bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of chemoradiotherapy with docetaxel for elderly patients with stage II/III esophageal carcinoma: An updated report.
Authors: Ohba Akihiro , Hashimoto Jun , Kato Ken , Ito Yoshinori , Hokamura Nobukazu , Katada Chikatoshi , Ishiyama Hiromichi , Yamamoto Sachiko , Ura Takashi , Kodaira Takeshi , Kudo Shigehiro , Nakamura Takayuki
Published: February 2017

208

Background: Definitive chemoradiotherapy (CRT) is one of the curative options for resectable esophageal carcinoma (EC). However, there are limited data on CRT in elderly patients, and it is difficult for elderly patients to receive chemotherapy containing cisplatin. The aim of this prospective study was to clarify the efficacy and safety of definitive CRT with docetaxel (DTX) in elderly patients. Methods: The eligibility criteria for this study were as follows: clinical stage II-III (UICC 6th, non-T4) EC; performance status (PS) 0-1; age > 70; and no desire for surgical treatment. Chemotherapy consisted of 6 cycles of a 1-h infusion of DTX (10 mg/m2) repeated weekly. Radiation was concurrently applied at a dose of 60 Gy in 30 fractions. We calculated that with a sample size of 37 patients, assuming that the expected and threshold 2-year survival was 50% and 30% with one-sided alpha of 5% with 80% power. Results: Between July 2008 and January 2011, 16 patients were enrolled. The study was closed prematurely due to poor accrual. The median age was 77 years (range, 73-81); male/female: 14/2; PS 0/1: 4/12; clinical Stage IIA/IIB/III: 3/4/9. Of the 16 patients, 14 (88%) completed the CRT, 1 patient (6%) could not complete the treatment because of grade 3 esophagitis, and 1 (6%) refused to continue the treatment. The median follow-up time was 57.9 months. Six patients achieved complete response (CR), resulting in a 37.5% CR rate (95% confidence interval (CI): 15.2-64.6). The 2-year overall survival rate was 62.5% (95% CI: 39.0-86.0). The median survival time was 27.8months (95% CI: 23.7-31.9). Acute toxicities included grade 3/4 esophagitis (31%), anorexia (13%), leukopenia (6%), neutropenia (6%), thrombocytopenia (6%), mucositis (6%), and infection (6%). No treatment-related deaths were observed. Grade 3 or 4 esophagitis, pleural effusion, pericardial effusion, and pneumonitis developed as late adverse events in 13%, 13%, 6%, and 6% of patients, respectively. Conclusions: Although it is difficult to conclude about efficacy of CRT with DTX for elderly stage II-III EC patients, considering that this study was terminated prematurely, CRT with DTX seemed to have substantial clinical activity. Clinical trial information: 000001846.
Usefulness of modified PERCIST for defining response of neoadjuvant chemotherapy in esophageal cancer.
Authors: Izumi Daisuke , Yoshida Naoya , Watanabe Masayuki , Ishimoto Takatsugu , Kosumi Keisuke , Tokunaga Ryuma , Harada Kazuto , Ida Satoshi , Hiyoshi Yukiharu , Iwagami Shiro , Baba Yoshifumi , Sakamoto Yasuo , Miyamoto Yuji , Baba Hideo
Published: February 2017

209

Background: It is sometimes difficult to exactly measure maximum diameters of tumor after chemotherapy in esophageal cancer. Richard et al. proposed PET Response Criteria in Solid Tumor (PERCIST) for assessing response of tumor after chemotherapy by PET in 2009. The first purpose is to investigate the utility of PERCIST after neoadjvant chemotherapy in esophageal cancer. The second purpose is to clarify the utility of modified PERCIST of which we use the SUV of normal (non-cancerous) esophagus as a reference of comparison for diagnosing complete response (CR) instead of the right lobe liver SUV. Methods: The clinicopathological data of the 71 esophageal cancer patients who received neoadjuvant chemotherapy (DCF) and underwent curative resection from November 2008 to May 2012 were collected. Among them, we compared pathological grade with PERCIST of the 26 esophageal cancer patients who were examined by PET before and after chemotherapy. Furthermore we investigated which reference of comparison is appropriate for diagnosing complete response between the right lobe of liver (L group) and normal esophagus (E group). Results: We could measure the tumor size of all cases after chemotherapy by PERCIST although 6 cases could not be assessed by RECIST. All of the 6 cases which were diagnosed as stable disease or progressive disease by PERCIST were pathological grade1a. The cases of complete response are 7 cases in L group and 3 cases in esophageal cases. Among the complete response cases in L group, 1 case were pathological grade1 a and 2 cases were grade 2 although all the complete response cases in E group were pathological grade 3. One case of L group relapsed after curative resection although there was no recurrent case in E group. Conclusions: The esophageal cancer patients often have history of massive alcohol intake or liver damage caused by viral hepatitis or fatty liver. Although PERCIST is useful for evaluating the effect of neoadjuvant chemotherapy of esophageal cancer, it is better to use normal esophagus as a comparison standard for diagnosing complete response.
The prognostic factors and the cause of death in patients with advanced or recurrent gastric cancer.
Authors: Lee Sang Woo , Choi In Keun , Lee Chang Min , Kim Seung Young , Hyun Jong Jin , Jung Sung Woo , Jung Young Kul , Koo Ja Seol , Kim Jong-Han , Park Seong-Heum , Kim Seung-Joo , Kim Jun Suk
Published: February 2017

