bluuebunny/crossref_metadata_2025_split huggingface dataset:
Magnitude of progression-free survival (PFS) improvement and treatment (Tx) duration in metastatic colorectal cancer (mCRC) for bevacizumab (BV) in combination with oxaliplatin-containing regimens: An analysis of two phase III studies
Authors: Giantonio B. J. , Meropol N. J. , Catalano P. J. , Ng V. , Oliver R. , Sirzen F. , Leonard S. , Cassidy J. , Benson A. B. 
Published: March 2020

4073 Background: In trials of BV with FOLFOX (fluorouracil, leucovorin, oxaliplatin) for mCRC, variability in the magnitude of PFS improvement has been reported [HR=0.61 in E3200 vs HR= 0.83 (FOLFOX or CAPOX (capecitabine and oxaliplatin)) in NO16966]. We propose that differences in rates of treatment discontinuation (D/C) for adverse events (AE) between these studies may have resulted in differences in the observed benefits associated with BV. We explored Tx duration (proportion of patients on Tx) and Tx D/C data at median PFS for the BV containing arms of each study. Methods: ECOG study E3200 randomized previously treated patients with mCRC to FOLFOX ± BV (10 mg/kg). NO16966 employed a 2x2 design that randomized previously untreated patients with mCRC to CAPOX vs FOLFOX and to BV (5 mg/kg) or placebo. In both trials, study Tx was defined as any component of the prescribed regimen. PFS was estimated from Kaplan-Meier curves, and hazard ratios (HR) for PFS were estimated by Cox regression. Results: Median PFS for the BV containing arm of the study: 30 weeks for E3200; 42 weeks for NO16966 Conclusion: These data suggest possible differences between the two studies in Tx duration and Tx D/C patterns with a greater proportion of patients on NO16966 discontinuing Tx for any AE. Duration of study Tx might have affected both the incidence of AEs and the magnitude of PFS benefit observed for the addition of bevacizumab to oxaliplatin-based chemotherapy in these studies. Attention to Tx duration and Non-PD Tx D/C in future clinical trials will be important when considering PFS as a primary efficacy endpoint. [Table: see text] No significant financial relationships to disclose.
Cost comparison of XELOX compared to FOLFOX4 with or without bevacizumab (bev) in metastatic colorectal cancer
Authors: Garrison L. , Cassidy J. , Saleh M. , Lee F. , Mena R. , Fuloria J. , Chang V. , Ervin T. , Stella P. , Saltz L. 
Published: March 2020

4074 Background: A recent randomized 2x2 phase III trial compared oral capecitabine + IV oxaliplatin (XELOX); IV 5FU/LV/oxaliplatin (FOLFOX4), XELOX+bev, and FOLFOX4+bev. FOLFOX4 was the regulatory control. XELOX was non-inferior to FOLFOX4 for progression-free survival, and bev-containing regimens were superior to comparison arms. This economic analysis compared expected costs in XELOX vs. FOLFOX4 arms in a US setting from a payer and societal perspective. Methods: Direct medical and indirect cost estimates (for patient time and travel) were compared. Resource use and patient time were estimated based on trial data and protocols. Data collected during the trial and used in the analysis were as follows: no. of visits / duration of drug administration, central venous access management, treatment of adverse events (AE), including hospital days for treatment-related AEs and total hours of ambulatory encounters. Unit costs were based on government fee schedules (i.e. Medicare reimbursements) and other published sources. Results: Total direct medical cost estimates were similar for bi-weekly FOLFOX4 and 3-weekly XELOX: $45,800 vs. $44,500. XELOX had higher drug costs while FOLFOX had higher drug administration costs, with about 15 more visits. Costs for hospitalization and ambulatory encounters were slightly lower for FOLFOX4; other medications and venous access were slightly higher for FOLFOX4. Similar patterns held for FOLFOX4+bev vs. XELOX+bev (total direct medical cost estimates $76,100 vs. $79,200). Indirect time cost estimates were lower with XELOX due to fewer cycles and visits: estimated savings range from $1000-$5000 depending on assumptions used. Conclusion: XELOX is estimated to have similar total direct medical costs and lower indirect costs compared with FOLFOX4. [Table: see text] No significant financial relationships to disclose.
Waterfall plots provide detailed information on magnitude of response to conventional chemotherapy in advanced colorectal cancer (ACRC) - lessons learned from N9741
Authors: Campbell M. E. , Grothey A. , Sargent D. J. , Goldberg R. M. 
Published: March 2020

