bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinicopathological features and prognosis of colorectal cancer with extranodal tumor deposits.
Authors: Lu Yun , Zhang Xianxiang , Hu Jilin , Wang Dongsheng , Gao Yuan , Zhang Maoshen , Liu Shisong , Liu Guangwei , Zhao Peng , Wu Jinhui , Li Zhenkai , Han Jiagang , Wang Guiying , Feng Yong , Wang Jiansheng
Published: September 2018

e15005

Background: The study discusses clinicopathological features of colorectal cancer with extranodal tumor deposits(ENTDs) and investigates whether ENTDs is a poor prognostic factor. Methods: 1. Clinicopathological data and follow-up of colorectal cancer with ENTDs who underwent surgery between June 2007 and June 2010 in seven hospitals in North China were collected retrospectively. Kaplan-Meier method was used for survival analysis. Cox proportional hazards model was used for multivariate analysis of prognostic factors. 2. The literatures on ENTDs and postoperative survival rate in colorectal cancer published from 1990 to 2016 were retrieved in English literature databases such as MEDLINE/PubMed, Web of Science and Chinese literature databases such as CNKI. Meta-analysis was conducted by Review Manager 5.3 software. Results: 1. A total of 253 cases of colorectal cancer with ENTDs were collected. The 5-year survival with only one ENTD was 49.2% (87/177), with median survival time 60 months. The 5-year survival with more than one ENTD was 17.1% (13/76), with median survival time 44 months. Cox regression analysis revealed that age, tumor size, number of ENTDs, N, m stage, surgical approach and adjuvant treatment were independent risk factors of prognosis of colorectal cancer with ENTDs. 2. The total sample size of the studies was 4731 cases with ENTDs (+) 917 cases. Meta analysis showed that: 5-year overall survival and 5-year relapse-free survival rate were significantly lower in ENTDs (+) group than ENTDs (-) group for colorectal cancer (OR:respectively 0.25,0.30; 95% CI:respectively 0.17-0.37,0.22-0.41; both P < 0.00001); 5-year overall survival rates were both significantly lower in ENTDs (+) group than ENTDs (-) group for patients with N0 and N+ colorectal cancer (N0 group: P = 0.003; N+ group: P = 0.0008; both P < 0.05). Conclusions: 1.Age, tumor size, number of ENTDs, N, m stage, surgical approach and adjuvant treatment were independent risk factors of prognosis of colorectal cancer with ENTDs. 2. ENTDs was a poor prognostic factor in colorectal cancer. The effect of ENTDs on postoperative survival rate might resemble that of between lymph node metastasis and distant metastasis.
Hepatectomy followed by adjuvant chemotherapy with capecitabine plus oxaliplatin for three months for colorectal cancer liver metastases: A multicenter phase 2 study.
Authors: Hashida Hiroki , Satake Hironaga , Tanioka Hiroaki , Miyake Yasuhiro , Yoshioka Shinichi , Watanabe Takanori , Matsuura Masato , Kyogoku Takahisa , Inukai Michio , Kotake Takeshi , Okita Yoshihiro , Hatachi Yukimasa , Yasui Hisateru , Kotaka Masahito , Kato Takeshi , Kaihara Satoshi , Tsuji Akihito
Published: September 2018

e15015

Background: Hepatic resection is one of the treatment strategies for resectable colorectal cancer liver metastases (CLM). The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable CLM is still unclear. Adjuvant chemotherapy consisting of capecitabine plus oxaliplatin (CapeOx) appears to be equivalent to FOLFOX in patients with stage III colon cancer. Furthermore, some studies suggest that adjuvant chemotherapy for three months after curative resection for stage II/III colorectal cancer has equivalent efficacy to adjuvant chemotherapy for 6 months. We initiated a multi-institutional, single-arm, open label, phase II trial to confirm the feasibility of adjuvant CapeOx for three months for post curative resection of CLM. Methods: Patients received one course of capecitabine followed by four courses of CapeOx for a total five courses (15 weeks) as adjuvant chemotherapy after curative resection of CLM. CapeOx consisted of a 2-hour intravenous infusion of oxaliplatin 130 mg/m2 on day 1 plus oral capecitabine 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle. The primary endpoint was completion rate of adjuvant chemotherapy. We set a threshold completion rate of protocol treatment of 45% and an expected completion rate of 70%. Given a one-sided α of 0.1 and statistical power of 80%, a minimum of 25 patients was required. Results: From May 2013 to November 2015, Twenty-eight patients were enrolled from six institutions: median age 69.5y, 54% male, 78.5% left-sided primary. Of the patients, 15 were synchronous metastases and 13 were metachronous. The locations of the metastases were unilobar in 20 patients and bilobar in 8. The mean number of lesions resected was two (range, 1 to 4). The mean size of largest tumor was 31 mm (range, 2 to 112 mm). Among the 28 patients, 20 (71.4 %: 95% CI, 53.6 to 89.3%) completed the protocol treatment. The most common grade 3 or 4 toxicities were neutropenia (29%). No treatment related death was observed. Conclusions: Adjuvant CapeOx for three months for post curative resection of CLM was feasible. Clinical trial information: UMIN000011164.
Outcome of use of regorafenib in metastatic colorectal cancer in routine clinic practice in Saudi Arabia.
Authors: Aljubran Ali Husain , Zahir Muhammad , Gad Ahmed , Al-Dalee Abdelmuniem , Bazarbashi Shouki , Elshenawy Mahmoud Abdelsatar , Al Zahrani Ahmad
Published: September 2018

