bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of a cell viability assay based on cultures of CTICs to identify treatment options in third-line pancreatic cancer.
Authors: Ricigliano Mark , Isacoff William H. , Ocean Allyson J. , Cooper Brandon , Welkie Mary , Bartlett Andrew , Yu Kenneth H.
Published: March 2017

338

Background: Standard of care treatment for pancreatic adenocarcinoma (PDAC) includes FOLFIRINOX or gemcitabine with nab-paclitaxel used in either the front-line or 2nd line treatment setting. There is no consensus for 3rd line treatment for this cohort of poor prognosis patients with clinical trials being the only viable option. We evaluated a cell viability assay using cultures of circulating tumor and invasive cells (CTICs) to identify effective 3rdline PDAC treatment options. Methods: CTICs were isolated from peripheral blood samples of 17 PDAC patients who previously had received one of the two standard of care regimens using an immunomagnetic separation for EPCAM epitope Ber-EP4 and cultured in enriched DMEM-F12 medium. After 14 days, seven chemotherapeutics (gemcitabine (G), oxaliplatin (O), fluorouracil (F), irinotecan (I), mitomycin C (M), cisplatin (C) and paclitaxel (P)) were added to the cultures and response to treatment was measured 48 hr. after treatment by immunofluorescence using a live-cell resazurin assay. Response to treatment was determined by a reduction of fluorescence in the treated cultures compared to control and the mean florescence (Fm) was calculated for each chemotherapeutic. A one-sample t-test was used to measure the variance between Fm control and treated samples. (p-value <0.005). Sensitivity to treatment was determined using linear regression based on Fm values and the sensitivity of each chemotherapeutic was interpolated from a standard curve (range 1.0-5.0, sensitive <2, intermediate 2-3, resistant >3). Results: m (Fm=1.6) demonstrated the most effective treatment option with marked resistance to treatment for G, I, P and O. (Fm=3.4, 3.7, 3.4 and 3.7). Intermediate response was observed for F and C (Fm=2.8 and 2.8). Patient treatment response to m will be described. Conclusions: CTICs can be routinely isolated and cultured for cell viability assays. m based regimens with C and F should be considered for 3rd line PDAC patients.
CA19-9-low and Lewis(+) pancreatic cancer: A unique subtype.
Authors: Luo Guopei , Yu Xian Jun
Published: March 2017

339

Background: Pancreatic cancer is a lethal malignancy and patients often survive within one year. CA19-9 is the most important biomarker for pancreatic cancer and Lewis (-) individuals have no or scarce CA19-9 secretion. We have met several patients with low CA19-9 and metastatic disease survived over one year without major treatments, prompted us to examine the characteristics of CA19-9-Low subgroup (Lewis (+)&CA19-9 ≤ 37 U/mL). Methods: Medical record of 1484 patients was retrieved from a prospectively maintained database. Lewis genotypes were determined by Sanger sequencing. Characteristics of CA19-9-Low pancreatic cancers were examined. Results: No significant difference was found between Lewis (-) (8.4%) and CA19-9-High (77.8%) patients in survival (HR = 1.16, P = 0.216). CA19-9-Low patients (13.8%) had strikingly better survival than CA19-9-High&Lewis (-) patients (HR = 0.52, P < 0.001). The 5-year survival rate of stage III, IV CA19-9-Low patients (28.2%) was even higher than that of stage I, II CA19-9-High&Lewis (-) patients (21.5%). Compared with CA19-9-High&Lewis (-) patients, CA19-9-Low patients had a lower proportion of nerve invasion (74.7% vs. 84.2%, P = 0.044), EGFR expression (37.5% vs. 51.2%, P = 0.047), a lower level of serum glucose (6.3 ± 1.9 vs. 7.4 ± 3.1, P = 0.001) and neutrophil-lymphocyte ratio (2.6 ± 2.4 vs.3.0 ± 3.1, P = 0.027), and poor response to Gemcitabine-based chemotherapy (stage I, II, HR = 0.73, P = 0.446; stage III, IV, HR = 0.70, P = 0.244). Conclusions: CA19-9-Low pancreatic cancer is a unique subtype with poor response to Gemcitabine-based chemotherapy.
Adjuvant chemoradiation for node-positive pancreatic adenocarcinoma: A propensity-matched analysis.
Authors: Raoof Mustafa , Melstrom Laleh Golkar , Warner Susanne , Woo Yanghee , Singh Gagandeep , Chen Yi-Jen , Fong Yuman
Published: March 2017

347

Background: American Society of Clinical Oncology guidelines recommend adjuvant chemoradiation (ACR) for margin-positive(R1) and/or node-positive (N+) pancreatic cancers. However, randomized trials and meta-analyses have have not shown superiority of ACR over AC. Methods: National Cancer Database (NCDB) was used to analyze patients with N+ and/or R1 pancreatic adenocarcinoma who underwent ACR or AC over a ten-year period (2004-2014). Patients who received neoadjuvant radiation, no adjuvant treatment or adjuvant radiation alone were excluded. Propensity score nearest-neighbor 1:1 matching (PSM) was performed between ACR and AC groups based on age, sex, race, insurance, comorbidities, T-stage, nodal status, margin status, grade, and neoadjuvant chemotherapy. Primary outcome was overall survival (OS). Results: A total of 9,732 patients were eligible. After PSM two well-balanced groups of 4000 patients each were analyzed. ACR resulted in superior OS in patients with N+ and/or R1 disease as compared to AC alone (HR: 0.83, 95% CI 0.78-0.87; Median OS 22 vs. 19 months, p<0.001). Subset analyses demonstrated overall survival benefit of ACR compared to AC in N+, margin-negative patients (HR: 0.82, 95% CI 0.77-0.88; Median OS 24 vs. 20 months, p<0.001), as well as N+, R1 patients (HR: 0.77, 95% CI 0.68-0.87; Median OS 17 vs. 15 months, p<0.001); but no benefit in node-negative, R1 patients (HR: 1.12, 95% CI 0.84-1.48; Median OS 18 vs. 22 months, p = 0.43). Conclusions: This is the largest study to date that shows superiority of ACR over AC in N+ patients irrespective of margin status. The study failed to show a survival benefit in R1, node-negative patients.
Quality-of-life findings in patients with midgut neuroendocrine tumors: Results of the NETTER-1 phase III trial.
Authors: Strosberg Jonathan R. , Wolin Edward M. , Chasen Beth , Kulke Matthew H. , Bushnell David L , Caplin Martyn E. , Baum Richard P. , Kunz Pamela L. , Hobday Timothy J. , Hendifar Andrew Eugene , Oberg Kjell E. , Lopera Sierra Maribel , Kwekkeboom Dik J. , Ruszniewski Philippe B. , Krenning Eric
Published: March 2017

