bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of a prospective multicenter study on the prevalence and genotype/phenotype correlation of the dihydropyrimidine dehydrogenase (DPD) gene exon-14 skipping mutation in patients treated with 5-fluorouracil (5-FU) chemotherapy
Authors: Raida M. , Friedrich A. , Borris H. , Niederwieser D. , Behnke D. , Kliche K. O. , Ruffert K. , Schalhorn A. , Schwabe W. , Hausler P. 
Published: March 2020

3076 Background: DPD represents the initial and rate-limiting enzyme in the catabolism of 5-FU. Deficiency of DPD has been linked to toxic side effects of 5-FU. The most common mutation of the DPD gene resulting in severe DPD deficiency is a G to A mutation in the GT 5’-splice recognition site of intron 14 (exon 14 skipping mutation). The corresponding mRNA lacks exon 14 and the enzymatic activity of the translated DPD protein is virtually absent. In a clinical setting heterozygous and homozygous carriers are being observed. Methods: We developed an RT-PCR based assay suitable for routine identification of the exon 14 skipping mutation. From February 2001 to October 2004 we performed an open, uncontrolled, prospective multicenter study to evaluate the prevalence and genotype/phenotype correlation of the exon 14 skipping mutation in patients treated with 5-FU chemotherapy. 1455 patients from 70 clinical centers in Germany were included in the study. Results: We identified 15 heterozygous carriers confirming a prevalence of 1% in the Caucasian population. For the analysis of 5-FU related toxicity WHO grades were ranked with a toxicity index revealing a significant higher toxicity in heterozygous compared to wildtype patients (p<0.0001). 50% of the heterozygote patients subsequently were treated with reduced doses of 5-FU. Nonetheless the positive predictive value of the screening test was still 50% indicating a strong correlation between genotype and phenotype. To identify patients in risk of severe 5-FU related toxicity we performed 5-FU pharmacokinetics in 12 heterozygous patients and 8 wildtype patients. All heterozygous patients showed a pathological 5-FU half-life with broad variations after intravenous bolus application of 450 mg/m2 5-FU while 75% of the wildtype controls had physiological results. Conclusions: We conclude that routine testing for the exon 14 skipping mutation and additional 5-FU pharmacokinetics for heterozygous patients prior to 5-FU treatment is an important step towards individually tailored therapy in cancer patients. [Table: see text]
Phase I dose escalation, pharmacokinetic, and biomarker study of imatinib mesylate plus capecitabine in advanced solid tumor malignancies
Authors: Favaro J. P. , Petros W. , Hong T. , Fernando N. , Bendell J. C. , Gockerman J. P. , George D. J. , Williams-Truax R. , Nixon A. , Yu D. , Hurwitz H. 
Published: March 2020

3093 Background: Preclinical data have suggested at least additive antitumor effects when imatinib (I) and 5-FU are combined. The goals of this study were to determine the maximal tolerated dose for the combination of I and capecitabine (C) in solid tumor patients (pts), as well as to describe non-dose limiting toxicities (non-DLT), pharmacokinetics (PK), and pharmacodynamics (PDGFR inhibition in granulation tissue). Methods: 24 pts (12 M, 12 F) with solid tumor malignancies received C plus I using a 21 day (d) cycle. C was dosed BID for 14/21 d. I was dosed QD x 21d. Results: 24 of 24 pts were fully evaluable for toxicity and efficacy. 6 pts were treated at dose level 1 (C 1000 mg/m2 BID, I 300 mg QD). The only dose limiting toxicity (DLT) at dose level 1 was grade (gr) 3 diarrhea in 1 patient; however 5 of 6 pts required dose reductions in a subsequent cycle. Therefore, the next 18 pts were treated at dose level -1 (C 750 mg/m2 BID and I 300 mg QD). One DLT (gr 3 fatigue) was seen at dose level -1. Non-DLT gr ¾ toxicities at any point at dose level -1 were gr 4 anemia (n=1) and gr 3 lymphopenia (n=6). Toxicities requiring dose reductions at any point on dose level -1 occurred in 7/18 patients. Gr ½ toxicities found in > 10% of all patients at any point in the trial were anemia (46%), leukopenia (17%), neutropenia (21%), lymphopenia (29%), thrombocytopenia (29%), nausea (71%), anorexia (41%), edema (42%), diarrhea (38%), hand foot syndrome (33%), vomiting (33%), headache (25%), insomnia (25%), skin rash (25%), constipation (21%), stomatitis (17%), lightheadedness (13%), fatigue (13%), numbness/tingling (13%), taste change (13%), and elevated transaminases (13%). 1 pt with carcinoid tumor had a partial response. 1 pt with non-small cell lung cancer had a minor response, and 5/21 pts had stable disease as their best response. 1 pt had stable disease for 8 months and another pt was stable for 6 months. Conculsions: On a 21 d cycle, the recommended phase 2 dose of C plus I is C 750 mg/m2 BID for 14 d, and I 300 mg QD. [Table: see text]
Complete radiological response of colorectal liver metastases (LM) after chemotherapy: Does it mean cure?
