most common cancer in men in the U.S., with 30% 5-year overall survival (OS) for patients (pts) with metastases. To take a precision medicine approach to the management of metastatic castrate-resistant prostate cancer (mCRPC), we developed a blood circulating tumor cell (CTC)-based test to identify mCRPC pts most likely to benefit from abiraterone (abi) or enzalutamide (enza). Methods: In this multi-institution prospective study, men with mCRPC were enrolled prior to starting abi (1,000 mg/d plus prednisone 10 mg/d) or enza (160 mg/d). At baseline (BL), 12 w, and progression, blood samples were collected for CellSearch-based CTC enumeration and qPCR-based gene expression analysis. Results: 69 pts (median age 68 y [50-82]) received abi (n = 25) or enza (n = 44) and had evaluable blood samples. Consistent with prior publications, among 43 pts with BL CTC > 0, clearance of detectable CTCs (BL CTCs > 0 and 12 w CTCs = 0), was achieved in 24 patients (55.8%), and was associated with greater median OS (31 mo vs. 18 mo, log-rank p = 0.03). The 43 pts with BL CTC > 0 were then randomly divided into training (n = 31) and validation (n = 12) sets. Baseline gene expression data for the training set was used to develop a model to predict CTC clearance, starting with a panel of 141 expressed genes/isoforms including those associated with prostate cancer. Of the models tested, random forest yielded the best performance, with respective training and validation set sensitivity of 0.7 and 1, specificity 0.75 and 0.71, AUC 0.88 and 0.91. Top genes identified include those previously associated with disease – HOXB13, ESRP2, KLK3, GRHL2, and KRT19, among others. Conclusions: A gene expression signature from a baseline blood sample with CellSearch-enriched CTCs can predict clearance of detectable CTCs in response to abi/enza with high AUC and may give insight into molecular mechanisms of response. A prospective study with a larger number of patients will be required to further validate our findings. Ultimately, this blood test has the potential to select the patients most likely to benefit from second-generation antiandrogen vs. non-hormonal systemic treatment.
DPP4 inhibitors as novel agents in improving survival in patients with prostate cancer: A SEER-Medicare study.
Authors: Shah Chintan , Hong Young-Rock , Bishnoi Rohit , ali azka , Skelton William Paul , Dang Long H. , Huo Jinhai , Dang Nam H.
Published: May 2019

e16532

Background: Dipeptidyl peptidase-4 (DPP4) is a cell surface protein expressed in variable amounts on different tissues and plays a vital role in tumor biology as well as regulation of the immune system. In-vitro studies have shown that the DPP4 biochemical activity is twice as high in prostate cancer cells compared to benign prostate tissues. Furthermore, blocking of DPP4 activity in-vitro was demonstrated to inhibit tumor angiogenesis and tumor invasiveness through a number of cellular mechanisms. Meanwhile, DPP4 expression is modest in normal as well as cancerous pancreatic cells. Methods: Using linked SEER and MEDICARE database, we identified patients with prostate cancer (PRC) or pancreatic cancer (PC) with coexisting type II diabetes mellitus. Furthermore, we analyzed the impact of DPP4 inhibition in the overall survival (OS) in these patients between 2001 and 2013. Analyses were performed using SAS, version 9.4. We excluded patients taking metformin. Results: We identified 7229 patients with PRC and 2401 patients with PC. OS was significantly better in PRC patients taking DPP4 inhibitors (262 patients) with HR 0.75 (95% CI: 0.59-0.97; P = 0.02) compared to those not on DPP4 inhibitors. Meanwhile, for patients with PC, OS was not significantly different between patients taking DPP4 inhibitors (177 patients) compared to those who were not (HR 1.03; 95% CI: 0.88-1.21; P = 0.7). Subgroup analyses of PRC patients demonstrated a trend toward a beneficial effect of DPP4 inhibitors, irrespective of stage (stage I, NR; stage II, HR 0.81; stage III, NR; stage IV, 0.76),use of chemotherapy (HR 0.83 with chemotherapy and HR 0.70 without chemotherapy) or hormonal use (ADT) (HR 0.87 with ADT and HR 0.71 without ADT), prostatectomy (HR 0.50 with prostatectomy and HR 0.77 with no prostatectomy) or radiation (HR 0.89 with radiation and HR 0.64 without radiation). Conclusions: This is the first population-based analysis showing the OS benefit of DPP4 inhibitors in PRC patients. On the other hand, OS was not improved in PC patients taking DPP4 inhibitors likely due to low levels of expression of DPP4 cell surface protein on pancreatic tissues. A prospective trial would help confirm our findings.
Interim analysis of a pilot study: Impact of high-dose, single fraction radiation on immunogenicity of sipuleucel-T in metastatic castration resistant prostate cancer patients.
Authors: Yang Yuanquan , George Saby , Levine Ellis Glenn , Schwaab Thomas , Muhitch Jason , Li Qiang , Attwood Kristopher , Groman Adrienne , Abrams Scott I , Kalinski Pawel , Singh Anurag K , Guru Khurshid , Chatta Gurkamal S.
Published: May 2019

