[Show abstract][Hide abstract] ABSTRACT: Preliminary results indicated that bortezomib (B) (Velcade*) as a single agent may have activity in pretreated NSCLC patients with similar or lesser toxicity compared to chemotherapy. This phase II study was initiated to determine the efficacy of single-agent B in chemonaïve patients with advanced NSCLC. An early tumor assessment (after 6 weeks of therapy) was performed to allow for rapid and appropriate management of non-responding patients.
Patients received B (1.5 mg/m2) twice a week for 2 consecutive weeks (days 1, 4, 8, and 11) followed by a 10-day rest period. The primary endpoint was non-progression rate (NPR) after 6 weeks of treatment. Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses included FDG-PET response at 6 weeks and circulating tumors cell (CTC) assessment at day 1 of each cycle in a subset of patients.
18 patients were enrolled from 06/06 to 02/07 from 3 French institutions. Demographics: male/female 15/3; median age 66 (54-79); PS 0/1/2, 3/12/3; pathology: adenocarcinoma 11, squamous cell carcinoma 5, large-cell carcinoma 2; smoking status never/former/current 1/10/7; stage IIIB/IV 2/16. Seventeen patients received B and 16 were assessable (1 early withdrawal and 1 progression at D26). The most frequent toxicity was fatigue (17 patients). Twelve patients (71%) had at least one grade 3 toxicity: 4 haematological, 1 infection, 5 gastro-intestinal toxicity, 9 fatigue, 1 neuropathy. The non-progression rate was 59% [33-82%] at 6 weeks (10/17 patients). No objective response was seen. With a median follow-up of 12.3 months, the median PFS and OS were 2.4 and 9.8 months respectively. Eleven deaths occurred. No PET response was observed, and CTC were detected only in 1 out of 8 patients evaluated.
Although according to the protocol rules the trial should not be stopped, the lack of any objective response either by CT-scan or PET-CT, along with substantial toxicity, did not argue in favor of the current strategy of B as a single agent in the front-line setting of NSCLC.
No preview · Article · Dec 2011 · Lung cancer (Amsterdam, Netherlands)
[Show abstract][Hide abstract] ABSTRACT: Physicians who are responsible for the delivery of systemic treatment in lung cancer should be aware of the potential risk of drug-induced pulmonary toxicity (DIPT), because such toxicity may develop in the context of a multifactorial clinical condition. First, most patients with lung cancer may suffer from other non-neoplastic, smoking-related lung diseases, such as emphysema and chronic obstructive lung disease, which may generate pathologic changes in lung parenchyma. In addition, lung cancer itself may worsen the respiratory function, inducing atelectasis and lymphangitic carcinomatosis. The superimposed iatrogenic damage may lead to respiratory failure and, sometimes, death. The risk of DIPT from chemotherapeutic agents has been widely examined in the past; and, currently, the potential for lung toxicity has been extended by the introduction of molecular targeted therapies. Because there are no univocal criteria with which to recognize DIPT, the diagnosis often is made by exclusion; consequently, it is hard to establish an early diagnosis. The objective of this review was to describe the major DIPTs associated with antineoplastic agents against nonsmall cell lung cancer to help physicians with this difficult diagnostic challenge.
[Show abstract][Hide abstract] ABSTRACT: Experimental and clinical findings suggest that low molecular-weight heparins may improve overall survival in patients with cancer. The evidence is still limited and additional studies are needed to confirm these preliminary findings.
Patients with completely resected stage I, II or IIIA (T3N1) histologically confirmed non-small-cell lung cancer will be included in a prospective, controlled, randomized, multicenter open trial. Patients in the control group will receive usual postoperative care including chemotherapy when indicated. Patients in the experimental group will receive tinzaparin given subcutaneously as a daily 100 IU/kg dose for 90 days along with usual postoperative care. Patients will be followed-up for three to eight years. Main end-point is the overall survival. Five hundred and fifty patients are needed to demonstrate a 10% absolute increase in survival in the experimental group.
A 10% absolute increase in the survival rate is expected in the patients receiving tinzaparin.
No preview · Article · May 2011 · Revue des Maladies Respiratoires
[Show abstract][Hide abstract] ABSTRACT: To determine, by using contrast material-enhanced ultrasonography (US), how quickly renal tumors grafted in mice begin to revascularize after stopping bevacizumab treatment.
All experiments were approved by the regional ethics committee. A human tumor cell line SK-NEP-1 was grafted at day 0 in the left kidney of 50 nude mice. Forty-two mice developed tumors and longitudinal follow-up was performed on 32 surviving mice. From day 13, 14 controls received biweekly saline; 11 mice received biweekly bevacizumab until day 35 (continuous); and seven received biweekly bevacizumab until day 22, then biweekly placebo until day 35 (discontinued). Contrast-enhanced US was performed on days 13, 14, 22, 27, and 35. Once the injected contrast material distribution reached an equilibrium phase, high-acoustic pressure pulses were applied to destroy microbubbles in the capillary bed in the imaged plane. Reperfusion was monitored, and time-signal intensity (SI) curves were obtained from the linear average of SIs in intratumoral and matched-depth renal cortex regions of interest. A kinetic parameter calculated from reperfusion curves reflects local perfusion, normalized with respect to adjacent renal cortex perfusion. Normalized perfusion obtained from each group was compared with that from the other groups and with necrosis percentages and microvascular density assessed histologically at day 35. Comparisons were made by using analyses of variance and Tukey-Kramer tests.
