bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of metformin as a radiation sensitizer in pancreatic cancer.
Authors: Dorth Jennifer Anne , Ferris Gina , Zeng Johnathan , Welford Scott
Published: February 2017

253

Background: Clinical study demonstrates that diabetic patients taking metformin while undergoing chemotherapy and/or radiation for localized pancreatic cancer have improved overall survival compared to diabetics not taking metformin or non-diabetic patients (Sadeghi, Clin Cancer Res 2012). Metformin may act as a radiosensitizer through direct effects on cancer cells and/or indirect effects on the host, such as the inhibition of hepatic gluconeogenesis or inflammation (Pollak, Clin Cancer Res 2012). In vitro study demonstrates that the direct effects of metformin include suppression of mTOR, G2/M cell cycle arrest, and toxicity to cancer stem cells with resultant increase in chemo and radiosensitivity, though some of these studies employed supra-physiologic doses of metformin (1-10mM) instead of physiologic doses (10uM) (Song, Sci Rep 2012; Sanli, IJROBP 2010). Methods: MiaPaCa-2 human pancreatic cancer cells were grown in physiologic (5mM) or supra-physiologic (25mM) glucose media. After exposure to metformin (10uM or 10mM) for 3-7 days in cell culture, phosphorylation of AMPK, a target of metformin, was measured by western blot and radiation survival was determined by clonogenic survival assay. Results: MiaPaCa-2 cells grown in 5mM glucose media with metformin have higher levels of AMPK phosphorylation than those grown in 25mM glucose media or without metformin. Radiation clonogenic survival was similar between cells exposed to any of the treatment conditions, including differences in glucose concentration and/or presence of metformin. Conclusions: MiaPaCa-2 pancreatic cancer cells do not demonstrate enhanced radiosensitivity to metformin in vitro. Future studies will investigate whether K-Ras wild-type cell lines exhibit enhanced radiosensitivity to metformin in vitro and whether metformin acts as a radiosensitizer in vivo.
Eligibility of metastatic pancreatic adenocarcinoma (MPA) patients for first-line palliative intent nab-paclitaxel plus gemcitabine (NG) versus FOLFIRINOX (FIO).
Authors: Peixoto Renata D'Alpino , Renouf Daniel John , Lim Howard John , Cheung Winson Y.
Published: February 2017

259

Background: The ACCORD 11 and the MPACT trials recently showed superiority of FIO and NG over gemcitabine alone, respectively. However, both trials had strict inclusion criteria. The aim of this study was to determine the proportion of patients (pts) with MPA who would be potentially eligible for first-line palliative intent chemotherapy with FIO and NG in routine clinical practice. Methods: 473 consecutive pts who presented with MPA and initiated palliative chemotherapy with gemcitabine from 2000 to 2011 at the BC Cancer Agency were identified using the provincial pharmacy database. Clinicopathological variables and treatment outcomes were retrospectively collected and compared among groups. Eligibility criteria for each regimen were in accordance with the criteria as described in the respective pivotal phase III trials. Results: In total, median age was 66 years (range 34–89) and 258 (55%) were men. Only 24.7% of the pts would be eligible for FIO as compared to 45.2% for NG. The main reasons for ineligibility for FIO were ECOG performance status (PS) ≥ 2 (56.5%), age > 76 years (19.0%), and bilirubin > 1.5 times the upper limit of the normal range (ULN) (18.6%). The main reasons for ineligibility for NG were bilirubin > ULN (24.5%), ECOG PS ≥ 3 (14.6%), and cardiac dysfunction (13.8%). Median overall survival (OS) for the entire cohort treated with gemcitabine was 5.8 months (95% CI 5.4-6.2). On univariate analyses, eligible pts for FIO had longer median OS than ineligible pts (8.6 vs 4.7 months, p<0.001). Eligible pts for NG also had longer median OS than those deemed ineligible (6.7 vs 4.9 months, p=0.008). After accounting for ECOG PS in the multivariate model, eligibility for either FIO or NG no longered predicted for better OS. Conclusions: In ourpopulation-based analysis, almost twice as many pts would be eligible for NG when compared to FIO, mostly due to ECOG PS. The longer OS observed in the FIO-eligible population likely reflects the exclusion of ECOG PS 2 pts.
Association of ALDH-expressing cancer stem cells with survival in patients with resected pancreatic adenocarcinoma treated with adjuvant chemoradiation.
Authors: Kumar Rachit , Dholakia Avani Satish , Herman Joseph M. , Maitra Anirban , Matsui William H. , Hong Seung-Mo , Wolfgang Christopher Lee , Laheru Daniel A. , Iacobuzio-Donahue Christine A , Rasheed Zeshaan
Published: February 2017

