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ABSTRACT: Brain metastases (BM) occur in up to 40% of non-small-cell lung cancer (NSCLC) patients. This trial assessed the safety and efficacy of pemetrexed-cisplatin in this population.
Chemonaive NSCLC patients with BM ineligible for (radio)surgery, performance status (PS) of 0 to 2, were eligible for up to six cycles of cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) every 3 weeks. Whole -brain radiotherapy was given in case of disease progression or at chemotherapy completion. Primary end point was objective response rate (RR) on BM. Secondary end points included extracerebral and overall RR, safety profile and survival.
Forty-three patients were enrolled. Initial characteristics were mean age 60.4 years; males 29; PS: 0 in 37.2%, 1 in 60.5% and 2 in 22.3% of patients; adenocarcinoma in 36 patients, large cell in 4 patients (nonsquamous, 93%) and squamous carcinoma in 3 patients. Functional classification of neurological status was stage I/II 86.0%, III 2.3% and IV 11.6%. Grade 3-4 hematological toxic effects were neutropenia, 11 patients (febrile neutropenia, 1 patient), and anemia, 6 patients. Non-hematological toxic effects were grade 2 urinary infection, one patient; grade 3 pneumonia, two patients; and grade 3 hypoacousia, one patient. Cerebral, extracerebral and overall RR by intent to treat analysis were 41.9%, 34.9% and 34.9%, respectively. Median survival time and time to progression were 7.4 and 4.0 months, respectively.
Pemetrexed-cisplatin is an effective and well-tolerated regimen as first-line therapy for NSCLC patients with BM who always suffer a poor prognosis.
Annals of Oncology 02/2011; 22(11):2466-70. · 6.43 Impact Factor
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F Barlési,
C Balleyguier,
B Besse,
F Bonodeau,
F Brenac,
O Corneloup,
E Dansin,
G Ferretti,
J Y Gaubert, R Gervais,
C Lacombe,
A Loundou,
D Moro-Sibilot,
D Planchard,
A Scherpereel,
Y Menu
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ABSTRACT: Bevacizumab (BVZ) combined with platinum-based therapy is registered for first-line treatment of nonsquamous non-small-cell lung cancer (NSCLC). Patients with centrally located tumors are stated ineligible for BVZ treatment. The goal of this study was to assess the consistency in evaluating eligibility of patients with central tumors for BVZ treatment. Materials and methods: The study group was composed of 150 NSCLC patients with centrally located tumors. Eligibility for BVZ was assessed by chest computed tomography (CT) scan. Eligibility was assessed independently using CT images reviewed on workstations. Inter- and intraobserver variations on 50 randomly extracted patients were estimated through a statistical modeling (multiple correspondence analysis).
Discordance in eligibility was found for 82 patients (55%). The interobserver strength of agreement was fair to moderate (average kappa = 0.40). Contrarily, the intraobserver strength of agreement was good to very good (average kappa = 0.74). At multivariate analysis, the risk of discrepancy was essentially related to the assessment of the contact between the tumor and the vessels (odds ratio = 13.3, 95% confidence interval 2.8-62.6, P = 0.001).
The consistency in evaluating eligibility of patients with central tumors for BVZ treatment is weak. The study group indicated more stringent criteria to help physicians in taking the best treatment choice that need however to be prospectively validated.
Annals of Oncology 08/2010; 21(8):1682-6. · 6.43 Impact Factor
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D Moro-Sibilot,
F Barlesi,
J F Timsit,
D Debieuvre,
P Fournel, R Gervais,
J Mazieres,
B Milleron,
F Morin,
M Perol,
J C Soria,
P J Souquet,
A Vergnenègre,
G Zalcman
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ABSTRACT: As chemotherapy gains wider acceptance for the treatment of earlier stages of NSCLC, particularly in the adjuvant and neoadjuvant setting, physicians face a growing population of high performance status patients who have relapsed after their first-line chemotherapy. The type of second-line chemotherapy after initial adjuvant or neoadjuvant treatment with a platinum-based regimen remains largely undefined. The current study has been designed to compare the classical mono chemotherapy docetaxel with a docetaxel cisplatin doublet.
