bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy and safety of sunitinib in patients with advanced well-differentiated pancreatic neuroendocrine tumors.
Authors: Raymond Eric , Kulke Matthew H. , Qin Shukui , Schenker Michael , Cubillo Antonio , Lou Wenhui , Tomasek Jiri , Thiis-Evensen Espen , Xu Jianming , Racz Dr. Karoly , Croitoru Adina E , Khasraw Mustafa , Sedlackova Eva , Borbath Ivan , Ruff Paul , Oberstein Paul Eliezer , Ito Tetsuhide , Fernandez Kathrine C. , Rosbrook Brad , Fazio Nicola
Published: March 2017

380

Background: Sunitinib was approved by the FDA in 2011 for treatment of progressive, well-differentiated, advanced pancreatic neuroendocrine tumors (pNETs) based on a pivotal phase III study (NCT00428597) that showed a significant increase in progression-free survival (PFS) over placebo following early study termination. Subsequently, the FDA requested a post-approval study to support these findings. Methods: In this open-label, phase IV clinical trial (NCT01525550), patients with progressive, well-differentiated, unresectable advanced/metastatic pNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to the phase III study. Primary endpoint was investigator-assessed PFS per RECIST 1.0. This study is ongoing. Results: Sixty one treatment-naïve and 45 previously treated patients with progressive pNETs were treated with sunitinib: mean age, 54.6 years; males, 59.4%; white, 63.2%; ECOG PS 0, 65.1% or PS 1, 34.0%; and prior somatostatin analog, 48.1% (treatment-naïve, 39.3%; previously treated, 60.0%). At the data cutoff date, 82 (77%) patients discontinued treatment, mainly due to disease progression (46%). Median duration of treatment was ~11.9 months. Investigator-assessed median PFS (mPFS) was 13.2 months (95% CI, 10.9–16.7) in the overall population, with comparable mPFS in treatment-naïve and previously treated patients (13.2 vs 13.0 months). mPFS per independent radiologic review was 11.1 months (95% CI, 7.4–16.6). Objective response rate (ORR) per RECIST was 24.5%: 21.3% in treatment-naïve and 28.9% in previously treated patients. Median overall survival, although not yet mature, was 37.8 months. Treatment-emergent, all-causality adverse events (AEs) reported by ≥ 20% of all patients included neutropenia, diarrhea, leukopenia, fatigue, hand–foot syndrome, hypertension, abdominal pain, dysgeusia, and nausea. Most common grade 3/4 AEs were neutropenia (22%) and diarrhea (9%). Conclusions: The mPFS of 13.2 months and ORR of 24.5% observed in this study support the outcomes of the pivotal phase III study of sunitinib in pNETs and confirm its activity in this setting. AEs were consistent with known safety profile of sunitinib. Clinical trial information: NCT01525550.
A phase I study of mFOLFOX6 and ADI-PEG-20 in patients (pts) with advanced hepatocellular carcinoma (HCC) and other gastrointestinal (GI) malignancies.
Authors: Harding James J. , Lowery Maeve Aine , Uhlitskykh Khrystyna , Wan Peter Justin , Hamilton Casey R , Barba Adalberto , Liu Kay Chia-Wei , Johnston Amanda , Bomalaski John S. , O'Reilly Eileen Mary , Saltz Leonard , Abou-Alfa Ghassan K.
Published: March 2017

384

Background: ADI-PEG-20 (pegylated arginine deiminase), an arginine degrading enzyme, and FOLFOX each exhibit clinical activity in a HCC pt subset. Preclinical data indicate that arginine depletion interferes with folate and pyrimidine metabolism as well as DNA damage repair pathways, suggesting a role for pairing AGI-PEG-20 with cytotoxic chemotherapy. Methods: This is a single center phase 1 trial of mFOLFOX-6 and ADI-PEG-20 in treatment-refractory advanced GI tumors to assess safety and tolerability, and to identify the recommended phase 2 dose (R2PD). mFOLFOX6 was administered intravenously biweekly at standard fixed doses and ADI-PEG-20 intramuscularly weekly at 18 or 36 mg/m2. Toxicity was assessed by CTCAE v4.03 and efficacy by RECIST v1.1. A HCC RP2D expansion was completed to explore efficacy. Serum arginine, citrulline, and anti-ADI-PEG-20 antibodies were monitored every other week. Results: 17 pts were treated—7 pts with GI tumors in dose escalation and 10 HCC pts in RP2D dose expansion. Histologies included HCC (13), pancreatic (3) and fibrolamellar carcinoma (1). All HCC pts had Child-Pugh A liver function and had progressed on sorafenib. Treatment-related grade ≥ 3 laboratory adverse events (AEs) occurred in 47% of pts, including neutropenia (4), thrombocytopenia (3), anemia (2), lymphocytopenia (2) and hyponatremia (1). Treatment-related grade ≥ 3 clinical AEs occurred in 2 pts, notably grade 3 fatigue and a grade 3 cardiac event not otherwise specified. No dose limiting toxicities, treatment-related deaths, or cases of hepatic failure were observed. Efficacy data for the 13 HCC pts revealed 3 (23%) PR, 6 (46%) SD, 3 PD and 1 NE. Arginine levels were depleted with therapy (mean ± SEM: baseline 85.3 ± 13.0 uM, 8 wks 4 ± 3.0 uM, 16 wk 1.1 ± 0.8uM). Anti-ADI-PEG-20 antibodies were not detected at 8 weeks (mean ± SEM: baseline 0.7 ± 0.5, 8 wks 1.5 ± 1). Conclusions: Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m2 weekly shows an acceptable safety profile with rapid and durable reduction in serum arginine. Further evaluation of this combination is warranted in advanced HCC pts. Clinical trial information: NCT02102022.
Treatment patterns of gastrointestinal neuroendocrine tumors (NET).
Authors: Broder Michael S. , Chang Eunice , Cai Beilei , Neary Maureen , Papoyan Elya , Benson Al Bowen
Published: March 2017

