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1 Pulmonary and Critical Care Medicine Division, Virginia Commonwealth University Medical Center, Richmond, Virginia; 2 Stanford Cancer Center, Stanford University, Stanford, California
Correspondence and requests for reprints should be addressed to Heather Wakelee, M.D., Stanford Cancer Center, Stanford University, 875 Blake Wilbur Dr., Stanford, CA 94305-5826. E-mail: hwakelee{at}stanford.edu
ABSTRACT
Lung cancer is the leading cause of cancer mortality worldwide, and efforts to improve outcomes of patients with this disease require a multidisciplinary approach. While surgical resection is the optimal treatment for early stage lung cancer, the high rates of recurrence after resection pose a distinct challenge. In recent years, substantial evidence has accumulated to support adjuvant chemotherapy in Stage II and III non–small cell lung cancer (NSCLC). A recent meta-analysis of large clinical trials of cisplatin-based adjuvant chemotherapy for resected NSCLC showed that the 5-year survival benefit in favor of chemotherapy was 5.3% (hazard ratio for death, 0.89; 95% confidence interval, 0.82–0.96; P = 0.005). The use of adjuvant chemotherapy in Stage I NSCLC remains controversial. Current and future efforts are being directed toward identification of prognostic and predictive markers to select patients at highest risk for recurrence, and of chemotherapeutic agents to which their tumors are most likely to respond. The role of targeted therapies, including those directed at the epidermal growth factor receptor and vascular endothelial growth factor in adjuvant treatment, is currently under investigation. At this time, there are no data to support the routine use of adjuvant radiation treatment, except in cases in which surgical margins are positive.
Key Words: adjuvant • lung cancer • non–small cell lung cancer
Lung cancer is the leading cause of cancer mortality worldwide. While surgery remains the optimal treatment for early stage non–small cell lung cancer (NSCLC), 5-year survival rates for resected NSCLC without additional treatment range from 23% for Stage IIIA disease to 67% for Stage IA disease (1). Recurrences that account for mortality occur most commonly at distant extrathoracic sites. The goal of effective systemic therapy in patients with resected NSCLC is to eradicate micrometastatic disease, reduce the risk of recurrence, and improve survival. In an effort to improve survival in resected NSCLC, various approaches based on the use of chemotherapy and/or radiation in the preoperative (neoadjuvant) or postoperative (adjuvant) settings have been studied. Recent clinical trials (2–4) have shown a survival benefit with adjuvant chemotherapy in patients with resected NSCLC. This has been validated in several meta-analyses (5, 6). Preoperative chemotherapy has been studied, but the available results are based on small numbers of patients and until further research is completed, decisions regarding preoperative chemotherapy should be individualized to each patient and made after discussion of the case by a multidisciplinary team. A meta-analysis (7) of the available data hints that the survival benefit with neoadjuvant chemotherapy may be as high as with adjuvant therapy, and a recent trial (8) showed a survival benefit, so this approach may be considered in some patients. Postoperative radiation treatment (PORT) has been shown to decrease local recurrence (9), but no survival benefit has been demonstrated with this modality. The next step will be incorporation of novel "targeted" agents into adjuvant protocols, and several ongoing trials are looking at agents that target the epidermal growth factor receptor (EGFR), the vascular endothelial growth factor (VEGF), and at vaccine strategies.
HISTORICAL PERSPECTIVE
In 1991, an international consensus panel recommended that postoperative chemotherapy for NSCLC was of unproven benefit and should be considered experimental (10). This was despite 50 randomized clinical trials enrolling a total of 10,000 patients over the preceding 30 years. Most of the studies suffered from small size, confounding clinical trial design, and older chemotherapeutic regimens. In 1995, a meta-analysis (11) was undertaken by the Non–Small Cell Lung Cancer Collaborative Group (NSCLCCG) to investigate the role of chemotherapy in NSCLC. Fourteen trials, with a total of 4,357 patients, addressed the role of postoperative chemotherapy after surgery. Five trials, with a total of 2,145 patients and based on long-term alkylating agents (such as cyclophosphamide and nitrosureas), showed lower survival among those who received chemotherapy (hazard ratio [HR] at 5 yr, 1.15; 95% confidence interval [CI], 1.04–1.27; P = 0.05). However, eight trials, with a total of 1,394 patients using a cisplatin-based regimen, showed a 5% improvement in survival among those who received chemotherapy (HR, 0.87; 95% CI, 0.74–1.02; P = 0.08), but this failed to reach statistical significance. While the results of this meta-analysis did not provide sufficient evidence to alter clinical practice, these findings led to a heightened interest in the study of adjuvant chemotherapy in patients with resected NSCLC.
