bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I multicenter study of the combination of temozolomide and pazopanib in advanced pancreatic neuroendocrine tumors (PNET).
Authors: Kalyan Aparna , Kircher Sheetal , Denlinger Crystal Shereen , Berlin Jordan , Mulcahy Mary F , Cohen Steven J. , Chiorean E. Gabriela , Zalupski Mark , Benson Al Bowen , Nimeiri Halla Sayed
Published: February 2017

TPS492

Background: Everolimus and sunitinib targeted therapy have proven efficacy in advanced PNET, with ORR 5-9% and PFS HR < 0.5 compared to placebo.Additionally, a single arm phase II study showed promising activity with temozolomide and capecitabine combination with an ORR of 70%. Rationale:PNETs are distinguished by their vascularlity and up-regulation of VEGF factors. In the preclinical setting, the combination of temozolomide and sunitinib appears to act synergistically by altering the tumor microenvironment enhancing activity of temozolomide. Pazopanib has shown activity in a single arm phase II study in advanced PNETs with a 6-month PFS rate of 80% and ORR of 17%. There is sufficient preclinical and clinical evidence suggesting that the combination of an anti-angiogenic agent with temozolomide is more efficacious, hence, our rationale for the current study. Methods: Objectives: (1) Determine the MTD and toxicity profile of temozolomide + pazopanib. (2) Describe the PK profile of this combination. (3) Observe the ORR. Trial Design:Open label Phase I study to determine the MTD and safety profile employing a 3+3 dose-escalation model of the combination of temozolomide and pazopanib in patients with advanced PNET who have received between 1-4 prior therapies. Cohort 1: temozolomide at 150 mg/m2 on Days 1-7 and 15-21, and pazopanib 400 mg orally once daily continuously throughout cycle of 28 days. Once MTD is determined, PK sampling will be performed in 6 additional patients enrolled at the MTD. To date, eleven patients have been enrolled in cohort 1 and cohort -1. Cohort -1 is currently accruing at the reduced dose level of temozolomide 100mg/m2 and pazopanib 400mg daily for the duration of the cycle. The trial is funded to proceed to a single arm phase II with exploratory end points: (1) Correlation of MGMT expression by IHC to ORR and PFS (2) tumor blood flow (perfusion CT imaging) relationship with ORR. (This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by GlaxoSmithKline.) Clinical Trial information: NCT01465659. Clinical trial information: NCT01465659.
Phase Ib study of PGG beta glucan in combination with anti-MUC1 antibody (BTH1704) and gemcitabine for the treatment of advanced pancreatic cancer.
Authors: Venepalli Neeta K. , Gandhi Chintan Chandrakant , Ozer Howard , Ho Dominic , Lu Yang , Xie Hui , Berg Stephanie A. , Chowdhery Rozina A. , Gargano Michele Anne , Braun Ada H. , Dudek Arkadiusz Z.
Published: February 2017

TPS493

Background: Mucin 1 (MUC1) is a tumor associated membrane-bound glycoprotein that promotes oncogenesis through promotion of epithelial cell polarity loss, anti-apoptosis, and hypoxia driven angiogenesis. MUC1 overexpression is associated with aggressive behavior and poor outcomes in pancreatic ductal adenocarcinoma (PDAC), and increased resistance to gemcitabine (G) in vitro. BTH1704 (BTH) is a humanized monoclonal antibody (MAb) targeting aberrantly glycosylated MUC1. Imprime PGG (PGG) is a soluble yeast-derived b 1,3/1,6 glucan that binds complement receptor 3 (CR3) on innate immune cells priming them to exert anti-tumor activity against complement (iC3b) opsonized tumor cells. Following incubation of PGG with whole blood from healthy subjects, variability in PGG binding to neutrophils and monocytes has been observed, with higher binding and functional changes correlating with higher levels of endogenous anti-b glucan antibodies. BTH binds to antigens (MUC1), leading to iC3b opsonization of tumor cells thus, allowing PGG-primed leukocytes to kill the iC3b-opsonized tumor cells. This forms the rationale for testing BTH1704 combined with G + PGG. Methods: This is a single institution Phase 1b dose escalation study with a standard 3x3 design to determine the maximal administered dose (MAD) of BTH combined with G + PGG in patients with previously treated advanced PDAC.Each dose cohort includes at least one subject with high and one low PGG binding capability. Primary objectives: establish MAD of BTH combined with G + PGG. Secondary objectives: characterize adverse effects, clinical response, time to progression, progression free and overall survival. Correlative objectives: quantify PGG binding, MDSC phenotyping of PBMC, anti b glucan antibody levels, MUC1 IHC. Inclusion criteria: confirmed advanced PDAC, ECOG PS 0-2, rest period 2-6 weeks from prior first- or second-line treatment. Exclusion criteria: uncontrolled chronic illness. Administration and design: BTH and PGG are administered on days 1, 8, 15, and 22 of a 28-day cycle; G is administered on days 1, 8, and 15. The study is currently enrolling patients. Clinical trial information: NCT02132403. Clinical trial information: NCT02132403.
Neonax (AIO-PAK-0313): Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer: A phase II study of the AIO Pancreatic Cancer Group.
Authors: Ettrich Thomas Jens , Berger Andreas W. , Muche Rainer , Lutz Manfred P. , Prasnikar Nicole , Uhl Waldemar , Tannapfel Andrea , Heinemann Volker , Seufferlein Thomas
Published: February 2017

