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Methot, N., und K. Basler. „Suppressor of fused opposes hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus“. Development 127, Nr. 18 (15.09.2000): 4001–10. http://dx.doi.org/10.1242/dev.127.18.4001.
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Hedgehog controls the expression of key developmental genes through the conversion of the transcription factor Cubitus interruptus (Ci) into either an activator (Ci[act]) or a repressor (Ci[rep]) form. Proteolytic cleavage of full-length Ci is important for the generation of Ci[rep], but little is known about how Ci[act] arises in response to Hh. Here we examine Hh signal transduction components for their role in the conversion of full-length Ci into either Ci[act] or Ci[rep]. We report that Cos2, PKA and Fused are necessary for the generation of Ci[rep], whereas the inhibition of either Cos2 or PKA activity is a prerequisite for Ci[act] formation. Fused (Fu) kinase stimulates a constitutively active form of Ci in a Hh-dependent manner, suggesting that Fu enhances the activity rather than the formation of Ci[act]. Su(fu) reduces the nuclear accumulation of the constitutively active form of Ci, arguing that Su(fu) can function subsequent to Ci[act] formation. We propose that Hh induces target gene expression by a two-step mechanism in which Ci[act] is first formed and then accumulates in the nucleus via Fu-induced neutralization of Su(fu) activity.
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Zhou, Mengmeng, Yuhong Han, Bing Wang, Yong Suk Cho und Jin Jiang. „Dose-dependent phosphorylation and activation of Hh pathway transcription factors“. Life Science Alliance 5, Nr. 11 (05.09.2022): e202201570. http://dx.doi.org/10.26508/lsa.202201570.
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Graded Hedgehog (Hh) signaling is mediated by graded Cubitus interruptus (Ci)/Gli transcriptional activity, but how the Hh gradient is converted into the Ci/Gli activity gradient remains poorly understood. Here, we show that graded Hh induces a progressive increase in Ci phosphorylation at multiple Fused (Fu)/CK1 sites including a cluster located in the C-terminal Sufu-binding domain. We demonstrated that Fu directly phosphorylated Ci on S1382, priming CK1 phosphorylation on adjacent sites, and that Fu/CK1-mediated phosphorylation of the C-terminal sites interfered with Sufu binding and facilitated Ci activation. Phosphorylation at the N-terminal, middle, and C-terminal Fu/CK1 sites occurred independently of one another and each increased progressively in response to increasing levels of Hh or increasing amounts of Hh exposure time. Increasing the number of phospho-mimetic mutations of Fu/CK1 sites resulted in progressively increased Ci activation by alleviating Sufu-mediated inhibition. We found that the C-terminal Fu/CK1 phosphorylation cluster is conserved in Gli2 and contributes to its dose-dependent activation. Our study suggests that the Hh signaling gradient is translated into a Ci/Gli phosphorylation gradient that activates Ci/Gli by gradually releasing Sufu-mediated inhibition.
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Köhne, C.-H., J. Wils, M. Lorenz, P. Schöffski, R. Voigtmann, C. Bokemeyer, M. Lutz et al. „Randomized Phase III Study of High-Dose Fluorouracil Given As a Weekly 24-Hour Infusion With or Without Leucovorin Versus Bolus Fluorouracil Plus Leucovorin in Advanced Colorectal Cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952“. Journal of Clinical Oncology 21, Nr. 20 (15.10.2003): 3721–28. http://dx.doi.org/10.1200/jco.2003.11.122.
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Purpose: This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV. Patients and Methods: A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m2 intravenously + LV 20 mg/m2 on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2,600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + LV)—all given weekly ×6 followed by a 2-week rest period. Survival was the major study end point. Results: With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P = .724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P = .029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms. Conclusion: Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.
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Kabbinavar, Fairooz, Herbert I. Hurwitz, Louis Fehrenbacher, Neal J. Meropol, William F. Novotny, Grazyna Lieberman, Susan Griffing und Emily Bergsland. „Phase II, Randomized Trial Comparing Bevacizumab Plus Fluorouracil (FU)/Leucovorin (LV) With FU/LV Alone in Patients With Metastatic Colorectal Cancer“. Journal of Clinical Oncology 21, Nr. 1 (01.01.2003): 60–65. http://dx.doi.org/10.1200/jco.2003.10.066.
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Purpose: This phase II trial investigated the safety and efficacy of two doses of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, plus fluorouracil (FU)/leucovorin (LV) versus FU/LV alone in patients with metastatic colorectal cancer. Patients and Methods: One hundred four previously untreated patients with measurable metastatic colorectal cancer were randomly assigned to one of the following three treatment groups: 36 to FU (500 mg/m2)/LV (500 mg/m2) alone, 35 to FU/LV + low-dose bevacizumab (5 mg/kg every 2 weeks), and 33 to FU/LV + high-dose bevacizumab (10 mg/kg every 2 weeks). FU/LV was given weekly for the first 6 weeks of each 8-week cycle. Results: Compared with the FU/LV control arm, treatment with bevacizumab (at both dose levels) plus FU/LV resulted in higher response rates (control arm, 17%, 95% confidence interval [CI], 7% to 34%; low-dose arm, 40%, 95% CI, 24% to 58%; high-dose arm, 24%, 95% CI, 12% to 43%), longer median time to disease progression (control arm, 5.2 months, 95% CI, 3.5 to 5.6 months; low-dose arm, 9.0 months, 95% CI, 5.8 to 10.9 months; high-dose arm, 7.2 months, 95% CI, 3.8 to 9.2 months), and longer median survival (control arm, 13.8 months; 95% CI, 9.1 to 23.0 months; low-dose arm, 21.5 months, 95% CI, 17.3 to undetermined; high-dose arm, 16.1 months; 95% CI, 11.0 to 20.7 months). After cross-over, two of 22 patients had a partial response to bevacizumab alone. Thrombosis was the most significant adverse event and was fatal in one patient. Hypertension, proteinuria, and epistaxis were other potential safety concerns. Conclusion: The encouraging results of this randomized trial support further study of bevacizumab 5 mg/kg plus chemotherapy as first-line therapy for metastatic colorectal cancer.
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Ku, Geoffrey Yuyat, Benjamin Haaland und Gilberto de Lima Lopes. „Cetuximab (C225) in the first-line treatment of advanced colorectal cancer (CRC) patients (Pts) with K-ras wild-type (WT) tumors: Does the choice and schedule of fluoropyrimidine (Fp) matter?“ Journal of Clinical Oncology 30, Nr. 4_suppl (01.02.2012): 576. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.576.
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576 Background: C225, a monoclonal antibody against the epidermal growth factor receptor, has been shown to inconsistently improve response rates (RR), progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced CRC Pts with K-ras WT tumors. Methods: We performed a meta-analysis of four trials where K-ras WT Pts received a Fp (capecitabine (C) or bolus (b) or infusional (CI) 5-fluorouracil (5-FU)) and oxaliplatin (oxali) or irinotecan (CPT) ± C225 (CRYSTAL, OPUS, COIN and NORDIC VII trials) and one trial, where K-ras WT and mutant Pts received C225 with capecitabine (C) and oxali or CPT (AIO study). We sought to determine if the choice of Fp affects the response to C225. A mixed effects model similar to that of DerSimonian and Laird was fit by restricted maximum likelihood and used to obtain an overall estimate of the effect of C225 in the presence of CI 5-FU, an indirect estimate of the decrease in the effect of C225 in the presence of C/b5-FU relative to CI 5-FU, and an estimate of the study-to-study variability. Results: Only Pts treated with CI 5-FU based chemo derived benefit from C225. Relative to CI 5-FU, Pts treated with C or b5-FU based doublet chemo had a decrease in RR, PFS and OS. The choice of oxali or CPT did not affect responses to C225. Conclusions: The lack of benefit for C225 with C or b5-FU chemo is unexpected. A possible explanation is increased toxicity with C225, which led to dose reduction of C only in the C225-arm of the COIN study; however, increased toxicity was not seen in the NORDIC VII study. Pending further study, only CI 5-FU regimens should be used with C225. [Table: see text]
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Wang-Gillam, Andrea, Chung-Pin Li, Gyorgy Bodoky, Andrew Dean, Yang-Shen Shan, Gayle S. Jameson, Teresa Macarulla et al. „Updated overall survival analysis of NAPOLI-1: Phase III study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.“ Journal of Clinical Oncology 34, Nr. 4_suppl (01.02.2016): 417. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.417.
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417 Background: NAPOLI-1 is a global, randomized Phase 3 study evaluating nal-IRI—a nanoliposomal irinotecan—with or without 5-FU/LV in 417 patients with mPAC previously treated with gemcitabine-based therapy. Primary survival analysis was based on 313 events. Nal-IRI+5FU/LV significantly improved overall survival (OS, primary endpoint), 6.1 months (mo) vs 4.2 mo; with 5-FU/LV (unstratified hazard ratio [HR] = 0.67; P = 0.012). Primary endpoint was supported by improved progression-free survival, time to treatment failure, objective response and CA19-9 tumor marker response rates, and manageable toxicities. An updated analysis of OS, 6- and 12-month-survival estimates, and safety is presented. Methods: The updated descriptive analysis of OS, based on 378 events (25 May 2015), includes data from all randomized patients across the 3 arms. Results: After 378 OS events, nal-IRI+5-FU/LV (n = 117) retained an OS advantage relative to 5-FU/LV (n = 119): 6.2 mo (95% confidence interval [CI], 4.8–8.4) vs 4.2 mo (95% CI, 3.3–5.3) with an unstratified HR of 0.75 (P = 0.0417). In contrast, there was no OS advantage with nal-IRI monotherapy (n = 151) vs 5-FU/LV (n = 149): 4.9 mo [95% CI, 4.2–5.6] vs 4.2 mo [95% CI, 3.6–4.9], HR = 1.08; P = 0.5. Six-month survival estimates were 53% (95% CI, 44–62%) for nal-IRI+5-FU/LV vs 38% (95% CI, 29–47%) for 5-FU/LV; 12-month survival estimates were 26% (95% CI, 18-35%) for nal-IRI+5-FU/LV vs 16% (95% CI, 10–24%) for 5-FU/LV. With events in nearly all patients, the OS curves converge at ~20 mo with 19 patients (16.2%) surviving beyond 20 mo. This is a reason for attenuation of the HR estimate and unstratified log rank p-value. The most common grade 3+ adverse events occurring at a ≥ 2% incidence in the nal-IRI-containing arms were neutropenia, diarrhea, vomiting, and fatigue. Conclusions: In an updated analysis, the median OS benefit for nal-IRI+5FU/LV over 5-FU/LV was maintained, with a similar safety profile. Nal-IRI+5-FU/LV may be a new standard of care for patients with mPAC previously treated with gemcitabine-based therapy. Clinical trial information: NCT01494506.
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Wagner, Anna D., Wilfried Grothe, Johannes Haerting, Gerhard Kleber, Axel Grothey und Wolfgang E. Fleig. „Chemotherapy in Advanced Gastric Cancer: A Systematic Review and Meta-Analysis Based on Aggregate Data“. Journal of Clinical Oncology 24, Nr. 18 (20.06.2006): 2903–9. http://dx.doi.org/10.1200/jco.2005.05.0245.
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Purpose This systematic review and meta-analysis were performed to assess the efficacy and tolerability of chemotherapy in patients with advanced gastric cancer. Methods Randomized phase II and III clinical trials on first-line chemotherapy in advanced gastric cancer were identified by electronic searches of Medline, Embase, the Cochrane Controlled Trials Register, and Cancerlit; hand searches of relevant abstract books and reference lists; and contact to experts. Meta-analysis was performed using the fixed-effect model. Overall survival, reported as hazard ratio (HR) with 95% CI, was the primary outcome measure. Results Analysis of chemotherapy versus best supportive care (HR = 0.39; 95% CI, 0.28 to 0.52) and combination versus single agent, mainly fluorouracil (FU) -based chemotherapy (HR = 0.83; 95% CI = 0.74 to 0.93) showed significant overall survival benefits in favor of chemotherapy and combination chemotherapy, respectively. In addition, comparisons of FU/cisplatin-containing regimens with versus without anthracyclines (HR = 0.77; 95% CI, 0.62 to 0.95) and FU/anthracycline-containing combinations with versus without cisplatin (HR = 0.83; 95% CI, 0.76 to 0.91) both demonstrated a significant survival benefit for the three-drug combination. Comparing irinotecan-containing versus nonirinotecan-containing combinations (mainly FU/cisplatin) resulted in a nonsignificant survival benefit in favor of the irinotecan-containing regimens (HR = 0.88; 95% CI, 0.73 to 1.06), but they have never been compared against a three-drug combination. Conclusion Best survival results are achieved with three-drug regimens containing FU, an anthracycline, and cisplatin. Among these, regimens including FU as bolus exhibit a higher rate of toxic deaths than regimens using a continuous infusion of FU, such as epirubicin, cisplatin, and continuous-infusion FU.
