bluuebunny/crossref_metadata_2025 huggingface dataset:
BIOSHARE multicenter neoadjuvant phase 2 study: Results of pre-operative sorafenib in patients with resectable hepatocellular carcinoma (HCC)—From GERCOR IRC.
Authors: Bouattour Mohamed , Fartoux Laetitia , Rosmorduc Olivier , Scatton Olivier , Vibert Eric , Costentin Charlotte , Soubrane Olivier , Ronot Maxime , Granier Muriel Magali , De Gramont Armand , Belghiti Jacques , Paradis Valerie , Wendum Dominique , Tijeras-Raballand Annemilai , Hadengue Alexandra , Brusquant David , Chibaudel Benoist , Raymond Eric , Faivre Sandrine J.
Published: February 2017

252

Background: This open-label, multicenter, phase II study aimed at investigating the activity of sorafenib including radiological, pathological and biological changes in tumor from patients with resectable HCC. Methods: Preoperative administration of sorafenib 400 mg bid for 4 weeks was followed by surgery. Primary endpoints were antitumor activity and histological changes on paired tumor samples and plasma biomarkers between baseline and post sorafenib. Secondary endpoints were safety, R0 surgery and post-surgical complications. Results: Among 30 patients enrolled, 28 were evaluable for safety. Neoadjuvant sorafenib was not feasible in 3 patients (early limiting toxicities). Twenty-five patients (21 men; median age: 61.5 years) were evaluable for the primary endpoints. Baseline median tumor size was 37 mm and 21 patients (84%) had a single lesion. Median duration and dosing of sorafenib were 28 days and 793 mg/day respectively. Overall, the safety profile of preoperative sorafenib was good. According to RECIST criteria, all patients showed stable disease. Among 19 patients evaluated according to mRECIST and Choi criteria, objective responses were observed for 6 (32%) and 10 (53%) patients respectively. All evaluable patients went on liver resection and no unexpected complication occurred. R0 tumor resection was achieved in 22 patients (88%). Surgical specimen showed macrovascular and microvascular invasion in 12% and 48%, respectively. Intratumor necrosis was observed in 17 (68%) surgical specimen with necrosis ≥ 50% in 24 % of cases. Blood biomarkers analysis showed a trend toward increased angiogenesis biomarkers (VEGF-A, VEGF-C and PlGF) after sorafenib treatment. Biomarkers from pre- and post-treatment tissue will be presented during the meeting. Conclusions: Neoadjuvant sorafenib displays a favorable toxicity profile and yields significant activity in patients with resectable HCC. BIOSHARE trial also allows exploration of drug effects on tumor biology. Clinical trial information: NCT01182272.
Evaluation of triptolide pro-drug (Minnelide) as an anti-stromal and anti-tumoral therapeutic option for pancreatic cancer.
Authors: Banerjee Sulagna , Modi Shrey , Zhao Xianda , Dudeja Vikas , Saluja Ashok
Published: February 2017

262

Background: In pancreatic cancer, the stromal microenvironment is considered to be the major reason behind the failure of conventional and targeted therapy. The desmoplastic stroma is responsible for compression of vasculature in the tumor resulting in impaired drug delivery. Pancreatic stellate cells contribute extensively to this desmoplastic reaction. Our group has recently evaluated a water-soluble pro-drug of triptolide (Minnelide) in pre-clinical studies for pancreatic cancer with very promising results. The current study evaluates the ability of Minnelide to deplete the stromal architecture and the stellate cell population in pancreatic cancer resulting in increased drug delivery. Methods: Patient tumor xenografts in SCID mice (PDX) and KRASG12DTP53-PDX-Cre spontaneous pancreatic tumor mice (KPC) were treated with 0.42mg/kg Minnelide. Vascular patency was studied by terminal perfusion of mice with 4% PFA following injection with tomato lectin. Drug delivery was determined by quantitating accumulated doxorubicin in the tumor tissue. Cell viability was studied by MTT assay and the invasion of cells in vitro was studied using Boyden Chamber assay. Results: Minnelide treatment decreased Hyaluronic acid (HA) in PDX (48% of control) as well as in KPC model (52% of control). Expression of HA synthase (HAS) genes were decreased in both tumor models in response to Minnelide (22% of control in PDX and 35% of control in KPC tumors). HAS Enzyme activity also consistently decreased in both the models after treatment with Minnelide (28% of control in PDX and 31% of control in KPC). In vitro, triptolide decreased the invasion of the tumor cells towards the stellate cells indicating an inhibition of crosstalk. Treatment with Minnelide resulted in “open” and functional vessels in the treated animals resulting in increased drug delivery. Median survival of animals increased by 38 days after treatment with Minnelide. Conclusions: Our study showed that Minnelide depleted the stromal architecture leading to increased functional vasculature and enhanced drug delivery in the tumor. This is an extremely promising observation for Minnelide that is currently under clinical trial.
The role of myeloid derived suppressor cells in cholangiocarcinoma: A potential target for therapy.
Authors: Dunne Richard Francis , Figueroa Nathania , Belt Brian , Findeis-Hosey Jennifer , Lunt Michael , Ye Jian , McMahon Loralee , Baran Andrea , Shubin Andrew , Noel Marcus Smith , Tejani Mohamedtaki Abdulaziz , Hezel Aram F. , Linehan David
Published: February 2017

