bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of chronic kidney disease in locally advanced rectal cancer patients treated with neoadjuvant chemoradiation.
Authors: Dudani Shaan , Marginean Horia , Gotfrit Joanna , Tang Patricia A. , Monzon Jose Gerard , Dennis Kristopher , Kennecke Hagen F. , Powell Erin Diana , Babak Sam , Cheung Winson Y. , Vickers Michael M. ,   On Behalf of the CHORD Consortium
Published: January 2019

794

Background: Chronic kidney disease (CKD) and cancer are common with advancing age. CKD may influence drug tolerance/efficacy and is an independent prognostic factor in some cancers. The impact of CKD on outcomes in patients (pts) with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiation (nCRT) has not been previously studied. Methods: We reviewed pts with LARC undergoing nCRT prior to surgery with curative intent from 2005-2013 across 4 Canadian provinces. Data regarding demographics, staging, baseline renal function, treatments and outcome were collected. CKD was defined as having an estimated glomerular filtration rate (eGFR) (Cockroft-Gault) < 60 ml/min. Primary endpoints were neoadjuvant treatment completion rate, disease-free survival (DFS), and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for an association between renal function and outcomes. Results: 1122 (71%) of 1580 pts were included for analysis. Median age was 61 (IQR 54-69), 70% male, 84% performance status 0-1. 28% and 68% had clinical stage II and III disease, respectively. Median eGFR was 93 ml/min (IQR 74-114), with 11% < 60 ml/min (n = 120). 97% of all pts received ≥ 44 Gy (median 50 Gy [range 20-80]). 53% received 5-fluorouracil and 44% received capecitabine as neoadjuvant chemotherapy (nCT). 84% completed nCT, 95% completed neoadjuvant radiotherapy (nRT), and 76% received adjuvant chemotherapy (aCT). Pts with CKD were less likely to receive aCT (62% vs 78%; p < 0.01). There was no significant difference in completion rate of nCT (80% vs 85%; p = 0.15) or nRT (93% vs 95%; p = 0.20) based on renal function. After a median follow up time of 62 months, 8% developed local recurrence, 21% developed distant recurrence and 21% have died. 5-year OS and DFS were 78% and 73%, respectively. Pts with CKD had decreased OS on univariate analysis (HR 1.59, 95% CI 1.11-2.28; p = 0.01), but not on multivariate analysis. DFS was not significantly different based on renal function (HR 1.27, 95% CI 0.89-1.81; p = 0.18). Conclusions: In LARC pts undergoing nCRT, CKD was associated with less use of aCT but did not have any independent association with nCT and nRT completion rate, DFS or OS.
Effect of adjuvant chemotherapy on stage II colon cancer: Analysis of Korean national data.
Authors: KIM Minki , Won Daeyoun , Oh Seong Taek , Lee In Kyu
Published: January 2019

798

Background: Debates exist regarding the effectiveness of adjuvant chemotherapy for stage II colon cancer. This study aimed to investigate the current status of adjuvant chemotherapy and its impact on survival for Korean stage II colon cancer patients by analyzing the National Quality Assessment data. Methods: A total of 7880 patients who underwent curative resection for stage II colon adenocarcinoma between Jan 2011 and Dec 2014 in Korea were selected randomly as evaluation subjects for the quality assessment. The factors that influenced overall survival were identified. The high-risk group was defined as having at least one of the following: perforation/obstruction, lymph node harvest less than 12, lymphovascular/perineural invasion, positive resection margin, poor differentiation, or pathologic T4 stage. Results: The median follow-up period was 38 (1-63) months. Chemotherapy was a favorable prognostic factor for either the high- (HR 0.50 [0.40-0.62], p < 0.001) or low-risk group (HR 0.74 [0.61-0.89], p = 0.002) in multivariate analysis. This was also the case in patients over 70 years of age. The hazard ratio was significantly increased as the number of involved risk factors was increased in patients who didn’t receive chemotherapy. However, there was no survival difference between low-risk group patients and patients who only had 1 risk factor among patients who received adjuvant chemotherapy (HR 1.19 [0.93-1.52], p = 0.165). Adding oxaliplatin showed no difference in survival (HR 1.36 [0.91-2.03], p = 0.132). Conclusions: Adjuvant chemotherapy can be recommended for stage II colon cancer patients, but the addition of oxaliplatin to the regimen must be selective.
Surgeon specific effects on the postoperative systemic inflammatory response and complications following surgery for colorectal cancer.
Authors: McSorley Stephen Thomas , Roxburgh Campbell SD , McMillan Donald C , Horgan Paul G.
Published: January 2019

799

Background: The present study examined the impact of surgeon specific differences on the postoperative systemic inflammatory response (SIR) as measured by postoperative C-reactive protein (CRP), and complications, following elective surgery for colorectal cancer. Methods: 684 patients who underwent elective colorectal cancer resection performed by 10 consultant surgeons at single centre between 2008 and 2016 were included. Exceeding the established C-reactive protein (CRP) threshold of 150mg/L on postoperative days (POD) 3 and 4 was used to identify outliers by funnel plot analysis. Surgeons with significant differences in the proportion of patients exceeding POD 3 CRP 150mg/L were compared. Significantly different perioperative variables amongst surgeons, and the surgeons themselves, were then entered into a multivariate binary logistic regression model to asses association with POD 3 CRP. Results: Perioperative factors were compared between 3 surgeons with the highest volumes and greatest difference in the proportion of patients exceeding POD 3 CRP 150mg/L (Figure 1); (35% of 137, 50% of 117, 60% of 92, p < 0.001). Amongst the 3 surgeons there were significant differences in comorbid state (p = 0.042), the proportion of patients undergoing minimally invasive surgery (p < 0.001), or surgery lasting over 4 hours (p < 0.001), requiring blood transfusion (p = 0.038), epidural anaesthesia (p < 0.001), and receiving perioperative steroids (p < 0.001). When those factors which were significantly different between surgeons were entered into a multivariate binary logistic regression model to predict exceeding the POD 3 CRP threshold of 150mg/L, only perioperative dexamethasone (OR 0.40, 95% CI 0.19-0.82, p = 0.012), and postoperative complications (OR 2.22, 95% CI 1.14-4.32, p = 0.018), remained independently associated whilst the surgeons themselves were not significantly associated (OR 1.16, 95% CI 0.59-2.30, p = 0.663). Conclusions: This study suggests that surgeon specific difference in the magnitude of the postoperative systemic inflammatory response are related to differences in surgical approach, anaesthetic technique and complications.
Claudin 18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer.
Authors: Cho Jang Ho , Lim Sung Won , Kim Seung Tae , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki
Published: January 2019