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Arkenau, Hendrik-Tobias, Dirk Arnold, Jim Cassidy, Eduardo Diaz-Rubio, Jean-Yves Douillard, Howard Hochster, Andrea Martoni et al. „Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis of Randomized Trials“. Journal of Clinical Oncology 26, Nr. 36 (20.12.2008): 5910–17. http://dx.doi.org/10.1200/jco.2008.16.7759.
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PurposeSix randomized phase II and III trials have investigated the role of oxaliplatin (OX) in combination with capecitabine (CAP) or infusional fluorouracil (FU) in metastatic colorectal cancer. This meta-analysis compared the efficacy of CAP/OX compared with infusional FU/OX.Patients and MethodsThis analysis compared all published CAP/OX versus infusional FU/OX regimens. A total of 3,494 patients (FU, n = 1,737; CAP, n = 1,757) were analyzed for response rate (RR), progression-free (PFS), overall survival (OS), and toxicity.ResultsThe fixed-effect pooled estimate for RR showed higher RR for FU-based regimens (Odds ratio [OR] = 0.85; 95% CI, 0.74 to 0.97; P = .02) whereas the analysis of chemotherapy-only trials, excluding the bevacizumab containing NO16966 and TREE 2 trials, led to an OR of 0.74 (95% CI, 0.60 to 0.92; P = .007). However, for PFS (hazard ratio [HR] = 1.04; 95% CI, 0.96 to 1.12; P = .17) and OS (HR = 1.04; 95% CI, 0.95 to 1.12; P = .41) all models suggested similar outcome within the range of noninferiority. Grade 3/4 toxicities (thrombocytopenia—HR = 2.07, 95% CI, 1.42 to 3.03; P < .0002; diarrhea—HR = 1.34; 95% CI, 1.08 to 1.66; P < .0009; and grade 2/3 hand-foot-syndrome [HFS]—HR = 3.54; 95% CI, 2.07 to 6.05; P < .00001) were less prominent with FU-based regimens whereas neutropenia (HR = 0.15; 95% CI, 0.11 to 0.19; P < .00001) was lower in the CAP regimens.ConclusionThe combination of CAP and OX resulted in lower RR, but this did not affect PFS and OS, which were similar in both treatment arms. The toxicity analysis showed the characteristic toxicity of each of the different FU schedules, with thrombocytopenia and HFS consistently more prominent in the CAP regimens.
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Nam, Ki-Woong, Chi Kyung Kim, Tae Jung Kim, Kyungmi Oh, Moon-Ku Han, Sang-Bae Ko und Byung-Woo Yoon. „FLAIR vascular hyperintensities predict early ischemic recurrence in TIA“. Neurology 90, Nr. 9 (31.01.2018): e738-e744. http://dx.doi.org/10.1212/wnl.0000000000005034.
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ObjectiveTo evaluate the relationship between fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) and early ischemic lesion recurrence (follow-up diffusion-weighted imaging [FU-DWI] [+]) in patients with lesion-negative TIA.MethodsWe recruited consecutive patients with lesion-negative TIA within 24 hours of symptom onset, who underwent follow-up MRI during the acute period. FVH was defined as a focal or serpentine high signal intensity on FLAIR images. Other potential confounders were adjusted to evaluate the relationship between FVH and FU-DWI (+). Furthermore, to compare clinical outcomes between the FU-DWI (+) and FU-DWI (−) groups, we assessed 1-year recurrent ischemic stroke or TIA.ResultsAmong 392 patients with lesion-negative TIA, 82 patients had FU-DWI (+) on the follow-up MRI. In the multivariate analysis, FVH remained an independent predictor of FU-DWI (+) (adjusted odds ratio [aOR] = 4.77, 95% confidence interval [CI] 2.45–9.29, p < 0.001). The time to initial MRI (aOR = 0.49, 95% CI = 0.33–0.70, p < 0.001) and intracranial atherosclerosis (aOR = 2.07, 95% CI = 1.10–3.92, p = 0.025) were also associated with FU-DWI (+), independent of FVH. In clinical outcomes, the FU-DWI (+) group showed more frequent 1-year recurrent ischemic stroke events than the FU-DWI (−) group (10.7% vs 3.1%, respectively, p = 0.007).ConclusionsFVH is associated with FU-DWI (+) in patients with lesion-negative TIA. As FU-DWI (+) frequently occurs during the acute period and has a subsequent worse outcome after discharge, additional radiologic or clinical markers for it are necessary.
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Poplin, Elizabeth A., Jacqueline K. Benedetti, Norman C. Estes, Daniel G. Haller, Robert J. Mayer, Richard M. Goldberg, Geoffrey R. Weiss, Saul E. Rivkin und John S. Macdonald. „Phase III Southwest Oncology Group 9415/Intergroup 0153 Randomized Trial of Fluorouracil, Leucovorin, and Levamisole Versus Fluorouracil Continuous Infusion and Levamisole for Adjuvant Treatment of Stage III and High-Risk Stage II Colon Cancer“. Journal of Clinical Oncology 23, Nr. 9 (20.03.2005): 1819–25. http://dx.doi.org/10.1200/jco.2005.04.169.
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Purpose Modest toxicity and possibly enhanced activity makes continuous-infusion fluorouracil (FU) an attractive alternative to FU plus leucovorin (FU/LV) for the adjuvant treatment of colorectal cancer. Intergroup trial 0153 (Southwest Oncology Group trial 9415) was developed to compare the efficacy of continuous-infusion FU (CIFU) plus levamisole to FU/LV plus levamisole in the adjuvant treatment of high-risk Dukes' B2 and C1 or C2 colon cancer. Patients and Methods After surgery, patients were randomly assigned to CIFU 250 mg/m2/d for 56 days every 9 weeks for three cycles or FU 425 mg/m2 and LV 20 mg/m2 daily for 5 days every 28 to 35 days for six cycles. All patients received levamisole 50 mg tid for 3 days every other week. The primary end point was overall survival (OS). Results The study closed in December 1999 after an interim analysis demonstrated little likelihood of CIFU showing superiority to FU/LV within the stipulated hazard ratio. A total of 1,135 patients were registered. At least one grade 4 toxicity occurred in 39% of patients receiving FU/LV and 5% of patients receiving CIFU. However, almost twice as many patients receiving CIFU discontinued therapy early compared with those receiving FU/LV. The 5-year OS is 70% (95% CI, 66% to 74%) for FU/LV and 69% (95% CI, 64% to 73%) for CIFU. The corresponding 5-year disease-free survival (DFS) is 61% (95% CI, 56% to 65%) and 63% (95% CI, 59% to 68%), respectively. For all patients, 5-year OS is 83%, 74%, and 55%; 5-year DFS is 78%, 67%, and 47% for N0, N1, and N2-3, respectively. Conclusion CIFU had less severe toxicity but did not improve DFS or OS in comparison with bolus FU/LV.
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Sisson, Barbara E., Suzanne L. Ziegenhorn und Robert A. Holmgren. „Regulation of Ci and Su(fu) nuclear import in Drosophila“. Developmental Biology 294, Nr. 1 (Juni 2006): 258–70. http://dx.doi.org/10.1016/j.ydbio.2006.02.050.
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Schilsky, Richard L., Jeremey Levin, William H. West, Alfred Wong, Bruce Colwell, Michael P. Thirlwell, Rafat H. Ansari et al. „Randomized, Open-Label, Phase III Study of a 28-Day Oral Regimen of Eniluracil Plus Fluorouracil Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Therapy in Patients With Metastatic/Advanced Colorectal Cancer“. Journal of Clinical Oncology 20, Nr. 6 (15.03.2002): 1519–26. http://dx.doi.org/10.1200/jco.2002.20.6.1519.
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PURPOSE: To compare the efficacy and tolerability of eniluracil (EU)/fluorouracil (5-FU) with that of 5-FU/leucovorin (LV) as first-line therapy for patients with metastatic/advanced colorectal cancer. PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study (FUMA3008) conducted in the United States and Canada compared the safety and efficacy of EU/5-FU (11.5 mg/m2/1.15 mg/m2 twice daily for 28 days every 35 days) with that of intravenous 5-FU/LV (425 mg/m2/20 mg/m2 once daily for 5 days every 28 days) in patients with previously untreated metastatic colorectal cancer. Overall survival (OS) was the primary end point. RESULTS: A total of 981 patients were randomized and 964 patients received treatment (485 EU/5FU, 479 5FU/LV). Survival for EU/5-FU was not statistically equivalent (but not statistically inferior) to that for 5-FU/LV (hazard ratio, 0.880; 95% confidence interval [CI], 0.75 to 1.03). Median duration of survival was 13.3 months in the EU/5-FU group and 14.5 months in the 5-FU/LV group. Median duration of progression-free survival for EU/5-FU was statistically inferior to that of the control group (20.0 weeks [95% CI, 19.1 to 20.9 weeks] v 22.7 weeks [95% CI, 18.3 to 24.6 weeks]; P = .01). Both treatments were well tolerated. Diarrhea was the most common nonhematologic toxicity in both groups; treatment-related grade 3 or 4 diarrhea occurred in 19% of patients treated with EU/5-FU and 16% of patients receiving 5-FU/LV (P = .354). Grade 3 or 4 granulocytopenia occurred in 5% of EU/5-FU patients and 47% of 5-FU/LV patients. CONCLUSION: Safety profiles of both treatments were acceptable. Although antitumor activity was observed, EU/5-FU did not meet the protocol-specified statistical criteria for equivalence to 5-FU/LV in terms of OS.
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Honing, Judith, Justin Smit, Christina Muijs, Johannes Burgerhof, Jannet Beukema, John Theodorus Plukker und Geke Hospers. „A comparison of carboplatin with paclitaxel and cisplatinum with 5-fluorouracil in definitive chemoradiotherapy in esophageal cancer patients.“ Journal of Clinical Oncology 32, Nr. 3_suppl (20.01.2014): 104. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.104.
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104 Background: In esophageal cancer (EC) patients not eligible for surgery definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard regime. Nowadays carboplatin and paclitaxel are also often used. In this study we compared survival and toxicity rates between both regimens. Methods: This multicentre study included 102 patients treated in five centres in the North Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU and 55 patients carboplatin/paclitaxel. Results: Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group (P=0.879, Hazard Ratio [HR] 0.97 confidence interval [CI] 0.62-1.51), with a median survival of respectively 16.1 (CI 11.8-20.5) and 13.8 (CI 10.8-16.9) months. Median disease free survival (DFS) was comparable (P=0.760, HR 0.93 CI 0.60-1.45) between the cisplatinum / 5-FU group (11.1 months, CI 6.9-15.3) and the carboplatin/paclitaxel group (9.7 months, CI 5.1-14.4). Groups were comparable except clinical T-stage was higher in the carboplatin/paclitaxel group (P=0.008), but a high clinical T-stage (cT4) was not related to OS and DFS in a univariate analysis (P=0.250 and P=0.201). A higher percentage of patients completed the carboplatin / paclitaxel regimen (82% compared to 57%, P=0.01). Hematological and non-hematological toxicity (≥ grade 3) was significantly lower in the carboplatin / paclitaxel group (4% and 18%) than in the cisplatinum/5-FU (19% and 38%, P=0.001). Conclusions: In this study we show comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared to cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with a higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment for cisplatinum/5-FU is a good candidate regimen for further evaluation.
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Sultana, Asma, Catrin Tudur Smith, David Cunningham, Naureen Starling, John P. Neoptolemos und Paula Ghaneh. „Meta-Analyses of Chemotherapy for Locally Advanced and Metastatic Pancreatic Cancer“. Journal of Clinical Oncology 25, Nr. 18 (20.06.2007): 2607–15. http://dx.doi.org/10.1200/jco.2006.09.2551.