273

Background: Cholangiocarcinoma (CC) is a highly lethal malignancy with a poor 5 year overall survival in the advanced setting. Benefits of treating CC with chemotherapy are limited and no FDA approved targeted therapies currently exist. CC is associated with a desmoplastic reaction comprised of extracellular matrix, fibroblasts and inflammatory leukocytes. Myeloid-derived suppressor cells (MDSC) are the predominant tumor infiltrating leukocytes in several cancers, but little is known about their role in CC. MDSCs are derived from a monocytic (M-MDSC) or granulocytic (G-MDSC) origin and infiltrate the tumor microenvironment (TME) where they suppress anti-tumor immunity and play a crucial role in tumor growth, chemoresistance and metastasis. Here, we characterize the prevalence and prognostic significance of MDSC in CC. Methods: A de-identified human CC clinical database (n = 220) with linked tumor tissue was collected under an IRB approved protocol. Total white blood cell count and percent monocytes (a surrogate marker for M-MDSC prevalence in peripheral circulation) before starting therapy were collected and correlated with overall survival in patients with unresectable CC. Immunohistochemistry for myeloid cell markers (CD33, CD11b, CD14, CCR2, and CD15) was performed on formalin-fixed paraffin embedded human CC and normal liver sections. Staining was scored by a pathologist or quantified with digital imaging software. Results: Analysis of chemotherapy naive blood specimens revealed that an increase in monocyte percentage inversely correlated with survival in patients with unresectable CC (p = 0.0117). Statistical significance was more pronounced in patients with intrahepatic CC (p = 0.0091) compared to other disease sites. There was an increased level of M-MDSC and G-MDSC in CC compared to normal liver tissue and all 22 tested CC samples stained positively for MDSC markers within the tumor stroma. Conclusions: The prevalence of circulating monocytes correlates negatively with prognosis and MDSCs infiltrate the TME in unresectable CC. Therefore, targeting MDSC is an attractive therapeutic strategy and future studies aim to fully characterize the TME and block MDSC recruitment in a mouse model of CC.
A phase Ib study of cancer stem cell (CSC) pathway inhibitor BBI-608 in combination with gemcitabine and nab-paclitaxel (nab-PTX) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Shahda Safi , El-Rayes Bassel F. , O'Neil Bert H. , Starodub Alexander , Hanna Wahid Tewfik , Borodyansky Laura , Oh Cindy , Li Chiang , Bekaii-Saab Tanios S.
Published: February 2017

284

Background: BBI-608 is an oral first-in-class cancer stemness inhibitor that works by blocking STAT3-mediated transcription of cancer stemness genes. Potent anti-CSC activity was observed in vitro and in vivo, in mono- and combination therapy. In phase I studies, BBI-608 was generally well tolerated with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with mPDAC was performed to determine RP2D, safety, tolerability, and preliminary anti-cancer activity of BBI-608 in combination with Gemcitabine and nab-PTX. BBI-608 was administered at 240 mg BID in combination with Gemcitabine 125 mg/m2 and nab-PTX 1000 mg/m2administered weekly for 3 out every 4 weeks until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 31 pts were enrolled and received BBI-608 in combination with Gemcitabine and nab-PTX for a total sum of 83 study cycles. 25 of 31 pts (80.6%) were treatment-naïve and 6 pts (19.4%) received 1 prior line of systemic therapy. Most common adverse events included grade 1 diarrhea, abdominal pain, nausea, and fatigue. Combination treatment was well tolerated with no dose-limiting toxicity observed and safety profile similar to that of each agent individually. One patient experienced grade 3 event of dehydration related to protocol therapy which resolved with hydration. Of the 8 pts enrolled in the RP2D determination portion of the study, 7 pts were evaluable for response with disease control (PR + SD) was observed in 7/7 pts (100%). Tumor regression was observed in 6/7 (85.7%) with 3 PR (41.3%, 37.6% and 33.3% regression) and 3 SD (25.8%, 21.1%, and 19.9% regression). The median progression free survival was 7.8 months with PR or SD of > 6 months in 6/8 pts (75%). Conclusions: This phase Ib study demonstrated that BBI-608 at 240 mg BID can be safely combined with Gemcitabine and nab-PTX. Encouraging anti-tumor activity with durable response was observed in pts with mPDAC. Clinical trial information: NCT02231723.
Neoadjuvant nab-paclitaxel and gemcitabine (AG) in borderline resectable (BR) or unresectable (UR) locally advanced pancreatic adenocarcinoma (LAPC) in patients ineligible for FOLFIRINOX.
Authors: Peterson Shawn , Loaiza-Bonilla Arturo , Ben-Josef Edgar , Drebin Jeffrey A. , Westendorf-Overley Colleen , Anthony Lowell Brian , DeSimone Philip A. , Goel Gaurav , Kudrimoti Mahesh R. , Dineen Sean Patrick , Tzeng Ching-Wei David , Hosein Peter J
Published: February 2017

