bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metastatic colorectal cancer (mCRC) patterns of care: Implications for clinical trial design
Authors: Denlinger C. S. , Collins M. A. , Wong Y. , Litwin S. , Meropol N. J. 
Published: March 2020

4079 Background: New approaches have expanded options for patients (pts) with mCRC. To characterize current practice paradigms that might bear on clinical trial design, we analyzed decision-making and treatment patterns in pts treated at a Comprehensive Cancer Center since the introduction of cetuximab (CET), and bevacizumab (BV). Methods: A retrospective review of all pts diagnosed with mCRC between 3/1/04 and 8/28/06 treated at Fox Chase Cancer Center. Results: 160 pts were treated, with 157 pts receiving at least one therapy regimen by 10 attending oncologists. There were 350 changes in therapy with 246 (70%) including continuation of at least one prior drug (92 BV, 111 fluoropyrimidines, 43 other). The most common reasons for treatment change were toxicity (33%), progressive disease (PD) (29%), treatment breaks (15%), and metastasectomy (11%) ( Table ). PD was a more common cause for treatment discontinuation in later phases of treatment (18% initial regimen vs. 36% subsequent regimens, p=0.0002). 24% of pts treated with oxaliplatin (OX) discontinued due to neuropathy. Hypersensitivity caused discontinuation in 5% of pts with OX and 7% of pts with CET. Resection of metastases was undertaken in 38% of pts. 43% of these pts received neoadjuvant therapy, and 56% received adjuvant therapy. 30% of pts have died, 29% remain on active treatment, 28% are on a treatment break, 3% are on hospice, and 11% are lost to follow-up. Conclusions: PD is no longer the primary reason for change of therapy in pts with mCRC. Metastasectomy is common and OX neuropathy is often treatment-limiting. These findings have important implications for endpoint selection and design of clinical trials in mCRC. Future clinical trials in mCRC must recognize treatment complexities and capture key components of decision-making that may result in prolonged survival. Furthermore, treatment breaks represent a potential window for the evaluation of new drugs. [Table: see text] No significant financial relationships to disclose.
A phase I study of vorinostat (suberoylanilide hydroxamic acid) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)
Authors: Fakih M. G. , Pendyala L. , Smith P. , Creaven P. , Toth K. , Zwiebel J. , Frankel S. , Litwin A. , Huffman L. , Egorin M. 
Published: March 2020

4088 Background: At 5μM, vorinostat decreases thymidilate synthase (TS) expression by ∼ 40 fold, which translates into synergistic antitumor activity when added to 5-FU. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design with a planned expansion of the maximum tolerated dose (MTD) cohort to 10 patients (pts). Vorinostat (100mg, 200mg, 300mg, 400 mg dose levels) was given twice daily for 1 week followed by 1 week break. FOLFOX was administered at a fixed standard dose every 2 weeks on the 4th day of vorinostat. Tumor biopsies were obtained from liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 19 pts were treated on study (M/F: 12/7; median age: 58; ECOG 0/1: 6/13). All pts had failed prior FOLFOX therapy. Dose-limiting toxicities (DLT) were noted in 3 pts: 2/4 pts at dose level (DL)4 (vorinostat 400mg BID) consisting of grade (G) 3 fatigue, & diarrhea in 1 pt and G3 fatigue in the other; 1/8 pts at DL3 (MTD, vorinostat 300mg BID) consisting of G3 fatigue, anorexia, nausea, and dehydration. 8 pts have been treated at the MTD for a total of 38 cycles. “All Cycles” G3–4 toxicities at the MTD consisted of 2 pts with G3 neutropenia and 2 pts with G3 thrombocytopenia along with the above described DLT. Responses were evaluable in 17 pts: 0 Objective Response, 8 Stable Disease (4 confirmed). TS expression by IHC and by RT-PCR showed modest decreases in 2/6 patients after vorinostat treatment. Cmax of SAHA was < 2μM at all investigated DL, which could explain the lack of adequate TS down-regulation. Conclusions: vorinostat 300mg PO BID × 1 week every 2 weeks in combination with FOLFOX is the established recommended dose. The lack of significant TS down-regulation may be due to the suboptimal serum vorinostat concentrations. Alternate shorter vorinostat schedules may allow for further daily dose escalations and hence for better likelihood of TS down-regulation. This study was partly supported by CTEP, NCI. No significant financial relationships to disclose.
Phase II study of infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for metastatic colorectal cancer
Authors: Kopetz S. , Glover K. Y. , Eng C. , Wolff R. A. , Chang D. Z. , Adinin R. B. , Morris J. , Abbruzzese J. L. , Hoff P. M. 
Published: March 2020

