bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognosis of unresectable hepatocellular carcinoma: Comparison of seven staging systems (TNM, Okuda, BCLC, CLIP, CUPI, JIS, CIS) in a Chinese cohort.
Authors: Zhang Feng JIN , Shu JUN ZHI , Xie YI CHUN , LI QI , Jin Hong XI , GU Wei , Jiang Jian FANG , Ling Quan CHANG
Published: February 2017

305

Background: Many liver staging systems that include the tumor stage and the extent of liver function have been developed. However, Prognosis assessment for hepatocellular carcinoma (HCC) remains controversial. In this study, the performances of 7 staging systems were compared in a cohort of patients with HCC who underwent non-surgical treatment. Methods: A total of 196 consecutive patients with HCC who underwent non-surgical treatment seen between January 1, 2004, and December 31, 2007, were included. Performances of TNM sixth edition, Okuda, Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Chinese University Prognostic Index (CUPI), Japan Integrated Staging (JIS), and China integrated score (CIS) have been compared and ranked using concordance index (c-index). Predictors of survival were identified using univariate and multivariate Cox model analyses. Results: The median survival time for the cohort was 7.6 months (95% CI 5.6-9.7). The independent predictors of survival were performance status (P <.001), serum sodium (P <.001), alkaline phosphatase (P <.001), tumor diameter greater than 5 cm (P =.001), portal vein invasion (P <.001), lymph node metastasis (P =.025), distant metastasis (P =.004). CUPI staging system had the best independent predictive power for survival when compared with the other six prognostic systems. Performance status and serum sodium improved the discriminatory ability of CUPI. Conclusions: In our selected patient population whose main etiology is hepatitis B, CUPI was the most suitable staging systems in predicting survival in patients with unresectable HCC. BCLC was the second top-ranking staging system. CLIP, JIS, CIS, and TNM sixth edition were not helpful in predicting survival outcome, and their use is not supported by our data. Clinical trial information: 1103-10.
Comparative effectiveness of FOLFIRINOX (FOL) versus gemcitabine and nab-paclitaxel (GNP) for the first-line treatment of metastatic pancreatic cancer.
Authors: Cheng Wei-Han , Sadeghi Sarmad , Lenz Heinz-Josef , Hay Joel W , Barzi Afsaneh
Published: February 2017

306

Background: ACCORD-11 and IMPaCT established the efficacy of combination chemotherapy with FOL and GNP in metastatic pancreatic cancer (mPC). These two regimens have different administration schedule and toxicity profile. In this study we compare the effectiveness and costs of the two regimens including the costs of toxicities and supportive medications from a societal perspective. Methods: A Markov model was developed to simulate a cohort of mPC patients to estimate the cost per life-year gained (LYG) and per quality-adjusted life-year (QALY) for treatment with FOL and GNP. The model has three states: stable disease, progressive disease, and death. The cohorts were modeled over a 3-year time horizon in a one-month cycle length. Efficacy data were obtained from respective trials. Drug acquisition costs were extracted from Veteran Affairs Federal Supply Schedules. Other costs including visits, tests, and procedures were derived from the Medicare physician-fee-schedule. Literature was reviewed to estimate the adverse event costs and the utility scores for each health state. One-way sensitivity analyses were performed to determine the robustness of the model to changes in key parameters. Results: The model projected a life expectancy of 9 months and 7 months for FOL and GNP, respectively. FOL group showed a higher QALY than GNP group (0.51 vs. 0.40). Although the drug acquisition costs were significantly lower in FOL compared with GNP, FOL yielded a slightly higher cost after 3-years period ($55,944 vs. $56,628). FOL treatment incurred an incremental cost of $1,334 per additional life-month ($16,012 per life-year) and an incremental cost of $30,870 per QALY gained. The median overall survival and progression-free survival point estimate greatly influenced model results based on the results of sensitivity analysis. Conclusions: Compared with GNP, FOL showed a slightly higher cost but higher life expectancy and QALY as a first-line treatment in mPC. Given that the toxicity profile account for a significant portion of cost for FOL providing best supportive care and management of side effects can significantly impact the overall costs of treatment.
Outcomes of multimodality therapy for gallbladder cancer in the United States (US): Analysis of the National Cancer Data Base (NCDB).
Authors: Hamid Fatima , Shafqat Hammad , Mantripragada Kalyan , Guerrero Thomas , Somasundar Ponnandai , Olszewski Adam J.
Published: February 2017

313

Background: Management of gallbladder cancer (GBCA) is largely based on small observational studies, and it is unknown how various treatment modalities are applied in the community. The objective of this study was to describe the utilization of surgery (S), chemotherapy (Ct) and chemoradiation (CRT), and associated overall survival (OS) in the US. Methods: We selected adult patients (pts) with GBCA diagnosed in 2004-2012 from the NCDB—a population-wide registry capturing > 70% of incident cancers in the US. We identified pts undergoing S, Ct and concurrent CRT. We assumed adjuvant (Adj) therapy if it was started within 4 months (mo) of S. Stage was grouped as: T1-T3N0, node-positive (N+), T4 (N0 or N+) or metastatic (M1). OS was calculated from diagnosis, with 95% confidence intervals (CI). Results: We identified 22,574 GBCA pts. Median age was 71 years. There were 69% women, 71% white non-Hispanic, 10% white Hispanic, 14% black and 4% Asian pts. Distribution of stage groups was: in situ, 4%; T1N0, 8%; T2N0, 16%; T3N0, 13%; N+, 14%; T4, 3%; M1, 38%; unknown, 4%. Most non-metastatic pts underwent S, but only a minority received Adj Ct or CRT (Table). Among M1 and T4 pts, 44% received Ct, but 29% got no cancer-directed therapy. Median OS for M+ or T4 pts was 4 and 7 mo, respectively. It was 8 and 11 mo, respectively, if Ct was given. Conclusions: These OS estimates provide realistic prognosis for GBCA pts treated with various modalities in the US. Adj therapy is rarely delivered in locally advanced (T3N0 or T1-3N+) GBCA. Survival in T4 and M1 GBCA remains poor even with palliative Ct. Novel therapeutic approaches for GBCA of all stages are needed. [Table: see text]
Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract and unknown primary: A subgroup analysis of the phase III RADIANT-4 trial.
Authors: Singh Simron , Carnaghi Carlo , Buzzoni Roberto , Pommier Rodney F. , Raderer Markus , Tomasek Jiri , Lahner Harald , Valle Juan W. , Voi Maurizio , Bubuteishvili-Pacaud Lida , Lincy Jeremie , Sachs Carolin , Okita Natsuko , Libutti Steven K. , Oh Do-Youn , Kulke Matthew H. , Strosberg Jonathan R. , Yao James C. , Pavel Marianne E. , Fazio Nicola ,   RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial (RADIANT-4) Study Group
Published: February 2017

