bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, double-blind, multicenter phase III study evaluating paclitaxel with and without RAD001 in patients with gastric cancer who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC).
Authors: Al-Batran Salah-Eddin , Riera-Knorrenschild Jorge , Pauligk Claudia , Goetze Thorsten Oliver , Hegewisch-Becker Susanna , Seraphin Jörg , Thuss-Patience Peter C. , Kopp Hans-Georg , Dechow Tobias Nicolaas , Vogel Arndt , Luley Kim Barbara , Pink Daniel , Stahl Michael , Kullmann Frank , Hebart Holger Frithjof , Siveke Jens T. , Egger Matthias , Homann Nils , Probst Stephan , Lorenzen Sylvie
Published: March 2017

4

Background: There is a need for effective treatments in the second- or further line setting in advanced gastric cancer, especially for new agents. In the current trial we evaluated paclitaxel with RAD001 (everolimus) in patients with gastric carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen. Methods: This is a randomized, double-blind, multi-center phase III study. Patients with gastric carcinoma or adenocarcinoma of the esophagogastric junction which has progressed after treatment with a fluoropyrimidine/platinum-containing regimen were randomly assigned to receive Paclitaxel (80 mg/m2) on day 1, 8 and 15 plus placebo (arm A) or RAD001 (10mg daily, arm B) d1-d28, repeated every 28 days as 2nd, 3rd or 4thline therapy. Primary end point was overall survival (OS), secondary endpoints were best overall response, disease control rate, progression free survival (PFS) and toxicity. Results: 300 patients (median age: 62 years; median lines prior therapy: 2) were randomly assigned (Arm A, 150, Arm B, 150). Response rate (complete and partial response) was 8.0% (95%CI: 4.2%-13.6%) in the paclitaxel/RAD001 arm and 7.3% (95% CI: 3.7%-12.7%) in the paclitaxel/placebo arm (p = 0.4).There was no significant difference in median PFS (placebo, 2.07 vs. RAD001, 2.2 months, HR 0.88, p = 0.3) and median OS (placebo, 5.1 vs. RAD001, 6.1 months, HR 0.92, p = 0.48). Combination of paclitaxel and RAD001 was tolerable, but the placebo arm was associated with significantly less (any grade) mucositis (15.8% vs. 37.2%), fever (10.3% vs 20.7%), leukopenia (11.6% vs. 21.4%), neutropenia (13.0% vs. 27.6%) and thrombocytopenia (2.1% vs 14.5%). Conclusions: The addition of RAD001 to paclitaxel/RAD001 did not significantly improve outcomes in pretreated metastatic gastric or esophagogastric junction adenocarcinoma. Additional biomarker studies are planned to look for subgroups that may have a benefit. Clinical trial information: NCT01248403.
Pancreatic neuroendocrine tumors: A population-based analysis of epidemiology and outcomes.
Authors: Alsidawi Samer , Westin Gustavo Figueiredo Marcondes , Hobday Timothy J. , Halfdanarson Thorvardur Ragnar
Published: March 2017

401

Background: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms comprising less than 2% of pancreatic tumors. Outcomes of PNETs vary by stage, grade, and clinical presentation. New therapies may have improved outcomes. We present an analysis of the epidemiology and prognosis of patients (pts) with PNETs evaluating a more recent period than previously reported. Methods: Using data from the SEER registry, we identified adults with PNETs between 2000 and 2013. Cases were identified using a combination of ICD-O-3 site and histology codes. The JMP and SEER*STAT 8.3.2 were used for statistical analysis. Overall survival (OS) was analyzed using the Kaplan–Meier method. The prognostic effect of variables was studied using multivariate Cox proportional hazards models. Results: We identified 5993 pts with PNETs. Over the study duration, there was an increase in the annual incidence from 0.3 to 1.2 per 100.000. This was largely explained by the increase in number of pts with localized disease. The OS for the entire cohort was 54 months (95%; CI 50-58) and 5-year OS rates in localized, locally advanced and metastatic disease were 81.7%, 62% and 26% respectively. New therapies were increasingly implemented after 2008 such as sunitinib, everolimus and capecitabine/temozolomide. OS was better for pts diagnosed after 2008 (HR 0.73; 95% CI, 0.69-0.79; P < 0.0001) and this remained significant after excluding pts with localized disease (HR 0.85; 95% CI, 0.78-0.92; P = 0.0002). Factors found to favorably affect OS included younger age, female sex, early stage, low grade, and surgery. In metastatic disease, pts who had surgery had better OS and this was significant after adjusting for possible confounders (HR 0.36; 95% CI, 0.3-0.45). Conclusions: In this large population-based study, we saw an increase in the annual incidence of PNETs mainly due to an increased number of pts with localized disease. The OS has improved over the study duration likely due to both stage migration and new therapies used in advanced disease. Younger age, female gender, low histologic grade, early stage and surgery were found to be factors that favorably affected survival. Surgery was found to be a predictor of better outcomes in metastatic disease.
A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Wang-Gillam Andrea , Du Lingling , Teague Andrea S. , Suresh Rama , Lim Kian-Huat , Amin Manik A. , Pedersen Katrina , Tan Benjamin R. , Huffman Jess , Lockhart Albert C.
Published: March 2017