4089 Background: When compared to bolus 5-fluorouracil (F), leucovorin (L), and irinotecan (I) regimens such as IFL, the infusional F, L, I regimen (FOLFIRI) resulted in a improved toxicity profile with a response rate (RR) of 35% and median progression free survival (PFS) of 6.7 months. When combined with bevacizumab (B) as first-line treatment, IFL demonstrated improved activity with a RR of 45% and a median PFS of 10.6 months. Combining FOLFIRI and B may further improve the efficacy. Methods: We designed a single-arm, phase II trial of FOLFIRI+B with B (5mg/kg), I (180mg/m2), bolus of F (400mg/m2) and L (400mg/m2) with a 46-hour infusion of F (2400mg/m2) every 2 weeks. The primary endpoint was PFS. Chemotherapy naïve mCRC patients (pts) with a performance status of 0–2 received B alone on Day -14, starting FOLFIRI+B on Day 1. Proteomic and radiographic correlative studies were completed and will be reported separately. Results: N=41 pts, median age 56 y/o (range 26–78), M:F = 16:25, 5 pts with prior adjuvant therapy, were enrolled from 1/2005 to 1/2007. A total of 502 cycles have been administered (median = 12). The median PFS is 12.6 months. Response rate by intention-to-treat analysis was 62% (24 pts), with 33% stable disease (13 pts). Responses occurred after a median of 4 months of therapy. Fifteen pts remain on treatment; 26 pts are off study: 7 for progressive disease, 2 withdrew consent, 7 for toxicity and 2 for surgery unrelated to cancer. Eight pts were removed from the study for metastasectomies. Grade 3 or 4 toxicities included 17 occurrences of grade = 3 neutropenia, including 1 grade 4 febrile neutropenia, 4 grade 4 pulmonary emboli, 2 grade 3 hand-foot syndrome, and 1 grade 3 diarrhea. One pt included in the analysis developed a possible microperforation, manifested by peritonitis, after B alone and never received FOLFIRI. Conclusion: FOLFIRI+B is well-tolerated and efficacious, with an impressive PFS that compares favorably to historical controls. This regimen is an excellent choice as a first-line treatment for mCRC. No significant financial relationships to disclose.
Vandetanib with mFOLFOX6 in advanced colorectal adenocarcinoma: An open-label, multicenter phase I study
Authors: Michael M. , Tebbutt N. , Gibbs P. , Smith R. , Godwood A. , Oliver S. 
Published: March 2020

4095 Background: Vandetanib (ZD6474) is a once-daily oral anticancer agent that selectively inhibits VEGFR- dependent tumor angiogenesis, and EGFR- and RET-dependent tumor cell proliferation. The primary objective of this Phase I study was to establish the safety and tolerability of the vandetanib + mFOLFOX6 combination in patients with metastatic colorectal cancer (CRC). Secondary objectives included an assessment of pharmacokinetic (PK) interactions between vandetanib and mFOLFOX6, and preliminary evaluation of efficacy (RECIST). Methods: Patients with CRC who were eligible for 1st- or 2nd-line chemotherapy received once-daily oral doses of vandetanib (100 mg) plus standard 14-day treatment cycles of mFOLFOX6 (oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 2-hr IV; 5-fluorouracil [5-FU] 400 mg/mg2 IV bolus and 5-FU 2400 mg/m2 46-hr IV). If <2 of 6 evaluable patients (ie, having completed 6 weeks of vandetanib treatment with associated mFOLFOX6 cycles) experienced a vandetanib-related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + mFOLFOX6. Results: Seventeen patients (12 male/5 female; 7 1st-line/10 2nd-line; mean age 61 years, range 48–75) received vandetanib 100 mg (n=9) or 300 mg (n=8) + mFOLFOX6; the median number of oxaliplatin cycles was 8. Two DLTs were reported: one patient receiving 100 mg vandetanib developed diarrhea (CTC grade 2), dehydration, electrolyte imbalance and QTc prolongation, and one patient receiving vandetanib 300 mg developed diarrhea (grade 3) that responded to dose reduction. Common adverse events (AEs), irrespective of grade, were diarrhea, nausea, lethargy (all n=11), neutropenia and peripheral neuropathy (both n=10); AEs =grade 3 reported in more than one patient were diarrhea (n=4, all grade 3) and neutropenia (n=5, grade 3; n=2, grade 4). There was no apparent PK interaction between vandetanib and oxaliplatin or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=3), stable disease =8 weeks (n=8), and progressive disease (n=3). Conclusions: In patients with advanced CRC, combining once-daily vandetanib (100 or 300 mg) with mFOLFOX6 was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies No significant financial relationships to disclose.
Phase II clinical study of combination therapy with irinotecan and S-1(IRIS) for inoperable recurrent advanced colorectal cancer (2nd report): For Hokkaido Gastrointestinal Cancer Study Group (HGCSG)
Authors: Komatsu Y. , Yuki S. , Iwanaga I. , Kudo M. , Tateyama M. , Amano T. , Sakata Y. , Asaka M. 
Published: March 2020