e16538

Background: Sipuleucel-T is known to have modest anti-tumor activity in pts with metastatic castration resistant prostate cancer (mCRPC). Synergy of radiotherapy and immunotherapy has been reported. We conducted a pilot study to assess the impact of radiation on immunogenicity of Sipuleucel-T. Methods: Pts with minimally symptomatic mCRPC and bone metastases were eligible. Pts received Sipuleucel-T every 2 wks x 3 infusions. 8 Gy RT to 1 bone lesion was given 2 days after the first infusion. Peripheral blood was collected at D0, 7d after each infusion, 3 and 6 m. Primary endpoint is the effect of RT on immunogenicity of Sipuleucel-T. Secondary endpoints were safety, PSA changes and survival. We will evaluate T cell proliferation and cytolytic response at baseline and post-treatment using thymidine incorporation assay, IFN-y ELISPOT and flow cytometry. Results: From 10/2013 to 7/2018, a total of 15 pts were enrolled. Median age was 69 years (59-77). 10 pts (67%) had GS > = 8 disease. 7 pts (47%) failed prior abiraterone or enzalutamide. 13 pts completed treatment per protocol (2 withdrew). During a median follow-up of 48 mos, the 3-year overall survival was 48% (95% CI, 21-71); median survival was 30.7 mos (95% CI, 14.6-NR). No PSA responses were observed. 11 pts had post-treatment imaging (non-mandatory). 10 had PD and 1 had SD. 10 pts (67%) had Grade 1-2 drug-related AEs (most common: dizziness and hematoma 20%). No DLT or grade 3-5 drug-related AEs were observed. Conclusions: Sipuleucel-T plus RT is well tolerated. Median overall survival in this limited subset of pts was encouraging, when compared with historical data (25.8 mos in IMPACT trial). The evaluation of immune response is ongoing. (Funded by DENDREON; ClinicalTrials.gov ID: NCT01833208) Clinical trial information: NCT01833208.
Abiraterone acetate in comparison to enzalutamide in African American patients with metastatic castrate-resistant prostate cancer: A single-center retrospective study.
Authors: Telfah Mohammad , Holzbeierlein Jeffrey M. , Shen Xinglei , Wulff-Burchfield Elizabeth Marie , Parikh Rahul Atul
Published: May 2019

e16547

Background: African American (AA) patients with metastatic castrate-resistant prostate cancer (mCRPC) represent a high-risk population with higher mortality. Recent data suggested that abiraterone acetate (AbA) is more effective in AA in comparison to white patients. There are limited data regarding enzalutamide (Enz) use in AAs. Here, we report the outcomes of (AbA) and (Enz) in AA patients with mCRPC at our center. Methods: A retrospective chart review included AA patients who had a diagnosis of mCRPC and were prescribed AbA and/or Enz at KUMC from 09-01-2008 through 09-01-2018. Patients were divided into two groups: those who started with AbA (abiraterone group) and those who started with Enz (enzalutamide group). Baseline characteristics were compared between the two groups using Fisher’s exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. The primary outcome was progression-free survival (PFS) on AbA and Enz. PFS was measured from the time of starting either of the two medications to the time of formal relapse, defined by relapse that required therapy change or prostate-cancer-related death. A stepwise Cox proportional-hazard model was used to adjust for potential confounders. Results: During the study period, 28 AA patients with mCRPC received AbA and/or Enz. Twenty-two patients received AbA first, while six patients received Enz first. There were no significant differences in the baseline characteristics between the two groups. Median PFS for the abiraterone group was 24.3 months, while it was 11.7 months for the enzalutamide group, Log-rank test p-value 0.04). After adjusting for potential confounders, the hazard ratio of progression remained significant, favoring the abiraterone group, HR: 0.11, p-value 0.009. Median PFS on AbA after progression on previous Enz was 5.7 months, while it was 4.5 months for Enz after progression on previous AbA, p-value 0.2. Conclusions: In this single-center retrospective study, AA patients with mCRPC who were started on AbA rather than Enz had longer PFS. More studies are needed to understand the best sequence of the two medications in this population.
Low dose enzalutamide in metastatic castration-resistant prostate cancer: A retrospective Caribbean study.
Authors: Vinh-Hung Vincent , Diakite Kadiatou , Joachim Clarisse , Bougas Stefanos , Furtos Cristina Ioana , Rakotonarivo Jean-Marc , Lababidi Wadah , Papadopoulou Eva , Escarmant Patrick , Veronique-Baudin Jacqueline , Verschraegen Claire F.
Published: May 2019

