bluuebunny/crossref_metadata_2025 huggingface dataset:
Final analysis of the phase 2 APEC study: Overall survival (OS) data and biomarker subanalyses for first-line FOLFOX or FOLFIRI with cetuximab (cet) once every 2 weeks in patients (pts) with KRAS or RAS (KRAS and NRAS, exons 2-4) wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Cheng Ann-Lii , Cornelio Gerardo H. , Shen Lin , Price Timothy Jay , Yang Tsai-Sheng , Chung Ik-Joo , Dai Guanghai , Lin Jen-Kou , Sharma Atul , Yeh Kun-Huei , Ma Brigette , Zaatar Adel , Guan Zhongzhen , Masood Nehal , Srimuninnimit Vichien , Yau Thomas Cheung , Beier Frank , Chatterjee Sudipto , Lim Robert S.C.
Published: February 2017

566

Background: The Asia-Pacific, multicenter, nonrandomized, phase II APEC study previously reported that first-line therapy for pts with KRAS ex 2 wt mCRC consisting of C once every 2 weeks combined with FOLFOX or FOLFIRI achieved efficacy and safety profiles comparable to those reported in analogous pivotal studies involving weekly C. This final analysis presents OS data from the KRAS wt intent-to-treat (ITT) population, as well as subgroup efficacy analyses stratified by BRAF, PIKC3A, and all RAS mutation status. Methods: Eligible pts received C once every 2 weeks (day 1 of each cycle, 500 mg/m2) with FOLFOX or FOLFIRI (investigator’s choice). Study treatment continued until disease progression, dose-limiting toxicity or consent withdrawal. The primary endpoint was best confirmed overall response as assessed by RECIST 1.0; progression-free survival (PFS) and OS were secondary endpoints. In the evaluable populations, the status of BRAF, PIK3CA, and all RAS mutations was assessed retrospectively by pyrosequencing. Results: 42 months after the last patient was enrolled, median OS in the KRAS wt population was 26.8 months (Table). There were no unexpected safety findings. Additional biomarker results—including objective response rate (ORR), PFS, and OS subgroup analyses stratified on BRAF, PIKC3A, and all RAS mutation status—will be presented. Conclusions: The observed median OS of 26.8 months in the KRAS wt population is comparable to that reported in prior pivotal studies involving weekly C plus FOLFOX or FOLFIRI in the first line. These results suggest that C plus FOLFOX or FOLFIRI in a once-every-2-weeks regimen is active and tolerable as first-line therapy in this Asia-Pacific study population and a convenient alternative to weekly administration. Clinical trial information: NCT00778830. [Table: see text]
Drug cost and outcome in metastatic colorectal cancer with emphasis on monoclonal antibodies.
Authors: Guirgis Helmy M.
Published: February 2017

567

Background: Patients with wild type KRAS metastatic colorectal cancer (mCRC), treated with first-line cetuximab (Cet) or bevacizumab (Bev) and chemotherapy demonstrated similar overall survival (OS). In the Western world, costs of anticancer drugs ranged from $59,000 to $100,000 per life-year gain (LYG). Hazard ratios (HR) have rarely been integrated in cost/outcome evaluation. Objective: Weigh drug cost against survival and hazard ratio (HR) in mCRC with emphasis on monoclonal antibodies (MABs). Methods: Estimated costs in United States dollars (US$) were calculated for 70 kg or 1.7/m2 patients. Costs were divided by the reported median OS gain over control in days (OSg) and by probability of survival (PoS) calculated as (1.0 – HR). Relative values (RV) were computed as 100,000/cost/outcome. Results: There was no significant difference in cost/outcome of Pan and Cet in first-line wild KRAS mCRC. At 12 week (w), the cost/LYG of panitumumab (Pan), Cet, and Bev were $64,947, $82,224, and $36,919 with RVs of 1.54, 1.22 and 2.71 respectively. Using HRs, the corresponding PoS were $140,082, $137,040, and $42,524 with RVs of 0.71, 0.73, and 2.35. Wild RAS testing improved the cost/outcome of Pan by 25%. Increasing number of cycles increased the cost/outcome and decreased the RVs of all MOAs. Conclusions: In first-line wild KRAS mCRC at 12 w, the cost/outcome of Bev was approximately 30% to 57% that of Pan and Cet. Cost/outcome of Pan significantly improved in RAS wild type. The cost/outcome of MABs was determined by the number of cycles.
Prognostic clinical factors in pretreated colorectal cancer patients receiving regorafenib: Implications for clinical management.
Authors: Del Prete Michela , Giampieri Riccardo , Loupakis Fotios , Prochilo Tiziana , Salvatore Lisa , Faloppi Luca , Bianconi Maristella , Bittoni Alessandro , Aprile Giuseppe , Zaniboni Alberto , Falcone Alfredo , Scartozzi Mario , Cascinu Stefano
Published: February 2017

591

Background: Most of the patients receiving regorafenib do not seem to benefit from this treatment approach and are therefore exposed to unnecessary toxicity. Angiogenesis and inflammation-related factors may have a relevant role in modulating the activity of anti-angiogenetic drugs such as regorafenib. In our study, we investigated LDH serum levels, platelet, neutrophil, and lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR) in predicting clinical outcomes for colorectal cancer patients receiving regorafenib. The final aim was to individuate an easy to use and reliable selection tool for these patients in the clinical practice. Methods: We collected LDH serum levels, neutrophil, lymphocyte, and platelet counts within one month before the start of regorafenib in 208 pretreated metastatic colorectal cancer patients. Cut-off values were calculated by ROC curve analysis. Survival analysis was performed by Kaplan-Meier method, and multivariate analysis by Cox method. Results: At multivariate analysis: high platelet count (p=0.0439), low lymphocyte count (p=0.0013), and high NLR (p=0.0237) were related to worse overall survival (OS); high neutrophil count and high NLR (p=0.0058) were related to worse progression free survival (PFS). Among 52 (25%) patients who were negative for all risk factors, a significant correlation was found with improved OS and PFS if compared with the group of patients with at least one risk factor. In particular, median OS was respectively 15.9 vs. 3.1 months (HR: 3.81, 95% CI: 2.32-4.82, p<0.0001) whereas median PFS was 5.9 vs. 2.1 months (HR: 2.62, 95% CI: 2.06-3.86, p<0.0001). Conclusions: We can speculate that colorectal cancer patients showing high neutrophil, high platelet, low lymphocyte count or high NLR may not be optimal candidates for regorafenib treatment. After confirmation in further prospective series, these clinical factors could play a role in the treatment strategy process.
K-RAS codon 13 mutation in advanced colorectal cancer: A single-center retrospective study investigating prognostic outcomes and treatment strategies.
Authors: Dadduzio Vincenzo , Basso Michele , Bensi Maria , Cona Silvia , Cerchiaro Eleonora , Strippoli Antonia , Campitiello Marco , Rossi Sabrina , Orlandi Armando , Plastino Francesca , Calegari Maria Alessandra , Cassano Alessandra , Barone Carlo , Semenova Diana
Published: February 2017

