[Good practice and what then? ].
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France↗
Biomedical subjects
F Demard
Publications and source records attributed to F Demard.
[Population study of dihydropyrimidine dehydrogenase in cancer patients].
Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme of 5-fluorouracil (5-FU) catabolism. The clinical importance of DPD has recently been demonstrated with the identification of severe and/or lethal 5-FU-related toxicity in patients with suspected or proven DPD deficiency revealed in lymphocytes. We conducted a prospective study on 185 cancer patients in order to evaluate the incidence of complete or partial DPD deficiency. The population comprised 152 men (mean age 62.1) and 33 women (mean age 59.2). Sixty eight were head and neck patients treated by a 5-day continuous infusion of 5-FU (starting dose 1 g/m2/day, with dose adaptation at mid-cycle) for which DPD activity was measured 2-3 days before 5-FU administration (94 cycles analyzed). DPD activity was measured by a radioenzymatic assay using 14C-5-FU. DPD activity showed a unimodal distribution, which globally fits a Gaussian distribution. Mean and median DPD activity were 0.222 and 0.211 nmol/min/mg prot respectively (range 0.065-0.559). No total DPD deficiency was found. Neither liver function nor age influenced DPD activity, but DPD activity was on average 15% lower in women than in men (0.194 and 0.228 nmol/min/mg prot respectively, p = 0.03). In patients treated with 5-FU, the risk of developing side effects was not linked to pretreatment DPD activity. 5-FU-related toxicity was linked to FU systemic exposure. The correlation between DPD activity and FU clearance was weak (n = 90, r = 0.31, p = 0.002). As a corollary, DPD activity in patients requiring a dose reduction was not significantly different from DPD activity in patients who did not require dose modification. From the present study it appears that total DPD deficiency is a very rare event. Although pre-treatment DPD activity cannot be a useful indicator for improving 5-FU dose adaptation strategy, the identification of partial DPD deficiency (< 0.100 nmol/min/mg prot, 3% of the population) could lead to starting the treatment with a markedly reduce 5-FU dose.
Adult↗
Population study of dihydropyrimidine dehydrogenase in cancer patients.
PURPOSE: We conducted a prospective study on a large set of cancer patients in an attempt to evaluate the incidence of complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency as found in peripheral mononuclear cells (PMNC). PATIENTS AND METHODS: One hundred eighty-five unselected consecutive cancer patients were included. The population consisted of 152 men (mean age, 62.1 years; range, 35 to 90) and 33 women (mean age, 59.2 years; range, 36 to 77). Sixty-eight were head and neck patients treated by a 5-day continuous infusion of fluorouracil (FU; starting dose, 1 g/m2/d, with dose adaptation based on pharmacokinetics) for which DPD activity was measured 2 to 3 days before FU administration (94 cycles analyzed). PMNC-DPD activity was measured by a radio-enzymatic assay using carbon-14-FU. RESULTS: DPD activity in the entire population showed a unimodal distribution, which globally fits a gaussian distribution. Mean and median DPD activity values were 0.222 and 0.211 nmol/min/mg protein, respectively (range, 0.065 to 0.559). No total DPD deficiency was found. Multifactor analysis of variance showed that liver function (biologic evaluation) and age did not influence DPD activity, but that DPD activity was, on average, 15% lower in women (0.194 nmol/min/mg protein) than in men (0.228 nmol/min/mg protein) (P = .03). No difference was demonstrated between premenopausal and postmenopausal women. In patients treated with FU, the risk of developing side effects was not linked to pretreatment DPD activity. FU-related toxicity was linked to FU systemic exposure. The correlation between pretreatment DPD activity and FU systemic clearance (CI) was weak (n = 90, linear regression r = .31, P = .002). Pretreatment DPD activity in patients who required a dose reduction was not significantly different from DPD activity in patients who did not require dose modification. CONCLUSION: From the present study, it appears that total DPD deficiency is a rare event. Although pretreatment DPD activity cannot be a useful indicator for improving FU dose adaptation strategy, the identification of severe DPD deficiency (< 0.100 nmol/min/mg protein) could lead to starting the treatment with a markedly reduced FU dose or even to using an alternative chemotherapy regimen.
