bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of targeted therapies after PD1/PD-L1 inhibitors in metastatic clear cell renal cell carcinoma (mRCC): A multi-institution retrospective cohort.
Authors: Albiges Laurence , Fay Andre Poisl , Xie Wanling , McDermott David F. , Heng Daniel Yick Chin , Dariane Charles , De Velasco Guillermo , Lester Renee Elizabeth , Escudier Bernard , Choueiri Toni K.
Published: February 2017

456

Background: Programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors showed activity in mRCC and are currently in development in first-line and previously treated patients (pts). Whether these drugs will modify efficacy of subsequent targeted therapy (TT) including VEGFR tyrosine kinase inhibitors (TKI) or mTOR inhibitors is unknown. Methods: Medical records of RCC patients treated with investigational PD-1 or PD-L1 inhibitors who received subsequent treatment with TT were reviewed in 4 institutions. Baseline characteristics at the time of subsequent therapy and outcome data including time to treatment failure (TTF), best response, 1 and 2 year overall survival (OS) were retrospectively collected. Results: Of 89 pts who received PD-1/PD-L1 inhibitors, 56 patients (M/F 39/17, clear-cell 53, IMDC good 3/intermediate 16/poor 11/unknown 26) have received a subsequent therapy after PD-1/PD-L1 blockade, while 7 patients are still on therapy and 26 patients did not receive subsequent therapy. Among these 26 patients, 12 died from disease and 14 are still alive off-systemic therapies. 43 pts received VEGFR TKI and 13 received mTOR inhibitors as first subsequent TT. Median follow up from start of the subsequent TT is 16.1 months (range: 0.2, 30.6 months). TT post PD-1/PD-L1 was administered as second line in 9 patients (16%), third line in 24 patients (43%), > fourth line in 23 patients (41%). Median TTF was 6.9 months (range: 0.2+, 23.0), and was 6.9 and 5.7 months in patients who received VEGFR TKI and mTOR inhibitors respectively. One-year and 2-year OS from the initiation of subsequent TT was 58% (95% CI: 41-72%) and 36% (95% CI: 18%-54%), respectively. Investigator-assessed best response to subsequent TT was evaluated in 53 out of 56 patients: PR (n=7, 13%), SD (n=33, 62 %), and PD (n=13, 25%). Conclusions: This is the first report of TT efficacy after PD-1/PD-L1 inhibition. In this selected population, median TTF suggests a sustained benefit of both VEGFR TKI and mTOR inhibitors after PD-1/PDL1 inhibition.
Clinical outcome of patients with metastatic renal cell carcinoma who interrupted VEGFR-TKI after achieving stable disease or better response.
Authors: Koo Dong Hoe , Park Inkeun , Lee Jae-Lyun , Ahn Jin-Hee , Lee Dae Ho , You Dalsan , Jeong In Gab , Song Cheryn , Hong Bum-Sik , Hong Jun Hyuck , Ahn Hanjong
Published: February 2017

459

Background: The purpose of the this study is to evaluate the clinical outcome of VEGFR-TKIs interruption in patients with metastatic renal cell carcinoma (mRCC) after achieving stable disease (SD) or better response. Methods: A retrospective analysis of medical records and imaging studies was performed on all patients with mRCC treated with VEGFR-TKIs between January 2008 and July 2014 (n=505). Patients who achieved SD or better response under VEGFR-TKI and later discontinued VEGFR-TKIs for any reason with the exception of disease progression were included in the analysis. Outcomes analyzed were progression free survival (PFS) after VEGFR-TKIs discontinuation, patterns of disease progression, time to subsequent therapy (TST), response to VEGFR-TKI resumption, and time to treatment failure (TTF) after TKI resumption. Results: We identified 32 patients (sunitinib=20, sorafenib=7, and pazopanib=5). The responses to VEGFR-TKIs were CR (n=4), PR (n=11), SD (n=15), and controlled but non-measurable (n=2). Median time to interruption from the initiation of VEGFR-TKI therapy was 16.6 months (95% CI, 12.8-20.3). The main causes of VEGFR-TKI interruption was toxicity (n=19, 59.4%), will to have treatment holiday (n=7, 21.8%), patient’s refusal (n=3, 9.4%), and others (n=3, 9.4%). At the time of analysis, 16 patients had disease progression and 1 patient was dead. With a median follow-up duration of 56.6 months (range, 12.6-167.4), median PFS from VEGFR-TKI interruption was 23.8 months (95% CI, 12.5-35.0), and the median TST was 26.2 months (95% CI, 15.9-36.6). The progression was observed in pre-existing lesions in 7 patients (43.7%) or new lesions developed in 9 (56.3%). Among 11 patients who received VEGFR-TKI resumption, 2 patients (18.2%) achieved a PR and the stable disease was observed in 9 (81.8%) with a median TTF of VEGFR-TKI resumption of 6.2 months (95% CI, 4.0-8.4). Conclusions: In patients with mRCC controlled with VEGFR-TKIs, VEGFR-TKI could be interrupted at least temporarily when clinically warranted.
Open partial nephrectomy with modified technique: Comparison to results from contemporary laparoscopic series.
Authors: Voegeli Thomas Alexander , Demming Richard
Published: February 2017

