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Olivier Rixe

Publications and source records attributed to Olivier Rixe.

At least 19 recordsLinked to original sources
PubMed2007

Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.

BACKGROUND: Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted. METHODS: We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety. RESULTS: The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P<0.001). Sunitinib was also associated with a higher objective response rate than was interferon alfa (31% vs. 6%, P<0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with interferon alfa, whereas diarrhea was more frequent in the sunitinib group (P<0.05). Patients in the sunitinib group reported a significantly better quality of life than did patients in the interferon alfa group (P<0.001). CONCLUSIONS: Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).

Adult↗
PubMed2006

Sunitinib malate.

Recently, there has been a growing interest in understanding the role of receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), in promoting tumor angiogenesis, tumor growth and metastasis. Sunitinib (sunitinib malate; SU11248; SUTENT; Pfizer Inc, New York, NY, USA) is a novel, orally bio-available, oxindole, multi-targeted tyrosine kinase inhibitor with high binding affinity for VEGFR and PDGFR which has shown anti-tumor and anti-angiogenic activities. This drug recently received approval from the US Food and Administration (FDA) in two indications simultaneously: advanced renal cell carcinoma (adRCC) and gastrointestinal stromal tumors (GIST), in patients who are resistant or intolerant to the treatment with imatinib. The present article reviews the recent pharmacologic and clinical data related to the use of this new promising drug in the field of oncology.

Antineoplastic Agents↗
PubMed2006

Cyclooxygenase-2 as a target for anticancer drug development.

The two isoforms cyclooxygenase-1 and -2 catalyze the initial step in the formation of prostaglandins in a variety of pathophysiological processes. More recently their role in carcinogenesis has become more evident. They seem to influence apoptosis, angiogenesis, and invasion, and play a role in the production of carcinogens. Usually, a high level of COX-2 expression is found in cancer cells. However, low COX-2 expression is observed in some cancers like prostate or breast cancer. This phenomenon is quite surprising and should influence on clinical trial designs. Large epidemiological trials studying users and non-users of aspirin have shown that cyclooxygenase (COX) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) could be of benefit against the development and growth of malignancies. Moreover, clinical trials in patients with familial adenomatosis polyposis syndrome have shown too the efficacy of non-selective COX inhibitors and recently also of selective COX-2 inhibitors in the reduction of the number and the size of colorectal polyps. However, a primary chemopreventive effect has not been demonstrated yet. NSAIDs are also supposed to have a preventive and growth inhibitory effect in extra-colonic epithelial malignancies. Several preclinical studies show promising results with combination treatments of either chemotherapy or radiotherapy with COX inhibitors. Preclinical studies with the simultaneous use of inhibitors of the epidermal growth factor receptor and COX-2 inhibitors have shown also promising results. Encouraging results with the first clinical trials combining chemotherapy with COX-2 inhibitors in patients with cancer in the advanced and neoadjuvant setting have recently been reported. However, NSAIDs effects in cancer cells are mediated not only by COX enzymes but also by interactions with downstream effectors of COX-2. Hence, we can state that targeting the COX-2 pathway is a promising strategy in the prevention and treatment of solid tumors. Ongoing trials are expected to answer - at least partly - the remaining questions concerning COX-2 and cancer.

Antineoplastic Agents↗
PubMed2006

An unexpected inverse correlation between soluble epidermal growth factor receptor and interleukin-6 in metastatic malignant melanoma patients.

The exact role of the soluble form of epidermal growth factor receptor (sEGF-R) in melanoma disease remains to be determined. We focused this study on the detection of circulating levels of sEGF-R in metastatic malignant melanoma patients and on the possible relationship between sEGF-R and clinicobiological parameters including circulating interleukin-6 (IL-6) and survival. sEGF-R and IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay in serum from 75 metastatic malignant melanoma patients and 30 healthy controls. In our patients, median sEGF-R level was significantly elevated (P < 0.0001) compared with that of healthy controls (173.4 vs. 91.9 fm/ml). Age or sex was not associated with sEGF-R levels. Regarding tumor burden, in contrary to the detected IL-6 levels, we found that median sEGF-R levels were significantly (P = 0.045) lower in patients with high tumor burden (163 fm/ml) than in those with low tumor burden (193.8 fm/ml). An inverse correlation between IL-6 levels and sEGF-R was observed (r =-0.33; P = 0.040). No relationship between sEGF-R and time to progression or overall survival was observed while circulating IL-6 was found as a predictive factor of survival. Our results showed that sEGF-R level was elevated in metastatic malignant melanoma patients but not related to time to progression or survival and demonstrated an inverse correlation between sEGF-R and IL-6 levels. These findings imply a better understanding of EGF-R and IL-6 cross-talk function in melanoma.