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PurposeThere are a large number of randomized controlled trials involving chemotherapy in the management of advanced pancreatic cancer. Several chemotherapeutic agents, either alone or in combination with other chemotherapy or novel agents, have been used. The aim of these meta-analyses was to examine the different therapeutic approaches, and the comparisons examined were as follows: chemotherapy versus best supportive care; fluorouracil (FU) versus FU combination chemotherapy; gemcitabine versus FU; and gemcitabine versus gemcitabine combination chemotherapy.MethodsRelevant trials were identified by searching databases, trial registers, and conference proceedings. The primary end point was overall survival.ResultsOne hundred thirteen randomized controlled trials were identified, of which 51 trials involving 9,970 patients met the inclusion criteria. Chemotherapy improved survival compared with best supportive care (hazard ratio [HR] = 0.64; 95% CI, 0.42 to 0.98). FU-based combination chemotherapy did not result in better overall survival compared with FU alone (HR = 0.94; 95% CI, 0.82 to 1.08). There was insufficient evidence of a survival difference between gemcitabine and FU, but the wide CI includes clinically important differences in both directions, making a clear conclusion difficult (HR = 0.75; 95% CI, 0.42 to 1.31). Survival was improved after gemcitabine combination chemotherapy compared with gemcitabine alone (HR = 0.91; 95% CI, 0.85 to 0.97).ConclusionThere was a significant survival benefit for chemotherapy over best supportive care and gemcitabine combinations over gemcitabine alone. This supports the use of gemcitabine-based combination chemotherapy in the treatment of advanced pancreatic cancer.
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Rao, Sheela, Francesco Sclafani, Cathy Eng, Richard A. Adams, Marianne G. Guren, David Sebag-Montefiore, Al Benson et al. „International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct“. Journal of Clinical Oncology 38, Nr. 22 (01.08.2020): 2510–18. http://dx.doi.org/10.1200/jco.19.03266.
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PURPOSE To compare cisplatin plus fluorouracil (FU) versus carboplatin plus paclitaxel in chemotherapy-naïve advanced anal cancer to establish the optimal regimen. PATIENTS AND METHODS Patients who had not received systemic therapy for advanced anal cancer were randomly assigned 1:1 to intravenous cisplatin 60 mg/m2 (day 1) plus FU 1,000 mg/m2 (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m2 (days 1, 8, and 15) every 28 days for 24 weeks, until disease progression, intolerable toxicity, or withdrawal of consent. Primary end point was objective response rate (ORR). Primary and secondary end points were assessed in a hierarchic model to compare the regimens and pick the winner. RESULTS We conducted an international multicenter randomized phase II study in 60 centers between December 2013 and November 2017. Median follow-up was 28.6 months. A total of 91 patients were randomly assigned: 46 to cisplatin plus FU and 45 to carboplatin plus paclitaxel. ORR was 57% (95% CI, 39.4% to 73.7%) for cisplatin plus FU versus 59% (95% CI, 42.1% to 74.4%) for carboplatin plus paclitaxel. More serious adverse events were noted in the cisplatin plus FU arm (62%) compared with the carboplatin plus paclitaxel arm (36%; P = .016). Median progression-free survival was 5.7 months (95% CI, 3.3 to 9.0 months) for cisplatin plus FU compared with 8.1 months (95% CI, 6.6 to 8.8 months) for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU (95% CI, 9.2 to 17.7 months) compared with 20 months (95% CI, 12.7 months to not reached) for carboplatin plus paclitaxel (hazard ratio, 2.00; 95% CI, 1.15 to 3.47; P = .014). CONCLUSION This is the first international randomized trial to our knowledge conducted in chemotherapy-naïve advanced anal cancer. Although there was no difference in ORR, the association with clinically relevant reduced toxicity and a trend toward longer survival suggest that carboplatin plus paclitaxel should be considered as a new standard of care.
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Schmoll, Hans-Joachim, Josep Tabernero, Jean Alfred Maroun, Filippo G. De Braud, Timothy Jay Price, Eric Van Cutsem, Mark Hill, Silke Hoersch, Karen Rittweger und Daniel G. Haller. „Capecitabine plus oxaliplatin (XELOX) versus bolus 5-fluorouracil/leucovorin (5-FU/LV) as adjuvant therapy for stage III colon cancer: Survival follow-up of study NO16968 (XELOXA).“ Journal of Clinical Oncology 30, Nr. 4_suppl (01.02.2012): 388. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.388.
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388 Background: The MOSAIC trial demonstrated that adding oxaliplatin to 5-FU/LV (FOLFOX4) improved 3-year disease-free survival (DFS) compared to infusional and bolus 5-FU/LV as adjuvant therapy in patients (pts) with stage II/III colon cancer [André et al. NEJM 2004]. A significant survival advantage for FOLFOX4 versus 5-FU/LV was not evident until after median duration of follow-up had exceeded 6 years [André et al. JCO 2009]. Study NO16968 demonstrated that XELOX was superior to bolus 5-FU/LV as adjuvant therapy in pts with stage III colon cancer in terms of DFS at 57 months median follow-up (HR 0.80; 95% CI 0.69–0.93; p=0.0045) [Haller et al. JCO 2011]. The difference between treatment groups in overall survival (OS) was not significant at 59 months median follow-up (HR=0.87; p=0.1486). Data from the planned final analysis of NO16968 are presented. Methods: Pts with resected stage III colon cancer were randomized to receive XELOX (8 cycles, 24w) or bolus 5-FU/LV (Mayo Clinic, 6 cycles; 24w or Roswell Park, 4 cycles; 32w). The primary study endpoint was DFS. Secondary endpoints included OS. Results: The ITT population included 1886 pts (XELOX, n=944; 5-FU/LV, n=942). After a median follow-up of 74 months, the HR (XELOX vs 5-FU/LV) for DFS was 0.80 (95% CI 0.69–0.93; p=0.0038). Seven-year DFS rates were 63% for XELOX and 56% for 5-FU/LV. After a median follow-up of 83 months, the HR for OS was 0.83 (95% CI 0.70–0.99; p=0.0367). Absolute 7-year OS rates were 73% with XELOX and 67% with 5-FU/LV. After adjusting for stratification and prognostic variables, HRs remained essentially unchanged for both DFS (0.79; 95% CI 0.68–0.91; p=0.0016) and OS (0.84; 95% CI 0.71–1.00; p=0.0477). Locoregional / systemic treatments after recurrence were given in 230 (24%) XELOX pts and 308 (33%) 5-FU/LV pts. Conclusions: The combination of oxaliplatin and capecitabine improves OS significantly compared with 5-FU/LV in the adjuvant treatment of stage III colon cancer after a median follow-up of 83 months; these data are comparable to those achieved with FOLFOX4 in the MOSAIC trial. XELOX is an effective adjuvant therapy option for pts with resected stage III colon cancer.
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Douillard, Jean-Yves, Paulo M. Hoff, Jamey R. Skillings, Peter Eisenberg, Neville Davidson, Peter Harper, Mark D. Vincent et al. „Multicenter Phase III Study of Uracil/Tegafur and Oral Leucovorin Versus Fluorouracil and Leucovorin in Patients With Previously Untreated Metastatic Colorectal Cancer“. Journal of Clinical Oncology 20, Nr. 17 (01.09.2002): 3605–16. http://dx.doi.org/10.1200/jco.2002.04.123.
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PURPOSE: This phase III study was designed to demonstrate equivalence in survival of oral uracil/tegafur (UFT) and oral leucovorin (LV) to conventional intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma. Safety was also compared. PATIENTS AND METHODS: Eight hundred sixteen patients were randomized to receive either UFT (300 mg/m2/d) and LV (75 or 90 mg/d) for 28 days every 35 days or IV bolus 5-FU (425 mg/m2/d) and LV (20 mg/m2/d) for 5 days every 28 days. RESULTS: UFT/LV produced survival comparable to the IV 5-FU/LV regimen. Median survival was 12.4 months (95% confidence interval [CI], 11.2 to 13.6 months) with UFT/LV and 13.4 months (95% CI, 11.6 to 15.4 months) with 5-FU/LV (P = .630). The hazard ratio for survival was 0.964 (95.6% CI, 0.826 to 1.125), supporting equivalent survival. The overall response rate did not differ between treatment arms (UFT/LV, 11.7%; 5-FU/LV, 14.5%; P = .232). Median time to progression favored 5-FU/LV (UFT/LV, 3.5 months; 5-FU/LV, 3.8 months; P = .011), but tumor assessment schedules differed between arms. UFT/LV significantly improved safety compared with 5-FU/LV. Diarrhea, nausea and vomiting, and stomatitis and mucositis were significantly less frequent with UFT/LV, as was myelosuppression. Patients treated with UFT/LV had fewer episodes of febrile neutropenia (P < .001) and documented infections (P < .05). Increased bilirubin, without other liver function abnormalities, was observed more often with UFT/LV (P < .001). Concomitant medications were more frequent with 5-FU/LV, including use of antibiotics, growth factors, and antiemetics. CONCLUSION: UFT/LV provided a safer, more convenient oral alternative to a standard bolus IV 5-FU/LV regimen for metastatic colorectal cancer while producing equivalent survival.
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Yang Seoung Duk. „A Study on the Ci-Fu Thoughts of Xie-Ling-Yun“. Journal of Chinese Language and Literature ll, Nr. 54 (Dezember 2009): 83–104. http://dx.doi.org/10.15792/clsyn..54.200912.83.
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Yang, Seoung Duk. „A Study on The theory of Dong-Jin,s Ci-Fu“. JOURNAL OF CHINESE HUMANITIES 76 (31.12.2020): 223–43. http://dx.doi.org/10.35955/jch.2020.12.76.223.
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Cassidy, J., N. Scotto und E. Diaz-Rubio. „Review of completed and ongoing trials of capecitabine-based adjuvant therapy in patients with early-stage colon cancer.“ Journal of Clinical Oncology 29, Nr. 4_suppl (01.02.2011): 495. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.495.
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495 Background: Capecitabine is an established alternative to 5-FU in gastrointestinal cancers. In metastatic colorectal cancer, capecitabine is non-inferior to 5-FU and capecitabine + oxaliplatin (XELOX) is non-inferior to FOLFOX4. Capecitabine is also an effective adjuvant treatment for early-stage colon cancer. Here we review the evidence available from completed studies of adjuvant capecitabine and describe ongoing trials in this setting. Methods: The X-ACT trial included 1,987 patients (pts) with resected stage III disease receiving either capecitabine (n=1,004) or bolus 5-FU/LV (n=983). NO16968 included 1,886 pts with resected stage III disease receiving either XELOX (n=944) or 5-FU/LV (n=942). The primary efficacy endpoint of both trials was DFS. Other large phase III trials of capecitabine in high-risk stage II/stage III pts include AVANT (XELOX + bevacizumab vs. FOLFOX4 ± bevacizumab), QUASAR2 (capecitabine vs. capecitabine + bevacizumab), SCOT (capecitabine or 5-FU/LV + oxaliplatin 12w vs. 24w), and a Japanese study of single-agent capecitabine. Results: In X- ACT, capecitabine was at least equivalent to 5-FU/LV in terms of DFS (HR=0.88; 95% CI, 0.77–1.01) and OS (HR=0.86; 95% CI, 0.74–1.01). In a preplanned multivariate analysis, capecitabine led to significantly superior DFS (p=0.02) and OS (p=0.02) vs. bolus 5-FU/LV [Twelves et al. WCGIC 2010]. In NO16968, DFS was significantly superior for XELOX vs. 5-FU/LV (HR=0.80; 95% CI, 0.69–0.93; p=0.0045) [Haller et al. ECCO-ESMO 2009]. There was a trend towards improvement in OS with XELOX (HR=0.87; 95% CI, 0.72–1.05; p=0.1486); follow-up is ongoing. Capecitabine-based therapy had an acceptable safety profile in both trials [Twelves et al. NEJM 2005; Schmoll et al. JCO 2007]. Data have yet to be reported from the AVANT, QUASAR2, SCOT and Japanese trials, although results from these trials in over 15,000 pts are awaited with interest. Conclusions: Adjuvant capecitabine is non-inferior to 5-FU/LV when given as monotherapy and superior to 5-FU/LV when given in combination with oxaliplatin. Capecitabine should be considered as a standard component of adjuvant treatment regimens for pts with stage III disease. [Table: see text]
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Merchant, Mark, Felix F. Vajdos, Mark Ultsch, Henry R. Maun, Ulrich Wendt, Jennifer Cannon, William Desmarais, Robert A. Lazarus, Abraham M. de Vos und Frederic J. de Sauvage. „Suppressor of Fused Regulates Gli Activity through a Dual Binding Mechanism“. Molecular and Cellular Biology 24, Nr. 19 (01.10.2004): 8627–41. http://dx.doi.org/10.1128/mcb.24.19.8627-8641.2004.
