bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of chemoradiotherapy (CRT) using carboplatin/paclitaxel (CP) versus cisplatin/5-FU (CF) for esophageal or gastroesophageal junctional (GEJ) cancer.
Authors: Sim Hao-Wen , Chan Bryan Anthony , Natori Akina , Lim Charles Henry , Jiang Di Maria , Moignard Stephanie , Chen Eric Xueyu , Liu Geoffrey , Darling Gail Elizabeth , Swallow Carol Jane , Brar Savtaj Singh , Brierley James D. , Ringash Jolie , Wong Rebecca , Kim John , Rogalla Patrik , Hafezi-Bakhtiari Sara , Knox Jennifer J. , Jang Raymond Woo-Jun , Elimova Elena
Published: September 2018

4053

Background: For resectable esophageal or GEJ cancer, trimodality therapy improves survival compared to surgery alone and represents the current standard of care. The optimal CRT regimen for neoadjuvant or definitive treatment of locoregional esophageal or GEJ cancer remains uncertain. Methods: A retrospective comparison of CF and CP for locoregional esophageal or GEJ cancer (2011-2015) was performed. Overall survival (OS) and disease-free survival (DFS) were assessed using multivariable Cox proportional hazards regression, controlling for age, performance status and Charlson comorbidity index. Results: 101 patients (pts) were identified (61 CF, 40 CP). 75% were male. Median age was 62 years (range 30-84). Primary sites were esophageal (52%, with 65% squamous histology) and GEJ (48%). Surgery was undertaken in 34 (56%) CF and 27 (68%) CP pts. Median follow-up was 43 months. Overall, there was a non-significant trend for improved OS with CF compared to CP (HR 0.61, 95% CI 0.33-1.14, p = 0.12). In the subgroup having surgery (N = 61), we found no significant difference in OS (HR 0.99, 95% CI 0.39-2.55, p = 0.99). In the subgroup without surgery (N = 40), CF was significantly superior to CP (HR 0.21, 95% CI 0.08-0.53, p < 0.001). Comparing only pts in this subgroup who received equitable radiation doses (N = 33), CF was still significantly superior to CP (HR 0.09, 95% CI 0.03-0.32, p < 0.001). OS was similar by histology (adenocarcinoma/squamous) in all-comers (p = 0.54), and in CF (p = 0.90) and CP subgroups (p = 0.63). DFS results corresponded with OS. There was a non-significant numerical difference in pCR rates between CF (31%) and CP (18%) (p = 0.35), which were lower than previously reported. Conclusions: Survival is similar for CF and CP CRT regimens in pts undergoing trimodality therapy, but for those who do not proceed to surgery, it appears that CF is more effective than CP. Clinicians may prefer CP for surgical candidates given its favourable toxicity profile. However, when treating with definitive CRT, CF may be preferable to CP as a standard regimen.
Safety results of a phase 3 study of comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in chemoradiotherapy for locally advanced esophageal carcinoma (ESO-Shanghai 1).
Authors: Chen Yun , Zhao Kuaile , Ye Jingjun , Zhu Zhengfei , Zhao Weixin , Li Ling , Zhou Jialiang , Wu Chaoyang , Tang Huarong , Xu Gang , Lin Qin , Li Jiancheng , Xia Yi , Li Yunhai , Zhang Zhen
Published: September 2018

4066

Background: Concurrent chemoradiotherapy (CCR) with cisplatin plus 5-Fu (PF) regimen is the standard modality for inoperable locally advanced esophageal squamous cell carcinoma (ESCC) patients. In this phase 3 trial, we aimed to assess the efficacy and safety of the paclitaxel plus 5-Fu (TF) regimen versus PF regimen in CCR for ESCC patients. Methods: ESCC patients presented with stage IIa to IVa were enrolled in a prospective multicenter phase 3 study. Patients were randomized to either PF group or TF group. Patients in PF group were treated with 2 cycles of CCR followed by 2 cycles of consolidation chemotherapy with PF (cisplatin 25 mg/m2/d, d1-3, plus 5-Fu 1800 mg/m2, civ 72h, q28d). Patients in TF group were treated with 5 cycles of weekly TF (5-Fu 300 mg/m2, civ 96h plus paclitaxel 50 mg/m2, d1) in CCR followed by 2 cycles of monthly TF (5-FU 1800 mg/m2, civ 72h, plus paclitaxel 175 mg/m2 d1) in consolidation chemotherapy. The radiotherapy dose in both groups was 61.2 Gy delivered in 34 fractions. Adverse events (AE) defined according to CTCAE 4.0. The primary end-point was 3-yr OS. The number and grade of participants with AE was analyzed by intention to treat. Results: Between April 2012 and July 2015, 436 ESCC patients in 7 centers were enrolled. TF group had a significant higher incidence of acute Grade 3/4 leukopenia (31.3% vs. 18.9%), hiccup (0.9% vs. 0.0%), dermatitis (17.5% vs. 7.5%), pneumonitis (9.8% vs. 2.3%), and esophagitis (6.0% vs. 3.2%), and lower incidence of anemia (0.5% vs. 1.9%), thrombocytopenia (0.5% vs. 13.8%), fatigue (5.6% vs. 17.3%), anorexia (0.5% vs. 14.1%), nausea (0.5% vs. 14.1%), and vomiting (0.9% vs. 17.7%) than PF group (P < 0.05). There were 3(1.4%) patients in TF group died of acute pneumonitis. For long-term AE, 1(0.5%) patient in each group died of pneumonitis. There was no significant difference in total numbers of incidence of ≥ Grade 3 AE between two groups. Until Jan 2017, the median survival has not reached. Conclusions: The safety results of this trial were acceptable. TF regimen showed a different AE profile compared with PF regimen used in CCR in ESCC patients. Clinical trial information: NCT01591135.
Predicting survival in gastric cancer patients randomized to docetaxel with mass spectrometric quantitation of TUBB3.
Authors: Cecchi Fabiola , Catenacci Daniel V.T. , Schwartz Sarit , Sellappan Shankar , Tian Yuan , Miceli Rosalba , Pietrantonio Filippo , Pellegrinelli Alessandro , Martinetti Antonia , Di Bartolomeo Maria , Hembrough Todd A.
Published: September 2018