315

Background: In the groundbreaking, phase 3 RCT RADIANT-4 study, everolimus (EVE) significantly prolonged median progression-free survival (PFS) by 7.1 mo in patients (pts) with advanced, progressive, nonfunctional NET of GI or lung vs placebo (PBO); HR, 0.48 (95%CI, 0.35-0.67), P<0.00001 [Yao JC et al, ECC-ESMO, 2015]. Methods: InRADIANT-4, pts with advanced, progressive, well-differentiated (G1/G2), nonfunctional GI or lung NET were randomized (2:1) to EVE (10 mg/d) or PBO. In this analysis, pts with NET of GI tract (stomach, colon, rectum, appendix, caecum, ileum, duodenum, jejunum, or small intestine) and unknown primary were included. Results: Of 302 pts, 175 had GI NET (EVE [n=118], PBO [n=57]); 36 had NET of unknown primary (EVE [23], PBO [13]). In GI NET pts, median age was 63 y; females: 55%; G1/G2: 75%/25%; WHO PS: 0, 78% or 1, 22%; Caucasian: 73%. Similar baseline characteristics were observed in pts with NET of unknown primary. Ileum (41%), rectum (23%) and jejunum (13%) were the most common locations in GI subgroup. The table below lists prior treatments. In pts with GI NET, median PFS (95% CI) by central review (EVE vs PBO) was 13.1 (9.2-17.3) mo vs 5.4 (3.6-9.3) mo with an estimated 44% risk-reduction in favor of EVE (HR, 0.56; 95% CI, 0.37-0.84). In pts with NET of unknown primary, median PFS (95% CI) by central review (EVE vs PBO) was 13.6 (4.1-not evaluable) mo vs 7.5 (1.9-18.5) mo (HR, 0.60; 95% CI, 0.24-1.51). The most frequent G3/4 adverse events irrespective of drug-relationship reported in ≥5% pts in GI subgroup were diarrhea, hypertension, stomatitis, abdominal pain, fatigue, and acute renal failure. Conclusions: The present subgroup analysis of RADIANT-4 study demonstrated improvement in PFS with EVE for pts with GI NET, and suggests efficacy in NET of unknown primary, with an estimated 40% to 44% risk-reduction in favor of EVE vs PBO. Safety profile for EVE is consistent with that previously reported. Clinical trial information: NCT01524783. [Table: see text]
Phase 1 dose escalation study of MEDI-565, a bispecific T-cell engager that targets human carcinoembryonic antigen (CEA), in patients with advanced gastrointestinal (GI) adenocarcinomas.
Authors: Pishvaian Michael J. , Morse Michael , McDevitt Jennifer T. , Ren Song , Robbie Gabriel , Ryan Patricia C. , Soukharev Serguei , Bao Haifeng , Denlinger Crystal Shereen
Published: February 2017

320

Background: MEDI-565, a bispecific single-chain antibody, targets human CEA on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex. In murine models, MEDI-565 showed antitumor activity in CEA-expressing tumors (J Immunother 2009;34:341-52). Methods: This phase 1, multicenter, open-label, dose-escalation study enrolled adults with GI adenocarcinomas (including esophageal, gastric, small intestine, colorectal, biliary tract, and pancreatic). MEDI-565 was given intravenously over 3 h on days 1–5 in 28-day cycles, with 4 single-patient (pt) (0.75–20 μg) and 5 standard 3+3 escalation (60 μg–3 mg; 1.5–7.5 mg with dexamethasone [dex]) cohorts. Primary objective was to determine the maximum tolerated dose (MTD); secondary objectives were to evaluate pharmacokinetics (PK), antidrug antibody (ADA), and antitumor activity. Results: Study enrolled39 pts: mean age 59 y; 56% male; 28 (72%) colorectal, 6 (15%) pancreatic, 5 (13%) other. Dose-limiting toxicities (grade ≥ 3 nonhematologic) were seen in 4 pts (2 at 3-mg; 2 at 7.5-mg + dex): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Grade 3 treatment-related adverse events (AEs) seen in 5 pts: diarrhea, CRS, increased alanine aminotransferase, hypertension (all n = 1), and hypoxia (n = 2). Treatment-related serious AEs seen in 6 pts: diarrhea, vomiting, pyrexia, CRS (all n = 1), and hypoxia (n = 2). Five pts discontinued treatment due to AEs: diarrhea, CRS, central nervous system metastases, and hypoxia (n = 2). MEDI-565 exposures increased in approximately dose-proportional manner, with clearance (35–77 L/d) and half-life (2–7 h) typical of drug class. ADA had minor impact; 19 pts (48.7%) had ADAs, 5/39 (12.8%) with high titer, with decreased MEDI-565 concentrations in 2 pts. Plasma inflammatory cytokines were elevated posttreatment in several pts at 1.5- and 3-mg (no dex) dose levels. No objective responses were observed; 11 (28%) pts had stable disease as best response. Conclusions: The MTD of MEDI-565 in pts with GI adenocarcinomas was 5 mg with dex. PK was linear, with fast clearance and short half-life. No objective responses were observed. Clinical trial information: NCT01284231.
Unresectable hepatocellular carcinoma: Is radio-embolization an alternative for chemo-embolization?
Authors: Lobo Laila , Yakoub Danny , Picado Omar , Ripat Caroline , Pendola Fiorella , Sharma Rishika , Venkat Shree , Yechieli Raphael
Published: February 2017

