bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor burden (TB) as a prognostic indicator in patients with metastatic colorectal cancer (mCRC).
Authors: Loh Kiley Wei Jen , Shapiro Jeremy David , Tran Ben , Wong Hui-Li , Wong Shu Fen , Richardson Gary Edward , Harold Michael , Gibbs Peter
Published: February 2017

572

Background: At initial diagnosis of mCRC, accurate assessment of patient prognosis is critical to defining the optimal initial treatment strategy. While performance status (PS) and number of metastatic sites are presumed surrogates of TB, to date TB assessment has not been formally examined as a potential prognostic marker in mCRC, despite supportive evidence in other malignancies. Methods: We developed a CT-based scoring system for TB on mCRC patients from the TRACC (Treatment of Recurrent and Advanced Colon Cancer) database. Objective (size and number of metastases) and subjective (clinical judgment) scoring systems were used to separate patients into high, moderate, or low TB subsets. Subjective scoring was repeated by a blinded second assessor on a subset of cases. Clinicopathologic correlates with TB were then assessed, along with survival outcomes for each subset. Results: 151 patients were assessed, median age was 68 years and 51% were male. Using subjective scoring, 55 (36%), 33 (22%), and 63 (42%) were categorized to high, moderate, and low TB subsets. Concordance between assessors using subjective scoring for 30 selected cases was 80% (high), 60% (moderate), and 90% (low). Factors correlating with increasing TB (high vs. low) on objective scoring were PS (31 vs 5% ≥ 2, p = 0.0002), number of disease sites (57 vs 9% ≥2, p < 0.0001) and for patients with mCRC at presentation, reduced likelihood of primary CRC resection. Median overall survival was superior in low compared to high TB subsets for subjective (not reached vs. 15.9mths, p < 0.0001) and objective (not reached vs. 14.7mths, p < 0.0001) scores. Survival difference for low vs high TB were maintained on objective scoring even when patients with resectable metastases were excluded (22.7 vs. 11.9mths, p = 0.0017). Conclusions: TB measured subjectively or objectively is associated with overall survival in mCRC, and is a potential novel prognostic marker. Multi-variate analyses will be performed, and an independent validation cohort is being examined. As TB inversely correlated with primary resection for patients with mCRC at presentation, including TB assessment in further analyses of the survival impact of primary CRC resection is one potential application of this measure.
Liver-directed therapies for colorectal cancer liver metastasis (CLRM): A Surveillance, Epidemiology, and End Results (SEER)-Medicare analysis.
Authors: Beg Muhammad Shaalan , Adhami Faisal , Xuan Lei , Hodges Joseph , Meyer Jeffery , Halm Ethan , Pruitt Sandi
Published: February 2017

577

Background: Oligometastatic CLRM comprises a distinct subset of stage IV colorectal cancer. Liver directed therapies (LDT) including surgery, ablation, radiation, and transarterial chemotherapy/embolization have been shown to improve cancer outcomes in smaller series. We sought to evaluate utilization of LDT and their impact on survival in patients with CLRM in a population-based database. Methods: We analyzed linked SEER-Medicare data. Eligible patients were ≥ 66 years, diagnosed between 1992-2009, carry a code for secondary malignancy of the liver (ICD-9 197.7) and survived ≥ 30 days after diagnosis. LDT (yes vs. no) were defined by ICD-9 and CPT codes of surgery (hepatectomy), ablation (e.g. radiofrequency and cryoablation), radiation (e.g., stereotactic surgery and brachytherapy), and transarterial/embolization (e.g., radioembolization). Treatment and non-treatment groups were matched using a propensity score comprised of a comprehensive set of patient and tumor characteristics including: age, sex, race, marital status, Medicaid status, and tumor histology, grade, and location. Cox Proportional Hazard models were used to compare the impact of the LDT on overall survival among propensity-matched pairs of treated and untreated patients. Results: LDT were performed in 12.7% (n = 1,793) of all 14,150 patients. There were 13.7% of patients over 85 years. Females were 52.1% and 83 % White. Off all, 5.4% had surgery, 3.9% had ablation, 4.6% had radiation, and 1.6% had transarterial chemotherapy/embolization. Unadjusted 5 year overall-survival (OS) was 26.9% for those underdoing LDT vs. 7.5% who did not (HR = 0.44, (CI 0.41,0.46)). Cox modeling demonstrated a survival benefit for each LDT with HR of 0.36 (0.33,0.39) for surgery, 0.35 (0.32,0.39) for ablation, 0.78 (0.72, 0.85) for radiation and 0.42 (0.36,0.49) for transarterial/embolization. Conclusions: While use of LDT for CLRM in this national sample of Medicare patients were low, those who received treatment had markedly improved survival compared to matched patients who did not. Surgery and ablation were the most effective therapies. These findings require evaluation in a prospective clinical study.
Analysis of fiducials implanted during endoscopic ultrasound (EUS) for locally advanced rectal cancer patients receiving high-dose rate endorectal brachytherapy (Endo-HDR).
Authors: Moningi Shalini , Malayeri Ashkan , Gearhart Susan , Efron Jonathan , Wick Elizabeth C. , Azad Nilofer Saba , Diaz Luis A. , Armour Elwood , Le Yi , Shin Eun Ji , Herman Joseph M.
Published: February 2017

