bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety, pharmacology, and preliminary clinical activity of MM-151: An oligocolnal anti-EGFR theraputic in patients with cetuximab-resistant CRC and other refractory solid tumors.
Authors: Lieu Christopher Hanyoung , Beeram Muralidhar , Harb Wael A. , Kearns Jeffrey D. , Sloss Callum Mortimer , Nering Rachel , Adjei Alex A. , Wolf Beni B.
Published: February 2017

647

Background: MM-151 is an oligoclonal anti-EGFR antibody combination designed to provide enhanced targeting of the EGFR network. This work describes the first in human experience of MM-151 alone and in combination with irinotecan. Methods: A standard 3+3 design was used to assess safety and tolerability of MM-151 monotherapy (QW, Q2W, Q3W) and MM-151 (QW) in combination with irinotecan 180mg/m2 (Q2W). A monotherapy expansion cohort has begun in cetuximab-resistant CRC. Results: Results presented are based on preliminary data as of September 2, 2014, for MM-151 monotherapy (n=65; QW/Q2W) and MM-151 in combination with irinotecan (n=10). The most common tumor types were CRC (29 [39%]), NSCLC (9 [12%]), HNSCC (8 [11%]). The monotherapy RP2D has been defined as 10.5 mg/kg QW and dosing continues at 18 mg/kg Q2W. Most adverse events were CTCAE grades 1 and 2. The most common AEs were toxicities related to the EGFR-pathway, including rash (70%), hypomagnesemia (24%), fatigue, dry skin, and diarrhea (21%). IRR was initially observed at high frequencies; however, standardized pre-medication and a modified infusion schedule significantly decreased this frequency. At doses >9 mg/kg QW, trough total antibody levels at steady state were in the expected therapeutic range. Of the CRC patients enrolled, 3 experienced Partial Responses (PRs) per RECIST criteria and a total of 8 (31%) pts had SD for >4 months. Initial biomarker data suggests particular clinical activity in triple-wildtype, EGFR-ligand positive CRC patients. Combination therapy with irinotecan continues with MM-151 at 9 mg/kg QW and 3 PRs have been observed (CRC, HNSCC, melanoma). Initial safety data is consistent with known toxicities of MM-151 and irinotecan. Preliminary results from the monotherapy expansion cohort (10.5 mg/kg QW) in CTX-refractory CRC will also be presented. Conclusions: These results demonstrate that MM-151 monotherapy has an acceptable tolerability profile and objective clinical activity alone and in combination with irinotecan. Results also support further clinical evaluation in triple-wildtype, EGFR-ligand positive CRC and other EGFR dependent cancers. Clinical trial information: NCT01520389.
Aflibercept in combination with FOLFIRI for the second-line treatment of patients with metastatic colorectal cancer: First interim safety data from AFEQT trial.
Authors: Ben Abdelghani Meher , Borg Christophe , Dourthe Louis-Marie , Deplanque Gael , Taïeb Julien , Metges Jean-Philippe , Laplaige Philippe , Lotz Veronique , Amrate Amele , Lledo Gérard
Published: February 2017

661

Background: In the randomized phase 3 VELOUR trial, aflibercept + FOLFIRI demonstrated a statistically significant overall survival benefit compared with FOLFIRI alone in metastatic colorectal cancer (mCRC) patients (pts) previously treated with an oxaliplatin-based regimen. Evidence from the VELOUR trial supported the initiation of a French clinical trial; AFEQT [NCT01670721] to capture utility values from QoL instruments and collect safety data from a target population similar to that in VELOUR. Interim data collected by French investigators are reported. Methods: AFEQT is single-arm, open-label trial evaluating safety and health-related QoL of aflibercept in mCRC pts previously treated with an oxaliplatin-based regimen. Estimated total enrollment is 200 mCRC pts. Eligible pts received aflibercept (4 mg/kg) q2wks on day 1 of each cycle followed by FOLFIRI up to disease progression, unacceptable toxicity, death, or investigator/patient decision, whichever occurred first. FOLFIRI starting dose and subsequent additional dose modifications were at the discretion of the treating physician. Safety assessments followed each cycle and continued until 30 days after last drug administration. The percentage of pts with grade 3/4 adverse events (G3/4 AEs) in the safety population of AFEQT was compared with that of VELOUR. Results: At data cut-off, the safety population comprised 123 pts with at least 1 completed cycle of treatment. Median age of pts was 64.6 vs. 61 years in VELOUR. At least 1 G3/4 AE was experienced by 67.5% of pts vs. 83.5% in VELOUR. Most reported G3/4 AEs were G3. There were no reports of G4 hypertension or diarrhea. Additional data will be reported during the meeting. Conclusions: In VELOUR, AEs occurred early in treatment, were often of single occurrence, generally reversible, and consistent with AEs commonly seen by oncologists. Interim safety analysis from AFEQT did not identify any new safety signal. Clinical trial information: NCT01670721. [Table: see text]
Association of modern era adjuvant chemotherapy with improved survival in patients with stage II colon cancer.
Authors: Casadaban Leigh , Villenes Dana , Rauscher Garth , Aklilu Mebea , Maker Ajay V.
Published: February 2017