RECENT CLINICAL TRIALS OF ADJUVANT CHEMOTHERAPY IN RESECTED NSCLC
A summary of the results of the trials discussed in this section can be found in Table 1.
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Big Lung Trial (BLT)
The Big Lung Trial (13) (BLT) examined the role of cisplatin-based chemotherapy in various treatment settings in NSCLC. Patients with stage I–III NSCLC treated with surgical resection were randomized to observation or chemotherapy (using four cycles of various cisplatin-based regimens: cisplatin/vindesine, mitomycin/ifosfamide/cisplatin, mitomycin/vinblastine/cisplatin, or vinorelbine/cisplatin). PORT was used at the discretion of the treating physician. After a median follow-up of 34.6 months, the HR for overall survival among those assigned to chemotherapy compared with those assigned to observation alone was 1.02 (95% CI, 0.77–1.35; P = 0.90). This trial was underpowered to find all but a substantial benefit with the addition of chemotherapy, but not even a trend was observed. The trial was included in the LACE meta-analysis.
Adjuvant Lung Project Italy (ALPI)
In this trial (14), patients with completely resected stage I, II, or IIIA NSCLC were randomized to three cycles of chemotherapy (mitomycin, vindesine, and cisplatin) or observation. The use of radiation therapy was at the discretion of the treating physician and individual participating site. After median follow-up time of 64.5 months, there was no statistically significant difference between the group of patients assigned to chemotherapy compared with observation in overall survival (HR, 0.96; 95% CI, 0.81–1.13; P = 0.589) or progression free survival (HR, 0.89; 95% CI, 0.76–1.03; P = 0.128). About 43% of patients did get postoperative radiation therapy. This study was included in the LACE meta-analysis.
International Adjuvant Lung Cancer Trial (IALT)
After the 1995 NSCLCCG meta-analysis, the International Adjuvant Lung Cancer Trial (2) (IALT) was the first clinical trial to show evidence of survival benefit with use of adjuvant chemotherapy in resected NSCLC. In this trial, 1,867 patients with completely resected stage I, II, or III NSCLC were randomly assigned to observation or four cycles of chemotherapy (cisplatin with vindesine, vinorelbine, or etoposide). The choice of chemotherapy regimen and the postoperative radiation therapy policy were left to the discretion of each participating center. Over 50% of patients received the cisplatin/etoposide combination and postoperative radiation was planned for 31% of patients. After a median follow-up of 56 months, overall survival was significantly better among patients assigned to chemotherapy compared with those assigned to observation (HR, 0.86; 95% CI, 0.76–0.98; P < 0.03). This translated into a 4% survival advantage at 5 years, almost exactly what was seen in the 1995 meta-analysis. This trial was not enough to uniformly change practice patterns, but it did start discussions about the use of adjuvant chemotherapy in resected lung cancer.
Long-term follow-up.
At the 2008 American Society of Clinical Oncology (ASCO) annual meeting, results of long-term follow-up of patients in the IALT study were presented (15), showing the survival curves coming together. After median follow-up of 7 years, the HR for overall survival among patients assigned to chemotherapy compared with those assigned to observation was 0.91 (95% CI, 0.81–1.02; P = 0.10), while that for disease-free survival (DFS) was 0.88 (95% CI, 0.78–0.98; P = 0.02). Thus the DFS benefit persisted, but the overall survival benefit was lost with longer follow-up. The diminished benefit beyond 5 years suggests possible unexplained chemotherapy-related late mortality. However, the trend still persists beyond 7 years, and many other factors must be considered in these patients. These results emphasize the importance of long-term follow-up of patients enrolled in clinical trials of adjuvant chemotherapy of NSCLC.
