Originally published as JCO Early Release 10.1200/JCO.2004.01.153 on August 23 2004

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Role of Adjuvant Chemotherapy in Patients With Resected Non–Small-Cell Lung Cancer: Reappraisal With a Meta-Analysis of Randomized Controlled Trials

From the Department of Medicine II, Okayama University Medical School, Okayama; Department of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.

Address reprint requests to Katsuyuki Hotta, MD, Department of Medicine II, Okayama University Medical School, 2-5-1, Shikata-cho, Okayama, 700-8558, Japan; e-mail: khotta{at}md.okayama-u.ac.jp

	ABSTRACT

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PURPOSE: The role of adjuvant chemotherapy in patients with resected non–small-cell lung cancer (NSCLC) remains to be defined. This study was aimed at re-evaluating the effectiveness of adjuvant chemotherapy in patients with resected NSCLC, by performing a meta-analysis of relevant trials.

METHODS: We performed a literature search to identify trials reported after the publication of a meta-analysis in 1995, comparing patients with NSCLC receiving chemotherapy after surgery with those undergoing surgery alone. The hazard ratio (HR) was estimated to assess the survival advantage of adjuvant chemotherapy.

RESULTS: Eleven trials conducted on a total of 5,716 patients were identified by the literature search. In these trials, hazard ratio estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR, 0.872; 95% CI, 0.805 to 0.944; P = .001). In a subset analysis, both cisplatin-based chemotherapy (HR, 0.891; 95% CI, 0.815 to 0.975; P = .012) and single-agent therapy with tegafur and uracil (UFT; HR, 0.799; 95% CI, 0.668 to 0.957; P = .015) were found to yield a significant survival benefit. The toxicities of adjuvant chemotherapy were found to be generally mild.

CONCLUSION: This is the first updated meta-analysis demonstrating the importance of cisplatin-based chemotherapy and single-agent UFT therapy as adjuvant chemotherapy in the treatment of resected NSCLC. Although the results must be carefully interpreted because of one limitation (the meta-analysis was performed with abstracted data), they raise critical issues that must be resolved in future studies.

	INTRODUCTION

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Lung cancer is the leading cause of cancer death in many countries.¹ Surgery remains the best treatment modality for potential cure in patients with non–small-cell lung cancer (NSCLC), and, at present, one-third of all patients are suitable candidates for surgery at the time of initial presentation. However, taking into account the annual incidence of lung cancer worldwide, which is estimated to be more than a million, the social burden of this category of patients is large.² Moreover, the long-term survival rate even after surgical resection is rather disappointing.³

To improve the postoperative survival of NSCLC patients, the development of effective postoperative therapy is essential. Prospective randomized trials investigating the role of postoperative adjuvant chemotherapy in NSCLC have been performed since the 1960s. A meta-analysis of adjuvant chemotherapy trials reported in 1995 revealed a hazard ratio (HR) of 0.87 for patients treated with cisplatin (CDDP) -based chemotherapy.⁴ However, this result was only of marginal significance. Furthermore, this meta-analysis had the following limitations: the trials evaluated included those using outdated chemotherapy regimens, including a small number of accrued patients, and recorded poor treatment compliance.

Subsequently, many randomized trials investigating the role of adjuvant chemotherapy using more active chemotherapy regimens and larger numbers of accrued patients have been conducted.^5-15 Recently, very large-scale trials have been reported from Japan, Chile, and Italy.^10,11,15 However, these trials yielded conflicting data in regard to the survival benefit. Therefore, we performed a meta-analysis using data from these trials to investigate the effect of adjuvant chemotherapy on the overall survival in patients with resected NSCLC.

	METHODS

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Research Objective
The primary objective of this study was to assess the survival advantage gained by adding adjuvant chemotherapy to surgery in patients with resectable NSCLC.

Searching for Trials
To update the data, we intended to eliminate the trials accrued in the previous meta-analysis published in 1995.⁴ Therefore, only those trials for which patient recruitment was completed after January 1, 1992, were eligible. To avoid publication bias, both published and unpublished trials were identified through a computer-based search of the PubMed database and abstracts from the previous 12 Annual Meetings of the American Society of Clinical Oncology. We conducted the search using the following search terms: "lung cancer," "chemotherapy," "adjuvant," and "postoperative." Only references published in English were included. The search was also guided by a thorough examination of reference lists of original articles, review articles, and relevant books.