Patients will be randomized in 2 arms. Arm: docetaxel cisplatin (cycles repeated every 21 days), 4 cycles followed by 2 cycles of docetaxel alone in case of objective response or stabilisation. Arm B: docetaxel alone (cycles repeated every 21 days), 4 cycles followed by 2 cycles of docetaxel alone in case of objective response or stabilisation.
300 patients will be randomized with a statistical hypothesis of a progression free survival of 3 months in the control arm and of 4.5 months in the experimental arm.
Revue des Maladies Respiratoires 02/2008; 25(1):91-6. · 0.59 Impact Factor
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ABSTRACT: There is no standard second-line treatment for small cell lung cancer (SCLC). The prognosis of these patients is poor and special attention should be paid to both quality of life and economic factors.
The aim of this phase II randomised trial (GFPC0501) is to compare, in patients with progressive SCLC after first-line platinum based chemotherapy, oral multi drug chemotherapy (CCNU, cyclophosphamide, etoposide) and classical intravenous chemotherapy with cyclophosphamide, doxorubicin and vincristine (CAV) in terms of tolerability, efficacy (response rate, median one year survival and overall survival), quality of life and consumption of health care resources. Based on a two-stage Bryant and Day approach, this study will require a total of 138 patients with an interim analysis of the first 38.
This trial will provide information on several aspects of second-line chemotherapy for patients with SCLC. Thirty six patients have been enrolled in 16 centres by December 2006 and the results of the interim analysis will be available in June 2007.
Revue des Maladies Respiratoires 06/2007; 24(5):653-8. · 0.59 Impact Factor
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J-L Pujol,
J-L Breton, R Gervais,
P Rebattu,
A Depierre,
J-F Morère,
B Milleron,
D Debieuvre,
D Castéra,
P-J Souquet,
D Moro-Sibilot,
E Lemarié,
R Kessler,
H Janicot,
D Braun,
D Spaeth,
X Quantin,
C Clary
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ABSTRACT: This multicenter, randomized, phase III study compared the efficacy, including progression-free survival (PFS), and safety of gemcitabine-docetaxel (GD) combination versus cisplatin-vinorelbine (CV) in the treatment of advanced non-small-cell lung cancer (NSCLC).
Chemonaive patients with stage IIIB or IV NSCLC were treated with GD (gemcitabine 1000 mg/m(2) days 1 and 8 plus docetaxel 85 mg/m(2) day 8, every 3 weeks for eight cycles) or CV (cisplatin 100 mg/m(2) day 1 plus vinorelbine 30 mg/m(2), days 1, 8, 15 and 22, every 4 weeks for six cycles).
A total of 311 patients were enrolled (155 GD and 156 CV). Neither PFS nor overall survival differed significantly between the two arms (median PFS 4.2 and 4 months; median survival 11.1 and 9.6 months; 1-year survival 46% and 42%, for GD and CV, respectively). For the GD arm compared with the CV arm, the hazard ratio for PFS was 1.04 [95% confidence interval (CI) 0.83-1.32], and for overall survival, it was 0.90 (95% CI 0.70-1.16). Objective response rates did not differ significantly (31% for GD, 35.9% for CV). Myelosupression, emesis and frequency of febrile neutropenia were less pronounced on the GD arm, whereas fluid retention and pulmonary events were more pronounced. The CV arm experienced a higher number of serious adverse events and a lower compliance with the protocol. There was no quality of life (QoL) difference between arms. Median time to definite impairment of health-related QoL was 153 and 168 days in GD and CV arms, respectively.