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ABSTRACT The Hedgehog pathway drives proliferation and differentiation by activating the Gli/Ci family of zinc finger transcription factors. Gli/Ci proteins form Hedgehog signaling complexes with other signaling components, including the kinesin-like protein Costal-2, the serine-threonine kinase Fused, and Suppressor of Fused [Su(fu)]. In these complexes Gli/Ci proteins are regulated by cytoplasmic sequestration, phosphorylation, and proteolysis. Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1. Furthermore, we have solved the crystal structure of the amino-terminal domain of human Su(fu)27-268 at 2.65 Å resolution. This domain forms a concave pocket with a prominent acidic patch. Mutation at Asp159 in the acidic patch disrupts Gli1 tethering and repression while not strongly disrupting binding, indicating that the amino-terminal domain of Su(fu) likely impacts Gli binding through a mechanism distinct from that for tethering and repression. These studies provide a structural basis for understanding the function of Su(fu).
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Maisey, Nick, Ian Chau, David Cunningham, Andrew Norman, Matt Seymour, Tamas Hickish, Tim Iveson et al. „Multicenter Randomized Phase III Trial Comparing Protracted Venous Infusion (PVI) Fluorouracil (5-FU) With PVI 5-FU Plus Mitomycin in Inoperable Pancreatic Cancer“. Journal of Clinical Oncology 20, Nr. 14 (15.07.2002): 3130–36. http://dx.doi.org/10.1200/jco.2002.09.029.
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PURPOSE: To compare protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin (MMC) in patients with advanced pancreatic cancer in a multicenter, prospectively randomized study. PATIENTS AND METHODS: Two hundred eight patients were randomized to PVI 5-FU (300 mg/m2/d for a maximum of 24 weeks) or PVI 5-FU plus MMC (7 mg/m2 every 6 weeks for four courses). The major end points were tumor response, survival, toxicity, and quality of life (QOL). RESULTS: The two treatment groups were balanced for baseline demographic factors, and 62% had metastatic disease. The overall response rate was 8.4% (95% confidence interval [CI]) 3.2% to 13.7% for patients treated with PVI 5-FU alone compared with 17.6%; 95% CI 10.3% to 25.1% for PVI 5-FU plus MMC (P = .04). Median failure-free survival was 2.8 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC (P = .14). Median survival was 5.1 months for PVI 5-FU and 6.5 months for PVI 5-FU plus MMC (P = .34). Toxicities in both arms were mild. There was an increased incidence of neutropenia in the 5-FU plus MMC arm (P < .01), although no differences in infection were seen. No patients developed hemolytic uremic syndrome. Global QOL improved significantly after 24 weeks of treatment compared with baseline for patients receiving 5-FU plus MMC, although there was no statistically significant difference in QOL between arms. CONCLUSION: PVI 5-FU plus MMC resulted in a superior response rate in comparison with PVI 5-FU alone in advanced pancreatic cancer, but this did not translate into a survival advantage. These results emphasize the importance of chemotherapy in this setting and the continuing value of the fluoropyrimidines in pancreatic cancer.
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Bertagnolli, Monica M., Donna Niedzwiecki, Carolyn C. Compton, Hejin P. Hahn, Margaret Hall, Beatrice Damas, Scott D. Jewell et al. „Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803“. Journal of Clinical Oncology 27, Nr. 11 (10.04.2009): 1814–21. http://dx.doi.org/10.1200/jco.2008.18.2071.
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Purpose Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) –based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers. Patients and Methods Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Results Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117). Conclusion Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.
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Wang-Gillam, Andrea, Richard Hubner, Beloo Mirakhur, Floris A. de Jong, Bruce Belanger und Li-Tzong Chen. „Dose modifications of liposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) in NAPOLI-1: Impact on efficacy.“ Journal of Clinical Oncology 36, Nr. 4_suppl (01.02.2018): 388. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.388.
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388 Background: In NAPOLI-1 (NCT01494506), a randomized phase 3 study in patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV improved overall survival (OS; primary endpoint) vs 5-FU/LV (6.1 mos vs 4.2 mos; HR = 0·67, 95% CI 0.490.92; P = 0.012). This exploratory analysis examined the impact of dose modifications or delays used to manage adverse events (AEs) on OS. The study protocol allowed ≤2 dose reductions for nal-IRI and 5-FU and for up to 3 weeks. Methods: Patient who had a dose delay or reduction within the planned first 6 weeks of the study were included. Delays were defined as any delay in dosing > 3 days from target dosing date and dose reductions were defined as any reduction in dose from initial administered dose. OS was compared within the nal-IRI+5-FU/LV arm and with the 5-FU/LV arm. Comparisons were made using the cohort of 5-FU/LV and nal-IRI+5-FU/LV patients enrolled under protocol version 2. Median OS was based on Kaplan-Meier estimates and Cox regression analysis was used to calculate HRs. Results: More patients in the nal-IRI+5-FU/LV treatment group experienced AEs that required dose delay and/or reduction than in the 5-FU/LV treatment group (62% vs 33%). Within the nal-IRI+5-FU/LV arm, median OS was numerically but not significantly different between patients who did (n = 34) vs did not (n = 83) have a dose reduction (9.3 vs 5.4 mos; HR = 0.66 [95% CI 0.43, 1.01]) and for those who did (n = 49) vs did not (n = 68) have a dose delay (8.4 vs 5.6 mos; 0.82 [95% CI 0.56, 1.23]). Between treatment arms, OS was greater in the nal-IRI+5-FU/LV arm regardless of dose delay or reduction (Table). Conclusions: Dose modifications in the nal-IRI+5-FU/LV arm did not significantly impact OS compared with those who did not need a dose modification, and OS remained greater than in 5-FU/LV-treated patients. This suggests that appropriate dose modification of nal-IRI+5-FU/LV for AEs may not adversely affect outcomes. Clinical trial information: NCT01494506. [Table: see text]
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Taïeb, Julien, Tim Maughan, Carsten Bokemeyer, Eric Van Cutsem, Thomas Brodowicz, Gunnar Folprecht, Regina Esser, Michael Schlichting und Josep Tabernero. „Cetuximab combined with infusional 5-fluorouracil/folinic acid (5-FU/FA) and oxaliplatin in metastatic colorectal cancer (mCRC): A pooled analysis of COIN and OPUS study data.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): 3574. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3574.
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3574 Background: Infusional 5-FU/FA + oxaliplatin is a widely used schedule in the first-line treatment of mCRC. In the randomized phase II OPUS study, the addition of cetuximab to one such regimen (FOLFOX4) significantly improved response and progression-free survival (PFS) in patients (pts) with KRAS wild-type (wt) mCRC. However, in the randomized phase III COIN study, a benefit for the addition of cetuximab to first-line fluoropyrimidine (administered as either infusional 5-FU or capecitabine) + oxaliplatin was not confirmed in pts with KRAS wt tumors. Methods: A pooled study-based analysis of treatment outcome in pts with KRAS wt tumors from the OPUS study and COIN subgroup who received infusional 5-FU/FA + oxaliplatin (as the OxMdG regimen) was carried out using a random effects model. Outcome in the pooled analysis was considered in the context of other randomized studies investigating first-line chemotherapy regimens +/- cetuximab in pts with mCRC. Results: The pooled KRAS wt population included 179 pts from the OPUS study and 244 from the OxMdG subgroup of the COIN study. A benefit for the addition of cetuximab to infusional 5-FU/FA was suggested for response (odds ratio 1.87, 95% CI 1.07–3.28) and PFS (hazard ratio, HR 0.69, 95% CI 0.52–0.92) but overall survival (OS) did not show a statistically significant improvement (HR 0.90, 95% CI 0.73–1.11). These response and PFS data are similar to those of the KRAS wt population of the CRYSTAL study investigating infusional 5-FU/FA and irinotecan +/- cetuximab (response: odds ratio 2.07, 95% CI 1.52–2.83; PFS: HR 0.70, 95% CI 0.56–0.87) whereas the improvement in OS was statistically significant in that study (HR 0.80, 95% CI 0.67–0.95). Similar efficacy of FOLFOX + cetuximab and FOLFIRI + cetuximab in the first-line treatment of mCRC was also suggested by data from the randomized phase II CORE 1.2.001 and CELIM studies. Overall, the safety profile of infusional 5-FU/FA and oxaliplatin + cetuximab was found to be acceptable and manageable. Conclusions: The pooled analysis supports the use of cetuximab combined with infusional 5-FU/FA and oxaliplatin in the first-line treatment of KRAS wt mCRC.
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Wagner, A. D., W. Grothe, J. Haerting, G. Kleber, A. Grothey und W. E. Fleig. „Combination chemotherapies in advanced gastric cancer: An updated systematic review and meta-analysis“. Journal of Clinical Oncology 25, Nr. 18_suppl (20.06.2007): 4555. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4555.
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4555 Background: Combination chemotherapy is widely accepted for patients with advanced gastric cancer, but uncertainty remains regarding the choice of the regimen. Methods: Our objectives were to assess the effect of: 1) 5-FU/cisplatin combinations with versus without anthracyclines; 2) 5-FU/anthracycline combinations with versus without cisplatin; 3) Irinotecan versus non-irinotecan containing combination chemotherapies; 4) Docetaxel versus non-docetaxel containing combinations; on overall survival and toxicity. Search strategy: We searched: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, proceedings from DDW, ECCO, ESMO, ASCO until october 2006. Selection criteria: Randomised controlled trials on different combination chemotherapies as above in advanced gastric cancer. Results: 13 trials including in total 2,184 patients (pts) are included in this meta-analysis. Comparison 1) including 501 pts (HR 0.77; 95% CI 0.62–0.95); and 2) including 1,147 pts (HR 0.83; 95%CI 0.76–0.91) both demonstrate a significant survival benefit for three-drug regimens including 5-FU, anthracyclines and cisplatin. Among these, the rate of treatment-related deaths was higher when 5-FU was administered as bolus compared to infusional 5-FU (exact Mantel-Haenszel OR 2.33, p=0.285). Comparison 3) including 536 pts results in a HR of 0.88; 95% CI 0.73- 1.06. The rate of treatment related deaths was 0.7% versus 2.6% in the irinotecan versus non-irinotecan-containing arms (exact Mantel-Haenszel OR 0.275, p=0.166). Comparison 4) 4 relevant trials were identified. A meta-analysis will be performed as soon as the final results of at least 3 trials are available. Conclusions: Three-drug regimens containing 5-FU, anthracyclines and cisplatin achieve superior survival results compared to cisplatin/5-FU or antracycline/5-FU combinations. Among these, ECF (epirubicin, cisplatin and 5-FU) is tolerated best. Combinations including irinotecan demonstrate a non-significant trend towards better survival in this meta-analysis, but have never been compared against three-drug regimens containing 5-FU/cisplatin and an anthracycline. Supported by: KKS Halle, grant number [BMBF/FKZ 01GH01GH0105]. No significant financial relationships to disclose.
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Schmoll, Hans-Joachim, Josep Tabernero, Jean Maroun, Filippo de Braud, Timothy Price, Eric Van Cutsem, Mark Hill, Silke Hoersch, Karen Rittweger und Daniel G. Haller. „Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial“. Journal of Clinical Oncology 33, Nr. 32 (10.11.2015): 3733–40. http://dx.doi.org/10.1200/jco.2015.60.9107.
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Purpose To report the final efficacy findings and biomarker analysis from the NO16968 trial comparing bolus fluorouracil/folinic acid (FU/FA) with capecitabine plus oxaliplatin (XELOX) in resected stage III colon cancer. Patients and Methods After curative resection, patients were randomly assigned to receive XELOX, as oxaliplatin 130 mg/m2 on day 1 and capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks, or bolus FU/FA, as the Mayo Clinic or Roswell Park regimens, for 6 months. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS). Results The intention-to-treat population comprised 1,886 patients (XELOX, n = 944; FU/FA, n = 942). Seven-year DFS rates were 63% and 56% in the XELOX and FU/FA groups, respectively (hazard ratio [HR], 0.80; 95% CI, 0.69 to 0.93; P = .004). Seven-year OS rates were 73% and 67% in the XELOX and FU/FA groups, respectively (HR, 0.83; 95% CI, 0.70 to 0.99; P = .04). A total of 68% and 77% of patients who experienced relapse or a new colorectal cancer in the XELOX and FU/FA groups, respectively, received drug treatment for metastatic disease. Four hundred ninety-eight patients consented to the biomarker analysis: 242 in the XELOX group and 256 in the FU/FA group. Low tumor expression of dihydropyrimidine dehydrogenase may be predictive for XELOX efficacy; in the XELOX group, for high versus low dihydropyrimidine dehydrogenase expression levels, DFS HR was 2.45 (95% CI, 1.55 to 3.86; P < .001), and OS HR was 2.75 (95% CI, 1.65 to 4.59; P < .001). In the FU/FA group, no statistically significant associations were observed between any tumor biomarker and outcomes. Conclusion XELOX improved OS compared with bolus FU/FA in patients with resected stage III colon cancer after a median follow-up of almost 7 years. XELOX should be considered a standard adjuvant treatment option in patients with stage III disease. Tumoral dihydropyrimidine dehydrogenase expression is a promising predictive, and potentially, highly clinically relevant, biomarker for XELOX efficacy requiring further prospective evaluation.