215

Background: The purpose of this study is to evaluate significant prognostic factor and compare the cause of death in patients with advanced or recurrent gastric cancer. Methods: We reviewed the medical records of 170 patients who had been diagnosed as advanced or recurrent gastric cancer between January 2006 and September 2013. The patients were divided into two groups. One group (advanced gastric cancer: AC) included 104 patients had undergone chemotherapy for advanced gastric cancer, and the other group (recurrent gastric cancer: RC) 66 for recurrence after surgical treatment. The causes of death and overall survival were compared between two groups, and the significant prognostic factors were investigated by multivariate analysis. Also, subgroup analysis was performed for 18 patients with gastrectomy for curative intent, and they were proved to have unresectable gastric cancer after surgery (non-palliative surgery for advanced gastric cancer: NS). Results: In the comparison for the causes of death, two groups showed no statistical difference, but AC group had more tendency to die because of bleeding ( p = 0.054) and infection ( p = 0.075). Overall survival of AC group did not differ from that of RC ( p = 0.901). In multivariate analysis, bone metastasis ( p = 0.013, HR = 1.923), peritoneal seeding ( p = 0.001, HR = 2.182) and the frequency of chemotherapy ( p < 0.001, HR = 0.887) were significantly associated with the overall survival. In a subgroup analysis, the overall survival of NS was significantly higher than AC ( p = 0.032). Conclusions: In the patients with advanced or recurrent gastric cancer, AC might have more possibility to die because of bleeding and infection than RC. Additionally, the prognosis of patients with advanced or recurrent gastric cancer was affected by the presence of bone metastasis, peritoneal seeding and frequency of chemotherapy. Non-palliative surgery for gastric cancer might show the better prognosis than AC in the specific conditions.
Impact of first-line fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with advanced gastroesophageal adenocarcinoma: A retrospective analysis.
Authors: Lino Aline Da Rocha , Moreira Raphael Brandao , Gomes Jessica Ribeiro , Sousa Tarcia Tarciane Soares de , Abrahao Carina Mina , Martins Junior Rodnei Merlrina , Alessandretti Matheus Bongers , Amarante Marcus Paulo Fernandes , Schutz Fabio Augusto Barros , Kawamura Carolina , Schmerling Rafael , Cruz Marcelo Rocha , Maluf Fernando C. , Buzaid Antonio C. , Peixoto Renata D'Alpino
Published: February 2017

216

Background: Despite a large number of randomized trials, there is no consensus as to the best regimen for advanced gastroesophageal cancer. Combination therapy with docetaxel, cisplatin, and 5-FU has shown increased response rates, progression-free survival (PFS) and overall survival (OS), but at the cost of significant toxicity. Based on a small phase II study, FLOT has been adopted by some groups given its better toxicity profile. We aim at reporting our experience with this regimen Methods: Patients with unresectable advanced gastroesophageal adenocarcinoma who received FLOT (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24h infusion in combination with docetaxel 50 mg/m2 on day 1 every 2 weeks) as first-line therapy at our institution were retrospectively evaluated. PFS and OS were estimated by the Kaplan-Meier method. Results: A total of 23 patients were reviewed, most of them with metastatic disease (60%). Median age was 56 years (range 26–76) and 74% were male. Median PFS and OS were 5,2 (95% CI 4,0-6,3) and 8,5 months (95% CI 4,4-12,6), respectively. Only 13%of the patients experienced prolonged PFS (>12 months). There were no deaths due to the treatment. Conclusions: Before FLOT could be adopted as a first-line regimen for metastatic gastroesophageal cancer, phase III trials are urgently needed comparing FLOT with more traditional regimens.
The comparison of the usefulness of nab-paclitaxel and paclitaxel for advanced or recurrent gastric cancer.
Authors: Kimura Yasue , Kusumoto Tetsuya , Kusumoto Eiji , Sugiyama Masahiko , Ohta Mitsuhiko , Tsutsumi Norifumi , Sakaguchi Yoshihisa , Ikejiri Koji
Published: February 2017

217

Background: For patients who do not respond to S-1-based treatment in Japan, weekly paclitaxel (PTX) therapy is more frequently used as second-line chemotherapy. On the other hand, the agent could not be used for alcohol hypersensitivity in some cases. Nab-Paclitaxel (N-PTX), which is the protein-bound paclitaxel, has recently been introduced in Japan. The purpose of this study was to retrospectively determine the more preferable agent, N-PTX or PTX, following the S-1-containing chemotherapy in patients with advanced or recurrent gastric cancer (ARGC). Methods: We conducted a retrospective review of the data for 40 patients with ARGC, who received either N-PTX monotherapy for 5 patients or PTX monotherapy for 35 patients. N-PTX was used as the second-line for all patients in this group. On the other hand, in the PTX group, 4, 28 and 3 patients received PTX monotherapy as the 1st-, 2nd- and 3rd-line, respectively. N-PTX was administered intravenously at a dose of 260 mg/m2 repeated triweekly. PTX was administered intravenously at a dose of 80 mg/m2repeated weekly (on days 1, 8 and 15) every four weeks. The objective response rate (ORR), adverse events, progression-free survival (PFS) were compared between the two groups. Results: For tumor response, in the N-PTX group, CR/PR/SD/PD were 0/3/1/1, respectively for an ORR of 60% and a DCR of 80%; in the PTX group, CR/PR/SD/PD were 0/3/15/13, respectively for an ORR of 10% and a DCR of 58%. The ORR of the N-PTX group was higher, which might result from the higher dose intensity in the group, compared with the PTX group. For the adverse toxicity, in the both group, events of grade ≥ 3 were not observed. Serious neurotoxicity (≥grade 3), as commonly described for treatment with paclitaxel, was not observed in this study. The survival data showed that the PFS was 253 days in the N-PTX group, compared with 176 days in the PTX group, which were not significantly different. Conclusions: We suggest the application of N-PTX in place of PTX after S-1 containing chemotherapy for ARGC, only from the perspective of the tumor response. Further data accumulation is required for overall survival.
Efficacy and feasibility of neoadjuvant chemotherapy for elderly patients with stage II/III esophageal cancer: Retrospective study.
Authors: Miyamoto Takahiro , Terazawa Tetsuji , Goto Masahiro , Asaishi Ken , Shimamoto Fukutaro , Kuwakado Shin , Nishitani Hitoshi , Kii Takayuki , Kawai Masaru , Higuchi Kazuhide
Published: February 2017