655

Background: Rectal cancer affects over 40,000 patients in the US per year. The current standard of care for patients with localized rectal cancer is neoadjuvant radiation therapy with concurrent chemotherapy (NCRT) followed by surgery; however, it has shown no proven survival benefit for locally advanced rectal cancer patients. Preliminary results show that a short course of radiation therapy, using high-dose rate endorectal brachytherapy (Endo-HDR), may be as effective with less toxicity and delay to time of surgery. This requires the placement of fiducial markers, using an endoscopic ultrasound guided method (EUS), into the tumor for accurate source placement and treatment. Our aim is to compare three different types of fiducials in terms of visibility and migration. Methods: 12 patients with locally advanced rectal cancer that received Endo-HDR and EUS guided fiducial placement were retrospectively evaluated at JHH. Results: 12 patients underwent EUS guided placement of 42 fiducials. For 11 of our 12 patients, the mean number of fiducials placed per patient was 3.63 (SD 1.03) using a 19-gauge needle. One patient received 2 fiducials using a 22- gauge needle. Of the 12 patients that received fiducials, 3 received traditional fiducials (TF), 8 received segmented fiducials (SF) and 1 received foldable fiducials. All fiducials were clearly visible. The mean number of fiducials that detached from implanted site before surgery for patients with TFs was 0.667, and for patients with SFs was 0.875 (p=0.744). The median migration distance, as measured by interfiduciary distance, for segmented fiducials was significantly larger when compared to traditional fiducials (0.45 cm for SF compared to 0.1 cm for TF; p=0.049) Conclusions: SFs appear to be less stable, with regards to migration, in the rectum when compared to traditional fiducials in our patient population. These differences could be due to placement difficulty or operator dependent differences. Improvement in fiducial structure is required in order to help decrease migration and detachment and maximize visualization, which will lead to more accurate administration of Endo-HDR.
Total bilirubin as a predictive marker for irinotecan-induced toxicity in patients with gastrointestinal cancer.
Authors: Makihara Katsuya , Azuma Sayaka , Hasegawa Hiroko , Ikeda Masataka , Fujitani Kazumasa , Mishima Hideyuki , Tsujinaka Toshimasa
Published: February 2017

68

Background: Irinotecan (CPT-11) is widely used for the treatment of patients with gastrointestinal cancer. However, CPT-11 can cause severe neutropenia and diarrhea.It has been reported that the AUC of SN-38, an active metabolite of CPT-11, correlated with Pre-treatment serum total bilirubin level (PTB), but there is no criteria of dose setting based on the PTB. Therefore, we retrospectively searched the PTB which can serve as an indicator for dose setting of CPT-11. Methods: We investigated the incidence of neutropenia and diarrhea at the first 28 days in patients with gastrointestinal cancer who were administered CPT-11 alone in Osaka National Hospital from June 2006 to July 2013. Correlation between PTB and grade 3-4 neutropenia or diarrhea were assessed. When toxicity of correlation exists, ROC (receiver operating characteristic) analysis was conducted to explore the cut-off value of the PTB. In addition, the incidence of febrile neutropenia (FN) in the cut-off value was compared. Results: 87 patients were analyzed. Of these, 65 were gastric cancer, 22 were colorectal cancer. Although PTB was significantly higher in patients who experienced grade 3-4 neutropenia than those who didn’t (p<0.001), PTB was not associated with grade 3-4 diarrhea. As the results of ROC analysis, cut-off value of PTB associated with grade 3-4 neutropenia was determined to 0.8 mg/dL. The incidence of FN was significantly higher in 20% of patients with PTB ≥ 0.8 mg/dL compared with 1.6% of patients with PTB < 0.8 mg/dL (OR: 15.5, p=0.01). On the other hand, in subgroup analysis showed no difference in the incidence of FN and neutropenia in patients whose dose was less than 100 mg/m². Conclusions: PTB was a predictive marker for CPT-11-induced severe neutropenia and FN. Results of this study suggested needs of dose reduction to less than 100 mg/m2 in patients with PTB ≥ 0.8mg/dL.
Monte Carlo (MC)-based volumetric modulated arc therapy (VMAT) in locally advanced esophageal cancer with potential for dose escalation.
Authors: Hasan Shaakir , Sethi Anil , Breunig Jennifer , Axelrud Gabriel , Small William , Thomas Tarita
Published: February 2017

77

Background: Previous attempts at dose escalation in esophagus radiotherapy (RT), mostly based on older planning techniques, have not shown improved outcomes. We aimed to investigate the importance of newer, sophisticated dose algorithms and treatment techniques in escalating target dose and reducing dose to organs at risk (OAR). Methods: Treatment plans for 10 patients were retrospectively evaluated using 3D conformal radiotherapy (3DCRT), MC based intensity modulated radiotherapy (IMRT), and VMAT. Prescription dose was 45 Gy to the planning target volume (PTV) in 25 fractions followed by a 5.4 Gy boost in 3 fractions. PTV (mean±s.d. = 681±236 cc) were planned with BrainLab iPlan 4.1 software as IMRT and VMAT. Dose distributions were calculated with both pencil beam (PB) and MC algorithms. Each PTV was normalized to receive at least 95% of 50.4 Gy or 60 Gy dose. OARs were evaluated as per RTOG1010 dose guidelines. Paired t-tests were used for statistical analysis. Results: IMRT vs. 3DCRT PTV 50.4 Gy: IMRT plans decreased heart and lung average Dmean by 4.7 Gy (p = 0.053) and 1.9 Gy (p = 0.001) respectively when compared to 3DCRT. In addition, average values of lung V5, V10, and V30 also reduced by 7.1%, 5.5%, and 3.6% respectively (p < 0.05). There was a 12.1% decrease in heart V40 (p=0.053) and 3.7% reduction in liver V30 (p=0.08). PTV 60Gy: IMRT plans at 60 Gy led to lower OAR doses compared to 3DCRT at 50.4 Gy. MC based IMRT results did not significantly differ from PB, with the exception of lung V5 which was 4.4% higher (p <0.001). VMAT vs. IMRT PTV 50.4 Gy: VMAT based planning, compared to IMRT, lowered V20 (3.4%, p=0.029), V30 (1.6%, p = 0.013), and spinal cord Dmax (5.4 Gy, p = 0.001). However, lung Dmean, V5, and V10 increased by 1.2 Gy, 11.7%, 16.7% respectively (p < 0.001). PTV 60 Gy: With VMAT planning, all OAR dose parameters were within the RTOG 1010 limits, although lung V5 and V10 exceeded acceptable limits by 1.6% and 2.6% respectively. Conclusions: Compared to 3DCRT, target dose escalation with IMRT and VMAT is possible with improved OAR dose sparing, as evaluated with MC algorithms. Increased dose values for V5 and V10 as seen in MC based VMAT plans call for reassessment of RTOG 1010 guidelines.
Impact of external-beam radiation therapy on outcomes among patients with resected gastric cancer: A multi-institutional analysis.
Authors: Ejaz Aslam , Spolverato Gaya , Kim Yuhree , Squires Malcolm Hart , Weber Sharon M. , Poultsides George A. , Votanopoulos Konstantinos Ioannis , Bloomston Mark , Fields Ryan C. , Kooby David A. , Acher Alexandra W. , Worhunsky David J. , Swords Doug S. , Saunders Neil , Jin Linda X. , Cho Clifford Suhyun , Schmidt Carl Richard , Herman Joseph M. , Maithel Shishir Kumar , Pawlik Timothy M. ,   US Gastric Cancer Collaborative
Published: February 2017

