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Frances A Shepherd,
Caroline Domerg,
Pierre Hainaut,
Pasi A Jänne,
Jean-Pierre Pignon,
Stephen Graziano,
Jean-Yves Douillard,
Elizabeth Brambilla, Thierry Le Chevalier,
Lesley Seymour, [......],
Gwénaël Le Teuff,
Robert Pirker,
Martin Filipits,
Rafael Rosell,
Robert Kratzke,
Bizhan Bandarchi,
Xiaoli Ma,
Marzia Capelletti,
Jean-Charles Soria,
Ming-Sound Tsao
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ABSTRACT: PURPOSEWe undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC). METHODSKRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. RESULTS: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). CONCLUSIONKRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.
Journal of Clinical Oncology 04/2013; · 18.37 Impact Factor
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Luc Friboulet,
Ken André Olaussen,
Jean-Pierre Pignon,
Frances A Shepherd,
Ming-Sound Tsao,
Stephen Graziano,
Robert Kratzke,
Jean-Yves Douillard,
Lesley Seymour,
Robert Pirker, [......],
Julien Adam,
Elsa Vanhecke,
Patrick Saulnier,
Jürgen Thomale, Thierry Le Chevalier,
Ariane Dunant,
Vanessa Rousseau,
Gwénaël Le Teuff,
Elisabeth Brambilla,
Jean-Charles Soria
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ABSTRACT: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation.
We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage.
We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance.
Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).
New England Journal of Medicine 03/2013; 368(12):1101-10. · 53.30 Impact Factor
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Ken A Olaussen,
Julien Adam,
Elsa Vanhecke,
Philippe Vielh,
Robert Pirker,
Luc Friboulet,
Helmut Popper,
Angélique Robin,
Fréderic Commo,
Jürgen Thomale,
Louis Kayitalire,
Martin Filipits, Thierry Le Chevalier,
Fabrice André,
Elisabeth Brambilla,
Jean-Charles Soria
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ABSTRACT: Evaluation of DNA repair proteins might provide meaningful information in relation to prognosis and chemotherapy efficacy in Non-Small Cell Lung Cancer (NSCLC) patients. The role of Poly(ADP-Ribose) Polymerase (PARP) in DNA repair of platinum adducts has not been firmly established. We used a DNA repair functional test based on antibody recognition of cisplatin intrastrand platinum adducts on DNA. We evaluated the effect of PARP inhibition on DNA repair functionality in a panel of cisplatin cell lines treated by the clinical-grade pharmacological inhibitor CEP8983 (a 4-methoxy-carbazole derivate) and the commercially available inhibitor PJ34 (phenanthridinone). We determined PARP1 protein expression in whole tumor sections from the International Adjuvant Lung cancer Trial (IALT)-bio study and tested a 3-marker PARP1/MSH2/ERCC1 algorithm combining PARP1 tumor status with previously published data. Chemosensitivity of cisplatin in NSCLC cell lines was correlated with the accumulation of cisplatin DNA adducts (P=0.0004). Further, the pharmacological inhibition of PARP induced a 1.7 to 2.3-fold increase in platinum adduct accumulation (24h) in A549 cell line suggesting a slow-down of platinum DNA-adduct repair capacity. In parallel, PARP1 inhibition increased the sensitivity to cisplatin treatment. In patient samples, PARP1 expression levels did not influence patient survival or the effect of platinum-based post-operative chemotherapy in the global IALT-bio population (interaction P=0.79). Among cases with high expression of all three markers (triple positive), untreated patients had prolonged survival with a median DFS of 7.8 years, (HR=0.34, 95%CI [0.19-0.61], adjusted P=0.0003) compared to triple negative patients (1.4 years). Remarkably, triple positive patients suffered from a detrimental effect (4.9-year reduction of median DFS) by post-operative cisplatin-based chemotherapy (HR=1.79, 95%CI [1.01-3.17], adjusted P=0.04, chemotherapy vs. control). Combinatorial sub-group analysis of the 3 markers further suggested that PARP1 tumor positivity might constitute a molecular context with high theranostic interest of ERCC1 and MSH2 in NSCLC. In conclusion, our data confirm that platinum DNA adduct accumulation is linked to chemosensitivity, which increase by pharmacological PARP inhibitors points to a role of PARP-dependent DNA repair in the process. We further suggest DNA repair biomarkers should be analyzed in a larger context of multiple DNA repair pathway regulation.
