89: Adjuvant and Neoadjuvant Chemotherapy

The most effective treatment for early-stage (I–IIIA) non–small-cell lung cancer (NSCLC) is surgical resection. Despite optimal surgical techniques employed for the resections, a substantial percentage of patients with stage I–IIIA NSCLC subsequently relapse and die from their lung cancer.¹ Studies that suggested adjuvant chemotherapy could prolong survival for some patients with early-stage lung cancer began to emerge. A number of trials have since documented that the use of chemotherapy in both the preoperative (neoadjuvant) and postoperative (adjuvant) settings can prolong survival. This chapter summarizes the evidence showing the benefit from adjuvant and neoadjuvant therapy for specific subgroups of patients with early-stage NSCLC.

Randomized trials including 29 to 841 patients with early-stage NSCLC performed over the last 30 years were jointly analyzed in an individual patient data meta-analysis published by the Non-Small Cell Lung Cancer Collaborative Group (NSCLCCG) in 1995.² This analysis, involving more than 4300 patients, showed a strong trend toward improved survival of approximately 5% at 5 years for patients with surgically resected early-stage NSCLC treated with adjuvant cisplatin-based chemotherapy compared with those on observation alone (hazard ratio [HR] = 0.87; 95% confidence interval [CI], 0.74 to 1.02; p = 0.08). These results prompted a new generation of larger randomized controlled trials to attempt to validate the observations made in the meta-analysis. The patient, treatment, and outcome information from the studies enrolling more than 300 patients and comparing surgery alone to surgery followed by chemotherapy is presented in Table 89-1. This chapter does not address the use of postoperative tegafur and uracil (UFT). Although Japanese trials have demonstrated a survival benefit with adjuvant UFT, there have been no confirmatory trials in Western populations, and this agent is not presently available in the United States so is not included in this chapter.⁹

Adjuvant Therapy Trials Showing a Difference in Survival

All of the six trials were initiated between 1994 and 1996 when the information from the meta-analysis became available. With the exception of the Big Lung Trial (BLT), which had only about 20% power to detect a 5% improvement in survival with adjuvant chemotherapy, five of the six trials had adequate power to detect up to a 13% difference in survival between the surgery alone and the chemotherapy arms. Three of the six trials listed in Table 89-1 reported a statistically significant survival advantage in the patients treated with chemotherapy after their resection. In the initial study referred to as the International Adjuvant Lung Trial (IALT), 1867 patients with stage I–IIIA NSCLC who underwent a complete resection of their tumor were randomly assigned to either observation or cisplatin given for three to four cycles in combination with etoposide, vinblastine, vinorelbine, or vindesine.⁴ Investigators from each institution had the option of administering chest radiotherapy after the completion of surgery and/or chemotherapy for patients with node-positive disease according to their institutional policy. Although the study was terminated early because of slow accrual (3300 patients initially planned), there was a significant improvement in survival in favor of the chemotherapy arm (HR = 0.86; 95% CI, 0.76 to 0.98; p < 0.03), translating into an absolute gain of 4.1% at 5 years (from 40.4% to 44.5%). An updated report after 7 years of follow-up, however, revealed that the overall survival advantage was no longer significant (HR = 0.91; 95% CI, 0.81 to 1.02; p = 0.10).¹⁰ This late loss of survival benefit appeared to be due to an excess of non–cancer-related deaths in the chemotherapy arm and an increased mortality rate from other causes in this smoking population.

The National Cancer Institute of Canada Clinical Trials Group reported another adjuvant chemotherapy trial (JBR.10) showing a difference in patient outcome.⁶ In this trial, 482 completely resected stage IB or II NSCLC patients were randomized to postoperative observation or to vinorelbine, 25 mg/m² weekly and cisplatin, 50 mg/m² on days 1 and 8 of a 4-week cycle for four cycles. No chest radiotherapy was administered. After a median follow-up of 5.1 years, overall survival was significantly prolonged for the patients treated with surgery plus chemotherapy compared with those treated with surgical resection alone (HR for death = 0.69; 95% CI, 0.52 to 0.91; p = 0.04). Five-year survival rates were 69% and 54%, respectively. An updated survival analysis of the JBR.10 trial reported a persistent survival advantage for patients treated with adjuvant chemotherapy after more than 9 years of follow-up.¹¹ Notably, in both these reports, the benefit was restricted to patients with resected stage II disease and was not seen in the subjects with stage IA and IB NSCLC.

