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BACKGROUND: Now that immunotherapy plus chemotherapy (CT) is one standard option in first-line treatment of advanced non-small cell lung cancer (NSCLC), there exists a medical need to assess the efficacy of second-line treatments (2LT) with antiangiogenics (AA). We performed an individual patient data meta-analysis to validate the efficacy of these combinations as 2LT. METHODS: Randomised trials of AA plus standard 2LT compared to 2LT alone that ended accrual before 2015 were eligible. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, main end-point), progression-free survival (PFS) and subgroup analyses. RESULTS: Sixteen trials were available (8,629 patients, 64% adenocarcinoma). AA significantly prolonged OS (HR = 0.93 [95% confidence interval {CI}: 0.89; 0.98], p = 0.005) and PFS (0.80 [0.77; 0.84], p < 0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.8% [-0.4; +4.0] and +3.5% [+1.9; +5.1], respectively. The OS benefit of AA was higher in younger patients (HR = 0.87 [95% CI: 0.76; 1.00], 0.89 [0.81; 0.97], 0.94 [0.87; 1.02] and 1,04 [0.93; 1.17] for patients

Background: Prophylactic cranial irradiation (PCI) was compared to observation in several randomized trials (RCTs), and a reduction greater than 50% was shown regarding the incidence of brain metastases (BM). However, none of these studies showed an improvement of overall survival (OS), possibly related to relatively small sample sizes and short follow-up. The aim of this meta-analysis was therefore to assess the impact of PCI on long term OS for stage III non-small cell lung cancer (NSCLC) compared to observation based on the pooled updated individual patient RCT data.Methods: Seven RCTs were eligible, and data from the four most recent trials (924 patients) could be retrieved. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Inter-trial heterogeneity was studied using the I-2 test. In addition, the 5-year absolute survival difference between arms was calculated for all endpoints. The pre-specified toxicities were reported descriptively.Results: The median follow-up was 97 months (74-108). Compared to observation, no statistically significant impact of PCI on OS was observed (HR 0.90 [0.76-1.07] p = 0.23, 5-year absolute difference 1.8% [-5.2-8.8]). PCI significantly prolonged progression-free survival (HR 0.77 [0.66-0.91] p = 0.002) and BM-free survival (HR 0.82 [0.69-0.97] p = 0.02). The number of patients with high-grade (>= 3) toxicity was 6.4% (21/330) for PCI.Conclusion: No OS benefit by PCI was observed, but PCI prolonged the progression-free survival and BM-free survival at an increased risk of late memory impairment and fatigue. (C) 2021 The Author(s). Published by Elsevier B.V.

Background: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer. / Methods: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta‐Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta‐Analysis of Chemotherapy in Head and Neck Cancer [MACH‐NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH‐NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS). / Results: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16‐negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85‐0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84‐0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90‐1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75‐0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78‐0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86‐1.08; P for interaction = .011). / Conclusions: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.

Introduction: Which neoadjuvant treatment for locally advanced thoracic oesophagus (TE) or gastro-oesophageal junction carcinoma is best remains an open question. Randomised controlled trials variously accrued patients with adenocarcinoma and squamous cell carcinoma, making strong conclusions hard to obtain. The primary objective of this individual participant data meta-analysis was to investigate the effect of neoadjuvant chemotherapy on overall survival (OS). Patients and methods: Eligible trials should have closed to accrual before 2016 and compared neoadjuvant chemotherapy and surgery (CS) to surgery alone. All relevant published and unpublished trials were identified via searches of electronic databases, conference proceedings and clinical trial registers. The main end-point was OS. Investigators were contacted to obtain the individual patient data, which was recorded, harmonised and checked. A random-effects Cox model, stratified by trial, was used for meta-analysis and subgroup analyses were preplanned. Results: 16 trials were identified as eligible. Individual patient data were obtained from 12 trial and 2478 patients. CS was associated with an improved OS versus surgery, hazard ratio (HR) = 0.83 [0.72–0.96], p < 0.0001, translating to an absolute benefit of 5.7% at 5-years from 16.8% to 22.5%. Treatment effects did not vary substantially between adenocarcinoma (HR = 0.73 [0.62–0.87]) and squamous cell carcinoma (HR = 0.91 [0.76–1.08], interaction p = 0.26). A somewhat more pronounced effect was observed in gastro-oesophageal junction (HR = 0.68 [0.50–0.93]) versus TE (HR = 0.87 [0.75–1.00], interaction p = 0.07). CS was also associated with a greater disease-free survival (HR = 0.74 [0.64–0.85], p < 0.001). Conclusions: Neoadjuvant chemotherapy conferred a better OS than surgery alone and should be considered in all anatomical location and histological subtypes.

Contains fulltext : 235407.pdf (Publisher’s version ) (Closed access) BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRT(P)) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRT(P) (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC(TaxPF)-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and IC(TaxPF) followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or IC(TaxPF)-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Background: The established role of morphological evaluation of tumour-infiltrating lymphocytes (TILs) with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. We aimed to determine TIL association with the outcome for ICIs and for chemotherapy in advanced NSCLC.Methods: This is a multicenter retrospective study of a nivolumab cohort of 221 patients treated between November 2012 and February 2017 and a chemotherapy cohort of 189 patients treated between June 2009 and October 2016. Patients with available tissue for stromal TIL evaluation were analysed. The presence of a high TIL count (high-TIL) was defined as >= 10% density. The primary end-point was overall survival (OS).Results: Among the nivolumab cohort, 64% were male, with median age of 63 years, 82.3% were smokers, 77% had performance status

Item does not contain fulltext BACKGROUND: The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. METHODS: For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. FINDINGS: Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0.94, 95% CI 0.90-0.98; p=0.0033), with an absolute difference at 5 years of 3.1% (95% CI 1.3-4.9) and at 10 years of 1.2% (-0.8 to 3.2). We found a significant interaction (p=0.051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0.83, 0.74-0.92), with absolute differences at 5 years of 8.1% (3.4 to 12.8) and at 10 years of 3.9% (-0.6 to 8.4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1.22, 1.05-1.42; p=0.0098), with absolute differences at 5 years of -5.8% (-11.9 to 0.3) and at 10 years of -5.1% (-13.0 to 2.8). INTERPRETATION: This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested. FUNDING: Institut National du Cancer; and Ligue Nationale Contre le Cancer.

Background and purposeThe Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.Materials and methodsPublished or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT+CT or adding another timing of CT to LRT+CT (main question), or comparing induction CT+radiotherapy to radiotherapy+concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p&nbsp

Background Hepatic arterial infusion (HAI) combined with systemic chemotherapy has shown promising results in patients with unresectable colorectal liver metastases (CRLM), even after failure to systemic therapy. Addition of systemic targeted therapies has been investigated with controversial results regarding tolerance, especially with HAI-floruxidine when combined with systemic bevacizumab. Our study aimed to analyse feasibility, safety and efficacy of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies. Methods Between 2005 and 2016, single-centre consecutive patients with unresectable CRLM who received at least one cycle of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies (cetuximab/panitumumab or bevacizumab) were analysed. Results A total of 89 patients (median age 55 years (range, 26–76 years) who previously received a median number of one systemic chemotherapy regimen (range, 0–5) including oxaliplatin in 78% of cases were included. Median number of HAI-oxaliplatin cycles was 9 (range, 1–28) combined with systemic chemotherapy and targeted therapies (LV5FU2 [63%], FOLFIRI [36%]) plus anti-EGFR (30%), or bevacizumab (70%). Grade 3/4 toxicities included neutropenia (40%), HAI-related abdominal pain (43%) and neurotoxicity (12%). The intent-to-treat objective response rate was 42%, and 45% had stable disease, allowing complete CRLM resection/ablation in 27% of patients. After a median follow-up of 72 months, median overall and progression-free survival was 20 and 9 months, respectively. Conclusion Addition of targeted therapy to systemic chemotherapy combined with HAI-oxaliplatin is feasible, safe and shows promising activity, even after systemic chemotherapy failure.

