bluuebunny/crossref_metadata_2025 huggingface dataset:
A preclinical trial to evaluate therapies for BRCA-associated pancreatic cancer.
Authors: Park Jin Yong Patrick , Hall Anita , Hedley David W. , Tsao Ming Sound , Gallinger Steven , Zogopoulos George
Published: March 2017

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Background: Pancreatic ductal adenocarcinoma (PDAC) associated with germline BRCA1 or BRCA2mutations may have selective sensitivity to agents that exploit homologous recombination DNA repair defects. We hypothesized that cisplatin, a DNA-crosslinking agent, and talazoparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, monotherapies are efficacious in BRCA-associated PDAC, while combination therapies with these agents have enhanced efficacy. Methods: A preclinical trial was performed in subcutaneous patient-derived tumor xenograft (PDX) mouse models with (n = 5) and without (n = 2) germline BRCA1 or BRCA2mutations. Mice harboring PDX tumors were treated with vehicle, talazoparib, cisplatin, gemcitabine, talazoparib with cisplatin (TC), talazoparib with gemcitabine (TG), or cisplatin with gemcitabine (CG). Twelve tumors were randomized into each trial arm, treated for 28 days, and then monitored without further treatment to assess tumor regrowth. Results: Treatment with cisplatin and talazoparib monotherapies resulted in 89.8% and 88.2% tumor growth inhibition (GI) in BRCA-associated cases versus 34.0% and 34.7% GI in the cases without germline BRCAmutations, respectively. Gemcitabine-based combinations were more effective than monotherapies in BRCA-associated cases (p < 0.001), with CG and TG resulting in tumor regression in five and three BRCA-associated cases, respectively. Although we also observed the treatment effect with these combinations in non-BRCA cases, it paralleled the gemcitabine monotherapy effect in these cases (p = 0.322). Following cessation of treatment, we observed heterogeneity in tumor regrowth. CG and TG demonstrated sustained responses across all BRCA-associated cases, however, TG had greater toxicity than CG. Conclusions: Our preclinical data suggest that targeted therapy with CG is efficacious with a sustained response and less toxicity than TG in BRCA-associated PDAC.
Prognostic factor of distal bile duct cancer (DBDC) and ampullary cancer (AC) after pancreatoduodenectomy.
Authors: Tomiyasu Shinjiro , Sakamoto Keita , Inoue Mitsuhiro , Iizaka Masayoshi , Ozaki Nobuyuki , Horino Kei , Takamori Hiroshi , Hirota Masahiko , Baba Hideo
Published: March 2017

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Background: Ampullay cancer (AC) is relatively good prognosis in the biliary tract cancer. Such as LN metastasis, pancreatic invasion is a prognostic factor in AC. On the other hand, Distal bile duct cancer (DBDC) is somewhat good prognosis in the biliary tract cancer. Such as ductal resection margin positive is a prognostic factor in DBDC. There are few papers considered to both difference. Therefore, we conducted this study to examine the difference of AC and DBDC. Methods: To evaluate Cancer-Specific Survival (CaSS), Recurrence-Free Survival (RFS) and prognostic factors after pancreatoduodenectomy (including pylorus-preserving pancreatoduodenectomy: PPPD, subtotal stomach-preserving pancreatoduodenectomy: SSPPD) based on a series of 80 patients of AC and 36 patients of DBDC from 1996 to 2015. We reviewed and analyzed the clinicopathologic data, recurrence and survival. Results: Five years CaSS and RFS of AC were 72.3% and 72.5%. In univariate analysis, pancreatic invasion, R1or R2 resection, duodenal invasion and lymph node metastasis are significantly poor prognosis. In multivariate analysis, pancreatic invasion and R1or R2 resection are poor prognostic factors (pancreatic invasion, p = 0.0012, hazard ratio (HR) 5.65 [confidence interval (CI) 1.92-19.5 95%], R1or R2 resection, p = 0.0043, HR 6.22 [CI 1.68-40.2 95%]). On the other hand, five years CaSS and RFS of DBDC were 35.8% and 46.8%. In univariate analysis, pancreatic invasion (+) ≥ 5 mm in depth, and duodenal invasion are significantly poor prognosis. In multivariate analysis, duodenal invasion is the only poor prognostic factors (p = 0.0227, HR 2.90 [CI 1.16-7.39 95%]). Conclusions: DBDC is considerable poor prognosis compared with AC. Lymph node metastasis is not prognostic factor depends on D2 LN dissection in AC, than pancreatic invasion. Cancer cells invaded pancreatic parenchyma in AC; pancreatic invasion may be the most important prognostic factor by biology-like pancreatic cancer. Duodenal invasion in DBDC was prognostic factor reflects the degree of development of the cancer beyond pancreatic parenchyma. Further clinicopathological and biological studies are needed to confirm our findings.
Intratumoral heterogeneity of intrahepatic cholangiocarcinoma.
Authors: Walter Dirk , Döring Claudia , Feldhahn Magdalena , Battke Florian , Hartmann Sylvia , Winkelmann Ria , Schneider Markus , Bankov Katrin , Schnitzbauer Andreas , Zeuzem Stefan , Hansmann Martin-Leo , Peveling-Oberhag Jan
Published: March 2017