671

Background: Patients are often selected for adjuvant therapy after resection of stage II colon cancer based on the presence of poor risk factors. However, the survival advantage of chemotherapy in this population is unclear and there remains variation in clinical practice. Methods: The National Cancer Data Base was analyzed for colon cancer patients treated 1998-2006. The primary outcome was OS between patients who did or did not receive adjuvant chemotherapy. Additional stratification variables included high-risk disease features, age, multi-agent chemotherapy, and diagnosis after 2004 when oxaliplatin was approved for adjuvant therapy. Demographic and disease information was compared using the Pearson Chi-squared test and binary logistic regression, effect size with Cramer's V/Phi for categorical variables, and survival data with Cox regression. Propensity score weighting was utilized to account for the possibility of selection bias. Results: Of 1,078,091 patients with colorectal cancer, 153,110 stage II colon cancer patients met inclusion criteria. Mean age was 72, 46% were male, 84% stage IIA (AJCC 6thed.), 9% stage IIB, and 20% received adjuvant chemotherapy. Predictors of receiving treatment included age<65, male gender, community treatment facility, geographical location, non-Medicare insurance, education level, and diagnosis before 2004. All patient sub-groups analyzed experienced improved OS with adjuvant chemotherapy regardless of the number of high-risk features, age, multi-agent chemotherapy, or adjustment for covariates. Median OS was 13.2 years in the chemotherapy group and 7.0 years in the no-chemotherapy group (p< 0.001). Median and 5-year OS was improved in both high and low-risk patients who received chemotherapy compared to those who did not with a median follow-up >5 years. Conclusions: This large-scale study with long-term follow-up demonstrated that adjuvant chemotherapy was associated with a clinically relevant improvement in OS regardless of treatment regimen, patient age, or high-risk features in patients with resected stage II colon cancer. The results of this retrospective analysis warrant further investigation in prospective trials.
Adjuvant treatment for resected rectal cancer: Effect of postoperative oxaliplatin added to 5-FU in the neoadjuvant era.
Authors: Garlipp Benjamin , Stuebs Patrick , Lippert Hans , Ridwelski Karsten , Ptok Henry , Gastinger Ingo , Otto Ronny , Bruns Christiane J.
Published: February 2017

672

Background: Oxaliplatin (Ox) added to postoperative 5-fluorouracil (5FU) based adjuvant treatment has shown a survival benefit in colon cancer. For rectal cancer, the impact of Ox on survival has almost exclusively been tested in studies using 5FU +/- Ox both as a component of preoperative chemoradiotherapy (CRT) and as adjuvant treatment. Only one study (NCT00807911) investigated adjuvant 5FU +/- Ox in patients undergoing preop 5FU based CRT without Ox. Thus, the evidence for the benefit of adding Ox to adjuvant 5FU in patients treated with preop 5FU based CRT is limited. Methods: Data from the prospective German multicenter Quality Assurance in Rectal Cancer observational trial involving more than 300 hospitals of all levels of care throughout Germany were retrospectively analyzed. Patients undergoing R0 total mesorectal excision (TME) for rectal cancer following neoadjuvant 5FU based treatment without oxaliplatin between 01/01/2008 and 12/31/2010 were included. Disease-free survival (DFS) in patients receiving adjuvant treatment with or without Ox was compared using the Kaplan Meier method. The impact of adjuvant treatment with 5FU with or without Ox on DFS was investigated in a Cox regression analysis including open vs. laparoscopic approach, pT stage, pN stage, tumor grading, TME quality grade, and presence of anastomotic leakage as potential confounding factors. Results: The entire data set included 1,861 patients. Data for all variables investigated were available for 599 patients of whom 512 (85%) and 89 (15%) received 5FU based adjuvant treatment without and with Ox, respectively. Mean DFS was not different in patients receiving 5FU only vs. 5FU with Ox (p=0.103). Cox regression analysis revealed no significant impact of adding Ox to adjuvant 5FU on DFS. Of all factors analyzed, only pN2 (vs. pN0) status had an independent adverse effect on DFS (Hazard ratio 4.22, p<0.001). Conclusions: These data indicate that adjuvant Ox added to 5FU does not provide a DFS benefit in rectal cancer patients treated with preoperative 5FU based CRT under routine care conditions. Rectal cancer patients may be different from patients with colon cancer with respect to benefit from adjuvant Ox.
A cost model of capecitabine versus continuous infusional 5-fluorouracil (CI5FU) as chemosensitization during long course radiotherapy in the neoadjuvant treatment of rectal cancer: From the perspective of the Australian health care system.
Authors: Paterson Robin John , Randall Kelly , Day Fiona
Published: February 2017

688

Background: Recent phase III clinical trials have shown that the use of capecitabine with long course radiotherapy in the neoadjuvant treatment of rectal cancer provides equivalent outcomes to the traditionally used CI5FU. In the Australian health system the dispensed price of capecitabine is higher; however CI5FU administration requires a peripherally inserted central catheter (PICC). This analysis was designed to test the comparative cost of capecitabine over CI5FU from the perspective of the Australian healthcare system. Methods: We determined fully itemised direct treatment costs for the administration of neoadjuvant long course chemoradiotherapy with each of capecitabine and CI5FU. A decision analytic model was then used to compare potential clinical adverse events with the respective agents. Clinical probabilities were derived from published studies and the management of adverse events costed using Australian refined diagnosis-related group (AR-DRG) coding. The results of the decision analytic model were integrated with the drug administration costs to produce an inclusive discriminating cost for capecitabine versus CI5FU. Results: The total cost to the Australian healthcare system for the administration of CI5FU was $2,110 per patient, compared with $1,170 for capecitabine. The costs of managing treatment complications were similar: mean $174 per patient for CI5FU and $72 for capecitabine. The integrated discriminating cost difference was a mean saving of $1,042 per patient with prescription of capecitabine. The presented base-case model utilised higher capecitabine costs where input data could vary, and hence in all sensitivity analyses capecitabine continued to demonstrate cost savings (minimum $286 and maximum $1,975 per patient) over CI5FU. Conclusions: Capecitabine is a cost effective alternative to CI5FU. Considering also the expected lower indirect costs with oral therapy, use of capecitabine in chemoradiotherapy for rectal cancer is economically superior.
Differences of mutation of helicobacter pylori cagA gene isolated from duodenal ulcer and gastric cancer.
Authors: Kim Sung Soo , Cheung Dae Young , Park Soo-Heon
Published: February 2017