The Adjuvant Navelbine International Trialist Association (ANITA) study also examined adjuvant vinorelbine and cisplatin following resection of the participants' lung cancer.⁸ Eight hundred forty patients with stage IB–IIIA NSCLC who had undergone a successful surgical resection were randomly assigned to either observation or chemotherapy. Patients on both arms of the study could receive chest radiation therapy at the discretion of the treating physician. Adjuvant treatment with cisplatin and vinorelbine was associated with significantly improved survival (HR = 0.80; 95% CI, 0.66 to 0.96; p = 0.017). The survival benefit for patients randomized to receive chemotherapy compared with controls was 8.6% at 5 years and was maintained at 7 years (8.4%). Again, this benefit was observed in patients with stage II and IIIA NSCLC.

Negative Adjuvant Therapy Trials

The benefits of postoperative chemotherapy demonstrated in the three adjuvant therapy trials that showed a survival advantage for the patients treated with chemotherapy after resection were challenged by three other randomized trials completed after the 1995 meta-analysis, which all failed to show a significant survival advantage with adjuvant chemotherapy. The Adjuvant Lung Project Italy (ALPI) studied patients with resected stage I–IIIA NSCLC by randomly allocating them to treatment with mitomycin, vindesine, and cisplatin (MVP) every 3 weeks for three cycles or to observation after complete surgical resection.³ Postoperative thoracic radiation was allowed at the discretion of each participating site. One thousand eighty-eight patients were analyzed after a median follow-up period of 64.5 months. In the chemotherapy arm, 69% of patients completed the MVP treatment and half of them required dose modifications or omission of part of the planned regimen. There was no difference between the outcome of patients treated with resection plus chemotherapy versus those treated with surgery alone (HR for death = 0.96; 95% CI, 0.81 to 1.13; p = 0.589). The use of the chemotherapy regimen of MVP is considered inferior by today's standards, which may have led to the high death rates during the first year after randomization and the poor compliance with chemotherapy, two strong criticisms of the study. Similarly, the BLT, a randomized trial conducted in the United Kingdom, investigated cisplatin-based chemotherapy in patients deemed potentially resectable or who had undergone resection of their lung cancer.⁵ The patients could be treated before (3%) or after (97%) surgical resection with cisplatin for three cycles combined with one of four different regimens (mitomycin and ifosfamide, mitomycin and vinblastine, vindesine, or vinorelbine) or observed without a course of chemotherapy. No benefit from adjuvant chemotherapy was seen among 381 patients. However, the trial was underpowered to detect the magnitude of difference in survival observed in the other trials, and a considerable proportion (15%) of patients had microscopically incomplete surgical resection, which was unlike the other trials.

The CALGB 9633 trial was unique in limiting enrollment to patients with resected stage IB NSCLC who were randomized to treatment with paclitaxel and carboplatin every 3 weeks for four cycles or to observation.⁷ The study was terminated early when an interim analysis in 2004 suggested a significantly higher survival rate with adjuvant therapy. After additional follow-up and reanalysis of the data in 2006, the survival benefit still favored chemotherapy but was no longer significant in the overall population (HR = 0.83; 90% CI, 0.64 to 1.08; p = 0.12), although the reduction in the hazard ratio of death was of a magnitude similar to that seen in the IALT (HR = 0.86) and ANITA (HR = 0.80) trials. With 344 patients, CALGB 9633 may have lacked statistical power to detect small but clinically meaningful improvements in survival in this relatively good risk population. Further, the use of a carboplatin regimen as opposed to a cisplatin backbone may have affected the results, as a recent meta-analysis demonstrated cisplatin-based chemotherapy to be slightly superior to carboplatin regimens in advanced NSCLC.¹² The role of postoperative chemotherapy in surgically resected stage I NSCLC is discussed further later in this section.