323

Background: Transarterial Radio-embolization (TARE) has emerged as a newer regional technique to Transarterial Chemo-embolization (TACE) for treatment of unresectable hepatocellular carcinoma (HCC). The aim of this study is to evaluate clinical outcomes of both techniques. Methods: Online search for studies comparing TARE to TACE from 2005 to present was performed. Primary outcome was overall survival rate for up to 4 years. Secondary outcomes included post-treatment complications and treatment response. Quality of included studies was evaluated by STROBE criteria. Relative Risk (RR) and 95% Confidence Intervals (CI) were calculated from pooled data. Results: The search strategy yielded 172 studies, 5 met our selection criteria and included 653 patients undergoing embolization for unresectable HCC. Of these patients, 284 underwent TACE and 269 underwent TARE. Median age was 63 and 64 years for TACE and TARE, respectively. Meta-analysis showed no statistically significant difference in survival for up to 4 years between the two groups (HR = 1.06; 95% CI: 0.81-1.46, p = 0.567). TACE required at least one day of hospital stay compared to TARE which was mostly an outpatient procedure. TACE had more post-treatment pain than TARE (RR = 1.96, 95% CI: 1.40-2.75, p < 0.01), but less subjective fatigue (RR = 0.62, 95% CI: 0.48-0.80, p < 0.01). There was no difference between the two groups in the incidence of post-treatment nausea, vomiting, fever or other complications. In addition, there was no difference in partial or complete response rates between the two groups. Conclusions: TARE appears to be a safe alternative treatment to TACE with similar complication profile and survival rates. Larger prospective randomized trials, focusing on patient-reported quality-of-life are required to consolidate these results, and to evaluate cost vs benefit for both techniques.
The characteristics of pancreatic neck cancer.
Authors: Yamaue Hiroki , Hirono Seiko , Kawai Manabu , Okada Ken-Ichi , Miyazawa Motoki , Shimizu Atsushi , Kitahata Yuji , Ueno Masaki , Hayami Shinya , Shigekawa Yoshinobu , Miyamoto Atsushi
Published: February 2017

337

Background: Pancreatic neck cancer occurs in the small region surrounded by the common hepatic artery (CHA), gastroduodenal artery (GDA), and portal vein (PV). The specific clinicopathological characteristics of pancreatic neck cancer remain unclear. This study aimed to identify specific biological behaviors of pancreatic neck cancer for the improvement of treatment outcomes. Methods: This study was a retrospective cohort study and comparative outcomes design. In 63 (19.4%) of 325 consecutive pancreatic cancer patients who underwent surgery, the tumor was located in the pancreatic neck. Clinicopathological characteristics and prognostic factors specific to pancreatic neck cancer were analyzed by comparison to those of pancreatic head or body/tail cancers. Results: The rates of radiographic and pathological PV and/or superior mesenteric vein (PV/SMV) invasion were higher in patients with pancreatic neck cancer (radiographic: 84.1%, pathological: 36.5%) than those with pancreatic head and body/tail cancers (radiographic, head: 67.3%, body/tail: 25.0%, pathological, head: 26.0%, body/tail: 6.3%). The most frequent lymph node metastasis was found in the region along the CHA in pancreatic neck cancer, and the spots most likely to show a positive surgical margin were the dissected surface of the PV and the root of the GDA and/or CHA. For pancreatic neck cancer patients, five independent poor prognostic factors were found: pathological PV/SMV invasion (P= 0.005), moderately or poorly differentiation (P= 0.001), positive lymph node ratio ≥ 0.1 (P< 0.001), surgical margin length ≤ 1 mm (P= 0.018), and no completion of planned postoperative adjuvant therapy (P< 0.001). Conclusions: Pancreatic neck cancer showed specific clinicopathological characteristics and prognostic factors after resection. Patients with these risk factors might need multimodality treatment strategies, including neoadjuvant therapy, in order to prolong the survival, although further studies will be necessary to confirm our findings.
Comparative analysis of resected duodenal and ampullary adenocarcinoma.
Authors: Crown Angelena , Edwards Alicia M , Rocha Flavio G. , Picozzi Vincent J. , Helton Scott , Biehl Thomas R , Alseidi Adnan , Lin Bruce S.
Published: February 2017

362

Background: Duodenal and ampullary adenocarcinomas are rare gastrointestinal cancers that share similar anatomic location and treatment strategy. We report a single-institution experience regarding the association between clinicopathologic features, treatment, and survival outcomes. Methods: A retrospective review of all patients resected with curative intent for duodenal adenocarcinoma (DUO) between 2005-2015 and ampullary adenocarcinoma (AMP) between 2011-2015 at VMMC was performed. For AMP, histologic subtyping into intestinal (IT) and pancreatobiliary (PB) phenotypes was determined. Demographic and clinicopathologic parameters were compared between DUO and AMP patients using Chi-square test. Overall survival was calculated using Kaplan-Meier analysis and prognostic factors were identified by univariate Cox regression. Results: Patients with DUO (n = 44) presented at higher T-stage (p = 0.002) and with larger tumors (4.35cm vs 2.33cm, p < 0.001) than AMP patients (n = 46). DUO patients had a higher rate of surgical complications (68% vs 41%, p = 0.01) with a trend for more pancreatic fistulas (36% vs 20%, p = 0.08). There was no difference in median overall survival between groups. Factors positively influencing survival included Caucasian race (p = 0.02) and normal CA19-9 level at diagnosis (p = 0.01). Tumor factors negatively influencing survival included positive lymph nodes (p = 0.04), lymphovascular invasion (p = 0.001), and perineural invasion (p = 0.02). Within AMP, the PB subtype presented at higher T-stage (p = 0.01) and with more positive lymph nodes (p = 0.03) than IT. There was no difference in survival between subtypes. Majority received adjuvant chemotherapy (88.8% in AMP, 76.3% in DUO), fewer received adjuvant radiotherapy (23.3% in AMP, 30% in DUO), but no survival difference was seen. Conclusions: DUO presents with larger tumors and higher T-stage than AMP and is associated with more surgical complications. The PB phenotype has more advanced pathologic features than IT. No survival difference was seen between anatomic locations or subtypes. Better surgical and chemotherapeutic strategies may be needed to overcome high risk features. Longer follow-up with more patients is needed to confirm these findings.
Survival impact of neoadjuvant therapy in resected pancreatic cancer.
Authors: Mirkin Katelin Anne , Hollenbeak Christopher S , Wong Joyce
Published: February 2017

