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Efficacy and safety of high-dose vs low-dose leucovorin in patients with colorectal cancer: systematic review and meta-analysis.
Hsu, CY, Chen, CY, Lin, YM, Tam, KW
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2020;(1):6-17
Abstract
AIM: The clinical benefits of a combination of leucovorin and fluorouracil have been established in the treatment of colorectal cancer. Due to a leucovorin shortage in 2008, many institutions revised their protocols to reduce the dose of leucovorin. After the shortage was resolved, some hospitals still maintained their modified protocols. Thus, we conducted a systematic review to evaluate the efficacy and safety of low- vs high-dose leucovorin in the treatment of colorectal cancer. METHOD The PubMed, Embase and Cochrane databases were searched for studies published before May 2019. The meta-analysis was performed to estimate the pooled effect sizes by using a random effect model. The primary outcomes were median survival time and tumour response rate. Secondary outcomes were haematological and nonhaematological toxicities. RESULTS Eight randomized controlled trials and four retrospective studies were reviewed. The pooled median survival time was similar between the two dose levels (standard mean difference -0.06, 95% CI -0.19 to 0.08). The pooled tumour response rate was comparatively higher in the high-dose leucovorin regimen (OR 0.81; 95% CI 0.55-1.18). No statistically significant difference was found between the haematological and nonhaematological toxicities of the two groups. However, there were fewer diarrhoea events in the low-dose leucovorin regimen. CONCLUSION Low-dose leucovorin regimens seemed feasible approaches for colorectal cancer treatment when the shortage happened, because both regimens manifested comparable outcomes in survival time and tumour response rate.
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Relative efficacy of 5-fluorouracil compared with other treatments among patients with actinic keratosis: A network meta-analysis.
Wu, Y, Tang, N, Cai, L, Li, Q
Dermatologic therapy. 2019;(3):e12822
Abstract
OBJECTIVE The purpose of this study was to compare the efficacy of 5-fluorouracil (5-FU) with that of other treatments of actinic keratosis (AK). METHODS A systematic literature review of five databases (including Medline and EMBASE) was first performed to identify randomized controlled trials (RCTs). A network meta-analysis (NMA) based on a random-effects Bayesian model was then performed on the outcomes for patients with total clearance and lesions reduced from baseline. Five treatments (viz., 0.5% 5-FU with 10% salicylic acid [5-FU/SA], 5% 5-FU cream, 3% diclofenac sodium, cryosurgery, and vehicle) were evaluated. RESULTS A total of 11 studies involving 2,256 patients with AK were included in this NMA. The overall risk of bias among the included studies was low. All treatments were significantly better than the vehicle both for patients with total clearance and for lesions reduced from baseline. Among patients with total clearance, 5% 5-FU cream (56.8%) and 5-FU/SA (35.7%) were likely to be more effective than the other treatments, whereas 5% 5-FU cream (98.6%) was likely the most effective in the group of lesions reduced from baseline. CONCLUSION 5-FU, diclofenac sodium, and cryosurgery are all useful for AK treatment, with 5-FU being the most effective.
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Which are the best Chinese herbal injections combined with XELOX regimen for gastric cancer?: A PRISMA-compliant network meta-analysis.
Zhang, D, Wu, J, Wang, K, Duan, X, Liu, S, Zhang, B
Medicine. 2018;(12):e0127
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Abstract
BACKGROUND The optimal Chinese herbal injections (CHIs) combined with XELOX regimen for patients with gastric cancer remains elusive. The aim of our network meta-analysis (NMA) is to explore the best options among different CHIs for gastric cancer. METHODS PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure Database (CNKI), Wan-fang Database, Cqvip Database (VIP), China Biology Medicine disc (CBMdisc) were searched to identify RCTs which focused on CHIs against gastric cancer. The quality assessment of included randomized controlled trials (RCTs) was conducted by the Cochrane risk of bias tool. Standard pair-wise and Bayesian NMAs were performed to compare the efficacy and safety of different CHIs combined with the XELOX regimen via Stata 13.0 and WinBUGS1.4 software. RESULTS A total of 2316 records were searched, the network of evidence included 26 eligible RCTs involving 13 types of CHIs and 2154 patients. The results suggested that Shenqifuzheng+ XELOX, Huachansu+ XELOX, Kangai+ XELOX, Javanica oil emulsion+ XELOX, Aidi injection+ XELOX might be the optimal treatment for gastric cancer in improving the performance status than using XELOX regimen single, with odds ratios (OR) and 95% confidence intervals (CIs) of 2.74 (1.24, 6.17), 8.27 (1.74, 42.43), 4.28 (1.80, 10.48), 5.14 (1.87, 16.28), 0.20 (0.090, 0.44). At the aspects of ADRs (adverse reactions), Compound Kushen+ XELOX, Lentinan+ XELOX, Xiaoaiping injection+ XELOX could obviously relieve leukopenia than only receiving XELOX regimen, and their ORs and 95% CIs were 5.62 (1.41, 36.24), 8.16 (2.25, 29.43), 5.69 (1.85, 15.77). Furthermore, Disodium cantharidinate and vitamin B6+ XELOX, Shenqifuzheng+ XELOX, Kangai+ XELOX, Lentinan+ XELOX could obviously relieve the nausea and vomiting than receiving the XELOX regimen alone, with ORs and 95% CIs of 5.29 (1.30, 23.96), 2.50 (1.16, 5.26), 2.42 (1.06, 5.63), 9.04 (3.24, 26.73). Nevertheless, CHIs combined with XELOX regimen did not confer higher better clinical effectiveness rate over receiving XELOX regimen alone, with nonstatistically significant between-group differences. CONCLUSIONS As the available evidence suggested that CHIs combined with XELOX regimen could provide treatment benefits for patients with gastric cancer. Among 13 types of CHIs, Javanica oil emulsion and Compound Kushen injection is the optimal treatment in improving the clinical effectiveness rate and performance status, and Lentinan injection was superior in relieving ADRs.