TPS497

Background: Resectable pancreatic cancer still has an unfavourable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Recently, two phase III trials demonstrated for the first time, a substantial improvement in overall response, PFS and OS in patients with metastatic pancreatic cancer compared to standard gemcitabine (FOLFIRINOX and nab-paclitaxel/gemcitabine). The combination of nab-paclitaxel/gemcitabine has a more favourable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. Methods: NEONAX is a study for patients (to be enrolled: n=166) with resectable ductal adenocarcinoma of the pancreas ≤ T3 in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) - tumor surgery - 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant only arm): tumor surgery - 6 cycles nab-paclitaxel/gemcitabine. NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 month with adjuvant gemcitabine). The randomization (1:1) is eminent to achieve two comparable patient groups. Primary objective is DFS at 18 months after randomization. Key secondary objectives are 3-year OS and DFS, progression during neoadjuvant therapy and QoL. In the perioperative group tumor tissue will be collected prior to and post-surgery and subjected to microdissection and exome sequencing of tumor tissue. Tumor regression will be assessed both in the perioperative and the adjuvant group, respectively. In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. Start of trial will be in IV/2014 in 20 high-volume centers for pancreatic surgery in Germany. Clinical trial information: NCT02047513. Clinical trial information: NCT02047513.
A multicenter randomized phase II study of NPC-1C (N) in combination with gemcitabine (G) and nab-paclitaxel (A) versus G and A alone in patients with metastatic or locally advanced pancreatic cancer (PC) previously treated with folfirinox (F).
Authors: Duffy Austin G. , Beg Muhammad Shaalan , Greten Tim F. , Beatson Melony A. , Mavroukakis Sharon , Patel Sandip Pravin , Morse Michael A. , Arlen Philip M.
Published: February 2017

TPS499

Background: PC carries a poor prognosis. F has improved overall survival (OS) compared to G leading to its use as a 1st line treatment for patients (pts) with advanced PC. Similarly, the combination of G and A has demonstrated OS benefit. No data exists for G/A in the 2nd line setting. Many oncologists continue to sequence F treatment followed upon disease progression by G/A for pts with advanced PC with good performance status. N is a chimeric monoclonal IgG1 antibody recognizing an aberrantly glycosylated MUC5AC specific to GI tumors. Its mechanism of action is through ADCC. An IHC based companion diagnostic assay is utilized to select pts whose tumors express the target (approx. 65-70%). A prior study administering N to pts with advanced PC refractory to chemotherapy was well tolerated with disease stabilization and prolongation of OS. Furthermore 2 of 5 pts receiving the combination of G+N following progression on F remain alive at 10 and 12 months respectively. Methods: The primary objective of this phase 2.5 study is to determine if the combination of N and G plus A can improve the OS for pts who have PC over G plus A alone in the post F setting. The trial is a 2-arm randomized 1:1 multi-institution trial of N plus G and A vs. G and A. Eligible pts would be expected to have an estimated 4.5 to 4.8 month median OS with G alone, but this may be enhanced somewhat with the addition of A. The goal is to determine if the use of N along with G and A will result in pts having an increased median OS of 8 months vs. an estimated 5 months without N. Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods. All pts must have tissue positive for the MUC5AC variant (≥20% by IHC). Because N has been established to be safe when given with G alone but not with the combination of G and A, stopping rules for safety will be adhered to for the first 6 pts randomized to G/A plus N. Enrollment to the study has commenced. Correlative studies will utilize both PBMCs and serum for immune monitoring. Frequency, phenotype and function of different immune cells (including CD8+ T cells, CD4+ T cells, Tregs and MDSCs) will be analyzed. Clinical trial information: NCT01834235.
S1406: Randomized phase II study of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , McDonough Shannon , Morris Van Karlyle , Lenz Heinz-Josef , Magliocco Anthony M. , Atreya Chloe Evelyn , Diaz Luis A. , Allegra Carmen Joseph , Lieu Christopher Hanyoung , Eckhardt S. Gail , Semrad Thomas John , Kaberle Kimberly , Guthrie Katherine , Hochster Howard S.
Published: February 2017

TPS790

Background: BRAFV600 mutations are associated with inferior survival and objective responses to the mutated BRAF inhibitor vemurafenib in patients with mCRC. Blockade of BRAFV600 by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. In murine models of BRAFV600 mCRC, the addition of irinotecan to vemurafenib and cetuximab leads to greater anti-tumor activity. Recent phase I studies with the combination of BRAF and EGFR inhibition resulted in response rates substantially higher than either agent alone, with objective responses in 4 of 8 BRAFV600 mCRC patients treated with vemurafenib, cetuximab, and irinotecan. Methods: The SWOG 1406 trial (NCT 02164916) is a randomized phase II study of irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days) with or without vemurafenib (960 mg PO twice daily). Eligible adult patients have histologically confirmed colorectal adenocarcinoma with metastatic disease. Tumors must have a BRAFV600 mutation and be wild-type for KRAS and NRAS. BRAF testing may be conducted using any CLIA-compliant lab. Alternatively, screening can be provided through a central lab. Patients must have received one or two prior systemic regimens for unresectable locally advanced or metastatic disease and must not have received anti-EGFR agents. Prior treatment with irinotecan is allowed. Patients randomized to the control arm may crossover to the experimental arm at progression. Target enrollment is 78 patients. The primary endpoint is PFS. Optional participation in a co-clinical trial will be offered in selected sites whereby patients’ biopsies will be used to establish patient-derived xenografts to study correlations between patient and PDX with respect to treatment responses and mechanisms of treatment resistance. This trial has support from all adult cooperative groups and utilizes the Central IRB to facilitate study initiation. Conclusions: mCRC patients harboring BRAFV600E mutations may benefit from EGFR and BRAF blockade. We encourage screening for the BRAF mutation early in the course of metastatic disease therapy and for second line therapy on this trial. Clinical trial information: NCT 02164916.
InterAACT: An international multicenter open label randomized phase II advanced anal cancer trial comparing cisplatin (CDDP) plus 5-fluorouracil (5-FU) versus carboplatin (CBDCA) plus weekly paclitaxel (PTX) in patients with inoperable locally recurrent (ILR) or metastatic disease.
Authors: Sclafani Francesco , Adams Richard A. , Eng Cathy , Benson Al Bowen , Glynne-Jones Robert , Sebag-Montefiore David , Arnold Dirk , Roy Amitesh Chandra , Guren Marianne Grønlie , Segelov Eva , Seymour Matthew T. , Bryant Annette , Peckitt Clare , Cunningham David , Bridgewater John A. , Welch Jack , O'Dwyer Peter J. , Dupont Elisabeth , McConnell Andrea , Rao Sheela
Published: February 2017

