bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal prognostic lymph node staging system for gallbladder adenocarcinoma: A multi-institutional study.
Authors: Amini Neda , Kim Yuhree , Wilson Ana , Ethun Cecilia Grace , Maithel Shishir Kumar , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Fields Ryan C. , Weber Sharon M. , Salem Ahmed Abdel-Fattah , Martin Robert C. G. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Hatzaras Ioannis , Shenoy Rivfka , Pawlik Timothy M.
Published: February 2017

364

Background: The American Joint Committee on Cancer (AJCC) classification is the most universally accepted lymph node (LN) staging system for gallbladder adenocarcinoma (GBA); however, it focuses more on location of LN metastasis than number of LN metastasis. Other lymph node staging systems have been proposed for GBA. We therefore sought to examine the performance of different staging systems including AJCC LN staging system, number of metastatic LN (NMLN), log odds of metastatic LN (LODDS), and LN ratio (LNR). Methods: Patients who underwent curative-intent resection for GBA between 2000 and 2015 and who had lymphadenectomy were identified from a multi-institutional database. The prognostic performance of four staging systems was compared by Harrell’s C and Akaike information criterion (AIC). Results: Overall 214 patients with a median age of 66.7 years (IQR 56.5, 73.1) were identified. A total 1,334 LNs were retrieved from 214 patients, with a median of 4 (IQR 2-8) LNs per patient. In the study cohort, 98 (45.5%) patients had LN metastasis with total of 271 positive LNs [median of 1 (IQR 1-3)]. Patients with LN metastasis had an increased risk of death (HR 1.87, 95%CI 1.24-2.82; P = 0.003). In addition, risk of death increased by each additional LN metastasis (HR 1.20, 95%CI 1.06-1.37; P = 0.005). In the entire cohort, LNR, in either a continuous (C-index: 0.603, AIC: 808.4) or a discrete scale (C-index 0.609, AIC 802.2), provided better discrimination versus LODDS, AJCC LN staging system, and NMLN. The relative performance of all scoring systems was better among patients who had ≥ 4 LN examined. In the cohort of patients with ≥ 4 LN examined, LODDS (C-index 0.621, AIC 363.8) had the best performance compared with LNR (C-index 0.615, AIC 368.7), AJCC LN staging system (C-index 0.601, AIC 373.4), and NMLN (C-index 0.613, AIC 369.5). Conclusions: LODDS and LNR performed better than the AJCC LN staging system. Among those who had more LN examined, LODDS performed better than LNR. LODDS and LNR should be incorporated into the AJCC LN staging system of GBA.
Effect of time to initiation of adjuvant chemotherapy on survival in resected pancreatic cancer.
Authors: Mirkin Katelin Anne , Hollenbeak Christopher S , Wong Joyce
Published: February 2017

368

Background: Pancreatic cancer carries a grim prognosis. Surgical resection followed by adjuvant chemotherapy is standard of care, but little is known about the temporal relationship of chemotherapy initiation and survival. This study analyzed the impact of time to initiation of adjuvant chemotherapy on survival in patients with resected pancreatic cancer. Methods: The National Cancer Data Base (2003-2011) was retrospectively reviewed for patients with clinical stages 1-3 resected pancreatic carcinoma. Time to chemotherapy was stratified at the 12-week post-operative timepoint. Univariate statistics, Kaplan-Meier estimates, and Cox proportional hazard modeling were performed. Results: 5,205 patients who had undergone surgical resection alone, 3,144 patients who had undergone surgical resection and adjuvant chemotherapy initiated at or before 12 weeks, and 906 patients who had undergone surgical resection followed by adjuvant therapy started after 12 weeks were included. Patients who received chemotherapy > 12 weeks tended to be older, have more co-morbidities, receive treatment at academic centers, and undergo whipple procedures. In all pathologic disease stages, adjuvant chemotherapy conferred a significant survival benefit over surgical resection alone (p < 0.0001). However, there was no significant overall survival benefit for patients receiving adjuvant chemotherapy before 12 weeks as compared to after (p = 0.85). When stratified by pathological stage, there was still no significant survival benefit for earlier initiation of chemotherapy (£ vs. > 12 weeks): stage I, p = 0.16, stage II, p = 0.12, stage III, p = 0.38. After controlling for patient, disease, and surgery characteristics, patients who received adjuvant chemotherapy after 12 weeks had a 31% lower odds of mortality at 5 years, while those who initiated it before 12 weeks had a 34% lower odds (p < 0.0001, p < 0.0001 respectively), versus surgery-alone. Conclusions: Earlier initiation of adjuvant chemotherapy does not significantly impact long-term survival in patients with resected pancreatic cancer. However, because adjuvant chemotherapy confers a survival benefit, delayed chemotherapy should be offered when appropriate.
Clinical outcomes of resectable small bowel adenocarcinoma treated by surgery alone: Case series in a Japanese single institution.
Authors: Noda Shoko , Honma Yoshitaka , Moro Hiroshi , Nakamura Shoko , Sasaki Yusuke , Takahashi Naoki , Iwasa Satoru , Okita Natsuko , Takashima Atsuo , Kato Ken , Hamaguchi Tetsuya , Boku Narikazu , Esaki Minoru , Shimada Kazuaki , Morita Shinji , Fukagawa Takeo , Katai Hitoshi
Published: February 2017