473

Background: To evaluate the surgical and oncological outcome of patients undergoing a modified procedure of open partial nephrectomy which was done with a new technique leaving out selective suturation of renal calices and vessels. Methods: We analyzed 120 consecutive open partial nephrectomies (2005-2010) which were performed with a modified technique at a mid-volume center. This technique included the use of an absorbable non-woven textile consisting of polyglycolic acid, extra-large needles and argon plasma coagulation. The surgical and oncological outcome was evaluated by statistical analysis of the medical records. Results: The mean patient age was 62.8 years (52.6% male). Mean pathological tumor size was 3.0 cm (± 1.4 cm), 53.3% of the tumors were renal cell carcinoma. The mean operative time was 101.7 minutes (±33.6 min) and the mean blood loss was 283.9 ml (±368.5 ml). Ischemia was performed in 23.1% with a mean warm ischemia time of 13.3 minutes ( ± 6.4 min). The operative complication rate was 1.7 %. Topical hemostatic agents were used in 20.2 %. The most frequent postoperative complications were bleeding (5%), pleural effusion (4.2%), urinoma (2.5%), pneumonia (2.5%), wound infection (2.5%) and acute renal failure (2.5%). Five-year cancer specific survival rate was 94.1%. Conclusions: The modified technique of open partial nephrectomy can be performed with high surgical and oncologic safety. Duration of the procedure and ischemia time are short. Due to the rare use of hemostatic agents, the costs can be reduced. Open partial nephrectomy with this technique achieve better results than reported from contemporary reported laparoscopic series, especially regarding warm ischemia and time needed for surgery.
Comparison of radiographic characteristics of renal cell carcinoma (RCC) brain metastases treated with vascular endothelial growth factor (VEGF)-directed therapies or radiotherapy.
Authors: Goud Ajay , DeWalt Kara , Carmichael Courtney , Hsu JoAnn , Pinnamaneni Manasvi , Pal Sumanta Kumar
Published: February 2017

479

Background: With improvements in systemic therapy for metastatic RCC (mRCC), an increased frequency of brain metastases (BM) has been observed, perhaps owing to the central nervous system (CNS) serving as a sanctuary site. The response of BM to VEGF-directed therapies has been poorly characterized. Methods: Patients (pts) with mRCC BM were identified from an institutional database. Selection of pts was further refined to pts who had received either VEGF-directed therapy during their diagnosis with BM or radiotherapy directed to their BM. Only those pts with brain MRI straddling systemic therapy and radiotherapy were selected for analysis. Imaging studies were anonymized and transmitted to an independent radiologist for review. Descriptive statistics were applied to characterize the change in sum of long axis dimensions (SLD) in two separate groups: (1) pts treated with VEGF-directed therapy and (2) pts treated with radiotherapy. Results: Of 276 pts with mRCC in our institutional database, 34 pts with BM were identified. Of these pts, 6 pts had serial MRI assessments at timepoints straddling receipt of VEGF-directed therapy. Pts had received sunitinib (n=2), sorafenib (n=2) or bevacizumab (n=2). A further 13 pts received radiotherapy with MRI imaging straddling delivery of either stereotactic radiation therapy (SRT) and whole brain radiotherapy (WBRT). Of these 19 patients, all patients had clear cell histology, and 13 patients were male. In pts receiving VEGF-directed agents, the average change in SLD of BM was -13.8%. In pts receiving radiotherapy, the average change in SLD was -6.5% (-13.0% in pts receiving SRT and +2.0% in pts receiving WBRT). Qualitatively, greater tumor necrosis and lesser rim enhancement was observed in post-treatment scans amongst pts receiving VEGF-directed agents. Conclusions: This pilot study suggested differences in CNS response with VEGF-directed therapy and radiotherapy. Multicenter collaborations are underway to validate these results in larger series.
The impact of clinical stage on renal cell carcinoma outcomes: Implications for neoadjuvant trial design.
Authors: Ball Mark Wayne , Gorin Michael A , Pierorazio Phillip M , Hammers Hans J. , Harshman Lauren Christine , Drake Charles G. , Allaf Mohamad E
Published: February 2017

482

Background: Outcomes for patients with RCC are reported by pathologic stage; however, determination of therapy and patient counseling are based on clinical staging. Moreover, the development of neoadjuvant therapies that may requires knowledge of clinical stage-specific outcomes for trial design. Because of a paucity of reported outcomes, we characterized pathologic upstaging, recurrence-free survival (RFS) and cancer-specific survival (CSS) by stage at our institution. Methods: Our renal mass registry was queried for patients with localized RCC who underwent extirpative surgery with from 2003-2013 stratified by clinical stage. The proportion of cases upgraded by stage were determined. Survival outcomes were analyzed using the Kaplan-Meier method. Results: A total of 2,144 cases were captured during the study period. Median follow-up was 44.5 months. Clinical to pathologic upstaging is listed in the table. The highest degree of upstaging occured in cT2 cases, with 47% of cT2a and 48% of cT2b upstaged to ≥cT3a. RFS at 60 months for cT1a was 98.4%, cT1b 95.5%, cT2a 78.4%, cT2b 74.4%, cT3a 68.0%, cT3b 63.5%, cT3c 27.8%. CSS at 60 months for cT1a was 99.3%, cT1b 96.3%, cT2a 82.7%, cT2b 81.7%, cT3a 88.7%, cT3b 66.8%, and cT3c 76.9%. Harrell's C index for CSS was similar for both clinical (0.68) and pathologic stage (0.75). Conclusions: While the rate of upstaging increases markedly with increasing clinical stage, survival models based on clinical stage perform as well as those based on pathologic staging. The high rate of upstaging in cT2 disease supports enrollment of these patients in adjuvant clinical trials. Knowledge of these clinical stage-specific outcomes may be helpful for trial design. [Table: see text]
Five-year survival analysis of interferon-a plus sorafenib versus sorafenib monotherapy as first-line treatment for metastatic clear cell renal cell carcinoma.
Authors: Ding-Wei Ye , Hai-Lang Zhang
Published: February 2017