4068

Background: No predictive biomarker for chemotherapy has been validated for clinical use. A relationship between resistance to taxanes and expression of class III β-tubulin (TUBB3) protein has been suggested by small clinical studies, but not confirmed in randomized trials. Immunohistochemical definitions of “TUBB3 positive” vary widely between studies and depend on subjective measures of strong vs weak staining. We retrospectively evaluated the relationship between survival and TUBB3 protein quantitated by mass spectrometry in the tumor samples of 247 patients from the Intergroup Trial of Adenocarcinoma of the Stomach (ITACA-S). Patients had been randomized to a docetaxel-containing adjuvant regimen or to monotherapy with fluorouracil and leucovorin (5-FU/LV). Methods: Archived tumor tissues were microdissected and solubilized for proteomic analysis. TUBB3 and 44 other protein biomarkers were quantified with a mass spectrometry-based assay. A TUBB3 protein cutoff of 750 amol/ug was predetermined based on the assay’s limit of detection. The Mantel-Cox log-rank test was used for survival comparisons. Results: Among gastric cancer (GC) patients treated with docetaxel-containing chemotherapy (n = 125), those with TUBB3 levels below the cutoff (750 amol/µg of total protein) had a longer median overall survival (mOS) than patients with TUBB3 levels above the cutoff (1563 vs 886 days, p = 0.04). TUBB3 level made no difference in survival among patients who received 5-FU/LV. Of note, among patients with high TUBB3 levels ( > 750 amol), those treated with 5-FU/LV survived 3 years longer than patients in the docetaxel arm (mOS = 1991 vs 886 days, p = 0.048). Conclusions: Quantitative proteomic analysis of TUBB3 identified a subset of GC patients who benefitted from the addition of docetaxel to adjuvant chemotherapy. GC patients with TUBB3-expressing tumors had worse outcomes on a docetaxel-containing regimen than on 5-FU/LV. An ongoing study of triple-negative breast cancer patients treated with docetaxel suggests that proteomic TUBB3 may be predictive in other cancer indications. Personalized chemotherapy based on quantitated TUBB3 is promising and warrants broader evaluation.
Comparison of efficacy and safety of first-line palliative chemotherapy with TX and XELOX regimens in patients with metastatic gastric adenocarcinoma: A randomized phase II trial.
Authors: Zhu Xiaodong , Li Jin , Xiaoying Zhao , Guo Weijian , Liu Xin , Zhang Wen , Chen Zhiyu , Qiu Lixin , Li Wenhua , Huang Mingzhu , Zhang Xiaowei
Published: September 2018

4070

Background: Docetaxel has shown antitumor activity in the treatment of MGC as a single or combination chemotherapy. This study was designed to compare the clinical outcome of docetaxel based and platinum based doublet regimen as first-line treatment in MGC patients. Methods: In an open, randomized, single center phase II trial, 134 pts were randomly assigned and treated with either TX (capecitabine 1g/m2/twice daily/ 1-14 days and docetaxel 75mg/m2 in 1st day) or XELOX (capecitabine 1g/m2/twice daily/ 1-14 days and oxaliplatin 130 mg/m2 in 1st day) as first-line chemotherapy. The primary endpoint is finding potential predictive factors, secondary endpoint is ORR, PFS, OS and safety. After progression, patients were switched into the other group. Results: Now, the potential predictive factors are testing in genomics and proteomics. In 134 randomly assigned and treated pts (TX = 69; XELOX = 65). Most pts were male (87pts).Overall survival was longer with TX versus XELOX (13.1m vs. 9.6m, p = 0.173), but no statistical differences. Progression free survival was similar with TX versus XELOX (4.57m vs. 5.27m, p = 0.297). Overall response rate was equal with TX versus XELOX (50.8% vs. 47.6%, p = 0.72). G3-4 treatment-related AE occurred in 60.6% (TX) v 55.4% (XELOX) of patients. Frequent G3-4 toxicities for TX v XELOX were: neutropenia (60.6% v 15.4%), febrile granulocyte deficiency (17.4% v 1.5%), anemia (10.1% v 10.8%), thrombocytopenia (1.4% v 15.4%), and all grade peripheral neurotoxicity (11.6% v 38.5%).After first-line treatment failure, 35 patients in the TX group switched to XELOX, and 27 patients in the XELOX group switched to TX, and there is also no significant difference in survival time from the first-line treatment between the two groups (p = 0.129). Conclusions: Although TX led to more neutropenia, first-line palliative chemotherapy with docetaxel based doublet regimens provides a new choice and can gain almost the same response rate and survival time as frequently-used fluorouracil and platinum based regimen. And potential predictive factors will indicate who will get more benefit from taxanes or platinums. Clinical trial information: NCT01963702.
PrE0204: A multi-institutional, single arm, two-stage phase II trial of nab-paclitaxel and gemcitabine for first-line treatment of patients with advanced or metastatic cholangiocarcinoma—A PrECOG LLC study.
Authors: Sahai Vaibhav , Catalano Paul J. , Lubner Sam Joseph , Menge Mark R. , Munshi Hidayatullah G. , Nimeiri Halla Sayed , Benson Al Bowen , O'Dwyer Peter J.
Published: September 2018