633

Background: Ras genes are markers of resistance to anti-EGFR therapies. Emerging evidences suggest that each mutation, independently from its predictive role of response/resistance to specific treatments, may be expression of different diseases with different biologic behaviours. We collected data of mCRC patients harbouring K-Ras codon 13 mutation to evaluate response to therapy, PFS and OS. Methods: We retrospectively collected data of advanced colorectal cancer patients harbouring K-Ras codon 13 mutation treated at our Institution between 2004 and 2014. Results: A total of n.33 K-Ras codon 13 mutated patients were analysed. N.24 patients (72,7%) had synchronous metastatic disease. None of the patients received anti-EGFR treatment, while n.25 patients received anti-VEGF agent bevacizumab in association to chemotherapy with fluoropirimidines plus oxaliplatin and/or irinotecan (n.21 as frontline therapy, n.4 in second line). ORR was 51,5% (17/33) on first-line therapy, 22,2% (6/27) on second-line therapy and 16,6% (2/12) on third-line therapy. Median PFS was 14,1 months after first-line therapy, 9,3 months after second-line therapy, 6,4 months after third-line therapy. Median OS was 35,5 months (events: 19/33). N.14 patients received metastases surgery with radical intent. OS in this population has not been reached yet at a median follow-up of 38 months, even though all patients had a relapse. OS among patients undergone to systemic only strategy was 31 months. Conclusions: At our knowledge, this is the first report suggesting a favourable prognosis for K-ras codon 13 mutated patients, with a median overall survival even superior to pan-RAS wild-type patients. Indeed, the high percentage of advanced patients at diagnosis (72.7%), the high responsiveness to chemotherapy even in third line, the high percentage of patients converted to surgery (42.4%) in an unselected population, together with the high risk or relapse after surgery, suggest K-ras codon 13 mutated disease is probably a biologically aggressive disease. Nevertheless our data prompt that these patients may benefit aggressive strategies of treatment and multidisciplinary evaluation.
Polymorphism of the chemokine CXCR4 to predict treatment benefit of first-line bevacizumab-based chemotherapy in patients with metastatic colorectal cancer.
Authors: Matsusaka Satoshi , Loupakis Fotios , Zhang Wu , Cao Shu , Yang Dongyun , Ning Yan , Stremitzer Stefan , Sunakawa Yu , Yamauchi Shinichi , El-khoueiry Rita , Parekh Anish , Mizunuma Nobuyuki , Lenz Heinz-Josef
Published: February 2017

635

Background: The chemokine receptor CXCR4 and its ligand CXCL12 promote angiogenesis and the migration of tumor cells into the metastatic sites in many cancers. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor. Therefore, we analyzed the association between CXCR4/CXCL12 polymorphisms and prognosis in metastatic colorectal cancer (mCRC) patients underwent bevacizumab-based chemotherapy. Methods: This study included 144 Japanese patients (pts) for evaluation set and 424 patients from two clinical trials (204 of TRIBE arm A and 220 of PROVETTA) for validation set, with mCRC treated with bevacizumab-based chemotherapy as first line. A total of 144 Japanese pts with (male/female; 81/63, median age 61 years, median follow-up 4.2 years) and 424 pts (male/female; 252/172, median age 62 years; median follow-up time; 2.8 years) were enrolled in a pharmacogenomics translational study. Genomic DNA was extracted from the pts’ blood or tissue. One CXCR4 single nucleotide polymorphisms (SNP) (rs2228014) and two CXCL12 SNPs (rs1801157, rs3740085) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with the clinical outcome. Results: In univariate analysis, CXCR4 rs2228014 showed a significant difference in PFS [(G/G 15.3 months, any A allele 13.7 months, HR (95% CI) 1.64 (1.01-2.68), p=0.036)]. After multivariate analysis, CXCR4 rs2228014 remained to be a significant for PFS [HR (95% CI) 1.67 (1.01-2.78), p =0.046]. However, this polymorphism was not associated with tumor response and survival. In the validation cohort, pts with GG genotype had significantly longer PFS compared to those with any A allele (10.5 vs 9.6 months, HR (95% CI) 1.40 (1.02-1.93), p =0.035). CXCL12 polymorphisms were not associated with the clinical outcome. Conclusions: This study shows for the first time that CXCR4 rs2228014 may serve as a predictive marker in patients with mCRC treated with bevacizumab-based chemotherapy.
Potential predictive and prognostic biomarkers identified in baseline plasma samples from the VELOUR trial.
Authors: Sims Tasha Nicholle , Gao Bo , Phillips Robert , Lowy Israel
Published: February 2017