387

Background: NET comprise a broad set of rare tumors. Almost 2/3 arise in the gastrointestinal (GI) tract. NCCN guidelines for unresectable GI NET recommend somatostatin analogues (SSA) first, however, guidelines do not recommend a particular sequence for remaining therapies. Our objective is to describe real world treatment patterns of GI NET. Methods: This retrospective study combined 2 claims databases to examine newly pharmacologically treated patients using tabular and graphical techniques. Treatments included SSA, cytotoxic chemotherapy (CC), targeted therapy (TT), interferon (IF) and combinations. Patients ≥ 18 years, with ≥ 1 inpatient or ≥ 2 outpatient claims for GI NET who received pharmacologic treatment from 7/1/09-6/30/14 were identified. A 6 month clean period prior to first treatment ensured patients were newly treated. Patients were followed until end of enrollment. Results: We identified 2,258 newly treated GI NET patients. 59.6% started first line therapy with SSA monotherapy, 33.3% CC, 3.6% TT, and 0.5% IF. The remainder received combination therapies. Mean follow up was 576 days. Mean duration of first line therapy was 361 days for all newly treated patients (449 SSA, 215 CC, 267 TT). 58.9% of patients had no subsequent pharmarcological treatment after discontinuation of first line therapy.The most common second line was combination therapy with SSA (i.e., CC or TT added). In patients who did not begin with SSA, most received SSA as second line. In graphical pattern analysis, there was no clear pattern visible after first line therapy. Conclusions: More than 1/2 of pharmacologically treated patients began treatment with SSA and 1/3 with CC, with duration of use > 1 year and just over 6 months, respectively. We found treatment patterns after first line were unclear, and more than 1/2 of patients had no subsequent pharmacological treatments after discontinuing first line therapy. It is unclear whether there is underutilization of the pharmacological therapy or this is due to stable disease status after alternative non-pharmacological treatment. Future studies directed at understanding treatment patterns using patient medical records are warranted. As new treatments emerge, reassessment of treatment patterns may be needed.
NM 23-H1 gene expression of a migration suppressor in gastric lymphoma.
Authors: Kim Il
Published: March 2017

39

Background: We previously describedthat the NDPK-A(nucleoside diphosphate kinase A) contributes variably to the migration of cancer cell. To investigate the role of the NDPK-A in gastric lymphoma, we evaluated the expression of NDPK-A in two different cancer cell lines of the same gastric lymphoma patient. Methods: The primary cell line of gastric lymphoma, RF-1, was cultured from the primary gastric lymphoma site, and the other cell line RF-48 was metastasized to the peritoneum of the same patient after 6 months. We have generated stable gastric lymphoma transfectants, pIRES-NDPKA-GFP-neo, that constitutively over-express transfected and vector form of NDPK-A, in addition to a reporter, green fluorescent protein(GFP). The transfected gastric lymphoma cell migration assay was performed 24-well modified chemotaxis chambers with FluroBloc membrane. Results: In regard to the migration rate of the gastric lymphoma cell lines, RF-1 vector was 75.8±7.5%, RF-1 transfected was 54.4±12.3%, RF-48 vector was 84.7±15.4%, RF-48 transfected type was 62.3±9.2%, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type. NDPK-A was presented more in RF-1 than RF-48, and presented more in the transfected type than the vector type, and concerning the migration rate, RF-48 migrated better than RF-1, and the vector type migrated better than the transfected type. Conclusions: Concerning NM 23-H1 gene encodes the NDPK-A in gastric lymphomas, more abundant was NDPK-A, poorer was migration, and thus it played a role of the suppressor of migration. Our analysis of pooled data found that NDPK-A acts as a migration suppressor in gastric lymphoma.
Treatment patterns among patients with metastatic GEP-NET treated at a tertiary referral center.
Authors: Jalbert Jessica J , Casciano Roman , Tao Biwen , Dutton Trevor , Brais Lauren K. , Pulgar Sonia J. , Berthon Anthony , Gabriel Sylvie , Dinet Jerome , Kulke Matthew H.
Published: March 2017

397

Background: Treatment options for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) have been increasing. We describe treatment patterns among patients with advanced GEP-NET evaluated at a tertiary referral center. Methods: We conducted a cohort study of patients with well-differentiated GEP-NET recruited between June 2003-May 2015 from Dana-Farber Cancer Institute’s (DFCI) gastrointestinal clinic, using data from an institutional research database and the electronic healthcare records of DFCI and partner hospitals. Patients were required to have been evaluated ≥ 2 at DFCI and to be diagnosed with metastatic GEP-NET. Medications were categorized as cytotoxic agents (CA), angiogenesis inhibitors (AI), mTOR inhibitors (mTORI), interferons (IFN), somatostatin analogues (SSA), or investigational therapies (IT). Combination therapy (combo) was defined as treatment overlap by ≥ 30 days. Results: Among 682 patients (mean age [SD]: 58.5 [11.9], 50.1% male, 96.5% white, 44.9% midgut NET, 28.7% pancreatic NET, 38.9% carcinoid symptoms, and 62.6% with < 1 year since metastatic GEP-NET diagnosis), 89.0% initiated ≥ 1 GEP-NET medication. First line treatment distribution was: 59.5% SSA, 17.5% SSA combo, 14.8% CA, 3.0% IT, 2.8% non-SSA combo, 1.2% AI, 0.7% IFN, and 0.5% mTORI. Among patients on first line SSA monotherapy, 68.4% remained on treatment until death or end of follow-up. Of the 296 patients advancing to second line treatments, 90.5% took SSAs (13.5% monotherapy and 77.0% combo), of which 95.9% were continuing their first line SSA treatment. 86.7% of third line therapy patients (157/181) were on SSAs (6.6% monotherapy and 80.1% combo), all of which had initiated SSAs as first or second line treatment. Most common SSA combo therapy was with CA, followed by with AI. Conclusions: SSA monotherapy and SSA combination therapy with CA were the most common treatments for metastatic GEP-NET between 2003 and 2015. Sustained SSA use was frequent, reflecting the continuous nature of SSA use throughout the disease course.
The effect of sorafenib (S) starting dose and dose intensity on survival in patients with advanced hepatocellular carcinoma (HCC).
Authors: Alghamdi Mohammed Abdullah , Lee-Ying Richard , Swiha Mina , Chan Kelvin K. , Cheung Winson Y. , Ho Maria , Tam Vincent C.
Published: March 2017

