bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does gap-free intensity modulated chemoradiation therapy provide a greater clinical benefit than 3D conformal chemoradiation in patients with anal cancer?
Authors: Dewas-Vautravers Claire , Maingon Philippe , Dalban Cecile , Petitfils Aurelie , Peignaux-Casasnovas Karine , Truc Gilles , Martin Etienne , Khoury Cedric , Dewas Sylvain , Crehange Gilles 
Published: February 2017

584 Background: Chemoradiation is the standard treatment for anal cancer. The purpose of this study was to compare outcomes and toxicities in patients treated with either intensity-modulated radiation therapy (IMRT) or 3D conformal radiotherapy (3D-CRT). Methods: Between 2004 and 2011, the data of 51 patients treated with exclusive radiotherapy with or without concomitant chemotherapy for non-metastatic anal carcinoma were retrospectively analyzed. Thirty-nine patients (76.5%) had concomitant chemotherapy: capecitabine alone (1), MMC combined with 5FU or capecitabine (36), MMC and CDDP (4). Twenty-seven patients were treated with 3D-CRT and 24 patients with IMRT, with a median dose delivered to the tumor of 59.4Gy [30.6-66.6], whatever the radiotherapy technique (p= 0.99). The median follow-up was 40 months [26.4-51.6]. Results: Median duration of the treatment was 56 days [22-103] (59 versus 47 days with 3D-CRT and IMRT respectively, p= 0.0007). A gap was planned in 29 patients (57%), 23 with 3D-CRT and 6 with IMRT (p< 0.0001). Treatment was stopped for toxicity in 9 patients (17.6%), 4 with 3D-CRT and 5 with IMRT (p= 0.48). There was no difference between the two groups for response to treatment (p= 0.46). Two-year overall survival (OS), locoregional relapse-free survival (LRS) and colostomy-free survival (CFS) rates were 88.5%, 63% and 60.3%, respectively for the IMRT group and 81%, 76.5% and 81.1% for the 3D-CRT group (all NS). Ten patients (37%) in 3D-CRT and 11 patients (45.8%) in IMRT (p= 0.524) had grade 3 (G3) acute toxicity. No grade 4 (G4) toxicity occurred. Conclusions: Our study suggests that further investigations concerning the use of IMRT to treat cancer of the anus are warranted. IMRT makes it possible to reduce treatment time, notably by abandoning the gap, but with no impact on the prognosis. Nonetheless, a longer follow-up is essential to determine whether or not IMRT has an impact on late toxicity, local control and survival compared with conventional 3D-CRT.
Secondary resection in a general mCRC population with cetuximab-based first-line treatment: Interim analysis of the German noninterventional study ERBITAG.
Authors: Overkamp Friedrich , Goehler Thomas , Reich Gernot , Schwerdtfeger Michael , Stuebs Patrick , Stenzel Karsten G , Neumann Ulf P 
Published: February 2017

590 Background: Resection of liver and/or lung metastases (LM) are a potentially curative option for patients with mCRC. Cetuximab in combination with irinotecan- or oxaliplatin-based chemotherapy has shown to increase the resection rate of primarily unresectable LM in mCRC patients. After approval of cetuximab in Germany for first-line treatment of pts with unresectable mCRC, this noninterventional study was initiated to evaluate safety and efficacy of cetuximab in combination with various first-line chemotherapy regimens in patients with unresectable mCRC. Methods: We conducted an interim analysis of the first 124 fully documented pts to evaluate the response rate (RR) and resection rate of LM. Enrolment was restricted to pts with mCRC with proven KRAS wildtype mutation status without prior systemic treatment in the metastatic stage. Predefined endpoints were amongst others RR, LM resection rate, TTF, PFS, OS, and safety. Results: From May 2010 to May 2012 360 eligible pts were enrolled at 109 sites (75% office-based physicians), documentation for 124 was finalised (data cut-off for this analysis 03 May 2012) and evaluated. The median age was 68 [range 34-84] years, ECOG performance status was 0, 1, 2 in 29%, 60%, and 9% of pts, respectively, in 2% of pts ECOG performance status was missing. Resection rate was 18.5% (n=23) performed at 18 sites with 16.9% R0 resections (n=21). 42% of pts (n=52) had liver-limited disease (LLD). Resection rate in pts with LLD was 34.6% (n=18) with a 30.6% R0-resection rate (n=16). Median treatment duration from start of cetuximab-based therapy to resection of LM was 3.7 months [0.7-12.0]. Objective response rate was 46.8% (CR 4.8%, PR 41.9%) and 59.6% (CR 5.8%, PR 53.8%) for pts with LLD. Conclusions: In a clinical practice setting cetuximab-based first-line treatment of an unselected population with KRAS wildtype mCRC resulted in an R0-resection rate of 16.9% overall, and 30.6% for LLD pts. These data compare fairly well with data from clinical trials: CRYSTAL, OPUS, and CELIM.
A phase (Ph) Ib study of irinotecan (IRI), levofolinate (LV), and 5-fluorouracil (5-FU) (FOLFIRI) plus ramucirumab (RAM; IMC-1121B) drug product in Japanese (JP) patients (pts) with metastatic colorectal carcinoma (mCRC) progressive during or following first-line therapy with bevacizumab (BEV), oxaliplatin (OXALI), and a fluoropyrimidine (FP) (CP12-1029/NCT01286818).
Authors: Yoshino Takayuki , Yamazaki Kentaro , Yoshida Motoki , Rutstein Mark Daniel , Yoshizuka Naoto , Ohtsu Atsushi 
Published: February 2017