4080 Background: Waterfall plots have been used to capture the anti-tumor efficacy of both biologic agents (Ratain JCO 2006), which mainly exhibit a cytostatic effect, but also of chemotherapeutic agents. We are not aware of an application to therapeutic studies in CRC. We conducted waterfall plot analyses on the data of N9741 which compared IFL, FOLFOX4, and IROX as first-line therapy in ACRC (Goldberg JCO 2004). Methods: 634 (IFL 215, FOLFOX 215, IROX 204) of the 795 pts presented in the published analysis had measurable disease, and are included. The percentage change in tumor measurements from baseline to 12 wks was calculated, allowing for a time window of assessment from 6 to 20 wks for those without a 12 wk measurement. Pts with progression before the 12 wk assessment were assigned a 100% increase. The average reduction in tumor burden (ARTB) was calculated as difference in waterfall AUC divided by the number of pts. ARTB captures the average percentage reduction in tumor measurements at 12 wks for a patient entering the trial. Results: Waterfall plot analysis demonstrated some tumor growth at 12 wks in 23.7% (IFL), 15.8% (FOLFOX), and 26.9% (IROX) of pts. In contrast, tumor shrinkage was observed in 67.9% (IFL), 71.6% (FOLFOX), and 61.4% (IROX) of pts. Total differential AUC was -34.4 (IFL), -61.6 (FOLFOX), and -30.4 (IROX) resulting in an ARTB of 16.0% (95% Confidence Interval (CI) (23.7%, 8.2%)) for IFL, 28.7% (35.1%, 22.2%) for FOLFOX, and 14.9% (22.5%, 7.3%) for IROX. Conclusions: Waterfall plot analyses are feasible in this and likely other CRC trials using conventional chemotherapy. Our analysis confirms the published results of N9741, but suggests a larger degree of benefit for individuals based on anti-tumor activity than captured by conventional response analysis. Waterfall plots provide a potentially useful new efficacy metric, the average reduction of tumor burden per pt, which should be validated in future trials. No significant financial relationships to disclose.
Safety and pharmacokinetics (PK) of AMG 706 with panitumumab plus FOLFIRI or FOLFOX for the treatment of patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Schwartzberg L. S. , Hurwitz H. , Stephenson J. , Kotasek D. , Goldstein D. , Tebbutt N. , McGreivy J. , Sun Y. , Yang L. , Burris H. 
Published: March 2020

4081 Background: AMG 706 is an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity, selectively targeting VEGF, PDGF and Kit receptors. Methods: This is an ongoing phase 1b, open-label, dose-finding study of AMG 706 with panitumumab plus FOLFIRI or FOLFOX in pts with mCRC. Objectives are to establish safety, PK, and the maximum tolerated dose of AMG 706 with this regimen. Pts =18 yrs with mCRC, ECOG 0–1, =1 prior chemotherapy for advanced disease and no prior oral VEGFr MKIs or anti-EGFR therapy, received either FOLFIRI or FOLFOX (based on prior therapy) plus panitumumab (6mg/kg IV day 1 of each 2-wk cycle), and escalating doses of AMG 706 (50, 75, 125mg QD; 75mg BID) given continuously from day 3 of cycle 1. Assessments included dose-limiting toxicities (DLT) during the first 2 cycles and tumor response (every 6–8 wks from wk 6). Results: As of Nov 2006, 45 pts were enrolled and received at least 1 dose of AMG 706 (FOLFIRI/FOLFOX n=33/12); 64% had prior chemotherapy. There were 6 DLTs: FOLFIRI n=4, all grade 3 (diarrhea n=2: 50mg QD, 75mg BID; deep vein thrombosis n=1: 75mg QD; high GI output n=1: 75mg BID); FOLFOX n=2 (all fatigue, grade 3: 50mg QD). Treatment-related adverse events (AE) occurring in =10% of pts included: any AE, FOLFIRI/FOLFOX 88/92% of pts (grade 3, 21/58%); fatigue 55/58% (12/33%), anorexia 24/50% (0/0%), diarrhea 24/33% (0/8%), epistaxis 27/0% (0/0%) and hypertension 15/8% (0/0%). There were no grade 4/5 AEs. 2 cases of cholecystitis (grade 3, n=1) occurred. Preliminary data showed that AMG 706 PK at 50mg QD (FOLFOX) and 50–125mg QD (FOLFIRI) was comparable to data from monotherapy studies at the same dose levels. AMG 706 did not markedly alter the PK profiles of irinotecan or its metabolites. Objective tumor response per RECIST is shown in the table . Conclusions: In this study of pts with mCRC, AMG 706 was tolerable when combined with panitumumab and FOLFIRI or FOLFOX, with little effect on AMG 706 PK. [Table: see text] No significant financial relationships to disclose.
Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: an open-label, multicenter Phase I study
Authors: Saunders M. , Van Cutsem E. , Wilson R. , Peeters M. , Smith R. , Godwood A. , Oliver S. 
Published: March 2020