84

Background: Use of perioperative chemotherapy (CTx) alone versus chemo-radiation therapy (cXRT) in the treatment of resectable gastric cancer remains varied. We sought to define the utilization and effect of CTx alone versus cXRT on patients having undergone curative-intent resection for gastric cancer. Methods: Using the multi-institutional U.S. Gastric Cancer Collaborative database, we identified 505 patients between 2000 and 2012 with gastric cancer who received perioperative therapy in addition to curative-intent resection. The impact of perioperative therapy on survival was analyzed by the use of propensity-score matching of clinicopathologic factors among patients who received CTx alone versus cXRT. Results: Median patient age was 62 years and the majority of patients were male (58%). Surgical resection involved either partial gastrectomy (54%) or total gastrectomy (46%). On pathology, median tumor size was 5.0 cm; most patients had a T3 (37%) or T4 (36%) lesion and lymph node metastasis (74%). Margin status was R0 in most patients (89%). 211 (42%) patients received perioperative CTx alone whereas the remaining 294 (58%) patients received 5-FU based cXRT. Factors associated with receipt of cXRT were younger age (OR 0.98), T3 tumors (OR 1.52), and lymph node metastasis (OR 2.03) (all P < .05). Recurrence occurred in 214 (39%) patients. At a median follow-up of 28 months, median overall survival (OS) was 33.4 months and 5-year survival was 36.7%. Factors associated with worse OS included tumor size (HR 1.1), T-stage (HR 1.5), and lymph node metastasis (HR 1.58) (all P<0.05). In contrast, receipt of cXRT was associated with improved long-term OS (CTx alone: 21 months vs. cXRT 45 months; p<0.001). In the propensity-matched multivariate model that adjusted for tumor size, T-stage, and nodal status, cXRT remained associated with an improved long-term disease-free (HR 0.43) and overall (HR 0.41) survival (both P<0.001). Conclusions: XRT was utilized in 58% of patients undergoing curative-intent resection for gastric cancer. Using propensity-matched analysis, cXRT was an independent factor associated with improved recurrence-free and overall survival.
Open versus minimally invasive management of gastric GIST: An international multi-institutional analysis of short- and long-term outcomes.
Authors: Bischof Danielle Anna , Kim Yuhree , Blazer Dan G. , Maithel Shishir Kumar , Gamblin T. Clark , Bauer Todd W. , Karanicolas Paul Jack , Law Calvin , Quereshy Fayez A. , Pawlik Timothy M.
Published: February 2017

85

Background: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the GI tract. Overall surgical experience with minimally invasive surgery (MIS) has increased, however, published reports on MIS resection of GIST are currently limited to small, single institution experiences. Methods: 397 patients who underwent surgical resection of a gastric GIST between 1998 and 2012 were identified from an international, multi-center database. The impact of the MIS approach on recurrence and survival was analyzed by the use of propensity-score matching by comparing clinicopathologic factors between patients who underwent open vs MIS resection. Results: Median patient age was 65 years and 50% were female. Median tumor size was 4.3cm (IQR 3.0-7.6cm). A minority of patients received neoadjuvant therapy (6%). Overall, 186 (47%) patients had a MIS approach: laparoscopic (89%), laparoscopic hand assist (4%), combined laparo-endoscopic (3%) and robotic (4%). There were 19 (10%) conversions to open; the most common reasons for conversion were tumor more extensive than anticipated (26%) and unclear anatomy (16%). Patients who underwent MIS resections had smaller tumors (MIS: 3.5cm vs open: 5.8cm; p<0.01). MIS resections were associated with minimal blood loss (MIS: 50 cc vs open: 225 cc) and shorter operative time (MIS: 160 min vs open: 201 min) (both p<0.01). There was no difference in rates of tumor rupture (MIS: 1.1% vs open: 0.9%; p=0.81). An R0 resection was achieved in the majority of patients (MIS: 98% vs open: 92%; p=0.07). MIS patients had a lower incidence of grade 3 or 4 complications (MIS: 3% vs open: 10%; p=0.01) and a shorter length of stay (MIS: 3d vs open: 8d; p<0.01). After propensity score matching for age, sex, tumor size, mitotic rate and tumor rupture, there was no difference in risk of recurrence or overall survival for the MIS treated group vs. the open group (HR 0.65 & HR 0.76, respectively; both p>0.05). Conclusions: An MIS approach for gastric GIST is associated with a low incidence of complications and a comparable R0 resection rate. The long-term oncological outcome following MIS is excellent and therefore the MIS approach should be considered preferable.
Clinical parameters’ model for predicting distant metastasis (DM) following definitive therapy in patients with localized esophageal and esophagogastric junction (E-EGJ) cancer.
Authors: Sudo Kazuki , Wang Xuemei , Wadhwa Roopma , Shiozaki Hironori , Hofstetter Wayne Lewis , Rice David C. , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Skinner Heath D. , Komaki Ritsuko , Maru Dipen M. , Blum Mariela A. , Ajani Jaffer A.
Published: February 2017