410

Background: Recent advances in front-line therapy have improved survival in patients with advanced PDAC. A fluorouracil-based regimen is recommended for patients who progress on a gemcitabine-based therapy. Tosedostat is an oral aminopeptidase inhibitor that disrupts the cleavage of amino acids from peptides downstream of proteasomal degradation. It prevents the recycling of free amino acids, leads to intracellular depletion of amino acids, and triggers an amino acid deprivation response that subsequently results in apoptosis. Because PDAC cells frequently upregulate expression of these aminopeptidases, tosedostat offers therapeutic promise, particularly in combination with fluoropyrimidines. Methods: This is a single institution phase I/II trial to evaluate the safety and toxicity of tosedostat plus capecitabine in patients with metastatic PDAC progressed on a gemcitabine-based therapy. The phase I portion is being conducted in a dose de-escalation fashion, with two dose levels of tosedostat (120 mg or 60 mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one out of 6 patients in the tosedostat (120 mg) cohort experience a dose limiting toxicity (DLT), then 6 more will be enrolled to the tosedostat (60 mg) cohort. The primary objective of the phase I portion is to determine the optimal phase II dose. The primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives include the overall response rate, overall survival and CA 19-9 response. To avoid futility, interim analysis is planned after 10 evaluable patients enrolled. Results: Up to date, a total of 11 patients have been enrolled in the study, and 10 patients are evaluable. No DLT have been observed. Tosedostat at a dose of 120 mg with capecitabine is extremely well tolerated. Prolonged stable disease has been observed in 4 (40%) patients with a time on treatment of 10 months, 7.5 months, 5.5 months and 4 months, and 3 of the 4 patients remain on the trial. Conclusions: The combination of tosedostat and capecitabine is a well-tolerated regimen with impressive clinical activity in the subset of patients studied thus far. Clinical trial information: NCT02352831.
Health care costs and treatment patterns among metastatic pancreatic cancer (MPC) patients (pts) initiating first-line (1L) on nab-paclitaxel/gemcitabine (nab-P+G) or FOLFIRINOX (FFX).
Authors: McBride Ali , Bonafede Machaon , Cai Qian , Princic Nicole , Tran Oth , Pelletier Corey , Patel Manish
Published: March 2017

415

Background: The economic burden of MPC is substantial while treatment options are limited. This study aimed to compare healthcare costs and treatment patterns in MPC patients who initiated nab-P+G or FFX in a large insured US population. Methods: A retrospective study was conducted using the Truven Health MarketScan administrative claims databases. Adults who had ≥2 claims for pancreatic cancer, ≥1 claim with a secondary malignancy, completed ≥ 1 cycle of nab-P+G or FFX as 1L during 1/1/2013 and 3/31/2015, and had continuous enrollment in health plans for ≥6 months prior to and 3 months following the start of 1L were selected. Total healthcare costs and MPC-related treatment costs were measured per patient per month (PPPM) during 1L. Kaplan-Meier curve was used to describe time to treatment discontinuation (TTD) between groups. Results: 550 MPC patients met selection criteria ( nab-P+G, n=294; FFX, n=256). Patients on nab-P+G were significantly older (mean age: 63.6 vs 58.8 years; p<0.001) and had higher counts of unique diagnostic categories (21.2 vs 19.0, p<0.001) vs FFX. There was no significant difference in median TTD of 1L (3.8 vs 4 months; log-rank test p=0.602) between nab-P+G and FFX. Compared with FFX, nab-P+G pts had higher chemotherapy drug costs but incurred lower total healthcare, supportive care, and treatment administration costs (Table). Conclusions: This claims analysis suggests patients treated with FFX had similar treatment duration and higher total healthcare costs driven by treatment administration and supportive care. Table: Mean Healthcare and Select MPC-related Treatment Costs During 1L (PPPM) [Table: see text]
Escalated dose somatostatin analogues (SSAs) in management of neuroendocrine tumors (NETs): A systematic review.
Authors: Chan David , Ferone Diego , Albertelli Manuela , Segelov Eva , Singh Simron
Published: March 2017

422

Background: SSAs are effective in controlling NET symptoms and more recently have been shown to have anti-proliferative properties. PROMID and CLARINET have established “standard” doses of octreotide and lanreotide, but dose escalation is often employed both for symptom relief and tumor control. Methods: We searched MEDLINE, EMBASE, Cochrane CENTRAL and abstracts of major conferences. Studies investigating patients treated with doses of octreotide higher than 30mg/28d or lanreotide higher than 120mg/28d were eligible for inclusion. Data extracted included patient population, interventions and prior SSA use. The primary endpoint was disease control rate; secondary endpoints included response rate, symptom control, biochemical response, progression-free survival and toxicity. Results: 19 studies (12 prospective; 981 patients) were identified from 609 search results. Of the 13 studies that mandated prior treatment, the reasons for dose escalation were tumor progression (5), symptoms (3), either (2) and not listed (3). SSAs used were octreotide LAR (10), lanreotide ATG (1), short-acting octreotide (3), short-acting lanreotide (3), and mixtures (2). Significant heterogeneity existed in dosing schedules as well as reporting of efficacy data. Disease control rates ranged from 40-100% (pooled rate 248/396) with response rates from 0-42% (pooled rate 24/396). Dose escalation was associated with improvement in carcinoid symptoms in at least 50% of patients. Biochemical response was variably defined but reported rates ranged from 33% to 100% (pooled rate 55/78). Median PFS ranged from 6 months to 30 months. Dose escalation was generally well tolerated with side effect profile and frequency comparable to normal dose SSA. Conclusions: Escalated dose SSA is well tolerated and results in significant rates of disease control and symptomatic improvement. Compared to a prior systematic review (Broder WJG 2015), this review includes studies of lanreotide, includes 721 additional patients, and restricts inclusion to clinical studies. Prospective randomized trials of escalated SSA therapy are warranted.
Sequential treatment in patients with metastatic pancreatic neuroendocrine tumors after progression on first-line therapy.
Authors: Tsang Erica S , Speers Caroline , Cheung Winson Y. , Kennecke Hagen F.
Published: March 2017