e16548

Background: There is scarce information on the efficacy of low-dose enzalutamide in metastatic castration-resistant prostate cancer. We report on a series treated with half dose enzalutamide. Methods: We observed a trend in our practice to initiate low-dose enzalutamide at the time of disease progression in older patients considered frail, presenting with cardio-vascular comorbidity or with history of neurological symptoms. Records were retrospectively reviewed. The selection criteria were: 1) Metastatic disease demonstrated by at least one imaging modality, CT, bone scan, or positron emission tomography. 2) Progression of prostate specific antigen (PSA). 3) Castrate testosterone level ( < 0.2 ng/mL). 4) Enzalutamide treatment at 80 mg or less, once daily. To estimate the rate of PSA response, we used linear interpolation to compute the time from the initiation of low-dose enzalutamide to 50% PSA reduction. Results: Between November 2015 and December 2018 at the Martinique University Hospital, 10 patients matching the selection criteria were treated with ≤ 80 mg enzalutamide od: 8 started de novo with the low dose, 2 started with 160 mg but required dose reduction for intolerance. The mean age was 78 years (range 67-84). Three had painful bone metastases. The mean PSA at start of low dose enzalutamide was 88 ng/mL (range 1.06 - 251.8). All patients were maintained with reduced dose. At the current follow-up of 9 months (range 0 - 36 months), PSA response was observed in 7 patients ( = 70%), 1 was not evaluable (PSA not assessed), 2 did not respond. Of the 2 non-responders, one had no sign or symptom of disease progression; the other presented with extensive disease progression previously treated with abiraterone, he refused to receive increased dose enzalutamide. Among the 7 responders, the time to 50% PSA reduction was 57 days (range 26 - 119). Currently, the decline of PSA remains sustained in 6 of the 7 responders, it increased in 1 who discontinued enzalutamide. Pain decreased in the 3 symptomatic patients, including the PSA non-responder. Conclusions: Low dose enzalutamide appears efficient in a large proportion of selected frail patients. Further follow-up is required to evaluate the long-term response.
Expression of human leukocyte antigen-a and b2-microglobulin in prostate cancer.
Authors: Shen Ying-Chun , Jeng Yung-Ming , Kuo Jhe-Cyuang , Tsai Yu-Chieh , Chen Chung-Hsin , Huang Kuo-How , Huang Chao-Yuan , Pu Yeong-Shiau , Cheng Ann-Lii
Published: May 2019

e16550

Background: Prostate cancer (PC) is generally resistant to current immune checkpoint blockade. Reduced expression of human leukocyte antigen-A (HLA-A) and b2-microglobulin (B2M) of cancer cells can cause deficit immune recognition and attack by cytotoxic T cells, and may be the major mechanism of intrinsic resistance to immune checkpoint blockade in PC patients. Methods: Formalin-fixed paraffin-embedded tissue of human localized or metastatic PC was used for evaluation of expression of HLA-A and B2M by Immunohistochemical staining. The expression was scored as: 0, no tumor cells stained; 1+, < 10% of tumor cells stained; 2+, 10-50% of tumor cells stained; and 3+, > 50% of tumor cells stained. Differences in HLA-A or B2M expression among groups were assessed by Chi-Square or Fisher’s exact test. Results: A total of 134 PC specimens [69 localized PC (LPC), 32 metastatic castration-naïve PC (mCNPC), and 33 metastatic castration-resistant PC (mCRPC)] from 115 patients were assessed. Significant loss (0 or 1+) of HLA-A was found in 56 (81.2%) LPCs, 30 (93.8 %) mCNPCs and 29 (87.9%) mCRPCs; while significant loss of B2M was found in 22 (32.6%) LPC, 11 (34.4%) mCNPCs, and 17 (51.2%) mCRPCs. In localized PCs, the expression of HLA-A or B2M was similar between high-grade prostate intraepithelial neoplasia foci and corresponding malignant counterpart, and did not significantly correlate to biochemical failure. In 14 patients with paired CN and CR PC specimens, significant loss of HLA-A was found in all tumors. B2M expression varied between CN and CR PCs, and progressive loss of B2M was found in 7 (50%) patients. Among 3 patients receiving immune checkpoint blockade, 1 patient with intact expression of HLA-A and B2M in pre-treatment tumor specimen achieved partial response; whereas the others with reduced expression of HLA-A (0) and B2M (1+) did not. Conclusions: Reduced expression of HLA-A or B2M is an early event in prostate carcinogenesis.
Effectiveness and tolerability of depot formulations of leuprorelin acetate in real life: Analysis of 932 patients with prostate cancer from Brazil.
Authors: Freitas Carla Simone Moreira , Soares Aleida Nazareth
Published: May 2019

