title: A nomogram to predict 5-fluorouracil toxicity: when pharmacogenomics meets the patient.
abstract: Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27-87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3-4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.
authors.affiliation: Departments of aClinical and Molecular Medicine bRadiological Oncological and Pathological Sciences cNeurosciences, Mental Health and Sensory Organs (NESMOS), 'Sapienza' University of Rome dDepartment of Medical Oncology, Sant'Andrea Hospital eLaboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute fIstituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Botticelli
authors.forename: Concetta E
authors.initials: CE
authors.lastname: Onesti
authors.forename: Lidia
authors.initials: L
authors.lastname: Strigari
authors.forename: Mario
authors.initials: M
authors.lastname: Occhipinti
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Di Pietro
authors.forename: Bruna
authors.initials: B
authors.lastname: Cerbelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Petremolo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Anselmi
authors.forename: Serena
authors.initials: S
authors.lastname: Macrini
authors.forename: Michela
authors.initials: M
authors.lastname: Roberto
authors.forename: Rosa
authors.initials: R
authors.lastname: Falcone
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.forename: Marina
authors.initials: M
authors.lastname: Borro
authors.forename: Annalisa
authors.initials: A
authors.lastname: Milano
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gentile
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
authors.forename: Federica
authors.initials: F
authors.lastname: Mazzuca
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D049451:Nomograms; D010597:Pharmacogenetics / Q000379:methods*; D012189:Retrospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil