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Originally published as JCO Early Release 10.1200/JCO.2007.13.9030 on May 27 2008 © 2008 American Society of Clinical Oncology. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group
From the Institut Gustave-Roussy, Villejuif; Centre René Gauducheau, St-Herblain; Pierre Fabre Oncology, Boulogne, France; University of Torino, Torino; Mario Negri Institute, Milano, Italy; University Health Network, Princess Margaret Hospital, Toronto; National Cancer Institute of Canada, Kingston, Ontario, Canada; Medical Research Council Clinical Trials Unit; University College Hospital, London; Glenfield Hospital, Leicester, United Kingdom; and Catalan Institute of Oncology, Badalona, Spain Corresponding author: Jean-Pierre Pignon, MD, PhD, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; e-mail: jppignon{at}igr.fr
Purpose Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non–small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy. Patients and Methods Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial. Results With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin. Conclusion Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.
Lung cancer is the most frequent cancer worldwide.1 Non–small-cell lung cancer (NSCLC) represents more than 80% of all lung tumors, and in its early stages, it is treated surgically with curative intent. However, 30% to 70% of patients undergoing resection develop recurrence and die of their disease.2 Adjuvant radiotherapy is no longer recommended after surgery because it has been shown to have a deleterious effect on long-term survival, at least for stage I and II disease.3 A large meta-analysis4 based on individual patient data suggested that adjuvant cisplatin-based chemotherapy could yield an overall survival (OS) advantage of 5% at 5 years.4 However, the difference in OS (hazard ratio [HR] = 0.87) was not significant (P = .08), and thus, randomized trials comparing various postoperative cisplatin-based chemotherapy regimens with surgery alone continued for another decade. Several recent large trials5-7 confirmed a benefit in OS, but others8,9 did not. Several literature-based meta-analyses support the beneficial effect on survival with cisplatin-based chemotherapy.10-12 We report here the results of a pooled analysis of the recent large trials of cisplatin-based adjuvant chemotherapy in patients with NSCLC. This Lung Adjuvant Cisplatin Evaluation (LACE) was planned to identify treatment options associated with a higher benefit or groups of patients benefiting more from adjuvant treatment.
The protocol (available on request) was finalized by a steering committee with representatives of each group in November 2005.
Inclusion and Exclusion Criteria
Data Collection and Checking
Analysis
Median follow-up was computed using the reverse Kaplan-Meier method.14 The two treatment groups were compared according to the intent-to-treat principle. Both the standard log-rank test method stratified by trial15 and the Cox model stratified by trial, planned radiotherapy, area of the world, and center size and adjusted for age, sex, stage, and associated drug(s) were used for survival analyses. Because the two methods led to similar results, only the results using the first method are reported. The log-rank observed minus expected (O-E) numbers of deaths and their variances were used to calculate individual HRs and the overall HR using a fixed effect model.15 To eliminate the potential bias of an incorrect determination of the cause of death after recurrence, the log-rank analysis of non–lung cancer mortality covered only the period before recurrence (ie, data were censored at the first recurrence).16 An unbiased, although potentially diluted, log-rank analysis of lung cancer mortality was obtained indirectly by subtracting the log-rank statistic for non–lung cancer mortality from the log-rank statistic for mortality from all causes (ie, the two observed values, the two expected values, and the two variances are each subtracted from each other).
Five trials with 4,584 patients were eligible.5-9 The 74 patients who had incomplete resection or neoadjuvant chemotherapy from the Big Lung Trial were excluded. The median follow-up time was 5.2 years (range per trial, 4.7 to 5.9 years). Table 1 lists the trials, and Table 2 lists the characteristics of the study population. Overall, administration of postoperative radiotherapy, after chemotherapy in the chemotherapy arm, was planned for 31% of patients (4% among pN0 patients, 39% among pN1 patients, and 74% among pN2 patients).
Effect of Chemotherapy on OS and DFS As shown in Figure 1, there was a statistically significant benefit (HR = 0.89; 95% CI, 0.82 to 0.96; P = .005) on OS for chemotherapy compared with no chemotherapy corresponding to an 11% reduction in the risk of death and absolute benefits of 3.9% and 5.4% at 3 and 5 years, respectively (Fig 2A). Heterogeneity among trials was not significant (P = .37; I2 = 6%). The effect on DFS also favored chemotherapy (HR = 0.84; 95% CI, 0.78 to 0.91; P < .001) with absolute benefits of 5.8% and 5.8% at 3 and 5 years, respectively (Fig 2B) without heterogeneity among trials (P = .27; I2 = 23%).
