bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer of unknown primary (CUP) with disseminated-lymphadenopathy presentation: Clinicopathological features, prognostic factors, and survival outcomes.
Authors: Raghav Kanwal Pratap Singh , Modha Jignesh , Lano Elizabeth A , Wang Huamin , Matamoros Aurelio , Overman Michael J. , Varadhachary Gauri R.
Published: March 2017

465

Background: Aside from traditional favorable localized-nodal CUP (LNC) subsets including solitary nodal disease, women with isolated axillary adenocarcinoma and squamous cell carcinoma of cervical/inguinal lymph nodes, there is limited data on disseminated nodal CUP (DNC) presentation. Our study describes the clinicopathologic features and outcomes in nodal CUP (NCUP) highlighting the DNC subset. Methods: We performed a retrospective review of 61 NCUP patients (pts) at UTMDACC (2008 - 2015). For control group (CG), we utilized a cohort of consecutive non-NCUP pts (N = 201) from MDACC CUP database (2012 - 2013). Kaplan-Meier method was used to estimate median overall survival (mOS) and compared with log-rank tests. Results: Median age of NCUP was 61 y, similar to CG (59 y; P = 0.26). In this cohort, 19/61 (31%) and 42 (69%) were classified as LNC and DNC. DNC pts were predominantly women (65%), had good performance status (0/1: 90%), and presented with intrabdominal lymphadenopathy (79%). Sixty percent had carcinoma and majority were high grade (74%). Median immunohistochemical stains performed were 9; most common positive stains were CK7 and pan-keratin. The mOS for entire NCUP cohort was 76 months (m). The mOS for LNC was not reached and was 33.1 m for DNC (HR 0.36; P = 0.04). The mOS of DNC was better than CG (18.8 m; HR 0.62; P = 0.03). Male sex and high neutrophil-lymphocyte ratio (NLR > 5) were poor prognostic factors in DNC ( P < 0.01). Among NCUP pts, 21 reported subsequent development of extra-lymphatic disease [peritoneum/retroperitoneum (29%), liver (24%), lung (19%), muscle/soft tissue (19%), bone (10%)]. Among 36 pts, who had first-line systemic therapy, combination platinum-taxane was used substantially (44%) and was associated with better mOS compared to other regimens (HR 0.20; P < 0.01). Conclusions: Disseminated–lymphadenopathy CUP presentation is a unique clinical subset of CUP which is associated with a significantly better survival than non-NCUP. This distinct entity warrants dedicated research efforts towards understanding biology, developing a cost effective integrated clinical algorithm for management and developing novel therapies.
Efficacy of chemotherapy in patients with recurrent pancreatic cancer.
Authors: Ohba Akihiro , Ueno Hideki , Inagaki Yuji , Sakamoto Yasunari , Kondo Shunsuke , Morizane Chigusa , Okusaka Takuji
Published: March 2017

466

Background: Gemcitabine (GEM) plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) are standard first-line chemotherapy regimens for metastatic pancreatic cancer (MPC) patients. GEM and S-1 are also used for these patients in Japan. However, the phase 3 trials included a small proportion of recurrent pancreatic cancer (RPC) patients, and patients who had received adjuvant chemotherapy were excluded. In clinical practice, RPC is treated in the same way as MPC. The aim of this study is to compare the efficacy of chemotherapy between RPC and MPC. Methods: We retrospectively analyzed the patients with RPC or MPC who received GnP, FFX, GEM, or S-1 as first-line chemotherapy between January 2014 and March 2016 in our institution. RPC was defined as pancreatic cancer with recurrence after R0 or R1 resection. Overall survival (OS), progression-free survival (PFS), response rate (RR), and disease control rate (DCR) were evaluated. Multivariate analyses of OS were performed with the use of a Cox proportional-hazard model. Results: A total of 181 patients, 40 RPC and 141 MPC, were selected in this study. RPC and MPC groups were similar with respect to age, sex, and performance status (PS). However, the RPC group had lower percentage of liver metastases (P < 0.001). The regimens were GnP/FFX/GEM/S-1: 10/3/20/7 in the RPC group and 37/34/67/3 in the MPC group, respectively. In the RPC group, 31 of 40 patients had received adjuvant chemotherapy; S-1/GEM: 24/7. The median OS was 16.6 months in the RPC group as compared with 9.7 months in the MPC group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.37–1.10, P = 0.11). The median PFS was 4.8 months in the RPC group and 4.4 months in the MPC group (HR 0.86, 95% CI 0.57–1.30, P = 0.47). The RR was 10% versus 14% (P = 0.79), the DCR was 50% versus 52% (P = 0.86), in the two groups, respectively. Multivariate analysis showed PS (HR 2.19, 95% CI 1.38–3.49) and liver metastases (HR 2.34, 95% CI 1.47–2.34) were independent predictors of OS. On the other hand, RPC or MPC was not found to be an independent prognostic factor (HR 1.19, 95% CI 0.67–2.13). Conclusions: It is suggested that chemotherapy in RPC may have similar efficacy compared to MPC. The relatively longer OS in the RPC group seems to associate with the lower percentage of liver metastases.
Determinants of first-line treatment selection in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Wong Hui-Li , Wang Ying , Yin Yaling , Kennecke Hagen F. , Cheung Winson Y. , Renouf Daniel John , Gill Sharlene
Published: March 2017