TPS792

Background: Metastatic squamous cell carcinoma of the anus (SCCA) is a rare condition with 5-year overall survival (OS) rate of 32%. CDDP/5-FU is commonly used in the first-line treatment of patients with ILR or metastatic disease. This practice is based on retrospective series and data from randomised trials are lacking. Recent retrospective studies showed promising activity of CBDCA/PTX in this setting. Methods: InterAACT is an international, multicentre, open label, randomised phase II trial comparing two chemotherapy regimens in patients with ILR or metastatic SCCA. Eligible patients are randomised in a 1:1 ratio to CDDP (60 mg/mq, D1q21) plus 5-FU (1000 mg/mq/24h, D1-4q21) or CBDCA (AUC 5, D1q28) plus PTX (80 mg/mq, D1,8,15q28). Stratification factors are: performance status, extent of disease, HIV status and country. The primary endpoint is response rate (RR). Secondary endpoints include progression-free survival, OS, toxicity and quality of life. Based on a RR estimate of 40% in the CDDP/5-FU arm 80 patients are to be recruited to detect 10% difference in RR between the two arms with 80% power (phase II selection trial design). Correlative biomarker analyses are planned in tumour tissue and blood samples. The trial is sponsored by The Royal Marsden NHS Foundation Trust and endorsed by the International Rare Cancer Initiative (IRCI) group. Approximately 50 centres in the UK, Europe (EORTC), Scandinavia, US (ECOG-ACRIN) and Australia (AGITG) are estimated to participate and recruitment is anticipated to be completed within 3 years. Recruitment started in December 2013. As of September 16, 2014, 6 sites in the UK are open to recruitment and 6 patients have been randomised (3 to CDDP/5-FU and 3 to CBDCA/PTX). InterAACT aims to provide the first randomised evidence for the treatment of ILR and metastatic SCCA, to identify the optimal chemotherapy backbone to combine with targeted agents in future studies and to confirm the feasibility of conducting an international multicentre trial for this rare tumour. Clinical trial information: NCT02051868.
Preoperative D-dimer measurement for assessment of venous thromboembolism in colorectal cancer cases.
Authors: Hatta Kazuha , Ogawa Shimpei , Bamba Yoshiko , Hirosawa Tomoichiro , Itabashi Michio , Kameoka Shingo
Published: February 2017

TPS799

Pre-operative D-dimer Measurement for Assessment of Venous Thromboembolism in Colorectal Cancer Cases Background: In Japan, the incidence of venous thromboembolism (VTE) has recently been increasing and gaining attention. Operation or Malignancy is one of the major factors leading to VTE. Thus, there is an urgent need for appropriate pre-operative risk assessment and thorough preventive measures. Caprini score has proven effective and is widely used, however, since the point system is a little cumbersome, there is a strong demand for a risk assessment system that can be more easily used extensively. Methods: This study involving general surgery cases was performed in our department a period of one-half of a year. In order to screen for pre-operative VTE, D-dimer level was measured in 471 general surgical cases (143 colorectal cancer cases, and 99 the other cancer cases, 229 non-cancer cases), and the cases with high D-dimer levels (>1 μg/mL) underwent venous duplex scanning and enhanced computed tomography. Caprini score was measured in all cases for individual VTE risk assessment. By comparing D-dimer levels and Caprini score, the significance of D-dimer testing for VTE screening and risk assessment was reviewed. Results: D-dimer levels were measured in 471 general surgical cases. The 157 cases with high D-dimer levels (>1 μg/mL) underwent venous duplex scanning and enhanced computed tomography. Pre-operative VTE was detected in 16 cases, and the overall prevalence of VTE was 3.4%. For individual VTE risk assessment, Caprini score was derived for all 471cases. Average Caprini score was 5.54 (±1.78) in the high D-dimer group and 4.67 (±1.76) in the low D-dimer group. Using the t-test, Caprini score increased with increasing D-dimer level (P=<0.001). Focused on 143 colorectal cancer cases, 55 with high D-dimer levels and pre-operative VTE detected in 5 cases (3.5%), and Caprini score was 6.51(±1.46) in the high and 5.91(±1.28) in the low (P=0.0141). Conclusion: This observational study suggested that simple D-dimer testing might be worth discussing and considering not only to screen for pre-operative VTE, but also to assess the perioperative VTE risk levels.
The first results of targeted screening with a distress thermometer and initiation of psycho-oncological care of cancer patients.
Authors: Angerer-Shpilenya Maria , Heidenreich Axel
Published: February 2017

