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PDF file - 344K, Supplementary methods, suppl. Figure 1 with with the specimens flow-chart, suppl. Figure 2 with the diagram of the clinical trial IFCT 0002 and sampling timepoints, suppl. Figure 4 with RASSF1A interactome, suppl. Table 1 & 2 with primers used in the study, suppl. Table 3 with all the molecular analyses in the bio-IFCT 0002 study, suppl. Table 4 comparing patients with or without molecular analyses, suppl. Table 5 with all the HRs and p-values forthe molecular and clinical variables in the final prognostic analysis

PDF file - 21K, Acknowledegements to IFCT staff (administrative and CRAs), to expert pathological panel, and list of investigators of the phase 3 clinical trial IFCT 0002

PDF file - 205K, Correlation between RASSF1 promoter gene methylation and RASSF1A protein expression by immunoblotting

Purpose: To evaluate prognostic and predictive molecular biomarkers in early-stage non–small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy.Experimental Design: The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes.Results: RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR = 1.88, 95% CI: 1.25–2.82, P = 0.0048) and shorter median overall survival (OS; adjusted HR = 2.01, 95% CI: 1.26–3.20, P = 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death = 3.85, 95% CI: 1.79–6.40) to more than 84 months for moderate (HR = 1.85, 95% CI: 0.97–3.52) and low-risk patients (reference group; P = 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR = 0.47, 95% CI: 0.23–0.97, Pinteraction = 0.042).Conclusions: Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC. Clin Cancer Res; 18(10); 2976–86. ©2012 AACR.

Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC.In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling.Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported.The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures.French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology.For the French translation of the abstract see Supplementary Materials section.

Objectives We evaluated the impact of age in a randomized phase II trial that compared three first-line drugs in elderly patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status (PS). Materials and Methods Patients with advanced NSCLC with a PS of 2 or 3 were enrolled into a multicenter randomized trial: arm A, gefitinib; arm B, gemcitabine; and arm C, docetaxel. We performed subgroup analyses according to age. Results Between December 2004 and June 2007, 127 patients were enrolled. Analyses were performed between the two subgroups aged n =56) and ≥70years (older, n =71). Patients mainly had adenocarcinoma (46% young vs. 51%: elderly), of which 62% vs. 75% had a PS of 2, respectively. Significantly more elderly patients were women and non-smokers, and there was a non-significant trend towards more PS-2 among the elderly. Progression-free survival (PFS) was 1.4months (95% CI: 1.1–1.9) for younger compared to 2.3months (95% CI: 2.1–2.9) for elderly patients. Overall survival (OS) was 2.0months (95% CI: 1.5–2.4) and 3.7months (95% CI: 2.4–4.8), respectively. Toxicity did not differ between younger and older patients. NSCLC was better controlled in elderly patients after three cycles of monotherapy compared to younger patients ( p =0.034). When adjusted for stratification criteria, age was the main prognostic factor for PFS. Adjusted HRs for PFS was 0.57 (95% CI: 0.38–0.85) for the elderly compared to patients aged p =0.004). Conclusions Older patients had a decreased risk of progression/death compared to younger patients. Single-agent chemotherapy can be considered for patients aged ≥70years with a PS of 2.

International audience; BACKGROUND: Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC. METHODS: 148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (10(8) plaque forming units) plus cisplatin (75 mg/m(2) on day 1) and gemcitabine (1250 mg/m(2) on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov, number NCT00415818. FINDINGS: 6-month PFS was 43*2% (32 of 74; 95% CI 33*4-53*5) in the TG4010 plus chemotherapy group, and 35*1% (26 of 74; 25*9-45*3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23*3%) versus six of 72 (8*3%), 12 (16*4%) versus two (2*8%), and four (5*5%) versus zero (0%), respectively. The most common grade 3-4 adverse events were neutropenia (33 [45*2%] of patients in the TG4010 plus chemotherapy group vs 31 [43*1%] in the chemotherapy alone group) and fatigue (18 [24*7%] vs 13 [18*1%]); the only grade 3-4 events that differed significantly between groups were anorexia (three [4*1%] vs 10 [13*9%]) and pleural effusion (none vs four [5*6%]). 38 of 73 patients (52*1%) in the TG4010 plus chemotherapy group and 34 of 72 (47*2%) in the chemotherapy alone group had at least one serious adverse event. INTERPRETATION: This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B-3 trial has been initiated. FUNDING: Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.