Adult↗
Relationship between fluorouracil systemic exposure and tumor response and patient survival.
PURPOSE: The aim of this study was to analyze the link between fluorouracil (FU) systemic exposure and tumor response and overall survival. PATIENTS AND METHODS: One hundred eighty-six patients (162 men, 24 women) with head and neck cancer were studied. All received cisplatin plus FU for three cycles as first-line chemotherapy. The treatment consisted of cisplatin (100 mg/m2 intravenously [IV]) followed by a 5-day continuous venous infusion of FU (1 g/m2/d). The median follow-up duration for the 104 patients alive was 24 months. For each cycle, we calculated the area under the curve over the duration of pharmacokinetic follow-up (AUC0-105 h) for plasma FU. For each patient, we analyzed the averaged AUC0-105 h and the averaged total dose for the three cycles. RESULTS: The response rate was 30% complete responses (CRs), 22% partial responses (PRs) more than 75%, 25% PRs less than 75%, and 23% no response (NR). Medians for averaged AUC and dose per cycle were 27,906 ng/mL h (first through third quartile, 25,398 to 31,060) and 7,000 mg (first through third quartile, 6,200 to 7,833), respectively. The tumor response was significantly linked to tumor stage (P < .001) and to averaged AUC (P = .05), but not to averaged dose. Analysis of parameters (continuous variable) expressing FU treatment intensity showed that dose did not influence survival contrary to the AUC (P = .001). The AUC remains significant (P = .025) in a multivariate analysis including tumor stage, demonstrating that the greater the FU systemic exposure, the longer the survival. CONCLUSION: These results strengthen the interest of individual FU dose adaptation based on pharmacokinetics.
Adult↗
[EGF receptor, a prognostic factor in epidermoid cancers of the upper aerodigestive tracts].
EGFR was determined, before treatment; in tumors biopsies obtained from 109 consecutive patients with head and neck cancer (100 men and nine women), using iodine labelled recombinant EGF. The median age of the study population was 60 years. EGFR levels varied from 2 to 2302 fmol/mg membrane protein (median 71). There was a significant difference of distribution for EGFR levels between stages I and II tumors and stages III and IV tumors (P = 0.03). The EGFR cut-off value for overall survival was 120 fmol/mg protein and the median follow-up was 18 months (3-35) EGFR overexpression was associated with shorter relapse-free (P = 0.0125) and overall survival (P = 0.028). By multivariate analysis the only significant variables were EGFR for relapse-free survival and tumor staging and EGFR for overall survival. Analyzed in 60 patients treated by first-line chemotherapy CDDP-5FU, the longest survival was achieved for patients who had a complete response to chemotherapy and the lowest EGFR levels (P = 0.018). EGFR expression in the primary tumor allows survival among first line chemotherapy responder categories to be discriminated.
Adult↗
[Intra-parotid nodule caused by Leishmania in a case of apparently cured visceral leishmaniasis].
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Aged↗
Dihydropyrimidine dehydrogenase activity in cancer patients.
Dihydropyrimidine dehydrogenase (DPD) is the major catabolic enzyme of pyrimidines and fluoropyrimidines. The clinical course of 2 patients with suspected DPD deficiency is described. Both patients had significantly delayed clearance of fluorouracil (5-FU), elevated plasma uracil concentrations, and subsequent lethal toxicity. The prevalence of DPD deficiency in the general population is unknown, but given the large number of cancer patients treated with 5-FU, it may be of great clinical significance. Lymphocytes have been previously shown to be a useful marker of systemic DPD activity. Because DPD activity has not been previously reported in a large population of cancer patients using 5-FU as the substrate, we determined DPD activity in lymphocytes from 66 patients with cancer. DPD activity was determined by a sensitive high performance liquid chromatography method. The mean DPD activity (S.D.) in 66 patients with head and neck cancer was 0.189 (0.071) nomol/min/mg protein with wide interpatient variability (range 0.058-0.357). DPD activity was not correlated to age (r = -0.164, P = 0.188). The mean DPD activity in men [0.192 (0.074)] was not significantly different from that in women [0.172 (0.057); t-test P = 0.418]. Likewise, there was no statistical difference in DPD activity in patients who had not received prior chemotherapy [0.195 (0.066)] to patients receiving one or more cycles of chemotherapy [0.186 (0.074); t-test P = 0.638].
