bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of primary tumor location on survival time in patients (pts) with metastatic colorectal cancer (mCRC) treated with cetuximab plus oxaliplatin-based chemotherapy: A subgroup analysis of the JACCRO CC-05/06.
Authors: Sunakawa Yu , Ichikawa Wataru , Tsuji Akihito , Denda Tadamichi , Segawa Yoshihiko , Negoro Yuji , Shimada Ken , Kochi Mitsugu , Nakamura Masato , Kotaka Masahito , Tanioka Hiroaki , Takagane Akinori , Tani Satoshi , Yamaguchi Tatsuro , Takeuchi Masahiro , Fujii Masashi , Nakajima Toshifusa 
Published: February 2017

613 Background: Sub-analyses of US and European randomized trials have demonstrated that primary tumor location is a critical prognostic factor in mCRC treated with 1st-line chemotherapy; moreover, left-sided tumor location may be a predictor of cetuximab efficacy in KRAS exon 2 wild-type tumors (Loupakis F, et al. J Natl Cancer Inst 2015; von Einem JC, et al. J Cancer Res Clin Oncol 2014). We therefore investigated the prognostic impact of primary tumor location on outcomes of Japanese pts enrolled in JACCRO CC-05 or CC-06 trial, which evaluated efficacy of cetuximab in combination with FOLFOX or SOX, respectively, for mCRC with KRAS exon 2 wild-type tumors. Methods: This study evaluated the association of tumor location with overall survival (OS) and progression-free survival (PFS) in mCRC pts from 2 phase II trials of 1st-line therapy; JACCRO CC-05 of cetuximab plus FOLFOX (n= 57, UMIN000004197) and CC-06 of cetuximab plus SOX (n= 67, UMIN000007022). Tumors proximal or from left flexure to rectum were defined as right-sided or left-sided, respectively. Results: In total of 124 pts of the 2 trials, 110 pts were assessable for the primary tumor location: 90 pts with left-sided tumors and 20 pts with right-sided tumors. In the population consists of 110 evaluable pts, median PFS was 9.4 months, and median OS was 33.9 months. Left-sided tumors were significantly associated with longer OS (36.2 months vs. 12.6 months, HR 0.28, 95%CI 0.15-0.53, p< 0.0001) and PFS (11.1 months vs. 5.6 months, HR 0.47, 95%CI 0.29-0.82, p= 0.0041) compared to right-sided tumors. The association was evident in the group of FOLFOX (p< 0.0001 for OS and p= 0.0002 for PFS), while there was a trend in OS of the group of SOX (p= 0.079). In the FOLFOX-group, median OS and PFS were 5.7 and 3.0 months, respectively, for right-sided tumors (n= 9) and 42.8 and 11.3 months, respectively, for left-sided tumors (n= 43). Conclusions: Our study demonstrates that primary tumor location may serve as a predictor of prognosis of mCRC pts treated with cetuximab plus oxaliplatin-based therapy, potentially confirming the prognostic impact of tumor location.
Relations of T-cell and B-cell area ratios and the number of natural killer cells (NK cells) in lymph nodes (LNs) to outcomes in patients with stage II colon cancer.
Authors: Okada Kazutake , Sadahiro Sotaro , Miyakita Hiroshi , Saito Gota , Tanaka Akira , Suzuki Toshiyuki , Masuda Shinobu 
Published: February 2017