Authors: Nordlinger B. , Brouquet A. , Penna C. , Julié C. , El Hajjam M. , Chagnon S. , Mitry E. , Rougier P. , Benoist S. 
Published: March 2020

3501 Background: Most of patients with colorectal LM receive systemic chemotherapy. Complete response on imaging is considered a good indicator of the efficacy of chemotherapy. Whether complete radiological response is correlated to complete pathological response is not well known. The objective of this study was to determine the significance of complete radiological response of LM after chemotherapy. Methods: Between 1998 and 2004, 586 patients were treated in one institution for colorectal LM. 38 with the following criteria were included in the study: less than 10 LM before chemotherapy, disappearance of one or several LM on helical CT scan and ultrasound after chemotherapy, surgery with liver examination and intraoperative ultrasound within 4 weeks after imaging, no extra-hepatic disease, follow-up at least one year after surgery. Results: Overall, 66 LM disappeared on imaging after chemotherapy (38 patients). In 9 patients, persistent macroscopic disease was observed at surgery at the site of 20/66 (30%) LM although there were considered in complete response on imaging. In 15 patients, with no remnant disease at surgery, the sites of 15 initial LM were resected. Pathological examination of theses sites of LM considered in complete response showed the presence of viable tumor cells in 12/15 cases (80%). In 14 other patients, the sites of 31 initial LM, which were not visible at surgical exploration were left in place during surgery. After one year of follow-up, 23/31 (74%) LM considered in complete response had recurred in situ (11/14 patients). Overall, persistent macroscopic or microscopic residual disease or early recurrence in situ were observed in 55/66 LM (83%) with complete radiological response (32/38 patients). Conclusions: Complete radiological response in patients who have received chemotherapy is a useful tool to evaluate the effect of chemotherapy but it does not mean cure in most patients. This should be taken into account when considering multimodality treatment including chemotherapy and surgery. No significant financial relationships to disclose.
Genetic polymorphisms, toxicity, and response rate in African Americans (AA) with metastatic colorectal cancer (MCRC) compared to Caucasians (C) when treated with IFL, FOLFOX or IROX in Intergroup N9741
Authors: Goldberg R. M. , McLeod H. L. , Sargent D. J. , Morton R. F. , Green E. M. , Fuchs C. , Ramanathan R. K. , Williamson S. K. , Findlay B. P. , Pitot H. C. , Alberts S. R. 