The lowest excised mean tumor weights (+/- standard deviation) corresponded to the longest bevacizumab-treatment duration: 1.4 g +/- 1.1 (continuous-treatment) compared with 2.3 g +/- 2.1 (discontinued) and 3.7 g +/- 1.9 (control) (P = .01). On day 35, the respective control and continuously treated groups had comparable and significantly larger necrotic areas: 37% +/- 14 and 32% +/- 17 larger than the discontinued-treatment group (15% +/- 9; P < .05). Normalized perfusion increased significantly with time (P = .02) in the discontinued-treatment group after therapy ceased (day 22).
Noninvasively measured contrast-enhanced US parameters demonstrated tumor revascularization after stopping antiangiogenic therapy in this murine tumor model.
[Show abstract][Hide abstract] ABSTRACT: Chemotherapy-induced febrile neutropenia represents a frequent emergency and evidence based management of this event remains an exigency for each patient. Appropriate use of antibiotics is mandatory, growth factors have to be proposed according to validated guidelines and benefits and risks of antiobioprophylaxy must be discussed. This review propose to summarize available data on these important questions, with a special focus on this management of febrile neutropenia in daily practice. triangle
No preview · Article · Feb 2010 · Bulletin du cancer
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis or new blood vessel formation is a complex and fundamental event in the process of tumor growth and metastatic dissemination. Actually, most of antiangiogenic agents target the VEGF considered like the most potent proangiogenic factor. These molecules directly inhibit VEGF or the kinase activity of its receptor (VEGFR) and represent a significant therapeutic progress in several solid tumors types. First clinical studies of antiangiogenic agents in thoracic and laryngopharyngeal carcinomas have shown promise mainly in combination with other therapies (chemotherapy, other targeted therapies or radiotherapy). Besides common antiangiogenic therapies-induced adverse events, risks of bleeding caused by tumor necrosis mainly in squamous cell lung carcinomas have been observed during early clinical trials. Assessment of surrogate markers of target inhibition could allow a better selection of patients able to benefit from antiangiogenic treatments eventually combined with chemotherapy or molecules targeting others metabolic pathways.
No preview · Article · Feb 2009 · Bulletin du cancer
[Show abstract][Hide abstract] ABSTRACT: Sunitinib, a multitargeted tyrosine-kinase inhibitor, extends survival of patients with metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumours. Between October 2005 and March 2007, we retrospectively reviewed blood glucose level variations associated with sunitinib therapy in patients treated for mRCC. Nineteen of the patients had type II diabetes. All 19 patients had a decrease in blood glucose level (mean 1.77 mmol l(-1)) after 4 weeks of treatment. This was followed by re-elevation in the 2-week rest period. After two cycles of sunitinib administration, two patients had stopped blood glucose-lowering drugs whereas five other patients had normalised their blood glucose level. On the basis of pre-clinical data, we hypothesise that several mechanisms could be involved in this process, such as capillary regression of pancreatic islets, IGF-1 modulation through HIF1-alpha or NF-kappaB activation. In addition, a decrease of glucose uptake in the context of concomitant gastrointestinal toxicity cannot be excluded. Glycaemic control should be carefully evaluated in diabetic patients treated with sunitinib, and routine monitoring is warranted.
Preview · Article · Nov 2008 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Microvascularization modifications should precede tumor size-changes during anti-angiogenic therapy. We applied contrast functional ultrasound imaging (fUSI) to detect changes in Wilms tumors with anti-angiogenic treatment (Bevacizumab). Human Wilms tumor cells was grafted in left kidney of 32 mice. Once tumors had >5mm diameter, mice received : placebo, N=14; Bevacizumab for 21days, N=11; and Bevacizumab for 10days followed by placebo for 11days, N = 7. On days -1, +1, +9, +14 and +21 with respect to treatment start, fUSI was performed (CPS mode, SonoVue). Linear time intensity curves were obtained from regions in kidney cortex and matched-depth of tumor for first bolus passage and 50s following acoustic destruction of contrast. Excised tumor weight decreased with increased treatment duration: 3.7+-1.8 g (placebo), 2.3+-1.9 g (Bevacizumab-10days, placebo-11days), 1.4+-0.7 g (Bevacizumab-21 days) [p<0.05]. Area under the bolus-passage curve (AUC) and the plateau intensity of the destruction-reperfusion were greater from D+9 to D+21 [p<0. 04] in the placebo than Bevacizumab-21day. For the group treated during the first 10 days, fUSI values were comparable to those of the treated group until D+14, then increased to become slightly superior to those of the placebo group by D+21. Noninvasive fUSI demonstrated revascularization after suspension of anti-VEGF therapy.