69

Background: H. pylori is the pathogen of both duodenal ulcer and gastric carcinoma. However, they are markedly different in terms of its physiologic and pathologic basis. CagA is 120-145-kDa protein of H. pylori and located one end of Cag PAI encoding components of type IV secretion system. H. pylori expressing CagA are associated with development of atrophic gastritis, peptic ulcer, and gastric carcinoma. This study was aimed to examine the differences of cagA mutations of H. pylori isolated from duodenal ulcer and gastric carcinoma. Methods: Isolated H. pylori from 29 patients with gastric carcinoma and 31 patients with duodenal ulcer were compared the frequency of mutations after cloning of cagA of H. pylori. Results: Even there were diverse mutations scattered on whole sequence of cagA, mutations were more frequent in amino acid sequence 200-400 and 850-1100. Amino acid loci G311, D371, M393, T899, and S1068 were mutated in more than half of patients regardless of diseases. The mutations of CagA in C-terminal area, especially Q889, T899, R952, A968, R997, K1034, Q1067, and S1068, were 20% or more frequent in H. pylorifrom duodenal ulcer than those from gastric carcinoma. EPIYA type was not different between the duodenal ulcer and gastric carcinoma. Conclusions: These results suggest that the mutations of cagA of H. pylori, especially in C-terminus are distinguishable between duodenal ulcer and gastric carcinoma.
Trends in the design and interpretation of metastatic colorectal cancer phase III clinical trials.
Authors: Parimi Sunil , Raissouni Soundouss , Lin Yongtao , Monzon Jose Gerard , Tang Patricia A. , Tam Vincent Channing
Published: February 2017

692

Background: Increasing use of subsequent lines of therapy and crossover in phase III randomized clinical trials (P3 RCTs) has shifted how we perceive the effectiveness of treatments for metastatic colorectal cancer (mCRC). This study aims to characterize the evolution of P3 RCTs in mCRC with respect to clinical trial design and result interpretation. Methods: Abstracts of P3 RCTs of systemic therapy for mCRC conducted between 1980 and 2014 were identified by searching PubMed, Medline, and ASCO abstracts. Data regarding trial design, agent(s) investigated, primary endpoint, secondary endpoint(s), primary endpoint significance and interpretation of the study results (conclusions) were extracted. Results: A total of 422 trials were identified by the search strategy, and 132 eligible trials were included. Over time the sample size of P3 RCTs in mCRC has been increasing and there has been a steady increase in trials studying targeted therapy (see table below for detailed results by decade). A trend towards a smaller percentage of P3 RCTs sponsored by co-operative groups has been observed in recent decades. The most common primary endpoint was overall survival (OS) which was used in 35% of the trials. A decreasing trend in the use of OS was observed since the 1990s. Other common primary endpoints include: progression-free survival (PFS) in 28% and response rate (RR) in 20% of the P3 RCTs. The primary endpoint was met in 45% of the trials. There was discordance between the primary endpoint significance and the authors’ conclusions in 14% of the trials. Conclusions: The design and interpretation of P3 RCTs for mCRC has changed over time from 1980 to present. The use of OS as the primary endpoint is decreasing, while the use of PFS is increasing. [Table: see text]
Exploratory RAS analysis of the phase Ib/II 20060447 trial of rilotumumab (R) or ganitumab (G) plus panitumumab (pmab) versus pmab alone in patients (pts) with previously treated metastatic colorectal cancer (mCRC).
Authors: Eng Cathy , Van Cutsem Eric , Nowara Elzbieta , Swieboda-Sadlej Anna , Tebbutt Niall C. , Mitchell Edith P. , Davidenko Irina , Lee Oliver , Oliner Kelly Smith , Schupp Marco , Loh Elwyn , Sidhu Roger , Tabernero Josep
Published: February 2017

694

Background: Pmab, R, and G are fully human monoclonal antibodies that target EGFR, HGF, and IGF-1R, respectively. In part 2 of this 3-part study in previously treated pts with wild-type (WT) KRAS mCRC, pmab+R met the pre-specified criterion for improvement in objective response rate (ORR) whereas pmab+G did not. We report an exploratory analysis of the treatment effect of pmab, R, and G in pts with activating RAS mutations beyond KRAS exon 2. Methods: Part 2 was a phase II, randomized, double-blinded trial of pmab+R or pmab+G vs. pmab+placebo, administered Q2W until disease progression or intolerance. The primary endpoint was ORR. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Mutations in KRAS exon 3 (codons 59/61) and exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), and exon 4 (codons 117/146); and BRAF exon 15 (codon 600) were detected by bidirectional Sanger sequencing. Results: Of 142 pts randomized, 92 (65%) were evaluable for RAS. Of 92 evaluable pts, 79 (86%) were WT RAS (WT in KRAS and NRAS exons 2, 3, and 4) and 13 (14%) had RAS mutations beyond KRAS exon 2 (mutant in any KRAS exon 3 or 4 or NRAS exon 2, 3, or 4). None of the pts with RAS mutations had an objective response (Table). Of 93 pts evaluable for BRAF, 7 (8%) had V600E mutations (all 7 were WT RAS). Two pts with BRAF V600E tumors had a partial response and were in the pmab+R arm (n=3). No new safety signals were identified. Conclusions: In this small, retrospective study, ORR, PFS and OS were similar between the arms of R or G plus pmab vs pmab alone in pts with WT RAS mCRC tumors. Our findings indicate that RAS mutations beyond KRAS exon 2 impact ORR, PFS, and OS. Clinical trial information: NCT00788957. [Table: see text]
Impact of perineural and lymphovascular invasion on oncological outcomes in rectal cancer treated with neoadjuvant chemoradiotherapy and surgery.
Authors: Cienfuegos Javier A. , Rotellar Fernando , Baixauli Jorge , Beorlegui Carmen , Sola Iosu , Arbea Leire , Pastor Carlos , Arredondo Jorge , Hernandez-Lizoain Jose Luis
Published: February 2017

