bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of bevacizumab in combination with irinotecan plus S-1 as first-line treatment in patients with KRAS mutant-type metastatic colorectal cancer.
Authors: Eto Tetsuya , Masuishi Toshiki , Suzuki Kohei , Shibata Isamu , Fukami Yuichi , Matsui Toru , Ichida Takashi , Kusano Fumihiko , Tazawa Junichi , Sakai Yoshinori 
Published: February 2017

676 Background: FOLFIRI+bevacizumab (BV) is considered as a first-line treatment in patients (pts) with metastatic colorectal cancer (mCRC). The FIRIS study showed the non-inferiority of irinotecan plus S-1 (IRIS) to FOLFIRI. Therefore, we conducted a phase II study to evaluate the efficacy and safety of BV in combination with IRIS as first-line chemotherapy for KRAS mutant-type (mt) mCRC (clinical trial information: UMIN000004630). Methods: Eligibility criteria included histologically confirmed mCRC, KRAS mt, no previous chemotherapy, ECOG performance status (PS) of 0/1, and adequate organ function. S-1 was administered at 80 mg/m2 on days 1–14 and irinotecan at 100 mg/m2 on days 1 and 15 every 28 days. BV was administered at 5 mg/kg on days 1 and 15 every 28 days. The primary endpoint was response rate (RR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. The sample size was calculated to reject a RR of 25% in favor of a target RR of 50% with a significance level of 0.05 and a statistical power of 80%. Results: Of 26 patients enrolled for the study between December 2010 and September 2015, 23 met the inclusion criteria. The patient characteristics were as follows: median age, 66 (range, 46–77) years; male/female, 15/8; PS 0/1, 9/14; number of metastatic tumors 1/ ≥ 2, 8/15; colon/rectum as the primary tumor site, 13/10; primary tumor +/−, 15/8; and unresectable/recurrent, 15/8. The RR was 60.9% (95% confidence interval (CI): 40.8%–77.8%) with complete response, 0; partial response, 14; stable disease, 8; progressive disease, 0; and not evaluable, 1. With a median follow-up period of 58.1 months, the median PFS and OS were 10.7 (95% CI: 4.7–16.8) and 28.5 (95% CI: 17.6–39.3) months, respectively. The most common grade 3 or 4 adverse events were neutropenia (35%), diarrhea (22%), leukopenia (17%), febrile neutropenia (13%), anemia (13%), and hypoalbuminemia (13%). Conclusions: BV in combination with IRIS as first-line chemotherapy showed promising anti-tumor effects and manageable toxicities for KRAS mt mCRC. Clinical trial information: UMIN000004630.
Prognostic significance of lymph node sampling in node-negative appendiceal carcinoids.
Authors: Raoof Mustafa , Dumitra Sinziana , Singh Gagandeep , Fong Yuman , Lee Byrne 
Published: February 2017

678 Background: Surgical resection is the primary therapy for local and locally advanced carcinoid tumors of the appendix. The extent of surgery is largely dictated by the size of the tumor. Tumors >2 cm require a right hemicolectomy with associated mesenteric lymphadenectomy. What constitutes an adequate mesenteric lymphadenectomy is not known. Methods: This is a study of a contemporary cohort from NCI’s SEER database (Jan, 2004- Nov, 2012). Patients with non-metastatic appendiceal carcinoid tumors were included. Surgical extent was defined as limited (appendectomy or illeocecectomy) or extended (hemicolectomy). Primary outcome was overall survival (OS). Survival analysis was performed using the Kaplan-Meier and Cox-proportional hazards model. Results: Of the total 1,104 patients that met the inclusion criteria, 52% were female, 88% were white and majority were middle aged (40-60y) 45%. Majority of the tumors were <2 cm (49.3%) and lymph node(LN) negative 85%. Median LN retrieved were 10 (IQR 0-17). Median follow-up was 32 months (IQR 10-61). A multivariate Cox-proportional hazard model demonstrated that increasing age, tumor size > 3cm, tumor spread to contiguous organs, LN positivity and LN count <11 (HR 1.78: 95%CI 1.17-2.69; p=0.006) are associated with worse OS. Five-year overall survival increased with the number of LN retrieved (LN 1-10, 81.4%; LN >10, 85.9%, p=0.035). Stratified analysis by LN status demonstrated that LN count <11 was an independent predictor of worse OS in node negative patients (HR 2.10: 95%CI 1.25-3.53; p=0.005) but not node positive patients (p=0.65). Subset analysis by tumors size demonstrated that prognostic value of LN count <11 was only significant for tumors greater than 3 cm (HR 2.32: 95%CI 1.15-2.03; p=0.018). Conclusions: This is the largest study to date that looks at prognostic significance of LN count for appendiceal carcinoids. The number of LNs evaluated is an independent prognostic factor in pathologic node-negative, appendiceal carcinoid tumors measuring greater than 3 cm. This data supports performing a formal lymphadenectomy (>10 LN) even if no mesenteric disease is visible for adequate staging.
A phase I study of MEK162 and FOLFOX in chemotherapy-resistant metastatic colorectal cancer.
Authors: Cho May Thet , Lim Dean , Synold Timothy W. , Frankel Paul Henry , Leong Lucille A. , Chao Joseph , Chung Vincent M. , Chen Yuan , Sentovich Stephen , Luevanos Eloise , Fakih Marwan 
Published: February 2017