Adult↗
Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer.
PURPOSE: To determine the expression of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma and to evaluate its prognostic value. MATERIALS AND METHODS: EGFR was determined in tumor biopsies obtained from 109 consecutive patients with head and neck cancer (100 men, nine women). Control biopsies were obtained from 94 patients in a symetric nontumoral area of the same anatomic site. EGFR was measured by a binding assay using human recombinant iodine 125-EGF. RESULTS: The presence of detectable EGFR levels was found in all explored tumors with highly marked differences between patients (median, 71 fmol/mg protein; range, 2 to 2,302). In 93 of 94 cases, EGFR levels were higher in tumor samples as compared with healthy control zones. There was no significant difference in EGFR expression according to the various anatomic sites explored or tumoral differentiation status. There was a significant difference of distribution for EGFR levels between stages I and II tumors and stages III and IV tumors. The tumor EGFR levels were not linked to the response to first-line chemotherapy by cisplatin (CDDP) and fluorouracil (5FU). Survival was assessable for 103 patients for overall survival and for 81 patients for recurrence. EGFR overexpression was associated with shorter relapse-free (P = .0125) and overall survival (P = .028) rates. By multivariate analysis, the only significant variable was EGFR for relapse-free survival and tumor staging for overall survival. The association of EGFR to tumor staging markedly improves the significance for overall survival predictability (P = .002). CONCLUSION: EGFR determination deserves particular attention in head and neck cancer, since it independently carries a strong prognostic value.
Adult↗
Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients.
Dihydropyrimidine dehydrogenase (DPD) is the initial key enzyme in the catabolism of 5-fluorouracil (5-FU). We measured DPD activity in lymphocytes from 57 consecutive head and neck cancer patients while simultaneously monitoring 5-FU pharmacokinetics during 5-day, continuous infusion (1000 mg/m2/day) 5-FU therapy (82 cycles in total). The mean value for DPD activity was 0.186 +/- 0.068 (SD) nmol/min/mg of protein (range, 0.058 to 0.357). The mean value for 5-FU clearance was 2522.6 +/- 684.2 ml/min/m2 (range, 1052 to 4029). A significant linear correlation was observed between DPD activity and 5-FU clearance (r = 0.716, P less than 0.0001). DPD activity was poorly correlated to plasma uracil concentrations (r = -0.260, P = 0.0215). Likewise, plasma uracil concentrations were poorly correlated to 5-FU clearance (r = -0.214, P = 0.0595). In patients evaluated for more than one cycle (n = 18), there was large intrapatient variability in both DPD activity and 5-FU clearance. No significant difference was noted between cycles for DPD activity or 5-FU clearance (Kruskal-Wallis test). Monitoring DPD activity in lymphocytes may be useful in identifying patients at risk for altered 5-FU disposition.
Adult↗
Soft-laser therapy for iatrogenic mucositis in cancer patients receiving high-dose fluorouracil: a preliminary report.
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Female↗
No effect of dose, hepatic function, or nutritional status on 5-FU clearance following continuous (5-day), 5-FU infusion.
One hundred and eighty seven patients (155 males, 32 females) with histologically proven and previously untreated head and neck cancer were entered in the study. A total of 222 cycles of therapy were analyzed (cisplatin 100 mg m-2 on day 1 and 5-day continuous intravenous infusion of 5-FU 550-1069 mg m-2 day-1, mean 875.5 mg m-2 day-1). Significant interpatient variability for various 5-FU pharmacokinetic parameters was observed including an almost ten-fold range in 5-FU clearance (5-FU Cl, ml min-1 m-2 = 791-7769, mean 2820.7). Log 5-FU Cl was not modified by 5-FU dose (r = -0.1034, P = 0.124, n = 222). Poor linear correlations between log 5-FU Cl and hepatic function tests were observed (respective r and P values for 222 cycles, log AST:0.0526, 0.4365; Log ALT: -0.1167, 0.0842; Log A1K. Phos.:0.154, 0.0214; Log GGT: 0.0652, 0.3436; Log LDH: -0.0984, 0.1563; Log bilirubin: 0.1278, 0.0601). The log 5-FU Cl was also poorly correlated with the serum concentration of various nutritional proteins (respective r and P values for 222 cycles, Albumin: 0.0110, 0.8714; prealbumin: -0.1067, 0.1129; transferrin: 0.0439, 0.5226). Laboratory data including indices of hepatic function and nutritional status cannot account for the interpatient variability in 5-FU disposition.