4105 Background: We planned to conduct a phase II clinical study of combination therapy with irinotecan and S-1, a new oral anticancer drug of the fluorinated pyrimidine type. We reported the interim reports of this study in colorectal cancer patients at ASCO 2006. Methods: The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20–75 years. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. Results: Forty patients were enrolled in the present study. There were 23 men and 17 women. The median age was 62 years (range: 34 to 74 years). Two patients showed grade 4 neutropenia, but the next course could be given safely after dose reduction. Three patients had grade 3 diarrhea, but therapy could be continued with addition of an antidiarrhea drug. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Forty pts. are evaluable for efficacy: RR was 52.5% (CR 1, PR 20, SD 17, PD 2, 95% CI, 37–68%) and Disease Control Rate (CR+PR+SD) was seen in 96.0% of pts. PFS of this regimen is 311 days. MST is not reached. Conclusions: IRIS therapy achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer. It seems that IRIS is a good treatment equal to FOLFIRI. Non-inferiority randomized phase III trial of IRIS vs. mFOLFOX6 (IFOX study) was planned, and it has been already started now. The latest data will be reported at the meeting. No significant financial relationships to disclose.
Microarray analysis of formalin-fixed paraffin-embedded specimens shows distinct gene expression patterns in tumors containing the transforming growth factor beta receptor 6A polymorphism (TGFBR1*6A)
Authors: Omori A. , Stephens C. , Cooc J. , Danenberg P. V. , Danenberg K. , Lenz H. , Pasche B. 
Published: March 2020

4111 Introduction: A frequent polymorphism of the type I transforming growth factor beta receptor (TGFBR1) is TGFBR1*6A (6A), which has a deletion of 3 CGC triplets coding for alanine within a 9-alanine (9A) repeat of TGFBR1 exon 1. 6A may act as a tumor susceptibility allele through switching TGF-beta growth inhibitory signals into growth stimulatory signals and also appears to be acquired in some cases by primary colon cancers and their liver metastases. Our aim in this study was to compare the gene expression profiles of colorectal tumors bearing the 6A and the more common 9A genotypes to discover pathways that might be differentially induced by the 6A polymorphism. Methods: 28 colorectal tumors with matched synchronous metastases and 23 non-metastatic colorectal tumors were analyzed for TGFBR1 exon 1 genotype by a PCR-based assay. Nine metastatic and 10 non-metastatic tumors were analyzed by gene expression microarrays. Following microdissection of paraffin-embedded specimens, RNA was isolated, amplified, labeled, and hybridized to Affymetrix U133 Plus 2.0 GeneChips. Results: Among the 28 primary metastatic tumors, 19 were 9A (68%), 8 were 9A/6A heterozygotes (29%) and 1 was a 6A homozygote (3%). There was 100% genotype correspondence with the matched metastases. Among the 23 non-metastatic tumors, 18 were 9A (78%), 3 were heterozygotes (13%) and 2 were 6A/6A (9%). Microarray analysis showed 578 differentially expressed genes in the metastatic tumors and 467 in the non-metastatic tumors between the 6A and 9A genotypes (p<0.01). Significant pathway deregulation between 9A and 6A genotypes included estrogen receptor signaling and histidine metabolism in the non-metastatic tumors and B cell receptor, GM-CSF, SAPK/JNK and IL-4 signaling in the metastatic tumors. Conclusion: Microarray analysis shows differentially expressed genes in the 6A genotype compared to 9A, with different deregulated pathways in metastatic and non-metastatic tumors. This alludes to 6A-specific downstream signaling effects, which may contribute to tumor development and progression. No significant financial relationships to disclose.
Evaluation of Spondin-1 as a predictive marker for palliative 5-FU-based chemotherapy in metastatic colorectal cancer
Authors: Brueckl W. M. , Wirtz R. M. , Croner R. S. , Boxberger F. , Papadopoulos T. , Kirchner T. , Hahn E. G. , Hohenberger W. , Wein A. 
Published: March 2020