638

Background: Biomarkers of resistance or susceptibility to vascular endothelial growth factor (VEGF) inhibition have not been validated. Ziv-aflibercept (ZALTRAP), a fusion protein that binds and neutralizes ligands of VEGFR1 and VEGFR2 (e.g., VEGFA, PLGF, and VEGFB), is approved for the treatment of metastatic colorectal cancer (mCRC) in combination with FOLFIRI in patients who have progressed after oxaliplatin therapy. We are currently analyzing plasma samples from VELOUR, the registration trial of FOLFIRI +/- ziv-aflibercept, in an effort to identify prognostic and predictive factors. Methods: VELOUR was a prospective, multicenter, multinational, randomized (1:1), double-blind, parallel-arm phase III study conducted in 1,226 patients. Retrospective analysis of circulating proteins from 553 baseline plasma samples was performed. Samples were analyzed for levels of 98 analytes using multiplex assays and ELISA. Biomarker values were dichotomized around the median value and analyzed with respect to overall survival (OS). Results: The biomarker study sub-population was similar to the overall VELOUR population. For OS, the hazard ratio (HR) was 0.809 in the plasma biomarker population vs. HR =0.817 in the overall VELOUR population. For PFS, the HR = 0.752 in the plasma biomarker population vs. HR = 0.758 in VELOUR. Patient demographics, including ECOG status, were similar between the groups. Several biomarkers were identified as potentially predictive or prognostic (or both) of OS, with a HR<0.7 (false discovery rate of 0.05 and interaction p < 0.10). No biomarker subset corresponded to worse OS with ziv-aflibercept treatment. Conclusions: Multiple potential prognostic and predictive biomarkers were identified in VELOUR and will be presented. These results are exploratory and require prospective studies for validation. Patient subsets with elevated expression of alternative angiogenic factors or increased pro-inflammatory markers may correlate with poor outcome overall, and in some cases are not improved by addition of ziv-aflibercept treatment. Further investigation of this dataset continues, including analysis of on-treatment plasma samples in a subset of patients.
Evaluation of circulating-tumor DNA (ctDNA) as a source material for molecular phenotyping of colorectal tumors.
Authors: Minarikova Petra , Benesova Lucie , Belsanova Barbora , Halkova Tereza , Cyrany Jiri , Bures Jan , Suchanek Stepan , Zavoral Miroslav , Minarik Marek
Published: February 2017

642

Background: Patients with advanced stages of colorectal cancer have elevated levels of circulating-tumor DNA (ctDNA) in peripheral blood. Its presence can facilitate acquisition of DNA material for tumor molecular profiling without the invasive procedures. In this work we present utility of ctDNA for the determination of tumor phenotype within the basic division into the mutator phenotype (microsatellite instability, MSI and chromosomal instability, CIN) or methylator phenotype (CpG island methylator phenotype, CIMP). Methods: Tumor biopsy tissue and 5mL of peripheral blood samples were prospectively collected from 148 patients with colorectal tumors. In addition, plasma was extracted from peripheral blood immediately upon collection. Samples were then transported to the molecular laboratory where DNA and ctDNA were isolated from tissue and plasma, by a modified spin-column ctDNA extraction. Somatic mutations in tumor suppressors denoting CIN phenotype were detected by denaturing capillary electrophoresis (DCE), microsatellite instability was detected by MSI Analysis System, Version 1.2 (Promega corporation, Madison, WI) and DNA methylation (CIMP phenotype) was obtained by multiplex ligation-dependent probe amplification (MRC Holland, NL). Results: The samples included 75 adenomas and 70 carcinomas. The detected rates in tissues were: 4% for MSI, 32% for CIN and 7% for CIMP in adenomas and 10% for MSI, 36% for CIN and 32% for CIMP in carcinomas. In adenomas, none of the detected molecular types could be confirmed in ctDNA. In carcinomas, the concordance between tissue and ctDNA was 25% for MSI, 23% for CIN and 60% for CIMP. The success rates were related to the ctDNA concentration yields with a minimum requirement of ~0.2ng/uL. Conclusions: ctDNA may serve as alternative source for molecular classification of colorectal tumors (MSI, CIN and CIMP). A low concordance between tissue and ctDNA was found for CIN and MSI in comparison to 60% of CIMP-phenotypes found in both tissue as well as ctDNA. The results are predominantly dictated by disease stage and the corresponding levels of ctDNA. Supported by a Czech Ministry of health grant no. 14383.
Cost-effectiveness analysis of regorafenib for metastatic colorectal cancer.
Authors: Goldstein Daniel A. , Ahmad Bilal B. , Chen Qiushi , Ayer Turgay , Howard David H. , Lipscomb Joseph , El-Rayes Bassel F. , Flowers Christopher
Published: February 2017

658

Background: Regorafenib was approved by the FDA in 2012 for the management of previously treated metastatic colorectal cancer (mCRC). It is now the standard of care in the third-line setting. Compared to placebo it improves median overall survival by 1.4 months but is associated with adverse effects and additional cost. The objective of this study was to examine the cost-effectiveness of regorafenib compared to best supportive care for patients receiving third-line treatment for mCRC. Methods: We developed a Markov model to compare the cost and effectiveness of regorafenib compared to best supportive care in the third-line treatment of mCRC based on randomized data from the CORRECT trial. Weibull models were fitted to the published overall and progression-free survival curves, and were used to extrapolate the cause-specific mortality and progression risks. Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services, and drug costs based on the Medicare average wholesale prices (all in 2014 US $). Health outcomes were measured in life years (LYs) and quality-adjusted life years (QALYs). Quality of life adjustments were calculated based on health utility values in the CORRECT trial and toxicity disutilities and durations were included for the most common toxicities: hand/foot syndrome, diarrhea, and hypertension. Model robustness was addressed by univariate and probabilistic sensitivity analyses (PSA). Results: In the model, regorafenib provided an additional 0.06 QALYs (0.12 LYs) at a cost of $40,373. The incremental cost-effectiveness ratio (ICER) was $734,153/QALY. In all one-way sensitivity analyses, the ICER of regorafenib was >$550,000/QALY. The ICER of regorafenib was greater than $200,000/QALY in >99% of PSAs. Conclusions: This is the first U.S.-based cost-effectiveness analysis of regorafenib in mCRC, and our findings show that regorafenib provides minimal incremental benefit at high incremental cost per QALY. The ICER of regorafenib could be improved by use of an effective biomarker to select patients most likely to benefit, or by a lower price for payers.
The role of systemic chemotherapy in adenocarcinomas of the appendix: Analysis of the National Cancer Database.
Authors: Asare Elliot A. , Compton Carolyn C. , Hanna Nader , Kakar Sanjay , Kosinski Lauren , Weiser Martin R. , Overman Michael J.
Published: February 2017