89

Background: For localized E-EGJ cancer patients, chemoradiation followed by surgery (trimodality therapy [TMT]) or definitive chemoradiation (bimodality therapy [BMT]) are considered the standard of care. However, ˜30-40 % of patients with localized E-EGJ cancer develop DM. We hypothesized that a clinical parameters’ model can be established to predict DM. Methods: We analyzed E-EGJ cancer patients who completed TMT or BMT from our prospectively maintained database. Logistic regression models were used for analysis. Overall survival (OS) was estimated by the Kaplan-Meier method. We used the AJCC 6th edition. Results: Between 2002 and 2013, 356 TMT patients and 273 BMT patients were analyzed. 33% (119/356) of TMT patients and 40% (109/273) of BMT developed DM as a first relapse. The median OS from DM were 10.2 months (95% CI: 7.8-12.7) for TMT patients and 7.8 months (95% CI: 5.7-9.9) for BMT patients. In a logistic regression analysis for all patients, the following parameters were associated with a significantly increased risk of DM: age (odds ratio [OR]: 0.97 [95% CI: 0.96-0.99]), initial standardized uptake value (iSUV) of PET (OR: 1.02 [95% CI: 1.00-1.04]), Stage III/IVa (vs. I/II) (OR: 2.43 [95% CI 1.65-3.57]) and male (vs. female) (OR 3.99 [95% CI: 1.89-8.42]). For TMT patients, baseline T3/T4 (vs. T1/T2) (OR 2.75 [95%CI 1.10-6.86]), baseline N1 (vs. N0) (OR: 1.69 [95% CI: 1.03-2.77]), and poorly differentiated cancer (vs. well/moderately differentiated) (OR 1.78 [95% CI: 1.13-2.82]) were significantly associated with DM. Conclusions: Our data suggest that younger men with Stage III/IVa cancer and high iSUV are at risk for DM irrespective of local therapy (TMT or BMT). A nomogram to predict DM will be developed with a larger cohort. Supported by UT M. D. Anderson Cancer Center Multidisciplinary Research Grants, CA138671, CA172741, CA129926 from NCI (JAA) and Generous Donors.
Analysis of KRAS/NRAS mutations in phase 3 study 20050181 of panitumumab (pmab) plus FOLFIRI versus FOLFIRI for second-line treatment (tx) of metastatic colorectal cancer (mCRC).
Authors: Peeters Marc , Oliner Kelly S. , Price Timothy Jay , Cervantes Andres , Sobrero Alberto F. , Ducreux Michel , Hotko Yevhen , Andre Thierry , Chan Emily , Lordick Florian , Punt Cornelis J. A. , Strickland Andrew , Wilson Gregory , Ciuleanu Tudor-Eliade , Roman Laslo , Van Cutsem Eric , Tian Ying , Jung Andre Scott , Sidhu Roger , Patterson Scott D.
Published: February 2017

LBA387

Background: Previously, this study showed significant improvement in progression-free survival (PFS) in pmab + FOLFIRI vs FOLFIRI (HR=0.73; 95% CI: 0.59-0.90; p=0.004) and a trend toward improved overall survival (OS; HR=0.85; 95% CI: 0.70-1.04; P=0.12; Peeters et al. JCO 2010). Recently, analysis from 1st-line mCRC PRIME study showed that mutations in RAS genes (KRAS/NRAS exons 2/3/4) predicted a lack of response to pmab (Douillard et al. NEJM 2013). Methods: The primary objective was to assess the tx effect of pmab + FOLFIRI vs FOLFIRI on OS and PFS based on RAS mutation status in the primary analysis population. Bidirectional Sanger sequencing was used to detect mutations in KRAS exons 3, 4 and NRAS exons 2, 3, 4 in patients (pts) with known WT KRAS exon 2 mCRC. Results: In this prospective retrospective analysis, overall RAS ascertainment rate was 85% (n=1008/1186). 18% of the WT KRAS exon 2 pts harbored additional RAS mutations (n=107/597). Efficacy is shown (Table). Tx HR for pts with WT RAS was 0.803 (95% CI: 0.629-1.024; P=0.077) for OS and 0.695 (95% CI: 0.536-0.903; P=0.006) for PFS. Conclusions: Improvements were observed in the tx effect of pmab + FOLFIRI vs FOLFIRI on OS and PFS in the WT RAS group vs the WT KRAS exon 2 group. Pts with MT RAS mCRC are unlikely to benefit by the addition of pmab to FOLFIRI, similar to pts with MT KRAS exon 2 mCRC in this study. These findings are consistent with previously reported outcomes by RAS status and support RAS testing to determine potentially appropriate pts for pmab tx. Clinical trial information: NCT00339183. [Table: see text]
Utility of multiparametric MRI at 3 tesla and MRI/ultrasound fusion-guided biopsy in detecting seminal vesicle invasion by prostate cancer.
Authors: Raskolnikov Dima , Rais-Bahrami Soroush , George Arvin , Turkbey Baris , Okoro Chinonyerem , Rothwax Jason , Shakir Nabeel , Walton-Diaz Annerleim , Siddiqui Minhaj , Su Daniel , Stamatakis Lambros , Wood Bradford J. , Choyke Peter L. , Pinto Peter A.
Published: February 2017

