bluuebunny/crossref_metadata_2025 huggingface dataset:
Sunitinib (SU) in patients with advanced, progressive pancreatic neuroendocrine tumors (pNET): Final overall survival (OS) results from a phase III randomized study including adjustment for crossover.
Authors: Raymond Eric , Niccoli Patricia , Castellano Daniel , Valle Juan W. , Hammel Pascal , Raoul Jean-Luc , Vinik Aaron , Bang Yung-Jue , Lee Se-Hoon , Borbath Ivan , Lombard Bohas Catherine , Metrakos Peter , Smith Denis Michel , Chen Jen-Shi , Seitz Jean Francois , Patyna Shem , Huang Xin , Ishak Jack , Faivre Sandrine J. , Ruszniewski Philippe B.
Published: February 2017

309

Background: In 2010, the pivotal double blind Phase III study met its primary endpoint with a median progression-free survival (PFS) of 11.4 months (mo) for sunitinib vs. 5.5 mo for placebo (PBO) (HR=0.42; 95% CI 0.26-0.66; P <0.001) in patients (pts) with advanced, progressive pNET. This trial showed an OS difference favouring sunitinib (HR=0.41; 95% CI 0.19-0.89; P = 0.02). At 2 years since study closure, median OS was 33.0 mo for SU and 26.7 mo for PBO (HR=0.71; 95% CI 0.47-1.09; P = 0.115). Methods: A total of 171 pts were randomly assigned 1:1 to SU 37.5 mg continuous daily dose (n = 86) or PBO (n = 85). The primary end-point was investigator assessed PFS. Pts receiving PBO could crossover to SU at disease progression. Final OS at 5 years follow-up since study closure was analyzed using the Kaplan-Meier method and Cox proportional hazards model in the intent-to-treat (ITT) population. In addition, a series of methods were used to adjust for cross-over including rank-preserving structural failure time (RPSFT). Clinical trial information: NCT00428597 . Results: At 5 years follow-up since study closure, the median OS was 38.6 mo for those randomized to SU and 29.1 mo for those randomized to PBO (HR=0.73, 95% CI 0.50-1.06; P = 0.094). In total, 59 pts randomized to PBO (69%) crossed over to SU. OS results obtained applying methods to adjust for cross-over are shown in Table 1. Conclusions: The 5-year OS difference (9.5 mo) between SU and PBO is confirmed. Correction for crossover yielded a stronger OS advantage with SU, confirming that crossover likely confounded the OS results. Clinical trial information: NCT00428597. [Table: see text]
Safety and feasibility of enhanced recovery after surgery in the patients underwent pancreaticoduodenectomy for hepatobiliary and pancreatic malignancy.
Authors: Kazama Keisuke , Aoyama Toru , Murakawa Masaaki , Yamaoku Koichiro , Atsumi Yosuke , Kanazawa Amane , Higuchi Akio , Shiozawa Manabu , Yukawa Norio , Oshima Takashi , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka , Morinaga Soichiro
Published: February 2017

338

Background: Pancreaticoduodenectomy (PD) remains the mainstay of surgical treatment for hepatobiliary and pancreatic malignancy and offers the only chance of long term survival. However, the morbidity and mortality after PD has been reported to be high. Therefore, it is important to determine the most appropriate perioperative care. This study assessed whether enhanced recovery after surgery (ERAS) program is safe and feasible in patients who underwent pancreaticoduodenectomy Methods: The subjects were patients who underwent consecutive PD between 2012 and 2014 at the Department of Gastrointestinal Surgery, Kanagawa Cancer Center. They received perioperative care according to ERAS program. All data were retrieved retrospectively. Outcome measures included postoperative mortality, morbidity, hospitalization and 30-day readmission rate. Key ERAS program targets were: nasogastric tube (NGT) removal [postoperative day (POD) 1]; resumption of oral fluids (POD 2); urinary catheter removal (POD 3); tolerating diet (POD 5); drain removal (POD 7). Results: A total of 109 patients were studied. The overall incidence of morbidity was 51.4%, the incidence of mortality was 1.8%, and the incidence of readmission was 1.8%. The median postoperative hospital stay was 23 days. The proportions of patients achieving key targets were: 93.6% for NGT removal; 94.5% for resumption of oral fluids; 31.2% for urinary catheter removal; 79.8% for tolerating diet; 80.7% for meeting mobility targets, and 37.6% for drain removal. Conclusions: ERAS program is safe and feasible in patients who undergo PD. However, achieving compliance on some targets, especially the removal of catcher and drain, were more challenging.
Overall survival and resection margin after hepatectomy for intrahepatic cholangiocarcinoma at academic cancer centers versus community cancer centers.
Authors: Berger Nicholas Gerard , Hammad Abdulrahman Y , Miura John Thomas , Johnston Fabian McCartney , Christians Kathleen K. , Tsai Susan , Turaga Kiran , Gamblin T. Clark
Published: February 2017