618 Background: In stage II colon cancer, patients with many retrieved LNs have good outcomes. We previously reported that the longest diameter of retrieved LNs correlates with the number of LNs and can be used as a prognostic factor (Int J Colorectal Dis 2015). LNs can be divided into three main regions, cortex, paracortex, and medulla, and consist mainly of T cells, B cells, NK cells, and histiocytes. We studied the relations of the T-cell, B-cell area ratios, and the number of NK cells in longest-diameter LNs to the number of retrieved LNs and outcomes. Methods: The subjects were 320 patients with stage II colon cancer who underwent curative resection. One LN with the maximum long-axis diameter was selected, and was immunostained with CD3 as a T-cell marker, CD20 as a B-cell marker, and CD56 as an NK-cell marker. Positive area ratio was determined by image analysis. The number of CD56-positive cells were examined and the mean number per 0.093 mm2was calculated. The relations were evaluated with the use of Spearman’s rank correlation coefficient. The cut-off values were calculated by ROC curve analysis. Results: The number of LNs was 14.8 ± 10.4 (mean ± SD). The CD3-positive area ratio was 0.39 ± 0.08. The CD20-positive area ratio was 0.42 ± 0.10. The number of CD56-positive cells was 9.9 ± 10.1. The correlation coefficients for the number of LNs with CD3-positive area ratio, CD20-positive area ratio, and the number of CD56-positive cells were respectively -0.07 (p = 0.220), 0.05 (p = 0.360), and 0.33 (p < 0.001). The number of LNs positively correlated with the number of CD56-positive cells. The median follow-up period was 118 months. Patients with a CD20-positive area ratio of 0.43 or greater (n = 160) had a significantly better survival (HR, 0.64; 95%CI, 0.44-0.92; p = 0.015). Patients with 3 or more CD56-positive cells (n = 276) had a significantly better survival (HR, 0.57; 95%CI, 0.37-0.93; p = 0.017). Conclusions: A high number of NK cells in longest-diameter LNs was associated with a higher number of retrieved LNs, a longer LN diameter, and better survival. NK cells in the longest LNs may reflect the host antitumor immune response in patients with Stage II colon cancer.
Frequency of HER2 mutations and amplification in GI malignancies and ability of pertuzumab to overcome neuregulin1 mediated drug resistance to a HER2 tyrosine kinase inhibitor in colon cancer.
Authors: Bose Ron , Ali Siraj , Jain Naveen , Gowen Kyle , Bertotti Andrea , Murray Elisa , Ross Jeffrey S. , Beattie Mary Stanley , Hurwitz Herbert , Hainsworth John D. 
Published: February 2017

630 Background: HER2 amplifications and activating mutations are an emerging drug target in the treatment of colorectal cancer (CRC). Ongoing studies, such as MyPathway (Clinicaltrials.gov NCT02091141), include basket trials of targeted therapies for multiple solid tumor types. The frequency of HER2 mutations in GI cancers and a drug resistance mechanism to the HER2 kinase inhibitor, afatinib, are presented here. Methods: The Foundation Medicine database of 53,126 cases was searched and clinical data from patients with GI tumors enrolled in the HER2 basket of MyPathway was included. Results: 10,358 patients with GI cancers and FoundationOne (FO) testing were identified and compared to the HER2 mutation frequency reported by The Cancer Genome Atlas (TCGA). In MyPathway, 28 GI tumors with HER2 alterations are enrolled: CRC (n = 13, all amplified), liver/biliary (n = 5), pancreatic (n =4), small intestine (n = 3), and esophageal (n = 2). Several CRC patients demonstrated responses to trastuzumab/pertuzumab (reported separately). The HER2 mutant CRC cell lines, CW-2 and CCK-81, are highly sensitive to afatinib (IC50=7-20 nM). Addition of the HER3 ligand, neuregulin1 caused afatinib resistance, but pertuzumab prevented HER3/HER2 activation and reversed this drug resistance. Conclusions: HER2 mutations or amplifications are commonly found in a wide range of GI cancers. Pre-clinical data provide rationale for inclusion of pertuzumab in the treatment strategy for these cancers. The MyPathway Trial is testing this approach. [Table: see text]
Efficacy of cetuximab immediately after bevacizumab: A phase III multicenter trial comparing two different sequences of cetuximab and FOLFOX in K-Ras WT metastatic colorectal cancer patients refractory FOLFIRI/bevacizumab.
Authors: Cascinu Stefano , Zaniboni Alberto , Lonardi Sara , Rosati Gerardo , Nasti Guglielmo , Giordano Monica , Corsi Domenico C. , Ferraú Francesco , Iaffaioli Rosario Vincenz , Marchetti Paolo , Aglietta Massimo , Bilancia Domenico , Ronzoni Monica , Floriani Irene Claudia , Labianca Roberto 
Published: February 2017

632 Background: FOLFOX/FOLFIRI are effective as first-line treatment but FOLFOX might be more effective in second line. The optimal first-line in RAS wild type mCRC is still unclear even after 2 trials comparing chemotherapy with bevacizumab or cetuximab. While bevacizumab seems to loose efficacy across treatment lines, cetuximab has a similar activity across all treatment lines. It might be a better choice for the third-line in the view of an optimal sequence strategy. We designed a phase III randomised trial to compare two different treatment sequences of cetuximab and FOLFOX in mCRC patients refractory to FOLFIRI/bevacizumab first-line. Methods: Pts were randomized to receive Irinotecan/Cetuximab as 2nd line followed by FOLFOX-4 as 3rdline (Arm A) or the inverse sequence. Primary endpoint was progression free survival (PFS); secondary endpoints were overall survival and toxicity. 101 events were required in order to detect an hazard ratio of 0.57, translating in an increase of median PFS from 4 to 7 months (two-sided type I error 5%, power 80%). Results: 110 mCC pts were enrolled in this trial: 64 pts were males and 46 females with a mean age of 61 years. Efficacy results are reported in the table. Treatment was well tolerated with a low number of serious adverse reactions (2 in each treatment arm). Conclusions: Cetuximab is less effective immediately after bevacizumab. This is in accordance with data suggesting that EGFR inhibition is not active after VEGF blockade. The sequence of biological agents seems to be more relevant than the first-line choice. In RAS wild type patients progressing after a first line bevacizumab based therapy cetuximab should be given as first line or third line. Clinical trial information: NCT01030042. [Table: see text]
Real-world cancer regimen costs for metastatic colorectal cancer patients treated with biologics in first- through second-line.
Authors: Johnston Stephen , Riehle Ellen , Varker Helen , Juneau Paul , Wilson Kathleen , Sommer Nicolas , Ogale Sarika 
Published: February 2017

