bluuebunny/crossref_metadata_2025 huggingface dataset:
False-positive elevations of carcinoembryonic antigen in patients with a history of resected colorectal cancer.
Authors: Litvak Anna Maria , Cercek Andrea , Segal Neil Howard , Reidy Diane Lauren , Stadler Zsofia Kinga , Yaeger Rona D. , Kemeny Nancy E. , Weiser Martin R. , Pessin Melissa , Saltz Leonard
Published: February 2017

403

Background: Routine monitoring of carcinoembryonic antigen (CEA) is standard practice in patients with a history of resected colorectal cancer. While it is known that false positive elevations of CEA can occur, the incidence of false positives and the upper limits of false positive elevations have not been previously well characterized. We evaluated these factors retrospectively in a large, single center, 10-year experience. Methods: Computerized medical records of Memorial Sloan-Kettering were searched electronically and then manually confirmed to identify patients who underwent an R0 resection of local-regional colorectal cancer between January, 2003 and December, 2012 and who had a rise in CEA above the normal range after a normal perioperative CEA. CEA elevations were regarded as false-positive if workup failed to identify the source of the CEA with at least 1 year follow up after the CEA first became abnormal. Results: 728 patients were identified who met all inclusion criteria. Of these, 358 patients (49%) were determined to have had a false-positive CEA elevation, 335 patients (46%) had a true-positive CEA elevation indicative of recurrent colorectal cancer, and 35 patients (5%) had a true positive CEA elevation indicative of development of a new, non-colorectal malignancy. Of those with false elevations, 111 had a single isolated CEA elevation (median highest CEA of 5.5ng/ml, range: 5.1-45.2ng/ml) with no further abnormal CEAs, while 247 had CEA elevations on two or more readings with median highest CEA of 6.7 (range: 5.2-34.9ng/ml). Of these 247 patients with confirmed false-positive CEA elevations, only 5 patients (2%) were above 15ng/ml and no confirmed CEA elevation over 35ng/ml was a false positive. Conclusions: False positive CEAs in the 5-15 range are relatively common. Confirmation of CEA elevation in this range prior to initiating imaging studies may be appropriate. False positive CEAs above 15 are rare. In our large data set, all CEAs above 35 were associated with actual cancer recurrence; hence CEA levels above 35 appear to be virtually diagnostic of the presence of cancer.
Tumor size as a prognostic indicator in colon cancer (CCa) patients undergoing sentinel lymph node mapping (SLNM) versus conventional surgery (CS) in National Cancer Data Base (NCDB).
Authors: Shaik Mohammed , Saha Sukamal , Saha Supriya Kumar , Johnston Gregory , Korant Alpesh K. , Wiese David , Dhar Vikrom K. , Eilander David , Arora Madan L. , Singh Trivor
Published: February 2017

411

Background: Unlike other solid tumors, tumor size (TS) is not included in TNM staging for CCa. We correlated TS with TNM staging and 5-year overall survival (5yrOS) for patients (pts) who underwent SLNM vs CS in NCDB. Methods: A retrospectively review of 312 CCa pts undergoing SLNM compared to 298,021 CCa pts from NCDB undergoing CS between 1996 and 2010 was done. The maximum diameter of the primary tumor as TS, T and Nodal status were reviewed. Pts in each group was subdivided into 4 groups: (<2cm; 2-4cm; 4-6cm; >6cm). Data were analyzed using Spearman’s rho correlation and Kaplan-Meier for 5yrOS. Hazard ratios (HR) were calculated using a Cox model adjusting for age, sex, grade, T, N-status, and TNM stage. Results: Pts with TS <2 cm were mainly T1&T2 (80.7%, 74.8%), whereas for tumors >6cm, majority of pts were T3&T4 (93.2%, 88.8%). T1&T2 percentage consistently decreased as TS increased and T3&T4 percentage consistently increased with TS (Table). Nodal positivity according to tumor size for SLNM were 17%, 49%, 56%, 46% and for CS were 18%, 38%, 48%, 51%, respectively. In both groups, nodal positivity increased as TS increased. The overall nodal positivity in both groups was 46% and 42%. For SLNM and CS, overall survival decreased as TS increased. Overall SLNM pts had better OS when compared to CS pts (65%, 54%). Conclusions: Nodal +vity and overall survival where slightly better in SLMN pts. Vs CS pts. TS had +ve correlation with T staging and N status in 5 yr OS. Hence, TS may be considered a prognostic factor in CCa pts. [Table: see text]
The relationship between the local inflammatory response and postoperative infective complications following resection for colorectal cancer.
Authors: Ramanathan Michelle Leana , Roxburgh Campbell S. D. , Horgan Paul G. , Mcmillan Donald C.
Published: February 2017