486

Background: We compared the short- and long-term efficacy and safety of interferon-a plus sorafenib with sorafenib monotherapy as first-line treatment in metastatic clear cell renal cell carcinoma (mRCC) patients. Methods: mRCC patients who had not received systemic treatment were administered either interferon-a (300 MIU IM every other day) plus sorafenib (400 mg bid n=24, Group A) or sorafenib monotherapy (400 mg bid; n=24, Group B). Objective responses (OR; RECIST criterion ver 1.0) and differences in OR, progression-free survival (PFS), overall survival (OS) and toxicity were compared. Results: Sixty eight percent males were present in both the groups with comparable baseline demographic characteristics. After a median follow-up of 68 months, the OR was comparable (p=0.726) in Group A vs B; complete remission (1 vs 0 cases), partial remission (6 vs 7 cases), stable disease (14 vs 15 cases), and progressive disease (3 vs 3 cases). No significant difference was observed in the median PFS (p=0.965) and median OS (p=0.223) between both groups [9.4 months (95% CI: 5.8-17.4), Group A vs 14.0 months (95% CI: 9.9-18.0), Group B] and [32.9 months (95% CI: 8.2-87.1), Group A vs 20.4 months (95% CI: 16.2-24.6), Group B], respectively. The 5-year survival rate was higher in Group A vs B (46% vs 25%). Toxicity symptoms like fever (13 vs 3 cases), fatigue (15 vs 9 cases) and neutropenia (6 vs 1 cases) were more pronounced in Group A vs B. The incidence of hand and foot skin reactions, alopecia, rash, hypertension, liver dysfunction, hypophosphatemia, anemia, and other toxicities was similar in both groups. There were 14 (58.3%) and 8 (33.3%) cases of dosage reduction or suspension in Groups A and B, respectively. Conclusions: Short-term effect of interferon-a plus sorafenib as first-line treatment for mRCC was comparable to sorafenib monotherapy in terms of OR and PFS. Although higher toxicity was reported for interferon-a plus sorafenib, the combination holds promise for improving long-term OS.
Efficacy of everolimus in poor risk patients: Result of the POORTOR study.
Authors: Escudier Bernard J. , Abadie-Lacourtoisie Sophie , Blanc Ellen , Guillot Aline , Priou Frank , Mahammedi Hakim , Thiery-Vuillemin Antoine , Geoffrois Lionel , Tubiana-Mathieu Nicole , Adenis Antoine , Ferlay Celine , Albiges Laurence
Published: February 2017

488

Background: Temsirolimus is currently the standard of care for poor risk RCC, based on the pivotal trial. Whether everolimus could be an alternative for such patients (pts) remain unknown. Methods: POORTOR is a prospective phase II study evaluating everolimus (10 mg daily) as first line therapy in RCC pts with at least 3 poor prognostic factors (IK <80%, LDH >1.5 NV, hemoglobin NV, time from diagnosis to treatment <1 year and more than one metastatic site. The primary endpoint was the 1-year overall survival (OS) rate. The sample size was calculated using a Simon’s two-stage Minimax design, with the following hypotheses: p0=40%, p1=54% (based on a 47% 1-year OS in the temsirolimus arm, NEJM 2007), an 8% one-sided alpha and a 90% power. Ninety-two (92) patients (pts) were needed with an interim analysis planned after 61 pts. Results: 62 pts have been enrolled in the first stage: median age 67, men 74%, clear cell 82.3%, nephrectomy 50%. 71% pts had IK <80%, 77% pts had more than one metastatic sites, and 90% pts had a time from diagnosis to treatment <1 year. All pts had at least 3 poor risk factors: 3 = 16.4 = 26. 5-6 = 20. Six pts had a partial response by investigator assessment. With a median follow up of 16.2 m, median PFS was 3.9 m (IC95%=[2.4;5.5]) and median OS was 6.0 m (IC95%=[4.2;8.6]). One-year OS rate was 29% (IC95%[19 \;42]) which resulted in premature stop of the study at the first step. SAE were reported in 22/62 pts (35.5%).Grade 3-4 AE related to everolimus were reported in 27/62 pts (43.5%). Dose reduction of everolimus was performed in 24 pts. Conclusions: This study confirms that poor risk patients still have a very short survival in RCC. Based on these results, everolimus is not a good option for this group of pts. However, our study population had a poorer prognosis compared to the temsirolimus arm of the Hudes et al. study, partly explaining the difference in OS between the 2 studies. Clinical trial information: NCT01888042.
Potential synergistic effects of bisphosphonates with sorafenib on renal cell carcinoma with bone metastases.
Authors: Ding-Wei Ye , Hai-Lang Zhang
Published: February 2017

496

Background: We evaluated the role of bisphosphonates in conjunction with sorafenib in improving progression-free survival (PFS) and overall survival (OS) in bone metastatic renal cell carcinoma (mRCC) patients. Methods: A total of 81 sorafenib-treated patients were retrospectively divided into 3 groups at our single study center: Group 1 (n=26, sorafenib single agent); Group 2 (n=26, sorafenib plus oral Bonefos); Group 3 (n=29, sorafenib plus intravenous zoledronic acid). Alkaline phosphatase (ALP) before and 12 weeks after treatment were evaluated as prognostic factor for PFS and OS. Results: The majority of the patients were males (67.9%) with mean age of 57.2 ± 11.2 years. Baseline demographic characteristics were similar across the 3 study groups, and the known prognostic factors were balanced across the cohort. There was no significant difference observed in the objective response between the 3 study groups (Group 1 vs. 2 vs. 3; p=0.659); partial remission (8% vs. 8% vs. 10%), stable disease (65% vs. 80% vs. 66%), progressive disease (27% vs. 12% vs. 24%). Median PFS was significantly higher in Group 2 vs 1 vs 2 (18.7 vs. 6.7 vs. 10.5 months; p=0.024). Median OS was 16.8, 22.1, and 20.7 months; p=0.052 in Group 1, 2 and 3, respectively. Multivariate analysis demonstrated that bisphosphonate use (hazard ratio [HR]=0.36, p=0.006), Memorial Sloan Kettering Cancer Center (MSKCC) score (HR=4.10, p<0.001), non-clear cell subtype (HR=1.26, p=0.039), and elevated ALP after 12 weeks’ treatment (HR=3.53, p<0.001) were associated with PFS. MSKCC score (HR=5.24, p<0.001), elevated ALP after 12 weeks’ treatment (HR=4.71, p<0.001), and metastatic organs (HR=1.93, p=0.008) were associated with OS. Bisphosphonates use was not an independent predictor of OS (HR=0.55, p=0.160). Conclusions: Bisphosphonates administered with sorafenib could synergistically improve PFS and OS in RCC with bone metastases, with the benefit of being more efficacious and safer than intravenous zoledronic acid. Elevated ALP following the treatment could be an independent predictor for both PFS and OS in bone mRCC.
Treatment-related deterioration of renal function as a biomarker to predict antitumor efficacy of sunitinib in patients with metastatic renal cell carcinoma.
Authors: Fukuda Hironori , Kondo Tsunenori , Omae Kenji , Takagi Toshio , Tanabe Kazunari
Published: February 2017