4072

Background: Pts with advanced or metastatic cholangiocarcinoma (CCA) have limited response to current chemotherapy regimens and poor overall survival (OS). Nab-Paclitaxel (nabPAC) can increase the intra-cellular concentration of gemcitabine (GEM) through depletion of its metabolizing enzyme, cytidine deaminase (CDA). We investigated the nabPAC+GEM combination in a ph II single arm trial in advanced or metastatic CCA pts with exploratory biomarker evaluation, including CDA, hENT1, SPARC and circulating tumor cells (CTCs). Methods: Key eligibility criteria: advanced or metastatic CCA with no prior systemic chemotherapy, age > 18, ECOG PS 0-1 and Child-Pugh < 8. Pts received nabPAC (125 mg/m2 IV) and GEM (1000 mg/m2 IV) days 1, 8 and 15 Q4 weeks until progression. Primary endpoint: progression-free survival (PFS) rate at 6 months. Secondary endpoints: safety, time to progression (TTP), objective response (ORR) and disease control rates (DCR), median PFS and OS, as well as correlation of change in CA 19-9 to clinical efficacy. The study required > 43 of 67 evaluable patients alive and progression-free at 6 months to conclude the 6-month PFS rate is at least 70% against a null hypothesis of 55% based on historical data. Results: 73 eligible patients (41.1% male, 91.8% Caucasian, 45.2% ECOG PS 0) were enrolled across 22 sites with a median age of 62 (range 36-87) years and received a median of 6 (range 1-18) cycles. The primary endpoint of PFS rate at 6 months was 54.7% on intention to treat analysis. Response evaluation is underway and will be reported at the meeting. The median PFS and OS were 6.5 (95% CI, 5.1-7.7) and 10.3 (95% CI, 9.1-14.6) months, respectively. The safety profile of nabPAC+GEM was similar to that reported in ph III MPACT trial. The most common treatment-related G3/4 toxicities were neutropenia (24.3%), fatigue (13.5%) and anemia (12.2%). Five patients remain on the trial. Exploratory analyses are pending. Conclusions: The observed PFS rate at 6 months with nabPAC+GEM in CCA is insufficient to reject the null hypothesis of 55% PFS at 6 months, and appears to be as effective as the historical control. Clinical trial information: NCT02181634.
BBI608-503-103HCC: A phase Ib/II clinical study of napabucasin (BBI608) in combination with sorafenib or amcasertib (BBI503) in combination with sorafenib (Sor) in adult patients with hepatocellular carcinoma (HCC).
Authors: El-Rayes Bassel F. , Richards Donald A. , Cohn Allen Lee , Richey Stephen Lane , Feinstein Trevor , Kundranda Madappa N. , El-Khoueiry Anthony B. , Melear Jason M. , Braiteh Fadi S. , Hitron Matthew , Ortuzar Waldo Feliu , Khan Waheed , Xu Bo , Li Wei , Li Youzhi , Li C J
Published: September 2018

4077

Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Amcasertib targets multiple serine threonine stemness kinases and inhibits Nanog and other cancer stemness pathways. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with sorafenib. Methods: A phase Ib/II open-label, multi-center study in adult patients with advanced HCC who have not received prior systemic chemotherapy was performed to determine the safety, tolerability, and recommended Phase II dose (RP2D) ,according to the criteria for DLT and for dose-escalation of Napabucasin (Arm 1), administered at 160 mg BID (dose level I) and at 240 mg BID (dose level II) in combination with sorafenib and of Amcasertib (Arm 2), administered at 100 mg QD (dose level I) and at 200 mg QD (dose level II) in combination with sorafenib. Results: 20 pts were enrolled, 10 in Arm 1 and 10 in Arm 2. 12 patients were evaluable for DLT determination; 2 pts d/c prior to starting protocol treatment; 11 pts received evaluation by RECIST, 6 pts in Arm 1 and 5 pts in Arm 2. The safety profile was consistent with that of each agent as monotherapy and most common AEs were attributed to (Sor) and included rash, PPE, grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. No signs of drug-drug interactions were observed in pharmacokinetics. Among all patients who received RECIST evaluation, Disease Control Rate (DCR=CR+PR+SD) for Arm 1 was 100% (6/6pts) and 100% (5/5pts) for Arm 2. DCR in ITT Arm 1 population was 67% and 50% in Arm 2. Median OS is not yet reached. Conclusions: In this phase Ib study, RP2D were determined for napabucasin and amcasertib to be safely combined with sorafenib at full dose, showing encouraging anti-tumor activity in patients with HCC who have not received prior systemic chemotherapy. A randomized phase II is schedule to start. Clinical trial information: NCD02279719. [Table: see text]
Predictive model for microvascular invasion of hepatocellular carcinoma among candidates for either hepatectomy or liver transplantation.
Authors: Nitta Hidetoshi , Allard Marc Antoine , Sebagh Mylene , Pittau Gabriella , Ciacio Oriana , Vibert Eric , Sa Cunha Antonio , Cherqui Daniel , Castaing Denis , Bismuth Henri , Guettier Catherine , Samuel Didier , Baba Hideo , Adam Rene
Published: September 2018

