Ariane Dunant

Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group

PURPOSE Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy. PATIENTS AND METHODS Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial. RESULTS With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin. CONCLUSION Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.

Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case–control study (EuroSCAR)

Background  Acute generalized exanthematous pustulosis (AGEP) is a disease characterized by the rapid occurrence of many sterile, nonfollicular pustules usually arising on an oedematous erythema often accompanied by leucocytosis and fever. It is usually attributed to drugs.

ERCC1 Isoform Expression and DNA Repair in Non-Small-Cell Lung Cancer

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.).

Long-Term Results of the International Adjuvant Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected Lung Cancer

PURPOSE Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients with non-small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up. PATIENTS AND METHODS Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration. Results The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06). CONCLUSION These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.

Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial

BACKGROUND The optimum dose of prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (SCLC) is unknown. A meta-analysis suggested that the incidence of brain metastases might be reduced with higher PCI doses. This randomised clinical trial compared the effect of standard versus higher PCI doses on the incidence of brain metastases. METHODS Between September, 1999, and December, 2005, 720 patients with limited-stage SCLC in complete remission after chemotherapy and thoracic radiotherapy from 157 centres in 22 countries were randomly assigned to a standard (n=360, 25 Gy in 10 daily fractions of 2.5 Gy) or higher PCI total dose (n=360, 36 Gy) delivered using either conventional (18 daily fractions of 2 Gy) or accelerated hyperfractionated (24 fractions in 16 days with two daily sessions of 1.5 Gy separated by a minimum interval of 6 h) radiotherapy. All of the treatment schedules excluded weekends. Randomisation was stratified according to medical centre, age (</=60 and >60 years), and interval between the start of induction treatment and the date of randomisation (</=90, 91-180, and >180 days). Eligible patients were randomised blindly by the data centre of the Institut Gustave Roussy (PCI99-01 and IFCT) using minimisation, and by the data centres of EORTC (EORTC ROG and LG) and RTOG (for CALGB, ECOG, RTOG, and SWOG), both using block stratification. The primary endpoint was the incidence of brain metastases at 2 years. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov number NCT00005062. FINDINGS Five patients in the standard-dose group and four in the higher-dose group did not receive PCI; nonetheless, all randomised patients were included in the effectiveness anlysis. After a median follow-up of 39 months (range 0-89 months), 145 patients had brain metastases; 82 in the standard-dose group and 63 in the higher-dose group. There was no significant difference in the 2-year incidence of brain metastases between the standard PCI dose group and the higher-dose group, at 29% (95% CI 24-35) and 23% (18-29), respectively (hazard ratio [HR] 0.80 [95% CI 0.57-1.11], p=0.18). 226 patients in the standard-dose group and 252 in the higher-dose group died; 2-year overall survival was 42% (95% CI 37-48) in the standard-dose group and 37% (32-42) in the higher-dose group (HR 1.20 [1.00-1.44]; p=0.05). The lower overall survival in the higher-dose group is probably due to increased cancer-related mortality: 189 patients in the standard group versus 218 in the higher-dose group died of progressive disease. Five serious adverse events occurred in the standard-dose group versus zero in the higher-dose group. The most common acute toxic events were fatigue (106 [30%] patients in the standard-dose group vs 121 [34%] in the higher-dose group), headache (85 [24%] vs 99 [28%]), and nausea or vomiting (80 [23%] vs 101 [28%]). INTERPRETATION No significant reduction in the total incidence of brain metastases was observed after higher-dose PCI, but there was a significant increase in mortality. PCI at 25 Gy should remain the standard of care in limited-stage SCLC. FUNDING Institut Gustave-Roussy, Association pour la Recherche sur le Cancer (2001), Programme Hospitalier de Recherche Clinique (2007). The European Organisation for Research and Treatment of Cancer (EORTC) contribution to this trial was supported by grants 5U10 CA11488-30 through 5U10 CA011488-38 from the US National Cancer Institute.

Comprehensive Survival Analysis of a Cohort of Patients with Stevens Johnson Syndrome and Toxic Epidermal Necrolysis

Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous adverse reactions that are of major concern because of high mortality rates. On the basis of data collected in the RegiSCAR study, the aim was to assess risk factors (including modalities of patient management) for mortality, regardless of the cause, up to 1 year after the reaction. Within this cohort, the mortality rate was 23% (95% confidence interval (CI) 19-27%) at 6 weeks and 34% (95% CI 30-39%) at 1 year. Severity of reaction was a risk factor for mortality only in the first 90 days after onset, whereas serious comorbidities and age influenced mortality beyond 90 days and up to 1 year after onset of reaction. The risk of death for patients with identified drug cause was borderline lower than for patients with a reaction of unknown cause (hazard ratio 0.66, 95% CI 0.45-0.96). The study could not provide conclusive evidence regarding patient management. This large-scale population-based follow-up study of such patients confirmed high in-hospital mortality and revealed a remarkable number of deaths after discharge, which could mainly be attributed to severe comorbidities and older age, whereas the impact of severity of reaction on the risk of death was limited to the first few weeks.

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

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.