National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) JBR.10
In this trial (4), 482 patients with completely resected stage IB or II NSCLC were randomized to four cycles of vinorelbine and cisplatin chemotherapy or to observation. Postoperative radiation treatment was not allowed. Both overall survival (HR, 0.69; 95% CI, 0.52–0.91; P = 0.0009, P = 0.04 after adjustment for interim analyses) and recurrence-free survival (HR, 0.60; 95% CI, 0.45–0.79; P < 0.001) were better in the group of patients assigned to chemotherapy compared with those assigned to observation. Subgroup analyses showed that among patients with stage IB NSCLC, there was no statistically significant improvement in overall survival in patients in the chemotherapy group compared with those in the observation group (P = 0.79). A similar trend toward higher benefit in those with more advanced stage disease was also seen in the IALT study. The results from this trial, combined with the IALT results presented a year earlier, changed practice patterns dramatically for patients with resected NSCLC. Longer-term follow-up is not yet available.
In a retrospective analysis (16) performed to examine the effect of age on survival, adjuvant chemotherapy delivery, and toxicity in the NCIC Group study JBR.10, elderly patients (> 65 yr) had improved overall survival with chemotherapy (HR, 0.61; 95% CI, 0.38–0.98), and this is similar to the benefit seen in all patients in this trial. This was despite the fact that the elderly received less chemotherapy overall. There were no significant differences in toxicities, hospitalizations, or treatment related death by age group.
Adjuvant Navelbine International Trialist Association (ANITA)
ANITA was an international trial (3) that randomized 840 patients with stage IB–IIIA resected NSCLC from 101 centers in 14 countries to observation or chemotherapy (four cycles of vinorelbine plus cisplatin). Postoperative chemotherapy was used at the discretion of every participating center. After a median follow-up of 76 months, adjusted risk for death was significantly lower in patients assigned to chemotherapy compared with those assigned to observation (HR, 0.80; 95% CI, 0.66–0.96; P = 0.017). This translates into an 8.6% survival advantage at 5 years, which persists at 7-year follow-up (8.4%). Hazard ratios with chemotherapy compared with observation for patients at each stage were as follows. Stage IB: HR, 1.10; 95% CI, 0.76–1.57. Stage II: HR, 0.70; 95% CI, 0.49–1.03. Stage IIIA: HR, 0.69; 95% CI, 0.52–0.90. This trial confirmed the benefit of adjuvant chemotherapy and, by 2005, the use of adjuvant chemotherapy, at least for resected stage II and III NSCLC, was widely adopted in clinical practice.
In this trial, 28% of patients (33% of patients in the observation group and 22% of patients in the treatment group) received postoperative radiation, and an unplanned analysis was conducted after trial completion looking at outcomes in the group that received postoperative radiation. Interestingly, this analysis showed that patients with N2 disease seemed to benefit from postoperative radiation treatment in combination with chemotherapy, while those with N1 disease may be harmed by the combination of postoperative radiation and chemotherapy. However, patients receiving no chemotherapy and with either N1 or N2 disease seemed to benefit from postoperative radiation treatment.
Cancer and Leukemia Group B (CALGB) 9633 Trial
This study (17) enrolled 344 patients with resected stage IB NSCLC and randomized them to chemotherapy (four cycles of carboplatin and paclitaxel) or observation. Notably, this is the only adjuvant chemotherapy trial in which carboplatin was used as the platinum compound and the only study to enroll only those patients with stage IB disease. Study patients did not receive PORT. The study was closed early when the first interim analysis showed a 12% survival advantage (71% versus 59% in chemotherapy versus observation group) at 4 years (HR, 0.62; 95% CI, 0.41–0.95; P = 0.028). These results were presented at the same meeting (2004 ASCO Annual Meeting) that included the JBR.10 presentation, and these two back-to-back demonstrations of adjuvant therapy benefit were very compelling.
