[Show abstract][Hide abstract] ABSTRACT: The Glass model developed in 2003 uses prognostic factors for noncastrate metastatic prostate cancer (NCMPC) to define subgroups with good, intermediate, and poor prognosis.
[Show abstract][Hide abstract] ABSTRACT: Toxicity, which is a key parameter in the evaluation of cancer treatments, can be underestimated by clinicians. We investigated differences between patients and physicians in reporting adverse events of androgen deprivation therapy (ADT) with or without docetaxel in a multicentre phase III trial in non-castrate metastatic prostate cancer.
The 385 patients included were invited to complete a 26-symptom questionnaire 3 and 6months after the start of treatment, among which eighteen symptoms were also assessed by physicians, reported in medical records and graded using the Common Toxicity Criteria of the National Cancer Institute. Positive and negative agreements as well as Kappa concordance coefficients were computed.
Data were available for 220 and 165 patients at 3 and 6months respectively. Physicians systematically under-reported patients' symptoms. Positive agreement rates (at respectively 3 and 6months) for the five most commonly reported symptoms were: 61.0% and 64.3% hot flushes, 50.0% and 43.6% fatigue, 29.4% and 31.1% sexual dysfunction, 24.4% and 14.4% weigh gain/loss, 16.7% and 19.3% for joint/muscle pain. For symptoms most frequently reported as disturbing or very disturbing by patients, the clinicians' failure to report them ranged from 50.8% (hot flushes) to 89.5% (joint/muscle pain) at 3months, and from 48.2% (hot flushes) to 88.4% (joint/muscle pain) at 6months.
Physicians often failed to report treatment-related symptoms, even the most common and disturbing ones. Patients' self-evaluation of toxicity should be used in clinical trials to improve the process of drug assessment in oncology.
French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, Astra-Zeneca, and Amgen.
European journal of cancer (Oxford, England: 1990) 01/2014; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the overall benefits of non-taxane chemotherapies in a non-selected population including unfit patients presenting with symptoms and pain.
This randomised phase 2 study reports data from 92 patients (52% > 70 yrs-old; 40% PS II) previously treated with taxane-based chemotherapy and collected at 15 centres in France. Patients received intravenous mitoxantrone (MTX), oral vinorelbine (VN), or oral etoposide (EP) associated with oral prednisone. Palliative benefit (pain response without progression of the disease), biological and tumoral responses, and toxicity profile as well as geriatric assessment (in elderly population) were analysed on an intention-to-treat basis.
The palliative response rate was 17% for the whole population, and reached 29% when considering the MTX arm. The control of pain was achieved in 40% of the patients. The median overall survival was 10.4 months, and was longer in palliative responders. Few grade 3-4 toxicities were observed. The subgroup analysis of elderly patients showed similar results regarding the number and dose-intensity of treatments, efficacy and safety.
In a population including frailty and/or elderly patients, who are poorly represented in most of the clinical studies, non-taxane chemotherapy may remain a relevant option for metastatic prostate cancer having relapsed after a docetaxel-based regimen.While new treatment options are now approved, decision-making process should take into account the expected benefit/risk ratio based on the patient status.
[Show abstract][Hide abstract] ABSTRACT: Background:There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients.Methods:We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates.Results:In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013).Conclusion:Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.