4079

Background: Microvascular invasion (MVI) is the strongest prognostic factor following surgery of hepatocellular carcinoma (HCC). However, it is usually not available on the preoperative setting. A predictive model of MVI in patients scheduled for hepatic resection (HR) or liver transplantation (LT) would thus help guiding treatment strategy. The aim of this study was to develop a predictive model for MVI of HCC before either HR or LT. Methods: HCC patients who consecutively performed HR or LT from January 1994 to June 2016 at a single institution were subdivided into a training and validation cohort. Risk factors for MVI in the training cohort were used to develop a predictive model for MVI, to be validated in the validation cohort. The outcomes of the HR and LT patients with high or low MVI probability based on the model, were compared using propensity score matching (PSM). Cut-off values for continuous factors were determined based on ROC curve analysis. Results: A total of 910 patients (425 HR, 485 LT) were included in the training (n = 637) and validation (n = 273) cohorts. In the training cohort, multivariate analysis demonstrated that alpha-fetoprotein ≥100ng/ml ( p < 0.0001), largest tumor size ≥40mm ( p = 0.0002), non-boundary HCC type on contrast-enhanced CT ( p = 0.001), neutrophils-to-lymphocytes ratio ≥3.2 ( p = 0.002), aspartate aminotransferase ≥62U/l ( p = 0.02) were independently associated with MVI. Combinations of these 5 factors varied the MVI probability from 15.5% to 91.1%. This predictive model achieved a good c-index of 0.76 in the validation cohort. In PSM (109 HR, 109 LT), there was no difference in survival between HR and LT patients among the high MVI probability (≥50%) patients, (5y-OS; 46.3% vs 42.2%, p = 0.77, 5y-RFS; 54.0% vs 28.8%, p = 0.21). Among the low probability ( < 50%), survival was significantly decreased following HR compared with LT (5y-OS; 54.1% vs 78.8%, p = 0.007, 5y-RFS; 17.3% vs 86.1%, p< 0.0001). Conclusions: This model developed from preoperative data allows reliable prediction of MVI, and may thus help with preoperative decisions about the suitability of HR or LT in patients with HCC.
Stereotactic body radiation therapy to generate comparable survival to surgery in treating hepatocellular carcinoma (HCC): Results of 756 patients.
Authors: Kong Feng Ming , Zang Yong , Pi Wenhu , Long David , Ellsworth Susannah , Saito Naoyuki , Ghabril Marwan , Lacerda Marco A , Agarwal David M , O’Neil Bert , Tann Mark , Zellars Richard C. , Maluccio Mary A.
Published: September 2018

4080

Background: Stereotactic Body Radiation Therapy (SBRT) has emerged as a viable treatment option in patients with hepatocellular carcinoma (HCC). This study aimed to compare survival outcomes after SBRT with other front line local treatments for HCC. Methods: This is a retrospective analysis of patients identified through our cancer registry from 2000 to 2016. Patients treated with any local therapy alone were eligible: SBRT, surgery, conventional external beam radiation (CEBRT), and other local therapies including brachytherapy. Patients treated with combined therapies such as SBRT plus liver transplant were excluded. The primary endpoint was overall survival which was estimated from the time of diagnosis. Differences between the groups were compared using log-rank test. The data are presented as median (95%CI). Results: A total of 756 patients with a median follow-up of 45 months (mo) met the selection criteria: 116, 380, 43, and 217 patients received SBRT, surgery, CEBRT, and other local treatment, respectively. Median age was 61, 60, 61 and 60 years, respectively. The median overall survival/3 year overall survival rate were 49 (32-66) mo /53% (44-65%) for patients treated with SBRT, which were not significantly different from 75 (57-94) mo /63% (58-69%) of surgery (p = 0.27), non-significantly better than 22 (13-31) mo /41% (27-60%) of CEBRT (p = 0.13), significantly better than 15 (13-20) mo /26% (20-34%) of other local treatments (p = 3×10-7). After adjusting for significant prognostic factors including age, race, status of tobacco abuse, history of alcohol use, tumor size, histology grade and stage, the survival outcomes of SBRT remained to be insignificantly different from surgery (HR = 0.8, p = 0.2), have a trend of significant difference from CEBRT (HR = 1.4, p = 0.1) and remarkably superior to that of other local treatments (HR = 1.8, p = 2×10-4). Conclusions: This study suggests that SBRT is an excellent front line option for HCC, potentially comparable to surgical resection and associated with longer survival than other front line local treatments. Randomized studies are needed to validate these findings.
Lanreotide depot (LAN) for symptomatic control of carcinoid syndrome (CS) in neuroendocrine tumor (NET) patients previously responsive to octreotide (OCT): Subanalysis of patient-reported symptoms from the phase III elect study.
Authors: Fisher George A. , Pommier Rodney F. , Wolin Edward M. , Kunz Pamela L. , Liyanage Nilani , Pitman Lowenthal Susan W. , Mirakhur Beloo , Shaheen Montaser F. , Vinik Aaron
Published: September 2018

4088

Background: In ELECT, LAN significantly reduced the need for short-acting OCT rescue therapy for symptomatic control of CS in NET patients (pts) vs placebo (PBO) (primary result). Here we present flushing and diarrhea symptom data and biochemical response for pts with or without prior OCT use from ELECT. Methods: Adults with histopathologically-confirmed NET and history of stable CS (diarrhea and/or flushing) who were OCT-naive or responsive to OCT long-acting release (LAR) (≤30 mg q4W) or short-acting OCT (≤600 μg daily) were randomized to LAN 120 mg (SC q4W) or PBO for 16 wks. Pts administered SC OCT if needed and recorded daily frequency and severity of symptoms using Interactive Voice/Web Response System for 1 month pre-randomization and throughout the study. 24-hr urinary 5-hydroxindoleacetic acid (5HIAA) and plasma chromogranin A (CgA) were assessed at baseline and wk 12. Results: Of 115 pts randomized, 51 were OCT-naive and 64 received prior OCT. The least squares (LS) mean percentages of days with moderate/severe diarrhea and/or flushing were lower in both naive and prior OCT LAN pts vs naive and prior OCT PBO pts; LS mean difference (LAN-PBO) was significant in the naive group (Table). By week 12, 5HIAA and CgA levels dropped by ≥30% to normal in 35.3% and 15.8% of naive LAN pts and 28.6% and 4.5% of prior OCT LAN pts; 5HIAA and CgA reductions were seen in 15.4% and 21.4% of naive PBO pts and 5HIAA in 7.1% of prior OCT PBO pts. Conclusions: Pts showed improvement in CS symptoms of flushing and diarrhea and reduction in 5HIAA levels with LAN treatment, indicating efficacy of LAN regardless of prior OCT use. Transition from OCT to LAN was well tolerated among prior OCT pts in ELECT. Clinical trial information: NCT00774930. [Table: see text]
68Ga-DOTATATE PET/CT to predict response to peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumours (NETs).
Authors: Sharma Rohini , Wang Wai Meng , Evans Joanne , Yusuf Siraj , Al-Nahhas Adil , Mauri Francesco , Barwick Tara , Aboagye Eric
Published: September 2018