348

Background: Neuroendocrine tumor progression is associated with decline in quality of life, both due to tumor and hormone-related symptoms. The Phase III NETTER-1 trial randomized patients with advanced, progressive midgut NETs to receive treatment with 177Lu-DOTATATE (177Lu; Lutathera) versus high-dose (60 mg) Octreotide LAR (Oct). EORTC questionnaires C30 and GINET21 were assessed during the trial in order to determine the impact of treatment on health-related quality of life (HRQoL). Methods: Patients completed EORTC QLQ-30 and QLQ-G.I.NET21 questionnaires at baseline and every 12 weeks thereafter until disease progression. Raw scores were converted to a 100-point scale and individual changes from baseline scores were assessed. Clinically relevant ( ≥ 10 point) deterioration/improvement was considered clinically significant. Results: Clinically and statistically significant improvements in QoL were observed in the 177Lu arm versus the Oct arm at certain time points in key domains of HRQoL including global health status and diarrhea. In mean, global health status improved in 28% of patients on 177Lu arm vs. 15% on Oct, and worsened in 18% of patients on 177Lu vs. 26% on Oct. Diarrhea improved in 39% of patients on 177Lu vs. 23% on Oct, and worsened in 19% of patients on 177Lu vs. 23% on Oct. There was a trend towards improvement in pain that was not statistically significant. Flushing appeared to improve compared to baseline in both arms of the study with no clear advantage to treatment with 177Lu vs. Oct. Conclusions: QoL analysis suggests benefit in important domains associated with 177Lu treatment compared to high-dose octreotide in patients with advanced midgut NETs, and confirms the treatment value of 177Lu on patient QoL, in addition to the meaningful increase in progression-free survival already reported. Clinical trial information: NCT01578239.
Two-stage hepatectomy for colorectal liver metastases: A multi-institutional retrospective review.
Authors: Berger Nicholas G , Kim Bradford , Gholami Sepideh , Margonis Georgios A , Ethun Cecilia , Silva Jack P , Tsai Susan , Christians Kathleen K. , Mogal Harveshp , Clarke Callisia , Maithel Shishir Kumar , Pawlik Timothy , D'Angelica Michael Ian , Aloia Thomas A. , Gamblin T. Clark
Published: March 2017

351

Background: A significant number of patients with colorectal liver metastases (CRLM) present with unresectable bilobar disease. Two-stage hepatectomy with portal vein embolization (PVE) have been described as a treatment for CRLM allowing for volume regeneration of a functional liver remnant. No large-scale multi-institutional studies exist. The aim of this project was to describe outcomes following two-stage hepatectomy, including overall survival (OS), recurrence-free survival (RFS), and complications. Methods: Patients completing two-stage hepatectomy for CRLM at five US institutions were identified and retrospectively analyzed (2000-2015). Overall survival and recurrence-free survival following second-stage surgery, short-term mortality, Clavien-Dindo complications, and readmission rates were examined. Results: A total of 209 patients were identified. Mean age was 52 (SD +/-11.4), 59.8% were male, and 87.0% had synchronous disease. A total of 65.1% of patients underwent PVE, and 27.3% underwent hepatic artery infusion pump placement. 88.3% of cases underwent neoadjuvant chemotherapy. Following the first stage, 30-day morbidity was 24.4%, with 4.8% major (Clavien-Dindo grade ≥3) complications, and 30-day readmission was 6.7%. Mean time between first and second stage was 4.1 months (S.D. +/-3.1), and 57.5% received systemic chemotherapy between the two resections. Following the second stage, overall complications were 47.4% with 23.9% major complications, and 30-day readmission was 9.7%. Mortality following second stage was 3.8% at 30 days, and 5.3% at 90-days. Following the second stage, RFS at 1-, 3-, and 5-years was 80%, 46%, and 29% respectively. OS at 1-, 3-, and 5-years was 87%, 64%, and 45% respectively. Conclusions: Two-stage hepatectomy for CRLM provides acceptable recurrence-free and overall survival in the context of advanced bilobar disease. Major complications and readmission following the first stage are rare. Following the second stage, short-term major morbidity, mortality, and readmissions are also acceptable. For well-selected patients, two-stage hepatectomy remains a safe and effective treatment for CRLM, with potential for more widespread adoption.
Stereotactic body radiation vs. intensity-modulated radiation for unresectable pancreatic cancer.
Authors: Park Joseph Junyong , Hajj Carla , Reyngold Marsha , Shi Weiji , Zhang Zhigang , Cuaron John J , Crane Christopher H , O'Reilly Eileen Mary , Lowery Maeve Aine , Yu Kenneth H. , Goodman Karyn A. , Wu Abraham Jing-Ching
Published: March 2017