Cell Cycle Regulators and Outcome of Adjuvant Cisplatin-Based Chemotherapy in Completely Resected Non–Small-Cell Lung Cancer: The International Adjuvant Lung Cancer Trial Biologic Program

PURPOSE The International Adjuvant Lung Cancer Trial (IALT) demonstrated that adjuvant cisplatin-based chemotherapy improves the survival of patients with completely resected non-small-cell lung cancer (NSCLC). The purpose of our study was to determine whether cell cycle regulators are of prognostic and/or predictive value in patients who were enrolled onto the IALT. PATIENTS AND METHODS Expression of p27Kip1, p16INK4A, cyclin D1, cyclin D3, cyclin E, and Ki-67 was immunohistochemically assessed in tumor specimens obtained from 778 IALT patients. Prognostic and predictive analyses were based on Cox models adjusted for clinical and pathologic parameters. RESULTS There was a relationship between p27Kip1 status and benefit of cisplatin-based chemotherapy (test for interaction, P = .02). Among patients with p27Kip1-negative tumors, cisplatin-based chemotherapy resulted in longer overall survival compared with controls (adjusted hazard ratio [HR] for death = 0.66; 95% CI, 0.50 to 0.88; P = .006). In patients with p27Kip1-positive tumors, overall survival was not different between patients treated with cisplatin-based chemotherapy and controls (adjusted HR for death = 1.09; 95% CI, 0.82 to 1.45; P = .54). The other cell cycle regulators and Ki-67 did not predict benefit of adjuvant cisplatin-based chemotherapy. None of these biomarkers was significantly associated with overall survival of the patients in the total study population. CONCLUSION NSCLC patients with p27Kip1-negative tumors benefit from adjuvant cisplatin-based chemotherapy after complete tumor resection. Before establishing p27Kip1 as a routine marker for selection of patients for adjuvant chemotherapy, the predictive value of p27Kip1 has to be confirmed in patients from other trials.

MutS Homologue 2 and the Long-term Benefit of Adjuvant Chemotherapy in Lung Cancer

Purpose: We sought to determine the long-term (median follow-up, 7.5 years) predictive power of human MutS homologue 2 (MSH2) immunohistochemical expression in patients who enrolled in the International Adjuvant Lung Trial. Experimental design: We tested the interaction between MSH2 and the allocated treatment (chemotherapy versus observation) in a Cox model adjusted on clinicopathologic variables. The significance level was set at 0.01. Results: MSH2 levels were low in 257 (38%) and high in 416 (62%) tumors. The benefit from chemotherapy was likely different according to MSH2 (interaction test, P = 0.06): there was a trend for chemotherapy to prolong overall survival when MSH2 was low [hazard ratio (HR), 0.76; 95% confidence interval (95% CI), 0.59-0.97; P = 0.03], but not when MSH2 was high (HR, 1.12; 95% CI, 0.81-1.55; P = 0.48). In the control arm, the HR was 0.66 (95% CI, 0.49-0.90; P = 0.01) when MSH2 was high. When combining MSH2 with excision repair cross-complementing group 1 (ERCC1) into four subgroups, the benefit of chemotherapy decreased with the number of markers expressed at high levels (P = 0.01). A similar decrease was noted when combining MSH2 and P27 (P = 0.01). Chemotherapy prolonged overall survival in the combined low MSH2/low ERCC1 subgroup (HR, 0.65; 95% CI, 0.47-0.91; P = 0.01) and in the combined low MSH2/low P27 subgroup (HR, 0.65; 95% CI, 0.46-0.93; P = 0.01). Conclusions: MSH2 expression is a borderline significant predictor of a long-term benefit from adjuvant cisplatin-based chemotherapy in patients with completely resected lung cancer. MSH2 combined with ERCC1 or P27 may identify patients most likely to benefit durably from chemotherapy. Clin Cancer Res; 16(4); 1206–15

Multidrug Resistance Proteins Do Not Predict Benefit of Adjuvant Chemotherapy in Patients with Completely Resected Non–Small Cell Lung Cancer: International Adjuvant Lung Cancer Trial Biologic Program

Purpose: The purpose of our study was to determine whether multidrug resistance proteins (MRP) are of prognostic and/or predictive value in patients who were enrolled into the International Adjuvant Lung Cancer Trial (IALT). Experimental Design: Expression of MRP1 and MRP2 was immunohistochemically assessed in tumor specimens obtained from 782 IALT patients. Prognostic and predictive analyses were based on Cox models adjusted for clinical and pathologic variables. Results: MRP1 expression was considered positive in 364 (47%) patients and MRP2 expression in 313 (40%) patients. MRP2-positive patients had a significantly shorter overall survival than MRP2-negative patients in the total patient population [adjusted hazard ratio for death, 1.37; 95% confidence interval (95% CI), 1.09-1.72; P = 0.007]. There was no significant association between MRP1 expression and overall survival. Neither MRP1 nor MRP2 predicted response to adjuvant cisplatin-based chemotherapy. Conclusions: MRP2 expression is an independent prognostic factor in patients with completely resected non–small cell lung cancer but neither MRP1 nor MRP2 was of predictive value in patients enrolled into the IALT.