British Journal of Cancer 03/2013; 108(4):887-900. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Early chemotherapy might improve the overall outcomes of patients with metastatic non-castrate (ie, hormone-sensitive) prostate cancer. We investigated the effects of the addition of docetaxel to androgen-deprivation therapy (ADT) for patients with metastatic non-castrate prostate cancer. METHODS: In this randomised, open-label, phase 3 study, we enrolled patients in 29 centres in France and one in Belgium. Eligible patients were older than 18 years and had histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease; a Karnofsky score of at least 70%; a life expectancy of at least 3 months; and adequate hepatic, haematological, and renal function. They were randomly assigned to receive to ADT (orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens) alone or in combination with docetaxel (75 mg/m(2) intravenously on the first day of each 21-day cycle; up to nine cycles). Patients were randomised in a 1:1 ratio, with dynamic minimisation to minimise imbalances in previous systemic treatment with ADT, chemotherapy for local disease or isolated rising concentration of serum prostate-specific antigen, and Glass risk groups. Patients, physicians, and data analysts were not masked to treatment allocation. The primary endpoint was overall survival. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00104715. FINDINGS: Between Oct 18, 2004, and Dec 31, 2008, 192 patients were randomly allocated to receive ADT plus docetaxel and 193 to receive ADT alone. Median follow-up was 50 months (IQR 39-63). Median overall survival was 58·9 months (95% CI 50·8-69·1) in the group given ADT plus docetaxel and 54·2 months (42·2-not reached) in that given ADT alone (hazard ratio 1·01, 95% CI 0·75-1·36). 72 serious adverse events were reported in the group given ADT plus docetaxel, of which the most frequent were neutropenia (40 [21%]), febrile neutropenia (six [3%]), abnormal liver function tests (three [2%]), and neutropenia with infection (two [1%]). Four treatment-related deaths occurred in the ADT plus docetaxel group (two of which were neutropenia-related), after which the data monitoring committee recommended treatment with granulocyte colony-stimulating factor. After this recommendation, no further treatment-related deaths occurred. No serious adverse events were reported in the ADT alone group. INTERPRETATION: Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer. FUNDING: French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen.
The Lancet Oncology 01/2013; · 25.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Le pronostic du cancer du testicule est excellent, avec un taux de survie à cinq ans supérieur à 95 %. Les patients atteints peuvent donc espérer une guérison après traitement. La réussite thérapeutique nécessite une évaluation de la maladie aux différents stades de sa prise en charge. L’imagerie joue un rôle majeur dans l’analyse initiale de l’extension lymphatique et dans la recherche de métastases. Elle est primordiale dans l’évaluation de la réponse thérapeutique et dans le suivi après traitement. La modalité d’imagerie la plus utilisée dans ce contexte est le scanner. Cependant, le rôle de la TEP évolue actuellement. Le but de cet article est de revoir la place des modalités d’imagerie couramment utilisées dans la prise en charge du cancer du testicule.
Journal de Radiologie Diagnostique et Interventionnelle. 04/2012; 93(4):334–343.
[Show abstract][Hide abstract] ABSTRACT: The prognosis for testicular cancer is excellent, with a 5-year survival rate greater than 95%. Patients affected can therefore expect to be cured after treatment. Successful treatment requires assessment of the condition at the various stages of its management. Imaging plays a major role in initial analysis of the lymphatic extension and in looking for metastases. It is essential for evaluating the response to treatment and during follow-up after treatment. CT is the most commonly used imaging method in this context, but the role of PET is currently developing. The purpose of this paper is to review the role of the imaging methods commonly used in the management of testicular cancer.
Diagnostic and interventional imaging. 03/2012; 93(4):310-8.
[Show abstract][Hide abstract] ABSTRACT: Six targeted agents [sorafenib, sunitinib, temsirolimus, bevacizumab (plus interferon), everolimus and pazopanib] have been approved for the treatment of patients with metastatic renal cell carcinoma. As disease progression is inevitable, most patients will receive several lines of treatment. However, the choice regarding which sequence of drugs to use remains unclear, particularly concerning the drug class, i.e. those targeting the vascular endothelial growth factor (receptor) [VEGF(R)] pathway versus those acting on the mammalian target of rapamycin pathway. There appears to be no absolute crossresistance between tyrosine kinase inhibitors (TKIs) acting on the VEGF(R) pathway, and there have been numerous reports of two TKIs being successfully used in sequence. We report the case of a 63-year-old woman who responded for 24 months to three successive lines of treatment with different TKIs (sunitinib, axitinib and sorafenib). This suggests that TKIs targeting VEGFR should be considered as individual drugs and not as a single class.
Anticancer research 02/2012; 32(2):697-700. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess docetaxel-estramustine in patients with localised high-risk prostate cancer.
After staging pelvic lymph node dissection, patients with high-risk prostate cancer randomly received androgen deprivation therapy (ADT) (3 years)+DE (4 cycles of docetaxel 70 mg/m(2)/3 weeks+estramustine 10mg/kg/dd1-5) or ADT alone. Local therapy was administered at 3 months.