e15021

Background: Regorafenib is a multi-kinase inhibitor that was FDA approved for the treatment of refractory advanced colorectal cancer. It has been found in the clinical trials to have modest benefit and relatively high toxicity, but the outcome of its routine use in the clinic practice is lacking. Our aim is to assess the outcome in our local clinic practice. Methods: Records of all colorectal cases who were treated with regorafenib were reviewed. Structured CRF was developed. Clinical, pathological and molecular data were collected. Efficacy and toxicity details were analyzed. Results: Thirty-two cases of metastatic colorectal cancer were treated with regorafenib from February 2014 to February 2016. All patients received prior oxaliplatin, irinotecan and bevacizumab based regimens, and cetuximab if wild type. Median age: 53.5 years. Male: 15 (46.9%). Primary tumor was right sided in 10 patients (31.3%), and left sided (including rectum) in 22 (68.7%). Pan RAS mutant: 21 (65.6%). Fifteen patients (46.9 %) had ECOG Performance Status of one, whereas 16 patients (50%) have ECOG 2. Starting dose was reduced to 120mg in 11 (34.4%). Only 5 (15.6%) continued beyond 3 cycles. 18 patients (56.3%) required dose reduction. Overall response: PR/CR: zero; Stable disease: 4 (12.5%); Progressive disease: 25 (78.1%); Clinical progression in 1 (3.1%), and 2 cases were not evaluated. After median follow up of 7 months, 22 patients (68.8%) have died, 5 (15.6%) are still alive and 5 (15.6%) are lost to follow up. Median survival: 9.3 months, and median PFS: 2.5 months. Conclusions: Regorafenib has poor tumor response in the routine clinic practice when given to patients with ECOG PS > 1. The median survival in this series is probably overestimated because of the relatively high rate of loss to follow up. Selection of patients is required in the routine clinic practice. Predictive markers are more important for such treatment with modest benefit, and significant toxicity and cost.
A phase II trial of total neoadjuvant treatment (TNT) (Capox plus radiotherapy) for local advanced rectal cancer patients with high risk factors.
Authors: Wang Xin , Yu Yongyang , Deng Xiangbing , Meng Wenjian , Zhu Hong , Jiang Dan , Zhuang Hua , Wu Bing , Li Zhiping , Qiu Meng , Gou Hongfeng , Bi Feng , Xu Feng , Wang Ziqiang , Zhou Zonggung
Published: September 2018

e15025

Background: Standard neoadjuvant concurrent chemoradiotherapy didn't achieve improved overall survival in stage II-III rectal cancer. Total neoadjuvant treatment (TNT) might be a proper treatment option for patients with high risk factors. Therefore, this phase II trial was conducted to evaluate the safety and efficacy of TNT (Capox and IMRT/VMAT) in rectal cancer patients with high risk factors. Methods:Patients who were diagnosed stage II-III rectal cancer with at least one of the following high risk factors were recruited: cT4b, cN2, EMVI +, MRF+, lateral LN +. Three cycles of induction Capox were followed by pelvic IMRT/VMAT and two cycles of concurrent Capox. Three cycles of consolidation Capox were delivered after radiotherapy. Primary endpoints were pathological complete response (pCR) and R0 resection rate. Secondary endpoints were DFS, OS, toxicities and QOL. Here we present the initial results of this study. Results: From Jun 2015 to Jan 2017, 42 patients were evaluable. One patient (2.4%) who had acute intestinal obstruction after the first cycle of chemotheraoy underwent emergency TME. A total of 27 patients (64.3%) completed 8 cycles of chemotherapy. Forty-one patients (97.6%) completed the planned radiotherapy. 15 of 42 patients (35.7%) achieved a pCR or cCR, in which 12 patients (80%) completed 8 cycles of chemotherapy. Five patients refused the operation and selected Watch & Wait. R0 resection rate of patients who underwent TME were 100%. The mean time of operation was 207 minutes (120-370 minutes). And the mean estimated blood loss was 89ml (10-500ml). The most common grade 3 or higher adverse events associated with the neoadjuvant administration were leucopenia (9.5%), diarrhea (4.8%), radiation dermatitis (4.8%) and thrombocytopenia (2.4%). The most common grade 3 or worse surgery-related complications were pelvic abscesses, anastomotic leaks and hemorrhage which were observed in one patient, respectively. Conclusions: Total neoadjuvant treatment (TNT) is effective and safe for local advanced rectal cancer patients with high risk factors. Long-term efficacies of TNT need to be evaluated.
EGFR-targeted treatments in patients with metastatic colorectal cancer: Experience of panitumumab.
Authors: Gumus Mahmut , Geredeli Caglayan , Ucar Mahmut , Kaya Serap , Demir Hacer , Unal Olcun Umit , Degirmenci Mustafa , Gokoz Dogu Gamze , Turan Nedim , Yildirim Nilgun , Basal Fatma Bugdaycı , Arpaci Erkan , Karaagac Mustafa , Harputluoglu Hakan , Turk Haci Mehmet , Dane Faysal , Ozkan Metin
Published: September 2018

e15028

Background: Overall survival times have been exceeded three years by the targeted treatments in metastatic colorectal cancer (MCC) . The sequence of these agents and the possible side effects constitute our discussions. We aimed to investigate the efficacy and tolerability of panitumumab use in this study. Methods: In this study 168 MCC patients from 15 different centers that were treated with panitumumab in first or second line settings were evaluated respectively. Progression free survival (PFS) and overall survival(OS) time were calculated in case of the patients treated with targeted treatments in first line setting. Results: The median follow-up time was 12(3-82) months. The median age was 60 (24-86) years and 36 % of the patients were female. Panitumumab as a component of first line treatment was used in 66 % of the patients. Median 6 (1-18) cycles treatment were given to the patients as first line chemotherapy. The median PFS was 11 (SE:2; 95% CI: 7-15) months in patients treated with panitumumab while 12 (SE:1; 95% CI: 10-14) months in patients treated with bevacizumab containing regimens as first line treatment (p:0.836). The median OS was 32 (SE:12; 95% CI: 7-56) months in patients treated with panitumumab containing regimen and the median OS has not been reached in bevacizumab group (p: NS). In univariate analysis, female gender and left-sided colon tumors have favorable PFS (p:0.030 and p:0.023 respectively). No difference between bevacizumab or panitumumab containing regimen in right- sided tumors have observed (p:0.812). But in left-sided tumors, the panitumumab containing regimens have favorable PFS (8 vs 13 months. p:0.023). Grade 2 or higher skin rash was observed in 49% . Diarrhea in 38%, neuropathy in 30%, different hematologic toxicity in 14% and infusion reaction in 2.2% of the patients were detected. The skin rash was associated to panitumumab containing regimen (p:0.000). Other toxicity frequencies were not statistically significant in both groups. Conclusions: Compilation of current life data in MCC treatment will reveal the efficacy and tolerability in our daily practice beyond as data in clinical trials. These data together with more experience will guide the optimization of the treatments.
Impact of the addition of bevacizumab, oxaliplatin or irinotecan to fluoropyrimidin in the first-line treatment of metastatic colorectal cancer in elderly patients.
Authors: Landre Thierry , Aparicio Thomas , Ghebriou Djamel , Nicolas Patrick , Taleb Cherifa , Chouahnia Kader , Zelek Laurent H. , Des Guetz Gaetan
Published: September 2018