400

Background: The SHARP trial showed that S improves survival in advanced HCC. In clinical practice full dose (FD) of S at 400mg bid can be difficult to tolerate and so a reduced dose (RD) is often required. The purpose of this study was to determine whether starting dose or dose intensity of S affects survival in patients with HCC. Methods: All patients treated with S for HCC in Alberta, Canada from January 2008 to July 2016 were included in this study. Patient demographics, clinical, tumor characteristics, S starting dose and dose intensity were collected and analyzed. Patients were dichotomized into starting FD or RD of S. A mean dose intensity of > 75% and < / = 75% were considered normal and reduced, respectively. Survival outcomes were assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox-proportional hazard model was constructed with starting dose, dose intensity and relevant clinical and pathologic factors to assess their impact on survival. Results: A total of 156 patients were included. Median age was 63, 78% were men, 34% were East Asian, 77% were Childs-Pugh A, and the most common causes of liver disease were hepatitis B (30%) and C (30%). Most patients had EGOG performance status of 0 and 1 prior to starting S (29% and 62%, respectively). S was started at FD in 58% of patients and 50% had a dose intensity > 75%. The median survival for both starting FD and RD was 10.3 months, and not significantly different (p = 0.14).The median survival for a dose intensity > 75% vs < / = 75% was 10.7 vs 9.5 months, respectively (p = 0.76). In multivariable models that adjusted for demographic, stage, performance status and liver function, starting dose (HR 0.8 95%CI 0.5-1.2) and dose intensity (HR0.9 95% CI 0.6-1.4) were not associated with survival. Conclusions: Starting S with a RD may be a reasonable strategy for HCC, since it does not appear to impact survival. Also, dose intensity did not impact survival, suggesting that additional dose modifications may not compromise effectiveness. Though limited by small numbers, we are planning to confirm these findings in a larger, pan-Canadian dataset.
Effectiveness and safety of sorafenib for unresectable and advanced intrahepatic cholangiocarcinoma: A pilot study.
Authors: Luo Xiangji , Jia Weidong , Huang Zhiyong , Li Xiangcheng , Xing Baocai , Jiang Xiaoqing , Li Jun , Yang Tian , Gao Chunfang , Lau Wan Yee , Shen Feng
Published: March 2017

405

Background: Patients with unresectable and advanced intrahepatic cholangiocarcinoma (ICC) usually have short survival due to a lack of effective treatment. This multicenter, single arm, open labeled, prospective study was conducted to evaluate the effectiveness and safety of the multikinase inhibitor, sorafenib, combined with best supportive care (BSC) in these patients. Methods: Forty-four patients with unresectable and advanced ICC were treated with sorafenib (400 mg, twice daily) and BSC. The primary endpoint was disease control rate (DCR) at week 12; secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), duration of therapy (DOT), and adverse events (AEs). Results: The DCR at week 12 was 15.9%. The median TTP was 5.6 months, and the median PFS and OS were 3.2 and 5.7 months (95% confidence interval [CI]: 2.4-4.1 months; 3.7-8.5 months), respectively. The median DOT was 1.8 months (95% CI: 1.9-3.9 months). Grades 1 and 2 AEs occurred in 75% of patients, and one grade 4 AE (hand and foot skin reaction) was observed in one patient. Conclusions: This is the first and only prospective pilot study to examine the use of sorafenib specifically for ICC. Sorafenib with BSC had an acceptable DCR and safety profile in patients with unresectable and advanced ICC. [Table: see text]
Characteristics of intrahepatic cholangiocarcinoma according to tumor location.
Authors: Shimada Mitsuo , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Iwahashi Shuichi , Saito Yu , Yoshikawa Masato , Teraoku Hiroki , Higashijima Jun
Published: March 2017

406

Background: Recently, the perihilar cholangiocarcinoma was defined as a tumor existing perihilar region between the right side of the umbilical portion of the left portal vein and the left side of the origin of the right posterior portal vein, in the General Rules for Clinical and Pathological Studies on Cancer of the Biliary Tract (The 6th edition). The study was aimed to investigate characteristics of intrahepatic cholangiocarcinoma (IHCC) according to tumor location. Methods: Study 1: Sixty-two IHCC patients who underwent hepatic resection were divided into the following 3 groups; peripheral type (n=41), perihilar type (n=10) and unclassified type (peripheral type with perihilar invasion: n=11). Clinicopathological data including CA19-9 and immnohistochemical staining of Ki67 and hypoxia inducible factor-1 (HIF-1) were compared. Study 2: The effect of 2 cycles of adjuvant gemcitabine combined with 5-FU and cisplatin (GFP) (Morine and Shimada. Hepatogastroenterology 2009) was retrospectively investigated, in advanced IHCC with one of 3 prognostic factors of LN metastasis, intrahepatic metastasis and R2 resection. Results: Study 1: There was no difference in background variables except for more frequent hilar biliary invasion in perihilar and unclassified types, and the largest tumor size in unclassified-type. The 5-year survival rate in the peripheral, perihilar and unclassified-types were 44%, 20% and 0%, respectively. In addition, CA19-9 level, Ki67 labelling index and positive rate of HIF-1 expression in the unclassified type were higher than those in other 2 types. Multivariate analysis revealed the unclassified type as an independent prognostic factor. Study 2: In 29 patients (47%) having one of the 3 prognostic factors, 9 patients including 4 unclassified-type IHCCs received the adjuvant GFP. The prognosis in GFP group tended to be better than that in non-GFP group (3-year survival rate: 38% vs. 6%, p = 0.07). Two patients with unclassified-type IHCC in non-GFP group died within 1 year after surgery. Conclusions: The unclassified-type IHCC indicated the most aggressive tumor biology, and the adjuvant GFP may be a useful strategy for such a highly malignant tumor with poor prognostic factors.
Impact of duodenal invasion on outcomes in patients with pancreatic cancer treated with stereotactic body radiotherapy.
Authors: Murimwa Gilbert , Mellon Eric Albert , Frakes Jessica M. , Jin Will , Hodul Pamela Joy , Pimiento Jose Mario , Kim Richard D. , Soares Heloisa P. , Malafa Mokenge Peter , Hoffe Sarah E.
Published: March 2017

