bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer: Clinical update on long term survival and biomarker correlates to overall survival.
Authors: Whiting Chan , Lutz Eric , Nair Nitya , Chang Serena , Lemmens Ed , Chen Shih- Yu , Solt Sara , Ferber Sandy , Maecker Holden , Murphy Aimee , Brockstedt Dirk G. , Jaffee Elizabeth M. , Le Dung T.
Published: February 2017

261

Background: In a phase 2a randomized study, metastatic pancreatic ductal adenocarcinoma (PDA) patients treated sequentially with two vaccine-based immunotherapies showed extended overall survival (OS) with tolerable side effects. Treatment included low-dose cyclophosphamide (CY) to inhibit T-regulatory cells prior to GVAX, an irradiated GM-CSF-secreting allogeneic PDA cell vaccine, which activates a broad antigenic response, followed by CRS-207, a live-attenuated, mesothelin-expressing Listeria monocytogenes vaccine which stimulates innate and adaptive immunity. Methods: Patients were enrolled with metastatic PDA who received or refused ≥1 prior chemotherapy, had ECOG ≤1 and adequate organ function. Patients were randomized 2:1 to receive 2 doses of CY/GVAX followed by 4 doses of CRS-207 (Arm A) or 6 doses of CY/GVAX (Arm B). PBMC and serum were collected over the course of treatment for immune and biomarker analyses. CyTOF, ELISPOT, and luminex were used to identify biomarker correlates of OS. Results: We previously reported phase 2a results demonstrating median OS in patients treated in arm A was 6.1 months compared to 3.9 months for those in arm B (HR=0.54, one-sided p=0.011). As of August 2014, 8 patients are still alive (median time on study: 768 days; range: 596-880), with 3 subjects on combination treatment. Mesothelin-specific CD8+T cell responses following CY/GVAX correlated with improved OS in both arms. Elevated frequencies of T cell subsets and a panel of baseline serum cytokines also correlated with longer OS. Strikingly, hierarchical clustering based on expression of biomarkers showed significant clustering of patients according to OS. Conclusions: Treatment with CY/GVAX and CRS-207 was well-tolerated and resulted in improved OS compared to CY/GVAX alone. A larger phase 2b, 3-arm, randomized trial is ongoing and plans to treat 240 adults with previously-treated metastatic PDA with CY/GVAX and CRS-207, CRS-207 alone, or standard chemotherapy. Preliminary results using patients’ PBMCs and sera revealed potential biomarkers for OS. Clinical trial information: NCT01417000. Clinical trial information: NCT01417000.
A phase II study of palbociclib (PD-0332991) in adult patients with advanced hepatocellular carcinoma.
Authors: Littman Susan Joy , Brus Christina , Burkart Ashlie
Published: February 2017

277

Background: The oral MKI sorafenib has been shown to significantly increase PFS, OS and DCR in treatment-naïve HCC in randomized Ph 3 trials. Despite these landmark studies OS benefit is modest, particularly for those with C-P cirrhosis grades B/C and toxicity is a major management problem. We report results of second-line treatment with palbociclib, PD-0332991, an orally available selective inhibitor of cyclin dependent kinases 4 and 6, which has potent anti-proliferative activity in pre-clinical studies. Methods: This is an open-label, nonrandomized single institution trial for pts with inoperable, advanced HCC, who have failed or are intolerant of first line therapy with sorafenib. Eligible subjects were treated with 125 mg PD-0332991 orally/day, 1-21 of a 28-day cycle, until disease progression, unacceptable toxicity, withdrawal from study or death. Tumor response by CT or MRI was assessed using mRECIST v1.1. Toxicity assessments were per NCI CTCAE v4.0. The primary endpoint is TTP. Secondary endpoints are safety/tolerability, OS & RR. Results: 21 pts (18 M, 3 F) have been enrolled. Median age: 62 (32-78) yrs. 47% Cauc, 19% AA and 33% Asian. 17 C-P A, 4 C-P B. ETOH 19%, HCV 48%, HBV 24%, NASH 5%, unknown 10%. 71% had >1 metastatic site. All had pathologically confirmed Retinoblastoma-positive HCC. Median duration of therapy was 17 (8-69) wks and (4.25 (2-17) cycles. Most common grade 3/4 AEs were neutropenia and thrombocytopenia. Non-serious AEs were anemia, pain, ascites and fatigue. 4 pts were non-evaluable, median OS = 10.5 (5.5-14) wks. In evaluable pts, there was 1 PR and 0 CRs. 6 pts died of ESLD without observable disease progression by RECIST, median OS = 19 (4 - 43) wks. Nine pts had disease control (PR or SD) followed by disease progression, median TTP was 24 (4-64) wks. Prolonged stability was seen in 3 pts. OS was 40 (24-96) wks, excluding 2 pts who are alive at 120 and 59 wks. 2 pts remain on trial. Conclusions: Palbociclib demonstrates activity in patients with advanced HCC after failure of first-line sorafenib. This trial will meet its primary endpoint. Consistent with a cytostatic MOA, some pts experienced HCC stabilization and OS was determined by ESLD. Palbociclib is well tolerated in cirrhotic patients with advanced HCC. Clinical trial information: NCT01356628.
Final results of phase Ib of anticancer stem cell antibody tarextumab (OMP-59R5, TRXT, anti-Notch 2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).
Authors: O'Reilly Eileen Mary , Smith Lon S. , Bendell Johanna C. , Strickler John H. , Zalupski Mark , Gluck William , Kapoun Ann , Yen Wan-Ching , Xu Lu , Hill Dawn , Zhou Lei , Dupont Jakob , Cohn Allen Lee
Published: February 2017