Four hundred and thirteen patients were accrued: T3-T4 (67%), Gleason score ~8 (42%), PSA >20 ng/mL (59%), pN+ (29%). In the chemotherapy arm, 94% of patients received the planned four cycles of docetaxel. Local treatment consisted of radiotherapy in 358 patients (87%) (median dose 74 Gy in both arms). ADT was given for 36 months in both arms. A PSA response (PSA ~0.2 ng/mL after 3 months of treatment) was obtained in 34% and 15% in the ADT+DE arm and in the ADT arm, respectively (p<0.0001). Febrile neutropenia occurred in only 2%. Moderate to severe hot flashes occurred less often in the ADT+DE arm (2% versus 22%; p<0.001). There was no toxicity-related death, no secondary leukaemia, and no excess second cancers. Chemotherapy had a negative impact on quality of life (global health status, p = 0.01; fatigue, p = 0.003; role functioning, p = 0.003; social functioning, p = 0.006) at 3 months but this effect disappeared at 1 year.
Docetaxel-estramustine can be combined safely with standard therapy in high-risk prostate cancer, with a promising PSA response rate and no negative impact on quality of life after 1 year. Long-term follow-up is required to assess the impact on relapse and survival.
European journal of cancer (Oxford, England: 1990) 11/2011; 48(2):209-17. · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With six targeted agents approved (sorafenib, sunitinib, temsirolimus, bevacizumab [+interferon], everolimus and pazopanib), many patients with metastatic renal cell carcinoma (mRCC) will receive multiple therapies. However, the optimum sequencing approach has not been defined. A group of European experts reviewed available data and shared their clinical experience to compile an expert agreement on the sequential use of targeted agents in mRCC. To date, there are few prospective studies of sequential therapy. The mammalian target of rapamycin (mTOR) inhibitor everolimus was approved for use in patients who failed treatment with inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) based on the results from a Phase III placebo-controlled study; however, until then, the only licensed agents across the spectrum of mRCC were VEGF(R) inhibitors (sorafenib, sunitinib and bevacizumab + interferon), and as such, a large body of evidence has accumulated regarding their use in sequence. Data show that sequential use of VEGF(R) inhibitors may be an effective treatment strategy to achieve prolonged clinical benefit. The optimal place of each targeted agent in the treatment sequence is still unclear, and data from large prospective studies are needed. The Phase III AXIS study of second-line sorafenib vs. axitinib (including post-VEGF(R) inhibitors) has completed, but the data are not yet published; other ongoing studies include the Phase III SWITCH study of sorafenib-sunitinib vs. sunitinib-sorafenib (NCT00732914); the Phase III 404 study of temsirolimus vs. sorafenib post-sunitinib (NCT00474786) and the Phase II RECORD 3 study of sunitinib-everolimus vs. everolimus-sunitinib (NCT00903175). Until additional data are available, consideration of patient response and tolerability to treatment may facilitate current decision-making regarding when to switch and which treatment to switch to in real-life clinical practice.
Medical Oncology 07/2011; 29(3):1896-907. · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The clinical use of the anticancer drug doxorubicin (DOX) is limited by strong side effects and phenomena of cell resistance.
Drug targeting by binding DOX to nanoparticles could overcome these limitations. We recently described a method to associate
DOX to superparamagnetic iron oxide nanoparticles (SPION) in view of magnetic drug targeting (Munnier et al. in Int J Pharm
363:170–176, 2008). DOX is bound to the nanoparticle surface through a pre-formed DOX–Fe2+ complex. The DOX-loaded SPION present interesting properties in terms of drug loading and biological activity in vitro. The
purpose of this study is to explore the possible mechanisms of the in vitro cytotoxicity of DOX-loaded SPION. The uptake of
SPION was followed qualitatively by conventional optical microscopy after Prussian blue staining and quantitatively by iron
determination by atomic absorption spectroscopy. The subcellular distribution of intrinsically fluorescent DOX was followed
by confocal spectral imaging (CSI) and the subsequent cytotoxicity by the MTT method. We reveal modifications of DOX intracellular
interactions for SPION-delivered drug and increased cytotoxicity. These results are discussed in terms of internalization
route of the drug and of a potential role of iron oxide nanoparticles in the observed cytotoxicity.