426

Background: Pancreatic neuroendocrine tumors (pNETs) are rare malignancies with an age-adjusted annual incidence of 0.32/100,000, with metastatic disease at diagnosis occurring in 64%. Patients with advanced disease are considered for surgery/ablative therapy (SG) or systemic therapy (ST), including chemo- and targeted therapy, somatostatin analogues, and peptide receptor radiotherapy (PRRT). Optimal sequence of therapy is unknown and we sought to characterize sequential treatment patterns in patients with metastatic pNETs and overall survival (OS). Methods: Patients diagnosed with metastatic pNETs referred to the BC Cancer Agency between 2000-2013 and received more than one line of therapy were reviewed. Results: Of 151 patients, 81 received one line of therapy while 45 patients received >1 treatment. Median age was 55.1 years (IQR 47.4-64.8) and 23 (51%) were male. Sites of metastases included liver (n=33), lymph nodes (n=5), lung (n=1), peritoneum (n=2), and bone (n=5). Median time to start of therapy was 1.5 months (IQR 0.4-3.0). First-line SG was associated with increased OS compared to first-line ST (88.9 vs. 38.2 months; p=0.004). There was no difference in OS between patients receiving second-line SG or ST, measured from start of second-line therapy. Second-line chemotherapy was associated with decreased PFS compared to alternate treatments, both after first-line chemotherapy (0.7 vs. 5.8 months; p=0.002) and after other treatments (4.8 vs. 16.7 months; p=0.002). Median length of follow-up was 48.3 months. Conclusions: We present the sequential treatment patterns of patients with metastatic pNETs. Results confirm the primary role of SG, reserving ST for secondary therapy. Upon progression, choice of second-line therapy was not prognostic and may be chosen based on disease and patient characteristics. [Table: see text]
A UGT1A1 genotype-guided dosing study of modified FOLFIRINOX (mFOLFIRINOX) in previously untreated patients (pts) with advanced gastrointestinal malignancies.
Authors: Sharma Manish , Catenacci Daniel V.T. , Karrison Theodore , Ganjoo Anubha , Allen Kenisha , Suh Grace K. , Phillips Brooke Elizabeth , Marsh Robert de Wilton , Kozloff Mark , Polite Blase N. , Kindler Hedy L.
Published: March 2017

427

Background: FOLFIRINOX improves survival compared with gemcitabine in advanced pancreatic cancer (PC), but with significant toxicity (Conroy, NEJM 2011). UGT1A1 clears SN-38, the active metabolite of irinotecan (IRI); UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. We hypothesized that dosing mFOLFIRINOX based on UGT1A1 genotype would improve tolerability. The primary objective of this study (NCT01643499) was to determine whether genotype-guided dosing of IRI in mFOLFIRINOX is tolerable. A secondary objective was to describe objective response rates (ORR) in PC and biliary tract cancers (BTC). Methods: mFOLFIRINOX was given every 14 days. CT scans were obtained every 8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 pts received initial IRI doses of 180, 135, and 90 mg/m2, respectively. 5-FU dose was 2400 mg/m2 over 46 hours (no bolus); leucovorin 400 mg/m2; oxaliplatin 85 mg/m2. In cohort 1 (tolerability cohort by genotype), prophylactic pegfilgrastim was not allowed in cycle 1 (28 days) unless clinically indicated. In cohort 2 (expansion tolerability cohort in PC and BTC), prophylactic pegfilgrastim was given. DLT during cycle 1 was defined as Grade (Gr) 3/4 neutropenia with fever; Gr 4 neutropenia lasting ≥ 5 days; Gr 4 thrombocytopenia, or Gr 3/4 non-hematologic toxicity despite optimal medical management. Doses were tolerable if the DLT rate during cycle 1 was ≤ 33% with 70-80% statistical confidence. Results: In cohort 1, DLTs were observed in 2/15 (13%) *1/*1 pts; 2/16 (13%) *1/*28 pts; 3/9 (33%) *28/*28 pts. In cohort 2, DLTs were observed in 6/19 (32%) PC pts and 4/19 (21%) BTC pts. DLTs in cohort 1 (some pts with multiple): neutropenic fever (5); Gr 3 fatigue (4); Gr 3 diarrhea (2). DLTs in cohort 2: Gr 3 fatigue (3); Gr 3 diarrhea (3); Gr 3 nausea/vomiting (2); Gr 5 sepsis without neutropenia (1); Gr 5 multi-organ failure (1); neutropenic fever (1); Gr 3 anorexia (1). To date, ORR is 13/39 (33%) in PC and 6/28 (21%) in BTC. Conclusions: mFOLFIRINOX is not tolerable in PC and BTC, even with UGT1A1 genotype-guided dosing of IRI and prophylactic pegfilgrastim. More needs to be done to improve the tolerability of this regimen. Clinical trial information: NCT01643499.
Short-term outcomes of laparoscopic D2 gastrectomy with complete mesogastrium excision (D2+CME) for advanced gastric cancer.
Authors: Xie Daxing , Gong Jianping
Published: March 2017