278

Background: Tarextumab (TRXT), fully human IgG2 antibody, inhibits signaling Notch 2, 3 receptors. Tumor regression seen in Notch 3 patient-derived PC xenografts when TRXT added to Nab-P+Gem. The maximum tolerated dose (MTD) of single agent TRXT was 7.5mg/kg every other week (Smith, EORTC 2012); the main dose limiting toxicity (DLT) was Grade 3 diarrhea. This study evaluates MTD, pharmacokinetics (PK), pharmacodynamics (PD) and early efficacy of TRXT + Nab-P+Gem in mPC. Methods: Cohorts of 3-6 pts treated at 6 dose levels of TRXT. TRXT IV Days 1 + 15 with GEM 1000mg/m2 alone (first two cohorts) or nab-P 125 mg/m2 and GEM 1000mg/m2on Days 1, 8, 15 of every 28-day cycle. Biomarker analysis of surrogate tissue and tumor undertaken. Results: By 08/22/14, N= 40 treated. TRXT 15 mg/kg selected as Phase 2 dose. 1 DLT Grade 3 diarrhea in 15 mg/kg cohort. Frequently reported (≥15%) TRXT adverse events(AEs) were: diarrhea(60%), fatigue(43%), anemia(28%), decreased appetite (18%) and nausea(15%); most grade 1 or 2 and managed supportively. Other AEs (≥ 30%) were: cytopenia, alopecia, vomitng and peripheral edema. GEM or Nab-P+Gem did not alter PK of TRXT. Notch pathway-related genes, HEYL, HES2, NOTCH2 and cancer stem cell markers were altered in hair follicles at TRXT > 7.5 mg/kg combined with Nab-P+Gem. Plasma, blood RNA biomarkers were also modulated by TRXT + Nab-P+Gem. Conclusions: TRXT + Nab-P+ Gem is well tolerated. 15 mg/kg is the selected Phase 2 dose of TRXT. Encouraging anti-tumor activity was observed. Final safety, efficacy, PK and PD results in surrogate and serial tumor tissues will be presented. The Phase 2 randomized, placebo-controlled ALPINE study is underway. Clinical trial information: NCT01647828. [Table: see text]
Comparative circulating tumor DNA levels for KRAS mutations in patients with nonresectable pancreatic cancer.
Authors: Johansen Julia S. , Vibat Cecile Rose T. , Calatayud Dan , Jensen Benny Vittrup , Hasselby Jane Preuss , Collisson Eric Andrew , Lu Timothy , Poole Jason C. , Erlander Mark
Published: February 2017

288

Background: Non-resectable pancreatic cancer patients have a wide range of median time for overall survival (OS). Currently there is a lack of diagnostic tools to predict patient outcome at diagnosis. KRAS mutations are present in the vast majority of pancreatic tumors. The study objective was to determine if quantitative baseline and longitudinal monitoring of KRAS mutations from plasma circulating tumor DNA (ctDNA) could be used to stratify patients for predicting outcome. Methods: Plasma was prospectively collected from the Danish BIOPAC study for non-resectable pancreatic cancer patients undergoing treatment with gemcitabine or FOLFIRINOX. Feasibility of monitoring ctDNA KRAS mutations was assessed in 10 patients with long OS (median 493 days; range 360-1031) and 10 patients with short OS (median 66 days; range 21-136). KRAS G12A/C/D/R/S/V, and G13D mutations were PCR enriched, sequenced by massively parallel deep sequencing, quantitated and standardized by reporting number of copies detected per 105 genome equivalents (GE). Results: In a pilot study of 20 patients, all 18 patients with evaluable DNA had detectable KRAS mutations. Of 18 patients, 12 had baseline plus longitudinal time points (7 short, 5 long OS). Mutant KRAS copies were higher for short OS (median=994; range 0-34305 copies/105 GE) vs. with long OS (median 196; range, 34-278 copies/105 GE). Longitudinally, KRAS mutation levels remained mostly low with long OS (last time point median 204; range 8-873 copies/105 GE) vs. short OS where levels increased or remained high (median 2363; range 71-47919 copies/105 GE). Identical KRAS mutations were consistently detected for a given patient with short OS. However, long OS patients had variable KRAS mutations in longitudinal analysis. Conclusions: High levels of ctDNA KRAS mutations at diagnosis and post-treatment elevation of KRAS mutations were more associated with short OS. Different levels of KRAS mutation at diagnosis may predict patient outcome and could reflect distinct underlying tumor biology. Expansion of this prospective-retrospective biomarker cohort will be reported.
A multinational assessment of gastric and esophageal cancer burden by age, gender, and disease characteristics.
Authors: Lowe Kimberly A , Katz Aaron , Kelsh Michael A. , Vaughan Thomas L.
Published: February 2017

29

Background: Gastric and esophageal cancers are the fourth and eighth most common cancers worldwide, with an estimated 1.5 million new cases combined in 2008. A comprehensive, international comparison of the descriptive epidemiology of these diseases is lacking. The objectives of this study are to (1) characterize the current and projected incidence rates and the current case fatality of these cancer types by age and gender within countries in Europe, Asia, the Americas, Oceania, and Africa; (2) describe the temporal variation in cardia and non-cardia gastric cancer and squamous and adenocarcinoma esophageal cancer in the U.S. by age and gender. Methods: Data from GLOBOCAN were used to calculate country-specific incidence rates (per 100,000) for 2012, 2015, and 2025, and the country-specific case fatality (%) in 2012. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program in the U.S. were used to estimate gastric cancer incidence rates from 2004-2011 (per 100,000) and 12-month survival (%) stratified by gender, age (0-64/65+), stage at diagnosis, gastric cancer subtype, and esophageal cancer histology. Joinpoint regression was used to quantify changes in the Average Annual Percent Change (AAPC) in these outcomes. Results: GLOBOCAN results showed wide geographic variation in gastric and esophageal cancer incidence rates. In most countries, the case-fatality among males and females 65+ years was > 60%. In the U.S., the annual incidence of all gastric cancer subtypes decreased significantly among males and females 65+ (AAPC= -2.4% & -1.6%, respectively). Esophageal cancer incidence decreased in both genders and age groups, with a significant decline observed among females 65+ with squamous histology (-3.5%). Twelve-month survival in esophageal cancer showed modest improvements, with a significant increase observed among males 65+ with adenocarcinoma histology (2.0%). Conclusions: The worldwide burden of gastric and esophageal cancers is substantial. In the U.S., declines in incidence and modest improvements in survival of these cancers were observed.
Genomic change index (GCI) and liquid biopsies in predicting and monitoring response to therapy in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Kundranda Madappa N. , Beck Julia , Braun Donald Peter , Urnovitz Howard B. , Mitchell William Marvin , Schütz Ekkehard
Published: February 2017