468

Background: Chemotherapy options currently available for the first-line treatment of advanced PDAC include FOLFIRINOX (FX), gemcitabine with nab-paclitaxel (GP) and single agent gemcitabine (Gem). GP was introduced most recently and funded for clinical use in British Columbia (BC) in September 2014. In this retrospective analysis, we explore the impact of GP availability on first-line treatment selection and overall survival (OS) in advanced PDAC. Methods: The BC Cancer Agency provincial pharmacy database was used to identify patients (pts) who started FX, GP or Gem between January and August 2014 (pre-GP) or January and August 2015 (post-GP). Pts were eligible for inclusion if they received at least one cycle of first-line therapy for locally advanced or metastatic PDAC. Clinical data were extracted from electronic medical records. OS was defined as time from diagnosis of advanced PDAC to death and compared by treatment era, adjusting for age, ECOG, comorbidities, disease extent and baseline CA19-9. Results: 286 pts fulfilled eligibility criteria: 88 (31%) with locally advanced and 198 (69%) with metastatic disease. 131 and 155 pts were treated in the pre- and post-GP eras respectively. Prior to GP approval, 44% and 49% of pts received Gem and FX; this decreased to 21% and 33% after GP funding, with 46% of pts receiving GP in the latter period. Nine (7%) pts received GP in the pre-GP era, either through self-pay or addition of nab-paclitaxel after approval. There were no significant differences in pt characteristics across both eras. 46% of pts who received GP post approval had ECOG ≥ 2. The proportion of pts receiving second-line therapy was lower in the post-GP era (22% vs. 38%). Median OS in the post-GP era was 8.1 vs. 10.1 months in the pre-GP era; adjusted HR 1.28 (95% CI 0.96–1.71). Pts with ECOG ≥ 2 who received GP had a median OS of 6.5 months. Conclusions: After GP was funded, it became the preferred first-line regimen for advanced PDAC. Its more frequent use instead of FX did not appear to compromise overall survival even though a substantial proportion of pts were ECOG ≥ 2 and few pts received second-line therapy.
Preliminary analysis of FOLFIRI regimen with or without bevacizumab as second-line systemic therapy in patients with metastatic gastroenteropancreatic neuroendocrine carcinoma.
Authors: Zhao Xiaoying , Wang Chen Chen , Zhang Wen , Zhu Xiaodong , Guo Weijian , Chen Zhi-Yu
Published: March 2017

469

Background: Patients with gastroenterpancreatic neuroendocrine carcinomas (NECs) have a very poor prognosis. And the role of the second-line therapy remains unknown. Methods: We retrospectively analyzed 11 patients with gastroenteropancreatic NEC after failure of first-line chemotherapy in the last two years in our cancer center. Data examined included clinical and pathological characteristics at the time of diagnosis, efficacy and safety. Results: Median age was 51 (17-64) years old. Most were male (81.8%). Tumor origin included pancreas (6pts, 54.5%), colon-rectum (3pts, 27.3%), one stomach and one liver. Metastatic disease was evident at diagnosis in all patients (liver metastases: 100%, celiac lymph nodes: 72.7%, bone: 18.2%, pleural effusion and peritoneal metastasis: 18.2%). Median Ki-67 index was 80%. Etoposide-cisplatin combinations as first line chemotherapy were administered in 8 (72.7%) patients and 2 (18.2%) capecitabine based regimen and 1(9.1%) gemcitabine with nab-paclitaxel. All patients received the FOLFIRI regimen with a median number of 8 (3-36) courses. Three patients (27.3%) had partial response, 4 (36.4%) stable disease, and 4 (36.4 %%) tumor progression. But in 6 patients received the FOLFIRI plus bevacizumab, disease control rate was 66.7%, 3 (50.0%) partial response, 1(16.7%) stable disease. The median PFS in all 11 pts was 3.77 (1.77-24.07) months, in 6pts with bevacizumab was 4.77(1.83-24.07) months. The most severe toxicities was grade 3 neutropenia (27.2%), the other adverse effects were mild to moderate, including mild anemia, transient transferase elevation and proteinuria. Conclusions: FOLFIRI regimen is a potentially effective and safe chemotherapy given as second-line in patients with NEC. Additional anti-VEGF therapy with bevacizumab may improve the disease control and PFS time.
Phase II study of first-line radioembolization with yttrium-90 glass microspheres for intrahepatic cholangiocarcinoma.
Authors: Shridhar Ravi , Frakes Jessica M. , Yue Binglin , Kim Richard D. , Springett Gregory M. , Arslan Bulent , Choi Junsung , Kis Bela , Yeatman Timothy Joseph , Meredith Kenneth L , Hoffe Sarah E.
Published: March 2017

482

Background: The standard of care for unresectable intrahepatic cholangiocarcinoma (ICC) is systemic chemotherapy. The role of liver directed therapy for ICC is controversial given the lack of level I data. We conducted a phase II study to determine the safety and effectiveness of first-line liver directed therapy with radioembolization with yttrium-90 (Y90) glass microspheres for ICC. Methods: Eligible patients were enrolled on an IRB-approved phase II study (NCT01253148). Patients were included if they had no evidence of extrahepatic metastases, Childs-Pugh A, without main portal vein thrombus, bilirubin < 2 mg/dL, ECOG performance status of 0-2, and no prior chemotherapy, liver embolization, or radiation therapy for ICC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and toxicity. Results: Twenty-five patients were enrolled between 2010 and 2013 with a median followup of 13 months (9-20 months). The median age was 76 years. Twenty patients came off study due to progression or death. The overall response rate was 56%. Median PFS was 6 months (95% CI: 4-12 months). This was likely due to tumors appearing larger after treatment due to tumor inflammation despite a decrease in CA19-9 levels. Univariate (UVA) and multivariate analysis (MVA) failed to identify any prognostic factors associated with PFS. Despite the low median PFS, median OS was 22 months (95% CI: 10 months to upper limit not reached). However, UVA and MVA failed to identify and prognostic factors for OS. Treatment was well tolerated with no reported grade 3 gastrointestinal or general disorder toxicities. Grade 3 ALT, AST, and alkaline phosphatase increase were reported in 4%, 4%, and 8%, respectively. Grade 4 hyperbilirubinemia and thrombocytopenia were reported in 4% and 4%, respectively. There were 2 patient who developed sepsis one patient who died within 30 days of treatment. Conclusions: First-line liver directed therapy with radioembolization with Y90 glass microspheres is a safe and effective treatment for ICC. Further prospective clinical trials are needed to identify the proper sequencing of liver directed therapy and systemic chemotherapy. Clinical trial information: NCT01253148.
Impact of nab-paclitaxel-based second-line chemotherapy on the outcomes of pancreatic cancer.
Authors: Dadi Neelakanta , Shahda Safi , O'Neil Bert H. , Sehdev Amikar
Published: March 2017