Background Pathologic complete response (CR) to preoperative chemotherapy has been shown to be a strong prognostic factor in resected non-small cell lung cancer (NSCLC). This preoperative setting offers the opportunity to evaluate the clinical prediction of CR by investigators and an evaluation committee (EC) using the “gold standard” pathologic examination as the reference. The only published large randomized trial of preoperative chemotherapy (to our knowledge), the French neoadjuvant study, constitutes an interesting database to evaluate CT scan-based CR assessment. Study objectives and design The French trial compared mitomycin-ifosfamide-cisplatin followed by surgery with surgery alone in stage I (except T1N0) to IIIa resectable NSCLC. Response was prospectively assessed in all patients receiving preoperative chemotherapy by the investigator in charge of the patient and by an EC, and was compared with pathologic postoperative data. Results In the preoperative chemotherapy study, 167 patients were operated on. Nineteen patients were found to have a pathologic CR. Only seven patients were classified as having a CR by investigators and five patients by the EC. Evaluation of CR was correct in six of these seven cases and in three of these five cases, respectively. Sensitivity of the CR diagnosis was 31.6% for investigators and 15.8% for the EC. Specificities of the CR diagnosis were 99.4% and 98.8%, respectively. Positive predictive values were 85.7% and 60%, respectively. Negative predictive values were 91.9% and 90.1%, respectively. Accuracies were 91.6% and 89.2%, respectively. Conclusion Investigator assessment of CR was highly predictive of pathologic CR. However, this study showed that clinical CT scan-based assessment, whether performed by investigators or the EC, underestimated the frequency of CR after preoperative chemotherapy in resectable NSCLC.

To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer (NSCLC).A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m(2), day 1), ifosfamide (1.5 g/m(2), days 1 to 3) and cisplatin (30 mg/m(2), days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy.Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P =.38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P =.15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P =.027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P =.044). Disease-free survival time was significantly longer in the PCT arm (P =.033).Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease.

Resume Nous rapportons le cas d’un homme de 80 ans, traite par levofloxacine pour un episode de surinfection bronchique, qui a developpe des ruptures tendineuses multiples, d’evolution favorable en neuf mois. La presence de facteurs de risque tels qu’un âge avance, une insuffisance respiratoire chronique et une corticotherapie par voie nasale semblent avoir favorise cet effet indesirable.

International audience; In this phase II study, gemcitabine and vinorelbine were combined at suboptimal doses for weekly administration in advanced non-small cell lung cancer (NSCLC). The primary objectives were to determine objective response rate (ORR) and time to progression (TTP). Secondary endpoints were safety and overall survival. Chemonaive patients with histologically or cytologically confirmed stage IIIB or IV NSCLC received vinorelbine (25 mg/m2) immediately followed by gemcitabine (800 mg/m2) once each week (on day 1) for 6 months without rest. From May 1998 to May 1999, 40 patients were enrolled (85% males; 70% stage IV) with a median age of 65.5. A total of 478 doses were administered, with a median of 9 per patient (range 2-72). The ORR was 27.5% (95% CI, 15.1-44.1%). The median TTP was 3.5 months (95% CI, 2.9-4.4 months). At a median follow-up of 6.5 months, the median survival was 11.6 months, and survival rates at 1 and 2 year(s) were 47.5% and 15.8%, respectively. The most common grade 3/4 hematologic toxicity was neutropenia, in 70% of patients, with febrile neutropenia in 28%. The most common grade 3/4 non-hematologic toxicity was transaminase elevation, in 22.5% of patients, which was transient and reversible. The other most prominent toxicities were, unexpectedly, pulmonary and cardiac toxicities. Based on these results, weekly, long-term administration of gemcitabine-vinorelbine appears to be an active regimen in NSCLC that warrants further investigation.