353

Background: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and may be more effective and less toxic than intensity modulated radiation therapy (IMRT). Methods: We retrospectively reviewed unresectable stage I-III pancreatic adenocarcinoma treated with SBRT (5 fractions, 30-33Gy) or IMRT (25-28 fractions, 45-56Gy with concurrent chemotherapy) between 2008-2016 at our institution. The groups were compared with respect to overall survival (OS), local failure (LF), distant failure (DF), any failure (AF), proportion of patients becoming resectable, and incidence of acute toxicity. Competing risks methods were used for univariate (UVA) and multivariate analysis (MVA) for LF, DF and AF. All endpoints were calculated from end of RT. Results: Median follow-up for surviving patients was 12.9 months. 44 patients received SBRT and 226 patients received IMRT. Patients who received SBRT were older (45% vs 29% > 70 years old, p = 0.05). Otherwise there was no significant difference in baseline characteristics, including stage and duration of induction chemotherapy. On MVA, there was no significant difference in OS, LF, DF, or AF between IMRT and SBRT (p = 0.73, 0.81, 0.44, and 0.39 respectively). Median OS was 15.7 months, and the 1-year rate of LF was 34.4% for SBRT and 30.2% for IMRT. Response to induction chemotherapy was associated with longer OS (p = 0.03). There was no significant difference in the proportion of patients who were subsequently resected between IMRT (17%) and SBRT (7%; p = 0.11). Significantly more IMRT patients experienced acute G2+ GI toxicity (24% vs. 7%, p = 0.008), G2+ fatigue (42% vs. 7%, p < 0.0001), and G3+ hematologic toxicity (26% vs. 5%, p = 0.001) compared to SBRT. Conclusions: SBRT achieves similar disease control outcomes as IMRT, and is associated with less acute toxicity. This data suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen suggests a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.
Initial gemcitabine/nab-paclitaxel (GA) followed by sequential (S) mFOLFIRINOX or alternating (A) mFOLFIRI in metastatic pancreatic cancer (mPC): The SEENA-1 study.
Authors: Picozzi Vincent J. , Leach Joseph W. , Seng John E. , Anthony Stephen Patrick , Mena Raul , Larson Tim , Borazanci Erkut Hasan , Weiss Glen J. , Lin Shih-Li Bruce , Jameson Gayle S. , Bolejack Vanessa , Stoll Amy C. , Von Hoff Daniel D. , Ramanathan Ramesh K.
Published: March 2017

359

Background: GA, FOLFIRINOX and FOLFIRI are standard chemotherapy (CTX) regimens for mPC.The optimal introduction of these regimens following GA is not known. This phase II study evaluated 2 different approaches to this question. Methods: Eligibility criteria included 1) untreated mPC, 2) ECOG PS 0/1, 3) organ function adequate for Rx. Patients (pts) were treated according to one of 2 methods following GA given per standard dose/schedule: FOLFIRINOX (bolus 5-FU omitted) for up to 12 cycles at 24 weeks or at time of disease progression (S); or GA alternating with FOLFIRI q8 weeks up to 48 weeks total Rx (A). Results: 54 evaluable pts (28S, 26A) were enrolled . Pt characteristics included median age 65, M/F 48/52% , liver involvement 89%. 17/53 pts (31%) did not achieve disease control at 8 weeks (8 toxicity/complications , 6 disease progression, 3 declined further protocol therapy). Of the remaining 37 pts, 24/13 were treated with S/A regimens, respectively. Grade ≥ 3 treatment toxicities reported while on study with frequency ≥ 10% included anemia 21%, neutropenia 43%, thrombocytopenia 15%, and fatigue 22%. Grade ≥ 3 neuropathy occurred in 8% of pts. For all 54 pts using RECIST 1.0, CR/PR/SD/DC was 2 (4%)/20 (37%)/19 (35%)/41(76%). Ca19.9 response ≥ 90% was seen in 20/37 (54%). For all pts, median OS was 12.3 months ( 95% CI 8.6-14.5 mo); 12 and 24 mo OS was 51% and 11%, respectively. For the 37 pts with DC on GA at 8 weeks (calculated from start Rx) median OS was 13.5 mo (95% CI 10.7-15.4 mo); 12 and 24 mo OS was 55% and 16% , respectively. No statistically significant differences were seen between S and A with respect to toxicity, response or survival. Conclusions: 1) As opposed to introduction of 5FU-based CTX at the time of disease progression/prohibitive toxicity, introduction prior to that time may be at least comparable regarding both toxicity and OS. 2) This approach may further enhance OS in pts who achieve DC on GA at 8 weeks. 3) Neither S nor A method of 5FU-based CTX introduction following GA was clearly superior in this study. 4) How best to combine 5FU-based combination CTX following GA in mPC merits further study. Supported by the Seena Magowitz Foundation.
Neoadjuvant therapy versus upfront surgery for pancreatic adenocarcinoma: A propensity score matched analysis of short-term outcomes.
Authors: Kasumova Gyulnara G. , de Geus Susanna W.L. , Tabatabaie Omidreza , Fadayomi Ayotunde B. , Miksad Rebecca A. , Ng Sing Chau , Moser Arthur J. , Hidalgo Manuel M. , Tseng Jennifer F.
Published: March 2017

361

Background: Neoadjuvant therapy is increasingly utilized and has demonstrated a survival advantage in borderline and locally advanced pancreatic cancer. However, many have feared that preoperative chemotherapy and radiation result in a more challenging operative field and consequently increased morbidity. Methods: ACS-NSQIP targeted pancreas database was queried for patients with adenocarcinoma who underwent PD in 2014. Propensity score matching was used to account for potential selection bias in pre-operative and intra-operative characteristics. Sensitivity analysis assessed the impact of neoadjuvant radiation. Results: 1,313 patients were identified, of whom 338 (25.7%) received neoadjuvant therapy. Patients who received neoadjuvant therapy vs upfront surgery were more likely to be: female (53.6% vs 47.2%; p=0.04), < 65 years of age (53.0% vs 39.2%; p < 0.0001), have BMI <25.0 (43.5% vs 36.6%; p = 0.03), and require vascular resection (37.6% vs 19.6%; p < 0.0001). Patients receiving neoadjuvant therapy were less likely to develop pancreatic fistulae (9.2% vs 14.0%; p = 0.02), more likely to require transfusion (27.8% vs 22.4%; p = 0.04), and had longer operative time (median: 405 vs 371 mins; p < 0.0001). After matching, there were no differences in baseline characteristics, approach, biliary stenting, and vascular resection. The only significant difference in outcomes between the two groups was longer operative time (median 405 vs 377, p = 0.006; Table). These results were robust on sensitivity analysis for use of radiation. Conclusions: Neoadjuvant therapy is safe and, despite prolonging operative time, does not affect 30-day outcomes. Concern for increased morbidity should no longer preclude treatment with neoadjuvant chemotherapy and/or radiation in borderline, locally advanced, and resectable pancreatic tumors. [Table: see text]
Curative treatment in gallbladder cancer: Adjuvant or multimodal concepts—Evidence from data of 975 cases of The German Registry of Incidental Gallbladder Carcinoma.
Authors: Goetze Thorsten Oliver , Al-Batran Salah-Eddin , Paolucci Vittorio
Published: March 2017