43

Background: D2 lymphadenectomy has been widely accepted as a standard procedure of surgical treatment for local advanced gastric cancer [1,2]. However, neither the dissection boundary nor the extent of the excision for perigastric soft tissues has been described [3-7]. Our previous researches demonstrate the existence of disseminated cancer cells in the mesogastrium [8, 9] and present an understandable mesogastrium model for gastrectomy [10]. Hence, the D2 lymphadenectomy plus complete mesogastrium excision (D2+CME) is firstly proposed in this study, aiming to assess the safety, feasibility and corresponding short-term surgical outcomes. Methods: All of these patients underwent laparoscopy assisted D2+CME radical gastrectomy with a curative R0 resection, and all the operation was performed by Prof. Jianping Gong, chief of GI surgery of Tongji Hospital, Huazhong University of Science and Technology. All participants provided informed written consent to participate in the study. This study was approved by the Tongji Hospital Ethics Committee. The standard surgical procedures in the video are described as follows. Reconstruction of the alimentary tract was done by extracorporeal anastomosis. Standard recovery protocols were followed in postoperative treatments. Results: 68 patients between September 2014 and March 2016 have been recruited with informed consent and underwent laparoscopic D2+CME by a single surgeon. The mean number of retrieved regional lymph nodes was 33.62±11.40 (ranges 14-55). The mean volume of blood loss was 12.44±22.89 ml (ranges 5-100). The mean laparoscopic surgery time was 127.82±17.63 mins (ranges 110-165). The mean hospitalization time was 16.5±3.3 days (ranges 8-28). No operative complication was observed during the hospitalization. Conclusions: The anatomical boundary of mesogastrium is well described and dissected within D2+CME surgical process. It proves to be safely feasible and repeatable with less blood lost, qualified lymph nodes, retrieval results, and other improved short-term surgical outcomes in advanced gastric cancer. Meanwhile, potential disseminated cancer cells fall into the mesogastrium can be eradicated by D2+CME. Clinical trial information: NCT01978444.
Identification of educational gaps among oncologists who treat patients with pancreatic cancer.
Authors: Barnes Justin A , Ellis Melissa L , Hwang Sharon , Musher Benjamin Leon , Emarine Joan , Merwin Patti A. , Salinas Gregory D
Published: March 2017

431

Background: Pancreatic ductal adenocarcinoma (PDA) is the fourth-most common cause of cancer-related death in the United States, with only 7.7% of patients surviving beyond 5 years. Given the poor outcomes associated with PDA, it is imperative that patients with PDA receive optimal care. Continuing medical education (CME) offers an effective means to improve physician performance, and CME programs are most effective when they address areas of greatest need. This study was conducted to identify and quantify the educational gaps in PDA management that can potentially be addressed with CME. Methods: A case-vignette survey instrument was developed to assess physicians’ practices related to PDA. Case vignettes are a validated means of assessing healthcare provider practice patterns. The survey instrument included three patient cases: 1) A 50 year-old man with resectable PDA; 2) a 75 year-old man with locally advanced, unresectable PDA; and 3) a 55 year-old woman with metastatic PDA. Each case was followed by a series of questions designed to assess medical decision-making, physician/patient communication, and barriers to optimal practice. Results: Survey responses were collected from 150 US oncologists in July 2016 (19% at academic centers). Several key educational gaps were identified. For Case 1, 44% of oncologists did not select an evidence-based adjuvant chemotherapy regimen from a list of options. For Case 2, in which the patient had developed metastases and neuropathy after first-line therapy, 57% of respondents did not select an evidence-based second-line option, and 35% selected a regimen with oxaliplatin. For Case 3, only 18% of oncologists recommended an initial diagnostic evaluation that included a biopsy, chest imaging, and liver function tests. Finally, for all 3 cases, little emphasis was placed on enrolling patients in clinical trials. Conclusions: This study identified appreciable discrepancies between respondents’ recommendations and standard evidence-based guidelines for treating all stages of PDA. Well-designed CME programs may help bridge the educational gaps among practicing oncologists and ultimately improve adherence to national guidelines.
Establishment of disease-specific graded prognostic assessment for patients with hepatocellular carcinoma and spinal metastasis.
Authors: Rim Chai Hong , Choi Chiwhan , Choi Jinhyun , Seong Jinsil
Published: March 2017

433

Background: Spinal metastasis (SM) of hepatocellular carcinoma (HCC) is a crucial clinical problem. It shows heterogenous length of survival suggesting a need for predicting prognosis. In this study, we aimed to develop and propose a graded prognostic assessment of SM of HCC (HCC-SM GPA). Methods: We previously reported the outcomes of 192 HCC patients with SM who received radiotherapy from April 1992 to February 2012. Prognostic factors with significant effects on survival in that study were used to establish the HCC-SM GPA. Validation was performed using an independent cohort of 63 patients recruited from September 2011 to March 2016. Results: We developed HCC-SM GPA using the following factors: Eastern Cooperative Oncology Group performance status ( < 2: 0, > 3: 1 point), controlled primary HCC (Yes: 0, No: 2 points), and extrahepatic metastases other than bone (No: 0, Yes: 1 points). Patients were stratified into low (GPA = 0), intermediate (GPA = 1–2), and high risk (GPA = 3–4). When applied to the validation cohort, the HCC-SM GPA determined median survival durations of 13.6, 4.8, and 2.6 months and 1-year overall survival rates of 58.3%, 8.9%, and 7.3% for the low-, intermediate-, and high-risk patient groups, respectively (p < 0.001). Conclusions: Our newly proposed HCC-SM GPA successfully predicted survival outcome. This index might be a useful tool for making treatment decision.
The effects of resident participation on patient morbidity and mortality in major gastrointestinal oncologic surgery.
Authors: Bellini Geoffrey , Teng Annabelle , Lee David Y , Rose Keith
Published: March 2017