Long-term follow-up and subgroup analyses.
However, at the 2006 ASCO annual meeting, updated results (18) for CALGB 9633 with a longer median follow-up duration of 57 months were presented with a loss of the overall survival benefit. With more events, the overall survival in the chemotherapy group was not significantly different from that in the observation group (HR, 0.80; 95% CI, 0.60–1.07; P = 0.10). The final publication with 74 months of follow-up found an overall survival HR of 0.83 (90% CI 0.64–1.08; P = 0.12) still trending in favor of chemotherapy, but even the statistical significance of the DFS improvement with chemotherapy was lost in the final analysis (46). Various explanations including an underpowered study, lack of benefit from adjuvant therapy in stage IB patients, and decreased benefit with carboplatin compared with cisplatin have been suggested to explain these results. The magnitude of benefit with standard chemotherapy in stage IB disease is likely to be small, and a much longer trial is needed to detect such a benefit. In an unplanned subset analysis, patients with tumors larger than 4 cm did have a significant improvement in overall survival (HR, 0.69; 95% CI, 0.48–0.99; P = 0.043) with adjuvant chemotherapy.
Lung Adjuvant Cisplatin Evaluation Meta-analysis
The LACE (5) meta-analysis was conducted with a goal of identifying treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy. Individual patient data for 4,584 patients who participated in the five largest trials of adjuvant cisplatin-based chemotherapy were collected and pooled (BLT, ALPI, IALT, JBR.10, ANITA). Median follow-up time was 5.2 years. The overall HR of death was 0.89 (95% CI, 0.82–0.96; P = 0.005), and this corresponds with a 5-year absolute survival benefit of 5.4% from chemotherapy. Further, the benefit from chemotherapy varied with stage of disease, with HR for death for stage IA = 1.40 (95% CI, 0.95–2.06), for stage IB = 0.93 (95% CI, 0.78–1.10), for stage II = 0.83 (95% CI, 0.73–0.95), for stage III = 0.83 (95% CI, 0.72–0.94). The effect of adjuvant chemotherapy did not differ significantly with the second drug (vinorelbine, etoposide, vinca alkaloid, or other) used in the cisplatin-based regimen, although it is noted that the HR with vinorelbine was 0.8 (95% CI, 0.70–0.91), with etoposide or vinca alkaloid was 0.92 (95% CI, 0.80–1.07), and with other drug was 0.97 (95% CI, 0.84–1.13), indicating that of the regimens tested, vinorelbine may be a better choice. Better performance status (PS) was associated with greater benefit from adjuvant chemotherapy, and the data suggest that chemotherapy may be detrimental for patients with a PS of 2. In this analysis, for both overall survival and disease-free survival, the chemotherapy effect did not vary with age, sex, planned radiation therapy, planned dose of cisplatin (< 300 mg/m2, 300 mg/m2, or > 300 mg/m2), histology (squamous, adenocarcinoma, or other), or type of surgery (pneumonectomy or other).
Other Recent Meta-analyses
The strength of the LACE meta-analysis lies in the use of individual patient data from the largest recent adjuvant chemotherapy trials. Multiple other analyses of these studies and others have been conducted recently. The group that did the initial 1995 meta-analysis presented their updated results at the ASCO meeting in 2007 (19). They analyzed individual patient data and included 8,147 patients from 30 randomized trials, of which 15 used cisplatin regimens and the rest used uracil/tegafur (UFT) either with or without chemotherapy. This analysis demonstrated a 4% absolute survival benefit at 5 years, with an overall survival HR of 0.86 (95% CI, 0.81–0.93; P < 0.000001). Stage was the only variable that seemed to influence the effect.