328

Background: AG is superior to gemcitabine in patients with advanced pancreas cancer. There are limited data on the use of AG in BR or UR LAPC. Although FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) is an option for such patients, many are not eligible due to age, poor performance status (PS) or comorbidities. Herein, we report our experience with neoadjuvant AG for BR/UR LAPC in patients ineligible for FOLFIRINOX. Methods: In this retrospective series, we included patients with BR/UR LAPC who received neoadjuvant AG. The treatment algorithm included AG for 3-4 months followed by radiation, then re-evaluation for surgery. The published AG regimen doses were modified based on patient tolerance. The primary outcome measure was R0 resection rate. Secondary outcomes were response rate, tolerability, and overall survival (OS). Results: Between 10/2013-9/2015, 20 patients (14 BR, 6 UR) at two institutions were treated with this approach. Median age was 69 years (range 44-90); 11/20 were female; PS ranged from 0-3; 14 patients have completed therapy and 6 remain on treatment. Five were converted to resectability by imaging and subsequently underwent operation; 4 had R0 resections (29% of patients who have finished therapy). To date, 6 patients died from progressive disease (PD), 2 are alive with PD and 12 remain alive on therapy or surveillance. All patients who achieved R0 resections are alive and disease free. The best response to AG was a partial response in 4 patients (20%), stable disease in 11, and progression in 2 with 3 patients still pending re-evaluation. Mean dose intensity was 77% for AG. Toxicities were similar to the published AG regimen. Conclusions: In this small series, both the R0 resection rate and the response rate were at least 20%, despite frequent dose reductions and relatively low dose intensity. Elderly and/or poor PS patients with LAPC have been historically excluded from curative-intent strategies. Our data suggest that these patients may now have a possibility for cure with the use of neoadjuvant AG.
A phase 1b study of the anti-cancer stem cell agent demcizumab (DEM) and gemcitabine (GEM) +/- nab-paclitaxel in patients with pancreatic cancer.
Authors: Hidalgo Manuel , Cooray Prasad , Carrato Alfredo , Jameson Michael B. , Parnis Francis , Jeffery Mark , Grimison Peter S. , Stagg Robert J. , Holmgren Eric , Kapoun Ann M. , Dupont Jakob , Tebbutt Niall C.
Published: February 2017

341

Background: Delta-like ligand 4 (DLL4) activates the Notch pathway. DEM is a humanized anti-DLL4 antibody that inhibits tumor growth & decreases cancer stem cell frequency in human tumor xenograft models. DEM also has an antiangiogenic effect & synergistic activity when combined with GEM & nab-paclitaxel in pt derived xenograft models of pancreatic cancer. Methods: Pts with 1st line pancreatic cancer were enrolled. Pts in cohorts 1-3 received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks including 3 truncated pts) & GEM 1000 mg/m2 7 of 8 wks, then 3 of 4 wks. Pts in cohorts 4, 5, 6 & 7 received truncated DEM (2.5, 3.5 or 5 mg/kg every 2 wks through Day 70) & nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 3 of 4 wks. The primary objective was to determine the MTD. Other objectives were safety, efficacy, immunogenicity, PK & biomarkers. Results: Fifty-six pts were enrolled; 8, 8, 8, 6, 8, 9 & 9 pts received 2.5 mg/kg every 2 wks, 2.5 mg/kg every 4 wks, 5 mg/kg every 4 wks, 2.5 mg/kg every 2 wks (truncated), 5 mg/kg every 2 wks (truncated), 3.5 mg/kg every 2 wks (truncated) & 3.5 mg/kg every 2 wks (truncated), respectively. Related AEs in > 20% of pts were fatigue (36%), nausea (32%), vomiting (23%), hypertension (21%) & diarrhea (20%). Hypertension was managed with anti-hypertensives. Increased BNP is an early indicator of the cardiac effects of DEM & mildly elevated values were used to initiate a cardioprotective ACE inhibitor or carvedilol. Two pts who received DEM continuously developed reversible pulmonary hypertension & 1 of these pts developed heart failure. As a result, DEM was limited to 70 days in cohorts 4, 5, 6 & 7. In cohorts 1-3, 4 of 16 (25%) pts had a PR. In cohorts 4, 5, 6 & 7, 14 of 28 (50%) pts had a PR & 11 had SD. The truncated DEM pts had a median PFS of 9.0 mos (95% CI: 3.7 mos-NR) & a median survival of 10.1 mos (95% CI: 6.5-16.2 mos), respectively. Conclusions: This therapy was generally well tolerated with fatigue, nausea & vomiting being the most common related AEs. Truncated DEM dosing (i.e., limited to 70 days) avoided clinically significant cardiopulmonary toxicity. Encouraging clinical activity was observed. Biomarker analysis showed modulation of the Notch pathway. Final data will be presented. Clinical trial information: NCT01189929.
Is neoadjuvant chemoradiation important in borderline resectable pancreatic cancer (BRPC)? Clinical and surgical outcomes associated with preoperative FOLFIRINOX alone in BRPC.
Authors: Kim Sunhee S. , Nakakura Eric K. , Wang Zhen J. , Kim Grace E. , Corvera Carlos U. , Harris Hobart W. , Kirkwood Kimberly S. , Hirose Ryutaro , Tempero Margaret A. , Ko Andrew H.
Published: February 2017