413

Background: In patients with colorectal cancer, the presence of both systemic and/ or local inflammatory responses are predictors of survival independent of tumour stage. The relationship between a raised perioperative systemic inflammatory response and the development of postoperative infective complications is also well established. The aim of the present study was to examine the relationship between the local inflammatory response and the development of postoperative infective complications, in patients undergoing resection for colorectal cancer. Methods: Patients with histologically proven colorectal cancer who, on the basis of laparotomy findings and preoperative abdominal computed tomography, were considered to have undergone potentially curative resection were included in the study (n = 310). Patient characteristics and postoperative complications within 30 days were recorded in a prospective surgical database. Local inflammation was analysed using Klintrup-Makinen criteria and Jass scoring on routine hematoxylin and eosin slides. Results: The majority of patients were 65 or older (66%), male (57%), had colonic tumours (68%) and node negative disease (60%). Most patients underwent elective resection (87%) and were from a deprived area (55%). During follow up 109 (35%) patients developed a postoperative complication; 88 (81%) of which had infective complications. There were no significant associations between local inflammation, as evidenced by Klintrup-Makinen criteria and Jass score, and all infective complications (p = 0.929, p = 0.317), surgical site infections (p = 0.956, p = 0.115), or anastomotic leak (p = 0.771, p = 0.157). Conclusions: The results of the present study show that there is no significant relationship between the degree of local inflammation, as evidenced by Klintrup-Makinen criteria and Jass score, and the development of postoperative infective complications following potentially curative resection for colorectal cancer.
Response to the first-line FOLFOX plus bevacizumab (BEV) therapy to predict responses to the subsequent therapies and survival in the BEV beyond progression (BBP) strategy for metastatic colorectal cancer: A retrospective analysis of CCOG-0801 study.
Authors: Nakayama Goro , Uehara Keisuke , Hayashi Naomi , Tanaka Chie , Kobayashi Daisuke , Kanda Mitsuro , Yamada Suguru , Fujii Tsutomu , Sugimoto Hiroyuki , Koike Masahiko , Nomoto Shuji , Fujiwara Michitaka , Ando Yuichi , Kodera Yasuhiro
Published: February 2017

428

Background: The aim of this study was to evaluate the association of early tumor response to the first-line bevacizumab (BEV) combination therapy with efficacy of the subsequent therapies and survival during the BEV beyond progression (BBP) strategy for metastatic colorectal cancer (mCRC) patients. Methods: We analyzed a pooled data set from the previous phase II studies of mCRC, testing BBP strategy with the first-line mFOLFOX plus BEV (N=47) and the second-line FOLFIRI plus BEV (N=31). Patients were classified into either responders (R group, n=29) with tumor shrinkage (complete response [CR] + partial response [PR]), sub-responders (SR group, n=11) with stable disease (SD) and non-responders (NR group, n=5) with disease progression (PD) at the point of initial three months of the first-line therapy. The tumor response and PFS in the subsequent therapies and OS were evaluated. Results: In the first-line FOLFOX+BEV therapy, further tumor shrinkage was not achieved after the initial three months. PFS was 15.0 months for the R group, 8.9 months for the SR group and 2.9 months for the NR group, respectively, and there was statistical significance favoring the R group (p=0.001). In the second-line FOLFIRI+BEV, RR and DCR were 39 and 78% in the R group, 14 and 57% in the SR group, and 0 and 0% in the NR group, respectively. No additional response to the first-line therapy was observed in all groups, except for only one patient in the SR group. PFS was 8.8 months for the R group, 6.0 months for SR group and 1.4 months for NR group, respectively, and the R group was significant predictor for prolonged PFS in the second-line setting. OS were 30.8 months for the R group, 24.7 months for the SR group, and 11.1 months for the NR group, respectively. Early disease control (R+SR) was significant predictor for OS (hazard ratio [HR]: 8.48, p<0.01) in multivariate analysis. Conclusions: These findings indicate that the tumor response within initial three months of first-line BEV combination chemotherapy could predict efficacies of subsequent treatments and OS in the BBP strategy for mCRC patients. Clinical trial information: UMIN000006818.
Disparities in stage at presentation and treatment of colorectal cancer among Hispanic and non-Hispanic white patients.
Authors: Rodriguez Rodrigo , Gonzalez Melissa , Fahy Bridget N. , Kinney Anita , Rajput Ashwani
Published: February 2017

433

Background: Although incidence rates for colorectal cancer (CRC) for Hispanics are similar to non-Hispanic whites (NHW) in New Mexico, the cause-specific mortality is higher among the Hispanic population. Hispanics have also been shown to be less likely to be current with colorectal cancer screening guidelines as compared to NHW. The purpose of this study was to determine if there was a difference between Hispanics and NHW in stage at presentation and if the care provided was concordant with NCCN guidelines at our NCI designated cancer center. Methods: A prospective data base of all patients who presented with colorectal cancer between June 2009 and July 2013 was queried. A total of 197 patients were identified. Data was extracted that included: demographics, stage of CRC at first diagnosis, treatments given, and pathology results. Frequencies of stage at presentation and NCCN guideline concordance (meeting the 12 lymph node metric, receipt of adjuvant therapy for stage III disease and radiation therapy for locally advanced rectal cancer) were recorded. Results: The Table shows the results. There were 107 (55%) males. There was not a statistical difference in the stage of presentation for Hispanics and NHW for patients with colon cancer. Hispanic patients with rectal cancer, however, presented with more advanced stage of disease as compared to NHW (p<0.05). There was no statistically significant difference in concordance with NCCN guidelines for the three metrics analyzed. Conclusions: Hispanics and NHW with colon cancer presented with similar stage of disease and were concordant with NCCN guideline metrics. Hispanics with rectal cancer, however, presented at a more advanced stage of disease as compare to NHW patients. The reason for this disparity remains to be elucidated. Future studies to include outreach, education, screening and molecular profiling of these disparate populations are planned. [Table: see text]
Prognostic and predictive blood-based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance).
Authors: Hatch Ace J. , Pang Herbert , Starr Mark D. , Brady John C. , Jia Jingquan , Niedzwiecki Donna , Venook Alan Paul , Cushman Stephanie M. , Hurwitz Herbert , Nixon Andrew B.
Published: February 2017

