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Neoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer.
Sah, BK, Zhang, B, Zhang, H, Li, J, Yuan, F, Ma, T, Shi, M, Xu, W, Zhu, Z, Liu, W, et al
Nature communications. 2020;(1):6093
Abstract
Neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT regimen) has shown promising results in terms of pathological response and survival rate in patients with locally advanced resectable gastric cancer (LAGC). However, tegafur gimeracil oteracil potassium capsule (S-1) plus oxaliplatin (SOX regimen) is the preferred chemotherapy regimen in Eastern countries. Here, we conduct an open label, two-arm, phase II randomized interventional clinical trial (Dragon III; ClinicalTrials.gov: NCT03636893) to evaluate the safety and efficacy of both regimens. Patients with LAGC are randomly assigned to receive either 4 cycles of the neoadjuvant FLOT regimen (40 patients) or 3 cycles of the SOX regimen (34 patients) before gastrectomy. The primary endpoint is the comparison of complete (TRG1a) or subtotal (TRG1b) tumor regression grading in the primary tumor. There are no significant differences in adverse effects or postoperative morbidity and mortality between the two groups. No significant differences in the proportion of tumor regression grading between the FLOT group and the SOX group are found. Complete or subtotal TRG is 20.0% in the FLOT group versus 32.4% in the SOX group. Therefore, our study does not find statistically significant differences between neoadjuvant FLOT and SOX regimens for the primary outcomes reported here in locally advanced gastric cancer.
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Consumption of Lactose, Other FODMAPs and Diarrhoea during Adjuvant 5-Fluorouracil Chemotherapy for Colorectal Cancer.
Holma, R, Laatikainen, R, Orell, H, Joensuu, H, Peuhkuri, K, Poussa, T, Korpela, R, Österlund, P
Nutrients. 2020;(2)
Abstract
Chemotherapy-induced mucosal injury of the small intestine may interfere with the enzymes and transporters responsible for the hydrolysis and absorption of dietary carbohydrates causing diarrhoea, abdominal discomfort and pain. The aim of this study was to investigate the association between the consumption of foods rich in FODMAPs (fermentable oligo-, di- and monosaccharides and polyols) and gastrointestinal symptoms in patients receiving adjuvant therapy for colorectal cancer. The patients (n = 52) filled in a 4-day food diary at baseline and during therapy and kept a symptom diary. The intakes of FODMAP-rich foods were calculated as portions and the intakes were divided into two consumption categories. Patients with high consumption of FODMAP-rich foods had diarrhoea more frequently than those with low consumption (for lactose-rich foods the odds ratio (OR) was 2.63, P = 0.03; and for other FODMAP-rich foods 1.82, P = 0.20). Patients with high consumption of both lactose-rich and other FODMAP-rich foods had an over 4-fold risk of developing diarrhoea as compared to those with low consumption of both (OR, 4.18; P = 0.02). These results were confirmed in multivariate models. Conclusion: Consumption of lactose-rich foods results in an increased risk of diarrhoea during adjuvant therapy for colorectal cancer, especially when the consumption of other FODMAP-rich foods is also high.
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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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Randomised study of tegafur-uracil plus leucovorin versus capecitabine as first-line therapy in elderly patients with advanced colorectal cancer--TLC study.
Kroep, JR, van Werkhoven, E, Polee, M, van Groeningen, CJ, Beeker, A, Erdkamp, F, Weijl, N, van Bochove, A, Erjavec, Z, Kapiteijn, E, et al
Journal of geriatric oncology. 2015;(4):307-15
Abstract
BACKGROUND Prospective data on chemotherapy for (frail) elderly patients with advanced colorectal cancer (aCRC) are scant. UFT/leucovorin might be as effective as and less toxic than capecitabine. We firstly randomized both agents in patients >65 years with aCRC not amenable to receive combination chemotherapy. PATIENTS AND METHODS Patients were randomised between first-line oral UFT/leucovorin and capecitabine in a Dutch multicentre trial. Primarily, efficacy and toxicity were determined. Secondary, quality of life (QoL) and abbreviated common geriatric assessment (aCGA) were analysed. RESULTS Sixty-seven patients were randomised with a median age of 77 years and 96% being frail. After interim analysis it was decided to stop recruitment because of low accrual. At a median follow up of 34 months, the median progression-free survival (PFS) and overall survival (OS) were similar for both therapies, being 21 weeks (p=0.17) and 12 months (p=0.83), respectively. The overall response rates were 24% and 21%, respectively. Two patients died of possible treatment related complications in the UFT/leucovorin arm and 3 patients in the capecitabine arm. For UFT/leucovorin significantly less grade 3 or 4 hand/foot syndrome (0 vs 5) was observed. Overall, PFS was related to Charlson-comorbidity index (p=0.049), LDH (p=0.0011) and albumin (p=0.009). OS was related to LDH (p=0.0003), albumin (p=0.0001), QoLC30/CR38 (p=0.041), QoL visual analogue scale (VAS; p=0.016), and GFI (p=0.028). CONCLUSION UFT/leucovorin and capecitabine had similar efficacy and different toxicity profiles in frail elderly patients with aCRC. Baseline serum levels of albumin and LDH, Charlson-comorbidity index, GFI and QoL were prognostic for clinical outcome.
