bluuebunny/crossref_metadata_2025_split huggingface dataset:
The consensus molecular subtypes of colorectal cancer as a predictive factor for chemotherapies against metastatic colorectal cancer.
Authors: Okita Akira , Takahashi Shin , Ouchi Kota , Inoue Masahiro , Yamada Yasuhide , Ishioka Chikashi 
Published: January 2019

736 Background: Since treatment options of chemotherapy for metastatic colorectal cancer (mCRC) have been diversified, biomarkers which could predict efficacy of chemotherapies are needed for optimal treatment. In this study, we analyzed the association of the treatment outcomes by several chemotherapies and the consensus molecular subtypes (CMS), which was developed from large-scale comprehensive gene expression analysis of colorectal cancer (Guinney J et al. Nat Med 21:1350-6, 2015). Methods: A total of 193 patients with previously treated mCRC were classified in 4 subtypes, CMS1 to CMS4 by using the microarrays data of primary tumors and the “CMS classifier” package for the R software. Then the association between the subtypes and the treatment outcomes was analyzed retrospectively. Results: The193 cases were classified into 21 CMS1, 53 CMS2, 69 CMS3 and 50 CMS4. The molecular characteristics of each subtype such as mutation status of KRAS and BRAF genes, and DNA methylation status were consistent with those of the previous study. First-line chemotherapies of the 193 patients were oxaliplatin (OX)-based treatment (121 patients), irinotecan (IRI)-based treatment (59 patients) and others (13 patients). In CMS4, the median progression-free survival (PFS) of the IRI-based group was significantly longer than that of the OX-based group (21.8 months vs. 10.5 months, p < 0.01). The median overall survival (OS) and objective response rate of the IRI-based group were also better than that of the OX-based group in CMS4. Among 193 patients, 103 were RAS wild-type and treated with anti-EGFR antibody. The effect of the anti-EGFR treatment was low in CMS1 (median PFS: 2.4 months, p < 0.01, median OS: 5.7 months, p < 0.01) and whereas was high in CMS2 (median PFS: 8.0 months, p = 0.05, median OS: 26.6 months, p = 0.02). CMS significantly correlated with PFS and OS after anti-EGFR treatment by univariate analysis. However the most useful predictive biomarker was a DNA methylation status by multivariable analysis. Conclusions: The biological characteristics of CMS may affect the therapeutic effect of anti-cancer agents in mCRC and, therefore, might be a new predictive factor of anti-cancer treatment.
The influence of hospital and surgeon volume on survival and local control in rectal cancer: Long-term results of the CAO/ARO/AIO-94 trial.
Authors: Sprenger Thilo , Beissbarth Tim , Sauer Rolf , Fokas Emmanouil , Hohenberger Werner , Liersch Torsten , Rödel Claus , Ghadimi Michael 
Published: January 2019

738 Background: The association of hospital and surgeon volume with the outcome of rectal cancer patients is under debate. In this study the long-term influence of the hospital as well as the surgeon volume on overall survival and local recurrence were investigated. Methods: In a post-hoc analysis of the randomized phase III CAO/ARO/AIO-94 trial after a follow-up of more than 10 years, 799 patients with locally advanced rectal cancers were evaluated. Survival and local recurrence rates were stratified by the hospital recruitment volume (≤20 vs. 21-90 vs. > 90 patients) and by the surgeon volume (≤10 vs. 11-50 vs. > 50 procedures). Results: Patients treated in „high-volume“ hospitals had a longer overall survival than those treated in hospitals with medium or low treatment volume (p = 0.03). The surgeon volume was significantly associated with decreased local recurrences (p = 0.01) but had no influence on overall survival. The effect of neoadjuvant chemoradiation on local control was the strongest in patients being operated by medium-volume surgeons. Conclusions: Patients with locally advanced rectal cancers might benefit from treatment in in specialized high-volume hospitals. In particular, the surgeon volume had significant influence on local control.
The impact of primary tumour resection and sidedness in patients with synchronous metastatic colorectal cancer (mCRC): Findings from the South Australian Metastatic Colorectal Cancer Registry (SAMCRC).