Adult↗
PubMed2005

Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study.

PURPOSE: To evaluate response rate and toxicity of irinotecan and oxaliplatin plus fluorouracil (FU) and leucovorin (Folfirinox) in advanced pancreatic adenocarcinoma (APA). PATIENTS AND METHODS: Chemotherapy-naive patients with histologically proven APA and bidimensionally measurable disease were treated with Folfirinox therapy every 2 weeks, which comprised oxaliplatin 85 mg/m(2) and irinotecan 180 mg/m(2) plus leucovorin 400 mg/m(2) followed by bolus FU 400 mg/m(2) on day 1, then FU 2,400 mg/m(2) as a 46-hour continuous infusion. Quality of life (QOL) was assessed using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). RESULTS: Forty-seven patients were entered, and 46 received treatment. Thirty-five patients (76%) had metastatic disease. A total of 356 cycles were delivered, with a median of eight cycles per patient (range, one to 24 cycles). All patients were assessable for safety. No toxic death occurred. Grade 3 to 4 neutropenia occurred in 52% of patients, including two patients with febrile neutropenia. Other relevant toxicities included grade 3 to 4 nausea (20%), vomiting (17%), and diarrhea (17%) and grade 3 neuropathy (15%; Levi's scale). The confirmed response rate was 26% (95% CI, 13% to 39%), including 4% complete responses. Median time to progression was 8.2 months (95% CI, 5.3 to 11.6 months), and median overall survival was 10.2 months (95% CI, 8.1 to 14.4 months). Between baseline and end of treatment, patients had improvement in all functional scales of the EORTC QLQ-C30, except cognitive functioning. Responders had major improvement in global QOL. CONCLUSION: With a good safety profile, a promising response rate, and an improvement in QOL, Folfirinox will be further assessed in a phase III trial.

Adult↗
PubMed2005

Preoperative sequential chemotherapy in locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Induction chemotherapy may contribute to decreased local and distant recurrences in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) resectable for cure. METHODS: Patients with previously untreated locally advanced stage III-IV (N0-2, M0) SCCHN received a dose-dense sequential regimen combining cisplatin/5-fluorouracil followed by bleomycin/methotrexate/hydroxyurea. Induction chemotherapy was followed by locoregional surgery and/or radiation therapy. RESULTS: Among 37 patients, 23 (62%) had T4 primary tumors. Grade 3 to 4 asymptomatic hematologic toxicity occurred in less than 15% of patients. Nonhematologic toxicities were limited to grade 1 to 2 in less than 20% of patients. In the overall cohort (intent-to-treat; n = 35), 24 (68.5%) of 35 patients had objective clinical responses, including nine complete responses (25.7%). Fifty-seven percent of patients were free of disease at 2.5 years. CONCLUSIONS: Sequential induction chemotherapy is feasible and active in patients with locally advanced head and neck cancers and may further include recent compounds such as taxanes.

Adult↗
PubMed2005

Pretreatment serum interleukin-6 concentration as a prognostic factor of overall survival in metastatic malignant melanoma patients treated with biochemotherapy: a retrospective study.

