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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

This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non–small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. The prognostic and predictive values of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathologic prognostic factors, and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed the association of TP53 mutation status and miR-34a/b/c expression, epidermal growth factor receptor and KRAS mutation status, and miR-21 and Let-7a expression. Finally, the association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 for which a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the microRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort with radically resected NSCLC, randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only. Cancer Res; 70(21); 8288–98. ©2010 AACR.

Supplementary Appendix 1 from MicroRNA Expression and Clinical Outcomes in Patients Treated with Adjuvant Chemotherapy after Complete Resection of Non–Small Cell Lung Carcinoma

Supplementary Figure 1 from MicroRNA Expression and Clinical Outcomes in Patients Treated with Adjuvant Chemotherapy after Complete Resection of Non–Small Cell Lung Carcinoma

Supplementary Tables 1-9 from MicroRNA Expression and Clinical Outcomes in Patients Treated with Adjuvant Chemotherapy after Complete Resection of Non–Small Cell Lung Carcinoma

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.

Introduction Individual patient data (IPD) present particular advantages in network meta-analysis (NMA) because interactions may lead an aggregated data (AD)-based model to wrong a treatment effect (TE) estimation. However, fewer works have been conducted for IPD with time-to-event contrary to binary outcomes. We aimed to develop a general frequentist one-step model for evaluating TE in the presence of interaction in a three-node NMA for time-to-event data. Methods One-step, frequentist, IPD-based Cox and Poisson generalized linear mixed models were proposed. We simulated a three-node network with or without a closed loop with (1) no interaction, (2) covariate-treatment interaction, and (3) covariate distribution heterogeneity and covariate-treatment interaction. These models were applied to the NMA (Meta-analyses of Chemotherapy in Head and Neck Cancer [MACH-NC] and Radiotherapy in Carcinomas of Head and Neck [MARCH]), which compared the addition of chemotherapy or modified radiotherapy (mRT) to loco-regional treatment with two direct comparisons. AD-based (contrast and meta-regression) models were used as reference. Results In the simulated study, no IPD models failed to converge. IPD-based models performed well in all scenarios and configurations with small bias. There were few variations across different scenarios. In contrast, AD-based models performed well when there were no interactions, but demonstrated some bias when interaction existed and a larger one when the modifier was not distributed evenly. While meta-regression performed better than contrast-based only, it demonstrated a large variability in estimated TE. In the real data example, Cox and Poisson IPD-based models gave similar estimations of the model parameters. Interaction decomposition permitted by IPD explained the ecological bias observed in the meta-regression. Conclusion The proposed general one-step frequentist Cox and Poisson models had small bias in the evaluation of a three-node network with interactions. They performed as well or better than AD-based models and should also be undertaken whenever possible.

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.

Nasopharyngeal carcinoma is a rare condition, with less than 300 cases occurring per year in France. Its treatment can be difficult due to the importance of side effects, but tumor control is usually excellent following a well conducted chemoradiotherapy. This article summarizes the recent advances in nasopharyngeal cancer diagnosis, classification, treatment, surveillance and management of recurrences. Chemotherapy timing is discussed, along with arguments in favor of induction chemotherapy in locally advanced cases. As a survival advantage has been suggested for when patients are treated in high volume center it seems reasonable to refer these young patients for treatment to tertiary expert centers, especially given the low incidence of the disease.

Background Adjuvant chemotherapy (ACT) provides modest benefit in resected non-small cell lung cancer (NSCLC) patients. Genome-wide studies have identified gene copy number aberrations (CNA), but their prognostic implication is unknown. Methods DNA from 1,013 FFPE tumor samples from three pivotal multicenter randomized trials (ACT vs. control) in the LACE-Bio consortium (median follow-up: 5.2 years) was successfully extracted, profiled using a molecular inversion probe SNP assay, normalized relative to a pool of normal tissues and segmented. Minimally recurrent regions were identified. P values were adjusted to control the false discovery rate (Q values). Results A total of 976 samples successfully profiled, 414 (42%) adenocarcinoma (ADC), 430 (44%) squamous cell carcinoma (SCC) and 132 (14%) other NSCLC; 710 (73%) males. We identified 431 recurrent regions, with on average 51 gains and 43 losses; 253 regions (59%) were ≤3 Mb. Most frequent gains (up to 48%) were on chr1, 3q, 5p, 6p, 8q, 22q; most frequent losses (up to 40%) on chr3p, 8p, 9p. CNA frequency of 195 regions was significantly different (Q≤0.05) between ADC and SCC. Fourteen regions (7p11-12, 9p21, 18q12, and 19p11-13) were associated with disease-free survival (DFS) (univariate P≤0.005, Q

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.