113

Background: Tumor disease has not only somatic but also psychological impact on patients with complete change of life dimension. This resonates not only to the patients, their relatives and friends, but also to the therapy. A precise screening helps to determine the stress factor, to capture the psychological comorbidity and to initiate an early psycho-social care. Methods: 420 patients with various tumors got since October 2011 in the Urological Clinic of Aachen University Hospital screening using a Distress Thermometer. 410 patients were stationary and 10 patients came to the outpatient (ambulant) chemotherapy. 23 of the 40 questions of the Distress Thermometer depend on somatic complaints of patients. The other 17 questions cover the psycho-social problems. Results: 141 of the 420 patients reported to have a low stress level by the tumor. 139 patients showed, according to the Distress Thermometer, an average and 140 patients significantly higher stress level. This means that 279 of the 420 patients need a psycho-oncological counseling and possibly even further care and treatment. The most common entered symptoms were fears, nervousness, sleep disturbances, fatigue, sadness and worry. Depending on the wishes of the patient the psycho-oncological consultation was initiated. Only completing the Distress Thermometer helps the patient to face their problems and worries and makes perhaps the first great step in the perception of the disease. Since January 2012 a new component was inserted into the discharge reports of the tumor patients. This component contains the recommendation, depending on the result of the Distress Thermometer, to start if necessary the professional psycho-oncological support. That gives the patients a sense of security and a feeling not to fight alone against the disease. Conclusions: A targeted screening and an interdisciplinary, together with psycho-oncologists, care to cancer patients support them and their families at all stages of the disease, helps to deal with the new life situation and can possibly also increase the patient's compliance and the therapeutic response.
Does incidental FDG PET uptake in the prostate have significance?
Authors: Brown Anna Mary , Lindenberg Maria Liza , Sankineni Sandeep , Johnson Linda M , Pruthy Suneha , Merino Maria J , Wood Bradford J. , Pinto Peter A. , Choyke Peter L. , Turkbey Baris
Published: February 2017

115

Background: 18F-FDG PET/CT is widely used to diagnose malignancy, but is not recommended for localized prostate cancer. This study explores the value of multi-parametric MRI (mpMRI) in characterizing incidentally detected prostate FDG uptake. Methods: Thirty-one patients who underwent FDG PET/CT and prostate MRI were eligible for this study. 14 patients were excluded (n=8 insufficient histopathology, n=6 radical prostatectomy before PET), with final analysis of 17 patients. The mpMRI sequences included T2-weighted, dynamic contrast enhancement (DCE), apparent diffusion coefficient (ADC), and MR spectroscopy (MRS). Nuclear medicine physicians, blinded to clinicopathologic findings, identified suspicious areas and maximum standardized uptake values (SUVmax) on FDG PET/CT. The lesion and sector-based imaging findings were correlated with annotated histopathology from whole-mount or MRI/TRUS fusion biopsy samples. Positive predictive values (PPVs) were estimated using generalized estimating equations with logit link. Results were evaluated with Kruskal-Wallis and Dunn’s multiple comparisons tests. Results: The PPV of FDG PET alone in detecting prostate cancer was 0.56. Combining FDG (base parameter) with mpMRI modalities (T2, DCE, ADC, MRS) increased the sector-based PPV to 0.79, 0.82, 0.80, and 0.89, respectively. All benign lesions had SUVmax < 5, and malignant lesions had higher mean SUVmax values that correlated with Gleason scores [Table]. This relationship between SUVmax and Gleason score was significant, with p=0.012 on the Kruskal-Wallis test and p=0.015 on the Dunn’s multiple comparisons test for Gleason 0 vs Gleason ≥ 4+5. Conclusions: Incidental prostate FDG uptake has low clinical utility alone, but these areas may harbor high-grade prostate cancer, especially if the SUVmax is greater than 5. [Table: see text]
Cholesterol metabolism and prostate cancer-specific mortality.
Authors: Stopsack Konrad Hermann , Sinnott Jennifer A. , Cerhan James Robert , Mucci Lorelei A. , Rider Jennifer R.
Published: February 2017

12

Background: Cholesterol is needed in prostate cancer cells for cell proliferation and for androgen biosynthesis. Cholesterol-lowering statin drug use is associated with a lower risk of total and advanced prostate cancer and lower prostate cancer-specific mortality (PCSM). We hypothesized that tumor expression of cholesterol synthesis enzymes, transporters and regulators is associated with PCSM. Methods: We studied mRNA expression of 43 cholesterol metabolism genes in surgical specimens from 249 participants in the Health Professionals' Follow-up Study diagnosed with prostate cancer between 1986 and 2004. We included 81 cases of lethal prostate cancer and 168 indolent cases who survived >8 years without metastases. After multivariate dimensionality reduction for the synthesis, transport and regulator pathways using principal components analysis, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We adjusted for age, year of diagnosis, body mass index, smoking status, family history, multivitamin use, high serum cholesterol and cholesterol-lowering drug use. Results: Reflecting the impact of the synthesis pathway and of the regulator pathway, respectively, the expression of squalene epoxidase (SQLE) and low-density lipoprotein receptor (LDLR) were significantly associated with lethal cancer in opposing directions. Compared to men with the mean level of SQLE expression, men with SQLE expression >1 standard deviation (SD) above the mean were 15.4 times more likely to have lethal cancer (95% CI: 3.31–71.53). For LDLR, expression >1 SD above the mean was associated with 96% lower odds of lethal cancer (95% CI: 0.01–0.70). Higher SQLE expression and lower LDLR expression were associated with higher Gleason grades (Fisher's test, p < 0.001 and p = 0.036, respectively) and were also predictive of PCSM independently from grade and tumor stage. Conclusions: These results suggest that the local cholesterol metabolism of the prostate tumor is tightly linked with mortality. Lethal cancers have higher activity of the second rate-controlling enzyme of cholesterol synthesis and are less dependent on cholesterol uptake.
Standard versus saturation biopsy before primary focal cryosurgery of the prostate: Does it matter?
Authors: Pak Jamie Sungmin , Cheetham Philippa J. , Katz Aaron , Wenske Sven
Published: February 2017