351

Background: Neoadjuvant therapy is recommended to increase the likelihood of margin-negative (R0) resection for BRPC. However, there is no consensus regarding the optimal treatment paradigm, including the respective roles of chemotherapy and radiation (RT), in this setting. Methods: Retrospective analysis was conducted of BRPC pts treated with neoadjuvant FOLFIRINOX followed by surgical resection at a single tertiary care referral center over a 4-year period. Data collected included baseline pt characteristics, toxicity profiles, radiographic and serum CA19-9 response, perioperative complication rate, R0 resection rate, histopathologic response, and frequency and patterns of recurrence. Results: 26 BRPC pts received neoadjuvant FOLFIRINOX, 22 w/o addn RT. Abutment of the SMV (n = 9, 40.9%), SMA (n = 4, 18.2%), CHA (n = 4, 18.2%), and narrowing of the SMV (n = 4, 18.2%) were the most common vascular involvement. 9 (40.9%) pts had both arterial and venous involvement. Median baseline CA19-9 level was 278.5 U/ml. Pts received a median of 9 treatment cycles (range, 4-12). Radiographic response was categorized as shrinkage (n = 11, 50%), stable (n = 9, 40.9%), or progression (n = 2, 9.1%). The Whipple procedure was the most common operation performed (n = 17, 77.3%), with 12 pts (54.5%) requiring vascular reconstruction. Clavien-Dindo complication rates of grade 0, I, II, and IIIa occurred in 25.9%, 11.1%, 44.4%, and 14.8% of pts, respectively. R0 resection rate was 90.9%, with 13 (59.1%) having negative lymph nodes. Treatment response of Evans grade III or IV, corresponding to < 10% residual tumor cells, was seen in 8 pts (36.4%), including one pathologic CR (4.5%). AJCC Stage: ypT3N0 (36.4%), ypT3N1 (18.2%), ypT1N1 (18.2%). With a median f/u time of 22.1 months, 8 pts (36.4%) have progressed, inc 7 (87.5%) with distant disease. Median PFS is 22.5 mos. Conclusions: This is one of the largest series to report on the use of neoadjuvant chemotherapy w/o RT in BRPC pts. FOLFIRINOX alone in this setting is associated with high R0 resection rates and favorable clinical outcomes, and should be further assessed in prospective study design for BRPC.
A phase Ib dose escalation, safety, and tolerability study of sonidegib in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.
Authors: Macarulla Teresa , Tabernero Josep , Palmer Daniel H. , Sharma Sunil , Yu Kenneth H. , Sellami Dalila B. , Zhou Jocelyn , Yi Wu , Boss Hildegard , Kwak Eunice L
Published: February 2017

371

Background: Sonidegib (LDE225) is a potent, selective, and orally bioavailable inhibitor of smoothened receptor that demonstrated preclinical activity in combination with gemcitabine (GEM). Here, we present data from a phase 1b trial of sonidegib in combination with GEM in patients (pts) with pancreatic adenocarcinoma (PA). Methods: Pts with histologically or cytologically confirmed, locally advanced, or metastatic PA who had not been treated previously or had progressed despite prior chemotherapy (other than GEM) were included in the study. Dose escalation started with sonidegib 400 mg, once a day, in combination with GEM 1000 mg/m2 IV infusion on days 1, 8, and 15 of a 28-day cycle. Results: A total of 18 pts were enrolled (9 pts each the in dose escalation and dose expansion phases). Pts discontinued the study because of disease progression (n = 11, 61.1%), consent withdrawal (n = 3, 16.7%), administrative problems (n = 3, 16.7%), and grade 3 or 4 blood creatine kinase (CK) elevation (n = 1, 5.6%). Three of 9 pts in dose escalation phase experienced dose-limiting toxicities during the first 8 weeks including grade 3 mucositis (n = 1), grade 3 CK elevation (n = 1), and grade 3 aspartate aminotransferase elevation (n = 1). Drug-related adverse events (AEs) of all grades were reported in 14 pts (77.8%) and grade 3 or 4 AEs were reported in 10 pts (55.6%). The most commonly reported AEs were anemia and nausea. No pharmacokinetic (PK) interaction was observed. Based on considerations of the statistical model, clinical assessment of safety, tolerability, PK, and pharmacodynamic results, maximum-tolerated dose and recommended dose were established as 400 mg of sonidegib in combination with the fixed standard dose of GEM (1000 mg/m2).The objective response rate was 11.1% and the median progression-free survival (PFS) was 4.9 months. Conclusions: The combination of sonidegib and GEM was generally well tolerated with moderate activity. Although no formal comparison can be made due to small sample size of this study, this combination provided a median PFS comparable to the current standard of care without conferring any additional clinical benefit. Clinical trial information: NCT01487785.
Knowledge-based planning for stereotactic body radiation therapy (SBRT) of the liver.
Authors: Gits Hunter C , Dow Janell , Matuszak Martha , Feng Mary Uan-Sian
Published: February 2017

375

Background: SBRT is emerging as a treatment option for patients with unresectable liver tumors. However, generating high quality liver SBRT plans is technically challenging and user-dependent. Aiming for high tumor doses and low normal tissue doses can demand lengthy planning times and result in plans of inconsistent quality. This study investigates knowledge-based planning (KBP) as a standardized method to ensure efficacy, safety, and efficiency for SBRT plans and allow for broader use of this therapy. Methods: SBRT treatment plans were manually optimized for 55 liver cancer cases by an expert liver dosimetrist in a commercial treatment planning system (Varian Eclipse v13.6). Each volumetric modulated arc therapy plan was approved by a physician using strict criteria for target coverage and normal tissue sparing. The plans were used to create a custom model in a KBP system (RapidPlan, Varian Eclipse v13.6) designed to improve both efficiency and standardization of quality. To validate the model, 15 new cases were optimized manually by an expert liver dosimetrist and then semi-automatically using the KBP model. The validation plans were compared based on target coverage, normal tissue sparing, and planning time. Results: Compared to manual plans created by an expert liver dosimetrist, KBP-generated plans showed similar target coverage and improved normal tissue sparing with similar planning times. Mean and minimum target doses were similar, as was D98, p > 0.2 for all. Normal tissue complication probability for liver damage was marginally lower with KBP, mean 3 vs. 1%, p = 0.07. Doses to adjacent organs including stomach, heart, and bowel were similar. Manual planning required a median and mean time of 15 and 20 minutes, respectively, range 8-55 min. KBP required similar times of 12 and 19 min, range 8-50 min. 9 of 15 KBP cases were automated, while 6 plans required dosimetrist improvement. Conclusions: Using KBP, high quality plans for liver SBRT can be created automatically or semi-automatically. These plans are comparable to those generated by an expert liver dosimetrist. KBP could be used to standardize treatments between institutions, particularly when experience with liver SBRT is limited.
Curative resection for hilar cholangiocarcinoma: Does adjuvant therapy impact overall survival? A multi-institution analysis from the U.S. Extrahepatic Biliary Malignancy Consortium.
Authors: Krasnick Bradley , Jin Linda , Davidson Jesse , Ethun Cecilia Grace , Pawlik Timothy M. , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Weber Sharon M. , Salem Ahmed I. , Hawkins William G. , Strasberg Steven M. , Martin Robert C. G. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Maithel Shishir Kumar , Fields Ryan C. ,   Extrahepatic Biliary Tumors
Published: February 2017