Authors: Klevansky Myron , Vatandoust Sina , Dykes Lukah , Padbury Rob , Price Timothy Jay , Roder David , Moore James , Piantadosi Cynthia , Roy Amitesh , Karapetis Christos 
Published: January 2019

739 Background: The benefit of primary tumour resection (PTR) in patients with synchronous mCRC is not clear. The influence of tumour location on PTR benefit is also uncertain. Methods: SAMCRC is a population based registry collating data from all patients in South Australia diagnosed with mCRC from February 2006. We examined outcomes according to whether the primary colorectal tumour was excised within 3 months of diagnosis or remained in situ; we also examined whether outcomes were affected by tumour side (right v left). Registry data was included for patients with synchronous metastic adenocarcinoma from colon or rectum. Exclusion criteria included metastasectomy, tumour resection within 7 days or death within 3 months of mCRC diagnosis. Kaplan Meier analysis was used for Survival. Tumour sidedness and PTR were analysed with a multivariate Cox proportional hazards model. Survival was measured from the landmark date (3 months from date of diagnosis). Results: 2575 patients with synchronous mCRC have entered the database, of which 1869 patients were eligible for the PTR analysis. 50.2% (n = 938) underwent PTR. 481 patients (51.3%) of the PTR analysis group had left-sided primary tumours whilst 436 had right sided tumours (46.5%) which was significant (p < 0.001). 63% of the PTR cohort were male (n = 1006). Site and age metastases were included in the multivariate analysis. PTR was associated with improved survival from landmark compared to no resection (15.0 mo vs 11.2 mo, 95% CI 15.0 – 16.3 vs 11.2 – 12.3, p = 0.031). In the entire synchronous mCRC group, left-sided tumours (62.1%) had a longer median survival (17.8 mo vs 10.4 mo, 95% CI 15.7 – 19.5 vs 10.4 – 11.7 p = < 0.001). An interaction test was performed for sidedness and was not significant. Conclusions: PTR was associated was associated with improvement in survival in this large population based registry. This finding did not differ signifcantly between right and left sided tumours. Survival was superior for patients with left sided tumours, in keeping with established data. Criteria for selection of patients with mCRC who benefit from PTR need to be defined.
MET-amplification (MET-amp) in relation to aggressive biology in esophagogastric cancer (EGC): An analysis of clinical outcomes of MET-amp vs non-MET-amp EGC.
Authors: Hong Theodore S. , Hwang Katie L. , Clark Jeffrey W. , Lennerz Jochen K , Shui Amy , Zheng Hui , Szymonifka Jackie , Corcoran Ryan Bruce , Heist Rebecca Suk , Russo Andrea Lyn , Parikh Aparna Raj , Borger Darrell R. , Blaszkowsky Lawrence Scott , Faris Jason Edward , Murphy Janet E. , Azzoli Christopher G. , Mullen John Thomas , Ryan David P. , Iafrate A. John , Kwak Eunice Lee 
Published: January 2019

74 Background: c-MET gene amplified ( MET-amp) tumors have been identified as a rare but targetable subset of esophagogastric cancer (EGC). In a phase I study, patients with MET-amp EGC had a 50% response rate to the oral MET inhibitor AMG 337, with some responses exceeding a year (Kwak EL, GI ASCO 2015). We evaluate clinical characteristics and outcomes were evaluated in patients with MET amplified esophagogastric cancer to facilitate identification of patients and establishment of treatment paradigms. Methods: Patients with metastatic MET amplified EGC were identified. MET-amplification was identified by fluorescent in situ hybridization (FISH) on paraffin-embedded tissue, with a gene to control ratio of > 2.2 defined as positive. Clinical characteristics, treatment factors, and survival were recorded. A group of metastatic non- MET amplified patients identified during the same time period who had undergone tumor genotyping and treatment at our institution was evaluated as a comparison group. Results: 21 patients were identified with metastatic MET amplified EGC and 65 patients with metastatic non- MET amplified EGC. The majority of MET amplified tumors occurred in the distal esophagus. 4 patients had co-amplification of HER2, 1 patient had PIK3CA mutation and 1 patient had a TP53 mutation. Compared to non- MET amplified tumors, MET-amplified tumors were more likely to have poorly differentiated tumors. There was no difference in initial sites of metastatic disease. Progression-free survival (PFS) for first line therapy was substantially shorter for patients with MET (6.5 mo vs 14.3 mo, p = 0.0033). MET amplified patients trended towards a shorter overall survival (OS) as well (12.3 mo vs. 20.1 mo, p = 0.0523). Conclusions: MET amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Given the efficacy seen with MET inhibition, patients need to be tested and identified early and directed to appropriate MET-targeted clinical trials.