339

Background: Margin status is an important prognostic factor of survival following hepatectomy for intrahepatic cholangiocarcinoma (ICC). R0 resection for ICC correlates with improved recurrence-free survival and overall survival (OS). The present study hypothesized that surgical resection margins and survival rates vary between centers. Methods: Patients with ICC undergoing hepatectomy were identified from the National Cancer Database (1998-2011). Treating centers were categorized as Academic Cancer Centers (ACC), and Community Cancer Centers (CCC). Rates of R0 vs. R1/2 resection were examined. OS was analyzed by Kaplan-Meier method, and Cox multivariate modeling identified independent predictors of survival. Results: A total of 2,774 patients were identified. Hepatectomy was most often performed at ACC compared to CCC: 1,928 (69.5%) vs. 846 (30.5%). Hepatectomy at ACC was associated with higher rates of R0 resections compared to CCC (72.5% vs. 68.1%, p= 0.018). Higher 30-day readmission rates were seen following hepatectomy at ACC (9.9% vs. 5.7%, p= 0.002). Improved median OS was seen in ACC across all stages (25.8 months vs. 20.1 months; p< 0.001). After adjusting for age, sex, ethnicity, cirrhosis, alpha-feto protein level, comorbidity, disease stage, and margin status, hepatectomy at ACC was independently associated with improved OS (Hazards ratio: 0.79 [95%CI 0.62-0.99, p= 0.046]). Conclusions: ACC have higher rates of negative resection margins for ICC, but higher readmission rates following surgery. Survival is higher at ACC compared to CCC, suggesting that site of care plays a role in patient outcomes.
Gemcitabine (G) + nab-paclitaxel (nab-P) versus G in patients (pts) with advanced pancreatic cancer (PDAC) after FOLFIRINOX: A single center, retrospective review.
Authors: Chan Edmond Mankee , Hong Theodore S. , Clark Jeffrey William , Blaszkowsky Lawrence Scott , Allen Jill N , Zhu Andrew , Goyal Lipika , Murphy Janet E , Kwak Eunice L , Wo Jennifer Y , Ryan David P. , Faris Jason Edward
Published: February 2017

348

Background: The MPACT study showed that G + nab-P improved OS and PFS over G as first line therapy for metastatic PDAC. However, there is limited data studying this combination after FOLFIRINOX. Here, we compared G + nab-P to G in pts with advanced PDAC previously treated with FOLFIRINOX. Methods: From 3/2010 to 5/2014, we identified all pts treated with FOLFIRINOX for PDAC who later received G +/- nab-P at the MGH. PFS and OS were calculated from the start of G +/- nab-P and analyzed using Kaplan-Meier and Cox-regression analyses. Results: 40 pts received G + nab-P and 36 pts received G. 29 of 36 pts in the G arm started G prior to the FDA approval of nab-P. Baseline characteristics were similar except 7 pts in the G + nab-P arm had locally advanced PDAC at start of G + nab-P while all other pts in both arms had metastatic PDAC. The median OS was 4.8 months (m) for G + nab-P vs 4.2m with G (HR 0.69, 95% CI 0.42 – 1.13). The median PFS was 2.4m for G + nab-P vs 1.8m for G (HR 0.70, 95% CI 0.44-1.12). The median OS did not change when the analysis was restricted to pts with metastatic PDAC – 4.8m vs 4.2m (HR 0.68, 95% CI 0.41-1.14). The median PFS for pts with metastatic PDAC was also similar – 2.7m for G + nab-P vs 1.8m with G (HR 0.69, 95% CI 0.42-1.12). Pts treated with G + nab-P received a median of 4m of treatment vs 2m for pts with G alone. The median relative dose of G was 50% of the maximum anticipated dose over the first 8 weeks for G + nab-P vs 66% with G. The median relative dose for nab-P was 50% of the maximum anticipated dose over the first 8 weeks. The most common reasons for discontinuing therapy were progression (62.5% vs 69%), patient decision (5% vs 11%), and infection (12.5% vs 0%). Conclusions: Although retrospective and limited by a small sample size, our data suggests that G + nab-P could be considered over G for advanced PDAC after FOLFIRINOX. However, G + nab-P affords marginal improvement in median OS and PFS, thus calling for the need to explore other agents in the second-line setting. Moreover, our experience suggests that the addition of nab-P led to a reduction in the achievable dose of G – raising the question of tolerability in combining further agents to G + nab-P in this setting.
Risk factors of hospital mortality after initial hepatic resection among patients with primary hepatocellular carcinoma.
Authors: Qin Hong-Gui , Zhong Jian-Hong , Wang Yan-Yan , Lu Shi-Dong , Xiang Bang-De , Ma Liang , Gong Wen-Feng , Li Le-Qun
Published: February 2017

352

Background: Hepatectomy is widely used to treat patients with hepatocellular carcinoma (HCC), even those with intermediate and advanced disease. Despite its well-demonstrated clinical efficacy in many patients, postoperative mortality is an inevitable problem. This study aims to investigate the risk factors of mortality after hepatectomy. Methods: A consecutive sample of 1518 patients with HCC who underwent initial hepatectomy from January 1, 2004 to October 31, 2013 were retrospective analyzed. Multivariate analysis to identify independent risk factors of postoperative mortality was carried out using the Cox proportional hazards model. Parameters for multivariate analyses included age, gender, tumor size, tumor number, preoperative serum albumin, alanine aminotransferase, total bilirubin, α-fetoprotein, prothrombin time, tumor capsule, macrovascular invasion, portal hypertension, diabetes mellitus, ascites, major hepatectomy, surgical time, blood loss, blood transfusion, and clamping portal hepatis time. Results: A total of 18 (1.19%) and 45 (2.96%) patients died within 30 and 90 days after hepatectomy, respectively. Multivariate analysis revealed that tumor number ( ≥ 4), macrovascular invasion, and major hepatectomy were independent risk factors of 30 and 90 days mortality, while portal hypertension was also an independent risk factor of 90 days mortality. Conclusions: Among HCC patients with tumor number equal or more than four, macrovascular invasion, portal hypertension, or underwent major hepatectomy, intensive postoperative care management are in particular.
Impact of preoperative chemotherapy on overall survival for borderline resectable colorectal liver metastases
Authors: Saiura Akio , Inoue Yosuke , Mise Yoshihiro , Takahashi Yu , Ichida Takafumi , Ishizawa Takeaki
Published: February 2017