4093

Background: PRRT represents a step change in NET management, significantly improving survival. However, objective response to PRRT, approximately 20%, is poor. There are no predictive biomarkers of response. Uptake on 68Ga-DOTATATE PET/CT imaging is used to assess patient suitability for PRRT, highlighting the presence of somatostatin receptors (SSTR) to which PRRT selectively binds. We hypothesise that the density of SSTRs, as defined by a minimum SUV uptake, predicts for response to PRRT. Methods: 54 patients underwent PRRT. Modified PERCIST assessment was performed: up to 2 target lesions per organ were identified and volume of interest drawn. Maximum 5 targets were counted. Average SUV (SUVave) was calculated by dividing sum of SUVmax of target lesions by number of lesions. Response was determined by RECIST 1.1. Ki67 and SSTR2 expression were assessed on tumour samples and compared with SUVave. Results: Response to PRRT: partial response (PR) 26%, stable disease (SD) 40% progressive disease (PD) 12%. Response to PRRT predicted progression free survival (PFS) with patients experiencing PR having a PFS 2.5x that of those with SD, and almost 20x as long as PD. Using ROC curve analysis, SUVave of 21.6 predicted for tumour response with high sensitivity (0.74) and specificity (1.0), p = 0.15, 95% CI 0.71-3.96. No association between baseline SUVave and SSTR2 or Ki-67 was observed. SUVave > 21.6 was an independent predictor of clinical outcome. Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study.
Effect of lanreotide depot (LAN) on 5-hydroxyindoleacetic acid (5HIAA) and chromogranin A (CgA) in gastroenteropancreatic neuroendocrine (GEP NET) tumors: Correlation with tumor response and progression-free survival (PFS) from the phase III CLARINET study.
Authors: Phan Alexandria T. , Wolin Edward M. , Liyanage Nilani , Mirakhur Beloo , Pitman Lowenthal Susan W. , Vinik Aaron , Fisher George A. , Pavel Marianne
Published: September 2018

4095

Background: 5HIAA or CgA are biomarkers in some GEP NETs. We present posthoc analyses using prospectively collected urinary 5HIAA and serum CgA data from CLARINET. Methods: Adults with moderately or well differentiated, nonfunctioning (no symptoms of carcinoid syndrome), locally advanced or metastatic GEP NETs were randomized to LAN 120mg or placebo (PBO) every 4 weeks (wks) for 96 wks. Tumor response evaluated centrally (RECIST 1.0) and PFS were assessed by treatment. Biochemical response was defined as baseline > upper limit of normal (ULN, 41.6µmol/d 5HIAA; 98.1µg/L CgA) and ≥50% decrease from baseline to ≤ULN value on study. CgA analyses excluded gastrinoma patients (pts). Results: 48% (82/171) (45LAN; 37PBO) and 66% (129/195) (65LAN, 64PBO) of pts had > ULN baseline 5HIAA and CgA. In those pts with no radiologic progression, significantly greater reductions in 5HIAA (Table) and CgA were observed in LAN vs PBO pts at all assessments (all P< 0.05). PFS was significantly prolonged in LAN 5HIAA responders vs nonresponders (median not reached vs 22.1 months, P= 0.0076) but was not significantly different in PBO 5HIAA responders vs nonresponders. There were no significant differences in PFS by CgA response (responders vs nonresponders) in either LAN or PBO pts. Conclusions: These data suggest that serotonin is secreted by nonfunctioning tumors, but does not reach the threshold required for clinical carcinoid symptoms. Monitoring 5HIAA and CgA may be useful during LAN treatment of nonfunctional GEP NETs. Clinical trial information: NCT00353496. [Table: see text]
A novel scoring system to predict survival in patients with advanced pancreatic adenocarcinoma: The Memorial Sloan Kettering Cancer Center (MSKCC) Prognostic Score (MPS).
Authors: Yang Andrew Chung , Wiesenthal Alison , Epstein Andrew S. , Goldberg Jessica , Meadows Jason , O'Reilly Eileen Mary , Glare Paul A.
Published: September 2018

4105

Background: A major limitation of several common prognostic tools, e.g. the Eastern Cooperative Oncology Group (ECOG), Karnofsky, and Palliative Performance Scales, is a reliance on subjective clinical assessment. An objective tool, the Glasgow Prognostic Score (GPS) derived from C-reactive Protein (CRP) and albumin levels, has been validated in patients with operable and inoperable malignancies but has the disadvantage that CRP is not routinely measured in the United States. We examined if the Neutrophil-Lymphocyte Ratios (NLR) (Ahn, H.K., et al., Neutrophil-Lymphocyte Ratio Predicts Survival in Terminal Cancer Patients. J Palliat Med, 2016) could be substituted for CRP in the GPS to predict survival in patients with advanced pancreatic adenocarcinoma. Methods: A retrospective review chart identified patients at MSKCC with pathology-confirmed stage IV pancreatic adenocarcinoma diagnosed between 2011 to 2014. Pre-treatment absolute neutrophil count, absolute lymphocyte count, and albumin were extracted. The NLR for each patient was calculated and assigned NLR ≤ 4 a value of 0; NLRs > 4 a value of 1, serum albumin > 4 g/dl assigned a value of 0; and serum albumin < 4 g/dl assigned a value of 1. Combining NLR and albumin scores results in a composite MPS score of 0-2, similar to GPS. We evaluated the association of the MPS with overall survival. Results: N = 833 patients were identified with median survivals in the table below. A log-rank test showed statistically significant differences in survival between MPS groups (p < 0.00005). The MPS on univariate analysis had a HR of 1.36 (95% CI 1.23 – 1.50, p < 0.0005) associated with overall survival. Conclusions: The MPS, a composite of NLR and albumin, is an objective prognostic tool that divided this sample of patients into three clinically and statistically significant subgroups. Further interrogation will control for performance status, disease characteristics and therapy. [Table: see text]
Phase II trial of neoadjuvant S-1 and concurrent radiotherapy for borderline resectable pancreatic cancer: Interim results of JASPAC05.
Authors: Takahashi Shinichiro , Ohno Izumi , Ikeda Masafumi , Konishi Masaru , Kobayashi Tatsushi , Akimoto Tetsuo , Kojima Motohiro , Morinaga Soichiro , Ku Yonson , Shimizu Yasuhiro , Nakamori Shoji , Hishinuma Shoichi , Takakura Norihisa , Kainuma Osamu , Hirano Satoshi , Otsubo Takehito , Nagino Masato , Kimura Wataru , Yamashita Yoichi , Uesaka Katsuhiko
Published: September 2018