388

Background: Surgical resection is the cornerstone of curative therapy for localized hilar cholangiocarcinoma. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall survival (OS) in those patients undergoing curative resection for hilar cholangiocarcinoma. Methods: We reviewed 294 patients who underwent curative resections for hilar cholangiocarcinoma between 1998 and 2015 from ten institutions participating in the U.S Extrahepatic Biliary Malignancy consortium. We analyzed the impact of AT on the primary outcome of OS. Probability of OS was calculated in the method of Kaplan and Meier and analyzed using multivariate Cox regression analysis. Statistical significance was set at p≤0.05. Results: Mean age was 65 years. OS at 5 years was 16%. A total of 146 patients (50%) received AT. Of these patients, 44 patients underwent solely chemotherapy, 5 underwent only radiation therapy (XRT), and 97 underwent combined therapy. On univariate analysis, patients who received AT and those who did not had similar demographic and preoperative features, with the major difference being in the rate of lymph node (LN) positive disease (50% AT group vs. 19% no AT group, p<0.01). In a multivariate Cox regression analysis, AT conferred a significant protective effect on OS (HR 0.578, p<0.01, 95% CI 0.38-0.86), even when adjusting for age, tumor size, R0 resection status, ASA classification, and LN positivity (Table). Conclusions: AT is associated with improved OS in resected hilar cholangiocarcinoma. This association remains even after adjusting for poor prognostic features. We acknowledge that there is an inherent selection bias when looking at those who underwent AT, and thus future prospective randomized trials are needed. [Table: see text]
Trends in treatment and survival for advanced pancreatic cancer: Progress or progression?
Authors: Eskander Mariam F. , Kasumova Gyulnara G. , Li Chun , Ng Sing Chau , Miksad Rebecca A. , Tseng Jennifer F.
Published: February 2017

421

Background: There are increasing therapeutic options for patients with advanced pancreatic cancer but it is unknown whether the overall prognosis of unresectable patients is improving. Here, we examine trends in treatment and survival in Stage III/IV pancreatic cancer. Methods: National Cancer DataBase 1998-2012 queried for unresected pancreatic adenocarcinoma patients from Commission on Cancer hospitals with Stage III and IV disease. Trends in stage at diagnosis and type of chemotherapy (single vs. multi-agent) assessed via Cochran Armitage trend tests. Timing of treatment compared by Kruskal-Wallis. Kaplan-Meier analysis and Cox proportional hazards models used to assess the association between 2-year time intervals (1998-2011) and survival. Results: 34,163 unresected patients with Stage III and 100,396 with stage IV identified. Rates of chemotherapy increased over time for stage III (p<0.0001) and stage IV (p<0.0001). Among patients who received systemic therapy, rates of multiagent chemotherapy have increased for both stage III (p<0.0001) and IV (p<0.0001). Time from diagnosis to treatment did not change (p=0.5121). Overall survival differed by year group for stage III (5.2 mos in 1998-1999 vs. 9.0 mos 2010-2011, log-rank p<0.0001) and stage IV (3.1 vs. 3.6 mos; log-rank p<0.0001). Among patients who received chemotherapy, overall survival also differed (Stage III, 7.6 vs. 11.4 mos, log-rank p<0.0001; Stage IV, 5.0 vs. 6.0 mos, log-rank p<0.0001). After stratification by clinical stage, type of chemotherapy, tumor location, and facility type, year remained a significant predictor of survival (p<0.0001). Conclusions: Survival of patients with Stage III and IV pancreatic cancer has significantly improved over the last fifteen years. This improvement in survival is not fully explained by changes in chemotherapy. [Table: see text]
Clinical and immune characteristics of rapid dropout and long-term survival in a phase II safety and efficacy study of combination CRS-207/GVAX immunotherapy in pancreatic cancer.
Authors: Le Dung T. , Whiting Chan C. , Lutz Eric R. , Nair Nitya , Engstrom Amanda , Lemmens Ed , Tagliaferri Margit Cecile , Murphy Aimee L. , Brockstedt Dirk G. , Jaffee Elizabeth M.
Published: February 2017

