bluuebunny/crossref_metadata_2025 huggingface dataset:
Observational cohort study of first-line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802): Sub-group analysis by KRAS Exon2 status.
Authors: Takahata Takenori , Yuki Satoshi , Nakatsumi Hiroshi , Harada Kazuaki , Fukushima Hiraku , Sato Atsushi , Kato Takashi , Meguro Takashi , Nakamura Michio , Ehira Nobuyuki , Iwanaga Ichiro , Tateyama Miki , Hatanaka Kazuteru , Eto Kazunori , Okuda Hiroyuki , Kobayashi Yoshimitsu , Muto Osamu , Abe Masakazu , Sakata Yuh , Komatsu Yoshito
Published: February 2017

782

Background: A few reports have shown the efficacy of bevacizumab (BV) independent of the KRAS Exon2 mutational status (KRAS). We performed a sub-group analysis by KRAS from the HGCSG0802 observational cohort study with investigated 115 patients (pts) treated with first line BV for metastatic colorectal cancer (mCRC). Methods: The objective of HGCSG0802 was to evaluate progression-free survival (PFS), overall survival (OS), time to treatment-failure (TTF), response rate (RR), safety, etc. The key eligibility criteria were with evaluable lesions, older than 20 years, ECOG PS 0-2. In this analysis, pts characteristics, RR and safety were compared using Fisher’s exact test. Univariate and multivariate analysis for PFS were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method, log-rank test, and Cox proportional hazards model. Results: Of 108 pts (the full analysis set), 98 pts were evaluable for KRAS. Sixty-one pts (62.2%) had KRAS wild-type (wt) and 37 pts (37.8%) had mutation (mt). The pts characteristics between those with wt and with mt were generally balanced except for PS 0 (91.8% in wt, 75.7% in mt; p=0.037) and lung metastasis (34.4% in wt, 62.2% in mt; p=0.012).The median TTF was 7.4 months in wt versus 6.6 months in mt, and RR was 69.5% in wt versus 65.7% in mt. Adverse events related to BV were almost balanced except for bleeding (any grade) (31.1% in wt, 13.5% in mt; p=0.056).The median PFS was 9.9 months in wt versus 7.9 months in mt (HR=1.506; p=0.071). Although KRAS mt showed shorter PFS, there were not significant difference regardless of KRAS in Cox multivariate analysis (HR 1.314, 95% CI, 0.820-2.107, p=0.257). Conclusions: The HGCSG0802 could be a database to investigate first line BV for mCRC in clinical practice. Depending on the KRAS Exon2 mutational status, efficacy, and adverse events were no significant difference. We plan to conduct further follow up for survival, and to perform this analysis again.
The impact of open colectomy on resection of colorectal liver metastases.
Authors: Robinson Stuart Michael , Arlott Lucas , Sen Gourab , French Jeremy J. , Charnley Richard M. , Manas Derek M. , White Steve A.
Published: February 2017

783

Background: Laparoscopic liver resection (LLR) is increasingly utilized in the management of patients with metastatic colorectal cancer. The aim of this study was to determine the impact of open vs. colonic resection of the primary tumour on outcomes following LLR. Methods: A prospectively maintained database was searched to identify all patients undergoing laparoscopic resection for colorectal liver metastases (CRLM) between 1/1/2007 and 31/12/2013. Demographic, histological, surgical outcome and survival data were collated retrospectively. Statistical analysis was performed using SPSS. Results: A total of 71 patients (median age 66 yr; 64% male) underwent resection in this study of whom 35 had a laparoscopic colectomy (LC). The presence of a previous open colectomy (OC) surgical morbidity (17% vs. 11%; p=0.53); conversion to open surgery (22% both groups; p=0.95); duration of surgery (240 min vs. 285 min; p=0.28); or length of hospital stay (5 vs. 6 days; p=0.98). Overall survival in this series was 47 months with no difference between groups (p=0.58). Patients who underwent OC appeared to have a poorer recurrence free survival (8 vs. 21 months; p=0.03) although on multivariate analysis the only factor predictive of early recurrence was a node positive primary (OR 3.8; p=0.05). Conclusions: In patients being considered for LLR for metastasic colorectal cancer the surgical approach to colectomy has no bearing on either short term surgical outcomes or longer term disease specific survival.
Association of histologic grade and subtypes of gastric cancer (GC) with chemoradiation response.
Authors: Charalampakis Nikolaos , Nogueras-Gonzalez Graciela M. , Wang Xuemei , Elimova Elena , Shiozaki Hironori , Wadhwa Roopma , Planjery Venkatram , Garris Jeana , Rogers Jane Elizabeth , Hiremath Adarsh , Blum Mariela A. , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Estrella Jeannelyn , Matamoros Aurelio , Das Prajnan , Badgwell Brian D. , Ajani Jaffer A.
Published: February 2017

97

Background: Patients with localized gastric cancer (LGC), when treated with preoperative therapy, tend to have heterogeneous and unpredictable outcomes. Currently, no clinical variables or biomarkers can predict response. Methods: We analyzed 107 LGC patients who were treated with chemoradiation followed by surgery (trimodality therapy; TMT). Tumors were grouped into poorly (G3) or moderately (G2) differentiated and signet ring cell (SRC) or non-SRC histology. Association was made with pathologic complete response (pathCR) or < pathCR. Descriptive statistics and survival analyses were utilized. Results: The majority of the patients were male (60%), had clinical stage III cancer (51%), and received chemotherapy before chemoradiation (94%). All had adenocarcinoma and most had G3 (78%) and SRC histology (58%). PathCR was noted in 18% of patients with G3 and 33% of patients with G2 (p=0.125). Overall survival (OS) was significantly shorter for G3 patients compared to G2 patients (p=0.045). Patients with SRC histology had a lower rate of pathCR than those with non-SRC (8% vs 40%, p<0.001). Patients with SRC histology had a trend towards shorter OS (p=0.063). Surgical pathologic stage was independently associated with OS and recurrence-free survival (RFS) (p<0.001). Conclusions: Our data suggest that histologic grade/ subtypes are associated with response to preoperative chemoradiation. Independent validation and addition of biomarkers could allow individualization of therapy of LGC patients. From U. T. M. D. Anderson Cancer Center (UTMDACC), Houston, Texas, USA. (Supported in part by UTMDACC, and CA 138671 and CA172741 from the NCI). Dr. Nikolaos Charalampakis has been awarded a scholarship from the Hellenic Society of Medical Oncology.
A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The RILOMET-2 trial.
Authors: Doi Toshihiko , Kang Yoon-Koo , Muro Kei , Jiang Yizhou , Jain Rajul K. , Lizambri Richard
Published: February 2017