695

Background: The prognostic significance of perineural and/or lymphovascular invasion (PLVI) and its relationship with tumor regression grade (TRG) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT) and surgery. Methods: A total of 324 patients with LARC treated with CRT were operated on between January 1992 and June 2007. Tumors were graded using a quantitative 5-grade TRG classification, and the presence of PLVI was studied histologically. Results: At a median follow-up of 79.0 months (range 3–250 months), a total of 80 patients (24.7%) relapsed. The observed 5- and 10-year overall survival (OS) was 83.2% and 74.9% respectively. The 5- and 10-year disease-free survival (DFS) was 75.1% and 71.4%, respectively. A significant correlation was found between the TRG and survival (log rank, p<0.001). The 10-year OS and DFS was 32.7% and 31.8% for grade 1; 63.8% and 58.6% for grade 2; 75.0% and 70.4% for grade 3; 90.4% and 88.4% for grade 3+, and 96.0% and 97.1% for grade 4. In patients with PLVI, the TRG had no impact on survival. When excluding patients with PLVI, TRG was an independent prognostic factor for OS and DFS. Conclusions: The presence of PLVI is a more powerful prognostic factor than TRG in LARC patients treated with neoadjuvant CRT followed by surgery. PLVI denotes an aggressive phenotype, suggesting that these patients may benefit from adjuvant systemic therapy.
The association of baseline anxiety and depression with overall survival (OS) in colorectal cancer (CRC).
Authors: Cheung Pierre Y. , Liu Tian Yang Darren , Kim Jason D. , Cheung Winson Y.
Published: February 2017

706

Background: Patient-reported measures such as psychosocial wellbeing and quality of life have been reported to correlate with cancer survival, but the specific factors within these constructs that associate with outcomes remains poorly defined. Our aim was to examine the effect of baseline anxiety and depression on OS in a population-based cohort of CRC patients. Methods: Patients diagnosed with CRC in 2008, referred to any 1 of 5 regional cancer centers in British Columbia, and who completed a baseline questionnaire to evaluate anxiety and depression were reviewed. We developed a scoring system based on these patient-reported survey data to characterize intensity and subsequently categorized patients as having no, mild, moderate or severe anxiety and/or depression. Vital statistics were captured by medical records. Unadjusted Kaplan-Meier methods and multivariate Cox regression models that controlled for additional socio-demographic and clinical characteristics were constructed to correlate anxiety and depression with OS. Results: A total of 449 patients were included: median age was 66 years (range 26-92), 52% were men, and 69% were white. A significant proportion of respondents reported anxiety (58%) or depression (45%) at baseline. Among them, the majority indicated their anxiety and depressive symptoms were severe (43% and 43%, respectively). Women and those who were single or unmarried were more likely to have anxiety and depression (p<0.001 and p=0.02, respectively). In unadjusted analyses, we observed a trend where increased severity of anxiety (p=0.07) and depression (p=0.04) correlated with worse outcomes. In Cox regression that considered other prognostic factors, however, this observation failed to persist, and neither anxiety nor depression associated with OS (Table). Conclusions: The impact of psychosocial wellbeing and quality of life on CRC outcomes that have been previously described in the literature are unlikely to be mediated through baseline anxiety or depression. [Table: see text]
Identifying variables that predict poor tumor biology and suboptimal outcomes in patients treated with cytoreduction and HIPEC.
Authors: Singla Smit , Francescutti Valerie , Kane John Michael , Skitzki Joseph J.
Published: February 2017

709

Background: Cytoreduction with HIPEC has improved survival in select group of patients with peritoneal carcinomatosis. Despite rigorous selection criteria, some patients invariably perform worse than others and are presumed to conceal poor tumor biology. Methods: A single institution analysis of all patients presenting with peritoneal carcinomatosis between 2003 and 2014. All patients who underwent CRS with HIPEC were included in the analyses. Clinical variables deemed high risk for poor outcome were categorized as ‘poor tumor biology’ and analyzed using the multivariate association for survival outcomes. Results: Based on pre-defined criteria, 160 patients (M: 68, F: 92; median age, 53 years) were identified and included in this study. The most common site of tumor origin was appendix (n=73, 45.6%), and the most common histology subtype was adenocarcinoma (n=91, 56.9%). Patients presenting with ascites (n=39, 24.3%, p<0.001) and perforation (n=18, 11.2%, p=0.036) performed poorly, while age (young versus old), gender and the timing of surgery from diagnosis did not affect survival outcomes (p>0.05). Patients who received pre-operative chemotherapy (n=77, 48%, p=0.007), complete cytoreduction (n=115, 71.9%, p=0.02) and fewer number of gastrointestinal anastomoses (=<1, p=0.005) during surgery performed better; however, patients who developed intra-abdominal abscess, anastomotic leak, fistula and bowel obstruction in the immediate peri-operative period (n=30, 18.8%, p<0.001) saw significant decline in survival outcome. The median overall survival and progression free survival in our patient cohort were 68.0 months (CI, 46.8-NR) and 19.3 months (CI, 14.7-37.4), respectively; but patients with colorectal adenocarcinoma, ascites, perforation and bowel complications performed poorly and were assumed to harbor poor biology. Conclusions: A thorough understanding of the presenting symptoms and peri-operative clinical variables can identify patients with poor tumor biology. These patients are unlikely to have significant improvement in outcome, and cytoreduction with HIPEC can be considered palliative in these patients.
Effect of TP53 mutation status on survival in the MAGIC trial.
Authors: Smyth Elizabeth Catherine , Hulkki Wilson Sanna , Nankivell Matthew Guy , Gonzalez de Castro David , Wotherspoon Andrew , Okines Alicia Frances Clare , Langley Ruth E , Stenning Sally Patricia , Cunningham David
Published: February 2017