365

Background: Treatment for borderline colorectal liver metastases (CLM) is often started with chemotherapy. However, the impact on overall survival (OS) is still unknown. Aims: The aim of this study is to analyze the impact of preoperative chemotherapy on the outcome for up-front resectable borderline CLMs (BLR-CLM). Methods: A retrospective review was performed of 169 patients who underwent liver resection of BLR-CLM among 510 patients underwent liver resection for CLM between 2005 and 2013. BLR-CRLM was defined as CRLM of four or more nodules or 5cm or larger nodule. Time to surgical failure (TSF) was defined as the time until unresectable relapse or death. OS, recurrence free survival (RFS) and TSF were compared between BLR-CLM treated with neoadjuvant chemotherapy (NAC) and up-front surgery (US). Results: After median follow-up period of 38 months, 5-year survival rate after liver resection of resectable cases (n = 263), BLR-CLM (n = 169), and initially unresectable CLM (n = 78) are 67.7%, 47.5% and 32.6%, respectively. For patients with BLR-CLM, 22 patients with early recurrence during or early after postoperative chemotherapy for the primary were excluded. In the remaining 147 patients, 75 patients were treated with NAC and 72 with US. Cumulative 5-year overall survival rates, progression free survival rates, and time-to surgical failure in NAC and US group are as follows: OS (60.1% vs 47.7%, p = 0.084), PFS (23.1% vs 15.5%, p < 0.0001), TSF (38.0% vs 34.4%, p = 0.020). Conclusions: Preoperative chemotherapy for BLR-CLM could improve PFS and TSF. The impact on OS was still marginal. Prospective controlled study will be necessary.
The influence of perioperative decreasing total psoas area on prognosis of esophagieal cancer patients.
Authors: Hirata Yuki , Takeuchi Hiroya , Kikuchi Yuji , Matsuda Satoru , Fukuda Kazumasa , Nakamura Rieko , Takahashi Tsunehiro , Wada Norihito , Kawakubo Hirofumi , Kitagawa Yuko
Published: February 2017

38

Background: Depression of skeletal muscle mass (sarcopenia) has been linked to postoperative mortality in several carcinomas and various types of surgeries. Total psoas muscle area (TPA) has received attention as one of the indicators of systemic total skeletal muscle volume. The objective of this study is to determine the correlation between the patients who decreased TPA during pre-post operation and prognosis of esophageal cancer treated by surgical resection. Methods: We enrolled 40 esophageal cancer patients who underwent esophagectomy between April 2008 and May 2009. TPA was estimated by measuring the cross-sectional area of the psoas major muscle at the level of the third lumbar vertebra using an image-analysing software, identified on a preoperative CT scan, and a postoperative CT scan, which was taken on post-operative day 6. We divided the patients who decreased TPA between pre-post operation, into “decreasing group”, and the patients who preserved or increased TPA, into “non-decreasing group”. We investigated their backgrounds and prognosis. Results: Eighteen patients (45.0%) were classified as decreasing group, and 22(55.0%) patients were classified as non-decreasing group. Tumor locations, TMN Stage, or rates of neo-adjuvant chemotherapy, did not significantly differ between the two groups. Five-year overall survival rates (54.2% vs 85.7%, P = 0.046) were significantly lower in decreasing group in comparison with non-decreasing group. Recurrence-free survival rates (42.9% vs 85.7%, P = 0.012) were also significantly lower in decreasing group. The incidences of anastomotic leakage, or postoperative pneumonitis, did not differ between the two groups. Conclusions: The patients who decreased TPA during perioperative period associated with poor prognosis of esophageal cancer. The surgical operation for esophageal cancer is highly invasive, therefore active nutrition support and early rehabilitation during perioperative period might be indispensable.
The influence of tumor location, histology, and patient ethnicity on the accuracy of EUS in staging gastric and gastroesophageal junction (GEJ) cancers.
Authors: Huang Andy Z. , Xu Yiqing , Huang Yiwu , Nyemba Vimbai , Aye Than Than , Liu Na , Bayewitz Ashrei Y , Homel Peter
Published: February 2017

39

Background: Endoscopic ultrasound (EUS) is a routine staging test performed in patients with gastric and GEJ cancers and is highly valuable in treatment planning. The reported accuracy varies from 40% to 90%. We aim to investigate the staging performance of EUS at our institution and hypothesize that EUS accuracy can be influenced by tumor location, histology, and patient ethnicity. Methods: We performed a retrospective analysis of patients diagnosed with gastric and GEJ cancer between January 2006 and June 2015 who had EUS proceeded directly by surgery. T and N staging by EUS were analyzed for their sensitivity, specificity, and positive (PPV) and negative predictive values using surgery as the gold standard. The following variables were evaluated: tumor histology (intestinal or diffuse type), location (GEJ, cardia, body, or antrum), and patient ethnicity (Asian versus non-Asian). Results: Over 46 patients who met the inclusion criteria, EUS had T and N accuracy of 47.8% and 58.7%, respectively (p <.05). EUS had high specificity (88%) but low sensitivity (38%) for N staging. In predicting T staging, EUS was most accurate when the tumor was located in the body (72%, n = 7) and least accurate in the cardia (33%, n = 6) with 46% (n = 13) in the GEJ and 45% (n = 20) in the antrum. EUS tended to upstage the T value when a tumor is located in the body or GEJ, and downstage it in the cardia or antrum. The PPV using EUS for T1, T2, T3, and T4 were 89%, 22%, 45%, and 57%, respectively. The PPV using EUS for N staging was 73%. EUS was more accurate for T in Asians (55%, n = 33) than in non-Asians (31%, n = 13), and in intestinal type (56%) than diffuse (36%). For N staging, it was most accurate in the body (86%) and least accurate in the GEJ (50%). It was also more accurate in diffuse tumors (79%) than intestinal (52%) and more accurate in non-Asians (77%) than in Asians (53%). Conclusions: EUS as a common tool in preoperative staging may be inaccurate when performed in community hospitals. The predictive rate appears to vary in Asian vs non-Asian patients and in intestinal vs diffuse tumors. It is most predictive when the tumor is T1 and located in the gastric body. A prospective study is needed to confirm these findings.
Long-term responders to palliative chemotherapy for advanced biliary tract cancer.
Authors: Doherty Mark , McNamara Mairead G , Aneja Priya , Horgan Anne M. , Jang Raymond Woo-Jun , Dhani Neesha C. , Hedley David W. , Knox Jennifer J.
Published: February 2017