448

Background: Previously, we identified potential predictive biomarkers of C sensitivity related to EGFR signaling from archived tumor tissue from CALGB 80203. Due to the fact that blood-based markers are more convenient and can be monitored over the course of treatment, baseline plasma samples were also collected and five (EGF, HB-EGF, sEGFR, sHER2, sHER3) of the 14 markers previously analyzed in archived tumor were evaluated in plasma. Methods: CALGB 80203 was a randomized (1:1) phase II trial of 238 pts with locally advanced or metastatic CRC comparing FOLFOX or FOLFIRI (chemo) vs. chemo combined with C. Baseline EDTA plasma samples from 154 pts were analyzed for the 5 candidate markers. The levels of each analyte were correlated with the primary endpoint of OS using univariate Cox proportional hazards models. Potential predictive markers were identified using a treatment by marker interaction term in the Cox model and the markers with significant p-values are reported. Hazard ratios between treatment groups are reported for low or high marker levels dichotomized at the median. Results: Univariate analyses indicated that plasma levels of EGF and sHER3 were negative prognostic markers (p<0.05) that correlated with OS for the overall pt population. Across all pts (KRAS mutant and wild-type), sHER3 was identified as a potential predictive biomarker for C. Pts with higher sHER3 levels had significant OS benefit from C treatment (interaction p=0.03; HR=0.57, 95% CI 0.36-0.92). Low levels of EGF predicted for OS benefit from C in KRAS WT tumors (interaction p<0.01; HR=0.39, 95% CI 0.18-0.87) and lack of benefit in the KRAS mutant pts (interaction p=0.03; HR=3.03, 95% CI 1.13-8.16), but were not predictive for C across all pts combined. Conclusions: Blood-based profiling of EGFR axis members identified sHER3 and EGF as candidate predictors for benefit from C. These data are consistent with our findings using mRNA expression from archived tumor samples and suggest a role for receptor shedding in HER3 biology. If further validated, these markers may help guide the development and use of anti-EGFR therapies and combination regimens.
Pretreatment and postresection epidermal growth factor receptor (EGFR) pathway mutations in a prospective phase II trial (EXCITE) of preoperative cetuximab-containing chemoradiation (CRT) in locally advanced rectal cancer (LARC).
Authors: Gollins Simon , Quirke Philip , Myint Sun , Saunders Mark P. , Sebag-Montefiore David , Susnerwala Shabbir , Essapen Sharadah , Samuel Leslie M. , Sizer Bruce , Beare Sandy , Emma Lawrie , Jitlal Mark , West Nicholas
Published: February 2017

458

Background: Little data exists comparing pre- and post-CRT EGFR pathway mutations in LARC. Methods: Patients had MRI-defined LARC threatening or involving the surgical resection margin. CRT used pelvic radiotherapy (RT) 45Gy in 25 daily fractions with concurrent capecitabine (650mg/m2 bid PO 5 days/week), IV cetuximab (400mg/m2 one week prior then weekly at 250mg/m2 weeks 1-5) and IV irinotecan (weekly at 60mg/m2weeks 1-4). Surgery was 8 weeks after CRT. EGFR pathway mutations were not assessed prospectively. After study completion DNA was extracted from pre-treatment biopsies and post-resection specimens by macrodissecting areas of greatest tumour cell density. KRAS codons 12, 13, 61, 146, NRAS codons 12, 13, 61, PIK3CA codons 542, 545, 546, 1047 and the BRAF V600E hotspot were then pyrosequenced. Results: From 04/09-10/11, 80 patients commenced RT. 76 patients had surgery, with pathological complete response (CR) in 14 (18%) and near-complete (microfoci) in 6 (8%). Four patients had no surgery due to clinical CR. Pre-treatment mutation status was available in 78 patients with a KRAS codon mutation in 34 patients, BRAF in 3, NRAS in 3, PIK3CA in 10 and pathway (any mutation) in 45 (58%). Post-resection data in 54 patients showed 35 mutated codons in 32 patients (59%). 18 patients (33%) showed a discrepancy compared to pre-treatment biopsy. In 17 this was at a single codon, from wild-type (wt) to mutant (mut) in 9 (7x KRAS 12, 1x KRAS 13, 1x PIK3CA 542), from mut to mut in 1 (KRAS 12 c.35G>A to c.34G>T) and mut to wt in 7 (1x KRAS 12, 2x KRAS 13, 2x KRAS 146, 1x PIK3CA 542, 1x PIK3CA 545). One patient changed in 3 codons (mut to wt at KRAS 146 and PIK3CA 545 and wt to mut at KRAS 12). In 12 patients (22%) this changed overall EGFR pathway status (6x wt to mut and 6x mut to wt). Conclusions: Intratumour heterogeneity may explain the EGFR pathway codon changes causing sequencing from single areas of macrodissection to underestimate the tumour genomic landscape and presenting a challenge to personalised medicine. Cetuximab may also drive growth of undetectable mutant clones to detectable levels on pyrosequencing. Clinical trial information: 2007-006701-25.
Prognostic role of microRNA-34a expression in colorectal cancer.
Authors: Lin Albert Y. , Kouzminova Natalia B. , Pollack Jonathan , Nuovo Gerard
Published: February 2017