Lung cancer (Amsterdam, Netherlands) 02/2013; · 3.14 Impact Factor
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ABSTRACT: Maintenance chemotherapy has a long history of use in hematologic malignancies, in which the benefits are considerable in terms of survival and quality of life. Recently, several studies have demonstrated that maintenance therapy in non-small-cell lung cancer can prolong overall survival in patients who have benefited from initial platinum-based chemotherapy. These studies have led to regulatory approval of two agents (pemetrexed and erlotinib) in this setting. We raise several issues regarding the design and execution of these studies, which question the validity of these conclusions, and explore aspects of the trial results concerning the optimal use of this approach, if it is to be accepted.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2012; 7(9):1331-6. · 4.55 Impact Factor
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ABSTRACT: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial.
To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC.
There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006.
Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.
Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen).
Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97).
Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.
Cochrane database of systematic reviews (Online) 01/2012; 4:CD004569. · 5.72 Impact Factor
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ABSTRACT: In the decade since the last Lancet Seminar on lung cancer there have been advances in many aspects of the classification, diagnosis, and treatment of non-small-cell lung cancer (NSCLC). An international panel of experts has been brought together to focus on changes in the epidemiology and pathological classification of NSCLC, the role of CT screening and other techniques that could allow earlier diagnosis and more effective treatment of the disease, and the recently introduced seventh edition of the TNM classification and its relation to other prognostic factors such as biological markers. We also describe advances in treatment that have seen the introduction of a new generation of chemotherapy agents, a proven advantage to adjuvant chemotherapy after complete resection for specific stage groups, new techniques for the planning and administration of radiotherapy, and new surgical approaches to assess and reduce the risks of surgical treatment.
The Lancet 05/2011; 378(9804):1727-40. · 38.28 Impact Factor
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ABSTRACT: The value of a nonanthracyclin regimen in thymic carcinoma and malignant thymoma is not well defined. These regimens may be useful in some patients, particularly with cardiac diseases. The objective of this study is to evaluate the response rate, progression free survival, overall survival and toxicity of combined etoposide, ifosfamide, and cisplatin in patients with advanced thymoma and thymic carcinoma.
From October 1995 to April 2001, 18 patients with advanced thymoma or thymic carcinoma were entered on trial, and receive etoposide (100 mg/m(2) on days 1-3), ifosfamide (1500 mg/m(2) on days 1-3), s and cisplatin (30 mg/m(2) on days 1-3). Cycles were repeated every 3 weeks for a total of six cycles.
Among 16 evaluable patients, there were no complete responses and four partial responses (complete and partial responses rate, 25%; confidence interval [CI] 95, 7-48%). The median follow-up was 32.6 months (range, <9-84 months), and the median overall survival has not yet been reached because more than 50% of patients are still alive. Based on Kaplan-Meier estimates, the 1-year and 2-year survival rates were 93.8 and 78.1%, respectively. The toxicity was predominantly myelosuppresion and alopecia.
The combined etoposide, ifosfamide, and cisplatin regimen has moderate activity in patients with advanced thymic tumors. Our results confirm the Eastern Cooperative Oncology Group trial published in 2001. Response rates appear to be lower to many phase II trials, but survival seems similar.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2010; 5(6):893-7. · 4.55 Impact Factor
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ABSTRACT: Introduction: The value of a nonanthracyclin regimen in thymic carcinoma and malignant thymoma is not well defined. These regimens may be useful in some patients, particularly with cardiac diseases. The objective of this study is to evaluate the response rate, progression free survival, overall survival and toxicity of combined etoposide, ifosfamide, and cisplatin in patients with advanced thymoma and thymic carcinoma.
Methods: From October 1995 to April 2001, 18 patients with advanced thymoma or thymic carcinoma were entered on trial, and receive etoposide (100 mg/m2 on days 1–3), ifosfamide (1500 mg/m2 on days 1–3), s and cisplatin (30 mg/m2 on days 1–3). Cycles were repeated every 3 weeks for a total of six cycles.
Results: Among 16 evaluable patients, there were no complete responses and four partial responses (complete and partial responses rate, 25%; confidence interval [CI] 95, 7–48%). The median follow-up was 32.6 months (range, <9–84 months), and the median overall survival has not yet been reached because more than 50% of patients are still alive. Based on Kaplan-Meier estimates, the 1-year and 2-year survival rates were 93.8 and 78.1%, respectively. The toxicity was predominantly myelosuppresion and alopecia.