459

Background: Baseline patient characteristics may impact duration on study and survivorship of patients in immunotherapy trials. In this study, GVAX pancreas (GM-CSF–secreting allogeneic pancreatic tumor cells) was administered with low-dose cyclophosphamide (Cy), with or without subsequent CRS-207 (live-attenuated Listeria monocytogenes–expressing mesothelin) infusion. Baseline clinical and immunological data were examined for two patient subsets based on duration on study. Methods: Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to 2 doses of Cy/GVAX followed by 4 doses of CRS-207 or 6 doses of Cy/GVAX every 3 weeks. Stable patients were offered additional courses. Patients were evaluated for post-randomization duration on study of < 60 days (rapid dropouts, RD) and > 18 months (long-term survivors, LTS). Baseline characteristics of these subsets were examined. Results: A total of 93 patients were randomized. Fifteen patients were RD; 13 were LTS. More RDs versus LTS had liver metastasis and lymph node involvement. On average, fewer RD patients had radiotherapy prior to randomization and fewer had prior surgical intervention. RD averaged 1.73 prior metastatic cancer treatment regimens versus 1.31 in LTS. RD also had higher average baseline CA 19-9 levels. Immune analysis showed higher circulating terminal effector CD8+ T cells and lower serum IL-6 in LTS compared to RD. Serum IL-6 concentration remained lower in LTS at four weeks following initiation of treatment. For patients who received CRS-207, CD8+ T cells specific to listeriolysin O (LLO) and mesothelin were higher in LTS than RD, as determined by ELISPOT. Conclusions: Baseline clinical and immunological characteristics may impact patient duration on immunotherapy trials. Immune monitoring and biomarker analysis in this study is ongoing to identify circulating cellular, tumor biomarkers and genomic (miRNA and mRNA) signatures that may correlate with survival. These findings warrant continued exploration of patient characteristics to identify best candidates for immunotherapy trials. Clinical trial information: NCT01417000.
Use of radiofrequency ablation and stereotactic body radiotherapy for the treatment of hepatocellular carcinoma: An analysis of the SEER-Medicare database.
Authors: Feng Mary Uan-Sian , Marshall Vincent D. , Parikh Neehar
Published: February 2017

463

Background: Hepatocellular carcinoma (HCC) is an increasingly common and highly morbid malignancy worldwide, including the US. For early stage patients ablative strategies are important potentially curative treatment options. Stereotactic body radiotherapy (SBRT) has emerged as a promising non-surgical ablative therapy, although it is technically demanding and its comparison with radiofrequency ablation (RFA) remains confined to a single institution retrospective review. We queried the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to assess RFA and SBRT use in the US. Methods: We identified patients greater than 65 years old who were diagnosed from 2004-11 with stage I or II HCC and treated with RFA or SBRT. Survival analysis was conducted using Kaplan-Meier curves and log rank test. Factors associated with overall survival (OS) and early ( ≤ 90 day) hospital admission post-treatment were identified using propensity score (PS) adjusted multivariate analysis. Results: 825 patients were identified, 747 treated with RFA and 78 SBRT. 22 pts received both treatments and were excluded from this analysis. The mean Charlson comorbidity index was 1.0±1.1. Median age was 74, range 66-90. Patients who received RFA were more likely to live in the West and have liver decompensation. Patients who received SBRT were more likely to be white and treated in the Midwest. After using PS matching there were 78 in each cohort. In these patients, mean overall survival (OS) was 2.25 and 2.04 yrs for RFA and SBRT, p = 0.06. Younger age, lack of liver decompensation, treatment in the West, and liver transplantation were associated with longer OS, HR 0.96, p = 0.05; HR 0.37, p = 0.002; HR 0.57, p = 0.04; HR 0.18, p = 0.008, respectively. 90 day hospitalization rates did not differ between treatments; only liver decompensation was predictive of hospitalization, OR 3.33, p = 0.032. Conclusions: In a national cohort of early stage HCC patients, treatment with RFA vs SBRT resulted in no significant difference in OS. SBRT appears to be a comparable ablative strategy to RFA in this population. This highlights the need for a randomized trial comparing these two modalities.
Expression of ERCC1, TUBB3, BRCA1, and TS as predictive markers of neoadjuvant chemotherapy for squamous cell carcinoma of the esophagus.
Authors: Ojima Toshiyasu , Nakamori Mikihito , Nakamura Masaki , Katsuda Masahiro , Hayata Keiji , Matsumura Shuichi , Kato Tomoya , Yamaue Hiroki
Published: February 2017

47

Background: No predictive biomarker of the response to neoadjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil (NAC-DCF) is available for patients with squamous cell carcinoma of the esophagus (SCCE) in a clinical setting. The aim of this study was to identify the biomarkers associated with chemotherapeutic efficacy and long-term survival for patients with advanced SCCE who had received NAC-DCF followed by surgery. Methods: This study included 45 patients with advanced SCCE who received NAC-DCF between January 2008 and December 2012. The NAC-DCF was conducted as a phase II study (UMIN000007408). The expressions of excision repair cross-complementing-1 (ERCC1), class III beta-tubulin, breast cancer susceptibility gene I (BRCA1), and thymidylate synthase were investigated simultaneously in the pre-treatment endoscopic tumor biopsy samples. Results: The multivariate logistic regression analysis indicated that pathological responses were significantly associated with tumors with low ERCC1 expression (P = 0.016) and with tumors with high BRCA1 expression (P = 0.014). The incidence of pathological responses to DCF in patients with low ERCC1 and high BRCA1 expressions was 100%. The multivariate Cox proportional hazard model analysis for relapse-free survival (RFS) revealed tumors with high BRCA1 expression (P = 0.031, hazards ratio, 4.39) as independent prognostic factors. Conclusions: Low ERCC1 expression and high BRCA1 expression in patients with SCCE were predictive biomarkers for chemotherapeutic efficacy. High BRCA1 expression was considered as prognostic factors for long-term RFS. These results may be a helpful tool for tailoring chemotherapy of patients with SCCE. Prospective validation of this biomarker panel is warranted. Clinical trial information: UMIN000007408.
Differential radiographic appearance of BRAF V600E mutant metastatic colorectal cancer (mCRC) in patients matched by primary tumor location.
Authors: Greene Claire , Atreya Chloe Evelyn , McWhirter Ryan , Ikram Nabia , Van Loon Katherine , Venook Alan P. , Yeh Benjamin M. , Behr Spencer
Published: February 2017