472

Background: Colorectal Cancer (CRC) is one of the leading causes of death worldwide. MicroRNA-34a (miR-34a), a tumor suppressor gene, is known to be down-regulated in CRC cell lines and recently shown to be a cell-fate determinant in early-stage dividing colon cancer stem cells. However, its prognostic significance is unclear. Methods: MiR-34a detection was performed by in situ hybridization on a CRC tissue microarray (n=127; stage I, 21 patients; II: 42; III: 33; IV: 31). Its expression was graded as negative (no signal), low (expression in 1-19% of cancer cells), moderate (20-49% of cancer cells), and strong (50-100% of cancer cells). The correlations between miR-34a expression and EGFR, osteopontin (OPN), p53, Ki67, LEF1, VEGF, COX2, MMR, stage and grade were evaluated by chi-squared test and Spearman's rank correlation coefficient. Kaplan-Meier survival analysis, log-rank test and Cox regression model were used to assess the association of miR-34a expression with recurrence-free survival (RFS) and disease specific survival (DSS). Results: MiR-34a expression had moderate positive correlation with genes associated with tissue proliferation and invasion, including Ki67 (Spearman's r=0.28, p=0.002), and weak correlation with EGFR (r=0.2, p=0.02) and LEF1 (r=0.18, p=0.039). In the subgroup of patients (n=75; stage II/III) with negative OPN expression (n=25), weak or negative miR-34a expression was associated with worse RFS (HR=4.1; 95%CI=1.1-15.9; p=0.036) and DSS (HR=10.5; 95%CI=1.2-94.5; p=0.036). Conclusions: Our results suggest that down-regulated or absent expression of miR-34a correlates with worse RFS and DSS in stage II - III CRC patients with negative OPN expression. Further investigation of miR34a in prospective randomized studies is warranted to establish its role as a prognostic factor for CRC outcome.
Retrospective evaluation of Middle Eastern patients (pts) with type II diabetes mellitus (DM) and colorectal cancer (CRC): Validation of metformin effect on overall survival (OS).
Authors: Al Omari Amal , Abdelkaleq Hadeel , Al-Hussaini Maysa , Turfa Rim , Awad Nour , Al Mutar Salwan S. , Hassabo Hesham M. , Sahin Ibrahim Halil , Hassan Manal , Garrett Chris R.
Published: February 2017

478

Background: Epidemiologic data suggest that anti-DM medications may impact OS in CRC pts who have type 2 DM. Although type 2 DM and CRC are major health problems in the Middle East, little data exists on pts with both conditions from this region. Methods: Medical records from 1,835 CRC pts seen at King Hussein Cancer Center between 1/1/2004 and 12/31/2012 were evaluated for prevalence of type 2 DM; those with both conditions were evaluated for anti-diabetic therapy and treatment outcomes (OS and progression-free survival [PFS]). Results: 285 type 2 DM CRC patients were identified (prevalence 15.5%); 19 pts were censored as their anti-DM medications were not known. Median age of 266 pts analyzed was 62.1 years (± 8.9), M: F ratio 1.6:1, non-metformin (n = 109, 41%), metformin only (n = 43, 16%), metformin + insulin (n = 11, 4%), metformin + another oral agent (n = 104, 39%). Metformin use increased over time (19% in 2004 to 71% in 2012). Adjusting for age, gender, body mass index, and stage, type 2 DM pts treated with metformin had a 40% improvement in OS (hazard ratio 0.624, 95% confidence interval 0.44-0.97). Conclusions: These data support previous findings that metformin use in CRC pts with type 2 DM is associated with a superior PFS and OS. Contrary to previously published data there was a statistically significant OS benefit in stage IV pts, while the trend toward OS benefit in stage I-III pts was not statistically significant (see Table). This study was supported by the King Hussein Cancer Center/MD Anderson Sister Institution Network Fund. [Table: see text]
Use of the essential autophagy protein beclin 1 to regulate DNA damage response and predict response to chemoradiation in rectal cancer.
Authors: Tougeron David , Park Jae Myung , Okamoto Koichi , Huang Shengbing , Sinicrope Frank A.
Published: February 2017

492

Background: Beclin 1 interacts with its cofactor UVRAG to promote autophagy, a cellular degradation process induced by cellular stress. While cells with defective autophagy are prone to genomic instability, it is unknown whether Beclin 1 and/or UVRAG can regulate DNA damage/repair. Methods: Colorectal cancer cell lines (HT-29, DLD1) with Beclin 1 or UVRAG siRNA were irradiated ± 5-FU. DNA damage (pATM, pH2Ax, 53BP1, RAD51), cell death (annexin V, caspase-3, clonogenic survival), and centrosome number (γ-tubulin staining), were determined. Beclin 1 protein expression was analyzed in pretreatment endoscopic biopsies from 96 rectal carcinoma patients who received radiation + 5-FU followed by surgery. Results: Beclin 1 or UVRAG knockdown was shown to enhance DNA double-strand breaks (DSBs) and cell death induced by radiation ± 5-FU. Suppression of either gene increased the percentage of irradiated cells with nuclear foci expressing 53BP1 (nonhomologous end joining), but not RAD51 (homologous recombination). Beclin 1 was shown to regulate UVRAG, and a UVRAG deletion mutant defective in Beclin 1 binding decreased protection against radiation-induced DSBs. Knockdown of Beclin 1 or UVRAG increased centrosome number in irradiated cells. While autophagy inhibition by ATG5 or LC3 siRNA enhanced radiation-induced DSBs, they did not alter centrosome number suggesting independence from autophagy. In rectal carcinomas, high vs low level Beclin 1 expression was detected in 56 (58.3%) and 40 (41.7%) tumors, respectively. Pre-treatment Beclin 1 was not associated with clinicopathological variables. However, high vs low Beclin 1 predicted a significantly reduced pathological response (macroscopic vs. microscopic or no residual tumor) to chemoradiation (high: 14.2% vs. low: 40%; p = 0.017). High vs low Beclin 1 was independently associated with poorer overall survival (HR, 4.30; 95% CI, 1.42-16.47; p = 0.009). Conclusions: Beclin 1 and UVRAG confer protection against radiation-induced DNA damage and maintain centrosome stability. The ability of Beclin 1 overexpression to confer resistance to chemoradiation, suggests its potential utility as a predictive biomarker in rectal cancer.
A randomized, placebo-controlled, double-blind phase II trial of peri-operative cimetidine in early colorectal cancer.
Authors: Jameson Michael B. , Findlay Michael P. N. , Bissett Ian , van Dalen Ralph , Lolohea Simione , Warren Judith , Romano Claudia
Published: February 2017