502

Background: Some on-target adverse events such as hypertension or thrombocytopenia have been reported as biomarkers predicting the efficacy of sunitinib as first-line therapy for patients with metastatic renal cell carcinoma (mRCC). Decrease of renal function is a major adverse event of sunitinib. However, it remains unclear whether the degree of deterioration of renal function can predict the anti-tumor efficacy of sunitinib. We investigated the relationship between treatment-related deterioration of renal function and anti-tumor efficacy in mRCC patients treated with sunitinib. Methods: We retrospectively reviewed the medical records of mRCC patients who were treated with sunitinib for more than 3 months. Patients receiving hemodialysis before receiving sunitinib as well as those who did not undergo nephrectomy were excluded from our analysis. Renal function was evaluated by the estimated glomerular filtration rate (eGFR) calculated using the MDRD equation modified for Japanese patients. The degree of deterioration in eGFR was compared with progression-free survival (PFS). Results: Sixty-two patients were enrolled, the median age was 65 years, and 44 patients (71%) were male. The median baseline eGFR was 49.1 ml/min/1.73m2, and median decrease of eGFR was 9.9 ml/min/1.73m2. Forty-seven patients (76%) had a decreased eGFR of more than 10% compared to baseline values. The patients showing this decrease had significantly longer PFS than those who did not (PFS: 15.5 months vs. 6.1 months, respectively; p=0.001). On multivariate analysis, a decrease in eGFR of more than 10% was a significant independent factor for predicting longer PFS (hazard ratio, 0.37; 95% confidence interval, 0.17-0.83; p=0.017) as well as MSKCC risk groups and cycles of sunitinib. Conclusions: Treatment-related deterioration of renal function is a biomarker to predict better treatment efficacy for use of sunitinib during first-line therapy for patients with mRCC.
Long-term survivorship in patients with metastatic renal cell cancer (mRCC) managed with metastasectomy: A retrospective study from the MD Anderson Cancer Center (MDACC).
Authors: Shah Amishi Yogesh , Campbell Matthew T. , Nautiyal Kirtan Das , Hashemi Neda , Matin Surena F. , Vaporciyan Ara A. , Rhines Laurence D , Moon Bryan , Lewis Valerae O. , Lin Patrick P. , Prabhu Sujit S. , Rao Ganesh , Corn Paul Gettys , Pagliaro Lance C. , Mehran Reza J. , Wood Christopher G. , Jonasch Eric , Tannir Nizar M.
Published: February 2017

504

Background: Overall survival (OS) in mRCC has improved with targeted therapy; however, metastasectomy is still an important tool in select patients. This study evaluated outcomes of patients managed with metastasectomy ± systemic therapies. Methods: After IRB approval, we retrospectively reviewed records of mRCC patients who were treated at MDACC between 1/1/2001 and 12/31/2008 and report on those who survived >4 years with metastatic disease. OS was calculated from diagnosis of metastatic disease to death or last follow-up. Descriptive statistics were used. Results: 168 long-term survivors were identified; 101 patients were treated with metastasectomy at some point (total 205 resections). 42 patients had single metastasectomy; 59 had multiple resections (most common in lung and bone). 12 patients underwent serial metastasectomy alone (no systemic therapy), and 8 remain alive (range 4.6-12.9 years from met diagnosis). Conclusions: Patients with mRCC selected for metastasectomy had a significantly longer OS than those who received systemic therapies only. Whether this reflects tumor biology, therapeutic effect, or selection bias is unknown in this retrospective study. However, the prolonged survival in this group supports continued use of metastasectomy in carefully selected patients. [Table: see text] [Table: see text] [Table: see text]
Comprehensive evaluation of the clinical utility of transperineal template guided mapping biopsy of prostate in the era of magnetic resonance imaging.
Authors: Sivaraman Arjun , Sanchez-Salas Rafael , Barret Eric , Galiano Marc , Rozet Francois , Prapotnich Dominic , Cathala Nathalia , Mombet Annick , Uriburu Facundo , Carneiro Arie , Cathelineau Xavier
Published: February 2017