4107

Background: Borderline resectable pancreatic cancer (BRPC) has a high probability of a positive surgical margin and poor prognosis because the tumor interacts with surrounding arteries or veins. Chemoradiotherapy (CRT) with S-1 has shown favorable activity in locally advanced pancreatic cancer. This study was designed to assess S-1 and concurrent radiotherapy in a neoadjuvant setting to determine whether it increases R0 resection rate for BRPC. Methods: This was a multicenter, single-arm phase II study. Patients with BRPC received S-1 (40 mg/m2 BID) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery if they fulfilled any of the following: (1) bilateral impingement of superior mesenteric vein or portal vein; (2) tumor contact with superior mesenteric artery ≤180°; or (3) tumor contact with common hepatic artery or celiac axis ≤180°. Primary endpoint was R0 resection rate in BRPC confirmed by central review. At least 40 patients were required, with one-sided α = 0.05 and β = 0.05, with an expected and a threshold values for primary endpoint of 30% and 10%. Results: Fifty-two patients were eligible between December 2012 and May 2016. CRT was completed in 50 patients (96%) and was safe, with mostly grade 1 or 2 adverse events. Protocol treatment was withdrawn before surgery in 12 patients because of progressive disease diagnosed by computed tomography, and in one because of treatment refusal. Ten patients received exploratory laparotomy, or palliative/noncurative resection. In the rest of 29, R0 resection was conducted in 27, and R1 and RX in 1 patient each. This gave an R0 resection rate of 52% in all 52 eligible patients. In the 41 cases of BRPC confirmed by central review, R0 was confirmed in 26 (63%). Destruction of > 50% of tumor cells was confirmed pathologically in 10 (32%). Postoperative grade III/IV adverse events according to Clavien–Dindo classification were observed in 6 (15%). Conclusions: S-1 and concurrent radiotherapy were well tolerated and found to be effective in BRPC. A randomized controlled trial comparing neoadjuvant CRT and chemotherapy, including gemcitabine+nab-paclitaxel, for BRPC is under planning. Clinical trial information: NCT02459652.
Characterization of germline genomic alterations in familial pancreas cancer.
Authors: Goldstein Jennifer Brooke , Zhao Li , Javle Milind M. , Overman Michael J. , Shroff Rachna T. , Varadhachary Gauri R. , Wolff Robert A. , Futreal Phillip Andrew , Fogelman David R.
Published: September 2018

4116

Background: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival in patients with pancreatic cancer (PC). We retrospectively compared family history of such cancers with clinical outcomes and underlying molecular aberrations. Methods: A retrospective chart review was conducted of 350 metastatic PC patients treated with first line FOLFIRINOX and Gem/Abraxane at MDACC from 1/2010 -1/2016. Family history was defined as 1st through 3rdgeneration relatives with breast, ovarian, or pancreas cancer. Germline DNA was collected and sequenced using a familial cancer panel using an Illumina 2500. Average coverage was 200X. Platypus calls were analyzed for germline mutations. We assessed mutations in BRCA1, BRCA2, PALB2, MMR genes, ATM, and PolE. Results: Average age was 61. 60% of patients were male. We sequenced blood and tissue samples where available. We found at lease one mutation in 47 of 129 patients tested. There were 56 mutations identified among the 47 patients. Of patients with 0-1,2, or 3 or more affected family members we found mutations in 44%, 47%, and 29%, respectively. Patients with 3+ family members affected tended to have mutations in BRCA1 or PolE. Among the subset of patients with possible deleterious mutations, there were trends towards improved survival in pts with BRCA or PALB aberrations (307d vs 271d, p = ns) but worse outcomes in those with MMR gene defects (181d vs 387d, p = .126). Table 1 indicates outcomes based on number of family members with cancer and their associated mutations. Conclusions: Approximately one third of all patients tested had at least one germline mutation in previously described familial pancreas cancer genes. Screening for inherited cancer susceptibility genes may have prognostic value. [Table: see text]
Neutrophil count and efficacy of chemoradiation in patients with locally advanced unresectable pancreatic carcinoma: An ancillary study of in the LAP 07 trial.
Authors: Schernberg Antoine , Vernerey Dewi , Goldstein David , Van Laethem Jean Luc , Glimelius Bengt , Van Houtte Paul , Bonnetain Franck , Louvet Christophe , Hammel Pascal , Huguet Florence
Published: September 2018

