Biomedical subjects

F Pein

Publications and source records attributed to F Pein.

At least 19 recordsLinked to original sources

PubMed2006

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours.

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, 'DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m(-2) for Group A and 100 mg m(-2) for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

Adolescent↗

PubMed2005

Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies.

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.

Adolescent↗

PubMed2004

Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy.

The purpose of this paper was to determine the cardiac status in children 15 years or more after adriamycin therapy for a solid tumour. Of the 447 pts, 229 pts were fully studied and 218 were not. The following cardiac evaluations were proposed to all the 447 consecutive patients (pts): (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-hour holter ECG; (3) (131)l-mlBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO(2) max measurement. The radiation doses delivered to 6 points in the heart were estimated for all patients who had received radiotherapy. Congestive heart failure was diagnosed in 24 of 229 (10%) evaluated pts, with a median interval of 15 years (0.3-24 years) from the first symptom after adriamycin treatment. Among the 205 remaining pts, 13 asymptomatic pts (6%) had severe (n=4) (FS<20%) or marked (n=9) (20< or =FS<25%) systolic dysfunction. In the 192 others, the median meridional end-systolic wall stress was 91 (53-135) and it exceeded 100 g cm(-2) in 52 pts. Using a Cox model, only the cumulative dose of adriamycin and the average radiation dose to the heart, were identified as risk factors for a pathological cardiac status. In conclusion, the risk of cardiac failure or severe abnormalities increases with adriamycin treatment, radiotherapy and time since treatment, even after a follow-up of 15 years or more. In our series, after an average follow-up of 18 years, 39% of the children had a severe cardiac dysfunction or major ventricular overload conditions. The risk increases with the dose of adriamycin and radiation received to the heart, without evidence for threshold.

Adolescent↗

PubMed2004

Intracranial relapse in Wilms tumor patients.

BACKGROUND: In children with nephroblastoma, recurrence with metastases in the central nervous system is rare. Recently, previous reports (NWTSG and UKCCSG) reported brain metastases with an incidence of respectively 0.5% and 0.6% in Wilms tumor (WT) patients (respectively n = 30/5,852 and n = 7/1,249). PROCEDURE: We retrospectively investigated the incidence and survival of patients with central nervous system relapse in WT patients, treated according to the consecutive SIOP protocols 1, 2, 5, 6, 9, and 93-01. All children with WT from 1971 until 2000 were enrolled in the study (3,040 eligible patients). Specimens at diagnosis and if possible at relapse were centrally reviewed. Patients with renal neoplasms other than WT were excluded. RESULTS: CNS relapse was documented in 14 patients (0.5%). Median time to CNS relapse was 16 months (3-69). The occurrence of relapse was not associated with specific histological subtypes. In seven patients intracranial metastases occurred at first relapse, of which two were isolated relapses. In five patients no treatment was started because of the poor condition of the patient, the other nine cases were treated with (a combination of) chemotherapy (n = 6), surgery (n = 4), and radiotherapy (n = 6). CONCLUSIONS: CNS relapse in WNT is rare. In contrast to reports of other Wilms tumor study groups, although four patients reached (local) CR, the SIOP registry showed that eventually none of the documented WT patients survived.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

[Pseudotumoral diseases: ten years of experience in a pediatric oncology department].

PURPOSE: Among the 350 new patients per year treated in the pediatric oncology department of the Gustave-Roussy Institute, about 2% have no tumor. This study analyzes these children presenting a pseudotumoral disease. PATIENTS AND METHODS: Ten-year-retrospective study. Patients for which no follow up in oncology was necessary after one consultation or hospitalization were selected. OUTCOME: Between 1990 and 2000, 64 patients were seen in the pediatric department for pseudotumoral disease. The reasons of orientation were mainly a soft tissue mass (15 cases), an abdominal mass (14 cases), or a bone lesion (13 cases). Diagnosis was most often infectious diseases (33 cases), or post-traumatic lesions (10 cases). Diagnosis was established following several consultations or an hospitalization for 29 of 64 patients. In 75% of the cases new investigations were necessary to determine the diagnosis. A biopsy was performed in 19. For two children, diagnosis was corrected after the beginning of chemotherapy. CONCLUSION: Pseudotumoral diseases leading to a consultation in pediatric oncology are rare and represent two per cent of the patients. For these difficult cases, only a pluridisciplinary discussion may lead to diagnosis.

Abdominal Neoplasms↗

PubMed2001

Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study.

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m(2)). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity.

Adolescent↗

PubMed2000

[Parents' opinions of pediatric oncology day hospitals].

