bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of a clinical pathway for borderline resectable pancreatic cancer.
Authors: Rashid Omar Maen , Pimiento Jose Mario , Springett Gregory M. , Malafa Mokenge Peter
Published: February 2017

374

Background: While multimodality therapy for borderline resectable pancreatic adenocarcinoma (BPA) is advocated, treatment regimens vary by institution without a standardized approach supported by prospective randomized data. We implemented a multidisciplinary multimodality clinical pathway (CP) for the management of BPA and examined outcomes to investigate optimal therapy. Methods: From January 1, 2006, to December 31, 2013, BPA cases as defined by the NCCN and AHPBA consensus guidelines were managed prospectively along CP. Resection rates, margin status, pathologic response, and overall survival were retrospectively examined. Standard statistical and survival analysis were used. Results: 121 patients were classified as BPA and 101 entered the CP. The neoadjuvant chemoradiation (NT) completion rate was 93.1%. Of those who entered the CP, 55 patients (54.5%) underwent pancreatectomy. R0, R1 and R2 margin rates were 96.3%, 3.7% and 0%, respectively. Of the 55 patients who underwent resection, 22 (40%) required vascular reconstruction, with R0, R1 and R2 margin rates of 95.2%, 4.8%, and 0%, respectively. Pathologic response to treatment was found in 70.8%, with a complete response rate of 15.9%. Median overall survival in the resected group versus the non-resected group was 34.2 months versus 14.7 months, p<0.001. Conclusions: Our series represents one of the largest reports of BPA in the literature and implementation of our CP resulted in a high NT completion rate and pancreatectomy with negative margin rate. Although 41.4% of cases were not resectable after NT, there was a high rate of negative margin resection with >70% pathologic response rate and a favorable median survival.
Efficacy of sorafenib in patients with oligometastatic hepatoceulluar carcinoma (HCC).
Authors: Thillai Kiruthikah , Ziogas Dimitrios , Korantzis Ippokratis , Chowdhury MH Ruhe , Papadatos-Pastos Dionysios , Suddle Abid , O'Grady John , Heaton Nigel , Ross Paul J. , Sarker Debashis
Published: February 2017

389

Background: HCC is the second leading cause of cancer related mortality worldwide. Standard treatment for advanced disease is sorafenib, which is associated with a modest improvement in overall survival. We hypothesized that patients with oligometastatic disease treated with sorafenib have improved outcomes over those with extensive metastases. Methods: A retrospective analysis of all patients with advanced HCC treated with sorafenib at a large HCC centre. 190 patients were identified (177 patients with sorafenib alone, 13 patients treated with a combination of sorafenib and erlotinib/placebo as part of the SEARCH trial). Disease distribution was defined as intra-hepatic, oligometastatic (3 or fewer extra-hepatic metastases) and extensive (more than 3 metastases) at the time of starting sorafenib. Overall survival (OS), progression free survival (PFS) and toxicities were recorded. Results: The median age for all patients was 66 years (26-87), 157 male and 33 female. Underlying liver disease included hepatitis B (N=39, 20.4%,) hepatitis C (N=38, 19.9%), alcoholic liver disease (N=38, 19.9%), non-alcoholic fatty liver disease (N=27, 14.1%), unknown aetiology (N=42, 21.9%) and other (N=7, 3.6%). 157 patients had Child-Pugh A status, 33 patients Child-Pugh B. 113 patients had intra-hepatic disease, 45 patients had extensive disease and 32 patients had oligometastatic disease. Median OS for all patients treated with sorafenib was 7.6months(m) and PFS was 4.3m. For patients with oligometastatic disease, OS was significantly longer than those with extensive disease (10.4m vs. 6.3m p=0.034). PFS was also increased at 5.9m vs. 2.8m p=0.028). 50 patients (26%) developed grade 3 or greater toxicity, including diarrhea (N=10, 5.2%), fatigue (N=15, 7.8%) and skin (N=12, 6.3%). There were no statistically significant differences in toxicities amongst patients with oligometastatic disease compared with those with extensive disease. Conclusions: This study suggests that patients with oligometastatic disease have improved survival outcomes compared with patients with extensive disease. Further prospective research is needed to confirm these findings.
The Glasgow whipple risk score to predict pancreas-specific complications after pancreaticoduodenectomy.
Authors: Palani Velu Lavanniya Kumar , Chandrabalan Vishnuvardhan , Carter Ross , McKay Colin , McMillan Donald , Jamieson Nigel B , Dickson Euan
Published: February 2017

394

Background: Pancreas-specific complications (PSC), comprising postoperative pancreatic fistula, post-pancreatectomy haemorrhage, and intra-abdominal collections, are drivers of morbidity following pancreaticoduodenectomy (PD). Intra-operatively derived pancreatic gland texture is a major determinant of postoperative PSC. We have previously demonstrated that a postoperative day 0 (PoD0) serum amylase ≥ 130 IU/L is an objective surrogate of pancreatic texture, and is associated with PSC. We sought to refine the PSC risk prediction model by including serial measurements of serum C-reactive protein (CRP). Methods: 230 consecutive patients undergoing PD between 2008 and 2014 were included in the study. Routine serum investigations, including amylase and CRP were performed from the pre-operative day. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP associated with clinically significant PSC. Results: 95 (41.3%) patients experienced a clinically significant PSC. ROC analysis identified post-operative day 2 (PoD2) serum CRP of 180 mg/L as the optimal threshold (P=0.005) associated with clinically significant PSC, a prolonged stay in critical care (P =0.032), and a relaparotomy (P = 0.045). Patients with a PoD0 serum amylase ≥ 130 IU/L who then developed a PoD2 serum CRP ≥ 180 mg/L had a higher incidence of postoperative complications. Patients were categorised into high, intermediate and low risk groups based on PoD0 serum amylase and PoD2 serum CRP. Patients in the high risk group (PoD0 serum amylase ≥ 130 IU/L and PoD2 serum CRP ≥ 180 mg/l) had significantly higher incidence of PSC, a return to theatre, prolonged lengths stay (all P≤ 0.05) and a four-fold increase in perioperative mortality compared patients in the intermediate and low risk groups (7 deaths in the high risk group versus 2 and nil in the intermediate and low risk groups respectively). Conclusions: A high risk profile, defined as PoD0 serum amylase ≥ 130 IU/L and PoD2 serum CRP ≥ 180 mg/l, should raise the clinician’s awareness of the increased risk of clinically significant PSC and a complicated postoperative course following pancreaticoduodenectomy.
Final analysis of a phase II study of Yale-modified FOLFIRINOX (mFOLFIRINOX) in metastatic pancreatic cancer (MPC).
Authors: James Edward Samuel , Cong Xiangyu , Yao Xiaopan , Hahn Carol , Kaley Kristin , Li Jia , Kortmansky Jeremy S. , Fischbach Neal A. , Cha Charles , Salem Ronald R , Stein Stacey , Hochster Howard S. , Lacy Jill
Published: February 2017