509

Background: A Cochrane meta-analysis of randomised trials using histamine-type 2 receptor antagonists with surgery for colorectal cancer (CRC) demonstrated a hazard ratio of 0.53 for mortality if patients used cimetidine. The benefit is likely to be specific to patients whose tumours express the antigens that allow circulating cells to bind to endothelial selectin (E-selectin), the expression of which is induced by inflammatory cytokines perioperatively and inhibited by cimetidine. This trial sought to evaluate several key issues critical to informing the conduct of a phase 3 trial. Methods: Patients with non-metastatic CRC planned for curative-intent surgery were randomised to receive cimetidine 800mg BID or placebo orally for 5 weeks, starting 2-7 days preoperatively. A subset of patients had serial blood sampling for inflammatory cytokines. In addition to DFS and OS, endpoints assessed include treatment compliance and toxicity, recruitment issues, post-operative stay and complications, and tumour characteristics including expression of sialyl Lewis antigens and COX-2. Results: 123 patients (36% female) have been recruited in 4 centres over 3.5 years; another 4 are required to complete the planned 120 treated patients. The primary tumour was rectal in 45% and pathological postoperative tumour stage was 0-I, II, III, and IV in 29%, 33%, 35%, and 2% respectively. About 50% of CRC patients were eligible and fewer than half of those were recruited. Patient compliance was excellent with 89% of patients taking their medication orally in the first 2 days postoperatively. Inflammatory cytokines were commonly elevated postoperatively for up to 2 weeks but normalised by 4 weeks. Immunostaining for tumour antigens is in progress and will be presented. DFS and OS data are immature. Conclusions: Oral administration of cimetidine for 5 weeks is well-tolerated and feasible over the perioperative period, and covers the duration of elevated inflammatory cytokines. Correlative immunostaining studies will be presented. Clinical trial information: 12609000769280.
The effect of different doses of bevacizumab and irinotecan on tumor growth of nude mice bearing human colon cancer DLD-1.
Authors: Cong Luo
Published: February 2017

518

Background: Anti-angiogenic therapy is an important therapeutic strategy in advanced colorectal cancer. However, the anti-angiogenic drug,such as bevacizumab(avastin) is expensive. So, clarifying whether different doses of avastin play the same effect in vivo is urgently needed. The aim of the study was to observe the different doses of avastin in combination with irinotecan in human colon tumor growth in nude mice and tumor angiogenesis. Methods: 21 nude mice inoculated with DLD-1 human colon cancer cells were randomly divided into four groups: sterile saline control (group A), 5mg/kg avastin plus irinotecan chemotherapy group (group B), 10mg/kg avastin plus irinotecan group (group C), and irinotecan chemotherapy group (group D). Drugs were administered in the first 1,5,9 days, mice were sacrificed in the 10th day after treatment, the tumor growth inhibitory rate was calculated and the tumor microvessel density (MVD) were detected by immunohistochemistry. Results: The tumor inhibition rate in groups B, C, and D were 62.85%, 47.91%, 39.59% respectively. A, B, C, and D groups’ MVD were 7.000 ± 0.71, 4.940 ± 0.58, 5.080 ± 1.25, 5.557 ± 2.04, The MVD in group B and C were significant different compared with group A by Dunnett's test, and the MVD expression difference between D, A groups and B, C groups did not reach statistical significance (P values were 0.086,0.083). Tissue necrosis was found in each group after HE staining of tumor tissue. Among them, the control group, mostly mild to moderate necrosis, and the necrosis area were increased after drug treatment. But there were no statistical differences of the necrotic area in drug treated groups graded by rank sum test (χ2 = 4.73, P = 0.193). And cell apoptosis was obviously seen in treated groups. Conclusions: Different doses of avastin with irinotecan inhibited the tumor growth on DLD-1 xenografted nude mice, Synergistic effects were observed in combination therapy, From cell morphology changes after staining with HE, we speculated that the mechanism may be related to the inhibition of tumor angiogenesis, and cell apoptosis increasing. The effect of 5mg/kg and 10mg/kg bevacizumab on tumor volume and MVD had no significant differences.
Early tumor shrinkage (ETS) and deepness of response (DoR) to predict progression-free, postprogression, and overall survival: Results from the phase III TRIBE trial.
Authors: Cremolini Chiara , Loupakis Fotios , Lonardi Sara , Trenta Patrizia , Antoniotti Carlotta , Masi Gianluca , Tomasello Gianluca , Ronzoni Monica , Ciuffreda Libero , Zaniboni Alberto , Carlomagno Chiara , Boni Corrado , Negri Francesca , Barone Carlo , Vitello Stefano , Giuntini Nicola , Bonetti Andrea , D'Amico Mauro , Boni Luca , Falcone Alfredo
Published: February 2017