Background LKB1/STK11 ( STK11 ) is among the most inactivated tumor-suppressor genes in non-small cell lung cancer (NSCLC). While evidence concerning the biologic role of STK11 is accumulating, its prognostic significance in advanced NSCLC has not been envisaged yet. Materials and methods This retrospective analysis included consecutive NSCLC patients with available STK11 information who underwent a platinum-based chemotherapy. STK11 mutational status was correlated to clinico-pathological and mutational features. Kaplan–Meier and Cox models were used for survival curves and multivariate analyses, respectively. Results Among the 302 patients included, 267 (89%) were diagnosed with stage IIIB/IV NSCLC and 25 (8%) harbored a STK11 mutation ( STK11mut ). No statistical differences were observed between STK11 status and clinico-pathological variables. We detected a significant correlation between STK11 and KRAS status (p = 0.008); among the 25 STK11mut patients, 13 (52%) harbored a concomitant KRAS mutation. Overall survival (OS) was shorter for STK11mut (median OS = 10.4 months) compared to wild-type patients ( STK11wt ; median OS = 17.3 months) in univariate analysis (p = 0.085). STK11 status did not impact upon OS in multivariate analysis (p = 0.45) and non-significant results were observed for progression-free survival. The co-occurrence of KRAS and STK11 mutations suggest a trend toward detrimental effect in OS (p = 0.12). Conclusions In our cohort enriched for advanced NSCLC patients who received platinum-based chemotherapy, STK11 mutations were not specifically associated with clinico-pathological features and they did not impact upon survival. We confirm the positive correlation between STK11 and KRAS mutations. The co-occurrence of KRAS and STK11 mutations could label a more aggressive molecular subtype of NSCLC.

Purpose Our previous work evaluated individual prognostic and predictive roles of TP53, KRAS, and EGFR in non–small-cell lung cancer (NSCLC). In this analysis, we explore the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations in randomized trials of adjuvant chemotherapy versus observation. Patients and Methods Mutation analyses (wild-type [WT] and mutant) for TP53, KRAS, and EGFR were determined in blinded fashion in multiple laboratories. Primary and secondary end points of pooled analysis were overall survival and disease-free survival. We evaluated the role of TP53/KRAS comutation in all patients and in the adenocarcinoma subgroup as well as the TP53/EGFR comutation in adenocarcinoma only through a multivariable Cox proportional hazards model stratified by trial. Results Of 3,533 patients with NSCLC, 1,181 (557 deaths) and 404 (170 deaths) were used for TP53/KRAS and TP53/EGFR analyses. For TP53/KRAS mutation status, no prognostic effect was observed ( P = .61), whereas a borderline predictive effect ( P = .04) was observed with a deleterious effect of chemotherapy with TP53/KRAS comutations versus WT/WT (hazard ratio, 2.49 [95% CI, 1.10 to 5.64]; P = .03). TP53/EGFR comutation in adenocarcinoma was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. Conclusion We could identify no prognostic effect of the KRAS or EGFR driver and TP53 tumor suppressor comutation. Our observation of a potential negative predictive effect of TP53/KRAS comutation requires validation.

// Angela Boros 1 , Ludovic Lacroix 2 , Benjamin Lacas 3, 8, 10 , Julien Adam 2 , Jean-Pierre Pignon 3, 8, 10 , Caroline Caramella 4 , David Planchard 5 , Vincent de Montpreville 6 , Eric Deutsch 1, 7, 9 , Antonin Levy 1 , Benjamin Besse 5, 7 , Cecile Le Pechoux 1 1 Radiation Oncology Department, Gustave Roussy, Villejuif, France 2 Biopathology Department, Gustave Roussy, Villejuif, France 3 Biostatistics and Epidemiolgy Unit, Villejuif, France 4 Imaging Department, Gustave Roussy, Villejuif, France 5 Medical Oncology Department, Gustave Roussy, Villejuif, France 6 Pathology Department, Marie Lannelongue, Le Plessis Robinson, France 7 Paris-Sud University, DHU TORINO, Paris, France 8 Paris-Saclay University, Paris, France 9 INSERM U1030, Villejuif, France 10 INSERM U1018, Villejuif, France Correspondence to: Benjamin Besse, email: Benjamin.BESSE@gustaveroussy.fr Keywords: locally advanced, non-small cell lung cancer, mutation, prognostic, chemotherapy Received: July 04, 2016 Accepted: February 15, 2017 Published: March 07, 2017 ABSTRACT Introduction: Chemo-radiation is standard treatment in locally advanced non-small cell lung cancers (NSCLC). The prognostic value of mutations has been poorly explored in this population. Results: Clinical data were collected from 190 patients and mutational profiles were obtained in 78 of them; 58 (74%) were males, 31 (40%) current smokers, 47/31 stage IIIA/IIIB and 40 (51%) adenocarcinoma. The following mutations were identified: EGFR 12% (9/78), KRAS 15% (12/78), BRAF 5% (3/65), PI3KCA 2% (1/57), NRAS 3% (1/32), and ALK+ (FISH) 4% (2/51). HER2 was not detected. Median follow-up was 3.1 years. Overall survival was evaluated by group; no significant differences were identified in median overall survival ( p = 0.21), with 29.4 months for the EGFR/ALK group ( n = 11), 12.8 months for other mutations ( n = 17), and 23.4 months for wild-type ( n = 50). The EGFR/ALK and other mutations groups had poorer median progression-free survival (9.6 and 6.0 months) compared to the wild-type group (12.0 months; multivariate hazard ratio 2.0 [95% CI, 0.9–4.2] and 2.8 [95% CI, 1.5–5.2] respectively, p = 0.003). Materials and Methods: We retrospectively reviewed all patients receiving radical treatment for locally advanced NSCLC in a single institution between January 2002 and June 2013. Next generation sequencing was performed on DNA from paraffin-embedded tissue. ALK rearrangements were detected by immunohistochemistry and/or FISH. Mutational prognostic value for Kaplan-Meier survival parameters was determined by log-rank tests and Cox proportional hazards models. Conclusions: Selected gene alterations may be associated with poorer progression-free survival in locally advanced radically treated NSCLC and their prognostic and/or predictive value merits further evaluation in a larger population.

International audience; IntroductionEvaluation of EGFR Mutation status for the administration of EGFR-TKIs in non-small cell lung Carcinoma (ERMETIC) was a prospective study designed to validate the prognostic value of EGFR/KRAS mutations in patients with advanced non–small-cell lung cancer (NSCLC), all receiving a first-generation tyrosine kinase inhibitor, erlotinib. ERMETIC2 was an ancillary project evaluating the clinical value of common EGFR/KRAS-mutated subclones regarding prognosis using highly sensitive molecular detection methods.Materials and MethodsTumor samples from 228 patients with NSCLC (59% adenocarcinoma, 37% women, and 19% never/former smokers) were available for reanalysis using alternative highly sensitive molecular techniques. A multivariate Cox model was used for prognostic analysis.ResultsUsing alternative highly sensitive techniques, 16 EGFR and 51 KRAS supplementary mutations were newly identified, all still exclusive, leading to an overall rate of 12.3% (n = 28) and 33.3% (n = 76), respectively. Using real-time polymerase chain reaction (hybridization probe), they were significantly associated with progression-free survival (P = .02) and overall survival (OS) (P = .01), which were better for EGFR-mutated patients for progression-free survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.28-0.78) and OS (HR, 0.56; 95% CI, 0.31-1), and worse for KRAS mutations and OS (HR, 1.63; 95% CI, 1.09-2.44). Using the most sensitive technique detection for KRAS–clamp polymerase chain reaction–KRAS mutated subclones did not impact OS.ConclusionsKRAS and EGFR mutations were detected in higher proportions by alternative highly sensitive molecular techniques compared with direct Sanger sequencing. However, minor KRAS-mutated subclones offered no prognostic value when representing less than 1% of the tumor cells.