367

Background: Incidental gallbladder cancer (IGBC) in T1b-3 stage do profit from radical cholecystectomy but nevertheless the cure rate in T2-3 carcinomas is disappointing. For improvement, following questions are of interest. What is significant regarding adjuvant or multimodal aspects? Which technique of liver resection (LR) and lymph- node dissection (LAD) is meaningful? Role of lymph node ratio (LNR)? Answers based on the data of 975 IGBC of the GR- platform. Methods: For data analysis we used the German- Registry- platform (GR). The GR is a network of more than 300 clinics in Germany. More than 1000 cases of IGBC are registered and to the knowledge of the authors the largest prospective gallbladder registry worldwide. Results: To date more than 1000 IGBC in the GR have been registered, n = 975 analyzed. In 44 of 119 T1b cases there was an IRR, with a significant survival benefit for T1b after IRR. There was also a significant survival benefit for the 244 T2 and 86 T3 with IRR of the 492 T2 and 228 T3 tumors. Comparison of LR showed good results for the wedge resection technique (WRT) in T1b and T2. For T3 more radical techniques showed better results. In 233 patients the LNR could be calculated. Statistic indicates that LNR has a significant influence on prognosis. The results show that the referral of patients from a LV to a HV has no practical relevance. In n = 433 T2 / T3 patients there are data calculated about adjuvant therapy, with a highly significant survival benefit after adjuvant therapy in T2 and a trend for a survival benefit in T3 carcinomas. Positive effect of adjuvant therapy exists in the subgroup with and without re- resection but was more evident in patients without radical resection. Conclusions: IGBC's up to T1b needs radical surgery. The WRT is attractive for T1b / T2 IGBC. LAD and LNR are of prognostic relevance. In 433 T2-3 IGBC's, adjuvant therapy has a positive effect, especially in cases without radical surgery. Regimen will be discussed at the meeting. For further improvement in T2-3 IGBC a multimodal therapy (GAIN-) trial has already been planned by the investigator of the GR under the support of the GR- platform with more than 300 clinics in Germany.
FOLFIRINOX (F-NOX) followed by individualized radiation for borderline-resectable pancreatic cancer: Preliminary toxicity and R0 resection rates from a prospective phase II study.
Authors: Murphy Janet E. , Wo Jennifer Yon-Li , Ryan David P. , Jiang Wenqing , Yeap Beow Y. , Blaszkowsky Lawrence Scott , Kwak Eunice Lee , Allen Jill N. , Clark Jeffrey W. , Faris Jason Edward , Zhu Andrew X. , Goyal Lipika , Mamon Harvey J. , Lillemoe Keith D , DeLaney Thomas F. , Fernandez-del Castillo Carlos , Ferrone Cristina , Hong Theodore S.
Published: March 2017

368

Background: F-NOX has been increasingly utilized in borderline resectable pancreatic cancer (BRPC) due to the improved response rate compared to gemcitabine. However, prospective data remains limited, with the largest series being a 22 patient (pt) cooperative group trial (Alliance A021101), in which 14 pts had R0 resection. In this study, we evaluate neoadjuvant F-NOX followed by individualized chemoradiation (CRT) for BRPC. Methods: Pts ECOG PS 0-1 with biopsy-proven BRPC as defined by NCCN criteria (SMV/PV involvement with suitable flow, abutment of SMA < 180 degrees or of hepatic artery) were enrolled in a single institution, NCI-sponsored phase II study (NCT01591733). Pts received F-NOX for 8 cycles. If after chemotherapy, the tumor was radiographically resectable, pts received short course CRT in 5 (protons 25 GyE) or 10 fractions (photons 30 Gy) with capecitabine 825 mg/m2 bid. If the tumor was still abutting vasculature, pts received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. The primary endpoint of the study was R0 resection rate. Results: 50 pts were enrolled from 8/2012 to 8/2016. One pt was ineligible (lung metastases) and 1 pt is still on treatment, thus 48 patients were evaluable for this analysis. Median age was 62y (46-74). Median tumor size was 37 mm (21-56). Tumor location was in the head of pancreas for 36 (75%) pts. Of the evaluable pts, 40 (83%) completed therapy. Reasons for not completing therapy included pt withdrawal (3), physician decision (3), unacceptable toxicity (1) and progression (1). Grade 3 or greater toxicity occurred in 21 (44%) pts, including diarrhea (6, 12%), febrile neutropenia (4, 8.5%), neutropenia (4, 8.5%), elevated AST/ALT (3, 6.2%), thrombocytopenia (2, 4.2%), anemia (2, 4.2%), elevated alkaline phosphatase (2, 4.2%). 27 (56%) had short course CRT, while 13 (27%) had long course CRT. In evaluable pts, R0 resection rate was 28/40 (58%). Conclusions: Preoperative F-NOX followed by individualized chemoradiation results in a high R0 resection rate. Final results including PFS outcomes on the entire cohort will be presented at the meeting. Clinical trial information: NCT01591733.
Exposure-response (ER) relationship of regorafenib (REG) in patients with hepatocellular carcinoma (HCC).
Authors: Solms Alexander , Ploeger Bart , Reinecke Isabel , Fiala-Buskies Sabine , Cleton Adriaan , Bruix Jordi , Meinhardt Gerold
Published: March 2017