Multiple other meta-analyses of adjuvant chemotherapy data have been conducted, but have used abstracted data instead of individual patient data and therefore lack the statistical strength of LACE and the updated meta-analysis discussed above. The most recently published included all phase III randomized trial and meta-analyses published from 1994 to 2007 and included 13 studies (7,000 patients). An absolute benefit in survival of 2.5% to 4.1% was calculated (20). Benefit with adjuvant chemotherapy was also found in meta-analyses published in 2004–2005 that used abstracted data (21–23).
Adjuvant Trials Based on Uracil/Tegafur
The use of oral uracil/tegafur (UFT) in adjuvant treatment of NSCLC has been studied in Japan in several clinical trials that use either uracil/tegafur alone or after one or more cycles of cisplatin-based chemotherapy. A meta-analysis (24) of six randomized clinical trials comparing long-term adjuvant treatment with UFT to surgery alone was conducted using data from 2,003 patients that participated in these trials. Both 5-year and 7-year survival rate was higher in the surgery plus UFT group compared with the surgery alone group. The overall pooled hazard ratio was 0.74 (95% CI, 0.61–0.88; P = 0.001). There have been no studies on the use of UFT in the adjuvant setting outside of Japan. UFT is currently not available in the United States.
SELECTING DRUGS AND COMBINATIONS FOR ADJUVANT TREATMENT
Most chemotherapeutic regimens used in clinical trials in the adjuvant setting consist of cisplatin-based regimens. CALGB 9633 is the only recent clinical trial in which carboplatin was used instead of cisplatin. The long-term follow-up of patients in this trial showed no significant survival benefit in the treatment group. It is difficult to evaluate the impact of carboplatin use on the results of this trial. However, the negative results of this trial are most likely not solely attributable to the use of carboplatin instead of cisplatin in the treatment regimen. The results of the CISplatin versus CArboplatin (CISCA) meta-analysis (25), which pooled individual patient data for 2,968 patients with advanced NSCLC that participated in 9 trials, showed that response rates were better with cisplatin-based chemotherapy compared with carboplatin-based chemotherapy (30% versus 24%; P < 0.001). There was no statistically significant difference in overall survival between carboplatin- and cisplatin-based regimens. However, when the analysis was restricted to patients with nonsquamous histology or patients treated with third-generation platinum-based regimens, cisplatin was superior to carboplatin in terms of overall survival. The small difference in efficacy based on choice of cisplatin versus carboplatin is probably less important in advanced NSCLC, where the intent of treatment is palliative. However, in the adjuvant setting, where intent is curative, this small difference in efficacy may be critical. Hence, the use of cisplatin-based regimen is recommended in the adjuvant setting unless the patient is unable to tolerate cisplatin. Cisplatin plus vinorelbine is the most studied chemotherapeutic regimen for adjuvant treatment of resected NSCLC. As mentioned previously, in the LACE meta-analysis, effect of chemotherapy did not differ significantly with the associated drug (vinorelbine, vinca alkaloid, etoposide, or other) in the cisplatin-based regimen. Though data are lacking, it is probably reasonable to extrapolate from what we know of equivalency of regimens in metastatic disease and consider other platinum doublets for use in the adjuvant setting. The updated NSCLCCG meta-analysis (19) presented by Stewart at ASCO 2007 also did not reveal any difference by chemotherapy regimen, including the UFT-containing regimens.
POSTOPERATIVE RADIATION TREATMENT
Over the last several decades, there has been an ongoing debate regarding the most appropriate use of PORT in the setting of resected NSCLC. The considerable controversies in the field are further compounded by the evolving nature of clinical practice patterns in radiation oncology with regard to equipment (cobalt machines used in the past), dose regimens, and method of delivery of radiation. Given the advances in the field, it would not be wise to base our conclusions regarding clinical benefit from PORT based on studies that used interventions that were quite different from what would be considered current standards of care in radiation oncology.