VOICE trial: Final results from multicenter phaseII study of assessment of clinical efficiency and safety in capecitabine plus intermittent oxaliplatin together with bevacizumab as first-line therapy for patients with advanced colorectal cancer.
Authors: Kosugi Chihiro , Koda Keiji , Denda Tadamichi , Ishibashi Keiichiro , Ishida Hideyuki , Seike Kazuhiro , Sakata Naoto , Yanagisawa Shinji , Miyazaki Akinari , Takayama Wataru , Koike Naoto , Matsubara Hisahiro , Yamazaki Masato , Shimizu Hiroaki , Shuto Kiyohiko , Mori Mikito , Narushima Kazuo 
Published: January 2019

740 Background: The FOLFOX with bevacizumab (B-mab) has been established as a standard first-line therapy for metastatic colorectal cancer (mCRC), and OPTIMOX1 study suggested that stop and go strategy for oxaliplatin reduced peripheral sensory neuropathy. The CapeOx is one of the standard treatments for mCRC that has been proven to be as effective as the FOLFOX regimen. Thus we accessed the efficacy and safety of the combination of intermittent CapeOx + B-mab as a first-line therapy in patients with mCRC in this trial. Methods: Eligibility criteria included ECOG PS: 0–1, No Peripheral neuropathy ( < Grade 1). Patients received CapeOX (oxaliplatin 130mg/m2, capecitabine 2000mg/m2 + B-mab 7.5mg/kg) q3 weeks for 5 cycles, maintenance without oxaliplatin for 5 cycles, and reintroduction CapeOX + B-mab for 5 cycles until progression. Primary endpoint was Progression Free Survival (PFS). Results: Between March 2011 and August 2013, 55 pts were enrolled. Baseline characteristics were median age of 67 years (range, 20–83); PS 0/1 (49/6 pts); male/female (33/22 pts), colon/rectum (28/27pts) and metastatic lesion liver/lung/lymph nodes (32/18/21 pts). A total of 47 pts were evaluated as Par Protocol Set population. 38 pts moved from initial CapeOX to maintenance Capecitabine. 20 pts moved to CapeOx reintroduction. Median PFS was 14.7months (95%CI, 8.6–19.5) and Median TTF was 12.3 months (95%CI, 10.3–14.3). Best overall response rate was 48.0%. Oxaliplatin reintroduction rate was 57.4%. Main grade 3/4 toxicity were: neutropenia (1 pt), anemia (1 pt), peripheral neuropathy (1 pt), allergic reaction of oxaliplatin (1 pt), deep vein thrombosis (1 pt), nausea (1 pt), hand-foot syndrome (1 pt), and hypertension (1 pt). Conclusions: This study met its primary endpoint PFS. CapeOx intermittent oxaliplatin indicated to reduce incidence of severe neutropenia and peripheral sensory neuropathy. The results suggested that our treatment strategy was well tolerate and effective for first line therapy in mCRC, and maintenance duration for 5 cycles, was reasonable. Clinical trial information: UMIN000005732.
Sidedness, mutations, and survival in stage IV colon cancer: A U.S. population-based study.
Authors: Lin Albert Y. , Kahl Amanda , Gribovskaja-Rupp Irena , West Michele , Lynch Charles F , Charlton Mary E. 