Pathologic complete response (CR) to preoperative chemotherapy has been shown to be a strong prognostic factor in resected non-small cell lung cancer (NSCLC). This preoperative setting offers the opportunity to evaluate the clinical prediction of CR by investigators and an evaluation committee (EC) using the "gold standard" pathologic examination as the reference. The only published large randomized trial of preoperative chemotherapy (to our knowledge), the French neoadjuvant study, constitutes an interesting database to evaluate CT scan-based CR assessment. STUDY OBJECTIVES AND DESIGN: The French trial compared mitomycin-ifosfamide-cisplatin followed by surgery with surgery alone in stage I (except T1N0) to IIIa resectable NSCLC. Response was prospectively assessed in all patients receiving preoperative chemotherapy by the investigator in charge of the patient and by an EC, and was compared with pathologic postoperative data.In the preoperative chemotherapy study, 167 patients were operated on. Nineteen patients were found to have a pathologic CR. Only seven patients were classified as having a CR by investigators and five patients by the EC. Evaluation of CR was correct in six of these seven cases and in three of these five cases, respectively. Sensitivity of the CR diagnosis was 31.6% for investigators and 15.8% for the EC. Specificities of the CR diagnosis were 99.4% and 98.8%, respectively. Positive predictive values were 85.7% and 60%, respectively. Negative predictive values were 91.9% and 90.1%, respectively. Accuracies were 91.6% and 89.2%, respectively.Investigator assessment of CR was highly predictive of pathologic CR. However, this study showed that clinical CT scan-based assessment, whether performed by investigators or the EC, underestimated the frequency of CR after preoperative chemotherapy in resectable NSCLC.

An 80-year-old man treated by levofloxacin developed multiple tendon ruptures. His symptoms resolved over 9 months after levofloxacin discontinuation. Nasal corticosteroid therapy, aging and chronic respiratory insufficiency were probably predisposing factors in this patient.

7515 Background: IFCT-0002 trial compared two perioperative CT regimens, CDDP-Gemcitabine vs.CBDCA-Paclitaxel in 528 stage I-II NSCLC patients. Paraffin-embedded post-chemo specimens were collected in the 490 non-complete responder patients for tissue expression studies of DNA-repair proteins. Methods: Surgical specimens were processed for immunohistochemistry as previously published. Variables were studied as continuous variables. Cut-off values were validated by bootstrap. Multivariate backward Cox regressions were used to adjust for patients’ characteristics associated with the corresponding outcome at p

TPS7111 Background: There are no robust data published on the follow-up after surgery for non-small cell lung cancer (NSCLC). Current international guidelines are informed by expert opinion. Most of them recommend regular follow-up with clinic visit and thoracic imaging, either chest X-ray of Chest CT-scan. The IFCT-0302 trial addresses the question whether a surveillance program with chest CT-scan and fiberoptic bronchoscopy can improve survival compared to a follow-up only based on physical examination and chest x-ray. There is no such trial ongoing over the world. Methods: The IFCT-0302 trial is a multicenter open-label controlled randomized phase III trial. The objective of the trial is to compare two follow-up programs after surgery for stage I-IIIa NSCLC. The primary endpoint is overall survival. Patients are randomly assigned to arm 1, minimal follow-up, including physical examination and chest x-ray; or arm 2, a follow-up consisting of physical examination and chest x-ray plus chest CT scan and fiberoptic bronchoscopy (optional for adenocarcinomas). In both arms, follow-up procedures are performed every 6 months during the first two postoperative years, and every year between the third and the fifth years. The main eligibility criteria include: completely resected stage I-IIIA (6th UICC TNM classification) or T4 (in case of nodules in the same lobe as the tumor) N0 M0 NSCLC, surgery within the previous 8 weeks. Patients who have received and/or who will receive pre/post-operative chemotherapy and/or radiotherapy are eligible. Statistical considerations: 1,744 patients is required. Accrual status: 1,568 patients from 119 French centers had been included. The end of accrual can be expected for September 2012. Ancillary study: Blood samples are collected in 1000 patients for genomic high density SNP micro-array analysis. This collection will contribute to the French genome wide association study (gwas) of lung cancer gene susceptibility, and the genetic factors predictive of survival and lung cancer recurrence will be analyzed.

7003 Background: To evaluate survival beyond 10 years of patients included in the French randomized trialcomparing neoadjuvant chemotherapy (CT-S) versus surgery alone (S) (initial publication: Dep...