A 1998 meta-analysis (26) showed a significant adverse effect on survival with use of PORT. However, subgroup analyses showed that this adverse effect was greatest for patients with N0-N1, while there was no clear evidence of adverse effect on survival for patients with N2 disease. In an analysis of the Surveillance Epidemiology and End Results (SEER) database (27), Lally and coworkers showed no evidence of overall survival benefit with use of PORT. This analysis also showed survival detriment with use of PORT in patients with N0-N1 disease. However, in contrast to the 1998 PORT meta-analysis, the SEER analysis showed a survival benefit with use of PORT in patients with N2 disease. Further, a retrospective analysis (28) of a single-institution experience of patients with N2 disease who underwent resection at Mayo Clinic showed evidence of improvement in local recurrence rate as well as 4-year survival in patients who received adjuvant radiation treatment compared with those who did not. An unplanned analysis of patients in the ANITA trial (3) that received radiation treatment showed that patients with N2 disease had a survival benefit with use of postoperative radiation treatment along with chemotherapy, while those with N0-N1 disease may suffer an adverse effect on survival with use of this combination. However, patients with N0-N1 disease that did not receive chemotherapy seemed to have a survival benefit with use of postoperative radiation. A recent analysis (29) of patients enrolled in the Eastern Cooperative Oncology Group (ECOG) 3590 showed that the risk of death from intercurrent disease (DID) in patients with resected stage II or IIIA NSCLC was not increased with use of PORT alone or use of concurrent chemotherapy and PORT. Another study (30) of patients with NSCLC treated with resection and postoperative radiation showed no increase in risk of DID with use of modern radiation.
These data suggest that careful interpretation of the available data in the context of an individual patient is necessary to make clinical decisions regarding postoperative radiation treatment at this time. Further research is necessary to define the exact role of postoperative radiation treatment in patients with resected NSCLC. The Lung Adjuvant Radiation Trial (LungART) is an ongoing phase III trial in which patients with resected N2 disease will be randomized to PORT and no PORT and stratified by use of postoperative chemotherapy.
PROGNOSTIC AND PREDICTIVE FACTORS: TOWARD CUSTOMIZED ADJUVANT CHEMOTHERAPY?
A prognostic factor is a baseline patient or tumor characteristic that provides information on outcome, regardless of which treatment is used. A predictive factor is a baseline patient or tumor characteristic that provides information on outcome with regard to a specific therapy. While these definitions help our understanding and streamline our discussions on this subject, it should be mentioned that many biomarkers may have both prognostic and predictive value and careful research is needed to identify the prognostic and predictive contributions of a particular biomarker. Given the recent interest and research in the area of prognosis and predictive markers, customized or individualized adjuvant chemotherapy appears to be the promise of the near future.
In a retrospective analysis using immunohistochemical (IHC) analysis to determine the expression of the excision repair cross-complementation group 1 (ERCC1) protein in operative specimens of NSCLC from patients who participated in the IALT trial, it has been shown that after complete resection, patients with ERCC1-negative tumors benefit from cisplatin-based adjuvant chemotherapy (HR, 0.76; 95% CI, 0.59–0.98), while patients with ERCC1-positive tumors may not (HR, 1.20; 95% CI, 0.91–1.59) (31). ERCC1 is involved in DNA repair, so it is logical that patients who are less able to repair DNA damage made by chemotherapy (ERCC1-"negative") are more susceptible to chemotherapy. It is also noteworthy that ERCC1 is a prognostic factor as well with ERCC1-positive patients overall doing better than those with low levels of the enzyme as discussed below. The ERCC1 IHC analysis has yet to be standardized, and no prospective trials looking at this marker have yet been done in the adjuvant setting, but the results are intriguing. Bepler and coworkers (32) showed that tumoral expression of RRM1, the gene that encodes the regulatory subunit of ribonucleotide reductase, is a major predictor of disease response to gemcitabine/platinum chemotherapy, and that ERCC1 expression is also predictive of response, although to a lesser degree.
Several prognostic biomarkers have also been studied, including k-ras mutation (21), p53 mutation (33, 34), ERCC1 (35), and RRM1 expression (36). Potti and colleagues (37)used gene-expression profiling to develop the lung metagene model in an effort to refine assessment of prognosis and identify patients at the highest risk of recurrence, and other gene-expression profiles have also been investigated.