Published: January 2019

742 Background: Despite recent diagnostic and therapeutic advances in colon cancer (CC), it remains one of the leading causes for cancer-related deaths worldwide. At time of diagnosis, 20% of CC patients (PTS) present with de novo stage IV. In recent years, clinical trials have identified sidedness and several molecular biomarkers (MBM), such as microsatellite instability high (MSI-H), KRAS and BRAF mutations, as prognostic and predictive factors for treatment response in stage IV CC. However, their impact and interactions in the population-based setting remain elusive. Methods: The National Cancer Institute’s 2014 Patterns of Care study included a sample of 1,444 stage IV CC PTS from Surveillance, Epidemiology, and End Results registries, and captured MSI, BRAF and detailed chemotherapy information not available in the public-use dataset. Demographic, tumor, molecular and treatment data were compared using chi-square tests. Cox proportional hazards models were used to compare overall survival (OS) across subgroups of demographic, tumor, MBM and treatment characteristics. Results: Compared to left-sided (L) CC, PTS diagnosed with right-sided (R) CC tend to be older (median age: 65 vs 60, respectively; p < 0.001), more females (54% vs 44%, p = 0.001), African Americans (25% vs 22%, p = 0.001), have poorly or undifferentiated tumors (27% vs 15%, p = 0.001), and harbor MSI-H (14% vs 7%, p = 0.018), KRAS (52% vs 36%, p < 0.001) or BRAF (29% vs 11%, p = 0.001) mutations. FOLFOX, with or without bevacizumab, accounted for > 50% of the first-line regimens. Multivariable Cox proportional hazards models revealed the following poor risk factors: right-sidedness, poorly or undifferentiated tumor, no surgery, no chemotherapy, no cetuximab/panitumumab or no bevacizumab therapy. In separate models for LCC and RCC among those tested for KRAS (n = 689), treatment with bevacizumab was associated with lower odds of death in both models (p < 0.05). Cetuximab/panitumumab were nearly significantly associated with lower odds of death in LCC (p = 0.06) but not RCC (0.35). Conclusions: Right-sidedness is a poor prognostic factor in stage IV CC. Regardless of sidedness, stage IV CC PTS can benefit from surgery, chemotherapy, or bevacizumab.
Prognostic value of neutrophil-to-lymphocyte ratio (NLR) on overall survival (OS), progression free survival (PFS) and disease control rate (DCR) in patients with metastatic colorectal cancer (mCRC) from the RECOURSE study.
Authors: Argiles Guillem , Yoshino Takayuki , Ohtsu Atsushi , Mayer Robert J. , Winkler Robert , Amellal Nadia , Fougeray Ronan , Kanehisa Akira , Van Cutsem Eric 
Published: January 2019

744 Background: Elevated neutrophil-to-lymphocyte (NLR) ratios may represent markers of a suboptimal host immune response to cancer and have been shown to correlate with prognosis in multiple tumor types. Trifluridine/tipiracil (FTD/TPI also known as TAS-102) compared with placebo significantly improved OS (median: 7.1 vs.5.3 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) [0.58;0.81], p < 0.0001), PFS, and DCR in the phase 3 RECOURSE study, conducted in patients with refractory mCRC. A post-hoc analysis was conducted to assess correlation between clinical outcomes and baseline NLR (in blood) in RECOURSE. Methods: A retrospective review on 782/800 patients, with available NLR, was performed on OS, PFS, and DCR in two subgroups of patients with low ( < 3) or high (≥ 3) NLR at baseline. Based on literature, the cutoff value of 3 was chosen as the number of patients was similar in each NLR subgroup. Between-group comparison was performed using a stratified Cox’s proportional hazard model for OS and PFS, and Fisher’s Exact test for DCR. Results: The median value of NLR at baseline was similar in each group, FTD/TPI (N = 519): 4.4 ± 6.3, placebo (N = 263): 4.7 ± 6.5. Almost 60% of patients in each group had high NLR. In the low NLR vs. high NLR subgroup, there were differences at baseline for ethnic origin (Asian: 45% vs.29%), ECOG PS 0 (69% vs. 49%), and number of metastatic sites ≥ 3 (32% vs. 46%). The median OS [95 % CI] was statistically significantly higher in the low vs. high NLR subgroup: 8.4 [7.8;9.5] vs. 5.3 [4.7;5.7] months, HR = 0.49, 95% CI [0.41;0.59], p < 0.0001. Irrespective of NLR, all patients benefited from FTD/TPI vs. placebo. The results of PFS and DCR were statistically significantly better in the low NLR vs. high NLR subgroup. The multivariate Cox analysis for OS with the interaction test between treatment groups and NLR showed that NLR is not a predictive factor (p = 0.15). Conclusions: In this retrospectively analyzed mCRC population, NLR was shown to be an independent prognostic factor. Further research is warranted to assess if NLR can be a stratification factor in mCRC clinical trials. Clinical trial information: NCT01607957.