335

Background: No personalized therapy regimens could demonstrate a benefit in survival in intrahepatic cholangiocarcinoma (iCCA). Since genetic heterogeneity might influence single biopsy based targeted therapy or the outcome of clinical trials, aim of the present study was to investigate intratumoral heterogeneity of iCCA by whole exome sequencing. Methods: Samples from tumor center and tumor periphery of large iCCA lesions as well as a control from healthy liver tissue were obtained from 4 patients and whole exome sequencing was performed. Mutations that occurred only in the tumor center or periphery were defined as private, whereas mutations present in both samples were regarded as common. Results: A mean of 3 non-synonymous private mutations (range 0-13) per sample compared to 31.8 common mutations per sample (range 23-39) was identified. Mean percentage of non-synonymous private mutations per sample was 12% (range 0-57). In all samples of patient 1-3 as well as the central sample of patient 4 ≤ 10% private mutations were found, whereas 57% of private mutations were identified in the peripheral sample of patient 4. In this sample, a private mutation in the DNA mismatch repair protein MSH6 as well as a spatial loss of expression of MSH6 could be identified most likely causing the high amount of private mutations. No substantial intratumoral heterogeneity was found in copy number variation analysis apart from a heterozygous duplication of chromosome 6p of patient 4. Conclusions: iCCA show a small but distinct intratumoral heterogeneity. Somatic mutations in mismatch repair proteins might contribute significantly to increased spatial tumor burden and thereby can have crucial impact on clinical management.
Role of nutritional and inflammatory status in the prognosis of advanced gastric cancer.
Authors: Cousillas Antía , Gallardo Elena , Carou Iria , Rodriguez Ángeles , Sacristán Víctor , Vázquez Lidia , López-Jato Cristina , Garcia Arroyo Francisco Ramon , Azpitarte Cristina , López-Clemente Pedro , Constenla Manuel
Published: March 2017

35

Background: This study explores the prognosis impact of nutritional and immune status in metastatic gastric cancer (GC). Recently research has been focused on a proinflammatory status and the relevance of inmune system of the patient in GC. Neutrophil-lymphocyte ratio (NLR) and prognostic nutritional index (PNI) has showed prognostic value in local disease. Our study was assesed in metastatic disease. Methods: One hundred and twenty patients with metastatic gastric adenocarcinoma were retrospectively evaluated between 2011 and 2015. 67.2% were metastatic at diagnosis and 32.8% had a recurrence of disease. Clinical, laboratory and histopathological characteristics were selected as risk factors. The optimal cut-off levels were defined as NLR = 3, PNI (10 x albumin concentration +0.005 x total lymphocyte count) = 43.8, albumin = 3.5 g/dL, body mass index (BMI) = 25. Patients with high NLR and hypoalbuminemia were defined as 2, patients who presented only one abnormally were defined as 1 and those with neither abnormality were defined as 0. Lab data levels were related with survival by Kaplan-Meier and compared by long-rank test. Results: Among 120 patients, mean age was 69 years old, 35% female and 72.5% had no comorbidity. NLR > 3 (6.7 vs 12.5months, p = 0.001), low PNI (7.7 vs 13.1months, p = 0.01) and low albumin (6.2 vs 11.2 months, p = 0.002) were correlated with OS. Significantly, patients with an BMI < 25 had a worse prognosis compared with patients with BMI ≥ 25 (7.4 vs 12.4months, p = 0.02). Obesity in metastatic GC was related with good prognosis in our review. In the group of patients with hypoalbuminemia and h-NLR (27.6%) OS was much worse than patients with normal albumin and low-NLR, 33.6% (4.4months vs. 12.8 months, p < 0.001) Conclusions: High NLR ( > 3) and low PNI ( < 43.8), albumin ( < 3.5g/dL) were correlated with worse outcomes. Moreover, the association in a score of NLR plus albumin showed eight months OS diference. As a recent data in other cancer sites, obesity was related with good prognosis in mGC in our review.
Nab-paclitaxel plus gemcitabine or plus simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic adenocarcinoma: A GERCOR randomized phase II study (AFUGEM).
Authors: Dubreuil Olivier , Bachet Jean Baptiste , Hammel Pascal , Desrame Jerome , Meurisse Aurelia , Andre Thierry , Debourdeau Philippe , Dauba Jérôme , Lecomte Thierry , Seitz Jean Francois , Tournigand Christophe , Aparicio Thomas , Guerin Meyer Véronique , Taïeb Julien , Hiret Sandrine , Volet Julien , Monier Amandine , Chibaudel Benoist , Bonnetain Franck , Louvet Christophe
Published: March 2017

350

Background: Nab-paclitaxel plus gemcitabine regimen (NABGEM) became a standard in first-line patients (pts) with metastatic pancreatic adenocarcinoma (mPAC). The AFUGEM trial evaluated the efficacy and safety of nab-paclitaxel plus simplified LV5FU2 (NABFU). Methods: Main eligibility criteria were: untreated mPAC, ECOG PS≤2. Pts received nab-paclitaxel (125 mg/m2 on d1, 8 and 15) plus gemcitabine (1000 mg/m2 on d1, 8 and 15) or plus simplified LV5FU2 (leucovorin 400 mg/m2, 5FU bolus 400 mg/m2 followed by 2400 mg/m2 given as a 46-hour continuous infusion on d1 and 15), one cycle every 4 weeks in both arms, ratio 1:2, respectively. The primary end point was observed progression-free survival (PFS) rate at 4 months (m). A Fleming 2-stage design was used with a targeted (H1) 4m-PFS rate of 50% in NABFU arm and an uninteresting 35% rate (H0, unilateral alpha of 5% and power of 80%). Results: 114 pts were included: NABGEM n=39, NABFU n=75. Baseline characteristics were well balanced: median age 66 years (45-86), ≥2 metastatic sites 36.8%, ECOG PS 0-1 84.2% and 2 15.8%, at the exception of pain more frequent in the NABFU arm (38.5% vs 56.0%). In mITT population, the observed 4m-PFS rates were of 55.4% [95% CI, 45-63] in NABFU Vs 53.9% [95% CI, 39.6-67.7] in NABGEM. Disease control rates were 65% (95% CI, 53-76) and 62% (95% CI, 45-77) respectively. After a follow-up of 24.3m, median PFS were 5.9 [95% CI, 3.6-7.4] v 4.9 months [95% CI, 2.1-7.7] [HR=0.79, 95% CI: 0.52-1.20]. Grade 3-4 adverse events were more frequent in NABGEM (77% v 87%). At tumor progression, in the NABFU arm, 50 patients (66%) and then 13 patients (17%) received a second and third line of chemotherapy respectively, versus 22 patients (56%) and 6 patients (15%) in the NABGEM arm. Median OS were 11.4 [95% CI, 8.8-16.5] v 9.2 months [95% CI, 6.0-13.6] [HR=0.61, 95% CI: 0.40-0.95], respectively. The 12 and 18-months OS rates in NABFU vs NABGEM arm were 48% Vs 41% and 34% Vs 13%, respectively. Conclusions: Nab-paclitaxel plus simplified LV5FU2 appears at least as active as gemcitabine plus nab-paclitaxel in mPAC. The toxicity profile is safe and tolerable. This regimen deserves evaluation in a phase III trial. Clinical trial information: NCT01964534.
Actual 5-year survivors following resection of hilar cholangiocarcinoma.
Authors: Tran Thuy , Ethun Cecilia Grace , Pawlik Timothy M. , Buettner Stefan , Idrees Kamran , Isom Chelsea A , Fields Ryan C. , Krasnick Bradley , Weber Sharon M. , Salem Ahmed , Martin Robert C. G. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Shenoy Rivfka , Maithel Shishir Kumar , Poultsides George A.
Published: March 2017