4112 Background: An individualized tumor tailored chemotherapy may improve survival of patients with metastatic colorectal carcinoma (CRC). Therefore, we analyzed gene expression profiles of liver metastases and primaries of patients with CRC before application of a palliative 5-Fluorouracil based chemotherapy (AIO regimen) due to find predictive markers. These potential markers had to: (1) be highly expressed in the primary (2) and in the metastases, (3) be applicable to qRT-PCR of formalin-fixed paraffin embedded (FFPE) sections, and (4) remain their predictive power in a test set cohort. Methods: The training set consisted of 30 specimen from primary CRC and metastatic liver, which were laser micro dissected, the RNA was amplified and hybridized to Affymetrix HG U-133A microarrays. Additionally, RNA was isolated from FFPE sections of the same tumors and a qRT-PCR was performed for specific gene expression analysis. After surgery of the primary tumor all patients were treated with the AIO regimen. The test set consisted of 61 metastatic CRC patients, who were treated with the AIO regimen and where FFPE sections were available. Markers who showed promising predictive power and fulfilled criteria 1–3 (cp. background) were tested in the validation cohort. Response to chemotherapy was verified by CT scans according to WHO criteria. Results: By using statistical tests we identified some markers showing promising predictive power. However, most of them did not fulfill the further criteria. Spondin-1 expressions were very predictive for response (CR, PR) with a sensitivity of 62.5% and a specifity of 87.5% in the training set. Additionally, Spondin-1 was highly expressed as well in the tumors as in the metastases of CRC. Furthermore, the Affymetrix expression values for Spondin-1 were highly comparable with the RT-PCR data using FFPE sections from the same specimen. In the FFPE test set Spondin-1 remained its predictive value with sensitivity and specifity rates of 53.3% and 70.0%, respectively. Conclusions: Spondin-1 is an attractive candidate for further evaluation of response in CRC tumors treated with a 5-FU based chemotherapy as it is predictive and robust in terms of use in FFPE material. Further research with additional predictive markers to increase accuracy is ongoing. [Table: see text]
Predictive value of EGFR mRNA levels assessed by quantitative RT-PCR in primary tumors of patients treated with cetuximab for metastatic colorectal cancer
Authors: Briasoulis E. C. , Papamichael D. , Tzachanis D. , Christodoulou C. , Samantas E. , Razis E. , Papakostas P. , Bakoyiannis C. , Wirtz R. M. , Kalogeras K. T. 
Published: March 2020

4121 Background: The epidermal growth factor receptor (EGFR) protein is the nominal target of the monoclonal therapeutic antibody cetuximab. Yet, repeated failure of EGFR immunohistochemistry (IHC) in predicting treatment outcome has questioned its value in colorectal cancer (CRC). Therefore search for a valid molecular predictor of cetuximab efficacy is highly justified. Methods: 64 CRC patients were treated with standard chemotherapy plus cetuximab in the metastatic setting. RNA was isolated from fixed tumor tissue samples employing an experimental method based on magnetic beads from Siemens Medical Solutions Diagnostics, followed by kinetic one-step RT-PCR for EGFR, HER-2, HER-3, and HER-4 analysis. EGFR protein levels were also assessed by IHC in 62 of the patients, using the 31G7 clone of the mouse monoclonal antibody (Zymed). Slides scored 1+, 2+ and 3+ were considered EGFR protein positive. Results: After a median follow-up of 17 months, median survival was 15.1 months, while median time to disease progression (TTP) was 6.6 months. For the RT-PCR results an objective cut-off at the 2nd quartile (median) for the HER family was chosen. EGFR RNA levels above the median value, demonstrated predictive value in terms of a prolonged TTP (9.3 vs. 5.5 months, p=0.017). No difference was found in terms of survival (24.6 vs. 12.6 months, p=0.106). EGRF assessed by IHC and the rest of the HER family markers assessed by RT-PCR failed to predict TTP outcome or survival. Finally, no agreement was found between the IHC and RT-PCR methods when assessing EGFR. Conclusions: The results of this retrospective study show a predictive value of EGFR RNA levels assessed by RT-PCR on TTP, as opposed to EGFR protein levels. Prospective validation studies are needed to prove if this biomarker is the missing molecular predictor of response to cetuximab. No significant financial relationships to disclose.
Vascular endothelial growth factor gene polymorphisms and risk of colorectal cancer
Authors: Cho Y. , Chae Y. , Kim J. , Shon S. , Moon J. , Jeon S. , Park J. , Lee I. , Lee I. , Choi G. , Jun S. 
Published: March 2020