55

Background: To evaluate the clinical utility of Transperineal Template guided Mapping Biopsy (TTMB) after the routine use of Magnetic Resonance Imaging (MRI) for prostate cancer in our institution. Methods: We retrospectively analyzed 208 TTMB performed at our institution from April 2013 - August 2014. Anterior cancer defined as ≥ 80% of the positive cores anterior to urethra. Clinically significant cancer detection verified at various thresholds of Maximum Cancer Core Length (MCL) – 2mm / 3mm / 4mm / 6mm ± Gleason score (GS) ≥ 3+4. We analyzed TTMB for the indications, cancer detection and correlation with TRUS, MRI and Radical Prostatectomy (RP) specimens. Results: The indications and cancer detection rates of TTMB are in the table. All the patients had MRI before TTMB and 87.7% had it prior to the initial TRUS and all target biopsies were by cognitive registration. Multivariate analysis showed higher number of TTMB cores and prior negative TRUS to predict detection of clinically significant anterior tumor. The laterality of cancer in TTMB correlated with TRUS, MRI and Radical Prostatectomy (RP) in 67.2%, 75.3% and 87.6% respectively. The Gleason upgrade from TRUS to TTMB was 19.2% and TTMB to RP was 14.8%.Clavien-Dindo grade 1 and 2 complication was noted in 40.2% and 7% patients respectively. Conclusions: Even with the routine of MRI prior to TRUS biopsy, TTMB had clinical utility and was very effective in detecting clinically significant cancers in specific clinical situations. [Table: see text]
Predictors of pathological upgrading and upstaging in patients eligible for active surveillance submitted to radical prostatectomy (RARP).
Authors: Autran-Gomez Ana Maria , Secin Fernando P. , Sivaraman Arjun , Sanchez-Salas Rafael , Monzo Juan I , Prapotnich Dominic , Barret Eric , Rozet Francois , Galiano Marc , Mombet Annick , Cathala Nathalia , Cathelineau Xavier
Published: February 2017

59

Background: To evaluate the pathological outcomes in patients who were suitable for Active Surveilance (AS) and underwent Radical Prostatectomy (RP) and to explore the potential predictive factors to identify Gleason upgrading and upstaging. Methods: A prospectively maintained database was used to evaluate 1,552 consecutive patients who underwent RP [Laparoscopic / Robotic] at our institution between 1998 and 2012. We identified 405 RP patients fulfilling the Memorial Sloan-Kettering Cancer Center criteria for AS (PSA ≤10 ng/ml, clinical stage ≤2a, Gleason≤6, ≤2 + cores and less 50% cancer in any one core). In the final RP specimen, upgrading was defined as identification of Gleason >6 and upstaging as presence of ≥ pT3. The clinical and the pathological features of upstaged/upgraded patients were compared with the remaining patients and the cox’s regression model was applied to identify potential predictors. Kaplan Meir curve was used to identify Biochemical Recurrence Free Survival (BCR-FS) at 5 years. Results: We noticed upstaging in 195 (48%) patients and Gleason upgrading in 55 (13%) at RP specimen. Multivariate analysis showed percent of positive core had significant association with upstaging/upgrading. Positive Surgical Margin (PSM) was noted in 66(16%) patients, and the PSM rate was significantly higher in upstaged patients. The mean follow-up of the study population was 28 months and the predicted BCR-FS at 5 years was 92% and 88% in the patients who were not and were upstaged/upgraded. Conclusions: Percentage of positive cores in patients subjected to Active Surveillance appears to predict pathological upstaging/upgrading at radical prostatectomy. [Table: see text]
PATRIOT Trial: Randomized phase II study of prostate stereotactic body radiotherapy comparing 11 versus 29 days overall treatment time.
Authors: Quon Harvey Charles , Ong Aldrich , Cheung Patrick , Chu William , Chung Hans T. , Vesprini Danny , Chowdhury Amit , Panjwani Dilip , Pang Geordi , Korol Renee , Davidson Melanie , Ravi Ananth , McCurdy Boyd , Zhang Liying , Bucher Oliver , Mamedov Alexandre , Deabreu Andrea , Lylyk Elizabeth , Loblaw D. Andrew
Published: February 2017

6

Background: Stereotactic body radiotherapy (SBRT) for the treatment of prostate cancer is rapidly increasing. Reported regimens differ in time, dose, and fractionation. We report the results of a multicentre, Canadian randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL) and toxicity. Methods: Men with cT1-2b, Gleason <=7, and PSA <= 20 ng/mL prostate cancer were randomly assigned to 40 Gy in 5 fractions delivered every other day (11 days) vs. once per week (29 days) using gantry-based SBRT. QOL was assessed using the Expanded Prostate Cancer Index Composite (EPIC) at baseline, weeks 2, 4, 6, 12, months 6 and 12, then annually. Toxicity was graded according to RTOG Criteria. The primary end point was the proportion of patients with a minimum clinically important change (MCIC) in bowel QOL at any time during the acute (<=12 week) period and was analyzed by Fisher’s exact test with a two-sided p < 0.05 considered significant. MCIC was defined as a decrease in EPIC score of >0.5 standard deviation of the baseline value. ClinicalTrials.gov NCT01423474. Results: 152 men from 3 centres were randomized with a median follow-up of 13.1 months. Baseline characteristics were similar in both arms except for the International Prostate Symptom Score with medians of 4 vs. 7 in the 11 and 29 day groups, respectively (p=0.02). There were significant differences between the 11 and 29 day groups in the proportion of patients with acute MCIC in bowel (90.0% vs. 69.6%, p<0.01) and urinary (95.7% vs. 74.6%, p<0.01) scores, respectively. No differences were found in acute sexual (p=0.38) or hormonal (p=0.48) QOL. Worst acute grade 1, 2, 3 toxicities were 64, 18, 0% vs. 41, 11, 0% (p<0.01) for GI and 38, 32, 1% vs. 30, 34, 3% (p=0.69) for GU in the 11 and 29 day groups, respectively. There were no late grade 3+ GI toxicities. Late grade 3 GU toxicity occurred in 1 vs. 0 patients in the 11 and 29 day arms (p=0.32). Conclusions: Prostate SBRT delivered over 29 days was associated with superior bowel and urinary QOL compared to 11 days in the first 3 months of treatment. There were few severe (grade 3+) toxicities in either group. Follow-up is continuing to compare long-term outcomes. Clinical trial information: NCT01423474.
Investigating the long noncoding RNA SChLAP1 as a prognostic tissue and urine biomarker in prostate cancer.
Authors: Feng Felix Yi-Chung , Zhao Shuang , Prensner John , Erho Nicholas , Schipper Matthew J , Shi Yang , Magi-Galluzzi Cristina , Siddiqui Javed , Davicioni Elai , Den Robert Benjamin , Dicker Adam , Karnes R. Jeffrey , Wei John Thomas , Klein Eric A. , Jenkins Robert B. , Chinnaiyan Arul M. , Mehra Rohit
Published: February 2017