80

Background: Alterations in claudin expression can impair tight junction functioning, influence signaling pathways, and act as a tumor promoting event in some epithelial cancers. Recently, IMAB362, a highly potent and tumor cell-selective therapeutic antibody to claudin 18.2, has been developed and investigated in clinical trials. Methods: We prospectively conducted claudin 18.2 immunohistochemistry on 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Results: Most patients (414/430, 96.2%) were evaluable for claudin 18.2 expression by immunohistochemistry. In total, 4.1% (17/414) were deemed claudin 18.2+, including patients with pancreatic (16.7%, 1 of 6), gastric (14.1%, 12 of 85), biliary tract (6.3%, 1 of 16), genitourinary/miscellaneous (2.2%, 1 of 46), and colorectal (0.9%, 2 of 203) cancers. Twelve of 17 patients positive for claudin 18.2 had gastric cancers; this subgroup showed no statistical difference by gender, age, disease extent, primary tumor site, pathologic differentiation, HER2 status, or EBV status with or without claudin 18.2 expression. However, claudin 18.2 was more frequently positive in intestinal-type compared to diffuse-type by Lauren classification (p = 0.026). There was no significant difference in overall survival between patients with and without claudin 18.2 expression (p = 0.101). Conclusions: Our results add to the emerging literature on claudin 18.2 expression in various cancer types and support the need for extended clinical exploration of IMAB362.
Cost-effectiveness of FOLFIRI + cetuximab vs FOLFIRI + bevacizumab in the first-line (1L) treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC) in Germany: Data from the FIRE-3 (AIO KRK-0306) study.
Authors: Stintzing Sebastian , van Oostrum Ilse , Pescott Chris , Steinbach-Buechert Alma Katharina , Heeg Bart , Heinemann Volker
Published: January 2019

800

Background: The randomized, phase 3 FIRE-3 trial evaluated 1L FOLFIRI + cetuximab or bevacizumab in patients with RAS wt mCRC; overall survival favored FOLFIRI + cetuximab by > 8 months. The purpose of this analysis was to evaluate the cost-effectiveness of FOLFIRI + cetuximab vs that of FOLFIRI + bevacizumab as 1L treatment for patients in Germany with RAS wt mCRC (including the patient subgroup with RAS wt, left-sided [LS] primary tumors, as LS is a predictive factor). Methods: A standard oncology 3–health-state partitioned survival cost-utility model was developed to analyze the costs and health benefits of FOLFIRI + cetuximab vs those of FOLFIRI + bevacizumab from a German payer perspective based on data from FIRE-3 and the literature. Health outcomes were reported in life-years (LYs) and quality-adjusted life-years (QALYs) gained. A 3.5% discounting rate was applied to the modeled costs and outcomes. Results: Discounted costs, health gains, and incremental cost-effectiveness ratios (ICERs) for patients with RAS wt (base case) and patients with RAS wt, LS (subgroup) mCRC are summarized in the Table. Probabilistic sensitivity analyses showed that at relevant European willingness-to-pay (WTP) thresholds of €55,000 and €80,000, FOLFIRI + cetuximab had a 64.0% and 81.6% (base case) and 80.5% and 92.4% (subgroup) probability of being cost-effective vs FOLFIRI + bevacizumab, respectively. Clinical trial information: NCT00433927. Conclusions: Based on our analyses, FOLFIRI + cetuximab is cost-effective compared with FOLFIRI + bevacizumab in patients in Germany with RAS wt mCRC at official WTP thresholds applied by relevant European health technology assessment agencies. The cost-effectiveness of FOLFIRI + cetuximab is more pronounced in the subgroup of patients with RAS wt, LS tumors.[Table: see text]
Clinical significance of morphologic response and tumor shrinkage as predictive factors of Capeox+bevacizumab in 1st line treatment of metastatic colorectal cancer.
Authors: Nagaoka Tomoyuki , Shinozaki Eiji , Watanabe Ryosuke , Ueno Eiko , Ota Yumiko , Osumi Hiroki , Nakayama Izuma , Wakatsuki Takeru , Ogura Mariko , Suenaga Mitsukuni , Ichimura Takashi , Takahari Daisuke , Chin Keisho , Yamaguchi Kensei
Published: January 2019

805

Background: Capeox + bevacizumab (BV) is one of the standard treatment for metastatic colorectal cancer (mCRC) and well known to sometimes cause morphologic response (MR). However, it is not well known the predictive value of MR in palliative chemotherapy of Capeox + BV as 1st line. The aim of this study was to investigate the clinical significance of MR and tumor shrinkage as predictive factors of Capeox+BV in 1st line treatment of mCRC. Methods: A total of 159 patients with CLM were selected from 316 mCRC patients treated with Capeox+BV as 1st line chemotherapy from February 2006 to August 2016. Among these patients, 92 patients were enrolled in the this study, who satisfied following criteria; (1) tumor responce was assesed by enhanced computed tomography (CT) images every 2-3 months, and (2) dose intensity of BV at first 4 courses were above 80%. Tumor response of RECIST1.1 and MR were evaluated by 2 radiologists. They classified them as optimal, incomplete or no morphologic response according to the morphologic criteria. Results: An optimal morphologic response (OR) was observed in 34% of all patients. The median progression-free survival (mPFS) was 9.3 months in this cohort, 13.5 months in patients with OR and 11.6 months in those with incomplete/no morphologic response. And the median overall survival (mOS) was 19.5 months, 30.3 months and 23.8 months, respectively. There were no statistical significance between OR and the other, irrespective of mPFS and mOS. On the other hand, mPFS was 14.6 months in responder as CR or PR of RECIST and 8.6 months in non responder as SD or PD (p < 0.0001). Furthermore, mOS, 31.9 months and 18.5 months, respectively (p < 0.0001). Besides in 17 patients fulfilled both responder of RECIST and OR, the mOS reached 45.4 months, which was remarkably longer compared to the other groups ( < 0.0001). Conclusions: Among mCRC patients with CLM treated with Capeox+BV as the 1st line, the response of RECIST well reflected the therapeutic effect. On the other hand, MR solely was not a predictor of therapeutic effect in this study. However, both responder of RECIST and OR may be on-treatment predictors to identify excellent prognostic group.
Microsatellite instability as a predictive marker for response to neoadjuvant chemoradiation in locally advanced rectal cancer.
Authors: Shulman Rebecca Maria , Avkshtol Vladimir , DeMora Lyudmila , Esnaola Nestor F. , Hall Michael J. , Handorf Elizabeth , Meyer Joshua E.
Published: January 2019