668

Background: Adenocarcinomas of the appendix represent a heterogeneous disease depending upon the presence of mucinous histology, histologic grade, and stage. We sought to explore the interplay of these factors with systemic chemotherapy in a large population dataset. Methods: Patients in the National Cancer Data Base (NCDB) with mucinous, non-mucinous and signet-ring cell type appendiceal neoplasms from 1985-2006 were selected and American Joint Committee on Cancer (AJCC) 7thedition stage was derived. Multivariable cox proportional hazards regression models to predict death using the available variables age, sex, histology, grade, stage, chemotherapy and surgery were developed. Results: 11,881 patients met our inclusion criteria: 50.3% mucinous, 40.5% non-mucinous and 9.2% signet ring cell. 5-yr OS was similar for mucinous (53.6%) and non-mucinous (46.2%), but differences in stage distribution existed with stage IV disease in 26.2% of mucinous vs. 10.6% of non-mucinous cases, p<0.0001. 5-yr OS stratified by grade was similar across stage I-III disease but not for stage IV disease. Median OS for stage IV mucinous and non-mucinous histology was 6.4 and 2.3 for well differentiated (p<0.0001), 2.5 and 1.0 for moderately differentiated (p<0.0001), and 1.5 and 0.8 for poorly differentiated (p<0.0001), respectively. In multivariable modeling for stage I-III disease, adjuvant chemotherapy improved OS for both mucinous and non-mucinous histologies: HR of 0.78 (0.68-0.89; p=0.0002) and 0.83 (0.74-0.94;p=0.002) respectively. For stage IV disease systemic chemotherapy was significant for non-mucinous 0.72 (0.64-0.82; p<0.0001) but not mucinous 0.95 (0.86-1.04;p=0.2), though this was grade dependent. Median OS for chemotherapy vs. no chemotherapy was 6.4 vs. 6.5 yrs (P=1.0) for mucinous well differentiated and 1.6 vs. 1.0 yrs (P=0.0007) for mucinous poorly differentiated. Conclusions: Adjuvant chemotherapy demonstrated a significant OS benefit regardless of histology. However, for stage IV disease the benefit of systemic chemotherapy varied by histology and grade, with well differentiated mucinous appendiceal adenocarcinomas deriving no survival benefit from systemic chemotherapy.
Comparative effectiveness of primary tumor resection in metastatic colon cancer: An instrumental variable analysis.
Authors: Alawadi Zeinab , Phatak Uma , Hu Chung-Yuan , Bailey Christina Edwards , Kao Lillian , You Y. Nancy , Chang George J.
Published: February 2017

674

Background: Although the safety of chemotherapy without primary tumor resection (PTR) has been established, questions remain regarding potential survival benefit with PTR. The purpose of this study was to compare mortality with and without PTR among patients with unresectable metastatic colon cancer using nationwide hospital based cancer registry data. Methods: An observational study was conducted of patients with stage 4 colon cancer identified from the National Cancer Data Base (2003-2005). Patients who underwent metastectomy were excluded. Patient, treatment, and hospital data were analyzed. Multivariate Cox regression stratified by receipt of chemotherapy was performed to compare survival with and without PTR. To account for treatment selection bias, Propensity Score Weighting (PSW) and Instrumental Variable (IV) analyses, using hospital-level PTR rate as the instrument, were performed. In order to account for the potential bias associated with early comorbidity or disease burden associated deaths (survivor treatment bias), 1 year landmark analysis was performed. Results: A total of 14,399 patients met inclusion criteria and 6,735 patients were eligible for landmark analysis. PTR was performed in 38.2% of the total cohort and 73.8% of those at landmark. Using multivariate Cox regression analysis, PTR was associated with a significant reduction in mortality (HR 0.39; 95% CI, 0.38-0.41). This effect persisted with PSW (HR 0.4; 95% CI, 0.38-0.43). However, IV analysis showed a much smaller effect, (RR 0.88; 95% CI, 0.83-0.93). While a smaller benefit was seen on landmark analysis using multivariate Cox regression (HR 0.6; 95% CI, 0.55-0.64) and PSW (HR 0.59; 95% CI, 0.54-0.64), IV analysis showed no improvement in survival with PTR (RR 0.97; 95% CI, 0.87-1.06). Stratification by chemotherapy did not alter the results. Conclusions: Among patients with stage IV colon cancer, PTR offered no survival benefit over systemic chemotherapy alone when the IV method was applied at the 1 year landmark. Subject to selection and survivor treatment bias, standard regression analysis may overestimate the benefit of PTR. Future study should focus on identifying patients most likely to benefit from PTR.
Efficacy of chemotherapy after treatment with regorafenib in metastatic colorectal cancer (mCRC).
Authors: Kidd Michael Todd , Wilcox Ryan Eldredge , Rogers Jane , Eng Cathy , Saadat Siamak , Lenz Heinz-Josef , Hubbard Joleen Marie , Grothey Axel
Published: February 2017