220

Background: From the result of JCOG 9907 study, which showed the supremacy of neoadjuvant chemotherapy (NAC) of 5-fluorouracil plus cisplatin infusion (FP) over adjuvant chemotherapy, NAC FP is standard therapy for stage II or III esophageal cancer in Japan. However, the efficacy and feasibility of NAC FP for elderly patients (pts) still remains unclear. Methods: We examined stage II or III esophageal cancer patients aged 70 or over, who received NAC FP at our institution between April 2008 and August 2014, retrospectively. Results: 12 pts received NAC FP at least 1 course. The pts characteristics were as follows: median age (range), 73 (70-78); male/ female, 11/1; PS 0/1, 3/9. Location of primary tumor and clinical stage based on UICC 2009 were as follows: upper/middle/lower, 3/6/3; stage IIA/IIB/IIIA/IIIB, 3/3/3/3. 2 pts (16.7%) occurred grade3/4 neutropenia (16.7%). grade3/4 non-hematotoxicities were nausea; 2 pts (16.7%), vomiting; 1 pt (8.3%), appetite loss; 4 pts (33.3%), stomatitis; 1 pt (8.3%) and acute kidney injury; 1 pt (8.3%). 3 pts were underwent surgery after 1 course of NAC FP due to renal dysfunction. 3 pts were not performed surgery because of decreased respiratory function, decreased PS and progression disease. 9 pts were performed surgery after NAC FP. The histological efficacy was 1a/1b/2/3; 4/3/1/1 and curativity was R0 (degree A)/R0 (degree B); 8/1. 4 pts (44%) had down staging. Median follow-up time was 16.5 months (range; 4-63), the 5-year relapse free survival rate was 19.0% (95% CI: 2.7-66.4%) and the 5-year overall survival rate was 67% (95% CI: 32-89%). Conclusions: NAC FP for stage II/III esophageal cancer might be effective even in pts ≥70 years of age. However, gastrointestinal toxicity and renal toxicity were developed frequently, therefore the indication of NAC FP for elderly pts must be decided carefully.
The possibilities of treatment of gastrointestinal stromal tumors.
Authors: Gluszek Stanislaw , Koziel Dorota , Matykiewicz Jarosław , Rylski Rafal
Published: February 2017

222

Background: Gastrointestinal stromal tumour (GIST) is the most common mesenchymal tumour of digestive tract, presesting less than 1% of all digestive tumours. This study is analyse a group of patients treated surgically due to GIST. Methods: The group of 71 patients consisted of 34 males and 37 females between the age of 32 and 89 (M 44-83, average 64.6; F 43-89, average 66.5) treated surgically due to GIST. Analysis included clinical symptoms, diagnosis, surgical treatment, location of tumour, outcome of histopathological and immunohistochemical examinations, recurrence of disease, metastases and mortality rate. Results: Among 71 GIST patients 35 were with low aggressivity level, 14 with average and 22 with high. Most of patients were subjected to surgical treatment (laparoscopic or open) on a planned basis and in 3 cases on an emergency basis due to the intensified symptoms of intestinal occlusion, 50 patients were found to have gastric tumours, 3 duodenal tumours, 13 small intestine tumours, 3 colonic tumours, 2 rectal tumours. Histopathological examination outcome showed radical tumour resection in all cases Tumours of size exceeding 5 cm in diameter were found in 30 cases. Most patients had definited type of mutation. Predominated mutations localized in exon 11. There was no perioperative mortality rate. During follow up (from 1 month to 130 months), 16 patients died, including 4 due to GIST dissemination, 4 were diagnosed with recurrence of GIST and two of them were qualified for imatinib treatment others died of cardio-vasculary diseases. Most of patient underwent resection of tumor with safety margin of gastric wall (21), 5 patients were treated by laparoscopic surgery. All patients, who subsequently had postoperative recurrence or died due to GIST metastases, were diagnosed with highly aggressive tumor. Conclusions: GIST - still unknown treatment possibilities [surgery, imatinib, other specific tyrosine kinase inhibitors, what next?]. Analysis of cases from our study confirms that large size of tumor (diameter > 5cm) and high mitotic index (MI >5/50 HPF) are factors associated with bad prognosis (metastases, recurrence).
Intraoperatively assessed macroscopic serosal changes in patients with curatively resected advanced gastric cancer (GC): Clinical implications for prognosis and peritoneal recurrence.
Authors: Yoo Changhoon , Ryu Min-Hee , Chang Heung-Moon , Yook Jeong Hwan , Park Young Soo , Ryoo Baek-Yeol , Park Sook Ryun , Oh Sung Tae , Kim Byung Sik , Kang Yoon-Koo
Published: February 2017