367

Background: Pancreatic cancer carries a dismal prognosis, with surgical resection and adjuvant therapy offering the only hope for long-term survival. In recent years, neoadjuvant therapy (NAT) has been employed to optimize outcomes. This study evaluates the impact of NAT on survival in patients with resected stage I-III pancreatic cancer. Methods: The National Cancer Data Base (2003-2011) was analyzed for patients with clinical stage I-III resected carcinoma of the pancreas who underwent NAT or surgery first +/- adjuvant therapy. Univariate statistics were used to compare characteristics between groups. Analysis of variance and Kaplan Meier analyses were used to compare median survival for each clinical stage of disease. Multivariate analyses were performed using a Cox proportional hazards model. Results: 16,122 patients who underwent NAT and 16,869 patients who underwent surgery-first were included. Patients who underwent NAT tended to be younger, covered by private insurance, have a higher median income, greater comorbidities, higher clinical stage disease, and undergo a whipple. Additionally, NAT patients had a greater number of positive regional lymph nodes (9 vs. 6, respectively), although a similar number of nodes retrieved, and higher pathological stage disease. In patients with clinical stage I disease, adjuvant therapy was associated with improved median survival than NAT and surgery-alone (24.8, 18.5, 17.9 months, p < 0.0001, respectively). However, in stage II, adjuvant and NAT offered similar median survival, which was improved over surgery-alone (20.5, 20.1, and 12.4 months, p < 0.0001, respectively). In stage III, NAT had improved median survival than the other groups (19.6, 14.2, 8.6 months, p < 0.0001, respectively). In the multivariate survival analysis, patients who received NAT had a 22% lower hazard of mortality up to 5 years as compared to adjuvant therapy (p < 0.0001). Conclusions: Neoadjuvant therapy in advanced stage pancreatic cancer confers a survival benefit and may allow more patients to undergo surgery; NAT appears to offer similar survival as adjuvant therapy in early stage pancreatic cancer.
Systemic therapy in elderly patients with advanced biliary tract cancer: Sub-analysis of ABC-02 and 10 other prospective studies.
Authors: McNamara Mairead G , Bridgewater John A. , Lopes Andre , Wasan Harpreet , Malka David , Jensen Henrik R , Okusaka Takuji , Knox Jennifer J. , Wagner Anna Dorothea , Cunningham David , Shannon Jenny , Goldstein David , Moehler Markus H. , Bekaii-Saab Tanios S. , Valle Juan W.
Published: February 2017

382

Background: Outcomes in elderly patients (pts), with advanced biliary tract cancer (ABTC) receiving palliative chemotherapy are unclear. The aim of this study was to assess the outcome of monotherapy vs combination therapy in elderly pts with ABTC in ABC-02, and 10 other prospective studies of systemic therapy. Methods: Multivariable analysis was employed to explore impact of therapy on progression-free (PFS) and overall survival (OS) in 2 age cohorts; non-elderly ( < 70 yrs) vs elderly ( ≥ 70 yrs). Results: Overall, 1163 pts were recruited from Jan 97-Dec 13. Median age of entire cohort was 63 yrs (range 23-85); 260 (22%) were ≥ 70 yrs, 18 (2%) were ≥ 80 yrs. In pts ≥ 70 yrs; 208 had ECOG PS 0-1, 129; male and 174; metastatic disease. Combination therapy was platinum-based in 9 studies. Among the 260 pts ≥ 70 yrs, 182 (70%) received combination therapy. Baseline characteristics/therapy received was balanced in both age cohorts. Median follow-up time for all pts was 42 months (95% CI 37-51). Median PFS for those < 70 yrs and ≥ 70 yrs was 6.0 (95% CI 5.5-6.4) and 5.0 months (95% CI 4.2-6.4) respectively. Median OS for pts < 70 yrs and ≥ 70 yrs was 10.2 (95% CI 9.6-11.1) and 8.8 months (95% CI 7.9-9.6) respectively. For the entire cohort, the PFS and OS were significantly better in those pts receiving combination therapy: HR 0.66, 95% CI 0.58-0.76, P < 0.0001 and HR 0.72, 95% CI 0.63-0.82, P < 0.0001 respectively, and in group ≥ 70 yrs: HR 0.54 (95% CI 0.38-0.77, P = 0.001) and HR 0.6 (95% CI 0.43-0.85, P = 0.004) respectively. In pts < 70 yrs, stage (locally advanced vs metastatic) and ECOG PS were prognostic for PFS (P < 0.001 and P = 0.04 respectively) and OS (P < 0.001 and P = 0.001 respectively) and in pts ≥ 70 yrs, they were prognostic for OS (P = 0.03 and P = 0.02 respectively). There was no evidence of interaction between age ( < 70 yrs and ≥ 70 yrs) and treatment (monotherapy and combination therapy) for PFS (P = 0.66) or OS (P = 0.75). Conclusions: In ABTC, PFS and OS in elderly pts receiving palliative chemotherapy (monotherapy or combination therapy) are comparable with that of non-elderly pts, therefore age in isolation should not influence treatment decisions. Clinical trial participation among elderly pts with ABTC is appropriate.
FOLFIRINOX and gemcitabine/nab-paclitaxel efficacy in the treatment of locally advanced unresectable pancreatic adenocarcinoma.
Authors: Bednar Filip , Ocuin Lee Mayer , Steve Jennifer , Zenati Mazen S , Winters Sharon , Hogg Melissa Ellen , Bahary Nathan , Zeh Herbert J. , Zureikat Amer H.
Published: February 2017