Published: March 2020

3503 Background: The association between race & toxicity or response to systemic chemotherapy is poorly understood. We correlated relevent polymorphisms with toxicity & outcome data in AA & C patients (Pts) enrolled in N9741, a large randomized MCRC trial. Methods: Toxicity, response rate (RR), time to progression (TTP), overall survival (OS), & dose intensity (DI) were examined as a function of race in 1412 Pts enrolled on IFL, both full and reduced dose, FOLFOX, or IROX including 486 Pts with pharmacogenomic data. Accrual by race permitted comparison of C (n=1297) to AA (n=112). Results: C & AA were similar in disease extent, PS, gender, prior adjuvant treatment, and DI at cycles 1, 3, 6, or 12. The impact of race on RR, toxicity & the distribution of four relevent drug metabolism genotypes are in the table . AA had lower RR overall & in each treatment arm. Lower toxicity rates were seen in AA Pts, mainly due to less diarrhea, as measured by both CTC V2 & patient reported outcome data. These relationships were maintained in multivariate models adjusting for arm, age, gender, & PS. In these multivariate models, the odds ratio between RR and race was 1.72 (p=0.012) (29% AA vs 41% C) & for severe toxicity the odds ratio was 1.76 (p=0.006) (34% AA vs 48% C). Overall, race was not a significant predictor of TTP or OS (p > 0.50 for each). The hazard ratio comparing FOLFOX to IFL for C was 0.67 and for AA was 0.55. TTP for FOLFOX was superior to both IFL and IROX for both C & AA. Significant differences in pharmacogenetic variants were observed between C & AA, although the sample size for investigating the three-way combination of Rx, race, & pharmacogenomics is too small (36 AA) to draw definitive conclusions. Conclusions: It appears that AA have less toxicity & a lower RR than C when treated with standard MCRC regimens. Different frequencies of polymorphisms in genes relevent to drug metabolism may help explain these clinical differences. [Table: see text] [Table: see text]
A randomized trial of first-line irinotecan/fluoropymidine combinations with or without celecoxib in metastatic colorectal cancer (BICC-C)
Authors: Fuchs C. , Marshall J. , Mitchell E. , Wierzbicki R. , Ganju V. , Jeffery M. , Schultz J. , Richards D. , Wang B. , Morrison M. 
Published: March 2020

3506 Background: This multicenter, randomized study assessed efficacy & safety for 3 irinotecan/fluoropyrimidines combinations in previously untreated mCRC. In a 3 × 2 factorial design, we also assessed whether celecoxib added to chemotherapy (CT) improved CT efficacy and/or reduced toxicity. Methods: Pts were randomized to: FOLFIRI - irinotecan (I) 180 mg/m2, leucovorin (LV) 400 mg/m2, 5-FU bolus 400 mg/m2, & infusional 5-FU 2400 mg/m2 over 46 hours q 2 wks; modified IFL (m-IFL) - I 125 mg/m2, LV 20 mg/m2, & bolus 5-FU 500 mg/m2 wkly × 2, q 3 wks; or CapeIri - I 250 mg/m2 day 1 & capecitabine 1000 mg/m2 po BID × 14 days, q 3 wks. Pts were also randomized to concurrent celecoxib (400 mg po BID) or placebo in a double-blind fashion. Time to progression (TTP) was the primary endpoint. Results: 430 pts were enrolled from 2/03 to 4/04, prior to an amendment that added bevacizumab to CT arms. Baseline characteristics were balanced. TTP for FOLFIRI (median = 8.2 mos) was significantly better than for either m-IFL (6.0 mos; p = 0.01) or CapeIri (5.7 mos; p = 0.01). Overall survival (OS) also favored FOLFIRI (median = 23.1 mos) compared to either m-IFL (17.6 mos; p=0.10) or CapeIri (18.8 mos; p = 0.19). Common grade ≥ 3 toxicities are listed below. CapeIri had the highest rates of nausea, vomiting, diarrhea, dehydration & hand-foot syndrome, whereas FOLFIRI had lower rates. Among all 430 pts, median TTP did not differ for pts randomized to celecoxib compared to placebo (6.9 vs 6.9 mos; p=0.71). Median OS was also similar for celecoxib vs placebo (19.5 vs 18.8 mos; p=0.63). CT toxicities did not differ for celecoxib vs placebo. Rates for MI/stroke were 1.5% for celecoxib and 1.9% for placebo. Conclusions: First-line FOLFIRI offers a superior TTP when compared to m-IFL or CapeIri; OS & toxicity analyses also favored FOLFIRI. Celecoxib neither improved CT efficacy nor reduced CT toxicity. Updated survival data & data on pts enrolled after the addition of bevacuzimab will be presented. [Table: see text] [Table: see text]
LiverMetSurvey: Analysis of clinicopathologic factors associated with the efficacy of preoperative chemotherapy in 2,122 patients with colorectal liver metastases
Authors: Adam R. , Aloia T. , Figueras J. , Capussotti L. , Poston G. , Mentha G. , Selzner M. 