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Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer.
Pectasides, D, Karavasilis, V, Papaxoinis, G, Gourgioti, G, Makatsoris, T, Raptou, G, Vrettou, E, Sgouros, J, Samantas, E, Basdanis, G, et al
BMC cancer. 2015;:384
Abstract
BACKGROUND The aim of the trial was to compare two active adjuvant chemotherapy regimens in patients with early stage colorectal cancer (CRC). METHODS Patients were assigned to oxaliplatin, leucovorin and 5-FU for 12 cycles (group A, FOLFOX6) or oxaliplatin and capecitabine for eight cycles (group B, CAPOX). Primary endpoint was disease-free survival (DFS). Tumors were classified as mismatch repair proficient (pMMR) or deficient (dMMR) according to MLH1, PMS2, MSH2 and MSH6 protein expression. KRAS exon two and BRAF V600E mutational status were also assessed. RESULTS Between 2005 and 2008, 441 patients were enrolled, with 408 patients being eligible. After a median follow-up of 74.7 months, 3-year DFS was 79.8 % (95 % CI 76.5-83.4) in the FOLFOX group and 79.5 % (95 % CI 75.9-83.1) in the CAPOX group (p = 0.78). Three-year OS was 87.2 % (95 % CI 84.1-91.1) in the FOLFOX and 86.9 % (95 % CI 83.4-89.9) in the CAPOX group (p = 0.84). Among 306 available tumors, 11.0 % were dMMR, 34.0 % KRAS mutant and 4.9 % BRAF mutant. Multivariate analysis showed that primary site in the left colon, earlier TNM stage and the presence of anemia at diagnosis were associated with better DFS and overall survival (OS), while grade one-two tumors were associated with better OS. Finally, a statistically significant interaction was detected between the primary site and MMR status (p = 0.010), while KRAS mutated tumors were associated with shorter DFS. However, the sample was too small for safe conclusions. CONCLUSIONS No significant differences were observed in the efficacy of FOLFOX versus CAPOX as adjuvant treatment in high-risk stage II or stage III CRC patients, but definitive conclusions cannot be drawn because of the small sample size. TRIAL REGISTRATION ANZCTR 12610000509066 . Date of Registration: June 21, 2010.
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Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial.
Klingbiel, D, Saridaki, Z, Roth, AD, Bosman, FT, Delorenzi, M, Tejpar, S
Annals of oncology : official journal of the European Society for Medical Oncology. 2015;(1):126-132
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BACKGROUND Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI. MATERIALS AND METHODS Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS). RESULTS In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14). CONCLUSIONS Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. CLINICALTRIALS.GOV IDENTIFIER NCT00026273.
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Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among patients with stage II or III rectal cancer (INT-0144; SWOG 9304).
Ulrich, CM, Rankin, C, Toriola, AT, Makar, KW, Altug-Teber, Ö, Benedetti, JK, Holmes, RS, Smalley, SR, Blanke, CD, Lenz, HJ
Cancer. 2014;(21):3329-3337
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BACKGROUND Recurrence and toxicity occur commonly among patients with rectal cancer who are treated with 5-fluorouracil (5-FU). The authors hypothesized that genetic variation in folate-metabolizing genes could play a role in interindividual variability. The objective of the current study was to evaluate the associations between genetic variants in folate-metabolizing genes and clinical outcomes among patients with rectal cancer treated with 5-FU. METHODS The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [MTHFR] [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], dihydrofolate reductase [DHFR] [Del19bp], TS 1494del,and TSER) involved in folate metabolism in 745 patients with TNM stage II or III rectal cancer enrolled in a phase 3 adjuvant clinical trial of 3 regimens of 5-FU and radiotherapy (INT-0144 and SWOG 9304). RESULTS There were no statistically significant associations noted between polymorphisms in any of the genes and overall survival, disease-free survival (DFS), and toxicity in the overall analyses. Nevertheless, there was a trend toward worse DFS among patients with the variant allele of MTHFR C677T compared with wild-type, particularly in treatment arm 2, in which patients with the MTHFR C677T TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06-2.93 [P = .03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12-3.03 [P = .02]) compared with those with homozygous wild-type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of SLC19A1 G80A in treatment arm 1 (P for trend, .06) and reduced esophagitis/stomatitis noted among patients with variants of TSER in treatment arm 3 (P for trend, .06). CONCLUSIONS Genetic variability in folate-metabolizing enzymes was found to be associated only to a limited degree with clinical outcomes among patients with rectal cancer treated with 5-FU.