4123 Background: Angiogenesis is closely related to the development, growth, and metastasis of solid tumors, including colorectal cancer (CRC), and the vascular endothelial growth factor (VEGF) is known to be a potent pro-angiogenic factor. Accordingly, the present study was conducted to evaluate the potential association between two VEGF polymorphisms (+405G > C, and 936C > T) and the risk of CRC. Methods: The VEGF genotypes were determined using fresh colorectal tumor tissue from 477 patients with CRC who underwent surgical resection and peripheral blood lymphocytes from 413 healthy controls based on a polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/DHPLC) assay. The incidence of genotypes and haplotypes of two VEGF polymorphisms was compared between the patients with CRC and the controls. Results: The distribution of genotypes and allele frequencies of the 936C > T polymorphism in the CRC group did not differ from those in the control group. However, compared with the combined GC and CC genotype, the GG genotype of +405G > C polymorphism was significantly associated with an increased risk of CRC [odds ratio (OR), 1.575; 95% confidence interval (CI), 1.178–2.104; P = 0.002]. In the haplotype analyses, haplotype +405G / 936C was also associated with a significantly increased risk of CRC (OR, 1.264; 95% CI, 1.043–1.531; P = 0.017), whereas haplotype +405C / 936C was associated with a decreased risk of CRC (OR, 0.818; 95% CI, 0.677–0.989; P = 0.038). None of the VEGF polymorphisms studied significantly influenced the clinical or pathologic features of CRC. Conclusions: These findings suggest that the VEGF +405G > C polymorphism may be associated with the risk of CRC in the Korean population. No significant financial relationships to disclose.
Assessment of the MMRpredict model for prediction of DNA mismatch repair gene mutations (Lynch Syndrome)
Authors: Nigon S. K. , Lindor N. M. 
Published: March 2020

4127 Background: The MMRpredict model, developed at the University of Edinburgh, is a web-based model developed to predict which patients diagnosed with colorectal cancer (CRC) under age 55 years have germline mutations in a DNA mismatch repair (MMR) gene [Barnetson et al., NEngJMed 2006;354:2751–63]. Stage 1 MMRpredict estimates the carrier probability for MMR mutations from clinical parameters (age of diagnosis of colorectal cancer, proximal vs distal site, family history, multiple primary CRCs). We evaluated the performance of Stage 1 of this model in a well characterized cohort of colorectal cancer patients. Methods: Cases with CRC were identified through the Minnesota Cancer Surveillance System (MCSS), a population based registry and Mayo Clinic Rochester, a clinical practice. All were consented participants in the Mayo Colon Cancer Family Registry. Of 342 cases tested for MMR mutations (MLH1, MSH2, MSH6), 45 had insufficient information on colon site and 62 were older than 55 and could not be used in the study. The remaining 235 included 110 females/125 males; 90 cases with proximal site/145 with distal site; 229/235 were self-identified as White. Results: We defined 5 probability risk groups based on output from the MMRpredict web model Stage 1: 1–10%, 11–25%, 26–50%, 51–75%, and 76–100%. In our study, the number of cases in each of these groups was 60, 45, 65, 34, and 31, respectively. The corresponding number of mutations in each group was 1 (1.7%), 4 (8.9%), 9 (13.8%), 3 (8.8%), and 11 (35.5%). Overall, 28/235 patients were found to have mutations (11.9%), compared to predicted range of 62–107 (26–45%). Conclusion: MMRpredict Stage 1 over-estimated the probability of detecting a MMR gene mutation in this study. This may reflect ascertainment issues or genetics of different populations. No significant financial relationships to disclose.