395

Background: Although FOLFIRINOX is superior to gemcitabine in MPC, the regimen is associated with significant toxicities (Conroy et al. N Engl J Med 2011;364:1817). In our prior retrospective analysis, efficacy was not compromised by dose attenuations of FOLFIRINOX (Gunturu et al. Med Oncol 2013;30:361). Based on this analysis, a prospective phase II open label study to evaluate the efficacy and tolerability of mFOLFIRINOX in pts with locally advanced (LAPC) and MPC was conducted. Herein, we report the final analysis of the toxicity in LAPC and MPC, and the efficacy in MPC. Methods: Previously untreated pts with MPC or LAPC received mFOLFIRINOX every two wks with 25% dose reductions of irinotecan & bolus 5FU until progression, unacceptable toxicity, or surgical resection. All pts received prophylactic pegfilgrastim. CAT scans were obtained every 4 cycles for response assessment by RECIST. Toxicities in the entire cohort, and response rate (RR) & pt characteristics in the MPC cohort were compared to historical data reported by Conroy. PFS was determined for MPC cohort. Results: 31 pts with LAPC and 43 pts with MPC with ECOG PS 0/1 were enrolled between 11/11 and 01/14. Characteristics of evaluable (37/43) MPC pts were: med age, 61 yrs (range 50-76); male, 21; ECOG PS 0, 17; med # metastatic sites, 2; peritoneal disease, 14; biliary stent, 9; med # of cycles 10 (range 4-31). Grade 3/4 toxicities in entire cohort were: vomiting & peripheral neuropathy, 2.7%; ALT elevated, thromboembolism and febrile neutropenia, 4.1%; anemia, 5.4%; diarrhea,16.2% (no grade 4 diarrhea reported); neutropenia & fatigue, 12.2%; thrombocytopenia, 9.5%. Neutropenia (p<0.0001), vomiting (p=0.0014), and fatigue (0.0194) were significantly decreased compared to historical data. RR in 37 pts with MPC was 35.1% (0 CR, 13 PR, 19 SD, 5 PD) and similar to historical data (36.9%; p 0.86). PFS in MPC pts was 6.11 mo with 95% CI (5.29, 8.31). Conclusions: mFOLFIRINOX with prophylactic pegfilgrastim in pts with MPC is associated with improved tolerability compared to full dose FOLFIRINOX, while RR and PFS in pts with MPC is similar to that reported by Conroy et all using full dose FOLFIRINOX. MPC pts are in follow-up for OS. Follow up for LAPC patients is ongoing. Clinical trial information: NCT01523457.
Phase I trial of sorafenib following liver transplantation in patients with high-risk hepatocellular carcinoma.
Authors: Siegel Abby B. , El-Khoueiry Anthony B. , Finn Richard S. , Guthrie Katherine , Venook Alan P. , Blanke Charles David , Brown Robert S.
Published: February 2017

401

Background: Liver transplantation (LT) offers excellent long-term survival for hepatocellular carcinoma (HCC) patients who are within established criteria. For those outside such criteria, or with high risk pathologic features in the explant, HCC recurrence rates after LT are high. No treatment has been shown to decrease risk of recurrence post-LT. We conducted a multicenter phase I trial of sorafenib in LT patients with high-risk HCC. Methods: Subjects had pathologically proven high-risk HCC defined as outside Milan (pre- or post-transplant), poorly differentiated tumors, or tumors with vascular invasion. We used a standard 3+3 phase I design, beginning drug between 4 and 16 weeks after LT, with planned duration of treatment of 24 weeks. Cohort dosages were: 1) 200 mg per day, 2) 200 mg twice a day, 3) 200 mg/400 mg per day 4) 400 mg BID. Correlative studies included circulating endothelial cells (CECs) and plasma biomarkers collected prior to treatment, at 1 month, and at recurrence in a subset of subjects, and tumor expression of p-Erk, p-Akt, and c-Met in tissue microarrays. Results: We enrolled 14 patients. Median age was 63 years, and 93% were men. 71% had underlying HCV and 21% had HBV. Maximum tolerated dose (MTD) was 200 mg BID; only 43% of patients received >80% of planned dose. Grade 3-4 toxicities seen in >10% of subjects included: leukopenia (29%), LFT abnormalities (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 953 days, 1 patient died and 4 recurred, with a median recurrence-free survival of 716 days for the 4 patients who recurred. Mean CEC number at baseline was 21 cells/4 ml for those who recurred, and 80 cells/4 ml for those who did not (p=0.10). Mean sVEGFR2 levels decreased after 1 month on sorafenib (p=0.09), but did not correlate with recurrence. There was a trend for tumor c-Met expression with increased risk of recurrence. Conclusions: Post-transplant sorafenib is feasible and tolerable at 200 mg PO BID. Recurrence-free survival appears longer than expected but needs further validation in a larger study. Clinical trial information: NCT00997022.
Neoadjuvant chemoradiation therapy for cholangiocarcinoma to improve R0 resection rate: The first report of phase II study.
Authors: Katayose Yu , Nakagawa Kei , Yoshida Hiroshi , Morikawa Takanori , Hayashi Hiroki , Okada Takaho , Mizuma Masamichi , Sakata Naoaki , Ohtsuka Hideo , Fukase Koji , Yabuuchi Shinichi , Ishida Masaharu , AOki Takeshi , Okada Ryo , Masuda Kunihiro , Kawaguchi Kei , Motoi Fuyuhiko , Naitoh Takeshi , Unno Michiaki
Published: February 2017