483

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with no standard second line chemotherapies. We conducted a retrospective study with the primary aim to examine the effect of second line chemotherapy with nab-paclitaxel-based regimen on the overall survival (OS) and progression-free survival (PFS) of locally advanced and metastatic PDAC patients. Methods: Indiana University Simon Cancer Center (IUSCC) Cancer Registry was used to identify patients with locally advanced or metastatic PDAC between 2009 and 2015. Only patients who received second line chemotherapies were included in the study. These patients were divided in to two groups: a) nab-paclitaxel-based treatment and, b) non-nab-paclitaxel-based treatment. Demographic (age, race, gender, year of diagnosis, family history, comorbidity), clinical (histology, CA 19-9, bilirubin, tumor location, performance status, metastatic sites, chemotherapy, surgery or radiation) and outcome (OS, PFS) characteristics were obtained. OS and PFS were estimate by using Kaplan-Meier method and 95% CI. Cox proportional-hazard model was used for multivariate analysis. Results: Forty-seven (39%) and seventy-three (61%) patients received nab-paclitaxel-based and non-nab-paclitaxel-based second line chemotherapy, respectively. In the univariate analyses, nab-paclitaxel-based treatment was only associated with younger age (60.4 vs. 64 years; P = 0.02). The median PFS was 2.8 and 2.1 months (HR 0.62; 95% CI 0.38-1.02; P = 0.06), and the median OS was 7.5 and 4.7 months (HR 0.67; 95% CI 0.45-1.00; P = 0.05) in patients who received nab-paclitaxel based second line treatment versus not, respectively. Multivariate analyses adjusted for age showed a significantly improved PFS (adjusted HR 0.60, 95% CI 0.36-0.98; P = 0.04) and a suggestion of improved OS (adjusted HR 0.67; 95% CI 0.44-1.01, P = 0.05) in the nab-paclitaxel based second line treatment group versus not, respectively. Conclusions: In a single institution retrospective study, we report significant improvement in the PFS and a suggestion of improvement in the OS with nab-paclitaxel based treatment as compared with non-nab-paclitaxel based treatment in the second line setting.
Adjuvant stereotactic body radiotherapy (SBRT) for resected primary and metastatic liver cancers.
Authors: Bazzi Latifa , Feng Mary Uan-Sian , Lawrence Theodore Steven , Cuneo Kyle Clifford , Owen Dawn
Published: March 2017

487

Background: Stereotactic body radiotherapy (SBRT) has been shown to be a safe and effective treatment for hepatobiliary cancers. However, little is known about the efficacy of adjuvant SBRT for resected liver tumors with positive margins. We examined the characteristics and outcomes of patients who received adjuvant SBRT for both primary and metastatic cancers of the liver. Methods: We retrospectively reviewed the charts of patients who had received liver SBRT from 2009-2015 at our institution. During that time frame, 11 patients were identified as having received adjuvant SBRT post resection. Patient data such as age, gender, portal vein thrombosis, cirrhosis, ECOG performance status, prior liver directed therapies, and SBRT dose were collected. Descriptive statistics were used for analysis given the small number of patients in this series. Results: Median age at the time of treatment was 63 years (range 51-79), and the majority of patients (72.7%) were male. Seven tumors (63.6%) were hepatocellular carcinomas, and 4 (36.4%) were adenocarcinomas. Of the tumors with adenocarcinoma histology, 3 were cholangiocarcinomas and one was metastatic colorectal cancer. Ten patients (90.9%) were treated for positive margins, and one was treated for inferior vena cava (IVC) invasion. Seven patients (63.6%) had no other liver-directed treatment prior to adjuvant SBRT. Two patients received systemic therapy prior to SBRT. Median EQD2 was 83.3 Gy (range 60-126), and 81.8% of patients received 5 fractions. There were no grade 3 or above late toxicities from treatment. Median follow-up was 14.1 months (range 5.4-38.1). None of the treated tumors progressed locally. Six patients (54.5%) progressed elsewhere in the liver, and one patient experienced distant metastatic progression. One patient experienced both intrahepatic progression and distant metastatic progression. Conclusions: Adjuvant SBRT appears to be a safe and feasible adjuvant treatment in patients with primary liver resection for either primary liver cancer or metastatic disease who are at high risk of recurrence.
Frequency of severe neutropenia occurring as an adverse events of gemcitabine plus cisplatin chemotherapy in patients with recurrent biliary tract cancer compared to those with unresectable biliary tract cancer.
Authors: Fujishiro Noriko , Mitsunaga Shuichi , Shinohara Akira , Takeno Misaki K , Funazaki Hideki , Kimura Gen , Watanabe Kazuo , Umemoto Kumiko , Sasaki Mitsuhito , Takahashi Hideaki , Imaoka Hiroshi , Hashimoto Yusuke , Ohno Izumi , Ikeda Masafumi
Published: March 2017