71

Background: In oesophagogastric cancer TP53 mutation may be prognostic and/or predict for chemoresistance, however available data are conflicting. We hypothesised that TP53 status would impact on survival for patients (pts) randomised to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. Methods: Genomic DNA FFPE tissue sections were extracted with QIAmp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). Mutations in exons 4-9 were screened for by fluorescent PCR -amplification of genomic DNA, followed by Capillary Electrophoresis-Single Strand Conformational Analysis (CE-SSCA). Mutations were characterised by bi -directional Sanger sequencing analysis performed on an independent PCR -reaction and the sequencing results were compared to the reference sequences in the COSMIC database. TP53 status was correlated with demographics and survival. Results: TP53 results were available on 154 pts (50% of pts with available DNA). The remainder failed CE-SSCA due to degraded DNA. Pts with/without TP53 data had similar demographics and survival. TP53 mutation was detected in 51/154 (33%) samples. Exon 4, 5, 6, 7 and 8 mutations occurred in 4%, 42%, 8%, 36% and 10% of specimens with a TP53 result. Pts with TP53 mutations were more likely to have an oesophageal or junctional tumor (vs. gastric) than TP53 wild type (WT) pts (38% vs. 17% respectively p = 0.016). Survival from surgery was comparable for pts with mutant and WT TP53 tumors in both arms of the trial (See Table). P-value for interaction between treatment group and TP53 status was 0.776, indicating no interaction was present. Conclusions: In the MAGIC trial, TP53 mutation status was not prognostic, and did not predict for lack of benefit from chemotherapy. Further study is required in order to evaluate the effect of differing TP53 mutations on treatment and survival. [Table: see text]
A clinical parameters-based predictive model to predict early efficacy for rectal cancer patients with neoadjuvant chemotherapy alone: Subgroup efficacy analysis of a phase II study.
Authors: Zhang Jianwei , Cai Yue , Hu Huabin , Lan Ping , Wang Jianping , Huang Meijin , Kang Liang , Deng Yanhong
Published: February 2017

716

Background: To avoid the damage of radiotherapy for a part of patients, we have an ongoing phase II study comparing Neoadjuvant FOLFOX6 chemotherapy with or without radiation in Rectal Cancer. To define the population who could obtain benefit from neoadjuvant chemotherapy alone, we aimed to develop a model in which clinical parameters are used to predict early efficacy of neoadjuvant chemotherapy for rectal cancer, including tumor regression grade (TRG) and ypTNM down-staging. Methods: Until now, 116 patients were enrolled into FOLFOX6 chemotherapy alone group. All the clinical parameters were collected, including gender, age, tumor location and size by MRI imaging, blood routine test, blood biochemistry and serum tumor markers, TRG and ypTNM staging. 96 patients were used to be training set and another 20 patients was the validation set. Binary logistic regression was used to analyze the effect of all clinical factors on TRG and ypTNM stage. Clinical variables were incorporated into the Cox models for multivariate analysis. Results: Among the 116 patients, 9 patients had TRG 0 (complete regression), 26 patients with TRG 1 and 81 patients with TRG 2 to 3 (poor regression). 47 (40.5%) patients had good down-staging with ypTNM stage 0 and stage I. The optimal multivariable predictive model for TRG (0-1 vs. 2-3) was a four-variable model consisting of age, ApoA1, tumor length and tumor encircle size (AUC=0.732, 95% CI, 0.614–0.849). The model for ypTNM (stage 0-I vs. II-III) was also the four parameters (AUC=0.725, 95% CI, 0.615–0.835). Patients with younger age, shorter tumor length, smaller encircle size and higher ApoA1 had better outcome with chemotherapy. Applying the four clinical parameters model to the validation cohort, a good performance (AUC=0.792, 95% CI, 50.54–0.95) was obtained. Conclusions: With this predictive model, the patients who might obtain good efficacy from neoadjuvant FOLFOX6 chemotherapy could avoid radiotherapy damage. And better suggestion would be provided for patients who might be high risk with chemotherapy alone.
Clinical significance of cellular and acellular mucin pools in rectal carcinoma following preoperative chemoradiotherapy.
Authors: Cienfuegos Javier A. , Rotellar Fernando , Baixauli Jorge , Sola Iosu , Arredondo Jorge , Pastor Carlos , Hernandez-Lizoain Jose Luis
Published: February 2017

718

Background: Currently, the standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) followed by surgery. Pathological findings in post-treated specimens remain the most significant prognostic factor. The presence of mucin pools and their prognostic significance is a controversial issue. Methods: The aim of this study was to analyze the incidence of cellular and acellular mucin pools and their clinical significance in 446 consecutive prospectively collected specimens from patients with stages II/III treated with preoperative CRT and surgery. Results: Mucin pools were present in 182 specimens (40.8%); 66 (14.7%) were acellular, and viable tumor cells were identified in 116 (26.0%). If acellular mucin is considered as a type of response and not residual tumor, the complete pathological response rate was 12.8% (57 of 446). With a median follow-up of 79.0 months, the 5- and 10-year disease-free survivals for patients with acellular and cellular mucin pools, were 81.8% and 63.4%, respectively (p < 0.0225). The presence of cells in the colloid response to treatment was associated with a 2.5-fold increase in the possibility of dying of rectal cancer (HR = 2.5 [1.1 − 5.76], p= 0.028 univariant Cox regression analysis). Conclusions: Thus, our results suggest that cellular mucin pools are an indicator of an aggressive phenotype and harbingers of a worse prognosis.
DEBIRI and capecitabine in refractory prevalently liver metastases of colorectal cancer: A phase II study.
Authors: Marsico Valentina Angela , Orlandi Armando , Cerchiaro Eleonora , Iezzi Roberto , Di Noia Vincenzo , Mannavola Francesco , Calegari Maria Alessandra , Corallo Salvatore , Cassano Alessandra , Barone Carlo
Published: February 2017