123

Background: Primary focal cryosurgery (PFC) has emerged as a viable option for local therapy in prostate cancer (PCa), most suitable for patients with clinical stage T1c-T3 disease of any tumor grade in whom potency is not of primary concern and who are not suitable for radical prostatectomy or radiation therapy. Success of 5-year biochemical recurrence (BCR)-free survival, depending on criteria, ranges from 60% to 90% in the literature. We hypothesize that saturation biopsy before PFC leads to lower rates of BCR compared to standard 12-core biopsy. Methods: We compiled a consecutive series of patients who underwent PFC at our institution for localized PCa. Parameters including demographics, PSA levels, and Gleason scores before primary treatment and at time of recurrence were assessed. Biochemical failure was defined by both Phoenix (PD) and Stuttgart (SD) definitions. Chi-square analysis was performed to compare outcomes. Results: One hundred and forty-seven patients underwent PFC at our institution between August 2000 and January 2014. Forty-five patients were excluded due to incomplete follow-up data and/or missing biopsy information. Median follow-up was 40.3 months (0.8-116, IQR 41). Conclusions: Zero of the six patients who underwent a saturation biopsy before PFC experienced biochemical failure or progression. This in contrast to those who underwent a standard 12-core biopsy before PFC, of which 19% experienced biochemical failure by PD and 26% by SD, and 6% underwent progression. This may be due to more informed selection for local therapy and more comprehensive assessment of the extent of tumor for treatment planning. Though these differences were not statistically significant in our study, we believe that our results lay the groundwork for a larger study to assess differences in outcomes after PFC depending on the extent of biopsy before treatment. [Table: see text]
Prostate brachytherapy implant quality on biochemical control.
Authors: Muller Don , Monsour Paul
Published: February 2017

128

Background: prostate brachytherapy at our institution was analyzed for implant quality on biochemical control. Methods: We treated 368 patients with clinically localized prostate cancer. All patients underwent 1 month CT based dosimetric analysis. Follow up data was available on 289 patients with a minimum follow up of 5 years. Gleason score was 6 in 80% (n=233), and 7 in 20% (n=56). Clinical stage was T1c in 90% of cases (n=260), T2a was 8% (n=23), T2b was <1% (n=3), T2c was < 1% (n=2). The initial prostate-specific antigen was < 10 ng/ml in 95% (n=274), 10.1-20 ng/ml in 5% (15).Patients with low risk disease ( clinical stage T1c, Gleason score 6 with a PSA < 10 ng/ml) n=228. Patients with intermediate risk disease Gleason 7 adenocarcinoma or with a PSA> 10 ng/ml < 20 ng/ml )n= 61. All patients were treated with I (125). All patients underwent a 1-month CT-based dosimetric analysis. The implant dose was defined as the dose delivered to 90% of the prostate volume on post implant dosimetry (D(90)). Results: At minimum follow up of 5 years overall freedom from biochemical failure was 91.4%. For Gleason grade 6 freedom from biochemical failure was 95%. For Gleason grade 7 freedom from biochemical failure was 77%. Based on PSA freedom from biochemical failure for PSA <10 ng/ml at diagnosis was 92 % and for PSA >10 ng/ml and <20 ng/ml was 80%. In patients with low risk disease ( clinical stage T1c, Gleason 6 adenocarcinoma with a PSA < 10ng/ml) the freedom from biochemical failure was 94%. In patients with intermediate risk disease (Gleason 7 adenocarcinoma or with a PSA >10 ng/ml <20 ng/ml ) freedom from biochemical failure was 84%. Patients with optimal dose implants n=264 freedom from biochemical failure was 95%. Patients with suboptimal dose implants n=25 freedom from biochemical failure was 52% Conclusions: With a minimum follow up of 5 years our data support the use of implant alone in low risk prostate cancer patients with a freedom from biochemical failure of 94%. Our data also shows the importance of implant quality in achieving optimal out comes.
Use of multiparametric MRI of prostate in active surveillance cohort of patients with localized prostate cancer in large urology group setting.
Authors: Kronhaus Richard , Telonis Dimitios , Pieczonka Christopher Michael , Williams Howard , Albala David , Mouraviev Vladimir , Buckingham Scott
Published: February 2017

129

Background: The aim of this study was to determine the feasibility of using mpMRI to monitor/reclassify patients with low grade Prostate Cancer (PCa) undergoing Active Surveillance in a large urology practice. Methods: This is a retrospective study reviewing the records of 28 total patients following active surveillance (AS) protocol. All patients have been diagnosed with biopsy proven prostate cancer (PCa) and have undergone at least one mpMRI as a means of surveillance. The median total PSA of the group at time of diagnosis was 5.93 ng/ml and the mean age of the group was 64 years old. Between the 28 patients, 38 mpMRI tests were conducted, consisting of T2-weighted, diffusion weighted, and dynamic contrast enhanced MRI. Targeted ‘cognitive’ TRUS-MRI guided biopsy was used to locate progression of the PCa and help to determine whether a patient should stay on AS versus choosing more aggressive, definitive treatment. Confirmatory random biopsy was also used to determine overall sensitivity and specificity of the mpMRI conducted for suspicious regions of interest (ROI). Results: The sensitivity and specificity for the group was 65% and 92% respectively. The positive predictive value for the group was 94% while the negative predictive value was 55%. mpMRI was able to detect all clinically significant cancers except in one case. It did not detect some small size lesions (≤5.5mm) of Gleason score 6 that did not have a relevant clinical value. In five of the 28 cases (18%), patients fit the criteria for reclassification (Gleason ≥7, ≥ 3 new positive cores) out of the AS group. Four of these five patients exhibited clear progression of PCa on mpMRI and elected for more aggressive definitive treatment . The progression of cancer in the fifth patient was not seen on mpMRI but only after biopsy. This patient elected to stay in AS because of his advanced age. Conclusions: Despite the limitation of small sample size, mpMRI can be used as an effective diagnostic tool in the AS cohort of a community practice. It can facilitate early detection and progression of suspicious lesion(s) towards clinically significant PCa, thus triggering the start of more aggressive treatment.
Active surveillance outcomes among a cohort of county hospital patients.
Authors: Wood Erika L. , Canfield Steven
Published: February 2017

