A randomised trial comparing preoperative to perioperative chemotherapy in early-stage non-small-cell lung cancer (IFCT 0002 trial)

Westeel, Virginie; Quoix, Élisabeth; Puyraveau, Marc; Lavolé, A.; Braun, Denis; Laporte, Silvy; Bigay-Gamé, L.; Pujol, Jean-Louis; Ozenne, G.; Rivière, Alain; Douillard, Jean-Yves; Lebeau, B.; Debieuvre, D.; Poudenx, M.; David, Philippe; Molinier, Olivier; Zalcman, Gérard; Lemarié, É.; Morin, Franck; Depierre, A; Milleron, B.

doi:10.1016/j.ejca.2013.04.013

Cited by 53 publications

(35 citation statements)

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“…However, it should be noted that more cycles of chemotherapy were planned in the trials of combined preoperative and postoperative chemotherapy (2–3 plus 2–3 cycles postoperatively) compared with those of just preoperative chemotherapy (2–3). Moreover, a recently reported trial that compared the use of preoperative chemotherapy plus postoperative chemotherapy 42 to responders with postoperative chemotherapy in 528 similar patients identified no evidence that preoperative plus postoperative chemotherapy was better (HR 1·01, 95% CI 0·79–1·30, p=0·92). Nevertheless, further head-to-head comparisons of these approaches might be warranted.…”

Section: Discussionmentioning

confidence: 99%

Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data

2014

The Lancet

685

254

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SummaryBackgroundIndividual participant data meta-analyses of postoperative chemotherapy have shown improved survival for patients with non-small-cell lung cancer (NSCLC). We aimed to do a systematic review and individual participant data meta-analysis to establish the effect of preoperative chemotherapy for patients with resectable NSCLC.MethodsWe systematically searched for trials that started after January, 1965. Updated individual participant data were centrally collected, checked, and analysed. Results from individual randomised controlled trials (both published and unpublished) were combined using a two-stage fixed-effect model. Our primary outcome, overall survival, was defined as the time from randomisation until death (any cause), with living patients censored on the date of last follow-up. Secondary outcomes were recurrence-free survival, time to locoregional and distant recurrence, cause-specific survival, complete and overall resection rates, and postoperative mortality. Prespecified analyses explored any variation in effect by trial and patient characteristics. All analyses were by intention to treat.FindingsAnalyses of 15 randomised controlled trials (2385 patients) showed a significant benefit of preoperative chemotherapy on survival (hazard ratio [HR] 0·87, 95% CI 0·78–0·96, p=0·007), a 13% reduction in the relative risk of death (no evidence of a difference between trials; p=0·18, I2=25%). This finding represents an absolute survival improvement of 5% at 5 years, from 40% to 45%. There was no clear evidence of a difference in the effect on survival by chemotherapy regimen or scheduling, number of drugs, platinum agent used, or whether postoperative radiotherapy was given. There was no clear evidence that particular types of patient defined by age, sex, performance status, histology, or clinical stage benefited more or less from preoperative chemotherapy. Recurrence-free survival (HR 0·85, 95% CI 0·76–0·94, p=0·002) and time to distant recurrence (0·69, 0·58–0·82, p<0·0001) results were both significantly in favour of preoperative chemotherapy although most patients included were stage IB–IIIA. Results for time to locoregional recurrence (0·88, 0·73–1·07, p=0·20), although in favour of preoperative chemotherapy, were not statistically significant.InterpretationFindings, which are based on 92% of all patients who were randomised, and mainly stage IB–IIIA, show preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in resectable NSCLC. The findings suggest this is a valid treatment option for most of these patients. Toxic effects could not be assessed.FundingMedical Research Council UK.

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Section: Discussionmentioning

confidence: 99%

Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data

2014

The Lancet

685

254

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“…Between 2001 and 2005, the IFCT 0002 Phase 3 trial accrued 528 patients [5], comparing two platinum-based perioperative chemotherapy regimens, gemcitabine plus cisplatin or paclitaxel plus carboplatin, in Stage I or II NSCLC patients. Specific informed consent was obtained for biological studies (Bio-IFCT 0002) and approved by the trial’s appointed ethics committee (CPPRB of the Besançon University Hospital, France).…”

