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Biomedical subjects

Jean-Pierre Droz

Publications and source records attributed to Jean-Pierre Droz.

At least 19 recordsLinked to original sources
PubMed2006

Failure of high-dose cyclophosphamide and etoposide combined with double-dose cisplatin and bone marrow support in patients with high-volume metastatic nonseminomatous germ-cell tumours: mature results of a randomised trial.

OBJECTIVES: To assess the impact on survival of high-dose chemotherapy with haematopoietic support in patients with high-volume, metastatic nonseminomatous germ cell tumours. METHODS: One hundred fifteen patients were randomised to receive either four cycles every 21 d of vinblastine (0.2 mg/kg on day 1), etoposide (100 mg/m2/d on days 1 through 5), cisplatin (40 mg/m2/d on days 1 through 5), and bleomycin (30 mg on days 1, 8, and 15) (arm A), or a slightly modified regimen followed by a high-dose chemotherapy including etoposide (350 mg/m2/d on days 1 through 5), cisplatin (40 mg/m2/d on days 1 through 5), and cyclophosphamide (1600 mg/m2/d on days 2 through 5) (arm B). RESULTS: In an intent-to-treat analysis, there were 32 (56%) and 24 (42%) complete responses in arms A and B, respectively (p=0.099). After a median follow-up of 9.7 yr, 31 and 27 patients have continuously shown no evidence of disease in arms A and B, respectively. There was no significant difference between the overall survival curves (p=0.167). According to the International Germ Cell Cancer Collaborative Group prognostic classification, the 5-yr survival rates were 88% and 82% in the intermediate group and 69% and 44% in the poor group (p=0.045) in arms A and B, respectively. CONCLUSIONS: This trial failed to demonstrate an impact on response and survival of high-dose chemotherapy with haematopoietic support in first-line treatment of patients with high-volume, metastatic nonseminomatous germ cell tumours.

Adult↗
PubMed2006

Chemotherapy practices and perspectives in invasive bladder cancer.

Bladder cancer is the fifth most common cancer in adult patients. Two-thirds of patients have superficial tumors and their treatment is conservative. Nevertheless, 30% of superficial tumors become infiltrative and represent a third of tumors at initial diagnosis. Overall mortality from bladder cancer is 30%. Important molecular events may explain the carcinogenesis and evolution of these tumors. Infiltrating bladder cancers are currently treated by radical cystectomy. Neoadjuvant chemotherapy has demonstrated a positive impact on patients' outcomes before cystectomy. Adjuvant chemotherapy after cystectomy is currently being studied in an international randomized trial. Patients with advanced disease are treated by chemotherapy with palliative intentions. Two regimens are standard: the combination of methotrexate, vinblastine, adriamycin and cisplatin, and the combination of gemcitabine and cisplatin. The addition of paclitaxel to the latter regimen is the subject of ongoing study. Only a few patients have long-term nonevolutive disease. Research must be focused on the combination of chemotherapy and targeted drugs directed through gene methylation, cytokine-receptor activation and signaling pathways.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Down-regulation of FAK and IAPs by laminin during cisplatin-induced apoptosis in testicular germ cell tumors.

The purpose of this present study was to investigate the role of inhibitor of apoptosis proteins (IAPs), their inhibitor, Smac, and the focal adhesion kinase (FAK) in the laminin enhancement of cisplatin-induced apoptosis in a testicular tumor germ cell line, NCCIT. We demonstrated that specifically in laminin-adherent NCCIT cells, cisplatin-induced apoptosis followed a significant decrease of c-IAP-2 protein expression and of both XIAP mRNA and protein expression. Smac expression was not modified in any tested conditions. We also found that FAK, which mediates the ECM-integrin antiapoptotic signal was down-regulated early in cells cultured on laminin. Our results provide a possible mechanistic explanation to cisplatin-induced apoptosis in NCCIT cells adhered on laminin. Cisplatin down-regulated FAK protein expression early, which therefore failed to activate c-IAP-2 and XIAP expression, resulting in a defect in the abrogation of the activation of caspases. Thus, the laminin signaling enhances the cisplatin-induced apoptosis, at least partly, through a down-regulation of survival signal molecules. Our data raise an interesting possibility that a therapeutic strategy targeting these survival molecules would be efficient to overcome chemo-resistance in testicular germ cell tumor.