Blood Proteins↗
Influence of sex and age on fluorouracil clearance.
PURPOSE: Currently, fluorouracil (5-FU) is one of the major drugs used in cancer chemotherapy. Several investigators, including ourselves, have demonstrated a link between abnormalities in 5-FU clearance (Cl) and the risk of developing more or less 5-FU-related toxicities. Age and sex are among the host factors that have been implicated in the pharmacokinetic variability of drugs. Presently, no data are available on the possible influence of sex and age on 5-FU Cl. PATIENTS AND METHODS: Three hundred eighty patients (mean age, 61.7 years; range, 25 to 91; 301 men and 79 women) with squamous cell carcinoma (sre) of the head and neck were treated in our institution between 1987 and 1991. 5-FU Cl was determined for a total of 1,092 chemotherapy cycles. Each cycle consisted of cisplatin and 5-day continuous intravenous infusion 5-FU (daily doses ranging between 365 and 1,224 mg/m2). RESULTS: 5-FU Cl values (L/h/m2) showed a wide dispersion for both men (median, 179; range, 29 to 739) and women (median, 155; range, 56 to 466). 5-FU Cl values were lower significantly for women compared with men (P = .0005). When adjusted for age and dose, the influence of sex on log Cl remained significant (P = .013). There was no evidence that age modified 5-FU Cl when adjusted for sex and dose. Interestingly, for both men and women, the oldest patients (greater than 70 years) maintained their ability to clear 5-FU with daily doses that ranged from 500 to 1,000 mg/m2. CONCLUSIONS: These data indicate that the capacities to clear 5-FU are lower in women compared with men and are not influenced by age. It would be of interest to know whether this sex-related difference in 5-FU Cl may be clinically relevant by considering both toxicity and tumor response to 5-FU treatment.
Adult↗
[Dihydropyrimidine dehydrogenase activity in lymphocytes: predictive factor for 5-fluorouracil clearance].
We previously have shown that pharmacokinetic monitoring of 5-fluorouracil (5-FU) could significantly improve the 5-FU therapeutic index when given in continuous venous infusion (Br J Cancer 59, 287-290, 1989). However, the more rational approach would be to find individual biological factors which could predict 5-FU clearance. Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-FU. DPD activity was measured in 57 head and neck cancer patients receiving CDDP (100 mg/m2, day 1) plus 5-FU (1 g/m2/day x 5, day 2-day 6). DPD activity was measured in lymphocytes using a radioenzymatic assay (2.5 mM MgCl2, 250 microM NADPH, 20 microM 14C-5-FU) with separation of 14C-5-FU from 14C-5-FUH2 by HPLC coupled with a radiodetector. The average DPD activity measured in lymphocytes was 0.186 +/- 0.068 nmol/min/mg protein (range 0.058-0.357) and the average 5-FU clearance (Cl) was 2,523 +/- 684 ml/min/m2 (range 1,052-4,029). A significant linear correlation was demonstrated between DPD activity and 5-FU clearance (Cl = 1,099 + 7,580 DPD, r2 = 0.613, P < 0.0001). In patients evaluated for more than one cycle (n = 18), variations in 5-FU clearance were associated with corresponding variations in DPD activity. The individual determination of DPD activity measured in lymphocytes could be useful for identifying patients at risk for altered 5-FU pharmacokinetics and could be used to adjust the optimal 5-FU dose for each patient before starting the treatment.