554

Background: BRAF mutation status and location of CRC primary each correlate with pattern of metastatic spread. We sought to determine whether presence of a BRAF V600E (BRAF) mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location. Methods: 40 patients with BRAF mutant mCRC were matched to 80 patients with BRAF wild-type CRC by location of primary tumor (right colon, left colon or rectum), sex, and age ( < 50; 50+). CT scans were reviewed for disease characterization. BRAF mutation status, clinicopathological characteristics, and sites of metastatic disease were associated using proportion tests. Results: Of the 120 matched patients,60% were female. The distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Median age at diagnosis was 57, range 20-88 yrs. Significantly higher frequencies of peritoneal metastases (p = 0.045) and ascites (p = 0.0038) occurred in patients with BRAF mutant tumors. Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. In patients with left colon primaries, BRAF mutations associated with less frequent liver metastases (42% vs. 79%, p = 0.024) and more frequent ascites (58% vs. 12%, p = 0.0038). Disease was not measurable by RECIST version 1.1 criteria in 20% of patients with BRAF mutations, most often with peritoneal metastases and ascites. Conclusions: Presence of a BRAF V600E mutation associated with a greater proportion of peritoneal metastases and ascites, even among patients matched for primary tumor location. Of 20 patients with BRAF mutant mCRC and peritoneal metastases plus ascites, 6 patients (30%) had disease that was not measurable by RECIST version 1.1. Radiographic characterization provides a window on BRAF mutant mCRC biology and also reveals a challenge for response evaluation on clinical trials. [Table: see text]
Prognostic impact of tumor-associated B cells and plasma cells in colorectal cancer.
Authors: Berntsson Jonna , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin
Published: February 2017

587

Background: Multiple studies have described associations between infiltrating immune cells, prognosis and treatment response in cancer. However, the clinical relevance has most often been attributed to the T-cell linage, whereas the humoral immune response is less investigated. In colorectal cancer (CRC), accumulation of CD20-positive B lymphocytes at the advancing margin of metastatic CRC has been demonstrated to correlate with prolonged survival. This study aimed to further investigate the clinicopathological correlates and prognostic impact of B cell and plasma cell infiltration in colorectal cancer (CRC). Methods: Immunohistochemical expression of CD20 and CD138 in was analyzed in tissue microarrays with tumors from 557 incident cases of CRC from the Malmö Diet and Cancer Study, a prospective population-based cohort. Kaplan-Meier analysis and Cox regression analysis were used to determine the impact of CD20 and CD138 expression on 5-year overall survival (OS). Results: CD20 expression could be evaluated in 549 (98.6 %) cases and CD38 in 534 (95.9 %) cases. CD20 expression correlated significantly with both immune cell-specific and tumor-specific expression of CD138 (p < 0.001 and p = 0.001, respectively). Furthermore, immune cell-specific CD20 and CD138 expression as well as tumor-specific CD138 expression correlated significantly with lower T-stage (p < 0.001, p < 0.001 and p = 0.002, respectively). A higher density of CD20+ cells correlated significantly with an improved OS (HR = 0.66, 95 % CI 0.50-0.86), remaining significant in multivariable analysis adjusted for age, TNM stage, differentiation grade and vascular invasion (HR = 0.65; 95% CI 0.48-0.90). Neither immune cell nor tumor cell-specific CD138 expression was significantly associated with prognosis. Conclusions: Our results demonstrate that increased B cell infiltration in CRC is an independent factor of improved prognosis. Moreover, the study provides a first demonstration of the expression and clinicopathological correlates of immune cell-specific CD138 expression in CRC, thus providing a further characterization of the immune landscape in this type of cancer.
Effect of 5-fluorouracil on membranous PD-L1 expression in colon cancer cells.
Authors: Goel Gaurav , Ramanan Krishnaveni , Kaltenmeier Christof , Zhang Lin , Freeman Gordon J. , Normolle Daniel Paul , Tang Daolin , Lotze Michael T.
Published: February 2017

592

Background: Colorectal cancer (CRC) is a major public health problem worldwide. Chemotherapy consisting of a fluoropyrimidine backbone constitutes a major therapeutic modality used in the treatment of CRC patients. However, cancer cells often develop resistance to such cytotoxic chemotherapy and this represents a major therapeutic challenge. B7-homolog 1 (B7-H1), also known as programmed death ligand-1 (PD-L1) is an immunoregulatory protein that belongs to the B7 family of T-cell co-regulatory molecules, and is overexpressed in several human tumors. Upregulation of PD-L1 expression is an important mechanism by which tumor cells can escape host T-cell immunity. Emerging evidence suggests that chemotherapeutic agents can regulate PD-L1 expression on cancer cells, which may have an impact on anti-tumor immunity and immune evasion. We performed this study to evaluate the effect of 5-Fluorouracil (5-FU) on PD-L1 expression in colon cancer cell lines, using an in vitro approach. Methods: Flow cytometry and western immunoblot analyses for PD-L1 expression were performed on human colon cancer cell lines (HCT116-WT, HCT116-p53 KO, SW480, HT29) upon treatment with IFN-ɣ and 5-FU. Results: We found that the tested human colon cancer cell lines rarely expressed PD-L1 protein on their cell surface at baseline, but a high level of expression was induced by treatment with IFN-ɣ. More importantly, we demonstrated that the chemotherapeutic agent 5-FU induces PD-L1 expression in colon cancer cells. Conclusions: It is therefore plausible that combining 5-FU with PD-1/PD-L1 blockade might help overcome some of the chemoresistance to 5-FU and thereby enhance its anti-cancer activity. Further experiments are being planned to formally test this hypothesis.
Hypermethylated circulating DNA detection using picoliter droplet-based PCR in colorectal cancer.
Authors: Perkins Geraldine , Garrigou Sonia , Garlan Fanny , Normand Corinne , Didelot Audrey , Le Corre Delphine , Mulot Claire , Niarra Ralph , Aucouturier Pascaline , Chatellier Gilles , Peyvandi Sanam , Bouche Olivier , Emile Jean-Francois , Pezet Denis , Bibeau Frederic , Link Darren R , Zaanan Aziz , Sobhani Iradj , Laurent-Puig Pierre , Taly Valerie
Published: February 2017