408

Background: Clinical trials for pancreatic adenocarcinoma patients treated with a uniform SBRT tumor dose prescription exclude tumors invading the duodenum due to potential for increased GI mucosal complications. We analyzed our non-trial patients to determine the impact of SBRT in the setting of known duodenal invasion. Methods: An IRB-approved institutional database was queried identifying all 220 localized borderline resectable or locally advanced pancreatic cancer patients treated with SBRT from 2009 to 2015. Eligibility included patients with head tumors, a minimum of 6 months of follow up, and duodenal invasion on pretreatment endoscopic ultrasound (EUS). Dose painted SBRT delivered 25-30 Gy to tumor abutting the duodenum and up to 50 Gy to focal tumor/vessel abutment. Analysis evaluated whether patients with duodenal invasion had increased incidence of grade ≥ 3 (G3+) toxicity, GI ulceration or bleeding, or worsened overall survival (OS). Fisher’s Exact Test (2-tailed) compared patient characteristics and binary outcomes. Survival estimates by Kaplan-Meier were compared using log-rank test. Results: The study population included 126 patients (median F/U 14.1 months). Of 23 patients with duodenal invasion, 14 (61%) underwent resection, 3 (13%) developed G3+ toxicity and 1 (4%) had acute pre-op G3 GI bleeding that was controlled endoscopically prior to surgery. Of 103 without duodenal invasion, 48 (47%) underwent resection, 9 (9%) suffered G3+ toxicity and 7 (7%) had any GI bleed or ulceration. None of the 7 patients with GI bleeding or ulceration underwent pancreatectomy, and 3 had bleeding from tumor progression into the duodenum. There was no association between duodenal invasion and the incidence of G3+ toxicity (p = 0.76) or GI ulceration/bleeding (p = 1.0). There was no worsened OS (p = 0.17) or G3+ toxicity (p = 0.22) for patients with duodenal invasion on EUS. Patients with a GI bleeding or ulceration event had decreased OS (p = .014). Conclusions: Duodenal invasion on EUS prior to SBRT did not worsen GI bleeding risk or survival. Our data suggests that excluding pancreatic adenocarcinoma patients with duodenal invasion from SBRT when using a dose-painted approach is unnecessary.
Phase I study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (Gem) in solid tumors: Interim results from the pancreatic cancer (PC) cohorts.
Authors: Wainberg Zev A. , Hochster Howard S. , George Ben , Gutierrez Martin , Johns Mark Emery , Chiorean E. Gabriela , Kwak Eunice Lee , Kalyan Aparna , Manax Victoria , Ye Moncy , Chen Tianlei , Trunova Nataliya , O'Dwyer Peter J.
Published: March 2017

412

Background: Immune checkpoint inhibitors, such as nivo, an anti−PD-1 antibody, have demonstrated antitumor activity in various cancers. Chemotherapy has demonstrated immune system activation via multiple mechanisms, providing a rationale for combination approaches. nab-P + Gem is a standard of care in PC which does not require immunosuppressive corticosteroids. Here we report interim results from 2 PC cohorts (Arms A and B) of a phase I study in patients (pts) receiving nivo + nab-P ± Gem for locally advanced or metastatic PC. Methods: This 2-part study was designed to identify dose-limiting toxicities (DLTs) of nivo + nab-P ± Gem in Part 1 and assess tolerability and efficacy in Part 2 dose expansion (+ Gem). Pts were DLT evaluable if they received ≥ 2 cycles of treatment and remained on study for 14 days after last dose or discontinued due to a DLT prior to completing 2 cycles. After Arm A, Part 1 was deemed safe, Arm B, Part 1 was initiated. In Arm A, pts with 1 prior chemotherapy regimen received nab-P 125 mg/m2 on days 1, 8, and 15 of a 28-day cycle (qw 3/4) + nivo 3 mg/kg on days 1 and 15 of a 28-day cycle starting with cycle 1. In Arm B, treatment-naive pts received the same regimen in Arm A + Gem 1000 mg/m2qw 3/4. Results: As of June 28, 2016, 11 and 6 pts were treated in Arms A and B in Part 1, respectively. No DLTs were reported in Arm A, and 1 in Arm B (nonimmune hepatitis, suspected to be due to Gem; resolved and pt continued nivo + nab-P without Gem). The most common grade 3/4 teatment-emergent AEs were pulmonary embolism, neutropenia, and anemia in 2/11 pts (18%) in Arm A and anemia in 2/6 pts (33%) in Arm B. Nine patients discontinued due to progressive disease (8 in Arm A, 1 in Arm B). Best overall response is shown in the Table. Median treatment duration was 12.6 and 15.5 weeks for Arms A and B, respectively. Clinical trial information: NCT02309177. Conclusions: These results indicate that adding nivo to nab-P ± Gem is feasible for pts with advanced PC, and antitumor activity of this regimen appears to be encouraging. Based on promising results from Part 1, Arm B, Part 2, is enrolling pts.[Table: see text]
Frailty: A major consideration for short- and long-term outcomes in resected pancreatic cancer.
Authors: Konstantinidis Ioannis , Lewis Aaron G , Tozzi Federrico , Ituarte Philip HG , Warner Susanne , Woo Yanghee , Singh Gapandeep , Fong Yuman , Melstrom Laleh Golkar
Published: March 2017