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Background: Although several studies have reported on actuarial survival outcomes following resection of hilar cholangiocarcinoma, the characteristics of patients who actually reached the 5-year milestone have not been adequately described. Methods: Patients who underwent resection for hilar cholangiocarcinoma from 2000-2015 in 10 US academic institutions participating in the Extrahepatic Biliary Malignancy Consortium were analyzed. Patients alive at last encounter with less than 5 years of follow-up were excluded. The clinicopathologic characteristics, perioperative, and long-term outcomes of actual 5-yr survivors and of patients who died within 5 years were compared. Results: Of 328 patients explored, 257 (78%) underwent curative resection and had an actuarial 5-year survival of 17%. After excluding 63 survivors with < 5 years follow-up, 194 patients were further classified as 5-year survivors (n = 23, 12%) and non-5-yr survivors. None of the 5-yr survivors had preoperative systemic biliary sepsis, portal vein embolization, T3 tumors with unilateral portal vein or hepatic artery invasion, or T4 tumors necessitating main portal vein or hepatic artery resection. However, actual 5-year survival was still achieved in the setting of bile duct resection only, R1 margins, poor differentiation, lymphovascular or perineural invasion, nodal metastasis, intraoperative blood transfusion, and serious postoperative complications. Five-year survival did not equal cure, as five 5-year survivors experienced disease recurrence, 2 before and 3 after the 5-year mark. There were ten actual 7-year survivors and four actual 10-year survivors. Conclusions: Although nodal metastasis, poor differentiation, and R1 margins are established predictors of poor outcome for hilar cholangiocarcinoma, the mere presence of these factors does not preclude patients from achieving a 5-year survival. In contrast, preoperative biliary sepsis, T3 or T4 stage, and the necessity for vascular resection and reconstruction appear to be prohibitive in reaching the 5-year milestone. This information can be utilized in the perioperative counseling of patients with this challenging malignancy.
Interim results of a multicenter phase II trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients (Pts) with locally advanced pancreatic cancer (LAPC).
Authors: Lacy Jill , Portales Fabienne , Hammel Pascal , Pazo Cid Roberto A. , Manzano Mozo Jose Luis , Kim Edward Jae-hoon , Dowden Scot D. , Borg Christophe , Sastre Javier , Bathini Venu Gopal , Terrebonne Eric , Lopez-Trabada Daniel , Rivera Fernando , Asselah Jamil , Damiani Azzurra , Hwang Jimmy J. , Ong Teng Jin , Nydam Thom , Shiansong Li Jack , Philip Philip Agop
Published: March 2017

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Background: Treatment options for pts with LAPC are limited and generally similar to those for metastatic PC (mPC). The phase 3 MPACT trial of pts with mPC demonstrated a > 3-fold shrinkage of primary tumors with nab-P + G vs G, suggesting the potential of nab-P + G for LAPC treatment. Here, we present interim results on disease control rate (DCR), adverse events (AEs), and quality of life (QoL) from the international phase 2 LAPACT trial. Methods: Pts with treatment-naive unresectable LAPC and ECOG performance status of 0 or 1 received 6 cycles (C) of nab-P 125 mg/m2 + G 1000 mg/m2 on days 1, 8, and 15 of each 28-day C. After the initial nab-P + G treatment phase, pts without PD and unacceptable AEs were eligible for investigator’s choice (IC) of continued treatment with nab-P + G, chemoradiation, or surgery. Surgery could occur prior to completing 6 C in the case of a major response. Pt-reported QoL was assessed via EORTC QLQ-C30 and QLQ-PAN26 questionnaires at screening and prior to infusion on day 1 of each C. Results: As of Aug 17, 2016, 47 pts completed (28/47, 60%) or discontinued (19/47, 40%) the initial nab-P + G treatment (median, 5 C). Median age was 66 years (range, 44 - 86). The most frequent reasons for discontinuation were AE (10/47 [21%], with the most common being neutropenia and abnormal liver function [2 pts each]) and PD (3/47, 6%). The most common grade ≥ 3 AEs were neutropenia (34%) and anemia (11%). The DCR ≥ 16 weeks was 76% (34/45 efficacy-evaluable pts [defined as having evaluable baseline and ≥ 1 postbaseline scan]; PR, n = 13; SD, n = 21). Twenty-two pts (47%) were assigned by the investigators to an IC treatment: 4 (9%) to continue nab-P + G, 8 (17%) to chemoradiation, and 10 (21%) to surgical resection. Mean QoL scores remained stable during the study, with improved symptom scores for appetite and pain. During the initial nab-P + G treatment phase, most patients reported a complete resolution of certain limitations, including depression (≈ 80%), constipation (≈ 62%), and nausea (≈ 93%). Conclusions: These interim results suggest that for pts with LAPC, nab-P + G is tolerable and produces a promising DCR. On average, QoL scores remained stable during nab-P + G treatments. Clinical trial information: NCT02301143.
Prognostic significance of preoperative plasma fibrinogen and Albumin Score in esophageal cancer patients.
Authors: Maeda Yusuke , Takeuchi Hiroya , Kawakubo Hirofumi , Suda Koichi , Nakamura Rieko , Wada Norihito , Kitagawa Yuko
Published: March 2017

