The Oncologist, Vol. 12, No. 3, 331-337, March 2007; doi:10.1634/theoncologist.12-3-331
© 2007 AlphaMed Press
Optimal Adjuvant Therapy for Non-Small Cell Lung Cancer—How to Handle Stage I Disease
Heather Wakeleea,
Sarita Dubeyb,
David Gandarac
aStanford University, Stanford, California, USA;
bUniversity of California–San Francisco, San Francisco, California, USA;
cUniversity of California–Davis, Sacramento, California, USA
Key Words. Lung cancer • Adjuvant chemotherapy • Stage I • Cisplatin
Correspondence: Heather Wakelee, M.D., Oncology, Stanford University, 875 Blake Wilbur Drive, Room 2233, Stanford, California 94305-5826, USA. Telephone: 650-723-9094; Fax: 650-724-3697; e-mail: hwakelee{at}stanford.edu
Received October 29, 2006;
accepted for publication January 10, 2007.
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:- Discuss adjuvant chemotherapy as a standard of care for resected stage II–IIIA non-small cell lung cancer.
- Interpret the controversy in treating stage IB non-small cell lung cancer patients with adjuvant chemotherapy.
- Define the future directions of adjuvant therapy for non-small cell lung cancer including new drugs under investigation and better "tailoring" of therapy.
Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com
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ABSTRACT
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The standard of care for resected stage II–IIIA non-small cell lung cancer (NSCLC) now includes adjuvant chemotherapy based on the results of three phase III studies using cisplatin-based regimens—the International Adjuvant Lung Trial, the National Cancer Institute of Canada JBR.10 trial, and the Adjuvant Navelbine International Trialist Association trial. The role of adjuvant chemotherapy for stage I disease remains controversial. A recent meta-analysis (the Lung Adjuvant Cisplatin Evaluation) showed potential harm with the addition of adjuvant cisplatin for stage IA disease and no survival benefit for this modality in stage IB disease. Updated results from the Cancer and Leukemia Group B 9633 trial, the only trial to focus exclusively on stage IB patients, no longer show a statistically significant survival benefit from adjuvant chemotherapy in this population, except for the subgroup of patients with larger tumors. It may be that trials have been underpowered to detect a small benefit for patients with stage IB disease, or there may really not be benefit to adding adjuvant therapy for this stage of disease. Additional markers, such as tumor size or the presence or absence of certain tumor proteins like ERCC1, may help to determine which patients with resected stage I NSCLC may benefit from adjuvant chemotherapy. Strategies such as inhibition of angiogenesis pathways and the epidermal growth factor receptor are under exploration.
Disclosure of potential conflicts of interest is found at the end of this article.
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EARLY ADJUVANT CHEMOTHERAPY TRIALS
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Adjuvant chemotherapy for resected early-stage non-small cell lung cancer (NSCLC) was still a research question until just a few years ago, but has now become the standard of care for patients with resected stage II and IIIA disease. The role of adjuvant therapy for stage I patients, though, continues to evolve. Prior to 2003, no large randomized studies had conclusively demonstrated the benefit of adjuvant chemotherapy after resection of NSCLC, despite the results of a 1995 meta-analysis demonstrating a nonsignificant 5% survival advantage at 5 years with the addition of cisplatin-based chemotherapy [1]. The first several phase III studies reported after the meta-analysis failed to show a significant benefit with adjuvant chemotherapy. These included the Eastern Cooperative Oncology Group (ECOG) 3590 (Intergroup 0115) trial [2] and the Big Lung Trial (BLT) [3], both of which were relatively small, but the Adjuvant Lung Project Italy (ALPI) [4] enrolled over 1,000 patients and showed no survival advantage with the addition of adjuvant chemotherapy.
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ADJUVANT CHEMOTHERAPY 2003–2006
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Starting in 2003, a series of positive trials have been presented. The International Adjuvant Lung Trial (IALT) reported a statistically significant 4% survival advantage at 5 years (hazard ratio [HR], 0.86; p < .03) with the addition of four cycles of cisplatin-based chemotherapy after complete resection of stage I–III NSCLC [5]. These results mirrored the results of the 1995 meta-analysis (Table 1). This was by far the largest lung cancer adjuvant trial to date and included 1,867 patients, nearly equally divided among stages I–III, who were randomized to cisplatin-based chemotherapy versus observation. The study was not stratified to evaluate results by stage, but a trend toward a greater benefit in stage II and III patients was identified. The similarity of the overall results to the meta-analysis and the size of the trial increased the credibility of this trial, despite the results from ALPI.