e16552

Background: Clinical trials have shown that androgen deprivation therapy (ADT) is a mainstay of treatment for locally advanced and metastatic prostate cancer. Real-life studies with broader selection criteria may help inform clinical practice. Methods: We reviewed the medical records of 1890 patients with prostate cancer seen at our institution between 01/07 and 07/18. We analyzed patients treated with long-acting leuprorelin acetate, grouping these patients into three strata according to the administration of ADT every 1, 3 or 6 months. The primary outcome was the prostate specific antigen (PSA) levels at 6 and 12 months after treatment initiation. We used Friedman test to compare the distribution of PSA levels over time within each treatment stratum, considering two-sided P values < 0.05 as statistically significant. Results: We analyzed a total of 932 eligible patients, with a median age of 72 years and a median time since diagnosis of prostate cancer of 8.5 months. ADT was administered every 1, 3 and 6 months in 115, 637, and 180 patients, respectively. Nearly half of the patients had locally advanced disease. The table presents PSA levels in each stratum at the three time points. Sexual impotence and hot flashes were the most frequently reported toxicities. Conclusions: Our study confirms that serum PSA levels can be effectively reduced, with a favorable toxicity profile, in most patients treated with long-acting leuprorelin acetate. Administration every 6 months may bring the added benefit of convenience and cost savings in clinical practice.[Table: see text]
Prostate carcinoma in African-Americans has miRNA expression and biological markers for aggressive disease.
Authors: Agrawal Malhaar , Bukhari Zaheer , Stevasarova Aksiniya , Tenniswood Martin , Gupta Raavi
Published: May 2019

e16558

Background: African American (AA) men have twice the incidence and mortality in Prostate Cancer (PCa) as compared to non-Hispanic Whites. The identification of a biological basis for this disparity is crucial in providing focused treatment. In this study, we have characterized the pathological features and molecular markers of PCa in AA men. Methods: 91 proctectomies for primary PCa and 23 biopsies for metastatic PCa with their pathological data were retrieved. Tissue microarrays were constructed and the expression of Programmed Cell Death 1 (PD-1), Programmed Death Ligand 1 (PD-L1) and Mismatch Repair (MMR) (MLH1, MSH2, MSH6 and PMS2) proteins was assessed by immunohistochemistry. miRNA expression of 24 cases of primary PCa and adjacent normal prostate tissue from proctectomies was identified by microarray in situ hybridization. Spearman’s rank-correlation was used to correlate variables and p < .05 was considered significant. TargetScan and DIANA analysis software were used to identify modulation in miRNA expression. Results: In a supervised heat map, overall the downregulation of microRNA was more than upregulation in tumor tissue; 11 miRNA were upregulated and 12 were downregulated, with a log fold change of 1.5. miR-345, a component of the mismatch repair and DNA Replication pathway, showed significant up-regulation (p = 9.4E-02); has been linked to more aggressive PCa. PD-L1 expression was lower in primary PCa (16%) than in metastatic PCa (35%). PD-1 expression was high in almost half of primary and metastatic PCa patients. MMR protein expression was largely intact in both primary and metastatic PCa cases. Both of these protein markers have been associated with biochemical recurrence and low survival. Conclusions: The biological characteristics (low expression of PD-L1, high expression of PD-1, intact MMR and distinct miRNA signature) identified in our cohort of exclusively AA men are indicators of aggressive PCa. These results explain the biological basis of widely documented poor prognosis of PCa in AA men.