591 Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) regulate angiogenesis and are overexpressed in CRC. RAM is a fully human IgG1 monoclonal antibody VEGF-receptor 2 antagonist. We assessed the safety of RAM + FOLFIRI among JP mCRC pts. Methods: Eligible pts had measurable or nonmeasurable disease, ECOG PS 0-1 with disease progression during or within 6 mos following 1st-line therapy with BEV, OXALI, and a FP. Pts received 8 mg/kg RAM IV every 2 wks + FOLFIRI (IRI: 180 mg/m2, LV: 200 mg/m2, 5-FU: 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46-48 hrs). Dose-limiting toxicities (DLTs) were assessed Cycle 1 Day 1 to Cycle 3 Day 1. We assessed the safety of RAM + FOLFIRI among JP mCRC pts to support the participation of Japan in a global Ph 3 mCRC study. Results: 6 pts were treated; all pts completed study as of 3/19/2012. Median age was 62 yrs (range 48-71). 4 pts had colon cancer and 2 pts had rectal cancer . 1 of 6 pts experienced a DLT (Grade [G] 2 proteinuria and G4 neutropenia resulting in dose delay >2 wks). All 6 pts (100%) experienced at least one G3 adverse event (AE): neutropenia (5 pts; 83%), proteinuria (2 pts; 33%), anemia, thrombocytopenia, hypertension (1 pt each, 17%). 3 pts (50%) experienced G4 neutropenia. 2 pts discontinued (D/C) RAM due to G2 and G3 proteinuria, respectively; 1 pt D/C FOLFIRI due to G3 neutropenia. There were no serious AEs or deaths. Best overall response: 1 PR (17%), 4 SD (67%), 1 PD (17%). Median PFS: 7.3m (range: 1.25-10.91m; 95% CI: 1.2 – 10.9). As of 9/24/2012, 57 JP pts have been enrolled into ongoing P3 study I4T-MC-JVBB. Conclusions: RAM + FOLFIRI were reasonably tolerated and demonstrated anti-tumor activity in JP mCRC pts previously treated with BEV, OXALI, and a FP. The incidence of proteinuria in this small cohort of JP pts appears higher than that observed in other studies evaluating RAM to date. These safety data supported the enrollment of JP pts into an ongoing global P3 mCRC study. Clinical trial information: NCT01286818.
Pharmacokinetics (PK) of panitumumab in a single patient with metastatic colorectal cancer (mCRC) and liver dysfunction.
Authors: Krens Lisanne , Baas Jara , de Jong Floris A. , Guchelaar Henk-jan , Gelderblom Hans 
Published: February 2017