No preview · Article · May 2008 · The Journal of the Acoustical Society of America
[Show abstract][Hide abstract] ABSTRACT: Résumé De nombreux agents incluant les substances cytotoxiques et non cytotoxiques peuvent entraîner une toxicité pulmonaire, qui
concerne essentiellement le parenchyme et moins fréquemment les voies aériennes, la plèvre et la circulation sanguine pulmonaire.
Les symptômes induits par la toxicitéde ces traitements sont peu spécifiques et peuvent être difficiles à distinguer de ceux
provoqués par plusieurs pathologies survenant dans ce contexte de cancer en cours de traitement. Ainsi, le diagnostic est
essentiellement réaliséaprès exclusion de toutes les autres causes possibles de pathologie pulmonaire, et repose aussi sur
la relation temporelle entre l’exposition du médicament et le début des symptômes respiratoires. Les signes cliniques et radiologiques
de ces traitements reflètent en général le processus histopathologique sousjacent et incluent la pneumopathie interstitielle
non spécifique, les dommages alvéolaires diffus, la bronchiolite oblitérante avec organisation pneumonique (BOOP), l’œdème
et l’hémorragie alvéolaire. De plus, plusieurs de ces traitements altèrent les tests fonctionnels respiratoires des patients.
La connaissance de l’ensemble de ces signes et des traitements les plus fréquemment incriminés peut faciliter le diagnostic
et l’initiation d’un traitement approprié. Pneumotox® (www.pneumotox.com) apporte une information régulièrement mise à jour
sur les pathologies respiratoires iatrogènes.
[Show abstract][Hide abstract] ABSTRACT: Developments in the knowledge of molecular biology of renal cell carcinoma (RCC) over the past 20 years have been identified. Angiogenesis is playing a key role in the physiopathology of RCC. Von Hippel-Lindau (VHL) alterations, HIFalpha accumulation and vascular endothelial growth factor (VEGF) overexpression are important mediators of this process. Several stategies have been developped to target angiogenesis for the treatment of metastatic RCC. These include inhibition of VEGF receptors (inhibition of the tyrosine kinase activity) or binding to the VEGF protein. Several additional kinases inhibitions including PDGF receptors are also targeted. Sunitinib (SU11248) is an orally biovailable small molecule that has demonstrated superiority over interferon-alpha for the treatment of metastatic RCC. In a recent randomized phase III study conducted in 750 patients, the response rate to sunitinib was 31% and to interferon 6%. The median of progression free survival (PFS) was 11 months for sunitinib and 5 months for interferon (p < 0.001). Sorafenib (BAY43-9006) was found to inhibit Raf1, but also VEGFR2 and 3, Flt3, PDGFR-a and b and c-kit, has been tested in a phase III study against placebo after one prior systemic therapy. The median of the time to progression (TTP) for sorafenib was 24 weeks versus 12 weeks for patients in the placebo arm (p = 0,01). Other molecules tested in metastatic RCC will be presented including axitinib, pazopanib and bevacizumab.
No preview · Article · Jul 2007 · Bulletin du cancer
[Show abstract][Hide abstract] ABSTRACT: The increasing use of biomarkers as molecular determinants of responsiveness to conventional chemotherapy or molecular targeted therapy has raised the question of the reliability and reproducibility of their evaluation in bronchial biopsies as compared with corresponding resected surgical specimens.
Immunohistochemical expression of five markers related to signal transduction [epidermal growth factor receptor (EGFR), phospho-Akt], cell proliferation (Ki-67), DNA repair [excision repair cross-complementing (ERCC)1] and cellular 'immortality' [human telomerase catalytic component (hTERT)], was assessed in 41 patients with operable non-small-cell lung cancer in both bronchial biopsies and whole surgical specimens.
High correlation coefficients were observed between the expression of ERCC1, hTERT and Ki-67 in the biopsies and the surgical specimens [0.83 (P < 0.0001); 0.55 (P < 0.001) and 0.64 (P < 0.0001), respectively]. On the other hand, biomarker expression in biopsy was less correlated with the expression in the whole tissue sample for the markers of signal response and transduction [0.24 (P = 0.17) and 0.29 (P = 0.09) for EGFR and phospho-Akt, respectively].
Our results indicate a lack of association in the expression of important biomarkers between lung biopsies and corresponding resected tumors, with discordance rates ranging between 9% and 41%. Although these results need to be further validated in larger cohorts, they indicate that the evaluation of the expression of biomarkers in bronchial biopsies can be misleading.
Full-text · Article · Jun 2007 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer death in France. Nearly 80% of lung tumors are non-small cell lung cancers (NSCLC). Surgery is the best curative approach, but it only concerns 30% of NSCLC, since the diagnosis is frequently made in patients with locally advanced or metastatic disease. Even when surgery is performed relapse occurs in up to 50% of patients. Several adjuvant trials have been led in the late 90's after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the IALT study, with 1 867 patients included, confirms the benefit of post-operative chemotherapy in resected NSCLC. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.
No preview · Article · Feb 2004 · Bulletin du cancer