Published: March 2020

3521 Background: LiverMetSurvey is an international, internet-based registry designed to assess the efficacy of multimodality treatment options for colorectal liver metastases (CLM) by analyzing outcomes following hepatic resection (HR) in a large number of patients. Methods: Data were analyzed for the 2,122 patients entered into LiverMetSurvey by six hepatobiliary centers from inception to August 2004 (HR: 1974 to 2004; 1,306 men: 816 women; mean age: 61 years). The distributions of potential prognostic factors including age, sex, primary tumor site, timing of metastasis diagnosis, tumor number, diameter of the largest metastasis, bilaterality, and treatment with chemotherapy were compared to survivals using univariate and multivariate statistics. Results: Metastases originated in the colon in 69% of patients and were synchronous (diagnosed within 3 mo of primary tumor treatment) in 49% of patients. 34% of patients had ≥ 3 metastases and tumors were distributed bilaterally in 43% of cases. The mean size of the largest metastasis was 41.8 mm. 55% of patients were treated with preoperative systemic chemotherapy. Following resection, 60-day mortality was 1.2% and median, 5-year, and 10-year overall survivals (OS) were 46 mo, 42%, and 26%, respectively. Variables independently associated with poor prognosis included number of metastases > 3 (p<0.0001), bilateral metastases (p=0.0002), and size of the largest metastasis > 5 cm (p=0.03). Preoperative chemotherapy (PC) did not appear to benefit patients with solitary CLM (5-yr OS: PC 45% vs. no PC 58%), but was associated with improved survival in patients with > 5 metastases (5-yr OS: PC 22% vs. no PC 12%). Conclusions: Assessment of outcomes for the first 2,122 registrants to LiverMetSurvey not only confirms the prognostic importance of intrahepatic tumor burden, but also indicates that the ability of preoperative systemic chemotherapy to improve survivals is limited to patients with multiple (> 5) metastases. In addition, this analysis demonstrates the potential for LiverMetSurvey, which is now prospectively enrolling patients from over 40 centers, to determine the therapeutic value of current and future treatment strategies. No significant financial relationships to disclose.
Circulating endothelial cells (CEC) and circulating tumor cells (CTC) in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Cohen S. J. , Terstappen L. W. , Punt C. J. , Mitchell E. P. , Fynan T. M. , Li T. , Matera J. , Doyle G. V. , Meropol N. J. 