23

Background: To validate the prognostic relevance of macroscopic serosal changes in patients with resected GC, we analyzed prospectively collected databases of two multicenter randomized phase III trials on adjuvant chemotherapy. Methods: In total, 655 patients in the control groups of AMC 0101 (NCT00296322) and 0201 (NCT00296335) trials were selected. Macroscopic serosal changes were determined according to disruptions in serosal continuity, such as changes in color or nodular texture by the operating surgeon. Correlations with recurrence-free survival (RFS), overall survival (OS), and time-to-peritoneal recurrence were analyzed. Results: About two-thirds of the patients were male (69%), and the median age was 55 years (range = 29–70 years). According to Lauren’s classification, 215 patients (33%) showed intestinal type. After a median follow-up period of 61.6 months (range = 2.6–113.9 months), the 5-year RFS and OS rates were 55.0% (95% CI = 51.2–58.9%) and 59.9% (95% CI = 56.2–63.6%), respectively. Intraoperatively assessed macroscopic serosal changes were identified in 432 patients (66%). This was significantly associated with multifocal or diffuse gastric cancer (p = 0.001), Borrmann type IV (p = 0.005), advanced pathological T stage (p < 0.001), advanced pathological N stage (p < 0.001), advanced pathological stage (p < 0.001), and total gastrectomy (p < 0.001). In multivariate analyses, which included prognostic factors of localized gastric cancer, macroscopically serosal changes were significantly associated with poor RFS (hazard ratio [HR] = 2.0, 95% CI 1.4–2.7; p < 0.001) and OS (HR = 2.1, 95% CI 1.5–3.0; p < 0.001). It was also significantly related with shorter time-to-peritoneal recurrence (HR = 2.9; 95% CI = 1.7–5.0; p< 0.001). Conclusions: Intraoperatively assessed macroscopic serosal changes confer a poor prognosis and increased peritoneal recurrence in patients with curatively resected GC. Macroscopic assessment of serosal changes may be a useful indicator that allows better risk stratification of patients with resected GC in terms of prognosis and peritoneal recurrence.
eNOS polymorphisms in relation to outcome in advanced HCC patients receiving sorafenib.
Authors: Casadei Gardini Andrea , Marisi Giorgia , Scarpi Emanuela , Scartozzi Mario , Faloppi Luca , Tenti Elena , Tamberi Stefano , Foschi francesco Giuseppe , Tamburini Emiliano , Frassineti Giovanni Luca , Cascinu Stefano , Ulivi Paola
Published: February 2017

230

Background: Cancer cells adapt to hypoxic microenvironment through the activation of many molecules, including endothelial nitric oxide synthase (eNOS). Sorafenib, by blocking the vascular endothelial growth factor receptors (VEGFRs), induces an inhibition of eNOS activity with a consequent decrease of the production of nitric oxide (NO). NO is associated with an increase of tumor angiogenesis, tumor invasion and metastasis formation. In our study we analysed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma treated with sorafenib. Methods: From a database of 257 patients diagnosed with hepatocellular carcinoma from 2004 to 2014, we selected 54 patients who received sorafenib. Peripheral blood samples or FFPE tumor tissues were available for DNA extraction and genotyping analysis. Three eNOS polymorphisms (eNOS +894 G/T, eNOS VNTR 27bp 4a/b, eNOS -786 C/T) were analyzed by direct sequencing or Real Time PCR method. We analyzed 21 patients for the VNTR 4a/b polymorphism and 32 patients for -786 C/T polymorphism. All the candidate genotypes were evaluated to identify a potential correlation with overall survival (OS) (log-rank test). Results: With regard to eNOS VNTR it was observed that patients carrying the b allele (5 repetitions of 27bp) both in homozygosity (4bb) and in heterozygosity (4ab) were associated with a better OS. The variants 4aa (4 repeats of 27bp in homozygosity), 4ab and 4bb, were associated with a median OS of 5.7, 13.9 and 23.6 months, respectively (p = 0.016). For eNOS-786 the presence of the T allele both in homozygosity (TT) and in heterozygosity(TC) was associated with a statistically significant longer OS with respect to patients with CC genotype (15.6 versus 13.9 months, respectively, p = 0.031). No correlations were observed in relation to PFS (p = 0.494). Conclusions: eNOS VNTR and eNOS -786 could represent prognostic markers in patients with advanced hepatocellular carcinoma treated with sorafenib.
Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): Analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study.
Authors: Zhu Andrew X. , Ryoo Baek-Yeol , Yen Chia-Jui , Kudo Masatoshi , Poon Ronnie Tung-Ping , Pastorelli Davide , Blanc Jean-Frédéric , Chung Hyun Cheol , Baron Ari David , Pfiffer Tulio Eduardo Flesch , Okusaka Takuji , Kubackova Katerina , Trojan Jorg , Sastre Javier , Chau Ian , Chang Shao-Chun , Abada Paolo , Yang Ling , Hsu Yanzhi , Park Joon Oh
Published: February 2017

232

Background: REACH was a global, multicenter, randomized, double-blind, phase 3 study evaluating the efficacy and safety of RAM as a single agent for the treatment of pts with advanced HCC after prior sorafenib therapy. The primary outcome for REACH was presented at ESMO 2014. The overall survival (OS) HR for the ITT population (RAM 283; placebo [PBO] 282) was 0.866 (95% CI 0.717, 1.046; p=0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. The pre-specified subgroup analysis of baseline AFP (cutoff 400 ng/mL) suggested AFP is a predictive marker for RAM survival benefit. Methods: Pre-specified subgroup analysis was performed based on baseline AFP with a cutoff of 400 ng/mL. Additional analyses were conducted using stratified/unstratified cox regression models and corresponding log rank test to evaluate the relationship between baseline AFP and RAM treatment effect. Results: In 250 pts with baseline AFP ≥400 ng/mL (RAM 119; PBO 131), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059). Median OS was 7.8m for RAM vs 4.2m for PBO. In 417 pts with a baseline AFP ≥1.5 × upper limit of normal (ULN; RAM 205; PBO 212), mOS was 8.6m for RAM vs 5.7m for PBO and the HR was 0.749 (95% CI: 0.603, 0.930) (p=0.0088). The interaction testing of baseline AFP and RAM treatment effect on OS using both cutoffs (400 ng/mL and 1.5 xULN) are significant (p-value = 0.0272 and 0.0372, respectively). The safety profile in these pt populations was similar to that observed in the overall safety population. Additional REACH analyses demonstrating the predictive value of baseline AFP for RAM treatment effect on OS will be presented. Conclusions: A clinically meaningful improvement in OS was observed in populations with a baseline AFP ≥400 ng/mL or ≥1.5 × ULN. Additional analyses demonstrated a consistent RAM OS benefit for the pt population with baseline AFP over a wide range of values above the normal range. Baseline AFP is a likely predictive marker for RAM OS benefit. Clinical trial information: NCT01140347.
Expanded analyses of napoli-1: Phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.
Authors: Chen Li-Tzong , Von Hoff Daniel D. , Li Chung-Pin , Wang-Gillam Andrea , Bodoky Gyorgy , Dean Andrew Peter , Shan Yan-Shen , Jameson Gayle S. , Macarulla Teresa , Lee Kyung-Hun , Cunningham David , Blanc Jean-Frédéric , Hubner Richard , Chiu Chang-Fang , Schwartsmann Gilberto , Siveke Jens T , Braiteh Fadi S. , Moyo Victor M. , Belanger Bruce , Bayever Eliel
Published: February 2017