262

Background: We and others have identified aldehyde dehydrogenase (ALDH) activity as a marker of pancreatic cancer stem cells (or tumor-initiating cells). The presence of cancer stem cells (CSCs) has been associated with decreased survival and treatment resistance in pancreatic adenocarcinoma. We investigate the role of ALDH expression in predicting survival and patterns of disease recurrence in patients treated with chemoradiation (CRT) following pancreatectomy. Methods: Tissue microarrays using surgical specimens from 1998 to 2002 were stained for ALDH1 and scored as ALDH-positive or ALDH-negative by two expert pancreatic pathologists blinded to patient outcomes. Physician documentation and radiology reports were used to determine follow-up information. Time to local failure (TLF), time to distant metastases (TDM), progression-free survival (PFS), and overall survival (OS) were analyzed using SPSS software. Results: Previously we found that ALDH expression was associated with worse OS in a cohort of 269 patients with resected pancreatic adenocarcinoma (Rasheed, JNCI 2009). From this cohort, adjuvant treatment information was available for 87 patients with ALDH-negative tumors (48.6%) and 41 patients with ALDH-positive tumors (45.6%). In patients treated with adjuvant CRT, median overall survival was superior in the ALDH-negative cohort vs. the ALDH-positive cohort, 26.3 months vs. 18.2 months (p=0.011). Further, in patients treated with adjuvant CRT, ALDH-negative patients had statistically greater TLF, TDM, and PFS than their ALDH-positive counterparts (see table). On multivariate analysis, ALDH positive tumor staining (HR 1.94, p=0.004) and tumor grade (HR 1.54, p=0.041) predicted lower OS, and ALDH positive tumor staining (HR 1.83, p=0.008), tumor grade (HR 1.52, p=0.038), and tumor size >3 cm (HR 1.65, p=0.023) predicted decreased PFS. Conclusions: This study suggests that adjuvant CRT improves TLF, TDM, PFS, and OS in patients with localized pancreatic adenocarcinoma not enriched with ALDH-expressing CSCs. Laboratory studies will help elucidate the mechanisms of treatment resistance in ALDH expressing CSCs.
Prospective phase II study of inoperable pancreatic adenocarcinoma with neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX).
Authors: Gulati Anthony Paul , Schreibman Stephen M. , Schrope Beth , Lee James A. , Allendorf John , Chabot John A. , Tsushima Dawn , Mowatt Kelley B. , Oprescu Anna , Chu Kyung , Sherman William H. , Ennis Ronald D. , Lee Yoomi , Fine Robert Lance
Published: February 2017

274

Background: Chemoradiation (CRT) is used in unresectable pancreatic cancer (PC) to convert patients to a resectable state. Those who go to surgery can have a similar survival as those initially deemed resectable, with a mOS of 8.2-9 mo. We recently reported a prospective phase II trial of our synergistic regimen (GTX) for patients with metastatic PC with a mOS of 14.7 mo. Methods: 35 patients with ECOG PS 0-2 and completely unresectable advanced PC (localized to the pancreas, small bowel, stomach and/or encasing at least 2 vessels such as the SMA, CA, HA, PV, or SMV) were treated with GTX: Capecitabine (Xeloda) PO 1500mg/m2 divided into 2 doses daily on days 1-14, gemcitabine 750mg/m2 IV given over 75 min on days 4 & 11, docetaxel 30mg/m2 IV infusion over 30 minutes preceded by dexamethasone 10mg IV/PO on days 4 & 11, in a 21 day cycle. 3 cycles were given before evaluation. If eligible, a patient was allowed to proceed to surgery without radiation. Otherwise, starting on week 12, 5040 cGy of conformal radiation was given over 5-6 weeks (Mon-Fri) with weekly gemcitabine 250-300mg/m2 IV infusion over 30 min. No adjuvant treatment was given on protocol. Primary objective was conversion rate to operable status, and secondary objectives included RR (based upon RECIST), OS, and PFS. Results: Duration of neoadjuvant chemotherapy was 9 weeks and 0% showed POD during this time. 20 of 35 patients (57%) became eligible for surgery. Of all 35 patients, there was a 49% rate of negative margins at surgery (in 85% of those patients who underwent surgery). 23 patients (66%) underwent CRT, and 11 of them (48%) ultimately went to surgery and had clean margins. Median OS from initiation of chemotherapy for all patients was 17.4 mo and >22 mo if they went to surgery (20/35 pts, 1 alive). PFS of patients who underwent surgery was 13.2 mo. Grade 3/4 toxicities primarily included neutropenia (25%), leukopenia (11%), and diarrhea (6%). No deaths were attributed to GTX. Conclusions: Neoadjuvant GTX +/- radiation with gemcitabine can be used as an effective treatment for patients with truly unresectable PC. Clinical trial information: NCT00869258.
Open-label prospective study of safety and efficacy of glass-based Y-90 radioembolization for infiltrative HCC with PVT.
Authors: Kokabi Nima , Camacho Juan C. , Xing Minzhi , Kauh John S. , El-Rayes Bassel F. , Kim Hyun Sik
Published: February 2017

276

Background: Safety and efficacy of Yttrium-90 (Y90) therapy for infiltrative unresectable hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) require further evaluation. Methods: A prospective single center, open-label, single arm safety and efficacy study recruited patients with unresectable (Barcelona Liver Cancer Stage C) infiltrative HCC with PVT. Safety was assessed according to Common Terminology Criteria for Adverse Events v.3.0 at 1 week and monthly thereafter for 6 months post therapy. Efficacy was assessed by overall survival (OS) as primary endpoint. Tumor response was assessed by dynamic contrast MRI according to Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST at 1, 3, and 6 months (secondary endpoint). To achieve 0.95 power (α=0.05) and predicting prolongation of mean OS by at least 50% over the best supportive care (4 months ± 2 months (SD)), the study was designed to recruit 30 patients. Survival analysis was performed using Kaplan-Meier estimation. Prognostic factors were tested using log-rank and univariate analysis. Results: Thirty (n=30) patients were enrolled and underwent Y90 therapy (median age 63). The median OS was 13 months (CI: 4.1-21.1 months). Six patients had transaminitis (70% grade 1, 30% grade 2) while 8 patients had biliary toxicity (50% grade 1, 10% grade 2, 40% grade 3). Grade 3 bilirubin toxicity occurred in the same 2 patients with grade 2 transaminase toxicity. Although all patients recovered from transient liver toxicities, grade ≥2 liver toxicity was found to be predictor of poor outcome with median OS of 3.6 months for patients with grade ≥2 toxicity vs. 13 months for those with grade 1 or no toxicity (p=0.004). Child-Pugh class B, INR ≥1.5, and grade ≥2 hepatobiliary toxicities were found to be poor prognostic factors by both log-rank and univariate analysis (p<0.05). Upon short-term imaging follow up (mean 34 days post Y90), 80% of patients were found to have complete (13%) or partial (67%) response according to targeted mRECIST criteria, with 93% stable disease according to targeted RECIST. Conclusions: In patients with unresectable infiltrative HCC and PVT, Y90 therapy is a viable and safe treatment option.
Effects of gemcitabine and stereotactic body radiotherapy on quality of life in locally advanced pancreatic cancer.
Authors: Dholakia Avani Satish , Chang Daniel Tandel , Goodman Karyn A. , Sugar Elizabeth , Hacker-Prietz Amy , Columbo Laurie Ann , Griffith Mary E , Wild Aaron Tyler , Moningi Shalini , Pawlik Timothy M. , Fisher George A. , Ellsworth Susannah G. , Koong Albert , Herman Joseph M.
Published: February 2017