521

Background: The TRIBE trial demonstrated that first-line FOLFOXIRI plus bevacizumab (bev) improves PFS, response rate (RECIST), and OS in comparison to FOLFIRI plus bev (ASCO Annual Meeting 2013). Recent experiences evidenced that both ETS and DoR may implement the assessment of response and correlate with survival in metastatic colorectal cancer (mCRC). Methods: ETS was defined as the relative change in the sum of longest diameters of RECIST target lesions at week 8 compared to baseline. A 20% decrease was adopted as cut-off value to discriminate early responders and non-responders. DoR was defined as the relative change in the sum of longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline. The median value was used as cut-off. Results: Out of 508 randomized patients, 443 and 484 patients were evaluable for ETS and DoR, respectively. Early responders achieved longer PFS (median PFS: 12.7 vs 10.0 mos, HR: 0.66 [0.52-0.79], p<0.0001), post-progression survival (median PPS: 17.1 vs 10.7 mos, HR: 0.64 [0.47-0.81], p=0.0005) and OS (median OS: 35.8 vs 22.4 mos, HR: 0.54 [0.39-0.67], p<0.0001). Patients achieving a DoR higher than the median reported longer PFS (median PFS: 13.1 vs 9.3 mos, HR: 0.61 [0.49-0.73], p<0.0001), PPS (median PPS: 18.4 vs 10.5 mos, HR: 0.58 [0.44-0.73], p<0.0001) and OS (median OS: 36.8 vs 21.3 mos, HR: 0.47 [0.35-0.58], p<0.0001). A significant correlation of DoR as a continuous variable with PFS (HR: 0.983 [0.979-0.986], p<0.0001), PPS (HR: 0.987 [0.984-0.991], p<0.0001) and OS (HR: 0.979 [0.975-0.983], p<0.0001) was observed. No differences across arms were reported. Conclusions: ETS and DoR predict PFS, PPS and OS. These findings support the hypothesis that the adoption of active upfront regimens, able to induce a rapid and deep tumor shrinkage, may positively affect the subsequent disease history, thus translating into an advantage in survival. Clinical trial information: NCT00719797.
Colorectal signet-ring cell carcinoma: Responsive to adjuvant chemotherapy but still a poor prognosis.
Authors: Hugen Niek , Verhoeven Rob H. A. , Lemmens Valery E. P. P. , Van Aart Carola J. C. , Elferink Marloes A. G. , de Wilt Johannes H. W. , Nagtegaal Iris D.
Published: February 2017

529

Background: Colorectal signet-ring cell carcinoma (SRCC) has been associated with a poor survival compared to mucinous adenocarcinoma (MC) and the common adenocarcinoma (AC). Prognostic impact of tumor localization is unknown and efficacy of adjuvant chemotherapy in SRCC has never been assessed. This study analyses prognostic impact of SRCC and determines whether SRCC patients benefit from adjuvant chemotherapy for colon cancer equally compared with AC. Methods: Data on 196,757 patients with CRC in the Netherlands in the period 1989 and 2010 was included in this nationwide population-based study. Five-year relative survival estimates were calculated and multivariate relative survival analyses using a multiple regression model of relative excess risk (RER) were performed. Results: SRCC was found in 1.0% of CRC patients. SRCC patients presented more frequently with stage III or IV disease than AC (75.2% versus 43.6%, P<0.0001) and SRCC was more frequently found in the proximal colon (57.7% versus 32.0%, P<0.0001). SRCC patients had a poor 5-year relative survival of 31% in colon and 20% in the rectum compared to 57% and 59% in AC (P<0.0001). This poorer survival for SRCC was found in stage II, III and IV. In comparison with AC, there was no significant interaction between SRCC and adjuvant chemotherapy (RER 1.10, 95% CI 0.81-1.51), suggesting a comparable benefit from adjuvant chemotherapy in AC and SRCC. Conclusions: Prognostic impact of SRCC is dismal in both colon and rectal cancer patients, but colonic SRCC patients seem to benefit from adjuvant chemotherapy equally compared with AC. Reduced efficacy of adjuvant chemotherapy therefore does not seem to explain the poor outcome in SRCC patients. We recommend to adhere to adjuvant treatment guidelines for all histological subtypes, but encourage clinical trials to take histological subtype into account for stratification.
Outcome after liver transplantation compared with chemotherapy in colorectal cancer patients with nonresectable liver-only disease.
Authors: Dueland Svein , Guren Tormod Kyrre , Hagness Morten , Glimelius Bengt , Line Pål-Dag , Pfeiffer Per , Foss Aksel , Tveit Kjell Magne
Published: February 2017

531

Background: Surgical treatment of colorectal liver metastases (CLM) is the only treatment option with curative potential; however, only about 10-20% of the patients are candidates for surgical resection. The majority of CLM patients has non-resectable disease, and receives palliative chemotherapy. These patients have poor prognosis with median OS of about 20-24 months after starting first-line chemotherapy and only about 10% survive five years. Methods: Individual data from patients with non-resectable liver only disease who had received liver transplantation (Ltx) (SECA-study, Hagness et al., Ann Surg. 2013) were compared to a similar group of patients with non-resectable liver only metastases included in the NORDIC VII study (first-line Flox chemotherapy ± Cetuximab, Tveit et al., J Clin Oncol. 2012). Twenty one patient included in the Ltx study were compared to 47 patients with liver only metastases included in the NORDIC VII study. All patients in the NORDIC VII study started first-line chemotherapy, whereas 57% of patients in the Ltx study had received second- or third-line chemotherapy at time of Ltx. Results: Median age of the Ltx group was 56 years (range 45-65 years) and 57 years (range 34-65 years) in the Nordic VII study. Median tumor size was 4.5cm (range 2.8-13.0cm) and 5.0cm (range 1.4-16.0cm) in the Ltx and Nordic VII groups, respectively. 5 year OS in the Ltx group was 60% compared to a 5 year OS of 9% in the NORDIC VII group. The 5 year OS of the 21 patients in the NORDIC VII data set with the longest OS was 19%. The patients in the Ltx study who had received only first-line chemotherapy at time of Ltx had a 5 year OS of 80%. Patients in the NORDIC VII study had an OS from end of second-line chemotherapy of 6-7 months. In comparison, patients with progressive disease on second-line/third-line chemotherapy at time of Ltx, had a median OS of 39 months and a 5 year OS of 30%. Conclusions: Patients with non-resectable CLMonly, has a dramatic improved OS after Ltx compared to chemotherapy. The difference could not be explained by patient selection. Selected patients with CRC obtain OS similar to Ltx patients transplanted for primary liver malignancies. Selected CRC patients should therefore be considered for Ltx. Clinical trial information: NCT01311453.
Meta-analysis of outcomes of VEGF and EGFR targeted biologic therapy in relapsed metastatic colorectal cancer (mCRC).
Authors: Chan David , Segelov Eva , Shapiro Jeremy David , Price Timothy Jay , Karapetis Christos Stelios , Tebbutt Niall C. , Pavlakis Nick
Published: February 2017

