[Recommendations for the management of gastro-intestinal stromal tumors].
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Consensus Statements as Topic↗
Biomedical subjects
F Duffaud
Publications and source records attributed to F Duffaud.
Phase II study of OSI-211 (liposomal lurtotecan) in patients with metastatic or loco-regional recurrent squamous cell carcinoma of the head and neck. An EORTC New Drug Development Group study.
The purpose of this study was to evaluate the activity and safety of OSI-211, the liposomal form of lurtotecan, in patients ineligible for curative surgery or radiotherapy and with metastatic/locoregional recurrent squamous cell carcinoma of the head and neck (SCCHN) and target lesions either within a previously irradiated field ("within") or outside a previously irradiated field ("outside"). OSI-211 was given intravenously over 30 min on days 1 and 8 at 2.4 mg/m2/day, repeated every 21 days (1 cycle). From July 2001 to March 2002, 32 patients from 14 institutions were enrolled in the "within" arm and 18 in the "outside" arm. In the "within" arm, two patients were ineligible because their tumour site was not allowed in the protocol (nasopharynx, skin) and two other patients never started treatment. Of the 46 eligible patients who started treatment, there was one objective response (response rate: 2.2% (95% Confidence Interval (CI): [0-11.5%]). Twelve patients in the "within" arm and 6 in the "outside" arm had stable disease, with a median duration of 18 weeks, 95% CI (12.7-25.7). The median time to progression was 6 weeks (95%CI: [5.9-12.7] weeks). Haematological toxicity was moderate in both arms. The most common haematological toxicity was grade 1-2 anaemia in 79% of patients. Non-haematological toxicity was mild in both arms. The most common grade 3-4 non-haematological toxicity was infection in 8.5% of patients. OSI-211 administered on d1 and d8, every 3 weeks, is well tolerated, but shows only minimal activity in locally advanced/metastatic SCCHN.
Adult↗
Totally implantable intravascular devices-related complications: effectiveness of insertion by trained team.
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Catheterization, Central Venous↗
EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer.
Cancer of the colon and rectum is one of the most frequent malignancies both in the US and Europe. Standard palliative therapy is based on 5-fluorouracil/folinic acid combinations, with or without oxaliplatin or irinotecan, given intravenously. Oral medication has the advantage of greater patient convenience and acceptance and potential cost savings. S-1 is a new oral fluorinated pyrimidine derivative. In a nonrandomized phase II study, patients with advanced/metastatic colorectal cancer were treated with S-1 at 40 mg m-2 b.i.d. for 28 consecutive days, repeated every 5 weeks, but by amendment the dose was reduced to 35 mg m-2 during the study because of a higher than expected number of severe adverse drug reactions. In total 47 patients with colorectal cancer were included. In the 37 evaluable patients there were nine partial responses (24%), 17 stable diseases (46%) and 11 patients had progressive disease (30%). Diarrhoea occurred frequently and was often severe: in the 40 and 35 mg m-2 group, respectively, 38 and 35% of the patients experienced grade 3-4 diarrhoea. The other toxicities were limited and manageable. S-1 is active in advanced colorectal cancer, but in order to establish a safer dose the drug should be subject to further investigations.
Aged↗
Recurrences following primary osteosarcoma in adolescents and adults previously treated with chemotherapy.
In this retrospective analysis, we report on the detailed management of 33 recurrent osteosarcoma patients from a population of 81 adolescents and adults previously treated (between November 1979 and November 1998) at the La Timone Adults Hospital, for an extremity-localised osteosarcoma. The site of the first recurrence was limited to the lung in 24 patients (73%), was local in 4 patients (12%), at multiple sites in 4 patients (12%), and limited to the bone for 1 patient (3%). The median interval between the diagnosis of the primary osteosarcoma and the first recurrence was 16 months (range 4-108 months). For all patients, the treatment combined aggressive chemotherapy and surgical resection of the recurrences whenever possible. 19 patients (58%) achieved a second complete remission. The median follow-up time from the first recurrence was 18 months (range 4-150 months). For all patients, the median overall survival from first recurrence was 17 months (95% confidence interval (CI), 11-22 months) and the projected 3- and 5-year survival rates were 31.6 and 23.7%, respectively. Patients with a second complete remission had a better 5-year survival than patients without (44.6% versus 0%, P=0.001). The achievement of a second complete remission has an independent significant prognostic value for an improved survival. Aggressive surgery with the removal of recurrence sites combined with multi-agent chemotherapy can either cure patients with recurrent osteosarcoma or significantly prolong their survival.
