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Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study).
Schwarz, L, Vernerey, D, Bachet, JB, Tuech, JJ, Portales, F, Michel, P, Cunha, AS
BMC cancer. 2018;(1):762
Abstract
BACKGROUND At time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC. METHODS PANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence. DISCUSSION The "ideal" cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC. TRIAL REGISTRATION ClinicalTrials.gov , NCT02959879 . Trial registration date: November 9, 2016.
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Uterine artery embolization combined with local infusion of methotrexate and 5- fluorouracil in treating ectopic pregnancy: A CONSORT-compliant article.
Gao, J, Li, X, Chen, J, Gong, W, Yue, K, Wu, Z
Medicine. 2018;(5):e9722
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BACKGROUND To compare the efficiency and safety of uterine artery embolization (UAE) combined with local infusion of methotrexate (MTX) or MTX and 5-fluorouracil (5-FU) in the treatment of ectopic pregnancy (EP). METHODS One hundred women with EP were prospectively enrolled from December 2012 to February 2015 and randomly allocated into 2 groups. One group was treated with UAE combined MTX, and the other with UAE combined with MTX and 5-FU. Local MTX was administrated at a dose of 80 to 120 mg, based on the initial β-human chorionic gonadotropin (β-HCG) levels, and 5-FU was given intra-arterially at a uniform dose of 0.5 g. RESULTS Bilateral UAE was successfully performed in all 100 patients, 88 of whom were clinically successfully treated, 45 (91.8%) in the MTX group, and 43 (87.8%) in the MTX + 5-FU group; 89% of the patients achieved normalization of β-HCG below 70,000 mIU/mL within 14 to 21 days postoperatively. The time to successful β-HCG resolution was 26.74 ± 5.57 days for patients receiving MTX + UAE treatment, and 27.57 ± 5.08 days for those treated with additional 5-FU. Six patients had subsequent intramuscular injections of MTX and 6 had a unilateral salpingectomy after the treatment failure. Mild immediate side effects accounted for 24.5% in the sole MTX and 58.3% in MTX + 5-FU group. CONCLUSION A combination of UAE and intrauterine infusion of MTX showed comparable efficiency to UAE combined with a local infusion of MTX and 5-FU in treating EP patients with the intention to preserve fertility.
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5-Fluorouracil Enhances Protoporphyrin IX Accumulation and Lesion Clearance during Photodynamic Therapy of Actinic Keratoses: A Mechanism-Based Clinical Trial.
Maytin, EV, Anand, S, Riha, M, Lohser, S, Tellez, A, Ishak, R, Karpinski, L, Sot, J, Hu, B, Denisyuk, A, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018;(13):3026-3035
Abstract
Purpose: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used agents for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK.Patients and Methods: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days, whereas the other side served as no-pretreatment control. Methylaminolevulinate cream was applied to both sides for 3 hours, and protoporphyrin IX (PpIX) levels were measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months after PDT.Results: PpIX levels were increased 2- to 3-fold in 5FU-pretreated lesions versus controls. Altered expression of heme-synthetic enzymes (coproporphyrinogen oxidase and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates after PDT with or without 5FU pretreatment were 75% versus 45% at 3 months, and 67% versus 39% at 6 months, respectively; these differences were statistically significant.Conclusions: Serial 5FU and PDT improve AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk. Clin Cancer Res; 24(13); 3026-35. ©2018 AACR.
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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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Tumour sidedness and intrinsic subtypes in patients with stage II/III colon cancer: analysis of NSABP C-07 (NRG Oncology).
Kim, SR, Song, N, Yothers, G, Gavin, PG, Allegra, CJ, Paik, S, Pogue-Geile, KL
British journal of cancer. 2018;(5):629-633
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BACKGROUND We tested the association of colon tumour sidedness with prognosis and with molecular subtypes recently shown to be predictive of oxaliplatin benefit in stage III colon cancer. METHODS NSABP/NRG C-07 trial (N=1603) was used to determine association of tumour sidedness with molecular subtypes and recurrence-free survival (RFS) and overall survival (OS). RESULTS Sidedness was associated with molecular subtypes except stem-like/CMS4 subtype. Patients with stage III, left-sided tumours showed superior OS but not RFS. Sidedness was not associated with prediction of oxaliplatin benefit when combined with 5-Fu+LV. However, greater benefit from oxaliplatin was observed in a small subset of stage III patients with left-sided, enterocyte-subtype tumours (interaction HR=0.17, P=0.01). CONCLUSIONS Sidedness was associated with molecular subtypes and was predictive of OS in stage III colon cancer but was not predictive of RFS or oxaliplatin benefit in C-07. Molecular subtypes may provide more predictive value for oxaliplatin benefit than tumour sidedness.
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Protocol digest of randomized phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel combination therapy for locally advanced pancreatic cancer: Japan clinical oncology group study (JCOG1407).
Mizusawa, J, Fukutomi, A, Katayama, H, Ishii, H, Ioka, T, Okusaka, T, Ueno, H, Ueno, M, Ikeda, M, Mizuno, N, et al
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2018;(7):841-845
Abstract
Gemcitabine is one of the standard treatments for locally advanced pancreatic cancer. Recent studies on metastatic pancreatic cancer have shown that combination chemotherapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP) prolonged the overall survival compared with gemcitabine alone. To select the most promising chemotherapy, a randomized phase II selection design trial was started in July 2016 to compare between modified FOLFIRINOX and GnP for patients with locally advanced pancreatic cancer. A total of 124 patients will be enrolled from 36 Japanese institutions within 2.5 years. The primary endpoint is the proportion of 1-year overall survival, and secondary endpoints are progression-free survival, distant metastasis-free survival, response rate in patients with target lesions, CA19-9 response, adverse events, treatment-related death, early death, grade 4 non-hematological toxicity, and dose intensity. This trial has been registered with the UMIN Clinical Trials Registry [http://www.umin.ac.jp/ctr/index.htm], and the registration number is UMIN000023143.
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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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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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First-line Treatment of Advanced Biliary Ducts Carcinoma: A Randomized Phase II Study Evaluating 5-FU/LV Plus Oxaliplatin (Folfox 4) Versus 5-FU/LV (de Gramont Regimen).
Schinzari, G, Rossi, E, Mambella, G, Strippoli, A, Cangiano, R, Mutignani, M, Basso, M, Cassano, A, Barone, C
Anticancer research. 2017;(9):5193-5197
Abstract
BACKGROUND/AIM: Few clinical trials are available for advanced biliary tract carcinoma (BTC). We conducted this randomized phase II clinical trial to explore efficacy and safety of 5-fluorouracil/leucovorin (5-FU/LV - de Gramont) or the same regimen plus oxaliplatin (Folfox 4) as first-line treatment of advanced BTC. PATIENTS AND METHODS Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), response and toxicity. RESULTS A total of 48 patients were enrolled, 23 in de Gramont arm and 25 in the Folfox arm. Disease control rate was 56.5% for de Gramont vs. 72% for Folfox. RR was 21.7% for de Gramont arm and 28% for Folfox arm (p=0.12). PFS was in favor of Folfox (5.2 vs. 2.8 months; p=0.031). OS was 7.5 and 13.0 months for de Gramont and Folfox arm respectively (p=0.0010). Toxicity was generally mild in both arms. CONCLUSION Folfox 4 could be considered a valid option as first-line treatment of BTC due to its efficacy and tolerability.
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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.