806

Background: Microsatellite instability (MSI) is a marker for hypermutability due to impaired DNA mismatch repair and has been shown to be a favorable prognostic marker in colon cancer. We examined the role of MSI in locally advanced rectal cancer (LARC) as a predictive marker for response to neoadjuvant chemoradiation (CRT). Methods: We identified T3-T4 or ≥ N1 rectal cancer with reported MSI status in the National Cancer Data Base from 2007 – 2012. Patients were eligible if they were treated with CRT followed by surgical resection. Squamous cell and carcinoid histologies were excluded. The primary outcome was neoadjuvant rectal (NAR) score, categorized as low ( < 8), intermediate (8-16), and high ( > 16), representing a good, intermediate, and poor response to CRT, respectively. The secondary outcomes were complete pathologic response (ypCR) rate and overall survival (OS). Chi-square, Fisher’s exact, and independent sample t-tests were used to compare MSI status. Multivariable logistic regression models were used to examine factors associated with increasing level of NAR score and ypCR. OS was examined using multivariable Cox proportional hazards models. Results: A total of 1849 patients were eligible for the study and were classified as MSI-high (n = 52) or MSI-low/stable (n = 1797). Patients in the MSI-high group were younger (median age 50.5 vs 57.0, p = 0.005) and had higher rates of mucinous and signet ring histology (p < 0.001), clinical T4 disease (p = 0.001), and clinically positive lymph nodes (p = 0.049). The two groups did not differ in gender, race, grade, or resection margin status. While clinical T and N stage, histology, LVI, tumor grade, and PNI were correlated with the NAR score groups, MSI-high status was not significantly associated with a higher NAR score group on multivariable analysis (OR 1.168, 95% CI 0.673 – 2.028). The MSI-high group also did not differ significantly from MSI-low/stable group in ypCR rate (OR 0.748, 95% CI 0.179 – 3.115) or OS (HR 1.727, 95% CI 0.864 – 3.453) on multivariable analysis. Conclusions: MSI status in LARC was not associated with NAR score, ypCR rate, or OS. Our results do not support the use of MSI status as a predictive marker for response to CRT in LARC.
Lymphocyte-to-monocyte ratio (LMR) compared to sidedness of primary tumor to predict outcome of anti-EGFR monotherapy in metastatic colorectal cancer.
Authors: Wyrwicz Lucjan , Temnyk Maciej , Rybski Sebastrian , Winiarek Mariola , Kokoszyńska Katarzyna
Published: January 2019

809

Background: In RAS-wild type metastatic colorectal cancer (mCRC) treatment with cetuximab or panitumumab is the standard of care. Previously, the association between overall survival (OS) and inflamatory biomarkers were reported in several studies in mCRC (NLR, LMR). According to recent observations, primary site location can predict the superior outcome of anti-EGFR agents in first line of treatment. Here we test the relationship between inflamatory biomarkers and sidedness on outcomes of anti-EGFR therapy. Methods: Total 186 consecutive patients treated with panitumumab (n = 106) or cetuximab (n = 80) in monotherapy in third or following lines of palliative treatment were identified via electronic survey of medical records of Maria Sklodowska-Curie Memorial Cancer Center, Poland. All identified patients were treated within the state reimbursment programme with pre-specified inclusion criteria (including ECOG 0-2 mCRC, failure of previous irinotecan, oxaliplatin and fluoropiridine, all RAS-wt tumors) and treatment was administered until RECIST progression. The pretreatment inflamatory biomarkers (NLR, dNLR, LMR, PLR) were obtained for all patients. Results: Median overall survival of the cohort was 31.5 months when calculated from the start of treatment, with no difference for left- and right-sided tumors (31.8 m. vs 29.5 m.; p = 0.58). In third line treatment no difference in PFS between left- and right-sided tumors were observed (p = 0.22; PFSleft 4.82 m. vs PFSright 3.44 m.). No prognostic effect of either biomarker was noted on OS or time to failure of first two lines of treatment. Only a high lymphocyte-to-monocyte ratio (LMR > 2.6) and low derived neutrocyte-to-lymphocyte ratio (dNLR < 3.0) were associated with longer PFS on anti-EGFR treatment (5.5 m. in LMR > 2.6; 2.5 m. in LMR < 2.6; HR 0.53; p = 0.008). Notable, the patients with LMR > 2.6 were more likely to be diagnosed with left sided tumor (p < 0.001; 54% and 15% of left- and right-sided tumors respectively). Conclusions: High limfocyte-to-monocyte ratio may indicate the potential subpopulation of patients which can benefit mostly from anti-EGFR treatment in monotherapy in the refractory setting.
Plasma biomarker analysis of ramucirumab in Japanese patients with advanced gastric cancer.
Authors: Takahari Daisuke , Wakatsuki Takeru , Mashima Tetsuo , Chin Keisho , Ichimura Takashi , Ogura Mariko , MATSUSHIMA TOMOHIRO , Osumi Hiroki , Nakayama Izuma , Ota Yumiko , Shinozaki Eiji , Suenaga Mitsukuni , Kawata Naomi , Horiike Yuki , Seimiya Hiroyuki , Fujita Naoya , Yamaguchi Kensei
Published: January 2019