391

Background: Standard palliative chemotherapy (PC) in patients (pts) with Advanced Biliary Tract Cancer (ABTC) since publication of ABC-02 study in 2010 is cisplatin/gemcitabine (cis/gem), with median overall survival (OS) of 11.7 months. Prior to this, institutional standard was gemcitabine/fluoropyrimidine combination. From the ABC-02 study, 8 cycles of PC is standard. Some pts benefit from continuing PC longer than 8 cycles. Methods: Pts treated for ABTC in Princess Margaret Cancer Centre between 06/1987 and 09/2015, receiving > 8 cycles of PC were included for analysis. Data was collected on demographics, clinicopathologic features, PC regimen, toxicities, and survival. Results: Of 553 pts who received PC, 119 pts met inclusion criteria of PC > 8 cycles. Median age was 60 (range 27-80). Site of tumour was ampullary in 11, distal bile duct in 14, gallbladder in 28, intrahepatic in 37, perihilar in 26, and unspecified in 3 pts. 61 (51%) required biliary stenting. 30 (25%) had definitive surgical resection at diagnosis, while 89 (75%) presented with ABTC. First-line PC regimens were cis/gem in 44 and gemcitabine/capecitabine in 62. Other regimens included gemcitabine and 5-fluorouracil alone or combined. Median time on first line PC was 10 months, with median of 12 cycles (range 9-47). 22 pts (19%) had treatment breaks > 8 weeks then restarted same PC. Any tumour shrinkage was seen in 73 pts (61%). The majority of pts discontinued PC due to disease progression (69), however 16 stopped due to toxicity such as thrombocytopenia, neutropenia, fatigue and neuropathy. At time of analysis, 103 pts had progressive disease, with median progression free survival of 11.8 months. 51 and 21 pts received second and third line chemotherapy, respectively. 27 pts are alive; median OS for the whole group was 22 months (95%CI 18.7-27.3 months). Conclusions: A cohort of ABTC pts continued to derive benefit from chemotherapy beyond 8 cycles, with median OS considerably greater than that seen in clinical trials. Toxicities were mostly manageable, with treatment breaks from PC for relief of side-effects observed. Further exploration of factors prognostic and predictive for continued benefit from PC will be explored and updated at presentation.
Viral hepatitis associated hepatocellular carcinoma outcomes with Y-90 radioembolization.
Authors: Frakes Jessica M. , Abuodeh Yazan , Naghavi Arash , Friedman Mark , Kim Richard D. , Kothari Nishi , El-Haddad Ghassan , Kis Bela , Biebel Benjamin , Sweeney Jennifer , Choi Junsung , Anaya Daniel A. , Giuliano Anna , Hoffe Sarah E.
Published: February 2017

414

Background: Viral associated malignancies have been shown to have improved outcomes. We sought to evaluate outcomes of patients with and without viral hepatitis (HBV and HCV) treated with lobar yttrium-90 radioembolization (RE) for multifocal, unresectable hepatocellular carcinoma (HCC). Methods: After IRB approval, an institutional database of patients with HCC who received RE between 2009-2015 was queried and 99 patients were identified that received a total of 122 lobar RE. Charts were reviewed to capture previous treatments, α-fetoprotein values (AFP), Child-Pugh class (CP), albumin-bilirubin score (ALBI), portal vein thrombosis (PVT), volumes treated and doses delivered. Comparison was made with Chi-Square and Mann-U Whitney when appropriate. Intrahepatic control (IHC), extrahepatic control (EHC), progression free survival (PFS), and overall survival (OS) were calculated according to the Kaplan-Meier method via log-rank. Hazard ratios were calculated using Cox regression. Results: Median follow up for viral hepatitis and non-viral hepatitis patients was 10.9 months (range 0.8-46.7 months) and 11.8 months (range 1.1-62.8 months), respectively. Patients with viral hepatitis associated HCC (n = 44) were younger and had smaller liver volumes; however there was no difference with respect to gender, pre-treatment AFP, CP, ALBI, PVT, extrahepatic disease, previous treatments, and dose given. Median dose for viral hepatitis and non-viral hepatitis patients was 129.5 Gy (range 90-215.8 Gy) and 131 Gy (range 100.9-265 Gy), respectively. 1 year IHC was 67% for viral associated HCC versus 34% for non-viral HCC (p = 0.067). 1 year EHC was 63% for viral associated HCC versus 86% for non-viral HCC (p = 0.027). 1 year PFS was 45% for viral associated HCC versus 31% for non-viral HCC (p = 0.56). 1 year OS was 46% for viral associated HCC versus 55% for non-viral patients (p = 0.55). On MVA, patients that received salvage treatments, CP A, no PVT, and without extrahepatic disease had improved OS. Conclusions: Patients with viral hepatitis associated HCC had improved IHC and significantly worse EHC. Consideration should be made for systemic therapy following Y-90 embolization in patients with viral hepatitis associated HCC.
Natural history of T1N0M0 hepatocellular carcinoma: Large scale study in the United States.
Authors: Al-Shamsi Humaid Obaid , Abdel-Wahab Reham , Hassan Manal , Botrus Gehan , Shalaby Ahmed S , Wolff Robert A. , Kaseb Ahmed Omar
Published: February 2017