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Sizer, B., A. Makris, C. Barone, P. Mainwaring und P. Eggleton. „QoL and resource use analysis of tegafur-uracil/LV or 5-FU/LV in first-line metastatic colorectal cancer (mCRC): Final results of a multicenter phase II study“. Journal of Clinical Oncology 24, Nr. 18_suppl (20.06.2006): 3631. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3631.
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3631 Background: Tegafur-uracil (UFT) is an effective oral fluoropyrimidine for patients with mCRC. Aims of this prospective phase II study were to evaluate quality of life (QoL), patient preference and healthcare resource use in patients receiving oral UFT/LV or i.v. 5-FU/LV as first-line therapy for mCRC. Safety and efficacy were also assessed. Methods: 243 patients in 3 countries (Austria, Italy and UK) were randomized in a 2:1 ratio to receive either UFT 300mg/m2/d + LV 90mg/d for 28d q5w, or i.v. 5-FU 425mg/m2/d + LV 20mg/m2/d for 5d q4w. Patients were assessed at baseline and every cycle for symptoms, adverse events (AEs), and overall response rate (ORR). QoL was evaluated using EORTC QLQ-C30, and patients completed a preference questionnaire at baseline, end of cycle 1, and end of study. Data on hospital attendances (in- and out-patient), physician visits, concomitant medication use and other healthcare resources were collected for every cycle and during study follow up. Results: 162 patients received UFT/LV (median 3 cycles) and 81 i.v. bolus 5-FU/LV (median 4 cycles). Patient demographics were similar in both groups: median age was 70y (range 39–83) for UFT/LV and 69y (41–80) for 5-FU/LV; 92% of patients were ECOG PS ≤1. QoL was maintained in the UFT/LV group with little variation across time whereas QoL deteriorated with 5-FU/LV. Most patients in the UFT/LV (85–95%) and 5-FU/LV (49–66%) groups stated a preference for oral treatment with the most common reason being ‘taken at home’ (83%). Fewer UFT/LV patients had one or more hospitalizations for AEs (21% vs. 36%). Clinical benefit (ORR+SD) was 32% with UFT/LV (41% evaluable for response) and 32% with 5-FU/LV (45% evaluable). Median time to disease progression was 173d (95% CI 140–199) for UFT/LV and 168d (95% CI 133–205) for 5-FU/LV. Median overall survival was 385d (95% CI 296–472) for UFT/LV and 330d (95% CI 252–484) for 5-FU/LV. Conclusions: UFT with LV has comparable efficacy to i.v. 5-FU/LV in first-line mCRC, with the advantages of favorable QoL, patient preference for oral treatment, and fewer hospitalizations for managing AEs. [Table: see text]
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Köhne, C. H., E. van Cutsem, J. Wils, C. Bokemeyer, M. El-Serafi, M. P. Lutz, M. Lorenz et al. „Phase III Study of Weekly High-Dose Infusional Fluorouracil Plus Folinic Acid With or Without Irinotecan in Patients With Metastatic Colorectal Cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986“. Journal of Clinical Oncology 23, Nr. 22 (01.08.2005): 4856–65. http://dx.doi.org/10.1200/jco.2005.05.546.
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Purpose To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). Patients and Methods Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m2 as a 2-hour infusion and FU 2.6 g/m2 by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m2 preceded by irinotecan 80 mg/m2 administered over 30 minutes (experimental group, n = 214). Results The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). Conclusion The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.
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Peng, Chengwei, Saad Saffo, Michael Shusterman, Daniel Jacob Becker, Jordan Berlin, Paul Eliezer Oberstein, Anil Nagar und Shun Yu. „Analysis of the impact of eliminating bolus 5-fluorouracil in metastatic colorectal cancer.“ Journal of Clinical Oncology 41, Nr. 4_suppl (01.02.2023): 59. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.59.
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59 Background: 5-Fluorouracil (5-FU) is a component of first-line treatment regimens for metastatic colorectal cancer (mCRC). Historically, 5-FU is administered as a bolus followed by an infusion. However, the bolus dose adds substantial toxicity and is often withheld in patients with limited functional status or high-risk comorbidities, but its impact on treatment outcomes remains unclear. Small studies suggest that it may be omitted. The aim of this study was to determine whether omission of the 5-FU bolus is associated with a difference in overall survival (OS). Methods: An electronic health record-derived national multicenter oncology database from Flatiron Health was queried to select patients with mCRC who received a first-line 5-FU-containing regimen. Demographics, relevant labs, treatment details, and survival outcomes were collected. Propensity score (PrS) matching and OS analysis were performed incorporating age, race, sex, ECOG score, combination drug regimen, and baseline creatinine and bilirubin. Variables with p < 0.10 in univariable Cox proportional hazards models were included in the multivariable analysis. Results: We included 9741 patients with mCRC who received 5-FU-based regimens. All individuals received a 5-FU infusion, and 7901 (81%) also received a 5-FU bolus. Among our entire cohort, 43% were female, 23% were > 70 years, 66% were white, and 89% had ECOG ≤ 1. Over a median follow-up time of 19 months, 5847 patients (60%) died. In the unmatched univariable (HR 0.94, 95% CI 0.88-1.00, p = 0.06) and multivariable (aHR 0.85, 95% CI 0.93-1.06, p = 0.85) analyses, there was no association between the use of bolus 5-FU and OS. A number of factors were associated with an increased risk of death, including older age, high ECOG scores, and elevated bilirubin or creatinine levels. Similarly, in our PrS-matched dataset (n = 6126), the use of a 5-FU bolus was not associated with OS (HR 0.98; 95% CI 0.91-1.06; p = 0.64). Conclusions: The findings of our PrS-matched multicenter cohort study indicate that, after adjusting for host and treatment factors, 5-FU bolus dosing was not associated with an overall survival benefit among patients with mCRC. These results suggest that, in mCRC, the addition of a 5-FU bolus does not appear to add efficacy to regimens utilizing infusional 5-FU. Future work is necessary to determine the role of bolus dosing in the adjuvant setting and its impact on other clinically-relevant outcomes.
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Fuchs, Charles S., Donna Niedzwiecki, Harvey J. Mamon, Joel E. Tepper, Xing Ye, Richard S. Swanson, Peter C. Enzinger et al. „Adjuvant Chemoradiotherapy With Epirubicin, Cisplatin, and Fluorouracil Compared With Adjuvant Chemoradiotherapy With Fluorouracil and Leucovorin After Curative Resection of Gastric Cancer: Results From CALGB 80101 (Alliance)“. Journal of Clinical Oncology 35, Nr. 32 (10.11.2017): 3671–77. http://dx.doi.org/10.1200/jco.2017.74.2130.
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Purpose After curative resection of gastric or gastroesophageal junction adenocarcinoma, Intergroup Trial 0116 (Phase III trial of postoperative adjuvant radiochemotherapy for high risk gastric and gastroesophageal junction adenocarcinoma: Demonstrated superior survival for patients who received postoperative chemoradiotherapy with bolus fluorouracil (FU) and leucovorin (LV) compared with surgery alone. CALGB 80101 (Alliance; Phase III Intergroup Trial of Adjuvant Chemoradiation After Resection of Gastric or Gastroesophageal Adenocarcinoma) assessed whether a postoperative chemoradiotherapy regimen that replaced FU plus LV with a potentially more active systemic therapy could further improve overall survival. Patients and Methods Between April 2002 and May 2009, 546 patients who had undergone a curative resection of stage IB through IV (M0) gastric or gastroesophageal junction adenocarcinoma were randomly assigned to receive either postoperative FU plus LV before and after combined FU and radiotherapy (FU plus LV arm) or postoperative epirubicin, cisplatin, and infusional FU (ECF) before and after combined FU and radiotherapy (ECF arm). Results With a median follow-up duration of 6.5 years, 5-year overall survival rates were 44% in the FU plus LV arm and 44% in the ECF arm ( Plogrank = .69; multivariable hazard ratio, 0.98; 95% CI, 0.78 to 1.24 comparing ECF with FU plus LV). Five-year disease-free survival rates were 39% in the FU plus LV arm and 37% in the ECF arm ( Plogrank = .94; multivariable hazard ratio, 0.96; 95% CI, 0.77 to 1.20). In post hoc analyses, the effect of treatment seemed to be similar across all examined patient subgroups. Conclusion After a curative resection of gastric or gastroesophageal junction adenocarcinoma, postoperative chemoradiotherapy using a multiagent regimen of ECF before and after radiotherapy does not improve survival compared with standard FU and LV before and after radiotherapy.
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Li, Jia-yi, Xuan-zhang Huang, Peng Gao, Xiao-wan Chen, Yong-xi Song, Xing-er Lv, Yv Fu, Qiong Xiao und Zhen-ning Wang. „Postoperative Adjuvant Treatment Strategy for Locally Advanced Rectal Cancer after Neoadjuvant Treatment“. BioMed Research International 2021 (27.03.2021): 1–21. http://dx.doi.org/10.1155/2021/8852699.
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Background. Neoadjuvant (chemo) radiotherapy is used as a standard treatment for locally advanced rectal cancer (LARC), but there is no general consensus on either the efficacy of postoperative adjuvant chemotherapy in patients with LARC after neoadjuvant treatment and surgery, or whether the addition of oxaliplatin to adjuvant chemotherapy provides survival benefits. Methods. We performed a meta-analysis of data from the PubMed and Embase databases. We included patients with LARC who received neoadjuvant (chemo) radiotherapy and curative surgery. Overall survival (OS), disease-free survival (DFS), toxicity, and compliance were analyzed in the oxaliplatin/fluorouracil- (OX/FU-) based group compared with the FU-based group, and in the chemotherapy group compared with the observation group. Results. Twenty studies were included in the analysis. Our results indicated that adjuvant chemotherapy prolonged OS (hazard ratio HR = 0.78 , 95 % CI = 0.67 – 0.91 ) in patients with LARC treated with neoadjuvant (chemo) radiotherapy and surgery compared with those in the observation group. Subgroup analysis showed the same results in both the ypStage II and ypStage III groups. Compared with those in the observation group, patients in the chemotherapy group also showed an increase in DFS ( HR = 0.75 , 95 % CI = 0.60 – 0.93 ). No significant increase was observed in OS ( HR = 1.04 , 95 % CI = 0.87 – 1.24 ) or DFS ( HR = 0.98 , 95 % CI = 0.76 – 1.27 ) when oxaliplatin was added to FU-based adjuvant chemotherapy, as compared with the FU-based treatment, and subgroup analysis also indicated no survival benefits in the clinical stage II, clinical stage III, ypStage II, and ypStage III groups. Conclusions. For patients with LARC who have already received neoadjuvant (chemo) radiotherapy and curative surgery, adjuvant chemotherapy improves OS over that in the observation group. Adding oxaliplatin to FU-based adjuvant chemotherapy does not confer survival benefits beyond those from FU-based adjuvant chemotherapy.
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Wang, Aiqing. „Cliché-ridden Online Danmei Fiction? A Case Study of Tianguan ci fu“. Acta Asiatica Varsoviensia 35 (2022): 281–314. http://dx.doi.org/10.60018/acasva.iray5065.