309

Background: Advanced PDAC is a lethal disease with dismal 5 year survival. The current modalities for monitoring therapy response using serum (CA) 19-9 levels have poor specificity and radiological responses have long lag times. Tests for rapid and accurate clinical assessment are needed for early decision making. Methods: 5 patients (pts) with locally advanced unresectable or metastatic PDAC were treated with gemcitabine and nab-Paclitaxel on a bi-weekly schedule. Tumor tissue was collected at baseline and plasma was collected at each cycle (3 time points). Tumor tissue and leukocyte DNA was used to prepare shotgun sequencing libraries and PCR-based enrichment of 124 genes for paired-end high-throughput sequencing. Copy-number variations were called by comparing tumor vs. leukocytes read counts in genomic windows. Algorithms were used to quantify a Genomic Change Index (GCI) from selected variations of the cancer genome. Somatic mutations were quantified in cell-free plasma DNA (cfDNA) of 3 pts using droplet digital PCR (ddPCR) as a function of treatment. Results: Of the 5 pts evaluated, the lowest GCI’s (<10) was present in a non-responding (NR) pt receiving chemotherapy. 4 pts with varying degrees of clinical, biochemical and radiological (ranging from partial (PR) to stable disease (SD) to complete (CR)] responses, showed elevated GCIs (≥15). Detected tumor mutations were followed by liquid biopsies. In a patient with SD, mutKRAS and mutTP53 cfDNA copies of 20-80 per mL plasma (cp/mL) did not significantly change over time. In a patient with CR and >70% decrease in CA19-9; no copies of mutKRAS and 4-10 cp/mL mutTP53 were detected at the 3 time points measured. In a pt with PR and rising CA19-9, there was also an increase in mutKRAS and mutTP53 cp/mL. Conclusions: 1.) Our pilot study indicates that GCI may be similarly predictive of PDAC response to therapy as we have previously reported with head/neck and colorectal carcinomas. 2.) ddPCR has sufficient sensitivity to monitor tumor mutations in the plasma of PDAC pts and could provide a specific biomarker to monitor response. Both tests are currently being validated with longer follow up and larger number of patients.
Relationship of programmed death 1 (PD-1) expression to the recurrence in gastric cancer.
Authors: Eto Shohei , Iwata Takashi , Yoshikawa Kozo , Higashijima Jun , Nakao Toshihiro , Nishi Masaaki , Takasu Chie , Shimada Mitsuo
Published: February 2017

31

Background: PD-1 (Programmed Death 1), a member of the B7-CD28 family, is a cell surface coinhibitory receptor expressed on T cells, B cells, monocytes, and natural killer T cells, following activation. Recently, PD-1 expression is involved with malignancy have been reported in cancer cells and virus-infected cells. The aim of this study is to clarify the impact of PD-1 expression on long term outcome of gastric cancer. Methods: Total of 105 patients who were performed gastrectomy in Stage 2/3 gastric cancer. For resected specimen was performed immunostaining of PD-1. We counted PD-1 positive T cells in the tumor across five adjoining high power fields (×400 magnification level). And, we calculated the percentage of the total cell number, it was considered PD-1 positive more than 40%. We investigated clinicopathological factors and survival. Results: 28 cases were PD-1 positive expression. There was no significant difference between the two groups in the clinicopathological factors (age, gender, tumor size, differentiation, depth of invasion, lymph node metastasis, stage, lymphatic invasion and venous invasion). There was no difference in overall survival rate at 3 years (PD-1 positive vs. negative 76% vs. 81%, p=0.552). PD-1 positive expression was significantly poorer in disease-free survival rate (36% vs. 65%, p=0.022). 10 cases were Foxp3 positive expression, and Foxp3 positive expression was related with PD-1 expression. Conclusions: The PD-1 expression in the tumor could be a potential prognostic factor in gastric cancer.
Sunitinib as second-line treatment in patients with advanced intrahepatic cholangiocarcinoma (SUN-CK phase II trial): Safety, efficacy, and updated translational results.
Authors: Neuzillet Cindy , Seitz Jean-François , Fartoux Laetitia , Malka David , Lledo Gérard , Tijeras-Raballand Annemilai , De Gramont Armand , Ronot Maxime , Bouattour Mohamed , Dreyer Chantal , Amin Alexandre , Brunisholz - Bourget Philippe , Hadengue Alexandra , Roldan Nelly , Chibaudel Benoist , Raymond Eric , Faivre Sandrine J.
Published: February 2017