A meta-analysis (Lung Adjuvant Cisplatin Evaluation or LACE) combining individual patient data from the five large adjuvant cisplatin-chemotherapy trials reviewed in this section (ALPI, BLT, IALT, ANITA, and JBR.10) has been published.¹³ This analysis has provided insights into the subsets of patients likely to benefit from adjuvant chemotherapy following resection of their NSCLC. In this pooled analysis, data were available on 4584 patients from the trials described earlier in this chapter. The pooled analyses confirmed a statistically significant benefit on overall survival for chemotherapy compared with observation (HR = 0.89; 95% CI, 0.82 to 0.96; p = 0.005), corresponding to an absolute gain of 5.4% at 5 years. The benefits of chemotherapy were confined to patients with resected stage II or III disease (HR = 0.83; 95% CI, 0.73 to 0.95, and HR = 0.83; 95% CI, 0.72 to 0.94, respectively). There was suggestion of a worse outcome with adjuvant chemotherapy for the 347 patients with stage IA disease (HR = 1.40; 95% CI, 0.95 to 2.06) and 183 patients with an Eastern Cooperative Oncology Group performance status of two. The LACE meta-analysis also found a trend for longer survival for the patients treated with cisplatin plus vinorelbine compared to cisplatin plus one or two other drugs. However, the higher planned doses of cisplatin in the cisplatin- and vinorelbine-treated patients may be responsible for the observations. Finally, an update of the 1995 meta-analysis presented at the 2007 Annual Meeting of the American Society of Clinical Oncology, involving greater than 8000 patients, showed a convincing and consistent benefit with adjuvant chemotherapy for surgically resected NSCLC, with an overall significant benefit of 4% at 5 years (HR = 0.86; 95% CI, 0.81 to 0.93; p < 0.000001).¹⁴

Stage I NSCLC

The data from the adjuvant trials and meta-analyses support the use of chemotherapy for resected stage II and IIIA NSCLC. However, the data for stage I NSCLC are less clear. Few patients with stage IA disease were included in the reviewed studies. The LACE meta-analysis showed that the benefit of adjuvant chemotherapy varied significantly with stage, with a potential detriment for those with stage IA NSCLC, although data were available on fewer than 350 patients. Similarly, evidence is not yet available from the randomized trials or the LACE meta-analysis to routinely recommend adjuvant chemotherapy for resected stage IB disease. Stage IB NSCLC comprises a heterogeneous group of node-negative tumors, encompassing a wide range of tumor sizes (more than 3 cm but 7 cm or less) and considerable variability in prognosis. The CALGB 9633 was composed exclusively of stage IB patients. The study design showed that patients given paclitaxel and carboplatin lived a bit longer but did not reach a significant survival benefit for the overall population because of the modest antitumor activity of the adjuvant carboplatin and paclitaxel and the lack of power due to the small patient numbers. However, in an unplanned subset analysis, the trial reported significant disease-free and overall survival benefits in favor of postoperative chemotherapy in patients with tumors ≥4 cm in diameter (HR for death = 0.69; p = 0.043). In a similar exploratory subgroup analysis of the JBR.10 trial, stage IB patients with tumors 4 cm or greater showed a nonsignificant trend toward improved survival rates with adjuvant chemotherapy.¹¹ However, there are currently no prospectively validated data supporting a survival benefit with adjuvant chemotherapy in stage IB patients with larger tumors. Likewise, the presence of visceral pleural invasion identifies a group of stage IB patients with poorer prognosis. In a large retrospective analysis of 9758 patients who underwent surgical resection of their NSCLC, the Japanese Joint Committee for Cancer Registration demonstrated poorer survival of resected T2 tumors with visceral pleural invasion (5-year overall survival rate, 53.0%) compared with T2 tumors without visceral pleural invasion (61.6%; p < 0.001).¹⁵ However, no analyses have yet reported on the impact of adjuvant chemotherapy in node-negative T2 tumors based on visceral pleural involvement.