374

Background: In the phase 3 RESORCE trial (N = 573), REG (160 mg QD, 3 weeks on/1 week off) significantly (P < 0.001) improved overall survival (OS) versus placebo in patients with HCC who progressed during sorafenib treatment (HR 0.63; 95% CI 0.50‒0.79). This exploratory analysis evaluated the ER relationship between REG and both OS and time-to-progression (TTP). Methods: Exposure estimates were available for 327 and 315 patients for the OS and TTP analysis, respectively. A multivariate Cox proportional hazard analysis was used to evaluate differences between exposure quartiles and efficacy, taking into consideration all preselected baseline covariates. Subsequently, the functional form of the ER relationship within the REG group was evaluated. Results: The baseline risk factors ECOG status, AFP category, and AST/ALT baseline levels were significantly associated with OS (P < 0.01), with higher HRs for ECOG category ≥ 1, AFP levels ≥ 400 ng/mL, and AST/ALT levels > 3 x ULN. For TTP, a significant correlation (P < 0.01) with age was observed, with a higher HR for patients < 65 years of age. After adjusting for these baseline risk factors, the average exposure over the first 28 days grouped in exposure quartiles for REG was significantly associated with OS and TTP (P < 0.01), i.e. the HR in all exposure quartiles was < 1 versus placebo. By contrast, the difference in HR between exposure quartiles was found to be small and not significant. While no statistically significant ER relationship could be identified between (continuous) individual exposure and efficacy in the REG group, the analysis of the functional form of the ER relationship indicates that OS and TTP improved with an increase in exposure, under the assumption of a linear and a non-linear ER relationship. Conclusions: In addition to a significant difference in OS and TTP between REG and placebo, a trend towards improved efficacy was observed with an increase in REG exposure in HCC patients, which was not statistically significant when taking into consideration ECOG status, AFP level, and AST/ALT risk factors (OS) or age (TTP). Therefore, similar efficacy was observed in patients with HCC who started on REG 160 mg QD 3 weeks on/1 week off over the entire exposure range. Clinical trial information: NCT01774344.
Efficacy of lanreotide depot (LAN) for symptomatic control of carcinoid syndrome (CS) in patients with neuroendocrine tumor (NET) previously responsive to octreotide (OCT): Subanalysis of patient-reported symptoms from the phase III ELECT study.
Authors: Pommier Rodney F. , Fisher George A. , Wolin Edward M. , Kunz Pamela L. , Liyanage Nilani , Pitman Lowenthal Susan W. , Mirakhur Beloo , Shaheen Montaser F. , Vinik Aaron
Published: March 2017

378

Background: In ELECT, LAN significantly reduced the need for short-acting OCT rescue medication 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 the ELECT study. Methods: Adults with histopathologically confirmed NET and history of 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 short-acting OCT if needed and recorded daily the 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) was assessed at baseline and wk 12. Results: Of 115 pts randomized, 51 (n=26 LAN; n=25 PBO) were OCT-naive and 64 (n=33 LAN; n=31 PBO) received prior OCT LAR (n=56) and/or short-acting OCT (n=24). The frequency of moderate or severe diarrhea and/or flushing decreased in both naive and prior OCT pts treated with LAN (Table). The least square mean percentage of days with moderate or severe diarrhea and/or flushing was significantly lower for pts treated with LAN (23.4%) vs PBO (35.8%) ( P=0.004, analysis of covariance adjusted for prior OCT use, region, and baseline values). By week 12, 5HIAA levels dropped by ≥30% to normal in 35% of OCT-naive pts and 29% of prior OCT pts treated with LAN. Among PBO pts, 5HIAA reductions were seen in 15% of OCT-naive pts and 7% of prior OCT pts. Conclusions: Pts showed improvement in CS symptoms of flushing and diarrhea and reduction in 5HIAA levels with LAN treatment, indicating efficacy of LAN in pts regardless of prior OCT use. Clinical trial information: NCT00774930; and EudraCT 2010-019066-92. [Table: see text]
A phase IB, multicenter, open-label study to assess the safety, tolerability, and efficacy of the pleiotropic pathway modifier CC122 administered orally to patients with advanced HCC.
Authors: Kelley Robin Kate , Shih Kent C. , Braiteh Fadi S. , Rasco Drew W. , Hollebecque Antoine , de Braud Filippo , Goncalves Anthony , Cervantes-Ruiperez Andres , Wei Xin , Hagner Patrick , Gandhi Anita K. , Hege Kristen , Pourdehnad Michael , Santoro Armando
Published: March 2017

379

Background: CC122 is a novel cereblon-modulating agent with multiple biologic activities including potent immunomodulatory and antiangiogenic effects. CC-122 binding to cereblon promotes ubiquitination and subsequent degradation of lymphoid transcription factors Ikaros and Aiolos resulting in activation of T cells. Methods: Following establishment of oral CC122 3 mg daily (QD) as the MTD in phase 1a (Blood 122:2905 2013), an expansion cohort of advanced Hepatocellular Carcinoma (HCC) subjects was enrolled. All subjects had progressed on or were intolerant to sorafenib. Efficacy was assessed per RECIST 1.1 criteria. Results: As of Jan. 13, 2016, 25 advanced HCC subjects were enrolled. The median age was 59.6 years, median Child-Pugh score was 5 (range 5-8) and all were ECOG 0-1. Viral status was HBV 28%, HCV 28%, HBV/HCV 12% and non-viral 32%. 52% had alpha-fetoprotein ≥ 200. CC122 was well tolerated. Two subjects discontinued due to AEs. Dose reductions occurred in 32% (n = 8). The most common ( ≥ 5%) grade 3/4 AEs were neutropenia, ALT elevation (each n = 4, 16%), AST elevation (n = 3, 12%), asthenia, ascites, anemia, hyperbilirubinemia, pneumonia, and rash (each n = 2, 8%). Drugrelated serious AEs included vomiting and rash. 19 subjects were evaluable for efficacy. ORR was 10.5% (n = 2 PR, 1 confirmed) and Disease Control Rate (CR+PR+SD > 7 weeks) was 36.8%. The duration of response was 108 and 125 days in the 2 PRs. The median PFS was 57 days (MinMax: 28334, 95% CI: 45-135). CC122 treatment resulted in a median increase from baseline in peripheral blood activated and memory cytotoxic T cells by 64% (range: 17-213%, n = 6) and 78% (range: 30-111%, n = 6 (p < 0.05), respectively, and activated helper T cells by 106% (range: 62-218%, n = 7 (p < 0.05). CC122-activated T cells from the blood increased IFNg (2.73 fold; range: 0.45-26.1, n = 13) and IL2 (9.5 fold; range: 0.85-24.3, n = 11) production when compared to baseline (both P < 0.05) upon ex-vivo stimulation. Conclusions: CC122 3 mg QD appears to be well tolerated and activates cytotoxic T cells in HCC patients. Combination studies with sorafenib or nivolumab are recommended and underway. Clinical trial information: NCT01421524.
Tumor infiltrative pattern predicts sites of recurrence after curative gastrectomy for gastric cancer.
Authors: Kanda Mitsuro , Kobayashi Daisuke , Tanaka Chie , Yamada Suguru , Fujii Tsutomu , Nakayama Goro , Sugimoto Hiroyuki , Koike Masahiko , Fujiwara Michitaka , Kodera Yasuhiro
Published: March 2017

