Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer: A Fading Effect?

Abstract

Non–small-cell lung cancer (NSCLC) is the leading cause of cancer death for men and women in most industrialized countries. Surgery is the primary treatment modality for patients with early-stage operable NSCLC. Approximately half of these patients eventually experience relapse after resection, with a twoto three-fold higher proportion of distant metastases over local recurrences. Five-year survival rates for early-stage NSCLC range from 60% to 70% in stage I, 40% to 50% in stage II, and only 25% to 30% in patients with stage IIIA tumors. The 1995 meta-analysis published by the Non–SmallCell Lung Cancer Collaborative Group suggested an absolute survival advantage at 5 years of 5% with cisplatin-based chemotherapy (hazard ratio [HR] 0.87; 95% CI, 0.74 to 1.02; P .08). However, most of the early trials were small and underpowered. In the late 1990s, larger adjuvant trials were performed, three of which demonstrated a statistically significant survival benefit from cisplatin-based chemotherapy. Absolute 5-year survival differences ranged from 4% to 15% (HR 0.69 to 0.86). In the recently updated individual data-based Medical Research Council meta-analysis and in Lung Adjuvant CisplatinEvaluation(LACE), the5-yearabsolutebenefitwithchemotherapy ranged from 4% to 5.3% (HR 0.87; 95% CI, 0.81 to 0.93; P .0000001; and HR 0.89; 95% CI, 0.82 to 0.96; P .004, respectively). In the updated Medical Research Council metaanalysis, the effect of chemotherapy in addition to surgery versus surgery alone was studied in 8,147 patients (from 30 trials), with a median follow-up of 5.3 years across all trials. In the LACE study, data were pooled from 4,584 patients in five recent randomized adjuvant cisplatin-based chemotherapy trials and reported with a median follow-up of 5.1 years (range, 3.1 to 5.9 years). On the basis of these results, postoperative cisplatin-based chemotherapy is now widely accepted as treatment for patients with NSCLC. In the current issue of the Journal of Clinical Oncology, Strauss et al report mature data from the Cancer and Leukemia Group B (CALGB) trial 9633. They randomly assigned 344 patients who underwent complete resection for stage IB (T2N0) disease to four postoperative cycles of paclitaxel (200 mg/m) and carboplatin (area under the curve 6), the most frequently used doublet chemotherapy for NSCLC in the United States, compared with surgery alone. Although the initial interim analysis for survival was positive and prompted early termination of the study, survival was no longer significantly different between the two arms after a median follow-up of 74 months (HR 0.83; 90% CI, 0.64 to 1.08; P .12. In an unplanned subgroup analysis, a benefit seemed to appear for patients with tumors 4 cm in diameter (HR 0.69; 90% CI, 0.48 to 0.99; P .043). This study highlights several issues.