Conclusions: The combined etoposide, ifosfamide, and cisplatin regimen has moderate activity in patients with advanced thymic tumors. Our results confirm the Eastern Cooperative Oncology Group trial published in 2001. Response rates appear to be lower to many phase II trials, but survival seems similar.
Journal of Thoracic Oncology 05/2010; 5(6):893-897. · 3.66 Impact Factor
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Nermine S Kamal,
Jean-Charles Soria,
Jean Mendiboure,
David Planchard,
Ken A Olaussen,
Vanessa Rousseau,
Helmut Popper,
Robert Pirker,
Pascale Bertrand,
Ariane Dunant, Thierry Le Chevalier,
Martin Filipits,
Pierre Fouret
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ABSTRACT: We sought to determine the long-term (median follow-up, 7.5 years) predictive power of human MutS homologue 2 (MSH2) immunohistochemical expression in patients who enrolled in the International Adjuvant Lung Trial. Experimental design: We tested the interaction between MSH2 and the allocated treatment (chemotherapy versus observation) in a Cox model adjusted on clinicopathologic variables. The significance level was set at 0.01.
MSH2 levels were low in 257 (38%) and high in 416 (62%) tumors. The benefit from chemotherapy was likely different according to MSH2 (interaction test, P = 0.06): there was a trend for chemotherapy to prolong overall survival when MSH2 was low [hazard ratio (HR), 0.76; 95% confidence interval (95% CI), 0.59-0.97; P = 0.03], but not when MSH2 was high (HR, 1.12; 95% CI, 0.81-1.55; P = 0.48). In the control arm, the HR was 0.66 (95% CI, 0.49-0.90; P = 0.01) when MSH2 was high. When combining MSH2 with excision repair cross-complementing group 1 (ERCC1) into four subgroups, the benefit of chemotherapy decreased with the number of markers expressed at high levels (P = 0.01). A similar decrease was noted when combining MSH2 and P27 (P = 0.01). Chemotherapy prolonged overall survival in the combined low MSH2/low ERCC1 subgroup (HR, 0.65; 95% CI, 0.47-0.91; P = 0.01) and in the combined low MSH2/low P27 subgroup (HR, 0.65; 95% CI, 0.46-0.93; P = 0.01).
MSH2 expression is a borderline significant predictor of a long-term benefit from adjuvant cisplatin-based chemotherapy in patients with completely resected lung cancer. MSH2 combined with ERCC1 or P27 may identify patients most likely to benefit durably from chemotherapy.
Clinical Cancer Research 02/2010; 16(4):1206-15. · 7.74 Impact Factor
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Jean-Yves Douillard,
Hélène Tribodet,
Delphine Aubert,
Frances A. Shepherd,
Rafael Rosell,
Keyue Ding,
Anne-Sophie Veillard,
Lesley Seymour, Thierry Le Chevalier,
Stephen Spiro,
Richard Stephens,
Jean Pierre Pignon,
on behalf of the LACE Collaborative Group
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ABSTRACT: Background: To evaluate the impact of adjuvant cisplatin-vinorelbine in completely resected non-small cell lung cancer and identify patients likely to benefit from this regimen in the Lung Adjuvant Cisplatin Evaluation (LACE) database. The overall LACE meta-analysis showed survival benefit with cisplatin-based adjuvant chemotherapy (5-year survival benefit of 5.4%, hazard ratio [HR] 0.89, p = 0.004). Subgroup analysis for the cisplatin-vinorelbine regimen was prespecified in the LACE statistical analysis plan. Patients randomized to cisplatin-vinorelbine or observation were the largest subgroup (41%) and the most homogeneous in terms of drug doses and eligibility.
Patients and Methods: The LACE-vinorelbine cohort included trials evaluating cisplatin-vinorelbine versus observation. Overall survival was the primary end point. Other studies randomizing patients to other chemotherapy or observation (LACE-other) were also evaluated.
Results: The LACE-vinorelbine cohort included 1888 patients from four studies (Adjuvant Navelbine International Trialist Association, Big Lung Trial, International Adjuvant Lung Cancer Trial, and National Cancer Institute of Canada Clinical Trials Group JBR.10). Baseline characteristics were similar to the LACE-other but had fewer patients with stage IA (2% versus 11%). Survival improvement at 5 years was 8.9% with cisplatin-vinorelbine versus observation (HR 0.80, 95% confidence interval: 0.70–0.91, p <0.001). Stage was a significant predictor for survival (test for trend, p = 0.02; benefit at 5 years: 14.7% [stage III], 11.6% [stage II], and 1.8% [stage I]). Similar benefits were seen for disease-free survival (HR 0.75 [0.67–0.85, p <0.001], stage III [HR 0.62, 0.50–0.76], stage II [HR 0.69, 0.57–0.83], and stage I [HR 0.95, 0.767ndash;1.19]). The overall result was statistically superior to LACE-other (LACE other HR 0.95, 0.86–1.05, interaction p = 0.04).