636 Background: This study examined real-world cancer regimen costs for metastatic colorectal cancer (mCRC) patients treated with biologics in first- (1L) through second-line (2L). Methods: Using a large U.S. commercial/Medicare supplemental insurance claims database, patients with mCRC initiating a 1L bevacizumab (BEV) or cetuximab (CET) containing regimen between 1/1/2008-8/31/2014 and transitioning to a 2L biologic-containing regimen (BEV, CET, panitimumab [PAN], regorafenib [REG], or ziv-aflibercept [ZAF]) were identified. Monthly costs of cancer regimens (biologic/administration, chemotherapy/administration) were measured over a follow-up period beginning at initiation of 1L therapy and ending at the discontinuation of 2L therapy, inpatient death, insurance disenrollment, or 9/30/2014. Results: Among 2,352 patients, mean monthly biologic costs for 1L+2L ranged from $6,738 in the 1LBEV-2LBEV group, to $12,568 in the 1LCET-2LOther group (Table). In contrast, chemotherapy costs ranged from $1,898 in 1LCET-2LOther group to $4,070 in the 1LBEV-2LBEV group. Conclusions: Mean total cancer regimen costs per month for the 1L+2L sequence tended to be lower for patients treated with 1L BEV-containing regimens, compared with 1L CET-containing regimens. The majority of 1L-BEV patients also received BEV in 2L (TML). These agents' real-world comparative costs are an important consideration in treatment decisions. [Table: see text]
Conversion to resectability in unresectable metastatic colorectal cancer chemotherapy (mCRC) trials.
Authors: Chrabaszcz Sarah , Rajeev Rahul , Klooster Brittany , Chinn Ashley , Gamblin T. Clark , Johnston Fabian McCartney , George Ben , Banerjee Anjishnu , Turaga Kiran 
Published: February 2017

641 Background: Patients with mCRC undergoing surgical metastasectomy have been shown to derive significant survival benefit with a potential for cure. We hypothesized that conversion to resectability (c2r) is correlated with increased overall survival in patients with unresectable mCRC. Methods: Prospectively registered systematic review (PROSPERO CRD42015024104) was utilized to identify randomized clinical trials published after 2003. Exposure of interest was c2r from unresectable disease, while the outcome was overall survival (OS). Clinical trials were classified into three groups based on difference in c2r between the two study groups ( < 2, 2-2.9, ≥ 3 %). Generalized estimating equations(GEE) were used to measure associations while adjusting for multiple observations from the same trial. The Cochrane risk of bias tool was used to evaluate the methodological quality. Results: Out of 2,902 studies reviewed, 30 satisfied selection criteria (n = 13,618 patients). All studies had two arms only (100%). Median c2r was 7.3% (Interquartile Range 5%-12.9%), with maximum c2r in FOLFOX/FOLFIRI+ cetuximab arm (28.6%). The median difference in c2r between two arms of the same study was 2.3% (IQR 1.3 – 3.4%) and the maximum difference was 15.4% seen in FOLFOX/FOLFIRI+ cetuximab vs. FOLFOX/FOLFIRI (Ye, 2013). Median OS for the entire cohort of patients was 20.7 months (IQR 18.9 – 22.7 months), with a between group difference of 1.3 (IQR -1.2 – 3.6 months). The maximum survival benefit between two study arms was 9.9 months. Median survival difference between the two study arms with a minimal c2r difference ( < 2%) was 0.8 months, as compared to 1.6 months with higher c2r ( ≥ 3%). Incremental dose effect response was noted with an increasing c2r leading to improved overall survival in regression models (p = 0.021, r2= 0.16). Higher response rates also correlated with higher c2r rates (p = 0.003, r2= 0.25). Conclusions: Conversion to resectability is positively correlated with an improvement in survival in trials examining therapies for unresectable mCRC. Patient level data examining the contribution of metastasectomy to the overall survival benefit of systemic chemotherapy needs to be further examined.
Effect of combined neoadjuvant chemoradiation on overall survival for patients with locally advanced rectal cancer.
Authors: Sun Zhifei , Adam Mohamed A , Kim Jina , Hsu Shiao-Wen D , Palta Manisha , Czito Brian G. , Migaly John , Mantyh Christopher 
Published: February 2017