e15034

Background: The clinical benefit of double-front-line therapy (including oxaliplatin or irinotecan or bevacizumab plus 5FU or capecitabine) compared to monotherapy (5FU or capecitabine) in elderly ( > 70 years) patients with metastatic colorectal cancer (MCRC) is controversial. We performed a meta-analysis of published randomized studies. Methods: The selection of the studies was carried out using PubMed with the following keywords: "metastatic colorectal cancer", "elderly", "oxaliplatin", "irinotecan", "bevacizumab", "survival". The efficacy endpoints were overall survival (OS) and progression-free survival (PFS). Hazard Ratios (HRs) with their 95% confidence intervals (CIs) were collected from the studies and pooled. By convention, a HR < 1 was a result in favor of bitherapy. Results: This meta-analysis (MA) included nine studies: three assess irinotecan (FFCD 2001-02, CAIRO and an already published MA); three others assess oxaliplatin (FOCUS2, FFCD 2000-05 and FOLFOX pivotal trial) and the last three ones assess bevacizumab (AVEX, AGITG-MAX and AVF2192g). Our MA included 1600 patients (62% of men). Concerning age, we chose a cut-off of 70 years or a cut-off of 75 years, corresponding to the available data for each study. The performance index (PS) was 0-1 for about 90% of patients, with the exception of FFCD 2001-02 and FOCUS2 which included 30% of patients with PS2. Overall, the addition of bevacizumab to fluoropyrimidin statistically improved both OS and PFS (HR = 0.78; CI: 0.62–0.98 and HR = 0.51; CI: 0.41–0.64, respectively). The addition of oxaliplatin statistically improved PFS (HR = 0.81; CI: 0.67–0.97) but not OS (HR = 0.99; CI: 0.85–1.17) as well as the addition of irinotecan (HR = 0.83; CI: 0.68–1.00 and HR = 1.01; CI: 0.84–1.22, respectively). Conclusions: In previously untreated elderly patients with MCRC, the addition of bevacizumab to fluoropyrimidin appears more effective in terms of OS or PFS than the addition of oxaliplatin or irinotecan.
Safety of trifluridine/tipiracil for metastatic colorectal cancer in African American patients participating in an expanded access program.
Authors: Philip Philip Agop , Smaglo Brandon George , El-Rayes Bassel F. , Lesuisse Christian , Makris Lukas
Published: September 2018

e15039

Background: A Phase 3 clinical trial (RECOURSE) showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (mCRC) (Mayer et al. NEJM 2015;372:1909-19). An expanded-access program (EAP) for patients with refractory mCRC assessed FTD/TPI safety in a real-world setting. One limitation of RECOURSE was the small number of African-American (AA) patients enrolled in the study (n=8). The EAP enrolled 45 AA patients, enabling assessment of FTD/TPI safety in this population. Methods: Patients aged ≥18 years with refractory mCRC resistant to ≥2 regimens of standard chemotherapy and an ECOG performance status of 0 or 1 were enrolled in this open-label EAP. Patients received FTD/TPI 35 mg/m2 twice daily for 5 days followed by 2 days’ rest repeated twice followed by 14 days’ rest over a 28-day treatment cycle until drug discontinuation. We investigated duration of exposure to FTD/TPI and associated adverse events (AEs) in AA patients to compare them with non-AA and US patients from RECOURSE. Results: Median duration of FTD/TPI therapy for AA patients in the EAP was 9.7 weeks, similar to non-AA patients in the EAP (9.7 weeks) and US patients in RECOURSE (8.9 weeks) (differences not statistically significant). 73.3% of AA patients (n=33) in the EAP discontinued treatment due to disease progression and 8.9% (n=4) discontinued due to AEs. AEs related to FTD/TPI are summarized in the table. Conclusions: Lung cancer patients in Eastern North Carolina possess a strikingly poor inflammatory signature with significant implications for quality of life and survival. Clinical trial information: NCT02286492. [Table: see text]
TAS 102 in refractory metastatic colorectal cancer: UK Expanded Access Programme experience.
Authors: O'Brien Ciara , Callaghan Sophia , Papaxoinis George , Bennett James , Lee Chern Siang , Evans Rhiannon Mai , Iveson Tim , Adams Richard , Mullamitha Saifee
Published: September 2018