128

Background: We aim to evaluate the correlation between multiparametric prostate MRI (MP-MRI) suspicion for seminal vesicle invasion (SVI) and pathology on MRI/US fusion-guided biopsy, as well as radical prostatectomy (RP). Methods: 822 patients underwent MP-MRI and MRI/US fusion-guided biopsy. 24 patients underwent targeted seminal vesicle biopsies. 5 patients had MRI findings suspicious for bilateral SVI, for a total of 29 lesions. MP-MRI targets were scored as low, moderate, or high suspicion for PCa involvement according to the validated NIH scoring system. Patient demographics were reviewed and positive predictive values (PPVs) of pre-biopsy suspicion levels were calculated with respect to correlative biopsy pathology and final RP pathology. Results: At the time of MP-MRI, the median age was 64 years with a median PSA of 10.74 ng/ml (Table). Thirteen (54.2%) had not been previously diagnosed with PCa. Of the 29 SV lesions on imaging, MP-MRI suspicions of low, moderate, and high were assigned to 3, 18, and 8 lesions, respectively. The PPVs of these MRI suspicion levels, confirmed by MRI/US fusion biopsy, were 0%, 77.7%, and 62.5%, respectively. The 3 patients in the low suspicion cohort all underwent RP, confirming targeted biopsy findings. Of those with moderate or high suspicion of SVI on MP-MRI, only 5 underwent RP, with a targeted biopsy accuracy of 80%. The overall accuracy of targeted SV biopsy was 87.5% (7/8) on final RP pathology. Conclusions: MP-MRI suspicion of SVI correlates highly with findings on targeted SV biopsy and final RP pathology, thus potentially playing a vital role in future preoperative staging for PCa. [Table: see text]
Impact of screening and treatment on racial and ethnic differences in health service use, cost, and mortality among advanced (T3 or greater) prostate cancer patients.
Authors: Malkowicz S. Bruce , Chhatre Sumedha , Schwartz Sanford , Jayadevappa Ravishankar
Published: February 2017

131

Background: Limited information is available regarding the association between race/ethnicity, health service use, cost, and mortality in older patients with advanced (T3 or greater) stage prostate cancer. The objective is to analyze the race/ethnic differences in mortality, cost, and assess the mediating effect of prostate cancer screening and treatment on these differences in fee-for-service Medicare patients with advanced prostate cancer Methods: Retrospective, observational, case-control study using SEER-Medicare linked data. Cohort consisted of 15,054 elderly men diagnosed with advanced stage prostate cancer between 2001and 2004 and followed retrospectively for up to 2009. Cancer-free controls from Medicare data were used to determine the incremental cost of advanced stage prostate cancer. Racial/ethnic variation in health service use, cost, and mortality were analyzed using Poisson, GLM log-link, and Cox regression models. Results: For the age 66 to 75 and 76 to 85, age groups, racial/ethnic differences in health service use, cost, and all cause mortality were observed. Blacks were less likely to have received prostate cancer screening in the year prior to diagnosis of advanced prostate cancer, less likely to have received any treatment after diagnosis and had higher disease specific mortality. After adjusting for prostate cancer screening and treatment across age groups however, odds of prostate cancer-specific mortality were comparable between racial/ethnic groups suggesting that screening may have some mitigating effect on outcomes in the AA population HR 1.23 (1.07-1.41) versus HR 1.12(0.98-1.29). Conclusions: The pattern of racial/ethnic disparity varies by age group with higher mortality among black men. This may be attributable to disparity in prostate cancer screening or treatment. This suggests that the lack of consideration for racial considerations in the U.S. Preventive Services Task Force PSA recommendations could have disparate racial impact.
Molecular characterization of circulating tumor cells (CTC) and CTC subpopulations in progressive metastatic castration resistant prostate cancer (mCRPC).
Authors: Dittamore Ryan , Louw Jessica , Krupa Rachel , Anand Aseem , Danila Daniel Costin , Arslan Zaina , Bales Natalee , Marrinucci Dena , Scher Howard I.
Published: February 2017

132

Background: Numerous resistance mechanisms have been postulated in progressive mCRPC. Determining the presence of putative predictive biomarkers in patients requires a real-time tumor assessment because the biology changes under the influence of the specific therapy(ies) that a patient (Pt) has received. We examined CTC and CTC subpopulation incidence and molecular characterization of tumors from Pts with progressive mCRPC to assess if determinants of resistance can be assessed through a CTC test. Methods: 48 samples from 21 unique progressive mCRPC pts treated with androgen receptor targeted (AR tx) therapies, 9 (43%) on Abiraterone plus Prednisone (AA+P) and 12 (57%) on Enzalutamide (E). Samples were collected and shipped to Epic Sciences, where cells were stained and CTC identified by fluorescent scanners and algorithmic analysis. CTCs, defined as classic (CK+ CD45- w/intact DAPI nuclei and distinct), apopotic (CK+, CD45-, non-intact nuclei) and CK- (CK-, CD45-, intact and distinct) were identified. CTCs reported per mL of blood and were examined for AR, PTEN & ERG. CTC data were analyzed in context of PSA, Veridex CTC (reported per 7.5mL of blood), and clinical history. Results: With Epic, all 21 pts had detectable CTCs (mdn 23 cells/ml, range 2 to 249), whereas with Veridex, 14 (67%) pts had > 5 CTC/7.5 ml (mdn 5 cells/7.5 ml, range 0 to >200). 0/7 (0%) with high AR responded to AA+P or E, 8/14 (53%) with low AR had a PSA decline and stable radiographic disease (median follow-up 12 wks). Variations in AR protein expression and localization heterogeneity was seen in all pts to varying degrees. 6/21 (29%) Pts demonstrated CK- CTC/CTC ratio >50% (mdn 9 cells/ml, range 5-38). ERG rearrangement and PTEN loss were correlated. Conclusions: Epic CTC analysis provides higher detection rates, while enabling individual cell analyses for predictive biomarkers of sensitivity to AR directed therapies. Notable was the marked heterogeneity of detection of AR, ERG, and PTEN of individual CTCs. Studies are ongoing to further explore associations with outcomes. [Table: see text]
A randomized phase I/II study to examine the contribution of carboplatin to cabazitaxel for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) with and without anaplastic features.
Authors: Corn Paul Gettys , Tu Shi-Ming , Zurita Amado J. , Araujo John C. , Pagliaro Lance C. , Logothetis Christopher , Aparicio Ana
Published: February 2017

