WITHDRAWN: Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease.

BACKGROUND: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVES: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. SEARCH METHODS: There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006. SELECTION CRITERIA: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen). MAIN RESULTS: Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97). AUTHORS' CONCLUSIONS: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

A predictor of unfavourable outcome in neutropenic paediatric patients presenting with fever of unknown origin.

BACKGROUND: No sensitive, specific marker able to discriminate favourable or unfavourable outcome of fever of unknown origin (FUO) at diagnosis has been identified. Procalcitonin, a recently assessed infection marker, may be useful in predicting the outcome of FUO. METHODS: We conducted a prospective study examining the following variables: age 0.5-22 years; solid tumour diagnosis; chemotherapy-related grade-4 febrile neutropenia (FN). A complete clinical, bacteriological and biological evaluation was performed at hospital admission (H0). Other investigations depended on clinical status. FUO was considered to be of unfavourable outcome if the fever was persistent or re-appeared at day 3 (or later), or if secondary clinical or microbiological infection occurred. To validate the results of the analysis the data set was randomly split into a training set and a validation set. RESULTS: Out of 172 episodes of FN, 136 episodes were classified as FUO (80%). Seventy-two (53%) were included in this study. PCT values were significantly higher in episodes of unfavourable outcome (P < 0.001). None of the other prediction candidates appeared to be significantly linked to the risk of unfavourable outcome. In the validation set, the best PCT cut-off was 0.12 micro/L, which was associated with a sensitivity of 80% and specificity of 64%. CONCLUSIONS: PCT-H0 level can predict FUO outcome. A protocol based on PCT-H0 measurement, integrating clinical and bacteriological evaluation, facilitates shorter hospital stays and less antibiotic treatment. Patients with a PCT-H0 value <0.12 micro/L could benefit from an outpatient treatment starting at H48 thus reducing hospitalisation costs and improving quality of life.

Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease.

BACKGROUND: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVES: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. SEARCH STRATEGY: There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006. SELECTION CRITERIA: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen). MAIN RESULTS: Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97). AUTHORS' CONCLUSIONS: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

Cross-validation study for epidermal growth factor receptor and KRAS mutation detection in 74 blinded non-small cell lung carcinoma samples: a total of 5550 exons sequenced by 15 molecular French laboratories (evaluation of the EGFR mutation status for the administration of EGFR-TKIs in non-small cell lung carcinoma [ERMETIC] project--part 1).

INTRODUCTION: The Evaluation of the epidermal growth factor receptor (EGFR) Mutation status for the administration of EGFR-Tyrosine Kinase Inhibitors in non-small cell lung Carcinoma (NSCLC) (ERMETIC) project part 1 assessed the accuracy of EGFR and KRAS mutations detection in NSCLC among 15 French centers. METHODS: The 15 ERMETIC centers selected 74 NSCLC surgical specimens from previously untreated patients. Paraffin and paired frozen DNA were sequenced for EGFR exons 18 to 21 and KRAS exon 2 by an external molecular laboratory, yielding a gold standard. The 74 blinded paraffin DNAs were redistributed to the 15 ERMETIC laboratories for sequencing of a total of 5550 exons. Results were compared with the gold standard and between centers by discordance rates and kappa statistics. RESULTS: The gold standard included 39 mutated samples with 22 EGFR and 17 KRAS mutated samples. Kappa statistics showed that 10, 6, and 6 of the 15 ERMETIC centers had a moderate to good kappa score, when compared with external laboratory for EGFR exon 19, EGFR exon 21, and KRAS exon 2, respectively. Kappa statistics showed moderate score between centers which increased to good for EGFR exon 19 mutation when removing 16 poor-quality samples with high nonamplificable rates. CONCLUSIONS: Paraffin-embedded specimens may represent a suitable source of DNA for sequencing analyses in ERMETIC centers. EGFR exon 19 deletions were most accurately detected by ERMETIC centers. Ease and accuracy of results, depended more on the quality of sample than on the difference in molecular sequencing procedures between centers, emphasize the need of preanalytical quality control programs.

Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer.

PURPOSE: The previous individual patient data meta-analyses of chemotherapy in locally advanced non-small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy. METHODS: Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity. RESULTS: Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity. CONCLUSION: Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.

Pooled analysis of the effect of age on adjuvant cisplatin-based chemotherapy for completely resected non-small-cell lung cancer.

PURPOSE: This pooled analysis was undertaken to assess the efficacy and toxicity of adjuvant cisplatin-based chemotherapy in elderly patients with non-small-cell lung cancer (NSCLC). METHODS: We used individual patient data from 4,584 patients enrolled onto five trials of cisplatin-based chemotherapy who form the basis for the Lung Adjuvant Cisplatin Analysis (LACE) pooled analysis. Patient and treatment characteristics, overall and event-free survival, cause-specific mortality, chemotherapy toxicity and delivery were compared among three age groups: 3,269 young (71%; < 65), 901 midcategory (20%; 65 to 69), and 414 elderly patients (9%; >or= 70). Log-rank tests stratified by trials were used with a test for trend to study the effect of chemotherapy on survival according to age. RESULTS: The hazard ratio (HR) of death for the young patients was 0.86 (95% CI, 0.78 to 0.94), 1.01 for the midcategory (95% CI, 0.85 to 1.21), and 0.90 for elderly patients (95% CI, 0.70 to 1.16; test for trend: P = .29). The HR for event-free survival was 0.82 for young (95% CI, 0.75 to 0.90), 0.90 for the midcategory (95% CI, 0.76 to 1.06), and 0.87 for elderly patients (95% CI, 0.68 to 1.11; test for trend: P = .42). More elderly patients died from non-lung cancer-related causes (12% young, 19% midcategory, 22% elderly; P < .0001). No differences in severe toxicity rates were observed. Elderly patients received significantly lower first and total cisplatin doses, and fewer chemotherapy cycles (chi(2) P < .0001). CONCLUSION: Adjuvant cisplatin-based chemotherapy should not be withheld from elderly patients with NSCLC purely on the basis of age.

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.

Operational response to malaria epidemics: are rapid diagnostic tests cost-effective?

OBJECTIVE: To compare the cost-effectiveness of malaria treatment based on presumptive diagnosis with that of malaria treatment based on rapid diagnostic tests (RDTs). METHODS: We calculated direct costs (based on experience from Ethiopia and southern Sudan) and effectiveness (in terms of reduced over-treatment) of a free, decentralised treatment programme using artesunate plus amodiaquine (AS + AQ) or artemether-lumefantrine (ART-LUM) in a Plasmodium falciparum epidemic. Our main cost-effectiveness measure was the incremental cost per false positive treatment averted by RDTs. RESULTS: As malaria prevalence increases, the difference in cost between presumptive and RDT-based treatment rises. The threshold prevalence above which the RDT-based strategy becomes more expensive is 21% in the AS + AQ scenario and 55% in the ART-LUM scenario, but these thresholds increase to 58 and 70%, respectively, if the financing body tolerates an incremental cost of 1 euro per false positive averted. However, even at a high (90%) prevalence of malaria consistent with an epidemic peak, an RDT-based strategy would only cost moderately more than the presumptive strategy: +29.9% in the AS + AQ scenario and +19.4% in the ART-LUM scenario. The treatment comparison is insensitive to the age and pregnancy distribution of febrile cases, but is strongly affected by variation in non-biomedical costs. If their unit price were halved, RDTs would be more cost-effective at a malaria prevalence up to 45% in case of AS + AQ treatment and at a prevalence up to 68% in case of ART-LUM treatment. CONCLUSION: In most epidemic prevalence scenarios, RDTs would considerably reduce over-treatment for only a moderate increase in costs over presumptive diagnosis. A substantial decrease in RDT unit price would greatly increase their cost-effectiveness, and should thus be advocated. A tolerated incremental cost of 1 euro is probably justified given overall public health and financial benefits. The RDTs should be considered for malaria epidemics if logistics and human resources allow.