There was no advantage in PFS with GD compared with CV; however, the CV regimen had higher rate of toxic events, mainly myelosuppression. The herein, non-platinum-containing regimen could be considered as a rational alternative to the cisplatin-based doublet.
Annals of Oncology 05/2005; 16(4):602-10. · 6.43 Impact Factor
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R Gervais,
A Ducolone,
J-L Breton,
D Braun,
B Lebeau,
F Vaylet,
D Debieuvre,
J-L Pujol,
J Tredaniel,
P Clouet,
E Quoix
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ABSTRACT: Taxotere (docetaxel) at the dose of 75 mg/m(2) every 3 weeks is a standard therapy for pretreated non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the safety profile of two schedules of docetaxel administration (every 3 weeks versus weekly) in patients with pretreated NSCLC.
From February 2000 to February 2001, 125 patients with locally advanced or metastatic NSCLC were randomised after failure of a previous platinum-based regimen to receive either docetaxel 75 mg/m(2) administered every 3 weeks (Dq3w) or docetaxel 40 mg/m(2) given weekly for 6 weeks followed by 2 weeks of rest (Dqw). Safety evaluations focused on grade 3-4 neutropenia, febrile neutropenia, nausea-vomiting and asthenia.
Patients' characteristics were well balanced between arms. The most common National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3-4 toxicity was neutropenia, which occurred in 48.4% of Dq3w patients versus 15.9% of Dqw patients (P=0.001). In addition, febrile neutropenia were observed in 6.5% of patients in Dq3w versus 0% in Dqw. Grade 3-4 asthenia was more frequent in Dqw. Other non-haematological toxicities were very rare. Regarding efficacy, there was a trend towards a better disease control rate in Dq3w: 32.2% versus 25.4% in Dqw. Median time to progression and survival were rather similar in both arms, respectively: 2.1 months (range 2-3.2) and 5.8 months (range 4.0-7.0) in Dq3w and 1.8 months (range 1.6-2.3) and 5.5 months (range 3.7-6.6) in Dqw.
While both schedules had a favourable safety profile, a significant lower rate of severe neutropenia was observed in the weekly arm. Both regimens had similar efficacy. The weekly regimen could be considered as a good alternative for patients at risk of severe neutropenia.
Annals of Oncology 02/2005; 16(1):90-6. · 6.43 Impact Factor
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J-Y Douillard, R Gervais,
G Dabouis,
A Le Groumellec,
M D'Arlhac,
D Spaeth,
B Coudert,
D Caillaud,
A Monnier,
C Clary,
B Maury,
M Mornet,
A Rivière,
P Clouet,
C Couteau
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ABSTRACT: This phase II trial compared docetaxel-cisplatin (DC) with vinorelbine-cisplatin (VC), both as first-line therapy followed by cross-over at progression to single-agent vinorelbine or docetaxel in advanced non-small-cell lung cancer (NSCLC).
Overall, 115 patients received DC (docetaxel 75 mg/m(2) and cisplatin 100 mg/m(2) both on day 1, every 3 weeks, arm A1) and 118 VC (vinorelbine 30 mg/m(2)/week on days 1 and 8 and cisplatin 100 mg/m(2) on day 1, every 3 weeks, arm B1) for six cycles, and subsequently maintained by monotherapy with docetaxel (A1) or vinorelbine (B1) with cross-over on disease progression to vinorelbine 30 mg/m(2) days 1 and 8 (A2), or docetaxel 100 mg/m(2), day 1, both every 3 weeks (B2). The primary end point was overall response rate (ORR).
Patient characteristics were balanced; median follow-up was 8.8 months. First-line response rate was 33.9% with DC and 26.3% with VC (P=0.20). In arms A1 and B1, respectively: duration of response was similar (8.2 versus 8.4 months); median time to progression was 5 months in both; median survival was 8 versus 9 months (P=0.38); 1-, 2- and 3-year survival was 36% versus 35%, 17% versus 10% and 13% versus 6% (P not significant). However, with a low number of long-term survivors, statistical significance was not reached. Overall, almost half of the patients crossed over to second-line therapy; there were no response with vinorelbine and 6 (11.2%) partial responses with docetaxel. Considering the safety profile, the occurrence of febrile neutropenia was 9.6% with DC and 26.3% with VC. Treatment-related mortality was 2.5% with DC and 8.5% with VC.