724

Background: Treatment options for metastatic colorectal cancer (mCRC) patients refractory to chemotherapy are limited and clinical outcome is poor. In mCRC patients with liver-dominant disease hepatic locoregional therapy might be a treatment option. In this pilot study we evaluated the safety, tolerance, and efficacy of drug-eluting beads irinotecan (DEBIRI) in combination with capecitabine in the treatment of patients with mCRC with predominally liver disease. Methods: Twenty patients affected by liver metastasis of colorectal cancer were included in this study. All patients had progression of disease after two or more lines of chemotherapy and liver was the major or the predominant site of disease. DEBIRI, beads loaded with 100 mg irinotecan, was administered biweekly via hepatic artery. All patients assumed capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks, until disease progression. Primary endpoints were safety, tolerance and overall responce rate (ORR); secondary endpoints were progression free servival (PFS) and overall survival (OS). Results: Twenty patients underwent a total of 54 DEBIRI treatments of the 66 planned; the median number was 3 (range 2-4) administrated for patients. Grade 1-2 toxic effects included fatigue (70%), diarrhea (45 %), anemia (45%), elevated liver enzymes (45%), nausea (40%), neutropenia (35%) and thrombocytopenia (25%). One grade 3 diarrhea and a case of acute vasospastic angina were observed and required patient hospitalization, but no deaths at 30 days post occurred. Two partial responses were reported (10%) with ORR of 60%. PFS and OS were 4 and 7, 3 months respectively. Univariate analysis showed that patients with KRAS wild-type, good ECOG performance status and single lobe metastases have a better prognosis. Multivariate analysis confirmed that only the good clinical conditions represent an important positive prognostic factor (p=0.03). Conclusions: DEBIRI with capecitabine seem to be a safe, technically feasible and well-tolerated treatment in chemotherapy refractory mCRC with prevalently liver metastases. It has a moderate but not negligible activity in this heavily treated group of patients and deserves further studies in a larger series.
A validation study of preventing oxaliplatin-induced hypersensitivity reactions by dexamethasone: The AVOID trial.
Authors: Hirata Keiji , Yoshida Yoichiro , Matsuoka HIroshi , Iwamoto Shigeyoshi , Kotaka Masahito , Fujita Hideto , Aisu Naoya , Hoshino Seiichiro , Kosaka Takeo , Maeda Kotaro , Yamashita Yuichi
Published: February 2017

727

Background: Patients treated with oxaliplatin are at risk for hypersensitivity reactions. The incidence of hypersensitivity reactions in clinical practice is estimated to be 12% to 20%. Prescribing information says that oxaliplatin is incompatible in solution with alkaline medications or media and must not be mixed these or administered simultaneously through the same infusion line. Because steroid is alkaline, the coinfusion of steroids and oxaliplatin can make oxaliplatin unstable due to the elevation of pH; further, the effectiveness of steroid in this therapy is unknown. Therefore, dexamethasone is routinely given to patients before they receive chemotherapy. However, we have reported that the pH after the addition of DEX (6.6 mg) to oxaliplatin was less than 7.4, and there is possibility that hypersensitivity reactions to oxaliplatin could have been prevented by coinfusion of dexamethasone (DEX) (Yoshida et al.2012 ASCO-GI) but just in a retrospective study. This prospective study was undertaken to evaluate the effectiveness of coinfusion of DEX to oxaliplatin for controlling hypersensitivity reactions caused by oxaliplatin. Methods: The AVOID trial is a prospective, multicenter, open-label, single-arm, phase II trial investigating hypersensitivity reactions to oxaliplatin could have been prevented by coinfusion of DEX. The study included 73 patients who received XELOX or XELOX +bevacizumab therapy for colorectal cancer. In all the patients, oxaliplatin (130mg/m²) was administered in combination with DEX (6.6 mg). Results: Hypersensitivity reactions developed in 3 patients (4.1%). Respiratory symptoms, ocular symptoms and anaphylaxis were not observed in 73 patients. The three patients experienced cutaneous reaction (erythema: grade1). Grade 3 or higher hemotoxicity was noted in 13.7% of the patients, and grade 3 or higher nonhematological toxicity was noted in 13.7%. The response rate was 58.1%. Conclusions: This trial supports coinfusion of dexamethasone and oxaliplatin reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive oxaliplatin, allowing treatment to be completed as planned. Clinical trial information: UMIN000009742.
A multi-institutional feasibility study of S-1/oxaliplatin (SOX) plus bevacizumab in patients with advanced/metastatic colorectal cancer: HiSCO-02 prospective phase II study.
Authors: Kurayoshi Manabu , Shinozaki Katsunori , Hinoi Takao , Kobayashi Tsuyoshi , Shimomura Manabu , Yoshimitsu Masanori , Toyota Kazuhiro , Nakahara Masahiro , Ishizaki Yasuyo , Hirata Yuzo , Kodama Shinya , Shimizu Yosuke , Kawaguchi Koji , Tokunaga Masakazu , Sumitani Daisuke , Ohdan Hideki
Published: February 2017