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Meta-analysis of Modified FOLFIRINOX Regimens for Patients With Metastatic Pancreatic Cancer.
Usón Junior, PLS, Rother, ET, Maluf, FC, Bugano, DDG
Clinical colorectal cancer. 2018;(3):187-197
Abstract
BACKGROUND We performed a meta-analysis of previous reports evaluating the effect of mFIO (modified FOLFIRINOX; leucovorin, 5-fluorouracil, irinotecan, oxaliplatin) regimens in advanced pancreatic cancer. MATERIALS AND METHODS We performed a meta-analysis of reported studies in PubMed, Scopus, and Web of Science (1950-2016) in December 2016. The inclusion criteria were randomized trials, prospective or retrospective cohorts, patients with metastatic pancreatic adenocarcinoma, the use of mFIO or FOLFIRINOX (FIO) chemotherapy, and available information for ≥ 1 efficacy endpoint (response rate, progression-free survival, and/or overall survival). The outcomes were compared according to the chemotherapy regimen using a random effects model. We also performed a meta-regression analysis to evaluate the effect of dose reductions on outcomes. RESULTS Of 2525 abstracts, 32 were considered eligible. Modifications in the FIO regimen included omission of the 5-fluorouracil bolus and/or dose reductions in infusional 5-fluorouracil, irinotecan, and/or oxaliplatin. mFIO was not associated with inferior response rates (32% vs. 33%; P = .879), lower rates of survival at 11 months (47% vs. 50%; P = .38), or lower 6-month progression-free survival rates (47% vs. 53%; P = .38). The meta-regression of the percentage of dose reduction failed to show any association. CONCLUSION The results of the present meta-analysis with a combined sample size of 1461 patients suggest that it is reasonable to consider mFIO regimens for patients with metastatic pancreatic adenocarcinoma.
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Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives.
Ribeiro, RA, Wanderley, CW, Wong, DV, Mota, JM, Leite, CA, Souza, MH, Cunha, FQ, Lima-Júnior, RC
Cancer chemotherapy and pharmacology. 2016;(5):881-893
Abstract
PURPOSE Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis. METHODS A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion. RESULTS Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1β contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis. CONCLUSIONS IL-1β, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.
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Chinese Herbal Medicine and Fluorouracil-Based Chemotherapy for Colorectal Cancer: A Quality-Adjusted Meta-Analysis of Randomized Controlled Trials.