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Popular literature online is often misconstrued as being cliché-ridden and formulaic, and has thus not attained as much critical attention as ‘serious’ literature. I propound that popular literature published in China’s cyberspace deserves more attention and hermeneutic scrutiny, and I place an emphasis on danmei (耽美) fiction that features male-male romantic and/or erotic relationships and is predominantly published on a female-oriented website called Jinjiang Literature City. In this research, I investigate an online danmei novel entitled Tianguan ci fu (天官赐福) that concerns a homosexual romance against a background of ‘immortality cultivation’ (xiuxian 修仙 or xiuzhen 修真), which had been maintaining the highest ranking on readers’ voting list since its release on Jinjiang Literature City in 2017. I postulate that Tianguan ci fu does not deploy clichéd plots pertaining to quasi-heterosexual relationships, which frequently occur in danmei fiction. Apart from conveying the theme of love, the narrative concerns the complexity of human nature via an array of characters possessing multifaceted personality traits. More significantly, with a setting of mortal and immortal realms, the narrative entails religious ideologies, especially the indigenous Daoist ascension, mortality-immorality polarity and yin-yang integration. Furthermore, ethic-religious Confucian precepts such as benevolence and filial piety are also demonstrated, along with the Sinicised Buddhist creeds of reincarnation and retribution, which embodies the amalgamation of (sub)religions as a preponderant ideal of ‘the unity of Confucianism, Buddhism and Daoism’ (san jiao he yi 三教合一). Therefore, analysing this exemplary online novel can shed light on (a)theistic attitudes adopted by creators and consumers of Internet danmei literature.
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Schmidt, Jan, Ulrich Abel, Jürgen Debus, Sabine Harig, Katrin Hoffmann, Thomas Herrmann, Detlef Bartsch et al. „Open-Label, Multicenter, Randomized Phase III Trial of Adjuvant Chemoradiation Plus Interferon Alfa-2b Versus Fluorouracil and Folinic Acid for Patients With Resected Pancreatic Adenocarcinoma“. Journal of Clinical Oncology 30, Nr. 33 (20.11.2012): 4077–83. http://dx.doi.org/10.1200/jco.2011.38.2960.
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Purpose Adjuvant chemotherapy prolongs survival in patients with pancreatic cancer, but its benefit is limited. Long-term survival times of up to 44 months after adjuvant chemoradioimmunotherapy in phase II trials motivated the present study. Patients and Methods Between 2004 and 2007, 132 R0/R1 resected patients received either fluorouracil (FU), cisplatin, and interferon alfa-2b (IFN α-2b) plus radiotherapy followed by two cycles of FU (arm A, n = 64) or six cycles of FU monotherapy (arm B, n = 68). One hundred ten patients (arm A, n = 53; arm B, n = 57) received at least one dose of the study medication, and these patients composed the per-protocol (PP) population. Biomarkers were analyzed longitudinally for their predictive value. Results Median survival for all randomly assigned patients was 26.5 months (95% CI, 21.6 to 39.5 months) in arm A and 28.5 months (95% CI, 20.4 to 38.6 months) in arm B. The hazard ratio was 1.04 (arm A v arm B: 95% CI, 0.66 to 1.53; P = .99). Median survival for the PP population was 32.1 months (95% CI, 22.8 to 42.2 months) in arm A and 28.5 months (95% CI, 19.5 to 38.6 months) in arm B (P = .49). Eighty-five percent of patients in arm A and 16% of patients in arm B experienced grade 3 or 4 toxicity. The quality of life was temporarily negatively affected in arm A. Conclusion The FU, cisplatin, and IFN α-2b plus radiotherapy regimen did not improve the survival compared with FU monotherapy. Given the substantial adverse effects, this treatment can currently not be recommended. Nevertheless, the outcome in both arms represents the best survival, to our knowledge, ever reported for patients with resected pancreatic cancer in randomized controlled trials. Future studies will demonstrate whether immune response to IFN α-2b challenge has a predictive value.
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Modest, Dominik Paul, Meinolf Karthaus, Stefan Fruehauf, Ullrich Graeven, Lothar Müller, Alexander Koenig, Ludwig Fischer von Weikersthal et al. „FU/FA maintenance therapy with or without panitumumab (pmab) in RAS wild-type metastatic colorectal cancer (mCRC) (PanaMa, AIO KRK 0212): Updated efficacy analyses.“ Journal of Clinical Oncology 42, Nr. 16_suppl (01.06.2024): 3506. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.3506.
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3506 Background: The randomized open-label phase II PanaMa trial compared FU/FA with or without pmab maintenance after mFOLFOX6+pmab induction for RAS wild-type mCRC. Updated efficacy results of the Full Analysis Set are presented. Methods: Median progression-free survival (PFS), overall survival (OS), PFS of re-induction (PFS re-ind.), time to failure of strategy (TFS), and objective response rates (ORR) were compared by log-rank test / Cox regression and Fisher’s exact test. Results: PFS was significantly (8.8 vs. 5.8 months, HR=0.73 (95%CI 0.56 – 0.94), P=0.015) and OS numerically longer (29.9 vs. 24.7 months, HR=0.85 (95%CI 0.64 – 1.12), P=0.24). PFS re-ind. was significantly shorter after pmab maintenance (4.1 vs. 7.4 months, HR=1.93 (95%CI 1.33 – 2.82), P<0.001). TFS was comparable (17.1 vs. 15.7 months, HR=0.98 (95%CI 0.68 – 1.42), P=0.92). Molecular subgroups are displayed in Table 1. ORR of FU/FA+pmab was comparable to FU/FA during induction (74.4% vs. 76.4%, P=0.77), higher during maintenance (40.8% vs. 29.3%, P=0.06), but lower at re-induction (8.0% vs. 35.9%, P<0.001). Conclusions: PFS remained improved by the addition of pmab to FU/FA maintenance therapy, while OS was not significantly longer. Re-induction of pmab+mFOLFOX6 did not provide benefit following pmab maintenance regarding PFS. Clinical trial information: NCT01991873 . [Table: see text]
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Yothers, Greg, Patricia A. Ganz, Samia H. Lopa, Clifford Y. Ko, D. Lawrence Wickerham und Norman Wolmark. „Patient-reported outcomes (PROs) comparison of 5-FU and capecitabine (cape) with concurrent radiotherapy (RT) for neoadjuvant treatment of rectal cancer: Results of NSABP R-04.“ Journal of Clinical Oncology 30, Nr. 4_suppl (01.02.2012): 391. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.391.
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391 Background: Preliminary results of NSABP R-04 indicated that 5-FU and cape have similar pathologic complete response (pCR) outcomes and that the addition of oxaliplatin did not improve pCR. We present PROs comparing 5-FU and cape treatments on quality of life (QoL), convenience of care (CoC), and symptoms. Methods: Clinical stage II or III rectal cancer patients were randomized to receive 5-FU (225mg/m2 5 days/wk) or cape (825 mg/m2 5 days/wk) along with RT (4,500cGy in 25 fractions over 5 wk + boost of 540-1080cGy in 3-6 daily fractions). About half of these patients were also randomized to receive oxaliplatin (50 mg/m2 /wk). QoL was assessed by the functional assessment of cancer therapy–colorectal (FACT-C) trial outcome index (TOI) and symptoms were assessed by the fluoropyrimidine specific symptom checklist (SCL) collected at baseline, after chemoradiation before surgery (post therapy), and at 1 year. CoC was assessed by the modified ECOG CoC scale post therapy. Primary hypotheses were to compare 5-FU and cape on the endpoints of change in TOI and SCL baseline to post therapy and CoC at post therapy. P-values, means, and confidence intervals (CI) are adjusted for clinical stage, sex, and intent for sphincter-saving surgery. Results: 625 5-FU and 650 cape patients completed baseline and post therapy data forms. Patient characteristics were similar by treatment. Change in TOI was similar by treatment post therapy (p = .21). Change in SCL post therapy was greater for cape patients than for 5-FU patients (mean difference 1.02, 95% CI 0-2.04, p = .05). CoC was superior with cape compared to 5-FU post therapy (mean difference 3.07, 95% CI 1.31-6.01, p = .002). The change from baseline to post therapy for all FACT-C subscales was similar by treatment. Change in TOI, SCL, and all FACT-C subscales were similar by treatment at the 1-year assessment. Conclusions: PROs indicate that patients treated with 5-FU and cape have similar QoL. Cape provides significantly greater convenience of care but slightly increased symptoms compared to 5-FU. NCI PHS grants U10CA37377, U10CA69974, U10CA12027, and U10CA69651, support from sanofi-aventis and Hoffmann La-Roche.
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Sargent, Daniel J., Silvia Marsoni, Genevieve Monges, Stephen N. Thibodeau, Roberto Labianca, Stanley R. Hamilton, Amy J. French et al. „Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer“. Journal of Clinical Oncology 28, Nr. 20 (10.07.2010): 3219–26. http://dx.doi.org/10.1200/jco.2009.27.1825.
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Purpose Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer. Methods MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS). Results Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04). Conclusion Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making.
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Liu, Guo-Chen, Jun-Ping Yan, Qing He, Xin An, Zhi-Zhong Pan und Pei-Rong Ding. „Effect of Neoadjuvant Chemoradiotherapy with Capecitabine versus Fluorouracil for Locally Advanced Rectal Cancer: A Meta-Analysis“. Gastroenterology Research and Practice 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/1798285.
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A meta-analysis was carried out to compare the efficacy and safety of capecitabine plus radiation with 5-fluorouracil (5-FU) plus radiotherapy (RT) as neoadjuvant treatment in locally advanced rectal cancer (LARC). We searched the Cochrane database, Ovid, Medline, Embase, ISI databases, and Chinese Biomedical Literature Database between January 1998 and October 2014. Trials of capecitabine compared with 5-FU plus RT as neoadjuvant treatment for LARC were considered for inclusion. RevMan software was used to analyze these data. Nine trials were included in this meta-analysis, which covered a total of 3141 patients. The meta-analysis showed that capecitabine group had statistically significant better pCR rates (OR, 1.34; 95% CI, 1.10–1.64;P=0.003), T downstaging rates (OR, 1.58; 95% CI, 1.22–2.06;P=0.0007), N downstaging rates (OR, 2.06; 95% CI, 1.34–3.16;P=0.001), less distant metastasis (OR, 0.63; 95% CI, 0.44–0.88;P=0.007), and lowered leucocytes (OR, 0.25; 95% CI, 0.11–0.54;P=0.0005), but with higher incidence of hand-foot syndrome (HFS) (OR, 4.43; 95% CI, 1.59–12.33;P=0.004). Capecitabine was more efficient than 5-FU in terms of tumor response in neoadjuvant treatment for patients with LARC and favourably low toxicity with the exception of HFS.
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Freeman, Karoline, Martin Connock, Ewen Cummins, Tara Gurung, Sian Taylor-Phillips, Rachel Court, Mark Saunders, Aileen Clarke und Paul Sutcliffe. „Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion“. Health Technology Assessment 19, Nr. 91 (November 2015): 1–322. http://dx.doi.org/10.3310/hta19910.
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Background5-Fluorouracil (5-FU) is a chemotherapy used in colorectal, head and neck (H&N) and other cancers. Dose adjustment is based on body surface area (BSA) but wide variations occur. Pharmacokinetic (PK) dosing is suggested to bring plasma levels into the therapeutic range to promote fewer side effects and better patient outcomes. We investigated the clinical effectiveness and cost-effectiveness of the My5-FU assay for PK dose adjustment to 5-FU therapy.ObjectivesTo systematically review the evidence on the accuracy of the My5-FU assay compared with gold standard methods [high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS)]; the effectiveness of My5-FU PK dosing compared with BSA; the effectiveness of HPLC and/or LC-MS compared with BSA; the generalisability of published My5-FU and PK studies; costs of using My5-FU; to develop a cost-effectiveness model.Data sourcesWe searched MEDLINE, EMBASE, Science Citation Index and other databases between January and April 2014.MethodsTwo reviewers independently screened titles and abstracts with arbitration and consensus agreement. We undertook quality assessment. We reconstructed Kaplan–Meier plots for progression-free survival (PFS) and overall survival (OS) for comparison of BSA and PK dosing. We developed a Markov model to compare My5-FU with BSA dosing which modelled PFS, OS and adverse events, using a 2-week cycle over a 20 year time horizon with a 3.5% discount rate. Health impacts were evaluated from the patient perspective, while costs were evaluated from the NHS and Personal Social Services perspective.ResultsA total of 8341 records were identified through electronic searches and 35 and 54 studies were included in the clinical effectiveness and cost-effectiveness reviews respectively. There was a high apparent correlation between My5-FU, HPLC and LC-MS/mass spectrometer but upper and lower limits of agreement were –18% to 30%. Median OS were estimated as 19.6 [95% confidence interval (CI) 17.0 to 21.0] months for PK versus 14.6 (95% CI 14.1 to 15.3) months for BSA for 5-FU + folinic acid (FA); and 27.4 (95% CI 23.2 to 38.8) months for PK versus 20.6 (95% CI 18.4 to 22.9) months for BSA for FOLFOX6 in metastatic colorectal cancer (mCRC). PK versus BSA studies were generalisable to the relevant populations. We developed cost-effectiveness models for mCRC and H&N cancer. The base case assumed a cost per My5-FU assay of £61.03. For mCRC for 12 cycles of a oxaliplatin in combination with 5-fluorouracil and FA (FOLFOX) regimen, there was a quality-adjusted life-year (QALY) gain of 0.599 with an incremental cost-effectiveness ratio of £4148 per QALY. Probabilistic and scenario analyses gave similar results. The cost-effectiveness acceptability curve showed My5-FU to be 100% cost-effective at a threshold of £20,000 per QALY. For H&N cancer, again, given caveats about the poor evidence base, we also estimated that My5-FU is likely to be cost-effective at a threshold of £20,000 per QALY.LimitationsQuality and quantity of evidence were very weak for PK versus BSA dosing for all cancers with no randomised controlled trials (RCTs) using current regimens. For H&N cancer, two studies of regimens no longer in use were identified.ConclusionsUsing a linked evidence approach, My5-FU appears to be cost-effective at a willingness to pay of £20,000 per QALY for both mCRC and H&N cancer. Considerable uncertainties remain about evidence quality and practical implementation. RCTs are needed of PK versus BSA dosing in relevant cancers.FundingThe National Institute for Health Research Health Technology Assessment programme.
