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Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
Kaufman, PA, Awada, A, Twelves, C, Yelle, L, Perez, EA, Velikova, G, Olivo, MS, He, Y, Dutcus, CE, Cortes, J
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;(6):594-601
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Abstract
PURPOSE This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). PATIENTS AND METHODS Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). RESULTS Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. CONCLUSION In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.
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Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial.
Greenhalf, W, Ghaneh, P, Neoptolemos, JP, Palmer, DH, Cox, TF, Lamb, RF, Garner, E, Campbell, F, Mackey, JR, Costello, E, et al
Journal of the National Cancer Institute. 2014;(1):djt347
Abstract
BACKGROUND Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. METHODS Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. RESULTS Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients. CONCLUSIONS Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.
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The Effect of Pyridoxine for Prevention of Hand-Foot Syndrome in Colorectal Cancer Patients with Adjuvant Chemotherapy Using Capecitabine: A Randomized Study.
Ota, M, Tatsumi, K, Suwa, H, Watanabe, J, Watanabe, K, Osada, S, Tanaka, K, Shoichi, F, Ichikawa, Y, Kunisaki, C, et al
Hepato-gastroenterology. 2014;(132):1008-13
Abstract
UNLABELLED BACKGROUND/Aims: To determine the effect of the pyridoxine for prevention of hand-foot syndrome in colorectal cancer patients with adjuvant chemotherapy using capecitabine. METHODOLOGY Colorectal cancer patients scheduled for capecitabine chemotherapy as adjuvant setting were randomly assigned to with or without concurrent oral pyridoxine (60 mg/d) groups. Patients were monitored whether being a development of National Cancer Institute Common Toxicity Criteria grade 2 or worse HFS until chemotherapy ended. RESULTS Sixty patients were enrolled in this study. Relative dose intensity was 89.5% in total. The median number of chemotherapy cycles to grade 2 or worse HFS was four in both groups. Grade 2 or worse HES developed in 18 (60.0%) of 30 control patients and in 18 (60.0%) of 30 pyridoxine patients. The cumulative dose of capecitabine to grade 2 or worse HFS was not different between the two groups. CONCLUSIONS Pyridoxine is not effective in prevention of capecitabine-associated HFS.
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Fixed-dose rate gemcitabine alone or alternating with FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) in the first-line treatment of patients with metastatic pancreatic adenocarcinoma: an AGEO randomised phase II study (FIRGEM).
Trouilloud, I, Dupont-Gossard, AC, Malka, D, Artru, P, Gauthier, M, Lecomte, T, Aparicio, T, Thirot-Bidault, A, Lobry, C, Asnacios, A, et al
European journal of cancer (Oxford, England : 1990). 2014;(18):3116-24
Abstract
BACKGROUND Fluorouracil and irinotecan-based, and gemcitabine-based regimens, are the standard of care in the first-line treatment of patients with metastatic pancreatic cancer. New approaches are needed to improve survival and quality of life. Whether a sequential approach alternating irinotecan, fluorouracil and gemcitabine may be effective and tolerable in patients with metastatic pancreatic cancer is unknown. METHODS In this randomised, multicentre, open-label, phase 2 trial, patients with metastatic pancreatic adenocarcinoma, World Health Organisation (WHO) performance status 0-1, and bilirubin levels <1.5 upper limit of normal values (ULN) were randomised 1:1 to receive as first-line treatment either FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) alternating with fixed-dose rate gemcitabine as 2-month periods (FIRGEM, arm A), or fixed-dose rate gemcitabine alone (arm B). Treatment was continued until disease progression or limiting toxicity. The primary end-point was the crude progression-free survival (PFS) rate at 6 months. The study is registered with EudraCT (N° 2006-005703-34). RESULTS Between October 2007 and March 2011, 98 patients were enroled. The observed 6-month PFS rate was 43.5% (95% confidence interval (CI), [28.6-58.4%]) in arm A reaching the Fleming decision rules criteria to reject H0 and 26.1% (95% CI [12.9-39.3%]) in arm B. Objective response rates were 37% (23-51%) in arm A and 10% (1-19%) in arm B. Median PFS (5.0 versus 3.4 months, hazard ratio (HR)=0.59 [0.38-0.90]) and overall survival (11.0 versus 8.2 months, HR=0.71 [0.46-1.10]) were higher in arm A compared to arm B. The most frequent grade 3-4 toxicities were neutropenia (49%/24%; febrile neutropenia, 4%/0% in arms A/B), diarrhoea (arm A, 12% and arm B, 0%), and nausea/vomiting (8%/4%). No toxic deaths occurred. CONCLUSION The FIRGEM strategy appears to be effective and feasible in patients with metastatic pancreatic cancer.