4120

Background: Predictive biomarkers of Overall Survival (OS) and Progression Free Survival (PFS) in locally advanced pancreatic cancer (LAPC) pts are mandatory. Baseline leukocyte, neutrophil and monocyte counts in addition to lymphocyte ratio (NLR) may predict OS in LAPC pts. Efficacy of chemoradiation (CRT) depending on neutrophil count was retrospectively analyzed in the largest Phase III cohort of LAPC. Methods: The international multicenter randomized LAP07 phase III trial (NCT00634725) has recruited 442 LAPC pts. We have studied the predictive and prognostic value of systemic inflammation, as defined: (i) baseline neutrophilia (neutrophil count > 7 G/L at first randomization) or (ii)increased absolute neutrophil count (IANC) after induction chemotherapy vs baseline. Univariate and multivariate Cox analysis evaluated the benefit of CRT for OS, PFS and Local Control (LC) in pts without systemic inflammation. Results: Patients with baseline neutrophilia (11%) had a worse OS (median 8.9 vs 13.3 months, p = 0.01). At 2nd randomization, 9% and 29% pts had baseline neutrophilia or IANC, respectively. Both neutrophilia (median OS 10.6 vs 16.1 months, p = 0.03) and IANC (median OS 14.6 vs 17.4 months, p = 0.02) predicted poor OS. Systemic inflammation predicted local resistance to CRT (p = 0.02, interaction = 0.015). After excluding pts with systemic inflammation, 1-year local control was 80% in CRT vs 54% in chemotherapy arms (p < 0.001). Pts without systemic inflammation in CRT arm had improved PFS vs chemotherapy arm (median 10.3 vs 8.3 months, p = 0.04). In multivariate analysis in this population, CRT increased PFS (HR = 0.66, 95%CI: 0.45 - 0.97, p = 0.03), after adjusting on age, tumor size, pain at enrollment, albumin, and CA 19.9 according to PROLAP nomogram parameters. Conclusions: In LAPC pts with tumor controlled after induction chemotherapy, systemic inflammation may help to better predict those who will benefit from CRT. This result may impact clinical management and the design of future clinical trials for LAPC. An external validation with a cohort from the ARCAD pancreas meta-analysis is under consideration. Clinical trial information: NCT00634725.
Selective benefit of adjuvant chemoradiation in resectable pancreatic cancer.
Authors: Wright Jesse P , Schlegel Cameron , Snyder Rebecca A , Du Liping , Shyr Yu , Cardin Dana Backlund , Merchant Nipun B. , Parikh Alexander A.
Published: September 2018

4122

Background: Although level 1 data supports the use of adjuvant chemotherapy (ACT) in resected pancreatic adenocarcinoma (PDAC), the role of adjuvant chemoradiation (ACRT) remains controversial. The objective of this study is to investigate the impact of adding ACRT to ACT on overall survival (OS), based on lymph node (LN) and margin status. Methods: Resected AJCC Stage I and II PDAC patients from 2004-2013 identified within the National Cancer Database were classified into groups based on treatment: surgery alone (SX), ACT alone, ACT+ACRT, and ACRT only. Kaplan-Meier analyses were performed to determine median OS. Multivariable (MV) Cox regression models with interactions of treatment with LN and margin status were constructed to examine the independent effects of ACT and ACT+ACRT in these subgroups. Results: Of 31,348 patients, 30% were treated with SX, 30% with ACT, 38% with ACT+ACRT, and 2% with ACRT alone. Median OS (mos.) for ACT (22.5, 95% CI 21.9-23.1) and ACT+ACRT (23.7, 23.3-24.2) were significantly longer than SX (14, 13.4-14.5) or ACRT (11.2, 9.8-12.9). MV analysis confirmed a significant OS benefit of both ACT and ACT+ACRT controlling for patient and tumor related factors. ACRT+ACT was associated with improved OS compared to ACT in patients with positive margins and/or LN. Those with negative margins and LN did not benefit from the additional use of ACRT (Table). Conclusions: This large hospital-based study demonstrates that ACT and ACRT are associated with improved OS when compared to SX. The addition of ACRT to ACT, however, was only beneficial in high-risk patients with positive margins and/or LN. ACT+ACRT in patients with both margin and LN negative disease may not be warranted. Future clinical trials should stratify patients based on LN and margin status in order to determine which patients are most likely to benefit from the use of ACRT. [Table: see text]
Initiation and shift of antidiabetic therapy and pancreatic cancer.
Authors: Autier Philippe , Franchi Matteo , Bota Maria , Leclercq Agnès , Guillaume Joeri , Van Damme Nancy , Corrao Giovanni , Partensky Christian , Boniol Mathieu , Boyle Peter
Published: September 2018

4126

Background: Concerns have been raised on the risk of pancreatic cancer associated with specific anti-diabetic therapies. We have examined the risk of pancreatic cancer among patients with diabetes prescribed with an oral anti-diabetic drug (OAD) or an incretin drug (DPP4i and GLP-1 RA) or insulin. Methods: The public health insurance databases of Belgium and of Lombardy Region, Italy include nearly 100% of the population living in these countries. We created within these databases two cohorts that included adult patients who were first prescribed an incretin drug or another noninsulin antidiabetic drug (NIAD) during 01/07/2008-31/12/2013 in Belgium and during 01/01/2008-31/12/2012 in Lombardy Region. The risk of pancreatic cancer after prescription of an anti-diabetic drug was evaluated using multivariate adjusted Cox models including time-dependent variables. Adjusted hazard ratios (aHRs) from Belgium and Italy were pooled using fixed effects meta-analyses. Results: Results in both cohorts were similar. Among those patients prescribed an OAD, 45% of pancreatic cancers occurred within the 6 months following first prescription, 20% in months 7 to 12 after first prescription and proportions decreased progressively during follow-up. The aHR of pancreatic cancer among subjects prescribed an incretin compared to an OAD was 2.14 [95% CI, 1.71 to 2.67]. The aHR decreased from 3.35 [CI, 2.32 to 4.84] in the first 3 months after first incretin prescription, 2.12 [CI, 1.22 to 3.66] in months 3 to 5.9, 1.95 [CI, 1.20 to 3.16] in months 6 to 11.9, to 1.69 [CI, 1.12 to 2.55] after 12 months. The risk of pancreatic cancer among subjects who were subsequently prescribed insulin was 6.89 [CI, 6.05 to 7.85]. The time from OAD prescription to a shift to incretins or to insulin was significantly lower in patients who were subsequently diagnosed with a pancreatic cancer. Conclusions: The increased risk of pancreatic cancer associated with anti-diabetic therapies could be the consequence of an occult pancreatic cancer that provokes diabetes (reverse causation bias). The search for an occult pancreatic cancer in subjects with newly diagnosed diabetes or patients shifting to more potent anti-diabetic therapy may lead to earlier detection of this cancer.
Circulating tumor (ct)-DNA alterations in urothelial/bladder cancer (UC/BC): Updates on a dynamic genomic landscape.
Authors: Grivas Petros , Nagy Rebecca J , Pond Gregory Russell , Gupta Sumati , Wang Jue , Vaishampayan Ulka N. , Pal Sumanta K. , Bilen Mehmet Asim , Naik Gurudatta , Ghatalia Pooja , Hoimes Christopher J. , Gopalakrishnan Dharmesh , Barata Pedro , Lanman Richard B. , Talasaz AmirAli , Sonpavde Guru
Published: September 2018