418

Background: Frailty has been associated with adverse postoperative outcomes. However, little is known about its correlation with survival in resected pancreatic cancer. This study examined the correlation of frailty with postoperative outcomes and survival after pancreatectomy for cancer. Methods: Data from National Surgical Quality Improvement Program (NSQIP) patients (n = 7400) who underwent pancreatectomy between 2011 to 2013. A modified frailty index (mFI) validated for use in NSQIP was used to examine correlations between frailty and postoperative outcomes. California Cancer Registry (CCR) data for patients (n = 4959) who underwent pancreatectomy for cancer between 2000 to 2012 was used to assess the association between the Charlson Comorbidity Index (CCI), as a surrogate for frailty, and overall survival. Results: The distribution of NSQIP patients according to the mFI was 0, 1, 2, 3, 4 in 2797 (37.8%), 3422 (46.2), 1074 (14.5), 104 (1.4) and 3 (0.04) respectively. The patients were divided to non frail (mFI = 0), mildly frail (mFI = 1-2), or severely frail (mFI3 ≥ 3). Overall, 8.7% of patients experienced a grade 4 Clavien complication and 3.1% experienced postoperative mortality. Worsening frailty correlated with an increase in grade 4 Clavien complications (non-frail: 6.3% vs. mildly frail: 9.7% vs. severely frail: 26.2%; p < 0.001) and mortality (1.9% vs. 3.8% vs. 4.7% respectively; p < 0.001). The majority of CCR patients had similarly few comorbidities: CCI: 0, 1, ≥ 2 in 3869 (77.8%), 861 (17.31%) and 243 (4.89%) respectively. Median survival decreased as CCI increased (for CCI 0, 1 and ≥ 2 was 23 vs. 19 vs. 15 months respectively; p < 0.001). Conclusions: Frailty is a powerful correlate of postoperative outcome and survival for resected pancreatic cancer patients and is an important consideration in planning for surgical intervention.
The relationship between antitumor effects and relative dose intensity of gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer.
Authors: Ishigaki Kazunaga , Ozaka Masato , Kataoka Seita , Kanata Ryo , Yamada Ikuhiro , Sasaki Takashi , Matsuyama Masato , Takano Kouichi , Sasahira Naoki
Published: March 2017

419

Background: Gemcitabine plus nab-paclitaxel (GEM+nab-PTX) is the standard first-line chemotherapy for unresectable pancreatic cancer, but the relationship between antitumor effects and relative dose intensity (RDI) remains unclear. Methods: A retrospective analysis of pancreatic cancer patients treated with GEM+nab-PTX as first-line chemotherapy between January 2015 and July 2016 at Cancer Institute Hospital of JFCR was performed. The RDI of GEM+nab-PTX was calculated as the delivered dose intensity divided by standard dose intensity. The patients were divided into two groups by median RDI. Kaplan Meier curves were constructed in order to analyze progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS), and differences between the two groups were compared with a log-rank test. Results: A total of 102 patients (52 male, a median age of 66 years) were enrolled. Eighty-two (80%) had metastatic disease. The best overall response was partial response in 30 (29%) and stable disease in 53 (52%). The median PFS, TTF and OS of the total cohort was 188 days (95% confidence interval: CI, 162 to 224), 161 days (95% CI, 146 to 183) and 369 days (95% CI, 309 to 440) respectively. The median RDI were 77% (range 30-100). In the RDI < 77% (n = 50) and the RDI ≥ 77% (n = 52) groups, the median PFS was 196 and 183 days (p = 0.33), the median TTF was 162 and 160 days (p = 0.186) and the median OS were 410 and 312 days (p = 0.10), respectively. Twenty-nine (28%) were eventually administered GEM+nab-PTX biweekly. The median RDI of biweekly regimen was 63% (range 29-86). The TTF of biweekly regimen and original weekly regimen was 196 and 160 days (p = 0.004) respectively. Conclusions: RDI is not a significant predictor of antitumor effects, and an appropriate dose reduction and extension of dosing interval may be permitted in pancreatic cancer patients treated with GEM+nab-PTX.
A new complementary approach to endoscopy for esophageal cancer diagnosis.
Authors: Jiang Gengxi , Tao Hongmei , Tang Xing , Lou Da , Lin Yue , Li Yutao , Wu Junjie , Wang Baoxia , Ding Ning , Xu Pengkun , He Xing , Hu Hao , Yu Chris Chang , Chen Hezhong , Du Xuedong
Published: March 2017

42

Background: For esophageal cancer, no viable non-invasive detection technologies are available today. In earlier investigations, Cancer Differentiation Analysis (CDA) Technology which measures information relating to both protein fragments and cellular signals in blood samples in a single test has showed a significant advantage in esophageal cancer diagnosis. Methods: Blood samples from 105 individuals in EDTA tubes were collected from Shanghai Changhai Hospital, China, between July and December 2014, CDA and endoscopy tests were carried out on all samples before clinically diagnosed. A performance predication model of CDA and endoscopy test results was built using pROC package in R Language for the data of Area Under the Curve (AUC) and CDA threshold values. Further analysis was carried out based on the CDA threshold values. Results: Out of the 105 individuals, samples from 6 individuals diagnosed as esophageal benign diseases were selected as control group. 99 samples from individuals diagnosed as esophageal cancer, of which 3 and 82 cases were adenocarcinoma and squamous carcinoma, 2, 26, 33, 31 and 7 cases were classified as stage 0,I,II, III, IV, respectively. Details of AUC results of endoscopy, and CDA plus endoscopy for each group were given in Table 1 below. Conclusions: Even though the sensitivity of the endoscopy is usually high due to its pathological examination, this investigation showed that CDA technology could further enhance the diagnosis sensitivity of endoscope, especially for early stage of esophageal cancer, and it (CDA) can be an effective complementary tool to clinical diagnosis and operation determination while obtaining the pathological information via endoscopy. In conclusion, CDA technology is of great value in esophageal diagnosis and therapeutic decision-making. [Table: see text]
Primary care vs. oncology-driven surveillance following adjuvant chemotherapy in resected pancreas cancer.
Authors: Samawi Haider H , Cheung Winson Y.
Published: March 2017