343

Background: There is no validated option beyond gemcitabine plus platinum standard first-line combination for advanced cholangiocarcinoma (CK). Second-line 5FU-based chemotherapy yields a median progression-free survival (PFS) and overall survival (OS) of 3 and 6-7 months, respectively. Intrahepatic CK subtypes overexpress VEGF, providing a rationale for testing sunitinib as second-line treatment in patients (pts) with advanced intrahepatic CK. Methods: A multicenter phase 2 study was designed for pts with locally advanced or metastatic intrahepatic CK after failure of first-line gemcitabine-based chemotherapy. Sunitinib was given at the dose of 37.5 mg/day continuously until disease progression or limiting toxicity. Pts were required to be ECOG PS 0-1 and with adequate liver function (alkaline phosphatase and transaminases < 5ULN, bilirubin <1.5ULN). Main objective was to exceed a median OS of 6.3 months. Secondary endpoints were PFS, response (RECIST 1.1 & Choi criteria), safety, pharmacokinetics (PK) and biomarker analysis (VEGFA, VEGFC, sKIT, HGF, SDF1, and osteopontin). Results: 53 pts were enrolled, with 34 pts evaluable for intermediate safety and efficacy analysis. Median age was 62 years (range 36–80), with 19 females/15 males. ECOG PS was 0/1 in 23/11 pts. Sixteen pts had prior surgical resection and 8 pts received adjuvant chemotherapy. Five pts (15%) had partial responses and 24 stable diseases (71%) by RECIST (disease control rate 85%). Ten pts had disease control > 6 months (range 6-14 months). With a median follow-up of 15.4 months, median OS was 9.6 months [95%CI: 5.8-13.1]. Median PFS was 5.2 months. Frequent adverse events were grade (Gr) 1-2 asthenia (80% of pts), mucositis (80%), diarrhea (60%), and hand-foot syndrome (43%). Gr 3/4 asymptomatic hematological toxicity occurred in 25% of pts (neutropenia n=8, thrombocytopenia n=7), Gr 3 hypertension was observed in 7 pts, and Gr 3 asthenia in 4 pts. Updated PK and biomarker analysis will be presented at the meeting. Conclusions: Second line sunitinib is well tolerated and shows promising activity with a 9.6-month OS in pts with advanced intrahepatic CK. Clinical trial information: NCT01718327.
Phase II study of preoperation mFOLFIRINOX and chemoradiation for high-risk resectable and borderline resectable pancreatic adenocarcinoma.
Authors: Varadhachary Gauri R. , Fleming Jason B. , Crane Christopher H. , Fogelman David R. , Shroff Rachna T. , Lee Jeffrey Edwin , Lee Jeffrey H. , Tamm Eric P. , Bhosale Priya , Das Prajnan , Krishnan Sunil , Javle Milind M. , Weston Brian , Wang Huamin , Wolff Robert A. , Katz Matthew H. G.
Published: February 2017

362

Background: Patients with high risk resectable and borderline resectable pancreatic adenocarcinoma (BRPC) are at a high risk for R1/R2 resection, early relapse with upfront surgery and poor OS. Preop therapy has a sound rationale and current retrospective data suggest resection rates of 40-60% with a possible impact on OS. Methods: We planned a prospective study of 33 pts. Eligibility includes diagnosis of pancreatic ductal carcinoma (PC) and >=1 criteria of BRPC (radiographic) A: (i) PC involves SMV with vein deformity or segmental occlusion; (ii) PC involves <=1800 SMA, CA or its branches (iii) abutment or encased short segment of CHA and/or BRPC (high-risk) B: (iv) CA19-9 >=500 mg/dl (v) malignant peripancreatic nodes outside planned surgical field (vi) indeterminate liver or peritoneal lesions. Enrolled pts receive mFOLFIRINOX (oxaliplatin 75 mg/m2 d1+ irinotecan 150 mg/m2 d1+ 5-FU 2000mg/m2 46h CI) for 6 cycles. Those without progression & good PS undergo EBRT 50.4Gy with weekly Gemcitabine 350 mg/m2. Surgery is planned 4-6 weeks after CRT in pts without progression. Results: 24/33 pts accrued. 18(75%) with A criteria alone; 1(4%) with B criteria alone and 5 (21%) with both. Median age is 66 yrs; ECOG PS0 42%, PS1 58%. Median CA19-9 is 219 (1-1185) mg/dl. 20/24 have completed all preop therapy and 10 underwent surgery (50%).10 patients did not proceed to surgery due to disease progression (5), poor PS (3) or withdrawal of consent (2). Grade ¾ hematologic and non-hematologic toxicity noted in 8/21 (38%). Of the 10 resected pts, all underwent vein reconstruction and R0 rate is 80%. Major pathologic response rate (>50 % tumor kill) was 30%. One (bleeding) major complication occurred within 90 d of surgery. 5/10 resected pts relapsed <1yr after surgery with a median TTP from surgery of 5mo (3-7mo). SMAD4 and CTC analysis pending. Conclusions: Although the sample size is limited, using strict criteria, resection rates with preop FOLFIRINOX and Gem-RT mirror retrospective data (50%). Half of the resected pts have recurred early suggesting aggressive preop therapy does not rescue aggressive biology. Further analysis may allow identification of pts who are poor candidates for an aggressive preop approach. Clinical trial information: NCT01560949.
Effects of lanreotide autogel/depot (LAN) in patients with neuroendocrine tumors (NETs) age 65 or younger versus older than age 65: Subgroup analyses from the CLARINET study.
Authors: Phan Alexandria T. , Caplin Martyn E. , Pavel Marianne E. , Cwikla Jaroslaw B , Raderer Markus , Sedláčková Eva , Cadiot Guillaume , Wolin Edward M. , Capdevila Jaume , Wall Lucy , Rindi Guido , Langley Alison , Gomez-Panzani Edda , Ruszniewski Philippe B. ,   on behalf of the CLARINET Study Group
Published: February 2017

367

Background: The somatostatin analog lanreotide Autogel 120 mg significantly prolonged progression-free survival (PFS) vs. placebo (PBO) in patients with metastatic grade 1 or 2 (Ki-67 <10%) non-functioning enteropancreatic NETs (hazard ratio [HR] for progressive disease [PD]/death: 0.47 [95% CI: 0.30, 0.73]). The large size of the trial (n=204) affords an opportunity to examine treatment effects within subgroups of particular interest. Here, we compare PFS and safety data for patients aged ≤65 years vs. aged >65 years. Methods: In this 96-week randomized double-blind trial, patients received LAN 120 mg or PBO every 4 weeks by deep s.c. injection (NCT00353496). Subgroup analyses were undertaken to investigate only the consistency of treatment effects as the study was not otherwise designed or powered for such analyses. Results: Median age (range) was 57 years (30, 65) for thegroup aged ≤65 years and 71 years (66, 92) for the group aged >65 years. Other baseline characteristics were similar between age groups, including tumor origins (≤65 years: pancreatic 43%, midgut 34%; >65 years: pancreatic 46%, midgut 38%) and hepatic tumor loads (>25%: 30% and 37% for ≤65 and >65 years, respectively). Disease was predominantly stable at baseline (94% vs. 98%, respectively). Therapeutic effects of LAN on PFS were similar for the age groups and there were no consistent differences in tolerabilities between age groups (Table). The most common AE was diarrhea irrespective of age and treatment (≤65 years: LAN 36%, PBO 32%; >65 years: LAN 33%, PBO 40%). Conclusions: The treatment effect with LAN in terms of PFS was consistent across age groups and LAN tolerability/safety was favorable in both cases. Clinical trial information: NCT00353496. [Table: see text]
Effect of coadministration of propranolol and etodolac (VT-122) plus sorafenib for patients with advanced hepatocellular carcinoma (HCC).
Authors: de la Torre Andrew N , Castaneda Ismael , Hezel Aram F. , Bascomb Newell F. , Bhattacharyya Gouri Shankar , Abou-Alfa Ghassan K.
Published: February 2017