372

Background: Small bowel adenocarcinoma (SBA) is known as a poor prognostic cancer even in surgically resected cases. Its five-year survival rates were reported as 65%, 48%, and 35% in stage I, II, and III SBA, respectively. However, clinical outcomes of curatively resected SBA, especially without peri-operative adjuvant chemotherapy, are still unknown in Japanese population. Methods: We retrospectively reviewed medical records of patients who were diagnosed as Stage I, II, and III SBA after curative surgery between July 1994 and June 2014 at National Cancer Center Hospital. Overall survival (OS) and relapse-free survival (RFS) were calculated by Kaplan-Meier method. Cox proportional-hazards analysis was performed to identify the prognostic factors. Results: From a total of 76 patients with SBA received surgical resection, 56 were selected in this study who underwent curative resection with histological confirmation and did not receive adjuvant chemotherapy. The median age was 64 years (range: 20-85). Thirty-five patients (61%) were male. Forty-five patients (80%) had tumors in duodenum, 6 (11%) in jejunum and 5 (9%) in ileum. Pathological T stage were pT1a/T1b/T2/T3/T4 in 9/2/4/14/27 patients, and pathological N stage (pN) were pN0/N1/N2 in 29/16/11. The 1/3/5-year OS in all patients were 92.5/77.5/71.6%, and 1/3/5-year RFS were 76.5/68.9/61.6%. The 5-year RFS of pN0 (stage I/IIA/IIB) / N1 (stage IIIA) /N2 (stage IIIB) were 81.2/51.6/20.8%, and 5-year OS were 88.2/71.6/26.7%, respectively. Univariate analysis demonstrated that pN, presence of lymphatic and venous invasion were associated with poor OS. In multivariate analysis, pN was a significant predictor of poor OS (HR: 5.39 [N0 vs N1], 21.74 [N0 vs N2], 4.03 [N1 vs N2], p = 0.042). These findings were also seen in RFS. Conclusions: This study showed survival outcome of curatively resected SBA was better compared with previous reports, and pN was a significant prognostic factor of RFS and OS.
Radiotherapy for intrahepatic cholangiocarcinoma: An analysis of the National Cancer Database.
Authors: Hammad Abdulrahman Y , Younan George , Rajeev Rahul , Berger Nicholas Gerard , Turaga Kiran , Johnston Fabian McCartney , Christians Kathleen K. , Gamblin T. Clark
Published: February 2017

379

Background: The role of radiotherapy (RT) for surgically resected intrahepatic cholangiocarcinoma (ICC) remains poorly defined. Radiotherapy is often considered when a positive resection margin exists. The present study sought to examine the impact of radiotherapy following liver resection. Methods: Patients with early stage ICC, who underwent surgical resection, were identified from the National Cancer Database (1998-2011). Patients were stratified by resection margin status and receipt of RT. Survival was analyzed by Kaplan-Meier method and a multivariate regression model was used to identify predictors of survival. Results: A total of 2,182 patients were identified. R0 status was obtained in 1,624 patients (74.4%). RT was delivered to 405 patients (R0=209, R1/R2=196). In the R1/R2 group, 196 patients received RT vs. 362 R1/R2 patients that did not receive RT. Survival for R0 vs. R1/R2 was 32m vs. 16.5m (p<0.001). RT appeared to trend toward improving survival for R1/R2 patients, though this was not significant (20.4m vs. 14.5m, p=0.191). In a multivariate model accounting for age, sex, comorbidities, disease stage and resection margins, RT was not a predictor of survival. Negative predictors of survival included age>65years (Hazards Ratio [HR]: 1.20 (95%CI: 1.04-1.39), p=0.013), and positive resection margins (HR: 1.95 (95%CI: 1.65-2.30), p<0.001). Female sex was the only positive predictor of survival identified (HR: 0.76 (95%CI: 0.65 -0.88), p<0.001). Conclusions: Surgical resection with negative margins provides the best outcome for patients with ICC. Radiotherapy does not appear to significantly impact survival in patients with positive resection margins.
Risks of thromboembolic events among patients diagnosed with metastatic pancreatic ductal adenocarcinoma treated with chemotherapy.
Authors: Bapat Bela , Bhurke Sharvari , Rosen Edward , Stokes Michael , Bhagnani Tarun , Nordstrom Beth , Zaknoen Sara , Qadan Ammar
Published: February 2017

380

Background: Clinical trials suggest that patients with metastatic pancreatic ductal adenocarcinoma (mPDA) are at a high risk of thromboembolic events (TEs) as a result of both disease and treatment. Real-world data on TE rates are limited for patients with mPDA. Methods: Using a retrospective cohort design, patients with mPDA aged ≥ 65 years and treated with chemotherapy during 2007-2012 were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients enrolled in Medicare parts A, B, and D were followed from the start of first-line chemotherapy (index date) to the earliest of disenrollment from Medicare, death, or 12/31/2012. The baseline (BL) period was defined as 12 months prior to the index date. The incidence of TEs was calculated as the number of events per 100 person-years (PY) of follow-up (F/U) among patients without a BL TE. Anticoagulant use during F/U was categorized as preventive (before first TE, if any) and treatment (on or after first TE date) among patients with no BL TE. Results: Of 1,308 patients meeting the selection criteria, the mean age was 74 years, and 56% were female. The prevalence of TEs during the study period (BL or F/U) was 58% (n = 755). Excluding the 427 patients (33%) with TEs during BL, 328/881 (37%) of patients had a first TE during F/U, for an incidence rate of 85/100PY, including 29/100PY arterial and 59/100PY venous events. In the full study cohort, only 467/1,308 (36%) had a claim for any anticoagulant during the study period, although inpatient anticoagulant use is likely under-reported. Among patients receiving anticoagulants, 287/467 (61%) received low molecular weight heparin (LMWH). Preventive anticoagulant use was observed in 74/881 (8%) of patients without a BL TE; anticoagulation treatment was observed for 159/328 (48%) patients with a first TE during F/U. Conclusions: Real-world mPDA patients face a significant risk of TEs both before and after starting chemotherapy. Although inpatient use of anticoagulants including LMWH is incomplete in this database, it is clear that use of anticoagulants for treatment, and for prevention, of TEs is sub-optimal.
Towards an absolute bilirubin threshold for preoperative biliary decompression in patients undergoing whipple.
Authors: Mosquera Catalina , Dorismond Vanessa G. , Zervos Emmanuel E.
Published: February 2017