657 Background: Prospective randomized trials have demonstrated that neoadjuvant chemoradiation improves local control and results in a higher rate of sphincter-sparing surgery for patients with locally advanced rectal cancer. However, neoadjuvant therapy utilization and population-based outcomes are not well defined. Methods: Adults with stage II/III rectal adenocarcinoma within the National Cancer Data Base undergoing surgery between 2006-2012 were analyzed. Patients were grouped by type of neoadjuvant therapy received: no therapy, chemotherapy only, radiotherapy only, or concomitant chemoradiation. Multivariable modeling was used to compare perioperative outcomes and overall survival between groups. Results: Among 32,978 patients included, 9,714 (29.5%) received no neoadjuvant therapy, 890 (2.7%) chemotherapy only, 1,170 (3.5%) radiotherapy only, and 21,204 (64.3%) concomitant chemoradiation. 5-year overall survival among groups was 62%, 69%, 71%, and 74%, respectively. Compared to no therapy, chemotherapy or radiotherapy alone was not associated with any differences in perioperative or oncologic outcomes (all p > 0.05). With adjustment for patient and disease characteristics, neoadjuvant chemoradiation was associated with a lower likelihood of margin positivity (OR 0.74, p < 0.001), need for permanent colostomy (OR 0.77, 95% CI 0.70-0.85, p < 0.001), 30-day mortality (OR 0.67, p = 0.003), and overall survival (HR 0.69, p < 0.001). When compared to chemotherapy or radiotherapy alone, neoadjuvant chemoradiation was still associated with improved overall survival (vs. chemotherapy: HR 0.83, p = 0.04; vs. radiotherapy: HR 0.75, p < 0.001). Conclusions: Neoadjuvant chemoradiation, not chemotherapy or radiotherapy alone, is important for sphincter-preservation and survival for patients with locally advanced rectal cancer. Despite this finding, one third of patients with locally advanced rectal cancer are failing to receive this therapy in the United States.
Stereotactic body radiation therapy for local control of liver metastases from colorectal cancer.
Authors: Joo Ji Hyeon , Kim Jong Hoon 
Published: February 2017

662 Background: Although possible candidates for surgical treatment are increasing, majority of colorectal cancer patients with liver metastases are ineligible for surgery. In our institution, SBRT for liver metastatic colorectal carcinoma has been adopted since 2005. By reviewing the treatment outcomes of relatively large cohorts treated with homogeneous technique, we aimed to report patterns of recurrence and the most effective dose fractionation schedule. Methods: Seventy patients with colorectal liver metastases were treated with SBRT from 2005 to 2014. Total number of treated lesions was 103. Median tumor size was 2.5 cm, with ≥ 3 cm in 42 (41%) lesions. Prescribed doses were biologically equivalent dose (BED) ≥ 112 Gy10, but, if small bowel is adjacent to target volume, dose was decreased according to the normal tissue tolerance dose. Prescription doses relevant to BED ≥ 112 Gy10 were ≥ 45 Gy in 3 fractions or ≥ 60 Gy in 5 fractions, in this study. Results: Median follow-up period was 34.2 months (range, 5.3-121.8). The 2-year local control rate was 92% when full prescription dose was delivered, and 73% if compromised dose group was included. On prognostic factor analysis for local control, N-stage (P= 0.008), and BED (P= 0.001) were significant factors. Overall survival rate was 86% for BED ≥ 112 Gy10 group, and 73% for total cohort. The major pattern of failure was out-of-field intrahepatic progression. On multivariate analysis, N stage (P= 0.001), lesion size (P= 0.010) and number of treated hepatic lesions (P< 0.001) were significant factors for intrahepatic control. Conclusions: Liver SBRT was an effective treatment option for colorectal liver metastases. If BED ≥ 112 Gy10 was delivered, we could expect long-term survival in substantial portion of patients. Major pattern of failure was out-of-field intrahepatic progression, which was related to number of treated hepatic lesions, lesion size and N-stage.
Assessment of treatment with panitumumab, cetuximab, and bevacizumab among mCRC patients with wild-type RAS or BRAF treated at community cancer centers in the United States.
Authors: Lowe Kimberly , Garawin Tamer , Kelsh Michael Anthony , Bohac Gerry C. 
Published: February 2017