Biological response parameters during biochemotherapy, including chemotherapy with immune modulating agents, have been studied extensively. Of these parameters, interleukin-6 (IL-6) has been implicated in advanced stage disease and tumour recurrence. However, there is limited information available about the significance of IL-6 in metastatic malignant melanoma (MMM). In this study, we evaluated the possible relationship between serum IL-6 level and overall survival. This retrospective study included 125 patients with MMM. Pretreatment serum IL-6 levels were determined using a highly sensitive enzyme-linked immunosorbent assay (ELISA) test. Kaplan-Meier survival curves were constructed and compared using the log-rank test. Cox proportional analysis was performed to assess the predictors of overall survival, which was calculated from the beginning of biochemotherapy until death. In order to establish the possible relationship between IL-6 level and overall survival, patients were divided into two groups according to a cut-off of 5 pg/ml, corresponding to the first quartile obtained by descriptive statistics of the pretreatment IL-6 level in all patients. Thirty-five patients were in the low IL-6 group and 76 patients were in the high IL-6 group. Based on this stratification, overall survival was shown to be affected by IL-6 serum level: it was higher (24.6 months) in the low IL-6 group when compared with the high IL-6 group (9.7 months) (P=0.0006). Furthermore, Cox multivariate analysis including standard melanoma prognostic factors showed that IL-6, as a variable, lactate dehydrogenase (LDH) and tumour burden were significant prognostic factors for overall survival. On the basis of this evidence, the pretreatment serum IL-6 level is a predictive factor of overall survival in MMM.

Adolescent↗
PubMed2005

Tirapazamine with cisplatin and vinorelbine in patients with advanced non-small-cell lung cancer: a phase I/II study.

This phase I/II study was conducted to evaluate the safety and efficacy of tirapazamine in combination with cisplatin and vinorelbine for patients with advanced-stage IIIB/IV chemonaive non-small-cell lung cancer. Seventy patients with a Karnofsky performance status of > or = 60% were included. In the phase I part of the study, 21 patients were treated on day 1 with tirapazamine (escalating doses of 260, 330, or 390 mg/m(2)), cisplatin (75 or 100 mg/m(2)), and vinorelbine (25 or 30 mg/m(2)) for a maximum of 6 cycles every 4 weeks. Vinorelbine was repeated every week. In the phase II part of the study, 49 patients were treated on day 1 with tirapazamine 390 mg/m(2), cisplatin 100 mg/m(2), and vinorelbine 30 mg/m(2). The maximum tolerated dose was not reached. Muscle cramps, vomiting, nausea, tinnitus, neutropenia, and diarrhea were the most frequently reported adverse events in the phase I part of the study. Most of these events were grade 1 or 2. In the phase II part of the study, response rate was 47%, and median survival was 50 weeks. The most frequently reported adverse event was neutropenia. Asthenia, fever, anemia, vomiting, weight decrease, nausea, and muscle cramps were also noted. For patients treated at the maximum dose, dose reductions occurred 14% of tirapazamine cycles and in 4% of cisplatin cycles. The median number of cycles was 3. This regimen has a manageable toxicity profile. Response rate and median survival suggest that this combination might be more active than the cisplatin/vinorelbine combination. This triplet is currently being evaluated in a phase III study.

Adult↗
PubMed2005

Sequential administration of docetaxel followed by cisplatin-vindesine: a pilot study in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).

In this phase II study, the feasibility and efficacy of sequential chemotherapy were tested with agents shown to be active as monotherapy. Patients with chemotherapy-naive, locally advanced or metastatic non-small cell lung cancer were selected for the study. Treatment involved four cycles of docetaxel (100 mg/m(2) on day 1, every 3 weeks) (sequence A), followed by four cycles of cisplatin-vindesine (cisplatin 120 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1, 8, 15, and 22, every 4 weeks) (sequence B). Responding patients received 3 cycles of docetaxel 100 mg/m(2) (day 1, every 3 weeks) as consolidation (sequence C). Thirty-two patients entered the study with thirty being evaluable for efficacy. Four patients showed a partial response and one patient a complete response, resulting in an objective response rate of 16.7 %. The median survival time (intent-to-treat) was 11 months (95 %CI = 8.0-15.4 months) with an estimated 1-year survival rate of 47%. The median time to progression was 17.6 weeks in the evaluable population. Main grade 4 toxicity was neutropenia (21.8 % and 68.2 % of patients in sequence A and B, respectively) while grade 3 peripheral neuropathy was documented in five patients during sequence B. There were no treatment-related deaths. Sequential chemotherapy may show promise for the treatment of advanced non-small cell lung cancer. Given the feasibility of this pilot study, sequential chemotherapy concept should be investigated with newer cisplatin-based regimens using this approach in larger prospective studies.

Adult↗
PubMed2005

Proteasome inhibition: a new approach for the treatment of malignancies.