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Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study.
Maréchal, R, Vos, B, Polus, M, Delaunoit, T, Peeters, M, Demetter, P, Hendlisz, A, Demols, A, Franchimont, D, Verset, G, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2012;(6):1525-30
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BACKGROUND Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.
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Double-blind, placebo-controlled, randomized study of chlorhexidine prophylaxis for 5-fluorouracil-based chemotherapy-induced oral mucositis with nonblinded randomized comparison to oral cooling (cryotherapy) in gastrointestinal malignancies.
Sorensen, JB, Skovsgaard, T, Bork, E, Damstrup, L, Ingeberg, S
Cancer. 2008;(7):1600-6
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BACKGROUND The purpose was to evaluate prevention of oral mucositis (OM) using chlorhexidine compared with placebo and with oral cooling (cryotherapy) during fluorouracil (5-FU)-based chemotherapy in gastrointestinal (GI) cancer. METHODS Patients with previously untreated GI cancer receiving bolus 5-FU/leucovorin chemotherapy were randomized to chlorhexidine mouthrinse 3 times a day for 3 weeks (Arm A), double-blind placebo (normal saline) with the same dose and frequency (Arm B), or cryotherapy with crushed ice 45 minutes during chemotherapy (Arm C). Patients self-reported on severity (CTC-grading) and duration of OM. RESULTS Among 225 patients randomized, 206 answered the questionnaire (70, 64, and 63 patients in Arms A, B, and C, respectively) and were well balanced with respect to diagnoses, stage, age, sex, smoking habits, and performance status. Mucositis grade 3-4 occurred more frequently in Arm B (33%) than in A (13%, P< .01) and C (11%, P< .005). Duration was significantly longer in B than in both A (P= .035) and C (P= .003). CONCLUSIONS The frequency and duration of OM are significantly improved by prophylactic chlorhexidine and by cryotherapy. The latter is easy and inexpensive but has limited use, as it is drug- and schedule-dependent. The current study is the first double-blind randomized evaluation of prophylactic chlorhexidine in a large adult patient population with solid tumors receiving highly OM-inducing chemotherapy. A role for chlorhexidine in the prevention of OM is suggested, which should be evaluated further.
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Hepatic arterial chemotherapy in combination with systemic chemotherapy compared with hepatic arterial chemotherapy alone for liver metastases from colorectal cancer: results of a multi-centric randomized study.
Fiorentini, G, Cantore, M, Rossi, S, Vaira, M, Tumolo, S, Dentico, P, Mambrini, A, Bernardeschi, P, Turrisi, G, Giovanis, P, et al
In vivo (Athens, Greece). 2006;(6A):707-9
Abstract
Hepatic arterial infusion (HAI) chemotherapy is accepted to be an option in patients with non-resectable metastases from colorectal cancer confined to the liver. In a multi-istitutional trial, 76 patients were randomly assigned to receive HAI versus HAI plus systemic bolus 5-fluorouracil and leucovorin. The primary endpoint was survival, followed by response, recurrence and toxicity. Survival was longer for HAI plus systemic chemotherapy (HAI+SYC) than HAI (median, 20 vs. 14 months; p = 0.0033), as were responses (47.5% and 41.7%; p = 0.09) and time to hepatic progression (12 vs. 8 months; p = 0.039). Side effects included haematological toxicity that was mostly mild and reversible in 432 cases. Neutropenia grade 3 occurred in four patients in the HAI+SYC arm and one in the HAI arm. Diarrhoea occurred in 20% and 7% of patients and stomatitis occurred in 18% and 2%, respectively. On the contrary biliary toxicity was significant; twelve patients had evidence of bilirubin elevations of more than 3 mg/dl (six in each arm), and two had asymptomatic arterial biliary-tree fistulae: one in the HAI+SYC arm and one in the HAI arm. Grade 3 elevation in alkaline phosphatase and aminotransferase levels occurred in 26% and 24%, respectively. In conclusion, the combination of HAI+SYC is active and safe showing a clinical advantage with respect to simple HAI, increasing overall survival, response rate and time to progression.