Conclusion: In subgroup analyses, adjuvant cisplatin-vinorelbine provides a superior survival benefit and can be recommended in completely resected stages II and III non-small cell lung cancer.
Journal of Thoracic Oncology 01/2010; 5(2):220-228. · 3.66 Impact Factor
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Jean-Yves Douillard,
Hélène Tribodet,
Delphine Aubert,
Frances A Shepherd,
Rafael Rosell,
Keyue Ding,
Anne-Sophie Veillard,
Lesley Seymour, Thierry Le Chevalier,
Stephen Spiro,
Richard Stephens,
Jean Pierre Pignon
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ABSTRACT: To evaluate the impact of adjuvant cisplatin-vinorelbine in completely resected non-small cell lung cancer and identify patients likely to benefit from this regimen in the Lung Adjuvant Cisplatin Evaluation (LACE) database. The overall LACE meta-analysis showed survival benefit with cisplatin-based adjuvant chemotherapy (5-year survival benefit of 5.4%, hazard ratio [HR] 0.89, p = 0.004). Subgroup analysis for the cisplatin-vinorelbine regimen was prespecified in the LACE statistical analysis plan. Patients randomized to cisplatin-vinorelbine or observation were the largest subgroup (41%) and the most homogeneous in terms of drug doses and eligibility.
The LACE-vinorelbine cohort included trials evaluating cisplatin-vinorelbine versus observation. Overall survival was the primary end point. Other studies randomizing patients to other chemotherapy or observation (LACE-other) were also evaluated.
The LACE-vinorelbine cohort included 1888 patients from four studies (Adjuvant Navelbine International Trialist Association, Big Lung Trial, International Adjuvant Lung Cancer Trial, and National Cancer Institute of Canada Clinical Trials Group JBR.10). Baseline characteristics were similar to the LACE-other but had fewer patients with stage IA (2% versus 11%). Survival improvement at 5 years was 8.9% with cisplatin-vinorelbine versus observation (HR 0.80, 95% confidence interval: 0.70-0.91, p <0.001). Stage was a significant predictor for survival (test for trend, p = 0.02; benefit at 5 years: 14.7% [stage III], 11.6% [stage II], and 1.8% [stage I]). Similar benefits were seen for disease-free survival (HR 0.75 [0.67-0.85, p <0.001], stage III [HR 0.62, 0.50-0.76], stage II [HR 0.69, 0.57-0.83], and stage I [HR 0.95, 0.767-1.19]). The overall result was statistically superior to LACE-other (LACE other HR 0.95, 0.86-1.05, interaction p = 0.04).
In subgroup analyses, adjuvant cisplatin-vinorelbine provides a superior survival benefit and can be recommended in completely resected stages II and III non-small cell lung cancer.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2009; 5(2):220-8. · 4.55 Impact Factor
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Rodrigo Arriagada,
Ariane Dunant,
Jean-Pierre Pignon,
Bengt Bergman,
Mariusz Chabowski,
Dominique Grunenwald,
Miroslaw Kozlowski,
Cécile Le Péchoux,
Robert Pirker,
Maria-Izabel Sathler Pinel,
Michèle Tarayre, Thierry Le Chevalier
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ABSTRACT: PURPOSE Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients with non-small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up. PATIENTS AND METHODS Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration. Results The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06). CONCLUSION These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.
Journal of Clinical Oncology 11/2009; 28(1):35-42. · 18.37 Impact Factor
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ABSTRACT: Despite aggressive surgical management, 5-year survival rates of patients with non-small-cell lung cancer (NSCLC) range from 73% for those with pathologic stage IA to 25% for stage IIIA. Given the low survival rate associated with treatment by surgery alone, numerous trials have investigated the use of induction or adjuvant strategies with chemotherapy or thoracic irradiation, either alone or in combination. A meta-analysis published in 1995 showed that cisplatin-based regimens produce the best adjuvant chemotherapy results in NSCLC patients, and this finding has been validated by three large randomized trials. Neoadjuvant chemotherapy offers theoretical advantages over adjuvant chemotherapy, including improved patient compliance, a smaller primary tumor, and pathologic evaluation of treatment efficacy. However, most large randomized trials of neoadjuvant chemotherapy have failed to show statistically significant results. This article reviews the pros and cons of each strategy, current guidelines, and treatment methods that are being explored.