7530 Background: Association of surgery and CT is standard for early-stage NSCLC. Meta-analyses showed comparable efficacy of adjuvant and neoadjuvant CT. The primary objective was to compare survival between two different CT strategies: all before surgery (PRE) versus perioperative (PERI). Methods: Between 2001 and 2005, 528 patients with a stage IA-II resectable NSCLC were randomized to 4 parallel arms (A: 2 GP + 2 GP in responders, then surgery, B:2 GP - surgery + 2 GP in responders, C: 2 TC + 2 TC in responders then surgery, D: 2 TC - surgery + 2 TC in responders; GP: Gemcitabine 1250 mg/m2/d1, 8 and cisplatin 75 mg/m2/d1 q3 wk; TC: Paclitaxel 200 mg/m2/d1 and carboplatin AUC 6, q3 wk). Results: 501 patients were operated on, 96.2% in the preoperative CT arms (PRE: A+C) and 95.8% in the perioperative CT arms (PERI: B+D). Ninety- day postoperative mortality was 4.9% and 4.2%, respectively. Pathological complete response was not significantly influenced by the number of preoperative cycles (PRE:8.6%, PERI:6.4%). In an intent-to-treat analysis, 3-yr survival was 67.8% and 68.6%, respectively (p=0.96). In responders, despite a dramatic difference in CT compliance (90.4% and 75.2% having received the 4 cycles, respectively, p=0.001), 3-yr survival was 75.1% and 79.5%, respectively (p=0.82). Survival did not differ with the CT regimen (GP versus TC, p=0.84). Three-yr survival increased from 68.1% in the PRE arms to 77.2% in the PERI arms in squamous cell carcinomas (SCC), and decreased from 67.7% to 61.6% in non SCC, respectively (Cox model interaction, p=0.35). Three-yr survival was 74.6% in the GP arms and 70.7% in the TC arms, in SCC, and was 64.2% and 65.4%, in non SCC, respectively (interaction, p=0.51). There was no interaction between CT strategy and stage. In stage II patients, 3-yr survival was 59.1% but 76.5% in responders, comparable to that of all stage I patients (72.9%). Conclusions: Despite an increased compliance of the all preoperative chemotherapy strategy, no difference was observed between the PRE and PERI arms. There might be an advantage for perioperative CT and for gemcitabine-based in SCC and for preoperative CT and for taxane-based in non SCC. No significant financial relationships to disclose.

7519 Background: Recent trials have shown a survival benefit of CT in resectable NSCLC. The primary objective was to define the best timing of CT (all before surgery versus perioperative). Another objective was to compare two regimens, gemcitabine-cisplatin (GP) and paclitaxel-carboplatin (TC). Methods: Between May 2001 and Dec 2005, 528 patients (pts) with a stage IA-II resectable NSCLC were randomized to 4 parallel arms: A: 2 GP + 2 GP in responders, then surgery, B: 2 GP - surgery + 2 GP in responders, C: 2 TC + 2 TC in responders then surgery, D: 2 TC - surgery + 2 TC in responders (GP: Gemcitabine 1250 mg/m2/d1, 8 and cisplatin 75 mg/m2/d1 q3 wk; TC: Paclitaxel 200 mg/m2/d1 and carboplatin AUC 6, q3 wk). Results: Pathological tumor volume and pathological complete response rate did not differ with the number of preoperative cycles. Proportions of pts receiving cycles 3 and 4 were higher when all CT was given before surgery. There were several significant differences in the main toxicities between GP and TC. Conclusions: 1- GP and TC were effective and safe. 2- Results of pathological response suggested that 2 cycles might be as effective as 4 cycles. 3- Dose intensity was higher when all chemotherapy was given before surgery compared to both before and after surgery. No significant financial relationships to disclose. [Table: see text]

Neo-adjuvant chemotherapy is a promising new concept in the treatment of resemble NSCLC. In 1991, a randomized study was initiated to compare two treatment strategies for patients (pts) with operable stages I (except T1N0), II or IIIa NSCLC. Pts are randomized into two arms. Surgery is performed first in group I. In group 2, pts start with two cycles of chemotherapy; following surgery, two more cycles are administered in responder pts. Chemotherapy is the MIP protocol: mitomycin 6 mg/m 2 day 1, ifosfamide 1.5 g/m 2 days 1 to 3, cisplatin 30 mg/m 2 days 1 to 3. In both groups, if the surgical staging is N2 or T3, a radiotherapy is performed. From June 1991 until Jan. 1995, 256 pts have been randomized; 35% are stage I, 16% are stage II. 205 pts have completed the treatment. In group 1, 105 out of 106 and in group 2, 91 out of 99 pts underwent thoracotomy. Surgery was complete in 85% of group 1, 83% of group 2, incomplete in 10% of group 1, 5% of group 2. The chemotherapy response rate assessed by surgical evaluation was as follow: complete and subcomplete response. 27%, 18%, partial response 31% (overall: 58%). The study is still ongoing as a total number of 350 patients should be included to reach the required power.