Confirmation of a benefit from adjuvant therapy was seen in 2004, when two additional positive adjuvant trials were reported (Table 1). The National Cancer Institute of Canada JBR.10 trial randomized 482 patients with completely resected stage IB–IIB NSCLC to receive four cycles of cisplatin and vinorelbine versus observation [6]. A 15% survival advantage was reported at 5 years (HR, 0.70; p = .012) with the addition of chemotherapy. The trial was stratified by stage, and in a subset analysis, no benefit was noted for stage IB patients (HR, 0.94). However, in the same year, the Cancer and Leukemia Group B (CALGB) trial 9633 of 344 patients with resected stage IB NSCLC did report a survival advantage for those receiving adjuvant carboplatin and paclitaxel chemotherapy versus observation [7]. This was the only adjuvant trial to use a carboplatin-based regimen. CALGB 9633 was closed early when the first interim analysis demonstrated a 12% survival advantage at 4 years (HR, 0.62). Thus, in 2004, the standard of care switched to include adjuvant platinum-based chemotherapy for those with resected stage IB–IIIA NSCLC.
Confirmation of the overall beneficial role of adjuvant therapy was demonstrated in 2005 with the results of the Adjuvant Navelbine International Trialist Association (ANITA) trial. That study of 840 patients with resected NSCLC, nearly equally balanced among stages IB–IIIA, found a 9% survival advantage at 5 years (HR, 0.79; p = .013) with four cycles of adjuvant cisplatin and vinorelbine [8]. Again, however, no benefit was found for the stage IB patients on subset analysis (HR, 1.10; 95% confidence interval [CI], 0.76–1.57). Thus, even though the only trial expressly designed for stage IB patients supported the use of adjuvant chemotherapy in this population, subset analysis from three other studies did not.
An update of CALGB 9633, presented at the American Society of Clinical Oncology (ASCO) 2006 meeting, has further weakened the support for adjuvant chemotherapy in stage IB disease. At the initial 2004 presentation of CALGB 9633, only 88 deaths (57% of the 155 required for final analysis) had occurred, and an HR for overall survival of 0.62 (p = .01) was reported. The 2006 update was based on 137 events, with an HR for overall survival of 0.80 (p = .10) [9]. A statistically significant survival advantage was still observed at 2 and 3 years, but, with the caveat of wide CIs, statistical significance was lost by 5 years. Failure-free survival still favored the chemotherapy arm (HR, 0.74; p = .03). Though 18 events (12%) are still awaited before results will be considered final, it is unlikely that the significant survival advantage will be regained. The total accrual to this trial was only 344 patients, versus 1,867 in IALT. The initial accrual target was 500 patients, but as a result of initial slow accrual, and early positive results at an interim analysis, the study was reduced in size. It must be noted that for an HR of 0.80 to be statistically significant, the trial would require over 1,000 patients. A variety of reasons may be offered to explain the statistically negative overall survival results of this trial. These include: the small size of the study, resulting in underpowered results; the possibility of lack of true benefit from adjuvant chemotherapy in stage IB disease; and the choice of carboplatin instead of cisplatin. The latter question is explored later in this article.
In an attempt to understand the overall results of the large adjuvant trials that have occurred since the 1995 meta-analysis, an individual patient meta-analysis of the five largest, cisplatin-based studies was conducted (ALPI, BLT, IALT, JBR.10, and ANITA)—the Lung Adjuvant Cisplatin Evaluation (LACE). That study found a 5.3% absolute survival advantage at 5 years (HR, 0.89; 95% CI, 0.82–0.96; p = .004) for adjuvant cisplatin therapy overall [10], thus reinforcing the need to adequately power adjuvant trials for this range of benefit. The stage IB subset analysis trended toward benefit (HR, 0.92), but failed to reach statistical significance (95% CI, 0.78–1.10), while a detriment for chemotherapy was suggested in stage IA patients (HR, 1.41; 95% CI, 0.96–2.09). Only 347 patients of the total 4,584 included in the analysis had stage IA disease, and the stage IA patients were far less likely to have received the more aggressive chemotherapy regimen. The HR for survival for stage II and III disease was 0.83 (95% CI, 0.73–0.95), thus endorsing the use of cisplatin-based chemotherapy regimens in this setting. This meta-analysis provides further validation that the benefit of platinum-based adjuvant chemotherapy, if it exists in stage IB, is small and would require a prohibitively large trial to be detected. Perhaps looking at higher-risk patients as opposed to the entire IB population would be a more appropriate strategy. To support this position, in an unplanned subset analysis, patients on CALGB 9633 with tumors of at least 4 cm (close to 100 patients on each arm) did have an overall survival advantage, with an HR of 0.66 (p = .04) [9]. The 74 patients in each arm with tumors <4 cm did not differ in survival based on treatment, with an HR of 1.02 (p = .51). These results are not conclusive, but support further studies looking at patients with stage IB disease with larger tumors.