278

Background: Existing literature on the impact of radiation therapy for locally advanced pancreatic cancer (LAPC) on quality of life (QoL) is limited and is specific to standard chemoradiation. We prospectively investigated patient-reported QoL after treatment with fractionated stereotactic body radiation therapy (SBRT). Methods: Forty-nine patients with LAPC treated were prospectively enrolled in a clinical trial at 3 institutions. Participants received a total of 33 Gy in 6.6 Gy daily fractions using SBRT either upfront (N=5) or after a single induction cycle of gemcitabine (N=44), followed by post-SBRT gemcitabine until evidence of disease progression. Two validated questionnaires, the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and pancreatic cancer-specific QLQ-PAN26, were administered to patients prior to SBRT and at 4-weeks and 3 to 4-months following SBRT. Results: QoL questionnaires were available for 43 patients (88%) in the clinical trial at enrollment, of which 38 (88%) and 22 (51%) also had data at 4-weeks and 3 to 4-months following SBRT, respectively. There was no significant change in global QoL scores from enrollment at 4-weeks (p=0.682) and 4-months (p>0.999) following SBRT. Patients demonstrated a significant improvement in pancreatic pain (p=0.001), body image (p=0.007) and jaundice (p=0.001) scores from the pre-SBRT values at 4 weeks following SBRT. The initial 4-week results were similar when restricted to those patients with both 4-week and 4-month QoL data (p=0.020) and jaundice (p=0.004); however, these symptoms had returned to enrollment levels by the 4-month follow-up. An improvement in body image (p=0.016) and decline in role functioning (p=0.002) were observed in patients with 4-month follow-up QoL questionnaires. Conclusions: LAPC patients undergoing SBRT experience no impairment in global QoL and have short-term improvements in symptoms commonly bothersome to this population including pancreatic pain, body image, and jaundice. Patients also experience a delay in impaired role functioning several months after treatment. These results warrant further investigation of SBRT for LAPC. Clinical trial information: NCT01146054.
Role of adjuvant radiation therapy in ampullary carcinoma: Propensity-score matched SEER analysis.
Authors: Byun John , Grover Surbhi , Hertan Lauren Michelle , Apisarnthanarax Smith
Published: February 2017

282

Background: Ampullary cancer outcomes have been reported to compare favorably with pancreatic and biliary malignancies. Consensus guidelines on the optimal adjuvant management after resection in these patients remain unclear. Propensity score matching was used to compare the outcomes of patients with ampullary cancer receiving or not receiving radiation therapy (RT) from the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Patients with a diagnosis of ampulla of vater carcinoma who underwent curative intent surgery were identified within 17 SEER registries from 1998-2008. Patients with M1 disease or follow up less than 5 months were excluded. Data on patient characteristics such as age at diagnosis, race, tumor characteristics including TNM staging and histologic subtype, and survival outcomes were extracted and compared between patients who received adjuvant RT and those who did not. Propensity score matching was used to minimize treatment selection bias within the specified characteristics and estimate the impact of RT on median survival times (MST). Matching algorithms used validated Mahalanobis nearest neighbor methods based on conditional probabilities of receiving RT. Results: Of the 1782 patients identified, 490 (25%) were treated with adjuvant RT: 318 (65%) T3/4 and 333 (68%) N1. Cox regression with propensity score analysis for patients with RT showed an overall decrease in survival time by 3.67 months (p<0.05). Propensity score analysis showed slightly worse survival in patients who received RT compared to those who did not (MST 2.7 vs. 3.0 years, respectively, p=0.04). There was a trend towards a survival benefit with RT in a subgroup of patients over the age of 66 years with T2N0 tumors (MST 4.7 vs. 2.7 years, respectively, p=0.14). Survival outcomes analyzed by other T and N stages were not statistically significant. Conclusions: Adjuvant RT does not confer a survival benefit in resected ampullary cancers as studied in the propensity-score adjusted SEER patient population. Further studies should be conducted in order to elucidate the role of adjuvant RT for ampullary cancers.
Effect of neoadjuvant chemoradiotherapy (nCRT) on survival in patients with borderline resectable (BR) pancreatic adenocarcinoma (PDA) with acceptable peri-operative morbidity.
Authors: Minter Rebecca Manget , Feng Mary Uan-Sian , Al-Hawary Mahmoud , Shen Jincheng , Schipper Matthew J , Bednar Filip , Proctor Erica , Warner Susanne Gray , Zalupski Mark M. , Simeone Diane M.
Published: February 2017

288

Background: The impact of nCRT for patients (pts) with BR PDA has been debated, with wide variation in practice. Most studies in pts undergoing nCRT have no or historic controls, rather than a direct comparison of BR pts treated in the same era. We aimed to assess the effect of nCRT on operative, pathologic, and survival endpoints in pts with BR PDA. Methods: 241 pts underwent pancreatectomy (177 without and 64 with nCRT) for PDA (2001-2011). CT scans at dx were re-reviewed by a pancreatic radiologist using a standardized template. Pts were categorized as resectable, BR, or unresectable according to 2012 NCCN criteria. BR pts (n=74) were extracted for analysis. Survival was compared using log-rank tests; pathologic features and peri-op factors were compared using Wilcoxon rank sum tests (continuous variables) or Fisher's exact test (binary variables). Results: Median follow up was 26 ±21 months. nCRT was associated with higher 1 and 3 yr OS, lower margin and node positivity, decreased pre-op CA19-9, and lower post-op pancreatic fistula (POPF), with higher operative time, vascular reconstructions, and transfusion (PRBCs). On univariate analysis, POPF negatively impacted survival (HR 2.34, 1.16-4.75, p=0.02) as did pre-op CA19-9>150 U/mL (HR 2.11, 1.16-3.87, p=0.015). Conclusions: Pts receiving nCRT for BR PDA had higher 1 and 3 yr OS, more negative margins, and fewer positive nodes, with minimal additional peri-op co-morbidity, compared with pts going directly to surgery. These data support consideration of enrolling all pts with BR PDA into a neoadjuvant program prior to resection. [Table: see text]
Survival benefit of second-line chemotherapy in advanced pancreatic adenocarcinoma: A systematic review of the literature.
Authors: Nagrial Adnan , Chin Venessa T. , Sjoquist Katrin , Chantrill Lorraine A. , Yip Desmond
Published: February 2017

296

Background: There is currently no standard of care for the second-line treatment of advanced pancreatic cancer. Very few randomised studies have been performed in this setting. The aim of this analysis was to compare the different therapeutic approaches in this setting, and the rate of second line treatment delivery and its influence on reported overall survival. Methods: We carried out a systematic analysis of studies in advanced pancreatic cancer. 1st and 2nd line chemotherapy trials were identified from MEDLINE, EMBASE & CENTRAL using the COCHRANE sensitive search strategy. Objective response rates (ORR) and survival (PFS & OS) were extracted and compared amongst groups using the Mann-Whitney U test. For 1st line studies, the percentage of patients who received 2nd line chemotherapy was also extracted and plotted against reported median overall survival (OS) and post-progression survival (PPS), defined as arithmetic difference between median OS and progression-free survival. Linear regression was used to explore the relationship between overall survival and second-line chemotherapy. Results: 20 first line clinical trials with 42 treatment arms met the inclusion criteria treating an aggregate total of 5,768 patients. Overall survival was positively correlated with use of second-line chemotherapy (r=0.65; p=0.012). 61 second-line studies were identified treating an aggregate total of 2,562 patients in 66 treatment arms. Combination treatment was associated with an improved response rate (p=0.045) and PFS (p=0.024) when compared to single agent therapy. Conclusions: In this exploratory analysis, these data suggest that there is a small benefit of second-line chemotherapy in pancreatic cancer. In first-line chemotherapy studies, the use of subsequent treatment correlates with improved overall survival. In second line studies, combination chemotherapy is associated with higher response rates and survival.
Effects of statin, aspirin, or metformin use on recurrence free and overall survival in patients with biliary tract cancer (BTC).
Authors: McNamara Mairead Geraldine , Aneja Priya , Le Lisa W , Horgan Anne M , McKeever Elizabeth , Knox Jennifer J.
Published: February 2017

303

Background: BTCs include intrahepatic (IHC), hilar, distal bile duct (DBD), and gallbladder carcinoma (GBC). Statins, aspirin and metformin may have antineoplastic properties. The impact of their use on overall survival and the recurrence free survival of patients who had curative resection of BTC has not been evaluated. Methods: Baseline demographics and use of statins, aspirin or metformin at diagnosis were evaluated in 913 patients with BTC from 01/87 - 07/13 treated at Princess Margaret Cancer Center, Toronto. Their prognostic significance for recurrence free and overall survival was determined using a Cox proportional hazards model. Results: The median age at diagnosis for the entire cohort was 65.7 years (range 23.7-93.7). 795 patients had a performance status < 2 and 461 (50.5%) were male. The primary site was GBC in 310 (34%) patients, DBD in 212 (23%), IHC in 200 (22%) and hilar in 191 (21%). Curative surgical resection was performed in 355 (39%) patients. Among the entire cohort of 913 patients, 151 (16.5%) reported statin use at diagnosis. Atorvastatin was the statin used in 55% of patients. 146 (16%) reported aspirin use and 81 (9%) reported metformin use at diagnosis. Age (p=0.05, p<0.01), and stage (p<0.001, p<0.001) were prognostic on multivariable analysis for recurrence free and overall survival respectively. GBC (p=0.01), DBD (p<0.01) primary and performance status ≥ 2 (p < 0.0001) were also prognostic for overall survival. Recurrence free and overall survival among statin users and nonusers was similar (Hazard Ratio (HR) 1.07, 95% confidence interval (CI) 0.78-1.48, p=0.68) and (HR 0.84 (95% CI 0.67-1.05, p=0.12) respectively. Recurrence free and overall survival among aspirin users and nonusers was similar (HR 0.91, 95% CI 0.64-1.29, P=0.58) and (HR 0.98 (95% CI 0.80-1.22, P=0.88) respectively. Recurrence free and overall survival among metformin users and nonusers was also similar (HR 0.71, 95% CI 0.43-1.17, p=0.18) and (HR 0.81 (95% CI 0.60-1.08, p=0.14) respectively. Conclusions: In this large retrospective cohort of BTC patients, statin, aspirin or metformin use was not associated with improved recurrence free or overall survival.
A prognostic examination of the chemotherapeutic selection for pancreatic cancer patients with peritoneal dissemination: A retrospective study from a single center.
Authors: Takada Ryoji , Ioka Tatsuya , Sueyoshi Hironari , Ishida Nobuko , Yamai Takuo , Fukutake Nobuyasu , Ashida Reiko , Katayama Kazuhiro
Published: February 2017