594 Background: Panitumumab is used for the treatment of metastatic KRAS wild type (WT) colorectal cancer (mCRC). It is likely that many of these patients will present with liver metastases and some with liver dysfunction. The pharmacokinetics in patients with hepatic impairment are unknown and dosage adjustments are undetermined. Here, we present a case of a patient with progressive mCRC and liver dysfunction. Methods: A heavily pre-treated KRAS WT mCRC patient with liver disease Child-Pugh class B was treated with two-weekly 6 mg/kg panitumumab. The patient received 2 doses of 490 mg iv panitumumab after which progressive disease was documented. Toxicities were graded using CTCAEv4.0. Serum samples were collected and panitumumab concentrations were determined using a validated immunoassay. PK parameters after the first dose, including dose-normalized AUC from time zero–day 14, clearance (CL), and elimination half-life (T1/2), were estimated via trapezoidal non compartmental methods. Data was compared to historical data from a normal population as reported by Stephenson (Clin Colorectal Cancer 2009). Values within the range of the mean ± 1 standard deviation (SD) were considered not deviant. Results: Calculated AUC after the first dose of 6 mg/kg panitumumab in this patient with hepatic dysfunction was 877 μg*day/mL (Stephenson’s cohort 1: 744 ± 195 μg*day/mL). Estimated T1/2was 3.58 days (5.28 ± 1.90 days) and CL was 6.9 mL/day/kg (8.21 ± 3.79 mL/day/kg). Estimated PK parameters during the first cycle were inside reported mean ± 1 SD of historical controls without liver dysfunction. No toxicity was reported during treatment, particularly, no diarrhea and skin toxicity. Conclusions: The pharmacokinetics of panitumumab in this patient suffering from colorectal cancer with liver dysfunction Child-Pugh class B was similar when compared to patients with adequate liver functions. Moreover, no substantial toxicity was detected. The here presented data may help clinical decision making in real life practice. Two-weekly panitumumab monotherapy seems to be safely applicable in patients with KRAS WT mCRC and hepatic dysfunction without the need for dose adjustments.
The impact of the peak (day 2) C-reactive protein (CRP) on the day 3 and day 4 CRP thresholds associated with infective complications following curative surgery in colorectal cancer.
Authors: Ramanathan Michelle Leana , Horgan Paul G. , Mcmillan Donald C. 
Published: February 2017

595 Background: The postoperative systemic inflammatory response, as evidenced by C-reactive protein (CRP) on day 3 (threshold ~170 mg/L) and day 4 (threshold ~130mg/L), have been reported to be associated with the development of infective complications following surgery for colorectal cancer. The aim of the present study was to assess the impact of the peak, day 2 CRP, on CRP concentrations at day 3 and day 4. Methods: Patients with colorectal cancer who were considered to have undergone elective curative resection were recorded in a prospective database (n=396). CRP was measured preoperatively and on days 1 to 4 postoperatively. Correlations between day 2 CRP and other perioperative CRP concentrations were examined. Results: The majority of patients were 65 or older (67%), male (55%), had colonic tumours (66%), had node negative disease (57%) and were from a deprived area (55%). Day 2 CRP was not associated not with age (p=0.055), sex (p=0.185), deprivation (p=0.103), tumour site (p=0.529) or stage (p=0.395). Day 2 CRP was directly associated with day 1 (r2=0.421, p<0.001), day 3 (r2=0.617, p<0.001) and day 4 (r2=0.315, p<0.001) CRP, but not preoperative CRP (r2=0.008, p=0.084). The median day 2 CRP that corresponded with the previously described thresholds (~170mg/L and ~130mg/L at day 3 and 4 respectively) for predicting infective complications was 190mg/L. Similarly, the median day 2 CRP corresponding to the previously described thresholds (~190mg/L and ~140mg/L at day 3 and 4 respectively) for predicting an anastomotic leak was 200mg/L. Conclusions: A day 2 CRP concentration >190 - 200mg/L, was associated with day 3 and 4 CRP concentrations above established CRP thresholds for the development of infective complications. It remains to be determined whether reduction in day 2 CRP concentrations will reduce infective complications following surgery for colorectal cancer.
Randomized phase III trial of irinotecan plus cisplatin versus irinotecan alone after S-1 based chemotherapy failure for patients with advanced and recurrent gastric cancer (AGC) (TCOG GI-0801).
Authors: Shimada Ken , Higuchi Katsuhiko , Hosaka Naoshi , Sasaki Eisaku , Nakayama Norisuke , Amagai Kenji , Takeda Yuiti , Moriwaki Toshikazu , Sekikawa Takashi , Sakuyama Toshikazu , Yajima Kazuhito , Tanabe Satoshi , Saito Yusuke , Maeda Yoshiharu , Nishimura Ken , Sasaki Tohru , Kobayashi Kouji , Shimoyama Tatsu , Hyodo Ichinosuke , Koizumi Wasaburo 
Published: February 2017