381

Background: There is no consensus as to when preoperative biliary decompression is indicated in patients with obstructive jaundice prior to pancreatoduodenectomy. The purpose of this study is to identify a bilirubin level whereby biliary decompression provides clear benefit despite potential drawbacks. Methods: Serial logistic regression analyses were undertaken to identify the bilirubin threshold upon which biliary decompression was associated with significant improvement in overall complications, mayor complications (Clavien-Dindo ≥ 3), length of stay, readmission rates and mortality. Results: Biliary decompression independently predicted a higher incidence of overall complications in patients presenting with bilirubin ≤ 10mg/dl, (p = 0.02). For patients with bilirubin > 10mg/dl - < 15mg/dl, there were no differences in complications, mortality, length of stay or readmissions. Biliary decompression in patients with bilirubin ≥ 15mg/dl independently predicted fewer overall (72% vs 100%), and mayor complications (11 % vs 50%), p < 0.05, and lower readmission rates (27.7% vs 62.5%), p = 0.02. Patients not undergoing biliary decompression underwent resection on average two weeks sooner than those having decompression (4.7 days vs 17.2 days), p = 0.01, with no significant change in bilirubin levels between presentation and surgery. Patients with bilirubin < 15mg/dl at presentation, who underwent biliary decompression, had a bilirubin decrease of more than 50% ( 6.3mg/dl to 2.5mg/dl), and the time to resection increased by more than one week (28 days vs 20.4 days), p < 0.001. Conclusions: All patients presenting with bilirubin ≥ 15mg/dl should undergo preoperative biliary decompression to minimize the risk of complications and readmissions. Patients presenting with bilirubin ≤ 10 mg/dl should forego stent placement to avoid stent related complications without clear benefit. The decision to stent between > 10mg/dl to < 15 mg/dl should be made on a case by case basis, taking into account anticipated bilirubin level at the time of surgery.
Nutritional status and outcomes of older versus younger patients (pts) with metastatic pancreatic cancer (mPC).
Authors: Vijayvergia Namrata , Seo Jenny Y , Devarajan Karthik , Denlinger Crystal Shereen , Cohen Steven J. , Dotan Efrat
Published: February 2017

386

Background: Older mPC pts are less likely to receive chemotherapy (Ctx) and receive fewer agents compared to younger pts, yet have similar overall survival (OS). Both obesity and malnutrition are linked with poorer outcomes in pancreatic cancer. We evaluated the effect of body mass index (BMI) and nutritional state on survival in < 65 y (GpA) and > 65 y (GpB) mPC pts. Methods: With IRB approval, we retrospectively analyzed charts of 579 mPC pts treated between 2000 and 2010. GpA and GpB were compared based on BMI alone (<19, 20-25 and >25) and also their nutritional status (poor: albumin <3 or weight loss>15% during disease course with any BMI; good: Alb>3.5 + Wt loss<15% + BMI >20; intermediate: all others). Log-rank tests and Cox proportional hazards models were used to analyze OS and Fisher’s exact test to compare categorical variables. Results: There were 299 pts in GpA (median age 57yr) and 280 pts in GpB (median age 73 yr). Information on BMI/albumin was missing for 126 pts; total study population was 454 (GpA 238, GpB 216).Groups were well balanced for gender (majority male), PS (majority ≤1), initial stage (majority IV), and primary site (majority head). There was no significant difference in Ctx and number of agents used between the 3 subgroups across GpA and GpB. BMI alone did not affect survival in both groups. Nutritional status was significantly associated with survival when evaluating the whole population and GpA, but not GpB (Table). Good nutrition GpA pts had a lower relative risk of death versus pts in intermediate and poor nutrition groups (RR 0.83, CI 0.71-0.96, p=0.02). Good nutritional status was associated with better survival in GpA on multivariate analysis (RR=0.81, CI 0.69-0.95; p=0.008,), but not in GpB. Conclusions: Nutritional status (defined by BMI, albumin and weight loss) was associated with survival in younger mPC pts but not in older pts. Greater attention to nutrition and cancer cachexia with possible interventions throughout treatment may improve survival in mPC pts undergoing chemotherapy, especially those < 65 yrs. Table [Table: see text]
Novel nomogram combining depth of invasion and size to predict the benefit of regional lymphadenectomy for appendiceal neuroendocrine tumors (A-NET).
Authors: Mosquera Catalina , Vora Haily , Fitzgerald Timothy Louis
Published: February 2017

389

Background: The need for regional lymphadenectomy for A-NET is predicated on the risk of nodal metastasis. Although depth of invasion is predictive of nodal metastases in other gastrointestinal NET, current guideline recommendations for A-NET are based solely upon size. Methods: Patients with A-NET from 1988-2012 were identified within the SEER registry. Depth of invasion was defined as limited to lamina propria (LP), invading or through muscularis propria (MP), and through serosa (TS). Results: A total of 1,024 patients met inclusion criteria, with majority being female (55.7%), white (86.8%), and node-negative (81.1%). On univariate analysis, risk of nodal metastases was associated with size ( < 1 cm 1.9%, 1-2 cm 19.7%, 2-4 cm 32.5%, and > 4 cm 37.2%), depth of invasion (LP 4.1%, MP 17.4% and TS 44.3%) and extent of surgery (appendectomy 8.7% vs colectomy 31.9%), p < 0.0001. On multivariate analysis, size ( < 1 cm vs 1-2 cm HR 8.80, vs 2-4 cm HR 15.68, and vs > 4 cm HR 15.16), depth of invasion (LP vs TS HR 6.67) and extent of surgery (appendectomy vs colectomy HR 2.98), continued to be associated with nodal involvement, p < 0.0001. When only patients with colectomy were considered results were similar on both univariate and multivariate analyses. On univariate survival analysis, size [ < 1cm 95.6%, 1-2cm 94.9%, 2-4cm 88.4%, and > 4cm 73.7% 5-year disease-specific survival (5-y DSS)], depth of invasion (LP 96.9%, MP 93.2%, and TS 77.1% 5-y DSS), extent of surgery (appendectomy 94.4% and colectomy 87.1%), and N stage (N0 94.7% and N1 77.7%) predicted survival, p < 0.002. In a Cox regression model, extent of surgery and N stage continued to predict survival. A nomogram was created to predict the risk of nodal metastases, AUC = 0.83. Conclusions: This simple nomogram, which incorporates size and tumor extension, accurately predicts the risk for regional nodal metastases in appendiceal NET. In addition to providing valuable information on risk for regional nodal metastases, depth of invasion independently predicts survival.
Palliative care for hepatocellular carcinoma: Analysis of the National Cancer Data Base.
Authors: Hammad Abdulrahman Y , Robbins Jared , Turaga Kiran , Christians Kathleen K. , Gamblin T. Clark , Johnston Fabian McCartney
Published: February 2017