IMPORTANCE Both α-emitting and β-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and β-emitting RIs. OBJECTIVE To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with β-emitting RIs. DATA SOURCES PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018. STUDY SELECTION Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data. DATA EXTRACTION AND SYNTHESIS Individual patient datawere requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I2 and was accounted by a random-effects (RE) model. MAIN OUTCOMES AND MEASURES Overall survival; secondary outcomeswere symptomatic skeletal event (SSE)–free survival and adverse events. RESULTS Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95%CI, 0.77-0.95; P = .004) with high heterogeneity (χ2 5 = 24.46; P < .001; I2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95%CI, 0.61-1.06; P = .12; τ2 = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the α-emitting RI 223Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the β-emitting RI strontium-89 (HR, 0.96; 95%CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95%CI, 0.73-0.92; P < .001) (between-trial heterogeneity: χ2 3 = 6.51; P = .09; I2 = 54%) using an FE model and an HR of 0.80 (95%CI, 0.65-0.99; P = .04; τ2 = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95%CI, 0.69-0.93; P = .004) (between-trial heterogeneity: χ2 3 = 6.71; P = .08; I2 = 55%) when using an FE model and was 0.76 (95%CI, 0.58-1.01; P = .06; τ2 = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95%CI, 1.17-1.88; P = .001). CONCLUSIONS AND RELEVANCE In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted α-emitting but not β-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity.

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.

In the last decade, a new method has emerged called 'network meta-analysis' to take into account all randomized trials in a given clinical setting to provide relative effectiveness between different treatments, whether or not they have been compared (pairwise) in randomized controlled trials. Network meta-analyses combine the results of direct comparisons from randomized trials with indirect comparisons between trials (i.e. when two treatments were not compared with each other, but have been studied in relation to a common comparator). The purpose of this note is to explain this method, its relevance and its limitations. A worked example in non-metastatic head and neck cancer is presented as illustration.

In oncology, the international WHO and RECIST criteria have allowed the standardization of tumor response evaluation in order to identify the time of disease progression. These semi-quantitative measurements are often used as endpoints in phase II and phase III trials to study the efficacy of new therapies. However, through categorization of the continuous tumor size, information can be lost and they can be challenged by recently developed methods of modeling biomarkers in a longitudinal way. Thus, it is of interest to compare the predictive ability of cancer progressions based on categorical criteria and quantitative measures of tumor size (left-censored due to detection limit problems) and/or appearance of new lesions on overall survival. We propose a joint model for a simultaneous analysis of three types of data: a longitudinal marker, recurrent events, and a terminal event. The model allows to determine in a randomized clinical trial on which particular component treatment acts mostly. A simulation study is performed and shows that the proposed trivariate model is appropriate for practical use. We propose statistical tools that evaluate predictive accuracy for joint models to compare our model to models based on categorical criteria and their components. We apply the model to a randomized phase III clinical trial of metastatic colorectal cancer, conducted by the Federation Francophone de Cancerologie Digestive (FFCD 2000-05 trial), which assigned 410 patients to two therapeutic strategies with multiple successive chemotherapy regimens.