TPS226

Background: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor, the only known ligand of the MET receptor. In a phase 2 study, trends toward improved progression-free survival (PFS) and overall survival (OS) were seen with rilotumumab plus epirubicin, cisplatin and capecitabine (ECX) vs ECX alone in pts with G/GEJ cancer; the treatment effect of rilotumumab was enhanced in MET-positive pts (Iveson et al. Lancet Oncol 2014;15:1007). In a phase 1/1b study, rilotumumab plus CX had manageable toxicities and a favorable pharmacokinetic (PK) profile in Japanese pts with MET-positive G/GEJ cancer (Doi et al. J Clin Oncol 2014;32:5s,abstract 4051). Methods: In this phase 3 study, 450 pts from Asian countries are randomized 1:1 to CX (intravenous [IV] cisplatin 80 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily on days 1−14) plus double-blind rilotumumab 15 mg/kg or placebo IV on day 1 every 3 weeks for up to 6 cycles. After cycle 6, pts will receive capecitabine plus rilotumumab or placebo. Randomization is stratified by disease extent (locally advanced vs metastatic), prior surgery for G/GEJ or esophageal cancer (yes vs no), and country (China vs other). Key eligibility criteria include previously untreated, pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma, ≥20 years, ECOG score ≤1, MET-positive by centralized immunohistochemistry, HER2-negative, adequate organ function, and ≥6 months since neoadjuvant/adjuvant therapy. The primary endpoints are PFS and OS. A log-rank test stratified by the randomization factors will compare PFS and OS between arms. Key secondary endpoints include 12-month survival rate, time to progression, objective response and disease control rates, duration of/time to response, safety, and PK. Enrollment began in July 2014, and the trial continues to recruit participants. The study is overseen by an independent data monitoring committee. ClinicalTrials.gov: NCT02137343. Sponsor: Amgen Inc. Clinical trial information: NCT02137343.
Phase 3 randomized, double-blind, controlled study of cabozantinib (XL184) versus placebo in subjects with hepatocellular carcinoma who have received prior sorafenib (CELESTIAL; NCT01908426).
Authors: Abou-Alfa Ghassan K. , Cheng Ann-Lii , Meyer Tim , El-Khoueiry Anthony B. , Ikeda Masafumi , Chun Hoo Geun , Furuse Junji , Knox Jennifer J. , Okusaka Takuji , Ping Jerry , Borgman-Hagey Anne E. , Kelley Robin Kate
Published: February 2017

TPS496

Background: Currently, there are no approved systemic therapies for patients with advanced hepatocellular carcinoma (HCC) who fail sorafenib. Cabozantinib is an oral receptor tyrosine kinase inhibitor (TKI) with activity against tyrosine kinases including MET, RET and VEGFRs. MET and VEGFR signaling have been implicated in tumor neo-angiogenesis and invasion. MET is overexpressed in HCC compared with non-tumor liver tissue, with higher MET expression linked to poor prognosis. Cabozantinib prolonged survival in a MET-driven transgenic mouse model of HCC, and has demonstrated clinical activity in multiple solid tumor types, including 41 subjects with advanced HCC treated in a phase 2 randomized discontinuation study. Methods: This phase 3, randomized, double-blind study evaluates the efficacy and safety of cabozantinib compared with placebo in subjects with advanced HCC previously treated with sorafenib and have progressed following 1-2 prior systemic treatments for HCC. Subjects must be ≥ 18 year old, have Child-Pugh Score of A and ECOG PS ≤ 1. Subjects are randomized 2:1 to receive either cabozantinib or placebo. Stratification factors are etiology of disease, geographic region and the presence of extrahepatic spread of disease and/or macrovascular invasion. The primary endpoint is overall survival. Secondary endpoints are progression-free survival and objective response rate by RECIST 1.1. Additional endpoints include safety, tolerability, circulating tumor cells, serum bone markers and plasma biomarkers, effects on bony disease assessed by bone scan and health-related quality of life (HRQoL) using the EuroQol Health questionnaire (EQ-5D-5L). Enrollment was initiated in September 2013. Target recruitment is 760 subjects. A total of 621 events planned with 2 interim analyses (at 311 and 466 events) would provide 90% power to detect a 31.6% increase in OS (HR=0.76). Clinical trial information: NCT01908426.
A phase II trial of regorafenib as a single agent in patients with advanced and metastatic biliary tract carcinoma and first-line chemotherapy failure.
Authors: Patel Anuj Kishor , Stoller Ronald G. , Rhee John C. , Lembersky Barry C. , Ohr James , Lee James J. , Bahary Nathan , Chu Edward , Sun Weijing
Published: February 2017