534

Background: Biologic therapies used in treatment of mCRC are expensive and there is debate about their value. We examined the impact of biologic therapy on overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3/4 toxicity for patients beyond first-line treatment. Methods: MEDLINE, EMBASE, and Cochrane libraries were searched for randomized studies in relapsed mCRC comparing treatment containing targeted therapy to the same treatment without targeted therapy. Biologic agents were classed as: EGFR-inhibitors (EGFR-I), VEGF antibody/trap and VEGFR tyrosine kinase inhibitors (TKI). Only KRAS wild-type patients were included for EGFR-I analysis. Results were aggregated according to standard meta-analytic techniques. Results: 10 studies evaluating 5,847 patients were identified. Considering subgroups and lines, OS and PFS benefit was demonstrated in all groups across all lines except for OS in 2nd line EGFR-I use (which may be due to subsequent crossover). A benefit to ORR was seen with EGFR-I 2nd line (Pooled ORR benefit +24%, Odds Ratio (OR) 4.44, 95% CI 3.20-6.18), EGFR-I 3rd line and beyond (Pooled ORR benefit +16%), VEGF antibody/trap (Pooled ORR benefit +7.2%, OR 2.00, 95% CI 1.57-2.54) and VEGFR TKI (Pooled ORR benefit +1.9%, OR 2.05, 95% CI 1.27-3.30). The risk of grade 3/4 toxicity was greater with the addition of all targeted agents. Conclusions: The use of VEGF and EGFR targeted biologic agents beyond first-line setting in mCRC results in a benefit to OS, PFS and ORR for all agents except for OS benefit with second-line EGFR-I. This benefit comes at the cost of increased toxicity. [Table: see text]
The impact of comorbidity on costs and effects of second-line treatment among elderly metastatic colon cancer patients.
Authors: Woldemichael Andinet , Onukwugha Ebere , Zheng Zhiyuan , Hanna Nader , Seal Brian S. , Mullins C. Daniel
Published: February 2017

536

Background: The Charleston Co-morbidity Index (CCI) was developed as in hospital mortality indicatory and subsequently has been used to both predict and adjust survival differences in cancer patients. We therefore sought to examine how the incremental cost effectiveness of treating elderly metastatic colon cancer (mCC) patients with second-line treatment (Tx2) will vary based upon their baseline CCI. Methods: We identified 2,897 elderly (age 66+) mCC patients who received NCCN recommended first-line treatment (Tx1) between 2003 and 2009 in the SEER-Medicare dataset. Approximately 6% and 1% of patients with missing CCI and outlier costs, respectively, were excluded. We categorized patients by their CCI for 12 months prior to diagnosis into three categories: low (CCI = 0), medium (CCI = 1) and high (CCI = 2+). We calculated 5-years cost-effectiveness of Tx2. Patients enrolled in HMOs, lost part A and/or B, and died of causes other than colon cancer are censored. Costs are inflation adjusted to January 2009 dollars using U.S. Medical Price Index (MPI). We adjusted for censoring using Inverse Probability Weighting (IPW) method and selection bias on observables using Propensity Score Bin Bootstrapping method. Results: Among patients who received Tx1, 56% (n = 1,285) proceeded to receive Tx2. Of those who received Tx2, 67% (n = 864), 23% (n = 289), and 10% (n = 132) have low, medium and high comorbidities, respectively. Compared to those who do not received Tx2, patients who received Tx2 with low, medium, and high baseline comorbidities live 18 (se = 4), 253 (se = 4), and 183 (se = 3) days longer and incur added costs of $66,693 (se = $675), $80,217 (se = $723), and $49,610 (se = $1,136), respectively. The median Incremental Cost-Effectiveness Ratios (ICERs) of Tx2 for patients with low, medium, and high comorbidity are $80,049, $114,693, and $151,627, respectively. Conclusions: Survival benefits from receiving Tx2 vary from an average of 18 days to 253 days and added costs from $49,610 to $80,217 depending on baseline comorbidity levels. The median ICERs associated with Tx2 increase as baseline comorbidity level of patients increase.
The host inflammatory responses, tumor stroma percentage, and survival in colorectal cancer.
Authors: Park James Hugh , Richards Colin H. , Mcmillan Donald C. , Horgan Paul G. , Roxburgh Campbell S. D.
Published: February 2017