Background This study aimed at applying the restricted mean survival time difference (rmstD) as an absolute outcome measure in a network meta-analysis and comparing the results with those obtained using hazard ratios (HR) from the individual patient data (IPD) network meta-analysis (NMA) on the role of chemotherapy for nasopharyngeal carcinoma (NPC) recently published by the MAC-NPC collaborative group (Meta-Analysis of Chemotherapy [CT] in NPC). Patients and methods Twenty trials (5144 patients) comparing radiotherapy (RT) with or without CT in non-metastatic NPC were included. Treatments were grouped in seven categories: RT alone (RT), induction CT followed by RT (IC-RT), RT followed by adjuvant CT (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival and locoregional control. The rmstD was estimated at t* = 10 years in each trial. Random-effect frequentist NMA models were applied. P score was used to rank treatments. Heterogeneity and inconsistency were evaluated. Results The three treatments that had the highest effect on OS with rmstD were CRT-AC, IC-CRT, and CRT (respective P scores of 92%, 72%, and 64%) compared to CRT-AC, CRT, and IC-CRT when using HR (respective P scores of 96%, 71%, and 63%). Of the 32 HR and rmstD analyzed, 5 had a different interpretation, 3 with a direction change (different direction of treatment effect) and 2 with a change in significance (same direction but a change in statistical significance). Results for secondary endpoints were overall in agreement. Conclusion The use of either HR or rmstD impacts the results of NMA. Given the sensitivity of HR to non-proportional hazards, this finding could have implications in terms of meta-analysis methodology. Electronic supplementary material The online version of this article (10.1186/s13643-019-0984-x) contains supplementary material, which is available to authorized users.

Introduction Innate immunity represents the first step of activation of the immune system and dictates the quality of adaptive immune responses. Studies have reported links between systemic inflammatory or innate immune markers and prognosis in patients with lung cancer. To our knowledge, the prospective and concomitant study of these systemic markers has never been performed. Methods Advanced treatment-naive non–small cell lung cancer (NSCLC) patients eligible for first-line platinum-based chemotherapy were prospectively included from December 2012 to July 2015 (N = 148). Blood samples of patients were collected before the first cycle for fresh NK cell phenotyping. Peripheral blood mononuclear cells were cryopreserved for natural cytotoxicity receptor (NCR) genotyping as well as sera for NCR's ligand quantification. Data on leukocytes, neutrophils and monocyte counts and lactate dehydrogenase (LDH) levels were extracted from electronic medical records. Results Among all studied markers, monocytosis, neutrophilia, leucocytosis, high LDH and sBAG6 levels and reduced levels of NCR3 transcripts were associated with poor overall survival (OS) in univariate analysis. The levels of NCR3 transcripts was linked to age, number of metastatic sites, monocyte counts, LDH and sBAG6 levels. Neutrophilia was associated to high sBAG6 levels. NCR3 was the unique innate immune parameter that remained as an independent factor associated with both OS (P = 0.003) and progression-free survival (P = 0.009) in the multivariate analysis. Conclusion This study brought evidence that these biomarkers are entangled; parameters associated with an inflammatory process were related to reduced levels of NCR3 transcripts. Finally, the level of NCR3 transcripts was independently associated with outcomes in treatment-naive patients with advanced NSCLC.

Objective To evaluate the effect of chemotherapy added to a surgical locoregional treatment (LRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Materials and Methods We studied the sub-group of trials with surgical LRT included in the meta-analysis on chemotherapy in head and neck cancer (MACH-NC). Data from published and unpublished randomized trials comparing the addition of chemotherapy to LRT in HNSCC patients were sought using electronic database searching for the period 1965–2000, hand searching and by contacting experts in the field. Trials with less than 60 patients, or preoperative radiotherapy or where the type of LRT could not be individually determined were excluded. All individual patient data were checked for internal consistency, compared with published reports, and validated with trialists. Data were pooled using a fixed-effect model. Heterogeneity was assessed using Cochrane test and I 2 statistic. Results Twenty-four trials were eligible (5000 patients). Chemotherapy improved overall survival (HR = 0.92 [95%CI: 0.85–0.99] p = 0.02). There was a significant interaction between treatment effect and timing of chemotherapy (p = 0.08 at pre-specified threshold of 0.10) with a greater effect for concomitant chemotherapy (HR = 0.79, 95%CI: 0.69–0.92). The benefit of chemotherapy was greater in women (HR women = 0.63, 95%CI: 0.50–0.80) compared to men (HR men = 0.96, 95%CI: 0.89–1.04; p for interaction = 0.001). Conclusions This analysis confirmed the benefit of concomitant chemotherapy added to surgical LRT. The role of induction therapy as yet to be determined as it did not improve OS. Women may benefit more than men from chemotherapy.

Objectives: This study compared the cost and quality of life (QoL) of 407 advanced colorectal cancer patients, randomly assigned to receive LV5FU2 followed by FOLFOX6 (sequential strategy) or FOLFOX6 followed by FOLFIRI (combination strategy). Methods: Costs were compared from the French health insurance perspective, until the end of the second line of treatment. Consumed resources, collected during the trial, included medicines, hospitalizations, examinations, and transportation. Valuations were made using 2009 and 2016 tariffs. QoL was assessed using the QLQ-C30 questionnaire and clinically significant variations were searched. Results: In 2009, the mean cost per patient was significantly lower for the sequential strategy compared to the combination strategy (18,061€ and 23,119€, p = 0.001). In 2016, the difference was no longer significant (16,876€ and 18,090€, p = 0.41) because oxaliplatin and irinotecan became generics. The QoL analysis (292 patients) showed that there was significantly less improvement of global health status in the sequential strategy than in the combination strategy (29% and 42%; p = 0.02) during first-line therapy. No significant differences were observed for emotional functioning (p = 0.45) and physical functioning (p = 0.07) or during second-line therapy. Conclusion: The choice to treat patients with advanced colorectal cancer using one or the other strategy cannot be based on costs or QoL.

// Antonin Levy 1,2,3 , Etienne Bardet 4 , Benjamin Lacas 5,6 , Jean-Pierre Pignon 5,6 , Julien Adam 7 , Ludovic Lacroix 7 , Xavier Artignan 8,10 , Pierre Verrelle 9 and Cecile Le Pechoux 1 1 Department of Radiation Oncology, Gustave Roussy, Universite Paris-Saclay, Institut Thoracique d’Oncologie (IOT), Villejuif, France 2 INSERM U1030, Molecular Radiotherapy, Gustave Roussy, Universite Paris-Saclay, Villejuif, France 3 Univ Paris Sud, Universite Paris-Saclay, Le Kremlin-Bicetre, France 4 Department of Medical Oncology, Institut de Cancerologie de l’Ouest, Nantes, France 5 Gustave Roussy, Universite Paris-Saclay, Department of Biostatistics and Epidemiology, Villejuif, France 6 INSERM U1018, CESP, Universite Paris-Sud, Universite Paris-Saclay, Villejuif, France 7 Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank (UMS3655 CNRS / US23 INSERM), INSERM Unit U981, Villejuif, France 8 Department of Radiation Oncology, University Hospital Grenoble, Grenoble, France 9 Department of Radiation Oncology, Centre Jean Perrin, Clermont-Ferrand, France 10 Department of Radiation Oncology, St Gregoire Hospital, St Gregoire, France Correspondence to: Cecile Le Pechoux, email: // Keywords : iressa, thoracic radiotherapy, lung cancer, phase II trial Received : July 06, 2016 Accepted : October 12, 2016 Published : October 18, 2016 Abstract Background: Gefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer. Patients and Methods: This phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status. Results: Due to a low accrual rate in this study, the sample size ( n = 50) was not reached. Sixteen patients were included in four centers, 50% had adenocarcinoma and 75% were male. Genomic alterations (7 patients studied) retrieved TP53 mutation in 2 patients and no EGFR mutation. Four weeks after radiotherapy, 3 patients (19%) had a partial response, 6 (38%) had a stable disease, and 7 had a progression (44%). Median overall survival was 11 months and median progression-free survival was 5 months. At the time of the last contact, 5 patients (31%) were still alive . Main toxicities were gastrointestinal (81%), cutaneous (81%), general (56%), and respiratory (50%). There were 12>G3 adverse events in 7 (47%) patients, and there was one toxic-death during the concomitant period due to an interstitial pneumonitis. There were two possible adverse events-related deaths during the chemotherapy period (pulmonary embolism ( n = 1) and sudden death after the administration of the 3 rd course of chemotherapy ( n = 1)). Conclusion: The benefit of Gefitinib-RT could not be confirmed due to premature trial discontinuation. Further evaluation is required, especially in patients with EGFR mutated NSCLC.