TPS498

Background: Biliary tract cancers (including cholangiocarcinomas) are rare but aggressive malignancies with limited options for treatment. Currently, the combination of gemcitabine and cisplatin is considered the upfront systemic chemotherapy for patients with advanced and metastatic diseases. There is no ‘standard’ for second-line treatment. Several signaling pathways have been identified that might play a role in the development of biliary tract cancer and that may represent targets for directed therapies. Overexpression of VEGF and alterations of the Ras/Raf pathway have been identified in the majority of cholangiocarcinoma; some studies have shown these mutations to be associated with metastasis and poorer prognosis. Regorafenib is an oral multikinase inhibitor of multiple angiogenic and oncogenic kinases (VEGFR1-3, TIE2, PDGFR-β, FGFR1, KIT, RET, RAF) which has shown efficacy as a single agent in multiple solid tumors. This study evaluates the efficacy of regorafenib in patients with advanced/metastatic biliary tract cancer following the failure of first-line chemotherapy. Methods: Enrollment in this phase II, single-arm trial is ongoing. Eligible patients have unresectable advanced or metastatic biliary tract adenocarcinoma, and have failed first-line systemic chemotherapy. Patients receive regorafenib 120 mg orally daily in a 21 days on, 7 days off cycle. Tumor measurements take place every 3 cycles by CT or MRI imaging. Patients continue on therapy until disease progression or unacceptable toxicities. The primary end point of this study is median progression-free survival (PFS). To evaluate for evidence of activity, defined as a median PFS of 3.5 months or greater, with 83% power (one-sided test, α=0.10), target enrollment is 37 patients. Secondary endpoints include safety, overall response rate, disease control rate, median overall survival, and changes in biomarker levels. The correlation of these biomarkers and of tumor mutations with response to treatment is built into the study as well. As of September 2014, 9 patients had been enrolled. ClinicalTrials.gov Identifier: NCT02053376. Clinical trial information: NCT02053376.
The MIRACLE trial: A randomized, controlled trial comparing green tea extract versus placebo for the prevention of metachronous colon adenomas in a screening population.
Authors: Ettrich Thomas Jens , Stingl Julia , Muche Rainer , Claus Katrin , Reiser Baerbel , Seufferlein Thomas
Published: February 2017

TPS786

Background: Prevention of colorectal cancer is a major health care issue. After polypectomy there is an increased risk of polyp recurrence and various means of chemoprevention have been tried to prevent this. NSAIDs have been shown to be effective but confer side effects such as gastrointestinal bleeding. Nutraceuticals such as polyphenols from tea plants have demonstrated remarkable therapeutic and preventive effects in molecular, epidemiological and some clinical trials. However, their value in preventing colorectal polyps has not been demonstrated in a large, randomized trial. The beneficial safety profile of decaffeinated green tea extract and accumulating evidence of its cancer preventive potential justify and require, in our view, a validation of this compound for the nutriprevention of colorectal adenoma. Good accessibility and low costs might render this neutraceutical a top candidate for wider use as nutritional supplement in colon cancer prevention. Methods: Randomized, double blinded, placebo-controlled, multicenter trial. After a one month run-in period with verum, 918 patients (age: 50-80 years) who have undergone polypectomy within the last 6 months will be randomized to receive either decaffeinated green tea extract (containing 150 mg epigallocatechin gallate (EGCG) two times daily) or placebo over a period of three years. Primary outcome: Incidence of metachronous colorectal adenomas (tubulovillous, tubular, villous, serrated lesions) at the 3 year follow-up colonoscopy. Secondary outcomes: Occurrences, number, localization, size and histological subtypes of adenomas, frequency of colorectal carcinoma. In addition, genetic and biochemical biomarkers in blood samples and genetic alterations (Ras, B-raf, microRNAs) in tissue samples of adenomas will be analyzed (biobanking subprojects). Additionally, nutrikinetics and nutrigenetics of EGCG and other catechins will be assessed in healthy volunteers. Patient recruitment has started in November 2011. At September 2014, 785 patients were recruited and 651 patients were randomized. We expect the last patient out in Spring 2018. (Trial identifier NCT01360320) Clinical trial information: NCT01360320.
Phase III study of regorafenib versus placebo as maintenance therapy in RAS wild type metastatic colorectal cancer (RAVELLO trial).
Authors: Martinelli Erika , Troiani Teresa , Venturini Filippo , Cervantes Andres , Douillard Jean Yves , Falcone Alfredo , Folprecht Gunnar , Köhne Claus-Henning , Taïeb Julien , Tabernero Josep , Cardone Claudia , Sforza Vincenzo , Martini Giulia , Napolitano Stefania , Capuano Annalisa , Auricchio Fabiana , Ciardiello Fortunato
Published: February 2017

TPS789

Background: Treatment of metastatic colorectal cancer (mCRC) has improved due to the introduction of more active chemotherapies (CT) and novel targeted agents that have significantly increased response rate (RR), progression free survival (PFS) and overall survival (OS). Recently, CORRECT and CONCUR trials have demonstrated both activity and efficacy of regorafenib, a small multi-kinase inhibitor, as monotherapy in pretreated mCRC. The wide range of action of regorafenib makes it an ideal candidate for monotherapy in earlier disease treatment lines in which different pathways could be involved in the acquisition of resistance. To improve long term efficacy of first line therapy several therapeutic approaches of maintenance treatment have been explored in mCRC. Methods: RAVELLO is an academic randomized, double-blind, placebo-controlled, multi-center, phase III study designed to evaluate efficacy and safety of regorafenib as maintenance treatment after first line therapy. Eligible patients: pathologically confirmed mCRC RAS wild type (KRAS and NRAS genes) treated with a first line fluoropyrimidine-based CT in combination with an anti-EGFR (epidermal growth factor receptor) monoclonal antibody for a minimum of 4 to a maximum of 8 months, with a stratification by response to the first line treatment (complete response/partial response or stable disease). 480 patients will be enrolled and randomly assigned in a 1:1 ratio to receive 160 mg regorafenib or placebo per os, every day for 3 weeks of every 4 weeks cycle, until disease progression or unacceptable toxicity. Primary endpoint is PFS. With a two-tailed alpha error of 0.05, the study will have 90% power to detect a 3-month prolongation of median PFS from randomization (corresponding to a hazard ratio of progression of 0.67 with 6-month median PFS expected in the control arm). Secondary endopoint are OS, safety, and biomarker correlative studies. Currently, one patient has been enrolled and is on treatment. EudraCT number: 2013-005428-41. Clinical trial information: 2013-005428-41.
Randomized phase II studies comparing pathological responses observed on colorectal cancer metastases resected after preoperative treatment combining bevacizumab or cetuximab with FOLFOX or FOLFIRI.
Authors: Van Den Eynde Marc , Castella Marie-Laure , Machiels Jean-Pascal H. , Humblet Yves , Canon Jean-Luc Re , Houbiers Ghislain , Demolin Gauthier , D'Hondt Lionel A. , Coche Jean-Charles , Van Daele Daniel , Delaunoit Thierry , Goeminne Jean Charles. , Beniuga Gabriella , Pairet Geraldine , Sempoux Christine , Jouret-Mourin Anne , Van Maanen Aline , Carrasco Javier
Published: February 2017