679 Background: Pre-clinical studies have shown that the combination of MEK inhibitors and 5-FU improves antitumor activity and that MEK inhibition overcomes both 5FU and platinum resistance. This phase I study was conducted to determine the maximum tolerated dose (MTD) of the combination MEK162 and FOLFOX. Methods: Patients (pts) with metastatic colon or rectal cancer who progressed or failed prior 5FU, irinotecan, oxaliplatin and anti-EGFR therapy (in cases of RAS wild type tumors) received twice daily MEK162 in combination with every-2-week FOLFOX. Two dose levels of MEK162 (30mg and 45mg) were investigated in a standard 3 + 3 escalation design in combination with standard doses of FOLFOX without bolus 5-FU. Dose limiting toxicity (DLT) was defined as any treatment-related grade (G) 3 or 4 non-hematological toxicity (with the exception of G3 diarrhea or vomiting < 48 hrs) or G 4 neutropenia or thrombocytopenia within the first 2 cycles (4 weeks) of the treatment. Limited pharmacokinetic (PK) analysis of 5FU, oxaliplatin and MEK162 was performed at the MTD level. Results: 16 pts were enrolled (median age (range) 53 yrs (49-78); 11 men; ECOG 0/1 in 9/7 patients). No DLT was noted on the study. The MTD of MEK162 was 45 mg PO BID. An additional 6 pts (for a total of 12) were enrolled at the MTD for PK analysis and none of them developed DLT defining toxicities. A median of 8 cycles (range 1-19) was administered. Treatment-related ≥ grade 3 toxicities included anaphylaxis due to oxaliplatin (n = 1), CPK elevation (n = 2), neutropenia (n = 1), peripheral neuropathy (n = 3), thrombocytopenia (n = 1), retinal vascular disorder (n = 1), and acneiform rash (n = 1). 10 pts had SD at 2 months (m) by radiographic assessment, 5 of whom with stabilizations of > 5 months (5-10 months). There were no significant differences in the PKs of 5FU or oxaliplatin when administered with or without MEK162. Conclusions: The combination of MEK162 and FOLFOX has a manageable toxicity profile and promising antitumor activity in heavily pretreated metastatic colorectal cancer patients. Clinical trial information: NCT02041481.
The relationship between systemic inflammation and postoperative outcomes following neoadjuvant chemoradiotherapy for rectal cancer.
Authors: McSorley Stephen Thomas , Khor Bo , Horgan Paul G. , McMillan Donald C 
Published: February 2017