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Background: The clinical outcome of esophageal cancer has recently improved. However, the relapse rate in any stages is still high. Prognostic classification in patients with esophageal cancer has not yet established. If the patients with poor prognosis could be extracted before surgery, we can add more intensive preoperative treatment, which might lead more favorable prognosis. We have previously reported clinical utility of fibrinogen (FNG) and Albumin (Alb) Score (FA score) in esophageal cancer. The purpose of this study was to analyze the utility of FA score comparing at each stage as a prognostic factor in esophageal cancer. Methods: Patient characteristics, clinicopathological factors, and preoperative biochemical markers (FNG, Alb, and CRP) were investigated in esophageal cancer patients who underwent transthoracic esophagectomy between January 2004 and November 2013. Correlation between preoperative FNG, CRP, Alb, clnicopathological factors and survival were investigated. We evaluated between recurrence-free survival (RFS), overall survival (OS) and FA score comparing at each stage. The cut-off value was defined according to previous reports; fibrinogen 350mg/dl, albumin 3.8mg/dl. Results: 252 patients were recorded. High FA score were correlated to worse OS and RFS (p < 0.001). Especially in cStageI, high FA score showed remarkably worse 5-year RFS (score0/ score1/ score2, 5-year RFS 84%/ 64%/ 33%; p = 0.038). Conclusions: FA score was significantly associated with postoperative survival in esophageal cancer patients. If the patients with poor prognosis in cStageI could be extracted before surgery, we can add more intensive preoperative treatment, which might lead more favorable prognosis.
Comparison of outcomes in patients with locally advanced pancreatic adenocarcinoma treated with stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation: An analysis of the National Cancer Database.
Authors: Zhong Jim , Patel Kirtesh R. , Switchenko Jeffrey M. , Gillespie Theresa Wicklin , Cassidy Richard John , Kooby David A. , Landry Jerome Carl
Published: March 2017

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Background: As systemic therapy has improved for locally advanced pancreatic cancer (LAPC), efforts to improve local control have become critical. While conventionally fractionated radiation therapy (CFRT) has more recently shown a limited role in LAPC, stereotactic body irradiation (SBRT) is an emerging approach that delivers higher doses of radiation therapy, to small volumes, over a much shorter period of time. With no studies to date comparing SBRT to CFRT for LAPC, we utilized the National Cancer Database (NCDB) to evaluate these two modalities. Methods: Using the NCDB, patients with AJCC clinic cT2-4, N0-1, M0 adenocarcinoma of the pancreas diagnosed from 2004-2013 were analyzed. Radiation therapy delivered at 2 Gy per fraction or less was deemed CFRT, and 4 Gy or more per fraction was considered SBRT to allow inclusion of practice variations. Kaplan-Meier, log-rank test, and multivariable Cox proportional hazards regression were performed with overall survival (OS) as the primary outcome. Propensity score matching was employed to reduce treatment selection bias. Results: Among 8,450 patients, 7,819 (92.5%) were treated with CFRT, and 631 (7.5%) underwent SBRT. The median dose per fraction and number of fractions for CFRT and SBRT cohorts were 1.8 Gy per fraction in 28 fractions and 8 Gy per fraction in 5 fractions, respectively. Using propensity score matching, 988 patients were matched, with 494 patients in each cohort. Within the propensity-matched cohorts, the median OS was higher with SBRT (13.9 vs. 10.7 months), and 2-year OS of 21.5% and 15.9% for the SBRT and CFRT groups, respectively ( p = 0.0014). Multivariable analysis confirmed SBRT was a significant predictor for OS (Hazard ratio:0.84; 95% confidence interval: 0.75-0.93, p = 0.001). Additionally, pancreatoduodenectomy, low comorbidity index, chemotherapy use, and node negative disease also positively impacted survival. Conclusions: SBRT appears to be associated with an improved OS compared to CFRT for LAPC. Further prospective studies investigating these hypothesis-generating results are warranted.
Evaluating associations of diabetes, insulin use, and BMI with efficacy in patients with resected pancreatic cancer: An ancillary analysis of NRG Oncology/RTOG 9704.
Authors: Hong Theodore S. , Winter Kathryn A. , Fuchs Charles S. , Regine William , Abrams Ross A. , Safran Howard , Hoffman John Parker , Benson Al Bowen , Macdonald John S. , Kasunic Timothy , Strauss James Fredric , DiPetrillo Thomas A. , Stella Philip J. , Chen Yuhchyau , Plastaras John Peter , Crane Christopher H
Published: March 2017

369

Background: Diabetes mellitus (DM) has been linked to poor prognosis in pancreatic cancer in numerous retrospective datasets, potentially due to higher levels of insulin and insulin-like growth factor increasing cellular proliferation. Additionally, the hyperglycemic state as well as obesity may lead to a pro-inflammatory state that may enhance tumor progression and metastases. In this analysis, the prognostic significances of diabetes, insulin use, and BMI are evaluated in a prospective, randomized trial of resectable pancreatic ductal adenocarcinoma. Methods: As previously reported, RTOG 9704 pts with resected pancreatic cancer were randomized to 5-fluorouracil (5-FU) or gemcitabine (Gem), given pre and post radiation (RT). Pts in both arms received RT to 50.4 Gy with 5-FU. DM and insulin use were collected on the RTOG 9704 CRFs. BMI was dichotomized as normal/underweight vs. overweight/obese. Overall survival (OS) and disease-free survival (DFS) were estimated by Kaplan-Meier method and variable levels were compared using log-rank test. Cox models were used for multivariable analyses. Results: 538 pts were enrolled from 1998-2002. 238 pts were eligible with analyzable diabetes and insulin use data, in addition to surgical pathology, and CA19-9 data. 32% and 35% of pts in the 5-FU and Gem arms, respectively, had DM. Of which, 24% and 19% used insulin in the 5-FU and Gem arms, respectively. 55% were overweight/obese. The 4 yr OS was 25% (95% CI: 18, 32) in pts with no diabetes, vs. 18% (10, 27) with DM (HR = 1.3 [0.9, 1.7]; p = 0.11). The 4-yr DFS was 14% (9, 20) in pts with no diabetes, vs. 9% (4, 16) with diabetes (HR = 1.2 [0.9, 1.5]; p = 0.31). Neither insulin use nor BMI was univariately associated with OS or DFS. On multivariate analysis, including nodal status, CA19-9, and other variables, DM, insulin use, and BMI were not associated with OS or DFS. Conclusions: DM, insulin use, and BMI were not associated with OS in pts with resected pancreatic cancer treated with adjuvant chemotherapy and chemoradiation. Node involvement and CA19-9 remain the most significant predictors of OS. Supported by NCI grants U10CA180868, U10CA180822, UG1CA189867 and Eli Lilly Clinical trial information: NCT00003216.
Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: A Japanese nationwide survey.
Authors: Kokudo Takashi , Hasegawa Kiyoshi , Matsuyama Yutaka , Takayama Tadatoshi , Izumi Namiki , Kadoya Masumi , Kudo Masatoshi , Kubo Shoji , Sakamoto Michiie , Nakashima Osamu , Kumada Takashi , Kokudo Norihiro
Published: March 2017