399

Background: Locally advanced (LA) unresectable pancreatic adenocarcinoma (PDA) historically portends a poor prognosis with a median OS of 9-11 months. Recently, two multi-drug regimens – FOLFIRINOX and gemcitabine/nab-paclitaxel – have proven effective in the metastatic setting. We hypothesized that use of these regimens in the LA setting may improve survival. Methods: A retrospective review of a single institution’s cancer registry of all consecutive LA (unresectable) PDA patients between 2010 and 2014 was performed. LA status was verified by review of the triphasic, pancreas protocol CT scan at diagnosis using the 2015 NCCN criteria for resectability. Patients were divided into 4 groups: Group 1 = no therapy, Group 2 = “old” gemcitabine or 5-FU-based chemotherapy (CTX), Group 3 = “new” CTX (FOLFIRINOX and/or Gem/nab-paclitaxel), and Group 4 = resection after downstaging. Demographic, tumor related variables, and treatment outcomes were analyzed. Results: LA disease was verified in 107 consecutive patients. Median age was 69 years (range 36-92) and 50.5% were male. Median follow-up was 13.2 months (range 0.6-60.4). Median OS for Groups 1 (n=15), 2 (n=24), 3 (n=49), 4 (n=19) was 1.4, 11, 17.3, and 32 months respectively (p<0.001). On Cox multivariate regression (adjusted for age, sex, anatomic variables, and CA19-9 level at diagnosis), radiation (HR 0.44, p=0.003), older CTX (HR 0.16, p=0.007), newer CTX (HR 0.10, p=0.001), use of 2 or more lines of CTX (HR 0.16, p=0.022), CA19-9 decrease by >50% with any line of therapy (HR 0.31, p<0.001), and surgery (HR 0.28, p=0.002) were all significant predictors of OS in this cohort. On multivariate analysis between groups 2 and 3, newer CTX compared to older CTX (HR 0.490, p=0.02) and radiation (HR 0.510, p=0.015) provided an OS benefit. Conclusions: Compared to older CTX regimens, FOLFIRINOX and Gemcitabine/nab-paclitaxel improve survival in verified LA PDA patients. For the subset that ultimately undergoes resection, survival outcomes rival those of historically published resectable cohorts.
Multicenter double-blind randomized phase II: FOLFOX + ziv-aflibercept/placebo for patients (pts) with chemo-naive metastatic esophagogastric adenocarcinoma (MEGA).
Authors: Enzinger Peter C. , McCleary Nadine Jackson , Zheng Hui , Abrams Thomas Adam , Yurgelun Matthew B. , Azzoli Christopher G. , Cleary James M. , Rubinson Douglas Adam , Brooks Gabriel , Chan Jennifer A. , Goyal Lipika , Meyerhardt Jeffrey A. , Ng Kimmie , Schrag Deborah , Savarese Diane M. F. , Graham Christopher , Carey Margaret M. , Fuchs Charles S.
Published: February 2017

4

Background: FOLFOX has RR 53% and PFS 6.8 months in MEGA (CALGB 80403). VEGF inhibition has improved survival in some but not all randomized trials in MEGA. Ziv-aflibercept binds VEGF-A, B and PlGF and has improved survival in refractory metastatic colorectal cancer. Methods: All pts received mFOLFOX6 q14d. Pts were randomized 2:1 to A) ziv-aflibercept 4mg/kg/d1 or B) placebo. Pts were restaged every 8wks. Primary endpoint: 6mos PFS. Results: 64 pts enrolled (Jan 2013-Apr 2015): sex: 55M/9F; age (median): 32-83 (62); ECOG PS 0/1/2: 33/28/3; primary tumor: esophagus 26/GEJ 18/gastric 20; measurable/evaluable: 52/12; metastases: LN 48/liver 25/lung 15, other 12/adrenal 4/bone 3. Of 64 pts: 34 POD, 9 off for tox, 4 died on tx, 3 withdrew, 4 other, 10 on tx (see Table). Conclusion: Ziv-aflibercept did not significantly improve the efficacy of FOLFOX. HTN was predictive of response to ziv-aflibercept. Except for HTN, there was no significant difference in toxicity between tx arms. Clinical trial information: NCT01747551. [Table: see text]
Neoadjuvant chemotherapy for gall bladder cancer: Does it increase resectability?
Authors: Raj Dheeraj , Singh Shivendera , Gupta Nikhil , Rathi Sudheer
Published: February 2017