682 Background: The magnitude of the systemic inflammatory response before and after surgery for rectal cancer is increasingly understood to have an impact on clinical outcomes. The aim of the present study was to examine the impact of neoadjuvant chemoradiotherapy (nCRT) on pre- and postoperative systemic inflammation and clinical outcomes in patients undergoing surgery for rectal cancer. Methods: Data was recorded prospectively for patients who underwent elective, potentially curative surgery for rectal cancer, from 2008 to 2015 at a single centre, n = 251. Patients had routine pre- and postoperative blood sampling. Results: Of the 251 patients, the majority were male (62%) and over 65 years old (57%) with node negative disease (66%). 85 patients (33%) were allocated to preoperative nCRT based on probable margin threatening disease at preoperative MRI. nCRT was significantly associated with a higher proportion of patients having neutrophil lymphocyte ratio (NLR) > 5 (39% vs. 12%, p < 0.001), and a modified Glasgow Prognostic Score (mGPS) of 2 (14% vs. 6%, p = 0.035) prior to surgery. There was no significant association between nCRT and the magnitude of the postoperative systemic inflammatory response or complications. Of the 85 patients who underwent nCRT, there was a small but significant reduction in CRP following treatment (3.25 mg/L vs. 4.1 mg/L, p = 0.007). Of the 16 patients who were systemically inflamed prior to nCRT, 9 patients achieved mGPS score 0 after treatment (p = 0.004). There was a significant association between having an mGPS score 1 or 2 both before and after nCRT and breaching established thresholds of CRP on postoperative days 2 (190mg/L, 86% vs. 33%, p = 0.002), 3 (170mg/L, 86% vs. 38%, p = 0.015) and 4 (145mg/L, 71% vs. 36%, p = 0.031). Conclusions: Allocation to nCRT was significantly associated with a systemic inflammatory response prior to surgery for rectal cancer. nCRT was significantly associated with attenuation of existing systemic inflammation. Such attenuation of the systemic inflammatory response may in part explain the efficacy of nCRT in patients with rectal cancer.
Activity of aflibercept (Afli) in combination with FOLFIRI (F) for patients with metastatic colorectal cancer (mCRC) in a real-life setting in Spain: Final results of the retrospective study Named Patient Program.
Authors: Sastre Javier , Feliu Jaime , Martinez Purificación , Buges Cristina , Mendez Jose Carlos , Alcaide Julia , Garcia Teresa , Valladares Manuel , Marrupe David , Delgado Ignacio , Salgado Fernandez Mercedes , Martin Valades Jose Ignacio , Juarez Asuncion , Martin Martinez Jose Miguel , Lopez Ana , Quintero Aldana Guillermo Alfonso , Donnay Olga , Vera Ruth , del Pozo Nieves , Diaz De Corcuera Frutos Isabela 
Published: February 2017

689 Background: InVELOUR trial the addition of aflibercept to FOLFIRI regimen, demonstrated a statistically significant overall survival improvement in mCRC patients (pts) who progressed on or after a prior oxaliplatin based regimen with or without biologic agents. Our goal is to assess in the real-life setting the activity and safety profile of Afli+F in mCRC. Methods: Retrospective data collection (baseline characteristics, progression free survival [PFS], objective response rate [ORR], salvage surgeries, and safety profile) of pts who received Afli+F as a 2nd line treatment on a compassionate use program in Spain. GERCOR prognostic model has been applied to evaluate PFS. These are the final results of the analysis (Cut-off date June 2015). Results: The retrospective study population comprised 71 pts (34 hospitals); 60.6% men and 39.4% women, median age 64 years (19.7% > 70) and 98.6% had ECOG scores = 0-1. 63.4% (n = 45) had ≥ 2 metastatic sites (liver [81.7%], lung [38.0%]) and 67.7% (46/68) patients were K-RAS mutated. 60.6% (n = 43) had received prior bevacizumab (BVZ) treatment, 16.9% (n = 12) had received prior cetuximab and 5.6% (n = 4) panitumumab. Patients received a median of 6 cycles (range: 1-30) of Afli+F. Median PFS with Afli+F was 5.3 months (CI 95%: 3.7-8.6); which was not significantly modified by the presence of K-RAS mutation (HR: 1.1663; 95%CI: 0.6676-2.0373; p = 0.5867), by prior BVZ treatment (HR: 1.2424; 95%CI: 0.7238-2.1327; p = 0.4283) or by anti-EGFRs treatment (HR: 0.5681; 95%CI: 0.3117-1.0356; p = 0.0604). ORR was 19.7% (CI 95%: 11.2-30.9) and 8.5% (n = 6) of salvage surgeries. The most frequent adverse events grade ≥ 3 related with treatment were asthenia (n = 8), neutropenia (n = 7) and diarrhea (n = 6). The characteristic anti-angiogenic events were hypertension (n = 8), proteinuria (n = 1), vascular events (n = 1), and one intestinal perforation resulting in death. GERCOR prognostic model: Median PFS = 8.30 months [1.28-18.71] low risk, 5.29 [4.08-9.93] intermediate risk and 2.56 [1.94-4.57] high risk. Conclusions: In spite of the differences in sample size, in the real-life setting, Afli+F achieve a PFS comparable to VELOUR, regardless of K-RAS status or prior BVZ and anti-EGFR’s treatment, with an appropriate safety profile. Funding: Sanofi.
Clinical significance of MET amplification in metastatic or locally advanced gastric cancer treated with first-line fluoropyrimidine and platinum (FP) combination chemotherapy.
Authors: Seo Seyoung , Park Seong Joon , Park Sook Ryun , Ryu Min-Hee , Ryoo Baek-Yeol , Park Young Soo , Na Young-Soon , Lee Chae-Won , Lee Ju-Kyung , Kang Yoon-Koo 
Published: February 2017