437

Background: While the effects of resident participation have been documented in various studies, there has yet to be a comprehensive study analyzing resident participation in overall gastrointestinal (GI) oncologic surgery. The aim of this study was to compare outcomes in major GI oncologic cases performed by an attending alone and those performed by an attending and resident. Methods: The ACS-NSQIP database from 2005-12 was utilized to study major (GI) operations (esophagectomy, gastrectomy, pancreatectomy, enterectomy, hepatectomy, and colectomy/proctectomy) in patients with an ICD-9 cancer diagnosis. Major complications and 30-day mortality were then compared in those patients who underwent surgery with an attending alone (AA) to those patients who underwent surgery with an attending and resident (AR). Results: A total of 64,637 patients met criteria for the study; AR n = 48,022 and AA n = 16,615. In 76.6% of AR cases, the resident assistance was classified as senior level PGY-4 or higher. On average, operative time was significantly increased in AR cases compared to AA cases (228 ± 130 vs 163 ± 104 min, p < 0.001). On multivariate analysis, AR cases were more likely to develop superficial incisional infection (OR 1.3, CI 95% 1.2-1.4, p < 0.001) and urinary tract infection (OR 1.2, CI 95%, 1.1-1.4, p < 0.001) compared to AA cases. However, on multivariate analysis, resident participation was associated with less likelihood of returning to the operating room (OR 0.9, 95% CI 0.8-0.9, p < 0.001) and lower mortality (OR 0.7, CI 95% 0.6-0.8, p < 0.001). Conclusions: The majority of major GI oncologic operations in the NSQIP database are performed by an attending with the assistance of a senior level resident. This may be due to the complex nature of GI oncologic operation. Potentially, operative time in cases with resident participation may be increased by teaching or by the complex nature of the operation due to the referral bias to teaching centers. However, even with potentially more complex operations, there was less mortality in cases performed by a resident and an attending.
Incidence and prognostic significance of extramural venous invasion in T3-4 esophageal cancer.
Authors: Faiz Zohra , Huijgen Lotte , Alqethami Hanadi , Kats-Ugurlu Gursah , Plukker John Theodorus
Published: March 2017

44

Background: Extra mural venous invasion (EMVI) is known as an adverse prognostic indicator of survival and an important predictor of systemic recurrences in colorectal carcinoma. However, the incidence and significance of EMVI in esophageal cancer (EC) have not been studied well. Aim: To estimate the incidence and the prognostic significance of EMVI in pathological stage T3-4 EC resection specimens without neoadjuvant chemoradiotherapy (nCRT) Methods: From a prospective maintained database we retrospectively review the resected specimens of patients with an EC. For adequate EMVI assessment we only included patients without nCRT and excluded patients without previous malignancies and patients with cardia/gastroesophageal junction tumors. A total of 76 patients were included between 2000 and 2012. EMVI was assessed on haematoxylin and eosin slides and for confirmation additional Elastica van Gieson staining was performed. Disease free survival was analyzed using a multivariable logistic regression and Kaplan-Meier method. Results: Evidence of EMVI was found in 18 patients (23.7%). The incidence of EMVI was significantly higher in squamous cell carcinomas (p < 0.05) and among tumors located in the mid-esophagus (p < 0.05). In the univariate analysis, pathological N- stage (HR 3.6 95%Cl: 1.5-8.5; p = 0.004) and positive circumferential resection margin (CRM) (HR 2.3 95% Cl: 1.2-4.5 p = 0.015) were independent prognostic factors. By stepwise multivariate Cox regression analysis, pathological tumor length (HR 2.5 95%Cl: 1.0-6.5 p = 0.05), pathological N- stage (HR 2.7 95%Cl: 1.3-6.2 p = 0.008), positive CRM (HR 2.3 95% Cl: 1.2-4.5 p = 0.009) and EMVI (HR 2.2 95% Cl: 1.0-4.5 p = 0.04) were shown to be independent prognostic factors for disease free survival. Conclusions: A search for EMVI may provide additional prognostic information in esophageal cancer, especially in squamous cell carcinoma.
Should functional renal scans be obtained prior to upper abdominal radiation for pancreatic cancer?
Authors: Blitzer Grace , Tsai Susan , Aldakkak Mohammed , Hellman Robert , Evans Douglas B. , Christians Kathleen K. , George Ben , Ritch Paul S. , Hall William Adrian , Erickson Beth
Published: March 2017

442

Background: Upper abdominal irradiation for pancreas cancer is given in close proximity to the radiation sensitive kidneys. While contemporary 3D and intensity modulated radiation therapy (IMRT) can decrease the total dose of radiation delivered to the kidneys; these plans may potentially exceed the established kidney dose constraints, especially if one kidney is providing most of the renal function. Less than 10% of the general population is estimated to have asymmetrical kidney function. Functional kidney scans using MAG3 clearance can give information about the contribution of each kidney to total renal function. We sought to determine if functional renal scans should be used to identify patients with occult renal dysfunction. Methods: Patients with resectable and borderline resectable pancreatic cancer who received abdominal irradiation therapy and had pre-radiation functional renal scans between 2009-2015 were studied. Asymmetrical kidney function was defined as a difference between the two kidneys that was ≥ 40%/60% on a functional renal scan. Serum studies (BUN, Cr, GFR) were routinely obtained pre-simulation. Restaging abdominal CT scans prior to radiation were screened for disparity in kidney size. Medical history that suggested decreased renal function was also collected. Results: Of the 205 patients examined, 24 (11.7%) had asymmetrical kidney function identified on pre-radiation functional renal scans. Of the patients with asymmetrical kidney function, 4 (2%) had a 75%/25% split or greater and 20 (9.7%) had kidney function between 60%/40% and 75%/25%. Elevated Cr or BUN, a GFR < 60, or a past medical history suggesting abnormal renal function were not significantly associated with asymmetrical kidney function. Only six (25%) of patients with asymmetrical kidney function scans had a notable difference in kidney size. Conclusions: In our series, approximately 12% of patients with pancreatic cancer have asymmetrical kidney function not identified by size, serum BUN, Cr, GFR, or a significant past medical history of renal compromise. These results provide important insight for cases when radiation plans may approach or exceed accepted dose constraints for the kidneys.
Ovarian metastasis from midgut neuroendocrine tumors: Incidence, clinical implications, and management options—An update.
Authors: Chauhan Aman , Anthony Lowell Brian , Beyer David T , Wang Yi-Zarn
Published: March 2017