402

Background: With the much-improved surgical techniques of hepatic lobectomy, but the long-term survival of patients undergoing such surgery remains far from satisfactory. Then, to improve the prognosis of cholangiocarcinoma patients, we have applied neoadjuvant chemoradiation therapy followed by conventional resection for possibly resectable cholangiocarcinoma, named NACRAC. Here, we analyzed and evaluated the Phase II (P-2) study. Methods: Patients with histologically or cytologically confirmed adenocarcinoma of the extra- and hilar cholangiocarcinoma were enrolled from 2008 to 2013 at Department Surgery, Tohoku University Hospital. The dose of gemcitabine was determined 600mg/m2 of gemcitabine with external beam radiation therapy (1.8-Gy daily fractions to a total dose of 45 Gy) ( Hepatogastroenterology. 2011;58(112):1866-72.). The primary endpoint of P-2 is R0-resection rate. We hypothesized that R0-resection rate become from 60% to 80%. Results: Total numbers of enrolled patients were 25 cases. 22 cases were operated, and 20 cases were resected. After chemoradiation, 3 cases were not operated by liver metastases, tumor progression, and heart failure. 2 cases were not resected by peritoneal carcinomatosis. One case was diagnosed as pancreatic cancer at the final pathological diagnosis. R0-resectinn cases were 17 cases. R0 resection rate was 89.6% (17/19) among operated cases. In recruited 24 cases (A pancreatic cancer was not included), R0 resection rate was 70.8% (17/24). Grade 3 and 4 adverse events (AE) were neutropenia, leukocytopenia, and Thrombocytopenia. No grade 5 AE and no fatal AE in this P-2 study. Conclusions: Neoadjuvant chemoradiation therapy with conventional resections appears to be effective and well tolerated. After both disease free survival and overall survival are going to be fixed, we will decide a proper indication of neoadjuvant therapy for cholangiocarcinoma. Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN UMIN000000992 and UMIN000001754 Clinical trial information: 000001754.
Multimodality management of borderline resectable pancreatic neuroendocrine tumors: Sentinel report of a single-institutional experience.
Authors: Ambe Chenwi , Nguyen Phuong , Centeno Barbara , Choi Junsung , Strosberg Jonathan R. , Kvols Larry K. , Hodul Pamela Joy , Hoffe Sarah E. , Malafa Mokenge Peter
Published: February 2017

418

Background: Pancreatic neuroendocrine tumors (PNET) constitute about 3% of pancreatic neoplasms. In borderline resectable disease, there is a lack of data to support an optimal neoadjuvant approach for curative outcomes. We describe our institutional experience with a multimodality approach. Methods: We identified all patients with borderline resectable PNET, using NCCN criteria for adenocarcinoma of the pancreas, who received neoadjuvant therapy at our institution between 2000 and 2013. The reason for borderline status was noted. Neoadjuvant regimen, radiographic response, pathologic response, surgical margins, nodal harvest, number of positive nodes, and recurrence were all documented. Results: A total of 112 patients had undergone pancreatic resections for neuroendocrine tumors during the study period. Six patients had borderline resectable disease. The mean age was 55 years (24-70). They all received at least 1 cycle of Temodar and Xeloda. Three of the six patients also received concurrent 5-FU and radiation. There was radiographic evidence of treatment response in all patients. Five of six patients (83 %) had negative margin (R0) resection. Low volume miliary metastatic disease in the liver was detected in 1 patient at the time of surgery. The median number of lymph nodes harvested was 12. Half of the patients had node positive disease. On pathologic review, 4 patients had histologic evidence of a moderate response. All patients are alive and 5/6 are free of disease. Range of follow up is 3.0-4.32 years. The patient with metastatic disease has had no progression and is the only one who is currently receiving any form of treatment. Conclusions: Neoadjuvant Temodar and Xeloda ± radiation with 5-FU sensitization can lead to R0 resection with durable response in patients with borderline resectable PNET. To our knowledge, this is the first report of the use of multimodality therapy (neoadjuvant chemotherapy ± chemoradiation and surgery) in the treatment of borderline resectable PNET.
A randomized phase II trial of antithrombin (AT) products in patients with disseminated intravascular coagulation (DIC) associated with sepsis in advanced pancreatic and biliary cancer.
Authors: Tamura Takeshi , Ioka Tatsuya , Sueyoshi Hironari , Takada Ryoji , Fukutake Nobuyasu , Ashida Reiko , Ohkawa Kazuyoshi , Katayama Kazuhiro
Published: February 2017