Published: March 2020

3531 Background: Lack of validated surrogate endpoints is an impediment to developing new cancer therapy. We hypothesized that CTC and CEC could predict outcome in pts undergoing treatment for mCRC. Methods: Eligible pts for this multicenter study had mCRC, and were initiating 1st, 2nd, or 3rd-line systemic therapy. Blood was obtained at baseline and 3–4 weeks after treatment initiation for enumeration of CTC/CEC. CTC/7.5ml and CEC/4ml of blood were measured with the CellSearch System. CTC were immunomagnetically enriched targeting CD326 (EpCAM), stained with DAPI, cytokeratin 8,18,19, and CD45. CEC expressing CD146 were immunomagnetically enriched and stained with DAPI, CD105, and counterstained with CD45. Cell morphology was confirmed in all cases. Results: In 139 controlsCTC were virtually absent (0 CTC in 135 and 1 CTC in 4). For 131 pts with mCRC, >1CTC was detected before therapy in 40/131(31%) (range 0–73) and 3–4 weeks after starting therapy in 12/131 (9%) (range 0–100) (p<0.0001, McNemar’s test). Pts with >1 CTC at baseline and 3–4 weeks did not differ by line of therapy (1st line: 28/93 [30.1%] at baseline, 7/93 [7.5%] at 3–4 weeks; second/third-line: 6/24 [25%] at baseline, 3/24 [12.5%] at 3–4 weeks, p=0.57, Breslow-Day test). For 15/131 (11.5%) a 2-fold increase and for 53/131 (40.5%) a 2-fold decrease in CTC was found after treatment. Using 249 controls, a normal reference range of 4–80 CEC/4 ml of blood was established. In 16/131 (12.2%) pts >80 CEC were detected before (range 1–1342) and in 18/131(13.7%) after start of therapy (range 2–519) (p=0.71, McNemar’s test). Pts with >80 CEC at baseline and 3–4 weeks did not differ by line of therapy (1st line: 9/93 [9.7%] at baseline, 13/93 [14%] at 3–4 weeks; 2nd/3rd line: 5/24 [20.8%] at baseline, 2/24 [8.3%] at 3–4 weeks, p=0.16, Breslow-Day test). In 37/131 (28.2%) a 2-fold increase and in 35/131 (26.7%) a 2-fold decrease in CEC was found after initiation of therapy. Conclusions: Isolating and enumerating CTC/CEC in pts receiving therapy for mCRC is feasible. CTC generally decrease with therapy, while change in CEC has greater variability. Enrollment in this 400 patient multicenter study is nearing completion, and definitive analysis of relationship of CTC/CEC change to clinical outcome is planned. [Table: see text]
Polymorphism in sodium-channel alpha 1-subunit (SCN1A) predicts response, TTP, survival, and toxicity in patients with metastatic colorectal cancer treated with 5-FU/oxaliplatin
Authors: Nagashima F. , Zhang W. , Yang D. , Gordon M. , Schultheis A. , Fazzone W. , Azuma M. , El-Khoueiry A. , Iqbal S. , Lenz H. J. 
Published: March 2020

3533 Background: Genetic polymorphisms in DNA repair and drug metabolism pathways have been shown to be associated with efficacy and toxicity in patients with metastatic colon cancer treated with 5-FU/oxaliplatin. Recent studies demonstrated in in vitro models that the neurotoxicity associated with oxaliplatin may be linked to an effect on neuronal voltage-gated sodium channels (VGSC). In vitro and in vivo models showed that increased VGSC alpha gene expression was associated with metastatic potential, proliferation and progression of breast and prostate cancer indicating a role in predicting toxicity and efficacy to chemotherapy. We tested the hypothesis whether VGSC gene polymorphisms may predict clinical outcome in a phase II study of combination oxaliplatin with 5-FU in patients with colorectal cancer refractory to 5-FU and/or irinotecan based chemotherapy. Methods: 173 patients were enrolled in this phase II study. 152 patients (male/female; 78/74, median age; 60), median follow up of 18.6 months, response rate of 19%, median time to tumor progression 4.2 months and median survival of 10.3 months. Grade 3/4 toxicity was seen in 60% with GI toxicity of 42% and Neurotoxicity of 11%. The dose of oxaliplatin was 130mg/m2 every 3 weeks and 5-FU was 200mg/m2/day CI for 10 weeks followed by 2 weeks rest. We tested the 12 VGSC genes polymorphisms (SCN1A, 1B, 1A1, 1A2, 1A3, 1A4, 1A5, 1A A3169G SNP, 1A C1702T Nonsense Mutation, 1A T1067A SNP, 1A C3637T SNP, SCN8A Ref SNP 303802). Genomic DNA was extracted from peripheral blood samples and polymorphisms were analyzed by PCR-based RFLP technique. Results: Patients with SCN1A T1067A SNP T/T genotype showed a significant better response rate (p=0.02, 21.9% [23/105] vs. 11.3% [5/44]), TTP (p=0.02, 4.6 months vs. 3.4 months), overall survival (p<.001, 12.3 months. vs. 8.0 months.), and frequency of grade 3/4 toxicity (p=.002) compare to patients with T/A genotype. No A/A genotype was observed. Conclusions: SCN1A gene polymorphism may be potential molecular marker for survival and toxicity in patients with colorectal cancer treated with 5-FU/oxaliplatin. In vitro studies are ongoing to identify the mechanism of resistance by SCN1A. [Table: see text]
Risk factors for gastrointestinal perforations in patients with metastatic colorectal cancer receiving bevacizumab plus chemotherapy
Authors: Sugrue M. , Kozloff M. , Hainsworth J. , Badarinath S. , Cohn A. , Flynn P. , Steis R. , Dong W. , Sarkar S. , Grothey A. 