421

Background: Major oncology societies outline different recommendations following curative intent treatment for pancreas cancer and this has resulted in wide variations in practice among institutions. We aim to describe patterns of surveillance and evaluate their impact on outcomes. Methods: A total of 147 adult patients who received at least one cycle of adjuvant chemotherapy with gemcitabine or 5-fluorouracil monotherapy at any of the British Columbia Cancer Agency centers between 2004 and 2015 were included in this analysis. Surveillance strategies were divided into two groups: discharged to primary care physicians (PCP) or follow up with oncologists that included regular clinical assessments, laboratory testing and/or diagnostic imaging. Results: Median age at diagnosis was 64 (range 38-85) years and 48% were men. More patients were followed by oncologists than PCP (66% vs. 44%). Among the measured prognostic factors, only patients with advanced tumor stage (T3/4) were more likely to be followed by cancer specialists (78% vs. 62%, P = 0.03), while age, gender, performance status, node status, pathologic grade and surgical margins were balanced between the two groups. In the entire cohort, 100 (68%) patients had a documented recurrence. Patient followed by oncologists were more likely to receive chemotherapy on recurrence than those followed by PCP (58% vs. 34%, respectively, P = 0.03). The median overall survival (OS) was 2.82 (95% CI 2.17-3.32) years in the oncology group and 3.35 (95% CI 2.85-5.06) years in the PCP group while the median relapse free survival (RFS) was 2.4 (95% CI 2.07-4.59) and 1.4 (95%CI 1.37-1.77) years, respectively. On multivariate analysis, there was no significant difference in OS between oncology and PCP-driven surveillance (HR 1.23; 95% CI 0.74-2.04, P = 0.4); however, RFS favored the PCP group (HR 1.62; 95% CI 1.01-2.56, P = 0.04, for oncology). Conclusions: In this population-based analysis, surveillance tests and imaging performed by oncologists detected recurrences earlier when compared to follow up by PCPs, but this did not result in OS differences. PCPs may have a larger role in the follow up care of selected patients with resected pancreas cancer.
Prognostic factors in patients (pts) with advanced biliary tract cancer (BTC) treated with first-line gemcitabine plus cisplatin (GEMCIS): Retrospective analysis of 740 pts.
Authors: Cho Hyungwoo , Kim Bumjun , Yoo Changhoon , Kim Kyu-Pyo , Hyung Jaewon , Lee Sang Soo , Park Do Hyun , Song Tae Jun , Seo Dong Wan , Lee Sung Koo , Kim Myung-Hwan , Park Jin-hong , Chang Heung-Moon , Ryoo Baek-Yeol
Published: March 2017

424

Background: BTC is a heterogeneous group of disease consisted of intrahepatic, extrahepatic cholangiocarcinoma and gallbladder cancer. Although GEMCIS has been established as a standard first-line chemotherapy based on the ABC-02 trial, more data is needed to define the clinical course of BTC and its prognostic factors. Methods: Between April 2010 and May 2015, 740 pts with histologically documented BTC were treated with first-line GEMCIS in Asan Medical Center, Seoul, Korea. All pts received GEMCIS as described in the ABC-02 trial. Response was graded according to the RECIST version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Maier curves. Multivariate analyses were performed to define prognostic factors. Results: Median age was 60 years (range, 27-82) and 425 (57%) pts were male. Initially metastatic disease was the most common disease status at GEMCIS (n = 377, 51%) followed by recurrence after surgery (279, 38%) and locally advanced unresectable disease (84, 11%). Liver (37%) and peritoneum (25%) were the common metastatic sites. Pts received a median 5 cycles of GEMCIS (range, 1-42). Objective response rates were 13% and there was no significant difference according to the primary tumor sites (p = 0.45). With a median follow-up duration of 27.3 months (mo) (95% CI, 24.2-30.5), median PFS and OS were 5.2 mo (95% CI, 4.7-5.6) and 10.4 mo (95% CI, 9.6-11.2), respectively. In the multivariate analyses, male gender (female vs male; HR = 0.83), pretreatment CA 19-9 level (elevated vs normal; HR = 1.31), initially metastatic disease (vs locally advanced disease, HR = 1.92), poor performance status (ECOG 2 vs 0-1; HR = 1.45), and measurable disease by the RECIST criteria (vs non-measurable; HR = 1.40) were significantly associated with poorer OS (p < 0.05 for all). Conclusions: Our retrospective analysis based on large number of pts demonstrated that first-line GEMCIS in the real world setting has comparable efficacy with the results of the ABC-02 trial. Prognostic factors demonstrated in this study may help to predict clinical outcomes and design future clinical trials for advanced BTC.
Efficacy of fluoropyrimidine-based chemotherapy in patients with advanced biliary cancer after failure of gemcitabine plus cisplatin: Retrospective analysis of 321 patients.
Authors: Kang Jihoon , Kim Bumjun , Yoo Changhoon , Hyung Jaewon , Kim Kyu-Pyo , Ryoo Baek-Yeol , Chang Heung-Moon
Published: March 2017