390

Background: Propranolol and etodolac (designated VT-122) target the adrenergic and prostaglandin stress systems activated in HCC. These stress-induced systems are proposed to induce changes in the tumor microenvironment and immune system leading to tumor promotion and immune tolerance. In a separate study, administration of VT-122 prior to sorafenib showed an increase in median overall survival (OS) of 21 months when VT-122 is administered before sorafenib compared to 10 months OS for sorafenib alone. The aim of the current study was to evaluate the effect of administering VT-122 at least 30 days after starting sorafenib. Methods: Patients with HCC receiving sorafenib for at least 30 days were eligible for this double-blind, placebo-controlled study. Patients were randomized to receive sorafenib with either VT-122 or placebo. Patients received therapy for up to 12 months or until treatment failure. VT-122 was administered twice daily. The primary endpoint was duration of therapy (DoT) and the secondary endpoint was OS. Results: Twenty patients were randomized, 11 and 9 patients to the VT122 and placebo arm, respectively. Each arm was balanced with regards to age (mean of 60.4 years), Child Pugh status (9 Child Pugh A, 11 Child Pugh B7), hepatitis virus status (6 HBV and 1 HCV positive) and C-reactive protein (CRP) (20.4 mg/L). VT122 with sorafenib was well tolerated with no unexpected serious adverse events reported. Mean OS was 13.9 months and 9.6 months in the VT-122 and placebo arms, respectively. Mean DoT (unvalidated) was 10.1 months and 7.5 months in the VT-122 and placebo arms, respectively. Conclusions: Co-administration of VT-122 with sorafenib was well tolerated and showed an increase in duration of therapy and OS versus sorafenib alone. The small sample size and number of events precludes the ability to make any significant efficacy conclusions. The increase in survival was not as great as that seen in a separate study in which VT122 was started prior to sorafenib. A further Phase 3 study of VT122 administered prior to sorafenib in patients with HCC is warranted. Clinical trial information: NCT01265576.
Morbidity and mortality after laparoscopy-assisted and open distal gastrectomy for stage I gastric cancer: Results from a multicenter randomized controlled trial (KLASS-01).
Authors: Lee Hyuk-Joon , Kim Hyung-Ho , Han Sang Uk , Kim Min-Chan , Hyung Woo Jin , Ryu Seung Wan , Cho Gyu Seok , Kim Chan Young , Yang Han-Kwang , Park Do Joong , Song Kyo Young , Lee Sang Il , Ryu Seung Yub , Lee Joo-Ho , Kim Wook ,   Korean Laparo-endoscopic Gastrointestinal Surgery Study Group (KLASS)
Published: February 2017

4

Background: Laparoscopy assisted distal gastrectomy (LADG) is widely performed for gastric cancer in Eastern countries, although large scale prospective data are still lacking. We conducted a phase III, multicenter randomized controlled trial (KLASS-01) to compare the short and long term outcomes of LADG versus open distal gastrectomy (ODG) in patients with clinical stage I gastric cancer in Korea. Methods: The primary end point was 5-year overall survival. The morbidity within 30 postoperative days and the surgical mortality were compared to evaluate the safety of LADG as a secondary end point. A total of 1,416 patients were randomly assigned to the LADG group (n = 705) or the ODG group (n = 711) between Feb 1, 2006 and Aug 31, 2010. Results: 1,256 were eligible for per protocol (PP) analysis (644 and 612, respectively). The overall complication rate was significantly lower in the LADG group (LADG vs. ODG; 13.0% vs. 19.9%, P =.001). In detail, the wound complication rate of the LADG group was significantly lower than that of the ODG group (3.1% vs. 7.7%, P <.001). The major intra-abdominal complication (7.6% vs. 10.3%, P =.095) and mortality rates (0.6% vs. 0.3%, P =.450) were similar between groups. Modified intention-to-treat analysis showed similar results with PP analysis. Conclusions: LADG for patients with clinical stage I gastric cancer is safe and has a benefit of lower occurrence of wound complication compared with conventional ODG. Clinical trial information: NCT00452751.
Impact of postoperative complications on pancreatic cancer survival and recurrence.
Authors: Asari Masahiro , Aoyama Toru , Katayama Yusuke , Murakawa Masaaki , Yamaoku Koichiro , Kanazawa Amane , Higuchi Akio , Shiozawa Manabu , Ueno Makoto , Morimoto Manabu , Akaike Makoto , Hayashi Tsutomu , Yamamoto Naoto , Oshima Takashi , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka , Morinaga Soichiro
Published: February 2017