678

Background: Improvements in outcome of medical therapy for mCRC are closely linked to availability of active agents. Based on phase III clinical data, regorafenib, a multikinase inhibitor, received FDA approval September 2012 for patients with mCRC previously treated with all approved therapies. Post regorafenib therapy (PRTx) has not been established. Based on clinical observations, we established a multi-institution collaboration to assess chemotherapy response in mCRC after regorafenib therapy. Methods: After IRB approval, patient records at Mayo Clinic (MC), MD Anderson (MDA) and the University of Southern California (USC) from April 2010 to February 2014 were reviewed for regorafenib use and outcomes for mCRC. Therapies, patient and tumor characteristics were reviewed. Response and progression were determined by investigator review. Kaplan-Meier method was used to calculate survival. Results: Regorafenib was given to 173 patients with mCRC (MC:59 MDA:95 and USC:19). Of these, 11 (6%) continued on regorafenib at time of analysis and 98 (57%) received no additional therapy. PRTx was given to 64 (37%) patients, 31 of which went on a clinic trial. 33 patients were treated with standard approved therapy of which 11 (33%) progressed, 20 (61%) showed response or SD, and 2 (6%) were not evaluable. Out of the 33 treated with standard agents, 8 (24%) had stable disease or response to a treatment previously discontinued without definitive PD, whereas 4 (12%) responded to rechallenge with chemotherapy previously discontinued due to PD. Response was noted in 8 (24%) patients that received an agent not given prior to regorafenib. After discontinuation of regorafenib, mOS was 6.5 mo (CI 4.9 – 9.4), and the probability of survival at 6 and 12 months was 52% and 27% respectively. Conclusions: With the caveat of a small sample size and a potential selection bias, our multi-institution study shows that re-utilizing standard treatment options after regorafenib may be beneficial in select patients with mCRC including in patients with progression on identical therapy before regorafenib. Further retrospective and prospective studies could be warranted to define the role of regorafenib as a chemotherapy re-sensitizing agent.
Phase II study evaluating the effect of concomitant ramucirumab (RAM) on the pharmacokinetics (PK) of irinotecan (IRI) and its metabolite SN-38 when coadministered with folinic acid (FA) and 5-fluorouracil (5-FU) (FOLFIRI) in patients (pts) with advanced malignant solid tumors.
Authors: Wang Ding , Braiteh Fadi S. , Lee James J. , Denlinger Crystal Shereen , Shepard Dale Randall , Chaudhary Archana , Lin Yong , Gao Ling , Asakiewicz Christopher John , Nasroulah Federico , LoRusso Patricia
Published: February 2017

691

Background: The primary objective was to assess the effect of concomitant RAM on the PK of IRI and its metabolite SN-38 when coadministered with FA and 5-FU. Methods: Key eligibility criteria included pts aged ≥18 years with metastatic or locally advanced malignant solid tumors resistant to standard therapy or for which no standard therapy was available, and an Eastern Cooperative Oncology Group performance status of 0 to 2. Pts received intravenous infusions of FOLFIRI and RAM 8 mg/kg on day 1 of a 2-week cycle. FOLFIRI was administered alone in cycle 1; RAM was administered followed by FOLFIRI in all subsequent cycles. Blood for PK was collected at regular intervals after infusions in cycles 1 and 2 to determine IRI and SN-38 plasma concentrations. Pts who completed the first 2 cycles of study treatment were included in the drug-drug interaction (DDI) population. All pts who received at least 1 dose of RAM or FOLFIRI were included in the safety population. Results: The safety population comprised 29 pts, and the DDI population included 25 of these 29 pts. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC(0-∞)] and the maximum observed drug concentration (Cmax) of IRI and SN-38 were comparable between cycle 1 (FOLFIRI alone) and cycle 2 (RAM+FOLFIRI). The ratios of geometric least-squares (LS) means for IRI were 0.93 (90% CI; 0.83, 1.05) for AUC(0-∞) and 1.04 (90% CI; 0.97, 1.12) for Cmax. The ratios of geometric LS means for SN-38 were 0.95 (90% CI; 0.88, 1.04) for AUC(0-∞) and 0.97 (90% CI; 0.85, 1.12) for Cmax. The most prevalent treatment-emergent adverse events (TEAEs) were fatigue/asthenia (n=19, 65.5%), diarrhea (n=16, 55.2%), neutropenia (n=15, 51.7%), nausea (n=14, 48.3%), and decreased appetite and anemia (n=13 each, 44.8%). Grade ≥3 TEAEs were rare, except for neutropenia in 7 (24.1%) pts. Conclusions: The PKs of IRI and its metabolite, SN-38, were not affected when coadministered with RAM. RAM with FOLFIRI was well-tolerated in this study without new safety concerns. Clinical trial information: NCT01634555.
Quality of life (QoL) during first-line treatment with FOLFOX4 with or without panitumumab (pmab) in RAS wild-type (WT) metastatic colorectal carcinoma (mCRC).
Authors: Siena Salvatore , Tabernero Josep , Bodoky Gyorgy , Cunningham David , Rivera Fernando , Ruff Paul , Canon Jean-Luc Re , Koukakis Reija , Terwey Jan-Henrik , Douillard Jean-Yves
Published: February 2017

693

Background: The benefits of anti-cancer treatment must be balanced with the impact of adverse events on QoL. In the PRIME study, first-line pmab + FOLFOX4 significantly improved overall survival vs. FOLFOX4 in patients (pts) with RAS WT (KRAS/NRAS WT exons 2, 3 and 4) mCRC, but was associated with typical EGFR inhibitor adverse events. Here we report pre-specified tertiary QoL endpoints for pts with RAS WT mCRC. Methods: PRIME was a randomised open-label phase III study of first-line pmab 6.0 mg/kg Q2W + FOLFOX4 vs. FOLFOX4 in mCRC pts. QoL was assessed every 4 weeks until disease progression, and once at safety follow-up, using the EuroQoL 5-domain (EQ-5D) health state index (HSI) and overall health rating (OHR; 0–100 visual analogue scale). Differences were assessed from baseline to disease progression, and to discontinuation of first-line treatment, using analysis of covariance (ANCOVA) and a mixed-effect piecewise linear model. Analysis of QoL by skin toxicity severity is also planned. Results: 505 pts had RAS WT mCRC; overall compliance rates (evaluable vs. expected assessments) were 57% for both HSI and OHR. When analysed by ANCOVA there were no significant differences between the pmab + FOLFOX4 and FOLFOX4 arms from baseline to progression (Table) or to discontinuation. In the mixed-effect model, there were no significant differences between pmab + FOLFOX4 and FOLFOX4 in terms of HSI (overall test of difference between arms from baseline to discontinuation, p=0.2433; baseline to progression, p=0.5364) or OHR (p=0.1312 and 0.1290, respectively). Significant differences in favour of pmab + FOLFOX4 were reported in the baseline to discontinuation analysis at week 8 for HIS (p=0.0267) and OHR (0.0137) and week 12 for OHR (p=0.0187), and in the baseline to disease progression analysis at week 16 for OHR (p=0.0163) (Table). Conclusions: Addition of pmab to FOLFOX4 in first-line mCRC improves OS with no negative effect on overall QoL. Clinical trial information: NCT00364013. [Table: see text]
Safety and efficacy of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Bendell Johanna C. , Powderly John D. , Lieu Christopher Hanyoung , Eckhardt S. Gail , Hurwitz Herbert , Hochster Howard S. , Murphy Janet E. , Funke Roel Peter , Rossi Cheryl , Wallin Jeffrey , Waterkamp Daniel , Pishvaian Michael J.
Published: February 2017