81

Background: Ramucirumab, anti-VEGFR2 receptor antibody, showed significantly improved survivals of gastric cancer in the second line with paclitaxel or single use. Recently we reported early elevation of plasma VEGF-A was associated with shorter survival as a preliminary result. We will report the results of final analysis. Methods: Patients with advanced gastric cancer who received ramucirumab combined with paclitaxel or single use were enrolled. Plasma samples were collected at pre-treatment and day 8 after administration. Nine kinds of plasma biomarker involved in angiogenesis, VEGF-A, C, D, PlGF, VEGFR1, 2, Angiopoietin 1, stromal cell derived factor-1α (SDF1α), and Neuropirin-1, were measured by means of ELISA. Patients were dichotomized by optimal cut-off value. Univariate and multivariate analysis were done by Cox proportion hazard model. Results: Forty-one patients were enrolled. Thirty-nine patients (95.1%) received ramucirumab with paclitaxel. Plasma VEGF-A, D, PlGF, and VEGFR2 levels were significantly increased one week after administration compared with baseline levels, while plasma VEGFR1 and NRP1levels were significantly decreased. Median PFS and OS were 5.6 (95% CI 4.66-6.54) and 9.8 (95% CI 5.41-14.19) months, respectively. In univariate analysis, higher baseline SDF1α and PlGF levels resulted in shorter OS with HR 2.71 95% CI 1.23-6.00, p =0.013 for SDF1α and HR 2.78 95% CI 1.16-6.65, p =0.022 for PlGF. Higher D8 VEGF-A was associated with shorter PFS with HR 2.77 95% CI 1.39-5.51, p =0.004. While higher D8 VEGF-D was associated with better PFS with HR 0.39 95% CI 0.20-0.77, p =0.007. In multivariate analysis, higher baseline SDF1α and PlGF were independent negative prognostic factor for OS with HR 2.45 95% CI 1.10-5.42, p =0.028 for SDF1α and HR 2.48 95% CI 1.03-5.96, p =0.043. With respect to PFS, higher D8 VEGF-A was also independent negative prognostic factor with HR 2.32 95% CI 1.13-4.77, p =0.022, while higher D8 VEGF-D was favorable predictor for PFS with HR 0.47 95% CI 0.23-0.96, p =0.038. Conclusions: Higher base line SDF1α and PlGF levels may be negative prognostic marker. While early VEGF-A and D elevation after ramucirumab administration may be predictive marker of ramucirumab.
Clinical outcomes of anti-EGFR antibody treatment for right-sided colon cancer patients without RAS, BRAF, and PIK3CA mutations in the later line.
Authors: Ushida Yuta , Shinozaki Eiji , Chin Keisho , Suenaga Mitsukuni , Takahari Daisuke , Ozaka Masato , Ogura Mariko , Ichimura Takashi , Wakatsuki Takeru , MATSUSHIMA TOMOHIRO , Osumi Hiroki , Ota Yumiko , Yamaguchi Kensei
Published: January 2019

812

Background: Several studies have reported that patients with right-sided colon cancers (RCC) have more unfavorable responses to anti-epidermal growth factor receptor (EGFR) antibody therapy than those with left-sided colon cancers (LCC). One of the causes is that RCC have more frequently genetic mutations such as RAS, BRAF, and PIK3CA than LCC. We investigated clinical outcomes of RCC patients treated with anti-EGFR antibody in the later line without these mutations. Methods: We reviewed 653 cases of colorectal cancer treated with anti-EGFR antibody from October 2009 to July 2017. There were 150 cases of RCC patients. Among them, 32 patients without KRAS status and 54 patients without enough genetic samples for gene re-analysis were excluded. We extracted 64 patients with status on RAS, BRAF, and PIK3CA , and finally enrolled 25 patients treated with anti-EGFR antibody plus irinotecan or anti-EGFR antibody alone in the later line. We analyzed the relationship of molecular status with clinical outcomes; overall response rate (RR), overall survival (OS) and progression-free survival (PFS) in this retrospective study. Results: Overall, there were 48% of cases with any mutations; among them 8.0% for KRAS, 4.0% for NRAS, 24.0% for BRAF and 4.0% for PIK3CA. Twenty percent of patients were treated as 2nd line therapy, while 72%, 16% treated as 3rd, 4th line therapy. RR of all cases, those whom without KRAS, RAS, RAS or BRAF, any mutations were 16.0%, 19.1%, 20.0%, 28.6%, 30.8%. The median OS and PFS in all wild-type patients were tended to be better than in those of all cases (OS; 14.9 vs. 11.6 months, hazard ratio = 0.70, p = 0.30, PFS; 8.17 vs. 5.37 months, hazard ratio = 0.67, p = 0.24). Conclusions: Even if primary tumors are in right-sided colon, in the enriched and selected patients anti-EGFR antibody therapy showed enough antitumor activity. Anti-EGFR antibody for RCC cases without using it at the front line is an effective option in the later line.
Impact of UGT1A1 gene polymorphism on survival in metastatic colorectal cancer patients treated with irinotecan-containing therapy.
Authors: Shirasu Hiromichi , Yamazaki Kentaro , Furuta Mitsuhiro , Kawahira Masahiro , Kawakami Takeshi , Yoshida Yukio , Kawai Sadayuki , Hamauchi Satoshi , Todaka Akiko , Tsushima Takahiro , Machida Nozomu , Yokota Tomoya , Fukutomi Akira , Onozawa Yusuke , Yasui Hirofumi
Published: January 2019

