Elsevier

The Lancet Oncology

Volume 6, Issue 9, September 2005, Pages 669-677
The Lancet Oncology

Fast track — Articles
Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials

https://doi.org/10.1016/S1470-2045(05)70255-2Get rights and content

Summary

Background

Chemotherapy is the standard treatment for advanced non-small-cell lung cancer, and myelosuppression is a common side-effect. We aimed to assess whether haematological toxic effects could be a biological measure of drug activity and a marker of efficacy.

Methods

We analysed data for 1265 patients who received chemotherapy (vinorelbine, gemcitabine, gemcitabine and vinorelbine, cisplatin and vinorelbine, or cisplatin and gemcitabine) within three randomised trials. Primary landmark analyses were restricted to 436 patients who received all six planned chemotherapy cycles and who were alive 180 days after randomisation. Neutropenia was categorised on the basis of worst WHO grade during chemotherapy: absent (grade 0), mild (grade 1–2), or severe (grade 3–4). All statistical analyses were stratified by treatment allocation. Analyses were repeated in the out-of-landmark group (829 patients), stratifying by treatment allocation and number of chemotherapy cycles. The primary endpoint was overall survival.

Findings

In the landmark group, hazard ratios of death were 0·65 (0·46–0·93) for patients with severe neutropenia and 0·74 (0·56–0·98) for those with mild neutropenia. Median survival after the landmark time of 180 days was 31·4 weeks (95% CI 25·7–39·6) for patients without neutropenia compared with 42·0 weeks (32·7–59·7) for patients with severe neutropenia, and with 43·7 weeks (36·6–66·0) for those with mild neutropenia (severe vs mild vs no neutropenia p=0·0118). Findings were much the same for the out-of-landmark group.

Interpretation

Neutropenia during chemotherapy is associated with increased survival of patients with advanced non-small-cell lung cancer, and its absence might be a result of underdosing. Prospective trials are needed to assess whether drug dosing guided by the occurrence of toxic effects could improve efficacy of standard regimens.

Introduction

Most patients diagnosed with advanced non-small-cell lung cancer are offered chemotherapy on the basis of studies that showed a small but significant survival advantage in adults,1 including elderly people.2 At present, a two-drug regimen consisting of a platinum agent is regarded standard treatment for adults with good performance status,3, 4 resulting in a median survival of about 8 months, and about 35% of patients alive at 1 year. However, the toxic effects of such treatment can be substantial, and vary with the drug that is added to cisplatin or carboplatin (usually vinorelbine, gemcitabine, or a taxane).5 For patients aged older than 70 years, no reliable data have shown that combination chemotherapy is more effective than a single agent, with vinorelbine2 or gemcitabine6 producing the most convincing results. Overall, although the efficacy of chemotherapy is modest at best, cytotoxic drugs will probably continue to be part of standard treatment of non-small-cell lung cancer in the next few decades.

Haematological toxic effects caused by most cytotoxic drugs could be a biological measure of drug activity and might predict treatment efficacy.7, 8 Studies9, 10, 11, 12 of adjuvant chemotherapy for breast cancer have shown that patients who have increased toxic effects during treatment had a better outcome than did those who had no, or less severe, toxic effects. However, the predictive (ie, estimation of the chance of benefit from chemotherapy) or prognostic (ie, estimation of the chance of survival) role of chemotherapy-induced neutropenia in advanced non-small-cell lung cancer have not been established. Thus, we reviewed data for three randomised phase III trials2, 6, 13 of chemotherapy in advanced non-small-cell lung cancer to assess whether chemotherapy-induced neutropenia was associated with increased survival. This analysis was not planned at the time of trials, but was prompted by independent evidence in scientific publications.

Section snippets

Patients and treatments

Patients with advanced non-small-cell lung cancer who participated in three randomised clinical trials2, 6, 13 done by the same cooperative group of Italian institutions coordinated by the Clinical Trials Unit of the National Cancer Institute, Naples, Italy, between 1996 and 2001 were selected for this study (figure 1). All three studies were approved by ethics committees, and all patients gave written informed consent. The three protocols included patients with stage IV or IIIB disease (with

Results

Figure 1 shows the study profile. Figure 2 shows the worst grade of neutropenia recorded at each cycle of chemotherapy in the 1265 patients analysed. 484 patients received six cycles of chemotherapy, 436 of whom were alive 180 days after randomisation and thus included in the landmark group.

Table 1 shows characteristics of patients in the landmark analysis. Median age was 71 years (range 36–84). Most patients were men, had a good performance status (ie, 0–1), and had metastatic disease.

Table 2

Discussion

We have shown that the presence, but not severity, of chemotherapy-induced neutropenia were prognostic for increased survival. The difference in survival for patients according to whether they had neutropenia was significant, and was similar to, and perhaps even greater than, that of the overall advantage attributed to platinum-based chemotherapy compared with supportive-care alone.1 Importantly, results should not be biased by the use of G-CSF because the protocols stipulated no prophylactic

References (26)

  • J Bergh et al.

    Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study

    Lancet

    (2000)
  • Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials

    BMJ

    (1995)
  • Effects of vinorelbine on quality of life and survival of elderly patients with advanced non small cell lung cancer

    J Natl Cancer Inst

    (1999)
  • C Delbaldo et al.

    Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis

    JAMA

    (2004)
  • DG Pfister et al.

    American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003

    J Clin Oncol

    (2004)
  • JH Schiller et al.

    Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer

    N Engl J Med

    (2002)
  • C Gridelli et al.

    Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung cancer in the Elderly Study (MILES) phase III randomized trial

    J Natl Cancer Inst

    (2003)
  • S Kvinnsland

    The leucocyte nadir, a predictor of chemotherapy efficacy?

    Br J Cancer

    (1999)
  • H Gurney

    How to calculate the dose of chemotherapy

    Br J Cancer

    (2002)
  • T Saarto et al.

    Haematological toxicity: a marker of adjuvant chemotherapy efficacy in stage II and III breast cancer

    Br J Cancer

    (1997)
  • P Poikonen et al.

    Leucocyte nadir as a marker for chemotherapy efficacy in node-positive breast cancer treated with adjuvant CMF

    Br J Cancer

    (1999)
  • C Mayers et al.

    Analysis of the prognostic effects of inclusion in a clinical trial and of myelosuppression on survival after adjuvant chemotherapy for breast carcinoma

    Cancer

    (2001)
  • DA Cameron et al.

    Moderate neutropenia with adjuvant CMF confers improved survival in early breast cancer

    Br J Cancer

    (2003)
  • Cited by (209)

    View all citing articles on Scopus
    View full text