446

Background: We investigated the impact of postoperative complications on pancreatic cancer survival and recurrence after curative surgery. Methods: This study included 164 patients who underwent curative surgery for pancreatic cancer between 2005 and 2014. The patients were classified into those with postoperative complications (C group) and those without postoperative complications (NC group). The risk factors for overall survival (OS) and recurrence-free survival (RFS) were identified. Results: Postoperative complications were found in 61 of the 164 patients (37.2%). The RFS rate at five years after surgery was 10.6% in the C group patients and was 21.0% in the NC group patients. The RFS tended to be worse in the C group than in the NC group (p=0.1756). The OS rate at five years after surgery was 7.4% in the C group and 22.8% in the NC group, which was significantly different (p=0.0189). The multivariate analysis demonstrated that postoperative complications and lymphatic invasion were significant independent risk factors for the RFS and OS. Conclusions: The development of postoperative complications was a risk factor for a decreased overall survival and for disease recurrence in patients who underwent curative surgery for pancreatic cancer. The surgical procedure, perioperative care and the surgical strategy should be carefully planned to avoid complications.
Safety and efficacy of modified dose-attenuated FOLFIRINOX chemotherapy in patients over 65 years with advanced pancreatic adenocarcinoma.
Authors: Alessandretti Matheus Bongers , Moreira Raphael Brandao , Brandao Erika Pereira , Gomes Jessica Ribeiro , Amarante Marcus Paulo Fernandes , Lino Aline Da Rocha , Martins Junior Rodnei Merlrina , Abrahao Carina Mina , Sousa Tarcia Tarciane Soares de , Peixoto Renata D'Alpino , Cruz Marcelo Rocha , Maluf Fernando C. , Buzaid Antonio C.
Published: February 2017

468

Background: There is only limited data regarding efficacy and safety of FOLFIRINOX in elderly patients with advanced pancreatic adenocarcinoma. We aim to evaluate our experience with dose-reduced FOLFIRINOX in patients > 65 years-old. Methods: All patients > 65 years-old with biopsy-proven advanced pancreatic adenocarcinoma who received at least one cycle of modified dose-attenuatedFOLFIRINOX (no bolus FU and reduced dose of oxaliplatin and/or irinotecan) at our institution were identified. Results: Twenty-one consecutive patients (62% males) were reviewed. Median age was 67 (range 65-79). Grade 3/4 toxicities were reported in 7 (33%) patients ; the most common toxicities were anemia (62%), and nausea/vomiting (45%). Elevations in AST and/or ALT above the upper limit of normality were identified in 38%. No deaths due to toxicities were reported. Prophylactic granulocyte colony stimulator factor (G-CSF) was given in 16 (70 %) patients. Dose reductions were substantial with median reductions of 27,8 % (range 15 - 50%) for 5-FU, 27,1% (range 6-50%) for oxaliplatin and 25% (range 12-75%) for irinotecan. Median overall survival (OS) was 11,8 months (95% CI 10,2 - 13,3). Median progression free survival (PFS) was 6,9 months (95% CI 5,3 - 8,5). Conclusions: Modified dose-attenuated FOLFIRINOX is a reasonable option for elderly patients with advanced pancreatic adenocarcinoma. Adverse events were manageable and no deaths due to toxicity were reported. Median OS and PFS were similar to the pivotal phase III trial, demonstrating that dose-attenuated FOLFIRINOX may be beneficial to elderly patients.
Phase I study of chemoradiation therapy (nab-paclitaxel/Gemcitabine) in 15 patients with unresectable locally advanced pancreatic cancer (UR-LAPC).
Authors: Sueyoshi Hironari , Ioka Tatsuya , Tamura Takeshi , Takada Ryoji , Fukutake Nobuyasu , Ashida Reiko , Ohkawa Kazuyoshi , Takahashi Hidenori , Teshima Teruki , Katayama Kazuhiro
Published: February 2017

475

Background: Pancreatic cancer (PC) is one of the most difficult cancers to treat. Over 90% of cases, they are UR-LAPC or metastatic PC (mPC) at the first time of diagnosis. To prolong survival time, radiation therapy is considered to be promising with strong local control. Some papers reported that RT with 5-FU is effective to LAPC, but they are far from standard regimen. Gemcitabine (Gem) has enhancing effect of sensibility to RT. Gem and nab-paclitaxel (G+NP) showed priority compared with Gem monotherapy in mPC patients with Phase III study. So, we performed Phase I study to decide recommended dose of G+NP when we administer for concurrent CRT in URPC patients. Methods: From Aug 2013, we have registered patients who were examined as UR-LAPC because of cancer invasion to major artery. Dose of G+NP are classified by each level. At Level 1, Gem 600mg/m2 and NP 50mg/m2. At Level 2, Gem 600mg/m2 and NP 75mg/m2. At Level 3, Gem 600mg/m2 and NP 100mg/m2. At each level, patients accepted RT (50.4Gy/28fr). During performing RT period, we prescribed G + NP weekly. So, G+NP are prescribed 4-5 times if pts accomplish the study.We evaluate effectiveness and side effect of the regimen, and try to decide maximum tolerated dose. Results: Until July 2014, 14 pts (11 males and 3 females) have been registered in this trial. 6 cases were performed at Level 1, 7cases at Level 2, 1 cases at Level 3. 13 cases accomplish the prescription. 1 case at Level 1 dropped out because the patient suffered liver abscess. Effectiveness of the regimen is as follows; 4cases are PD (progressive disease), 6cases are SD (stable disease), and 2cases are PR (partial response). Conclusions: Now we prescribe the regimen at Level 3. We have not yet decided MDT. But, CRT with G + NP may be promising regimen for LAPC. When we accumulate more cases, and decide MDT, we will report later. Clinical trial information: UMIN000012254.
Association of gemcitabine (GEM) efficacy on unresectable invasive pancreatic carcinoma with intraductal papillary mucinous neoplasms.
Authors: Hashimoto Yusuke , Shimizu Satoshi , Watanabe Kazuo , Umemoto Kumiko , Okuyama Hiroyuki , Takahashi Hideaki , Ohno Izumi , Mitsunaga Shuichi , Ikeda Masafumi
Published: February 2017