e15043

Background: Trifluridine/tipiracil (TAS-102), an oral combination of a nucleoside analogue and thymidine phosphorylase inhibitor, showed significant survival benefit in the RECOURSE study. We assessed TAS-102 clinical activity in an unselected patient population with refractory metastatic colorectal cancer in the UK Expanded Access Programme (EAP). Methods: Pharmacy databases were used to identify patients treated with TAS-102 on the UK EAP at three tertiary referral Cancer Centres (Manchester, Cardiff and Southampton) between December 2015 and December 2016. Case notes, laboratory tests and histopathology were reviewed to ascertain survival data and prognostic variables. Results: Of the 78 patients treated with TAS-102, median ECOG PS was 1, 56% of patients were male and median age was 64 years (range 27- 80 years). 31 patients had 3 or more metastatic sites of disease. 26 patients were RAS mutant and 1 patient was B-RAFmutant. Median number of cycles of TAS-102 was 2 cycles (range 1-11 cycles) with one third of patients requiring a dose reduction due to toxicity. 39% of patients developed grade 3 or 4 neutropenia and 12% febrile neutropenia. Response assessment was not performed in 12 patients due to death prior to assessment (6 patients) or withdrawal of patient consent for TAS-102 treatment (6 patients). Where best disease response was assessed by RECIST 1.1 criteria, 26.6% patient showed clinical benefit (stable disease or partial response) whereas 73.3% of patients had confirmed progressive disease. Median follow-up period was 5.2 months with 45 deaths in the study period. Median overall survival (OS) was 6.6 months. OS was significantly worse for patients with hypoalbuminemia (Albumin < 30g/dl) at cycle 1 day 1 TAS-102 (p = 0.028). Anaemia, renal or liver impairment and number of metastatic sites of disease had no impact on patient survival. RAS mutant colorectal cancer patients showed a trend to improved outcome on TAS-102 which did not reach statistical significance within the study follow-up period. Conclusions: TAS-102 shows modest clinical benefit in treatment refractory metastatic colorectal cancer patients on the UK expanded access programme.
The effect of post-operative chemotherapy and prognostic factors for colorectal cancer liver: Only metastasis (CRLM) after R0 or R1 resection.
Authors: Sym Sun Jin , Kim Koen Kook , Kim Young Saing , Park Inkeun , Lee Won-Suk , Baek Jeong-Heum , Park Yeon Ho , Ahn Hee Kyung , Cho Eun Kyung , Shin Dongbok
Published: September 2018

e15047

Background:Complete removal of all known tumor is the most important indicator that correlated with survival of CRLM. However, the role of post-operative chemotherapy for resected CRLM has not yet been clarified. We evaluate the role of post-operative chemotherapy in setting for curatively resected CRLM. Methods:We reviewed all 164 patients (pts) underwent resection of CRLM in our institute between Nov 2002 and Apr 2016, and selected 109 pts underwent R0 or R1 resection of primary and CRLM. Pts with R2, extra-hepatic, and non-regional lymph nodes metastasis were excluded. Kaplan-Meier and log-rank test was used for survival analysis. Results:The median age was 62.9 (29-88) years; male (70%). Primary tumor locations were right (24.8%), left (52.3%), and rectum (22.9%). The median number and total sum of maximum diameter of CRLM were 2 (1-13) and 4.2 (0.6-19.7) cm, respectively. Eight-one pts (74%) underwent R0 resection of both primary tumor and CRLM and 84 pts (77%) received post-operative chemotherapy (66 pts with cytotoxic chemotherapy only, 18 with cytotoxic chemotherapy with biologics). With a median follow-up of 35.7 months, median overall survival was 57.0 months, and disease free survival (DFS) was 13.7 months. Univariate analysis revealed that node-stage of primary tumor ( p= 0.024), preoperative CEA (≤ 5 v > 5 ng/ml)( p= 0.002), total sum of maximum diameter (≤ 5 v > 5 cm)( p= 0.013), and complete resection of tumor (R0 v R1)( p< 0.001) were significantly associated longer DFS. Post-operative chemotherapy did not show difference of DFS (median 7.5 months with no treatment, 14.2 months with cytotoxic chemotherapy, and 14.8 months with biologics, p= 0.739). In multivariate analysis, complete resection of tumor (Hazard Ratio (HR); 0.381, 95% confidence interval (CI); 0.215-0.646, p= 0.001) and preoperative CEA level (HR; 0.453, 95% CI; 1.015-3.621; p= 0.045) was independent factor for longer DFS. Conclusions: The post-operative chemotherapy for CRLM after R0 or R1 resection shows no difference in survival. Complete resection with negative surgical margin is the most important indicator for longer survival.
Stage IV colorectal cancer: An NCDB analysis of the surgical treatment of peritoneal carcinomatosis versus liver metastases.
Authors: Naffouje Samer A , Salti George I.
Published: September 2018

e15067

Background: Traditionally, peritoneal carcinomatosis (PC) secondary to colorectal cancer (CRC) was perceived as a terminal disease, for which the only palliation was offered. With the emergence of new surgical approaches such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), surgical intervention in select patients with ‘curative’ intent was made possible. In this study, we compared the outcomes of the surgical intervention on stage IV CRC patients with isolated liver metastases (LM) to those with PC only. Methods: The National Cancer Database (NCDB) for CRC was analyzed excluding patients with PMP. Patients with isolated LM or with PC were identified, then divided into 2 treatment groups per the current treatment of each scenario: LM patients treated with surgery±chemotherapy (LM group), and PC patients treated with surgery+chemo±HIPEC (PC group). Results: 21,829 patients were identified; 18,932 fell in the LM group, and 2,897 in the PC group. Mean age in the LM and PC groups was 62.94±13.54 vs. 59.59±13.73. No significant difference was noted in the 30-day readmission rates (6.0% vs. 6.6%; p = 0.103). LM group had higher rates of 30- and 90-day mortality (4.3% vs. 0.3% and 8.6% vs. 1.8%, respectively; p < 0.0001), but a slightly shorter hospitalization (7.70±8.64 vs. 7.92±7.07; p = 0.024) Median overall survival was not different between the groups (27.3 vs. 25.36 months; p = 0.214). Conclusions: Surgery with systemic and IP chemotherapy can be a viable treatment option in stage IV CRC patients with PC with comparable short-term and survival outcomes to the widely accepted liver resection in patients with isolated LM.
Demographic, clinicopathologic and survival differences among left sided versus right sided metastatic colorectal adenocarcinoma.
Authors: Giri Smith , Mehta Kathan , Shrestha Shreesh , Sharma Santosh , Bhatt Vijaya Raj
Published: September 2018