Panitumumab versus cetuximab in patients with wild-type KRAS exon 2 metastatic colorectal cancer who received prior bevacizumab therapy: A combined analysis of individual patient data from ASPECCT and WJOG6510G.
Authors: Taniguchi Hiroya , Yamanaka Takeharu , Sakai Daisuke , Yamazaki Kentaro , Muro Kei , Peeters Marc , Price Timothy Jay 
Published: January 2019

745 Background: The ASPECCT (Price T, et al. Eur J Cancer 2016) and WJOG6510G (Sugimoto N, et al. ASCO-GI 2017) trials demonstrated noninferiority of panitumumab (Pmab), compared with cetuximab (Cmab), regarding the overall survival (OS) for chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). However, the subgroup analyses of both trials revealed a longer survival with Pmab than Cmab in patients who previously received bevacizumab (Bev). We performed a combined analysis of both trials using individual patient data. Methods: In both trials, patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to CPT-11- or L-OHP-based chemotherapy were randomized to receive Pmab or Cmab monotherapy (ASPECCT) or in combination with CPT-11 (WJOG). The patient subgroup with prior Bev was eligible for enrollment in this analysis. Results: In the combined data of 374 patients, 185 patients were enrolled in the Pmab arm (ASPECCT, 126; WJOG, 59) and 189 patients in the Cmab arm (ASPECCT, 132; WJOG, 57). The patient characteristics were well-balanced in both arms. Of the 374 patients, 341 (91%) and 369 (99%) had the OS and progression-free survival (PFS) events, respectively. The median OS was 12.8 months in the Pmab arm and 10.1 months in the Cmab arm ( P = 0.0031; the log-rank test stratified by trial). The hazard ratio (HR) for OS was 0.72 (95% confidence interval [CI], 0.58–0.90). The median PFS in the Pmab and Cmab arms were 4.7 and 4.1 months, respectively (P = 0.0207). HR for PFS was 0.79 (95% CI: 0.64–0.97). Response rates in the Pmab and Cmab arms were 23% and 16%, respectively (P = 0.114). Although the incidence of skin toxicities was similar, the infusion reaction was observed more in the Cmab arm (any grade, 1.1% vs 8.6%), whereas hypomagnesemia was noted more in the Pmab arm (48% vs 33%). Conclusions: This combined analysis demonstrated that Pmab significantly prolonged OS and PFS compared with Cmab, raising the potential that Pmab is the more reliable anti-EGFR option for patients with wild-type KRAS exon 2 metastatic colorectal cancer who previously received Bev.
A phase I dose-escalation trial of intraperitoneal oxaliplatin with systemic capecitabine and bevacizumab following cytoreduction in patients with peritoneal carcinomatosis from appendiceal or colorectal cancer.
Authors: Oza Aabha , Grierson Patrick , Glasgow Sean , Pedersen Katrina , Barman Stephen , Westbrook Thomas , Mutch Matthew G , Wang-Gillam Andrea , Suresh Rama , Morton Ashley , Marquez Samantha , Fleshman James W , Tan Benjamin R. 