704

Background: Cancers can mediate immune evasion via upregulation of PD-L1; blocking PD-L1 may restore tumor-specific T-cell immunity. MPDL3280A, a human anti-PD-L1 mAb containing an engineered Fc domain, prevents PD-L1 binding to its receptors PD-1 and B7.1 on activated T cells. Single-agent MPDL3280A has shown clinical activity in various indications, including NSCLC, bladder cancer, RCC and CRC. VEGF blockade has shown immunomodulatory properties, and certain chemotherapies may have immunogenic effects. Therefore we examined the safety and efficacy of MPDL3280A + bev with or without FOLFOX. Methods: MPDL3280A + bev in refractory mCRC pts (Arm A) and MPDL3280A + bev + FOLFOX in oxaliplatin-naive mCRC pts (Arm B) were evaluated in an open-label, multicenter Phase Ib study. Arm A pts received MPDL3280A 20 mg/kg q3w and bev 15 mg/kg q3w. Arm B pts received MPDL3280A 14 mg/kg q2w, bev 10 mg/kg q2w and mFOLFOX6 at standard doses. Responses were assessed by RECIST v1.1. Potential biomarkers were assessed in pre- and on-treatment liver biopsies. The clinical data cutoff was July 7, 2014. Results: 14 mCRC pts in Arm A and 30 in Arm B were evaluable for safety. In Arm A, median age was 56 y, 29% were male and all had ≥3 prior systemic regimens. In Arm B, median age was 57 y, 53% were male and 70% had no prior systemic therapy. In Arm A, grade 3-4 AEs regardless of attribution were 64%, including abdominal pain, hyperbilirubinemia and pneumonia (14% each). 73% of Arm B pts had grade 3-4 AEs, including neutropenia (40%), diarrhea (13%), increased ALT (10%) and increased AST (10%). Grade ≥3 MPDL3280A-related AEs were 7% in Arm A and 20% in Arm B. For pts with ≥1 tumor assessment, the unconfirmed ORR was 8% (1/13) in Arm A and 36% (9/25) in Arm B. The unconfirmed ORR was 44% (8/18) for Arm B first-line pts. Minimum follow-up was 1.9 mo in Arm A and 2.2 mo in Arm B. Updated data, including biomarkers, will be presented. Conclusions: MPDL3280A + bev with or without FOLFOXwas well tolerated with no unexpected toxicities. Clinical activity was observed with both treatment combinations. Longer follow-up and randomized studies will be needed to estimate the potential benefit of adding MPDL3280A to chemotherapy. Clinical trial information: NCT01633970.
Subgroup analysis of patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) in the CORRECT trial who had progression-free survival (PFS) longer than 4 months.
Authors: Grothey Axel , Falcone Alfredo , Humblet Yves , Bouche Olivier , Mineur Laurent , Adenis Antoine , Tabernero Josep , Yoshino Takayuki , Lenz Heinz-Josef , Goldberg Richard M. , Xu Lei , Wagner Andrea , Van Cutsem Eric
Published: February 2017

710

Background: In the CORRECT phase III trial (NCT01103323), the multikinase inhibitor REG significantly improved overall survival (OS) and PFS vs placebo in patients with mCRC who had disease progression after other standard therapies (HR for OS: 0.77; 1-sided p =0.0052; Grothey 2013). A post-hoc exploratory subgroup analysis was conducted to evaluate patients in the REG treatment group who had a PFS longer than 4 months (long-PFS) defined as patients who progressed, died, or discontinued treatment for other reasons after 4 months. Methods: Of the505 patients randomized to REG in CORRECT, 98 (19.4%) were classified as having a long-PFS benefit. Baseline characteristics, safety, and dosing parameters were analyzed descriptively. Results: The long-PFS subpopulation was representative of the overall study population (Table). Long-PFS patients received a median of 6 cycles of REG (1-12), 92% received ≥5 cycles, and 20% had > 8 cycles. Overall 34% of patients had dose reductions and 87% had dose interruptions. The actual mean daily dose was 139 mg and the mean percent of the planned dose was 81%. Adverse events (AE) of any grade were experienced by all long-PFS patients, and the most common grade ≥3 AEs were hand-foot skin reaction (20%), hypertension (17%), diarrhea (17%), and fatigue (16%). Conclusions: A subset of 98 (19.4%) patients treated with REG in the CORRECT study had a PFS > 4 months, confirming the clinical benefit and tolerability of REG as a treatment option for patients with mCRC. Prospective validation of these findings in conjunction with biomarker analysis from real-life clinical experience is needed. Clinical trial information: NCT01103323. [Table: see text]
Palliative oxaliplatin-based chemotherapy after exposure to oxaliplatin in the adjuvant setting for colon cancer.
Authors: Peixoto Renata D'Alpino , Kumar Aalok , Gill Sharlene , Lim Howard John
Published: February 2017