813

Background: UGT1A1 polymorphisms have been reported to be associated with increased irinotecan (IRI)-induced toxicity. However, influence of the polymorphisms on survival in metastatic colorectal cancer (mCRC) patients (pts) treated with IRI-containing therapy remains controversial. Methods: We retrospectively reviewed data of consecutive mCRC pts who received FOLFIRI/IRI with or without an anti-VEGF agent as 2nd line therapy at the Shizuoka Cancer Center between April 2008 and December 2015. The primary selection criteria were histologically confirmed adenocarcinoma, prior history of oxaliplatin-containing therapy, and adequate organ function. UGT1A1 polymorphisms were screened and pts with homozygous (*6/*6, *28/*28) or compound heterozygous (*6/*28) were excluded. Results: Among 103 pts found eligible for this analysis, 63 were wild type (W) (−/−) for UGT1A1, and 40 were heterozygous type (H) (-/*6, -/*28), with the following characteristics: median age (range), 60 (30–77) vs 67 (37–84); male/female, 41/22 vs 18/22; PS 0/1/2, 40/21/2 vs 21/18/1; tumor location right/left, 16/47 vs 9/31; peritoneal metastasis −/+, 49/14 vs 33/7; disease status metastasis/recurrence, 49/14 vs 23/17; RAS wild type/mutant, 25/37 vs 18/21; IRI regimen doublet/mono, 51/12 vs 33/7; anti-VEGF agent use −/+, 16/47 vs 12/28; and median IRI dose intensity, 63.7 vs 60 mg/m2/week. Incidences of grade 3/4 neutropenia, febrile neutropenia, and diarrhea in W/H pts were 36%/48%, 5%/9%, 5%/13% (initial IRI dose 180 mg/m2). Median PFS was 6.2 M in W, and 3.9 M in H (p = 0.36). Median OS was 12.1 M in W and 10.9 M in H (p = 0.86). RR was 13% in W, and 10% in H (p = 0.68). DCR was 81% in W, and 58% in H (p = 0.012). Multivariate analysis identified no liver-limited disease, disease status (metastatic), UGT1A1 H type, IRI monotherapy, and no anti-VEGF as independent predictors of poorer PFS (HR 1.76, 2.01, 1.67, 2.17, 2.58), and initial dose of CPT < 180mg/m2 and no anti-VEGF as independent predictors of poorer OS (HR 1.85 and 1.85). UGT1A1 polymorphism was not detected as an independent predictor of RR or DCR. Conclusions: UGT1A1 polymorphism may be useful in predicting PFS in mCRC pts treated with IRI-containing therapy.
Feasibility and value of incorporating pharmacogenomic testing for genetic variants in UGT1A1 and DPYD genes in patients receiving irinotecan and/or 5-fluorouracil chemotherapy.
Authors: Baldeo Candice , Hughes Caren , Kasi Pashtoon Murtaza
Published: January 2019

814

Background: The importance of pharmacogenomics in optimizing drug doses and avoiding adverse events is increasingly being recognized. The FDA has listed pharmacogenomic biomarkers as part of drug labeling in many medications including chemotherapies such as 5-fluorouracil and irinotecan. Pharmacogenomics may enable selection of the most tolerable treatment without compromising treatment success. Variation in the dihydropyrimidine dehydrogenase ( DPYD) and UGT1A1 gene mutations can increase the risk of 5-FU and irinotecan based chemotherapy respectively. Also, the feasibility of testing in real-time and incorporating results into management has not been demonstrated. The focus of our study was to demonstrate this in the real world scenario as a quality improvement project. Methods: In July-August 2017, 89 patients who were on irinotecan and/or 5-FU chemotherapy were tested for DPYD and UGT1A1 genetic variations at Mayo Clinic Florida. Testing was done through blood sample which was collected at routine clinic visit prior to starting therapy or in patients already receiving chemotherapy. Pharmacy electronic consultation was obtained for recommendations regarding current and/or future chemotherapy regimens, based on pharmacogenomics results. A medication therapy management (MTM) consultation from the pharmacist was incorporated and included into the patient’s chart. Results: Total number of patients who has some variation in the UGT1A1 and/or DPYD gene was 60 (67%). Specifically, there were 12 patients who were homozygous for the UGT1A1 gene and 3 homozygous for DPYD gene. Both genes were affected in 3 patients. One patient was triple heterozygous for DPYD and homozygous for UGT1A1. Pharmacogenomic results were obtained for these patients within 5 business days. Conclusions: A higher prevalence of UGT1A1 and DPYD variants were reported in our patient cohort tested than what is reported in the literature. Additionally, we were able to obtain results for these patients in a timely fashion. This was then further incorporated into medication therapy management consultation from the pharmacist, which added further value.
Impact of adding oxaliplatin to fluoropyrimidines in the adjuvant colon cancer: Experience in Ramon y Cajal University Hospital.
Authors: Martinez Saez Olga , Barquín García Arantzazu Martínez , Villamayor Delgado Maria , Saavedra Serrano Cristina , Corral de la Fuente Elena , Serrano Domingo Juan José , Martín Huertas Roberto , Reguera Puertas Pablo , LONGO FEDERICO , Pachon Vanessa , Rodríguez Garrote Mercedes , Guillen Carmen , Carrato Alfredo , Ferreiro Monteagudo Reyes
Published: January 2019