Compliance and Toxicity In the chemotherapy arm, 9% of patients never received chemotherapy mainly because of patient refusal (43%), but 59% of patients received at least 240 mg/m2 of cisplatin. According to chemotherapy regimens (Table 1), three or four cycles of chemotherapy were planned; 14% of the treated patients received only one cycle, and 10% received two cycles. The main reasons for receiving less than the planned number of cycles were patient refusal (35%), toxicity (34%), and early death or progression (9%). The median delay between surgery and the start of chemotherapy was 39 days (> 60 days in 7% of patients). One percent of patients in the control arm received adjuvant chemotherapy. Among 1,439 patients (705 in the chemotherapy arm and 734 in the control arm) planned to receive adjuvant thoracic radiotherapy, only 64% in the chemotherapy arm and 72% in the control arm actually received this treatment. Among the 3,145 patients not planned to receive radiotherapy, 2% in the chemotherapy arm and 3% in the control arm received radiotherapy. Only the maximum grade of toxicity was collected. Data on grade 3 toxicity were not collected in the International Adjuvant Lung Trial. In the 1,190 patients treated with chemotherapy in the chemotherapy arms of the four other trials, the rate of overall grade 3 to 4 toxicity was 66%. In the five trials, the rate of overall grade 4 toxicity was 32%. The most frequent toxicity was neutropenia (9% grade 3 and 28% grade 4). The toxicity rate was highly variable among the trials. This cannot be explained only by the difference of chemotherapy regimens. It is also likely to be related to the method of toxicity surveillance and data collection. There were 19 chemotherapy-related deaths (0.9%) reported.
Effect of Chemotherapy on Lung Cancer and Non–Lung Cancer Death
Variation of Treatment Effect According to Trial and Patient Characteristics
There was a significant interaction between chemotherapy effect and stage (test for trend, P = .04 for both OS and DFS). Cisplatin plus vinorelbine was planned for 13% of the patients with stage IA disease compared with 43% of patients with other stages. If the small group of patients with stage IA was excluded, the test for trend was no longer significant (P = .35 for OS and P = .33 for DFS). There was a significant interaction between chemotherapy effect and WHO PS (test for trend, P = .009 for OS and P = .01 for DFS). Chemotherapy effect increased with better PS and may be detrimental for PS of 2. Data on PS were not available in the Adjuvant Lung Cancer Project Italy trial, and the National Cancer Institute of Canada Clinical Trial Group JBR10 trial did not include patients with PS of 2. For both OS and DFS, no variation of chemotherapy effect was observed with sex, age, type of surgery, and histology.
This pooled analysis of the recent large adjuvant trials of cisplatin-based chemotherapy in NSCLC confirms the effect of chemotherapy on both OS (5.4% absolute benefit at 5 years) and DFS (5.8% benefit).10-12 Gilligan et al,19 in their update of the Medical Research Council meta-analysis of the literature, which is based on approximately 1,500 patients and showed an HR of death of 0.88 (95% CI, 0.76 to 1.01; P = .07) with an absolute benefit of 5%, concluded that the relative effect of adjuvant and neoadjuvant chemotherapy might be similar.20 Because the results for adjuvant chemotherapy were expected, the main objective of this study was to identify trials or patient characteristics associated with the greatest benefit from chemotherapy through a set of preplanned exploratory analyses. The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other doublet or triplet regimens included in this study should be interpreted with caution because the total dose of cisplatin received was significantly higher in patients treated with vinorelbine and it was impossible to separate the effect of cisplatin dose from that of the companion drug. The effect of chemotherapy was similar whether thoracic radiotherapy was planned or not. Most of the patients who received postoperative radiotherapy had stage III (pN2) tumors. Although there is general agreement that postoperative radiotherapy is not indicated and likely detrimental in stage I and II NSCLC, its role in stage III remains controversial.3,21 An unplanned analysis of postoperative radiotherapy in the Adjuvant Navelbine International Trialist Association 01 trial showed that patients with stage III (pN2) NSCLC had the best survival when they received adjuvant chemotherapy followed by thoracic radiation.7 Similarly, a recent analysis of the Surveillance, Epidemiology, and End Results database showed a significant survival advantage for stage III patients treated with postoperative radiotherapy.22 A randomized trial to address this question is currently open in Europe.23 The significant variation of the chemotherapy effect according to stage was related mainly to patients with stage IA disease. After exclusion of the small numbers of stage IA patients, there was no significant variation of chemotherapy effect according to stage. The effect on OS observed in stage IB (HR = 0.92; 95% CI, 0.78 to 1.10) is fully compatible with that observed in the Cancer and Leukemia Group B 9633 trial, which was a trial of adjuvant carboplatin plus paclitaxel in patients with stage IB disease. The updated HR of death, which is equal to 0.80 (95% CI, 0.57 to 1.13), falls within the 95% CI of the LACE HR.24,25 The updated results of the ongoing NSCLC cancer meta-analysis with 37 trials should clarify whether patients with stage IB NSCLC should receive adjuvant chemotherapy.4,26,27 A significant increase of chemotherapy effect with better PS was observed, and our data suggest that chemotherapy may be detrimental for patients with a PS of 2. Thus, at this time, adjuvant cisplatin-based chemotherapy cannot be recommended for these patients. Therefore, the results of the Adjuvant Navelbine International Trialist Association 02 trial of postoperative single-agent vinorelbine in patients not fit for platinum-based chemotherapy are awaited with interest. Because we chose to include in this study only recent, large trials of adjuvant cisplatin-based chemotherapy, it was possible to collect a large amount of homogenous data on patient and treatment characteristics. Trials using concurrent radiochemotherapy were excluded because of the possibility that the concurrent administration of radiation and chemotherapy might interfere with chemotherapy delivery in view of increased toxicity.24,28 Trials using carboplatin also were excluded because the efficacy of cisplatin and carboplatin may differ, as has been reported in advanced NSCLC.29,30 A small excess of deaths not related to lung cancer was observed with adjuvant chemotherapy in the 6 months after random assignment. It was mainly related to chemotherapy toxicity and an excess of pulmonary/cardiovascular deaths. This effect did not vary according to the drug combined with cisplatin or to the administration of radiotherapy. The excess in cardiopulmonary deaths might be, in part, related to the detrimental cardiovascular effect of cisplatin. Rare occurrences of cardiac or cerebrovascular complications of cisplatin have been reported previously.31-33 Two recent studies pointed out the under-reporting of vascular events in patients treated by cisplatin-based chemotherapy.34,35 Patients with NSCLC and tobacco-induced cardiovascular or lung disease may be more prone to cardiovascular complications of cisplatin than patients treated for other malignancies who may, for the most part, be younger and not have the same smoking history. Finally, a recent study showed an association between chemotherapy and venous thromboembolism in NSCLC.36 Our analysis clearly confirms that adjuvant cisplatin-based chemotherapy is of benefit in completely resected NSCLC and further supports its use in routine clinical practice. The benefit of this treatment did not vary with classical clinical factors, except perhaps stage IA disease and PS of 2. Interactions between tumor markers and chemotherapy effect have been shown in individual trials37,38; the LACE group is undertaking a collaborative project to validate these findings.