38

Background: In East Asia, the tumor infiltrative pattern (INF) has been routinely evaluated by hematoxylin and eosin-stained sections as a pathologic characteristic of surgically resected specimens. Methods: The infiltrative pattern of gastric cancer (GC) has been histopathologically classified as INFa (expansive growth), INFb (intermediate type) and INFc (infiltrative growth) according to the Japanese Classification of Gastric Carcinoma. The prognostic value and characteristics of the disease recurrence pattern for each INF type were assessed in 785 patients with various stages of GC and also in 243 patients with stages 2 and 3 GC. Results: Comparison of the overall survival experienced by patients independently of stage showed that INF was significantly associated with prognosis. Specifically, peritoneal metastasis was present in 91 % of stage 4 patients in the INFc group, whereas hepatic metastasis was present in 39 % of stage 4 patients in the INFa and INFb group. After curative gastrectomy of patients with stages 2 or 3 GC, INF was not significantly associated with survival. The prevalence of peritoneal recurrence was significantly higher in the INFc group than in the INFa and INFb group, whereas the prevalence of hepatic recurrence was significantly higher in the INFa and INFb group than in the INFc group. Multivariate analysis identified INFc as an independent risk factor for peritoneal recurrence after curative gastrectomy. The association of the INF type with the incidence of peritoneal recurrence was observed with all disease stages regardless whether the patient was given adjuvant chemotherapy or not. Conclusions: Evaluation of the INF type shows promise for its role as a predictor of postoperative recurrence sites in patients with GC.
A nomogram to predict pathologic lymph node positivity in clinical stage I-II pancreatic adenocarcinoma.
Authors: Swords Douglas S. , Zhang Chong , Presson Angela P. , Firpo Matthew A. , Mulvihill Sean J. , Scaife Courtney L.
Published: March 2017

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Background: Clinical nodal staging in PDAC is inaccurate. Most pts are cN0, but > 70% are pN+. We hypothesize that preoperative variables are associated with pN+ and could be used to create a predictive nomogram. Methods: The NCDB was reviewed from 2010-13 for pts with clinical stage I-II PDAC. Exclusions were neoadjuvant therapy, < 12 nodes examined, and missing data for clinical/pathologic stage, size, and number of nodes examined/positive. Logistic regression assessed factors associated with pN+ and an interaction was included for extrapancreatic extension and cN stage. A logistic regression based nomogram was constructed and 10-fold cross validation evaluated model discrimination. Results: Of 7,475 pts, 28% were cN+ but 74% were pN+ (P < 0.001). Associations of preoperative factors with pN+ are shown. Size was pathology based. We recommend multiplying imaging based size estimates by 1.33 for use in the nomogram based on studies showing that imaging underestimates size by 25%. Interestingly, extrapancreatic extension was protective for cN0 pts but associated with increased odds of pN+ for cN1 relative to cN0 ps. A nomogram was created to predict pN+ using these variables. The 10-fold cross validated AUC was 0.77. Conclusions: Our nomogram has good discrimination to preoperatively predict lymph node positivity for patients with resectable PDAC. It could potentially be useful in identifying biologically aggressive resectable PDAC pts at higher risk of pN+ in order to select pts for neoadjuvant therapy. [Table: see text]
Survival analysis of yttrium-90 radioembolization for unresectable intrahepatic cholangiocarcinoma.
Authors: Gangi Alexandra , Shah Jehan , Shridhar Ravi , Kumar Ambuj , Hoffe Sarah E. , Choi Junsung , Frakes Jessica M. , Springett Gregory M. , El-Haddad Ghassan , Anaya Daniel A. , Sweeney Jennifer , Biebel Benjamin , Malafa Mokenge Peter , Kim Richard D. , Kis Bela
Published: March 2017