69 Background: Amplification of the MET proto-oncogene has been reported in a subset of gastric cancer (GC). However, clinical information of MET amplified GC is limited, especially in the metastatic setting. We investigated the clinical significance of MET amplification in GC patients treated with palliative chemotherapy. Methods: MET amplification was analyzed in formalin-fixed, paraffin-embedded GC tissues by a quantitative PCR-based copy number assay, using advanced GC cohorts between 2008 and 2014 in Asan Medical Center (AMC), Seoul, Korea. A total of 327 patients with tumor portion ≥ 70% were analyzed for clinical features and among them, 260 patients treated with first-line FP were analyzed for survival. MET amplification was defined as > 5 copy number. Results: Twenty one out of 327 patients (6.4%) were classified as harboring MET amplification. Clinical characteristics were compared between patients with or without MET amplification (AMP vs. no AMP group). The AMP group was related with ECOG performance status ≥ 2 (33.3% vs. 10.5% p = 0.007), peritoneal metastasis (76.2% vs. 46.2%, p = 0.008) and poor risk category (47.6% vs. 14.2%, p = 0.001) by AMC prognostic model (Koo et al. Cancer Chemother Pharmacol 2011, 68:913-921). A total of 174 patients had measurable lesions from 260 patients treated with FP and 80 patients (51.4%) obtained objective responses. There were no significant differences in response rate between two groups (61.5% vs. 52.2%, p = 0.518). With a median follow-up of 27.8 months (range, 8.2-68.5), median overall survival (OS) and progression-free survival (PFS) were 12.7 and 5.8 months, respectively. In univariate analysis, neither PFS nor OS was different between two groups (hazard ratio [HR] = 0.677, 95% confidence interval [CI] 0.347-1.322, p = 0.254 for PFS; HR = 0.676, 95% CI 0.347-1.318, p = 0.251 for OS). Conclusions: In advanced GC, MET amplification was associated with poor performance status, peritoneal metastasis, and poor risk category. However, MET amplification was not an independent prognostic predictor in patients with metastatic or locally advanced GC treated with palliative FP chemotherapy.
Utilization and effectiveness of adjuvant chemotherapy (ACT) for colon cancer (CC) in the general population.
Authors: Biagi James Joseph , Mackillop William J. , Nanji Sulaiman , Wei Xuejiao , Peng Yingwei , Hanna Timothy P , Krzyzanowska Monika K. , Booth Christopher M. 
Published: February 2017

702 Background: International guidelines recommend ACT for patients (pts) with stage III CC based on level I evidence showing improved survival. For stage II CC ACT is not routinely recommended but may be considered for pts with high-risk features. Here we describe practice patterns and outcomes associated with ACT in a routine population-based setting. Methods: All CC cases treated with surgery in Ontario 2002-2008 were identified using the population-based Cancer Registry. Electronic treatment records were linked to the registry to identify surgical procedures and utilization of ACT. Pathology reports were obtained for a 25% random sample of all cases to obtain details of extent of disease; pts with stage II or III were included in the study population. High-risk stage II was defined as: T4, <12 lymph nodes, poorly differentiated histology and/or lymphovascular invasion. Logistic regression was used to evaluate factors associated with ACT utilization. Cox proportional hazards model was used to evaluate cancer-specific (CSS) and overall (OS) survival. Results: The study population included 2,801 stage III and 2,488 stage II pts (47% of which were high-risk). In the stage III subgroup 66% received ACT, but was 90% among ages 20-49 vs 68% for ages 70-79 (p<0.001). ACT was associated with increased CSS (HR 0.63, 95% CI 0.54-0.73) and OS (HR 0.63, 95% CI 0.55-0.71). Among all stage II pts 18% received ACT but 24% in the high-risk disease subset. ACT utilization was higher in younger patients (51% for ages 20-49 vs. 16% ages 70-79, p<0.001) and varied across geographic regions (range 10-39%, p<0.001). Among all stage II pts ACT was not associated with improved CSS (HR 1.41, 95%CI 1.09-1.82) or OS (HR 1.16, 95%CI 0.94-1.42). Stratified analysis for high-risk stage II disease also did not show benefit to ACT (CSS HR 1.14, 95%CI 0.84-1.55; OS HR 1.02, 95%CI 0.79-1.31). Conclusions: One third of pts with stage III CC in the general population do not receive ACT, with age the strongest predictor of treatment. For stage II pts, ACT utilization varies substantially across age groups and geographic regions. ACT is associated with improved CSS and OS in stage III pts but not stage II pts, including those with high-risk disease.
Randomized phase II trial of prophylactic use of celecoxib for the prevention of oxaliplatin-related peripheral vascular pain in CapeOX for stage II/III colon cancer patients (YCOG1205).
Authors: Watanabe Jun , Ota Mitsuyoshi , Watanabe Kazuteru , Saito Shuuji , Nagamine Koutaro , Suwa Yusuke , Suwa Hirokazu , Momiyama Masashi , Ishibe Atsushi , Ichikawa Yasushi , Oba Mari Saito , Endo Itaru 
Published: February 2017