4085 Background: Vandetanib (ZD6474) is a once-daily oral agent in Phase III development that selectively targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinases. Methods: Patients with metastatic colorectal adenocarcinoma who were eligible for 1st- or 2nd-line chemotherapy received once-daily oral doses of vandetanib (100 mg) in combination with standard 14-day treatment cycles of FOLFIRI (irinotecan 180 mg/m2 1.5-hr and leucovorin 400 mg/m2 2-hr i.v. infusions, followed by 5-fluorouracil [5-FU] 400 mg/mg2 i.v. bolus and 5-FU 2400 mg/m2 46–48-hr i.v. infusion). If <2 of 6 evaluable patients (i.e., having completed 6 weeks of treatment) experienced a vandetanib- related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + FOLFIRI. The primary objective of the study was to establish the safety and tolerability of vandetanib + FOLFIRI. Secondary objectives included an assessment of any pharmacokinetic (PK) interaction between vandetanib, irinotecan (SN-38) and 5-FU, and preliminary evaluation of efficacy (RECIST). Results: Twenty- one patients (12 male/9 female; mean age 53 years, range 33–72) received vandetanib 100 mg (n=11) or 300 mg (n=10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort, with one DLT of hypertension (CTC grade 3) with QTc prolongation in the 300 mg cohort. The most common adverse events (AEs; all grade 1/2) were diarrhea (n=20), nausea (n=12), fatigue (n=10) and alopecia (n=9); AEs =grade 3 reported in more than one patient were neutropenia (n=4, all grade 3), hypertension (n=3, all grade 3), catheter-related complication (n=2, both grade 3) and pulmonary embolism (n=2, both grade 4). There was no apparent PK interaction between vandetanib and irintotecan (SN-38) or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=2), stable disease =8 weeks (n=9), and progressive disease (n=3). Conclusions: In patients with advanced colorectal adenocarcinoma, combining once-daily vandetanib (100 or 300 mg) with a standard FOLFIRI regimen was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies. No significant financial relationships to disclose.
A phase I study of bortezomib in combination with 5FU/LV plus oxaliplatin in patients (pts) with advanced colorectal cancer (CRC): EORTC 16029
Authors: Lacombe D. A. , Caponigro F. , Anthoney A. , Bauer J. , Govaerts A. , Milano A. , Marréaud S. , Twelves C. 
Published: March 2020

4090 Background: Bortezomib is a potent and reversible inhibitor of the ubiquitin-mediated proteasome pathway, whose inhibition results in the stabilization of p53, p21Cip1, p27Kip1, Bax, in cell-cycle dysregulation and, finally, apoptosis. A phase I study of the combination of 5FU/LV and bortezomib has shown a significant stable disease rate in advanced CRC (Iqbal, ASCO 2004). Methods: In this phase I study bortezomib was given as an IV push over 3 to 5 seconds on days 1, 8 and 15 in combination with standard FOLFOX-4 every 28 days in chemo-naïve pts with advanced CRC. Bortezomib starting dose level was 1.3 mg/m2. A 3+3 study design was utilized at predefined dose levels (DL). Dose-limiting-toxicity (DLT) was assessed during cycle 1. Exploratory pharmacogenetics research was conducted. Results: 15 pts were treated and 46 cycles given. At DL2 (1.6 mg/m2), 2/4 pts experienced a DLT: G3 febrile neutropenia causing treatment delay and bortezomib dose reduction in 1pt and one bortezomib dose skipped due to persistent G2 peripheral neuropathy and myalgia in 1pt. At DL1 (1.3 mg/m2), 2/6 pts had a DLT. Both pts experienced a G3 neutropenia on day 15, which prevented treatment from being given as scheduled. DL-1 (1 mg/m2) was therefore investigated and no DLT was observed among 5 pts. The most frequently reported toxicities in cycle 1 were γGT (64%), nausea, fatigue and sensory neuropathy (53%), pain (33%), diarrhea and fever (27%), vomiting (20%), anorexia, dyspnea and mucositis (13%) and neutropenia 29% (G2,3). 12 pts are currently evaluable for response; 6 had a partial response, 3 stable disease and 3 disease progression. Conclusion: The toxicity profile of this combination is predictable and early evidence of clinical activity has been observed. The recommended bortezomib dose for further investigation within this regimen is 1 mg/m2. No significant financial relationships to disclose.
Phenotypic and genotypic characteristics of epidermal growth factor receptor (EGFR) in colorectal cancer patients
Authors: Milano G. A. , Etienne-Grimaldi M. C. , Francoual M. , Benchimol D. , Chazal M. , Letoublon C. , André T. , Gilly N. , Delpero J. , Formento J. L. 
Published: March 2020