390

Background: Palliative care is provided to a subset of hepatocellular carcinoma (HCC) patients with the aim of symptomatic relief and improving quality of life. The present study sought to assess and compare the prevalence and efficacy of different palliative therapies for HCC from the National Cancer Database (NCDB). Methods: The NCDB, a retrospective national database that captures approximately 70% of all patients treated for cancer, was queried for patients with HCC who were deemed non-resectable from 1998-2011. Patients were stratified by receipt of palliative care. Descriptive analyses were performed. Survival analysis was examined by log-rank test and Kaplan Meier curves, and a multivariate proportional hazards model was utilized to identify the predictors of survival. Results: A total of 3,267 patients were identified; 287 (8.7%) received surgical palliation, 827 (25.3%) received radiotherapy, 877 (26.8%) received chemotherapy, 1,067 (32.6%) received pain therapy, while 209 (6.4%) received a combination of the previous 3 modalities. The median age was 61 (54-72), and 81.3% of the patients were males, and of Caucasian ancestry (72.5%). Difference in the Charlson Comorbidity Index (CCI) existed between the comparison groups (p< 0.001). On a multivariate hazards model, palliative radiotherapy was identified as a positive predictor of survival (Hazards Ratio (HR): 0.71 [95%CI:0.56-0.90]), while pain therapy was a negative predictor of survival (HR: 1.79 [95%CI: 1.43-2.25]). Stratifying by disease stage, palliative radiotherapy provided a significant survival benefit for patients with stage IV disease. Examining the RT cohort, most patients received external beam radiation (80%) and palliative radiation was most frequently delivered to the spine (35%) followed by the liver (19%). The survival benefit was more significant when the liver was targeted (OS: 3.7 months vs. 7.3 months, p= 0.03). Conclusions: Amongst the palliative therapies examined, radiotherapy appear to extend survival and should be considered for patients presenting with late stage HCC. Pain therapy alone acts as a negative predictor of survival and should not be considered as a sole intervention for patients with late stage disease.
Intraoperative radiotherapy (IORT) in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for locally advanced and borderline resectable adenocarcinoma of the pancreas (PDAC).
Authors: Keane Florence K. , Wo Jennifer Yon-Li , Ferrone Cristina , Clark Jeffrey W. , Blaszkowsky Lawrence Scott , Allen Jill N. , Kwak Eunice Lee , Ryan David P. , Lillemoe Keith D , Fernandez-del Castillo Carlos , Hong Theodore S.
Published: February 2017

393

Background: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic PDAC have prompted incorporation of these regimens into neoadjuvant treatment of PDAC. While some patients are still found to be unresectable after neoadjuvant treatment, others are able to undergo resection. Our aims are to evaluate outcomes and toxicities associated with use of IORT in this setting. Methods: We retrospectively analyzed records of 85 patients with locally advanced/ borderline resectable PDAC who received neoadjuvant treatment with chemotherapy and/or chemoradiotherapy followed by surgical exploration in an IORT-equipped operating suite between 2010-2015. Descriptive statistics were used to compare surgical outcomes. Survival analysis was used to calculate overall survival (OS). Results: Of 85 patients, 49 (57.6%) underwent resection after neoadjuvant treatment, 27 (31.8%) were unresectable, and 9 (10.6%) were found to have distant metastases. 24 of 49 patients who underwent resection received IORT for close/positive margins on intraoperative frozen section. There was no significant difference in operative times, postoperative complications, or operative morbidity in patients who underwent resection and IORT vs those who underwent resection alone. Median OS was 31.1 months in patients who underwent resection alone and 35.1 months in patients who underwent resection and IORT. Despite the increased incidence of close/ positive margins in patients who underwent resection and IORT, the rates of local recurrence were similar to those who underwent resection alone. 26 of 27 patients with unresectable disease upon exploration received IORT. Median OS was 20.5 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative time or morbidity. Conclusions: IORT is not associated with increased toxicity when used in conjunction with resection or surgical exploration after neoadjuvant therapy. IORT resulted in median OS of 35 months for patients with close or positive margins and of 20.5 months for patients with unresectable disease.
Rapid immunohistochemical analysis of pancreatic cytology from endoscopic ultrasound-guided fine-needle aspirates: A prospective clinical trial.
Authors: Tsai Susan , Ritch Paul S. , Erickson Beth , George Ben , Johnston Fabian McCartney , Mackinnon Alexander C. , Evans Douglas B. , Christians Kathleen K.
Published: February 2017