Published: January 2019

746 Background: Peritoneal carcinomatosis (PC) is the intraperitoneal spread of cancer. Optimal treatment for PC is controversial. Systemic chemotherapy offers limited benefit (Franko, 2011). Intraperitoneal (IP) chemotherapy following cytoreductive surgery (CRS) improves outcomes (Verwaal, 2008). Oxaliplatin (Ox), capecitabine, and bevacizumab are standard agents for the treatment of metastatic colorectal cancer (CRC). Evidence suggests benefit of IP Ox at high doses. However, the optimal dose of IP Ox combined with standard systemic therapy is unclear. Methods: We conducted an IRB-approved phase I dose-escalation study of IP Ox D1 at 25mg/m2-100mg/m2, with systemic bevacizumab D1 at 5mg/kg, and capecitabine 850mg/m2 BID for 7 days (cycle = 14 days), in patients with PC from appendiceal or CRC after CRS. The primary aim was to determine the recommended phase II dose (RP2D)/maximum tolerated dose (MTD) for this regimen. Dose limiting toxicities (DLTs) were assessed during cycle 1. DLTs included grade 3 or 4 non-hematological toxicities, or grade 4 hematological toxicities. Results: 18 patients (12 females, median age 56) were enrolled on the study. No DLTs were observed during cycle 1 in the first 4 cohorts. One DLT (abdominal pain) was observed in cohort 5. Another patient in cohort 5 experienced grade 3 abdominal pain soon after cycle 2, thus limiting repeated treatment for this cohort. Other toxicities included fatigue (72%), nausea (61%), peripheral neuropathy (50%), constipation (50%), mucositis (39%) and dizziness (39%). See table below for average # of cycles per cohort and responses. Conclusions: IP Ox combined with capecitabine and bevacizumab is feasible. Our recommended dose for IP Ox is 85 mg/m2 with systemic therapy (cohort 4). An expansion cohort is underway for this dose level. Based on these data, further investigation of IP Ox with systemic chemotherapy for PC is warranted. Clinical trial information: NCT01061515. [Table: see text]
Impact of primary tumor side (TS) on outcomes of once-every-2-weeks (q2w) cetuximab + first-line (1L) FOLFOX or FOLFIRI in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the phase 2 APEC trial.
Authors: Price Timothy Jay , Shen Lin , Ma Brigette , Esser Regina , Chen Wen-Feng , Gibbs Peter , Lim Robert S.C. , Cheng Ann-Lii 
Published: January 2019

747 Background: In the RAS wt population of APEC, q2w cetuximab combined with 1L FOLFOX or FOLFIRI achieved a best confirmed overall response rate (BORR), median progression-free survival (PFS), and median overall survival (OS) similar to those reported in prior 1L pivotal studies involving weekly (qw) cetuximab. In this hypothesis-generating subgroup analysis, we evaluated the impact of TS in APEC study patients with RAS wt mCRC. Methods: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region, with BORR as the primary endpoint. Patients with KRAS exon 2 wt tumors received q2w cetuximab + investigator’s choice of FOLFOX or FOLFIRI; subsequent analyses considered patients who were RAS wt ( KRAS/ NRAS, exons 2-4). TS was categorized in evaluable patients with RAS wt tumors (left [L]-sided = splenic flexure, descending colon, sigmoid colon, and rectum; right [R]-sided = appendix, cecum, ascending colon, hepatic flexure, and transverse colon). Results: Among 167 patients with RAS wt mCRC, 159 were evaluable for TS; 130 (81.8%) had L-sided and 29 (18.2%) had R-sided mCRC. Baseline characteristics in the TS subgroups reflected the known differences between L- and R-sided mCRC. Efficacy data for the TS subgroups are summarized in the table. Conclusions: Consistent with prior 1L pivotal studies involving qw cetuximab, a prognostic effect of TS in patients receiving 1L q2w cetuximab was confirmed in APEC. BORR remained ≥50% in patients with R-sided mCRC, in line with prior evidence that use of cetuximab may be appropriate when tumor shrinkage/cytoreduction is the goal. These hypothesis-generating data also raise the possibility of synergy between cetuximab and, in particular, irinotecan for PFS and OS in patients with R-sided tumors, although numbers are small. Clinical trial information: NCT00778830. [Table: see text]