815

Background: The addition of oxaliplatin to fluorouracil and leucovorin as adjuvant therapy for patients with stage II and III colon cancer (CC) has been analyzed in two large, randomized trials, MOSAIC and C-07 trials. The updated results of these studies showed that the addition of oxaliplatin enhances overall survival by approximately 5% in patients with stage III disease but has no effect in patients with stage II disease. Methods: We retrospectively included patients with stage II and III CC that were operated between 2009 and 2014 in the Ramón y Cajal University Hospital from Madrid. We perform a multivariable Cox model analysis to estimate the benefit of the chemotherapy stratifying by oxaliplatin in each stage. The model was further adjusted by including the following confounders: ECOG-PS, number of removed nodes, perforation, obstruction, grade and age. Stata 13.1 was used to analyze the data. Results: 564 patients were identified (281 stage II and 283 stage III). 305 did not receive any chemotherapy, 61 received monotherapy with fluoropyrimidines (FP) and 198, FP and oxaliplatin. The median follow-up in the entire cohort was 49 months. Globally, adjuvant chemotherapy (either with FP alone or with the combination with oxaliplatin) showed no benefit in DFS (HR of 1.18 and 0.98, respectively). The benefit in OS was significant either for FP alone (HR: 0.46, p: 0.029) and for the combination treatment (HR: 0.41, p: 0.001). Patients with stage II treated with FP in monotherapy showed no benefit, neither in DFS nor OS (HR for DFS: 2.2, p: 0.1; HR for OS: 0.5, p: 0.22). The benefit was neither seen with the addition of oxaliplatin (HR for DFS: 2, p: 0.11; HR for OS: 0.85, p: 0.7). Stage III patients treated with FP presented a HR for DFS of 0.76 (p: 0.5) and a HR for OS of 0.42 (p: 0.087). The HR for DFS with oxaliplatin was 0.53 (p: 0.07). A significant improvement in OS was observed, with a HR of 0.22 (p < 0.001). Conclusions: The addition of oxaliplatin in the adjuvant treatment of stage III patients showed a trend towards improvement in DFS and a significant benefit in OS compared to not receiving chemotherapy. On the contrary, patients with stage II did not benefit from this treatment, neither in DFS nor OS.
Relation between the size of nonmetastatic lymph nodes and outcomes in patients with stage III colorectal cancer.
Authors: Okada Kazutake , Sadahiro Sotaro , Miyakita Hiroshi , Saito Gota , Tanaka Akira , Suzuki Toshiyuki
Published: January 2019

822

Background: In stage II colon cancer, retrieval of less than 12 lymph nodes (LNs) is a risk factor for recurrence. We previously reported that the great long-axis diameter of the largest retrieved lymph nodes (maximum LNs) is associated with a higher number of retrieved LNs and better outcomes (Int J Colorectal Dis 2015). We examined whether the long-axis diameter of maximum LNs is a prognostic factor in node-positive stage III colorectal cancer. Methods: The study group comprised 260 patients (pts) with stage III disease who underwent curative resection from 2005 through 2014. Pts who underwent laparoscopic or emergency surgery were excluded. The long-axis diameter was measured on H-E stained specimens and one non-metastatic LN with the greatest long-axis diameter was selected. The cut-off value (COV) for the long-axis diameter was determined by using receiver ROC curves with recurrence or overall mortality as events. Results: Tumors were located in right colon in 86 pts (33%), left colon in 104 pts (40%), and rectum in 70 pts (27%). In pts with rectal cancer, 49 (70%) received chemoradiotherapy (CRT). The mean long-axis diameter was 8.0 ± 3.5 mm. Factors related to the long-axis diameter were tumor location (right colon 9.5 ± 3.8 mm, left colon 7.7 ± 3.4 mm, rectum 6.6 ± 2.4 mm, p < 0.001), CRT (absent 8.4 ± 3.6 mm, present 6.3 ± 2.3 mm, p < 0.001), TNM stage (IIIA 6.6 ± 3.0 mm, IIIB 8.0 ± 3.5 mm, IIIC 8.8 ± 3.7 mm, p = 0.025), and the number of retrieved LNs (less than 12, 6.5 ± 2.9 mm; 12 or more, 9.0 ± 3.5 mm, p < 0.001). The COV for the long-axis diameter from the ROC curves was 8.0 mm. A long-axis diameter of ≥8.0 mm (106 pts 41%) were associated with significantly better outcomes than a long-axis diameter of < 8.0 mm (154 pts 59%) (5y RFS: < 8.0 mm 57%, ≥8.0 mm 70%, p = 0.012). On multivariate analysis, sex (female/male, HR 0.61, p = 0.019), venous invasion (absent/present, HR 0.58, p = 0.042), TNM stage (IIIB/IIIA, HR 3.19, p = 0.021; IIIC/IIIA, HR 3.47, p = 0.033), and the long-axis diameter (≥8.0 mm/ < 8.0 mm, HR 0.55, p = 0.005) were independent prognostic factors. Conclusions: In pts with stage III colorectal cancer, the long-axis diameter of maximum LNs was a prognostic factor. The size of maximum LNs might thus reflect the tumor immunity of the host.
A phase II trial of the effect of perindopril on hand foot syndrome (HFSR) incidence and severity in patients receiving regorafenib with refractory metastatic colorectal carcinoma (mCRC).
Authors: Melosky Barbara L. , Lim Howard John , Davies Janine , Gill Sharlene , Kollmannsberger Christian K. , Ho Maria , Vandt Solomon A. , Renouf Daniel John
Published: January 2019

824

Background: Regorafenib is an oral multi-kinase inhibitor (MKI), with a demonstrated overall survival benefit in mCRC refractory to standard therapy ( PMID 23177514). The most common grade 3 adverse event (AE) reported in this trial was HFSR, with 47% of patients (pts) experiencing HFSR of all grades, and 17% with grade 3 severity. The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. Perindopril is an Angiotensin Converting Enzyme (ACE) Inhibitor indicated for the treatment of hypertension, and may also play a role in preventing endothelial dysfunction ( PMID 17140552). We hypothesized that perindopril may prevent or reduce the severity of regorafenib-induced HFSR. Methods: In this single center Phase II, open label trial, 34 pts with refractory mCRC were planned to be treated with regorafenib (160 mg/day) and perindopril (4 mg/day) with both agents given 3 weeks on and 1 week off. An interim analysis was planned after 10 evaluable pts. The primary objective was to assess the proportion of pts with any grade HSFR toxicity. Secondary endpoint included time to development of worst (grade 3) HSFR toxicity, proportion of all grades of hypertension and all grade toxicities, and progression free survival. All toxicities were evaluated using CTCAE v4.03. Results: 12 pts were accrued over a 9 month time period, and 10 pts were considered evaluable as they completed one cycle of treatment. Pt characteristics included (6 M/ 6F, mean age 62, ECOG PS 0 (25%)/ 1 (75%). A planned interim analysis was performed after 10 evaluable pts had completed their first cycle of study treatment. 5/10 (50%) experienced Grade 3 HFSR, and based on the statistical plan it was deemed highly unlikely that perindopril would lead to reduced levels of regorafenib induced HSFR compared with regorafenib alone thus enrolment was stopped. The most frequent other grade 3 toxicities included hypertension (16.7%), and increased AST (16.7%). Conclusions: The addition of perindopril to regorafenib did not appear to reduce HSFR incidence and severity in pts with refractory mCRC. Clinical trial information: NCT02651415.
Contemporary multi-modal management of colorectal cancer: Evolving patterns of care in an Irish cohort.
Authors: Greally Megan , Harrold Emily , Fenlon Helen M , Eaton Donna , McCarthy Jim , Redmond Karen C , Conneely John B , McEntee Gerry P , Brannigan Ann E , Shields Conor J , Mulsow Jurgen , Gallagher David James , Carney Desmond N. , Higgins Michaela Jane , Kelly Catherine Margaret , McCaffrey John
Published: January 2019