AIM: The aim of this study was to assess parental opinions on the advantages and disadvantages of a pediatric oncology day hospital (DH) so that the structure can be better adapted to the children's needs and parents' expectations, and provide a potentially valid alternative to conventional hospitalization (CH). METHODS: Over a 15-days period, 39 parents of children treated at a DH were approached and asked to fill in a questionnaire on their opinion of the advantages and disadvantages of a DH compared to a CH. RESULTS: The results of this survey were significant. The majority of parents preferred the DH to the CH (69% versus 15%). The illness was perceived as being less severe; and as the child was not continually in the CH context, he/she was able to forget the illness and the hospital to some extent, and was therefore not as anxious. The DH appeared to be better adapted to the child's needs and facilitated the pursuit of normal family life and everyday activities, but imposed constraints on social and professional activities. On the other hand, the CH provided a reassuring treatment context including more comprehensive information, and in particular a better integration of the child and careful monitoring of the disease within the oncology department, and closer relations between the different parents visiting the hospital. In spite of the high preference rate for the DH, in some instances certain disadvantages could outweigh the advantages, e.g., fatigue due to journeys to and from the hospital, or living too far away from the DH; a lack of punctuality, which meant that the parents were unable to plan their day with any certainty; insufficient comfort (noise, a limited number of rooms available); inadequate information; a lack of privacy; and the anxiety connected with having to assume too much responsibility. CONCLUSION: Overall, it was concluded that the parents appeared to appreciate the aims of the DH (i.e., limiting the treatment constraints imposed on the patient and on the parents themselves, thereby maintaining the quality of family life, assuring adequate treatment, reducing cost of treatment). However, the authors consider that the DH has to be organized in such a way that it takes into account the following: the social aspects, i.e., living conditions, parents' social, economic and professional status; parents' and children's psychological traits, expectations; and access to a local care system. The DH should also have sufficient means and staff at its disposal. Without taking these factors into consideration, the DH and other alternatives to the CH will not be able to adequately care for the patients, or meet the parents' expectations, and may even have a negative effect on the family.

Adult↗

PubMed2000

Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans.

7-Ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin (CPT-11), a DNA topoisomerase I inhibitor, undergoes several metabolic pathways to generate conjugated and unconjugated derivatives that could be excreted from the body. The objective of this study was to determine the oxidative metabolites of CPT-11 recovered in human urine samples and to identify cytochrome P450 (CYP) involved in their formation. In addition to the already known metabolites of CPT-11 [SN-38, SN-38-G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC), and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC)], we isolated three oxidized metabolites from the urine of two children and two adults given CPT-11. M1 and M2 (molecular weight, 602) were hydroxylated, respectively, on the CPT moiety and on the terminal piperidine ring of CPT-11. M3 had a molecular mass of 602, but its urine concentration in patients was too low to establish its chemical structure by liquid chromatography/mass spectrometry. In vitro incubations with cells expressing CYP2C8, CYP2C9, CYP1A1, CYP1A2, or CYP3A7 did not produce any detectable metabolites. Only CYP3A4 produced both APC and NPC, resulting from the oxidation of the piperidinylpiperidine side chain of CPT-11 along with metabolite M2. The metabolism of CPT-11 by CYP3A5 was markedly different because neither APC or NPC nor M2 was produced, whereas only one new metabolite, M4 (molecular weight, 558), was generated by de-ethylation of the CPT moiety. No previous study has reported the presence of the M4 metabolite. Production of APC, NPC, M2, and M4 was prevented by ketoconazole, a specific CYP3A inhibitor. The parameters of CPT-11 biotransformation into M2 and M4 were examined using cell lines expressing, respectively, with CYP3A4 and CYP3A5, indicating that CPT-11 is preferentially metabolized by CYP3A4. In conclusion, CYP3A plays a major role in the metabolism of CPT-11, with some differences of the metabolic profile exhibited by 3A4 and 3A5.

Adolescent↗

PubMed2000

[A century of progress in the knowledge and treatment of nephroblastoma].

Since its initial description by Max Wilms over a century ago, nephroblastoma has benefited from considerable improvements both in terms of basic knowledge about it and management of it. Today, the majority of these very young patients can expect a long-term survival in excess of 90% at the price of a light therapy that combines surgical resection, chemotherapy based on ill-toxic agents, and in selected cases, radiotherapy of remarkably low toxicity. The contribution of large international studies will be emphasized here.

Child↗

PubMed1999

Prognosis of children with malignant pheochromocytoma. Report of 2 cases and review of the literature.