TPS795

Background: Even if the use of targeted therapies combined with chemotherapy has demonstrated increase response rate and survival benefit in non resectable metastatic colorectal cancer (mCRC), the administration of these combinations in frontline resectable disease is source of debate and optimal association is still unclear. Based on a retrospective analysis, we previously reported thatthe chemotherapy partner combined with VEGF or EGFR inhibitors influenced pathological responses (pR) on the resected colorectal cancer metastases (CRCM) with a significant advantage for oxaliplatin with anti-VEGF or irinotecan with anti-EGFR combinations. We aimed to design 2 parallel studies (BEV-ONCO, CET-ONCO) to prospectively precise optimal combination between oxaliplatin and irinotecan with bevacizumab or cetuximab before CRCM resection. Methods: The 2 studies are open label randomized multi-centric trials and concern mCRC patients with resectable disease in whom a preoperative treatment is considered. The primary objective is to assess the CRCM pR rate according the Tumor Regression Grade classification (Rubbia-Brandt) after allocated preoperative treatment (bevacizumab combined with FOLFOX vs. FOLFIRI without consideration of RAS/BRAF for BEV-ONCO trial (EUDRACT 2012-005376-34) and cetuximab associated with FOLFOX or FOLFIRI only for RAS/BRAF wild type tumor for CET-ONCO trial (EUDRACT 2012-005249-19)). According investigator’s choice, patient will received 3 to 6 treatment cycles before CRCM resection. Patient’s survival, safety, surgical complications and treatment associated liver-toxicity are secondary end-points. Up to 60 patients (30 per treatment group) will be randomised in each study (power: 80%, type I error of 5% to detect a difference in proportion of pR rate between FOLFOX or FOLFIRI association of 0.40). Formal comparison will not be done across studies. Translational research projects are ongoing (CRCM immune response, tumour specific genetic rearrangements as new specific biomarkers). Clinical trial information: NCT01858649 (BEV-ONCO); NCT01858662 (CET-ONCO). Clinical trial information: NCT01858649 (BEVONCO) NCT01858662 (CETONCO).
FGFR1, a new FISH biomarker, to predict recurrence of prostate cancer after prostatectomy.
Authors: Zhang Ying , Du Jing , Liu Ping , Buckingham Lela , Colpitts Tracey , Pestova Ekaterina
Published: February 2017

100

Background: To identify prostate cancer (CaP) with high recurrence risk after Radical Prostatectomy (RP) is a challenge. FGFR1 (Fibroblast Growth Factor Receptor 1) plays a critical role in prostate development and tumorigenesis. In this study, we explored the possibility of using FGFR1 fluorescence in situ hybridization (FISH) to predict recurrence after RP in the Formalin fixed paraffin embedded (FFPE) tissue from CaP patients. Methods: FFPE histological specimens from 52 RP cases were evaluated with FGFR1 (8p12) / CEP 8 probe mix. While 32 of the 52 patients recurred within 5 years (PSA progression or death of disease), and 20 remained disease-free with 8 to 15 years. Median age of patients was 62 with Gleason Score range from 4 to 9. Percent of FGFR1 gain and FGFR1 loss per specimen, as well as mean number of FGFR1 signals per specimen were calculated. CEP8 was used as a control to assess hybridization quality. Statistical analysis (Cox Proportional Hazards model) was conducted using SAS 9.2. Results: Survival analysis demonstrated that percent FGFR1 loss in a specimen could identify recurrent CaP with the Harzard Ratio (HR) of 3.34 (p=0.0011), which indicated that the risk of recurrence for FGFR1 loss-positive group is 3.34 times than that for FGFR1 loss-negative group. On the other hand, survival analysis of the percent FGFR1 gain showed that FGFR1 gain (amplification) is favorable for survival with HR of 0.36 (p=0.0043), which indicated that the risk of recurrence for FGFR1 gain-positive group is 0.36 times than that for FGFR1 gain-negative group. By using mean FGFR1 signals per specimen in the Kaplan-Meier analysis, the patient specimens stratified into three distinct groups (overall logrank p=0.0011): normal for FGFR1, FGFR1 gain (more favorable outcome), and FGFR1 loss (highest risk of recurrence). Conclusions: This study shows the utility of FGFR1 copy number abnormalities in CaP. Our results indicate that gain and loss of FGFR1 may have a different effect on disease recurrence. Therefore, FGFR1 FISH may provide predictive value for CaP recurrence in post RP patients, either by itself, or as an adjunct to the currently clinical prognostic indicators.
Intermediate-risk prostate cancer: A Medicare-based cost comparison of five radiotherapy regimens.
Authors: Nichols Romaine Charles , McIntyre Kathy , Gifford Juana , Ritz Steve K. , Klein Stuart , Bryant Curtis , Henderson Randal H. , Mendenhall William M. , Mendenhall Nancy Price , Hoppe Bradford S.
Published: February 2017

