fluorouracil
Sources réglementaires consultées
Indications approuvées
- Cancer colorectal métastatique ; traitement adjuvant du cancer du côlon ou du rectum ; cancers gastrique, pancréatique ou œsophagien avancés ; cancer du sein avancé ou métastatique ; traitement adjuvant du cancer du sein invasif primitif opérable ; et carcinome épidermoïde de la tête et du cou inopérable, localement avancé non traité, récidivant ou métastatique, selon le schéma autorisé.
Contre-indications
Absolues
- Hypersensibilité au fluorouracile ou aux excipients ; infection potentiellement sévère ; patient gravement affaibli ; dépression médullaire après radiothérapie ou autres antinéoplasiques ; traitement d’une maladie non maligne.
- Déficit complet en DPD ; allaitement ; myélosuppression sévère, infection sévère, insuffisance hépatique sévère ; brivudine, sorivudine ou analogues inhibiteurs de la DPD récents ou concomitants.
Mises en garde cliniques
- Déterminer le statut DPD avant le traitement. Un déficit complet peut entraîner une toxicité mortelle ; un test négatif n’élimine pas tout le risque. Contrôler leucocytes et plaquettes avant chaque dose ; leucocytes ≤3 500/mm³ ou plaquettes ≤100 000/mm³ peuvent imposer une interruption. Envisager une réduction en cas de cachexie, chirurgie majeure dans les 30 jours précédents, réserve médullaire réduite ou insuffisance rénale ou hépatique. — CIMA/AEMPS, ficha técnica 71868
- Surveiller myélosuppression, diarrhée, mucite, cardiotoxicité et neurotoxicité. Interrompre immédiatement en cas de toxicité sévère et prendre en charge selon le protocole oncologique. — CIMA/AEMPS, ficha técnica 71868
- Un surdosage exige une évaluation urgente : administrer le triacétate d’uridine dans les 96 heures suivant la fin de l’administration de la fluoropyrimidine. — DailyMed, fluorouracil injection
Interactions médicamenteuses
- ModéréeBrivudine, sorivudine ou analogues
Mécanisme: L’inhibition de la DPD peut provoquer une accumulation et une toxicité fluoropyrimidinique mortelle.
Recommandation: Ne pas coadministrer et respecter au moins 4 semaines entre l’inhibiteur de la DPD et le fluorouracile.
CIMA/AEMPS, ficha técnica 71868
- SévèreAcide folinique
Mécanisme: Peut augmenter à la fois l’efficacité et la toxicité du fluorouracile.
Recommandation: Utiliser uniquement dans un schéma défini et surveiller étroitement diarrhée, mucite et myélosuppression.
CIMA/AEMPS, ficha técnica 71868
- SévèreVaccins vivants
Mécanisme: L’immunosuppression peut provoquer une infection vaccinale disséminée.
Recommandation: Les vaccins vivants ne sont pas recommandés pendant l’immunosuppression.
CIMA/AEMPS, ficha técnica 71868
- ModéréeClozapine
Mécanisme: L’association augmente le risque d’agranulocytose.
Recommandation: Ne pas administrer le fluorouracile avec la clozapine.
CIMA/AEMPS, ficha técnica 71868
- SévèrePhénytoïne
Mécanisme: Le fluorouracile peut augmenter les concentrations et la toxicité de la phénytoïne.
Recommandation: Surveiller concentrations et toxicité ; réduire la phénytoïne si nécessaire.
CIMA/AEMPS, ficha técnica 71868
- SévèreWarfarine ou autres coumariniques
Mécanisme: Le fluorouracile peut augmenter l’effet anticoagulant.
Recommandation: Contrôler régulièrement l’INR et ajuster l’anticoagulant.
CIMA/AEMPS, ficha técnica 71868
- SévèreCimétidine, métronidazole ou interféron
Mécanisme: Ils peuvent augmenter l’exposition ou la toxicité du fluorouracile.