148

Background: We recently described “anaplastic” prostate carcinomas (PC), a clinically distinct variant of lethal castration-resistant prostate cancer (CRPC) that share clinical features with small cell carcinomas despite heterogeneous morphology. To test the hypothesis that anaplastic PC are uniquely sensitive to platinum-based chemotherapy, we designed a randomized study of cabazitaxel with or without carboplatin in men with metastatic CRPC (mCRPC) stratified for the presence of at least 1 of 7 previously published anaplastic criteria (Aparicio, Clin Cancer Res 2013;19). Here we report results of the phase I study. Methods: Patients (pts) received intravenous cabazitaxel with carboplatin every 21 days with growth factor support and were imaged every two cycles. A 3+3 sequential dose-escalation design was employed to assess the frequency of dose-limiting toxicity after cycle one and establish a maximal tolerated dose (MTD). Three cohorts were tested: (i) cabazitaxel 20mg/m2 – carboplatin AUC 3, (ii) cabazitaxel 25 mg/m2 – carboplatin AUC 3, and (iii) cabazitaxel 25 mg/m2 - carboplatin AUC 4. Up to 10 cycles were administered in the absence of progression or toxicity. Results: Nine men with mCRPC (five anaplastic) previously treated with docetaxel, received a median of six cycles (2 to 10). All had bone involvement and 6 of 9 had RECIST measurable disease. An MTD was not identified. All pts reported 1 or more adverse event (AE) possibly treatment related (120 Grade 1; 53 Grade 2; 13 Grade 3), most commonly fatigue, anemia, nausea, and diarrhea. Grade 3 AE included anemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesemia (n=1), diarrhea (n=1), hypokalemia (n=1), and anorexia (n=1). Prostate-specific antigen declines of more than 70% occurred in 6 of 9 (67%) pts. Two of 6 pts had a partial response, three had stable disease, and one progressed. For pts with elevated bone markers at baseline, 2 of 3 had more than 50% declines in BAP and 4 of 7 had more than 30% declines in urinary N-telopeptide levels. Conclusions: The combination of cabazitaxel and carboplatin is safe and has significant clinical activity. The randomized phase II portion combines cabazitaxel 25 mg/m2 and carboplatin AUC4. Results will be updated at the time of the meeting. Clinical trial information: NCT01505868.
An automated, sensitive, high-throughput biomarker protocol for tissue microarrays containing archival prostate specimens: The prognostic potential of an ERG EMT panel.
Authors: Brown Mick D. , Salman Ahmad , Hart Claire , Clarke Noel W.
Published: February 2017

181

Background: Tissue microarrays (TMAs), linked to clinical databases containing clinical outcome data, offer a great potential for defining and validating new biomarkers in urological oncology. The long term follow up required for true clinical outcome prostate cancer results in the use of archival material for TMA construction. The use of such material has inherent problems which must be overcome to unlock the full potential of prostate TMAs. Methods: A prostate 2,450 core TMA containing normal, prostatic intraepithelial neoplasia and malignant prostate tissue from 524 archival patient specimens was constructed and analysed. Each core was independently verified histologically. An automated, high throughput fluorescent staining (Leica BOND-MAX), image capture (Carl Zeiss Microimaging Mirax scanner) and scoring (Definiens Tissue Studio) protocol was compared with standardised conventional staining and manual scoring techniques. Results: Image analysis showed excellent correlation (r=0.785) and absolute agreement between the automated and manual scoring protocols (ICC=0.769, 95% CI [0.629-0.877]). Replicate analysis demonstrated that the automated, high throughput protocol was more reliable and consistent than the standardised manual staining and scoring protocols. The increased sensitivity of fluorescent staining in the automated protocol highlighted significant (p>0.0001) antigen degradation (pan-cytokeratin), hence poorly persevered regions, in 50.7% of the archival TMA cores. Using well preserved cores the potential of combining Erg expression with EMT markers as a prognostic marker will be presented. Conclusions: This study shows that archival TMAs can be utilised for biomarker characterisation and validation. However there are caveats to their use, namely antigen preservation. The use of multicolour automated protocols, which utilise a house keeping antigen, circumvents these caveats and releases the full potential of TMAs in biomarker research.
The effect of selective JAK2 inhibitor SAR302503 on tumorigenic STAT3 signaling in human prostate cancer in vivo.
Authors: Moreira Dayson , Pal Sumanta Kumar , Sun Fangxian , Kortylewski Marcin
Published: February 2017

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Background: STAT3 transcription factor is a critical mediator of signaling by IL-6, a cytokine promoting aggressive, castration-resistant prostate cancers (CPRCs). Importantly, STAT3 activation propagates from cancer cells to the tumor-associated immune cells, thereby generating immunosuppressive and proangiogenic tumor microenvironment. Janus kinase inhibitors provide an attractive method for disrupting IL-6/Jak/STAT3 signaling in both cancer and immune cells to amplify therapeutic effects. Methods: We tested the effect of selective Jak2 inhibitor, SAR302503, in xenotransplanted DU145 CPRCs and the tumor-associated myeloid immune cells in NSG mice. Results: Our initial results confirmed verified that oral gavage of 75 to 100 mg/kg SAR302503 results in dose-dependent inhibition of Jak2 phosphorylation in lysates from whole s.c. growing DU145 tumors within 18 h after treatment. Repeated daily treatment using SAR302503 (75 mg/kg) reduced phosphorylation of both Jak2 and STAT3, induced cancer cell death and significantly reduced growth of aggressive DU145 tumors. More detailed flow cytometric analysis revealed confirmed STAT3 inhibition in cancer cells and even greater extent in tumor-associated myeloid cells. SAR302503 did not reduce the total percentage of tumor-infiltrating myeloid cells. However, it promoted maturation of myeloid-derived suppressor cells. Conclusions: Our findings indicate that SAR302503 can potentially induce both direct and immune-mediated effects on castration-resistant prostate tumors. These preliminary results merit further studies in syngeneic tumor models that will assess whether Jak2/STAT3 inhibition can disrupt immunosuppressive and/or angiogenic functions of prostate cancer-associated myeloid cells. Further, these results may support clinical examination of SAR302503 either alone or in combination with other immunomodulatory therapies for metastatic CPRC.
Clinical characteristics and management of late symptom flare following stereotactic body radiation therapy for clinically localized prostate cancer.
Authors: Woo Jennifer Ai-Lian , Chen Leonard N. , Oermann Eric , Chen Viola , Yung Thomas M. , Kim Joy S. , Collins Brian Timothy , Suy Simeng , Lynch John H. , Dritschilo Anatoly , Collins Sean P.
Published: February 2017