488

Background: In patients (pts) with biliary tract cancer (BTC), relapse occurs at a high frequency even after curative resection. It remains unclear whether in pts with postoperative recurrence receiving chemotherapy, the surgery exerts any influence on the risk of development of toxicities. The aim of this study was to compare the outcomes and incidences of adverse events between recurrent BTC (rBTC) pts and unresectable BTC (uBTC) pts receiving gemcitabine plus cisplatin chemotherapy (GC). Methods: Data of pts with rBTC or uBTC receiving GC as the first-line chemotherapy were analyzed. The GC regimen consisted of gemcitabine 1000 mg/m2 plus cisplatin 25 mg/m2on days 1 and 8, administered every 3 weeks. All adverse events occurring during the first 180 days of GC were evaluated according to CTCAE, version 4.0. Results: A total of 151 pts, including 55 pts with rBTC and 96 pts with uBTC, were enrolled. In regard to the baseline characteristics, no significant differences between the rBTC and uBTC groups were found in the gender distribution [male: 69% vs. 57%], age [median: 68 vs. 68], or ECOG performance status (PS) [PS0: 67%vs. 55%]. The distribution of the primary tumor site (intrahepatic bile duct [27% vs. 33%] / extrahepatic bile duct [45% vs. 20%] / gallbladder [20% vs. 44%] / ampulla [7% vs. 3%]) was unbalanced between the two groups ( p < 0.01). The overall survival (OS) was significantly longer in the rBTC group than that in the uBTC group [median 15.8 months vs. 10.0 months, p = 0.02], however, there was no significant difference in the progression-free survival [median 6.8 months vs. 5.8 months] between the two groups. Grade 3-4 neutropenia was more frequent in the rBTC group [69%] as compared to that in the uBTC group [44%, p < 0.01], whereas Grade 3-4 cholangitis was significantly less frequent in the rBTC [5%] group than that in the uBTC group [21%, p = 0.02]. Conclusions: The incidence of Grade 3-4 neutropenia developing during GC was significantly higher in the rBTC group as compared to that in the uBTC group.
Assessment of the incidence of medical events reported following Y90 treatment.
Authors: Prins Petra , Wahnschafft Simone , Guevara Kiara Rivera , Khan Ahsum , Fishbein Anna , Unger Keith Robert
Published: March 2017

491

Background: Radioembolization (Y90) is a minimally invasive procedure combining embolization and radiation therapy to treat primary and metastatic liver tumors. During radioembolization, resin beads loaded with the radioactive isotope, yttrium Y-90, are administered through the hepatic arterial vasculature. Although the safety profile of Y90 is well described, the number of dosage errors associated with treatment delivery is unknown. The purpose of this study is to assess incidence of medical events reported following Y90 treatment. Methods: A search was conducted of the US Nuclear Regulatory Commission events notification database for reported medical events between January 2000 and July 2016 using the following search terms: Y90, SIRS spheres, and TheraSpheres. Results: We recorded 96 reported medical events related to Y90 treatment: 26% were related to human error, 20% to equipment malfunction, 14% to catheter blockage, 2% were caused by catheter movement, 5% were the result of improper microsphere migration, and 33% had undetermined cause. The human error-related events consisted of application of an incorrect dose (82%), administration to the incorrect liver lobe (7%), or targeting of the wrong organ (11%). For the events involving incorrect dose administration, the total dosage exceeded the prescribed dose by greater than 20% in 5 events, while the total dosage was less than the prescribed dose by > 20% in 86 events. In 12 cases, dose inaccuracies were indicated but final dose administered was not reported. Conclusions: Although the incidence of medical events was relatively small, equipment failure and human errors were frequent. Under dosages occurred more often than over dosages. Stopcock malfunction and catheter blockage were common causes and equipment redesign should be considered. Human errors involving administration of the incorrect dose are potentially avoidable with procedural modifications.
Stereotactic body radiotherapy for hepatocellular carcinoma in the setting of poor liver function: A case series.
Authors: Valakh Vladimir , Williams Graeme
Published: March 2017

493

Background: Role of stereotactic body radiotherapy (SBRT) to the liver for patients with poor hepatic function after transcatheter arterial chemoembolization (TACE) has not been established. We reviewed results of SBRT for men with hepatocellular carcinoma (HCC) and Child-Pugh (CP) score ≥ 8 cirrhosis after TACE. Methods: Following a median of 3 TACE treatments, five males with severe cirrhosis received SBRT for persistent or progressive HCC in 2011-14. Clinico-pathologic characteristics and treatment details were retrospectively retrieved. Results: Median age at diagnosis was 55 years (range, 48 – 55). Median interval between cancer diagnosis and SBRT was 38 months (range, 3 – 60). All 5 patients experienced decline in CP score after TACE, for a median of drop of 1 point (range, 1 – 3) between the initiation of TACE and referral for radiotherapy. At time of SBRT, 4 had CP class B and 1 class C cirrhosis with median CP score of 9 (range, 8 – 11). There were no distant metastases and one patient had extrahepatic tumor extension. Three of 5 exhibited clinical symptoms of decompensated cirrhosis within 30 days before radiotherapy and one had portal vein thrombosis. Median MELD score at SBRT was 15 (range, 12 – 18). SBRT to a median total dose of 27.5 Gray (range, 27.5 – 30) was delivered in 5 once daily fractions. Median radiotherapy course duration was 9 days (range, 5 – 18). All patients had single radiation therapy targets with median largest tumor dimension of 3.6 cm (range, 2.4 – 6.2). Median planned target volume was 24 cm3(range, 17 – 197). Sorafenib was given prior to SBRT to one patient, concurrently to one, and sequentially after radiotherapy to another. There were no acute complications. Two patients died within 20 days from completion of SBRT. Median follow up for surviving > 20 days was 10 months (range, 5 – 13). None experienced radiographic tumor progression after radiotherapy. Estimated overall survival was 40% at 6 months (95% confidence intervals, 0 – 83.8%). Conclusions: For HCC patients with CP score ≥ 8 following TACE, prognosis after liver SBRT was poor.
Clinical outcomes in borderline resectable pancreatic cancer: A cohort study.
Authors: Sohal Davendra , Altujjar Mohammad , Tullio Katherine , Abazeed Mohamed , Pelley Robert James , McNamara Michael J. , Estfan Bassam N. , Shapiro Marc A. , Khorana Alok A.
Published: March 2017