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Background: Intrahepatic cholangiocarcinoma (ICC) is a rapidly progressing malignancy that frequently presents at an advanced stage and is often chemorefractory. The median overall survival (OS) with best medical treatment is approximately 12 months. The current study examines survival and characterizes predictors of mortality for ICC patients treated with transarterial yttrium-90 radioembolization (TARE). Methods: All patients with unresectable ICC who underwent TARE between May 2009 and May 2016 at a single institution were included and clinicopathologic variables reviewed. Primary endpoint was OS from time of TARE. Secondary endpoints included OS from time of diagnosis, post procedure toxicities and predictors of mortality. Results: A total of 134 TARE were performed on 85 patients. Average age at treatment was 73.4 ± 9.3 years and most patients were female (52%). More than one third of patients had an ECOG of 2 and had no significant post procedure sequalae. Thirty-six patients (42%) had extrahepatic disease at time of treatment and 61 patients (72%) were treated with systemic chemotherapy prior to TARE. A majority of patients (92.9%) received treatment to one lobe with an average radiation dose of 180.1±127.1 Gy. The median OS from time of the first TARE was 12 months (95% CI 7.8–16.1). The median OS from time of diagnosis was 21.4 months (95% CI 14.9-27.8). 51.8% and 26% of treated patients were still alive at 1 and 3 years, respectively. On univariate analysis, age at treatment, ECOG score, presence of extrahepatic disease, baseline albumin, alkaline phosphatase and AST correlated with OS. On multivariate analysis only low ECOG score and higher baseline albumin predicted improved OS (p < 0.01). Conclusions: Y90 radioembolization demonstrates a survival benefit for patients with unresectable ICC compared to historic controls of best medical treatment and should be considered an effective therapy in select patients. A multi-institutional randomized control trial should be performed to evaluate efficacy of TARE in select patients as both 1st line and salvage therapy.
Survival outcomes of adjuvant chemotherapy combined with radiation versus chemotherapy alone following pancreatectomy for distal pancreatic adenocarcinoma: Single institution experience.
Authors: Batukbhai Bhavina D O , Herman Joseph M. , Zahurak Marianna , Laheru Daniel A. , Le Dung T. , Wolfgang Christopher Lee , Zheng Lei , De Jesus-Acosta Ana
Published: March 2017

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Background: There is limited data of survival following distal pancreatectomy and adjuvant therapy in patients with distal pancreatic adenocarcinoma. This study aimed to evaluate the survival following combined modality (chemo-radiation and chemotherapy) compared to chemotherapy alone following distal pancreatectomy (DP). Methods: Patients who underwent DP for adenocarcinoma of the body or tail of the pancreas between the years 2000 and 2015 at Johns Hopkins were included. Comparison analysis was performed between patients who received combined modality versus chemotherapy alone. Kaplan- Meier curve was used to estimate the median overall survival (OS) and the disease free survival (DFS) at 1, 3 and 5 years after pancreatectomy. Results: A total of 294 patients underwent DP at our institution. Patients were excluded if adjuvant therapy was not administered, developed metastasis prior to adjuvant therapy, had stage IV disease at the time of surgery, received neoadjuvant therapy or had inadequate follow up at our institution to assess survival outcomes. We included a total of 105 patients, of which 45 patients received chemotherapy alone and 60 patients received combined modality. The two groups were similar with respect to nodal and margin status. Patients treated with combined modality had larger > 3cm tumors (p = 0.02). Median OS with combined modality was 60.6 mo and 50.2 mo with chemotherapy only. DFS was 15.2 mo with combined modality and 17.6 mo with chemotherapy only. There was no significant difference between the groups for OS (p = 0.73) or DFS (p = 0.495). Further analysis showed a trend away from chemoradiation in the recent years. Thirty patients (29%) received multi-agent chemotherapy in the adjuvant setting. A tumor diameter > 3cm was a predictive factor for receiving chemoradiation (chi-square p value 0.02). Conclusions: There is no difference in survival with combined modality compared to chemotherapy alone as adjuvant therapy following DP. All patients in this study received adjuvant therapy. We report a higher survival than previously described which could suggest a different biology for distal tumors.
Gemcitabine/taxane adjuvant therapy in resected pancreatic cancer: A signal of improved survival?
Authors: Kanji Zaheer S , Edwards Alicia M , Mandelson Margaret T , Lin Bruce , Badiozamani Kasra , Song Goubin , Alseidi Adnan , Biehl Thomas , Kozarek Richard A. , Helton William Scott , Picozzi Vincent J. , Rocha Flavio G.
Published: March 2017

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Background: Gemcitabine-taxane combination chemotherapy has demonstrated a survival benefit in metastatic pancreatic cancer (PC). We present our experience with gemcitabine/docetaxel (gem/tax) based adjuvant treatment (Rx) following curative intent surgery. Methods: Patients with upfront resectable PC from January 1, 2010 to December 31, 2015 were identified from our institutional database and tumor registry. We included resected patients who received gem/tax as initial Rx administered exclusively at our institution with or without chemoradiation (CRTx). Patients were excluded if they died or recurred prior to Rx or received neoadjuvant Rx. Survival was estimated by Kaplan-Meier methods and prognostic factors identified by Cox regression. Results: Of 185 eligible patients, 58 met study criteria. Characteristics included: median age of diagnosis 64.9 years, female gender 56.9%, Whipple procedure 69% and R1 resection in 55.2%%. Tumour characteristics included: median size 28.0mm, poor differentiation 53.5% and AJCC stage 2A/2B 27.6%/67.2%. Patients completing ≥ 80% of 24 week Rx was 89.7% (n = 52). Of those patients, 71.2% received post gem/tax CRTx. With a 51.2 month median follow-up (95%CI: 37.1-55.7), median disease-free survival (DFS) and overall survival (OS) were 35 months (95%CI: 20.7-NR) and 52.3 months (95%CI: 27.4-NR), respectively. Five year OS was 49.5% (95%CI: 33.7-63.4). Patients receiving CRTx (n = 37) had a superior OS compared to patients who only completed gem/tax Rx (n = 15)(61.5 vs. 26.7 months, p = 0.04). Prognostic variables impacting OS on multivariate analysis (HR, 95%CI) included: margin status (4.55, 1.46-14.2, p = 0.01), AJCC stage (10.9, 2.46-47.9, p = 0.002) and administration of CRTx (0.08, 0.03-0.24, p < 0.000). Variables impacting DFS included: AJCC stage (3.29, 1.15-9.41, p = 0.03), tumour size (2.59, 1.11-6.04, p = 0.03) and administration of CRTx (0.23, 0.09-0.56, p = 0.001). Conclusions: In this select cohort of resected PC patients with adverse pathologic features, adjuvant gem/tax with or without CRTx is feasible with favorable DFS and OS. These findings support further prospective studies of gem/taxane-based adjuvant Rx in PC.
Retrospective cohort analysis of neoadjuvant treatment and survival in resectable and borderline resectable pancreatic ductal adenocarcinoma in a high-volume referral centre.
Authors: Itchins Malinda , Arena Jennifer , Rabindran Joel , Christopher Nahm , Kim Sia , Gibbs Emma , Gill Anthony J. , Maher Richard , Schembri Geoffrey , Bailey Elizabeth , Mittal Anubhav , Bergamin Sarah , Wong Matthew , Hruby George , Kneebone Andrew , Pavlakis Nick , Samra Jaswinder S. , Clarke Stephen
Published: March 2017