400

Background: Acquisition of pancreatic cancer (PC) tissue specimens from endoscopic ultrasound-guided fine needle aspirates (EUS-FNA) is crucial to investigational pancreatic cancer trials seeking to utilize molecular profile directed therapy. Methods: In an ongoing prospective clinical trial we have utilized molecular profiling of EUS-FNA specimens from patients with resectable and borderline resectable pancreatic cancers. Cytologic specimens were evaluated for six biomarkers to guide the choice of neoadjuvant therapy: secreted protein acid rich in cysteine (SPARC), thymidylate synthase (TYMS), ribonucleotide reductase M1 (RRM1), human equilibrative nucleoside transporter 1 (ENT1), excision repair cross-complementing 1 (ERCC), and topoisomerase 1 (TOPO). Final immunohistochemical (IHC) interpretation was scored by a single pathologist using both staining intensity and percent immunochemically reactive cells. Results: The trial has enrolled 99 patients to date; 47 (47%) resectable patients and 52 (52%) borderline resectable patients. No patient experienced a EUS-FNA related complication. IHC profiling was reported in a median of 5 business days (IQR:3). Of the 99 patient samples, 73 (74%) had adequate cellularity for IHC profiling and this was not affected by stage of disease (n = 35, resectable; n = 38 borderline resectable; p = 0.82). Analysis of SPARC expression was limited to specimens with adequate stromal cells for analysis (n = 50, 51%). Among the 73 patients with adequate tissue for profiling, expression profiling was interpreted to be favorable for the following therapeutic agents: nab-paclitaxel, (SPARC, n = 35, 48%), 5-fluorouracil (TYMS, n = 68, 93%), gemcitabine (RRM1, n = 34, 47%; ENT1, n = 38, 52%), platinum agents (ERCC, n = 30, 41%), and irinotecan (TOPO, n = 62, 85%). Conclusions: The use of EUS-FNA specimens for molecular diagnostics is feasible and IHC analysis was possible in 74% of patient specimens, with preservation of stromal components in over 50%. Further refinement of molecular techniques may expand the breadth of analysis which may be performed, to include quantitative polymerase chain reaction and genetic sequencing Clinical trial information: NCIT01726582.
Bridging therapy effectiveness in the treatment of hepatocellular carcinoma prior to orthotopic liver transplantation.
Authors: Zlobinsky Rubinstein Maria M , Kaubisch Andreas , Kinkhabwala Milan , Reinus John , Liu Qiang , Chuy Jennifer W.
Published: February 2017

401

Background: Orthotopic liver transplantation (OLT) is the only curative intervention for both hepatocellular carcinoma (HCC) and underlying cirrhosis. OLT is limited by both donor organ shortages and long waitlists for transplant. In order to halt tumor progression, various bridging therapies (BT) have been utilized. Despite complete radiologic responses following BT, viable tumor is often present on explant analysis. We present an update of our experience and include novel bridging modalities. Methods: 35 patients were retrospectively evaluated in a transplant center prior to OLT for HCC. A total of 68 locoregional therapies were utilized. Success of BT was assessed by radiologic response and histopathological examination of the explanted livers. Results: 61 nodules were studied in liver explants. Pre-transplant treatments included: TACE, alcohol ablation (ETOH), radiofrequency ablation (RFA), microwave ablation, selective internal radiation therapy (SIRT) and stereotactic body radiation therapy (SBRT). Radiologically, 36 nodules (59 %) achieved complete response compared to 20 nodules (33%) on explant analysis. Approximately 1/3 of treated nodules with complete tumor necrosis (CTN) were treated with TACE + RFA. 60% of nodules (12/20) with CTN were treated with more than one bridging modality. 75% of nodules (3/4) treated with SIRT alone showed CTN. Patients underwent a mean of 2.2 BT. Four out of 35 (11%) patients had no residual HCC on explant analysis. Conclusions: Although favorable radiologic responses are seen following BT, viable HCC is often seen in liver explants. Newer strategies like SIRT may enhance locoregional control and should be explored as part of an aggressive approach for patients awaiting transplant. [Table: see text]
The minimal effective relative dose intensity (RDI) for modified FOLFIRINOX in advanced pancreatic cancer: Suggestion for modified Hryniuk’s calculation method.
Authors: Lee Jong-chan , Paik Kyu-hyun , Kim Hyoung Woo , Kang Jingu , Park Young Soo , Kim Jaihwan , Hwang Jin-Hyeok
Published: February 2017

402

Background: Since FOLFIRINOX (5-fluorouracil, oxaliplatin, leucovorin and irinotecan) improved efficacy but also increased toxicity in pancreatic ductal adenocarcinoma (PDA) patients, several reports have been published about modified FOLFIRINOX as a concept of dose reduction. However, the lower limit of dose reduction is still unclear. The aim of this study is to find the minimal relative dose intensity (RDI, %) of FOLFIRINOX that can be expected to yield tumor response in advanced pancreatic ductal adenocarcinoma. Methods: A total of 95 PDA patients treated with FOLFIRINOX as a first line therapy were retrospectively reviewed. Based on Hryniuk’s arithmetic formula, we defined an extended Hryniuk’s calculation and launched a calculator site ( http://www.rdicalc.com ). Using receiver operator characteristic (ROC) curve, we investigated minimal RDI with a view to obtaining tumor response rate (RR) and disease control rate (DCR). The toxicity profile was also described. Results: Among the 95 patients, 85 patients completed the initial treatment until the first radiological evaluation with median 3 cycles and 56 days. Thirty one patients had locally advanced PDAC and 54 had metastatic disease. As the minimal effective thresholds, the ROC curve showed 71.5% RDI for RR (78.1% sensitivity, 83.0% specificity) and 54.5% RDI for DCR (91.3% sensitivity, 56.3% specificity). When divided by 5% units, the minimal RDI for RR and DCR was 70% and 55%, respectively. Among the 95 patients, including the dropout group, grade III/IV neutropenia, febrile neutropenia and vomiting was 45%, 13% and 31%, respectively. Early period toxicities and RDI did not show dose-response relationships. Conclusions: Although reduced dose FOLFIRINOX could be effective in advanced PDAC, our data suggest that more than 70% RDI for RR and 55% for DCR should be preserved. Toxicity rates were not influenced by RDI level in the early therapeutic period.
Correlation between change of FA score and postoperative recurrence in esophageal cancer patients who received neoadjuvant treatment.
Authors: Matsuda Satoru , Takeuchi Hiroya , Fukuda Kazumasa , Nakamura Rieko , Takahashi Tsunehiro , Wada Norihito , Kawakubo Hirofumi , Kitagawa Yuko
Published: February 2017