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Background: Because of the rarity of hepatic vein tumor thrombus (HVTT), compared with portal vein tumor thrombus (PVTT), in patients with hepatocellular carcinoma (HCC), little is known about this disease entity. The aim of this study was to evaluate the prognosis of each treatment modality for HVTT through an analysis of data collected in a Japanese nationwide survey. Methods: We analyzed data for 1,021 Child-Pugh A HCC patients with HVTT without inferior vena cava invasion registered between 2000 and 2007. Of these patients, 540 patients who underwent liver resection (LR) and 481 patients who received other treatments were compared. The propensity scores were calculated and we successfully matched 244 patients (52.5% of the LR group). Results: The median survival time (MST) in the LR group was 2.89 years longer than that in the non-LR group (4.47 years vs 1.58 years; P < 0.001) and 1.17 years longer than that in the non-LR group (2.93 years vs 1.76 years; P = 0.009) in a propensity score-matched cohort. After curative resection, the MSTs were similar between patients with HVTT in the peripheral hepatic vein and those with HVTT in the major hepatic vein (4.85 years vs 4.67 years; P = 0.974). In the LR group, the postoperative 90-day mortality rate was 3.4% (16patients). In patients without PVTT, the MST was significantly better than that in patients with PVTT (5.67 years vs. 1.88 years; P < 0.001). Conclusions: LR is associated with a good prognosis in HCC patients with HVTT, especially in patients without PVTT.
Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy.
Authors: Chung Seung Yeun , Chang Jee Suk , Lee Byung Min , Lee Kyong Joo , Song Si Young , Seong Jinsil
Published: March 2017

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Background: In locally advanced pancreatic cancer, radiotherapy (RT) is an effective treatment modality, but challenged by conflicting results. Now, in the era of intensity-modulated radiation therapy (IMRT), dose escalation is possible without increasing the dose to organs-at-risk. We investigated whether RT dose escalation would improve treatment outcomes without increasing severe toxicity. Methods: From 2005 to 2015, a total of 497 locally advanced - including both borderline resectable and unresectable - pancreatic cancer patients who received neoadjuvant or definitive chemoradiotherapy were included. A total of 281 (56.5%) patients received 3D conformal RT and 216 (43.5%) patients received IMRT. Most common dose scheme for IMRT was 58.42 Gy in 23 fractions (EQD2 61.05 Gy). Patients were divided into two groups; < 61 Gy group (n = 345) and ≥ 61 Gy group (n = 152). Overall survival (OS), progression-free survival (PFS), local failure-free rate (LFFR), distant failure-free rate (DFFR) and toxicity rates were assessed. Results: At a median follow-up time of 14.1 months (range, 2.3-128.5 months), OS, PFS, LFFR, and DFFR rates were significantly higher in ≥ 61 Gy group. The 1-year OS rates were 74.7% and 60.6% (p = 0.001) and 1-year PFS rates were 46.2% and 30.9% (p < 0.001), for ≥ 61 Gy and < 61 Gy group, respectively. The 1-year LFFR was 86.9% and 70.9% (p = 0.001) and 1-year DFFR was 56.4% and 45.8% (p = 0.007), respectively. After multivariate analysis, ≥ 61 Gy group remained a favorable significant factor for OS (p = 0.019), PFS (p = 0.001), LFFR (p = 0.004), and DFFR (p = 0.008). When 152 patients in each group were matched by propensity score matching, ≥ 61 Gy group still showed higher OS (p = 0.011), PFS (p = 0.016), and LFFR (p = 0.002), but not DFFR (p = 0.205). There was no acute gastrointestinal toxicity higher than Grade 3 in both groups. Late toxicity rates were also similar, with RT-related duodenal and gastric hemorrhage ( ≥ Grade 3) in 19 patients (5.5%) in < 61 Gy group and 7 patients (4.6%) in ≥ 61 Gy group. Conclusions: Patients who received higher RT dose showed not only improved PFS and LFFR but improved OS without an increase in severe toxicity. Dose escalation via IMRT is recommended for RT in locally advanced pancreatic cancer patients.
Prognostic significance of chromogranin A in small pancreatic neuroendocrine tumors.
Authors: Raoof Mustafa , Jutric Zeljka , Melstrom Laleh Golkar , Warner Susanne , Woo Yanghee , Fong Yuman , Singh Gagandeep
Published: March 2017