Antineoplastic Agents↗
PubMed2006

[What's new in geriatric oncology?].

Remarkably, although 60% of new cancer cases and over 70% of cancer deaths occur in patients aged 65 years and older in Europe, standard treatment strategies have been mostly validated in younger adults. This demographic trend has led to the emergence of a new medical discipline, geriatric oncology and the development worldwide of geriatric oncology programs for the individualized management of elderly cancer patients. Elderly cancer patients represent an increasing share of the population and strategies for treating cancer must evolve to face this ineluctable reality. Treatment should take into account the highly heterogeneous physiological age of the elderly, their individual life expectancy, functional reserves, social support and preferences. French geriatric oncology programs have been mostly based on the interdependence of geriatricians, oncologists and auxiliary nursing people. This approach represent the best way to offer patients optimal management; oncologists and geriatricians collaborate to assess both global health status by means of Comprehensive Geriatric Assessment (CGA) and tumor stage by means of Comprehensive Tumor Assessment (CTA) and to initiate individualized care plans, involving comprehensive management and follow-up of all identified problems. This paper focuses on progress observed in the field of geriatric oncology both in France and worldwide.

Aged↗
PubMed2005

Alpha6 integrin subunit mediates laminin enhancement of cisplatin-induced apoptosis in testicular tumor germ cells.

Our study demonstrates that laminin potentiates cisplatin-induced apoptosis in NCCIT, a testicular tumor germ cell line. When cultured on laminin, NCCIT cells displayed a significantly higher susceptibility to cisplatin-induced apoptosis than on plastic or on other ECM components including fibronectin, Type IV collagen and vitronectin. This high cisplatin sensitivity observed on NCCIT cell cultured on laminin was mediated by the alpha6-integrin signaling. The knockdown of the alpha6-integrin subunit by small interfering RNAs suppressed the higher cisplatin-sensitivity supporting the existence of a crosstalk between laminin-alpha6-integrin signaling and cisplatin-induced apoptosis. Our findings indicate that in cisplatin-treated NCCIT cells, the laminin-alpha6-integrin signaling induces the activation of executioner procaspase-3 and -6 as well as apoptosis-inducing factor (AIF) transcription and expression. The ability of integrin-mediated specific stroma-tumor cell interactions to modulate the chemosensitive phenotype of a tumor cell might provide new insights to overcome cisplatin resistance of tumor cells.

Apoptosis↗
PubMed2005

Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam.

Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model. Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check. The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir. A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules.

Adult↗
PubMed2005

Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG).

BACKGROUND: As more and more cancers occur in elderly people, oncologists are increasingly confronted with the necessity of integrating geriatric parameters in the treatment of their patients. METHODS: The International Society of Geriatric Oncology (SIOG) created a task force to review the evidence on the use of a comprehensive geriatric assessment (CGA) in cancer patients. A systematic review of the evidence was conducted. RESULTS: Several biological and clinical correlates of aging have been identified. Their relative weight and clinical usefulness is still poorly defined. There is strong evidence that a CGA detects many problems missed by a regular assessment in general geriatric and in cancer patients. There is also strong evidence that a CGA improves function and reduces hospitalization in the elderly. There is heterogeneous evidence that it improves survival and that it is cost-effective. There is corroborative evidence from a few studies conducted in cancer patients. Screening tools exist and were successfully used in settings such as the emergency room, but globally were poorly tested. The article contains recommendations for the use of CGA in research and clinical care for older cancer patients. CONCLUSIONS: A CGA, with or without screening, and with follow-up, should be used in older cancer patients, in order to detect unaddressed problems, improve their functional status, and possibly their survival. The task force cannot recommend any specific tool or approach above others at this point and general geriatric experience should be used.

Advisory Committees↗
PubMed2005

Phase I study and pharmacokinetic of CHS-828, a guanidino-containing compound, administered orally as a single dose every 3 weeks in solid tumours: an ECSG/EORTC study.