Adolescent↗
Population pharmacokinetics of cisplatin after 120-h infusion: application to routine adaptive control with feedback.
OBJECTIVE: A Bayesian population pharmacokinetics study of data from routine therapeutic drug monitoring cisplatin during a 5-day infusion of cisplatin. METHODS: A total of 95 kinetics data sets (58 patients) were available to perform this study. Individual pharmacokinetic parameters, estimated from 20 courses of treatment in 18 patients, were used to calculate the population parameters (cl: 0.175 +/- 0.034 L/h; t(1/2): 327 +/- 91 h). The accuracy of Bayesian forecasting was tested by comparing in 40 other patients the clearance values calculated either from a complete kinetics profile (eight sampling times) or from three early samples and the new population parameters. Finally, drug monitoring efficacy was assessed by comparing the target Cmax values with the Cmax obtained after dose adjustment based upon early Bayesian estimation of the individual pharmacokinetic parameters. RESULTS: : No significant difference was found between Bayesian and experimental clearances. Besides, dose-individualization proved to successfully adjust Cmax values around their respective target. CONCLUSION: The new reference pharmacokinetic population parameters lead to accurate estimation of individual pharmacokinetic parameters from a limited number of samples, thus allowing efficient therapeutic drug monitoring during 5-day infusion regimens of cisplatin.
Adolescent↗
Acentromeric micronuclei are increased in peripheral blood lymphocytes of untreated cancer patients.
Increased micronucleated cell rates, dicentric chromosomes, and other chromosomal damages have been reported in lymphocytes of cancer patients prior to the initiation of chemotherapy, and/or radiotherapy. The cause of these chromosomal damages in these lymphocytes remains unclear. In the present work, we investigated whether these micronuclei mainly reflect structural or numerical chromosomal aberrations by applying the cytokinesis-blocked micronucleus (CBMN) assay in combination with fluorescent in situ hybridization (FISH) of a DNA centromeric probe on blood samples of 10 untreated cancer patients (UCPs), and 10 healthy subjects (HSs). Micronucleated binucleated lymphocyte rate was significantly increased in patients (mean+/-S.D.: 19.0 per thousand +/-14.1 versus 9.2 per thousand +/-4.6 in controls). Trinucleated cytokinesis-blocked cells were not significantly higher in patients than in controls. Acentromeric, centromeric, and multicentromeric micronucleus levels were two-fold higher in patients than in controls, but the difference was significant only with acentromeric micronuclei. The percentage of micronuclei containing one or more centromeres averaged 69.2, and 71.5% in patients, and controls, respectively. The percentage of micronuclei containing several centromeres was 44.7% in patients, and 54.6% in controls. Among centromere-positive micronuclei, the percentage of micronuclei containing several centromeres averaged 59.7% in patients, and 75.4% in controls. These results indicate that genetic instability in peripheral blood lymphocytes of UCPs occurs because of enhanced chromosome breakage. However, a substantial proportion of this genetic instability occurs because of defects in chromosome segregation.
Adult↗
Phase II study of XR 5000, an inhibitor of topoisomerases I and II, in advanced colorectal cancer.
XR 5000 is one of a series of tricyclic carboxamide-based cytotoxic agents. It binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II, thus possibly overcoming the resistance resulting from downregulation of either enzyme. Twenty patients with advanced or metastatic colorectal cancer, unpretreated for metastatic disease, received XR 5000 at the dose of 3010 mg/m(2) in a 120-h central intravenous (i.v.) infusion every 3 weeks. Response was evaluated every two cycles. No complete (CR) or partial responses (PR) were observed in eligible patients (response rate, 0 of 19, 0%; 95% confidence interval (CI): 0-18%). 5 patients had stable disease, which lasted from 79 to 157 days. Haematological toxicity was low, since only one grade 4 neutropenia and two grade 3 anaemia were observed. Other treatment-related grade 3-4 toxicities were: deep venous thrombosis (2 cases), liver toxicity, diarrhoea, anorexia, dyspnoea, chest pain, infection (1 case each). Despite the good toxicity profile, these results do not support further trials with XR 5000 in metastatic colorectal cancer.
