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Originally published as JCO Early Release 10.1200/JCO.2008.18.1081 on September 22 2008 © 2008 American Society of Clinical Oncology.
Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer: A Fading Effect?Department of Medicine Institute Gustave Roussy, Villejuif, France
Department of Medicine Institute Gustave Roussy, Villejuif, France; and Glaxo SmithKline, Research and Development Oncology, London, United Kingdom Non–small-cell lung cancer (NSCLC) is the leading cause of cancer death for men and women in most industrialized countries.1 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 two- to three-fold higher proportion of distant metastases over local recurrences.2 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.2 The 1995 meta-analysis published by the Non–Small-Cell 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).3 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.4-6 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 Cisplatin Evaluation (LACE), the 5-year absolute benefit with chemotherapy 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).7,8 In the updated Medical Research Council meta-analysis, 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 al9 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/m2) 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 = .12.10 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. IS THE BENEFIT OF ADJUVANT CHEMOTHERAPY TRANSIENT? CALGB 9633 was initially reported as a positive trial both for overall survival and disease-free survival after 2.8 years of median follow-up and, subsequently, as a negative trial after 4.5 and 6.1 years of follow-up (Tables 1 and 2). The CALGB study was underpowered because of early termination, but a similar situation recently emerged with a larger trial. International Adjuvant Lung Cancer Trial (IALT), the largest cisplatin-based adjuvant study, was positive after a median follow-up of 56 months, but the significant effect was no longer present after a median follow-up of 90 months.10 It is noteworthy that the positive effect of adjuvant chemotherapy increases with time in colorectal and breast cancer studies.11,12 One explanation of the fading effect of adjuvant NSCLC chemotherapy could be linked to the cytotoxic agents. Late effects of cisplatin-containing chemotherapy regimens, particularly vascular disease, have been well characterized after treatment of testicular cancer.13 Regarding patients with lung cancer, the high rate of comorbidity at baseline may induce more long-term chemotherapy-associated toxicity. A higher rate of non–cancer-related deaths has been reported in IALT after 5 years of follow-up.10 In the CALGB study, there were 35 deaths (20.2%) from causes other than lung cancer were in the chemotherapy arm and 31 (18.1%) in the control arm. Among the deaths from other causes, there is no clear separation of cancer- and non–cancer-related deaths that suggests a negative effect of chemotherapy. Results from LACE and the recently updated meta-analysis merit confidence in the benefit of chemotherapy, but long-term follow-up in all recent randomized adjuvant trials in NSCLC should be carefully considered.
SHOULD WE PROPOSE ADJUVANT CHEMOTHERAPY TO PATIENTS WITH STAGE IB DISEASE? CALGB 9633 is the only trial specifically analyzing the question of adjuvant chemotherapy in patients with stage IB disease. No significant interaction with stage was observed in IALT, even with the observed trend for a better activity of adjuvant chemotherapy in larger tumors. A subgroup analysis of the JBR10 NCI-Canada adjuvant study and Adjuvant Navelbine International Trialist Association trials failed to demonstrate any benefit for patients with stage IB disease.5,6 The updated individual patient data-based meta-analysis considered 2,661 patients with stage IB diseases7: the study reports that adjuvant chemotherapy is effective for the IB subgroup, but the conclusion is arguable because a large proportion of patients with stage I disease come from the adjuvant uracil-tegafur studies.7 In the LACE study, the benefit varied with stage (test for trend, P = .046), with an HR of 1.41 (95% CI, 0.96 to 2.09) for stage IA, 0.93 (95% CI, 0.78 to 1.10) for stage IB, 0.83 (95% CI, 0.73 to 0.95) for stage II, and 0.83 (95% CI, 0.73 to 0.95) for stage III disease.8 This trend for a benefit in stage IB disease is insufficient to recommend adjuvant cisplatin-based chemotherapy as standard treatment in this setting. Other adjuvant treatments, such as postoperative radiotherapy, have failed to improve survival for patients with early-stage NSCLC.6 This issue could be resolved by the identification of other prognostic factors, and a meta-analysis including unreported studies and further trials is currently