CHS 828 is a new guanidino-containing drug. The aim of this study was to determine the maximum tolerated dose (MTD), the recommended dose and the toxicity of CHS 828. CHS 828 was given orally once every 3 weeks. The starting dose was 50 mg, which was escalated to 500 mg. A total of 107 courses was administered to 37 patients. At the 500-mg dose level, two of three patients experienced dose-limiting toxicities (DLT) (grade 3 mucositis and grade 4 thrombocytopenia), establishing this as the MTD. One of seven patients treated at 420 mg dose experienced DLT (grade 4 leucopenia, grade 4 mucositis and grade 4 diarrhoea), and this was considered the recommended dose for phase II studies. Vomiting, haematuria, leucopenia and thrombocytopenia were other significant toxicities. The pharmacokinetics of CHS 828 showed large variations both between and within patients. No objective responses were seen. A dose of 420 mg of CHS 828 administered every 3 weeks is the recommended dose, while 500 mg is the MTD.

Administration, Oral↗
PubMed2005

[Practical use of o,p'DDD in adrenocortical carcinoma].

Adrenocortical carcinoma (AC) is a rare tumor of poor prognosis. Its treatment by o,p'DDD remains a reference after initial surgery. Two galenic forms were recently available in France: Lysodren and Mitotane AP-HP. As Lysodren got a European registration in april 2004, Mitotane is no more produced. O,p'DDD is an adrenolytic and cytotoxic agent. It also reduces the hormonal secretion in AC. Its blood level must reach a therapeutic window (14-20 mg/l) to be effective and to limit toxicity. It is given orally three times a day (3 grams a day for Lysodren and 6-12 grams a day for Mitotane. Its posology is adapted according to serum levels of o,p'DDD and tolerance. Side effects are essentially gastrointestinal (GI), neurologic and hepatic. Five patients (four with AC and one with a metastatic Leydig cell tumor of the testis) were treated by Lysodren. Three patients had early Lysodren discontinuation due to toxicity (skin rash, weight loss, GI toxicity). Studies of combination with other treatments as chemotherapy and targeted drugs are warranted. Surgery is an important part of metastatic disease treatment.

Adrenal Cortex Neoplasms↗
PubMed2004

Analysis of p16INK4A gene promoter in male germ-cell tumors: identification of a new point mutation.

Human male germ-cell tumors of seminoma type display aberrant expression of INK4-family inhibitors of the cell cycle including CDKN2-encoded p16INK4A. The mechanisms underlying the altered p16INK4A expression are not fully understood. Indeed, neither genetic/epigenetic alterations in CDKN2 coding sequence nor its promoter hypermethylation could explain all anomalies. To assess whether the aberrant p16INK4A expression could be related to the alterations in CDKN2 regulatory sequence, we screened seminoma DNAs from 19 patients for the promoter mutations. Combined polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and automated DNA-sequencing approaches indicated an adenine insertion at the position-1973 (relative to the ATG codon at+1) of CDKN2 promoter in one particular patient. The immunohistochemical analysis pointed to the correlation between the observed promoter mutation and the loss of p16INK4A protein expression. These data suggest that in addition to previously characterized anomalies, the identified CDKN2 promoter mutation may be relevant for altered p16INK4A protein expressions in at least some seminoma.

Adult↗
PubMed2004

Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors.

PURPOSE: The prognostic relevance of the rate of decline of serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) during the first 3 weeks of chemotherapy for nonseminomatous germ cell tumors (NSGCT) was studied in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) classification. PATIENTS AND METHODS: Data from 653 patients prospectively recruited in clinical trials were studied. Tumor markers were obtained before chemotherapy and 3 weeks later. Decline rates were calculated using a logarithmic formula and expressed as a predicted time to normalization (TTN). A favorable TTN was defined when both AFP and HCG had a favorable decline rate, including cases with normal values. RESULTS: The median follow-up was 50 months (range, 2 to 151 months). Tumor decline rate expressed as a predicted TTN was associated with both progression-free survival (PFS; P <.0001) and overall survival (OS; P <.0001). The 4-year PFS rates were 64% and 38% in patients from the poor-prognosis group who had a favorable and an unfavorable TTN, respectively. The 4-year OS rates were 83% and 58%, respectively. This effect was independent from the initial tumor marker values, the primary tumor site, and the presence of nonpulmonary visceral metastases: tumor marker decline rate remained a strong predictor for both PFS (hazard ratio = 2.5; P =.01) and OS (hazard ratio = 4.6; P =.002) in patients from the IGCCCG poor-prognosis group in multivariate analysis. CONCLUSION: Early predicted time to tumor marker normalization is an independent prognostic factor in patients with poor-prognosis NSGCT and may be a useful tool in the therapeutic management of these patients.