4110 Background: Colorectal tumors express EGFR and are responsive to anti-EGFR therapies. However, there is no tumoral predictive factor for anti-EGFR therapy in colorectal cancer and EGFR gene copy number is currently a good candidate. The aim of this study was to examine relationships between EGFR germinal polymorphisms, EGFR gene copy number and EGFR expression. Methods: Eighty primary colorectal tumors were analyzed along with 39 normal mucosas. Tumor staging was : 4 stage 0, 13 stage I, 22 stage II, 23 stage III and 18 stage IV. EGFR -216G>T and -191C>A genotypes were analyzed by PCR-RFLP, CA-repeats polymorphism in intron 1 by fluorescent genotyping and gene copy number was measured by PCR amplification. EGFR expression was quantified with the reference Scatchard binding assay giving high- and low-affinity sites along with Kd values (Francoual M et al. Ann Oncol 17, 2006). Results: The number of CA- repeats varied from 14 to 21. Considered genotypes were superimposable between tumoral and normal tissues. A linkage disequilibrium was noted between -216G>T and -191C>A genotypes (p = 0.011). CA-repeats polymorphism and -216G>T genotype were not independent (p = 0.002). No relationship was observed between any of the analyzed EGFR genotypes and EGFR expression. EGFR expression was not related to gene amplification. EGFR gene amplification in tumor and normal tissue varied over a 4.7- and 2.9-fold range, respectively, and were not correlated. The mean value of the tumor/normal mucosa amplification ratio was 1.16 (range 0.55–2.68) and 14% of patients exhibited lower amplification in the tumor relative to the normal mucosa (ratio < 0.75). The mean ratio of high-affinity sites between tumor and normal mucosa was 1.20 (range 0.03–13.33). Conclusions: In colorectal tumors, neither EGFR gene amplification nor EGFR germinal gene polymorphisms influenced EGFR expression quantified with a specific ligand-binding assay. No significant financial relationships to disclose.
Identification of prognostically-relevant signature genes differentially expressed between primary colorectal carcinoma and hepatic metastasis
Authors: Lin A. Y. , Chua M. , Choi Y. L. , Yeh W. , Kim Y. H. , Azzi R. , So S. K. , Pollack J. R. 
Published: March 2020

4116 Background: Colorectal cancer (CRC) is the third most common cancer in the US. Hepatic metastasis (HM), the most common distant metastasis from CRC and occurring in about 60% of CRC patients during the course of their treatment, is a significant clinical problem. Although several clinical prognostic factors for HM from CRC have been identified, little is known about its molecular aspect. Methods: Under IRB approved protocols, we profiled gene expression in a set of 30 specimens from primary CRC and 31 unmatched specimens of HM from CRC. To survey the molecular variations between the two groups, we used cDNA microarrays containing ∼22,000 human genes, and identified differentially expressed genes using the Significance Analysis of Microarrays (SAM) method. To further characterize the clinical relevance of differentially expressed genes, we used immunohistochemistry (IHC) on tissue microarrays of tumor tissues obtained from an independent dataset of 154 patients with primary CRC. Results: Supervised analysis using SAM identified >200 genes with significantly higher expression in HM from CRC compared to primary CRC (and also compared to normal liver), with a false discovery rate (FDR) of <1%. IHC staining of two highly ranked differentially expressed signature genes, SPP1 (osteopontin) and LEF1 (lymphoid enhancer factor-1; a transcriptional mediator of Wnt pathway activation), showed protein overexpression (OE) in 60% and 44% of CRC cases, respectively; with a significant correlation with liver involvement in LEF1 expression (chi-square p=0.04) vs. SPP1 OE (p=0.14). Kaplan Meier analysis revealed significantly worsening survival in patients with LEF1 OE (p<0.01), but not SPP1 (p=0.14). Multivariate analysis identified several relevant prognostic markers: stage (p<0.001), nodal status (p <0.01) and LEF1 OE (p=0.02). Conclusions: Among signature genes differentially expressed between CRC and HM, we demonstrate LEF1, not SPP1, OE to be a poor prognostic factor for survival. Further studies are needed to characterize other signature genes, and to refine our understanding of the role of altered LEF1 expression in CRC tumorigenesis. No significant financial relationships to disclose.
Use of microsatellite instability in non-hereditary advanced colorectal cancer to predict response to chemotherapy and overall survival: A study of the Dutch Colorectal Cancer Group (DCCG)
Authors: Koopman M. , Kortman G. A. , Mekenkamp L. , Ligtenberg M. J. , Hoogerbrugge N. , Mol L. , Antonini N. F. , Punt C. J. , van Krieken J. H. 
Published: March 2020