406

Background: Surgery is the treatment of choice for patients with carcinoma gall bladder patients (GBC). However, most of the patients are metastatic at the time of diagnosis with only a fraction of patients deemed non metastatic. Many are locally advanced either infilterating liver, orinvolving adjacent other organs. Studies with gemcitabine for metastatic biliary tract cancers have shown promising results. Extrapolating these results to locally advanced GBC might improve the outcomes in these otherwise poor risk patients. Methods: Patients with locally advanced GBC from January 2013 to June 2014 who were considered borderline resectable on cross sectional imaging were planned for preoperative gemcitabine based chemotherapy to downsize the tumor and make them resectable. Gemcitabine and cisplatin based chemotherapy was given to all these patients and evaluated after 3 cycles. Those who became resectable were taken up for surgery and rest were given additional three cycles of chemotherapy. Results: 840 patients of GBC were seen in the out patient department since January 2013. Of these, 40 patients with locally advanced GBC were considered for neoadjuvant chemotherapy (Gemcitabine and cisplatin). However, only 22 patients actually received neoadjuvant chemotherapy. Out of these 22 patients, 4 are still receiving chemotherapy. Of 18 patients who completed there chemotherapy schedule, 2 patients lost to follow up after receiving 3 cycles of chemotherapy. 15 patients (83.3%%) had good radiological response to chemotherapy and were advised surgery. One patient had no radiological response. 3 patients refused surgery inspite of good radiological response. 13 patients (including the patient who did not have radiological response) underwent surgery. Out of 13 patients, 4 patients had metastatic disease intraoperatively. 9 out of 16 patients (56.25%) underwent R0 resection. Conclusions: Best surgical outcomes are seen with those undergoing RO resection. Neoadjuvant chemotherapy can downsize the tumor in approximately 50% of the patients leading to R0 resection. Neoadjuvant chemotherapy should be considered in locally advanced GBC with the aim of increasing the resectablility in these patients.
Prognostic effect of angiotensin-converting-enzyme inhibitors (ACEI) and diuretics in patients with pancreatic cancer.
Authors: Al-Shamsi Humaid Obaid , Shalaby Akram , Dar Aneeqa Yousaf , Hassan Manal , Wolff Robert A. , Li Donghui
Published: February 2017

420

Background: Prior history of chronic medical conditions and medical treatment exposure has been significantly associated with the development and prognosis of different cancers. Population-based studies reported a reduced cancer-related mortality among patients with pancreatic cancer who were Statin or Metformin users as compared with non-users. We aimed to study the effect of antihypertensive medications on the survival outcome of pancreatic cancer. Methods: Under institutional ethical approval, medical records were reviewed and clinical characteristics at baseline (time of diagnosis) were retrieved. Blood pressure and antihypertensive medications use were documented including Angiotensin Converting Enzyme Inhibitor (ACEI), diuretics, Angiotensin Receptor Blockers (ARBs) and Beta-Blockers (BB). Hazard ratios (HRs) and 95% CIs were calculated by using Cox proportional hazard models with a backward stepwise selection procedure to identify independent prognostic factors for overall survival. Results: A total of 1,204 patients with adenocarcinoma of the pancreas were diagnosed at MD Anderson Cancer center between 1999 and 2009 were identified. The mean age value (± SD) is 61.9± 10 where 58.6% (N=705) were men and 87.5% (N=1,054) were white. The majority of patients were Caucasian (87%). 41.9% had metastatic disease. A total of 639 (53%) patients had chemotherapy with or without radiation. ACEI and diuretics use independently reduced all-cause mortality, ACEI by 24% with HR 0.76 (CI 0.63-0.91), and diuretics by 26% with HR 0.73 (CI 0.60- 0.89). Neither ARBs nor beta blockers use was statistically significant in reducing all-cause mortality (HR.80, CI 0.63 -1.0), BB HR 0.85 (CI 0.7-1.0). Conclusions: Our findings indicate a significant impact of anti-hypertensive medications including ACEI and diuretics on pancreatic cancer outcomes with improved survival in users versus non-users, this effect was independent of the cancer treatment received, tumour histology and site of metastasis. The potential antitumor activities of these agents in pancreatic cancer should be studied further.
Association of the immune checkpoint molecule expression with neutrophil-lymphocyte ratio in patients with gastric cancer: A retrospective study.
Authors: Tanaka Hiroaki , Tamura Tatsuro , Kimura Kenjiro , Sakurai Katsunobu , Toyokawa Takahiro , Amano Ryosuke , Kubo Naoshi , Muguruma Kazuya , Ohira Masaichi , Hirakawa Kosei
Published: February 2017

48

Background: Programmed cell death (PD) -1, one of immune checkpoint molecules, expresses on T cells and induces immune tolerances in tumor microenvironment by binding to the ligand PDL-1 on the cancer cells. The clinical effect of immune checkpoint inhibitors such as anti-PD-1/PDL-1 antibody was demonstrated in various cancer including malignant melanoma, lung cancer and gastric cancer. The development of biomarkers for case selection that these inhibitors are effective will be in urgent need. We previously showed that neutrophil-lymphocyte ratio (NLR), a marker for general immune response, was related with postoperative recurrence and advanced stage of gastric cancer. In this study, we report the association of pretreatment NLR with PD-1/PDL-1 expression in the primary tumor of gastric cancer. Methods: Using immunohistochemistry, we retrospectively examined the expression of PDL-1 and infiltration of PD-1+ cells in primary tumor from 180 patients who had undergone surgery for gastric cancer between 2007 and 2010 at the Department of Surgical Oncology of Osaka City University. Results: Positive expression of PDL-1 was observed in 78 (43%) patients. PDL-1 expression was correlated with tumor infiltrated PD-1+ cells and related poor prognosis of the patients with Stage II/III. NLR was correlated with pathological stage and lymph node metastasis. In the positive PDL-1 group, NLR was significantly increased compared with negative group. However, the number of infiltrated PD-1+ cells was not correlated with NLR. Conclusions: PDL-1 expression in gastric cancer tissues was associated with pretreatment NLR, indicating that local immune suppression could be reflected in the systemic immune responses. Our data also suggested that NLR might be one of surrogate marker for PD-1/PDL-1 blockade therapy for gastric cancer.
Neoadjuvant chemoradiation for fixed cT3 or cT4 rectal cancer: Results of a Polish II multicentre phase III study.
Authors: Bujko Krzysztof ,   on behalf of the Polish Colorectal Study Group
Published: February 2017