423

Background: A randomized phase 2 trial was conducted in order to investigate the most effective administration method of antithrombin (AT) products in patients with disseminated intravascular coagulation (DIC) associated with sepsis during treatment for advanced pancreatic and biliary cancer (aPBC). Methods: Diagnoses of DIC were made according to the criteria of acute DIC of the Japan Association of acute Medicine. We examined 42 patients who were diagnosed with septic DIC and showed a level of AT lower than 70% during treatment for aPBC. The patients were evenly divided into two groups: Group A (21 patients) received continuous infusions of AT products 1500 IU per day for three days, and the group B (21 patients) received intermittent infusions of AT products 500 IU×3 per day for three days. Changes in the coagulation parameters, inflammatory markers, SIRS positive scores, and DIC scores that occurred during treatment were compared between the two groups. Furthermore, the survival outcomes of the patients were evaluated using the Kaplan-Meier method. Results: Before treatment, there were no significant differences between the two groups with respect to their backgrounds. During treatment, statistically significant differences were seen in the platelet counts, D-dimer test results, Fibrinogen levels, and CRP levels between the two groups. However, no differences were observed between the two groups regarding the changes of AT activity levels, SIRS positive scores, and DIC scores. No statistically significant differences were noted between the groups in regards to their survival outcomes (28 day survival rates: 85.7% versus 71.4%, p=0.283). A multivariate analysis indicated that baseline AT activity levels were the sole factor associated with the 28-day survival rates. The survival outcomes didn’t depend on the administration method of AT products. Conclusions: In this trial, we found that baseline AT activity levels were the sole factor associated with the 28-day survival rates. There was no difference in therapeutic effects between the continuous and intermittent infusions of AT products. Clinical trial information: UMIN 000015105.
Pretreatment diffusion weighted imaging for clinical outcome assessment in patients undergoing definitive chemoradiation for pancreatic adenocarcinoma.
Authors: Buchwald Zachary S , Olsen Jeffrey R. , Badiyan Shahed Nicolas , DeWees Todd A. , Hu Yanle , Fields Ryan C. , Wang-Gillam Andrea , Parikh Parag J.
Published: February 2017

432

Background: Factors predicting patterns of failure for pancreatic ductal adenocarcinoma (PDA) are not well-established. Diffusion-weighted MRI (DWI) is useful in predicting recurrence for other gastrointestinal malignancies. The purpose of this study was to evaluate for correlation between tumor DWI parameters and clinical outcomes following chemoradiotherapy (CRT) for pancreatic adenocarcinoma. Methods: From 2009 to 2013, 27 patients with locally advanced (n=14), borderline resectable (n=12) or resectable (n=1) PDA underwent CRT. All patients received upfront FOLFIRINOX or gemcitabine-based chemotherapy prior to CRT, and gemcitabine (median weekly dose 800 mg/m2) concurrent with radiotherapy. DWI was obtained during radiotherapy treatment planning, and apparent diffusion coefficient (ADC) maps were generated to allow determination of median tumor ADC. Tumor-directed CRT was administered with respiratory gated intensity modulated radiation therapy, 55Gy in 25 fractions without elective nodal coverage. Patients were followed by imaging every 2-3 months. Log rank test was used to estimate an optimal ADC cut-point of 1.4*10-3mm2/sec based on distant metastasis free survival (DMFS) and overall survival (OS). Analysis of local recurrence was not performed due to limited events. The log-rank test was used to evaluate differences in outcome between groups based on ADC classification. Results: The median time to last follow-up from completion of CRT was 9.7 months for all patients and 11 months among living patients. 5 patients underwent resection following CRT. The 1-year DMFS for patients with median ADC<1.4*10-3mm2/sec was 79.5 percent, compared to 47.6 percent for those with median ADC >1.4. The 1-year OS for patients with median ADC<1.4 was 100 percent, compared to 46.3 percent for those with median ADC >1.4. Both DMFS (p=.041) and OS (p=.003) were significantly improved on log-rank test for ADC<1.4 compared to ADC>1.4. Conclusions: A correlation was observed between DWI parameters and clinical outcomes for PDA. Further prospective study should be explored to validate DWI as a prognostic imaging biomarker.
Pretreatment albumin may help select patients for intrahepatic Y-90 microsphere transarterial radioembolization (TARE) for malignancies of the liver.
Authors: Orwat Kelly Elizabeth , Cooper Samuel Lewis , Ashenafi Michael , Anderson M. Bret , Guimaraes Marcelo , Marshall David T.
Published: February 2017

453

Background: Systemic therapies for unresectable liver malignancies may provide a survival benefit, but eventually prove intolerable or ineffective. TARE provides an additional liver-directed treatment option to improve local control for these patients, but there is limited data on patient factors associated with survival. Methods: All patients that received TARE at the Medical University of South Carolina from March 2006 through May of 2014 were included in this analysis of overall survival (OS) and toxicity. Kaplan-Meier estimates of OS from date of first procedure are reported. Potential prognostic factors for OS were evaluated using log rank tests and Cox proportional hazards models. Results: In 114 patients that received TARE at our institution, median follow-up was 6.4 months [range 0-86], with the following tumor histology: colorectal (CR) n=55, hepatocellular (HC) n=20, cholangiocarcinoma (CC) n=16, neuroendocrine (NE) n=12, breast (BR) n=6, other n=5. At least 1 line of systemic therapy prior to TARE was noted in 79% of patients. Median OS was 6.6 months and 1-year OS was 30.7%. The percentage of patients who died within 3 months of TARE were 46.2% for patients with albumin < 3 but only 20.3% for patients with albumin ≥ 3. Grade ≥ 2 toxicity was observed in 22 patients (19.3%) including 9 (7.9%) with Grade 3 and 1 (0.9%) with Grade 4 toxicity. A single patient with a pre-existing pulmonary arteriovenous malformation experienced Grade 3 pneumonitis that resolved with steroids. No deaths were attributed to radiation-induced liver disease. Conclusions: TARE is a relatively safe and effective treatment for unresectable intrahepatic malignancies. Patients with NE or BR histology as well as those with better hepatic synthetic function were associated with significantly better survival. Our data suggest that patients with albumin below 3 may not benefit from TARE. [Table: see text]
Incidence of brain metastasis in esophageal cancer.
Authors: McCann Brendan , Bhatti Kiran , MacLaren Vivienne
Published: February 2017