331

Background: Pancreatic cancer(PC) patients(pts) with peritoneal dissemination are poor prognosis. This retrospective study evaluated the prognosis of Gemcitabine(GEM)-based current chemotherapy(G), GEM plus S-1 combination therapy(GS) and single agent of S-1 as 1st line chemotherapy regimen in PC pts with peritoneal dissemination. Methods: This is a retrospective study of PC pts with ascites or peritoneal nodules in the CT or US image who underwent chemotherapy between 2002 and 2011. We collected data on age, sex, Performance Status(PS), tumor location, other metastasis location, status of peritoneal dissemination, CA19-9, CEA, albumin, CRP. We classified 1st line chemotherapy regimen in G, GS and S-1, and we evaluated 1-year survival rate, progression free survival(PFS), overall survival(OS) for the 3 regimens. Results: A total of 81 pts were included. Median age were 64 (38-78), males 50%, PS 0-1 89%. The number of pts treated with G, GS, S-1 was 54, 14, 13. The 1-year survival rate of G, GS and S-1 were 20.3%, 28.5% and 53.8%. The median PFS were 106 days, 84 days and 88 days, respectively. The median OS were 196 days, 154 days, 359 days, respectively. The 1-year survival rate of S-1 was significantly better than that of G (p=0.01). Median PFS and median OS of S-1 didn’t demonstrate the superiority compared with that of G (p=0.40, p=0.08). Conclusions: We suggest the selection of S-1 as 1st line chemotherapy regimen in PC pts with peritoneal dissemination might be effective and we need further investigation.
A phase I/II study of capecitabine combined with peginterferon alfa-2a in sorafenib-refractory advanced hepatocellular carcinoma patients.
Authors: Ogasawara Sadahisa , Chiba Tetsuhiro , Ooka Yoshihiko , Kanogawa Naoya , Motoyama Tenyu , Suzuki Eiichiro , Tawada Akinobu , Kanai Fumihiko , Yokosuka Osamu
Published: February 2017

346

Background: Several studies have demonstrated the effectiveness of combining a pyrimidine fluoride drug with interferon. Therefore, this study examined the dose of capecitabine in combination with peginterferon alfa-2a (PEG-IFN α-2a) (Phase I part) and evaluated its safety and efficacy in sorafenib-refractory advanced hepatocellular carcinoma patients (Phase II part). Methods: Capecitabine was administrated daily on days 1–14 and PEG-IFN α-2a was given on days 1, 8, and 15. The cycles were repeated every 21 days. Patients were scheduled to received capecitabine (mg/m2/day) and PEG-IFN α-2a (μg/week) at one of three dose levels in phase I: 1200/90, 1600/90, and 2000/90 (levels 1–3, respectively). Results: Thirty patients were enrolled. The recommended dose was level 3. Of the 24 patients given the drug at the recommended dosage, two (8%) showed partial responses, nine (38%) had stable disease, ten (42%) had progressive disease, and three (13%) were not evaluated. The median time to progression was 3.0 months. The most common toxicities were decreased white blood cell, neutrophil, and platelet counts, palmar-plantar erythrodysesthesia syndrome, and fatigue. Dose modification was required in ten (42%) patients. Four (17%) patients discontinued treatment because of severe adverse events. Conclusions: Capecitabine at 2000 mg/m2/day combined with PEG-IFN α-2a 90 μg/week had moderate, but manageable toxicity. Further investigation is needed to refine the efficacy. Clinical trial information: UMIN000005697.
Cost-effectiveness of nab-paclitaxel plus gemcitabine versus erlotinib plus gemcitabine in metastatic pancreatic cancer.
Authors: Chiorean E. Gabriela , Whiting Scott , Binder Gary , Dranitsaris George , Manax Victoria
Published: February 2017

353

Background: In a recent phase III trial nab-paclitaxel (albumin-bound paclitaxel) + gemcitabine (nab-P/G) demonstrated a 1.8 month, or 27%, improvement in median overall survival (OS) (HR = 0.72, P < 0.001) vs gemcitabine (G) in first-line metastatic pancreatic cancer (mPC). nab-P/G had higher 1 year OS (35% vs 22%) and improved PFS by 1.8 months (HR = 0.69, P < 0.01). nab-P/G is the first taxane based therapy to show a significant OS improvement in a phase III mPC trial. Erlotinib + gemcitabine (E/G) has also demonstrated activity in mPC, with a 0.3 month OS benefit vs G (HR = 0.82, P = 0.04), a 1 year OS of 23% vs 17%, and 0.2 months PFS benefit (HR = 0.77, P = 0.004) vs G. A cost-effectiveness analysis measuring the cost per life year (LY) gained for nab-P/G and E/G was conducted from the US payer perspective. Methods: Costs and clinical outcomes were evaluated fromnab-P/G vs G and E/G vs G trials of mPC. Health care resource use and the management of grade III/IV adverse events (AE) were collected from a large multisite US oncology clinic, expert opinion, and literature (2012 US dollars). Drug cost per cycle was multiplied by the median cycles delivered from the trials for nab-P/G and E/G. Results: Duration of therapy was 4 months for nab-P/G vs 3.9 months for E/G. Total cost for nab-P/G was $24,984 vs $23,044 for E/G, including drug, administration and AE management. AE costs were similar between the two therapies (Table). Differences of > 5% were noted in neutropenia (rates: nab-P/G = 33%; E/G = 24%), neuropathy (nab-P/G = 17%; E/G = 1%), and rash (nab-P/G = 0%; E/G = 6%). The net survival advantage for nab-P/G vs E/G was 1.5 incremental life months gained. Nab-P/G was cost-effective relative to E/G, at a cost of $15,522 per incremental life year gained. Conclusions: nab-P/G is a cost-effective alternative to E/G in mPC, bringing more months of OS at < $16,000 cost per incremental life year gained. [Table: see text]
Resection of isolated metastases to the pancreas: An institutional retrospective review.
Authors: Goldenberg Benjamin Adam , Gill Sharlene
Published: February 2017