Recommandation: Utiliser uniquement avec une surveillance oncologique renforcée et ajuster selon la toxicité.
CIMA/AEMPS, ficha técnica 71868
Grossesse et allaitement
Pendant la grossesse, n’utiliser le fluorouracile que si le bénéfice potentiel justifie le risque fœtal. L’allaitement est contre-indiqué. La fertilité peut être altérée ; fournir un conseil reproductif oncologique.
Bibliographie récente (PubMed)
Perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is a standard therapy for resectable gastric and gastroesophageal junction adenocarcinomas, but recurrence rates remain high. Immunotherapy plus chemotherapy may improve outcomes. In a phase 3, multinational, double-blind, randomized trial, we assigned participants with resectable gastric or gastroesophageal junction adenocarcinoma, in a 1:1 ratio, to receive durvalumab at a dose of 1500 mg or placebo every 4 weeks plus FLOT for 4 cycles (2 cycles each of neoadjuvant and adjuvant therapy), followed by durvalumab or placebo every 4 weeks for 10 cycles. The primary end point was event-free survival; secondary end points included overall survival and pathological complete response. A total of 474 participants were randomly assigned to the durvalumab group, and 474 to the placebo group (median follow-up, 31.5 months; interquartile range, 26.7 to 36.6). Two-year event-free survival (Kaplan-Meier estimate) was 67.4% among the participants in the durvalumab group and 58.5% among those in the placebo group (hazard ratio for event or death, 0.71; 95% confidence interval [CI], 0.58 to 0.86; P<0.001). Two-year overall survival was 75.7% in the durvalumab group and 70.4% in the placebo group (piecewise hazard ratio for death during months 0 to 12, 0.99 [95% CI, 0.70 to 1.39], and during the period from month 12 onward, 0.67 [95% CI, 0.50 to 0.90]; P = 0.03 by a stratified log-rank test [exceeding the significance threshold of P<0.0001]). The percentage of participants with a pathological complete response was 19.2% in the durvalumab group and 7.2% in the placebo group (relative risk, 2.69 [95% CI, 1.86 to 3.90]). Adverse events with a maximum grade of 3 or 4 were reported in 340 participants (71.6%) in the durvalumab group and in 334 (71.2%) in the placebo group. The percentage of participants with delayed surgery was 10.1% and 10.8%, respectively, and the percentage with delayed initiation of adjuvant tr
Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited. In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival. Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates. Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.
Pancreatic ductal adenocarcinoma (PDAC) is a relatively uncommon cancer, with approximately 60 430 new diagnoses expected in 2021 in the US. The incidence of PDAC is increasing by 0.5% to 1.0% per year, and it is projected to become the second-leading cause of cancer-related mortality by 2030. Effective screening is not available for PDAC, and most patients present with locally advanced (30%-35%) or metastatic (50%-55%) disease at diagnosis. A multidisciplinary management approach is recommended. Localized pancreas cancer includes resectable, borderline resectable (localized and involving major vascular structures), and locally advanced (unresectable) disease based on the degree of arterial and venous involvement by tumor, typically of the superior mesenteric vessels. For patients with resectable disease at presentation (10%-15%), surgery followed by adjuvant chemotherapy with FOLFIRINOX (fluorouracil, irinotecan, leucovorin, oxaliplatin) represents a standard therapeutic approach with an anticipated median overall survival of 54.4 months, compared with 35 months for single-agent gemcitabine (stratified hazard ratio for death, 0.64 [95% CI, 0.48-0.86]; P = .003). Neoadjuvant systemic therapy with or without radiation followed by evaluation for surgery is an accepted treatment approach for resectable and borderline resectable disease. For patients with locally advanced and unresectable disease due to extensive vascular involvement, systemic therapy followed by radiation is an option for definitive locoregional disease control. For patients with advanced (locally advanced and metastatic) PDAC, multiagent chemotherapy regimens, including FOLFIRINOX, gemcitabine/nab-paclitaxel, and nanoliposomal irinotecan/fluorouracil, all have a survival benefit of 2 to 6 months compared with a single-agent gemcitabine. For the 5% to 7% of patients with a BRCA pathogenic germline variant and metastatic PDAC, olaparib, a poly (adenosine diphosphate [ADB]-ribose) polymerase inhibitor, i