46

Background: Brain metastasis in oesophageal cancer is a rare but often fatal complication. In previous studies the incidence has ranged from 1.4% - 13% with the largest studies from China and Japan that have been retrospectively based over fifteen to twenty years. (Ogawa K, Toita T, Sueyama H. Brain metastases from esophageal carcinoma: natural history, prognostic factors, and outcome. Cancer. 2002 Feb 1;94(3):759-64.) With improving diagnostic techniques and differing histology of oesophageal cancer from Eastern countries we undertook a study to determine the incidence of brain metastases in oesophageal cancers in the West of Scotland. Methods: Data from all the new patients diagnosed with oesophageal cancer was obtained with permission from the Regional Managed Clinical Network from the years 2011 and 2012 yielding a total of 701 patients. The individual clinical records were examined to ascertain if the patient developed brain metastases on CT/MRI scan, their tumour type and management. Results: Of the 701 patients diagnosed with oesophageal cancer, 19 developed brain metastasis demonstrating an incidence of 2.7%. 12 of these patients primary diagnosis was adenocarcinoma. The others were small cell (3), neuroendocrine (2), squamous (1) and no histology (1). At the time of writing 17 out of 19 patients had died from their oesophageal cancer. The 2 surviving patients had a single brain metastasis that was resected and treated with adjuvant radiotherapy. 6 other patients had whole brain radiotherapy, 1 patient had partial brain radiotherapy and 10 were managed with best supportive care. Mean survival from diagnosis of brain metastasis for best supportive care was 26 +/- 14 days versus mean survival for radiotherapy treatment from 100+/- 57 days (p = 0.003) demonstrating a difference between the groups. Conclusions: The incidence of brain metastasis in oesophageal cancer in the West of Scotland was 2.7% with the prognosis generally poor unless resected.
The use of an interposed graft during portal vein and/or superior mesenteric vein reconstruction in pancreatic resection for pancreatic cancer.
Authors: Yamaue Hiroki , Hirono Seiko , Kawai Manabu , Okada Ken-Ichi , Miyazawa Motoki , Shimizu Atsushi , Kitahata Yuji , Ueno Masaki
Published: February 2017

482

Background: Combined portal vein and/or superior mesenteric vein (PV/SMV) resection with pancreatectomy sometimes leads to prolonged survival for patients with periampullary tumors. In this study, we evaluated outcomes of patients with PV/SMV reconstruction, and we considered indications for the use of a graft during this procedure. Methods: We performed PV/SMV resection with pancreatectomy in 128 patients with periampullary tumors, including 14 using grafts. Short and long-term outcomes associated with PV/SMV reconstruction and harvesting venous grafts and reconstructed PV/SMV patency during follow-up were assessed. Results: Of the 128 patients with periampullary tumors, 5 underwent total pancreatectomy, 99 pancreaticoduodenectomy, and 24 distal pancreatectomy. In the 14 patients who underwent PV/SMV reconstruction with grafts, the grafts were harvested from external iliac vein in 10 patients and internal jugular vein in the other 4. Five patients (3.9%) had intraoperative or postoperative acute thrombus or stenosis of reconstructed PV/SMV after direct end-to-end anastomosis. However, PV/SMV patency was excellent after reconstruction using grafts. Among 228 patients with common pancreatic cancer, there were no significant differences in overall survival (OS) between the patients with PV/SMV resection (n=99) and without PV/SMV resection (n=206) (P=0.354), although the lymph node metastasis rates in the patients with PV/SMV resection were higher than those without PV/SMV resection (78.8 vs. 64.6%, P=0.012). Furthermore, the tumor size in the patients with the use of a graft was larger than that without a graft (Mean size; 40.5 vs. 29.3 mm, P=0.047), and the R0 rates and OS were not different between the patients with and without a graft (R0 rates; 50 vs. 73%, P=0.129 and OS; 23.4 vs. 16.6 months, P=0.323). Conclusions: Depending on the length and/or position of the removed PV/SMV segment, an interposed graft may be required for reconstruction in some patients.
Second primary cancers in young adult colorectal cancer survivors.
Authors: Shameem Raji , Hamid Muhammad Saad , Godwin James Luke , Sonpal Niket , Sullivan Kevin M.
Published: February 2017

516

Background: Second primary cancers are a major concern for young adult colorectal cancer (CRC) survivors. The impact of treatment with radiation on the risk for second solid and hematological malignancies, as well as the typical latency period before development of a second cancer, requires elucidation. Methods: The Surveillance Epidemiology and End Results (SEER) database was used to detect CRC cases in young adults (aged 20-40 years) diagnosed up to 12/31/2011. The Standardized Incidence Ratio (SIR) was calculated as the ratio of observed to expected cases of second primary malignancy based on incidence data in the general United States population. The latency exclusion period from the date of diagnosis was 5 years. We investigated the possible effect of radiation therapy on risk for a second cancer, and established the typical latency period after initial diagnosis (5-10 years and >10 years). Results: A total of 9,537 cases of CRC in young adults were available for analysis. Radiation was administered in 1,823 (19.1%) patients. Second primary cancers occurred in 798 cases, 754 (94.5%) solid tumors and 44 (5.5%) hematological malignancies respectively. In the latency period 5-10 years after initial diagnosis, “All Solid Tumors” (SIR: 1.85, p<0.05) and female genital tumors (SIR: 3.52, p<0.05) were increased. In the latency period >10 years after initial diagnosis, an increased risk of developing pancreatic cancer (SIR: 1.90, p<0.05) and female genital tumors (SIR: 1.77, p<0.05) was observed. In patients who received radiation the only significantly increased risk was for “All Solid Tumors” (SIR: 1.42, p<0.05). No significant increase in second hematological malignancies was observed in the entire cohort, including cases that received radiation. Conclusions: An increased risk of second primary female genital tumors was seen in both the 5-10 years and >10 years latency periods. Pancreatic cancer risk was increased specifically in the >10 years latency period. Radiation treatment did not pose an increased risk for any specific second primary cancers. Interestingly, young adult CRC survivors did not have an increased risk for hematological malignancies compared to the general population.
Circulating tumor DNA (ctDNA) in nonmetastatic colorectal cancer (CRC): Potential role as a screening tool.
Authors: Tie Jeanne , Wang Yuxuan , Kinde Isaac , Steel Malcolm , Elsaleh Hany , Singh Madhu Sudan , Turner Natalie Heather , Tran Ben , Strausberg Robert , Diaz Luis A. , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Gibbs Peter
Published: February 2017