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: Delphine Aubert, Pierre Fabre Oncology (C); Thierry Le Chevalier, GlaxoSmithKline (C) Consultant or Advisory Role: Giorgio V. Scagliotti, Eli Lilly & Co (C) Stock Ownership: Delphine Aubert, Pierre Fabre Oncology Honoraria: Giorgio V. Scagliotti, Eli Lilly & Co, Sanofi-aventis, Roche; Jean-Yves Douillard, Pierre Fabre Oncology; Frances A. Shepherd, Pierre Fabre Oncology; Richard J. Stephens, Pierre Fabre Oncology Research Funding: Jean-Pierre Pignon, Sanofi-aventis; Giorgio V. Scagliotti, Eli Lilly & Co Expert Testimony: None Other Remuneration: None
Conception and design: Jean-Pierre Pignon, Hélène Tribodet, Giorgio V. Scagliotti, Jean-Yves Douillard, Frances A. Shepherd, Richard J. Stephens, Ariane Dunant, Valter Torri, Lesley Seymour, Stephen G. Spiro, Roldano Fossati, Keyue Ding, David Waller, Thierry Le Chevalier Provision of study materials or patients: Giorgio V. Scagliotti, Jean-Yves Douillard, Frances A. Shepherd, Richard J. Stephens, Ariane Dunant, Valter Torri, Rafael Rosell, Lesley Seymour, Stephen G. Spiro, Roldano Fossati, Delphine Aubert, Keyue Ding, David Waller, Thierry Le Chevalier Collection and assembly of data: Jean-Pierre Pignon, Hélène Tribodet, Giorgio V. Scagliotti, Jean-Yves Douillard, Frances A. Shepherd, Richard J. Stephens, Ariane Dunant, Lesley Seymour, Stephen G. Spiro, Estelle Rolland, Roldano Fossati, Delphine Aubert, Keyue Ding Data analysis and interpretation: Jean-Pierre Pignon, Hélène Tribodet, Giorgio V. Scagliotti, Jean-Yves Douillard, Frances A. Shepherd, Richard J. Stephens, Ariane Dunant, Lesley Seymour, Stephen G. Spiro, Estelle Rolland, Roldano Fossati, Thierry Le Chevalier Manuscript writing: Jean-Pierre Pignon, Hélène Tribodet, Giorgio V. Scagliotti, Jean-Yves Douillard, Frances A. Shepherd, Richard J. Stephens, Ariane Dunant, Valter Torri, Rafael Rosell, Lesley Seymour, Stephen G. Spiro, Estelle Rolland, David Waller, Thierry Le Chevalier Final approval of manuscript: Jean-Pierre Pignon, Hélène Tribodet, Giorgio V. Scagliotti, Jean-Yves Douillard, Frances A. Shepherd, Richard J. Stephens, Ariane Dunant, Valter Torri, Rafael Rosell, Lesley Seymour, Stephen G. Spiro, Estelle Rolland, Roldano Fossati, Delphine Aubert, Keyue Ding, David Waller, Thierry Le Chevalier
Lung Adjuvant Cisplatin Evaluation Collaborative Group Steering committee: Jean-Yves Douillard, Patricia His, Thierry Le Chevalier, Jean-Pierre Pignon, Giorgio V. Scagliotti, Lesley Seymour, Frances A. Shepherd, Stephen G. Spiro, Richard J. Stephens, Valter Torri, and Hélène Tribodet. Investigators. Bengt Bergman, Lucio Crino, Mario De Lena, Keyue Ding, Jean-Yves Douillard, Ariane Dunant, Roldano Fossati, Nicole Gower, Delphine Aubert, Thierry Le Chevalier, Jean-Pierre Pignon, Rafael Rosell, Giorgio V. Scagliotti, Lesley Seymour, Frances A. Shepherd, Stephen G. Spiro, Richard J. Stephens, Valter Torri, David Waller, and Timothy Winton.
We acknowledge the investigators who agreed to share and update their data. We thank Denise Avenell for secretarial assistance.
published online ahead of print at www.jco.org on May 27, 2008. Supported by Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, Sanofi-Aventis (unrestricted grants), and Pierre Fabre Oncology (unrestricted grants). Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. Members of the Lung Adjuvant Cisplatin Evaluation Collaborative Group are listed in the Appendix (online only). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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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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ABSTRACT
INTRODUCTION
2 tests were used to study heterogeneity among trials and trial groups.
300 or > 300 mg/m2) were considered, there was a trend in favor of higher dose cisplatin (P = .10 for OS and P = .09 for DFS). The total dose of cisplatin varied according to the associated drug and was more than 300 mg/m2 in 86% of the patients in the cisplatin plus vinorelbine group, in 54% of patients in the cisplatin plus another drug group, and in 0% of patients in the three-drug group. Patients on three-drug regimens received significantly less cisplatin (P < .001) than patients on doublet regimens (median total dose of cisplatin, 214 v 300 mg/m2 for both cisplatin plus vinorelbine and for other doublet regimens, respectively). Further analyses could not differentiate the effect of cisplatin dose and associated drugs. For both OS and DFS, no variation of chemotherapy effect was observed with planned (