494

Background: The management of borderline resectable pancreatic cancer (BRPC) remains unsettled and the predictors of outcome are uncertain. We evaluated the role of neoadjuvant therapy (nRx) and outcomes in patients with BRPC. Methods: We conducted a retrospective cohort study of consecutive patients with BRPC who received nRx and were followed at the Cleveland Clinic. A histopathologic diagnosis of pancreatic carcinoma was required. Tumor anatomy was assessed by contrast-enhanced cross-sectional imaging (CT or MRI), and BRPC was defined as a tumor-vessel wall interface involving one or more of: celiac artery, superior mesenteric artery, common hepatic artery, main portal vein, superior mesenteric vein; making margin-negative resection unlikely. Baseline laparoscopy was performed to rule out occult metastatic disease. Chemotherapy (CT), radiation (RT), surgery details, and pathologic and survival outcomes were evaluated. Hazard ratios (HR) with 95% confidence intervals (CI) and 2-sided p-values are presented. Results: The study population comprised 79 patients from 2009 to 2014. Median age was 64 years; 52% were male; 85% were Caucasian. Pancreatic head/neck were the primary site in 81%; body/tail in 19%. Vascular involvement included arterial in 32 (41%), and venous in 65 (82%) patients. nRx included RT in all patients; 77 (97%) received CT; gemcitabine (n = 50, 63%) was the most common agent. After CT/RT, 36 (46%) patients had unresectable/inoperable disease: 29 (37%) for anatomic reasons, 4 (5%) for physiologic reasons, and 3 (4%) for both. Surgical resection was performed in 43 (54%) patients; 38 (88%) had negative margins; 30 (70%) had negative nodes; 32 (74%) received adjuvant CT. There were no statistically significant predictors of resection. After median follow-up of 27 mths, there have been 45 deaths (57%); median overall survival (mOS) is 23.5 mths (95% CI: 16-28 mths). Only cancer resection was associated with survival (mOS, resected: not reached; mOS, not resected: 12.8 mths; HR: 0.30, 95% CI: 0.16-0.56, p = 0.0002). Conclusions: Surgical resection, if feasible, of BRPC is associated with improved OS. Strategies to improve the odds of resection should be evaluated in prospective studies.
Nab-paclitaxel and gemcitabine in advanced pancreatic cancer: The one-year experience of the National Cancer Institute of Naples.
Authors: Ottaiano Alessandro , Capozzi Monica , De Divitiis Chiara , Von Arx Claudia , Di Girolamo Elena , Nasti Guglielmo , Cavalcanti Ernesta , Tatangelo Fabiana , Romano Giovanni , Tafuto Salvatore
Published: March 2017

497

Background: Pancreas adenocarcinoma is the sixth cause of cancer-related death worldwide and the mortality is increasing in the Western Countries. Recently, the association between nab-paclitaxel (nab-P) and gemcitabine (GEM) has significantly improved progression-free (PFS) and overall survival (OS) compared to GEM monotherapy (PFS: 5.5 vs 3.7 months; OS: 8.5 vs 6.7 months). Methods: Patients affected by metastatic pancreas adenocarcinoma were treated at the Department of Abdominal Oncology of the National Cancer Institute of Naples from July 2015 to July 2016 with nab-P at 125 mg per square meter of body-surface area followed by GEM at 1000 mg per square meter on days 1, 8, and 15 every 4 weeks. Computed tomography (CT) was done every three months of therapy. Toxicity was graded with NCI-CTC criteria v4.0. Objective responses were evaluated with RECIST. Analysis of time-to-progression is only descriptive. Pain was evaluated with a visual analogic scale. Results: Twenty-three patients were treated. Median age was 67 years (range: 45-81); 8 patients were ≥ 70 years old. Performance Status (PS) ECOG was 2 in 8 patients, 1 in 10 and 0 in 5. Twelve patients presented with diffuse hepatic metastases, 4 with carcinosis, 7 with more than one organ involvement. They received a median number of 13 administrations (range: 3-32) of therapy. During therapy Nab-P was reduced at 100 mg per square meter in all patients. The most common G3/G4 adverse events were neutropenia (13.0% G4, 8.6% G3, none was febrile), neuropathy (30.4% G3) and asthenia (G3 17.3%). The disease control rate was 43.4% (PR+SD 10/23); PR was registered in three patients (response rate: 13.0%). Twelve patients progressed and seven dead at September 20. The median time-to-progression was 7.9 months (95% confidence interval 5.8-11.2). After three months of therapy the PS improved in 14 patients as well as pain in 18 patients. Conclusions: We present an experience with nab-P and GEM association in a series with poor PS and highly metastatic disease relatively to the previous randomized study. The schedule is feasible with nab-P at 100 mg per square meter and it achieves a good disease control rate as well as a clinical benefit.
Borderline resectable pancreas adenocarcinoma managed with neoadjuvant chemoradiotherapy: A prospective case series.
Authors: Mandaliya Hiren A. , Martin Jarad , Majid Adeeb , Gani Jon , Sridharan Swetha , Ackland Stephen P. , Kumar Mahesh , Shah Kalpesh , Chen Stanley , Fay Michael , Lynam James F. , Van Der Westhuizen Andre , Mallesara Girish , Philcox Stephen , Bonaventura Tony , Day Fiona
Published: March 2017