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Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial.
Gourgou-Bourgade, S, Bascoul-Mollevi, C, Desseigne, F, Ychou, M, Bouché, O, Guimbaud, R, Bécouarn, Y, Adenis, A, Raoul, JL, Boige, V, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;(1):23-9
Abstract
PURPOSE To compare the quality of life (QoL) of patients receiving oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine as first-line chemotherapy and to assess whether pretreatment QoL predicts survival in patients with metastatic pancreatic cancer. PATIENTS AND METHODS Three hundred forty-two patients with performance status 0 or 1 were randomly assigned to receive FOLFIRINOX (oxaliplatin, 85 mg/m(2); irinotecan, 180 mg/m(2); leucovorin, 400 mg/m(2); and fluorouracil, 400 mg/m(2) bolus followed by 2,400 mg/m(2) 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m(2) weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. QoL was assessed using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every 2 weeks. RESULTS Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and improvement in emotional functioning (P < .001) was observed in both arms, along with a decrease in pain, insomnia, anorexia, and constipation in both arms. A significant increase in diarrhea was observed in the FOLFIRINOX arm during the first 2 months of chemotherapy. Time until definitive deterioration ≥ 20 points was significantly longer for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation). Physical functioning, constipation, and dyspnea were independent significant prognostic factors for survival with treatment arm, age older than 65 years, and low serum albumin. CONCLUSION FOLFIRINOX significantly reduces QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer. Furthermore, baseline QoL scores improved estimation of survival probability when added to baseline clinical and demographic variables.
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Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study.
Maréchal, R, Vos, B, Polus, M, Delaunoit, T, Peeters, M, Demetter, P, Hendlisz, A, Demols, A, Franchimont, D, Verset, G, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2012;(6):1525-30
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BACKGROUND Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.
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A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens.
Hainsworth, JD, Cebotaru, CL, Kanarev, V, Ciuleanu, TE, Damyanov, D, Stella, P, Ganchev, H, Pover, G, Morris, C, Tzekova, V
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2010;(10):1630-6
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Abstract
INTRODUCTION AZD6244 (ARRY-142886) is a potent, selective MEK inhibitor. This study aimed to evaluate the efficacy and safety of AZD6244 versus pemetrexed as second- or third-line treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS In this randomized phase II study, patients received either 100 mg oral AZD6244 free-base suspension twice daily or 500 mg/m(2) intravenous pemetrexed once every 3 weeks after pretreatment with a corticosteroid, folic acid, and vitamin B12. The primary end point of the study was the disease progression event count. RESULTS Eighty-four patients were randomized. Disease progression events were experienced by 28 (70%) and 26 (59%) patients in the AZD6244 and pemetrexed groups, respectively. Median progression-free survival was not statistically significantly different between the AZD6244 and pemetrexed groups (67 versus 90 days, respectively; hazard ratio 1.08, two-sided 80% confidence interval = 0.75-1.54; p = 0.79). Two patients in the AZD6244 group had a best response to treatment of partial response. In the pemetrexed group, one patient achieved a complete response and one patient a partial response. Dermatitis acneiform, diarrhea, nausea, and vomiting were the most frequently reported adverse events with AZD6244, compared with fatigue, anemia, nausea, anorexia, and dermatitis acneiform with pemetrexed. CONCLUSIONS Oral AZD6244 showed clinical activity as second- or third-line therapy for patients with advanced NSCLC. In an unselected NSCLC population, there is no suggestion that AZD6244 monotherapy offers any advantage over standard treatment with pemetrexed. Based on preclinical data and recent clinical observations, further development of AZD6244 in NSCLC should focus on BRAF or RAS mutation-positive patients and/or AZD6244-based combination regimens.
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Arsenic trioxide in patients with adenocarcinoma of the pancreas refractory to gemcitabine: a phase II trial of the University of Chicago Phase II Consortium.