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Zafar, Amna, Zsofia D. Drobni, Matthew Lei, Carlos A. Gongora, Thiago Quinaglia, Uvette Y. Lou, Ramya Mosarla et al. „The efficacy and safety of cardio-protective therapy in patients with 5-FU (Fluorouracil)-associated coronary vasospasm“. PLOS ONE 17, Nr. 4 (07.04.2022): e0265767. http://dx.doi.org/10.1371/journal.pone.0265767.
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Background Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and efficacy of re-challenge with 5-FU after pre-treatment with calcium channel blockers (CCBs) and long-acting nitrates among patients 5-FU associated coronary vasospasm. Methods We conducted a retrospective study of patients with 5-FU coronary vasospasm at a single academic center. By protocol, those referred to cardio-oncology received pre-treatment with either combination [nitrates and CCBs] or single-agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcome was overall survival. Other important outcomes included progression-free survival and safety. Results Among 6,606 patients who received 5-FU from January 2001 to Dec 2020, 115 (1.74%) developed coronary vasospasm. Of these 115 patients, 81 patients continued 5-FU therapy, while 34 stopped. Of the 81 who continued, 78 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU, while the remaining 3 continued 5-FU without cardiac pre-treatment. Of the 78, 56.4% (44/78) received both nitrates and CCBs, 19.2% (15/78) received CCBs alone, and 24.4% (19/78) received nitrates alone. When compared to patients who stopped 5-FU, those who continued 5-FU after pre-treatment (single or combination therapy) had a decreased risk of death (HR 0.42, P = 0.005 [95% CI 0.23–0.77]) and a trend towards decreased cancer progression (HR 0.60, P = 0.08 [95% CI 0.34–1.06]). No patient in the pre-treatment group had a myocardial infarct after re-challenge; however, chest pain (without myocardial infarction) recurred in 19.2% (15/78) among those who received cardiac pre-treatment vs. 66.7% (2/3) among those who did not (P = 0.048). There was no difference in efficacy or the recurrence of vasospasm among patients who received pre-treatment with a single agent (nitrates or CCBs) or combination therapy (14.7% (5/34) vs. 25.0% (11/44), P = 0.26). Conclusion Re-challenge after pre-treatment with CCBs and nitrates guided by a cardio-oncology service was safe and allowed continued 5-FU therapy.
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Ikawati, Muthi, und Endah Puji Septisetyani. „Pentagamavunone-0 (PGV-0), a Curcumin Analog, Enhances Cytotoxicity of 5-Fluorouracil and Modulates Cell Cycle in WiDr Colon Cancer Cells“. Indonesian Journal of Cancer Chemoprevention 9, Nr. 1 (28.02.2018): 23. http://dx.doi.org/10.14499/indonesianjcanchemoprev9iss1pp23-31.
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The use of 5-fluorouracil (5-FU) in colon cancer as the primary chemotherapy has not been meet satisfactory effectiveness. Therefore, the development of new chemicals as a chemopreventive agent and a combination agent (co-chemotherapeutic agent) for colon cancer is important. Pentagamavunone-0 (2,5-bis-(4'-hydroxy-3'-methoxybenzylidine) cyclopentanone) (PGV-0), one of curcumin analogs, exhibits cytotoxic effect and apoptosis induction in various cancer cell lines, including colon cancer cell, better than curcumin. This study aimed to investigate the cytotoxic potency of PGV-0 in combination with 5-FU and their effects, in single or in combination, on cell cycle toward WiDr colon cancer cell line. The cells were treated with combination concentrations of PGV-0 and 5-FU, and examined by MTT cell viability assay. The value of combination index (CI) as a parameter of cytotoxic combination assay was measured by a combination index method. Cells were stained with propidium iodide and the cell cycle distribution was determined by flowcytometry. CI calculation showed additive effects between PGV-0 and 5-FU. Combination of PGV-0 and 5-FU gave synergism on cell cycle. Single treatment of PGV-0 increased apoptosis, illustrated as subG1-phase accumulation, stronger than single treatment of 5-FU. Meanwhile, combination of PGV-0 and 5-FU demonstrated S-phase arrest. Based on these results, it can be concluded that PGV-0 has the potential to be developed as a co-chemotherapeutic agent for colon cancer but still requires further tracking of its molecular mechanisms.Keywords: Pentagamavunone-0 (PGV-0), 5-fluorouracil (5-FU), colon cancer,combination, cell cycle
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Sholihah, Imroatus, Meirizky Zulharini S., Amalia Miranda, Refki Riswansyah und Riris Istighfari Jenie. „Jure Leaf Extract (Nerium indium Mill.) Increased 5-Fluorouracil Sensitivity through Inhibition of NF-κB Activation and Transporter Protein in WiDr Colon Cancer Cell“. Indonesian Journal of Cancer Chemoprevention 7, Nr. 3 (01.02.2017): 87. http://dx.doi.org/10.14499/indonesianjcanchemoprev7iss3pp87-92.
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5-Fluorouracil (5-FU) is the first line chemotherapeutic agents for colon cancer therapy. Long term used of 5-FU caused cancer cell resistency. Thus, co-chemoteraputics agent should be developed to increase cells sensitivty towards 5-FU. Jure leaf (Nerium indicum Mill) extract (JLE) contains oleandrin which has cytotoxic effect on colon cancer cell. The ain of this study was to investigated the mechanism of JLE to sensitized colon cancer cell toward 5-FU through NF-κB inhibition and MRP protein repression. JLE was extracted by soxhletation method. Based on molecular docking to MRP protein, docking score of oleandrin (-50,496) was higher than native ligand ATP (-125,817). Oleandrin could interfere interaction with MRP. JLE increased 5-FU sensitivity a dose of 2 µg/mL JLE dan 12,5 µM 5-FU with the combination index (CI) of 0,594. Combination of JLE and 5-FU also inhibit p65 protein expression on WiDr cell.Keywords: cytotoxic, Nerium indicum Mill., oleandrin, immunofluorescence, molecular docking
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Al-Thani, Hassan, Ayman El-Menyar, Valsa Koshy, Ahmed Hussein, Ahmed Sharaf, Mohammad Asim und Ahmed Sadek. „Implications of Foot Ulceration in Hemodialysis Patients: A 5-Year Observational Study“. Journal of Diabetes Research 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/945075.
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Foot ulceration (FU) remains a serious concern for patients worldwide. We analyzed the incidence, risk factors, and outcome of FU in hemodialysis (HD) patients. A retrospective cohort study was conducted for 252 HD patients who were followed up for 5 years. Patients were categorized according to whether they developed FU or not. The FU group (17%) was older and had significantly higher incidence of nephropathy, retinopathy, peripheral (PAD), coronary artery disease (CAD), and diabetes mellitus (DM) as compared to no-FU group. FU group had higher frequency of major amputation (P=0.001) and HD vascular access (P=0.01). Patients with combined DM and PAD had a 10-fold increased risk of FU in comparison to those who had DM alone. Presence of PAD was the main independent predictor for development of FU in HD with an adjusted odd ratio (aOR) of 16.0 (95% CI: 4.41–62.18;P=0.001). After adjusting for age, sex, and CAD, predictors for mortality were PAD (aOR 4.3), FU (aOR 3.6), and DM (aOR 2.6). FU is common in HD patients regardless of DM. However, the presence of PAD is significantly associated with more FU and mortality in HD. HD patients need intensive foot care and warrant progressive modification of vascular risk factors.
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Mohamed, Yehia I., Aliya Qayyum, Manal Hassan, Lianchun Xiao, Dan G. Duda, Rikita Hatia, Sunyoung S. Lee et al. „Treatment outcome and prognostic indicators in 26 cases of fibrolamellar hepatocellular carcinoma under interferon based therapy.“ Journal of Clinical Oncology 38, Nr. 15_suppl (20.05.2020): e16626-e16626. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16626.
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e16626 Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is a variant of HCC that comprises ∼1%–9% of all HCCs, with about 200 annual cases reported globally, most often affects younger patients (10–35 years of age) with no underlying liver disease. There is no current standard of care therapy for unresectable FLHCC. We report an analysis of the treatment outcomes, and prognostic indicators of 26 cases. Methods: We retrospectively collected clinicopathologic and treatment outcome data from 26 FLHCC patients who received interferon alfa-2b (IFN) based therapy. Median overall survival (OS) and PFS were calculated using Kaplan-Meier curves, and survival rates were compared by the log-rank test. Results: 21 patient underwent treatment with continuous infusion (CI) 5-Fluorouracil (FU) at 200 mg/m2/day for 7 days on, 7 days off plus IFN at 4 million units/m2, subQ every other day for 7 days on, 7 days off, 1 patient FU+IFN+bevacizumab and 4 patients had PIAF (cisPlatin+IFN+Adriamycin+FU). Median age was 24 years (15-44), 13 males and 13 females, 8 of the 26 patients died, the median overall survival was 33.9 months (95% CI, 20.9, NA), estimated 3-year survival was 20.2% (95% CI: 4.1%, 98.5%), median follow up time was 13.4 months (95% CI: 9.79, NA) and median progression-free survival was 11.7 months (95% CI: 5.09, NA). The estimated 1-year survival was 47.9% (95% CI: 29.9%, 76.8%). Finally, FU+IFN combination was the most frequently used systemic therapy. 3/26 pts underwent surgical resection following neoadjuvant treatment with interferon based therapy; Interferon based therapy for the 26 patients had limited side effects, with only 3 of the 26 patients discontinued treatment due to grade 3-4 adverse event in the form of mucositis, severe fatigue and/or hematologic toxicity. Conclusions: Our analyses indicate that CI FU + IFN could be an effective treatment for FLHCC, and may have a neoadjuvant role in this disease with 3/26 were resectable following neoadjuvant treatment with interferon based therapy. This regimen can be well tolerated. Unfortunately, nonsurgical options for patients with FLC remain limited with no approved local or systemic therapies. Therefore, future research is needed to identify better multimodality therapies.
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Haller, Daniel G., Josep Tabernero, Jean Maroun, Filippo de Braud, Timothy Price, Eric Van Cutsem, Mark Hill, Frank Gilberg, Karen Rittweger und Hans-Joachim Schmoll. „Capecitabine Plus Oxaliplatin Compared With Fluorouracil and Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer“. Journal of Clinical Oncology 29, Nr. 11 (10.04.2011): 1465–71. http://dx.doi.org/10.1200/jco.2010.33.6297.
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PurposeThis multicenter, randomized trial compared capecitabine plus oxaliplatin (XELOX) with bolus fluorouracil (FU) and folinic acid (FA) as adjuvant therapy for patients with stage III colon cancer.Patients and MethodsPatients who had undergone curative resection were randomly assigned to XELOX (oxaliplatin 130 mg/m2on day 1 plus capecitabine 1,000 mg/m2twice daily on days 1 to 14 every 3 weeks for 24 weeks) or a standard bolus FU/FA adjuvant regimen (Mayo Clinic for 24 weeks or Roswell Park for 32 weeks). The primary study end point was disease-free survival (DFS).ResultsThe intention-to-treat population comprised 1,886 patients; 944 patients were randomly assigned to XELOX and 942 to FU/FA (Mayo Clinic, n = 664; Roswell Park, n = 278). After 57 months of follow-up for the primary analysis, 295 patients (31.3%) in the XELOX group had relapsed, developed a new primary colon cancer, or died compared with 353 patients (37.5%) in the FU/FA group (hazard ratio [HR] for DFS, 0.80; 95% CI, 0.69 to 0.93; P = .0045). The 3-year DFS rate was 70.9% with XELOX and 66.5% with FU/FA. The HR for overall survival (OS) for XELOX compared to FU/FA was 0.87 (95% CI, 0.72 to 1.05; P = .1486). The 5-year OS for XELOX and FU/FA were 77.6% and 74.2%, respectively. Follow-up is ongoing. Preplanned multivariate and subgroup analyses supported the robustness of these findings.ConclusionThe addition of oxaliplatin to capecitabine improves DFS in patients with stage III colon cancer. XELOX is an additional adjuvant treatment option for these patients.