549

Background: The role of host inflammatory responses in determining colorectal cancer (CRC) outcome is increasingly recognised. In particular, a marked local inflammatory response is associated with improved survival. However, determinants of this response are not clear. A plausible factor in the density, location and type of the inflammatory cell infiltrate is the extent of tumor stroma. The aim of the present study was to examine the relationship between tumor stroma percentage (TSP), tumor inflammatory infiltrate and survival in patients undergoing elective CRC resection. Methods: 335 patients who had undergone elective resection for stage I-III CRC at a single institution between 1997-2008 were included. TSP at the invasive margin (IM) was assessed on H and E sections and grouped as low (≤50%) or high (>50%). Local inflammatory response was assessed at the IM using Klintrup-Mäkinen (K-M) score and at the IM, tumor stroma and cancer cell nests (CCNs) using the following T-cell markers: CD3, CD8, CD45R0, FOXP3. Systemic inflammatory response was assessed using modified Glasgow Prognostic Score (mGPS). Results: Eighty-three patients (25%) had high TSP. High TSP was associated with increased T stage, N stage (both p < 0.01), margin and serosal involvement (both p < 0.05), an infiltrative invasive margin (p < 0.001) and tumor necrosis (p = 0.001). TSP was associated with decreased infiltration by CD3+ and CD8+ cells at the CCNs (p < 0.01 and p < 0.05 respectively) but not at the IM or stroma. K-M score showed a trend towards an inverse association with TSP (p = 0.067). CD45R0+ and FOXP3+cell infiltration and mGPS were not associated with TSP. On multivariate analysis, TSP was associated with poorer cancer-specific survival (HR 1.93, 95% CI 1.15-3.23, p = 0.012), independent of N stage, VI (both p < 0.05), low CD8 at the IM and CCNs (both p < 0.01) and mGPS (p = 0.001). Conclusions: TSP was associated with the presence of high risk pathological characteristics and down-regulation of host intra-tumoral immune responses and was independently associated with poorer cancer survival. The extent of tumor stroma is an important factor in the nature of the tumor inflammatory cell infiltrate and outcome in patients undergoing elective surgery for CRC.
Phase I and IIa studies of simtuzumab alone and in combination with FOLFIRI in patients with advanced solid tumors.
Authors: LoRusso Patricia , Hecht J. Randolph , Thai Dung Luong , Hawkins Michael J. , Dong Hua , Tolcher Anthony W.
Published: February 2017

554

Background: Simtuzumab (SIM) is a monoclonal antibody that inhibits lysyl oxidase like molecule 2 (LOXL2), an extracellular matrix enzyme involved in tumor growth and metastasis. Methods: A phase I dose escalation study evaluated the safety and pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Dose escalation occurred at doses up to 20 mg/kg of SIM every 2 weeks by IV infusion followed by a dose expansion of 20 pts at 10 mg/kg of SIM every 2 weeks. PK was evaluated following the first and fourth doses. In a separate Phase IIa study, 11 pts with KRAS mutant colorectal cancer (CRC) were given SIM at 700 mg IV combined with FOLFIRI every 2 weeks in the 2nd line setting. All pts continued until disease progression or unacceptable toxicity. CT or MRI was performed every 8 weeks. Results: In the phase I study, 12 pts (3 per cohort) received SIM at doses of 1, 3, 10 and 20 mg/kg. Tumor types included CRC (5), pancreatic neuroendocrine (PNE, 1), and other tumors (1 each). In the dose expansion, 20 CRC pts (11 KRAS mutant and 9 KRAS wild-type) received SIM at 10 mg/kg. Treatment-emergent AEs (TEAEs) included fatigue and constipation. No DLTs or drug-related SAEs were observed. The mean terminal T1/2 was ~20 days, and exposure was dose proportional between 1 and 20 mg/kg. Decreased tumor size (-56% for PNE and -17%, -8%, -5%, -5%, and -4% for CRC) as measured by the sum of the linear diameter of the target lesions was observed in 6 pts following treatment with SIM alone. In the Phase IIa trial of SIM/FOLFIRI, the most common TEAEs were diarrhea, fatigue, and nausea. Median PFS was 7.8 months. Conclusions: SIM was well tolerated as a single agent and when combined with FOLFIRI and showed promising efficacy in pts with CRC. A randomized, double-blind, placebo controlled phase II study in KRAS mutant CRC pts is ongoing. Clinical trial information: NCT01323933.
A multicenter exploratory study of irinotecan-based chemotherapy on UGT1A1 polymorphisms for patients with colorectal cancer.
Authors: Chikakiyo Motoya , Sato Hirohiko , Kurita Nobuhiro , Iwata Takashi , Yoshikawa Kozo , Kashihara Hideya , Mikami Chie , Matsumoto Noriko , Eto Shohei , Shimada Mitsuo , Hotchi Masanori , Okitsu Hiroshi , Sonaka Yasuhide , Yoshida Sadahiro
Published: February 2017

563

Background: Recent pharmacogenetic studies have revealed a significant association between uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6 and toxicities such as severe diarrhea and neutropenia under treatment with irinotecan. Moreover, the latter of these two polymorphisms is specifically detected in East Asian populations. We performed a prospective study to determine the optimal dose of this drug depending on which polymorphism is present in order to maximize the effectiveness of therapy while avoiding side effects. Methods: 59 patients from 11 institutions were enrolled in this study. Patients were assigned to one of the following three groups: wild type (*1/*1), heterozygous (*28/*1, *6/*1), or homozygous (*28/*28, *6/*6*, *28/*6*). The double heterozygous state (*28/*6) was included within the homozygous group. Second-line FOLFIRI was administered, with the dose of irinotecan at 150 mg/m2, in the wild type and heterozygous groups and at 100 mg/m2 in the homozygous group. The incidences of severe toxicities according to UGT1A1 gene type, response rate, and progression-free survival were investigated. Results: 26 (44.1%) were assigned to the wild type group, 28 (47.4%) to the heterozygous group, and 5 (8.5%) to the homozygous group. Grade 3 or higher severe toxicities were observed in 8 patients (30.8%) in the wild type group, 5 (17.9%) in the heterozygous group, and 1 (20.0%) in the homozygous group. No significant difference was observed among the three groups. The most frequently observed severe toxicities were neutropenia, nausea, vomiting, and diarrhea. The overall response rate (complete response + partial response) was 2 patients (7.7%) in the wild type group, 2 (7.1%) in the heterozygous group, and none (0.0%) in the homozygous group. Conclusions: In terms of tolerability and safety, the present results suggest that irinotecan should be administered at a dose of 150mg/m2 in heterozygous patients and 100 mg/m2 in homozygous patients receiving second-line FOLFIRI.