518

Background: CRC screening significantly reduces cancer incidence and mortality. Participation rates in screening, both stool based and endoscopic, are often low. The value and safety of endoscopic screening in older individuals is also uncertain. Preliminary data indicate ctDNA can be detected in a high proportion of patients with early stage CRC, suggesting promise as a screening test that should have broad community acceptance. Methods: Plasma samples were collected at diagnosis from 100 patients (pts) with newly diagnosed CRC. Surgical, clinicopathologic and outcome data were prospectively captured. All samples were sent to Johns Hopkins Kimmel Cancer Center, where tumors were sequenced using a panel of 15 genes frequently mutated in CRC to identify candidate mutations for ctDNA analysis. For each pt, one tumor mutation was selected to assess for ctDNA in plasma samples using the Safe-SeqS digital genomic assay. Results: Preliminary data is available on 68 pts. Median follow-up is 15.2 months. Candidate mutations for ctDNA analysis were identified in all cases, with a matching mutation detectable in the plasma cell-free DNA in 41 pts (60%). Median mutant allele fraction was 0.24% (range 0.11% - 8.39%). Tumor stage did not appear to have a major impact on the detection rate of ctDNA (Table), and ctDNA detection was independent of CEA levels. Five pts have recurred, all of whom had detectable ctDNA at diagnosis, whereas CEA was elevated in only 1 of these cases. Conclusions: Preliminary data suggests ctDNA is detectable at diagnosis in the majority of pts with non-metastatic CRC. The potential for ctDNA as a CRC screening tool, and as a prognostic marker for patients with early stage cancer, should be further explored. [Table: see text]
Observational cohort study of first-line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802): Comparison of infusional FU/oxaliplatin(OX)+BV and oral FU/OX+BV.
Authors: Hatanaka Kazuteru , Yuki Satoshi , Nakatsumi Hiroshi , Fukushima Hiraku , Naruse Hirohito , Kato Takashi , Meguro Takashi , Nakamura Michio , Iwanaga Ichiro , Uebayashi Minoru , Tateyama Miki , Eto Kazunori , Kudo Mineo , Kato Sosuke , Okuda Hiroyuki , Sogabe Susumu , Miyashita Kencho , Sakata Yuh , Komatsu Yoshito
Published: February 2017

527

Background: A few reports have shown no difference between the efficacy of infusional FU and that of oral FU (Capecitabine/S-1) for colorectal cancer, and some studies have reported the non-inferiority between infusional FU/Oxaliplatin (OX) and oral FU/OX for metastatic colorectal cancer (mCRC). We performed a sub-group comparison between infusional FU/OX (mFOLFOX6 + BV: iFU) and oral FU/OX (CapeOX/SOX + BV: oFU) from the HGCSG0802 observational cohort study with investigated Japanese patients (pts) treated with first line BV for mCRC. Methods: The objective of HGCSG0802 was to evaluate progression-free survival (PFS), overall survival (OS), time to treatment-failure (TTF), response rate (RR), safety and so on. The key eligibility criteria of HGCSG0802 were with evaluable lesions, older than 20 years, ECOG PS 0-2, and this analysis used the cohort treated with OX-based regimens.In this analysis, pts characteristics, RR and safety were compared using Fisher’s exact test. PFS and TTF were compared using log-rank test. Results: Of 108 pts (the full analysis set), 95 pts were evaluable for treated with OX-based regimens. Forty-eight pts (50.5%) were treated with iFU and 47 pts (49.5%) were treated with oFU (CapeOX + BV 42 pts/SOX + BV 5 pts). The pts characteristics between those were generally balanced except for PS 0-1 (72.9% in iFU/93.6% in oFU; p=0.012) and synchronous liver metastases (mets) (93.8% in iFU/78.8% in oFU; p=0.040). Adverse events ≥grade 3 were balanced except for leucopenia (25.0% in iFU versus 2.1% in oFU; p=0.002) and neutropenia (43.5% in iFU and 10.9% in oFU; p=0.001). Hand-foot skin reaction was not different between two cohorts. RR was 62.5% in iFU versus 71.1% in oFU (p=0.835). The median PFS was 8.3 months in iFU versus 8.2 months in oFU (p=0.835). Conclusions: The HGCSG0802 could be a database to investigate first line BV for mCRC in clinical practice. As a result of this analysis, in Japanese daily practice, efficacy was no significant difference between infusional FU/OX and oral FU/OX, and the profiles of adverse events varied from each regimens.
Incidence of hyponatremia in a cohort of patients with colorectal cancer.
Authors: Castillo Jorge J. , Glezerman Ilya , Boklage Susan , Chiodo Joseph , Schulman Kathy L.
Published: February 2017