International audience; Head and neck cancers are a leading cause of cancer incidence and mortality, with over 800 000 new cases and 400 000 deaths estimated in 2018 by GLOBOCAN[1]. Over the years, a wide range of randomized controlled trials have been conducted to define the best treatment strategies for each disease site and tumor stage. These trials have evaluated the role of chemotherapy, altered fractionated radiotherapy, targeted therapy or radioprotectants. To help define treatment guidelines, individual patient data meta-analyses were conducted by collaborative groups led by the meta-analysis unit at Gustave Roussy Cancer Center, launched in 1994 by Jean Bourhis and Jean-Pierre Pignon. They have focused on the role of chemotherapy[2,3] or altered fractionation radiotherapy[4] in locally advanced head and neck squamous cell cancers (HNSCC), amifostine[5], and chemotherapy in nasopharyngeal cancer (NPC)[6]. Additional works have studied surrogate endpoints for HNSCC[7] and NPC[8], network meta-analyses for HNSCC[9] and NPC[10]; but also the impact of missing data on trial characteristics[11] or the use of alternative relative efficacy metrics such as the restricted mean survival time difference[12].The aim of this article is to focus on the relevance of meta-analyses today and tomorrow in a world where patients’ and tumors’ genomic profiling and tailored treatment could become the rule. We will concentrate on individual patient data meta-analyses, which is the gold standard for collecting and synthesizing evidence[13]. The medical literature is currently flooded with meta-analyses based on published data. A quick search on Pubmed performed on December 28th 2018 using the keywords “head neck cancer” and the built-in filter “meta-analysis” retrieved 2080 references, with more than 250 new “meta-analyses” performed each year since 2014. A minority of these is synthesizing comparative data prospectively collected, and only a handful is based on individual patient data.

Purpose Some publications suggest high rates of healthcare-associated infections (HAIs) and of nosocomial pneumonia portending a poor prognosis in ICU cancer patients. A better understanding of the epidemiology of HAIs in these patients is needed. Methods A retrospective analysis of all the patients hospitalized for ≥ 48 h during a 12-year period in the 12-bed ICU of the Gustave Roussy hospital, monitored prospectively for ventilator-associated pneumonia (VAP) and bloodstream infection (BSI) and for use of medical devices. Results During 3388 first stays in the ICU, 198 cases of VAP and 103 primary, 213 secondary, and 77 catheter-related BSIs were recorded. The VAP rate was 24.5/1000 ventilator days (95% confidence interval [CI] 21.2–28.0); the catheter-related BSI rate was 2.3/1000 catheter days (95% CI 1.8–2.8). The cumulative incidence during the first 25 days of exposure was 58.8% (95% CI 49.1–66.6%) for VAP, 8.9% (95% CI, 6.2–11.5%) for primary, 15.1% (95% CI 11.6–18.5%) for secondary and 5.0% (95% CI 3.2–6.8%) for catheter-related BSIs. VAP or BSIs were not associated with a higher risk of ICU mortality. Conclusions This is the first study to report HAI rates in a large cohort of critically ill cancer patients. Although both the incidence of VAP and the rate of BSI are higher than in general ICU populations, this does not impact patient outcomes. The occurrence of device-associated infections is essentially due to severe medical conditions in patients and to the characteristics of malignancy. Electronic supplementary material The online version of this article (10.1007/s00520-019-04800-6) contains supplementary material, which is available to authorized users.

Purpose The survival benefit with adjuvant chemotherapy for patients with resected stage II-III non–small-cell lung cancer (NSCLC) is modest. Efforts to develop prognostic or predictive biomarkers in these patients have not yielded clinically useful tests. We report findings from the Lung Adjuvant Cisplatin Evaluation (LACE)-Bio-II study, in which we analyzed next-generation sequencing and long-term outcomes data from > 900 patients with early-stage NSCLC treated prospectively in adjuvant landmark clinical trials. We used a targeted gene panel to assess the prognostic and predictive effect of mutations in individual genes, DNA repair pathways, and tumor mutation burden (TMB). Methods A total of 908 unmatched, formalin-fixed, paraffin-embedded, resected lung cancer tumor specimens were sequenced using a targeted panel of 1,538 genes. Stringent filtering criteria were applied to exclude germline variants and artifacts related to formalin fixation. Disease-free survival, overall survival, and lung cancer—specific survival (LCSS) were assessed in Cox models stratified by trial and adjusted for treatment, age, sex, performance score, histology, type of surgery, and stage. Results Nonsynonymous mutations were identified in 1,515 genes in 908 tumor samples. High nonsynonymous TMB (> 8 mutations/Mb) was prognostic for favorable outcomes (ie, overall survival, disease-free survival, and LCSS) in patients with resected NSCLC. LCSS benefit with adjuvant chemotherapy was more pronounced in patients with low nonsynonymous TMBs (≤ 4 mutations/Mb). Presence of mutations in DNA repair pathways, tumor-infiltrating lymphocytes, TP53 alteration subtype, and intratumor heterogeneity was neither prognostic nor predictive. Statistically significant effect of mutations in individual genes was difficult to determine due to high false-discovery rates. Conclusion High nonsynonymous TMB was associated with a better prognosis in patients with resected NSCLC. In addition, the benefit of adjuvant chemotherapy on LCSS was more pronounced in patients with low nonsynonymous TMBs. Studies are warranted to confirm these findings.

International audience; BACKGROUND:After curative-intent surgery for colorectal liver metastases (CRLM), liver recurrence occurs in more than 60% of patients, despite the administration of perioperative or adjuvant chemotherapy. This risk is even higher after resection of more than three CRLM. As CRLM are mostly supplied by arterial blood flow, hepatic arterial infusion (HAI) of chemotherapeutic agents after resection of CRLM is an attractive approach. Oxaliplatin-based HAI chemotherapy, in association with systemic fluoropyrimidines, has been shown to be safe and highly active in patients with CRLM. In a retrospective series of 98 patients at high risk of hepatic recurrence (≥4 resected CRLM), adjuvant HAI oxaliplatin combined with systemic chemotherapy was feasible and significantly improved disease-free survival compared to adjuvant, 'modern' systemic chemotherapy alone.METHODS/DESIGN:This study is designed as a multicentre, randomized, phase II/III trial. The first step is a non-comparative randomized phase II trial (power, 95%; one-sided alpha risk, 10%). Patients will be randomly assigned in a 1:1 ratio to adjuvant systemic FOLFOX (control arm) or adjuvant HAI oxaliplatin plus systemic LV5FU2 (experimental arm). A total 114 patients will need to be included. The main objective of this trial is to evaluate the potential survival benefit of adjuvant HAI with oxaliplatin after resection of at least 4 CRLM (primary endpoint: 18-month hepatic recurrence-free survival rate). We also aim to assess the feasibility of delivering at least 4 cycles of HAI (or i.v.) oxaliplatin after surgical treatment of at least 4 CRLM, the toxicity (NCI-CTC v4.0) of adjuvant HAI plus systemic chemotherapy, including HAI catheter-related complications, compared to systemic chemotherapy alone, and the efficacy of adjuvant HAI on hepatic and extra-hepatic recurrence-free (survival and overall survival).DISCUSSION:If 18-month hepatic recurrence-free survival is greater than 50% in the experimental arm, the study will be pursued in phase III, for which the primary endpoint will be 3-year recurrence-free survival rate. Patients randomized in the phase II will be included in the phase III, with an additional number of 106 patients.TRIAL REGISTRATION:ClinicalTrials.gov, NCT02494973 . Trial registration date: July 10, 2015.