6523 Background: Based on an individual patient data (IPD) network meta-analysis (NMA) of 20 randomized trials and 5,144 patients (pts), the MAC-NPC collaborative group has shown that the addition of adjuvant chemotherapy (AC) to chemo-radiotherapy (CRT) achieved the highest survival benefit in nasopharyngeal carcinoma (NPC; Ribassin-Majed JCO 2017). Here, we updated the meta-analysis with the addition of 8 trials. Methods: Trials of Radiotherapy (RT) with or without chemotherapy (CT) in patients with non-metastatic NPC were identified and updated IPD obtained. Both Western and Chinese medical literatures were searched. Overall Survival (OS) was the main endpoint. Fixed and random-effects frequentist NMA models were applied, network heterogeneity and consistency were evaluated. P-score was used to rank the treatments. R software - netmeta package was used to perform the analyses. Treatments were grouped in the following categories: RT alone (RT), induction chemotherapy followed by RT (IC-RT), induction chemotherapy without taxanes followed by concomitant chemoradiotherapy (ICtax(-)-CRT), induction chemotherapy with taxanes followed by concomitant chemoradiotherapy (ICtax(+)-CRT), concomitant chemoradiotherapy (CRT), concomitant chemoradiotherapy followed by adjuvant chemotherapy (CRT-AC) and RT followed by adjuvant chemotherapy (RT-AC). Results: Overall 28 trials and 8,214 pts were included. Median follow-up was 7.2 years. There was no heterogeneity in the NMA. There was inconsistency in the main analysis, which disappeared after the exclusion of 2 outlier trials. ICtax(+)-CRT ranked the best treatment for OS with a P-Score of 91%. Hazard ratio [HR, 95% Confidence Interval] for ICtax(+)-CRT was 0.75 [0.59-0.96] compared to CRT and 0.92 [0.69-1.24] compared to CRT-AC (second best treatment in raking with a P-Score of 85%; see league table below). When the 2 types of IC were merged, CRT-AC ranked the first followed by IC-CRT with P-Scores of 93% and 86% respectively, with a HR of 0.97 [0.84-1.14] for CRT-AC vs. IC-CRT. Conclusions: This IPD NMA of the treatment of locally advanced NPC demonstrates that the addition of IC or AC to CRT improves disease control probability and survival over CRT alone. Data on progression-free survival, locoregional and distant control will be presented at the meeting. [Table: see text]

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.

Background: Predictors to identify which patients with locoregionally advanced head and neck cancer (LAHNC) benefit from intensive treatment are lacking. We sought to test the hypothesis that patients with a higher risk of cancer recurrence relative to competing mortality (ω score) selectively benefit from altered fractionation (AFX; MARCH data) and/or chemotherapy (MACH-NC data). Methods: We analyzed 22,339 LAHNC patients treated on 81 randomized trials testing AFX (MARCH data set) or chemotherapy (MACH-NC dataset). We applied generalized competing event regression to the control arms in MARCH, stratifying patients by tertile according to ω score. Model covariates were age, performance status (PS), sex, site, T and N category, p16 status, and smoking history. We externally validated the classifier on the MACH-NC dataset. We tested for interactions between ω score and treatment effects on overall survival (OS). Findings: Factors associated with a higher ω score were lower age, better PS, oral cavity site, higher T/N category, and p16 negative/unknown status. The effect of AFX on OS was greater in patients with high (hazard ratio [HR], 0.92; 95% CI, 0.85 to 0.99) and medium (HR, 0.91; 95% confidence interval [CI], 0.84 to 0.98) vs. low ω score (HR, 0.97; 95% CI, 0.90 to 1.05; p=0.086 for interaction). The effect of chemotherapy on OS was significantly greater in patients with high (HR, 0.81; 95% CI, 0.75 to 0.88) and medium (HR, 0.86; 95% CI, 0.78 to 0.88) vs. low ω score (HR, 0.96; 95% CI, 0.86 to 1.08; p=0.011 for interaction). Interpretation: 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. Funding Statement: Ligue National Contre le Cancer, Institut National du Cancer (PHRC-K 10-02-58; PHRC-K-15-189), Programme d'Actions Integrees de Recherche (2011-1-VADS-04), UC San Diego Head and Neck Cancer Center. Declaration of Interests: KZ, BL, LKV, QTL, VG, JO, AH, BZ, MKBP, BB, MGG, GS, BO, CF, JB, HS, JH, SM, JPP, LKM – none; FR is an employee of Innate Pharma, Marseille (France). Ethics Approval Statement: Analysis and reporting conformed to the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, and followed a pre-specified protocol for the analysis.

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.

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.