Since last years, the proteasome has emerged as a real and exciting target for anticancer therapy. Velcade (bortezomib, formerly known as PS341) remains the first selective proteasome inhibitor that has demonstrated significant preclinical activity in several tumor models and a significant efficacy in patients with refractory or relapsed multiple myeloma, resulting in an accelerated approval in US and Europe in such a setting. The major biological effect of bortezomib is the inhibition of the nuclear transcription factor NFkappaB, with subsequent inhibition of the growth tumor cells, induction of apoptosis, inhibition of angiogenesis and of cellular adhesion. The better understanding of the role of proteasome in the regulation of tumor cell growth has led to the development of new therapeutic approaches, notably in patients with multiple myeloma but also seems to hold interesting promises in other hematologic malignancies and solid tumors. This review provides a summary of the rationale for using proteasome inhibitors and an update on available and ongoing clinical studies involving human malignancies.

Animals↗
PubMed2004

Pharmacokinetic linearity of i.v. vinorelbine from an intra-patient dose escalation study design.

As pharmacokinetics represents a bridge between pharmacological concentrations and clinical regimens, the pharmacokinetic exploration of the therapeutic dose range is a major outcome. This study was aimed at assessing pharmacokinetic linearity of i.v. vinorelbine through an open design with intra-patient dose escalation (3 doses/group). Three groups of six patients received either 20-25-30 mg/m2; or 25-30-35 mg/m2; or 30-35-40 mg/m2. The inclusion criteria were: histologically confirmed tumour with at least one assessable target lesion, age 25-75 years, WHO PS < or =2, normal haematology and biochemistry, life expectancy > or =3 months. The pharmacokinetics was evaluated in both whole blood and plasma over 120 h. Twenty-six patients were recruited and 18 were evaluable for pharmacokinetics. The toxicity consisted in grade < or =3 leucopenia and neutropenia (<20% of courses) and two grade 4 constipation with rapid recovery (2/54 courses). Compared to blood, plasma was demonstrated to underestimate the pharmacokinetic parameters. In blood, the drug total clearance was about 0.6 l/h/kg, with minor contribution of renal clearance, steady state volume of distribution close to 13 l/h/kg, and elimination half-life at about 40 h. A pharmacokinetic linearity was demonstrated up to 40 mg/m2, and even up to 45 mg/m2 when pooling data from another study. A pharmacokinetic-pharmacodynamic relationship was evidenced on leucopenia and neutropenia when pooling the data from the two studies.

Adult↗
PubMed2004

Incidence of renal insufficiency in cancer patients and evaluation of information available on the use of anticancer drugs in renally impaired patients.

BACKGROUND: Chronic renal failure is a common pathology. The high frequency of this disease in the general US population has been assessed in the NHANES III study. However, the frequency of chronic renal insufficiency among cancer patients remains unclear. MATERIAL/METHODS: 316 cancer patients were in a one-month study, included regardless of their pathology, treatment (antineoplastic drugs used or programmed to be used, pretreated, or no treatment), or any other criteria. RESULTS: Among the patients, 287 (90.8%) had normal serum creatinine levels (<110 micromol/l), i.e. a frequency of 9.2% for renal insufficiency in our population. However, when renal function was estimated by calculating creatinine clearance using the Cockcroft and Gault formula, 33% of the patients had an estimated GFR of less than 80 ml/min. Among these, 28% had a creatinine clearance ranging form 80 to 50 ml/min and 5% had a creatinine clearance of less than 50 ml/min. Renal insufficiency is frequent in cancer patients since almost one third of the patients present renal insufficiency. Furthermore, among patients with normal serum creatinine levels, one patient out of five has asymptomatic renal insufficiency. CONCLUSIONS: Therefore, it is of major importance that renal function be assessed by calculation of creatinine clearance using the Cockcroft and Gault formula in every patient, even when serum creatinine is within the normal range.

Aged↗
PubMed2004

Pharmacokinetic advantage of intra-arterial hepatic oxaliplatin administration: comparative results with cisplatin using a rabbit VX2 tumor model.