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PLATINUM AGENTS IN ADJUVANT CHEMOTHERAPY
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While most positive adjuvant chemotherapy trials used cisplatin-based regimens, CALGB 9633, which failed to show a statistically significant overall survival advantage, used a carboplatin-based regimen. CALGB 9633 was also a small study, and the only trial that exclusively included stage IB patients. The impact that carboplatin had in these results is therefore difficult to evaluate. In the LACE meta-analysis, the combination of cisplatin plus vinorelbine was found to be superior to other cisplatin combinations. But these other regimens also included the lower doses of cisplatin, suggesting that dose intensity may be more important than merely the choice of platinum agent. Using this argument makes the substitution of carboplatin for cisplatin even less appealing. Despite these hints of inferiority of carboplatin in the adjuvant setting, we do not have any clear data. Instead, we must extrapolate from data in advanced stage NSCLC to get a better sense of whether or not carboplatin and cisplatin are likely to be equivalent in the adjuvant setting.
The cisplatin versus carboplatin (CISCA) meta-analysis presented at ASCO 2006, based on individual patient data from 2,968 patients in nine trials that compared a cisplatin- with a carboplatin-based regimen in advanced stage disease, is of value in making this assessment [11]. This study differed from the earlier Hotta et al. [12] and Zojwalla et al. [13] meta-analyses comparing cisplatin with carboplatin, which were based on published information and showed a slight superiority of cisplatin. In the meta-analysis by Hotta et al. [12], cisplatin effected a statistically superior overall survival benefit in comparison with carboplatin, albeit a small difference, only when combined with newer-generation chemotherapy agents (HR, 1.106; 95% CI, 1.005–1.218; p = .039). In the CISCA analysis, response rates were 33% with cisplatin and 26% with carboplatin, which correlated with an HR for response of 1.37 (95% CI, 1.16–1.62; p < .001). The HR for survival favored cisplatin, at 1.07, but this was not statistically significant (95% CI, 0.99–1.15; p = .10). The median survival duration for the cisplatin-treated patients was 9.1 months, versus 8.4 months for the carboplatin-treated patients (p = .101). Subset analyses, however, did show a statistically significant survival benefit for cisplatin regimens over carboplatin regimens for patients with nonsquamous histology (HR, 1.12; 95% CI, 1.01–1.23; p = .026) and with third-generation chemotherapy drugs (HR, 1.11; 95% CI, 1.01–1.21; p = .026). The trend toward superiority of cisplatin over carboplatin may lead to debate in metastatic disease, because subtle differences between agents is less critical when the goal is palliative. When cytotoxic chemotherapy is administered in the adjuvant setting with the goal of cure, however, even small differences matter. Thus the use of a cisplatin-based regimen for the adjuvant treatment of resected early-stage NSCLC should remain the standard, with carboplatin as a substitute only in patients with clear contraindications to cisplatin.
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ADJUVANT CHEMOTHERAPY IN THE ELDERLY
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The Elderly Vinorelbine Study (ELVIS) was a landmark trial in advanced NSCLC, which in a randomized fashion demonstrated that the elderly enjoy not only a survival benefit from chemotherapy, but an improvement in quality of life as well [14]. Given that the median age at diagnosis of lung cancer is 70 years, the question of treating the elderly with adjuvant chemotherapy becomes an important one. A retrospective analysis of the JBR.10 trial was done to evaluate this [15]. There were 155 patients who were aged 65 years or older. In spite of fewer doses of cisplatin and vinorelbine being administered in this subgroup, there was an overall survival benefit with chemotherapy—5-year survival rates of 70% and 46% in the chemotherapy and observation arms, respectively (HR, 0.61; 95% CI, 0.38–0.98; p = .04). On the other hand, overall survival for patients >75 years compared with those aged 66–74 years was worse with adjuvant chemotherapy (HR, 1.95; 95% CI, 1.11–3.41; p = .02). This analysis concluded that patients over the age of 65 years with a good performance status benefit from adjuvant chemotherapy, but those over 75 years of age require further study.