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Background: Stereotactic body radiation therapy (SBRT) is increasingly utilized as primary treatment for clinically localized prostate cancer. While acute urinary symptoms are well recognized, late toxicities of SBRT have not been fully described. Here, we characterize the clinical features of late symptom flare and describe symptom management approaches. Methods: Two hudred sixteen patients with clinically localized prostate cancer were treated with SBRT between February 2008 and January 2011 at Georgetown University Hospital. Twenty-nine patients who experienced late-symptom flare were included in this retrospective analysis. Treatment was delivered using the CyberKnife (35 Gy to 36.25 Gy in five fractions). Prevalence of urinary toxicities was determined using CTCAE v.4. Patient-reported urinary symptoms were assessed using the American Urological Association Symptom Score (AUA) and the Expanded Prostate Cancer Index Composite (EPIC) short form. Results: Median age was 66 with 55% being of African descent. Late grade 2 frequency/urgency peaked at 12 months (17.2%), then returned to baseline at 18 months. Late grade 2 retention peaked at 18 months (65.5%), then returned to baseline at 24 months. Late grade greater than or equal to 1 dysuria peaked at nine months (25.0%), then returned to baseline at 24 months. Alpha-antagonist usage peaked at 18 months (85%) then decreased at 24 months. At 12 months, 21% required anti-inflammatories and/or urethral analgesics. Median AUA score rose from a baseline of 6 to 15 at 12 months, then returned to baseline by 24 months. EPIC urinary function and bother scores dropped to a nadir at 9 to 12 months post-treatment, then returned to baseline at 24 months. Conclusions: Symptom flare is a late syndrome consisting of various degrees of urinary frequency/urgency, retention and dysuria. It occurs approximately one year following SBRT, resolves spontaneously, and urinary function returns to baseline by two years. Early identification and initiation of conservative symptomatic management may decrease the need for invasive interventions. Anticipatory counseling prior to treatment may limit bother due to these transient urinary symptoms.
Efficacy of combined androgen blockade with zoledronic acid treatment in prostate cancer with bone metastasis: The Zoledronic Acid/Androgen Blockade Trial on Prostate Cancer (Zabton-PC) study.
Authors: Ueno Satoru , Mizokami Atsushi , Fukagai Takashi , Fujimoto Naohiro , Ohoka Hitoshi , Kondo Yukihiro , Arai Gaku , Ide Hisamitsu , Namiki Mikio
Published: February 2017

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Background: Zoledronic acid (ZA) reduces the onset risk of skeletal-related events (SRE) caused by bone metastasis in prostate cancer (PCa) patients and improves the QOL. Therefore ZA has become a standard supportive therapy for PCa with bone metastasis. However, it remains unclear when the physicians should start ZA treatment. In the present study, we investigated whether combination of ZA could delay PSA relapse of PCa and prevent SREs. Methods: The patients were randomly classified in two groups (combined androgen blockade (CAB) alone group and CAB + ZA treatment group). In the CAB + ZA group, 4 mg ZA was intravenously administered every 4 weeks with the start of treatment. The first end point was a period to PSA relapse, and the secondary end point was SREs rate. Results: Untreated 60 PCa patients with bone metastasis were enrolled by 2011 from 2006. Thirty one patients were treated with CAB alone and 29 patients were treated with CAB + ZA. There were no significant differences in the baseline characteristics in the both groups, and the mean observation period was 27.4 months and 32.1 months, respectively. Although there was no significant difference in progression free survival (PFS) (p=0.073), tendency that CAB + ZA shows better PFS than CAB alone group was observed (time to 50% PFS was extended 11.6 months than CAB alone group). Moreover, the sub analysis using the patients with more than Gleason score 7, CAB +ZA group showed significantly longer PFS than the CAB group (p=0.021). And statistically significant difference was recognized in SRE rate between the two groups (p=0.019), ZA tended to delay the occurrence of SRE in PCa patients. Conclusions: This result indicates that the use of ZA at the beginning of hormonal therapy have not only a preventive effect on the occurrence of SREs but also a relapse-delaying effect, especially in the patients with high Gleason score and severe bone metastasis. Though careful observation is essential, since the long-term use of ZA may increase the incidence of adverse effects, CAB-ZA treatment may be recommended for the treatment of PCa patients with bone metastasis.
Bicalutamide (150 mg) monotherapy versus LHRHa as neoadjuvant treatment in intermediate- and high-risk prostate cancer: A case matched study.
Authors: Mitchell Darren M. , McDowell Cliona , McGivern Ursula , Corey Gemma , O'Hare Jolyne , O'Sullivan Joe M.
Published: February 2017