416

Background: Prognostic modeling of hepatocellular carcinoma (HCC) is complex due to preexisting cirrhosis in most cases. Tumor features and factors related to functional hepatic reserve must be taken into account when considering treatment options or counseling patients about their survival. The key prognostic factors may vary at different stages of the disease especially for early stage. Methods: From 1992 to 2011 total of 397 HCC patients with T1N0M0 were referred to MD Anderson Cancer Center for treatment. Detailed clinical-pathologic information were retrieved from medical records. Univariate analysis was done using the c2or Fisher’s exact test for categorical variables. Kaplan-Meier used to estimate the median overall survival (OS). Multivariate cox regression analysis was performed to estimate the hazard ratio (HR) and 95% confidence interval (CI). Results: The male to female ratio was3:1. The mean age ± standard deviation was 65.04 ± 12.5, 57.2% were non-viral related, 59.7% had cirrhosis, and 9.3% had poorly differentiated tumor (PDT). Median OS (95% CI) was 28.5 months (23.6 – 33.4). First line therapy is summarized in table 1. Surgical intervention was similar to systemic therapy with 76% reduction in mortality compared to non-treated group. Restricted analysis among cirrhotic patients showed similar results. PDT was associated with significant poor prognosis compared to well-differentiated tumor, HR (95% CI) was 2.42 (1.36-4.28) after adjustment for demographic, epidemiological, and clinical factors. Conclusions: Our results indicate that T1N0M0 HCC patients have similar outcome with systemic therapy and surgery which could be beneficial for patients with underlying cirrhosis and high risk of postsurgical complications. [Table: see text]
The use of stereotactic body radiotherapy as a bridge to liver transplantation for hepatocellular carcinoma.
Authors: Barry Aisling S , Sapisochin Gonzalo , Russo Moises , Brade Anthony M. , Brierley James D. , Kim Joon-Hyung J. , Greig Paul D , Grant David , Dawson Laura A.
Published: February 2017

418

Background: Approximately 30% of patients with hepatocellular carcinoma (HCC) on the wait list for liver transplant (LT) fall off the transplant list due to progressive HCC. Stereotactic Body Radiotherapy (SBRT) has been used as a “bridge” to LT in patients who are not amenable to RFA or TACE. Methods: Baseline patient characteristics, radiotherapy details and outcomes were reviewed in HCC patients who received SBRT as a bridge to LT. Results: Between July 2004 and Dec. 2014, 601 patients with HCC were listed for LT, of which 400 (66.5%) received bridging therapy. 38 patients, at high risk for HCC progression, were unsuitable for RFA or TACE, receiving SBRT as a bridging therapy. Median SBRT dose was 36Gy in 6 fractions (range 8.5-48Gy in 1 – 6 fractions), including 1 patient who was transplanted after receiving one fraction. 25 of 38 patients (67%) had all lesions treated (median number of lesions 2 {1-8}); 13 patients received SBRT only to the dominant lesion at highest risk of growing or rupturing. At the time of SBRT, 42% had HCC within Milan criteria, and median Child Pugh score was A6 (range A5-B8). 5 patients (13%) dropped off the transplant wait list due to development of metastatic disease (4) and macrovascular invasion with progressive disease (1). Median irradiated HCC volume was 60.5cc (range 7-216cc). Median liver volume (minus HCC) was 1491cc (737-2728cc). Median mean dose to the liver minus HCC was 11.2Gy (2.8-18.6Gy) and median effective liver volume irradiated was 28% (11-66%). 1 patient was admitted 2 months post SBRT with hepatic pain - possibly attributable to SBRT and another patient developed a rib fracture 8 months post SBRT (max rib dose 43Gy in 6 fractions). No other specific SBRT toxicity was noted. The 1-, 3- and 5-year disease free survival and actuarial survival of HCC patients treated with SBRT who went on to have transplant was 93%, 79% and 79%, and 89%, 76% and 76% respectively. Including patients who dropped off the transplant list, the intent-to-treat 1-, 3 - and 5-year survival was 89%, 65% and 65%. There was no reported increase in operative morbidity at the time of transplant in patients treated with SBRT. Conclusions: SBRT can be used safely and effectively in HCC patients as a bridge to liver transplant.
Pathological heterogeneity after trastuzumab and combination chemotherapy in HER2+ gastroesophageal adenocarcinoma xenograft.
Authors: Yip Connie , Weeks Amanda , Cook Gary J. R. , Shaw Karen , Siddique Muhammad , Landau David B. , Goh Vicky
Published: February 2017

42

Background: Trastuzumab (T) is the standard of care in advanced HER2+ gastroesophageal (GE) adenocarcinoma with response in 47% of patients. We evaluated its pathological effects in a HER2+ OE19 xenograft model aiming to improve future treatment intensification/response assessment. Methods: SCID mice (n = 23) bearing subcutaneous OE19 tumors were treated with intraperitoneal saline (control), Cisplatin 4mg/kg once a week (C), Trastuzumab 20mg/kg twice a week (T) or Cisplatin and Trastuzumab (CT) for 2 weeks. Volumetric tumor response was measured by MRI. Excised tumors were stained for IHC markers of hypoxia (Pimonidazole), proliferation (Ki-67) and angiogenesis (CD34). Hypoxic (HF) and proliferative fractions (PF) were defined as the ratios of tumor area positively stained for Pimonidazole/Ki-67 to area of whole tumor section. Microvessel density (MVD) was defined as the average number of blood vessels/endothelial cells identified within 0.01cm2field at x100 magnification. Pathological assessment was performed for whole tumor, centre and rim. Mean±SD are presented. Kruskal-Wallis test was used to compare HF, PR, MVD and volumetric change between groups; significance at < 0.05. Results: Tumor growth was reduced in CT (+83% from baseline MRI) compared to control (+600%), C (+275%) and T (+129%) groups (p= 0.015). Monotherapy treated tumors had lower HF (C 0.08±0.03, T 0.09±0.07) compared to CT (0.16±0.06) and control (0.15±0.04) (p= 0.039). T and CT treated animals had higher MVD (T 23.5±12.7, CT 37.3±10.3) compared to control (18.1±10.4) and C (18.1±7.5) (p= 0.014). Whole tumor PF was lower in the monotherapy groups but this was not significant (p =0.123). PF and MVD were higher in tumor centre compared to rim in T and CT groups compared to control but there was no spatial difference in hypoxia distribution. Conclusions: Tumor control was improved with combination treatment but no synergistic pathological effect was seen; CT treated tumors were more hypoxic/angiogenic compared to monotherapy with greater cellular density/angiogenesis within tumor centre. This could be due to predominant early cytostatic effect and ongoing angiogenic normalisation with CT therapy at 2 weeks.
Interim results of a randomized phase II study of PEGPH20 added to nab-paclitaxel/gemcitabine in patients with stage IV previously untreated pancreatic cancer.
Authors: Hingorani Sunil R. , Harris William Proctor , Seery Tara Elisabeth , Zheng Lei , Sigal Darren , Hendifar Andrew Eugene , Braiteh Fadi S. , Zalupski Mark , Baron Ari David , Bahary Nathan , Wang-Gillam Andrea , LoConte Noelle K. , Springett Gregory M. , Ritch Paul S. , Hezel Aram F. , Ma Wen Wee , Bathini Venu Gopal , Wu Xionghua W. , Jiang Ping , Bullock Andrea J.
Published: February 2017