827

Background: The last 15 years have seen significant improvements in the outcomes of patients (pts) with CRC. More effective systemic therapy (Rx) and wider use of surgery (Sx) in stage IV disease (Dx) are key drivers of this. We evaluated the impact of intense surveillance in concert with greater use of metastasectomy and improved systemic Rx on CRC outcomes. Methods: This is a retrospective review of the clinical, radiologic and histological records for consecutive pts with CRC who were referred to the multi-disciplinary CRC team from 2003-2016. Pts with stage I/II Dx were included when referred for adjuvant Rx for high-risk features. We recorded pt characteristics, Rx received and outcomes. Survival was assessed using Kaplan-Meier analysis. Results: We identified 600 pts. Median age was 65 (22-97 years). 71.2% (n=427) of pts had left sided CRC and 25.7% (n=154) had right sided Dx. 211 pts (35.2%) had de novo metastatic Dx. 163 of 389 pts (41.9%) with stage II/III disease relapsed. Median Dx-free interval was 16 months. Of 163 relapses, 121 (74%) were detected by radiologic surveillance and 14 (9%) by rise in CEA. Symptomatic relapse occurred in 20 pts (12%). Median overall survival (OS) was significantly improved in pts with relapse detected by CT, PET/CT or CEA rise (54, 53 and 54 months respectively) vs pts with symptomatic relapse (4 months, p<0.001). Metastasectomy rates were higher in pts with image-detected relapse ( p=0.017). Median OS for pts with stage IV CRC who received any Rx was 27 months. Pts with right sided Dx had shorter median OS vs pts with left sided Dx (24 months vs 40 months, p=0.002). 195 pts (52.8%) underwent metastasectomy; median OS was 71 months vs 16 months in those who did not undergo Sx. 84 pts (14%) with stage IV CRC are currently Dx-free after Sx. Median OS was improved with increasing lines of Rx. Survival in pts receiving best supportive care was 5 months vs 17, 25, 34, 38 and 42 months for pts receiving 2, 3, 4 and 5 lines of Rx respectively ( p<0.001). Conclusions: CRC outcomes are improving with effective multi-disciplinary care, close surveillance, sequencing of systemic Rx and judicious use of salvage Sx following relapse. Our findings support long-term benefit for surgical metatastectomy in stage IV CRC.
Predictive value of primary tumor location (TL) in patients (pts) with pan-RAS wild-type (wt) metastatic colorectal cancer (mCRC) receiving chemotherapy (CTX) ± cetuximab or panitumumab (C/P): An updated meta-analysis.
Authors: Wang Zi-Xian , He Ming-ming , Wang Ying-Nan , Wang Feng , Xu Rui-hua
Published: January 2019

830

Background: Previous evidence suggests that TL may be predictive of the efficacy of C/P versus bevacizumab. This meta-analysis was aimed to evaluate the efficacy of CTX plus C/P versus CTX only as a first-line (1L) or second-line (2L) treatment for RAS wt right- and left-sided mCRC (R- and L-mCRC) in randomized controlled trials (RCTs). Methods: A systematic literature review was performed of PubMed and oncology congress websites (2000–present). RCTs studying the additional efficacy of C/P to CTX in RAS wt R- and L-mCRC were included. Assessed outcomes included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Random-effects meta-analytic models were used in the presence of significant heterogeneity ( I2> 50%). Otherwise, fixed-effects models were performed. Random-effects meta-regression models were used to evaluate the interaction between TL and the efficacy of C/P. Results: A total of three 1L RCTs (CRYSTAL, PRIME, and TAILOR) and one 2L RCT (20050181) were included (325 pts with R-mCRC and 1214 with L-mCRC). Pooled estimates of the efficacy of C/P are summarized in the table. In both R- and L-mCRC pts, the addition of C/P to CTX significantly improved PFS and ORR. A significant OS benefit from C/P was observed in L-mCRC but not R-mCRC pts. No significant interaction was detected between TL and the efficacy of C/P on PFS, OS, and ORR ( P= 0.69, 0.09, and 0.22, respectively). Conclusions: Adding C/P to CTX clearly benefits RAS wt L-mCRC pts in terms of PFS, OS, and ORR. Considering the improvements in PFS and ORR versus CTX only, anti-EGFR agents remain an option for pts with RAS wt R-mCRC. [Table: see text]
A retrospective cohort study evaluating the safety and efficacy of TAS-102 in patients with metastatic colorectal cancer (HGCSG1503): Analysis of cases of prior regorafenib.
Authors: Ishiguro Atsushi , Yuki Satoshi , Nakatsumi Hiroshi , Saiki Takuro , Tsuji Yasushi , Hatanaka Kazuteru , Yoshita Hiroki , Minami Shinya , Ohta Tomoyuki , Eto Kazunori , Nakajima Junta , Nakamura Michio , Suzuki Kazuhiro , Koike Masahiko , Kato Kanji , Tateyama Miki , Asada Chiaki , Sekiguchi Mari , Sakata Yuh , Komatsu Yoshito
Published: January 2019