499

Background: Borderline resectable pancreas cancers (BRPC) often require vascular reconstruction, have higher rates of operative margin positivity and confer a poor prognosis. In 2014, our high-volume pancreatectomy, gastrointestinal tumor multidisciplinary treatment (GI MDT) group endorsed a consensus anatomical definition of BRPC consistent with NCCN criteria. Diagnostic and staging tests were standardized and a neoadjuvant chemoradiotherapy protocol adopted with the goals to (1) improve R0 resection rate and (2) prevent futile surgery in rapidly progressive disease. Methods: Neoadjuvant chemoradiotherapy (CRT) consisted of 50.4Gy in 28# and concurrent capecitabine 830mg/m2 bd. Pancreatectomy was planned 4-8 weeks later unless repeat imaging showed progressive disease. Comprehensive, prospectively defined data items were collected on all patients (pts) diagnosed with BRPC. Results: Nine pts have been diagnosed with BRPC by the GI MDT. Seven pts received full dose of CRT, one pt progressed during CRT hence stopped early and one pt didn’t receive CRT due to significant deterioration beforehand. CRT was tolerable in all eight pts who received it; there were no dose modifications for toxicity. Post-CRT, three pts underwent curative-intent resection and all are still alive (494, 319 and 172 days post-CRT). One was found to have a solitary liver metastasis during surgery (resected), R1 resection (SMV margin involvement) of T3N1 tumor and is receiving palliative chemotherapy. Two other pts underwent R0 resections (T3N0, T3N1) with histopathologic response to CRT. Four pts showed progressive disease on post-CRT imaging (all local & distant progression) and subsequently received palliative therapy. Median survival (first dose CRT to death) in the 5 CRT pts who have succumbed was 509 days (range 363-577). Conclusions: In this small prospective, unselected cohort the majority of pts diagnosed with BRPC demonstrated disease progression during/after neoadjuvant CRT and did not proceed to surgical resection, underscoring the poor prognosis of this pancreas cancer subset. Neoadjuvant CRT is well tolerated and did not preclude subsequent surgery in those patients with stable disease.
Molecular staging of gastric cancer with a novel panel of prognostic microRNAs.
Authors: Woo Yanghee , Behrendt Carolyn E. , Fong Yuman
Published: March 2017

52

Background: Molecular heterogeneity of gastric cancer discerns patient survival in ways that clinically-based prediction models cannot. To date, individual microRNAs(miRs) expressed by gastric tumors have been associated with survival. We offer a unique molecular-based method of prognosticating the survival of gastric cancer patients with an efficient panel of miRs. Methods: From The Cancer Genome Atlas(TCGA), we studied subjects with gastric adenocarcinoma, who had undergone R0-R1 resection and had data on clinical characteristics, overall survival (OS), and miR expression. Of miRs quantified by TCGA, miRs expressed by at least 15% of subjects’ tumors were evaluated as continuous variables. From 10 replicate samples, each containing 80% of current subjects, miRs were selected using proportional hazards regression adjusted for age with stepwise selection. Cross-validated miRs were retained for the panel if they optimized an accelerated failure-time model of OS using the full cohort. Results: Among subjects (n=254, age 64.7+10.9 years), median OS was 2.38 (95% Confidence Interval: 2.09-3.85) years. Of the 913 evaluable miRs, 10 distinct miRs (miR-373, miR-548ay, miR-659, miR-891a, miR-1243, miR- 4685, miR-6718, miR-6733, miR-6808, and miR-8072) were cross-validated as being prognostic and retained for the age-adjusted panel. Panel-predicted survival estimates, grouped into tertiles, distinguished progressively worse survival at 2 years, OS was 81.0%+5.1% for upper tertile, 61.5%+6.3% for middle tertile, and 29.6%+6.3% for lower tertile. As shown in Table 1, each tertile included subjects at all levels of TNM stage, and tertile was not significantly associated with stage (chi-square test, p=0.26). Conclusions: This unique miRs panel represents a molecular staging system for gastric cancer that has the potential to prognosticate patients' survival more accurately than existing clinical systems can. [Table: see text]
Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406).
Authors: Kopetz Scott , McDonough Shannon L , Morris Van Karlyle , Lenz Heinz-Josef , Magliocco Anthony Martin , Atreya Chloe Evelyn , Diaz Luis A. , Allegra Carmen Joseph , Wang Stephen E. , Lieu Christopher Hanyoung , Eckhardt S. Gail , Semrad Thomas John , Kaberle Kimberly , Guthrie Katherine A , Hochster Howard S.
Published: March 2017

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Background: BRAF V600 mutations are associated with rare objective responses to the mutated BRAF inhibitor vemurafenib in patients with mCRC. Blockade of BRAFV600 by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. In murine models of BRAFV600 mCRC, the combination of irinotecan, cetuximab, and vemurafenib leads to greater anti-tumor activity, as suggested by a prior Phase 1B study. Methods: Patients (pts) with BRAFV600 mutated and extended RAS wild-type mCRC were randomized to irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days) with or without vemurafenib (960 mg PO twice daily). Patients had received 1 or 2 prior regimens, with no prior anti-EGFR agents, although prior irinotecan was allowed. Crossover from the control arm to the experimental arm was allowed after documented progression. The primary endpoint was progression-free survival (PFS, investigator assessed), with 90% power to detect a HR of 0.5, with two-sided type 1 error of 5%. Results: 106 patients were enrolled (54 in the experimental arm) from 12/2014 to 4/2016, with ECOG PS ≤ 1. Median age of 62 years, 59% female, and prior irinotecan therapy in 39%. PFS was improved with the addition of vemurafenib (HR = 0.42, 95% confidence interval [CI] of 0.26 to 0.66, P < 0.001) with median PFS of 4.4 (95% CI: 3.6 – 5.7) months vs 2.0 (95% CI: 1.8 – 2.1). Response rate was 16% vs 4% (P = 0.09), with disease control rate of 67% vs 22% (P < 0.001). Grade 3/4 adverse events higher in the experimental arm included neutropenia (28% vs 7%), anemia (13% vs 0%), and nausea (15% vs 0%). There was no increase in skin toxicity or fatigue. No new safety signal was observed. Approximately 50% of patients in the control aim crossed over at the time of progression. Overall survival and efficacy at cross-over data remain immature. Conclusions: The addition of vemurafenib to the combination of cetuximab and irinotecan resulted in a prolongation of progression-free survival and a higher disease control rate, indicating that simultaneous EGFR and BRAF inhibition is effective in BRAFV600 mutated CRC. Clinical trial information: NCT02164916.
The International Watch & Wait database (IWWD) for rectal cancer: An update.
Authors: Valk Maxime van der ,   International Watch and Wait Database Consortium
Published: March 2017

