bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.