Selection of Trials
We included only those trials in which patients were randomly assigned to at least two arms—surgery followed by chemotherapy or surgery alone—and that included only patients with pathologically proven NSCLC who underwent a curative resection. Although optional thoracic irradiation was allowed as one of the adjuvant treatments, trials initially designed to randomly assign patients to surgery, followed by chemotherapy plus radiation, or surgery plus radiation, were considered ineligible. Trials that evaluated immunotherapy as adjuvant therapy and that were designed mainly to evaluate neoadjuvant chemotherapy and/or radiotherapy, were also excluded from the analysis.

Validity Assessment
We performed open assessments of the trials and used the instrument reported by Jadad et al.¹⁶ The Jadad score that we used was the original version reported in 1996. It included three simple questions: (1) was the study described as randomized? (2) Was the study described as double blind? (3) Was there a description of withdrawals and dropouts? The overall scores for these three items were calculated for each trial. Briefly, we gave a score of 1 point for each "yes" and 0 for each "no." There were no in-between scores.

Data Abstraction
To avoid bias in the data abstraction process, two observers (K.H. and H.U.) independently abstracted the data from the trials and compared the results. The following information was culled from each report: year of publication, number of patients, sex, pathological stage, performance status, chemotherapy regimen, treatment compliance, overall survival, and specific toxicity data. An attempt was also made to contact all the principal investigators of the trials to confirm or update the published data. In general, treatment compliance was defined as the number of patients who received the all planned courses of chemotherapy as a percentage of all the assessable patients in the trials evaluating cisplatin-based chemotherapy, and as the number of patients treated for the planned treatment period as a percentage of all the assessable patients in the trials evaluating single-agent therapy with tegafur and uracil (UFT).

Quantitative Data Synthesis
The HR was estimated to assess the survival advantage conferred by adjuvant chemotherapy. The crude log HR and its variance in each trial were calculated using the abstracted survival probabilities at each time-point from the Kaplan-Meier (KM) curves, according to the methods of Parmar et al.¹⁷ The HR provided in the report was used wherever available with 95% CIs. The minimum and maximum follow-up periods were used to estimate the number of censored subjects under the assumption that censoring occurs consistently throughout the follow-up period. If the minimum follow-up time was not available, time zero was substituted for it. Assuming a constant hazard for two types of therapy within an individual trial, all the survival probabilities available in each trial were used to obtain a representative HR for each trial, instead of limiting the time points to specified times. The HRs were calculated to estimate how many times higher the probability of death from any cause would be in patients receiving adjuvant chemotherapy after surgery, compared with that in patients undergoing surgery alone. Therefore, an HR below unity was taken to indicate that adjuvant chemotherapy after surgery was superior to surgery alone. Trials including two experimental arms were treated as two independent trials.^9,13

The general variance-based method was used to estimate the summary HRs and their 95% CIs. We also calculated the between-study variation (²) from the Q statistic, according to the method described by DerSimonian and Laird.¹⁸ We decided to apply a random effect model, which allows meta-analyses to take between-study variations into consideration based on the statistical significance of the Q test. We also used Begg's funnel plots¹⁹ and Egger's test²⁰ to identify possible publication bias. Metaregression analysis was applied to detect the source of heterogeneity in the analysis.²¹ The factors examined in the meta-regression analysis were the study quality score,¹⁶ inclusion of platinum agents in the regimen, inclusion of UFT, type of report (abstract form or original article), year of start of the trial, disease stage in the enrolled patient (I, II, or III), proportion of patients with a performance status (PS) score of 0-1, and proportion of male patients. Cumulative meta-analysis was applied in the event of heterogeneity being probable in an ordinal variable with statistical significance (P < .15). Subgroup meta-analysis was performed for platinum-based therapy and single-agent UFT therapy. The probable sources of heterogeneity (P < .20) for categorical variables were also evaluated by subgroup meta-analysis.

All the statistical analyses were conducted using the Stata version 8 software (Stata Corp, College Station, TX). We defined a statistical result with a P value of less than .05 as significant.

	RESULTS

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Trial Flow
Our computer-based search of the PubMed database, and manual search of the abstracts and relevant articles yielded 527, four, and two reports, respectively, published throughout a 12-year period. These included 31 potentially relevant randomized clinical trials that evaluated postoperative adjuvant therapy in patients with resected NSCLC. Of the 31 possibly appropriate trials, 20 were excluded from our meta-analysis, including seven that assessed immunotherapy and eight which assessed radiotherapy and two vitamins as adjuvant therapy, and three trials which were initially designed to randomize patients into surgery followed by chemotherapy plus radiation, or surgery followed by radiation.