234

Background: MM-398 is a nanoliposomal encapsulation of irinotecan. OS in the ITT population was significantly longer with MM-398+5FU/LV over 5FU/LV alone, and the most frequent grade 3+ AEs included neutropenia, fatigue, and GI effects (diarrhea and vomiting). Expanded, pre-specified analyses of the Phase 3 study are presented. Methods: Patients (n=417) with mPAC previously treated with gemcitabine-based therapy, were randomized 1:1:1 in an open-label study to receive: (A) MM-398 (120 mg/m2 IV over 90 min) q3w; (B) 5FU (2,000 mg/m2 over 24 h) plus racemic leucovorin (LV) (200 mg/m2 over 30 min) x 4w followed by 2w rest; or (C) combination of MM-398 (80 mg/m2 IV over 90 min) prior to 5FU (2,400 mg/m2 over 46 h) and racemic LV (400 mg/m2 over 30 min) q2w. The primary endpoint was OS. The Intent To Treat (ITT) population included all randomized patients; the Per Protocol (PP) population included patients who received at least 80% of the target dose in the first 6 weeks and did not violate any inclusion/exclusion criteria. Results: Analysis of the PP populations confirmed the favorable OS, which was also reflected by the PFS, ORR and CA19-9 levels, of the combination MM-398+5FU/LV arm over the control 5FU/LV arm. The MM-398 monotherapy arm did not show a statistically significant improvement in OS compared with the control arm. Analysis of subgroups, based on pretreatment characteristics including stage at diagnosis, time since initial histological diagnosis, prior lines of therapy, time since last prior therapy, and CA19-9 levels, consistently favored OS for the MM-398+5FU/LV arm over the 5FU/LV arm. Conclusions: Expanded analysis of the PP population and sensitivity analyses support the favorability of MM-398+5FU/LV over 5FU/LV, with a manageable safety profile. Clinical trial information: NCT01494506. [Table: see text]
New prognostic staging system from the multivariate survival analysis (MVA) of the patients with unresectable hepatocellular carcinoma (HCC) treated with doxorubicin drug eluting beads transarterial chemoembolization (DEB TACE).
Authors: Prajapati Hasmukh J. , Kim Hyun Sik
Published: February 2017

236

Background: To develop the staging system from MVA in pts with unresectable HCC treated with DEB TACE. Methods: Consecutive unresectable and non-tranplantable pts with HCC, who received DEB TACE over the 88 months(m), were studied. 420 pts (mean age, 61.4 yrs) were included in the study. Survivals were analyzed according to different parameters from the time of the 1st DEB TACE. Kaplan Meier estimator by log rank test and Cox Proportional Hazard model were used for survival analysis. The staging system was constructed from the survival analyses. Results: The overall median survival (OS) was 20m. Pts with Child Pugh (CP) class A(54.5%), B(40.2%) and C(5.3%) had OSs of 28m, 12.9m and 4.1m respectively (p<0.0001). Pts with BCLC A(9.3%), B(21.2%), C(61.4%) and D(8.1%) had OSs of 37m, 30m, 17.2 and 4.4m respectively (p<0.0001). In HCC pts with venous thrombosis (VT) of large vein (main PV, right or left PV, HV, IVC) (72.7%) versus (vs) small vein (segmental/subsegmental PV) had OSs of 5.8m versus 17.3m accordingly (p=0.008). Pts with Alfa-feto protein (AFP) >400ng/dl had OS of 7.6m vs 24.3 m with AFP<400 (p<0.0001). On MVA, the significant independent PFs of survival were CP class, ECOG PS, number (no) of HCC, index HCC (iHCC) size, site of Portal or hepatic VT, extra-hepatic metastasis (mets), serum(s) creatinine, and s.AFP. Based on these PFs, the staging system was constructed, which is shown in table 1 and named as CIS (Clinical, Imaging and Serum examination) staging system. The OSs of stage I, II, III and IV were 40.4m, 24m, 10.6m, and 2.6m respectively (p<0.0001). Conclusions: We propose the new CIS prognostic staging system for advanced HCC from the MVA of survival after DEB TACE in pts with unresectable HCC. [Table: see text]
The management of small asymptomatic pancreatic neuroendocrine tumors: A matched case-control study.
Authors: Sadot Eran , Reidy Diane Lauren , Tang Laura H. , Gonen Mithat , D'Angelica Michael Ian , DeMatteo Ronald P. , Kingham T. Peter , Jarnagin William R. , Allen Peter J.
Published: February 2017