136

Background: The standard of care for managing localized prostate cancer includes offering patients active surveillance. With the 10-year prostate cancer specific survival between 96-100% for both low and low-intermediate risk patients, active surveillance has proven to be a safe and effective option. Most studies have examined cohorts of patients within a tertiary referral center but data is sparse on county hospital patients, where health insurance coverage among other concerns pose barriers for patients to receive consistent medical care. We were interested in how active surveillance was performing amongst a cohort of county hospital based patients. Methods: A retrospective chart review was conducted on fifty patients placed on active surveillance for low and low-intermediate risk prostate cancer (by D’Amico criteria) between July 1, 2007 and August 1, 2013. Overall and cause-specific survival were the main outcome measures. Data was also collected on loss to follow-up rates. Results: In the cohort, the mean age at diagnosis was 62.2, mean body mass index was 28.0, most were African American or Hispanic (50% and 46%, respectively) and the majority had low-risk disease (84%). The median length of follow-up after diagnosis was 22 months. Nearly half of patients stopped active surveillance (44%), the most common reason being reclassification of their disease after second biopsy. All patients who were reclassified received definitive treatment with the exception of one patient who was lost to follow-up. Cause-specific and overall mortality were both 100% in this cohort. Nearly a quarter of patients (22%) were lost to follow-up (either had less than 12 months of surveillance following diagnosis or had not presented to clinic within the last 12 months). Conclusions: High rates of loss to follow-up present a significant challenge to managing localized prostate cancer with active surveillance in a county hospital population. In this small cohort, active surveillance appears to be a safe and effective management option for localized prostate cancer, yet undetected disease progression remains a significant concern.
Impact of crossover and baseline prognostic factors on overall survival (OS) with abiraterone acetate (AA) in the COU-AA-302 final analysis.
Authors: Ryan Charles J. , Smith Matthew Raymond , Fizazi Karim , Saad Fred , Sternberg Cora N. , Logothetis Christopher , Small Eric Jay , Carles Joan , Flaig Thomas W. , Taplin Mary-Ellen , Higano Celestia S. , De Souza Paul L. , De Bono Johann Sebastian , Griffin Thomas W. , De Porre Peter , Park Youn Choi , Li Jinhui , Kheoh Thian San , Molina Arturo , Rathkopf Dana E.
Published: February 2017

142

Background: AA + prednisone (P) significantly increased OS, time to opiate use, and was well tolerated at the COU-AA-302 final analysis. Here we further characterize OS benefit adjusting for crossover therapy and for baseline prognostic factors. Methods: Patients (N = 1,088) were randomized 1:1 to receive AA (1 g) + P (5 mg po BID) vs P. Co-primary end points were radiographic progression-free survival and OS. Median time to events with 95% CI was estimated using the Kaplan-Meier method. Stratified log-rank test was used to test the difference in treatment effect. Adjustment for crossover utilized the iterative parameter estimate (IPE) and impact of baseline prognostic factors was examined via the multivariate Cox proportional hazard model. Results: With a median follow-up of 49.2 months and 741 deaths (96% of required), AA + P significantly reduced the risk of death vs P (19%) and prolonged median OS (34.7 vs 30.3 months) (Table). 44% of patients initially receiving P alone subsequently received AA + P as crossover per protocol (17%) or as subsequent therapy (27%). IPE adjustment resulted in a 26% reduction in the risk of death (Table). By multivariate analysis, AA + P treatment led to a 21% reduction in the risk of death; baseline prostate-specific antigen (PSA), lactate dehydrogenase (LDH), hemoglobin, alkaline phosphatase (ALP), bone metastases, and age were significant OS prognostic factors (Table). Conclusions: AA + P yielded a statistically significant improvement in OS. Greater improvement in OS was observed after adjusting for the 44% of patients originally on P who ultimately received AA + P. Adjusting for baseline prognostic factors also demonstrated an AA + P OS benefit. Clinical trial information: NCT00887198. [Table: see text]
Increase in higher risk prostate cancer cases following new screening recommendation by the US Preventive Services Task Force (USPSTF).
Authors: Hall Matthew David , Schultheiss Timothy E. , Farino Ginamarie , Wong Jeffrey Y.C.
Published: February 2017