Acridines↗
D-TRP-6-LHRH (Triptorelin) is not effective in ovarian carcinoma: an EORTC Gynaecological Cancer Co-operative Group Study.
Between March and September 1988, 74 patients with progressive ovarian cancer after prior platinum-based therapy were treated with the luteinizing hormone-releasing hormone (LHRH) agonist Triptorelin (Decapeptyl degrees). Treatment consisted of i.m. injection of 3.75 mg of microencapsulated Triptorelin on days 1, 8 and 28 followed by 4-weekly injections until tumor progression. No objective responses were observed. Eleven out of 68 evaluable patients (16%) had stable disease. The median progression-free survival was 5 months in patients with disease stabilization and 2 months for all evaluable patients. The median survival for patients with disease stabilization was 17 months, whereas for all patients it was 4 months. The treatment was well tolerated; the only reported adverse events were incidental hot flushes. This study showed that the LHRH agonist Triptorelin has only modest efficacy in patients pretreated with platinum-containing chemotherapy.
Adult↗
[Nutritional workshops for cancer patients: a pilot approach].
The authors describe an original experience with 3 years of a nutritional workshop for cancer patients. This intervention combine an information about nutritional aspects of cancer with psychosocial support, to buffer psychological and nutritional consequences of cancer. The workshop, leaded by two specialized teams, one in medical oncology, the other in public health, is proposed to patients during and after a specific treatment. In one day, it provided information about nutrition and cancer, diet education and psychosocial support with supportive-expressive group. At this day, the evaluation of this intervention is only subjective. Fifty-six patients participated in at least one workshop, with majority of women (91%). Nineteen workshops were leaded with average participant number of 7 per workshop the third year. The authors believe that nutritional workshops are of great help for cancer patients, by enhancing social reinsertion, giving opportunity of emotional expression and humanizing the treatment. Our experience show it is possible to propose psychosocial intervention in institution in the context of Mediterranean country. We are leading currently a study that will permit a more systematic evaluation of the effects of this intervention.
Adult↗
[Adenocarcinomas of the distal esophagus and gastric cardia: what chemotherapy or chemoradiotherapy for recurrent or metastatic disease?].
Adenocarcinomas of esophagus and cardia represent in France approximately 20 to 40% of the esophagus cancers. They have a high risk to develop lymph nodes metastases and liver metastases. Currently, only 50 to 70% of patients may benefit from surgical curative resection at diagnosis, but more than 50% of them will recur. The standard of treatment of these metastatic adenocarcinomas is chemotherapy. Three large randomized comparative studies, between chemotherapy and supportive care, showed that chemotherapy significantly extends the median of survival (from 3-4 months to 10-12 months) and improves the quality of life. Currently, the combination of epirubicin-cisplatin-continuous 5FU (ECF) is the most effective regimen but it is difficult to administer and tolerate because of the long continuous 5FU infusion. In France, the most commonly used combination regimen still associates 5FU and cisplatin. New drugs (such as docetaxel, CPT11, oxaliplatin) used alone or in combination, especially with 5U, are very promising. Radio-chemotherapy is the preferred treatment for locoregional recurrences, because it improves dyphagia and enables to obtain complete tumor responses. Current results from concomitant radio-chemotherapy studies for esophagus cancer, based on 5FU alone, 5FU-cisplatin or 5FU-mitomycin, given as preoperative treatment or as exclusive treatment, support to use radio-chemotherapy for the treatment of loco-regional recurrences after surgical resection. Nevertheless, the optimal radio-chemotherapy schedule still remain to be defined (dose, duration, splitting of radiotherapy, choice of anticancer drugs).
Adenocarcinoma↗
Osteosarcomas of flat bones in adolescents and adults.