663 Background: There is limited observational data on the use of RAS test results and treatment patterns with chemotherapy and biologics among metastatic colorectal cancer (mCRC) patients. Our objective was to use real world data to evaluate the treatment sequences of mCRC patients who have wild-type RAS (KRAS, NRAS), or BRAF and who are treated at community cancer clinics within the United States (U.S.). Methods: The sample included 536 patients in the Oncology Services Comprehensive Electronic Records (OSCER) database who were diagnosed with mCRC between 1/1/2011 and 8/31/2015. All patients had available treatment data and were confirmed to have wild-type RAS or BRAF. Patients were stratified into mutually-exclusive categories based on 1st line treatment with chemotherapy in combination with either bevacizumab (Bmab), cetuximab (Cmab), panitumumab (Pmab), a combination of Pmab, Cmab or Bmab, or no biologics. Descriptive statistics were used to summarize the data. Results: The demographics of the sample were as follows: mean age 67 years (standard deviation = 12), 55% male, 70% White, and 50% with ECOG value of zero. The use of Bmab, Cmab, or Pmab in combination with chemotherapy in 1st line treatment was follows: Bmab only (n = 270, 50%), Cmab only (n = 81, 15%), Pmab only (n = 28, 5%), and a combination of either Bmab, Cmab and/or Pmab (n = 6, 1%). No biologics were administered to 151 (28%) of the sample in 1st line. There were no statistically significant differences in age, gender, race, insurance type, region of the U.S. or ECOG status at mCRC diagnosis across the 1st line treatment categories. Of the 385 patients who received a biologic in 1st line, 94 (24%) of those who survived and selected to continue treatment received a biologic in 2nd line. Of these 94 patients, 25 (27%) of those who survived and selected to continue treatment also received a biologic in 3rd line. Conclusions: Bmab was the most commonly-used biologic among mCRC patients with wild-type RAS or BRAF in this descriptive study. Future research is needed to better understand what factors impact treatment decisions among mCRC patients.
Two-stage hepatectomy for colorectal metastases: Association of a good pathologic response to intensified preoperative chemotherapy with second stage completion and longer survival.
Authors: Quenet François , Pissas Marie-Hélène , Gil Hugo , Roca Lise , Carrere Sebastien , Alline Mathias , Rouanet Philippe , Saint-Aubert Bernard , de Forges Helene , Khellaf Lakhdar , Samalin Emmanuelle , Portales Fabienne , Sgarbura Olivia , Ychou Marc , Bibeau Frederic 
Published: February 2017

666 Background: The two-stage surgical resection (TSR) of bilobar colorectal liver metastases (CRLM) is widely used and has shown encouraging survival results. The risk of drop-out after the first-stage hepatectomy remains high and associated with poor survival rates. Our objective was to evaluate the predictive factors of long-term survival, based on the pathologic response to an intensified systemic chemotherapy administered preoperatively. Methods: Data from 899 patients treated for CRLM in our institution were collected prospectively between January 2003 and August 2013. We evaluated the pathologic response to preoperative chemotherapy, and its impact on the second-stage completion and on survival. Results: Sixty-seven patients were eligible for the TSR first stage. All patients underwent an intensified chemotherapy in combination with a biotherapy (Bevacizumab or Cetuximab) in 38cases. The Tumour Regression Grade (TRG), the Blazer grade, and the modified-TRG were used to classify patients as responders (TRG and mTRG 1-3, Blazer 0-1) or non-responders (TRG and mTRG 4-5, Blazer 2) after the first stage. Responders in the three classifications (TRG: p = 0.033; mTRG: p = 0.03, Blazer:p = 0.005), and initial metastases number (p = 0.001) were independent predictive factors for the second-stage completion. Triple chemotherapy were associated with responders in the three classifications (TRG and mTRG: 73.7% versus 26.3% p < 0.0001 ; Blazer : 84.2% versus 15.8% p = 0.001). Median overall survival (OS) of patients who completed TSR was significantly different (44, 84 versus18,39 months; p < 0.0001). There was no statistical difference in OS and recurrence-free survival between the responders and non-responders. Conclusions: A good pathologic response to intensified preoperative chemotherapy is associated with completion of the second stage of TSR, and thus with a longer survival. Knowing this response before the first-stage resection may allow avoiding useless resections for patients who will not benefit from this strategy.