489

Background: The study tested whether preoperative 5x5 Gy and consolidation chemotherapy is more locally efficacious than standard preoperative chemoradiation in “unresectable” cancer (ClinicalTrials.gov NCT00833131). Methods: Patients with fixed cT3 or cT4 rectal cancer without distant metastases were randomized either to 5x5 Gy and 3 courses of FOLFOX4 after one week rest (experimental group) or to 50.4 Gy delivered in 28 fractions given simultaneously with a 5-Fu bolus, leucovorin and oxaliplatin (control group). For the second study part, oxaliplatin was delivered to the two groups at the discretion of the participating centre. Both groups underwent surgery about 12 weeks after starting radiation and about 6 weeks after neoadjuvant treatment. Results: 515 patients were eligible for analysis; 261 in the experimental group and 254 in the control group. Acute toxicity of neoadjuvant treatment was recorded in 74% of patients in the experimental group and in 83% in the control group, p = 0.007; the rate of patients with grade 3+ toxicity was identical in the two groups - 24%. R0 resection rates (primary endpoint) and pathological complete response rates were respectively in the experimental group and in the control group 77% vs. 71% (p = 0.081) and 16% vs. 11.5% (p = 0.19). Median follow-up was 35 months. At 3 years, rates of overall survival, disease-free survival and cumulative incidence of local failure were respectively in the experimental group and in the control 73% vs. 64.5%, p = 0.055; 53% vs. 52%, p = 0.74 and 22% vs. 21%, p = 0.82. Conclusions: The trial showed no difference in local efficacy between preoperative 5x5 Gy with consolidation chemotherapy and standard preoperative chemoradiation. The trend towards improved overall survival, lower toxicity, lower cost and convenience favors 5x5 Gy with consolidation chemotherapy. Clinical trial information: NCT00833131.
Overall response rate (ORR) in STEAM, a randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for the first-line (1L) treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Bendell Johanna C. , Tan Benjamin R. , Reeves James Andrew , Xiong Henry , Somer Bradley G. , Lenz Heinz-Josef , Hochster Howard S. , Scappaticci Frank , Sommer Nicolas , Day Bann-mo , Hurwitz Herbert
Published: February 2017

492

Background: 3-drug chemotherapy (CT) + BEV (cFOLFOXIRI-BEV) significantly improved efficacy vs FOLFIRI-BEV for 1L mCRC tx, but safety and the impact of subsequent fluoropyrimidine-BEV maintenance tx require further definition. The phase 2 STEAM (NCT01765582) trial assessed efficacy of 1L cFOLFOXIRI-BEV vs FOLFOX-BEV and safety of alternating 2-drug CT (FOLFOX and FOLFIRI) + BEV tx monthly in a sequential sFOLFOXIRI-BEV regimen. Methods: Pts with unresectable, previously untreated mCRC were randomized 1:1:1 to BEV-containing (5 mg/kg) arms (cFOLFOXIRI, sFOLFOXIRI [alternating FOLFOX and FOLFIRI every 4 weeks {q4w}], or FOLFOX q3w) in a 4–6 month induction phase, followed by BEV-containing maintenance tx. Stratification factors included extent of metastatic disease and tumor location. Primary objectives: 1L ORR, 1L progression-free survival (PFS), safety. Secondary objectives: resection and conversion to resectable disease rates, time to 2L PFS, overall survival. ORR was tested with a 1-sided alpha of 5%; tx arms were compared with a stratified 1-sided Cochran-Mantel-Haenszel test. PFS was analyzed descriptively. Results:Among 280 enrolled pts (median age, 57.5 yrs), 186 remainined in the study on July 1, 2015. Efficacy and safety are shown (see Table). Conclusion: While not statistically significant, there was a trend of increased ORR with cFOLFOXIRI-BEV vs FOLFOX-BEV in 1L mCRC tx. Analysis of PFS is ongoing. All 3 regimens were well tolerated. Clinical trial information: NCT01765582. [Table: see text]
Association of TLR9 polymorphism with overall survival in metastatic colorectal cancer patients treated with FOLFIRI plus bevacizumab enrolled in FIRE3.
Authors: Okazaki Satoshi , Stintzing Sebastian , Heinemann Volker , Cao Shu , Zhang Wu , Yang Dongyun , Ning Yan , Matsusaka Satoshi , Berger Martin D. , West Jordan D. , Miyamoto Yuji , Suenaga Mitsukuni , Lenz Heinz-Josef
Published: February 2017

498

Background: Toll-like receptors (TLRs) play crucial roles in carcinogenesis and evolution of the tumor microenvironment. TLR9 dependent stimulation is known to cause antitumor activity not only by activating anti-tumor immunity but also by interfering with angiogenesis. We tested the hypothesis that genetic variations in TLR9 will be associated with clinical outcome in metastatic colorectal cancer (mCRC) patients treated with bevacizumab based chemotherapy. Methods: Genomic DNA was isolated from tissue samples from 301 mCRC patients enrolled in the FIRE3 trial and treated in first-line with FOLFIRI plus bevacizumab. Three single nucleotide polymorphisms (SNPs) in the TLR9 gene, rs187084 A/G, rs352140 C/T, and rs5743836 T/C, were analyzed by PCR-based direct sequencing. These SNPs were tested for the association with tumor response, progression free survival (PFS), and overall survival (OS). Subgroup analyses by gender, tumor location, and Kras status were also analyzed. Results: The patients carrying variant genotype (T/C or C/C) for rs5743836 showed a strong trend toward shorter OS compared to those with a wild-type T/T genotype (median: 21.2 vs. 24.8 months, HR: 1.35, P = 0.069). This difference remained statistically significant in the multivariate analysis (HR: 1.53, 95%CI: 1.09-2.15, P = 0.014). In the subgroup of Kras-mutant type, the variants (T/C and C/C) were significantly associated with worse PFS (8.1 vs. 11.3 months, HR 2.06, p = 0.043) and OS (16.4 vs. 25.1 months, HR: 2.44, p = 0.012), which retained statistical significance in the multivariate analysis. No association with clinical outcome was observed for rs187084 and rs352140. Conclusions: Our findings suggest that TLR9 polymorphism of rs5743836 is a prognostic marker of mCRC patients, especially of those with Kras-mutant type, who were treated with FOLFIRI plus bevacizumab.
TGF-β inhibitor LY2157299 (galunisertib) in combination with standard chemotherapy and inhibition of signaling to pSmad and EMT and suppression of tumor growth in gastric cancer.
Authors: Miyoshi Sawako , Kudo Masahisa , Shitara Kohei , Yamauchi Mayumi , Doi Toshihiko , Matsumura Yasuhiro
Published: February 2017