Radiotherapy is the primary treatment of nasopharyngeal carcinoma and combination chemotherapy can enhance treatment outcomes for locoregionally advanced disease. The Intergroup 0099 study using concurrent-adjuvant cisplatin-based chemoradiotherapy was the first trial to demonstrate a survival benefit. Since then, there have been attempts to further improve the treatment results by altering the chemotherapy sequence, using different chemotherapeutic agents or schedules, and extending the use of chemotherapy to early-stage disease. This review provides an overview of the data and highlights the current controversies behind international guidelines.

Purpose The classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and WHO is based on the predominant histologic pattern—lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MIP), or solid (SOL)—present in the tumor. This classification has not been tested in multi-institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT). Patients and Methods Of 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups (LEP, ACN/PAP, and MIP/SOL). Primary end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. Significance level was set at .01 for pooled analysis. Results A total of 575 patients were included in this analysis. OS was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for MIP/SOL compared with LEP or ACN/PAP subgroup (P < .01); this remained marginally significant after adjustment. MIP/SOL patients (but not ACN/PAP) derived DFS and SDFS but not OS benefit from ACT (OS: HR, 0.71; 95% CI, 0.51 to 0.99; interaction P = .18; DFS: HR, 0.60; 95% CI, 0.44 to 0.82; interaction P = < .01; and SDFS: HR, 0.59; 95% CI, 0.42 to 0.81; interaction P = .01). Conclusion The new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for OS, but it seems predictive for disease-specific outcomes.

BACKGROUND AND PURPOSE: Evaluate the prognostic and predictive impact of HPV-associated p16-expression and assess the combined prognostic impact of p16 and smoking on altered fractionated radiotherapy (AFRT) for oropharyngeal cancer (OPC) within the frames of the update of the Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH). MATERIALS AND METHODS: Patients with OPC, known tumor p16-status and smoking history were identified from the MARCH update, resulting in a dataset of 815 patients from four randomized trials (RTOG9003, DAHANCA6&7, RTOG0129, ARTSCAN). Analysis was performed using a Cox model stratified by trial and adjusted on gender, age, T-stage, N-stage, type of radiotherapy fractionation, p16, smoking. Primary endpoint was progression-free survival (PFS). RESULTS: In total, 465 patients (57%) had p16-positive tumors and 350 (43%) p16-negative. Compared to p16-negative, p16-positive patients had significantly better PFS (HR = 0.42 [95% CI: 0.34-0.51], 28.9% absolute increase at 10 years) and OS (HR = 0.40 [0.32-0.49], 32.1% absolute increase at 10 years). No interaction between p16-status and fractionation schedule was detected. Smoking negatively impacted outcome; in the p16-positive subgroup, never smokers had significantly better PFS than former/current smokers (HR = 0.49 [0.33-0.75], 24.2% survival benefit at 10 years). CONCLUSIONS: No predictive impact of p16-status on response to AFRT could be detected but the strong prognostic impact of p16-status was confirmed and especially p16-positive never smoking patients have superior outcome after RT. BACKGROUND AND PURPOSE: Evaluate the prognostic and predictive impact of HPV-associated p16-expression and assess the combined prognostic impact of p16 and smoking on altered fractionated radiotherapy (AFRT) for oropharyngeal cancer (OPC) within the frames of the update of the Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH). MATERIALS AND METHODS: Patients with OPC, known tumor p16-status and smoking history were identified from the MARCH update, resulting in a dataset of 815 patients from four randomized trials (RTOG9003, DAHANCA6&7, RTOG0129, ARTSCAN). Analysis was performed using a Cox model stratified by trial and adjusted on gender, age, T-stage, N-stage, type of radiotherapy fractionation, p16, smoking. Primary endpoint was progression-free survival (PFS). RESULTS: In total, 465 patients (57%) had p16-positive tumors and 350 (43%) p16-negative. Compared to p16-negative, p16-positive patients had significantly better PFS (HR = 0.42 [95% CI: 0.34-0.51], 28.9% absolute increase at 10 years) and OS (HR = 0.40 [0.32-0.49], 32.1% absolute increase at 10 years). No interaction between p16-status and fractionation schedule was detected. Smoking negatively impacted outcome; in the p16-positive subgroup, never smokers had significantly better PFS than former/current smokers (HR = 0.49 [0.33-0.75], 24.2% survival benefit at 10 years). CONCLUSIONS: No predictive impact of p16-status on response to AFRT could be detected but the strong prognostic impact of p16-status was confirmed and especially p16-positive never smoking patients have superior outcome after RT.

Background: A marginal interaction between sex and the type of alkylating agent was observed for event‐free survival in the Euro‐EWING99‐R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta‐analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. Methods: A literature search produced two more eligible RCTs (EICESS92 and IRS‐IV). The endpoints were progression‐free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment‐by‐sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. Results: The meta‐analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro‐EWING99‐R1 (n = 856), EICESS92 (n = 155), and IRS‐IV (n = 517). There were 224 PFS events in Euro‐EWING99‐R1 and 200 in the validation set (EICESS92 + IRS‐IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment‐by‐sex interaction for PFS in Euro‐EWING99‐R1 (HR = 1.73, 95% CI = 1.00–3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55–1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment‐by‐sex interaction was not significant (HR = 1.31, 95% CI = 0.89–1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment‐by‐sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). Conclusion: Our meta‐analysis did not confirm the hypothesis of a treatment‐by‐sex interaction on efficacy or toxicity outcomes. Refereed/Peer-reviewed

BACKGROUND: There is increasing evidence that metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and that tumours arising from different sides of the colon (left versus right) have different clinical outcomes. Furthermore, previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type (wt) or RAS wt mCRC suggest that primary tumour location (side), might be both prognostic and predictive for clinical outcome. METHODS: This retrospective analysis investigated the prognostic and predictive influence of the localization of the primary tumour in patients with unresectable RAS wt mCRC included in six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus EGFR antibody therapy (experimental arm) with chemotherapy or chemotherapy and bevacizumab (control arms). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) for patients with left-sided versus right-sided tumours, and odds ratios (ORs) for objective response rate (ORR) were estimated by pooling individual study HRs/ORs. The predictive value was evaluated by pooling study interaction between treatment effect and tumour side. RESULTS: Primary tumour location and RAS mutation status were available for 2159 of the 5760 patients (37.5%) randomized across the 6 trials, 515 right-sided and 1644 left-sided. A significantly worse prognosis was observed for patients with right-sided tumours compared with those with left-sided tumours in both the pooled control and experimental arms for OS [HRs = 2.03 (95% CI: 1.69-2.42) and 1.38 (1.17-1.63), respectively], PFS [HRs = 1.59 (1.34-1.88) and 1.25 (1.06-1.47)], and ORR [ORs = 0.38 (0.28-0.50) and 0.56 (0.43-0.73)]. In terms of a predictive effect, a significant benefit for chemotherapy plus EGFR antibody therapy was observed in patients with left-sided tumours [HRs = 0.75 (0.67-0.84) and 0.78 (0.70-0.87) for OS and PFS, respectively] compared with no significant benefit for those with right-sided tumours [HRs = 1.12 (0.87-1.45) and 1.12 (0.87-1.44) for OS and PFS, respectively; P value for interaction