545

Background: Hyponatremia (HN), a common electrolyte disturbance in hospitalized patients, is a prognostic factor in some cancers. The incidence of HN in patients diagnosed with colorectal cancer (CRC) is unknown and is investigated here. Methods: This retrospective cohort analysis combined electronic medical record and tumor registry data from an integrated delivery network. Patients included were adults diagnosed with incident invasive CRC between 2005 and 2011 with ≥1 administration of radiation or chemotherapy within 6 months of diagnosis who met continuous clinical activity criteria. Exclusions included unknown index cancer stage or ≥1 post-index hypovolemic HN episode. Patients were followed until study end, death, clinical trial entry, new primary cancer onset, or end of continuous clinical activity. HN incidence (serum sodium ≤135 mEq/L) was measured per 1,000 person years (PY) of observation (95% confidence intervals [CI]) and classified as mild (131–135), moderate (125–130) or severe (<125) based on the lowest observed value. Results: In all, 132 CRC patients were included (52% male; mean [SD] age 64±13.1 years, 99% Caucasian). Mean (SD) follow-up was 3±2.6 years. Thirty-six percent of patients had metastatic disease at diagnosis and 80% received chemotherapy, 39% radiation therapy and 83% surgical resection. Patients with HN post-CRC diagnosis had significantly greater incidence of metastatic disease during follow-up (p=0.033) and exposure to anti-metabolites (p=0.023) or platinum based agents (p=0.017). Episodes of HN (n=262) occurred in 81 patients (61%) at a rate of 598 per 1,000 PY (95% CI, 523–680). Mean (SD) episodes per patient were 1.8±2.6. Overall, 84% of episodes were mild, 14% moderate and 2% severe; 52% were classified as syndrome of inappropriate antidiuretic hormone secretion. Mean (SD) time to first hyponatremia episode was 139±296 days, with a median duration of 12 days; 84% of patients had a first episode within the first 6 months. Conclusions: The incidence of HN after diagnosis with CRC was about 61% and episodes occurred primarily within 6 months of diagnosis. Based on these results, along with emergent evidence from other studies, clinicians should anticipate HN in newly-diagnosed CRC patients.
Clinical significance of serum vascular cell adhesion molecule-1(VCAM-1) in colorectal cancer.
Authors: Ciftci Rumeysa , Aykan Nuri Faruk , Aksit Ece , Tilgen Yasasever Ceren , Vatansever Sezai , Yasasever Vildan
Published: February 2017

550

Background: Vascular cell adhesion molecule-1 (VCAM-1) is a transmembrane glycoprotein, which is expressed on endothelium and contributes in leukocyte adhesion and extravasation during inflammation. It has been demonstrated that VCAM-1 is over-expressed on colorectal cancer (CRC) cells and plays role in metastasis development and angiogenesis. We aimed to compare serum VCAM-1 levels of CRC patients with heathy controls and evaluate its relationship with clinicopathologic parameters, treatment response and overall survival (OS). Methods: The study enrolled 111 patients with histopathologically confirmed CRC followed up between February 2010-September 2013 in Institute of Oncology, Istanbul University and 30 sex- and age-matched healthy controls. Pre-treatment serum VCAM-1 levels were determined by the solid-phase sandwich ELISA method. Results: The cancer localisation was rectum in 40% and colon in 60% of patients. Metastatic disease was present in 51.4%. Forty percent of 40 metastatic patients who received palliative chemotherapy (CT) was CT-responsive (partial or complete response). The median serum VCAM-1 level was significantly higher in CRC patients than controls (p<0.001). In addition, serum VCAM-1 level was significantly higher in diabetic CRC patients than those without diabetes (p=0.03). There was no significant relationship between other clinicopathologic parameters, stage, carcinoembrionic antigen (CEA), CA19.9 and VCAM-1. The median follow-up period was 12 (±8.2) months. Progression was observed in 16.2 % of patients and 18 % of patients had died at the time of analysis. The presence of metastasis (p<0.001) and elevated CEA level (p<0.001) were factors affecting OS significantly. Serum VCAM-1 did not have a significant impact on OS in both univariate (p=0.55) and multivariate analysis (p=0.23). Conclusions: Serum VCAM-1 level is significantly higher in patients with CRC than controls. However, it has no prognostic or predictive role for CT response. Studies randomising CRC patients in more homogenous treatment arms to evaluate the effect of systemic treatment on serum VCAM-1 with longer follow-up period are needed.
Treatment and outcomes of goblet cell adenocarcinomas (GCAs) of the appendix.
Authors: Tsang Erica , McConnell Yarrow Jean , Schaeffer David , Lee Lawrence , Zerhouni Siham , Schaff Kimberly , Speers Caroline , Kennecke Hagen F.
Published: February 2017