622

Background: Circulating tumor DNA (ctDNA) is thoroughly investigated as a surrogate biomarker of tumor follow-up, in different cancer types, such as colorectal cancer (CRC). Droplet-based digital PCR (ddPCR) is a highly sensitive and also quantitative method for detection of very low amount of ctDNA. Since many different genes can be mutated within a specific tumor type and also wide mutation spectrum can occur within a specific gene, procedures for ctDNA monitoring can be time consuming and need to be improved for a routinely use. To overcome these drawbacks, we characterized the methylation status of 3 genes frequently hypermethylated in CRC to identify universal markers for tumor follow-up. Methods: The characterization of the methylated status of the WIF, NPY and PENK genes in the tumor DNA was performed in 56 CRC of different stages and 45 corresponding plasma samples using droplet-based dPCR, after DNA bisulfite conversion. A two-panels assay (with albumin as a reference) was developed. Methylation level of these 3 genes in tumor tissues was compared to corresponding normal tissues (n = 22) and plasma samples (MetctDNA). To validate, plasma samples of additional 91 patients were analyzed for the presence of ctDNA both by the characterization of KRAS, BRAF, TP53 and PIK3CA mutations (MutctDNA) and of MetctDNA, at various stages of their follow-up, and 9 of them had MetctDNA assessment during treatment follow-up. Results: All tumor samples were positive for WIF1 and/or NPY markers. Hypermethylation of these two genes was significantly higher in tumor tissue compared to normal, independently of the tumor stage (p < 0.0001). MetctDNA could be detected in 75% of metastatic CRC patients and 24% of localized CRC patients (stage 1 to 3). MetctDNA and MutctDNA fractions were strongly correlated (R2 > 0.9, p < 0.0001). During follow-up, MetctDNA levels changes allowed monitoring of tumor evolution in different stages CRC patients. Conclusions: These results indicate that determination of MetctDNA by droplet-based dPCR can reach same efficiency than MutctDNA for ctDNA assessment, using only 2 markers, and thus could be considered as a universal surrogate marker of tumor follow-up in CRC patients.
The prospective French participitation to IDEA (International Duration Evaluation of Adjuvant Chemotherapy) study in stage III colon cancer: Patients’ characteristics and safety analysis of 3 versus 6 months of adjuvant chemotherapy.
Authors: Andre Thierry , De Gramont Aimery , Mineur Laurent , Desramé Jérôme , Faroux Roger , Bennouna Jaafar , Dauba Jérôme , Louvet Christophe , Pernot Simon , Dupuis Olivier Jean Marie , Becouarn Yves , Mabro May , Egreteau Joëlle , Bouche Olivier , Bonnetain Franck , Hug de Larauze Marine , Le Malicot Karine , Taieb Julien ,   GERCOR, FFCD, and UNICANCER (PRODIGE) Study Groups
Published: February 2017

633

Background: The IDEA international collaboration was established to prospectively combine/analyze data from six randomized trials to assess whether a 3-month course of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month current standard treatment in stage III colon cancer (CC). The primary endpoint of IDEA was 3-year disease-free survival. The accrual goal for the French IDEA study was 2,000 patients. Methods: French IDEA randomized patients with stage III CC between 3 months (arm A) and 6 months (arm B) of adjuvant CT with modified (m) FOLFOX6 or XELOX (depending on physician/patient choice). Oxaliplatin was stopped in case of persistent neuropathy grade ≥2 with fluoropyrimidines continuation for the planned duration. Toxicity was graded during treatment and follow-up using NCI-CTCAE v3.0. Results: From May 2009 to May 2014, 2,023 patients were randomized in 129 French centers either to arm A (n=1009, 49.9%) or to arm B (n=1014, 50.1%). 2012 (99.5%) patients had stage III disease (N1: 75%; N2: 25%) and 11 patients had stage II (n=2) or stage IV disease (n=9). Median age was 64 years (18-85). 89.4% of patients received mFOLFOX6, 10.1% of patients received XELOX, and 0.5% of patients did not receive any study treatment. Overall, 94.1% and 77.5% of patients completed 3 months (arm A) and 6 months (arm B) of CT, respectively. Median oxaliplatin dose was 500 mg/m2 in arm A and 747 mg/m2in arm B. Toxicity profiles depended on the FU backbone with more grade 3/4 neutropenia on mFOLFOX6 (15.0% vs 6.5%) and more grade 3/4 diarrhea (4.7% vs 8.1%) on XELOX. Grade 2/3-4 peripheral neuropathy was less common in arm A than in arm B (23.2/6% vs 37.9/20.4%). Grade 2/3-4 residual neuropathy for patients with a follow-up of at least 3 years (n=811, median follow-up of 3.91 years) was 2.3/0.5% in arm A vs 3.9/ 2.4% in arm B. At 6 months after randomization, mortality rate was 0.7% (n=7) on arm A and 0.5% (n=5) on arm B. Median follow-up is 2.74 years for the whole population. Conclusions: Both mFOLFOX6 and XELOX were safe. Peripheral neuropathy was lower in arm A than in arm B. Clinical trial information: 2009-010384-16.