446

Background: Midgut neuroendocrine tumors (NETs) are rare malignancies that can produce carcinoid syndrome and/or carcinoid heart disease. The incidence of ovarian metastasis, their clinical implications, and the optimal management strategy for these metastasis have not been well studied. We hypothesized that patients with ovarian metastasis will have a high incidence of carcinoid syndrome and carcinoid heart disease. Methods: Charts of 431 female patients seen in our NET clinic between October 2006 and December 2014 with a diagnosis of midgut NET were reviewed. Patients who had a previous bilateral oophorectomy with or without total abdominal hysterectomy were excluded. The incidence of ovarian metastasis, carcinoid syndrome and carcinoid heart disease was calculated. Median survival and 5-year survival rates were determined via the Kaplan-Meier Method. Results: Forty-one (41/431, 10%) patients were found to have ovarian metastasis. Twenty-four (24/41, 59%) patients exhibited carcinoid syndrome and three (3/24, 13%) patients with carcinoid syndrome developed carcinoid-related heart disease. 5-year survival rates for the patients with and without ovarian metastasis were 92% and 87%, respectively. Conclusions: Ovarian metastasis was found in 10% patients with metastatic midgut NET. Fifty-nine percent of these patients exhibited carcinoid syndrome and thirteen percent of which developed carcinoid heart disease, in spite of aggressive somatostatin analog therapy. To improve quality of life, routine therapeutic or prophylactic oophorectomy is recommended for female patients undergoing cytoreductive surgery for their midgut NET, especially for those who are peri- or post-menopausal.
Efficacy of S-1 compared to modified FOLFIRINOX as second-line chemotherapy regimens after gemcitabine plus nab-paclitaxel for patients with metastatic pancreatic cancer.
Authors: Kimura Gen , Takahashi Hideaki , Umemoto Kumiko , Watanabe Kazuo , Sasaki Mitsuhito , Hashimoto Yusuke , Imaoka Hiroshi , Ohno Izumi , Mitsunaga Shuichi , Ikeda Masafumi
Published: March 2017

449

Background: Recently, gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) has been frequently used as a first-line chemotherapy regimen for the treatment of metastatic pancreatic cancer (mPC) in Japan. Nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (MM-398 plus 5FU/LV) has not yet been approved in Japan. Under these circumstances, a modified FOLFIRINOX (mFFX) regimen or S-1 is commonly used as a second-line chemotherapy regimen for patients with mPC after GEM plus nab-PTX has failed. Methods: Between December 2014 and March 2016, 45 patients with mPC received second-line chemotherapy after the failure of GEM plus nab-PTX (standard dose regimen) at the National Cancer Center Hospital East. Twenty-two patients received mFFX (irinotecan, 150 mg/m2; bolus of 5FU was eliminated), 19 received S-1 (80 mg/m2/d; d1-28, q6w or d1-14, q3w), and 4 received other chemotherapy regimens. The clinical records of the patients were reviewed retrospectively. Results: At baseline, S-1 group had a more severe disease status than the mFFX group (performance status of 0: 21% vs. 68%, P = 0.003; median CA19-9 level: 1832 vs. 577 U/mL, P = 0.30). No significant difference in the response rate (S-1, 5.3% vs. mFFX, 9.1%, P = 0.56) or the disease control rate (S-1, 42% vs. mFFX, 36%, P = 0.71) was seen between the two groups. The progression free survival (PFS) (median: S-1 vs. mFFX: 2.7 vs. 2.4 months (m), P = 0.77), the overall survival (OS) from the second-line treatment (median: 6.1 vs. 6.4m, P = 0.87) and the OS from the first-line treatment (median: 10.9 vs. 12.4m, P = 0.77) were not significantly different between the two groups. These results were similar to those observed for MM-398 plus 5FU/LV (PFS, 3.1m; OS, 6.1m) in a pivotal Phase III study (NAPOLI-1). The incidences of peripheral neuropathy (5.3% vs. 32%, P = 0.04), fatigue (11% vs. 50%, P = 0.007), and neutropenia (11% vs. 64%, P = 0.001) were significantly lower in the S-1 group. Conclusions: S-1 was less toxic than mFFX and exerted a similar anti-tumor effect in the present study. S-1 could be a treatment option for patients with mPC refractory to GEM plus nab-PTX.
Optimal indications for chemotherapy in elderly patients with unresectable pancreatic cancer.
Authors: Nakazuru Shoichi , Nakamori Shoji , Kato Seiya , Shoji Ayaka , Kiyota Ryosuke , Shinkai Kazuma , Tashiro Taku , Nakagawa Kentaro , Ishida Hisashi , Mita Eiji
Published: March 2017