439

Background: Poor outcome in pancreatic cancer (PDA) is associated partly with stromal hyaluronan (HA) accumulation, which compromises chemotherapy perfusion. PEGPH20, PEGylated recombinant human hyaluronidase, potentiates chemotherapy by depleting HA in tumors. Methods: In an ongoing, phase II, open-label, randomized study of PEGPH20+nab-paclitaxel (Nab)+Gemcitabine (Gem) (PAG) vs Nab+Gem (AG) in previously untreated stage IV PDA, pts receive PEGPH20 3 µg/kg twice weekly (C1), then weekly (C2+) with standard AG dosing. HA status was tested retrospectively. After a temporary clinical hold (Apr-Jul 2014) for an imbalance in thromboembolic (TE) events (29% PAG vs 15% AG), the protocol was amended to exclude high-TE-risk pts and add enoxaparin (LMWH) prophylaxis. Endpoints are PFS and TE events (primary); PFS and ORR by HA level and OS (secondary). Efficacy and safety data through Dec 2014 are for pts enrolled up to clinical hold (Stage 1); TE data are through Sep 2015 (Stage 2). Results: 135 pts were treated (74 PAG, 61 AG). PFS results are shown below (median follow-up 7 mo). In HA-high pts receiving PAG vs AG, ORR was 52% (1 CR) vs 24% (P=.038); ORR was 37% vs 38% in HA-low pts. OS was 12 mo vs 9 mo (HR=0.62) despite 12/23 PAG pts discontinuing PEGPH20 at clinical hold. Common ADRs (PAG vs AG) included peripheral edema (58% vs 31%), muscle spasms (55% vs 1.6%), and neutropenia (32% vs 18%). TE events were: Stage 1 42% vs 25% (no LMWH); Stage 2 (with LMWH; 40 mg/d or 40 mg/d increased to 1 mg/kg/d) 28% vs 29%; (1 mg/kg/d) 5% vs 6%; overall (40 mg/d or 1 mg/kg/d) 13% each arm (to be updated). Conclusions: Pts with HA-high tumors receiving PAG, vs AG, showed significant improvements in PFS and ORR and a trend toward improved OS. PAG was well tolerated, with TE events reduced with LMWH prophylaxis. A global phase III trial of PAG will initiate Q1 2016. Clinical Trial Information: NCT01839487. Clinical trial information: NCT01839487. [Table: see text]
Diverse clinical outcome and predictors for clinical outcome in patients with HCC treated with TACE.
Authors: Bhardwaj Prarthna , Prins Petra , Kim Alexander Y. , Jha Rheena , Wang Hongkun , Sullivan David , Taher Salha , Zhang Tiger , Zhu J , Marshall John , He Aiwu Ruth
Published: February 2017

442

Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer, and the second leading cause of cancer-related death, worldwide. This reflects the challenges facing HCC treatment. Methods: Patients (pts) with HCC receiving TACE treatment (n = 96) were examined retrospectively for clinical outcome and its possible predictors. The number of TACE treatments and the time elapsed between each treatment were assessed and correlated with overall survival (OS) using the log rank test of Kaplan Meier curves. T-stage, level of differentiation, vascular invasion, and Child Pugh score at the time of HCC diagnosis were compared among pts who received different numbers of TACE treatments (Kaplan-Meier survival analysis, ANOVA and student T test). Results: TACE treated pts had a median OS of 46 month (mo) and progression free survival of 12 mo (difference in time between the date of first progression and the date of diagnosis). Pts received 1-2 (n = 52), 3-4 (n = 28), or 5-6 (n = 16) TACE treatments. We found that pts who had only 1-2 TACE treatments had significantly shorter median OS (38 mo) than those who received 3-4 or 5-6 treatments (48 and 83 mo; p < 0.05). Of the 96 pts studied 22, 33, 37, and 3 pts had T1, T2- T3 and T4-stage HCC, respectively. Only 39 pt tumors underwent pathological analysis, and 13 were well-differentiated (WD), while 24 were moderately- or poorly- differentiated (MPD) (p > 0.05). Tumor T-stage and differentiation were correlated with the number of TACE treatments received. Thus, 30% of pts (n = 10) with T2-stage disease compared with 10% (n = 4) with T3-stage disease received 5-6 TACE treatments (p < 0.001). Similarly, 30% of WD cases (n = 4) compared with only 8% of MPD cases (n = 2) received 5-6 TACE treatments (p < 0.001). The duration between the second and third TACE treatments ( < 4 mo, 5-8 mo or > 8 mo) seemed to correlate with outcome (p < 0.05). Conclusions: Pt survival time following TACE treatment is diverse and correlates with the number of TACE treatments. Pts with T3-stage, or MPD HCC tended to receive fewer TACE treatments than those with T2-stage or WD HCC, and have worse outcomes. Other therapies should certainly be considered for pts with T3-stage and/or MPD tumors.
Two-arc volumetric modulated arc therapy to provide dosimetric advantages for pancreas stereotactic body radiotherapy.
Authors: Molitoris Jason K , Brown Christopher , Chen Shifeng , Marter Kimberly , Spaeth Kristin , Regine William , Chuong Michael David
Published: February 2017