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Background: Theincidence of non-functional pancreatic neuroendocrine tumors (PNETs) < 2 cm is rising. The biologic behavior of these tumors is variable and therefore their management remains controversial. We hypothesized that chromogranin A (CgA) levels are prognostic in these patients and may help guide management. Methods: Patients with PNETs measuring < 2 cm, without distant metastases were identified from the National Cancer Database (NCDB) over a ten-year period (2004-2014). Patients were categorized as CgA high (> 36.4 ng/ml) or CgA low (<36.4 ng/ml), and those lacking data on CgA levels were excluded from the study. Univariate and multivariate analyses were performed using Cox proportional hazards model. Results: Of the 445 eligible patients, 149 (33.5%) were CgA Low and 296 (66.5%) were CgA High. Median CgA level was 71 (Inter-quartile range, IQR 24-294) ng/ml. On multivariate analysis, CgA levels independently predicted overall survival after controlling for tumor size, grade, clinical nodal status and academic status of the facility (p = 0.001). At a median follow up of 26.5 months there were no deaths in the CgA Low group whereas 8% of the patients in CgA High group had died (p = 0.0068). Only CgA High patients benefited from surgical resection (HR 0.31, 95% CI 0.11-0.86, p = 0.025). Conclusions: Serum CgA levels can be incorporated in surgical decision making for patients with small PNETs. Patients with a high CgA should be strongly considered for resection.
A propensity-matched analysis of laparoscopic versus open distal pancreatectomy for pancreatic adenocarcinoma.
Authors: Raoof Mustafa , Dumitra Sinziana , Ituarte Philip HG , Woo Yanghee , Warner Susanne , Singh Gagandeep , Fong Yuman , Melstrom Laleh Golkar
Published: March 2017

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Background: Laparoscopic-assisted distal pancreatectomy (LDP) has improved perioperative outcomes over open distal pancreatectomy (ODP). Concerns regarding failure to achieve proper oncologic resection and compromised survival remain. Methods: Using the National Cancer Database (NCDB), we analyzed patients undergoing distal pancreatectomy for resectable pancreatic adenocarcinoma over a four-year period (2010-2014). Propensity score nearest-neighbor 1:1 matching (PSM) was performed between LDP and ODP patients based on age, sex, race, insurance, hospital volume, comorbidities, T-stage, N-stage, grade, neoadjuvant therapy, adjuvant therapy. Primary outcome was overall survival. Results: Of the 1,947 eligible patients, 605 (31%) underwent LDP. After PSM two well-balanced groups of 544 patients each were analyzed. There was a trend towards improved overall survival (OS) in patients undergoing LDP as compared to ODP (HR: 0.83, 95% CI 0.68-1.0; Median OS 29 vs. 23 months, p = 0.06). Patients undergoing ODP had a higher margin positive rate compared to those undergoing LDP (21.1% vs. 14.9%, p-value = 0.007). Overall conversion rate was 27%. Patients undergoing ODP had comparable outcomes to LDP in regards to median time to chemotherapy (50 vs. 48 days, p-value = 0.96); median nodes examined (12 vs. 12, p-value = 0.61); 30-day mortality (1.6% vs. 1.1%, p-value = 0.43); 90-day mortality (3.5% vs. 2.4%, p-value = 0.28); 30-day readmission rate (8.6% vs. 9.4%, p-value = 0.67). However, the median length of stay was shorter in the LDP group (6 vs. 7 days, p = 0.0001). Conclusions: In the absence of randomized trials, this is the largest comparative study demonstrating LDP as an acceptable alternative ODP, associated with a lower margin positive rate and shorter length of stay, and with no detriment in long term survival.
Propensity score matched analysis of neoadjuvant therapy for resectable pancreatic cancer.
Authors: Meredith Kenneth L , Huston Jamie , Patel Anjan Jayantilal , Brown Richard H. , Kayali Fadi , Koehler Kevin , Shridhar Ravi
Published: March 2017

381

Background: Neoadjuvant therapy (NT) for resectable pancreatic cancer continues to be debated. There is little data to demonstrate survival benefit over patients who were treated with up front surgery (UFS) vs NT. We sought to examine the impact of neoadjuvant chemotherapy (NCT), neoadjuvant chemoradiation (NCRT), and UFS on survival in pancreatic cancer patients. Methods: The NCDB was accessed to identify patients with pancreatic adenocarcinoma. Propensity score matching (PSM) was performed against age, tumor size, margin status, and institutional surgery volume. Patient characteristics (continuous and categorical variables) were compared using Mann-Whitney U, Kruskal Wallis and Pearson’s Chi-square test as appropriate. Survival analyses were performed using the Kaplan-Meier method. Multivariable cox proportional hazard models (MVA) were developed to identify predictors of survival. All statistical tests were two-sided and α < 0.05 was considered significant. Results: After PSM, 5,034 patients (UFS 2,517; NT 2,517: 1,143 NCT and 1,374 NCRT) were included in the analysis. There was no difference in age, tumor size, or grade among cohorts. The mean nodes positive were 1.6 ± 2.6 in NT and 2 ± 3.3 in UFS, p = 0.02. In the pre-matched cohort R0 resections were performed in 75.9% UFS, 82.9% NCRT, and 79.6% NCT, p < 0.001. The median and 5 year survival for NCT, NCRT and UFS was 28.6 months and 25.2%, 25.7 months and 22.2%, and 21.3 months and 21.7%, p < 0.001. Adjuvant therapy (chemotherapy (CT) or CRT) in the UFS did demonstrate a survival benefit 22.5 months vs 18.6 months, p < 0.001, however this did not benefit NCT or NCRT, p = 0.8 and p = 0.8 respectively. Additionally survival in the UFS with adjuvant therapy either CT or CRT was still decreased compared to either NCT or NCRT, p < 0.001 and p = 0.001 respectively. MVA demonstrated that age, T-stage, lymph nodes positive, R0 resection, grade, NCT and NCRT were predictors of survival. Conclusions: Neoadjuvant therapy improves survival in resectable pancreatic cancer patients. NCT and NCRT demonstrated survival benefit compared to UFS even with adjuvant therapy. Patients with resectable pancreatic cancer should be considered for neoadjuvant therapy.
Up-titration of sorafenib for hepatocellular carcinoma: Impact on duration of exposure and cost.
Authors: Kaplan David Edward , Yu Shun , Taddei Tamar H. , Reiss Kim Anna , Mehta Rajni , D'Addeo Kathryn , Aytaman Ayse , Hunt Kristel , Fox Rena , Baytarian Michelle , Valdarrama Adriana ,   VOCAL Study Group
Published: March 2017

