Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected Non-Small-Cell Lung Cancer

Authors: The International Adjuvant Lung Cancer Trial Collaborative Group
Source:New England Journal of Medicine (2004) Volume 350, Issue 4, Pages 351-360

Introduction

In the United States, lung cancer accounted for an estimated 171,900 new cancer diagnoses and 157,200 deaths from cancer in 2003. Despite continuing development of new therapies, the prognosis for the majority of patients diagnosed with non-small cell lung cancer (NSCLC) remains poor. Even with potentially curative resection of small, localized NSCLC lesions, approximately 30% of patients will go on to die from either locally recurrent or metastatic disease. Therefore, there has been tremendous interest in using post-operative chemotherapy in attempts to eradicate any remaining microscopic deposits of disease. A NSCLC Collaborative Group meta-analysis published in 1995 concluded that the post-operative use of alkylating agents in patients with NSCLC showed an absolute detriment of chemotherapy of 5% at 5 years. However, cisplatin-containing regimens showed a trend toward increased survival (50% to 55% at 5 years) that failed to reach statistical significance. The current study was therefore designed to evaluate the effect of cisplatin-based adjuvant chemotherapy on survival after complete resection of NSCLC.

Methods

Patients with completely resected NSCLC were randomly assigned to receive either to three or four cycles of post-operative cisplatin -based chemotherapy or to observation alone. Because of uncertainty regarding the optimal cisplatin-containing regimen, each sponsoring institution was allowed to select a single combination of cisplatin (ranging from 80 mg/m2 x 4 cycles to 120 mg/m2 x 3 cycles) with either weekly vindesine (3 mg/m2/day), weekly vinblastine (4 mg/m2/day), weekly vinorelbine (30 mg/m2/day) or Etoposide (100 mg/m2/day, given on days 1 and 3 with cisplatin). In addition, each center determined the pathological stages to include and its postoperative radiotherapy policy. The main end point was overall survival.

Results

• 1867 patients (36.5% stage I, 24.2% stage II, and 39.3% stage III) underwent randomization.
• The drug allocated with cisplatin was etoposide in 56.5% of patients, vinorelbine in 26.8%, vinblastine in11.0%, and vindesine in 5.8%.
• Of the 932 patients assigned to chemotherapy, 73.8% received at least 240 mg/m2 of cisplatin.
• With a median follow-up of 56 months, patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (44.5% vs. 40.4% at 5 years, hazard ratio for death, 0.86; 95% confidence interval, 0.76 to 0.98;P < 0.03).
• Patients assigned to chemotherapy also had a significantly higher disease-free survival rate than those assigned to observation (39.4% vs.34.3% at five years
• Seven patients (0.8%) died of chemotherapy induced toxic effects.

Discussion

In the past 2 years, several trials of adjuvant, post-operative chemotherapy in NSCLC have been reported. In one study, 979 patients with pathological stage T1N0 or T2N0 adenocarcinoma of the lung were randomly assigned to adjuvant uracil–tegafur vs. observation. A significant survival benefit was observed with adjuvant chemotherapy (P=0.04). However, not all of these studies supported the use of post-operative chemotherapy in completely resected NSCLC. A North-American Intergroup trial that enrolled 488 patients compared postoperative radiotherapy alone with radiotherapy plus concurrent treatment with etoposide and cisplatin. No significant difference was observed in overall survival (hazard ratio for death in the chemotherapy group, 1.08; 95 percent confidence interval, 0.85 to 1.35). In a study by the Japanese Clinical Oncology Group (JCOG), patients with completely resected, pN2 NSCLCa were randomly assigned to receive either cisplatin and vindesine vs. observation. Due to slow accrual, only 119 patients were registered and underwent randomization. In this trial, although the patient number was relatively small, there was no indication of survival benefit. Similarly, in a study of 1088 NSCLCa patients by the Adjuvant Lung Project Italy–European Organization for Research and Treatment of Cancer, trial post-operative mitomycin, vindesine, and cisplatin the hazard ratio for death in the adjuvant-therapy group, as compared with the control group, was 0.96 (95 percent confidence interval, 0.81 to 1.13). However, these potentially contradictory results are not without proposed explanation. The intergroup trial used combined modality chemoradiation and the dose of cisplatin given was dose-reduced to 60 mg/m2 x 4 cycles. Similarly, the overall cisplatin dose received in the JCOG trial was also lower. Only 58% of patients received at least 240 mg/m2 of cisplatin vs. 74% in the current trail. Finally, mitomycin C has been previously associated with increased early deaths from toxicity.

Author's Conclusions

In this large, well-conducted, multi-institutional trail, cisplatin based adjuvant chemotherapy improved survival among patients with completely resected NSCLC. The magnitude of benefit (4.1% increase in overall survival at 5 years) is consistent with the benefit of post-operative cisplatin-based chemotherapy predicted by the NSCLC Collaborative Group meta-analysis and similar to the magnitude of benefit observed for post-operative systemic chemotherapy in other malignancies. However, there was a 0.8% chance of death from the chemotherapy. Patients should be advised to the potential risks and benefits of postoperative chemotherapy for NSCLC. Appropriate selection of patients for postoperative chemotherapy should include those with good performance status and minimal weight loss.