Clinical trials are being planned to investigate the use of prognostic and predictive biomarkers in the setting of adjuvant chemotherapy of NSCLC. In CALGB 30506, the lung metagene model will be applied to enrolled patients with 2- to 4-cm stage I NSCLC. Patients on the trial will be randomized to observation or chemotherapy, but outcomes will be measured relative to whether the patients had a low lung metagene score (and low risk for recurrence according to the model) or high lung metagene score (and high risk for recurrence according to the model). The two primary objectives of the trial are validation of the positive prognostic value of a low lung metagene score and identification of effect of adjuvant chemotherapy on survival in patients with a high lung metagene score.
The Southwestern Oncology Group (SWOG) is planning a novel proof-of-concept trial with use of pharmacogenomics in directed adjuvant chemotherapy. In this study, ERCC1 and RRM1 analysis will be conducted on tumor specimens from patients with resected stage I (
2 cm) NSCLC. Patients will then be randomized to adjuvant chemotherapy with cisplatin/gemcitabine or to observation. The primary goal is feasibility, defined by the proportion of patients that can be assigned treatment, reflecting the adequacy of tumor specimen collection and analysis.
THE ROLE OF NOVEL AGENTS IN ADJUVANT TREATMENT
Given recent evidence of benefit with use of targeted agents in advanced stage NSCLC, there is a great interest in evaluating the use of such novel agents in the adjuvant setting. With several ongoing trials, this remains an area of active investigation.
Epidermal Growth Factor Receptor Inhibitors
The randomized phase III Intergroup trial JBR.19 was designed to investigate the role of the EGFR tyrosine kinase inhibitor gefitinib (Iressa) in patients with resected stage IB–IIIA NSCLC randomized after surgery to 2 years of gefitinib or placebo, with results expected in the next few years. This trial was closed early after the negative results of the Iressa Survival Evaluation in Advanced Lung Cancer (ISEL) trial (38) and negative results of the interim analysis of the Southwest Oncology Group trial 0023 (SWOG 0023) (39). The SWOG 0023 trial actually showed a survival detriment with the addition of gefitinib after definitive chemotherapy and radiation for stage IIIB NSCLC. Given that gefitinib is no longer in clinical use in the United States, the focus has shifted toward erlotinib, another epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). The Randomized Double-blind Trial in Adjuvant NSCLC with Tarceva (RADIANT) trial is an ongoing clinical trial designed to investigate the role of erlotinib in the adjuvant setting. Enrolled patients have resected stage I to IIIA NSCLC and may receive up to four cycles of platinum-based chemotherapy before randomization. Only patients who have EGFR-positive tumors by either Fluorescent In Situ Hybridization (FISH) or IHC will be randomized to 2 years of erlotinib or placebo.
Targeting Vascular Endothelial Growth Factor
In advanced NSCLC, the Eastern Cooperative Oncology Group (ECOG) 4599 trial (40) studied the use of carboplatin and paclitaxel with or without bevacizumab, a monoclonal antibody against VEGF. The results demonstrated a survival benefit favoring the bevacizumab-containing regimen (12.3 mo vs. 10.3 mo; P = 0.003). Another trial (41) with bevacizumab showed improved response rate and improved progression-free survival with the addition of bevacizumab to cisplatin and gemcitabine in advanced stage disease. ECOG 1505 is an ongoing trial designed to investigate the role of bevacizumab in adjuvant chemotherapy. In this study, patients with stage IB ( 4 cm tumors), II, and IIIA are randomized to receive adjuvant chemotherapy (one of three options per the choice of the treating physician) with or without bevacizumab. All patients receive chemotherapy that is initiated at 6 to 12 weeks postoperatively, with four cycles of cisplatin-based adjuvant chemotherapy (either cisplatin/vinorelbine, cisplatin/docetaxel, or cisplatin/gemcitabine) administered. Patients randomized to receive chemotherapy with bevacizumab will receive concurrent bevacizumab at 15 mg per kilograms (mg/kg) every 3 weeks with chemotherapy. The single-agent bevacizumab treatment continues for 1 year. With the differences that have been seen in all recent adjuvant trials based on staging, adequate lymph node sampling (N1 and selected N2 nodes, including level 7 in all patients and level 4 for right-sided tumors and level 5 or 6 for left-sided tumors) are required for enrollment on ECOG 1505. Target accrual for this trial is 1,500 patients. Given the mechanism of action of bevacizumab, with blockade of the VEGF necessary for development of neovasculature, it is hoped that this agent will be particularly effective at preventing the growth of micrometastases.