832

Background: The J003 trial and RECOURSE trial revealed the safety and efficacy of TAS-102 for patients with metastatic colorectal cancer (mCRC). In March 2014, TAS-102 was approved in Japan. However, in these pivotal trials, there were few cases in which regorafenib was administered as prior treatments, and also there were few reports on the effectiveness and safety of TAS-102 after administration of regorafenib. Methods: We retrospectively analyzed the clinical data of 126 patients who received TAS-102 after administration of regorafenib in the multi-institutional retrospective study (HGCSG1503). This study was analyzed by CTCAE v4.0 for adverse events (AEs), RECIST v1.1 for response rate (RR)/disease control rate (DCR), and Kaplan-Meier method for progression free survival (PFS) and overall survival (OS). Results: Patients characteristics were as follows; male/female 75/51, median age 66.5 (range 38-84), ECOG PS (0/1/2/3) 48/64/12/2, KRAS Exon2 wild/mutant 64/60 (2 patients; KRAS Exon2 was not tested). The initial starting dose was 70 mg/m2 (n = 100, 79.4%) and reduced dose (n = 26, 20.6%). Dose reductions were required in 30 patients (30.9%). The common ≥grade 3 AEs were neutrophil count decreased (45.1%), white blood cell decreased (34.9%), and anemia (28.6%). RR and DCR were 0% and 36.5%, respectively. Median PFS and OS were 2.1 and 5.7 months. In the analysis on the relationship between ECOG PS 0-1 and PS 2-3, median PFS was 2.2 vs. 1.4 months (HR 2.187, p = 0.008), and MST was 6.5 vs. 2.7 months (HR 2.424, p = 0.002). Conclusions: In this analysis, TAS-102 after administration of regorafenib in the real-world clinical practice showed similar efficacy and safety to the pivotal clinical trials, except for patients with PS 2-3. Clinical trial information: 000020551.
First line treatment of metastatic colorectal cancer: Are clinical trial results reproducible in real-life practice?
Authors: Lewin Ron , Gal Omer , Sulkes Aaron , Gordon Noa , Ben-Aharon Irit , Purim Ofer , Perel Gali , Kundel Yulia , Moore Assaf , Ulitsky Olga , Brenner Baruch
Published: January 2019

836

Background: Treatment of metastatic colorectal cancer (mCRC) has greatly advanced over the past decade, based on data from randomized controlled trials (RCTs). This raises the question whether results of RCTs, performed on selected patients (pts), do reflect outcomes in real-life practice. The aim of this study was to summarize our experience in the treatment of mCRC and compare it to data reported in RCTs. Methods: A retrospective single-institution study on consecutive mCRC pts treated with first-line bevacizumab-containing regimens in our institute between 2006 and 2014. Results: The study included 300 pts, of whom 54% were males. Median age was 67 years (range 28-90), 26% aged ≥ 75 years. ECOG performance status was ≤1 in 93%. The primary tumor site was right colon in 37%, left colon in 40%, rectal in 23% and 1% of pts had synchronous tumors. RAS status was available in 60%, of whom 55% had wild-type alleles. 46% of pts had a single metastatic site, including 27% with liver-limited disease, and 54% had multiple metastatic sites. Irinotecan-based chemotherapy was used in 66%, oxaliplatin-based chemotherapy in 29% and flouropyrimidine monotherapy in 5%. Curative metastasectomy during 1st line treatment was performed in 29%. Grade ≥3 hematological and non-hematological toxicities were reported in 24% and 38% of pts, respectively. Second and third line treatments were administered to 75% and 66% of pts, respectively; 73% of pts received both irinotecan and oxaliplatin through their treatment course and 76% of those with wild-type RAS were treated with anti-EGFR therapy. Overall response rate and disease control rate were 69% and 89%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 17 and 28 months, respectively. In a sub-group analysis on "RCT-like population", excluding pts ≥ 75 years, ECOG PS ≥ 3 and/or mutated/unknown RAS status, median PFS and OS were 15 and 29 months, respectively. Conclusions: The results of this study suggest that, if adhered to international clinical guidelines, outcomes reported in RCTs are indeed reproducible in routine clinical practice in unselected real-life pts. Additional data, with more pts and longer follow-up, will be presented.
Rectal cancer in the elderly: A review of treatment variances between younger and older patients.
Authors: Corrigan Lynda , O'Leary Connor Gerard , Kroes Jeska , Calvert Paula , O'Connor Miriam , Martin Petra , Cooke Fiachra , Horgan Anne M.
Published: January 2019

839

Background: Rectal cancer (RC) treatment involves multiple modalities with tolerability a concern for some older patients (pts). However, fit older pts have outcomes similar to those of younger pts. We examined the treatment of RC in older pts compared to younger counterparts. Methods: Pts diagnosed with early stage and locally advanced RC from January 2014 to January 2016 were identified from a prospectively maintained electronic database. Characteristics were ascertained through retrospective analysis of pt records. Associations between categorical variables was tested using chi- square. Results: 116 pts diagnosed with RC were identified. Median age was 67 (range 36- 95). 47 (41%) were ≥ 70 years old. Stage distribution is summarised in the Table. Eight pts with stage I disease had rectal polyp cancers, fully resected at endoscopy. 108 were discussed at multidisciplinary meeting (MDM). Treatment (tx) recommendations based on clinical stage and ultimate tx received are outlined in the Table. Clinical Stage and MDM Outcomes Older pts were less likely to receive recommended NACRT than those < 70 (52% and 85% respectively). All pts ≥ 70 who received NACRT completed a full course successfully. Older pts were less likely to proceed to curative resection than younger pts (76% and 94% respectively). Average length of hospital stay was longer in pts ≥ 70: 22.9 vs. 16.6 days in pts < 70. Hospital readmission within 30 days in ≥ 70 vs. < 70 was 9% and 3% respectively. There was no statistical difference in the likelihood of receiving AC based on age. 25% of older pts required dose reductions of AC; 38% did not complete the planned number of cycles. Conclusions: While most older pts tolerated NACRT without significant toxicity, post- operative recovery and tolerability of AC varies widely. Comprehensive geriatric assessment may be useful in guiding tx decisions, and ensuring best outcomes, in this heterogeneous group.[Table: see text]