Three randomized controlled trials of postoperative cisplatin-based chemotherapy (IALT, JBR.10, and ANITA) and two large individual patient data meta-analyses have convincingly demonstrated that cisplatin-doublet adjuvant chemotherapy causes a statistically significant and clinically meaningful survival advantage for patients with adequately resected early-stage NSCLC. The most consistent benefit from adjuvant chemotherapy has been reported in patients with surgically resected stage II and IIIA NSCLC. Based on this evidence, postoperative adjuvant cisplatin-based chemotherapy is now the standard of care for the management of completely resected stage II and IIIA NSCLC.¹⁶ Data are not specifically available from the randomized trials or the LACE meta-analysis to inform the use of adjuvant chemotherapy in patients with separate tumor nodule(s) in the same lobe as the primary tumor, without lymph node involvement. Tumors with same-lobe nodules were reclassified as T3 instead of T4 on the basis of similar survival rates in the 7th edition of the tumor node metastasis (TNM) staging system for lung cancer of the American Joint Committee on Cancer (AJCC).¹ Our de facto practice is to consider these patients with T3 tumors with separate tumor nodule(s) in the same lobe for cisplatin-based adjuvant chemotherapy based on their similar survival to patients with T3 tumors without satellite nodule and data supporting adjuvant systemic therapy for resected stage IIB NSCLC. The benefit of adjuvant chemotherapy in patients with resected stage IB NSCLC is less concrete. There is incomplete data in studies of NSCLC patients with stage IB disease. Given the currently available information, we recommend strongly considering the stage IB patients with larger tumors (>4 cm) for cisplatin-based adjuvant chemotherapy in an individualized manner, after careful discussion of the risks and perceived modest benefits. Adjuvant systemic therapy may also reasonably be considered in patients with resected node-negative T2 tumors with visceral pleural invasion given their poorer prognosis for survival, although data from adjuvant trials are not yet available in this subgroup. Adjuvant chemotherapy is not recommended for patients with resected stage IA NSCLC. These recommendations are summarized in Table 89-2.

Two of the positive adjuvant therapy trials (JBR.10 and ANITA) used cisplatin and vinorelbine as the adjuvant regimen, and the LACE meta-analysis found that the effect of cisplatin plus vinorelbine was marginally better than the effect of other drug combinations. There are no prospective data suggesting a benefit of carboplatin-based adjuvant chemotherapy. Thus, based on the available evidence, the recommended chemotherapy in the adjuvant setting is cisplatin and vinorelbine. It remains to be determined whether a cisplatin doublet combined with more contemporary cytotoxic agents that have been shown to be more active in patients with stage IV NSCLC (gemcitabine, docetaxel, or pemetrexed) can be substituted for cisplatin and vinorelbine with similar or more favorable results. The prevailing assumption is that the efficacy of modern cisplatin-based combinations in advanced NSCLC will likely translate to similar efficacy in the adjuvant setting. Correspondingly, the ongoing ECOG 1505 trial (NCT00324805) incorporates adjuvant chemotherapy regimens of cisplatin combined with vinorelbine, gemcitabine, docetaxel, or pemetrexed. The use of these four agents in combination with cisplatin reflects the consensus of the experienced investigators putting together the study. Given that it takes 7 to 10 years from the start of the study to get meaningful survival information, one begins to extrapolate information coming from the trials for patients with advanced disease before the information from the randomized adjuvant chemotherapy trials becomes available.