Introduction The class I human leucocyte antigen (HLA) molecules play a critical role as an escape mechanism of antitumoral immunity. HLA-A2 status has been evaluated as a prognostic factor in lung cancer, mostly in localized disease and with inconsistent findings. We evaluated the role of HLA-A2 status as a prognostic factor in a large and homogeneus cohort of advanced NSCLC patients. Methods Advanced NSCLC patients eligible for platinum-based chemotherapy were consecutively included in a single center between October 2009 and July 2015 in the prospective MSN study (NCT02105168). HLA-A2 status was analysed by flow cytometry. Clinical, pathological and molecular data were collected. A Cox model was used for prognostic analyses. Results Of 545 stage IIIB/IV NSCLC patients included, 344 (63%) were male, 466 (85%) were smokers, 447 (83%) had PS 0–1, 508 (93%) had stage IV, 407 (75%) had an adenocarcinoma and median age was 61 years (range, 21–84). Incidence of patients with EGFRmut, ALK-positive and KRASmut was 14% (49/361), 9% (29/333) and 31% (107/350), respectively. The overall rate of HLA-A2 positivity was 48%. No association was observed between HLA-A2 status and any patient or tumor characteristics analyzed. With a median follow-up of 27.1 months, median OS was 12.8 months [95%CI 11.0–14.6] in HLA-A2+ vs. 12.5 months [95%CI 10.4–15.3] in HLA-A2- patients (HR 1.05 [95%CI 0.86–1.29], p = 0.61). Median progression-free survival was similar in the two cohorts. Conclusion HLA-A2 status was not identified as prognostic for benefit in a large advanced NSCLC population treated with platinum-based chemotherapy.

Background We performed a randomized, non-comparative phase II study evaluating docetaxel in combination with either daily continuous (protracted IV) 5-fluorouracil or cisplatin administered weekly, concurrent to radiotherapy in the treatment of locally advanced pancreatic carcinoma. Results of the docetaxel plus cisplatin regimen are reported. Methods Forty chemotherapy-naive patients with locally advanced pancreatic carcinoma were randomly assigned to receive 5-fluorouracil and docetaxel or docetaxel 20 mg/m2 and cisplatin 20 mg/m2/week, plus concurrent radiotherapy for 6 weeks. The radiation dose to the primary tumour was 54 Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate. Results 51 patients from 7 centres were included in the docetaxel–cisplatin treatment group. Six-month non-progression rate was 39% (95% confidence interval: 26–53). Median overall survival was 9.6 months (95% confidence interval: 2.4–60.7); 6 complete and 8 partial responses were obtained. Six patients survived more than 2 years after their inclusion in the trial. Grade ≥3 toxicity was reported in 63% of patients; no treatment-related death occurred. Severe toxicities were mainly anorexia (22%), vomiting (20%) and fatigue (24%). Conclusions Despite inadequate efficacy according to the main end point, this regimen gave a satisfactory rate of objective response (27%) with tolerable toxicity.

Background Complete resection of non–small-cell lung cancer (NSCLC) offers the potential for cure after surgery and adjuvant chemotherapy. Patients may not benefit and may experience severe toxicity. There are no validated molecular tools to allow better patient selection. Materials and Methods The LACE-Bio (LACE [Lung Adjuvant Cisplatin Evaluation]) project includes 4 trials (International Adjuvant Lung Cancer Trial [IALT], Adjuvant Navelbine International Trialist Association [ANITA], JBR10, and Cancer and Leukemia Group B (CALGB)-9633). Immunohistochemistry biomarkers shown in one trial to have a prognostic/predictive effect on overall survival were tested. Results The majority of the promising biomarkers could not be validated; the prognostic effect of tumor infiltrating lymphocytes and β-tubulin was confirmed. Potential causes include tissue fixation, storage, the use of tissue microarrays, and varying reagent/antibody batches. Conclusions Immunohistochemistry assays from single trials may be misleading and require validation before being used for patient selection. LACE-Bio-2 is evaluating potential genomic biomarkers that may allow more precise selection of patients with NSCLC for adjuvant chemotherapy in NSCLC.

Introduction: Modified fractionation radiotherapy (RT), delivering multiple fractions per day or shortening the overall treatment time, improves overall survival for non -small-cell lung cancer (NSCLC) patients compared with conventional fractionation RT (CRT). However, its cost effectiveness is unknown. Therefore, we aimed to examine and compare the cost effectiveness of different modified RT schemes and CRT in the curative treatment of unresected NSCLC patients. Methods: A probabilistic Markov model was developed based on individual patient data from the meta-analysis of radiotherapy in lung cancer (N = 2000). Dutch health care costs, quality-adjusted life years (QALYs), and net monetary benefits (NMBs) were compared between two accelerated schemes (very accelerated RT [VART] and moderately accelerated RT [MART]), two hyperfractionated schemes (using an identical (HRTI) or higher (HRTH) total treatment dose than CRT) and CRT. Results: All modified fractionations were more effective and costlier than CRT (1.12 QALYs, Euro24,360). VART and MART were most effective (1.30 and 1.32 QALYs) and cost Euro25,746 and Euro26,208, respectively. HRTI and HRTH yielded less QALYs than the accelerated schemes (1.27 and 1.14 QALYs), and cost Euro26,199 and Euro29,683, respectively. MART had the highest NMB (Euro79,322; 95% confidence interval [CI], Euro35,478-Euro133,648) and was the most cost-effective treatment followed by VART (Euro78,347; 95% CI, Euro64,635-Euro92,526). CRT had an NMB of Euro65,125 (95% CI, Euro54,663-Euro75,537). MART had the highest probability of being cost effective (43%), followed by VART (31%), HRTI (24%), HRTH (2%), and CRT (0%). Conclusion: Implementing accelerated RT is almost certainly more efficient than current practice CRT and should be recommended as standard RT for the curative treatment of unresected NSCLC patients not receiving concurrent chemo-radiotherapy.

Purpose We 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). Methods KRAS 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 Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: 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). Conclusion KRAS 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.

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.).

Background: The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods: We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings: In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95% CI 0·83-0·83 in trials without radiotherapy, and 0·87, 0·87-0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95% CI 0·88-0·95 in trials without radiotherapy and 0·99, 0·98-1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77-0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89-0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95% CI 0·71-0·71 for concurrent chemotherapy and ρ2=0·61, 0·61-0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95% CI 0·77-0·92 for concurrent chemotherapy and R2=0·95, 0·91-0·98 for modified vs standard radiotherapy). Interpretation: We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding: Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis. © 2013 Elsevier Ltd., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Our objective was to evaluate progression-free survival (PFS) and distant metastasis–free survival (DMFS) as surrogate end points for overall survival (OS) in randomized trials of chemotherapy in loco-regionally advanced nasopharyngeal carcinomas (NPCs). Methods: Individual patient data were obtained from 19 trials of the updated Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) plus one additional trial (total = 5144 patients). Surrogacy was evaluated at the individual level using a rank correlation coefficient ρ and at the trial level using a correlation coefficient R2 between treatment effects on the surrogate end point and OS. A sensitivity analysis was performed with two-year PFS/DMFS and five-year OS. Results: PFS was strongly correlated with OS at the individual level (ρ = 0.93, 95% confidence interval [CI] = 0.93 to 0.94) and at the trial level (R2 = 0.95, 95% CI = 0.47 to 1.00). For DMFS, too, the individual-level correlation with OS was strong (ρ = 0.98, 95% CI = 0.98 to 0.98); at trial level, the correlation was high but the regression adjusted for measurement error could not be computed (unadjusted R2 = 0.96, 95% CI = 0.94 to 0.99). In the sensitivity analysis, two-year PFS was highly correlated with five-year OS at the individual level (ρ = 0.89, 95% CI = 0.88 to 0.90) and at the trial level (R2 = 0.85, 95% CI = 0.46 to 1.00); two-year DMFS was highly correlated with five-year OS at the individual level (ρ = 0.95, 95% CI = 0.94 to 0.95) and at the trial level (R2 = 0.78, 95% CI = 0.33 to 1.00). Conclusions: PFS and DMFS are valid surrogate end points for OS to assess treatment effect of chemotherapy in loco-regionally advanced NPC, while PFS can be measured earlier.