551

Background: GCAs are rare mucinous neoplasms with mixed epithelial and endocrine differentiation, which behave more like mucinous adenocarcinomas than appendiceal neuroendocrine tumors. Optimal therapy is poorly described. Objectives of this study were to define prognostic factors and describe management of patients presenting with stage I-IV disease. Methods: Patients diagnosed with GCAs between 1990-2010 were identified from the British Columbia province-wide cancer registry and linked to an electronic pathology archive. Pathology was reviewed in 79 of 87 cases where archival tissue was available. Treatment and outcome data were obtained from the BC Cancer Agency, GI Cancer Outcomes Unit, and Provincial Pharmacy databases, combined with chart review. Kaplan Meier survival analysis was used to compare outcomes. There were insufficient events for robust multivariate analysis. Results: 87 cases of appendiceal GCAs were identified for an annual population incidence of 0.2/200,000. Median age was 54 (range 25-91) years, and 42 (48%) were male. There were no stage I patients. For stage II-III (n=68) and stage IV (n=19) patients, median overall survival (OS) was 42.8 and 15.4 months, respectively (p=0.009). Of stage II-III patients, 51 (76%) underwent right hemicolectomy and 9 (16%) received adjuvant chemotherapy: 5-FU (n=5), 5FU/oxaliplatin (n=4). Median recurrence-free survival (RFS) was 38.2 months (10 recurrences: 9 peritoneal, 1 hepatic). Univariate analysis demonstrated no prognostic effect of adjuvant chemotherapy, surgical approach (hemicolectomy vs. appendectomy), T4 tumors, number of nodes resected, or lymph node positivity. 5-year RFS was 90.2% in patients who presented with appendicitis, compared to 63.7% in those without appendicitis (p=0.016). Of 19 patients with stage IV disease, 10 (63%) received palliative chemotherapy including FOLFOX (n=4), FOLFIRI (n=1), FOLFIRI/bevacizumab (n=2), and capecitabine (n=2). Only high mitotic rate was associated with reduced OS. Conclusions: GCAs are rare tumors and the majority present with non-metastatic disease. Presentation with metastatic disease carries a poor prognosis and chemotherapy agents used for advanced colorectal tumors are most commonly applied.
Impact of liver fibrosis on effects and adverse effects of unresectable colorectal cancer under first line chemotherapy including CPT-11.
Authors: Yahagi Masashi , Tsuruta Masashi , Hasegawa Hirotoshi , Okabayashi Koji , Seishima Ryo , Takahashi Hidena , Matsui Shimpei , Yamada Toru , Kondo Takayuki , Shimada Takehiro , Matsuda Mutsuhito , Yoshikawa Yusuke , Asada Yusuke , Sugiura Kiyoaki , Suzuki Yoshiyuki , Tajima Yuki , Nakadai Junpei , Kitagawa Yuko
Published: February 2017

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Background: Liver dysfunction is one of the irritating adverse effects in chemotherapy for colorectal cancer. Polymorphisms of UGTIA1, which is related to metabolism of CPT-11 in the liver, cause severe adverse events. In addition, long-term induction of CPT-11 may involve steatohepatitis. Thus, it is critical to surrogate liver dysfunction in chemotherapy including CPT-11. In this current study, we evaluated whether NAHLD fibrosis score (NFS) which is liver fibrosis marker of nonalcoholic steatohepatitis, is feasible for predicting the effects and adverse events of chemotherapy including CPT-11 for colorectal cancer. Methods: From January 2007 to May 2013, of 118 patients who were diagnosed with unresectable advanced/recurrent colorectal cancer in our hospital, we retrospectively analyzed 89 patients who underwent first line chemotherapy including CPT-11. We statistically analyzed the value of the pretreatment NFS on response rate (RR), progression-free survival (PFS), and hematologic or non-hematologic toxicity of chemotherapy including CPT-11. Results: The median NFS was -1.302 (range=-5.158 to 2.62). Multivariate analysis revealed that NFS was an independent negative predictive marker for RR (coef -0.373 (-0.712 to -0.035), p = 0.031), although no contribution of NFS was observed to PFS (coef 0.958(0.786|1.168), p=0.672). In terms of the adverse events, high value of NFS is an independent risk factor in hematological toxicity (coef 0.93 (0.20 to 1.65), p = 0.012), while not in non-hematological toxicity (coef 0.198 (-0.218|0.613), p=0.351). Conclusions: The pretreatment NFS might be a feasible for predicting response and hematological toxicity in first line chemotherapy including CPT-11 against colorectal cancer.
Therapeutic drug monitoring of 5-fluorouracil (5-FU) in the treatment of patients with colorectal cancer (CRC).
Authors: Goel Gaurav , Sehgal Rajesh , Meisner Dennis James , Sun Min , Pasricha Gurleen , Chu Edward , Lee James J.
Published: February 2017

563

Background: 5-FU continues to serve as the backbone of systemic combination chemotherapy for treatment of CRC in the adjuvant and metastatic disease settings. The dosing of 5-FU has traditionally been based on body surface area (BSA). Growing evidence suggests that BSA-based 5-FU dosing has several limitations, and that pharmacokinetic (PK)-guided dosing of 5-FU improves clinical efficacy with reduced toxicity. We conducted a QI study to evaluate the clinical feasibility of PK-guided 5-FU dose adjustment and its impact on clinical outcome. Methods: CRC patients treated with combination chemotherapy regimens containing infusional 5-FU who underwent PK-guided optimization of 5-FU dosing using an antibody-based immunoassay (OnDose or MyCare) were included in the analysis. Results: A total of 58 patients (34 males, 24 females) meeting the entry criteria have been identified to date. The median age was 61 years (range, 27-85). Fifteen patients had stage III disease, and the remaining 43 patients had stage IV disease. The 5-FU infusional regimens included mFOLFOX6 (n=45) and FOLFIRI (n=13). A total of 143 5-FU PK tests were performed for these 58 patients. The median number of tests performed per patient was 2 (range, 1-5). On initial testing, only 36% (n=21) patients had 5-FU systemic exposure, measured as area under the curve (AUC), within the suggested target range of 20-30 mg.hr/L. Fifty-five percent of the patients were below the target AUC while 9% (n=5) patients were above the target range. Of the 32 patients below the target range on 5-FU AUC test, the 5-FU doses were increased in 22 patients for the subsequent treatment cycle. The median number of dose modifications required to achieve the target AUC levels in these patients was 1 (range, 1-2). The majority of these patients (86%, n=19) tolerated the increased 5-FU dose well without worsening of 5-FU related toxicity. Conclusions: Our data provides further evidence that 5-FU dosing based on BSA results in sub-optimal 5-FU exposure levels for the majority of patients (64%). PK-guided dose adjustment of 5-FU appears to be a practical and feasible approach that can be applied in routine clinical practice.