425

Background: In advanced biliary tract cancer (BTC), the role of 2nd line chemotherapy after failure of 1st line gemcitabine plus cisplatin (GEMCIS) has not been established. Fluoropyrimidine(FP)-based regimens are widely used as 2nd line treatment in clinical practice. We retrospectively analyzed the efficacy of 2nd line FP-based chemotherapy in patients(pts) with advanced BTC after failure of GEMCIS. Methods: Histologically confirmed advanced BTC pts who received 1st line GEMCIS at Asan Medical Center between December 2010 and June 2016 were identified. Among 748 pts treated with GEMCIS, 331 patients (44%) subsequently received 2nd line chemotherapy and FP-based regimens were used in 321 pts (97%). Results: The median age was 60 years (range, 27-82) and 57% of pts were male. Intrahepatic cholangiocarcinoma(IH-CCC) (44%) was the most common type, and followed by extrahepatic cholangiocarcinoma (32%). Most pts (n = 289, 89%) had metastatic/recurrent disease at the time of 1st line treatment. FP alone and FP plus platinum combination were used in 255 pts (79%) and 66 pts (21%), respectively. In pts with measurable disease, response rate (RR) was 3% (8/301) and disease control rate was 47% (142/301). After a median follow-up of 27.6 months (0.9-70.4 months), the median progression free survival (PFS) and overall survival (OS) were 1.9 months (95% CI, 1.6-2.2) and 6.5 months (95% CI, 5.9-7.0). RR was significantly higher in pts with combination of FP and platinum compared to FP alone (8% vs 1%, p = 0.009). However, there were no statistically significant differences in terms of PFS (p = 0.43) or OS (p = 0.88) between two groups. In the multivariate analysis for OS, IH-CCC, initially metastatic disease and elevated CA 19-9 level at the time of 1st line treatment, and time-to-progression at 1st line GEMCIS > 4 months were independent poor prognostic factors. Conclusions: In this analysis, FP-based regimen showed modest efficacy as 2nd line chemotherapy for advanced BTC patients after failure of 1st line GEMCIS. Combination of FP and platinum was not associated with improved survival outcomes compared to FP monotherapy, despite of higher RR.
Risk factors associated with recurrent cholangitis in pancreatic and hepatobiliary cancers.
Authors: Jain Apurva , Song Juhee , Javle Milind M. , George Marina C.
Published: March 2017

428

Background: Acute cholangitis due to malignant biliary obstruction is frequent in patients with pancreatic and hepatobiliary cancers. Recurrent cholangitis (RC) results in repeated hospitalization and delayed cancer care. The risk factors associated with RC are not yet defined. Methods: A pilot review was done on 146 patients admitted with a diagnosis of cholangitis from 2005 to 2014. We included demographics, cancer stage, details of first admission (FA) and interventions. Univariate and multivariate Fine-Gray models were used for statistical analysis. Results: The mean age at FA was 62 yrs, 84 (58%) were males and 99 (68%) were white. Most common cancer was pancreatic 100(69%) and 27(19%) pts had primary cholangitis at FA. During FA, interventions were performed in 114(78%), of whom 51 (45%) had percutaneous drainage (PTBD) and 63 (55%) had endoscopic drainage (ED). Readmission with cholangitis was noted in 35 (24%) cases. Univariate analysis did not show a difference between PTBD and ED. However, subgroup analysis showed external only PTBD and covered metallic stent ED had lower risk of RC. These variables remained significant on multivariate analysis (Subdistribution HR= 0.00, p<.0001 for both). Multiple previous PTBD (≥2) before FA was significantly associated with increased risk of RC (Subdistribution HR= 2.64, p= 0.01) on univariate analysis. Conclusions: Having multiple previous PTBD is associated with recurrent cholangitis. Though no significant difference was noted between PTBD and ED, the subgroups indicated a trend towards less recurrent cholangitis with covered metallic stent. [Table: see text]
A phase II study of combretastatin A4-phosphate (CA4P) in the treatment of well-differentiated, low- to intermediate-grade, unresectable, recurrent, or metastatic pancreatic, or GI neuroendocrine tumors/carcinoid (GI-NETs/PNETs) with elevated biomarkers.
Authors: Libutti Steven K. , Anthony Lowell Brian , Chaplin David J. , Sosa Julie Ann
Published: March 2017

432

Background: GI-NETs/PNETs are highly vascular tumors. CA4P, a vascular disrupting agent (VDA), occludes tumor vasculature resulting in ischemic necrosis. Pre-clinical studies of CA4P have shown activity in GI-NETs/PNETs. Methods: OX4218s is a phase II, single-arm, open-label study (NCT02132468) of CA4P in patients (pts) with GI-NETs/PNETs with elevated biomarkers who relapsed during or after standard-of-care treatment. Pts received CA4P 60 mg/m2 IV on days 1, 8, and 15 of a 21-day cycle for 3 cycles. Primary endpoint was change in biomarkers from baseline. Secondary endpoints were safety, tolerability, symptoms, and QOL. Exploratory endpoints were ORR (RECIST 1.1). Pts achieving biomarker or symptom response were eligible for a rollover study. Results: 18 pts were enrolled; 7 subsequently entered the rollover study. Pts were on average aged 58 years, white (89%), male (50%) with ECOG status of 0-1. The majority (94%) had well-differentiated disease (GI-NETS 78%) and received prior Tx (94%). There were no meaningful changes in biomarkers. Eleven (61%) pts had stable disease (SD) and 1 (6%) had a partial response (PR). In the rollover study, 5 (71%) had SD, and 1 had SD for 14 cycles prior to progression (PD). 77% of pts had treatment-related AEs. Key grade 3-5 AEs (> 10%): anemia, abdominal pain, fatigue, hypertension, ALT and AST increases, with 1 grade 5 carcinoid syndrome. Conclusions: The primary endpoint was not met. However, the number of pts entering the rollover study and ORR suggest that CA4P conferred some activity and was generally safe and well tolerated. These findings suggest that due to their inherent variability, tumor biomarkers may not be an ideal endpoint for this population. Clinical trial information: NCT02132468. [Table: see text]
Biweekly cisplatin (C) and gemcitabine (G) in patients (pts) with advanced biliary tract cancer (ABTC): A retrospective analysis.
Authors: Ahn Daniel H. , Reardon Josh , Ahn Chul , Bupathi Manojkumar , Ciombor Kristen Keon , Wu Christina Sing-Ying , Bekaii-Saab Tanios S.
Published: March 2017