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Background: Invasive pancreatic carcinoma associated with intraductal papillary mucinous neoplasms (IC-IPMN) has showed more favorable prognosis than invasive pancreatic ductal carcinoma (IPDC) following surgical resection in some studies. IC-IPMN differs from IPDC in clinical manifestation and biology profile and is mostly surgically resectable in initial presentation. Chemotherapeutic effect on unresectable IC-IPMN is not described in the literature yet. Methods: Our pancreatic cancer database was reviewed to identify 43 patients with IC-IPMN between 2006-2013. IC-IPMN was determined with surgical pathology or with radiological diagnosis and biopsy evidence of adenocarcinoma. Of 43 patients, 14 unresectable IC-IPMN patients received GEM as first-line chemotherapy regimen. We investigated GEM efficacy, Overall Survival (OS), Progression Free Survival (PFS) and 1-year survival rate. Results: Characteristic baseline included gender (male: 9, female: 5), age (median: 73 years old), ECOG performance status (0-1, 92%), location (head 7, body/tail 6, diffuse 1), prior surgical resection (8), biliary intervention (5), metastasis (11), CRP (median: 0.15mg/dl, 0.1-1.0), CA19-9 (median: 29U/ml, 8-20820), CEA (median: 3.1ng/ml, 0.1-237). Median OS, PFS and 1-year survival rate were 24.0 months, 8.0 months and 86%. Gemcitabine therapy demonstrated 14% (2/14) response rate and 79% (11/14) disease control rate. Conclusions: UnresectableIC-IPMN indicates favorable survival and fair response to GEM in our study. Limitations are retrospective study at single center and small population due to its disease rarity.
Hybrid minimally invasive versus open oesophagectomy for patients with oesophageal cancer: A multicenter, open-label, randomized phase III controlled trial, the MIRO trial.
Authors: Mariette Christophe , Meunier Bernard , Pezet Denis , Dalban Cecile , Collet Denis , Thomas Pascal-Alexandre , Brigand Cecile , Perniceni Thierry , Carrere Nicolas , Bonnetain Franck , Piessen Guillaume
Published: February 2017

5

Background: Surgical resection is regarded as the only curative option for resectable oesophageal cancer. Postoperative morbidity, in particular pulmonary complications, continues to be of great concern and occurs in more than half of patients after open oesophagectomy (OO). We assessed whether hybrid minimally invasive oesophagectomy (HMIO) reduces morbidity compared with OO. Methods: We performed a multicentre, open-label, randomised controlled trial at 12 study centres between October 2009 and April 2012. Patients aged 18-75 years old with resectable cancers of the middle or lower third of the oesophagus were assigned by a computer-generated randomisation sequence to undergo either transthoracic OO or HMIO. Surgical technique was standardised by both on site visits and the use of videos, and was based on an Ivor Lewis procedure with laparoscopic gastric mobilisation and open right thoracotomy. Randomisation was stratified by centre. The primary outcome was 30 day grade II-IV postoperative morbidity as defined by the Dindo-Clavien classification. Analysis was by intention to treat. Results: We randomly assigned 104 patients to the OO group and 103 to the HMIO group. Sixty-seven (64.4%) patients in the OO group had major postoperative morbidity compared with 37 (35.9%) in the HMIO group (OR 0·31, 95% CI 0·18-0·55; p=0·0001). Thirty-one (30.1%) patients in the OO had major pulmonary complications compared with 18 (17.7%) in the minimally invasive group p=0·037), whereas 30-day mortality was 5 (4.9%) vs. 5 (4.9%), respectively. Conclusions: These findings provide evidence for the short-term benefits of HMIO for patients with resectable oesophageal cancer (NCT00937456 ClinicalTrials.gov). Clinical trial information: NCT00937456.
Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405 (Alliance).
Authors: Ng Kimmie , Venook Alan P. , Sato Kaori , Hollis Bruce W. , Niedzwiecki Donna , Ye Cynthia , Chang I-Wen , O'Neil Bert H. , Innocenti Federico , Lenz Heinz-Josef , Blanke Charles David , Mayer Robert J. , Fuchs Charles S. , Meyerhardt Jeffrey A.
Published: February 2017

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Background: Prospective epidemiologic data suggest that higher levels of 25-hydroxyvitamin D [25(OH)D] are associated with improved survival in patients with colorectal cancer (CRC), however, the relationship between 25(OH)D and outcome in metastatic CRC, specifically, is unknown. Methods: We prospectively assessed the association between plasma 25(OH)D and overall survival (OS) in previously untreated metastatic CRC patients enrolled in CALGB 80405, a randomized phase III trial of chemotherapy + bevacizumab, cetuximab, or both, prior to the KRAS WT amendment. Progression-free survival (PFS) was a secondary endpoint. Plasma 25(OH)D levels were measured at baseline by radioimmunoassay, and dietary and lifestyle behaviors collected from self-administered questionnaires. Cox proportional hazards models were used to calculate hazard ratios adjusted for other prognostic factors. In sensitivity analyses, patients who died within 3 or 6 months of blood draw were excluded to address the possibility of reverse causation. Results: Among 1,043 patients, median plasma 25(OH)D was 17.2 ng/mL (range 2.2-72.7). Older and black patients, those with lower dietary and supplemental vitamin D intake, ECOG performance status 1 (vs. 0), higher body-mass index, lower physical activity, and blood draws during the winter and spring had significantly lower levels of 25(OH)D. Patients in the highest quintile of 25(OH)D had significantly improved OS compared to those in the lowest after adjusting for pathologic and clinical prognostic factors (median 32.6 vs. 24.5 months; HR 0.67, 95% CI, 0.53-0.86; p trend 0.002). Increasing concentrations of 25(OH)D were also associated with improved PFS (median 12.2 vs. 10.1 months; HR 0.80, 95% CI, 0.64-1.01; p trend = 0.02). The results were consistent across subgroups of patient characteristics, including KRAS status, and remained unchanged after excluding patients who died within 3 or 6 months of blood draw. Conclusions: Higher concentrations of plasma 25(OH)D are associated with significantly improved survival in metastatic CRC patients treated with chemotherapy + biologics. Randomized trials of vitamin D supplementation are warranted and are currently underway.
Reflex Lynch syndrome screening by example: A review of existing programs.
Authors: Daly Corinne , Rotenberg Carolyn , Facey Marcia , Baker Natalie A. , Baxter Nancy N.
Published: February 2017