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Background: The role of neo-adjuvant Lutenising Hormone Releasing Hormone Agonist (LHRHa) therapy prior to radical radiotherapy of intermediate and high risk prostate cancer (PC) has been clearly defined. Anti-androgen (AA) monotherapy is often used as an alternative to castration therapy in this setting due to a more favorable toxicity profile, however the evidence base is weaker. We compared biochemical failure free survival (BFFS) and prostate-specific antigen (PSA) kinetics in men receiving radical radiotherapy for localised prostate cancer and neo-adjuvant hormones with either AA or LHRHa therapy. Methods: All men with intermediate and high risk PC treated with AA monotherapy prior to radical prostate radiotherapy between April 2004 and December 2008 were individually case matched for key prognostic factors with men treated with neoadjuvant LHRHa monotherapy at our institution. BFFS, PSA kinetics, and absolute pre-RT, post neo-adjuvant hormone PSA (PRPH-PSA) level were analyzed. Results: Sixty five men treated with AA monotherapy were matched to with 65 men treated with LHRHa. The median follow-up was 74 months and 67 months, respectively. Phoenix BFFS was seen in 14 (23.4%) and nine (13.8%) of AA and LHRHa patients respectively with the log rank test indicating no statistically significant difference between the groups. Statistically significant differences were seen between groups in the PRPH-PSA with a geometric mean of 2.0ng/ml (range 0.1 – 11.2) for AA patients and 1.0ng/ml (range 0.1 – 11.1) for LHRHa patients (p<0.001). There was no significant difference between groups in the geometric mean PSA halving time or velocity during the neo-adjuvant period. A PRPH-PSA of less than 1.0ng/ml and less than 0.1ng/ml was seen in 16 (24.6%) and two (3%) of the AA patients and 34 (52.3%) and three (4.6%) of LHRHa patients, respectively. Conclusions: Our case matched study demonstrates that there was no statistical difference in BFFS between patients receiving neo-adjuvant AA versus LHRHa at median follow-up of 72 months. AA monotherapy resulted in less PRPH-PSA suppression when compared to neo-adjuvant LHRHa alone. Longer follow-up is required to determine if the differences in PSA kinetics translate into clinically meaningful differences.
A predicitve algorithm for response to abiraterone in metastatic castration relapsed prostate cancer (CRPC).
Authors: Afshar Mehran , Al-Alloosh Fawaz , James Nicholas David , Clarke Helen , Pirrie Sarah , Porfiri Emilio
Published: February 2017

238

Background: Numerous novel therapies for castration relapsed prostate cancer (CRPC) have led to a rapidly evolving approach to its management. Rationalisation of treatment combinations and sequencing of therapy requires identification of men who are more likely to benefit from a particular treatment. An unmet clinical need exists in this domain. We present the findings of a review of patients treated with abiraterone at our centre, and describe a novel predictive algorithm in this setting employing previously undefined pre-determinants of response. Methods: Patients with CRCP treated with abiraterone post-docetaxel at Queen Elizabeth Hospital between August 2010 and February 2012 were identified. Electronic patient records were utilised to extract variables including patient demographics, tumor characteristics, treatment history and other potential predictors of response such as prostate-specific antigen (PSA), hemoglobin (Hb), and alkaline phosphatase (ALP). Outcome measures included overall survival (OS), adverse events and PSA response rate. OS was estimated using the Kaplan-Meier method, and univariate and multivariate analyses were performed on potential prognosticators. Multivariate Beta coefficients were used to generate a predictive algorithm to identify two distinct risk groups. Results: Sixty one patients met the inclusion criteria. From starting abiraterone, the median OS was 12.6m, and median duration of follow-up was 11.5m. In univariate analysis seven factors impacted OS: age, response duration to androgen deprivation therapy (ADT), Hb, time from diagnosis to starting abiraterone, and ALP. Subsequent multivariate analysis identified three independent predictors of OS: duration of response to ADT (HR: 0.95, p=0.006), performance status (HR: 0.71, p=0.013), and baseline Hb (HR: 0.47, p=<0.001). A predictive algorithm dividing the cohort into high- and low-risk groups derived a diverging Kaplan-Meier curve without overlapping 95% CI’s. The low risk group did not reach median survival. Conclusions: This retrospective review has identified a predictive scoring algorithm for response to abiraterone in CRPC. We suggest that further analysis in the form of external validation is needed in order to justify its use in individualisation of patient management and stratification of patients for prospective clinical trials.
Surgical pathology and the patient: A systematic review evaluating the primary audience of pathology reports.
Authors: Mossanen Matthew , Wright Jonathan L. , True Lawrence D. , Vakar-Lopez Funda , Lavallee Danielle , Gore John L.
Published: February 2017

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Background: For patients with a diagnosis of cancer, the pathology reports represent a sentinel document that dictates prognosis and management. However, a substantial subset of patients may lack the ability to comprehend this complex document while making medical decisions. As a result, many cancer patients may stand to benefit from more patient-centered pathology reports. We sought to review the available literature in order to identify the primary audience of surgical pathology reports for the most common malignancies in men and women in the U.S. Methods: A systematic review was conducted using PubMed,MEDLINEdatabases, Cochrane Reviews,and Google Scholar. Data from the American Cancer Society were used to determine the most common cancers projected for 2013 for men and women in the U.S. (prostate and breast cancer, respectively, followed by lung and colorectal cancers). An expert panel developed a list of search criteria and an iterative search was performed and articles were screened for relevance. We summarize the results of the literature search with descriptive statistics. Results: No articles addressed the patient as the target audience of oncologic pathology reports. No articles evaluated the readability of pathology reports or literacy levels required to interpret pathology reports. We did not identify any articles that described standardized approaches for discussing the pathology of the most common cancers in men and women with patients or their caregivers. Twelve articles were devoted to renovation of pathology reports to promote the exchange of information between physicians, most of which (58%) addressed breast cancer pathology. Conclusions: Patient-centered cancer communication is a common theme in the care of oncology patients and represents an important metric in determining patient satisfaction. Yet, oncologic pathology reports do not include patients or their caregivers as target audiences. Limited resources are available to help patients comprehend their pathology reports. Efforts to improve patient centered communication, such as through the use of patient-centered pathology reports, may address this overlooked aspect of cancer care.