Kindler, HL, Aklilu, M, Nattam, S, Vokes, EE
American journal of clinical oncology. 2008;(6):553-6
Abstract
OBJECTIVES There is no effective therapy for patients with metastatic pancreatic cancer who fail initial therapy with gemcitabine. Arsenic trioxide has potent antiproliferative and proapoptotic effects in pancreatic cancer cell lines. We conducted a multicenter phase II trial in patients with advanced pancreatic cancer who experienced disease progression on or after a gemcitabine-containing regimen. METHODS Arsenic trioxide 0.3 mg/kg was administered intravenously over 1 hour daily for 5 consecutive days every 28 days. Restaging computed tomography scans were obtained every 2 cycles. RESULTS Thirteen patients were enrolled between December 2002 and November 2003. Twenty-four cycles were administered (median 2; range 1-2). There were no grade 3/4 hematologic toxicities; grade 1/2 anemia and leukopenia occurred in 50% and 25% of patients, respectively. Grade 3 toxicities included fatigue and thrombosis in 17% of patients. Only 1 patient developed a prolongation of the QTc interval. There were no objective responses. Median progression-free survival was 1.6 months (95% confidence interval, 1.2-1.9). Median survival was 3.8 months (95% confidence interval, 1.6-6.8). CONCLUSIONS Despite promising in vitro data, arsenic trioxide has no activity in pancreatic cancer patients who develop progressive disease after gemcitabine. Multicenter phase II trials are feasible in this patient population, and novel agents are clearly needed.
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Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms and toxicity to capecitabine in advanced colorectal cancer patients.
Sharma, R, Hoskins, JM, Rivory, LP, Zucknick, M, London, R, Liddle, C, Clarke, SJ
Clinical cancer research : an official journal of the American Association for Cancer Research. 2008;(3):817-25
Abstract
PURPOSE To evaluate the effect of thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR) genotypes on toxicity in patients treated with capecitabine for advanced colorectal cancer and to determine the effect of these polymorphisms on the pretreatment levels of serum folate and plasma homocysteine. EXPERIMENTAL DESIGN Fifty-four patients with a diagnosis of metastatic colorectal cancer were treated with fixed-dose capecitabine. Germ line DNA from patients was genotyped for TYMS TSER, TSER*3G>C, and 3'-untranslated 6 bp insertion/deletion (3' untranslated region insertion/deletion), and MTHFR c.677C>T and c.1298A>C using PCRs and RFLP. Toxicity was graded by National Cancer Institute Common Toxicity Criteria version 2.0. Response was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS MTHFR c.677C>T and c.1298A>C genotypes and diplotypes predicted for grade 2/3 toxicities, whereas the TYMS genotypes had no influence. MTHFR c.677 genotype tended to predict overall survival (P = 0.08). MTHFR c.677 influenced pretreatment homocysteine (P < 0.05) and serum folate levels (P < 0.05). Multivariate analysis suggests that MTHFR c.1298 is an independent predictor of toxicity. CONCLUSIONS This study suggests that common genetic variation in MTHFR but not TYMS may be useful for predicting toxicity from capecitabine in patients with advanced colorectal cancer. In addition, MTHFR single nucleotide polymorphisms predicted serum folate and plasma homocysteine levels, and, combined, these factors may be important predictors of capecitabine-induced toxicity.
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Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group.
Schwab, M, Zanger, UM, Marx, C, Schaeffeler, E, Klein, K, Dippon, J, Kerb, R, Blievernicht, J, Fischer, J, Hofmann, U, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;(13):2131-8
Abstract
PURPOSE To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase (DPYD ), thymidylate synthase (TYMS ), and methylene tetrahydrofolate reductase (MTHFR ) and of nongenetic factors for severe leukopenia, diarrhea, and mucositis related to fluorouracil (FU) treatment. PATIENTS AND METHODS A multicenter prospective clinical trial included 683 patients with cancer treated with FU monotherapy. Toxicity was documented according to World Health Organization grades. DPYD, TYMS, and MTHFR genotypes were determined, and DPYD was resequenced in patients with severe toxicity. RESULTS Grade 3 to 4 toxicity occurred in 16.1% of patients. The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% (95%CI, 0.02 to 0.11), with a positive predictive value of 0.46 (95% CI, 0.19 to 0.75; P = .01). Inclusion of additional DPYD variants improved prediction only marginally. Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia, whereas TYMS was associated with diarrhea. Genotype, female sex, mode of FU administration, and modulation by folinic acid were identified as independent risk factors by multivariable analysis. A previously unrecognized significant interaction was found between sex and DPYD, which resulted in an odds ratio for toxicity of 41.8 for male patients (95% CI, 9.2 to 190; P < .0001) but only 1.33 (95% CI, 0.34 to 5.2) in female patients. Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold (95% CI, 1.08 to 2.22; P = .02). CONCLUSION DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.