753

Background: Little is known regarding the efficacy of oxaliplatin-based chemotherapy for metastatic colon cancer patients who have already received adjuvant oxaliplatin-based chemotherapy. Methods: We retrospectively reviewed 22 consecutive patients who developed recurrence after adjuvant oxaliplatin-based chemotherapy for stage III colon cancer and received another course of oxaliplatin-based chemotherapy for their metastatic disease. The main endpoint was progression-free survival (PFS). Results: 635 patients received oxaliplatin-based chemotherapy for stage III colon cancer at the British Columbia Cancer Agency from 2006 to 2011. 176 pts recurred, 22 (12.5%) of whom were re-exposed to oxaliplatin in the metastatic scenario. Oxaliplatin in combination with fluoropyrimidine was given as first line in 3 pts (13.6%), as second line in 14 (63.6%), and third line in 5 (22.7%). Median time from the last cycle of adjuvant oxaliplatin-based chemotherapy to the first cycle of palliative oxaliplatin-based chemotherapy was 44.3 months. Median PFS and OS were 3.3 (95% CI 1.4-5.1) and 10.0 months (95% CI 5.3-14.6), respectively. There was no difference in PFS for patients who were re-exposed to oxaliplatin in less than 36 months or later than that (3.6 versus 3.1 months, p=0.793, HR=0.88). Conclusions: In this population-based study, only a small proportion of pts who recurred after oxaliplatin-based adjuvant therapy received oxaliplatin in the metastatic setting. Re-exposure of oxaliplatin in combination with fluoropyrimidine is associated with only modest PFS benefit. Larger studies evaluating the role of oxaliplatin re-exposure are needed.
Age-specific prognostic factors in patients treated surgically for pulmonary metastases of colorectal cancer: A multi-institutional cumulative follow-up study.
Authors: Nakao Sayumi , Itabashi Michio , Ubukata Mamiko , Bamba Yoshiko , Hirosawa Tomoichiro , Ogawa Shimpei , Kameoka Shingo , Sugihara Kenichi
Published: February 2017

773

Background: The aim of this study was to investigate the age-specific prognostic factors for overall survival (OS) and disease-free interval (DFI) after pulmonary metastasectomy for colorectal cancer (CRC). Methods: We performed a retrospective analysis of 1,179 patients who underwent lung resection for colorectal metastases from 2001 to 2012 in 109 affiliated institutions of the Japanese Society for Cancer of the Colon and Rectum study group. The patients were divided into three groups by the age at pulmonary resection: Group A (GA) comprised of 396 patients who underwent lung resection under the age of 60 years old; Group B (GB) comprised of 604 patients who underwent lung resection between the ages of 61 and 74 years old; Group C (GC) comprised of 179 patients who underwent lung resection over the age of 75 years old. We used the Cox proportional hazard regression to identify independent prognostic factors for OS and DFI. Results: Median OS times after pulmonary resection were 45 months, 43 months, and 43 months for GA, GB, and GC, respectively. Two-year and 5-year overall survival rates were 73% and 54% for GA, 77% and 63% for GB, and 82% and 68% for GC, respectively. The independent unfavorable prognostic factors were recurrence after pulmonary resection (p<0.0001) in GA, detection of liver metastases before lung resection (p=0.0126), a high level of carcinoembryonic antigen (p=0.0003), and recurrence after pulmonary resection (p<0.0001) in GB, and recurrence after pulmonary resection (p<0.0001) in GC. Median DFI times were 11 months in all groups. The independent unfavorable prognostic factor was a removal of mediastinal lymph node (p=0.0335) in GB. Conclusions: Elder patients (GC) showed nearly the same OS rate compared with non-elder patients (GB), while younger patients (GA) showed poor OS rate. Recurrence after pulmonary resection revealed to be a poor prognostic factor in all groups.
Colorectal cancer mortality among Cuban and non-Cuban Hispanics.
Authors: Sussman Daniel A. , Tannenbaum Stacey L. , McClure Laura A. , Hernandez Monique N. , Zheng D. Diane , Koru-Sengul Tulay , Carrasquillo Olveen , Lee David J.
Published: February 2017

775

Background: We examined all-cause mortality of Floridian colorectal cancer (CRC) patients among Hispanics of Cuban and non-Cuban origin, non-Hispanic Whites (NHWs) and non-Hispanic Blacks (NHBs). We hypothesized that Cuban Hispanics would have a higher mortality risk relative to other Hispanics in Florida with CRC. Methods: We obtained data from the Florida Cancer Data System for all incident CRC cases (2007-2011) among Floridians 18+ years and linked these files with data from Florida’s Agency for Health Care Administration and the 2006-2010 American Community Survey (n=46,579). Race/ethnic groups were Cuban, non-Cuban Hispanic, NHW, and NHB. Log-rank tests were performed among race/ethnic groups with multivariable Cox proportional hazard regression models for mortality adjusting for demographic and clinical factors to produce adjusted hazard ratios (HR). Results: Cubans’ mortality were not significantly different from NHWs (p=0.8254) or NHBs (p=0.3047) but significantly different from non-Cuban Hispanics (p=0.0006). Adjusting for all covariates and compared with highest SES within each race/ethnicity, residing in lower SES neighborhoods was associated with increased mortality risk for NHWs (HR=1.19; 95%CI=1.12-1.27) and NHBs (1.33; 1.13-1.57) but not for Hispanics. Among Hispanics, Cubans with proximal CRC had a 42% higher mortality risk than those with distal disease (1.42; 1.11-1.82); however, tumor location was not predictive of mortality for other racial/ethnic groups. Single or widowed Cuban Hispanics had higher mortality risk compared to those who were married (1.42; 1.07-1.88 for both comparisons) but this was not true for non-Cuban Hispanics. Conclusions: Cuban Hispanics are a distinct and understudied population group who should not be aggregated into a general category of Hispanic with respect to CRC mortality studies. Further research to understand the Cuban Hispanic differences in CRC mortality risk is needed to reduce the burden of disease, especially in the ever growing Hispanic population.
Triplet chemotherapy (TC) with FOLFIRINOX regimen in metastatic colorectal cancer (mCRC): Experience of two French centres.
Authors: Samalin Emmanuelle , De La Fouchardiere Christelle , Thézenas Simon , Sarabi Matthieu , Assenat Eric , Portales Fabienne , Carrere Sebastien , Rivoire Michel , Rouanet Philippe , Bleuse Jean-Pierre , Quenet François , Ychou Marc
Published: February 2017