41

Background: We previously reported that fibrinogen and albumin score (FA score), which was consisted of plasma fibrinogen level (FNG) and serum albumin level (Alb), was shown to predict postoperative survival in esophageal cancer patients who underwent transthoracic esophagectomy. In this study, in patients who received neoadjuvant chemotherapy (NAC), change of FA score during NAC was reviewed and the correlation with recurrence free survival (RFS) was investigated. Methods: We retrospectively reviewed 125 patients who received neoadjuvant chemotherapy and underwent transthoracic esophagectomy in our institution between 2001 and 2012. FNG and Alb before (preTx) and after (preope) NAC were confirmed in 92 patients. Based on our previous reports, patients with elevated fibrinogen ( > 350 mg/dL) and decreased albumin ( < 3.8 g/dl) levels were allocated a FA score of 2, those with only one of these abnormalities were allocated a FA score of 1, and those with neither of these abnormalities were allocated a FA score of 0. Regarding change of FA score, based on the preTx and preope FA score, we classified into decrease group and increase (no change or increase) group. Patient characteristics, clinicopathological factors, preTx FA score, and preope FA score were reviewed, and correlation with RFS was investigated. Results: The number of preTx and preope FA score 0/1/2 was 39/41/12, 36/37/19. Regarding change of FA score, FA score decreased in 70 patients (76%), increased in 22 (24%). There was no significant difference in patient background and clinicopathological factors between groups. In survival univariate analysis, change of FA score (Increase group, HR 2.023, p = 0.025) were significantly correlated with RFS. In multivariate analysis, using preTx clinical stage as a covariate, FA score was shown to be an independent predict factor (Increase group, HR 2.076, p = 0.023) for RFS significantly. Conclusions: Change of FA score between before and after NAC was shown to be a predictive factor of RFS in esophageal cancer patients who received NAC. Both fibrinogen and albumin are popular indicators routinely measured in daily clinical practice, FA score may be highly validate and feasible.
Updated overall survival analysis of NAPOLI-1: Phase III study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.
Authors: Wang-Gillam Andrea , Li Chung-Pin , Bodoky Gyorgy , Dean Andrew , Shan Yang-Shen , Jameson Gayle S. , Macarulla Teresa , Lee Kyung-Hun , Cunningham David , Blanc Jean-Frédéric , Hubner Richard , Chiu Chang-Fang , Schwartsmann Gilberto , Siveke Jens T , Braiteh Fadi S. , Moyo Victor M. , Belanger Bruce , Bayever Eliel , Von Hoff Daniel D. , Chen Li-Tzong
Published: February 2017

417

Background: NAPOLI-1 is a global, randomized Phase 3 study evaluating nal-IRI—a nanoliposomal irinotecan—with or without 5-FU/LV in 417 patients with mPAC previously treated with gemcitabine-based therapy. Primary survival analysis was based on 313 events. Nal-IRI+5FU/LV significantly improved overall survival (OS, primary endpoint), 6.1 months (mo) vs 4.2 mo; with 5-FU/LV (unstratified hazard ratio [HR] = 0.67; P = 0.012). Primary endpoint was supported by improved progression-free survival, time to treatment failure, objective response and CA19-9 tumor marker response rates, and manageable toxicities. An updated analysis of OS, 6- and 12-month-survival estimates, and safety is presented. Methods: The updated descriptive analysis of OS, based on 378 events (25 May 2015), includes data from all randomized patients across the 3 arms. Results: After 378 OS events, nal-IRI+5-FU/LV (n = 117) retained an OS advantage relative to 5-FU/LV (n = 119): 6.2 mo (95% confidence interval [CI], 4.8–8.4) vs 4.2 mo (95% CI, 3.3–5.3) with an unstratified HR of 0.75 (P = 0.0417). In contrast, there was no OS advantage with nal-IRI monotherapy (n = 151) vs 5-FU/LV (n = 149): 4.9 mo [95% CI, 4.2–5.6] vs 4.2 mo [95% CI, 3.6–4.9], HR = 1.08; P = 0.5. Six-month survival estimates were 53% (95% CI, 44–62%) for nal-IRI+5-FU/LV vs 38% (95% CI, 29–47%) for 5-FU/LV; 12-month survival estimates were 26% (95% CI, 18-35%) for nal-IRI+5-FU/LV vs 16% (95% CI, 10–24%) for 5-FU/LV. With events in nearly all patients, the OS curves converge at ~20 mo with 19 patients (16.2%) surviving beyond 20 mo. This is a reason for attenuation of the HR estimate and unstratified log rank p-value. The most common grade 3+ adverse events occurring at a ≥ 2% incidence in the nal-IRI-containing arms were neutropenia, diarrhea, vomiting, and fatigue. Conclusions: In an updated analysis, the median OS benefit for nal-IRI+5FU/LV over 5-FU/LV was maintained, with a similar safety profile. Nal-IRI+5-FU/LV may be a new standard of care for patients with mPAC previously treated with gemcitabine-based therapy. Clinical trial information: NCT01494506.
RAINIER: A randomized, double-blinded, placebo-controlled phase II trial of gemcitabine (gem) plus nab-paclitaxel (nab-P) combined with apatorsen (A) or placebo (Pl) in patients (pts) with metastatic pancreatic cancer (mPC).
Authors: Ko Andrew H. , Murphy Patrick B. , Peyton James D. , Shipley Dianna , Al-Hazzouri Ahmed , Rodriguez Frank A. , Womack Mark S. , Xiong Henry Q. , Waterhouse David M. , Tempero Margaret A. , Bendell Johanna C.
Published: February 2017