4118 Background: Microsatellite instability (MSI) is present in 10–20% of patients (pts) with non-hereditary colorectal cancer (CRC) and is generally associated with improved overall survival. The effect of chemotherapy in such pts is uncertain, and most data are derived from early stage CRC. Therefore the outcome of treatment in relation to presence or absence of MSI was studied in pts with non- hereditary advanced CRC. Methods: Data were collected from previously untreated advanced CRC pts randomized between 1st line capecitabine (Cap), 2nd line irinotecan (Iri), and 3rd line Cap + oxaliplatin (CapOx) vs 1st line CapIri and 2nd line CapOx. Formalin-fixed, paraffin embedded blocks of primary tumors and normal tissue were collected and tissue microarrays were made. Expression of the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 was examined by immunohistochemistry. Additionally MSI analysis and hypermethylation of the MLH1-promoter were performed. Pts with a tumor showing MSI caused by hypermethylation of the MLH1-promoter were included to study the correlation between MSI status and response to 1st line treatment and overall survival. Results: MSI caused by hypermethylation of the MLH1-promoter was found in 14 (3%) of 512 eligible pts. In 461 evaluable pts, disease control (CR+PR+SD=4 months) in 12 pts with MSI was 58% [95% CI 28%- 85%] and in 449 without MSI 83% [95% CI 79%-86%, p= 0.03].The median OS in pts with MSI was 7 months [95% CI 4–17] and in pts without MSI 18 months [95% CI 16–19, log rank p=0.08]. Conclusions: MSI in advanced non-hereditary CRC is very rare, and predicts a significantly worse outcome in terms of response to chemotherapy with a trend towards a decreased OS. No significant financial relationships to disclose.
Immunohistochemical test for MLH1 and MSH2 is an independent prognostic factor in sporadic colorectal cancer
Authors: Öhrling K. , Edler D. , Hallström M. , Karlberg M. , Ragnhammar P. 
Published: March 2020

4126 Background: Microsatellite instability (MSI) is the hallmark of a defective DNA mismatch repair (MMR) and occurs in 10- 20 % of sporadic colorectal cancer (CRC). The loss of the MLH1 protein is the cause of MSI in almost all sporadic colorectal MSI tumours. The second most common protein to be lost is MSH2. There is evidence that MSI is a prognostic factor in CRC. The role of MSI status as a predictive factor of benefit from adjuvant 5-fluorouracil (5-FU) based chemotherapy is controversial. Methods: Monoclonal antibodies that recognize the mismatch repair protein by immunohistochemistry (IHC) have been commercially available for several years. Previous reports have found a strong correlation between MMR results obtained by immunohistochemical and genetic analysis. This study included 1006 CRC patients (488 Stage II and 518 Stage III) with a median follow-up of 5 years. The patients were included in Nordic trials randomised between surgery alone and surgery plus adjuvant 5-FU. The MMR status was retrospectively assessed on paraffin-embedded formalin-fixed samples using IHC. Results: One hundred fifty seven patients (15.6 %) showed a loss of MMR protein expression (139 MLH1 negative, 15 MSH2 negative and 3 MLH1+MSH2 negative) and were classified as MMR protein negative. A normal MMR protein expression was found in 851 patients who were defined as MMR protein positive. The median overall survival (OS) was 84 months (range 2–181 months). MMR protein expression was a significant prognostic marker in the entire study group where a better OS was seen among patients with MMR protein negative carcinomas compared to patients with MMR protein positive tumours (p=0.005). In multivariate analysis the MMR protein expression was significantly associated with OS, (hazard ratio for death, 0.67 [95 per cent confidence interval, 0.38 to 0.96]; p=0.008). However, in this study the MMR status did not predict response to 5-FU adjuvant chemotherapy. Conclusions: This study reveals that immunohistochemical analysis of MLH1 and MSH2 expression can yield important prognostic information but is not a predictive factor in sporadic CRC. No significant financial relationships to disclose.