50

Background: TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) of tumor cells, thus producing tumor progression, invasion, and metastasis. Therefore, this signaling has been expected to be a new target of cancer therapy. In this study, we evaluated the antitumor effect of LY2157299, a TGF-βR1 kinase inhibitor, alone and in combination with 5-fluorouracil (5-FU) or paclitaxel (PTX), key agents in the treatment of gastric cancer (GC). Methods: TGF-β inhibition impedes phosphorylation of Smad2 and induces the expression of vimentin, an EMT marker. Vimentin expression was examined +/- LY2157299 by western blot. The phenotypic change of human GC cell, 44As3-Luc after TGF-β and LY2157299 treatment was assessed by Matrigel migration/invasion assay. The in vitro cytocidal effect and in vivo antitumor effect of LY2157299 alone or with either 5-FU or PTX were evaluated by water soluble tetrazolium-1 (WST-1) assay and by xenograft mouse model, respectively. Results: The phosphorylation of Smad2, the expression of vimentin and the optical mesenchymal transformation in 44As3-Luc induced by TGF-β were successfully suppressed by LY2157299. Accordingly, the activity of migration and invasion evoked by TGF-β was suppressed significantly by co-administration of LY2157299 with TGF-β. Although LY2157299 monotherapy did not show a tumor suppressive effect and LY2157299 did not potentiate the cell toxicity of 5-FU and PTX in vitro, LY2157299 reduced tumor volume (TV) of 44As3-Luc xenografts by 64% of control (p < 0.05). 5-FU + LY2157299 treatment reduced TV of 5-FU alone by 52% (p < 0.05) and PTX + LY2157299 treatment also reduced TV of PTX alone by 52% (p < 0.05). These results suggest that LY2157299 suppresses tumor growth possibly through some effect of LY2157299 in tumor-stroma environment. Conclusions: LY2157299 inhibited migration and invasion of GC cell line. Moreover, the monotherapy of LY2157299 and the combination therapy of LY2157299 with 5-FU or PTX significantly suppressed tumor growth. These findings warrant clinical evaluation of LY2157299 in patients with GC.
The FAMKOL trial: Trans-sectoral screening in high-risk populations, comparing nurse-led counselling versus written information materials in first-degree relatives of patients with colorectal cancer.
Authors: Bauer Alexander , Seufferlein Thomas , Reinshagen Max , Hollerbach Stephan , Ritter-Herschbach Madeleine , Boese Stephanie , Riemann Juergen F.
Published: February 2017

509

Background: Prevention of colorectal cancer (CRC) is a major health care issue. First-degree relatives (FDR) of patients with colorectal cancer have a 2-4-fold increased risk for colorectal cancer. Thus, in this population an adequate participation in the screening colonoscopy is of particular importance. However, appropriate strategies to increase the participation in screening colonoscopy are still lacking. Methods: Cluster-randomized, single blinded, controlled, multicenter trial. At 64 trial sites, 2,411 patients treated for CRC (index patients) were enrolled and n = 1,158 randomized to either paper-based information material only or additional barriers-focused counselling. Index patients were asked to forward trial materials to their FDR. FDR in the intervention group (IG) also received an additional individualized nurse-led counselling on barriers against colonoscopy and were assisted in making appointments to office-based gastroenterologists. Results: N = 313 FDR (IG n = 148; n = 165 controls) aged 28-85 years participated in the trial. A total of 197 FDR underwent preventive colonoscopy (IG n = 99 [66.9%] vs. n = 98 [59.3%]; p >.05). In these 197 patients, polypectomy was performed in n = 69 patients (IG n = 39 [39.4%] vs. n = 30 [30.6%]; p <.05]). Histological examination revealed n = 2 colorectal carcinoma in 197 patients. Conclusions: The FAMKOL trial confirmed the high effectiveness of an interdisciplinary and trans-sectoral invitation to the screening colonoscopy. FAMKOL also verified the significantly higher risk for adenomas and CRC in the targeted patient population. Hence, the permanent implementation of this invitation program may contribute to decrease CRC mortality. Clinical trial information: NCT01903395.
Prevalence of colorectal adenoma in patients with multiple gastric adenoma or cancers.
Authors: Choe Jung Wan , Kim Seung Young , Hyun Jong Jin , Jung Sung Woo , Koo Ja Seol , Park Jong-Jae , Chun Hoon Jai , Lee Sang Woo
Published: February 2017

517

Background: It has been reported that patients with single gastric cancer or adenoma are at increased risk of colorectal cancer or adenoma. However, the incidence of colorectal adenoma in patients with multiple gastric neoplasms has not been discussed yet. Methods: We retrospectively analyzed the esophagogastroduodenoscopic and colonoscopic findings as well as the clinicopathologic features between October 2012 and July 2014. The aim of this study was to investigate whether the incidence of colorectal adenoma is higher or not in patients with multiple gastric neoplasms than those with a single gastric neoplasm. Results: A total of 164 patients with gastric neoplasm were divided into two groups whether the number of lesions was single or multiple. Among the 138 patients with single gastric neoplasm, 51 patients performed colonoscopy for surveillance study and 9 patients underwent colonoscopy among the 26 patients with multiple gastric neoplasms. Colorectal adenoma were detected in 58.8% (30/51) of the single gastric neoplasm group, and in 88.8% (8/9) of the multiple gastric neoplasms group (p < 0.001). The mean number of colorectal adenomas was significantly higher in the multiple gastric neoplasm group than in the single group. (4.78 vs. 1.94, p = 0.013). The age, sex, BMI, presence of underlying diseases and the degree of gastric dysplasia were not significantly different between the two groups. Conclusions: The prevalence and the number of colorectal adenoma were significantly higher in patients with multiple gastric neoplasms than in those with single gastric neoplasm. Clinical trial information: KUGH14308-001.