underway. In addition, it is not clear whether patients with stage IB disease represent a homogeneous population. The 4-cm cutoff in tumor size suggested in the subgroup analysis of CALGB 9633 may represent a reasonable limit for an adjuvant treatment. IS THE PACLITAXEL-CARBOPLATIN REGIMEN AN OPTIMAL REGIMEN? In the metastatic setting, a recent randomized trial suggested that there is not equivalence between carboplatin and cisplatin when combined with paclitaxel.14 The Cisplatin Versus Carboplatin meta-analysis based on individual data for 2,968 patients came to a similar conclusion: the response rate for chemotherapy involving cisplatin (30%) is better than that of the chemotherapy involving carboplatin (24%), with an odds ratio of 1.37 (95% CI, 1.16 to 1.61; P < .001).15 Nevertheless, the conclusions in the metastatic setting cannot automatically be translated to the adjuvant setting and vice versa. As an example, single-agent uracil-tegafur benefit has been demonstrated in the adjuvant setting, whereas it is not a validated regimen in patients with metastatic disease.16 The control arms of the Eastern Cooperative Oncology Group 1505 trial (which is currently underway to investigate the value of the antiangiogenic monoclonal antibody bevacizumab) will generate useful data, because three different cisplatin-based regimens are being included: combinations of cisplatin with gemcitabine, docetaxel, and vinorelbine. At present, cisplatin should be the platinum compound of choice in the adjuvant setting, unless there are medical contraindications. SHOULD WE WAIT FOR BIOMARKER ANALYSES BEFORE OUR FINAL DECISION? In CALGB 9633, authors showed that dichotomy between small (eg, < 4 cm) and large tumors may allow selection of patient subgroups more likely to benefit from adjuvant chemotherapy. Others factors such as sex or histology did not seem to interact with chemotherapy benefit (of note, smoking habits are not reported). No biomarker has been fully validated as a method to identify subgroups of patients. Published adjuvant trials have failed to show that biomarkers such as p53 mutations, p53 protein expression, and KRAS mutations have any prognostic or predictive value.17-19 Excision repair cross-complementation group 1 (ERCC1) protein has been proposed as predictive of cisplatin benefit.20 In the biological analysis of IALT samples, (n = 761), the survival of patients with ERCC1-negative tumors (assessed by immunohistochemistry) was significantly prolonged by cisplatin-based chemotherapy (56% of the cases, HR = 0.65; 95% CI, 0.50 to 0.86; P = .002), whereas chemotherapy had no effect (HR = 1.14; 95% CI, 0.84 to 1.55; P = .40) in patients with ERCC1-positive tumors.21 In patients with p27Kip1-negative tumors, cisplatin-based chemotherapy also prolongs survival compared with surgery alone (HR = 0.66; 95% CI, 0.50 to 1.45; P = .006), whereas overall survival was not influenced by chemotherapy in p27Kip1-positive tumors.22 In the updated data of the IALT, the ERCC1 predictive value remains, but it has to be proven in other retrospective studies. An analysis of ERCC1 is planned in CALGB 9633. Other biomarkers may predict for the benefit of selected drugs, as RRM1 or beta-tubulin 3 expression.23-25 HOW DO WE IMPLEMENT OUR CURRENT KNOWLEDGE WITH THE UPCOMING TNM CLASSIFICATION? The seventh edition of the TNM Classification of Malignant Tumors is currently being discussed on the basis of the International Association for the Study of Lung Cancer proposal.26 The new TNM version may be applied next year. Present T2 lesions more than 7 cm will be reclassified as T3 disease on the basis of survival data for 6,052 patients with N0 disease. Strauss et al9 conclude that adjuvant paclitaxel and carboplatin could be an option for patients with tumors more than 4 cm. This conclusion will have to be put in perspective with the new classification. Given that patients with future stage IB disease will have a better prognosis than patients with present stage IB disease, there is a reasonable possibility to invalidate this conclusion, and chemotherapy efficacy in these new populations of patients will have to be investigated in specific randomized trials. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Thierry Le Chevalier, GlaxoSmithKline (C) Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Benjamin Besse, Thierry Le Chevalier Provision of study materials or patients: Benjamin Besse, Thierry Le Chevalier Collection and assembly of data: Benjamin Besse, Thierry Le Chevalier Data analysis and interpretation: Benjamin Besse, Thierry Le Chevalier Manuscript writing: Benjamin Besse, Thierry Le Chevalier Final approval of manuscript: Benjamin Besse, Thierry Le Chevalier
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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