NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

In 2010, approximately 222,520 new cases of lung or bronchial cancer will be diagnosed in the USA, and 157,300 patients are expected to die of this disease [1]. Lung cancer is the leading cause of cancer-related death in both men and women, and non-small cell lung cancer (NSCLC) accounts for about 80 % of these cases. Lung cancer is most often asymptomatic in its early stages; consequently, the disease is usually diagnosed at an advanced stage, when it is much more difficult to treat. One or more genes are believed to be responsible for an inherited increase in risk of developing lung cancer in the general population. Smoking remains one of the main environmental factors associated with the development of lung cancer [2]. Although the development of lung cancer seems to be the result of several sequential molecular abnormalities in individuals at high risk of developing the disease, the genetic mechanisms by which an individual develops lung cancer remain largely unknown. These steps involve abnormalities in the expression of angiogenic factors (e.g., vascular endothelial growth factor, or VEGF and epithelial growth factor receptors, or EGFRs) [3]. The heterogeneity of lung cancer and the diversity of its morphologic appearance and molecular properties make the application of molecular targeted therapies used in other cancers more complex, but such therapies are certainly a goal for the future.

Non–Small Cell Lung Cancer

Methods We systematically searched for trials that started after January, 1965. Updated individual participant data were centrally collected, checked, and analysed. Results from individual randomised controlled trials (both published and unpublished) were combined using a two-stage fi xed-eff ect model. Our primary outcome, overall survival, was defi ned as the time from randomisation until death (any cause), with living patients censored on the date of last follow-up. Secondary outcomes were recurrence-free survival, time to locoregional and distant recurrence, cause-specifi c survival, complete and overall resection rates, and postoperative mortality. Prespecifi ed analyses explored any variation in eff ect by trial and patient characteristics. All analyses were by intention to treat. Findings Analyses of 15 randomised controlled trials (2385 patients) showed a signifi cant benefi t of preoperative chemotherapy on survival (hazard ratio [HR] 0·87, 95% CI 0·78–0·96, p=0·007), a 13% reduction in the relative risk of death (no evidence of a diff erence between trials; p=0·18, I²=25%). This fi nding represents an absolute survival improvement of 5% at 5 years, from 40% to 45%. There was no clear evidence of a diff erence in the eff ect on survival by chemotherapy regimen or scheduling, number of drugs, platinum agent used, or whether postoperative radiotherapy was given. There was no clear evidence that particular types of patient defi ned by age, sex, performance status, histology, or clinical stage benefi ted more or less from preoperative chemotherapy. Recurrence-free survival (HR 0·85, 95% CI 0·76–0·94, p=0·002) and time to distant recurrence (0·69, 0·58–0·82, p<0·0001) results were both signifi cantly in favour of preoperative chemotherapy although most patients included were stage IB–IIIA. Results for time to locoregional recurrence (0·88, 0·73–1·07, p=0·20), although in favour of preoperative chemotherapy, were not statistically signifi cant. Interpretation Findings, which are based on 92% of all patients who were randomised, and mainly stage IB–IIIA, show preoperative chemotherapy signifi cantly improves overall survival, time to distant recurrence, and recurrencefree survival in resectable NSCLC. The fi ndings suggest this is a valid treatment option for most of these patients. Toxic eff ects could not be assessed.

Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data

Improvements in outcomes for patients with resectable lung cancers have plateaued. Clinical trials of resectable non-small-cell lung cancers with overall survival as the primary endpoint require a decade or longer to complete, are expensive, and limit innovation. A surrogate for survival, such as pathological response to neoadjuvant chemotherapy, has the potential to improve the efficiency of trials and expedite advances. 10% or less residual viable tumour after neoadjuvant chemotherapy, termed here major pathological response, meets criteria for a surrogate; major pathological response strongly associates with improved survival, is reflective of treatment effect, and captures the magnitude of the treatment benefit on survival. We support the incorporation of major pathological response as a surrogate endpoint for survival in future neoadjuvant trials of resectable lung cancers. Additional prospective studies are needed to confirm the validity and reproducibility of major pathological response within individual histological and molecular subgroups and with new drugs.

/pdf/pathological-response-after-neoadjuvant-chemotherapy-in-4tr2n9gkjj.pdf

Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.

Purpose This study aimed to determine whether three preoperative cycles of gemcitabine plus cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients with stages IB to IIIA non–small-cell lung cancer (NSCLC). Patients and Methods Patients with chemotherapy-naive NSCLC (stages IB, II, or IIIA) were randomly assigned to receive either three cycles of gemcitabine 1,250 mg/m 2 days 1 and 8 every 3 weeks plus cisplatin 75 mg/m 2 day 1 every 3 weeks followed by surgery, or surgery alone. Randomization was stratified by center and disease stage (IB/IIA v IIB/IIIA). The primary end point was progression-free survival (PFS). Results The study was prematurely closed after the random assignment of 270 patients: 129 to chemotherapy plus surgery and 141 to surgery alone. Median age was 61.8 years and 83.3% were male. Slightly more patients in the surgery alone arm had disease stage IB/IIA (55.3% v 48.8%). The chemotherapy response rate was 35.4%. The hazard ratios for PFS and overall survival were 0.70 (95% CI, 0.50 to 0.97; P .003) and 0.63 (95% CI, 0.43 to 0.92; P .02), respectively, both in favor of chemotherapy plus surgery. A statistically significant impact of preoperative chemotherapy on outcomes was observed in the stage IIB/IIIA subgroup (3-year PFS rate: 36.1% v 55.4%; P .002). The most common grade 3 or 4 chemotherapy-related adverse events were neutropenia and thrombocytopenia. No treatment-by-histology interaction effect was apparent. Conclusion Although the study was terminated early, preoperative gemcitabine plus cisplatin followed by radical surgery improved survival in patients with clinical stage IIB/IIIA NSCLC.

Tadeusz M. Orlowski

Papers

Randomized Phase III Study of Surgery Alone or Surgery Plus Preoperative Cisplatin and Gemcitabine in Stages IB to IIIA Non–Small-Cell Lung Cancer