e15068

Background: Clinical outcomes may differ between left versus right sided (CA) independent of stage. We utilized a large database to identify real world differences in characteristics and overall survival (OS) of left versus right sided CA. Methods:We used the National Cancer Database (NCDB) to identify 36,271 patients with metastatic (stage IV) CA diagnosed between the years 2010 to 2012. Right-sided CA was defined as CA of the cecum, ascending colon or hepatic flexure, and left-sided CA was defined as CA of splenic flexure, descending colon, sigmoid colon and rectum. We compared demographic and pathologic features (tumor size, grade, lymphovascular invasion, metastatic site) as well as OS of CA based on laterality. Results:36% of metastatic CAs were right sided. Left versus right sided CAs were more likely to be diagnosed in older patients (median age 68 vs. 62 yr; p<0.01), females (52% vs. 43%; p<0.01), and African Americans (17% vs. 13%; p <0.01). Left-sided CAs were more likely to be >5 cm (58% vs. 54%, p<0.01), grade 3 or 4 (35% vs. 22%; p<0.01), have lymphovascular invasion (62% vs. 50%; p <0.01) and liver metastasis (72% vs 67%; p<0.01) and less likely to have lung (20% vs. 27%;p <0.01) or bone metastasis (5% vs. 6%; p value <0.01). The median OS was lower in right versus left-sided CAs(12 vs. 20 months; p <0.01) Conclusions:Our study suggests important differences in metastatic CAs based on laterality. Patients with right-sided CAs are more likely to be older, females and African Americans, present with larger tumor, lymphovascular invasion and differ in sites of metastases. Future studies should assess any difference in molecular characteristics and tumor biology based on laterality. [Table: see text]
Microsatellite instability as a prognostic factor in stadium II colon cancer patients. A meta-analysis of published literature.
Authors: Novotny Jan , Gkekas Ioannis , Pecen Ladislav , Strigard Karin , Palmquist Richard , Morgan Gilberto , Gunnarson Ulf
Published: September 2018

e15075

Background: The prognostic role of microsatellite instability (MSI) in stage II colon cancer patients remains controversial despite it has been investigated in a number of studies. Hazard ratios differ considerably among these studies. We performed a meta-analysis to define the significance of MSI in this group of patients. Methods: Studies indexed in PubMed presenting separate data on MSI status and survival outcomes for stage II colon cancer patients have been analyzed using fixed-effect meta-analysis of hazard ratio according to the method of Peto. Results: Analysis was performed on 19 studies including 5998 patients. 47.2% patients received postoperative chemotherapy, 52.8% were males and 47.2% females. Eight studies included also rectal cancer patients. MSI was detected in 20.8 % of the patients. Hazard ration (HR) for overall survival (OS): MSI vs MSS for the entire population: 0.73 (95% confidence interval (CI): 0.33-1.65); HR for disease free survival (DFS): 0.60 (95% CI: 0.27-1.32). No statistical significant difference was found when comparing studies analyzing MSI with genotyping (MG) and immunohistochemistry (IHC) (MG vs IHC: HR OS 0.45, 95% CI 0.10-2.05 vs. 0.95, 95% CI 0.57–1.58; HR DFS 0.51, 95% CI: 0.14-1.85 vs. 0.67, 95% CI 0.26-1.70). However, numerically MSI determination with genotyping shows remarkably lower hazard ratios (further from HR equal to one) for both OS and DFS. Separate analysis of studies investigating colon cancer patients only showed HR OS 0.72 (95% CI: 0.31-1.71); HR DFS 0.60 (95% CI: 0.27-1.31). Conclusions: This is the first meta-analysis that evaluates the prognostic role of MSI in the well defined population of colon cancer patients with stage II disease. No significant relation was found between MSI status and various survival outcomes. Routine determination of MSI status to guide postoperative management of stage II colon cancer patients cannot be recommended based on the presently included studies. This study was supported from the unrestricted grant of Cancerforskningsfonden i Norrland/Lions Cancerforskningsfond LP 14-2065 and Akademisk Miljö NLL-576531.
The prognostic value of serum IL-6 and YKL-40 in colorectal cancer patients before liver resection.
Authors: Holsey Gramkow Mathias , Peltonen Reetta , Dehlendorff Christian , Osterlund Pia J. , Johansen Julia S. , Isoniemi Helena
Published: September 2018

e15078

Background: IL-6 and YKL-40, markers of inflammation and cancer growth, are high in serum in patients with colorectal cancer (CRC) and associated with shorter overall survival (OS). We hypothesized that preoperative serum IL-6, YKL-40 and CEA are associated with disease free survival (DFS) and OS in patients with metastatic (mCRC) treated with liver resection. Methods: 457 patients (male/female: 267 (58%)/190 (42%), median age 65 [IQR: 58-71]) diagnosed with mCRC who underwent liver resection were included between March 1998 and February 2013. Preoperative serum samples were collected and stored at -80°C until analysis. Serum IL-6 (R&D Systems, UK) and YKL-40 (Quidel, USA) were determined by ELISA. For DFS and OS we estimated crude and adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CIs) with Cox regression for each biomarker separately. The biomarkers were included as log2-transformed continuous variables and adjustment included mutual adjustment between the biomarkers in addition to adjusting for sex and age. Results: The median (IQR) preoperative biomarker levels were: IL-6 (3.5 pg/ml, 2.1-6.1), YKL-40 (75 ng/ml, 48-127) and CEA (5.2 kU/L, 2.6-18.8). Univariate analysis showed that high serum IL-6 and YKL-40 were associated with shorter DFS (IL-6: HR = 1.18, 1.06-1.31, p < 0.01; YKL-40: HR = 1.19, 1.08-1.32, p < 0.01). Serum CEA was not (p = 0.80). Multivariate analysis (all biomarkers) showed that high IL-6 was associated with shorter DFS (HR = 1.15, 1.02-1.29, p = 0.02), whereas YKL-40 (p = 0.08) and CEA (p = 0.51) were not. Univariate analysis showed that high preoperative serum IL-6 and YKL-40 were associated with shorter OS (IL-6: HR = 1.16, 1.03-1.29, p = 0.01; YKL-40: HR = 1.27, 1.14-1.42, p < 0.01). Serum CEA was not associated with OS (p = 0.16). Multivariate analysis (all biomarkers) showed that high YKL-40 was associated with shorter OS (HR = 1.19, 1.05-1.34, p = 0.01), whereas IL-6 (p = 0.25) and CEA (p = 0.26) were not. Patients with elevated serum levels of all 3 biomarkers had the shortest OS (HR = 2.12; 1.29-3.50, p < 0.01). Conclusions: Serum IL-6 and YKL-40 determined before liver resection may be valuable prognostic biomarkers in patients with metastatic CRC.
Inflammatory biomarkers as independent predictive and prognostic markers in metastatic colon cancer patients over several treatment lines.
Authors: Riedl Jakob M. , Posch Florian , Bezan Angelika , Moik Florian , Smolle Maria Anna , Szkandera Joanna , Pichler Martin , Stoger Herbert , Stotz Michael , Gerger Armin
Published: September 2018