Biomarkers, Tumor↗
PubMed2004

A Phase I and pharmacological study of the platinum polymer AP5280 given as an intravenous infusion once every 3 weeks in patients with solid tumors.

PURPOSE: This Phase I study was designed to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of AP5280 in patients with solid tumors. Furthermore, the platinum (Pt) pharmacokinetics after AP5280 administration and preliminary antitumor activity were evaluated. AP5280 is a Pt agent linked to the water-soluble, biocompatible copolymer N-(2-hydroxypropyl)methacrylamide, which potentially increases Pt accumulation in tumors via the enhanced permeability and retention effect. In this way, it is anticipated that a higher activity of therapeutic Pt can be reached. The pharmaceutical product contains approximately 8.5% of Pt by weight and has a molecular weight of approximately 25,000. EXPERIMENTAL DESIGN: Adult patients with solid tumors received AP5280 as a 1-h i.v. infusion every 21 days. Pharmacokinetics of total and unbound Pt were determined during the first treatment course and before the start of each new cycle using noncompartmental pharmacokinetic analysis. Pt-DNA adduct concentrations in WBCs and, if available, in tumor tissue were quantified using a sensitive (32)P postlabeling assay. RESULTS: Twenty-nine patients were treated at eight dose levels (90-4500 mg Pt/m(2)). The dose-limiting toxicity was Common Toxicity Criteria grade 3 vomiting and was experienced at 4500 mg Pt/m(2) in two of six patients. The maximum tolerated dose on this schedule was therefore 4500 mg Pt/m(2), and the recommended dose for a Phase II study is 3300 mg Pt/m(2). Renal toxicity and myelosuppression, toxicities typically observed with cisplatin and carboplatin, were minimal for AP5280. The area under the curve of total Pt increased with increasing AP5280 dose. Plasma clearance of total Pt was 644 +/- 266 ml/h, and the terminal half-life was 116 +/- 46.2 h. After AP5280 administration, Pt-guanine-guanine DNA adduct concentrations in WBCs ranged from 70 to 1848 amol/microg DNA, concentrations that were substantially lower than concentrations measured after administration of therapeutic doses of cisplatin. CONCLUSIONS: AP5280 can be administered safely as a 1-h i.v. infusion at a dose of 3300 mg Pt/m(2) once every 3 weeks and produces prolonged plasma exposure compared with any of the free Pt-containing drugs. However, it remains to be determined whether AP5280 can actually increase Pt delivery to the DNA of tumor cells in man as has been shown in experimental models.

Acrylamides↗
PubMed2004

Statements on the interdependence between the oncologist and the geriatrician in geriatric oncology.

Geriatric oncology is defined by the multidimensional and multidisciplinary approach of the elderly cancer patients. Autonomy, beneficence, non-maleficence and justice are the four fundamental principles on which are based the treatment objectives and practical management of these patients. The comprehensive geriatric assessment is the tool the most likely to detect the functional problems in these elderly patients. The standard oncologic managements of cancer are applicable to these patients. However treatment plan and geriatric interventions must be tailored to each individual patient characteristics. Thus a strong interdependence between oncologic and geriatric teams is warranted. This implies specific teaching programs during initial medical studies and in the setting of continuous medical education. Furthermore, such worldwide teaching programs may help to the implementation of geriatric oncology programs which is only based, to date, on personal experiences as described in this report.

Aged↗
PubMed2003

[Metastatic prostate cancer].

Metastatic prostate cancer is an uncurable disease. Treatment is only palliative. Median survival of patients is 3 years. Prostate cancer is an hormonodependent cancer, androgen blockade is the most active treatment. However hormone resistance occurs after a median interval of 2 years. The major symptom is pain, others are urinary obstruction, neurological complications of bone metastases and hematological disorders. Androgen deprivation is the first-line treatment, impotency and osteoporosis being the main side effects. Other treatments are radiotherapy, radiopharmaceutics and chemotherapy. The most important treatment issue is quality of life.