108

Background: Patients with intermediate risk prostate cancer choosing radiotherapy may be treated with a number of regimens. The current study compares the direct treatment cost for five therapeutic options based on Fiscal Year 2014 Medicare allowable reimbursements. Methods: Hypothetical charge sheets were generated along with the expected Medicare allowable reimbursements (based on global billing where applicable) for the following regimens: 1.) Image Guided Intensity Modulated Radiotherapy (IGIMRT) to a dose of 78Gy in 39 fractions with one field reduction (IGIMRT); 2.) Dose escalated IGIMRT to 84.60Gy in 47 fractions with one field reduction (MSKCC-IGIMRT); 3.)IGIMRT to a dose of 45Gy in 25 fractions followed by a 90 seed I125 prostate implant (IGIMRT-BTX); 4.) Image Guided Proton Therapy to a dose of 78Gy(RBE) in 39 fractions with one field reduction (SFPT); 5.) Image Guided Hypofractionated Proton Therapy to a dose of 72.50Gy(RBE) in 29 fractions with one field reduction (HFPT). Results: Based on Fiscal Year 2014 Medicare allowable reimbursements, the direct cost for each of these interventions including professional fees, technical fees, isotope costs and facility fees is shown in the Table. Conclusions: This data presents a framework for evaluating the cost effectiveness of proton therapy as compared to competing therapeutic options. Under current Medicare allowable reimbursements, the cost of proton therapy relative to the cost of other therapeutic options is highly dependent on the number of radiotherapy fractions delivered. The feasibility of delivering hypofractionated proton therapy for patients with localized prostate cancer is being investigated at a number of institutions as well as within the framework of a multicenter protocol. Ultimately the cost of proton therapy will need to be weighed against tumor control probabilities as well as the economic and quality of life benefits associated with reduced normal tissue exposure. [Table: see text]
Are patients with Gleason 6 pathology safe from developing metastatic castration-resistant prostate cancer (mCRPC)?
Authors: von Klot Christoph A. J. , Boeker Alena , Herrmann Thomas R. W. , Kramer Mario W. , Kuczyk Markus A. , Merseburger Axel S.
Published: February 2017

110

Background: Prostate cancer may remain clinical unapparent for decades, however at the stage of metastatic castration resistant prostate cancer (mCRPC), patients have only limited survival even with new therapeutic options. Recent evidence from histology studies regarding random prostate biopsies hint toward a relationship between higher biopsy Gleason score and the development of mCRPC. A few patients with initial low risk prostate cancer also seem to develop mCRPC. However, prostate biopsy underestimates final pathology in about one third of patients. We therefore evaluated the final whole gland pathology from radical prostatectomy to better assess the risk of progressing to mCRPC for patients with Gleason 6 prostate cancer in particular. Methods: Clinical data was assessed for patients with confirmed mCRPC between 3/2007 and 10/2014. Whole gland pathology workup was not available for patients with either metastatic disease on diagnosis, external radiation therapy or no curatively intended initial therapy. Results: Out of 605 screened patients we identified a total of 77 patients with confirmed mCRPC. Mean PSA at initial diagnosis was 29.5 ng/mL (range 1 - 58 ng/mL ). Mean PSA at the end of follow up was 34.1 ng/mL (range 1 - 71 ng/mL ). A total of 30 patients died during follow up. Distribution of Gleason scores for gleason 6, 7, 8, 9 and 10 were 2, 24, 28, 18, 5 patients respectively. Pathological evaluation obtained from laparoscopic or retropubic radical prostatectomy was available in 43 of 77 cases. cases. Interestingly, out of the only two patients with a documented gleason score of 6, one had radiation/I125 brachytherapy while the other had primary anti hormonal therapy. Therefore an understaging may be possible. Out of the confirmed final pathologies, non of the patients had a Gleason score below 7. Conclusions: Our observations suggest a non significant occurrence of mCRPC during the development of prostate cancer for patients with Gleason pathology of less than 7. Our results may potentially help better counseling for patients and need further validation in a larger series.
Prostate patterns of care.
Authors: Burt Lindsay , Shrieve Dennis C. , Tward Jonathan D.
Published: February 2017

117

Background: The aim of this study is to describe initial treatment of men diagnosed with prostate cancer in the United States (US) between 2004 and 2011. Methods: Subjects with adenocarcinoma of the prostate were identified using the National Cancer Institute’s (NCI) Surveillance, Epidemiology and End Results (SEER) Program between 2004 and 2011. Subjects were staged according the American Joint Committee on Cancer (AJCC) 7th edition criteria. The National Comprehensive Cancer Network (NCCN) risk group classifications were used to stratify subjects into low risk (LR) including very low risk, intermediate risk (IR), high risk (HR) and very high (VHR) groups. Surgical intervention was grouped into no surgery, prostatectomy or other which included cyroablative therapy, hyperthermia, laser ablation, TURP, etc. Descriptive statistics and analysis were performed using Microsoft Office 2013 Excel. Results: There were 306,694 PC subjects with sufficient data to be risk categorized. Overall, 35.0% of subjects had LR, 36.1% had IR, 22.5% had HR, 1.2% had VHR, 0.6% had node positive and 4.6% had metastatic disease. Table 1 reveals the surgical and radiation treatment distribution for each risk group. Between 2004 and 2011 the use of prostatectomy, no treatment and external beam RT (EBRT) increased and the use of brachy including brachy monotherapy and brachytherapy in combination with EBRT decreased. Age is a strong influence on treatment delivered. Conclusions: This patterns of care study shows the heterogeneity of therapy for PC stratified by risk group in a contemporary series. Trends in treatment may reflect the development of new technology and findings from randomized trials. [Table: see text]
Combined HDR brachytherapy boost plus external beam radiotherapy by IMRT versus external beam radiotherapy alone IMRT in intermediate- and high-risk prostate cancer: Dosimetric analysis from a randomized control trial.
Authors: Annamalai Manikandan , MA Laviraj , Kunhiparambath Haresh , Sharma Dayanand , Gupta Subhash , Mallick Supriya , Julka Pramod Kumar , Rath Goura Kishor
Published: February 2017