Malignant pheochromocytomas are rare in childhood and the prognosis of children with this tumor is not well known. We present 2 pediatric observations of malignant pelvic pheochromocytoma. Symptoms in both cases were headache and hypertension. The tumor invaded the sacral bone. Angiogram helped to localize the tumor and metastases, and allowed preoperative embolization of the tumor in 1 case. The first child underwent incomplete surgical resection, (131)I-MIBG therapy and radiotherapy, and is still alive 2 years after diagnosis. The second child died from metastatic invasion a few weeks after discovery of the tumor. We reviewed previous reports of children with malignant pheochromocytomas (30 cases). Primary tumor was extraadrenal in 50% of cases. The 3-year survival rate was 73 +/- 9% (mean +/- SD). Apart from surgical resection, no particular treatment appeared to be more effective than others in reducing mortality.

3-Iodobenzylguanidine↗

PubMed1998

Preclinical development of camptothecin derivatives and clinical trials in pediatric oncology.

Although the prognosis of childhood cancers has dramatically improved over the last three decades, new active drugs are needed. Camptothecins represent a very attractive new class of anticancer drugs to develop in paediatric oncology. The preclinical and clinical development of two of these DNA-topoisomerase I inhibitors, i.e. topotecan and irinotecan, is ongoing in paediatric malignancies. Here we review the currently available results of this evaluation. Topotecan proved to be active against several paediatric tumour xenografts. In paediatric phase I studies exploring several administration schedules, myelosuppression was dose-limiting. The preliminary results of topotecan evaluation in phase II study showed antitumour activity in neuroblastoma (response rate: 15% at relapse and 37% in newly diagnosed patients with disseminated disease) and in metastatic rhabdomyosarcoma (40% in untreated patients). Topotecan-containing drug combinations are currently investigated. Irinotecan displayed a broad spectrum of activity in paediatric solid tumour xenografts, including rhabdo-myosarcoma, neuroblastoma, peripheral primitive neuroectodermal tumour, medulloblastoma, ependymoma, malignant glioma and juvenile colon cancer. For several of these histology types, tumour-free survivors have been observed among animals bearing an advanced-stage tumour at time of treatment. The clinical evaluation of irinotecan in children is ongoing. Irinotecan undergoes a complex in vivo biotransformation involving several enzyme systems, such as carboxylesterase, UDPGT and cytochrome P450, in children as well as in adults. Preclinical studies of both drugs have shown that their activity was schedule-dependent. The optimal schedule of administration is an issue that needs to be addressed in children. In conclusion, the preliminary results of the paediatric evaluation of camptothecin derivatives show very encouraging results in childhood malignancies. The potential place of camptothecins in the treatment of paediatric malignant tumours is discussed.

Animals↗

PubMed1998

[Treatment of chemotherapy induced emesis in children].

In recent years, the management of chemotherapy-induced emesis in children has been greatly modified by the introduction of a new therapeutic class: serotonin antagonists. Based on a better knowledge of mechanisms, the treatment now uses combinations of different drugs. These treatments need to be carefully adapted to the patient and to the emetic risk of the chemotherapy, also taking into account the minimal cost. A gradual treatment proposal in five steps is described.

Antiemetics↗

PubMed1998

[Combined chemoradiotherapy of tumors in the child].

The high chemosensitivity of pediatric tumors along with their natural propensity for an early distant dissemination have stimulated the interest for chemo-radiation combinations in children since the mid 50s. Following the early experiments in nephroblastomas on the interaction of Actinomycin-D and radiotherapy, multiple national and international studies have been conducted since the mid 70s with considerable success: nowadays most pediatric tumors enjoy a long term survival in excess of 70%. Like their adult counterparts, these associations aim to induce an early control of the primary tumor and distant spreading (spatial cooperation) but also, more specifically in children, to limit the toxicity on normal tissues when treatment intensity can be further reduced. The association of an initial chemotherapy followed by local radiation at a dose and in a volume adapted to the response to chemotherapy along with associated prognostic factors has become widely tested in national and international studies conducted in Hodgkin's disease, Ewing's sarcoma, medulloblastomas, and brain tumors in the very young. Conversely, concomitant associations have remained limited to high-risk subgroups (parameningeal rhabdomyosarcomas for example) due to their potential hazards.

Adult↗

PubMed1998

High-dose melphalan, etoposide, and carboplatin followed by autologous stem-cell rescue in pediatric high-risk recurrent Wilms' tumor: a French Society of Pediatric Oncology study.