Journal of Nanoparticle Research 01/2011; 13(3):959-971. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MUC1 over-expression in renal clear-cell carcinoma (RCC) is associated with poor prognosis. This phase II study determined the efficacy and tolerability of TG4010, a cancer vaccine based on a modified vaccinia virus expressing MUC1 and interleukin-2, in combination with cytokines, as first-line therapy in metastatic RCC. Thirty-seven patients with progressive, MUC1-positive RCC received TG4010 10(8) pfu/inj weekly for 6 weeks, then every 3 weeks until progression, when TG4010 was continued in combination with interferon-α2a and interleukin-2. Assessments included clinical response (primary endpoint), safety, time to treatment failure (TTF), overall survival (OS), and immune response. No objective clinical responses occurred. Five of the 27 evaluable patients (18%) had stable disease for >6 months with TG4010 alone and six of 20 patients (30%) had stable disease for >6 months with TG4010 plus cytokines. Median TTF was 4.1, 3.6, and 9.3 months for monotherapy, combination therapy, and overall, respectively. Median OS was 19.3 months for all patients and 22.4 months combination therapy recipients. The most frequent TG4010-related adverse events were minor-to-moderate injection-site reactions, fatigue, and flu-like symptoms. Six of 28 patients showed a MUC1 CD4+ T cell proliferative response during therapy. Anti-MUC1 CD8+ T cells were detected before and after therapy in 3 and 4 patients, respectively. MUC1-specific CD8+ T cell responses were associated with longer survival. Therapy with TG4010 plus cytokines appears to be feasible and well tolerated in patients with metastatic RCC. However, these data should be interpreted with caution, as additional prospective studies are necessary to clarify the clinical efficacy of this therapy.
Cancer Immunology and Immunotherapy 11/2010; 60(2):261-71. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vascular endothelial cell growth factor is studied in different malignant tumors as a key endothelial cell mitogen. Many single nucleotide polymorphisms in the VEGF gene have been described. We compared VEGF gene polymorphisms between a control group and a renal cancer group.
This study was performed in 202 control, white, healthy blood donors (control group) and in 51 consecutive patients with renal cell carcinoma. We studied VEGF genotype polymorphisms at positions -2549, -460, -1154, +405 and +936 using polymerase chain restriction fragment length polymorphism, and looked for correlations with clinical data.
No association was found between VEGF gene polymorphism and renal cell carcinoma prognostic parameters. However, in contrast as observed for controls and other polymorphisms the patient group displayed a heterozygote excess (p = 0.0179, 35.9% more than that expected) at the -460 polymorphism. Comparing the control group and the renal cell carcinoma group we detected a significantly increased risk of renal cell carcinoma in subjects with the C-460T polymorphism. T carrier genotypes and the T allele increased the risk of renal cell carcinoma with an OR of 14.15 (95% CI 1.900-105.41, p = 0.0017) and 2.14 (95% CI 1.34-3.419, p = 0.0018), respectively. The genotype at the -2549 polymorphism exhibited a nonsignificant trend for increased risk but the D allele was significantly associated with increased risk (p = 0.0305).
Our results suggest that the -460 polymorphism is a risk factor for renal cancer. An individual screening test could be proposed for high risk populations.
The Journal of urology 10/2010; 184(4):1273-8. · 3.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A new method of reversible association of doxorubicin (DOX) to superparamagnetic iron oxide nanoparticles (SPION) is developed for magnetically targeted chemotherapy. The efficacy of this approach is evaluated in terms of drug loading, delivery kinetics and cytotoxicity in vitro. Aqueous suspensions of SPION (ferrofluids) were prepared by coprecipitation of ferric and ferrous chlorides in alkaline medium followed by surface oxidation by ferric nitrate and surface treatment with citrate ions. The ferrofluids were loaded with DOX using a pre-formed DOX-Fe(2+) complex. The resulting drug loading was as high as 14% (w/w). This value exceeds the maximal loading known from literature up today. The release of DOX from the nanoparticles is strongly pH-dependent: at pH 7.4 the amount of drug released attains a plateau of approximately 85% after 1h, whereas at pH 4.0 the release is almost immediate. At both pH, the released drug is iron-free. The in vitro cytotoxicity of the DOX-loaded SPION on the MCF-7 breast cancer cell line is similar to that of DOX in solution or even higher, at low-drug concentrations. The present study demonstrates the potential of the novel method of pH-sensitive DOX-SPION association to design novel magnetic nanovectors for chemotherapy.