450

Background: Pancreatic cancer is seen predominantly in elderly patients. Since many patients with pancreatic cancer have locally advanced unresectable tumors or distant metastases at diagnosis, they require chemotherapy. However, it is difficult to appropriately select elderly patients who are likely to benefit from chemotherapy. This study aimed to identify prognostic factors for elderly patients with unresectable pancreatic cancer treated with chemotherapy. Methods: We retrospectively analyzed the data of 191 patients with pancreatic cancer, aged ≥ 70 years, who had been diagnosed at our hospital between January 2006 and August 2016. Their overall survival (OS) was calculated using Kaplan-Meyer analysis. Prognostic factors were evaluated using Cox regression analysis. Results: Of the 191 patients, 52 patients with unresectable pancreatic cancer were treated with chemotherapy. Their median age was 76.5 years (range, 70–85 years). Twenty-two patients (42%) were men, and 44 (85%) had metastatic disease. Forty-one (79%) and 11 (21%) patients had ECOG performance status (PS) 0–1 and 2–3, respectively. Thirty-eight (73%), 10 (19%), and 4 (8%) patients received gemcitabine, gemcitabine-based combination regimens, and S-1, respectively, as first-line chemotherapy. The median OS was 219 days (range, 7–920 days). On univariate analysis, ECOG PS ≥ 2 (hazard ratio [HR], 4.37; P = 0.0005), carcinoembryonic antigen ≥ 10 ng/mL (HR, 2.32; P = 0.0162), serum AST ≥ 30 U/L (HR, 2.02; P = 0.0263), serum albumin < 3.0 g/dL (HR, 2.38; P = 0.0247), serum C-reactive protein ≥ 0.5 mg/dL (HR, 2.21; P = 0.0140), neutrophil-to-lymphocyte ratio ≥ 5.0 (HR, 3.25; P = 0.0066), and presence of ascites on computed tomography (CT) scans (HR, 3.02; P = 0.0016) were significantly associated with shorter survival times. On multivariate analysis, ECOG PS ≥ 2 (HR, 5.49; 95% confidence interval [CI], 2.18–13.32; P = 0.0005) and presence of ascites on CT scans (HR, 2.53; 95% CI, 1.20–5.24; P = 0.0148) were associated with poor OS. Conclusions: Elderly patients with unresectable pancreatic cancer who have a good performance status and do not show ascites on CT scans are likely to benefit from chemotherapy.
Role of lymph node dissection for intrahepatic cholangiocarcinoma.
Authors: Hibi Taizo , Takemura Yusuke , Itano Osamu , Shinoda Masahiro , Kitago Minoru , Abe Yuta , Yagi Hiroshi , Kitagawa Yuko
Published: March 2017

457

Background: The prognosis of intrahepatic cholangiocarcinoma (ICC) with lymph node metastases is dismal. Recent studies have highlighted the importance of lymph node retrieval from disease staging and therapeutic standpoints. To define the role of lymph node dissection for ICC, this study aimed to evaluate the patterns of lymph node metastases and their prognostic implication. Methods: A retrospective cohort analysis was conducted for 56 consecutive patients who underwent R0/R1 resection for ICC between 1990 and 2015. In principle, lymph nodes in the hepatic hilum and around the pancreas head were systematically removed. For left-sided tumors, lymph nodes in the lesser curvature of the stomach and the root of left gastric artery were also dissected. Clinicopathologic predictors of 3-year survival were identified by Cox multivariate analyses. Lymph node mapping was performed and positive nodes were classified into 3 compartments based on metastatic rates and prognoses. Results: Median tumor size, 4.5 (1.5–16.0) cm; Mass-forming and its dominant type, 42 (75%); R0 resection, 47 (84%). Nineteen (34%) patients had lymph node metastases. After excluding 4 in-hospital deaths, the overall and recurrence-free survival rates at 3 years were 66% and 33%, respectively (median follow-up, 36 months). Cox multivariate analysis revealed lymph node metastases [hazard ratio (HR) 6.3, 95% confidence interval (CI) 1.9-21.7, P = 0.003] and R1 resection (HR 7.8, 95% CI 1.6-38.3, P = 0.01) as independent negative predictors of overall survival. Patients with ≥ 4 positive nodes ( n = 7) had significantly decreased survival compared with those with 1–3 positive nodes ( n = 10, P= 0.005). Metastatic lymph nodes were classified into compartments I (metastatic rates ≥ 10% and longest survival ≥ 3 years), II (5%–10% and 1-year survival ≥ 50%), and III ( < 5% and 1-year survival < 50%). Lymph nodes in the suprapyloric area, celiac trunk, and paraaorta belonged to compartment III and appeared less important to be dissected. Conclusions: Systematic lymph node dissection for ICC based on tumor location provides accurate staging and may prolong survival in patients with limited number of positive nodes. Compartment classification is useful to determine the extent of dissection.
Characteristics and treatment patterns of elderly patients with biliary tract cancers.
Authors: Yang Ji Hyun , Kim In-Ho , Jeong Joon Won , Ro Sang Mi , Lee Myung Ah
Published: March 2017