The aim of this study was to compare intra-arterial hepatic administration (IAH) versus i.v. administration of oxaliplatin and cisplatin in a VX2 tumor model in rabbits. VX2 tumors were implanted in the livers of White New Zealand female rabbits and 2 weeks later they received either cisplatin (4 mg/kg) or oxaliplatin (6 mg/kg) administered by IAH or i.v. Platinum pharmacokinetic parameters were measured by atomic absorption spectrometry at baseline, 2, 5 10, 20, 40 and 60 min, and then at 2, 4, 6 and 24 h after drug administration. Animals were sacrificed 24 h after drug administration to measure platinum concentrations in various tissues. After IAH oxaliplatin administration, we observed a significant decrease for total and filterable platinum in the Cmax compared with i.v. administration (12.4 versus 18.2 microg/l; p=0.02 and 11.2 versus 17.3 microg/l; p=0.02, respectively). Significant differences in various tissue concentrations were reported when comparing IAH and i.v. administration of oxaliplatin with IAH administration offering an advantage over i.v. administration. No differences in pharmacokinetic parameters or platinum tissue accumulation were apparent between the IAH and i.v. administration with cisplatin. We conclude that there is a significant pharmacokinetic advantage to using oxaliplatin for locoregional IAH chemotherapy compared with i.v. administration.

Animals↗
PubMed2004

Lung cancer in patients with HIV Infection and review of the literature.

BACKGROUND: The improved survival of patients since the use of highly active antiretroviral treatments has lead to the reporting of non-AIDS defining tumors, such as lung cancer. METHODS: Analysis of the records of 22 HIV-infected patients with lung cancer (LC) diagnosed in three hospitals located in the Paris area (France). RESULTS: Twenty-one patients were smokers. The patients (86% male, 14% female) had a median age of 45 yr (range, 33-64 yr). Risk factors for HIV infection were intravenous drug use in 5 patients, homosexual transmission in 10 patients, and heterosexual transmission in 7 patients. At diagnosis of LC, seven patients had previously developed a CDC-defined AIDS manifestation, the median CD4 cell count was 364/mm3 (range 20-854/mm3) and median HIV1 RNA viral load was 3000 copies/mL. The most frequent histological subtype was squamous cell carcinoma (11 cases). A stage III-IV disease was observed in 75% of the patients. Only one patient had a small-cell lung carcinoma. Twenty-one patients received combined specific therapy, of which six patients underwent surgery for the LC. The median overall survival was 7 mo. No opportunistic infections occurred during LC therapy. CONCLUSIONS: LC occurs at a young age in HIV-infected smokers. LC is not associated with severe immunodeficiency. The prognosis is poor because of their initial extensive disease and a poor response to therapy. However, surgery appears to improve outcome in much the same way as in the general population.

Adult↗
PubMed2003

Subcutaneous interleukin-2 and interferon alfa administration in patients with metastatic renal cell carcinoma: final results of SCAPP III, a large, multicenter, phase II, nonrandomized study with sequential analysis design--the Subcutaneous Administration Propeukin Program Cooperative Group.

PURPOSE: This outpatient multicenter trial tested the hypothesis that subcutaneous administration of an interleukin-2 (IL-2)/interferon alfa (IFN alpha) combination produces a response rate greater than 20% in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with metastatic RCC received a 12-week induction treatment with subcutaneous IL-2 (5 days/wk, 9 and 18 million U/d)/IFN alpha (3 days/wk, 6 million U/d). After evaluation, patients with objective response or stable disease were randomly assigned to maintenance treatment or short consolidation treatment. RESULTS: Lack of benefit was shown at the 12th sequential analysis, and the trial was closed. At the end of the induction period, 26 (21%) of 122 patients had objective responses (including six complete responses). Thirty-three patients (27%) developed severe toxicity requiring dose reductions, delayed treatment, or treatment termination. Survival rates at one, two, and four years were 63%, 38%, and 17%, respectively. Three-year survival was 20% in patients with two poor prognosis factors and 37% in patients with one or no poor prognosis factors (P =.016). Three-year survival was significantly better (P < 10-3) in patients with erythrocyte sedimentation rate less than 35 mm (43%) compared with those with 1-hour sedimentation rate greater than 35 mm (19%). CONCLUSION: This study confirms the importance of prognostic factors when initiating cytokine immunotherapy in patients with metastatic RCC and underlines the prognostic value of erythrocyte sedimentation rate before treatment initiation. Nonetheless, this subcutaneous IL-2/IFN alpha combination does not improve response rate or survival compared with subcutaneous IL-2 alone, although a definitive conclusion cannot be drawn in the absence of a randomized study comparing the two treatments.

Adult↗