e15084

Background: The aim of this study is to quantify the value of the inflammatory biomarkers neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), platelet/lymphocyte ratio (PLR), C-reactive protein (CRP) level and the advanced lung cancer inflammation index (ALI) as predictive and prognostic markers for treatment and survival outcomes over the first three chemotherapy lines in metastatic colorectal cancer (mCRC) patients. Methods: 258 patients with mCRC undergoing palliative chemo(immuno-)therapy were included in this retrospective study. Primary endpoints were 6-month progression free survival (PFS) and overall response rate (ORR) during 1st-line, 2nd-line, and 3rd-line treatment, and 6-month OS during best supportive care. Results: In multivariable analysis adjusting for polychemotherapy, 1 standard deviation (SD) increase in NLR was associated with a 8.5% absolute lower ORR in first line (95%CI: 11-7, p < 0.0001), 3% lower ORR in second line (4-2, p < 0.0001), and 3% lower ORR in third line (8-2, p = 0.24), respectively. The other inflammatory markers were not significantly associated with ORR. Regarding PFS, a higher NLR was consistently associated with higher risk of progression or death across all treatment lines, with rising hazard ratios (HR) over treatment lines (HR 1.30, p = 0.021 first line); (HR 1.37, p < 0.0001 second line); (HR 1.44 , p = 0.042 third line). The PLR was associated with 6 month PFS over all lines. (HR 1.43 (95%CI 1.09 – 1.88, p = 0.009 first line); (HR1.67 (95%CI 1.34 – 2.09, p < 0.0001 second line) and (HR 1.43 (95%CI 1.04 – 1.98, p = 0.029 in third line)) For CRP, the prognostic association was significant in the first two chemotherapy lines and in case of BSC. (HR 1.49 (95%CI 1.23 – 1.80, p < 0.0001 first line); (HR1.25 (95%CI 1.06 – 1.47, p = 0.007 second line); (HR 1.09 (95%CI 0.81 – 1.48, p = 0.552 third line and HR 1.43 (1.15 – 1-79, p = 0.002 in BSC)). More detailed results concerning the other biomarkers will be presented at the meeting. Conclusions: Our data demonstrate that inflammatory biomarkers are important and independent indicators of response to antineoplastic chemotherapy, relevant not only in first, but also in later treatment lines.
Effect of molecular mechanisms mediating bevacizumab (BEV) and vanucizumab (VAN) on gastrointestinal perforation: Use of artificial neural networks for integrated data analysis.
Authors: Wagg Jonathan , Krieter Oliver , Ooi Chia-Huey , Croset Samuel , Leddin Mathias , Valls Raquel , Mas Jose Manuel , Boetsch Christophe
Published: September 2018

e15108

Background: VAN is a novel bispecific mAb targeting VEGF & ANG-2. A randomized phase 2 study (McCAVE) investigating VAN & BEV, each combined with chemotherapy (mFOLFOX-6), in 1L metastatic colorectal cancer patients was completed. Reported gastrointestinal perforation (GIP) events (including GI fistula & abdominal abscess) in both arms (approx. 10%) exceeded those expected with BEV+CTx. The present work focused on identifying the explicit molecular pathways mediating VAN/BEV associated GIP. Methods: Clinical data from McCave (safety outcomes & gene expression profiling) was integrated with data from other clinical/preclinical VAN/BEV studies. Machine learning was applied to the dataset to computationally infer GIP mechanisms. The methodology was constrained by relevant biological & clinical knowledge. Literature reviews & database queries mapped 194 unique proteins to 8 biological processes previously hypothesized to play a role in GIP. Identified proteins guided construction of a GIP protein interaction network which was transformed into an artificial neural network and was fitted to the dataset to predict molecular pathways/biological processes most likely linking VEGF-A and/or ANG-2 inhibition to GIP. Results: VAN/BEV were predicted to enhance GIP risk via 4 out of 8 previously suggested biological effects: (i) reduced GI mucosal integrity; (ii) impaired wound healing; (iii) inhibition of angiogenesis (iv) increased thromboembolic risk. The specific proteins & associated interactions predicted to mediate these 4 effects were identified as solely VEGF-A inhibition driven. These effects may drive increased susceptibility to GIP triggered by secondary insults, e.g. preclinical ulcer & intramural lesion. Candidate GIP biomarkers for monitoring these effects were identified, e.g., aPTT, citrulline & I-FABP. Conclusions: The molecular pathways mediating GIP in VAN/BEV treated patients are likely driven by VEGF inhibition with no contribution from ANG-2 inhibition. It is proposed, that in addition to VAN/BEV, one or more secondary insults to the GI tract wall are required to drive perforation.
Deregulation of methylation of transcribed-ultra conserved regions in colorectal cancer and their diagnostic and prognostic value.
Authors: Kottorou Anastasia E , Antonacopoulou Anna G , Dimtrakopoulos Fotinos-Ioannis D. , Kalofonou Melpomeni , Diamantopoulou Georgia , Theodorakopoulos Theodoros , Oikonomou Chrysa , Katsakoulis Evangelos , Dimopoulos Nikos , Stephanou Georgia , Makatsoris Thomas , Stavropoulos Michalis , Thomopoulos Konstantinos , Kalofonos Haralabos
Published: September 2018