Adult↗
[Laser therapy in the prevention and treatment of mucositis caused by anticancer chemotherapy].
The appearance of mucositis is a frequent and painful secondary effect of anticancer chemotherapy. Patients who develop oral toxicity during the first course of treatment will almost assuredly show identical side effects during each subsequent course unless the drugs are changed or the doses are lowered. In the absence of an efficacious antidote or preventive prophylaxis for such lesions to date, this report presents the results of a preliminary retrospective non-randomized study of the effect of soft-laser treatments on mucositis in cancer patients receiving combination chemotherapy, including 5-fluorouracil. Iatrogenic mucositis was observed during 43% of 53 chemotherapy cycles in the case control population. Curative laser therapy reduced the time to repair lesions and the rate of therapeutic modifications. For patients who received soft-laser therapy as a preventive measure, the incidence of oral complications was reduced to 6% during 101 cycles of chemotherapy. All of these patients, even those who have encountered mucositis before receiving preventive laser therapy, terminated their cancer therapy as originally scheduled. Well designed and carefully controlled trials will be necessary to define the place of helium-neon laser therapy in the repair and prevention of oral complications due to cancer chemotherapy.
Antineoplastic Combined Chemotherapy Protocols↗
Dose reduction without loss of efficacy for 5-fluorouracil and cisplatin combined with folinic acid. In vitro study on human head and neck carcinoma cell lines.
Folinic acid (FA) and cisplatin (CDDP) both potentiate the cytotoxicity of 5-fluorouracil (5-FU). The activity of various drug combinations including 5-FU, CDDP and FA was tested on two human cell lines derived from squamous cell carcinomas of the head and neck. Cytotoxicity was assessed by the semi-automated colorimetric MTT test. The drugs were tested in clinically achievable conditions (concentrations and duration of exposure). The dose response curves for 5-FU (0-100 ng ml-1) associated with FA (10(-7)-10(-5) M) reflected a progressive increase in 5-FU cytotoxicity with increasing FA concentrations. When CDDP (0-5 micrograms ml-1) was associated with 5-FU, CDDP-mediated enhancement of 5-FU cytotoxicity was apparent only when CDDP was given before 5-FU. The triple association CDDP, 5-FU and FA was also tested. In this case, for an identical final cytotoxicity, the presence of FA (10(-6) M) permitted reduction of the 5-FU concentration between 24.2 and 42% and reduction of the CDDP concentration between 13.8 and 72.7%. These observations may be beneficial for the design of more rational therapeutic trials associating CDDP, 5-FU and FA.
Antineoplastic Combined Chemotherapy Protocols↗
[Post-radiation mandibular fibrous histiocytoma. Apropos of a case and literature review].
Postirradiation sarcoma of the head and neck has rarely been reported. A case of malignant fibrous histiocytoma (M.F.H.) occurring in the mandible is presented. Head and neck region was previously irradiated for Hodgkin's disease. The interval from initial radiation to diagnosis of sarcoma was 10 years. Aggressive treatment with early radical excision is the treatment of choice. In spite of extensive surgery, the patient died one year after treatment with local recurrence.
Adult↗
[Extemporaneous anatomopathologic test of the thyroid body. Value, limitations and practical implications. Report of 1,680 thyroidectomies].
The analysis of the results of 1,680 immediate histopathological studies of thyroidectomy specimens allows assessing the value, limitations and pitfalls of this method. Although its specificity for the diagnosis of cancer is 100%, its sensitivity is 70.5% only. Misinterpretation is accounted for by the difficulty to identify the criteria of malignancy in an immediate study. The experience of a pathologist is essential and it ensures the reliability of the method, which is aimed at allowing an optimum one-stage surgical treatment.
Adenocarcinoma↗
[Autograft procedures in reparative cancer surgery of the loss of substance of the nose. Critical study].
Using several examples, the authors analyse the choice of reconstructive methods available after excision of cutaneous tumours of the nose. Although a variety of procedures exist, one or two specific flap procedures may be preferred in terms of their safety and cosmetic result. Before describing these procedures, the authors briefly review the basis of surgical treatment in the particular case of the nasal region.
Adult↗