459

Background: Biliary tract cancers do not respond well to multipmodal treatment and generally show poor prognosis, and this may be a reason to make elderly patient consider best supportive care only. Methods: We reviewed 108 elderly patients of 80 years of age or older who diagnosed as biliary tract cancers from 2008 to 2014 at Seoul St. Mary's Hospital, Korea. Results: The mean age was 83.76 years ranging from 80 to 100. The patients included 24 intrahepatic(22.2%), 17 common bile duct(15.7%), 21 perihilar(19.4%), 37 gall bladder(34.3%), and 9 Ampulla of Vater(8.3%) cancers. 47 patients (43.5%) was initially resectable and 19(40.4%) of them underwent curative surgery, 17(36.2%) had percutaneous or endoscopic biliay drainage, and 11(23.4%) had best supportive care only. Mean survival was 29.8 months, 15.1 months, and 12 months, following the above treatment, respectively(p = 0.004). The mean hospitalized time for the curatively resected patients was 9.8 days. One died of traumatic SAH after surgery, 2 underwent adjuvant chemotherapy, and 10 experienced recurrence. Unresectable patients included 13 (12%) with locally advanced disease and 48 (44.4%) with distant metastasis. Among them, 4(6.6%) received palliative radiotherapy or chemotherapy, 30(49.2%) had biliary drainage, and 27(44.3%) had just best supportive care. Mean survival was 10.2 months, 7.3 months, and 3.6 months, respectively(p = 0.109). One with radiotherapy did not completed his treatment course due to intolerance. Three received chemotherapy with dose reduction from 75% to 70% considering their old age and poor performance status. Among those patients, 1 patient with stage IV intrahepatic cholangiocarcinoma showed partial response at 1st line of chemotherapy and had received totally 3 lines of chemotherapy. He survived 16.4 months. Conclusions: Elderly patients with early stage cancers who undewent curative resection and some selected advanced stage patients with palliative chemotherapy showed good response and survival improvement. There should be careful decision making for the management for geriatric biliary tract cancer patients and further investigations are needed to find more predictive factors.
Molecular characterization of early vs. late onset gastroesophageal cancers.
Authors: Qureshi Sadaf , Xiu Joanne , Sarraf Yazdy Maryam , Shields Anthony Frank , Philip Philip Agop , Marshall John , Lenz Heinz-Josef , Salem Mohamed E.
Published: March 2017

46

Background: Gastric and esophageal adenocarcinomas (GA and EA) in young patients (pts) are more likely driven by genetic factors than environmental carcinogens. Tumor molecular variations defining individual differences in age of onset have not been well elucidated. Methods: Protein expression (IHC), gene amplification (ISH), and next generation sequencing (NGS) were tested on GA and EA tumors. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Chi-square and t-tests were used for comparative analyses. Results: In total, 1670 tumors were examined; older (age >60) vs. younger (<45)comparisons were made in 599 GA and 491 EA (Table). In GA, significantly higher TOPO2A and TOPO1 expression was seen in older vs. younger pts, while higher mutation rates of FGFR2, IDH1, and NRAS were seen in younger pts. In EA, EGFR expression was higher in the older pts, while ATM and BRCA1 mutations were higher in the younger pts. When only primary tumors were studied, younger GA had a higher NRAS mutation rate (4.5% vs. 0, p=0.02) than older GA, and younger EA had higher cMET amplification (10% vs. 0, p=0.002) and ATM mutations (25% vs. 0, p=0.01) than older EA. In metastatic EA, higher BRCA1mutations (1/2 [50%] vs. 0/12 [0%], p=0.01) and lower EGFR overexpression (81% vs. 29%, p = 0.004) were seen in younger vs. older pts. No differences were seen in the PD-1 or PD-L1 expression rates between the two groups. Mean TML was lower in young GA than old GA (6.2 mutation/megabase vs. 10.4, p=0.005) but was not different between young EA and old EA (5.3 vs. 6.9, p=0.1). Conclusions: Younger GA/EA has a molecular profile unique from older pts, suggesting molecular aberrations play a different part in early-onset disease. Prevalence of aberrations in the young, such as cMET amplification and FGFR2, IDH1, BRCA1mutations may indicate important therapeutic targets. [Table: see text]
A single institutional experience of carbon-ion radiotherapy for locally advanced pancreatic cancer.
Authors: Shinoto Makoto , Shioyama Yoshiyuki , Suefuji Hiroaki , Toyama Shingo , Matsumoto Keiji
Published: March 2017

461

Background: Carbon-ion radiotherapy (C-ion RT) has the potential advantages in terms of improved dose localization and enhanced biological effectiveness compared to conventional radiotherapy or proton therapy. C-ion RT is expected to contribute to the prolongation of survival in patients with pancreatic ductal adenocarcinoma (PDAC). We started C-ion RT for pancreatic cancer at SAGA HIMAT since April 2014. The aim of this study is to evaluate the clinical results of C-ion RT for locally advanced PDAC. Methods: From April 2014 to May 2016, 76 patients with pancreatic cancer were treated with definitive C-ion RT. 44 patients who were confirmed as unresectable locally advanced PDAC were included in this retrospective analysis. 32 patients were excluded because of resectable disease (n = 8), borderline disease (n = 6), without pathological confirmation (n = 20). C-ion RT was performed with 55.2 Gy (RBE) at 12 fractions in 3 weeks. The anti-tumor effect was evaluating using CT and FDG-PET according to RECIST ver. 4.0. Results: The median follow-up period was 12.8 (range 3.4-27.5) months from the initiation of C-ion RT. In all patients, planned C-ion RT was completed. Induction chemotherapy was performed in 35 (80%) and the median duration time was 3 (range 1-19) months. Forty patients (91%) underwent concurrent chemotherapy with gemcitabine or S-1. Local effect using CT criteria was CR in 2, PR in 5, and SD in 37. The evaluation adding FDG-PET criteria was CR in 25, PR in 6, and SD in 13. Five patients (11%) experienced local recurrence during follow-up period. Two patients who had SD by CT and CR by FDG-PET performed tumor resection and were revealed pathological CR. One and two-year survival rate from C-ion RT were 82% and 66%, respectively. The two-year survival rate from initial treatment was 75%. Only three patients (7%) experienced grade 3 toxicities that were leukopenia, anorexia, and gastric ulcer. There was no grade 4 or 5 toxicity. Conclusions: C-ion RT for locally advanced PDAC was effective and well tolerated. FDG-PET was useful for the evaluation of local effect after C-ion RT.