365

Background: Resection of isolated metastases in good performance status patient (pts) has increasingly become an accepted standard of care. While resection of hepatic and pulmonary metastases from selected cancers such as CRC and RCC have supportive evidence, the safety and effectiveness of pancreatic resections for metastases from these same tumour sites is not as well established. We aim to identify the optimal assessment and selection criteria which would best predict a favourable outcome from pancreatic metastatectomy. Methods: A prospective pathology database was used to identify pts who underwent partial or total pancreatectomy for solid tumour metastases to the pancreas between Sept 2000 to May 2013. Demographic, histologic, surgical and survival data was collected and analyzed using descriptive statistics. Results: 19 pts were identified and included. Follow-up time ranged from 5 months to 8 years. Most common primary sites were RCC (42%,) CRC (11%) and GIST (11%). Favourable outcome, defined as an event-free survival greater than 12 mos from pancreatectomy, was observed in 63% (12/19) and was associated with a higher proportion of RCC (50% vs 14%), pancreas as M1 presentation (58% vs 43%), longer time from presentation to resection (median 5mos vs 2mos), multidisciplinary conference (MDC) review (33% vs 14%) and preop PET (42% vs 14%). No differences were observed by age or gender. Median postoperative length of stay was 22.1 days. Conclusions: Resection of pancreatic metastases remains a rare indication. Given the morbidity and extended LOS associated with pancreatectomy, careful patient selection is required. In this small retrospective series, favourable outcomes were more frequently associated with RCC primary, delayed resection, pre-op MDC and PET staging. Multicentre surgical registries would enhance future analysis and better guide patient selection.
Validation of hepatectomy for elderly patients with hepatocellular carcinoma.
Authors: Kishida Norihiro , Hibi Taizo , Itano Osamu , Shinoda Masahiro , Kitago Minoru , Yagi Hiroshi , Abe Yuta , Kitagawa Yuko
Published: February 2017

380

Background: Hepatectomy for hepatocellular carcinoma (HCC) and its outcomes in the elderly population have yet to be defined. We aimed to validate our current strategy to determine surgical indication regardless of age. Methods: A single-center, retrospective cohort study was conducted for 104 patients who underwent hepatectomy for HCC from 2005 to 2010. The patients were divided into 2 groups according to age; i.e. <75 years (non-elderly cohort; n=82) and ≥75 years (elderly cohort; n=22), and short-/long-term results were compared. Results: In the elderly cohort, the prevalence of ECOG performance status 1 preoperatively (p<0.001) and HCV or non-HBV/non-HCV were higher than in the non-elderly cohort (p=0.04). Otherwise, patient/tumor characteristics were comparable between the 2 groups. The elderly cohort suffered postoperative complications more frequently (42% vs. non-elderly, 16%, p=0.01) but the length of hospital stay was equivalent. Ninety-day mortality occurred in 1 case each (elderly, respiratory failure; non-elderly, liver failure; p=0.38). During a median follow-up period of 47 months, unadjusted 5-year disease-free and overall survivals were comparable per log-rank comparison (elderly, 25% and 80% vs. non-elderly, 33% and 79%, p=0.96 and 1.00, respectively). Cox univariate analyses on recurrent HCC showed hypertension, Child-Pugh grade B, tumor size, recurrent/multiple tumors, preoperative alpha-fetoprotein level, moderate/poor differentiation, portal invasion, intrahepatic metastases, and positive margins to have p values <0.20. After adjustment, the hazard ratio of recurrent HCC at 5 years in the elderly cohort was 0.87 (95% CI, 0.40-1.91; p=0.74). Tumor size, alpha-fetoprotein level, and intrahepatic metastases emerged as independent predictors of diminished 5-year disease-free survival in the entire cohort. Conclusions: Although postoperative complications develop more frequently, hepatectomy in the elderly patients affords comparable short- and long-term prognoses to the non-elderly patients. Surgical strategy for HCC should be based on tumor factors and hepatic reserve and not by age alone. Perioperative management needs to be individualized according to coexisting disorders.
Reinitiating nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer.
Authors: Borazanci Erkut , Schroeder Katy , Jameson Gayle S. , Ramanathan Ramesh K. , Von Hoff Daniel D.
Published: February 2017

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Background: The recent results of the phase III trial MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) demonstrated an improvement in progression free survival, overall response rate, and overall survival for the combination of nab-paclitaxel plus gemcitabine compared to gemcitabine alone. Methods: A retrospective analysis of patients with advanced pancreatic adenocarcinoma was undertaken to determine the disease control rate (CR+PR+SD ≥ 16 weeks) in patients who had received prior nab-paclitaxel plus gemcitabine and were retreated with nab-paclitaxel plus gemcitabine again after receiving other interval therapies. Results: Nine patients were identified. The median time between treatments of nab-paclitaxel plus gemcitabine was 7.67 months (range 2.53 to 54.03 months). The regimens used in between treatments of nab-paclitaxel plus gemcitabine were 5FU-based in 8 of the 9 patients, with the other patient undergoing temozolomide, cetuximab, and sorafenib sequential treatment. Five of the nine patients received repeat nab-paclitaxel plus gemcitabine > 6 months after their initial nab-paclitaxel/gemcitabine regimen and four of the nine received repeat nab-paclitaxel plus gemcitabine < 6 months after their initial nab-paclitaxel/gemcitabine regimen. The disease control rate seen for the second treatment with nab-paclitaxel plus gemcitabine was 44% (four of nine patients). Two of these patients received repeat nab-paclitaxel plus gemcitabine < 6 months after their first nab-paclitaxel plus gemcitabine regimen and two of these patients received repeat nab-paclitaxel plus gemcitabine > 6 months after their first nab-paclitaxel plus gemcitabine regimen. Three of nine patients (33%) had treatment a third time with nab-paclitaxel plus gemcitabine, with 2 of 3 of these patients having disease control. As of September 1st, 2013, two of nine patients are still undergoing repeat nab-paclitaxel plus gemcitabine therapy. Conclusions: Nab-paclitaxel plus gemcitabine can be an effective repeat regimen in patients with advanced pancreatic adenocarcinoma. In this very small series, the time between reinitiation of nab-paclitaxel plus gemcitabine appears to not play a role in disease control rate.
Chemoradiation (CRT) followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant CRT and surgery for locally advanced rectal cancer: Results of the Spanish GCR-3 randomized phase II trial after a median follow-up of 5 years.
Authors: Fernandez-Martos Carlos , Pericay Carles , Aparicio Jorge , Safont Maria Jose , Salud Antonia , Massuti Bartomeu , Alonso Vicente , Vera Ruth , Escudero Pilar , Martin-Richard Marta , Bosch Carlos , Maurel Juan
Published: February 2017