134

Background: Dose escalation by IMRT or brachytherapy significantly improves biochemical control in localized prostate cancer. In this prospective randomized study we compared dose conformity between two modalities HDR brachytherapy and IMRT to deliver a boost to the prostate after External beam Radiotherapy (EBRT). Methods: 20 patients with localized prostate cancer were randomized to receive IMRT alone or IMRT plus brachytherapy. After randomization, all patients received EBRT 45Gy/25#/5 weeks by IMRT in phase I. In phase II patients received either HDR brachytherapy 19Gy/2# (Arm A) or EBRT 29Gy/15#/3weeks (Arm B) and EQD2–DVH parameters were calculated for comparison. EQD2 was calculated with α/β ratio of 1.5Gy and 3Gy for prostate & 3Gy for rectum and bladder. Results: The median age, stage distribution, Gleason score, PSA and prostate volume of the cohort were 69.5 years, T2b–T3b, 7, 38.5ng/ml and 47.4cc respectively.The HDR BT delivered higher mean doses to PTV. In phase II, HDR BT vs IMRT the mean EQD2 for 95% of prostate volume, 33% of rectal volume was 45.7Gy vs 28.4Gy, 6.8Gy vs 17.4 Gy respectively; Dmean of rectum and bladder was 7.4 Gy vs 13.5Gy and 5.4Gy vs 12.7Gy respectively. Conclusions: HDR BT produced more conformal plan and lower OAR doses than IMRT. Dose escalation for prostate tumors by HDR BT may be preferred as easily achievable. [Table: see text]
Current state of genetic biomarkers for prostate cancer.
Authors: Cooper Meghan Anastasia , Lee Jae K , Pow-Sang Julio
Published: February 2017

135

Background: The heterogeneity of prostate cancer presents a challenge in accurately predicting disease behavior. Several biomarker models have recently been developed to allow better risk stratification and more definitive treatment. Methods: We surveyed the literature to find relevant articles on three commercially available prostate cancer biomarkers: Prolaris, Decipher and Oncotype DX. Articles were chosen based on the following criteria: adequate sample size for reliable statistical analysis, original and validation studies utilizing datasets from independent patient cohorts, and studies reporting appropriate statistical evaluations. Results: After screening 32 articles, eight were chosen for review that met the aforementioned criteria. Hazard ratio, odds ratio, area under the curve (AUC), or precision and reproducibility were used to quantify the assay’s predictive capability (Table). Conclusions: From our independent review we concluded that these biomarker models have not yet fully justified their claimed clinical utilities. Also, it is difficult to directly compare performance of these markers and no prospective studies have been reported to validate these assays. [Table: see text]
Predictive biomarkers of sensitivity to androgen receptor signaling (ARS) and taxane-based chemotherapy in circulating tumor cells (CTCs) of patients (pts) with metastatic castration resistant prostate cancer (mCRPC).
Authors: Scher Howard I. , Louw Jessica , Jendrisak Adam , Bambury Richard Martin , Danila Daniel Costin , Rathkopf Dana E. , Arslan Zaina , Schreiber Nicole A. , Lu David , Krupa Rachel , Marrinucci Dena , Landers Mark , Dittamore Ryan Vance
Published: February 2017

147

Background: The optimal sequence to administer approved life prolonging ARS inhibitors: Abiraterone (A) and Enzalutamide (E),and taxanes: Docetaxel (D) and Cabazitaxel (C), to maximize individual pt benefit is an unmet medical need. Sensitivity to an individual agent is dependent on the intrinsic biology of the tumor and the treatment to which it has been exposed. For each agent, response rates are lower in pts who have received prior treatment with any of the other drugs, but for the individual, sensitivity to one does not necessarily predict sensitivity to the other. We sought to develop response and resistance signatures to A & E or D & C from a baseline blood sample. Methods: 91 pt blood samples collected from 79 pts for CTC analysis with the Epic Sciences platform prior to treatment (27 pre-A, 28 pre-E, 28 pre-D, 8 pre-C). Epic analysis identified traditional CTCs (CK+, CD45-, intact nuclei, morph distinct), CK- CTCs (CK-, CD45-, intact nuclei, morph distinct), small CTCs (CK+, CD45-, intact nuclei, small cell size), and CTC clusters. IF staining for AR N, AR C exp were performed, digital pathology algorithms analyzed CTC morphology. A classifier was developed to associate clinical phenotypes with outcome to a specific agent. Results: A and E signatures included: AR N/C exp. and presence of CK+, AR+, Nucleoli+ CTCs. D and C signatures by: presence of CK+, small, AR-, Nucleoli+ CTCs. Multivariate algorithms for A and E and D & C were statistically associated with de novo resistance. Line of therapy was not a univariate predictor of response. Conclusions: Characterization of CTCs identified predictive biomarkers of sensitivity to ARS Tx and taxane chemotherapy in mCRPC pts. The proposed A&E signature differs from C and D, providing the opportunity to better guide treatment selection and improve patient outcomes using a real-time, non-invasive blood biopsy. Prospective trials to validate results are planned. [Table: see text]
Statin use at the time of initiation of androgen deprivation therapy (ADT) and time to progression (TTP) in patients with hormone-sensitive prostate cancer.
Authors: Harshman Lauren Christine , Nakabayashi Mari , Xie Wanling , Wang Xiaodong , Valenca Loana , Werner Lillian , Mucci Lorelei A. , Lee Gwo-Shu Mary , Sweeney Christopher , Pomerantz Mark , Kantoff Philip W.
Published: February 2017