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FUTURE DIRECTIONS FOR PLATINUM-BASED ADJUVANT THERAPY
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Where should we go from here in the study of platinum-based adjuvant therapy for NSCLC? The ECOG 4599 trial evaluated carboplatin plus paclitaxel with or without bevacizumab, an anti–vascular endothelial growth factor (VEGF) antibody, and found a median survival time of 10.3 months versus 12.3 months (p = .003) favoring the bevacizumab-containing regimen in patients with advanced stage NSCLC [16]. These results make the addition of bevacizumab to adjuvant chemotherapy a compelling research question. E1505 is the proposed North American intergroup trial to investigate the addition of bevacizumab to adjuvant chemotherapy (Fig. 1). That study has an 85% power to detect an HR of 0.79 (26.5% overall survival advantage) with the addition of bevacizumab. The study will include 1,500 patients with stage IB–IIIA resected NSCLC, stratified by stage, histology, gender, and chemotherapy regimen. Investigators have the choice of three cisplatin-based chemotherapy regimens. The regimen must be chosen prior to randomization to bevacizumab or no bevacizumab. This trial includes patients with IB disease who have tumors of at least 4 cm in size, but excludes those with smaller tumors. This is based on the subset analysis of the CALGB 9633 trial that showed a benefit only in patients with larger tumors. The three chemotherapy options are cisplatin plus vinorelbine (the agents used in the JBR.10 and ANITA trials), cisplatin plus docetaxel (superior to cisplatin plus vinca alkaloid in two large, randomized, phase III trials for advanced NSCLC) [17, 18], and cisplatin plus gemcitabine (different toxicity profile, proven equivalent efficacy to other platinum doublets in advanced disease) [19]. An ongoing European trial examining the latter regimen of cisplatin plus gemcitabine with bevacizumab has not disclosed any unexpected toxicity to date. All three regimens have a common cisplatin backbone of 75 mg/m2 given on an every-3-weeks schedule for four cycles. Patients randomized to receive bevacizumab receive the drug at 15 mg/kg every 3 weeks for a total of 1 year. The first dose of bevacizumab is concurrent with the first dose of chemotherapy. The E1505 trial includes extensive correlatives that may help us better identify the patients who will benefit from adjuvant therapy.
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Figure 1. Schema of the E1505 intergroup trial enrolling 1,500 patients with resected stage IB ( 4 cm) to IIIA non-small cell lung cancer to receive four cycles of adjuvant cisplatin-based chemotherapy with or without 12 months of bevacizumab.
Abbreviations: Chemo, chemotherapy; Squam, squamous; XRT, radiation therapy.
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NONPLATINUM AGENTS
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Other agents besides platinum agents are also of considerable interest in stage I NSCLC. While the studies cited above all consisted of platinum-based therapy, the largest trials in stage I NSCLC adjuvant therapy have been conducted in Japan with the oral agent uracil-tegafur (UFT), given daily for 2 years. A randomized phase III study of 978 stage I adenocarcinoma patients was reported in 2003, demonstrating an HR for survival of 0.71 (p = .04) [20]. The HR for survival for UFT in a meta-analysis of six trials (95% stage I) is 0.74 (p = 0.001, in an analysis of just over 2,000 patients) [21] (Table 1). The benefit was limited to those with tumor size of at least 2 cm. These studies are now the only trials showing a positive survival benefit with adjuvant chemotherapy in stage IB NSCLC. However, UFT, a drug not available in North America, was employed in a very different manner, as prolonged daily maintenance.
A maintenance oral drug delivery strategy is under investigation with the oral epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib. Gefitinib was approved for the second- or third-line treatment of advanced stage NSCLC based on phase II results, but this approval was later severely restricted based on the results of the Iressa Survival Evaluation in Advanced Lung Cancer (ISEL) study, which failed to show a survival advantage for the drug versus placebo [22]. When the ISEL results became known, this led to an early interim analysis of the Southwest Oncology Group (SWOG) 0023 trial designed to look at maintenance gefitinib after completion of concurrent chemoradiotherapy and consolidation chemotherapy for stage IIIB NSCLC. At this interim analysis, it was clear that gefitinib therapy could not improve survival even if accrual was complete, and even more discouraging was a trend toward a survival disadvantage from the maintenance drug [23]. The overall survival time for the gefitinib arm was 19 months, versus 29 months in the group of patients randomized to placebo. The JBR.19 study was closed soon after these results were known. JBR.19 enrolled 500 of the planned 1,200 patients who had resected stage IB–IIIA NSCLC and were randomized to 2 years of gefitinib versus placebo (after receiving adjuvant chemotherapy at the discretion of the treating physician). Results are awaited.