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Bang, Kyunghye, Jaekyung Cheon, Jae Ho Jeong, Hyeon-Su Im, Kyu-Pyo Kim, Baek-Yeol Ryoo und Changhoon Yoo. „Efficacy and safety of liposomal irinotecan plus fluorouracil/leucovorin after progression on conventional irinotecan-containing chemotherapy for metastatic pancreatic adenocarcinoma.“ Journal of Clinical Oncology 39, Nr. 3_suppl (20.01.2021): 382. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.382.
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382 Background: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has demonstrated its clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on prior gemcitabine-based chemotherapy. However, its role in patients who previously treated with conventional irinotecan has not been investigated. We analyzed clinical outcomes of nal-IRI + 5-FU/LV in mPAC patients after progression on conventional irinotecan-containing chemotherapy. Methods: In this multicenter retrospective analysis, a total of 35 patients with mPAC who received nal-IRI + 5-FU/LV after progression on irinotecan-containing regimen, between January 2017 and March 2020, were included. The ratio of time-to-progression (TTP) with nal-IRI + 5-FU/LV to TTP with conventional irinotecan (TTPr) was correlated with duration and cumulative dose of prior conventional irinotecan. Results: The median age was 58 years (range, 35-73) and 16 patients (46%) were male. All patients received prior irinotecan as the component of FOLFIRINOX. The median duration of prior irinotecan was 4.6 months (range, 0.5-16.8) and median cumulative dose of prior irinotecan was 1230 mg (range, 150-4650). Objective response rate of nal-IRI + 5-FU/LV was 2.9% (1 partial response) and stable disease was achieved in 31.4% (n = 11). With median follow-up duration of 9.2 months [95% CI, 7.8-10.5], the median PFS and OS were 2.0 months [95% CI, 1.4-2.6] and 4.4 months [95% CI, 3.6-5.7], respectively. 6-month PFS rate was 16.3% and OS rate was 37.5%. The median TTPr was 0.41 (range 0.07-2.07) and this showed negative correlation between cumulative dose of prior irinotecan (R = -0.37, p = 0.041). There was a tendency for the negative correlation between TTPr and duration of prior irinotecan (R = -0.35, p = 0.062). Most common grade 3-4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusions: Nal-IRI + 5-FU/LV showed only modest efficacy for mPAC patients who progressed on conventional irinotecan-containing chemotherapy. Cumulative dose of prior conventional irinotecan may be correlated with the efficacy of nal-IRI + 5-FU/LV.
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Bang, Kyunghye, Jaekyung Cheon, Jae Ho Jeong, Hyeon-Su Im, Kyu-pyo Kim, Baek-Yeol Ryoo und Changhoon Yoo. „Clinical outcomes of liposomal irinotecan plus fluorouracil/leucovorin for metastatic pancreatic adenocarcinoma in patients previously treated with conventional irinotecan-containing chemotherapy“. Therapeutic Advances in Medical Oncology 13 (Januar 2021): 175883592110030. http://dx.doi.org/10.1177/17588359211003053.
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Introduction: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has shown clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on gemcitabine-based chemotherapy. However, its role in patients with mPAC previously treated with conventional irinotecan-containing chemotherapy has not been appropriately investigated. Methods: In this retrospective analysis, patients with mPAC who received nal-IRI plus 5-FU/LV after conventional irinotecan-containing regimen between January 2017 and March 2020, were identified from two referral cancer centers in South Korea. The ratio of time to progression (TTP) with nal-IRI plus 5-FU/LV to TTP with conventional irinotecan (TTPr) was analyzed with respect to the duration and cumulative dose of conventional irinotecan treatment. Results: In total, 35 patients treated with nal-IRI plus 5-FU/LV after the irinotecan-containing regimen were analyzed. The median age was 58 years and 16 (46%) patients were male. The median duration of conventional irinotecan therapy was 4.6 months at a median cumulative dose of 1230 mg. The objective response rate of nal-IRI plus 5-FU/LV was 2.9%, and stable disease was achieved in 11 (31.4%) patients. During the median follow-up of 9.2 [95% confidence interval (CI): 7.8–10.5] months, the median progression-free survival (PFS) and overall survival (OS) were 2.0 (95% CI: 1.4–2.6) months and 4.4 (95% CI: 3.6–5.7) months, respectively. The 6-month PFS and OS rates were 16.3% and 37.5%, respectively. The median TTPr was 0.41 (range, 0.07–2.07), showing a negative correlation with the cumulative dose of prior irinotecan therapy (R = −0.37, p = 0.041). A tentative negative correlation between TTPr and duration of prior irinotecan therapy was observed ( R = −0.35, p = 0.062). The most common grade 3–4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusion: Nal-IRI plus 5-FU/LV showed modest effectiveness and manageable toxicities for patients with mPAC previously treated with conventional irinotecan-containing chemotherapy. The cumulative dose of prior conventional irinotecan therapy may be inversely correlated with the effectiveness of nal-IRI plus 5-FU/LV.
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McCaffrey, J. A., S. Hilton, M. Mazumdar, S. Sadan, M. Heineman, J. Hirsch, W. K. Kelly, H. I. Scher und D. F. Bajorin. „Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma.“ Journal of Clinical Oncology 15, Nr. 6 (Juni 1997): 2449–55. http://dx.doi.org/10.1200/jco.1997.15.6.2449.
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PURPOSE A phase II randomized trial of gallium nitrate/fluorouracil (5-FU) versus dose-intense methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was performed in poor-risk patients with advanced urothelial tract tumors. The efficacy and toxicity of these regimens were compared. Assessment of dose-intense M-VAC as salvage treatment in patients who failed to respond to the gallium nitrate/5-FU regimen was also performed. PATIENTS AND METHODS Thirty-four patients who had not received prior systemic chemotherapy were randomized to either arm of the study. All patients had one or more clinical features predicting a low likelihood of durable complete response to standard chemotherapy, ie, weight loss, visceral metastases, and low performance status. Gallium nitrate and 5-FU were each administered by continuous 5-day infusions every 28 days. M-VAC was recycled every 21 days, with prophylactic recombinant human granulocyte colony-stimulating factor (rh-G-CSF). RESULTS Two of 17 patients (12%; 95% confidence interval [CI], 1.4% to 36.4%) had a major response to gallium nitrate/5-FU. Sixteen of 17 patients treated with M-VAC (94%; 95% CI, 71.3% to 99.8%) demonstrated a major response. Five of 12 patients who failed to respond to the gallium nitrate/5-FU combination responded to M-VAC as second-line therapy (42%; 95% CI, 15.2% to 72.3%). Median survival for the gallium nitrate and 5-FU arm was 19 versus 17 months for the M-VAC arm, with a median follow-up duration of 35 months (range, 2 to 51) for all patients. Dose-intense M-VAC was associated with a greater incidence of neutropenia and thrombocytopenia. CONCLUSION Dose-intense M-VAC is superior to gallium nitrate/5-FU in poor-risk patients (P < .0001). Despite the overall high response rate, the median survival for patients with M-VAC remained unsatisfactory. Similar survival distributions were observed for patients who received investigational therapy followed by cisplatin-based therapy and patients treated with initial cisplatin-based therapy.
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Testa, Luca, Azeem Latib, Nedy Brambilla, Federico De Marco, Claudia Fiorina, Marianna Adamo, Cristina Giannini et al. „Long-term clinical outcome and performance of transcatheter aortic valve replacement with a self-expandable bioprosthesis“. European Heart Journal 41, Nr. 20 (06.01.2020): 1876–86. http://dx.doi.org/10.1093/eurheartj/ehz925.
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Abstract Aims In the last decade, transcatheter aortic valve (TAV) replacement determined a paradigm shift in the treatment of patients with severe symptomatic aortic stenosis. Data on long-term TAV performance are still limited. We sought to evaluate the clinical and haemodynamic outcomes of the CoreValve self-expandable valve up to 8-year follow-up (FU). Methods and results Nine hundred and ninety inoperable or high-risk patients were treated with the CoreValve TAV in eight Italian Centres from June 2007 to December 2011. The median FU was 4.4 years (interquartile range 1.4–6.7 years). Longest FU reached 11 years. A total of 728 died within 8-year FU (78.3% mortality from Kaplan–Meier curve analysis). A significant functional improvement was observed in the majority of patients and maintained over time, with 79.3% of surviving patients still classified New York Heart Association class ≤ II at 8 years. Echocardiographic data showed that the mean transprosthetic aortic gradient remained substantially unchanged (9 ± 4 mmHg at discharge, 9 ± 5 mmHg at 8 years, P = 0.495). The rate of Grade 0/1 paravalvular leak was consistent during FU with no significant change from post-procedure to FU ≥5 years in paired analysis (P = 0.164). Structural valve deterioration (SVD) and late bioprosthetic valve failure (BVF) were defined according to a modification of the 2017 EAPCI/ESC/EACTS criteria. In cumulative incidence functions at 8 years, moderate and severe SVD were 3.0% [95% confidence interval (CI) 2.1–4.3%] and 1.6% (95% CI 0.6–3.9%), respectively, while late BVF was 2.5% (95% CI 1.2–5%). Conclusion While TAVs are questioned about long-term performance and durability, the results of the present research provide reassuring 8-year evidence on the CoreValve first-generation self-expandable bioprosthesis.
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Hendlisz, Alain, Marc Van den Eynde, Marc Peeters, Geert Maleux, Bieke Lambert, Jaarke Vannoote, Katrien De Keukeleire et al. „Phase III Trial Comparing Protracted Intravenous Fluorouracil Infusion Alone or With Yttrium-90 Resin Microspheres Radioembolization for Liver-Limited Metastatic Colorectal Cancer Refractory to Standard Chemotherapy“. Journal of Clinical Oncology 28, Nr. 23 (10.08.2010): 3687–94. http://dx.doi.org/10.1200/jco.2010.28.5643.
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Purpose Liver dissemination is a major cause of mortality among patients with advanced colorectal cancer. Hepatic intra-arterial injection of the β-emitting isotope yttrium-90 (90Y) bound to resin microspheres (radioembolization) delivers therapeutic radiation doses to liver metastases with minimal damage to adjacent tissues. Patients and Methods We conducted a prospective, multicenter, randomized phase III trial in patients with unresectable, chemotherapy-refractory liver-limited metastatic CRC (mCRC) comparing arm A (fluorouracil [FU] protracted intravenous infusion 300 mg/m2 days 1 through 14 every 3 weeks) and arm B (radioembolization plus intravenous FU 225 mg/m2 days 1 through 14 then 300 mg/m2 days 1 through 14 every 3 weeks) until hepatic progression. The primary end point was time to liver progression (TTLP). Cross-over to radioembolization was permitted after progression in arm A. Results Forty-six patients were randomly assigned and 44 were eligible for analysis (arm A, n = 23; arm B, n = 21). Median follow-up was 24.8 months. Median TTLP was 2.1 and 5.5 months in arms A and B, respectively (hazard ratio [HR] = 0.38; 95% CI, 0.20 to 0.72; P = .003). Median time to tumor progression (TTP) was 2.1 and 4.5 months, respectively (HR = 0.51; 95% CI, 0.28 to 0.94; P = .03). Grade 3 or 4 toxicities were recorded in six patients after FU monotherapy and in one patient after radioembolization plus FU treatment (P = .10). Twenty-five of 44 patients received further treatment after progression, including 10 patients in arm A who received radioembolization. Median overall survival was 7.3 and 10.0 months in arms A and B, respectively (HR = 0.92; 95% CI, 0.47 to 1.78; P = .80). Conclusion Radioembolization with 90Y-resin microspheres plus FU is well tolerated and significantly improves TTLP and TTP compared with FU alone. This procedure is a valid therapeutic option for chemotherapy-refractory liver-limited mCRC.