Elsevier

The Lancet Oncology

Volume 7, Issue 9, September 2006, Pages 719-727
The Lancet Oncology

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Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial

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Summary

Background

Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC.

Methods

840 patients with stage IB–IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m2 vinorelbine plus 100 mg/m2 cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centre's policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737.

Findings

367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17–108] vs 59% [17–100]). After a median follow-up of 76 months (range 43–116), median survival was 65·7 months (95% CI 47·9–88·5) in the chemotherapy group and 43·7 (35·7–52·3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0·80 [95% CI 0·66–0·96]; p=0·017). Overall survival at 5 years with chemotherapy improved by 8·6%, which was maintained at 7 years (8·4%).

Interpretation

Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.

Introduction

The International Agency for Research on Cancer reported 1·2 million cases of lung cancer worldwide in 2000, with 1·1 million deaths.1 Despite surgery, about 40% of patients with stage I non-small-cell lung cancer (NSCLC), 60% of patients with stage II disease, and 75% of patients with stage IIIA disease die within 5 years.2, 3 In 1995, a meta-analysis4 showed a non-significant 5% survival advantage at 5 years with cisplatin-based adjuvant chemotherapy in resected NSCLC compared with surgery alone. This finding prompted the planning of additional randomised trials.5 The International Adjuvant Lung Trial (IALT)6 showed a significant 4% benefit at 5 years for cisplatin-based chemotherapy in combination with various agents after curative surgery in stage I–III NSCLC. The Adjuvant Lung Cancer Project Italy (ALPI)7 did not find a survival benefit for chemotherapy, although the study used a toxic regimen. Subset analysis by stage showed that the hazard ratio of death was 0·80 (95% CI 0·60–1·06) for stage II versus 0·97 (0·71–1·33) and 1·06 (0·82–1·38) for stages I and III, respectively. The Cancer and Leukemia Group B (CALGB) 9633 study8 reported a 12% reduction in mortality at 4 years with adjuvant carboplatin plus paclitaxel in stage IB NSCLC, and an update8 with extended follow-up (54 vs 34 months) showed that improvement in survival was no longer significant. The National Cancer Institute of Canada JBR.10 trial9 showed a 15% improvement in overall survival for stage IB–II NSCLC treated with vinorelbine plus cisplatin. The subset analysis by stage showed a greater benefit at 5 years for stage II (20%) than for stage I (7%); at 6 years, the benefit for stage I disappeared, and survival was greater in the control group. In 1994, the Adjuvant Navelbine International Trialist Association (ANITA) initiated a randomised phase III trial in patients with completely resected stage IB, II, and IIIA NSCLC, to assess the survival benefit of adjuvant vinorelbine plus cisplatin versus control.

Section snippets

Patients

This open-label study was done in 101 centres in 14 countries. It was approved by the ethics committee of every centre and undertaken according to the Declaration of Helsinki. Written informed consent was obtained for all patients. Eligibility criteria included: histologically proven primary NSCLC (apart from bronchoalveolar carcinoma) after examination of the resected tumour by institution pathologist, and pathological TNM (tumour, node, metastasis) staging. Patients were eligible if they had

Results

From December, 1994, to December, 2000, 840 patients were enrolled in the trial: 407 were assigned to chemotherapy and 433 to observation (figure 1). On Aug 1, 2004, median potential follow-up was 76 months (range 43–113) in the chemotherapy group and 77 months (43–116) in the observation group.

Table 1 shows the patients' characteristics. Overall, 486 (58%) patients had a lobectomy and 310 (37%) a pneumonectomy; 325 (39%) had postoperative stage IIIA disease, 203 (24%) had stage II disease, and

Discussion

In this trial, we showed that the combination of vinorelbine and cisplatin significantly improved overall survival in patients with stages IB–IIIA NSCLC. However, our subgroup analysis indicated that the benefit is seen mainly in patients with stage II and IIIA disease.

Analysis took place after 458 patients had died instead of the planned 466; the steering committee allowed the analysis at this point, judging that the difference of eight deaths would not affect the results. Because of

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