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Background: Few data exist how sorafenib starting dose impacts duration of exposure and cost of sorafenib therapy for patients with HCC. Methods: HCC patients exposed to sorafenib, initial doses, number of sorafenib fills, and medication exposure days were identified from the VA CDW using ICD9 codes and pharmacy records. ICD9 codes, CPT codes, AUDIT-C surveys and laboratory tests were utilized to characterize underlying liver disease, calculate Child-Turcotte-Pugh (CTP) and MELD scores. Two abstractors achieved 100% chart verification of tumor number, size, MVI/EHS on imaging proximate to sorafenib to quantify Barcelona Clinic Liver Cancer (BCLC) stage and to determine the provider specialty initiating sorafenib. Results: 2292 patients with BCLC B-C HCC, CTP A cirrhosis with ECOG PS ≤ 2 prescribed sorafenib for HCC between 2007 and 2015 were included in this interim analysis. Median age was 62; 98.8% were male, 61.8% white/26.0% black; Pre-sorafenib BCLC B-43%/C-57%. Prescription at full-dose became less common over 2007-2015, dropping from 80% to 48%. First-dose up-titration was more commonly done by hepatologists (21% vs. 4.5%, p < 0.0001), but oncologists were more likely to up-titrate at the second prescription (8.9% vs. 3.8%, p < 0.001). Overall, 38% of first sorafenib prescriptions were initiated at doses below 800mg/day; 43% were up-titrated whereas 57% never up-titrated. Patients starting at < 800 mg/d received fewer total pills (median 284 vs. 360, p = 0.008) but a greater number of prescription fills (median 4 vs. 3, p < 0.0001) and longer exposure duration (median 120 vs 90 days, p = 0.0012) at lower total cost (median $8,143 vs $9,685, p < 0.0001). Median overall survival for those starting < 800mg/d was not significantly different from full dose initiators (median 284 vs. 292 days, p = 0.33). Conclusions: Initiation of sorafenib < 800mg/d was associated with lower pill utilization, but longer exposure duration and equivalent survival at lower cost. Starting at a lower dose with uptitration may select patients with a higher likelihood of sustained benefit and improve cost-effective utilization of resources. This approach should be tested prospectively.
TGF-B1 inhibition with losartan in combination with FOLFIRINOX (F-NOX) in locally advanced pancreatic cancer (LAPC): Preliminary feasibility and R0 resection rates from a prospective phase II study.
Authors: Murphy Janet E. , Wo Jennifer Yon-Li , Ferrone Cristina , Jiang Wenqing , Yeap Beow Y. , Blaszkowsky Lawrence Scott , Kwak Eunice Lee , Allen Jill N. , Clark Jeffrey W. , Faris Jason Edward , Zhu Andrew X. , Goyal Lipika , Mamon Harvey J. , Lillemoe Keith D , Ryan David P. , DeLaney Thomas F. , Fernandez-del Castillo Carlos , Boucher Yves , Hong Theodore S.
Published: March 2017

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Background: F-NOX is utilized in LAPC due to improved response over gemcitabine, with theoretical potential for curative resection. However the response rate remains well below 50%. Preclinical data suggest that inhibition of the renin-angiotensin system with losartan reduces the activity of TGF-B1, enhancing intratumoral penetration of chemotherapy by remodeling desmoplastic stroma and improving vascular perfusion. In this study, we evaluate the feasibility of adding losartan to F-NOX in LAPC. Methods: Pts ECOG PS 0-1 with LAPC (NCCN criteria) were enrolled in a single institution, NCI-sponsored phase II study (NCT01821729). Pts received F-NOX/losartan for 8 cycles. If the tumor was radiographically resectable after chemotherapy, pts received short-course chemoradiation (CRT) in 5 fractions (protons 25 GyE, capecitabine 825 mg/m2 bid). If it was still abutting vasculature, pts received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. The primary endpoint was proportion of pts remaining progression-free after 8 cycles of F-NOX/losartan. Results: 32 pts were enrolled from 8/2013 to 6/2016. One pt withdrew prior to treatment, 6 pts are still receiving F-NOX/losartan or CRT. 25 were included in this analysis. Median age was 62y (46-75). Median tumor size was 42mm (22-68). Tumor was in the head of the pancreas in 16 (64%) pts. Of evaluable pts, 18 (72%) completed F-NOX/losartan followed by CRT. Reasons for discontinuation included losartan intolerance (3), failure to thrive (2), investigator discretion (1), and progression (1). Grade 3 or greater toxicity occurred in 11 (40%) pts, including diarrhea (4, 16%), thrombocytopenia (3, 12%), nausea (3, 12%), neutropenia (2, 8%), and febrile neutropenia (1, 4%). Two pts (8%) had short course CRT, 16 (64%) had long course CRT. In evaluable pts, 4 remained unresectable while one pt had R1 resection. R0 resection was achieved in 13 (52%). Conclusions: Based on the low discontinuation rate of the F-NOX/losartan combination, it met criteria for feasibility. The high R0 resection rate in the feasibility cohort has prompted expansion as a phase II study with an R0 resection endpoint. Clinical trial information: NCT01821729.
Proton beam therapy for liver cancer is well tolerated: Outcomes from the Proton Collaborative Group REG001-09 trial.
Authors: Chuong Michael David , Apisarnthanarax Smith , Hartsell William F. , Larson Gary L. , Tsai Henry K. , Rossi Carl , Vargas Carlos E.
Published: March 2017