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Background: Statin use has been associated with a decreased risk of recurrence after local therapy and a lower risk of prostate cancer mortality. There is little known about the association between statin use and prostate cancer progression among men newly initiating ADT. We undertook an analysis of the association between statin use at the time of ADT initiation and TTP. Methods: We queried our institutional clinical database (Prostate CRIS), which captures clinicodemographic data, treatment details, and clinical outcomes of our prostate cancer patients (pts), to identify pts treated with ADT for biochemical recurrence or metastatic disease. Date of progression and statin use at ADT initiation were collected by medical record review. Progression was defined as 3 PSA rises. Date of progression was defined as date of first rise (nadir + >0.02 ng/ml). The association between statin use and TTP on ADT was estimated from multivariable Cox regression, adjusting for known prognostic factors: biopsy Gleason score, primary therapy type, metastatic status, and PSA at ADT initiation. Results: Of the 926 patients eligible for analysis, 283 (31%) were taking a statin at ADT initiation. Statin users were less likely to have M1 (11 vs. 18%) or N1 (5 vs 10%) disease at diagnosis and more likely to have received local therapy +/-ADT compared to nonusers. They were also less likely to have metastases at ADT initiation (53 vs 63%). Median PSA at diagnosis and at ADT initiation were lower among statin users. Duration from diagnosis to ADT initiation was longer in users. After a median follow-up of 5.8 years, 644 pts (70%) had progressed on ADT and median TTP on ADT was 20.3 months (95% CI: 18,24). Men on statins had a longer median TTP on ADT compared to nonusers (27.5 vs 17.4 months). The association remained statistically significant after adjusting for known prognostic factors [adjusted HR=0.83 (p=.039)]. Conclusions: In our cohort, statin use at the time of ADT initiation was associated with a significant increase in TTP on ADT even after adjusting for established prognostic factors. Further investigation into the mechanisms behind this observation is planned.
Phase II trial of abiraterone acetate (AA) treatment for metastatic prostate cancer (PC) patients with a PSA of more than four following initial androgen deprivation therapy: SWOG S1014.
Authors: Flaig Thomas W. , Tangen Catherine M. , Hussain Maha , Agarwal Neeraj , Mitsiades Nicholas , Deshpande Hari Anant , Vaishampayan Ulka N. , Thompson Ian Murchie
Published: February 2017

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Background: Metastatic PC patients with a poor response to initial androgen deprivation therapy (ADT) as reflected by a PSA > 4 ng/ml after 7 months of ADT have a poor prognosis. In the S9346 trial, about 25% of all enrolled patients had a PSA > 4 ng/ml after 7 months of ADT with a subsequent median survival (OS) of 13 months. S1014 examined the efficacy of AA in this setting. Methods: Eligible patients with metastatic PC and a PSA of > 4ng/ml between 6-12 months after starting ADT were treated with 1,000 mg of AA daily + 5 mg of prednisone twice daily. PSA could be rising or falling at the time of enrollment, but had to be > 4 ng/ml. No chemotherapy or secondary hormonal therapies were allowed, except in patients receiving an anti-androgen at the time of enrollment, who were continued on this therapy. The primary endpoint was a PSA of ≤ 0.2ng/ml within 12 months of starting AA. The null hypothesis was a 5% rate and alternative was 20%, requiring 6 or more patients with PSA < 0.2 ng/ml to conclude the regimen is promising (one-sided α=0.048, power=0.92). Results: Forty-one patients were enrolled between 7/2012 and 7/2013. One patient was deemed not analyzable due to not receiving any protocol treatment. Fourteen patients remain on treatment. Five (13%) patients achieved an undetectable PSA of ≤ 0.2ng/ml (95% CI 4%, 27%). Nine (23%) additional patients had PSA level > 0.2 but < 4 ng/ml. Twenty-one patients had no PSA response and six were not assessable and assumed to be non-responders. The median progression-free survival (PFS) was 17.4 months. There was one incident each of Grade 4 ALT elevation and rectal bleeding. Twelve patients reported Grade 3 adverse events as their worst level of severity. Conclusions: Although encouraged by 5 patients attaining “undetectable” PSA responses to AA in this poor prognosis setting, this study did not reach the protocol pre-specified level of 6 responses. OS and PFS will be updated with further follow-up. The therapy was generally well tolerated, without any clear signal of any unexpected toxicity. Clinical trial information: NCT01309672.
Precision medicine program for whole-exome sequencing (WES) provides new insight on platinum sensitivity in advanced prostate cancer (PCa).
Authors: Beltran Himisha , Sboner Andrea , Mosquera Juan Miguel , Rickman David , Eng Kenneth , Prandi Davide , Kossai Myriam , Faltas Bishoy , Pauli Chantal , Fontugne Jacqueline , Collins Colin , Gleave Martin , Wang Yuzhuo , Robinson Brian D. , Romanel Alessandro , Nanus David M. , Tagawa Scott T. , Demichelis Francesca , Elemento Olivier , Rubin Mark A.
Published: February 2017