Published: March 2020

3535 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival when added to standard chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of pts with mCRC receiving BV plus first-line chemotherapy (CT). Incidence rate, temporal pattern, and potential risk factors associated with gastrointestinal perforation (GIP) were explored. Methods: Baseline patient characteristics (BC), including prospectively identified potential risk factors for GIP, were collected at study entry. Safety data were collected every 3 months (mo). Logistic regression models, adjusted and unadjusted for treatment assignment, were used to identify BC potentially associated with GIP. Results: 1968 pts were enrolled between Feb 2004 and Jun 2005. Median study follow-up was 10 mo as of Nov 4, 2005. GIPs were observed in 34 pts (1.7%). For pts with GIP, median time to first event was 2.1 mo; the majority of events were non-fatal and occurred within the first 3 mo after starting BV. BC including GI medical history (chronic aspirin or NSAID use, peptic ulcer disease, diverticulosis) were similar in pts with or without GIP and with earlier or later GIP onset (≤ or >3 mo from start of BV). Although adjusted models did not show any significant BC, GIP rates were numerically higher in pts with primary tumor intact (2.6%) vs. resected (1.6%). Furthermore, univariate analyses revealed a significant difference between intact (2.3%) and resected (0.8%) primary tumor for earlier GIP (≤3 mo from start of BV). The majority of pts with GIP had at least one of the following: acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, tumor at GIP site, abdominal carcinomatosis, prior abdominal or pelvic radiation therapy. Conclusions: Preliminary analyses indicate the incidence of GIP in this large, community-based observational registry is similar to that previously reported in phase III mCRC trials with BV. No associations between specific BCs and an increased risk of GIP were identified. Patients with primary tumor intact were more likely to incur a GIP within the first 3 mo of starting BV and CT. [Table: see text]
Impact of bevacizumab dose reduction on clinical outcomes for patients treated on the Eastern Cooperative Oncology Group’s Study E3200
Authors: Giantonio B. J. , Catalano P. J. , O’Dwyer P. J. , Meropol N. J. , Benson A. B. 
Published: March 2020

3538 Background: E3200 demonstrated improved survival (OS) for previously treated metastatic colorectal cancer patients who received second-line therapy with bevacizumab (10 mg/kg) in combination with FOLFOX4. Dose reductions of bevacizumab to 5 mg/kg were allowed for: hypertension, bleeding and thrombosis of ≤ grade 2; proteinuria of > 2 grams/24 that resolved to <0.5 grams/24hrs; liver function abnormalities ≥ grade 3 that resolved to ≤ grade 1. Methods: Data on dose modifications of bevacizumab were obtained from a post-study survey of participating institutions for all participants. Median OS and progression-free survival (PFS) were determined based upon a dose reduction any time during treatment. Hazard ratios (HR) for OS and PFS were stratified by number of cycles (1–5, 6–10, 11+) to adjust for the time-varying nature of dose reductions. Results: Surveys were received on 84% of E3200 patients treated with bevacizumab. Dose reductions of bevacizumab were performed in 134 of 240 (55.8%) patients treated with FOLFOX + bevacizumab (Arm A) and 77 of 205 (37.6%) patients treated with bevacizumab alone (Arm C). The average number of cycles of bevacizumab administered at a dose reduction for Arm A is 42% and for Arm C is 52%. Conclusions: OS and PFS on E3200 were not compromised for patients who underwent dose reductions of bevacizumab. [Table: see text] [Table: see text]