e15130

Background: Expression of Transcribed Ultra Conserved Regions (T-UCRs) is often deregulated in cancer. We investigated the role of three T-UCRs (Uc160, Uc283 and Uc346) in colorectal adenocarcinomas and their prognostic and diagnostic value. Methods: Expression and methylation levels of the T-UCRs were assessed in neoplastic and paired non-malignant fresh frozen (FF) tissue specimens from 64 colorectal cancer (CRC) patients, as well as in 6 FF adenoma tissue specimens. In addition, T-UCR methylation levels were assessed in FFPE tumor tissues from 80 CRC patients and in plasma from 161 patients (50 CRC, 59 adenoma patients, 40 healthy subjects and 12 patients with colon inflammation or diverticulosis). Results: Expression levels of all three T-UCRs were lower in neoplastic, compared to non-malignant tissues, although at a statistically significant level only for Uc160 ( p< 0.001). Also, methylation levels of Uc160, Uc283 and Uc346 were higher in tumors compared to non-malignant tissues ( p< 0.001, p= 0.001 and p= 0.004 respectively). Tissue methylation levels of Uc160 were associated with TTP ( p= 0.017). The combination of Uc283 and Uc346 methylation levels was related to OS, however without reaching statistical significance ( p= 0.066). Methylation status of Uc160 and Uc346 in plasma differed significantly among the four patient groups with CRC patients exhibiting the higher levels. Moreover, a strong correlation was found between Uc160 plasma methylation levels and adenoma or adenocarcinoma size and lymph node infiltration ( p< 0.001 and p= 0.024 respectively). When methylation status was used to predict if a subject has CRC, sensitivity and specificity were 35% and 89% respectively, while the values changed to 45% and 74.3% respectively when we combined the sum of the three T-UCR plasma methylation levels. For adenomas, the combination of Uc160 and Uc346 plasma methylation displayed 30.2% (sensitivity) and 80.7% (specificity). Conclusions: T-UCR expression and methylation is deregulated in CRC while their methylation has prognostic value and appears a promising non-invasive screening test for CRC and adenomas, provided that the sensitivity of the assay is improved.
Validation of the NCI colorectal cancer risk assessment tool in the CSP 380 veterans cohort.
Authors: Musselwhite Laura W. , Redding Thomas S. , Sims Kellie J. , O'Leary Meghan , Hauser Elizabeth R. , Hyslop Terry , Lieberman David A. , Provenzale Dawn T.
Published: September 2018

e15135

Background: Refining screening to colorectal cancer (CRC) risk may promote screening effectiveness. We applied the National Cancer Institute (NCI) CRC Risk Assessment Tool to estimate 5- and 10-year CRC risk in an average-risk Veterans cohort undergoing screening colonoscopy with follow-up. Methods: This was a prospective evaluation of predicted to actual risk of CRC using the NCI CRC Risk Assessment Tool in male Veterans undergoing screening colonoscopy with a median follow-up of 10 years.Family, medical, dietary and physical activity histories were collected at enrollment and used to calculate absolute 5- and 10-year CRC risk, and to compare tertiles of expected to observed CRC risk. Sensitivity analyses were performed. Results: For 2,934 male Veterans with complete data (average age 62.4 years, 15% minorities), 1.3% (N=30) and 1.7% (N=50) were diagnosed with CRC within 5 and 10 years of survey completion. The area under the curve for predicting CRC was 0.69 (95% CI; 0.61-0.78) at 5 years and 0.67 (95% CI, 0.59-0.75) at 10 years. We calculated the sensitivity (0.60, 95% CI; 0.45-0.73), specificity (0.67, 95% CI; 0.65-0.69) positive predictive value (0.031, 95% CI; 0.02-0.04) and negative predictive value (0.99, 95% CI; 0.98-0.99). Conclusions: The NCI CRC Risk Assessment Tool was well-calibrated at 5 years and overestimated CRC risk at 10 years, had modest discriminatory function, and a high NPV in a cohort of ethnically diverse male Veterans. This tool reliably excludes 10-year CRC in low-scoring individuals and may inform patient-provider decision making when the benefit of screening is uncertain. [Table: see text]
Clinical and neurophysiologic prospective study with time-event and long-term analysis of the chronic neurotoxicity associated with oxaliplatin in patients with colorectal cancer (CRC).
Authors: Cassinello Javier , Serrano Carolina , Alvarez De Mon Melchor
Published: September 2018