McCulloch, M, Ly, H, Broffman, M, See, C, Clemons, J, Chang, R
Integrative cancer therapies. 2016;(3):285-307
Abstract
Background Chinese herbal medicines reportedly increase efficacy and minimize toxicity of chemotherapy; however, little attention has been paid to how poor study quality can bias outcomes. Methods We systematically searched MEDLINE, TCMLARS, EMBASE, and Cochrane Library for randomized controlled trials of Chinese herbal medicines combined with fluorouracil-based chemotherapy compared with the same chemotherapy alone. We screened for eligibility, extracted data, and pooled data with random-effects meta-analysis. Outcome measures were survival, toxicity, tumor response, performance status, quality of life, and Cochrane Risk of Bias (ROB) criteria to critically evaluate the quality of reporting in the randomized trials included in the meta-analysis. Results We found 36 potentially eligible studies, with only 3 (those with low ROB) qualifying for meta-analysis. Two reported chemotherapy-related diarrhea reduced by 57% (relative risk [RR] = 0.43; 95% CI = 0.19-1.01; I(2) test for variation in RR due to heterogeneity = 0.0%), with nonsignificant results. Two reported white blood cell toxicity reduced by 66% (RR = 0.34; 95% CI = 0.16-0.72; I(2) test for variation in RR due to heterogeneity = 0.0%), with statistically significant results. Stratifying analysis by studies with high versus low ROB, we found substantial overestimation of benefit: Studies with high ROB overestimated by nearly 2-fold reduction of platelet toxicity by Chinese herbal medicines (RR = 0.35, 95% CI = 0.15-0.84 vs RR = 0.65, 95% CI = 0.11-3.92). Studies with high ROB overestimated by nearly 2-fold reduction of vomiting toxicity (RR = 0.45, 95% CI = 0.33-0.61 vs RR = 0.87, 95% CI = 0.48-1.58). And, studies with high ROB overestimated by 21% the reduction in diarrhea toxicity (RR = 0.34, 95% CI = 0.20-0.58 vs RR = 0.43, 95% CI = 0.19-1.01). Studies with high ROB also overestimated by 16% improvement in tumor response (RR = 1.39, 95% CI = 1.18-1.63 vs RR = 1.20; 95% CI = 0.81-1.79). Not accounting for ROB would have exaggerated evidence of benefit and failed to detect nonsignificance of results. Conclusions In the present analysis, involving 36 studies, 2593 patients, 20 outcomes, 36 medical institutions, and 271 named research authors, 92% of the data points were from studies at high ROB. Given the poor quality of the data in studies identified, it cannot be concluded whether combining Chinese herbs with chemotherapy reduces toxicity of chemotherapy.
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Doublet chemotherapy vs. single-agent therapy with 5FU in elderly patients with metastatic colorectal cancer. a meta-analysis.
Landre, T, Uzzan, B, Nicolas, P, Aparicio, T, Zelek, L, Mary, F, Taleb, C, Des Guetz, G
International journal of colorectal disease. 2015;(10):1305-10
Abstract
BACKGROUND The clinical benefit of first-line doublet chemotherapy (including oxaliplatin or irinotecan) compared to single-drug therapy (5FU) in elderly patients (>70 or >75 years old) with metastatic colorectal cancer (MCRC) is controversial. Therefore, we undertook a meta-analysis of all published phase III studies. MATERIAL AND METHODS We performed a PubMed search using keywords metastatic colorectal cancer, phase III studies, oxaliplatin, irinotecan, survival. We also screened Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) proceedings. Few studies have been published corresponding to our inclusion criteria. The efficacy outcomes were overall survival (OS) and progression-free survival (PFS). Toxicity was also examined when available. Hazard ratios (HRs) with their 95 % confidence intervals (CI) were collected from the studies and pooled. By convention, HRs <1 corresponded to a better outcome for doublets. p values <0.05 were considered statistically significant. A fixed-effect model was used. We used Comprehensive Meta-Analysis Software (Biostat, Englewood, NJ, USA). RESULTS This meta-analysis (MA) included five original studies (Mitry and Venderbosch for CAIRO both assessing irinotecan, De Gramont and Seymour for FOCUS2 and Ducreux assessing oxaliplatin) and an already published MA (Folprecht) of four trials comparing FOLFIRI with 5FU (Saltz, Douillard, Köhne and Seymour). Our MA included 1225 patients (70 % men). For age, we chose a cut-off of 70 years for oxaliplatin and a cut-off of 75 years for irinotecan. The performance status (PS) score was 0-1 in about 90 % of patients except for the studies by Mitry and Seymour FOCUS2 which both included 30 % of PS2 patients. Overall, doublet chemotherapy, compared to 5FU alone, did not improve OS (HR = 1.00; CI: 0.89-1.13) but significantly improved PFS (HR = 0.82; CI: 0.72-0.93). When assessed separately, FOLFIRI and FOLFOX both significantly improved PFS (HR = 0.83; 0.68-1.00 and HR = 0.81; 0.68-0.97, respectively). The main grade 3-4 toxicities for FOLFIRI were diarrhoea, nausea, vomiting and neutropenia, which occurred significantly more often than with 5FU alone. CONCLUSION Addition of oxaliplatin or irinotecan to 5FU in metastatic CRC significantly improved PFS in elderly patients more than 70 years old but was associated with an increased risk of toxicity as shown for irinotecan.
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Irinotecan or oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer: a meta-analysis.