61 Background: S-1based chemotherapy is the standard first-line chemotherapy for AGC in Japan. Currently, there is no high level evidence established for second-line treatment. Irinotecan (CPT-11) plus cisplatin (CDDP) are active in AGC. The combination of these 2 agents is synergistic effect in preclinical and clinical studies. We conducted a phase III study of CPT-11 plus CDDP (CP) compared with CPT-11 alone (C) in patients with AGC refractory to S-1 based chemotherapy. Methods: Patients with previously treated with S-1-based chemotherapy for AGC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either CPT-11 60 mg/m2 plus CDDP 30 mg/m2 on day 1 every 2 weeks or CPT-11 150mg/m2on day 1 every 2 weeks. The primary endpoint is progression free survival (PFS). The statistical design is based on superiority hypothesis; PFS is 110days in CP, 65days in C; two-sided α=0.05, 1-β=0.8; and planed accrual is 130 pts. Secondary endpoints include Overall Survival (OS), Time to Treatment Failure (TTF), Response Rate (RR), and safety. Results: From April 2008 to July 2011, 130 patients from 21 sites in Japan were randomized to CP (n=64) or C (n=66). Patient demographics were well balanced between the two groups. At the final analysis, total of 117 PFS events were observed. The primary endpoint was met. PFS for CP was superiority to C (median PFS, 4.17(95%CI 3.03-4.80) vs. 3.03(95%CI 2.20-3.33) months, respectively; HR=1.490(1.029-2.155), p=0.0324,). There were no significant differences in the TTF and RR (TTF was 3.4(95%CI 2.7-4.2) vs. 2.9(95%CI 2.2-3.3) months, RR was 21.9(95%CI 12.5-34.0) % vs. 16.4(95%CI 7.9-27.3) % with CP and C. OS is analyzing now. The most common grade 3/4 toxicities in CP/C (%) were neutropenia, 40.6/38.7; diarrhea, 1.6/7.9; anorexia, 4.7/11.1. Related adverse events were comparable with CP and C.Conclusions: CP has promising efficacy for the second-line chemotherapy compared with C for AGC.CP suggested to be one of the standard second-line chemotherapy regimen for AGC. Clinical trial information: 000001028.
Prediction of gastric cancer survival after gastrectomy using nomogram from 10,621 patients: Developed and validated using international databases.
Authors: Woo Yanghee , Hyung Woo Jin , Song Ki Jun , Hu Yanfeng , Okumura Naoki , Cho Gyu Seok , Noh Sung Hoon 
Published: February 2017

66 Background: Patient-specific prognosis for gastric cancer is difficult to determine. Internationally accepted AJCC TNM staging system currently provides the best framework for predicting a patient’s prognosis. However, a major weakness of the TNM system is that significant survival differences exist even within its subgroups. The objective of this study was to create a simple tool to accurately predict patient survival from gastric cancer after gastrectomy. Methods: Between December 1986 to March 2007, 10,621 patients were surgically treated for gastric cancer at a single institution and observed until death. A nomogram was determined using Cox proportional hazard regression for multivariate analysis and the Kaplan-Meier method for estimation of 5-year overall survival. Overall survival was the endpoint. The predicted probability of the nomogram for actual overall survival was compared to the 7th edition AJCC TNM staging system. Then, the nomogram was validated using external data sets from four different institutions from Korea, Japan, and China. The number of patients in each data set was 1573 (A), 297 (B), 78 (C) and 767 patients (D). Results: Variables selected for the prediction model included age, gender, depth of invasion, number of metastatic lymph nodes (LN), total number of LN retrieved, and the presence of distant metastasis. The newly developed nomogram more accurately predicted a gastric cancer patient’s overall 5-year survival than the 7th Edition AJCC TNM system (p=0.0024) with area under the curve 0.8023 (our nomogram) and 0.7869 (AJCC TNM staging system). The concordance indexes of the different validation sets were 0.824 (A), 0.835 (B), 0.916 (C), and 0.767 (D). Conclusions: Our simple nomogram requires minimal patient and tumor information. It accurately predicts the 5-year overall survival for a patient with gastric cancer after surgical resection. Already internationally validated with data sets of various sample sizes and from different countries, our new nomogram provides a useful tool for prognostication after gastrectomy with wide applicability in different patient populations and institutions.
Randomized phase II study of S-1/CDDP plus TSU-68 versus S-1/CDDP in patients with advanced gastric cancer.
Authors: Yamaguchi Kensei , Koizumi Wasaburo , Hosaka Hisashi , Takinishi Yasutaka , Nakayama Norisuke , Hara Takuo , Muro Kei , Baba Hideo , Sasaki Yasutsuna , Nishina Tomohiro , Fuse Nozomu , Esaki Taito , Takagi Masakazu , Gotoh Masahiro , Kitamura Ryuichi , Matsumoto Hideki , Sasaki Tsuneo 
Published: February 2017