703 Background: CapeOX is widely used as a six month adjuvant chemotherapy regimen of colorectal cancer which does not need central vein catheter insertion. However, oxaliplatin-related vascular pain interferes with peripheral administration. We assessed the prophylactic effect of COX-2 inhibitors on oxaliplatin-related vascular pain. Methods: A multicenter of Yokohama Clinical Oncology Group in Japan, open label, randomized non-comparative phase II study with 400mg of celecoxib with CapeOX group (C+ group) and CapeOX group (C- group) was conducted. Stratification factors were performance status 0/I, usage of low dose aspirin and institution. Primary endpoint is the appearance frequency of grade 2 or more vascular pain assessed using the Verbal Rating Scale (VRS) by a medical therapist who has no information about celecoxib administration. C- group patients who developed grade 2 or more vascular pain received celecoxib and were estimated with VRS. Results: Between October 2012 and February 2014, 81 patients were recruited from nine institutions in this study and randomly divided into two groups: 42 patients in C+ group and 39 patients in C- group. Grade II or more vascular pain rate was 55.3% in C+ group and 56.8% in C- group (p = 1.000). Fourteen patients in C- group who developed grade II or more vascular pain were given celecoxib and 50% of patients showed downgrading of vascular pain. Rate of grade II or more peripheral neuropathy was 36.6% in C+ group and 39.5% in C- group (p = 0.7916). Conclusions: Celecoxib has no prophylactic impact on either vascular pain or peripheral neuropathy. However, celecoxib effectively diminished vascular pain in patients with onset of grade II or more vascular pain. Clinical trial information: 000008814.
Efficacy and safety of bevacizumab combined with fluoropyrimidine monotherapy in unfit or older metastatic colorectal cancer patients: A systematic review and pooled-analysis.
Authors: Antonuzzo Lorenzo , Aprile Giuseppe , Barni Sandro , Maiello Evaristo , Masi Gianluca , Petrelli Fausto , Porcu Luca , Scartozzi Mario , Torri Valter , Pinto Carmine 
Published: February 2017

705 Background: Bevacizumab (BEV) improves progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) patients (pts) when added to doublets in first-line setting. Yet, its use in unfit and older mCRC pts remains controversial. This systematic review and pooled-analysis evaluated the efficacy and safety data of BEV combined with first-line fluoropyrimidine monochemotherapy in unfit or elderly mCRC pts. Methods: A literature search to identify studies using first-line fluoropyrimidine monochemotherapy plus BEV in unfit pts was performed in PubMed and EMBASE databases up to May 2015. Unfit pts were selected based on age, comorbities and health status, along with monochemotherapy as the only therapeutic option. The random-effects model was used to combine the effect estimates and the I2 index to quantify the between-study heterogeneity unexplained by sampling error. Results: We screened 1,304 papers and, after a double check, 56 were considered for full text evaluation: 38 were excluded and 10 were deemed not evaluable for lack of data on unfit pts, whereas 8 (3 RCTs, 4 single arm phase II trials and 1 prospective cohort study), including 782 pts, were considered eligible for the meta-analysis. Administered monochemotherapy was capecitabine in 531 (67.9%) pts and 5-fluorouracil (5-FU) in 251 (32.1%); 500 (63.9%) pts also received BEV. Median age was 75 years, 441 (56.4%) pts were male, ECOG performance status was 0-1 in 684 (87.7%) pts. The combination with BEV produced advantages in terms of both OS (HR 0.79; 95% CI: 0.64-0.98, P = 0.03; I2= 0%) and PFS (HR 0.52; 95% CI: 0.43-0.64, P < 0.00001; I2= 0%; pooled effect estimates of RCTs have been previously reported). As expected, higher rates of all grade hypertension (27% vs 4.9%), bleeding (24% vs 6.4%), thromboembolic events (10% vs 5%) and proteinuria (25.6% vs 8.2%) were observed in the BEV combination. Conclusions: Adding BEV to first-line fluoropyrimidine monochemotherapy, either capecitabine or 5-FU, significantly improved PFS and OS in unfit and elderly pts with mCRC, with a manageable safety profile and no unexpected side effects.