BACKGROUND: Osteosarcomas typically are long bone tumors and rarely affect the flat bones of the axial or appendicular skeleton. METHODS: The authors examined cases of high grade osteosarcoma of flat bones diagnosed at La Timone Adults University Hospital during a 16-year period. RESULTS: Sixteen patients with flat bone osteosarcomas were treated between 1980-1997. The median age of the patients was 25 years, with a male-to-female ratio of 14:2. Common presenting symptoms were swelling, pain, or both. Primary therapy included resection (n = 11 patients: alone in 8 patients and with radiation therapy in 3 patients), radiation therapy (n = 2 patients), or no local treatment (n = 3 patients). All patients received polychemotherapy, 7 preoperatively and postoperatively and 9 in the adjuvant setting. The overall 5-year survival rate was 47.7%; the overall median survival was 39 months (range, 4-211 months). The adequate local control rate was 68.7%. The local recurrence rate in patients who benefited from local treatment was 54%. Significant adverse prognostic factors on survival included the presence of synchronous metastases (three patients), metastases at any time during the course of the disease (eight patients), and inadequate local control (five patients). The overriding predictor of survival appeared to be the presence of metastases. Local recurrence appeared to have no influence on survival. No patient with metastases was alive at 3 years, whereas patients without recurrence or with local recurrence alone had a 5-year survival rate of 100%. Because the majority of patients with flat bone osteosarcomas ultimately die of metastatic disease, intensive systematic polychemotherapy should be an important component of treating these tumors. CONCLUSIONS: Based on the very encouraging results observed in the treatment of long bone osteosarcomas, the therapy for flat bone osteosarcomas should combine radical surgery with preoperative and postoperative adjuvant chemotherapy.
Adolescent↗
[New guidelines to evaluate the response to treatment in solid tumors].
Anticancer agents go through a process by which their antitumor activity, on the basis of the amount of tumor shrinkage they could generate, has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization (WHO) introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical cancer research joined together to undertake the review of these response evaluation criteria on the basis of their experience and knowledge. After several years of intensive discussions, new guidelines are ready and will replace the previous WHO criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors (Recist) Group and integrated into the present guidelines. This special article provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesion (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified. All other aspects of response evaluation have been discussed, reviewed, and amended whenever suitable.
Antineoplastic Agents↗
Micronucleated lymphocyte rates from head-and-neck cancer patients.
We investigated whether head-and-neck cancers are associated with an increased micronucleated cell rates (MN cell rates) and whether risk factors for these cancers are associated with alterations in micronucleated lymphocytes. MN cell rates were assessed in cytokinesis-blocked lymphocytes of 57 head-and-neck cancer patients (CP) before any anticancer treatment and of 198 male and female healthy subjects (HS). In the HS group, only smoking status significantly affect MN cell rates. In CP group age, sex, tobacco status, alcohol status, tumor stage, family history of cancer had no significant effect. For the non-smokers, the comparison between MN cell rates in HS and CP adjusted for age and sex showed a significant difference. The increase of MN cell rates in non-smokers patients may be attributable to cancer status. For the smokers, the comparison of MN cell rates in HS and CP matched for age and sex showed no significant difference. Pathological status could mask the smoking effect on peripheral blood lymphocytes in patients. Moreover, it probably could partly explain why MN cell rates in matched-CP smokers and HS smokers were similar. The authors do not recommend the CBMN assay in this present form to study smoking DNA-damage effects in peripheral blood lymphocytes of cancer patients, especially for patients with upper aero-digestive tract cancers or lung cancers for which tobacco is the major risk factor.
Adult↗
Evaluation of the genotoxic activity of paclitaxel by the in vitro micronucleus test in combination with fluorescent in situ hybridization of a DNA centromeric probe and the alkaline single cell gel electrophoresis technique (comet assay) in human T-lymphocytes.
Paclitaxel is a recent chemotherapeutic agent that inhibits tubulin depolymerization in tumoral cells. Despite its increasing use against various human cancers, the genotoxicity of paclitaxel has never been studied on normal human cells. The in vitro genotoxic effects of the drug were evaluated with two complementary mutagenesis tests on human T-lymphocytes: (1) the cytokinesis-blocked micronuclei assay (CBMN) in combination with fluorescent in situ hybridization (FISH) of nonspecific centromeric probes and (2) the comet assay performed in three ways: on stimulated lymphocytes as in the CBMN, and on freshly isolated lymphocytes at both 4 and 37 degrees C. A slight cytotoxicity of 2.5 to 10 nM paclitaxel was found in the CBMN and a significant increase in the binucleated micronucleated cell rates was observed, with a concentration-dependent manner. In the FISH analysis, more than 85% of the micronuclei (MN) were centromere positive, and a ratio of 72. 2 to 78.6% of these MN contained more than one centromere. Moreover, at 10 nM of paclitaxel, 35.6% of the cells are multimicronucleated lymphocytes. Unexpectedly, paclitaxel induced single-strand breaks on proliferating lymphocytes at 5 and 7.5 nM but not in resting cells, even at 5 to 15 microM. These in vitro results showed that (1) paclitaxel does not present any direct DNA action in resting cells, (2) DNA damage detected in stimulated lymphocytes may be linked either to a high frequency of cells in the S-phase cell cycle or to a direct DNA damaging effect on replicating cells, and (3) paclitaxel is a strong in vitro aneugenic drug on human normal cells, at clinically relevant concentrations.