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Background: mFOLFOX6 regimen, which is a standard regimen for metastatic colorectal cancer (CRC), is inconvenient owing to its requirement for continuous infusion via vascular access. We aimed to investigate the efficacy and safety of S-1/oxaliplatin (SOX) plus bevacizumab, a promising alternative treatment to replace mFOLFOX6. Methods: We undertook a clinical phase II trial in 12 institutions in Hiroshima, Japan. We enrolled individuals aged 20–80 years who had metastatic CRC, had an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1, had assessable lesions, and had received no previous chemotherapy. Eligible patients were assigned SOX plus bevacizumab (S-1: 80-120 mg/body/day, day 1–14 orally administrated, oxaliplatin: 130mg/m2 day 1 i.v., bevacizumab: 7.5mg/kg day 1 i.v. q3w). The primary endpoint was response rate (RR), and the secondary end points were progression-free survival (PFS), overall survival (OS), and safety. Results: From May 2011 to January 2014, 55 patients (mean age, 64 years) were enrolled. The number of metastatic organs were one: 29 cases (52.7%), two or more: 25 cases (45.4%), and 2 cases had no target lesions (3.6%). Median follow up time was 12.8 months (range, 1.4-38.6 months). RR was 45.4% (95% CI, 32.2%-58.6%) and disease control rate was 87.3% (95% CI, 78.5-96.1%). Median PFS and OS time were 9.2 months (95% CI, 7.6-10.8) and 22.0 months (95% CI, 17.7-26.2), respectively. The median number of cycles of chemotherapy was 7 (range, 1-16). The median relative dose intensity of oxaliplatin, S-1, and bevacizumab were 85%, 85%, and 87%, respectively. Major toxic effects (grade 3/4) were thrombocytopenia (5.7%), neutropenia (7.5%), sensory neuropathy (13.2%), and anorexia (17.0%). Conclusions: These data indicated that the SOX plus bevacizumab regimen is effective and well tolerated in patients with metastatic CRC. Clinical trial information: UMIN000004976.
Angiopoietin-like protein 2 as a novel biomarker for diagnosis and prognosis in esophageal cancer.
Authors: Ide Shozo , Toiyama Yuji , Shimura Tadanobu , Mori Koichiro , Noguchi Tomofumi , Imaoka Hiroki , Okigami Masato , Yasuda Hiromi , Kitajima Takahito , Saigusa Susumu , Ohi Masaki , Tanaka Koji , Araki Toshimitsu , Inoue Yasuhiro , Mohri Yasuhiko , Kusunoki Masato
Published: February 2017

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Background: Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein with homology to the angiopoietins and overexpression of ANGPTL2 is known to act as a causative mediator of chronic inflammatory carcinogenesis. Recently, expression in tumor cells which are associated with tumor progression has been recognized in lung, breast, colon and gastric cancer. However, to our knowledge, functional and clinical significance of ANGPTL2 expression has not been investigated in esophageal cancer (EC). Aim: We investigated the functional roles of ANGPTL2 in vitro assay and evaluated the clinical significance of ANGPTL2 expression in both primary tumor and matched serum in patients with EC. Materials and Methods: First, in vitro assays were performed for functional analysis of ANGPTL2 using small interfering RNA (siRNA). Next, ANGPTL2 expression in EC tissues was evaluated by immunohistochemically (IHC) in 71 EC patients. Finally, we investigated serum ANGPLT2 levels from EC patients (n=71) and healthy controls (n=35) by ELISA. Results: Knockdown of ANGPTL2 expression decreased proliferative, invasive and migrated capacity in EC cell lines. ANGPTL2 expression in EC tissues was significantly elevated in EC patients with high T stage, squamous cell carcinoma, and high TNM stage. Kaplan–Meier analysis showed that patients with high expression of ANGPTL2 had significantly poorer overall (p<0.01) and disease-free survival (p<0.01) than those with low expression, respectively. Furthermore, multivariate analysis revealed that high ANGPTL2 expression in EC tissues was an independent predictive marker for poor prognosis (HR: 2.30, p=0.04). On the other hands, serum ANGPTL2 levels in EC patients was significantly elevated compared to healthy controls (p<0.001), and it can discriminate EC patients from healthy controls with high accuracy (AUC=0.913). However, no significant association between serum ANGPTL2 levels and clinicopathological findings were recognized in EC patients. Conclusions: We have demonstrated several novel evidences for biological and clinical significance of ANGPTL2 in EC. This study indicates ANGPTL2 had the potential to be useful as a biomarker in EC.
Factors associated with receipt of radiation therapy for rectal cancer.
Authors: Sussman Daniel A. , McClure Laura A. , Hernandez Monique N. , Tannenbaum Stacey L. , Bonner Judith M. , Zheng D. Diane , Lee David J.
Published: February 2017