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Background: Reflex screening for Lynch Syndrome (LS) has been recommended, however occurs in few jurisdictions worldwide. We aimed to explore program structure, pathology testing, implementation challenges and future directions of existing reflex LS screening programs in various jurisdictions to develop best practices for future programs. Methods: We identified existing reflex LS screening programs through a literature search and expert opinion. Information on program implementation, patient population, family care involvement, monitoring and improvements was collected through semi-structured interviews with program leaders, pathologists, technical staff, and family physicians. Pattern, thematic and content analysis were used to analyze and extract program features, sequence of pathological testing and best practices. Results: 26 participants across 7 programs completed interviews. There were 3 government-funded, population-based programs (Manitoba, Western Australia, and New South Wales), 2 private health management organization programs implemented across affiliated healthcare centers (Pennsylvania and Southern California); and 2 hospital-based programs (Ohio and Utah). Five programs screened all patients with CRC for LS while 2 programs designated an upper age limit for screening. The majority of programs tested tumor samples for LS using a combination of immunohistochemistry and BRAF mutation analysis. In jurisdictions relying on surgeons' referral to genetic counseling without navigation, uptake of genetic testing was lower than expected. Programs implementing early education of surgeons and pathologists in reflex screening procedures reported confidence in skills, collaboration and communication. Communication materials for family members of affected individuals were recommended to increase family engagement in genetic counselling. Conclusions: There are a variety of reflex LS screening programs with varying standards and protocols. Program design influences uptake of genetic testing; programs with an imbedded navigation plan for those who need genetic counseling enhance rates of adherence. This should be an important consideration when planning future reflex screening programs.
Genomic profiling of esophagogastric (EG) tumors in clinical practice.
Authors: Riches Jamie Cathleen , Schultz Nikolaus , Ku Geoffrey Yuyat , Imtiaz Tooba , Kelsen David Paul , Ilson David H. , Solit David B. , Berger Michael F. , Ladanyi Marc , Arcila Maria E. , Vakiani Efsevia , Janjigian Yelena Yuriy
Published: February 2017

57

Background: Esophagogastric (EG) cancer is a phenotypically heterogeneous disease. The Cancer Genome Atlas (TCGA) identified four distinct subsets: 1) Epstein Barr Virus (EBV) tumors with PIK3CA mutations, PD-L1/2 amplification (amp), 2) Tumors with Microsatellite instability (MSI-H), 3) chromosomally unstable (CIN) tumors with frequent amplifications, 4) chromosomally stable/diffuse type tumors with RHOA mutations. We explore the utility/feasibility of genomic profiling of EG tumors in routine clinical practice. Methods: Patients (pts) with metastatic EG adenocarcinoma undergoing treatment at MSKCC were consented for molecular testing under institutional protocol. Archival formalin fixed paraffin embedded (FFPE) samples were analyzed using an on-site 341 cancer-associated gene bait capture, next generation sequencing (NGS) assay. Results: Of 70 analyzed EG tumors, 66 (94%) harbored at least one genomic alteration, the most frequent being TP53 mutations (77%), HER2 amp (30%) and EGFR amp (10%). Alterations in PI3K/AKT/mTOR (9%) and G1-S1 cell cycle regulators (CDK12 (11%), CDKN2A (10%)) were also observed. A comparison with the TCGA results revealed an over-representation of the CIN subtype (65% vs 50% in TCGA). We found very few EBV or MSI tumors (3% each), with the remaining 29% being chromosomally stable. Data is reported in the clinical medical record and maintained in the MSKCC-internal cBioPortal for Cancer Genomics ( http://cbioportal.org ) (Gao, et al.). The portal is a web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data and when available, to link these data to therapeutic interventions and clinical outcomes. Conclusions: CIN tumors with frequent amplifications represent majority of metastatic EG cancer at our institution. Optimal development of target-specific therapy for EG tumors will require genomic characterization. Comprehensive molecular profiling is feasible in routine clinical practice and has created a roadmap for pt stratification and genome-guided trial development.
Full report of the TROG 03.01, NCIC CTG ES2 multinational phase III study in advanced esophageal cancer comparing palliation of dysphagia and quality of life in patients treated with radiotherapy or chemoradiotherapy.
Authors: Penniment Michael Gordon
Published: February 2017

6

Background: RT relieves dysphagia of advanced oesophageal cancer, without data from randomised phase III trials determining response, toxicity, or role of palliative CRT. Aims (1) to establish effective and least toxic treatment for symptom relief (2) determine effects of common cancer treatments on QoL (3) establish an evidence base for patient decision making. Methods: 220 patients were randomised to receive a course of palliative RT [35 Gy in 15 fractions, (n=115) or 30 Gy in 10 fractions (n=105) in Canada and UK], or concomitant CRT with Cisplatin and 5FU (D1-4) (n=111). Dysphagia measured using the Mellow score, toxicity using CTCAE v2, and QoL using EORTC QLQ30, oesophagus module (OES-18). The primary end point was proportion of patients with improved dysphagia measured at week 9 maintained until week 13. Results: Radiotherapy alone showed a dysphagia response (at any point) of 68% compared to CMT 74%, not a significant difference (p=0.343). the primary endpoint of maintained swallowing improvement was achieved in 41% with RT, 47% CMT again not statistically significant(p=0.4163).There was increased toxicity in patients receiving CRT, (nausea (p=0.0019) and vomiting (p=0.0072)). Median survival was 210 days for CRT, 203 days for RT. Although the results of the trial showed equally poor survival prognosis in both arms, there were some patients (n=21) still alive at 2 years post treatment.Quality of life analysis showed no statistical difference between arms. 17 patients in the RT alone arm ultimately received chemotherapy for specific palliative endpoints, thus 92 patients did not require chemotherapy. Conclusions: Although the CRT group had slightly better dysphagia response and median survival, the bowel toxicity was worse. Nearly 10% of patients were alive at 2 years indicating this is a group of patients who should not be denied active cancer treatment, but it should be tailored to offer maximum symptom relief minimising treatment toxicity. This multicentre trial, conducted in the UK, Canada, Australia, and New Zealand reflects practice in several countries. Clinical trial information: ACTRN12606000526572.