445

Background: Stereotactic body radiation therapy(SBRT) is increasingly used in locally advanced pancreatic cancer (LAPC). SBRT can be delivered using 3D conformal, static intensity modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT) techniques. Prior data suggest advantages of using VMAT over IMRT for single-fraction pancreas SBRT. We performed the first dosimetric comparison of IMRT with one and two arc VMAT for 5-fraction pancreas SBRT, a more commonly used regimen. Methods: We generated 5-fraction SBRT plans for 12 LAPC patients who were previously treated at our institution with standard fractionation. The prescription dose was 33 Gy delivered in 6.6 Gy fractions. Assuming breath hold, 3 plans were generated for each patient: 9-beam static IMRT, 1-arc VMAT (VMAT1), and 2-arc VMAT (VMAT2) targeting the primary tumor. Target coverage and normal tissue doses were compared between the delivery techniques. Results: Each plan met target coverage planning goals. More VMAT2 plans (100%) were able to meet all normal tissue constraints than VMAT1 (83.3%) or IMRT (75%). Duodenal dose was most lowest for VMAT2 compared to VMAT1 and IMRT for mean dose (8.66 vs. 9.00 vs. 8.99 Gy); D4% (25.9 vs. 26.6 vs. 26.3 Gy); V10Gy (38.02 vs. 39.33 vs. 40.11%), V15Gy (23.98 vs. 25.88 vs. 25.97%), V20Gy (12.73 vs. 13.84 vs. 14.95%), and V25Gy (5.96 vs. 6.85 vs. 6.78%)(all p < 0.05). The tumors closest to the duodenum had statistically significantly improved V30Gy for VMAT2 compared to VMAT1 and IMRT (both p < 0.001). VMAT1 and VMAT2 reduced dose to the stomach, spinal cord, and liver compared to IMRT; kidney dose, however, was lowest using IMRT. VMAT2 plans had the highest conformity, but required the most monitor units to deliver. Delivery time was significantly longer with IMRT, compared to VMAT1 and VMAT2 (8.25 vs. 2.16 vs. 3.33 mins). Conclusions: These data suggest that VMAT2 should be strongly considered for 5-fraction pancreas SBRT because of superior normal tissue sparing, more conformal target volume coverage, and faster treatment delivery time (compared to IMRT). Further evaluation is needed to clarify whether the dosimetric advantages of VMAT2 are clinically significant.
A prospective study evaluating stereotactic body radiation therapy in unresectable, recurrent, or residual pancreatic adenocarcinoma.
Authors: Rosati Lauren M. , Moningi Shalini , Hacker-Prietz Amy , Laheru Dan , Zheng Lei , De Jesus-Acosta Ana , Le Dung T , Moore Joseph A. , Fishman Elliot K. , Raman Siva P. , McNutt Todd R. , Pawlik Timothy M. , Eckhauser Fred E , Weiss Matthew J. , Herman Joseph M.
Published: February 2017

454

Background: The purpose of this prospective, non-randomized phase II single-institution study was to evaluate if local control can be achieved with reasonable acute and late GI toxicity using fractionated SBRT in patients with unresectable, recurrent, or residual locally advanced pancreatic cancer (LAPC). Methods: A total of 24 patients with LAPC were enrolled from June 2013 to August 2014. Eligibility required stability after induction chemotherapy or residual disease or local failure after surgery. Induction chemotherapy regimens consisted of: (1) gemcitabine alone (8%); (2) gemcitabine-based regimens (17%); (3) FOLFIRINOX-based regimens (63%); or (4) combination regimens (13%). Chemotherapy was discontinued one week prior to SBRT. Patients received a median cumulative dose of 33 Gy in 5 fractions (5-6.6 Gy/fraction). Patients were permitted to resume chemotherapy one week post-SBRT. Toxicity was assessed using the NCI CTCAE version 4.0. Results: Of the 24 patients, 58% were male and 50% had tumors in the head of the pancreas. Median age at diagnosis was 66.8 years, and median follow-up from the date of diagnosis was 11.9 months (range, 7.4-29.7 months). There have not been any acute or late grade ≥ 2 gastritis, enteritis, fistula, or ulcer toxicities (primary endpoint). Median OS has not yet been reached, median LPFS was 19.3 months (95% CI, 12.3-14.8), median DMFS was 13.6 months (95% CI, 9.2-17.9) and median PFS was 13.6 months (95% CI, 13.5-25.2). Plasma CA 19-9 level was non-significantly reduced after SBRT, displaying a -9.15 average percent change from baseline (median time after SBRT, 1.2 months). FFLP at 1 year was 83.9%. Eight (33%) patients underwent successful surgery following SBRT, with rates of both margin- and node-negative resection being 75%. Conclusions: Chemotherapy followed by fractionated SBRT results in favorable local control and survival with minimal acute and late GI toxicity. A notable proportion of patients initially deemed unresectable underwent successful resection. This study suggests that SBRT can be safely given following more aggressive multiagent chemotherapy in patients with LAPC. Clinical trial information: NCT01781728.
Palliative treatment in extrahepatic biliary malignancies: A multi-institutional cohort.
Authors: Wilson Ana , Ethun Cecilia Grace , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Fields Ryan C. , Krasnick Bradley , Weber Sharon M. , Salem Ahmed I. , Martin Robert C. G. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Shenoy Rivfka , Maithel Shishir Kumar , Pawlik Timothy M.
Published: February 2017