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Background: In 2014 the IWWD was established by EURECCA and the Champalimaud Foundation. The main goal of this database is to collect all available data to expand knowledge on the benefits, risks and oncological safety of organ preserving strategies in rectal cancer. In April 2015 the database was opened for data registration. Methods: An international multicentre observational study. Data was collected by participating centres and stored in a highly secured NEN7510 certified and encrypted research data server. Each centre always retains full ownership of their data. Results: In August 2016 the database included 775 patients from 11 countries and 35 participating institutes. 90% of all patients were included because of a clinical complete response (n = 679). All other reasons for a watch-and-wait regimen were excluded for the present analyses. As shown in table 1, imaging modalities used to assess response after induction therapy were variable. Induction treatment consisted of chemo-radiotherapy in 90% of cases. Median follow-up time is 2.6 years (range 0-24 years). Local regrowth occurred in 25% (n = 167) of all patients, of which 84% in the first 2 years of follow-up. A local regrowth was located endoluminal in 96% (n = 161) and in the loco-regional lymph nodes in 4% (n = 7). Distant metastasis occurred in 7% (n = 49). The overall 3 year-survival of all patients was 91% and for patients with a local regrowth this was 87%. Conclusions: This is the largest series of patients with rectal cancer in which surgery was omitted after induction therapy. These data illustrate differences in induction therapy as well as imaging strategies and provide some crude outcome data. Further data collection on the Watch-and-Wait strategy for rectal cancer is needed to increase knowledge on oncological safety of omitting surgery. This may contribute to international consensus on staging, treatment and surveillance guidelines in rectal cancer care. [Table: see text]
Expression of COX-2 and 15-PGDH in adenomas removed during pretreatment colonoscopy to predict chemopreventive efficacy of the selective COX-2 inhibitor, celecoxib.
Authors: Wang Jiping , Cho Nancy L , Zauber Ann G. , Hsu Meier , Dawson Dawn , Srivastava Amitabh , Mitchell-Richards Kisha , Markowitz Sanford D. , Bertagnolli Monica M.
Published: March 2017

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Background: The APC trial showed that patients at high risk for colorectal adenoma development experienced a 33-45% reduction in post-polypectomy adenoma detection when treated with the selective cyclooxygenase-2 (cox-2) inhibitor, celecoxib. Unfortunately, this study also found a small increased risk of cardiovascular toxicity among celecoxib users, preventing broad use of this agent for chemoprevention. Celecoxib inhibits expression of prostaglandin E2 (PGE2), an inflammatory mediator produced by fatty acid metabolism via cyclooxygenases, and degraded through the activity of 15-prostaglandin dehydrogenase (15-PGDH). Methods: Adenomas collected from APC trial participants prior to treatment were examined using immunohistochemistry (IHC) to assess expression of cox-2 (high vs. low) and 15-PGDH (present vs. absent). A combined variable to estimate tumor PGE2 levels identified cases as PGE2 low (Cox-2 low/15-PGDH present) or PGE2 high (Cox-2 high/15-PGDH present; Cox-2 high/15-PGDH absent; or Cox-2 low/15-PGDH absent). Mantel–Cox test was used to evaluate whether markers of PGE2 expression in these adenomas predicted benefit from celecoxib treatment for the primary study outcome of adenoma detection. Results: Biomarker determinations were achieved for 1295 cases, or 71% of patients with available outcome data. Patients whose baseline adenomas demonstrated elevated Cox-2 achieved the greatest overall reduction in adenoma risk with celecoxib treatment (RR 0.37; p = 0.0001). This risk reduction was less significant in the low Cox-2 category (RR 0.64). Patients with low estimated tumor PGE2 did not benefit from celecoxib for adenoma prevention (RR 0.95; p = 0.83). This is compared to a 41% reduction in adenoma detection with celecoxib treatment for patients in the high PGE2 category (RR 0.59; p < 0.0001). Conclusions: IHC to determine expression of target enzymes in pre-malignant adenomas provides significant prognostic and predictive information in patients treated with celecoxib for prevention of colorectal adenomas.
Effect of thymidine kinase 1 expression on prognosis and treatment outcomes in refractory metastatic colorectal cancer: Results from two randomized studies of TAS-102 versus a placebo.
Authors: Yoshino Takayuki , Shinozaki Eiji , Yamazaki Kentaro , Komatsu Yoshito , Nishina Tomohiro , Baba Hideo , Tsuji Akihito , Tsuji Yasushi , Yamaguchi Kensei , Sugimoto Naotoshi , Denda Tadamichi , Muro Kei , Takayama Tetsuji , Esaki Taito , Hamamoto Yasuo , Moriwaki Toshikazu , Shimada Yasuhiro , Goto Masahiro , Tanase Takanori , Ohtsu Atsushi
Published: March 2017