The RADIANT (Randomized Double-blind Trial in Adjuvant NSCLC with Tarceva) trial, a large phase III study, will evaluate the role of erlotinib in the adjuvant treatment of patients with resected stage IB–IIIA NSCLC (Fig. 2). Erlotinib is an oral EGFR inhibitor, like gefitinib, but it is now approved for the therapy of advanced stage NSCLC based on a positive trial in this patient population, JBR.21 [24]. Though both gefitinib and erlotinib are EGFR inhibitors, the different results in advanced stage disease warrant the investigation of erlotinib in the adjuvant setting. In this double-blind, placebo-controlled study, 975 patients will be randomized to either 2 years of daily oral erlotinib therapy at 150 mg/day or placebo. Only patients with EGFR-positive tumor tissue by either fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) will be randomized. Patients will be allowed to receive up to four cycles of a platinum-based adjuvant chemotherapy regimen prior to randomization.
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Figure 2. Schema of the RADIANT trial enrolling 975 patients with resected stage IB–IIIA non-small cell lung cancer to receive 2 years of erlotinib versus placebo after completion of four cycles of adjuvant chemotherapy (at the discretion of the investigator). Only patients who are epidermal growth factor receptor (EGFR) positive will be randomized.
Abbreviations: Adj, adjuvant; Chemo, chemotherapy; DFS, disease-free survival; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; Squam, squamous.
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MOLECULAR PROFILING
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Recent studies have also indicated a new hope of being able to prospectively identify patients who are most likely to benefit from adjuvant therapy. The RADIANT trial capitalizes on what is known about predictors of outcome to EGFR inhibitors in advanced disease, and only randomizes patients most likely to benefit, namely, those with expression of EGFR by FISH or IHC. A retrospective analysis of a subset of patients from the IALT trial indicates that IHC staining for ERCC1 may help predict those patients most likely to benefit from adjuvant cisplatin-based therapy [25]. ERCC1 is a nucleoside excision repair enzyme involved with the repair of cisplatin-induced DNA adducts. In that analysis, those patients with ERCC1-positive tumors were far less likely to benefit than those with lower levels of this DNA repair enzyme. The adjusted HR for death in ERCC1-negative tumors was 0.65 (95% CI, 0.50–0.86; p = .002), whereas that for ERCC1-positive tumors was 1.14 (95% CI, 0.84–1.55; p = .40). This observation will need to be studied in a prospective manner in order to influence a change in practice patterns. Nevertheless, it is an important step toward identifying the group of patients most likely to benefit from adjuvant cisplatin-based therapy. In the current situation, in which the overall survival benefit from adjuvant therapy is on the order of 5%–10%, and the treatment includes 3 months of relatively toxic chemotherapy, the ability to identify those most likely to benefit is crucial. How best to help those who may be less likely to benefit from cisplatin-based therapy needs further exploration. The use of non–platinum based chemotherapy combinations is one such approach.
Adjuvant therapy at this time is not indicated in patients with stage IA disease, and yet up to 30% of those patients will relapse and ultimately die of their disease. A group at Duke University has identified a gene-expression profile that predicts for poor outcome in those with early-stage NSCLC [26]. The lung "metagene" model, which evaluated three data sets with a total of 198 patients with early-stage lung cancer, was able to stratify patients into high and low risk of recurrence with 72%–90% accuracy. Because no treatment intervention was offered in this study, it is unclear whether the "metagene" model, a prognostic indicator in early disease, will prove to be a predictor of therapy as well. To ascertain the predictive power of this model, its impact on response to chemotherapy in the high-risk group should be studied in a prospective randomized trial.
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CONCLUSION
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In summary, we have reached a new era of adjuvant therapy for NSCLC, but continued progress must be made. At this time, the role of adjuvant cisplatin-based chemotherapy is clear for resected stage II and IIIA NSCLC, but it remains controversial for patients with stage IB disease and is contraindicated for those with resected stage IA disease. The subset of stage IB patients with larger tumors (at least 4 cm in size) may be more likely to benefit, but this hypothesis needs further validation. As the data stand today, adjuvant platinum-based chemotherapy should be discussed with patients with stage IB disease, but not strongly encouraged.
When adjuvant platinum-based therapy is used, cisplatin is the agent of choice. Carboplatin should only be used as a substitute in patients with contraindications to cisplatin. Bevacizumab is the only targeted therapeutic agent ever shown to prolong survival when added to front-line chemotherapy for advanced NSCLC. As such, extending the benefit of bevacizumab into early-stage NSCLC is clearly the next logical research question in adjuvant therapy for NSCLC and is under exploration in the E1505 intergroup trial. Erlotinib is also being studied in this setting for patients with tumors that express EGFR. Perhaps with the addition of these targeted agents, and with better pretreatment predictors of response, more benefit will be realized in the stage I patient population.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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The authors indicate no potential conflicts of interest.
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