7

Background: Improved prognostic biomarkers are needed for localized prostate cancer. We undertook an unbiased large-scale analysis of genes associated with metastatic progression and validated the prognostic ability of the top candidate gene. Methods: Prostate cancer samples from prostatectomy patients were analyzed for gene expression using a clinical-grade, high-density Affymetrix GeneChip platform, encompassing >1 million genomic loci and assessed in a CLIA-certified laboratory. Nomination of prognostic candidate genes was performed on a discovery cohort (n=545) and validated on 3 independent cohorts (n=463). Multivariate analyses were performed for the primary endpoint of metastasis. The top prostate-specific gene was further evaluated in 208 additional tumor samples with a novel RNA in-situ hybridization (ISH) assay and in urine samples from 230 patients using PCR. Results: Of all known genes, the long noncoding RNA SChLAP1 ranked first for elevated expression in patients with metastatic progression by receiver-operator-curve analyses. Validation in three independent cohorts confirmed the prognostic value of SChLAP1. On multivariate modeling, SChLAP1 expression independently predicted metastasis within 10 years (odds ratio (OR) = 2.45, 95% confidence interval (CI) 1.70 – 3.53), death within 10 years (OR = 1.93, 95% CI 1.31 – 2.85), and biochemical recurrence within 5 years (OR = 1.76, 95% CI 1.28 – 2.41) with ORs comparable to Gleason score. Evaluation of SChLAP1 expression by RNA ISH confirmed a significant association with disease recurrence (OR = 1.99, 95% CI 1.06 – 3.73). Evaluation of urine SChLAP1 levels demonstrated increased expression in patients at higher risk for disease progression. Conclusions: We perform the largest high-throughput, unbiased study of prostate cancer prognostic biomarkers to date and discover SChLAP1 as a top gene predictive of metastatic progression. We validate SChLAP1 extensively with a clinical-grade assay. We show feasibility of a RNA ISH assay and a non-invasive urine test for SChLAP1. Our results, spanning 1,446 patients from 6 independent patient cohorts, suggest that SChLAP1 represents a very promising biomarker for aggressive clinical course.
Fluorescence-targeted laparoscopic lymph node dissection in prostate cancer.
Authors: Hruby Stephan , Englberger Christine , Lusuardi Lukas , Schaetz Tobias , Kunit Thomas , Magdy Ahmed , Hager Martina , Janetschek Guenter
Published: February 2017

70

Background: Recently we have introduced fluorescence by means of Indocyanin Green(ICG) in addition to radio-guided dissection using Technetium 99(Tc99) for laparoscopic pelvic sentinel node dissection (Urology 2012). Hence we could show that ICG alone gave equal results compared to TC99. Since ICG visualizes the complete drainage system we have as an evolution now left the sentinel concept to completely remove this template. Methods: 38 consecutive men with intermediate and high risk prostate cancer have undergone targeted Lymphnode dissection during laparoscopic radical prostatectomy. 2ml ICG were injected transpeineally into each lobe under TRUS guidance. After removal of the complete ICG visualized Lymphnode template of each side, a standard ePLND was added as control. All Lymphnodes were evaluated by 250 ym sections and imunohistochemistry. Results: Transperineal Injection allowed for precise deposit without any periprostatic extravasation. Fluorescence stained (F+) nodes were found on both sides in all patients except one. In total 596 nodes (17,9 +-8,4/patient) were removed, of which 473 nodes (14,3 +- 8,51/pat.) were F+. LN Metastases were found in 15 pat.(39,5%), of which 2 pat. (5,3 %) had solitary micrometastases. In addition 3 patients (7,9 %) the LN contained Tumor Cell Cluster. No non-stained metastases were found in addition to F+ Metastases. Met outsi de the template of extended PLND occurred in 5 patients(27,8% of N+). Conclusions: Fluorescence-targeted lymphnode dissection allows to identify the lymphatic drainage of the prostate with great reliability. It proved to be more precise than extended lymphnode dissection in patients with intermediate and high grade prostate cancer
Utilization and impact of surgical technique on the performance of pelvic lymph node dissection at radical prostatectomy: Results from the SEARCH database.
Authors: McGinley Kathleen F. , Sun Xizi , Howard Lauren E. , Aronson William J. , Terris Martha K. , Kane Christopher J. , Amling Christopher L. , Cooperberg Matthew R. , Freedland Stephen J.
Published: February 2017

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Background: Performance of a pelvic lymph node dissection (PLND) with radical prostatectomy (RP) is critical for staging and treatment of high-risk prostate cancer (PC). Conversely, performance of a PLND in low-risk PC contributes to morbidity with minimal benefit. Robot-assisted laparoscopic RP (RARP) is associated with decreased PLND use. We evaluated PLND use over time, stratified by PC risk group and surgical technique. Methods: We used SEARCH to identify men who had open RP (ORP) or RARP from 2006-2013 with complete data. Univariable logistic regression was used to test the association between age, race, BMI, number of positive cores, AUA risk group, year, center, and surgical technique on PLND use. Multivariable logistic analysis was used to examine surgical technique and PLND performance stratified by AUA risk-group. Spearman correlation was used to examine temporal changes in PLND utilization stratified by risk-group and surgical technique. Results: 1,439 men met inclusion criteria. Of these, 66% had a PLND. On univariable analysis, age, year, number of positive cores, AUA risk group, center, and surgical technique were significantly associated with PLND performance (all p<0.02). On multivariable analysis, when adjusted for age, race, BMI, number of positive cores, year, and center, RARP was associated with a 89% decreased use of PLND in the low-risk group, 85% decreased in intermediate risk, and 86% decreased in high risk men (all p≤0.002). Over time, PLND was increasingly used with RARP in low-risk patients (p=0.022); a trend of increased PLND performance with RARP in high risk men was noted (p=0.077) reaching ~85% in 2012-2013 vs. ~95% in ORP. For ORP, PLND use did not significantly change over time except a trend of fewer PLND in low-risk men which decreased to ~35% (p=0.064) in 2012-2013. Conclusions: Regardless of risk group, PLND is markedly less likely to be performed when a RARP is done. While improved over time, PLND remains over-utilized in low-risk men and under-utilized in high risk men regardless of surgical technique.
Association of magnitude of cancer of the prostate risk assessment score change following biopsy gleason upgrade during prostate cancer active surveillance with adverse pathology at prostatectomy.
Authors: Leapman Michael S. , Ameli Niloufar , Chu Carissa , Welty Christopher J. , Hussein Ahmed , Cooperberg Matthew R. , Carroll Peter
Published: February 2017