776

Background: TC is a treatment option for mCRC to improve the tumour response rate in selected patients (pts) and the conversion rate of initially nonresectable liver metastases. The aim of this study was to evaluate the impact and feasibility of FOLFIRINOX regimen in mCRC pts. Methods: We selected all mCRC pts from the ICM and CLB French centres with unresectable disease treated from October 2000 to May 2012 with FOLFIRINOX alone or combined with bevacizumab or cetuximab. Clinical data were collected in a mCRC-specific data base and analysed. Results: 159 pts (52% of men), median age 58 yrs (range: 24-76) were treated with FOLFIRINOX (D1 oxaliplatin 85 mg/m² IV over 2H, then irinotecan 180 mg/m² IV over 90 min and elvorin 200 mg/m², then 5-fluorouracile 200 mg/m² and 2,400 mg/m² IV over 46H, D1=D15) alone (68%) or combined with cetuximab (24%) or bevacizumab (8%) as first–line treatment (88%). Primary tumour was located in colon (77%) or rectum (23%), and 134 pts (84%) presented with synchronous metastases: liver (96%), lung (46%), peritoneum (11%) and nodes (20%). Median number of courses was 8 (range: 1-26). There was 1 toxic death. Grade 3-4 toxicities were as follows: diarrhoea (23%), neuropathy (24%), cutaneous (9%), neutropenia (21%), febrile neutropenia (1%), thrombopenia (4%). Objective response rate according to RECIST V1.0 was 72% [95% CI: 65-79] including 12 pts with complete response. The primary tumour was resected in 127 pts (79%) and 19% had KRAS mutated tumour. Among the 105 pts (66%) with initially non-resectable liver-limited disease (LLD), 59 pts (56%) were eligible for secondary resection and a R0 resection rate was achieved for 44 pts. Median overall survival was 49 months [95% CI: 37-62] and 72 months [95% CI: 48-84] in resected LLD population. Conclusions: These results confirm the feasibility of FOLFIRINOX regimen with or without targeted therapies and its efficacy in LLD selected mCRC population.
Gastrointestinal organoid cultures for functional evaluation of oncogenic loci.
Authors: Salahudeen Ameen Abdulla , Li Xingnan , Cantrell Michael , Kuo Calvin Jay
Published: February 2017

85

Background: Novel in vitro methods surpassing limitations of current gastrointestinal cancer models such as gastric and esophagus cancer are required to functionally validate putative oncogenic loci discovered by genome sequencing efforts. The in vitro culture of primary, non-transformed tissues as three-dimensional organoids that accurately recapitulate organ structure and physiology has diverse applications including cancer biology. Methods: Mouse wild type, or p53flox/flox in tandem with lox-stop-lox KRASG12D upper digestive tract tissue containing epithelial and mesenchymal components were cultured in an air-liquid-interface and subjected to adenovirus expressing either immunoglobulin Fc (control) or GFP tagged Cre recombinase. Results: 3-dimensional organoids were generated with histological adherence to normal tissue architecture including that seen in esophagus and were able to be maintained in long term culture. Organoids exposed to GFP tagged Cre adenovirus demonstrated green fluorescence not seen in organoids exposed to control virus. Conditional allele organoids that were exposed to Cre adenovirus demonstrated increased rate of growth compared to controls. Histology of these rapidly growing organoids demonstrated cellular features consistent with dysplasia. Conclusions: 3-dimensional organoids can be generated from upper digestive tract tissues, can undergo adenoviral mediated transfection to achieve oncogenic gene expression or inactivation resulting in dysplastic morphology. 3-dimensional organoids are therefore an attractive model to study or identify candidate oncogenic loci identified by recent genomic sequencing studies.
Evolution in the treatment of esophageal disease at a single institution: 2004-2013.
Authors: Pham David V , Dolan James P. , Diggs Brian S. , Gilbert Erin W. , Sheppard Brett C. , Tieu Brandon , Schipper Paul , Giraud Fernando M , Thomas Charles R. , Hunter John G.
Published: February 2017

96

Background: The aim of this study was to analyze the evolution in the surgical management of esophageal disease at an academic medical center during the last decade. Methods: We reviewed a retrospective cohort of patients who underwent esophagectomy between 2004 and 2013 for benign and malignant esophageal disease. Patient, institutional and postoperative variables were abstracted and reviewed across the study period. Results: 317 patients were analyzed. The median age was 63.5 years and 80% were male. Malignancy accounted for 88% of esophagectomy patients in 2004 and 97% in 2013. Operations for high grade dysplasia (HGD) decreased 75% in the same period (p=0.008). In 2004, an Ivor Lewis esophagectomy was the most common surgical technique but the 3-Field technique has become the operation of choice in 2013 (54% vs.71%, p<0.001). Likewise, a laparoscopic approach was used in 19% of cases in 2004 and 100% of cases in 2013 (p<0.001). Median lymph node harvest increased from 7 to 18 nodes (p=0.001). Atrial fibrillation was the most common perioperative complication (24%) and anastomotic leaks ranged between 3 to 14% (p=0.18), occurring in 3% of patients in 2013. Hospital stay decreased from 15 to 8 days over the study period (p=0.001). In 2013, 89% of patients were discharge to home compared to 73% in 2004 (p=0.04). The average mortality rate for our cohort was 3.5%. Conclusions: Over the last decade, our treatment of esophageal disease has evolved from a predominant open Ivor Lewis to a laparoscopic 3-Field approach. Operations for malignancy have also increased dramatically. Postoperative complications and mortality has been consistently low during the latter years of the study.