419

Background: Heat shock protein 27 (Hsp27) is over-expressed in PC, enabling tumor growth and metastasis. A is an antisense oligonucleotide that binds to Hsp27 mRNA and inhibits production of Hsp27 protein. This randomized phase II trial evaluates the efficacy of gem/nab-P plus A or Pl in pts with mPC. Methods: Pts with untreated mPC were randomized 1:1 to Arm A (gem, nab-P, A) or Arm B (gem, nab-P, Pl). 3 loading doses of 600mg A IV or Pl IV were given, then 600 mg A or Pl weekly with chemotherapy in 28 day cycles. Both arms received gem 1000mg/m2 IV, nab-P 125mg/m2 IV days 1, 8, and 15. Restaging was every 2 cycles. Serum Hsp27 levels were collected at baseline and on treatment. Primary endpoint compared overall survival (OS); secondary endpoints were progression free survival (PFS), response rate (RR), CA 19-9 response, and toxicity. Results: 132 pts were randomized: median age 66 yrs, 57% male, 47% ECOG 0. Demographics were similar for both arms. 36% of pts on Arm A and 48% of pts Arm B discontinued due to progressive disease, and 24% and 14% due to adverse events (AEs). There was a higher incidence of ≥Grade (G) 4 and serious adverse events (SAEs) in Arm A. The most frequently reported G 3/4 treatment-related AEs were anemia (20%), neutropenia (17%), and fatigue (16%) on Arm A and anemia (27%), neutropenia (19%), and thrombocytopenia (13%) on Arm B. Overall RR was 18% on each arm. With a median f/u of 9.1 mos, median PFS and OS are 2.7 and 5.2 mos on Arm A and 3.8 and 6.9 mos on Arm B (p=NS). Correlative analyses between Hsp27 expression and clinical outcomes will be presented. In a statistical model using only Arm B data, 3 base attributes, ECOG >0, liver mets, and neutrophil levels had a strong prognostic relationship to OS. Conclusions: This study showed no improvement in clinical outcomes adding A to gem plus nab-p. G 4 AEs and SAEs were increased with A. We await analysis for Hsp 27 and CA 19-9 levels and further analysis to identify any pt subgroup who might have benefited from the experimental treatment. Clinical trial information: NCT01844817.
Safety and efficacy of dose-modified FOLFIRINOX on toxicity and effectiveness in Japanese patients with unresectable pancreatic cancer (PC).
Authors: Uesugi Kazuhiro , Asagi Akinori , Terasawa Hiroyuki , Nadano Seijin , Ishii Hiroshi
Published: February 2017

422

Background: FOLFIRINOX has been shown superior to GEM in terms of OS, PFS and/or RR for treatment of metastatic PC in Accord 11, and this regimen has become the standard of care for the first-line chemotherapy. However, the major disadvantage of FOLFIRINOX is significantly higher toxicity, and, in particular, quite higher incidence of neutropenia (78%) and febrile neutropenia (22%) was observed in the PII clinical trial of FOLFIRINOX performed in Japan (LOHP-PII-05, JSCO 2013). Thus, in clinical practice for the Japanese patients, it should be needed to make modification on this regimen in terms of dose reduction without compromising in its effectiveness. We evaluated the safety and efficacy of modified (m) FOLFIRINOX in Japanese patients with unresectable locally advanced PC (LAPC), metastatic PC (MPC), and/or postoperative recurrence. Methods: The modifications to FOLFIRINOX include discontinuation of the bolus 5-FU and dose-reduction (25%) of irinotecan. 36 patients with unresectable LAPC, MPC and postoperative recurrence were treated with mFOLFIRINOX, and toxicity and efficacy were evaluated. Results: Patient characteristics were as follows: LAPC/MPC/Postoperative recurrence 6/20/10; median age 65 years (range 39-75); male/female 27/9. Median number of cycles was 5 (range 1-28). Grade 3/4 toxicities included neutropenia (16.7%), leukopenia (13.9%), diarrhea (13.9%) and enteritis (11.1%) in order. Febrile neutropenia was only in 2 patients (5.6%). Both hematologic and non-hematologic toxicities were reduced, although diarrhea was observed in a bit higher incidence compared to those in LOHP-PII-05. The response rate and disease control rate evaluated in 28 patients were favorable, in LAPC, MPC and/or post operative recurrence, which were similar to those in LOHP-PII-05. In response of CA19-9 was evaluated in 26 patients. 20 patients (76.9%) showed a decline in CA19-9 levels from baseline, and a greater than 50% decline was noted in 15 patients (57.7%). Conclusions: mFOLFIRINOX has an improved safety profile with maintained efficacy in the selected population of MPC. mFOLFIRINOX has promising activity also in LAPC with respect to RR.
Phase II study of individualized adaptive stereotactic body radiotherapy (SBRT) for patients at high risk for liver damage.
Authors: Feng Mary Uan-Sian , Suresh Krithika , Schipper Matthew J , Bazzi Latifa , Ben-Josef Edgar , Matuszak Martha , Parikh Neehar , Welling Theodore Hobart , Ten Haken Randall K , Lawrence Theodore Steven
Published: February 2017