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Background: The occurrence of pathologic upgrading in men with prostate cancer (PCa) managed with active surveillance (AS) is a cause for concern and may prompt treatment; however the degree to which upgrading impacts further risk status is unclear. We evaluated the association between the Cancer of the Prostate Risk Assessment (CAPRA) score and adverse pathological outcomes following biopsy Gleason upgrading in men with PCa on AS. Methods: We retrospectively evaluated men with low and intermediate risk PCa managed with AS at our institution between 1993 and 2013 who received a minimum of two biopsies. We assessed change in CAPRA score between initial diagnosis and Gleason upgrade at repeat biopsy. Among patients proceeding to radical prostatectomy, multivariate models incorporating CAPRA change and reclassified CAPRA score were constructed to evaluate factors associated with adverse pathology and time to treatment. Results: We identified 312 men with PCa on AS who experienced pathologic upgrade on surveillance biopsy at a median of 24 months (IQR 12-47) and at a median age of 65.7 years (IQR 61-71). The median CAPRA score at diagnosis was 1 (IQR 1-2), and median change at upgrade was +2 (IQR 1-3). 196 patients (63.0%) were reclassified to higher CAPRA scores at upgrade, while 108 (34.7%) had CAPRA classification that remained unchanged. Seven (2.3%) patients had a decrease in CAPRA risk category after biopsy upgrade. In a multivariate logistic regression model, reclassification to high CAPRA risk category at upgrade was significantly associated with adverse pathology at RP (OR=21.34, 95% CI 2.58-176.57, p=0.0097). Conclusions: Recalculated CAPRA score following biopsy Gleason upgrade during AS is a strongly associated with adverse surgical pathology among treated patients. This finding supports the role of refined risk reassessment in men with PCa on AS, particularly in those experiencing upgrading on subsequent biopsy.
Cost-effectiveness of a biopsy-based 8-protein prognostic assay to optimize treatment decisions in intermediate-risk early-stage prostate cancer.
Authors: Roth Joshua A. , Ramsey Scott David , Carlson Josh John
Published: February 2017

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Background: Clinico-pathologic factors alone are insufficient to predict the likelihood of progression of Gleason 3+3 and 3+4 prostate cancer at the time of biopsy. As a result, many patients receive treatment, despite having unaggressive tumors. There is a need for tests that provide a clearer picture of risk to enable more individualized treatment decisions. A novel prognostic assay (ProMark) that uses quantitative measurements of protein biomarkers has been validated to predict prostate cancer aggressiveness at the time of biopsy. Our objective was to evaluate the potential cost-effectiveness of using the 8-protein assay to inform treatment decisions. Methods: We developed a simulation model to estimate quality-adjusted life-year (QALY) and cost outcomes for assay and usual care (NCCN guidelines) strategies. The proportion of patients classified as low, intermediate, and high-risk by the assay and guidelines was derived from the assay’s validation study. Treatment distributions, costs, health state utilities, and mortality rates were derived from peer-reviewed literature. The health outcome impacts of the assay strategy come from increased use of active surveillance (AS) vs treatment, and we evaluated a base case increase in AS of 14.5% (vs usual care), and small and large shift scenarios with 7.8% and 20.2% increases, respectively. We calculated the incremental QALYs, costs, and cost-effectiveness ratio in each scenario. Results: The assay strategy was dominant in all scenarios evaluated. In the base case, the assay strategy resulted in 0.04 more QALYs and $700 less in costs. The small and large shift scenarios resulted 0.02 and 0.05 more QALYs, and $5 and $1,300 less in costs, respectively. Cost-effectiveness outcomes were most sensitive to the assay cost, the AS health state utility, and the proportion of low-risk patients receiving AS in usual care. Conclusions: Our results suggest that the 8-protein prognostic assay has the potential to be a cost-effective alternative to usual care in patients with Gleason 3+3 and 3+4 prostate cancer. Future studies will evaluate the impact of the assay on patient and physician treatment choices in real-world settings.
An impact of pelvic MRI (PMRI) to radiotherapy (RT) target volumes definition in prostate cancer patients (pts).
Authors: Rouvinov Keren , Mermershtain Wilmosh , Beloshicki Olga , Ariad Shmuel , Lavrenkov Konstantin
Published: February 2017