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Background: WES has provided insight into the genomic landscape of PCa. The next step for precision medicine requires prospective patient (pt) follow-up and clinical and functional validation of both common and low frequency mutations. We describe a precision medicine WES program and illustrate how this can be used to identify novel biomarkers associated with response. Methods: Metastatic PCa pts were prospectively enrolled. WES of metastatic biopsies or rapid autopsies and normal DNA were sequenced by Illumina HiSeq 2500. Results: Tumor-normal pairs from 71 pts with metastatic PCa (11 hormone naïve, 38 CRPC, 23 NEPC) were sequenced including 3 rapid autopsies, with a biopsy success rate of >95%, avg tumor purity 10-95%, avg coverage 85X. The spectrum of mutations across metastatic PCa and how serial biopsies and rapid autopsies were used to assess heterogeneity and clonal evolution will be presented. WES from a metastatic PCa pt (PM12) with exceptional response to platinum with complete remission of liver and lung metastases at 2 years follow-up, demonstrated a hypermutated genotype and hemizygous deletion of the DNA repair gene FANCA in both his primary and metastatic PCa. A loss of function germline variant was detected within the second allele, and only the mutated allele was expressed in his tumor. Genome editing of FANCA using CRISPR in PCa cell lines resulted in cisplatin hypersensitivity and a significant decrease in FANC complex formation. In patient derived xenograft (PDX) models, PM12’s PDX was significantly more sensitive to cisplatin compared to a control Pca PDX of similar morphology but lacking FANCA deletion. By screening larger cohorts, FANCA loss was detected by FISH in 16% of localized PCa (n= 69), 14% metastatic Pca (n= 29), and not detected in any benign prostate (n=69). Conclusions: Our study provides a proof of principle for developing a precision medicine approach to cancer care with the capability to identify potential biomarkers of response. Our findings suggest that a subset of PCa with FANCA loss may be particularly vulnerable to cytotoxic therapy and provides biologic rationale to help explain the exceptional response of pt PM12 to platinum chemotherapy.
Risk for death from prostate cancer predicted from complete family history of lethal prostate cancer (LPC).
Authors: Albright Frederick S. , Agarwal Neeraj , Lowrance William Thomas , Stephenson Robert A , Alex Anitha , Cannon-Albright Lisa A
Published: February 2017

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Background: There are few published reports of relative risk (RR) for LPC based on family history of prostate cancer (PC) lethality. This study provides LPC RR using complete LPC family history data obtained from a statewide Cancer Registry linked to a genealogy database. Methods: The Utah Population Data Base (UPDB), which includes a statewide SEER cancer registry, includes 1,192,768 individuals with at least 12 of their 14 immediate ancestors. All males (probands) with specific LPC constellations were identified in the UPDB, and the observed number of LPC cases among these probands was compared to the expected number of LPC cases using internal cohort-specific rates from Utah death certificates including all deceased males with no 1st, 2nd, or 3rd degree relatives with LPC. LPC Family history was estimated for 1st degree to 3rd degree relatives for: number of LPC relatives affected, paternal versus maternal family history, and age at first PC diagnosis. Results: 3,921 individuals in UPDB were diagnosed with histologically confirmed PC, and had a Utah death certificate indicating PC as a cause of death and were designated LPC. The RR for LPC was significantly elevated with each additional first-degree relative (FDR) with LPC; even in the absence of FDR family history of LPC, significantly increased risk for LPC was observed in the presence of at least 1 LPC affected second degree relative (SDR). In the absence of positive FDR and SDR family history for LPC, there was still increased risk for LPC for males with 2 or more third degree relatives with LPC. Early age PC diagnosis in the LPC relative did not appear to affect LPC RR. Higher risks of LPC were associated with the maternal compared to the paternal lineages. Conclusions: Examination of lethal prostate cancer family history (in FDRs through TDRs) may be useful in identifying the cohort of men with prostate cancer most at risk for death from prostate cancer. Focused screening and treatment of this cohort holds potential to decrease the rates of undertreatment of lethal disease while avoiding over diagnosis and overtreatment in inconsequential disease.
Comparison of active surveillance with other treatment options for low-risk prostate cancer.
Authors: Musunuru Hima Bindu , Morton Gerard , Klotz Laurence , Vespirini Danny , Cheung Patrick , Chung Hans T. , Zhang Liying , Mamedov Alexandre , Sethukavalan Perakaa , Jethava Vibhuti , D'Alimonte Laura , Deabreu Andrea , Jain Suneil , Yamamoto Toshihiro , Loblaw D. Andrew
Published: February 2017

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Background: To evaluate outcomes and treatment history of low risk (LR) prostate cancer patients(pts) diagnosed between 2006-2008 in a single academic institute. Methods: Treatment and toxicity details were retrieved through retrospective chart review,apart from surgery where toxicity data was not available in detail.Biochemical RFS following primary and salvage treatments and CSS were computed.Pts who underwent salvage treatment for local failure and subsequently remained under biochemical control were censored as disease free for the salvage bRFS. Results: 594 pts were eligible for this study. Treatment options were active surveillance (AS=178 pts), low dose rate brachytherapy (LDR=192 pts, I-125 implant), stereotactic ablative body radiotherapy (SABR =84 pts; 35Gy in 5 weekly fractions), external beam radiation (EBRT=81 pts; 76Gy ) and radical prostatectomy (RP=59 pts). Median follow was > 70 months in all cohorts. 17.9% on AS protocol underwent active treatment. Biochemical failures were detected in 9 (5%), 10 (5.2%), 3 (3.5%), 6 (7.4%) and 9 (15.3%) pts respectively. Out of these, 4 pts in AS cohort, 2 in SABR group, and 7 in RP underwent local/salvage treatment. The 7-year bRFS was 94.4%, 93.6%, 95.8%, 90.1% and 89.5% for primary treatment and 95.7%, 93.6%, 98.7%, 90.1% and 98.3% following salvage treatment. 1 pt in AS, 2 in LDR, 1 pt in SABR and EBRT group developed metastatic disease. The 6 year CSS was 100% in all groups apart from LDR (99.4%) and EBRT (98.8%). Significant dysuria (20.8%) and hematochezia (7.4%) were noticed in EBRT cohort (Table). One grade 4 toxicity was noted in LDR, SABR and EBRT pts. Conclusions: AS has CSS comparable to other treatment options in LR prostate cancer setting with minimal toxicity. In the primary setting all treatment modalities apart from RP and EBRT have 7-year bRFS >93%. Differences in bRFS following salvage treatment might be due to pt and treatment selection. [Table: see text]