Section: Methodsmentioning

confidence: 99%

“…The benefit offered by adjuvant chemotherapy is modest, with an absolute improvement in 5-year overall survival (OS) ranging from 4 to 15% [2–4]. The French Cooperative Thoracic Intergroup (IFCT) initiated a large Phase 3 trial in 2001 to evaluate i) tolerance and efficacy of gemcitabine-cisplatin versus paclitaxel-carboplatin perioperative chemotherapies; ii) the potential prognostic molecular biomarkers that could be helpful in defining therapeutic options and identifying genes/pathways that could be therapeutically targeted [5]. Lethal cisplatin-induced cell injury was extensively studied in vitro : cisplatin binds to DNA and induces adducts by covalent cross-linking between DNA strands, thereby inhibiting DNA replication and leading to cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early-stage lung cancer patients from the IFCT-0002 Phase 3 Trial

et al. 2016

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IntroductionDNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks.MethodsWe used immunohistochemistry (IHC) to assess MSH2, XRCC5, and BRCA1 expression in 443 post-chemotherapy specimens from patients randomized in a Phase 3 trial, comparing two neoadjuvant regimens in 528 Stage I-II non-small cell lung cancer (NSCLC) patients (IFCT-0002). O6MGMT promoter gene methylation was analyzed in a subset of 208 patients of the same trial with available snap-frozen specimens.ResultsMedian follow-up was from 90 months onwards. Only high BRCA1 (n = 221, hazard ratio [HR] = 1.58, 95% confidence interval [CI] [1.07-2.34], p = 0.02) and low MSH2 expression (n = 356, HR = 1.52, 95% CI [1.11-2.08], p = 0.008) significantly predicted better overall survival (OS) in univariate and multivariate analysis. A bootstrap re-sampling strategy distinguished three patient groups at high (n = 55, low BRCA1 and high MSH2, median OS >96 months, HR = 2.5, 95% CI [1.45-4.33], p = 0.001), intermediate (n = 82, median OS = 73.4 p = 0.0596), and low (high BRCA1 and low MSH2, n = 67, median OS = ND, HR = 0.51, 95% CI [0.31-0.83], p = 0.006) risk of death.InterpretationDNA repair protein expression assessment identified three different groups of risk of death in early-stage lung cancer patients, according to their tumor MSH2 and BRCA1 expression levels. These results deserve prospective evaluation of MSH2/BRCA1 theranostic value in lung cancer patients treated with combinations of DNA-damaging chemotherapy and drugs targeting DNA repair, such as Poly(ADP-ribose) polymerase (PARP) inhibitors.

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“…In the IFCT-0002 phase III trial [34], a robust cost-effective methylation-specific PCR assay was used, which produced reproducible results in two independent laboratories in the same series of patients and showed a prognostic and predictive role for RASSF1A [35]. In this study, RASSF1A methylation was associated with a significantly worse overall survival despite perioperative chemotherapy, suggesting that patients with RASSF1A methylation should have benefitted from alternative adjuvant treatments (e.g.…”

Section: Biomarkers Of Platinum-based Chemotherapy Efficacymentioning

confidence: 78%

Predictive biomarkers in patients with resected non-small cell lung cancer treated with perioperative chemotherapy

et al. 2013

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The aim of this article is to summarise the published data on prognostic and predictive biomarkers for early-stage non-small cell lung cancer (NSCLC), and discuss how to integrate them into clinical trials. Large phase III trials have been published in resected NSCLC with biomarkers identifying subsets of patients benefitting from perioperative chemotherapy. Initial findings of predictive implications for the DNA repair protein, ERCC1, were not confirmed in a larger series of patients due to the versatility of the commercially available monoclonal ERCC1 antibody. Prediction of survival by RRM1 tumour expression was not confirmed in a prospective phase III trial in 275 patients with stage IV disease, precluding its use in early-stage NSCLC. BRCA1 mRNA tumour content also failed to predict platinum resistance in 287 stage IV NSCLC patients included in a phase II trial, and the results of a similar trial in early-stage patients are still pending. Of the several cDNA gene expression studies in early-stage NSCLC with non-overlapping prognostic signatures, few have been replicated in independent cohorts for prognostic value, and none received external validation for predictive value. Therefore, use of biomarkers predicting chemotherapy efficacy still needs additional validation before becoming routine practice in oncogenedriven pan-negative NSCLC patients. @ERSpublications Predictive biomarkers to tailor NSCLC perioperative chemotherapy are not validated yet and better tools are still needed

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A randomised trial comparing preoperative to perioperative chemotherapy in early-stage non-small-cell lung cancer (IFCT 0002 trial)

Cited by 53 publications

References 23 publications

Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data

Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data

MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early-stage lung cancer patients from the IFCT-0002 Phase 3 Trial

Predictive biomarkers in patients with resected non-small cell lung cancer treated with perioperative chemotherapy

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