PURPOSE: The three-drug combination of melphalan (M), etoposide (E), and carboplatin (C) followed by autologous stem-cell (ASC) rescue has been evaluated prospectively by the French Society of Pediatric Oncology (SFOP) in pediatric high-risk recurrent (HRR) Wilms' tumor (WT) patients with chemotherapy-responsive disease. PATIENTS AND METHODS: From October 1988 to October 1994, 29 patients with HRR WT were treated in nine SFOP centers. Two additional patients with stage IV anaplastic WT were consolidated in first complete response (CR) with the same regimen and have been studied separately. The regimen consisted of M 180 mg/m2 for 1 day, E 200 mg/m2/d for 5 days, and C at a daily targeted area under the concentration-time curve (AUC) of 4 mg x min/mL for 5 days. ASCs were reinfused 48 hours after M. RESULTS: Twelve of 28 assessable patients with HRR WT are still in continuous CR at a median of 48.5 months (range, 36 to 96) after consolidation. Disease-free survival (DFS) and overall survival (OS) estimated by the Kaplan-Meier method at 3 years were 50%+/-17% and 60%+/-18%, respectively. Sixteen patients relapsed at a median of 8.5 months (range, 3 to 53) after consolidation. Toxicity data are available in 31 grafted patients. Grade III and IV toxicities included hematologic side effects (n=31), hemorrhage (n=8), mucositis (n=24), diarrhea (n=12), renal disorders (n=8), and pneumonitis (n=3). CONCLUSION: The adverse prognostic factors (APF) used to select patients for this dose-intensive chemotherapy define children with very-poor-risk recurrent WT. Despite high treatment-related toxicity, about half of these patients remain disease-free at 3 years. Patient outcome is statistically better when high-dose chemotherapy (HDCT) is performed as early as the second CR or partial response (PR). Novel therapeutic approaches with innovative preparative regimens are warranted for the remaining high-risk patients.

Adolescent↗

PubMed1998

Conduct of phase I trials in children with cancer.

PURPOSE AND METHODS: Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. RESULTS AND CONCLUSION: Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect the relative unavailability of appropriate patients. The application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.

Antineoplastic Agents↗

PubMed1998

[Nephroblastoma, model of childhood cancer responding to chemotherapy].

Cancer incidence is low in children. Childhood tumors are different from cancers seen in adults: their growth is rapid, but they respond well to radiotherapy and chemotherapy. In the case of Wilms Tumor, Actinomycin D, Vincristine and Doxorubicin were first used with success. Ifosfamide, Etoposide and Carboplatin are now also used in selected cases. But efficient treatments have important drawbacks: growth defects in the case of radiotherapy, late cardiac toxicity due to Doxorubicin, leukemias as second tumors following Etoposide. Treatment strategy is based on prognostic factors in Wilms' tumor, and the risk/benefit ratio assessment for each group of patients, considering survival probability and the risk of late effects. Large randomised studies in the USA and in Europe resulted in cure rates over 90%, with very few expected sequelae. Preoperative chemotherapy is now successfully applied to other tumors in children.

Antineoplastic Agents↗

PubMed1997

Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology.

The aim of this phase II study was to determine the efficacy of high-dose ifosfamide with moderate dose etoposide in childhood osteosarcoma. From January 1992 to January 1995, 27 children (15 male, 12 female) with relapsed or refractory evaluable osteosarcoma were included in a phase II study of two courses of ifosfamide 3g/m2/day and etoposide 75 mg/m2/day for 4 days. Median age was 14 years (7-19 years). All but one had received high-dose methotrexate and doxorubicin as first-line treatment. 22 patients had previously received ifosfamide. This regimen was given as first-line in 1 patient, second-line in 23 and third-line in 3. Evaluable disease was lung metastases in 21 patients, local relapse in 5 and adenopathy in 1. There were six complete responses, seven partial responses, three minor responses, six stable disease and five progressive disease (including one mixed response). Response rate was 48% (95% confidence interval, 29-67%). Duration of response was not available (10 responding patients had other treatments). Response rate was equivalent in the subgroup of 22 patients who had previously received ifosfamide (4 CR, 6 PR). Among 3 patients who received the phase II regimen as third-line chemotherapy, there was 1 PR. All but 4 patients had a well tolerated grade 4 neutropenia. Transient mild confusion or seizures were each observed once. 5 patients are alive 15-31 months after the beginning of chemotherapy. This combination of drugs at this dosage has tolerable toxicity, is efficient and deserves evaluation in phase III studies.

Adolescent↗

PubMed1997

[Granulocytic sarcoma of the testis without hematological manifestations].

A 30-year-old man with a testicular tumor ressembling a "round cell sarcoma" was treated for rhabdomyosarcoma. Complete remission was achieved but the patient relapsed and died of the disease. A retrospective diagnosis of granulocytic sarcoma was established using an anti-myeloperoxidase antibody, unfortunately not available at the time of the initial diagnosis. No hematological disorders were observed during the course of the disease. Four cases of granulocytic sarcoma of the testis have been reported in the literature. All these cases where accompanied or followed by leukemia. The present case seems to be the first case of granulocytic sarcoma of the testis not accompanied by hematological disorders.

Adult↗