383

Background: In locally advanced rectal cancer in contrast with the conventional approach the administration of chemotherapy prior to chemoradiation (CRT) and surgery allow most patients receive planned treatment with better toxicity profile without compromising the pCR and complete resection rates, as we previously demonstrated. (J Clin Oncol 28:859-865, 2010). We now report on the 5-year outcomes of this randomized trial. Methods: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinoma selected by Magnetic Resonance +/- endorectal ultrasound, were randomly assigned to arm A—preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)—or arm B— four cycles of CAPOX followed by CRT and surgery. The following five-year outcomes were assessed: the cumulative incidence of local-regional (LRF) and distance failure (DF), disease-free (DFS) and overall (OS) using the Kaplan-Meier method. Results: Of 108 patients accrued, 52 were randomly assigned to arm A and 56 to arm B. According to intention-to-treat analysis with a median follow-up time of 69.5 months, the 5-years DFS rates were 64.3% (95% CI, 49% to 76%) in arm A and 60.7% (95 CI, 46% to 72%) in arm B (P=0.73). The 5-year cumulative incidences of local relapse were 1.9 % and 7.1% in A and B arms respectively (P= 0.36). No significant differences were detected for 5-year cumulative incidence of distant metastases (21.1% and 23.2%; P = 0.80) and 5-years overall survival (77.9% and 74.7%; P= 0.64). Conclusions: Both approaches yield similar 5-y outcomes. Because of the associated acute toxicity sparing and better compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy prior to CRT and surgery may well be the next step in phase III testing versus the standard strategy to capture meaningful differences in DFS.
Regular aspirin (ASA) use and survival in patients with PIK3CA-mutated metastatic colorectal cancer (CRC).
Authors: Kothari Nishi , Kim Richard D. , Gibbs Peter , Yeatman Timothy Joseph , Schell Michael J. , Desai Jayesh , Tie Jeanne , Lipton Lara Rachel , Jorissen Robert N. , Wong Hui-Li , Sieber Oliver , Day Fiona , Faragher Ian , Jones Ian , Tran Ben
Published: February 2017

386

Background: Recent data has demonstrated that regular ASA use improves overall and cancer-specific survival in the subset of CRC patients harboring PIK3CA mutations. However, as this series only analyzed 15 PIK3CA mutant CRC patients with metastatic disease at diagnosis, it remains uncertain whether the survival benefit associated with regular ASA use extends to patients with metastatic disease. We combined data from two large academic institutions to explore the association between regular ASA use and survival in metastatic CRC. Methods: Patients with PIK3CA mutated CRC were identified at Moffitt Cancer Center (MCC) in Tampa, FL and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data (including age, sex, site of disease) and survival data were available. At MCC, PIK3CA mutations were identified by exome sequencing using an Illumina Next Generation Sequencing platform with 50-100X coverage. At RMH, Sanger sequencing was used to identify PIK3CA mutations. Survival analyses were conducted using Cox regression. Results: We identified 187 CRC patients who harbored a PIK3CA mutation. Median age was 72 years and median follow up was 48 months. 49 (26%) patients used ASA regularly. 47 (25%) patients had metastatic disease at diagnosis. In univariate analyses, regular ASA use was not associated with improved overall survival (HR 0.87, p = 0.60), although there was a trend towards improved cancer-specific survival (HR 0.48, p = 0.06). In patients with stage-II or stage-III disease, regular ASA use did not improve overall, cancer-specific or recurrence-free survival. However, in stage-IV patients, regular ASA use was significantly associated with improved overall (HR 0.35, p = 0.04) and cancer-specific (HR 0.28, p = 0.02) survival in a univariate analysis. Conclusions: Our study demonstrates that in patients with metastatic CRC harboring a PIK3CA mutation, regular ASA use is associated with a significant overall and cancer-specific survival advantage. However, we were not able to confirm the survival advantage across all stages. To our knowledge, our study is the largest to examine ASA use in PIK3CA mutated CRC.
Predictors of pathologic complete response after neoadjuvant treatment for rectal cancer: A multicenter study.
Authors: Armstrong Dawn Elizabeth , Raissouni Soundouss , Price Hiller Julie A. , Mercer Jamison , Powell Erin Diana , MacLean Anthony , Jiang Maria , Doll Corinne M , Goodwin Rachel Anne , Batuyong Eugene , Zhou Kevin , Monzon Jose Gerard , Tang Patricia , Heng Daniel Yick Chin , Cheung Winson Y. , Vickers Michael M.
Published: February 2017