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Background: TAS-102 is an oral nucleoside antitumor agent, comprising trifluridine (FTD) and tipiracil. FTD is incorporated into DNA after phosphorylation by thymidine kinase 1 (TK1). This study aimed to investigate the association between TK1 expression and TAS-102 efficacy in refractory metastatic colorectal cancer (mCRC) patients (pts). Methods: Data from two randomized phase 2 and phase 3 studies of mCRC pts refractory to standard therapies were analyzed for treatment outcomes in relation to TK1 expression. Expression was measured using immunohistochemistry, and staining was classified according to intensity and scored 0, 1+, 2+, or 3+. Occupancy rates of the areas scored 2+ and 3+ in tumor cells were calculated in 5% intervals, and divided into two groups (high or low TK1) at each cut-off point. Results: TK1 expression was evaluated in 329 pts. Baseline characteristics and treatment outcomes were comparable between the TK1-refined and intention-to-treat populations. Pts with high TK1 expression who received the placebo had a poor prognosis, while those receiving TAS-102 showed a significant improvement in overall survival (OS) at cut-off points of 5% to 15%, and 30%. Conclusions: High TK1 expression could be a poor prognostic factor and a predictive factor of TAS-102 efficacy in mCRC pts. [Table: see text]
Phase II study of conversion therapy using S1/paclitaxel chemotherapy plus apatinib in unresectable gastric cancer (Ahead-G325 trial).
Authors: Cheng Xiangdong , Xu Zhiyuan , Du Yian , Hu Ping , Yu Guofa , Hu Conggang
Published: March 2017

53

Background: Occasionally, an initially unresectable gastric cancer (GC) can be converted to a resectable one by chemotherapy. Combination with inhibitors against VEGFR-2 can lead to a clinical improvement. We aimed to investigate the efficacy and safety of S1/paclitaxel chemotherapy plus apatinib, a novel inhibitor of VEGFR-2, in the conversion therapy of unresectable GC. Methods: This was a multicentre, single-arm, open-label, phase II design. Eligible patients (pts) were aged 20-70 years and had histologically proven unresectable, HER-2 negative, advanced GC with a single non-curable factor confined to either the liver (H1), peritoneum (P1), or para-aortic lymph nodes (16a1/b2). The ECOG performance status was 0-2. No prior radiotherapy, chemotherapy, target therapy or immunotherapy was allowed. Patients received 2 cycles of S1/paclitaxel chemotherapy (S1: 60 mg, oral, bid for 2 weeks followed by a drug-free interval of 1 week; paclitaxel: 150 mg/m2, iv, 3h, on day 1) plus apatinib (500 mg, oral, qd) and 1 cycle of S1/paclitaxel chemotherapy prior to radical surgery. Three cycles of adjuvant chemotherapy (S1 and apatinib) were given 4-6 weeks after surgery. Primary endpoint was R0 resection rate. Thirty-three pts were enrolled. Results: Among the 28 pts eligible for preoperative efficacy evaluation, 21 achieved partial response (PR), 5 had stable disease (SD), and 2 had progressive disease (PD), resulting in an overall response rate of 75.0% and a disease control rate of 92.9%. Of the 21 pts with PR, 3 refused consents for surgery and 18 achieved R0 resection. The incidence of adverse events (AEs) was 73.9%. The common hematologic AEs were neutropenia (60.9%), leukopenia (52.2%) and hemoglobin decrease (47.8%), and nonhematologic AEs included hyperbilirubinemia (56.5%), hand-foot syndrome (34.8%), oral mucositis (30.4%), fatigue (30.4%), proteinuria (21.7%) and hypocalcemia (21.7%). There was no severe surgery-related complication. Conclusions: Combination of apatinib with S1/paclitaxel chemotherapy shows clinical benefits in unresectable GC, with acceptable safety profile. Clinical trial information: NCT02529878.
Do patients and doctors have the same conversation about colorectal cancer screening?
Authors: Talcott James Austin , Bezuhly Maureen , Herzstein Jessica , Osborne Michael P. , Cassano Kelly , Chadha Manjeet
Published: March 2017

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Background: Participant characteristics affect shared decision making. In a randomized trial of physician (MD) educational interventions to improve cancer screening guideline compliance, we studied patient (PT) and MD recall of discussions and how PT characteristics affected recall. We report the first results for colorectal cancer screening. Methods: In a cluster-randomized trial of educational supports for MDs, we are enrolling an age- (30-89 years) and sex-stratified sample of 216 PTs who underwent a physical examination at two urban hospitals, 18 for each of 12 primary care MDs. Screening guideline formatting (color-coding) and academic detailing were randomly assigned to MDs in a 2x2 design. Immediate post-encounter surveys recorded PT and MD recall of screening discussions and recommendations. Results: We report on the first 174 participants. They were diverse (63% white) and well educated (77% college degree). When MDs reported a colorectal screening discussion, 20% of PTs did not, and MDs had similar disagreement when PTs reported the discussion. Greater disagreement occurred on the MD recommendation: 15% of PTs disagreed when the MD reported screening was recommended, and 33% of MDs disagreed when their patients reported they had recommended it. Agreement between PTs and MDs on whether screening was recommended was fair (kappa = 0.33), and there was no agreement for PTs over 70 years (kappa = -0.15). When PTs under 50 or 75 and older differed from their MDs on screening recommendations, it was for screening not against (8 vs. 2). PTs reported more elements of shared decision making than MDs (data not shown). Conclusions: In a highly educated population of PTs and MDs surveyed immediately after their encounter, reports of whether colorectal screening was discussed, the shared decision making elements and the MD recommendation had important discrepancies, especially for older PTs. Clinical trial information: NCT02430948.