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Background: PMRI is a standard pre-RT evaluation procedure in pts with intermediate and high-risk prostate cancer. We conducted a retrospective study to evaluate an influence of PMRI to delineation of RT clinical target volume (CTV). Methods: Medical records of prostate cancer pts treated with intensity-modulated RT (IMRT) in single institution retrieved and examined retrospectively. Initial risk group affiliation was defined using D'Amico method. PMRI reports of pts with intermediate and high-risk prostate cancer were reviewed and risk group affiliation was re-defined in regards of T- and N-stage. IMRT treatment plans were re-assessed. In regards to PMRI T-stage, extra-capsular extension (ECE) and seminal vesicles invasion (SVI) were included to high-dose CTV. Pelvic lymph nodes (PLN) were planned to treat in all high-risk pts. PLN considered pathological by PMRI were included to separate CTV to receive RT dose higher than unaffected PLN stations. Results: Between 2008 and 2014, 169 pts with intermediate and high-risk prostate cancer underwent PMRI at around 1 month before commencing IMRT. Initially, 89 pts were affiliated to intermediate-risk and 80 to high-risk group. In general, PTV-changes based on PMRI data required in 77 pts (45.5%). Thirty seven of 89 intermediate-risk pts (41.6%) have been switched to high-risk group, necessitating irradiation of PLN. ECE and SVI were included to high-dose CTV in 64 (37.8%) and 29 pts (17.2%) respectively. PLN were thought pathological in 10 pts (5.9%), which demanded contouring of a separate CTV. Conclusions: In our series PMRI-scans had a significant impact on RT target coverage decision in pts with intermediate and high-risk prostate cancer.
A biomarker panel associated with distant metastasis in prostate cancer patients treated with radiotherapy as prognostic for DM in a large cohort of prostatectomy patients.
Authors: Pollack Alan , Erho Nicholas , Noronha Roshan , Lam Lucia L.C. , Buerki Christine , Abraham Sakhi , Klein Eric A. , Karnes R. Jeffrey , Den Robert Benjamin , Dicker Adam , Ishkanian Adrian , Davicioni Elai , Feng Felix Yi-Chung , Stoyanova Radka
Published: February 2017

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Background: A number of biomarkers related to cell cycle, angiogenesis or apoptosis have been found to be associated with patient outcome in tissue samples from men treated with first line radiation therapy in RTOG clinical trials using immunohistochemical staining and analysis. In a prior study, four biomarkers (Ki-67, MDM2, p16 and Cox-2) and clinical covariates were included in a model of distant metastasis (DM; Pollack et al, Clin Cancer Res, 2014 [epub ahead of print]) risk. The current study tested the hypothesis that these genes are prognostic for DM in men treated primarily with total prostatectomy using RNA expression profiling. Methods: RNA fromprostatectomy samples from Cleveland Clinic (CC, n=182); Mayo Clinic (MC)-I (n = 545) and II (n=235); Memorial Sloan Kettering Cancer Center (MSKCC, n=131); Erasmus Medical Center (EMC, n=48) and Thomas Jefferson University (TJU, n=130) were profiled using 1.4 million RNA features. A Cox proportional hazards model was built on the MC-I training set to combine the 4 biomarkers into a prognostic risk score (4BMSig). 4BMSig was subsequently evaluated for its prognostic significance separately and in combination with clinical risk factors (biopsy Gleason Score, cT-category and Preop-PSA) for DM. Results: 4BMSig was found to discriminate DM patients significantly for the MC-II (AUC = 0.66, p < 0.001), CCF (AUC = 0.68, p < 0.001), and MSKCC (AUC = 0.71, p = 0.04) datasets, and achieved borderline significance for EMC (AUC = 0.70, p = 0.06). 4BMSig did not discriminate DM in the TJU dataset (only 10 DM events). Pooled multivariable analysis (n = 726) with clinical covariates revealed that 4BMSig is a strong independent prognostic covariate for DM (p < 0.001) and prostate cancer specific mortality (p = 0.005). Conclusions: The four genes identified previously as being associated with DM in radiotherapy patients were incorporated herein into 4BMSig, which was found to have potential as a pretreatment prognostic DM risk assessment tool for men treated with prostatectomy. Further validation would consist of testing 4BMSig from RNA in diagnostic tissue from prostate cancer patients prior to prostatectomy.
Expression of the leukocyte chemoattractant chemerin in human prostate tumors.
Authors: Pachynski Russell Kent , Zabel Brian , Leong Weng-In , Crowder Robert , Peehl Donna , Butcher Eugene
Published: February 2017

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Background: The infiltration of immune cells into the tumor microenvironment can regulate growth and survival of neoplastic cells. Several studies have shown a correlation between increases in the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including prostate. The field of prostate cancer immunotherapy continues to grow, with sipuleucel-T already approved and a recombinant vaccinia-PSA (Prostvac) currently in a Phase III clinical trial. Recent studies have shown immune cell infiltration into prostate tumors after systemic administration of sipuleucel-T, suggesting infiltration of these cells may be a key step in the mechanism of action. Methods: Here, in a survey of public whole genome expression datasets we found that the gene for chemerin (RARRES2), a widely expressed endogenous chemoattractant protein for immune cells, is downregulated in prostate cancer. In mouse models, we have previously shown that forced re-expression of chemerin at sites of tumor results in an increase in immune cell infiltration (e.g. NK and T cells), as well as significantly reduced tumor growth (Pachynski JEM 2012). Results: In addition to this published analysis, using RT-qPCR we have gone on to confirm that human prostate tumors have significantly less chemerin (RARRES2) compared to normal prostate tissue. Preliminary immunohistochemistry results in human tumors using an anti-human chemerin antibody, are consistent with our qPCR results, suggesting human prostate tumors downregulate chemerin during their malignant transformation. Conclusions: We have shown, for the first time, that human prostate tumors downregulate chemerin compared to normal prostate tissue. We hypothesize that this is one mechanism of “immune escape.” Therapeutic forced re-expression of chemerin in human tumors may restore anti-tumor immunity within the tumor microenvironment resulting in slowed growth and regression of established tumors. Additionally, chemerin’s ability to recruit NK and T cells into the tumor microenvironment may make it an ideal therapy to combine with other treatments aimed at boosting the immune response, such as sipuleucel-T or checkpoint inhibition (e.g. anti-CTLA4, anti-PD1/PDL1).