e15150

Background: The sensitive, symmetric, chronic neurotoxicity is a frequent dose-dependent and dose-limiting secondary effect of oxaliplatin (COXALIN). Time-event and long-term studies about COXALIN and its progression after the end of treatment ( coasting) are lacking. Methods: A prospective, translational, clinical and neurophysiologic study was performed in patients (p) with CRC treated with oxaliplatin. We analyzed COXALIN during and after treatment (at the time of initial, maximum coasting, improvement and maximum improvement). We followed p every 3 months the first year and every 6 months thereafter. The NCI-CTC V3.0 sensitive and modified TNSc (without motor and autonomic skills) clinical scales and Quantitave Sensitive Test and ENG were used. Results: 41 chemo naive p with CRC were included, 22 men, median age 60 y (IA:55-73).Oxaliplatin was administrated as adjuvant treatment in 36p. FOLFOX combination was used in 40p. The median cumulative doses was 825,25 mg/m2 (IA: 697-963). The median follow-up was 21,5m (11-27). 38 p developed COXALIN at median 5,5 m (IA: 4,4-6,6) and maximum coasting at median 8,5 m (IA: 7,6-9,5); in multivariant analysis, cumulative dose at 3 months (p = 0,039; OR 2,5; p = 0,027; HR 0,5) was predictive factor and female gender (p = 0,017; OR 0,11) was protective factor. Fine fiber neuropathy was detected in 47,4% p. All p improved at median 8,7m (IA: 7,1-10,2) since COXALIN, reaching the maximum improvement at 13,4 m (IA:16,0-20,4); on multivariate analysis, the COXALIN intensity was the predictive factor (p = 0,03; HR 0,42). 76,6%p showed residual COXALIN (73,9% p subclinical/mild, 17,4% p moderated and 8,7% p severe). A high correlation was found between clinical scales and neurophysiologic studies along the study (p < 0,0001). Sensitive NCI-CTC scale was more sensible than modified TNSc to evaluate COXALIN intensity in our study. Conclusions: We confirm coasting in COXALIN which prolongs 6 months after treatment. About 80% p showed residual COXALIN in the long-term but it was subclinical or mild in most cases. Sensitive NCI-CTC 3.0 scale is a simple and reliable method for the follow-up of COXALIN.
Impact of Immune response-associated gene polymorphisms on tumor response in rectal cancer patients treated with capecitabine +/- oxaliplatine and radiation in the ACCORD-12/PRODIGE-2 phase III trial.
Authors: Boige Valerie , Mollevi Caroline , Chaput Nathalie , Gourgou Sophie , Azria David , Seitz Jean-François , Bigot Ludovic , Juzyna Beata , Miran Isabelle , Gerard Jean-Pierre , Laurent-Puig Pierre
Published: September 2018

e15151

Background: We examined whether 133 germline polymorphisms (SNPs) in 15 candidate genes (CSF1R, IL8RA, TLR4, IL10, IL10RA, CTLA4, IL2, IL2RA, TGF b1, ICOS, IL13, IL13RA2, IFNgR, IL15 and IL15RA) would predict clinical outcome in the ACCORD-12 phase III trial which randomly compared neoadjuvant radiotherapy (RT) plus capecitabine (CAP45) with dose-intensified RT plus capecitabine and oxaliplatin (CAPOX50) in T3-4 Nx M0 resectable rectal cancer. Methods: A candidate-gene association study was conducted in 316 patients (n = 161 in the CAPOX50 and n = 155 in the CAP45 arm). The primary end-point was tumor response according to the Dworak score in each arm. Logistic regressions were used to assess univariate/multivariate associations. The Storey and Tibshirani method based on the control of false discovery rate was used ( q-value < 0.10 (adjusted p-value) considered as true discovery). Multivariate models adjusted on treatment arm and T stage were performed to determine prognostic and predictive values of SNPs for tumor response. Results: In univariate analysis, two SNPs in IL2RA (rs11256456: OR = 5.1 [2.38; 11] and rs706781: OR = 4.2 [1.98 ; 8.74]) were significantly associated with the Dworak score in the CAP45 arm, and one in IL2RA the CAPOX50 arm (rs2104286: OR = 0.11 [0.01 ; 0.90]. All were confirmed in the multivariate analysis. A significant haplotypic effect was observed in the CAP-45 arm (p = 0.0001). Interaction was significant for IL2RA rs11256456 ( p= 0.03) and rs706781 ( p= 0.002) and no significant for IL2RA rs2104286 ( p= 0.722), suggesting a predictive deleterious effect the first two ones for response to oxaliplatin-based chemoRT, and a prognostic effect of the third one for response to chemoRT (+/- oxaliplatin). None of the three IL2RA SNPs were correlated with survival in the multivariate analysis. Conclusions: This pharmacogenetic analysis shows that SNPs in IL2RA have a significant association with response to chemoRT with capecitabine in patients with locally advanced rectal cancer. Their predictive effect may identify patients in whom oxaliplatin addition to chemoRT is deleterious.
Comparative analysis of survival in colon cancer undergoing sentinel lymph node mapping vs conventional surgery based on number of positive lymph nodes.
Authors: Ramanathan Sabarina , Saha Sukamal , Mukkamala Suresh , Hicks Michael , Knight Patrick , Bajaj Vinay , Mazzaferro Daniel , Siva Thushy , Hutcherson Lori , Livert David , Oza Rajen , Wiese David , Arora Madan L.
Published: September 2018

e15154

Background: Unlike in breast cancer or melanoma, resection during sentinel lymph node mapping (SLNM) in colon cancer (CCa) includes regional lymphadenectomy including SLNs and non-SLNs. However, SLNM often identifies micrometastases that can be missed by conventional (Conv) surgery and pathologic examination. It is unknown whether this impacts survival or recurrence. Hence, a retrospective analysis was undertaken to study overall (OS) and disease -specific (DSS) survival between patients (pts) undergoing SLNM vs Conv surgery based on the number of +ve LNs. Methods: SLNM was done by subserosal injection with blue dye followed by segmental resection including regional lymphadenectomy. All SLNs were ultrastaged and other nodes were examined by conv. methods with H&E. Results: There were 309 pts in SLNM (GpA) vs 499 pts in Conv surgery (GpB); with average no. of lymph nodes (LNs) and +ve LNs 17.3/1.6 vs 14.4/2.49 respectively. For GpA, success rate was 99.6% and the average no of SLN was 3. Of the pts in GpA vs GpB, 1+ve LN were found in 38% vs 27%, 2+ve LNs in 10% vs 16%, and > 2 LNs in 53% vs 57%, respectively. Comparing 5 years OS between GpA vs GpB, for 1+ve LN was 62.8% vs 52.38%, for 2 +ve LNs 72.7% vs 48.65% and for > 2 +ve LNs 35% vs 33.33%, respectively. Similarly, DSS for 1 +veLN was 54.4% vs 47.6%, 2+ve LNs 40% vs 40.54% and > 2+ve LNs, 30.4% vs 25.76%, respectively (Table). Conclusions: Compared to Conv surgery, SLNM identified higher no. of LNs per pt with high success rate. Five-year OS and DSS also are better in SLNM vs Conv surgery for all +ve LN gps. Hence, SLNM in CCa may have prognostic value. A larger multicenter trial needs to be done to validate such data. [Table: see text]