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Background: In 2011, the USPSTF issued a draft recommendation that PSA not be used for prostate cancer screening in men irrespective of age. Here we present early measures of the potential consequences of this recommendation. Methods: Data on men diagnosed with prostate cancer from January, 2005 through June, 2013 were extracted from the National Oncology Data Alliance (Elekta/IMPAC Medical Systems, Inc., Sunnyvale, CA). This proprietary database of merged tumor registries captures newly diagnosed cancer cases at more than 150 hospitals in the United States. Data were available through 2013 compared to 2011 in Surveillance, Epidemiology, and End Results (SEER). The data in the NODA are identical to the data sent to state tumor registries and SEER in regions that participate in SEER. Date of diagnosis, age, race, T stage, Gleason score, and PSA were collected. Patients were classified into their respective National Comprehensive Cancer Network (NCCN) risk group. Data were available and analyzed for 87,562 men. Frequencies were examined by date of diagnosis, grouped in six-month intervals. Trends were assessed using linear regression. Results: From 2005 to 2011, the percentage of men with PSA>10 decreased gradually. From 2011 to 2013, the percentage increased by 3.0% per year (p<0.0004). The fraction of men with age ≥75 years to present with PSA>10 increased by nearly double the rate for men of all ages from 2011 to 2013. No significant trends in Gleason score were observed; the frequency of men with higher T stages generally decreased over the entire period without a notable change after 2011. The percentage of men with intermediate or higher risk cancer was stable at 70-73% prior to 2011, but rose by 2.9 % per year after 2011 (p<0.003) without evidence of a plateau. Conclusions: The proportion of men diagnosed with intermediate or higher risk cancer increased by nearly 6% from 2011 to 2013. Given an estimated 233,000 new prostate cancers in 2014, approximately 14,000 men per year will shift from low risk into a higher risk disease group. Our findings suggest an increase in the fraction of men diagnosed with higher risk prostate cancer after 2011.
A phase IIb trial of docetaxel concurrent with radiotherapy plus hormotherapy versus radio hormonotherapy in high-risk localized prostate cancer (QRT SOGUG trial): Preliminary report for design, tolerance, and toxicity.
Authors: Carles Joan , Gallardo Diaz Enrique , Domenech Montserrat , Font Albert , Bellmunt Joaquim , Mellado Begoña , Suárez Cristina , Bonfill Teresa , Saez M Isabel , Guix Marta , Mendez Maria Jose , Maroto Pablo , de Portugal Teresa , Figols Mariona , Luque Raquel , Aldabo Ramon , Morales Rafael , Bonet Marta , Maldonado Xavier , Foro Palmira
Published: February 2017

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Background: Docetaxel improves survival in patients (pts) with metastatic hormonosensitive prostate cancer (PC) and castration-resistant prostate cancer. The objective of this phase IIb trial was to assess the activity of low dose docetaxel concurrent with radiotherapy plus standard hormonal treatment in pts with high risk localized CaP. Methods: High-risk localized CaP was defined by ≥ 1 of the following criteria: T3-T4, Gleason score (GS) ≥ 8, PSA > 20 ng/mL, pN+. Pts were randomly assigned to either arm A (LH-RH analogs every 3 months for 3 years and radiotherapy 73.8 Gy [1.8 Gy x 41 fractions] or 74 Gy [2Gy x 37 fractions]) or arm B (LH-RH analogs every 3 months for 3 years, radiotherapy and concurrent weekly docetaxel at 20 mg/m2 for 9 weeks). Chemotherapy was started one week before of radiotherapy. Primary endpoint was PSA relapse according to the Phoenix definition. The planned number of pts was 130 to detect a 15% difference with a power of 80% and an alpha of 0.05 (two-sided). Results: From 12/2008 to 9/2012, 130 pts were accrued (Arm A: 64, Arm B: 66). Median age was 68 years (61-73). Patients had T3-T4 (82.6%), GS ≥ 8 (76.3%), PSA > 20 ng/mL (26.9%) and pN+ (18.9%). All characteristics were well-balanced between arms. Median dose of radiotherapy was 74 Gy (72–74.8) in arm A, and 73.8 Gy ( 72-75.6) in arm B. 75.7% of pts received the planned 9 treatments of docetaxel and median number of cycles delivered per patient was 9. After a median follow-up of 29.6 months (9.6-40.2), most common grade 1/2 toxicities (arm A and arm B) were: cystitis ( 12.5% vs 8.3%), diarrhea (35.9% vs 70%), proctitis (12.5% vs 13.3%), rectal tenesmus (3.1% vs 23.3%), asthenia (23.4% vs 61.6%) and dysuria ( 28.1% vs 30.0%). Toxicity G3/G4 diarrhea was reported in 8.3% of pts in arm B and 0% in arm A. G3/G4 lymphopenia occurred less often in arm A than in arm B (3.1% vs 23.3%). %). There was no toxicity-related death. Conclusions: The QRT SOGUG phase IIb trial met its accrual target and shows that concurrent weekly docetaxel can be administered with standard doses of radiotherapy and without increasing toxicity profile. Clinical trial information: 2008-003554-14.
A genomic classifier to improve prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed by radical prostatectomy without adjuvant therapy.
Authors: Klein Eric A. , Yousefi Kasra , Haddad Zaid , Choeurng Voleak , Buerki Christine , Stephenson Andrew J. , Li Jianbo , Kattan Michael W. , Magi-Galluzzi Cristina , Davicioni Elai
Published: February 2017