The trend in favour of the DC arm in ORR, even though statistical significance was not reached, is consistent with previous reports. This study suggests an activity of first-line DC in advanced NSCLC, and that second-line vinorelbine does not provide additional clinical benefit. As already shown in other studies, the use of DC in first-line should provide a better percentage of long-term survivors, despite the absence of efficacy of the second-line in our study.
Annals of Oncology 02/2005; 16(1):81-9. · 6.43 Impact Factor
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ABSTRACT: Chemotherapy of advanced non-small cell lung cancers is based on cisplatin, which prolongs survival. However, the high toxicity of double-type combinations including cisplatin warrants the search for alternatives. New anti-cancer cytotoxic agents exhibit improved efficacy-toxicity ratio. Bitherapy, without cisplatin and with new molecules, provides hope of improvement in survival without deterioration in quality of life. Several randomised trials, already published or presented with mature results, suggest that certain bitherapies with new cytostatic agents are an alternative to the classical cisplatin-based bitherapies. The recent modifications in the guidelines of the American Association of Clinical Oncology take into account these recent results by admitting that "chemotherapy without cisplatin can be used as an alternative to the first-line platin-based chemotherapies". This brief review of the literature underlines the methodological questions raised by the publication of randomised studies essentially assessing gemcitabine-vinorelbine or gemcitabine-taxane combinations, by confronting them with either mono-chemotherapies or reference chemotherapy based on cisplatin. The assessment criteria selected in such studies are discussed.
Revue de Pneumologie Clinique 11/2004; 60(5 Pt 2):3S60-7. · 0.24 Impact Factor
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ABSTRACT: Vascular immunotargeting, the administration of drugs conjugated with antibodies to endothelial surface antigens, has the potential for drug delivery to the endothelium. Our previous cell culture studies showed that biotinylated antibodies to PECAM-1 (a highly expressed endothelial surface antigen) coupled with streptavidin (SA, a cross-linking protein that facilitates anti-PECAM internalization and targeting) may provide a carrier for the intracellular delivery of therapeutic enzymes. This paper describes the PECAM-directed vascular immunotargeting of a reporter enzyme (beta-galactosidase, beta-Gal) in intact animals. Intravenous injection of [125I]SA-beta-Gal conjugated with either anti-PECAM or IgG led to a high 125I uptake in liver and spleen, yet beta-Gal activity in these organs rapidly declined to the background levels, suggesting rapid degradation of the conjugates. In contrast, anti-PECAM/[125I]SA-beta-Gal, but not IgG/[125I]SA-beta-Gal, accumulated in the lungs (36.0+/-1.3 vs. 3.9+/-0.6% injected dose/g) and induced a marked elevation of beta-Gal activity in the lung tissue persisting for up to 8 h after injection (10-fold elevation 4 h postinjection). Using histochemical detection, the beta-Gal activity in the lungs was detected in the endothelial cells of capillaries and large vessels. The anti-PECAM carrier also provided 125I uptake and beta-Gal activity in the renal glomeruli. Predominant intracellular localization of anti-PECAM/SA-beta-Gal was documented in the PECAM-expressing cells in culture by confocal microscopy and in the pulmonary endothelium by electron microscopy. Therefore, vascular immunotargeting is a feasible strategy for cell-selective, intracellular delivery of an active foreign enzyme to endothelial cells in vivo, and thus may be potentially useful for the treatment of acute pulmonary or vascular diseases.
The FASEB Journal 03/2001; 15(2):416-26. · 5.71 Impact Factor