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Background: The 5 year (yr) overall survival (OS) of pancreas cancer (PC) is < 5%. Surgical resection is the only curative treatment (tx), most relapse within 2yrs. Neoadjuvant (NA) tx can benefit by eradicating micro-metastases, avoids futile surgery if metastases develop, improves dose intensity and may down stage disease. Currently, there are no data that clearly demonstrate improved OS with NA tx. Randomised trials are in progress. Methods: A retrospective analysis of all patients (pts) who received NA therapy across campuses,in Sydney, was performed. Pt records were identified and all were discussed in a MDT by a panel of PC specialists. Results: 588 PC pts were treated between August 2011-July 2016. After consideration of anatomy, pt characteristics and preference 82 pts (14%) received NA tx, 30% were resected upfront. 26 pts were ‘borderline’ and received sequential chemo-radiotherapy (ctxRT). Median age at diagnosis (dx) was 73 yrs, 50% were men. Median follow up time was 31.2 months (m). 84% pts were resected. There was 1 death at 90 days. An R0 was achieved in 74%. A detailed tx overview will be provided. Most received gemcitabine/abraxane. For those who had PET, low SUV pre-operative correlated with high pathological regression score, 3 pts 0%. Median OS for all pts was 25.9 m (95% CI 21.2, 30.2). Survival by stage: 1- 21.2 mo (11.8, 29.5); 2- 25.2 m; stage 3-4 (not reached). Pts who received ctx alone OS 25.3mo (17.2,29.5); ctxRT 29.0 m (17.3, NA) (p = 0.03). R0 survival was 29.0 m (21.2, NA) and R1, 23 m. 30% were alive at 3 yrs. Time to recurrence was 22.3 m (14.3, NA). Weight > 74kg was predictive of survival; OS 23.0 m v 29.5m (p = 0.002). There was a trend to survival benefit in females (p = 0.099) and baseline LDH < 280 (IU/L) (p = 0.07). Age at dx, ECOG (0 v 1), baseline albumin, bilirubin, Ca 19.9, NLR ( < 3.1) and CRP and stage at dx were not predictive of survival. Conclusions: This pt cohort demonstrates superior survival with NA therapy in selected pts across stages in a high volume multi-disciplinary PC centre. Outside a clinical trial, NA therapy is evolving to be our standard of care in fit pts with any degree of vessel involvement.
Nab-paclitaxel (Nab-P) and gemcitabine (G) first-line chemotherapy (CT) in patients (pts) with metastatic pancreatic cancer (mPC) who relapsed after adjuvant treatment (ADJ T): A “REAL LIFE” study.
Authors: Giordano Guido , Milella Michele , Lo Re Giovanni , Di Marco Mariacristina , Melisi Davide , Passardi Alessandro , Febbraro Antonio , Iop Aldo , Vaccaro Vanja , Foltran Luisa , Bertocchi Paola , Bergamo Francesca , Vecchiarelli Silvia , Giommoni Elisa , Ricci Vincenzo , Aloi Maria Bernardetta , Vasile Enrico , Zaniboni Alberto , Zagonel Vittorina , De Vita Ferdinando
Published: March 2017

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Background: Nab-P and G represents a standard of care in first line mPC treatment. Only 5% of pts in Nab-P + G arm received ADJ T in the MPACT phase III trial. Accordingly, there is a lack of information about Nab-P + G benefit in this population. Aim of this analysis was to evaluate outcomes in mPC “real life” pts receiving first-line Nab-P + G after relapsing from ADJ T. Methods: Clinical records of 330 mPC pts receiving Nab-P + G with standard schedule as first line CT were retrospectively reviewed, investigating, efficacy (Progression Free Survival, PFS and Overall Survival, OS defined as time elapsed from the start of Nab-P + G to progression or death respectively) in pts treated with prior ADJ T. Analysis was then performed in ADJ T subgroup according disease free survival (DFS) cut-off ( ≤ 6 vs 6-12 vs ≥ 12 months). OS and PFS were estimated with Kaplan-Meyer method with 95% CI. Cox-regression model was applied to the data with univariate and multivariate approach. Results: At time of data analysis in the entire cohort median (m) OS was 11.3 months (95% CI 9.157-13.443); mPFS 7 months (95% CI 5.827-8.173). 90 out of 330 pts (27.3%) had received G-based ADJ T with mDFS of 29.2 months (95% CI 25.62-32.78). In the overall population at multivariate analysis, ADJ treatment was an independent prognostic factor related to better OS (HR 0.53, 95% CI 0.40-0.66; p < 0.001) and PFS (HR 0.69, 95% CI 0.49-0.89; p = 0.024). Median OS in ADJ T pts was significantly higher than pts who had not received ADJ T (15.0 vs 10.8 months respectively; p = 0.012). A similar trend in mPFS was observed in ADJ T versus non ADJ T pts (8.6 vs 6.9 months; p = 0.06). Pts with longer DFS after ADJ T showed major benefit in mOS (16.3 vs 13.1 vs 8.7 months in ≥ 12 vs 6-12 vs ≤ 6 months DFS respectively; p < 0.001). No significant differences in mPFS were observed in the three subgroups (p = 0.271). Conclusions: Nab-P + G is a standard of care also in pts treated with ADJ T. ADJ treatment is an independent prognostic factor related to better survival, maybe reflecting the effect of prior radical surgery. Pts who received G-based ADJ T may benefit of Nab-P+G combination with an increased survival in pts with longer DFS.