The Role of Vaccine Therapy
Vaccine therapy in the adjuvant setting remains an area of ongoing investigation. The MAGRIT (MAGE-A3 Adjuvant Non–Small Cell LunG CanceR ImmunoTherapy) trial investigates the use of a MAGE-A3 vaccine in stage IB/II MAGE-A3–positive, completely resected NSCLC. MAGE-A3 is a tumor antigen found in 30 to 50% of resected lung cancers. Target accrual for this trial is over 2,000 patients.
PROPOSED NEW STAGING SYSTEM: IMPLICATIONS FOR ADJUVANT TREATMENT
In preparation for the seventh edition of the TNM Classification of Malignant Tumors to be published in 2009, the International Association for the Study of Lung Cancer (IASLC) has proposed a new staging system for lung cancer (42). The proposed changes are based on the results of analysis of a large database of patients with lung cancer, who were treated in 19 countries during the period 1,990 to 2,000. These analyses were conducted as part of the Lung Cancer Staging Project established by the IASLC in 1998. The proposed T and M descriptors and changes in staging are summarized in Table 2. It is unclear how the use of the new staging system in clinical practice will influence clinical decision-making in the adjuvant setting. A thoughtful approach, keeping in mind that the clinical trials published so far use the sixth edition of TNM classification, will be needed to interpret the data appropriately and apply it in a clinical setting where the seventh edition of TNM classification is in use.
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This is an exciting time in the area of adjuvant treatment of NSCLC. Adjuvant chemotherapy, an approach that was considered experimental less than two decades ago, is now the standard of care in the treatment of resected stage II and III NSCLC. Treatment guidelines from ASCO (43) and the American College of Chest Physicians (ACCP) (44, 45) include recommendations on the use of adjuvant chemotherapy in patients with resected NSCLC. The benefits are modest, with 5 to 10% improvement in overall survival at 5 years, and options for chemotherapeutic agents are limited. Further research is needed to define the role of adjuvant chemotherapy in stage IB NSCLC after surgery. Efforts are now directed toward identifying methods of increasing the benefit from adjuvant chemotherapy in NSCLC. There is an urgent need to find reliable methods to identify patients who are at the highest risk of recurrence and, therefore, are likely to benefit most from adjuvant treatment. Further, methods to identify tumor resistance or sensitivity to chemotherapeutic agents will help to plan an appropriate chemotherapeutic regimen for the individual patients. Demonstrating efficacy of newer drugs, including novel targeted agents, is yet another approach toward improving outcomes in patients with resected NSCLC. Trials are ongoing with agents that target the EGFR and VEGF pathways, as well as vaccine strategies. Further research is needed to better define the role of PORT in resected NSCLC, particularly in stage IIIA disease. Based on the current status of the field, it appears that designing an individualized treatment plan for patients with NSCLC based on clinical features and tumor biology will be a reality in the near future, and it is hoped that this will significantly improve the outlook for patients with resected NSCLC.
FOOTNOTES
Conflict of Interest Statement: L.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.A.W. served on an Advisory Board in 2006 for Sanofi-Aventis and received $2,000; she has research funding for ongoing trials from Genentech, Eli Lilly, Cell Therapeutics Inc., and Exelixis Inc.
(Received in original form July 9, 2008; accepted in final form November 6, 2008)
REFERENCES
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