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Background: The liver is one of the most radiosensitive organs, making radiation therapy (RT) for liver tumors extremely challenging. RT is appropriate only for a minority of liver patients with limited tumor burden; a reduction in the prescribed radiation dose may be needed to lower the probability of radiation-induced liver disease especially in the presence of cirrhosis. Proton beam therapy (PBT) delivers less dose to the liver than photon therapy and is expected to reduce toxicity while also permitting safe dose escalation for some patients with liver tumors. Methods: The Proton Collaborative Group REG001-09 trial (NCT01255748) prospectively collects data for PBT patients with a variety of cancer types. To better understand treatment details and outcomes associated with liver PBT, patients enrolled on the PCG registry trial from 5 institutions who received liver PBT for any cancer between 2012 and 2016 were analyzed. Results: A total of 43 liver cancer patients were included, most with hepatocellular carcinoma (48.8%) or cholangiocarcinoma (25.6%). The vast majority did not have surgery at any time (86%). Most were treatment naive prior to PBT; 2 previously had RT and 8 had prior chemotherapy (mostly cholangiocarcinoma patients). The median total prescribed PBT dose was 58.05 Gy(RBE) (range 21.7-67.5). The median number of prescribed fractions was 15 (range 12-37). PBT was delivered to only the liver in 90.7% of patients; inclusion of lymph nodes was rare. Uniform scanning was used in 26 (72.1%) and pencil beam scanning in 2 patients (4.7%); the delivery technique used for the remaining patients was unknown (23.2%). With median follow up of 4.4 months (range 1.3-17.9), 3 patients (7%) had an intrahepatic recurrence, 2 patients (4.6%) developed distant metastasis, and 10 patients (23.3%) died. No grade 3 or higher toxicity was reported although 17 patients (39.5%) had grade 2 toxicity predominantly fatigue, anorexia, nausea, or vomiting. Conclusions: Although longer follow up is needed to assess late toxicities as well as disease control, early outcomes from the PCG registry trial for liver cancer patients shows that predominantly hypofractionated PBT has a very favorable acute toxicity profile.
Impact of adjuvant therapies on treatment outcomes for patients with resected gallbladder cancer and changes in treatment patterns in the United States over the past decade: An analysis from the National Cancer Data Base.
Authors: Mitin Timur , Enestvedt C. Kristian , Jemal Ahmedin , Sineshaw Helmneh M.
Published: March 2017

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Background: There are no randomized data to guide clinicians treating patients with gallbladder cancer (GBC). Several retrospective studies reported the survival benefits of adjuvant radiotherapy (RT) and chemoradiation (CRT). The aims of this study were to examine whether these publications have impacted the utilization of adjuvant therapies and whether their survival benefits were evident in contemporary cohort of patients. Methods: Using the National Cancer Data Base, we identified 5,029 patients diagnosed with T1-3N0-1 GBC and treated with surgical resection from 2005 to 2013. We described trends in receipt of adjuvant treatments for three time periods (2005-2007, 2008-2010, 2011-2013) and calculated 3-year overall survival (OS) probabilities for 2,989 patients treated in 2005-2010. Results: The percentage of patients who received no adjuvant treatment was unchanged from 2005 to 2013. Adjuvant RT decreased from 4.3% to 1.7% (p < 0.01), adjuvant chemotherapy increased from 8% to 14% (p < 0.01), and adjuvant CRT remained stable at 16% (p = 0.98). Even for locally advanced disease (T3N0 and T1-3N1) or in the setting of positive resection margins, over 50% of patients in US did not receive adjuvant treatments. Adjuvant treatments were associated with improved 3-year overall survival in patients with resected GBC, as listed in Table. Adjuvant CRT was associated with improved survival in all stages, except T1N0, and in patients with negative and positive margins. Conclusions: Over the past decade there was no increase in the utilization of adjuvant therapies in the US for patients with resected GBC. Adjuvant therapy is associated with significantly improved 3-yr OS. In the absence of randomized data, this analysis should form the basis for clinical recommendations and national guidelines should be amended to support adjuvant treatment.[Table: see text]
Outcomes of FOLFIRINOX (FFX) and gemcitabine+nab-paclitaxel (GnP) in initially unresectable locally advanced pancreatic cancer (uLAPC): A population-based study.
Authors: Chan Kelvin K. , Guo Helen , Beca Jaclyn Marie , Redmond-Misner Ruby , Isaranuwatchai Wanrudee , Qiao Lucy , Earle Craig , Berry Scott R. , Biagi James Joseph , Welch Stephen , Meyers Brandon , Mittmann Nicole , Coburn Natalie , Pardhan Aliya , Arias Jessica , Gavura Scott , Kennedy Erin Diane
Published: March 2017

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Background: Data regarding the benefits of FFX and GnP in patients (pts) with initially uLAPC is limited. FFX and GnP have been universally publicly funded for first-line uLAPC in Ontario, Canada, since April 2015. The aims of this study are to determine (1) the overall survival (OS) of pts receiving FFX and GnP, (2) the surgical conversion rate of FFX and GnP, and (3) whether resection is associated with better OS in pts with uLAPC in an unselected, real world population. Methods: All pts in Ontario who started first-line FFX, GnP or gemcitabine (G) for uLAPC between April 2015 and March 2016 were identified in Cancer Care Ontario’s New Drug Funding Program database. They were linked to the Ontario Cancer Registry and other population-based databases to ascertain baseline characteristics (age, sex, performance status (PS), locating of tumor, income quintile, and rural residence) and outcomes (pancreatic cancer resection and vital status). Crude and adjusted models of OS were generated using Kaplan-Meier the method and Cox regression. Surgical resection was modelled as a time-dependent variable to examine its association with OS. Results: We identified 147 pts with uLAPC (mean age = 65, 44% female, 31% ECOG PS 0, 61% PS 1, 60% pancreatic head). Ninety (61.2%), 40 (27.2%) and 17 (11.6%) patients were treated with FFX, GnP and G, respectively. With a median follow-up of 7.5 months, median OS was not reached. The 6-month OS rate was 87.8%, 75.1% and 76.4% for FFX, GnP and G, respectively (p = 0.33). Resection occurred in 12 (8.2%) patients, with 10 (11.1%) and 2 (5.0%) treated with FFX and GnP, respectively ( p= 0.34). Surgical resection after initial chemotherapy was not associated with better OS in multivariable analysis (HR 0.26, 95%CI 0.03-1.98, p= 0.19). Conclusions: Pts with uLAPC treated with FFX and GnP appeared to have a reasonable OS in the real world, with > 75% of pts alive at 6 months. Surgical conversion rate in this unselected population appeared to be less than other single institutional studies. The current findings do not appear to show an early surgical benefit, but longer follow-up will be required to assess the potential long-term benefit of surgery.