One of the remaining 11 trials, a British one¹² was a unique trial, because all clinically operable patients were included in the trial, whether or not they had undergone curative resection. However, since the majority of patients in the trial did in fact have an R0 (complete resection) or R1 operation (microscopically incomplete resection), and only two (0.5%) of the total of 381 patients had pathological stage IV disease, we included this trial in our analysis. Thus, ultimately, data from 11 trials were included in this meta-analysis.^5-15

Characteristics of the 11 Trials
The baseline characteristics of the 11 trials are listed in Table 1. In total, 5,716 patients were randomized to surgery followed by adjuvant chemotherapy (2,873 patients), or to surgery alone (2,843 patients). Four trials were reported in abstract form only.^6,9,12,13 In the adjuvant chemotherapy arm, CDDP was used in eight trials including 3,907 patients, and vindesine was frequently combined with CDDP (six of the eight trials). Single-agent UFT was also frequently used in five trials including 1,809 patients.

Overall Survival
Data on survival were available for all trials (5,538 patients, Table 2). A total of 178 randomized patients in four trials were excluded from the survival analysis.^6,10,14,15 The main reasons for this exclusion were problems with data integrity, incomplete resection, incorrect clinical stage, and incorrect pathological diagnosis; on the other hand, postoperative deaths were not generally excluded from the survival analysis. The accuracy of the HRs estimated from the KM curves was assessed by comparing them with the HRs recorded in the original reports, and three trials were eligible for the assessment (Scagliotti et al,¹⁰ Arriagada et al,¹¹ and Waller et al¹²). The HRs and their CIs based on the KM curves were 0.94 (0.80 to 1.12), 0.87 (0.77 to 0.98), and 1.07 (0.82 to 1.38), and the HR in the reports for the same trials were 0.96 (0.81 to 1.13), 0.86 (0.76 to 0.98), and 1.02 (0.77 to 1.35), respectively.

View larger version (15K): [in this window] [in a new window]   Fig 1. Overall survival with adjuvant chemotherapy compared with surgery alone. The summary hazard ratio (HR) was 0.872 (95% CI, 0.805 to 0.944; P = .001) for adjuvant chemotherapy compared with surgery alone. PVdU, cisplatin, vindesine, and tegafur-uracil; UFT, tegafur and uracil.

View larger version (12K): [in this window] [in a new window]   Fig 2. Overall survival with adjuvant cisplatin–based chemotherapy compared with surgery alone. The summary hazard ratio (HR) was 0.891 (95% CI, 0.815 to 0.975; P = .012) for adjuvant chemotherapy compared with surgery alone. PVdU, cisplatin, vindesine, and tegafur-uracil.

View larger version (10K): [in this window] [in a new window]   Fig 3. Overall survival with adjuvant tegafur and uracil (UFT) therapy compared with surgery alone. The summary hazard ratio (HR) was 0.799 (95% CI, 0.668 to 0.957; P = .015) for adjuvant chemotherapy compared with surgery alone.

Toxicity
The toxicity profiles were obtained for 2,594 (90%) of the 2,873 patients assigned to the adjuvant chemotherapy arms. Toxicities were generally mild and acceptable. Grade 4 neutropenia, grade 4 thrombocytopenia, grade 3 or more severe nephrotoxicity, and grade 3 or more severe nausea and vomiting were observed in 14%, 2%, 2%, and 10%, respectively, of the patients who received CDDP-based chemotherapy. Grade 3 or more severe nausea and vomiting, diarrhea, and hepatic toxicity were observed in 0.7%, 0.2%, and 0.2% of the patients treated with UFT, respectively. There were 16 treatment-related deaths (0.6%) in 10 trials, including 2,559 assessable patients assigned to adjuvant chemotherapy arms.