424

Background: Patients (Pts) with pre-existing liver dysfunction are at high risk for further damage after SBRT. We completed a phase 2 study of individualized SBRT, utilizing pre- and during-treatment indocyanine green (ICG) clearance to adapt treatment and maximize both safety and efficacy. Methods: From 5/10-10/14, pts with hepatocellular carcinoma (HCC) or metastases (mets) were enrolled and underwent SBRT planning up to a target dose of 50-60 Gy or as limited by a 15% normal tissue complication probability for radiation-induced liver disease (RILD). ICG retention at 15 minutes (ICGR15) was measured prior to and 1 month after 3 of 5 planned treatments. Using a Bayesian adaptive model, RT dose was scaled down as necessary for the final 2 treatments to keep ICGR15 < 44% after the full treatment and thus minimize toxicity. Follow up was every 3 months for 2 years. Results: 90 pts received SBRT to 116 tumors and had at least 1 year of potential follow up. Median age was 62 years, range 34-85. 69 had HCC, 4 intrahepatic cholangiocarcinoma, and 17 mets. 62 had cirrhosis, most commonly HCV and alcoholic. Median Child-Pugh (CP) score was 6, range 5-9. 20 pts were CP B/C. Median pre-RT ICGR15 was 22, range 4-75, normal 4-10. Pts had a median of 1.5 (range 0-6) prior liver-directed therapies, most commonly transarterial chemoembolization (70), prior RT (36), and radiofrequency ablation (13). Median tumor size was 3 cm, and 12 had portal vein involvement. 63 received all 5 fractions (48 full dose, 15 with dose reduction due to elevated ICGR15); 27 received only 3 treatments. Median prescription dose was 47 Gy. Treatment was well tolerated with no classical RILD and a lower complication rate than expected without adaptation. 4 pts had grade 3 ascites. 2 pts had GI bleed after SBRT. 14% and 10% of pts experienced at least a 1 or 2 point increase in CP 6 months post SBRT. Local control (95%CI) at 1 and 2 yrs was 99 (96,100)% and 90 (81,100)%. 4 recurrent tumors were 3 HCC and 1 met, measuring 26, 12, 30, 38mm; treated to 30, 50, 33, 30 Gy. Conclusions: Individualized adaptive SBRT, based on ICG clearance is a promising method of allowing pts to receive the maximally aggressive dose based on each pt’s individual tolerance to RT. Funded by P01 CA59827
Effect of baseline carbohydrate antigen 19-9 (CA19-9) level on overall survival (OS) in NAPOLI-1 trial: A phase III study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.
Authors: Chen Li-Tzong , Siveke Jens T , Wang-Gillam Andrea , Hubner Richard , Pant Shubham , Dragovich Tomislav , Chung Vincent M. , Chang David Z. , Ross Paul J. , Cooray Prasad , Tebbutt Niall C. , Franke Fabio A. , Belanger Bruce , Dhindsa Navreet , De Jong Floris , Mamlouk Khalid , Von Hoff Daniel D.
Published: February 2017

425

Background: CA19-9 has been shown to correlate with response to therapy and OS in patients with mPAC. NAPOLI-1, a randomized phase 3 study evaluated nal-IRI, a nanoliposomal formulation of irinotecan, with or without 5-FU/LV vs 5-FU/LV in patients with mPAC previously treated with gemcitabine-based therapy. Nal-IRI+5-FU/LV significantly improved OS (primary endpoint) vs 5-FU/LV (6.1 mo vs 4.2 mo; unstratified hazard ratio [HR] = 0.67; P = 0.012). CA19-9 response (≥50% decline from baseline) was superior with nal-IRI+5FU/LV compared with 5-FU/LV (29% vs 9%; P=0.0006). Nal-IRI alone did not show a statistical improvement in survival. Methods: Patients with a recorded baseline CA19-9 measurement were divided into quartiles to evaluate the treatment effect pattern of CA19-9 from nal-IRI+5-FU/LV and 5-FU/LV arms. Quartile ranges were based on 404 available CA19-9 values from randomized patients (N=417). Unstratified Cox proportional hazards regression was used to estimate HRs and corresponding 95% CIs. Effect of baseline CA19-9 on time to response, progression-free survival, and response will be presented. Results: Of patients randomized to receive nal-IRI+5-FU/LV (n = 117) or 5-FU/LV enrolled contemporaneously (n = 119), 218 received study drug and had a baseline CA19-9 measurement. Results show a greater treatment effect on OS with higher CA19-9 level relative to 5-FU/LV. Conclusions: In patients with mPAC previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV significantly improved OS supported by progression free survival and objective response rate. The CA19-9 serum level can provide important information with regards to overall survival. Clinical trial information: NCT01494506. [Table: see text]
Multidisciplinary approach to patients with recurrent colorectal liver metastases.
Authors: Vigano Luca , Costa Guido , Comito Tiziana , Pedicini Vittorio , Poretti Dario , Scorsetti Marta , Solbiati Luigi , Torzilli Guido
Published: February 2017

426

Background: Recurrence after liver resection (LR) for colorectal metastases (CLM) is common. Re-resection is the standard treatment. In unresectable patients, radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) have been proposed, but they did not show a clear survival benefit in comparison with chemotherapy alone. The present study aims to elucidate the outcome of patients with recurrent CLM according to the received treatment. Methods: A series of 323 consecutive patients undergoing first LR between 2004 and 2013 was considered. Of these, 206 (63.8%) had recurrence and were analyzed. Redo surgery was scheduled whenever possible. If surgery was excluded, RFA was considered for hepatic lesions, while SBRT for both hepatic and extra-hepatic lesions. Results: Among the 206 analyzed patients with recurrence, 72 underwent re-resection, 19 RFA and 14 SBRT. Liver-only recurrences were treated in 68.3% of cases (69/101, 47 surgery), pulmonary ones in 57.9% (22/38, 15 surgery) and other extra-hepatic ones in 20.9% (14/67, 10 surgery). After a median follow-up of 32 months, three-year survival after the diagnosis of recurrence (OS) was 42.2% (median 37.4 months). OS was associated with the administered treatment: at three years 70.5% if surgery, 53.8% if RFA/SBRT, and 15.0% if chemotherapy alone, p < 0.0001. The same association was observed focusing the analysis on patients with a total of three lesions in the liver and/or the lung (1-3 liver/lung group, n = 86): three-year OS was 82.6% if surgery, 55.8% if RFA/SBRT, and 29.2% if chemotherapy, p < 0.0001. Progression-free survival after the treatment of recurrence (PFS) was associated with the received treatment: at two years 29.0% if surgery, 14.4% if RFA/SBRT, and 2.6% if chemotherapy, p < 0.0001. The same result was observed in the “1-3 liver/lung” group: two-year PFS was 32.1% if surgery, 18.3% if RFA/SBRT, and 0% if chemotherapy, p = 0.001. RFA and SBRT groups had similar OS and PFS. Conclusions: Aggressive management of recurrent CLM prolongs OS and PFS. Surgery is the best treatment option. Despite potential selection biases, RFA and SBRT should be considered in unresectable patients because they are associated with better outcome than chemotherapy alone.