397

Background: Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) for rectal cancer is associated with better long-term outcomes, and is used as an early indicator of response to novel agents. To assess the rate and predictors of pCR, we performed a retrospective population based study in four Canadian provinces. Methods: Cancer Registries identified consecutive patients with clinical stage I-III rectal cancer from the Tom Baker Cancer Center, Cross Cancer Institute, BC Cancer Agency, Ottawa Hospital Cancer Centre and the Dr. H. Bliss Murphy Cancer Centre who received fluoropyrimidine-based CRT and had curative intent surgery (Sx) from 2005 to 2012. Patient, tumor, and therapy characteristics were correlated with response. Results: Of the 891 patients included, 885 patients had pCR data available. 161 (18.2%) had a pCR to CRT, while 724 (81.8%) did not. Patients with a pCR had a lower pre-treatment (tx) CEA, and higher hemoglobin on univariate analysis (see table). On multivariable analysis, statin use at baseline (OR 1.7, 95% CI 1.04-2.89, p=0.044), lower pre-tx CEA (OR 1.03, 95% CI 1.003-1.05 p=0.028) and distance closer to anal verge (OR 1.07, 95% CI 1.004-1.15, p=0.039) were significant predictors of pCR. The 3yr DFS was 86% in those with pCR vs 62.5% in those without a pCR (P<0.0001). Conclusions: Lower pre-tx CEA, distance closer to anal verge and statin use are predictors of pCR. Clinical trials investigating statins combined with neoadjuvant CRT may be warranted. [Table: see text]
Outcomes of adjuvant chemotherapy (AC) in young (YP) and elderly patients (EP) with high-risk stage II colon cancer (CC).
Authors: Kumar Aalok , Kennecke Hagen F. , Lim Howard John , Renouf Daniel John , Gill Sharlene , Woods Ryan , Speers Caroline , Cheung Winson Y.
Published: February 2017

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Background: High-risk stage II CC is defined as those presenting with T4 stage, obstruction or perforation, <12 lymph nodes retrieved, positive resection margins, and lymphovascular or perineural invasion. Our prior findings suggest that improved outcomes from AC are limited to specific high-risk features, such as T4 disease (Kumar et al, ASCO 2012). It is unclear if this benefit is seen across all ages. Our aim was to compare patterns of AC use and outcomes in YP and EP with high-risk stage II CC. Methods: All patients diagnosed with high-risk stage II CC from 1999 to 2008 and evaluated at any 1 of 5 regional cancer centers in British Columbia were categorized into YP (age <70 years) or EP (age >/=70 years). Kaplan-Meier methods and Cox regression were used to correlate receipt of AC with overall survival (OS), disease specific (DSS), and relapse-free survival (RFS), stratified by age group. Results: A total of 1,236 patients were identified: 636 (51%) YP and 600 (49%) EP among whom 363 (57%) and 85 (14%) received AC, respectively. Individuals who received AC in either age group had better performance status than those who did not (ECOG 0/1 47% vs. 34%, p=0.02). After adjusting for known prognostic factors, a significant advantage in OS, but not DSS or RFS, from AC was observed for both YP and EP (Table). The impact of AC on these outcomes was similar across age groups (p interaction of age and treatment = 0.46, 0.64, and 0.69 for OS, DSS, and RFS, respectively). In the entire cohort, individuals with T4 lesions had significantly improved OS (HR 0.50, 95%CI 0.33-0.77, p=0.002), DSS (HR 0.59, 95%CI 0.37-0.93, p=0.03), and RFS (HR 0.63, 95%CI 0.42-0.95, p=0.03). The effect of AC in the T4 subgroup was also similar for both YP and EP in terms of OS, DSS and RFS (p interaction of age and treatment = 0.41, 0.71, and 0.77, respectively). Conclusions: In this population-based cohort of high-risk stage II CC, improvements in outcomes from AC were seen mainly in those with T4 disease, regardless of age. [Table: see text]
Prevalence of KRAS, BRAF, NRAS, PIK3CA, and PTEN alterations in colorectal cancer: Analysis of a large international cohort of 5,900 patients.
Authors: Basu Gargi Dan , Xiu Joanne , Arguello David , Feldman Rebecca A. , Millis Sherri Z. , Bender Ryan P. , Gatalica Zoran , Paul Les , Braiteh Fadi S.
Published: February 2017

399

Background: Colorectal cancer (CRC) is the third most common cancer worldwide, with metastatic disease accounting for 40 to 50% of newly diagnosed patients. EGFR monoclonal antibodies (Mab), cetuximab and panitumumab, are effective treatment for KRAS wild type CRC. Although mutations in KRAS predict resistance to EGFR Mab therapy, only 80% of CRC patients with KRAS wild-type (WT) status respond to treatment. This study is a retrospective evaluation of genomic alterations in the EGFR pathway such as alterations in KRAS, BRAF, NRAS, PIK3CA and PTEN that may predict lack of response to EGFR Mab therapy in CRC patients. Methods: A large database of 5,900 consecutive CRC patients was analyzed from 2011 onwards for demographics (sex, age, geography, site of tumor) and biomarkers that might correlate with response to EGFR Mab therapy. Comprehensive testing included gene sequencing for KRAS, BRAF, NRAS, PTEN, and PIK3CA (next-generation sequencing, Sanger, pyrosequencing) and immunohistochemistry for PTEN protein expression. Results: Analysis revealed the incidence of KRAS mutation of 42% which is consistent with published literature. Analysis of the KRAS WT cohort revealed a mutation rate of 13.8 % for BRAF, 6.8% for NRAS, and 40% for patients with either PTEN loss of expression/mutation or a PIK3CA mutation. Earlier studies support that mutations in NRAS, BRAF and activation of the PI3K pathway by PTEN/PIK3CA analysis result in lower response rates to EGFR Mab therapy in CRC. Furthermore, multiplex biomarker testing revealed the rare occurrence of concurrent mutations: 1/5,900 subject harboring a BRAF and NRAS mutations, 7/5,900 others with BRAF and PIK3CA mutations, and 8/5,900 subjects with NRAS and PIK3CA mutations. Conclusions: This is a comprehensive analysis of a large international cohort evaluating the prevalence of predictive molecular aberrations suspected of lack of response to EGFR Mab therapy in patients with WT KRAS. Prospective controlled studies are in progress to validate the role of BRAF, NRAS, PIK3CA, and PTEN in clinical management of CRC. It is imperative to further explore the molecular pathology of CRC beyond KRAS in patient selection for EGFR Mab therapy.