	DISCUSSION

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To our knowledge to date, in the present study, we demonstrated, for the first time, the survival benefit of adjuvant chemotherapy using updated data. Notably, for the case of CDDP-containing regimens, our meta-analysis included data from three times more patients than the previously reported meta-analysis,⁴ and the trials employed more effective regimens. As a result, we were able to show that CDDP-based chemotherapy yielded a significant survival benefit, while the previous meta-analysis indicated only a marginal effect of CDDP-based chemotherapy as adjuvant therapy on the overall survival.⁴

We also demonstrated a significant survival advantage of adjuvant UFT therapy in patients with resected NSCLC. However, the objective response rate to single-agent UFT was only 6.3% in patients with advanced NSCLC,²² indicating the need for clarifying the discordance of UFT activity against early versus advanced NSCLC. Two reports may be helpful in understanding the effect of UFT. First, Tanaka et al reported an antiangiogenic effect of UFT in a preclinical study.²³ Second, Wada et al noted in their adjuvant chemotherapy study that the incidences of death from second primary tumors (SPT) were only 2% and 3%, respectively, in the two UFT arms, which was low compared with 5% in the control arm.²⁴ In the report by Kato et al also, the SPT incidence was slightly lower in the UFT arm than in the control arm.¹⁵ These results suggest an additional potential benefit of UFT in the prevention of SPT.

Several technical issues have to be mentioned in relation to this meta-analysis. All our analyses were based on abstracted data and not on individual patient data (IPD). The results must therefore be interpreted cautiously, as an IPD-based meta-analysis would give more reliable estimation than one based on abstracted data.²⁵ Publication bias is a significant threat to the validity of the results of this meta-analysis. Although we found no evidence of publication bias in relation to the graphical or statistical methods, it is difficult to completely rule out this possibility from all aspects of the trials. Heterogeneity among trials may be another limitation of our meta-analysis, even though we applied a random-effect model that takes possible heterogeneity into consideration. We identified the pathological stage of the cancer as a source of heterogeneity. Regarding heterogeneity due to inclusion of stage III patients, subgroup meta-analysis indicated that the effect of adjuvant chemotherapy was stronger in trials without stage III patients. A similar trend was observed for trials with stage II patients. Accordingly, the effects of adjuvant chemotherapy may be greater in stage I patients than in stage II-III patients, though careful interpretation of the heterogeneity detected by metaregression analysis is necessary, as the statistical power was low due to the limited number of trials. Additionally, inclusion of results presented in the abstract form, which may be only preliminary, might also have biased our final result. However, as we endeavored to obtain the most updated and precise data possible by direct contact with the principal investigators, any bias due to this factor is likely to be small. The accuracy of the HRs estimated from the KM curves is another important issue. We obtained fairly good correlation between the HRs reported in this article and those obtained based on the KM curves, suggesting that curve-based HRs can be substituted in cases where the HRs are not available.

Several other problems also remain unresolved. We analyzed patients with various stages of resected NSCLC who received several types of CDDP-based regimens, as one group. Thus, further clarification of which stage of cancer would be especially benefited by adjuvant chemotherapy, and which drug is best added to CDDP, is essential. It also remains unclear whether new drugs, such as paclitaxel, docetaxel, vinorelbine, and gemcitabine should be combined with platinum agents. Additionally, although the treatment compliance seemed to have improved somewhat in the trials that were included in our study as compared with that reported in the previous meta-analysis⁴ (median, 64% v 52% of the planned treatment), further efforts to improve chemotherapeutic regimens to minimize toxicities are clearly warranted. Also, neoadjuvant chemotherapy is rapidly becoming one of the most promising modalities for the improvement of the overall survival of operable patients.²⁶ We have demonstrated the usefulness of adjuvant chemotherapy, but it remains unclear whether adjuvant chemotherapy would be more beneficial for operable patients than neoadjuvant chemotherapy. A Spanish randomized study on 600 patients has been initiated to compare neoadjuvant chemotherapy, surgery alone, and postoperative chemotherapy.²⁷ The results of this study will hopefully shed light on the most suitable treatment modality in operable patients. Finally, our results should be confirmed by an IPD-based meta-analysis.

In conclusion, this is the first updated meta-analysis to demonstrate the benefit of adjuvant chemotherapy in the treatment of resected NSCLC, though the strength of our main conclusion was limited by the fact that it was based on abstracted data. As for adjuvant therapy using a combination of platinum plus new agents, or molecular-targeted therapy, the results of ongoing and recently completed randomized trials are eagerly awaited.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We wish to thank Drs Tommaso Claudio Mineo and Vincenzo Ambrogi,⁷ Drs Hirohito Tada and Yukito Ichinose,⁸ Drs Thierry Le Chevalier and Jean-Charles Soria,¹¹ Dr Richard Stephens,¹² Dr Munehisa Imaizumi,¹³ and Drs Chiaki Endo and Masami Sato¹⁴ for their valuable comments and/or important data.

	NOTES

 
Katsuyuki Hotta and Keitaro Matsuo contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted January 26, 2004; accepted May 20, 2004.

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