Androgen Antagonists↗
PubMed2003

Are older French patients as willing as older American patients to undertake chemotherapy?

PURPOSE: A view often held in Europe is that older Europeans are less willing than older Americans to undertake chemotherapy. This study assesses whether this view is valid. PATIENTS AND METHODS: Three-hundred twenty outpatients aged 70 years and older were interviewed via anonymous questionnaires: French patients with and without cancer and American patients with and without cancer. The response rate was 61% (195 of 320 questionnaires). Ages ranged from 70 to 95 years (29% aged 80 years and older). Two scenarios were presented: a strong chemotherapy (platinum/taxane combination-like) and a milder chemotherapy (weekly vinorelbine-like). The options were to refuse chemotherapy or to accept for a threshold chance of cure, of life prolongation, or of symptom relief. Functional status, education, self-rated health, and depression were controlled for. RESULTS: French noncancer patients (34%) were less willing to accept the strong chemotherapy than French cancer patients (77.8%), American noncancer patients (73.8%), and American cancer patients (70.5%) (P <.001 for each pair). This was also true for the moderate chemotherapy (67.9% v 100%, 95.2%, and 88.5%, respectively; P <.001). Age and sex did not correlate with response, but self-rated health, cancer status, and nationality did. Thresholds varied from patient to patient. CONCLUSION: Whereas older French people without cancer are more reluctant than older Americans to envision chemotherapy, older cancer patients in both countries have the same amenability to treatment. Chemotherapy options should be fully discussed with older cancer patients, given that most are willing to consider them.

Aged↗
PubMed2003

A phase II study of irinotecan in patients with advanced renal cell carcinoma.

BACKGROUND: Patients with disseminated renal cell carcinoma (RCC) have a poor outcome, and the disease is considered highly resistant to chemotherapy. Irinotecan is an active drug in the treatment of a number of neoplastic diseases and is not concerned with the multidrug-resistance phenotype of tumor cells, a common mechanism of drug inactivation and resistance in patients with RCC. Therefore, the authors tested the antitumor activity of irinotecan in patients with RCC. METHODS: Patients with disseminated RCC received irinotecan (350 mg/m(2)) every 3 weeks. The primary objective of the study was to determine the overall response rate. Two groups of patients were defined: previously treated patients (Group A) and nonpretreated patients (Group B). RESULTS: Forty-two eligible patients were recruited: Twenty-six patients (Group A) had received previous chemotherapy or immunotherapy, and 16 patients had received no previous systemic therapy (Group B). The median number of cycles received per patient was 3 cycles (range, 1-6 cycles). A dose reduction was required in only 8% of cycles. Two patients, one in each group, had minor responses. Eleven patients (42%) in Group A and 1 patient (12%) in Group B had disease stabilization. Overall, therapy was tolerated well. Grade 4 neutropenic fever occurred in 17% of patients. The 1-year overall survival rate was 61% (95% confidence interval, 42-80%) in Group A and 19% (95% confidence interval, 0-49%) in Group B. CONCLUSIONS: Irinotecan was tolerated well and had limited activity in patients with disseminated RCC at the dose and schedule used in the current study. A high percentage of disease stabilization was observed in cytokine-pretreated patients.

Adult↗
PubMed2003

Rules allowing the reimbursement of cares of elderly cancer patients in France.

The concept of old age has changed recently: elderly, autonomous patients are now expected to participate in city social life. The objective of French public health authorities was to help elderly people stay at home as long as possible. To that aim, they have developed a variety of community support services. On one hand, the costs induced by the care of the elderly can be divided in three distinct categories: accommodation, dependency and care. Funding is based on these three cost groups. On the other hand, cancer belongs to the list of 30 diseases with 100% reimbursement. The financial aspects of health care, accommodation and dependency for elderly patients with cancer are crucial. The cost is huge, and the organisation of assistance is complex. Even if laws have settled the direction to follow and the schedule of improvements needed, the resolution of this problem will require long-term political willingness.

Aged↗