The best multimodal approach for resectable locally advanced esophageal adenocarcinoma is unclear. An important question is whether perioperative chemotherapy is preferable to preoperative chemoradiotherapy. In this phase 3, multicenter, randomized trial, we assigned in a 1:1 ratio patients with resectable esophageal adenocarcinoma to receive perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus surgery or preoperative chemoradiotherapy (radiotherapy at a dose of 41.4 Gy and carboplatin and paclitaxel) plus surgery. Eligibility criteria included a primary tumor with a clinical stage of cT1 cN+, cT2-4a cN+, or cT2-4a cN0 disease, in which T indicates the size and extent of the tumor (higher numbers indicate a more advanced tumor), and N indicates the presence (N+) or absence (N0) of cancer spread to the lymph nodes, without evidence of metastatic spread. The primary end point was overall survival. From February 2016 through April 2020, we assigned 221 patients to the FLOT group and 217 patients to the preoperative-chemoradiotherapy group. With a median follow-up of 55 months, overall survival at 3 years was 57.4% (95% confidence interval [CI], 50.1 to 64.0) in the FLOT group and 50.7% (95% CI, 43.5 to 57.5) in the preoperative-chemoradiotherapy group (hazard ratio for death, 0.70; 95% CI, 0.53 to 0.92; P = 0.01). Progression-free survival at 3 years was 51.6% (95% CI, 44.3 to 58.4) in the FLOT group and 35.0% (95% CI, 28.4 to 41.7) in the preoperative-chemoradiotherapy group (hazard ratio for disease progression or death, 0.66; 95% CI, 0.51 to 0.85). Among the patients who started the assigned treatment, grade 3 or higher adverse events were observed in 120 of 207 patients (58.0%) in the FLOT group and in 98 of 196 patients (50.0%) in the preoperative-chemoradiotherapy group. Serious adverse events were observed in 98 of 207 patients (47.3%) in the FLOT group and in 82 of 196 patients (41.8%) in the preoperative-chemoradioth
In Western countries, the current standard of care for resectable gastric cancer is perioperative chemotherapy. Preoperative chemoradiotherapy has been considered, but data are limited regarding this treatment as compared with perioperative chemotherapy alone. We conducted an international, phase 3 trial in which patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive preoperative chemoradiotherapy plus perioperative chemotherapy or perioperative chemotherapy alone (control). In both groups, patients received either epirubicin, cisplatin, and fluorouracil or fluorouracil, leucovorin, oxaliplatin, and docetaxel both before and after surgery; the preoperative-chemoradiotherapy group also received chemoradiotherapy (45 Gy in 25 fractions of radiation, plus fluorouracil infusion). The primary end point was overall survival, and secondary end points included progression-free survival, pathological complete response, toxic effects, and quality of life. A total of 574 patients underwent randomization at 70 sites in Australasia, Canada, and Europe: 286 to the preoperative-chemoradiotherapy group and 288 to the perioperative-chemotherapy group. A higher percentage of patients in the preoperative-chemoradiotherapy group than in the perioperative-chemotherapy group had a pathological complete response (17% vs. 8%) and greater tumor downstaging after resection. At a median follow-up of 67 months, no significant between-group differences in overall survival or progression-free survival were noted. The median overall survival was 46 months with preoperative chemoradiotherapy and 49 months with perioperative chemotherapy (hazard ratio for death, 1.05; 95% confidence interval, 0.83 to 1.31), and the median progression-free survival was 31 months and 32 months, respectively. Treatment-related toxic effects were similar in the two groups. The addition of preoperative chemoradiotherapy to perioperative chemotherapy did not