Oncology (Williston Park, N.Y.) 06/2009; 23(6):520-7. · 1.03 Impact Factor
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Journal of Clinical Oncology 10/2008; 26(31):5014-7. · 18.37 Impact Factor
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Jean-Pierre Pignon,
Hélène Tribodet,
Giorgio V Scagliotti,
Jean-Yves Douillard,
Frances A Shepherd,
Richard J Stephens,
Ariane Dunant,
Valter Torri,
Rafael Rosell,
Lesley Seymour,
Stephen G Spiro,
Estelle Rolland,
Roldano Fossati,
Delphine Aubert,
Keyue Ding,
David Waller, Thierry Le Chevalier
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ABSTRACT: Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy.
Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial.
With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin.
Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.
Journal of Clinical Oncology 08/2008; 26(21):3552-9. · 18.37 Impact Factor
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Martin Früh,
Estelle Rolland,
Jean-Pierre Pignon,
Lesley Seymour,
Keyue Ding,
Hélène Tribodet,
Timothy Winton, Thierry Le Chevalier,
Giorgio V Scagliotti,
Jean Yves Douillard,
Stephen Spiro,
Frances A Shepherd
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ABSTRACT: This pooled analysis was undertaken to assess the efficacy and toxicity of adjuvant cisplatin-based chemotherapy in elderly patients with non-small-cell lung cancer (NSCLC).
We used individual patient data from 4,584 patients enrolled onto five trials of cisplatin-based chemotherapy who form the basis for the Lung Adjuvant Cisplatin Analysis (LACE) pooled analysis. Patient and treatment characteristics, overall and event-free survival, cause-specific mortality, chemotherapy toxicity and delivery were compared among three age groups: 3,269 young (71%; < 65), 901 midcategory (20%; 65 to 69), and 414 elderly patients (9%; >or= 70). Log-rank tests stratified by trials were used with a test for trend to study the effect of chemotherapy on survival according to age.
The hazard ratio (HR) of death for the young patients was 0.86 (95% CI, 0.78 to 0.94), 1.01 for the midcategory (95% CI, 0.85 to 1.21), and 0.90 for elderly patients (95% CI, 0.70 to 1.16; test for trend: P = .29). The HR for event-free survival was 0.82 for young (95% CI, 0.75 to 0.90), 0.90 for the midcategory (95% CI, 0.76 to 1.06), and 0.87 for elderly patients (95% CI, 0.68 to 1.11; test for trend: P = .42). More elderly patients died from non-lung cancer-related causes (12% young, 19% midcategory, 22% elderly; P < .0001). No differences in severe toxicity rates were observed. Elderly patients received significantly lower first and total cisplatin doses, and fewer chemotherapy cycles (chi(2) P < .0001).
Adjuvant cisplatin-based chemotherapy should not be withheld from elderly patients with NSCLC purely on the basis of age.
Journal of Clinical Oncology 07/2008; 26(21):3573-81. · 18.37 Impact Factor
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04/2008: pages 221 - 232; , ISBN: 9780470696330
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Johan Vansteenkiste,
Primo N Lara, Thierry Le Chevalier,
Jean-Luc Breton,
Philip Bonomi,
Alan B Sandler,
Mark A Socinski,
Catherine Delbaldo,
Brent McHenry,
David Lebwohl,
Ronald Peck,
Martin J Edelman,
Mark Edelman
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ABSTRACT: Ixabepilone is the first in a new class of antineoplastic agents, the epothilones and their analogs. This international, randomized, phase II trial assessed two administration schedules of ixabepilone as second-line therapy in patients with non-small-cell lung cancer (NSCLC).
Patients had experienced disease progression after one prior cisplatin- or carboplatin-based chemotherapy regimen. Ixabepilone was administered as a single 32 mg/m(2) 3-hour infusion (77 patients; arm A) or a 6 mg/m(2) 1-hour infusion daily for 5 consecutive days (69 patients; arm B) in a 3-week cycle.