456

Background: Extrahepatic biliary malignancies (EBM) are often first diagnosed at advanced stages when the disease is no longer surgically resectable. While palliative resection may provide a more definitive solution for patients with jaundice, it also carries a higher risk of complications than endoscopic or percutaneous drainage. Herein, we analysed patients undergoing both methods of palliation to better delineate these risks. Methods: 172 patients who underwent palliative treatment for EBM between 2000 and 2014 were identified from 10 major hepato-biliary centers participating in the EBM Consortium. Clinicopathologic, operative and outcome data were collected and analyzed. We used propensity score matching to correct for confounding by indication. Results: 113 patients underwent surgery with palliative resection of their tumor (65.7%), while 59 underwent diagnostic surgery, but were treated with percutaneous or endoscopic biliary drainage instead of resection (34.3%). Patients who were not resected were more frequently jaundiced preoperatively (p = 0.001), and were more likely to undergo repeat drainage procedures (p < 0.001). After matching for functional status, age, and clinical jaundice, patients who underwent resection had significantly more complications (55.6% vs. 34.0%; p = 0.035), a higher median number of complications (1 vs. 0; p = 0.0149), a higher Clavien Dindo Grade (IIIa vs. II; p = 0.0261), a longer hospital stay (8 vs. 4 days; p < 0.001), and a notable trend towards higher perioperative mortality (10.9% vs. 1.96%; p = 0.069). Meanwhile the postoperative bilirubin level was equal among the resected (1.80 mg/dL (IQR, 0.60-8.90)) and drainage groups (2.45 (IQR 0.60-10.5))(p = 0.477), and both groups had a statistically significant drop after treatment (resection 8.30 mg/dL to 1.80 mg/dL, p < 0.001; drainage 8.4 to 2.45, p < 0.001). Conclusions: Both palliative resection and biliary drainage successfully treated EBM patients’ hyperbilirubinemia. However, in a propensity score matched group, palliative resection patients had more complications and a trend towards more perioperative mortality, urging caution in the selection of patients for these procedures.
Early detection of colorectal neoplasia: Combination of eight cancer-associated blood-based protein biomarkers.
Authors: Christensen Ib J. , Wilhelmsen Michael , Gawel Susan , Yang Xiaoqing , Brunner Nils , Martens Frans , Heijboer Annike , Davis Gerard , Nielsen Hans J.
Published: February 2017

488

Background: Assessment of 8 blood based protein markers for identifying colorectal neoplasia. Methods: 4,698 subjects scheduled for first time ever colonoscopy with symptoms potentially attributable to colorectal neoplasia were accrued. Plasma levels of AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3, and TIMP-1 were determined by using the Abbott ARCHITECT i2000 automated immunoassay platform. Three clinical endpoints were chosen for this presentation: 1. CRC, 2. CRC and high risk adenoma, 3. CRC and other cancers. Logistic regression was used for statistical analysis of each endpoint. A final reduced model was selected choosing the best combination of 4 markers with the highest likelihood score statistic. Results: 512 CRC’s were identified, 323 CC and 189 RC. Malignancies other than CRC were detected in 177 subjects, 699 adenomas were identified including 298 with high risk, 1342 subjects had non-invasive bowell disease, and 1978 had a “clean” colon. Univariate analysis of each endpoint demonstrated that all markers were statistically significant. Multivariable logistic regression showed that the blood based markers in combination significantly predicted the 3 endpoints. The reduced model resulted in the selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the 3 endpoints. The area under the receiver operating characteristic curves were 0.83, 0.74 and 0.82 respectively. The postive predictive value (PPV) at 90% sensitivity was 18% for endpoint 1 and the negative predictive value (NPV) was 97%. For endpoints 2 and 3, the PPV’s were 25% and 20% and the NPV’s were 93% and 96%. Conclusions: A subset of 4 biomarker in combination identify subjects with a high risk of CRC.
Changes in apparent diffusion coefficient evaluated with diffusion-weighted MRI to predict complete pathologic response after neoadjuvant therapy for rectal cancer: Literature review and meta-analysis.
Authors: Desiato Vincenzo , Rosman Alan S , Newman Elliot , Berman Russell S. , Pachter H. Leon , Melis Marcovalerio
Published: February 2017

503

Background: A complete pathological response (pCR) is observed in 9-38% of all patients undergoing neo-adjuvant chemo-radiation therapy (CRT) for locally advanced rectal cancer (ARC). Imaging techniques that can reliably assess CRT results may enhance identification of those pCR patients for which surgery may potentially be avoided. Recently, several studies have suggested that diffusion-weighted magnetic resonance imaging (DW-MRI) may predict pathologic response by measuring tumor apparent diffusion coefficient (ADC). ADC can be measured before (pre-ADC) and/or after CRT (post-ADC). Both pre- and post-ADC, as well as the variation between pre- and post-ADC (Δ-ADC) can be used to assess pCR. We aimed to assess the reliability of ADC at predicting pCR in ARC patients treated with CRT. To determine the most effective ADC timing to evaluate pCR. Methods: A systematic review of available literature was conducted to compare all the studies of DW-MRI for identification of pCR after CRT for ARC. For each parameter (pre-ADC, post-ADC and D-ADC) we pooled sensitivity and specificity and calculated the area (AUC) under the summary receiver operating characteristics (sROC) curve. Results: We found 10 prospective and 8 retrospective studies examining correlation of ADC and CRT results. Overall, pCR rate was 25%. Pooled sensitivity, specificity, and AUC were: 0.743, 0.755, and 0.841 for pre-ADC; 0.745, 0.706, and 0.782 for post-ADC; and 0.832, 0.806, and 0.895 for D-ADC. Conclusions: Our meta-analysis confirms that at least 25% of patients with ARC experiences pCR after CRT. DW-MRI is a promising technique for assessment of CRT results and D-ADC appears to be the most effective parameter for prediction of pCR.