4534

Background: Cell-free ctDNA may be potentially actionable, may have prognostic/predictive role and evolve after therapy. We updated our analysis of our retrospective study to shed light on UC/BC biology. Methods: Patients (pts) with UC/BC with ctDNA analysis for potentially actionable alterations using Guardant360 were identified. A 70-gene ctDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing for 29 cancer genes, critical exons in 39 genes and amplifications (16 genes), fusions (6 genes) and indels (3 genes) harvested from 10 mL of peripheral blood. Descriptive statistics were used. Results: There were 246 pts with 276 samples. At least 1 alteration was detected in 249 (90%) samples. Median age at time of ctDNA collection was 67 years (39-85), 78% men, median number of alterations per sample was 3.5 (1-35) most pts had MIBC. In MIBC pts, the most common alterations at the 1st ctDNA sample were in TP53 (52%), PI3KCA (18%) ARID1A (17%), FGFR2 (15%), MET & NF1 (14%), EGFR (13%), BRAF (12%), FGFR3 (11%), RAF1 (10%), BRCA1 & CCNE1 (9%). In MIBC pts, the most common genes with increased copy number were RAF1 & CCNE1 (8%), ERBB2 & PI3KCA (7%), EGFR, BRAF, FGFR1, MYC (each 5%), MET (4%), KRAS (3%). Most common altered pathways included TP53 signaling (56%), RAS/RAF/MEK/ERK (51%), RTK (48%), cell cycle (38%), FGFR family (34%), DNA damage response (25%), PI3KCA/AKT/mTOR (23%) and chromatin remodeling (17%). Interestingly, FGFR3 and RAS alterations were mutually exclusive in most cases, but each may co-occur with TP53alterations. 54 serial ctDNA samples from 24 pts (18 pts with 2 samples; 6 pts with 3 samples) revealed persistent, lost and new gene alterations. Conclusions: ctDNA was detected in 90% of pts and alterations were similar to those previously seen in UC tumor tissue. Tumor heterogeneity, interim therapy, genomic instability and clonal evolution can explain differences in serial samples. Correlation assessment with prior therapies and outcomes is being pursued to inform trial designs. Prospective validation, assessment of ctDNA concordance with tumor tissue DNA, and evaluation of clinical utility is warranted.
Neoadjuvant chemotherapy followed by concomitant chemoradiation with gemcitabine in muscle invasive bladder cancer.
Authors: Mateen Abdul , Adil Allah Rakha , Hashmi Quratul Ain , Duraishi Arif Moin , Abdullah Famya
Published: September 2018

4541

Background: Urinary bladder cancer is one of the most prevelent genitourinay cancer in Pakistan. It is especially common in population that consumes smokeless tobacco. Advanced stage at diagnosis is usual presentaion due to illiteracy, poverty and lack of primary health facilities. The study was aimed to optimize treatment of muscle invasive bladder cancer in poor resource country. Methods: A total of 65 patients were enrolled for the study. All patients had muscle invasive disease on transurethral resection. Patients were to in stage range from T2-3, N0 and M0 to be selected. The patients were planned for gemcitabine and cisplatinum (GC) every three weeks in a dose of 1000 mg/m² and 40 mg/m² on D1 and D8 of each cycle respectively. Ultrasonography was performed to assess for any bladder mass at this point. The patients with no visible tumor were planned for whole bladder external radiotherapy (ERT) along with weekly gemcitabine 100 mg/m². A total of 63 Gray (Gy) was planned with 1.8 Gy per fraction and five fractions a week. Gemcitabine was given on 1st day of every week during whole course of ERT.Treatment interruptions were allowed depending upon chemotherapy and ERT related toxicity. Primary end point was to assess disease free survival (DFS) while overall survival was also assessed as a secondary end point. Results: 54 patients (83%) were available for assessment to treatment and to assess DFS and OS. Rest of the patients 11/65 (17%) were excluded from the analysis due to inability to complete the treatment. Five patients (8%) showed disease recurrence during treatment and were switched to other treatment. 11 patients (20%) showed bowel, 15 patients (28%) showed bladder and 8 patients (15%) showed hematological related grade 1-2 toxicity. Four year DFS and OS were 43% and 52% respectively. Mean and median DFS (year) were 3.16±0.36 (95% confidence interval [CI] 2.91 to 3.42) and 2.68±0.54 (95% CI 2.41 to 2.93) respectively. Mean and median OS (year) were 3.95±0.43 (95% CI 3.67 to 4.21) and 3.55±0.31 (95% CI 3.37 to 3.76) respectively. Conclusions: Neoadjuvant chemotherapy with GC followed by concomitant CRT using gemcitabine is an excellent choice for bladder preservation in poor resource countries.