434

Background: Based on the ABC 02 trial, standard therapy for ABTC is CG for up to 8 cycles. However, a recent abstract (Doherty et al, ASCO 2016) confirmed that a cohort of pts does benefit from continued therapy. The weekly administration of G and C can add significant toxicities that may prohibit prolonged treatment (trmt). Previous studies have shown that a biweekly schedule (Ko AH et al JCO 2012) of fixed dose rate (FDR) G helps optimize the prescribed regimen with an improved toxicity profile and added convenience to pts while maintaining efficacy. Methods: Pts with ABTC treated with FDR G (1000mg/m2 at 10mg/m2/min) with C 20mg/m2(GC) on days 1 and 15 of every 28-day cycle were included for analysis. Pts received trmt until time of progression. Data was collected including demographics, clinico-pathologic features, toxicities and survival. Kaplan-Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). Results: The study included 109 evaluable pts with ABTC who received CG. Pts had disease that was locally advanced (16.5%) or metastatic (83.5%). Median age was 60 years (28-86). Sites of tumor included gallbladder (21.1%), ampullary (3.6%) and bile duct (75.2%). Median number of cycles was 6 (1-27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade 3 or 4 adverse events included neutropenia (11%), fatigue (10%), thrombocytopenia (TCP) (6.4%), anemia (2.8%), and abnormal liver function tests (2.8%). Fifty-two percent of pts received second line therapy. Conclusions: Biweekly CG in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many. Further prospective exploration should consider evaluating the role of biweekly gemcitabine and cisplatin regimen in ABTC especially as a potentially more favorable platform to combine with novel agents. [Table: see text]
Discharge to a skilled nursing facility as the strongest modifiable risk factor for readmissions following pancreaticoduodenectomy.
Authors: Mirkin Katelin Anne , Hollenbeak Christopher S , Cooper Amanda Beth , Gusani Niraj Jaysukh
Published: March 2017

435

Background: Pancreaticoduodenectomy is a technically difficult and notoriously morbid procedure. As payers begin to link reimbursement to readmission rates, there is growing interest in understanding and preventing readmissions. The objective of this study was to evaluate factors contributing to 30-day readmission rates for patients undergoing pancreaticoduodenectomy. Methods: Data from the Pennsylvania Health Care Cost Containment Council (PHC4) were reviewed for patients undergoing pancreaticoduodenectomy from 2011-2014 (n = 1,552). Outcomes included 30-day readmission and length of stay (LOS). Univariate comparisons were performed between characteristics of those readmitted (n = 404) and not readmitted (n = 1,148). Readmission and LOS were modeled using multivariate logistic regression and linear regression, respectively. Results: Of the 404 (26.0%) patients who were readmitted, the most common causes for readmission were post-operative infection (26.2%), anastomotic complications (8.0%), and dehydration (5.7%). Patients who were readmitted were more likely to be discharged to a skilled nursing facility (SNF) and were associated with a longer LOS of index admission (p < 0.001, both). In multivariate analysis, black race (HR 1.96, p = 0.001), discharge to a SNF (HR 1.73, p = 0.006) and increased LOS (HR 1.36, p = 0.019), were associated with increased odds of readmission. After controlling for patient, admission, and facility characteristics, black race, urgent and emergent admissions, and discharge to a SNF or home with home healthcare, were predictive of a longer LOS (p < 0.05). High surgeon volume, and high hospital volume were associated with a shorter LOS (p < 0.05). Conclusions: The most common causes of readmission following pancreaticoduodenectomy in Pennsylvania from 2011-2014 were post-operative infection, anastomotic complications, and dehydration. Patients with a longer initial hospital stay and those discharged to a SNF were associated with higher odds of readmission. Understanding the interplay of these factors may result in opportunities to prevent readmissions, and improve outcomes in patients undergoing this complex surgery.
Correlation of circulating IL-8 levels with improved overall survival in advanced pancreatic cancer patients in response to antisense OT-101 (trabedersen) therapy.
Authors: Trieu Vuong N. , D'Cruz Osmond , Qazi Sanjive , Ng Kevin , Hwang Larn
Published: March 2017

444

Background: Overexpression of the transforming growth factor-beta 2 (TGF-β2) has been suggested as a pivotal factor for malignant progression of pancreatic cancer (PAC). OT-101 (Trabedersen) is a phosphorothioate antisense oligodeoxynucleotide target the human TGF-β2 mRNA. A Phase I/II study of OT-101 was characterized by outstanding overall survival (OS) in patients with advanced PAC. In this study, we examined the association between plasma levels of 31 cyto-/chemokines and OS outcomes in PAC patients treated with OT-101. Methods: Plasma levels of 31 cyto-/chemokine were tracked over a period of 11 days at 8 time points during 3 cycles of intravenous OT-101 therapy (140 mg/m2/day) for 12 PAC patients. A mixed ANCOVA model was developed to time evolution of 19 cyto-/chemokine levels with median expression 1 following OT-101 therapy. Pearson pairwise correlation coefficients of cyto-/chemokine levels across all time points and all patients were utilized to construct a correlation cluster to identify co-regulated cyto-/chemokines. Regression and hierarchical cluster analyses were performed to identify potential cytokine signatures. Protein-protein interaction networks were constructed using STRING10 algorithm. Plasma cyto-/chemokine levels were compared with OS outcome. Results: Three highly correlated subsets of cyto-/chemokines (Cluster 1: EGF, MIP-1α, MIP-1b; Cluster 2: FGF-2, IL-1R, MIG, IP-10, IL-15, IFN-α, IL-12A; Cluster 3: IL-2R, IL-6, IL-8, HGF) were identified following OT-101 therapy. An increasing trend was observed among 13 cytokines. 4 of the 12 patients exhibited a consistent increase in MIP-1α and IL-1b. Suppression of TGF-b signaling by OT-101 led to upregulation of IL-15, IP-10 and HGF. 3 significant associations of cyto-/chemokine and OS were observed at Cycle 1 measurements. The ANCOVA model that examined the levels of 31 cyto-/chemokines with OS as the co-variate resulted in IL-8 exhibiting a significant positive association with OS ( P= 0.0039). Conclusions: Levels of IL-8 were positively associated with OS across 12 PAC patients serving as potential biomarkers for treatment outcome following OT-101 therapy. Clinical trial information: NCT00844064.