Purpose The role of adjuvant chemotherapy (AC) or induction chemotherapy (IC) in the treatment of locally advanced nasopharyngeal carcinoma is controversial. The individual patient data from the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma database were used to compare all available treatments. Methods All randomized trials of radiotherapy (RT) with or without chemotherapy in nonmetastatic nasopharyngeal carcinoma were considered. Overall, 20 trials and 5,144 patients were included. Treatments were grouped into seven categories: RT alone (RT), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). P-score was used to rank the treatments. Fixed- and random-effects frequentist network meta-analysis models were applied. Results The three treatments with the highest probability of benefit on overall survival (OS) were CRT-AC, followed by CRT and IC-CRT, with respective hazard ratios (HRs [95% CIs]) compared with RT alone of 0.65 (0.56 to 0.75), 0.77 (0.64 to 0.92), and 0.81 (0.63 to 1.04). HRs (95% CIs) of CRT-AC compared with CRT for OS, progression-free survival (PFS), locoregional control, and distant control (DC) were, respectively, 0.85 (0.68 to 1.05), 0.81 (0.66 to 0.98), 0.70 (0.48 to 1.02), and 0.87 (0.61 to 1.25). IC-CRT ranked second for PFS and the best for DC. CRT never ranked first. HRs of CRT compared with IC-CRT for OS, PFS, locoregional control, and DC were, respectively, 0.95 (0.72 to 1.25), 1.13 (0.88 to 1.46), 1.05 (0.70 to 1.59), and 1.55 (0.94 to 2.56). Regimens with more chemotherapy were associated with increased risk of acute toxicity. Conclusion The addition of AC to CRT achieved the highest survival benefit and consistent improvement for all end points. The addition of IC to CRT achieved the highest effect on DC.

Meta-analyses of randomized trials using individual-participant data, which represent the highest level of evidence for the evaluation of a treatment effect, are now used in different contexts in clinical research. This article aims at reviewing some of these new applications. Meta-analyses are increasingly used in economic evaluation, which implies new measure outcomes of the treatment effect, as well as in biomarkers evaluations thanks to their higher statistical power and the possibility to validate findings on independent data. This article also considers the perspectives opened up by new data sources, such as randomized trials registers, and data sharing policies.

Background The role of postoperative radiotherapy (PORT) in the treatment of patients with completely resected non-small cell lung cancer (NSCLC) was not clear. A systematic review and individual participant data meta-analysis was undertaken to evaluate available evidence from randomised controlled trials (RCTs). These results were first published in Lung Cancer in 2013. Objectives To evaluate the effects of PORT on survival and recurrence in patients with completely resected NSCLC. To investigate whether predefined patient subgroups benefit more or less from PORT. Search methods We supplemented MEDLINE and CANCERLIT searches (1965 to 8 July 2016) with information from trial registers, handsearching of relevant meeting proceedings and discussion with trialists and organisations. Selection criteria We included trials of surgery versus surgery plus radiotherapy, provided they randomised participants with NSCLC using a method that precluded prior knowledge of treatment assignment. Data collection and analysis We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. We sought data on all participants from those responsible for the trial. We obtained updated individual participant data (IPD) on survival and date of last follow-up, as well as details on treatment allocation, date of randomisation, age, sex, histological cell type, stage, nodal status and performance status. To avoid potential bias, we requested information on all randomised participants, including those excluded from investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. Main results We identified 14 trials evaluating surgery versus surgery plus radiotherapy. Individual participant data were available for 11 of these trials, and our analyses are based on 2343 participants (1511 deaths). Results show a significant adverse effect of PORT on survival, with a hazard ratio of 1.18, or an 18% relative increase in risk of death. This is equivalent to an absolute detriment of 5% at two years (95% confidence interval (CI) 2% to 9%), reducing overall survival from 58% to 53%. Subgroup analyses showed no differences in effects of PORT by any participant subgroup covariate. We did not undertake analysis of the effects of PORT on quality of life and adverse events. Investigators did not routinely collect quality of life information during these trials, and it was unlikely that any benefit of PORT would offset the observed survival disadvantage. We considered risk of bias in the included trials to be low. Authors' conclusions Results from 11 trials and 2343 participants show that PORT is detrimental to those with completely resected non-small cell lung cancer and should not be used in the routine treatment of such patients. Results of ongoing RCTs will clarify the effects of modern radiotherapy in patients with N2 tumours.

Background: Estimates of life-expectancy are a key input to cost-effectiveness analysis (CEA) models for cancer treatments. Due to limited follow-up in Randomized Controlled Trials (RCTs), parametric models are frequently used to extrapolate survival outcomes beyond the RCT period.However, different parametric models that fit the RCT data equally well may generate highly divergent predictions of treatment-related gain in life expectancy. Objectives: We investigate the use of information external to the RCT data to inform model choice and estimation of life-expectancy.Methods: We used Bayesian multi-parameter evidence synthesis to combine the RCT data with external information on general population survival, conditional survival from cancer registry databases, and expert opinion on the time course of the treatment effect. We illustrate with a 5 year follow-up RCT of cetuximab plus radiotherapy versus radiotherapy alone for head and neck cancer.Results: Standard survival time distributions were insufficiently flexible to simultaneously fit both the RCT data and external data on general population survival. Using spline models we were able to estimate a model that was consistent with the trial data and all external data. A model integrating all sources of internal and external evidence achieved an adequate fit and predicted a 4.7 months (95% CrL: 0.4; 9.1) gain in life expectancy due to Cetuximab. Conclusions: Long-term extrapolation using parametric models based on RCT data alone is highly unreliable and these models are unlikely to be consistent with external data. External data can be integrated with RCT data using spline models to enable long-term extrapolation. Conditional survival data could be used for many cancers and general population survival may have a role in other conditions. The use of external data should be guided by knowledge of natural history and treatment mechanisms.