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Background: Appropriate treatment for rectal cancer is vital to increasing the likelihood of survival. Disparities in receipt of appropriate radiation treatment have been observed with respect to race/ethnicity and socioeconomic status. We used enriched cancer registry data to identify alternative factors associated with receipt of appropriate radiation therapy for rectal cancer. Methods: Data were obtained from the Florida Cancer Data System and were enriched with detailed treatment information collected from a Centers for Disease Control and Prevention Comparative Effectiveness Research study. Using multivariable regression, we evaluated factors associated with receipt of radiation therapy among rectal cancer cases summary stage II/III. Our sample (n=403) included cases diagnosed in Florida in 2011 who were 18 years and older. Cases clinically staged as 0/1/4 were excluded. Though patients over age 80 years (n=67) and those with stage IIA disease (n=185) may not routinely be prescribed radiation, these cases were included in order to maximize the sample size. Results: Our sample was an average of 64 years-old, more often male (59%), NH White (56%), diagnosed with stage III disease (54%), insured (92%), had received surgical intervention (87%), chemotherapy (68%), or radiation (57%), were in the highest SES quartile (56%), and had one or more comorbid condition (57%). Older age (OR=0.96; 95%CI=0.94-0.97), the presence of more than one comorbidity (0.61; 0.39-0.96), and receipt of surgical intervention (0.44; 0.22-0.90) were predictors of not receiving radiation. Conclusions: Contrary to our hypothesis, socio-demographic factors such as race/ethnicity, insurance status, and socioeconomic status, did not influence the receipt of radiation. Further research is needed, however, to understand why age, comorbidity, and surgery present a barrier to radiation, particularly given that radiotherapy is a well-tolerated modality.
Association of early tumor shrinkage with progression-free survival in patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy: HGCSG0802.
Authors: Nakatsumi Hiroshi , Yuki Satoshi , Muranaka Tetsuhito , Fukushima Hiraku , Kato Takashi , Meguro Takashi , Nakamura Michio , Iwanaga Ichiro , Ehira Nobuyuki , Sonoda Norikazu , Kudo Mineo , Kato Kanji , Miyashita Kencho , Abe Masakazu , Miyamoto Noriyuki , Sakamoto Keita , Kudo Kohsuke , Sakamoto Naoya , Sakata Yuh , Komatsu Yoshito
Published: February 2017

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Background: It was reported that early tumor shrinkage (ETS) was associated with better overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) receiving cetuximab. We investigated association of ETS with progression free survival (PFS) in pts with unresectable colorectal liver metastases (CLM) from HGCSG0802 observational cohort study in pts with mCRC treated with first-line bevacizumab (BV)-based chemotherapy. Methods: The objective of HGCSG0802 was to evaluate PFS, OS, time to treatment failure (TTF), response rate (RR), safety and so on. The key eligibility criteria were evaluable lesions, older than 20 years old, ECOG PS 0-2. In this analysis, association of ETS at 8 weeks from the start of chemotherapy with pts characteristics, PFS and TTF was evaluated. Pts characteristics were compared using Student-t test, chi-square test and Fisher’s exact test. PFS and TTF were analyzed with Kaplan-Meier method and compared using log-rank test. Univariate analysis for the association of pts characteristics with PFS and TTF was performed using log-rank test, and multivariate analysis was performed using Cox proportional hazards model. Results: Of 108 pts (the full analysis set), 74 pts with CLM were evaluable for ETS. Forty-nine pts (66.2%) had ETS ≥20%. The pts characteristics between ETS ≥20% and <20% were well balanced. The median PFS was 7.3 months in ETS <20% versus 10.0 months in ETS ≥20% (HR 0.55; p=0.025). In multivariate analysis for PFS, there was no significant difference between ETS ≥20% and <20% (HR 0.585; p=0.066). The median TTF (ETS <20% v ≥20%) was 5,1 months vs. 7.7 months (HR 0.46; p=0.003). In multivariate analysis for TTF, there was significant difference between ETS ≥20% and <20% (HR 0.509; p=0.017). Conclusions: In this analysis, ETS ≥20% might be positive predictive marker for PFS and TTF in pts with CLM receiving first-line BV-based chemotherapy.
Intratumor heterogeneity of DNA copy number aberrations in gastric and oesophageal adenocarcinomas.
Authors: Davies Matthew N , Alpar Donat , Griffiths Beatrice , Barber Louise J , Lipinski Kamil A , Eltahir Zakaria , Agoston Emese , Harsanyi Laszlo , Wotherspoon Andrew , Szasz A Marcell , Gerlinger Marco
Published: February 2017

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Background: DNA copy number aberrations (CNAs) are common in oesophageal and gastric adenocarcinomas (OGCs) and display extensive inter-tumour heterogeneity. CNA patterns define gastric cancer molecular subtypes and ERBB2 amplifications, present in a small fraction of patients with OGC, are predictive for ERBB2-targeted drug sensitivity. Together, this suggests a critical role of CNAs determining OGC tumour biology and clinical outcomes. Despite this, predictive and prognostic CNA biomarkers have not been identified for the majority of OGCs, precluding the development of effective personalized therapy approaches for these aggressive tumours. Intra-tumour heterogeneity, characterized by the presence of multiple subclones with distinct genetic profiles within an individual cancer, can hinder the accurate molecular analysis and classification of tumours. The aim of this pilot study was to assess whether chemotherapy-naïve localized OGCs display intra-tumour macroheterogeneity of CNA profiles. Methods: Tissue specimens from four tumour regions representing the macroscopic spatial extent of each of five OGCs were systematically collected after surgical resection. DNA extracted from these FFPE specimens was analysed by molecular inversion probe SNP arrays for high resolution CNA detection. Results: Comparison of genome wide copy number and B-allele frequency profiles suggested highly concordant CNA profiles across the regions from individual primary tumours. Eight driver CNAs leading to amplification of the MET, KRAS, ERBB2, PIK3CA or FGFR2 oncogenes were identified in 4/5 tumours. Only one out of these eight driver CNA’s, harbouring the KRAS oncogene, was heterogeneous within a tumour. Conclusions: Although chromosomal instability is thought to be common in this tumour type, this pilot study suggests that macroheterogeneity is limited and that CNA profiles assessed from a single tumour biopsy are likely to be representative of the dominant CNA profile of localized OGCs. Thus, clinical correlative CNA analyses may be possible from single biopsies of localized OGCs. Mutational heterogeneity and microheterogeneity in microdissected and single cells are currently being investigated.