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Background: Surgery is a standard first line therapy for most intermediate-high risk men diagnosed with prostate cancer. While clinical factors such as tumor grade, stage and prostate specific antigen (PSA) are currently used to identify patients at risk of cancer recurrence, novel biomarkers that can improve risk stratification and distinguish local from systemic recurrence are needed. The Decipher Genomic Classifier (GC) is a validated model for predicting men at risk of metastasis. We evaluated its performance in predicting metastatic disease within 5 years after surgery (rapid metastasis, RM) in an independent cohort. Methods: Tumors and clinicopathologic data were obtained from a cohort of 2,641 RP patients treated between 1987-2008 at Cleveland Clinic. The final study cohort consisted of 15 RM patients and 154 patients as non-RM controls who met the following criteria: 1) preoperative PSA>20 ng/mL, stage pT3 or margin positive, or Gleason score ≥8; 2) pathologic node negative; 3) undetectable post-RP PSA; 4) no neoadjuvant or adjuvant therapy; and 5) minimum 5 year follow-up for the controls. Results: RM patients developed metastasis with a median of 2.3 (IQR: 0.8-5) years. In multivariable analysis, GC was a significant predictor of RM (OR=1.48, p=0.018) after adjusting for clinical risk factors. GC had the highest c-index, 0.77, compared to the Stephenson model (c-index 0.75) and CAPRA-S (c-index 0.72) as well as a panel of previously reported prostate cancer biomarkers unrelated to GC. Integration of GC into the Stephenson nomogram increased the c-index from 0.75 (95% CI: 0.65-0.85) to 0.79 (95% CI: 0.68-0.89). Conclusions: GC was independently validated as a genomic metastasis signature for predicting RM in a cohort of high-risk men treated with RP and managed conservatively without any adjuvant therapy. Integration of GC into clinical nomograms led to improvement in prediction of RM. GC may further allow identification of men most at risk for metastatic progression who should be considered for multimodal therapy or inclusion in clinical trials.
External validation of multiparametric MRI and fusion-guided prostate biopsy: A matched cohort analysis.
Authors: Abboud Steven F. , Rastinehad Ardeshir , George Arvin Koruthu , Frye Thomas P , Ho Richard , Shakir Nabeel Ahmad , Chelluri Raju , Fascelli Michele , Walton-Diaz Annerleim , Sankineni Sandeep , Turkbey Baris , Choyke Peter L. , Merino Maria J , Pinto Peter A.
Published: February 2017

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Background: MRI/US fusion-guided biopsy has been shown to improve the detection of clinically significant prostate cancer (PCa). As adoption of this novel technology expands, the reproducibility of outcomes from expert centers becomes essential. The objective of our study was to validate the comprehensive NCI experience of multiparametric MRI and fusion-guided biopsy (FB) with an external, independent, matched cohort of patients. Methods: We compared 1,003 patients enrolled from August 2007 through February 2014 in a prospective trial comparing systematic 12-core biopsy (SB) to FB at the NCI to 256 patients that underwent an identical procedure at Long Island-Jewish Hospital (LIJH) from February 2012 to June 2014. Patients from LIJH were matched 1:1 for age, PSA, and MRI suspicion score to a corresponding cohort of NCI patients. Clinically-significant (CS) disease was defined as a Gleason score of ≥4+3 in any biopsy core. Results: The overall cancer detection rate was 564/1,003 (56%) of NCI patients and 167/256 (65%) of LIJH patients. In the matched cohort analysis, cancer detection rate (CDR) by FB between cohorts was 52% NCI vs. 54% LIJH (p=0.67). Both cohorts demonstrated a similar rates of upgrading by FB compared to SB, 29% NCI vs. 23% LIJH (p=0.42). This trend applied to patients that upgraded to CS disease by FB, 12.7% NCI vs. 12.6% LIJH (p=0.42) (Table). Conclusions: The improved detection of clinically-significant cancer by mpMRI and FB is reproducible in the hands of an experienced multi-disciplinary team. Our results suggest that with appropriate training in the interpretation of mpMRI and performance of FB, dissemination of this technology can render equivalent outcomes. [Table: see text]
HSD3B1 and resistance to androgen deprivation therapy in prostate cancer.
Authors: Hearn Jason W.D. , AbuAli Ghada , Magi-Galluzzi Cristina , Reddy Chandana A. , Chang Kai-Hsiung , Klein Eric A. , Sharifi Nima
Published: February 2017

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Background: The somatic mutation HSD3B1(1245A>C) has been mechanistically linked to castration-resistant prostate cancer by encoding a mutant enzyme that augments intratumoral dihydrotestosterone synthesis. Given the HSD3B1(1245C) allele is also frequently found in the germline, we hypothesized men inheriting this variant allele would exhibit resistance to androgen deprivation therapy (ADT), as manifested by worse clinical outcomes. Methods: We used a prospectively maintained prostate cancer registry to identify men treated with ADT for biochemical failure in the post-prostatectomy setting who were without evidence of metastatic disease at the time of ADT initiation. We analyzed progression-free survival, distant metastasis-free survival, and overall survival according to HSD3B1 genotype using Kaplan-Meier methods. Cox proportional hazards regression was performed to evaluate potential gene-dosage effects, with homozygous wild-type men serving as the reference group. Demographic and treatment characteristics were compared across genotypes to assess for possible confounders using Fisher’s exact test and Kruskal-Wallis analysis of variance. Results: Of 118 men genotyped, 37% were homozygous wild-type, 53% were heterozygous, and 10% were homozygous variant. Demographic and treatment characteristics did not differ across groups. Median progression-free survival diminished as a function of the number of variant alleles inherited (6.6 years in homozygous wild-type men, 4.1 years in heterozygotes, and 2.5 years in homozygous variant men; P=0.01). Median distant metastasis-free survival likewise decreased according to the number of variant alleles inherited (9.1 years in homozygous wild-type men, 6.8 years in heterozygotes, and 3.6 years in homozygous variant men; P=0.01). Finally, overall survival also diminished with the number of variant alleles inherited (5-year and 10-year overall survival: 82% and 55% in homozygous wild-type men, 74% and 35% in heterozygotes, and 58% and 0% in homozygous variant men; P=0.006). Conclusions: Inheritance of the variant HSD3B1(1245C) allele that enhances dihydrotestosterone synthesis may predict resistance to ADT for prostate cancer. These findings require validation.