239

Background: Overdiagnosis and overtreatment has become an evolving challenge for several cancer sub-types. We hypothesized that a substantial portion of incidentally diagnosed small pancreatic neuroendocrine tumors(PanNET) are overtreated as a result of overdiagnosis and that non-operative management may be reasonable for selected patients. Methods: Consecutive patients evaluated for incidentally discovered, sporadic, stage I-II PanNET were analyzed retrospectively. Diagnosis was determined either by pathology or unequivocal imaging characteristics. Patients selected for radiographic surveillance (RS) were matched with patients who underwent resection based on tumor size at initial imaging. Clinicopathological characteristics were compared between the groups. Results: During the study period (2000-2013), RS was recommended for 80 patients, and 79 matched patients underwent resection (resection group). Pathologic diagnosis was obtained in 42 (53%) of the 80 RS patients. Median initial tumor size was similar between the RS vs resection groups (1.2cm (0.8-1.7) vs 1.3 cm (1-1.9), respectively, p=0.4). The resection group was younger and had a longer median follow-up compared to the RS group (58 vs 65 years, p<0.001; 50 vs 29 months, p=0.006; respectively). At the time of last follow-up of the RS group, median tumor size had not changed (1.2cm, p=0.4), no patient had developed metastases, and no patient had experienced radiographic changes in the primary tumor that prompted resection. Within the resection group, low-grade (G1) pathology was recorded in 74 (95%) tumors, one patient had node positive disease, and five developed recurrence (6%). The postoperative complication rate was 36%. No patient in either group died from disease. Death from other causes occurred in 7 out of 159(4%) patients. Conclusions: In this study, no patient who was selected for observation developed metastases or died from disease after a median follow-up of almost 2.5 years.Radiographic surveillance for stable, small, incidentally discovered PanNETs is reasonable in selected patients.
A phase I/II multicenter study of the chimeric monoclonal antibody NEO102 (NPC-1C) in adults with refractory pancreatic (PC) and colorectal cancer (CC).
Authors: Beg Muhammad Shaalan , Morse Michael , Patel Sandip Pravin , Mavroukakis Sharon , Beatson Melony A. , Arlen Philip M. , Azad Nilofer Saba
Published: February 2017

240

Background: NPC-1C (NEO102) is a novel chimeric monoclonal antibody that recognizes a variant form of MUC5AC expressed specifically by human pancreatic (P) and colorectal (CC) tumors. The mechanism of action is through Antibody-dependent cell-mediated cytotoxicity (ADCC). We are presenting results of dose escalation and preplanned expansion cohort of NEO-102. Methods: This is a Phase Ib/IIa, open label, multicenter clinical trial and expansion cohort of NEO102. Patients are preselected based on an Immunuhistochemistry (IHC) companion diagnostic assay. Antigen expression cut off was set at 20% expression. NEO102 was administered every 2 weeks IV with tumor assessments every 8 weeks. The primary objective was to determine safety and tolerability of NEO102. Secondary objectives include overall survival, clinical benefit, pharmacokinetics and explore the immunologic correlates. Results: Twenty-six patients (3 pancreatic and 23 colon cancer) are evaluable for toxicity and response. Median age is 55 (32 - 68) years, 14 are male. Two dose limiting toxicities were experienced at 4.0 mg/kg: grade 3 hyperbilirubinemia (n=4) and grade 3 anemia (n=1). The maximum tolerated dose (MTD) and recommended phase-2 dose (RP2D) was established at 3.0 mg/kg. Of 12 patients evaluated for response, 5 demonstrated stable disease by RECIST (42%; 4 CC, 1 P) after the first course (Day 57) and 1 PC had SD after the second course (Day 114). OS is 4.5+ months (1+ - 13.5+), median duration of treatment of 74+ days (36-133). Of those screened, 60-70% tumors were IHC positive. Immune correlates (including cytokine profile, HAMA) will be presented. Conclusions: Treatment with NEO102 is well tolerated with a manageable safety profile. RP2D is 3.0 mg/kg. Preliminary results with NEO102 have demonstrated signs of clinical activity based on stabilization of disease in heavily pretreated patients with PC and CC. A Phase II study of NEO102 monotherapy in pancreatic and colon cancer is now enrolling patients. In addition, a combination study using NEO102 with cytotoxic chemotherapy in metastatic pancreatic cancer is underway. Clinical trial information: NCT01040000.
Discussing treatment (Tx) and clinical trials for pancreatic cancer (PC): Learnings from the Pancreatic Cancer Action Network (PanCAN) survey.
Authors: Engebretson Anitra , Matrisian Lynn , Thompson Cara
Published: February 2017

241

Background: In 2014, 46,420 patients (pts) in the US will be diagnosed with PC, and only 6.7% are expected to survive ≥ 5 years after diagnosis. Enrollment in clinical trials is recommended to improve pt outcomes. Methods: Funded by Celgene, PanCAN developed a 25-minute survey and distributed it online between 7/30/13 and 9/18/13 to pts with PC or caregivers whose loved ones were alive or had died of PC within the past 6 months. Results: Respondents included 184 pts (81 with metastatic PC) and 213 caregivers (145 for pts with metastatic PC). Pts and caregivers answered similarly with a few exceptions. Quality of life (QoL), extending survival, and symptom management were the 3 most important issues to all respondents. Caregivers placed statistically significantly more emphasis on QoL and managing symptoms vs pts (88% vs 71% and 68% vs 33%, respectively). A total of 196 respondents reported that Tx options were not offered at diagnosis, and 20% of these respondents stated that Tx options were never discussed with an MD. Most pts (95%) followed their doctors’ Tx recommendation, and 83% received chemotherapy. Almost half of respondents (49%) reported that their MD never discussed clinical trials; of those that did, oncologists (52%) were the primary source used to learn about possible clinical trial participation, followed by caregivers (16%) and loved ones (13%).Twelve percent of pts enrolled in clinical trials (> the US average of 4.6%; J Clin Oncol 31:3432-3438). Forty-eight percent of respondents were aware of the Pt and Liaison Services (PALS) program, a support service from PanCAN. PALS-aware respondents were more likely than others to report that the pt had undergone chemotherapy (89% vs 78%), surgery (64% vs 41%), or radiation (47% vs 32%) and more likely to state that the pt followed a Tx recommendation because it was the best/most realistic option (19% vs 11%). PALS-aware pts also participated more often in clinical trials (15% vs 9%). Conclusions: These results underscore the importance of discussing Tx options, clinical trials, and support services with pts. Such steps could increase Tx and enrollment in clinical trials, possibly improving QoL, survival, and symptom management.
The identification of the age effects in 1,287 patients with biliary tract cancer.
Authors: Umemoto Kumiko , Mitsunaga Shuichi , Watanabe Kazuo , Okuyama Hiroyuki , Hashimoto Yusuke , Takahashi Hideaki , Ohno Izumi , Shimizu Satoshi , Ikeda Masafumi
Published: February 2017