The intent-to-treat objective response rate was 14.3% in arm A and 11.6% in arm B. Median duration of response was 8.7 months (95% CI, 5.3 to 9.5 months) in arm A and 9.6 months (95% CI, 6.1 to 19.7 months) in arm B. Median time to progression was 2.1 months (95% CI, 1.4 to 2.8 months) for arm A and 1.5 months (95% CI, 1.4 to 2.8 months) for arm B. Median survival was 8.3 months (95% CI, 5.8 to 11.5 months) for arm A, and 7.3 months (95% CI, 5.7 to 11.7 months) for arm B; the 1-year survival rate (both cohorts) was 38%. Responses occurred in patients with taxane-pretreated and platinum-refractory tumors. Both regimens had an acceptable toxicity profile. Myelosuppression was manageable, manifesting primarily as neutropenia and leukopenia. Neuropathy was primarily sensory, generally mild to moderate in severity, and mostly reversible (both regimens).
Single-agent ixabepilone had clinically relevant activity and an acceptable safety profile in patients with advanced NSCLC whose tumors had failed one prior platinum-based chemotherapy regimen.
Journal of Clinical Oncology 09/2007; 25(23):3448-55. · 18.37 Impact Factor
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Martin Filipits,
Vincent Haddad,
Katharina Schmid,
Anh Huynh,
Ariane Dunant,
Fabrice André,
Elisabeth Brambilla,
Rolf Stahel,
Jean-Pierre Pignon,
Jean-Charles Soria,
Helmut H Popper, Thierry Le Chevalier,
Robert Pirker
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ABSTRACT: The purpose of our study was to determine whether multidrug resistance proteins (MRP) are of prognostic and/or predictive value in patients who were enrolled into the International Adjuvant Lung Cancer Trial (IALT).
Expression of MRP1 and MRP2 was immunohistochemically assessed in tumor specimens obtained from 782 IALT patients. Prognostic and predictive analyses were based on Cox models adjusted for clinical and pathologic variables.
MRP1 expression was considered positive in 364 (47%) patients and MRP2 expression in 313 (40%) patients. MRP2-positive patients had a significantly shorter overall survival than MRP2-negative patients in the total patient population [adjusted hazard ratio for death, 1.37; 95% confidence interval (95% CI), 1.09-1.72; P = 0.007]. There was no significant association between MRP1 expression and overall survival. Neither MRP1 nor MRP2 predicted response to adjuvant cisplatin-based chemotherapy.
MRP2 expression is an independent prognostic factor in patients with completely resected non-small cell lung cancer but neither MRP1 nor MRP2 was of predictive value in patients enrolled into the IALT.
Clinical Cancer Research 08/2007; 13(13):3892-8. · 7.74 Impact Factor
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Martin Filipits,
Robert Pirker,
Ariane Dunant,
Sylvie Lantuejoul,
Katharina Schmid,
Anh Huynh,
Vincent Haddad,
Fabrice André,
Rolf Stahel,
Jean-Pierre Pignon,
Jean-Charles Soria,
Helmut H Popper, Thierry Le Chevalier,
Elisabeth Brambilla
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ABSTRACT: The International Adjuvant Lung Cancer Trial (IALT) demonstrated that adjuvant cisplatin-based chemotherapy improves the survival of patients with completely resected non-small-cell lung cancer (NSCLC). The purpose of our study was to determine whether cell cycle regulators are of prognostic and/or predictive value in patients who were enrolled onto the IALT.
Expression of p27Kip1, p16INK4A, cyclin D1, cyclin D3, cyclin E, and Ki-67 was immunohistochemically assessed in tumor specimens obtained from 778 IALT patients. Prognostic and predictive analyses were based on Cox models adjusted for clinical and pathologic parameters.
There was a relationship between p27Kip1 status and benefit of cisplatin-based chemotherapy (test for interaction, P = .02). Among patients with p27Kip1-negative tumors, cisplatin-based chemotherapy resulted in longer overall survival compared with controls (adjusted hazard ratio [HR] for death = 0.66; 95% CI, 0.50 to 0.88; P = .006). In patients with p27Kip1-positive tumors, overall survival was not different between patients treated with cisplatin-based chemotherapy and controls (adjusted HR for death = 1.09; 95% CI, 0.82 to 1.45; P = .54). The other cell cycle regulators and Ki-67 did not predict benefit of adjuvant cisplatin-based chemotherapy. None of these biomarkers was significantly associated with overall survival of the patients in the total study population.
NSCLC patients with p27Kip1-negative tumors benefit from adjuvant cisplatin-based chemotherapy after complete tumor resection. Before establishing p27Kip1 as a routine marker for selection of patients for adjuvant chemotherapy, the predictive value of p27Kip1 has to be confirmed in patients from other trials.
Journal of Clinical Oncology 08/2007; 25(19):2735-40. · 18.37 Impact Factor