Adult↗
[Chondrosarcoma in nasal fossae and Maffucci's syndrome].
INTRODUCTION: Maffucci's syndrome is a congenital non-hereditary disease very similar to Ollier's disease and associates multiple cutaneous hemangiomas, dyschondroplasia and often enchondromas. EXEGESIS: We report a unique case involving synchronous localization of chondrosarcoma in nasal fossae and anterior chest wall, disclosing Maffucci's syndrome. CONCLUSION: Atypical chondrosarcoma localization must lead to further investigation of potential multiple enchondromatosis.
Adult↗
[Importance of micronucleus tests in cultured binuclear T lymphocytes for the detection of genotoxic events in cancer patients].
The cytokinesis-blocked micronucleus assay (CBMN) is a short-term mutagenesis test which offers an easier and less tedious alternative to metaphase chromosome analysis, with the advantage that exposure to both clastogens and aneugens may be detected. The CBMN assay has been used in evaluating the genotoxic consequences of exposures to environmental and occupational mutagens and carcinogens. Micronucleated cell rates (MN cell rates) were assessed in cytokinesis-blocked lymphocytes of 70 male and female cancer patients prior to any anticancer treatment. The study of interindividual variation factors showed that only age significantly affect MN cell rate, whereas sex, tobacco, alcohol, imaging techniques and tumour stage had no significant effect. The comparison of micronucleated cell rates in 198 healthy subjects and 70 cancer patients matched for age and sex showed a statistically significant difference. Spontaneous elevated MN cell rates of cancer patients refer to previous exposition of genotoxic or mutagenic environmental agents. Moreover, the MN cell rates in cancer patients most probably refers to various cellular lesions and genetic damages.
Adult↗
A Bayesian dosing method for carboplatin given by continuous infusion for 120 h.
Carboplatin (CBDCA), an analogue of cisplatin, exhibits reduced toxicity but wide interpatient variability of its pharmacokinetic parameters. Individualization of the CBDCA dose is therefore necessary. Although various formulas have been developed for this purpose, major side effects have been reported on CBDCA administration by short-term infusion (0.5 or 1 h). We therefore propose a new schedule of CBDCA administration. Instead of a dosing method based on the estimation of renal function when a classic administration schedule is used, we propose a pharmacokinetic dosing method (Bayesian method), whereby CBDCA is given by continuous infusion for 120 h. First, CBDCA was given to 21 patients to determine the population pharmacokinetic parameters of carboplatin. Then, on the basis of total platinum plasma concentration measurements and Bayesian estimation of pharmacokinetic parameters, it was possible to individualize the CBDCA dose within the first 24 h of the infusion. This new protocol for CBDCA administration was evaluated in 36 new patients (60 courses). Three theoretical end points at the end of the infusion were considered. For a given theoretical end point, 20 courses were taken into account. The theoretical end points (i.e., 1, 1.5, and 1.8 mg/l) were compared with the concentrations measured at the end of the infusion, which were 0.99 +/- 0.10, 1.41 +/- 0.13, and 1.72 +/- 0.20 mg/l, respectively. This Bayesian dosing method can easily be used in clinical practice, and the determination of predictive performances has shown that the method is precise and unbiased. With no more toxicity or practical difficulties than those produced by other methods, and with acceptable tolerance, it was possible to reach a median dose that was 20% higher than the usual dose (484 +/- 190 mg/m2 as compared with 400 mg/m2). In conclusion, this new schedule of CBDCA administration appears to be interesting in terms of tolerance. However, new studies are required to confirm that this new scheme leads to equal or better efficacy than the classic protocol.
Adult↗