72^ Background: Gastric cancer (GC) is the second leading cause of cancer death in Japan as well as globally. Effective treatment of GC remains a therapeutic challenge. Although in the AVAGAST trial, bevacizumab was found to offer no survival benefit. Angiogenesis continues to be the standard treatment for GC, and thus, clinical trials on many anti-angiogenic drugs have been conducted. TSU-68 (orantinib) is an oral, angiokinase inhibitor targeting the vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factor receptor 1. The present study evaluated the progression-free survival (PFS) and pharmacokinetics (PK) of TSU-68 in combination with Japanese standard S-1 and cisplatin (S-1/CDDP) in patients with advanced GC. Methods: In this open-label, multicenter, randomized, controlled, parallel-group, phase II trial, patients were randomized to Arm A (S-1/CDDP) or Arm B (TSU-68 plus S-1/CDDP). All patients received oral S-1 (40-60 mg/m2) twice daily for 21 days followed by a 14 day rest plus intravenous CDDP (60 mg/m2) on Day 8, repeated every 35 days. In Arm B pts received oral TSU-68 (400 mg/dose) alone, twice daily by addition 35 days. The primary endpoint was PFS. Results: In total, 93 patients were enrolled. For Arm A [male:female ratio], n=47 [35:11]; Arm B, n=45 [30:15]; the respective median age was 63.5 and 62.0 years. The median PFS was 7.0 and 6.8 months in Arms A and B, respectively (HR, 1.23; 95%CI, 0.74 to 2.05; P=0.425); the respective response rates were 56.5% and 62.2%. The most common grade 3/4 toxicities were neutropenia (Arms A and B, 34.8% and 31.1%) and hemoglobin (Arms A and B, 26.1% and 48.9%). There were no differences in other toxicities between the 2 arms, both treatments were tolerated, and no treatment-related deaths were observed. In the PK study, although Arm B had a significantly lower plasma exposure to FT, CDHP, and Oxo compared to Arm A, the exposure to 5-FU was not different between the 2 arms. The exposure to CDDP in Arm B was significantly but slightly lower than that in arm A. Conclusions: Thus,TSU-68 plus S-1/CDDP therapy did not prolong PFS of patients with advanced GC as compared with S-1/CDDP. Clinical trial information: JapicCTI-101327.
A phase I dose-finding study of vorinostat (V) combined with capecitabine (X) and cisplatin (P) as first-line therapy in patients with advanced gastric cancer.
Authors: Yoo Changhoon , Ryu Min-Hee , Ryoo Baek-Yeol , Koo Dong Hoe , Park Inkeun , Kang Yoon-Koo 
Published: February 2017

73 Background: The purpose of this trial is to determine the recommended dose (RD) of vorinostat (V), a histone deacetylase inhibitor, in combination with capecitabine (X) and cisplatin (P) and to explore feasibility of V-XP at the RD in advanced gastric cancer. Methods: The standard 3+3 method was used to determine the RD of 3-weekly V-XP during the first cycle. The doses of X (days 1-14, p.o.), P (day 1, i.v.), and V (days 1-14, p.o.) were escalated as following scheme; X 1,600 mg/m2/day, P 60 mg/m2, V 300 mg/day in level 1; X 1,600 mg/m2/day, P 60 mg/m2, V 400 mg/day in level 2A; X 2,000 mg/m2/day, P 60 mg/m2, V 300 mg/day in level 2B; X 2,000 mg/m2/day, P 60 mg/m2, V 400 mg/day in level 3; X 2,000 mg/m2/day, P 80 mg/m2, V 400 mg/day in level 4. Results: A total of 24 patients were enrolled. Median age was 50 years (range, 25-66), and 11 (46%) were male. Dose limiting toxicity (DLT) was noted in 1 of 6 in level 1 (Grade 4 thrombocytopenia), 0 of 3 in level 2A, 1 of 6 in level 2B (Grade 3 fatigue), 1 of 6 in level 3 (Grade 3 stomatitis) and 2 of 3 in level 4 (Grade 4 thrombocytopenia, and discontinuation of X or V more than 25% of prescribed dosage due to Grade 3 anorexia and Grade 3 fatigue). Level 4 was maximal tolerated dose, and RD was determined as level 3. Six additional patients were enrolled at level 3 to confirm the feasibility, and DLT was not occurred. In 12 patients who received dose level 3, median 6 cycles (range, 3-10) of chemotherapy were given and most frequent Grade 3/4 toxicities were neutropenia (n=5, 42%) and anorexia (n=3, 25%). In overall, the objective responses were confirmed in 9 (47%) out of 19 patients with measurable lesions. With a median follow-up of 9 months, median progression-free survival was 7 months (95% confidence interval, 4 to 10 months), and median overall survival was not reached. Conclusions: Major DLTs of V-XP were thrombocytopenia, fatigue, anorexia and stomatitis. The 3-weekly schedule of X (2,000 mg/m2/day on day 1-14), P (60 mg/m2 on day 1), and V (400 mg/day on day 1-14) is recommended for further development of this regimen in patients with advanced gastric cancer. Clinical trial information: NCT01045538.