International Journal of Pharmaceutics 08/2008; 363(1-2):170-6. · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This work describes a method for preparation of sub-micron poly(d,l-lactide-co-glycolide) (PLGA) particles loaded with magnetite/maghemite nanoparticles to be used as magnetically-controlled drug delivery systems. The methodology of simple emulsion/evaporation technique has been optimized to provide greater iron oxide loading rates. The surface of iron oxide nanoparticles was coated with oleic acid (OA) for better compatibility with organic phase containing the polymer. To increase their loading into polymeric sub-micron particles, we added dried iron oxide nanoparticles in variable ferrite/polymer ratio of 1:1; 1:1.5 and 1:2 w/w. Composition and surface properties of obtained composite sub-micron particles have been studied in comparison with those of ferrite-free PLGA sub-micron particles. Presence of magnetite/maghemite was qualitatively confirmed by characteristic bands in the FT-IR spectra of composite sub-micron particles. Quantification of the incorporated iron was achieved by AAS. The highest incorporation rates of ferrite (up to 13.5% w/w) were observed with initial ferrite/polymer ratio of 1:1 w/w. TEM images indicate that the composite sub-micron particles are nearly spherical. According to laser granulometry data, average hydrodynamic diameter of the composite sub-micron particles is close to 280nm, independently of ferrite presence. Electrophoretic properties (zeta potential) were very similar for both composite and ferrite-free PLGA sub-micron particles, thus indicating that the polymeric coating should mask the surface of ferrite nanoparticles buried inside. Finally, composite sub-micron particles exhibit superparamagnetic property.
European Journal of Pharmaceutics and Biopharmaceutics 09/2007; 67(1):31-8. · 4.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increase of lipophilicity of cationic doxorubicin (DOX) by its association with a fatty acid ion is of interest for pharmaceutical formulations and could have an impact on the drug delivery into cancer cells. On the basis of spectroscopic analysis of intrinsic DOX fluorescence, this study provides an experimental evidence of DOX-oleate interactions as function of ion/drug molar ratio (R) and pH. An electrostatic attraction to oleates is dominant for the cationic form of DOX (pH 6.5) and a hydrophobic interaction is characteristic of the molecular form of DOX (pH 8.6). A high content of sodium oleate vesicles ([oleate]>/=0.2 mM, R>/=20) limits the electrostatic and hydrophobic interactions at pH 6.5 while favoring the hydrophobic interactions at pH 8.6. The influence of these interactions on the lipophilicity of the cationic form of DOX is analyzed by measuring the apparent partition coefficient (aqueous buffer pH 6.5/methylene chloride). The results show a lipophilicity gain for the cationic form of DOX in presence of 10 : 1 ion/drug molar ratio, while no lipophilicity increase is observed at 50 : 1 molar ratio.
CHEMICAL & PHARMACEUTICAL BULLETIN 07/2007; 55(7):1006-10. · 1.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During the last decade, the application of nanotechnologies for anticancer drug delivery has been extensively explored, hoping to improve the efficacy and to reduce side effects of chemotherapy. The present review is dedicated to a certain kind of anticancer drug nanovectors developed to target tumors with the help of an external magnetic field. More particularly, this work treats anticancer drug nanoformulations based on superparamagnetic iron oxide nanoparticles coated with biocompatible polymers. The major purpose is to focus on the specific requirements and technological difficulties related to controlled delivery of antitumoral agents. We attempt to state the problem and its possible perspectives by considering the three major constituents of the magnetic therapeutic vectors: iron oxide nanoparticles, polymeric coating and anticancer drug.
International Journal of Nanomedicine 02/2007; 2(4):541-50. · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxel-estramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP).
One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m2 on day 2 or 35 mg/m2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg p.o. tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m2 every 3 weeks; all patients received prednisone (10 mg daily).
One hundred twenty-seven patients were assessable for PSA response and safety. A > or = 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P = .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P = .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P = .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P = .00001). Treatment-related toxicities were mild and mainly hematologic.
The results of this randomized phase II study showed significantly higher PSA decline < or = 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting.
Journal of Clinical Oncology 06/2005; 23(15):3343-51. · 17.88 Impact Factor