Liang, XB, Hou, SH, Li, YP, Wang, LC, Zhang, X, Yang, J
Chinese medical journal. 2010;(22):3314-8
Abstract
BACKGROUND To compare clinical efficacy and toxicity of irinotecan combined with 5-fluorouracil and leucovorin with those of oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer. METHODS Literature search was performed by keywords "irinotecan", "oxaliplatin" and "colorectal cancer" on all randomized controlled trails reported on irinotecan versus oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer in MEDLINE, OVID, Springer, Cochrane Controlled Trials Register (CCTR) and CBMdisc (Chinese Biology and Medicine disc) before January 2010. Two authors drew the details of trial design, characteristics of patients, outcomes, and toxicity from the studies included. Data analysis was performed by RevMan 4.2. RESULTS According to the screening criteria, 7 clinical studies with 2095 participants of advanced colorectal cancer were included in this meta analysis. The baseline characteristics of irinotecan group were similar to those of oxaliplatin group. The response rate of oxaliplatin group was higher than that of irinotecan group (relative risk (RR) = 0.82, 95% confidence interval (95%CI) (0.70, 0.96), P = 0.01), and the median overall survival of oxaliplatin group was longer by 2.04 months than that of irinotecan group (95%CI (-3.54, -0.54), P = 0.008). In the comparison of grade 3 - 4 toxicity between the two groups, the incidences of nausea, emesis, diarrhoea and alopecia in irinotecan group were higher than those in oxaliplatin group (RR = 1.94, 95%CI (1.22, 3.09), P = 0.005; 1.71, 95%CI (1.34, 2.18), P < 0.001; 14.56, 95%CI (4.11, 51.66), P < 0.0001), respectively. However, the incidence of neurotoxicity, neutropenia and thrombocytopenia in irinotecan group were lower than those in oxaliplatin group (RR = 0.06, 95%CI (0.03, 0.14), P < 0.00001; 0.70, 95%CI (0.55, 0.91), P = 0.006; 0.18, 95%CI (0.05, 0.61), P = 0.006), respectively. CONCLUSIONS Both irinotecan and oxaliplatin combined with 5-fluorouracil and leucovorin were effective in the first-line therapy of advanced colorectal cancer. However, the combined regimen of oxaliplatin plus 5-fluorouracil and leucovorin is more excellent. Irinotecan tended to result in more gastrointestinal tract reactions than oxaliplatin did, but the myelosuppression and neurotoxicity were more frequent in oxaliplatin regimen than irinotecan regimen.
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Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?
Gill, S, Loprinzi, CL, Sargent, DJ, Thomé, SD, Alberts, SR, Haller, DG, Benedetti, J, Francini, G, Shepherd, LE, Francois Seitz, J, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004;(10):1797-806
Abstract
PURPOSE Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain. PATIENTS AND METHODS Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets. RESULTS Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. CONCLUSION Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs. This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.
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Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer.
Thirion, P, Piedbois, P, Buyse, M, O'Dwyer, PJ, Cunningham, D, Man, A, Greco, FA, Colucci, G, Köhne, CH, Di Constanzo, F, et al
British journal of cancer. 2001;(5):611-20
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Two meta-analyses were conducted to quantify the benefit of combining alpha-IFN to 5FU in advanced colorectal cancer in terms of tumour response and survival. Analyses were based on a total of 3254 individual patient data provided by principal investigators of each trial. The meta-analysis of 5FU +/- LV vs. 5FU +/- LV + alpha-IFN combined 12 trials and 1766 patients. The meta-analysis failed to show any statistically significant difference between the two treatment groups in terms of tumour response or survival. Overall tumour response rates were 25% for patients receiving no alpha-IFN vs. 24% for patients receiving alpha-IFN (relative risk, RR = 1.02), and median survivals were 11.4 months for patients receiving no alpha-IFN vs. 11.5 months for patients receiving alpha-IFN (hazard ratio, HR = 0.95). The meta-analysis of 5FU + LV vs. 5FU + alpha-IFN combined 7 trials, and 1488 patients. This meta-analysis showed an advantage for 5FU + LV over 5FU + alpha-IFN which was statistically significant in terms of tumour response (23% vs. 18%; RR = 1.26;P = 0.042), and of a borderline significance for overall survival (HR = 1.11;P = 0.066). Metastases confined to the liver and primary rectal tumours were independent favourable prognostic factors for tumour response, whereas good performance status, metastases confined to the liver or confined to the lung, and primary tumour in the rectum were independent favourable prognostic factors for survival. We conclude that alpha-IFN does not increase the efficacy of 5FU or of 5FU + LV, and that 5FU + alpha-IFN is significantly inferior to 5FU + LV, for patients with advanced colorectal cancer.