Use of high-dose cytarabine to enhance cisplatin cytotoxicity-effects on the response and overall survival rates of advanced head and neck cancer patients.

UNLABELLED: It has been reported that cytarabine, acting by at least two different mechanisms, enhances the cytotoxic effect of cisplatin in in vitro systems. The aim of this open, prospective, randomised study was to estimate the eventual benefits from the inclusion of high-dose cytarabine in the cisplatin-5-fluorouracil (5-FU) regimen as first-line treatment of patients with advanced head and neck cancer. The study recruited successive patients with unresectable grade I/II head and neck cancer who were not suitable for irradiation treatment (T any N3 or T4 N2C), metastatic or previously irradiated. All patients gave their informed consent. A joint ear, nose and throat (ENT) oncological committee performed the selection. A total of 170 patients were included in the study. Patients randomised to arm A were given 1000 mg/m(2) cytarabine on day 1 preceding for 6 h cisplatin infusion, 30 mg/m(2)/24 h cisplatin intravenous (i.v.) bolus days 1-4 and 1000 mg/m(2)/24 h 5-FU in a 4-h infusion on days 1-4. Patients in arm B were given cisplatin and 5-FU in the same dosage and schedule as in arm A. Additional irradiation+/-surgery was performed if and when feasible. Patients in both arms were well balanced with regard to clinical variables. The following results were obtained: Arm A: 84 patients were included, 74 were evaluable for activity; RESPONSE: complete response (CR) 8 (11%), partial response (PR) 40 (54%), stable disease (SD) 11 (15%), progressive disease (PD) 15 (20%). The overall response rate (RR) based on the evaluable patients was 48/74 (65%, 95% confidence interval (CI) 54-75%); The RR based on an intent-to-treat analysis was 57%, 95% CI 47-67%; Median survival was 13 months; There were 50 episodes of granulocytopenia grade IV and 15 of febrile neutropenia per 316 cycles. Arm B: 86 patients were included, 80 were evaluable for activity; RESPONSE: CR 7 (9%), PR 29 (36%), SD 10 (12.5%), PD 34 (42.5%); The overall RR based on the evaluable patients was 36/80 (45%, 95% CI 35-56%); The RR based on an intent-to-treat analysis was 42%, 95% CI 32-52%; Median survival was 8 months; There were 14 episodes of granulocytopenia grade IV and 7 febrile neutropenias per 324 cycles. The RR was significantly higher in arm A (P=0.013), power (one-sided) 80%. The proportion of patients from the appropriate subset who achieved a clinical response making additional treatment feasible was higher in arm A (P=0.00015), as well as the proportion of patients with a performance status 2+3 achieving a response (P<0.0001). Using the Log-rank test, patients from arm A achieved a significantly longer survival (P=0.009), with the probability of survival at 12 months of 0.58 for patients in arm A and 0.28 for patients in arm B. Grade IV granulocytopenia and thrombocytopenia were more frequent in arm A. Due to its haematological side-effects, cytarabine might not be the ideal drug to modulate the cytotoxicity of cisplatin. However, other modulators of its activity could be of interest for further studies in head and neck cancer patients.

[Folic acid in the prevention of neural tube defects]. / Folna kiselina u prevenciji defekta neuralne cevi.

INTRODUCTION: The term neural tube defects (NTD) stands for anencephaly, iniencephaly, cephalocoele and spina-bifida. The cause of these anomalies is failure of brain spinal cord to properly develop, together with their protective shield of skull and spine, around the 4th gestational week. The prevalence of NTD in continental Europe is 11.2 10,000 live births. THE LEVEL OF FOLATES IN SERUM AND NTD: The level of folates in serum can influence the risk of a child affected with NTD. Studies on women with previous pregnancies with NTD showed that supplementary intake of folic acid, with or without other vitamins, preconceptual period throughout the first trimester has a preventive effect on its recurrence. Inadequate intake of folic acid is also connected with preterm delivery, intrauterine growth retardation and placental abruption and infarction. FOLATES IN NUTRITION: It is not folic acid, but folates, from the vitamin B group, that can naturally be found in food. There are several groups of folates that differ in the quantity by which they can be absorbed from food. Folates are temperature and storage sensitive and cooking can cause a significant fall of their concentration in food. FOLIC ACID SUPPLEMENTATION: The mean daily intake of folates by food is 0.218 mg whereas a reference nutritive intake for a woman of reproductive age is 0.2 mg per day. The currently recommended daily dose for prevention of first NTD occurrence is 0.4 mg, so it is clear that a certain amount of folic acid has to be supplemented preconceptionally and during the first trimester. It can be done in two ways, by telling all women to take it before conceiving, or to fortify food with sufficiently high doses of folic acid in order to achieve adequate serum levels. Neither of the ways is ideal, for not all women would take the supplement, and by aggressively fortifying the food, we create a potential hazard to those that do not need it and may have some problems with the excess of it. The best solution would be a widespread campaign about the need for folic acid and the risks of NTD. CONCLUSION: Recommendations of The Expert Advisory Group on Folic Acid in prevention of neural tube defects has several aspects (1) reducing the risk of the first NTD occurrence by preconceptional vitamin supplementation of folic acid in the dose of 0.4 mg day, which would go on until the end of the 12th week (2) reducing the risk of NTD recurrence in offspring of men and women with spina-bifida or with obstetric history affected with NTD by preconceptional vitamin supplementation of folic acid in the dose of 4 mg daily during the first 12 weeks and (3) organizing educational programmes for medical staff as well as the whole population in order to popularize vitamin supplementation.