244

Background: Age is a mirror for pathogenesis in some of biliary tract cancer (BTC) as liver fluke- or pancreaticobiliary maljunction-associated BTCs. However, the age effects including prognosis in BTC were not fully understood. The identification of the age effects might be helpful for the management of BTC. Methods: For the years 1992-2014, 1287 patients receiving initial treatment for BTC in our institution were reviewed. According to age at diagnosis of BTC, patients were divided into the five age groups as <50, 50-59, 60-69, 70-79, and ≥80. The relationships between overall survival time (OS) and the five age groups were analyzed using wilcoxon test to choose a prognostic cut-off of age. On the basis of a prognostic cut-off of age, the prognostic age classification was constructed. The multivariate analysis with logistic regression modeling was performed to determine the influence of gender, Eastern Cooperative Oncology Group performance status scale [ECOG-PS], primary site, and metastatic site on the prognostic age classification. Results: Median age was 67 years with male 59%. ECOG PS of 0 was 63.7%.The sites of primary tumor included intrahepatic (25.2%) and extrahepatic bile duct (34.0%), gallbladder (31.9%) and ampulla of Vater (8.9%). The prognostic cut-off of age was age less than 60 (21.8% of all). Median OS in younger patients (age<60, median OS: 7.9mo) was shorter than that in elder patients (age≥60, median OS 12.4mo, P<0.01). In univariate analysis, the prevalence of bone metastasis, distal lymph node metastasis and peritoneal dissemination was higher in younger BTC than elder patients. Multivariate analysis revealed that peritoneal dissemination was an independent younger BTC related-factor (OR=1.9, P<0.01). Conclusions: Younger BTC patients (age<60) showed poor prognosis and the high frequency of peritoneal dissemination, compared to elder BTC patients. The relationship between age and peritoneal dissemination of BTC might be a key to elucidate the age effect concomitant with poor prognosis.
Molecular profiling with the 92-gene assay and decision-impact on cancer treatment: Interim results from a prospective, multidisciplinary study.
Authors: Thomas Sachdev P. , Braiteh Fadi S. , Cherkis Karen Ann , Operana Theresa N. , Blatner Nichole Renee , Schroeder Brock , Schnabel Catherine A.
Published: February 2017

249

Background: Metastatic lesions with unknown (CUP), unclear, or differential diagnoses pose significant challenges, particularly when presenting in the GI tract, leading to suboptimal treatment and outcomes. In clinical studies, molecular classification with the 92-gene assay demonstrated improved diagnostic accuracy compared to standard pathology techniques and improved survival in patients treated based on assay results. The current study assessed the utility of the 92-gene assay in diagnoses and treatment decision-making in clinical practice. Methods: Cases in which the 92-gene assay was ordered as part of routine clinical care were submitted into a study database via web-based, standardized, discipline-specific questionnaires. Utilization and impact of the assay were characterized for medical oncologists and pathologists. Physician-reported results from medical oncologists are included in this interim analysis of 134 cases. Results: Results from this registry-based reporting study showed that molecular profiling impacted treatment decisions in 53% of cases. Significantly, 46% of these cases reported a change in treatment regimen associated with integration of 92-gene assay results. Clinical scope included 18 tumor types with 52% having a molecular diagnosis of GI origin. The top 3 diagnoses were pancreaticobiliary, intestine, and gastroesophageal adenocarcinoma. The pre-assay working diagnosis was unknown in 41%, a differential diagnosis in 26%, and a single suspected site in 33% of cases. Conclusions: Findings from this study demonstrate that use of the 92-gene assay impacted treatment decisions and selection in a significant proportion of patients, and further define its role in clinical practice in the diagnosis and treatment planning of diagnostically-challenging metastatic cancer. [Table: see text]
Predictors of long-term survival with metastatic pancreatic cancer (mPC) in the gemcitabine era: The Fox Chase Cancer Center experience.
Authors: Vijayvergia Namrata , Dotan Efrat , Devarajan Karthik , Lewis Bianca , Cohen Steven J.
Published: February 2017

253

Background: Although median survival (OS) for patients (pts) with mPC was ~6 months (m) in the gem era, a subset of pts lived significantly longer as long term survivors (LTS). We compared the patterns of care and outcomes of pts living < 12 m (Gp 1) and ≥ 12 m (Gp 2) to identify predictors for LTS. Methods: With IRB approval, we retrospectively analyzed medical charts of mPC pts treated at our center between 2000 and 2010. Gp 1 and Gp 2 were compared with respect to pt, tumor and treatment characteristics. Fisher’s exact and Mann-Whitney tests were used, respectively, to compare categorical and continuous variables, and the log-rank test to compare OS. All tests were two-sided and a Type I Error of 5% was used to determine statistical significance. Results: 579 mPC pts (median age 64 y, 56% males) were identified, 476 pts in Gp1 and 103 in Gp 2 (OS 4m vs 18 m, respectively). There was no significant difference in the age, site of pancreatic primary, comorbidities, tobacco use or stage at diagnosis between the two. 341 (72%) pts in Gp1 and 86 (83%) in Gp 2 had an initial PS <2 (p 0.06). Alcohol use was more prevalent in LTS [170 (36%) in Gp1 vs 50 (49%) in Gp2 (OR 1.8, p 0.008)]. 170 (36%) pts in Gp 1 and 55 (52%) in Gp 2 had serum albumin (alb) > 3.5 gm/dl (p< 0.001) and this predicted survival (OS 4m if Alb < 3.5 and 7m if Alb > 3.5, p <0.001). Use of chemotherapy in the metastatic setting (66% in Gp1 vs 93% in Gp 2) and number of agents used also predicted survival with 202 (42%) pts in Gp 1 and 79 (87%) in Gp 2 having received > one agent in the metastatic setting (p < 0.001). Liver metastases were more common as an initial site in Gp1 vs Gp2 [329 (70%) vs 48 (47%) respectively, p < 0.001]. In contrast, lung metastases were more common in Gp 2 [42 (9%) Gp 1 vs 20 (19%) in Gp 2, p< 0.001]. The median survival for pts with liver as initial metastatic site was worse than those with lung metastases (5m vs 7m, p < 0.001). Conclusions: Use of chemotherapy and increasing number of agents are associated with better survival in mPC, in line with the current practice of using combination chemotherapy. The site of initial metastasis and serum albumin also predict for survival. Clinical trial designs should consider the latter as stratification factors.
Interleukin-6 (IL-6) as an inflammatory biomarker in patients with hepatobiliary cancers.
Authors: Anwar Sidra , Miller Austin , Fetterly Gerald J. , Iyer Renuka V.
Published: February 2017

257

Background: IL-6 is an inflammatory cytokine that modulates growth and differentiation of tumor cells. The role of IL-6 as a biomarker in this cancer subset population remains questionable. We aimed to study IL-6 levels in patients with hepatobiliary cancer and the associated patient characteristics. Methods: Stored serum from 91 patients with treatment-naïve hepatobiliary cancers (hepatocellular carcinoma, gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma) were measured for IL-6 levels. Demographics and clinical parameters were collected from retrospective chart review. IL-6 was measured in stored serum from 91 controls, matched for age, gender and BMI. Associations between baseline covariates and IL6 measurements and differences in Overall Survival (OS) were assessed using Accelerated Failure Time (AFT) models. P-values <0.05 were considered statistically significant. All data analyses were generated using SAS/STAT software, Version 9.4. Results: A total of 91 cases+91 controls were analyzed: 68% males in each set. IL-6 levels were significantly higher in the cases than the controls [median: 15.2pg/ml vs 1.7pg/ml p<0.01]. Amongst cancer patients the following elements were associated with significantly higher levels of IL-6: cirrhosis (AF=3.18 p<0.01), uncontrolled pain (AF=1.97 p<0.01), worse ECOG status (p<0.01) and portal vein thrombosis (AF=1.57, p=0.03). A 3-fold increase in Alpha fetoprotein (AFP) corresponded with a 9% increase in IL-6 (AF=1.09, p=0.015). IL-6 appeared to be modestly higher in males [median: 4.47 vs 5.32 p=0.5]. IL-6 remained an independent predictor of OS after controlling for several possible confounders (AFP, Cirrhosis, portal vein thrombosis). Each 10-unit increase in IL-6 resulted in an 8% reduction in the time to death (AF=0.92 (95% CI:0.78 to 1.00) p=0.033). Conclusions: IL-6 levels are significantly elevated in hepatobiliary cancers, directly correlating with AFP. Higher IL-6 levels are associated with aggressive tumors and poorer survival. These findings suggests the potential prognostic/predictive value of IL-6 and should initiate early palliative care referrals. Anti-IL6 therapy could increase meaningful survival time for patients.
A comparison of the WHO 2004 and 2010 classification systems in pancreatic neuroendocrine tumors (PNET).
Authors: Sama Ashwin Reddy , Asija Aakanksha , Casey James , Andrel-Sendecki Jocelyn , Lewis Nancy , Lavu Harish , Winter Jordan Michael , Brody Jonathan Robert , Mitchell Edith P. , Yeo Charles , Prestipino Anthony , Pillai Madhavan V.
Published: February 2017

267

Background: PNETs are rare tumors with multiple classification systems. We compared the WHO 2004 and 2010 classification systems for predicting mortality and metastasis. Variables associated with mortality were explored. Methods: Descriptive statistics were calculated for characteristics of 50 PNET patients. The relationship between the WHO 2004 and 2010 system was investigated using an exact Chi squared test. WHO grade categorization was explored by vital status, by the exact method, in order to determine if there was a difference in survivorship and metastasis by grading system. Associations between death and categorical variables were tested using exact methods and between death and continuous variables by the Wilcoxon test. Survival was explored using Cox Proportional Hazards regression (COX). Results: 62 % of patients were female and the median age was 60 years. Both grading systems were strongly associated with predicting mortality (table 1); all cases of mortality were in the higher grades. The 2010 grades do slightly better in predicting metastasis as metastases occur only in high grades (G2 and G3). Patients with lymphovascular or perineural invasion had significantly higher mortality. Mitotic Index was significantly different with a median of 0 in live patients versus 15 in deceased, p <0.001. This was similarly borne out in the survival analysis using COX, where for every one unit increase in Mitotic Index, there was about a one third increase in the hazard of death (p = 0.001). There was no significant difference in survival by tumor size, comorbidities, or margins. Conclusions: The WHO 2010 grading system is strongly associated with predicting mortality and performs better in predicting metastasis than the 2004 grading system. [Table: see text]