International audience; BackgroundChemotherapy combined with radiotherapy is the standard treatment of “limited-stage” small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and chemotherapy.Material and methodsWe performed a meta-analysis of individual patient data in randomised trials comparing earlier versus later radiotherapy, or shorter vs. longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival.ResultsTwelve trials with 2,668 patients were eligible. Data from nine trials comprising 2,305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, “earlier or shorter” vs. “later or longer” thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of “earlier or shorter” radiotherapy among trials with a similar proportion of patients who were compliant with chemotherapy (defined as having received 100% or more of the planned chemotherapy cycles) in both arms (HR 0.79, 95% CI 0.69–0.91) and in favour of “later or longer” radiotherapy among trials with different chemotherapy compliance (HR 1.19, 1.05–1.34, interaction test p

Introduction Tumor protein p53 gene ( TP53 ) mutations are common in stage I through III non–small cell lung cancer, but clinical trials have shown inconsistent results regarding their relationship to the effects of adjuvant therapy. The objective is to clarify their putative prognostic and predictive effects. Methods A pooled analysis of TP53 mutations (exons 5–8) was conducted in four randomized trials (the International Adjuvant Lung Cancer Trial, J BRonchus 10, Cancer and Leukemia Group B-9633, and Adjuvant Navelbine International Trialist Association trial) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Hazard ratios (HRs) and 95% confidence intervals (CIs) of mutant versus wild-type (WT) TP53 for overall survival (OS) and disease-free survival (DFS) were estimated using a multivariable Cox model stratified on trial and adjusted on sex, age, and clinicopathological variables. Predictive value was evaluated with an interaction between treatment and TP53 . Results A total of 1209 patients (median follow-up 5.5 years) were included. There were 573 deaths (47%) and 653 DFS events (54%). Mutations (434 [36%]) had no prognostic effect (OBS HR OS = 0.99, 95% CI: 0.77–1.28, p = 0.95; HR DFS = 0.99, 95% CI: 0.78–1.25, p = 0.92) but were marginally predictive of benefit from ACT for OS (test for interaction: OS, p = 0.06; DFS, p = 0.11). Patients with WT TP53 had a tendency toward better outcomes with ACT than did those in the OBS group (HR OS = 0.77, 95% CI: 0.62–0.95, p = 0.02; HR DFS = 0.75, 95% CI: 0.62–0.92, p = 0.005). In the ACT arm, a deleterious effect of mutant versus WT TP53 was observed (HR OS = 1.40, 95% CI: 1.10–1.78, p = 0.006; HR DFS = 1.31, 95% CI: 1.04–1.64, p = 0.02). Conclusions TP53 mutation had no prognostic effect but was marginally predictive for survival from ACT. In patients who received ACT, TP53 mutation tended to be associated with shorter survival than wild-type TP53 .

Purpose In lung cancer, randomized trials assessing hyperfractionated or accelerated radiotherapy seem to yield conflicting results regarding the effects on overall (OS) or progression-free survival (PFS). The Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group decided to address the role of modified radiotherapy fractionation. Material and Methods We performed an individual patient data meta-analysis in patients with nonmetastatic lung cancer, which included trials comparing modified radiotherapy with conventional radiotherapy. Results In non–small-cell lung cancer (NSCLC; 10 trials, 2,000 patients), modified fractionation improved OS as compared with conventional schedules (hazard ratio [HR] = 0.88, 95% CI, 0.80 to 0.97; P = .009), resulting in an absolute benefit of 2.5% (8.3% to 10.8%) at 5 years. No evidence of heterogeneity between trials was found. There was no evidence of a benefit on PFS (HR = 0.94; 95% CI, 0.86 to 1.03; P = .19). Modified radiotherapy reduced deaths resulting from lung cancer (HR = 0.89; 95% CI, 0.81 to 0.98; P = .02), and there was a nonsignificant reduction of non–lung cancer deaths (HR = 0.87; 95% CI, 0.66 to 1.15; P = .33). In small-cell lung cancer (SCLC; two trials, 685 patients), similar results were found: OS, HR = 0.87, 95% CI, 0.74 to 1.02, P = .08; PFS, HR = 0.88, 95% CI, 0.75 to 1.03, P = .11. In both NSCLC and SCLC, the use of modified radiotherapy increased the risk of acute esophageal toxicity (odds ratio [OR] = 2.44 in NSCLC and OR = 2.41 in SCLC; P < .001) but did not have an impact on the risk of other acute toxicities. Conclusion Patients with nonmetastatic NSCLC derived a significant OS benefit from accelerated or hyperfractionated radiotherapy; a similar but nonsignificant trend was observed for SCLC. As expected, there was increased acute esophageal toxicity.

Introduction: Surgical resection of an undiagnosed lung lesion may lead to unintentional removal of small-cell lung cancer (SCLC). The benefit of perioperative chemotherapy in resected SCLC or large-cell neuroendocrine carcinomas (LCNEC) is not clear. Methods: This retrospective analysis included limited disease SCLC and LCNEC that had been surgically removed between 1979 and 2007 at a single institution. Perioperative treatments were analyzed, and survival followed up. Log rank tests were used to compare overall survival. Results: Among 74 patients who had a tumor resection, 45 received chemotherapy, four had preoperative radiotherapy, and 21 had postoperative radiotherapy. Eleven patients were women. The median age was 64 in the surgery group and 58 in the surgery plus chemotherapy group, and four and 11 patients in these groups, respectively, had LCNEC. There were 10 node positive tumors and only two incomplete resections in the surgery group versus 27 node positive tumors and three incomplete resections in the surgery plus chemotherapy group. The median follow-up was shorter in the group with surgery alone: 4.5 years (1.4–7) versus 5.8 years (0.6–19.6). Among the patients with a survival or a follow-up of at least 6 months, the median survival was 2.3 and 6.1 years in the surgery (n = 20) and surgery plus chemotherapy (n = 39) groups, respectively, such that the hazard ratio for death was 0.48 (95% confidence interval, 0.24–0.99, p=0.04). Conclusion: These results suggest that perioperative chemotherapy may be beneficial in patients with resected SCLC or LCNEC.

Objective. Hepatocellular carcinoma (HCC) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis. We assessed the safety, efficacy, and potential biomarkers of activity of bevacizumab in patients with advanced HCC. Methods. In this phase II trial, eligible patients received bevacizumab, 5 mg/kg or 10 mg/kg every 2 weeks. The disease-control rate at 16 weeks (16W-DCR) was the primary endpoint. Circulating endothelial cells (CECs) and plasma cytokines and angiogenic factors (CAFs) were measured at baseline and throughout treatment. Results. The 16W-DCR was 42% (95% confidence interval, 27%–57%). Six of the 43 patients who received bevacizumab achieved a partial response (objective response rate [ORR], 14%). Grade 3–4 asthenia, hemorrhage, and aminotransferase elevation occurred in five (12%), three (7%), and three (7%) patients, respectively. During treatment, placental growth factor markedly increased, whereas vascular endothelial growth factor (VEGF)-A dramatically decreased (p < .0001); soluble VEGF receptor-2 (p < .0001) and CECs (p = .03) transiently increased on day 3. High and increased CEC counts at day 15 were associated with the ORR (p = .04) and the 16W-DCR (p = .02), respectively. Lower interleukin (IL)-8 levels at baseline (p = .01) and throughout treatment (p ≤ .04) were associated with the 16W-DCR. High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times (p ≤ .04). Conclusion. Bevacizumab is active and well tolerated in patients with advanced HCC. The clinical value of CECs, IL-6, and IL-8 warrants further investigation.

Background 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 chemonaive 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. Methods Patients received B (1.5 mg/m 2 ) 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. Results 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. Conclusions 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.

Objective Different treatments have been investigated in head and neck cancers (HNCs) but not all of them have been appraised using pairwise comparison. This has resulted in failure to directly identify the best treatment with standard methods. Mixed treatment comparison (MTC) meta-analysis allows one to perform simultaneous inference regarding all treatments and select the best among them. Study Design and Setting We applied MTC models to the Meta-Analyses of Chemotherapy and Radiotherapy in HNC, which pooled individual patient data concerning more than 24,000 patients involved in 102 trials. Fixed- and random-effects models, models with or without consistency factors, possibly adapted to multiarm trials are discussed. Results Altered fractionated concomitant chemoradiotherapy (AF-CRT) leads to the highest probability of survival in nonmetastatic HNC. The probability that AF-CRT is the best treatment is 94% with random-effects models. There was no relevant inconsistency. When only the most recent trials were selected, AF-CRT and concomitant chemoradiotherapy (CRT) were the two best treatments. AF-CRT remains better than CRT but with a lower posterior probability. Conclusion MTC is a powerful method for investigating networks of randomized trials. Homogeneity, similarity of trial designs, populations, and the consistency of the network should be thoroughly checked.