Current research efforts aim at identifying subsets of patients who derive the greatest benefit from adjuvant chemotherapy and those who do not benefit from adjuvant therapy by employing pharmacogenomic approaches to help assess potential efficacy and predict toxicity. In addition, there are ongoing efforts to use gene-expression profiling to identify individuals who are potential candidates for adjuvant systemic treatment for resected NSCLC patients. An example of this is expression of ERCC1 determined by mRNA expression or immunohistochemistry. ERCC1 is a key enzyme involved in DNA repair after cisplatin damage. This was specifically examined in the IALT Biology (IALT Bio) study, where adjuvant chemotherapy did not seem to confer a survival advantage in patients whose tumors had high expression of ERCC1.¹⁷ The predictive value of ERCC1 expression on the effect of adjuvant chemotherapy is being prospectively evaluated in the Tailored Post-Surgical Therapy in Early Stage (TASTE) trial, conducted in Europe (NCT00775385; Table 89-3). Moreover, modern adjuvant therapy trials are attempting to integrate novel biological therapeutics, such as bevacizumab, into standard treatment paradigms. The addition of bevacizumab to paclitaxel and carboplatin has been successful in advanced NSCLC, and is now being investigated in the early-stage setting within the context of a large, phase III randomized controlled trial in the United States (NCT00324805; Table 89-3). The optimal adjuvant therapy for patients whose tumors harbor activating mutations of the epidermal growth factor (EGFR) is also being studied. Subjects with resected NSCLC and EGFR mutations are being treated with adjuvant chemotherapy with or without erlotinib (Table 89-3). Whether these approaches will improve upon the current standard of adjuvant cisplatin-based doublet chemotherapy remains to be determined.

The role of chemotherapy prior to surgery has also been explored in patients deemed to have resectable NSCLC. The potential advantages of neoadjuvant chemotherapy over adjuvant administration include a reduction in tumor size thereby facilitating surgical resection, early eradication of micrometastases, in vivo assessment of the chemosensitivity of the cytotoxic regimen, and improved patient tolerability. However, neoadjuvant chemotherapy might delay potentially curative surgery.

In the early 1990s, two small, randomized trials generated marked interest in the role of neoadjuvant chemotherapy. These two trials, each of which involved 60 patients, compared surgery alone with surgery plus cisplatin-based preoperative or perioperative chemotherapy in patients with stage IIIA (T3 and/or N2) NSCLC.^18,19 Early stopping rules were applied in both studies after interim analyses. Both trials found improved survival rates in patients receiving chemotherapy, although criticisms of these studies include their small size and unusually poor survival of the patients in the control arms. Nonetheless, these trials suggested a need for further research to address the role of neoadjuvant chemotherapy in resectable NSCLC.

Since publication of these early small studies demonstrating the feasibility and potential efficacy of neoadjuvant chemotherapy, a number of large randomized controlled trials have been conducted to evaluate the impact of preoperative chemotherapy for early-stage NSCLC. Summaries of the studies enrolling more than 300 patients are presented in Table 89-4. In the French study by Depierre et al., 355 patients with clinical stage IB–IIIA NSCLC were randomly assigned to undergo immediate surgery or to receive two cycles of mitomycin, ifosfamide, and cisplatin before surgical resection.²⁰ Patients who responded to preoperative chemotherapy received an additional two cycles postoperatively. In both arms, patients with pT3 or pN2 disease and/or those who had incomplete surgical resection received chest radiotherapy (n = 113) after either surgery or postoperative chemotherapy. Median (37 vs. 26 months; p = 0.15) and 4-year (43.9% vs. 35.3%) survival were prolonged for patients in the chemotherapy arm compared with those in the surgery alone arm, although these differences did not reach statistical significance. There was a nonsignificant excess of postoperative morbidity and mortality in the chemotherapy arm compared with the primary surgical arm (8.9% vs. 5.1%; p = 0.16). A subset analysis suggested that the benefit of chemotherapy was restricted to patients with N0/N1 disease.

In the largest trial reported to date, 519 patients (of 600 planned) with potentially resectable NSCLC were randomized to surgery alone or to receive three cycles of platinum-based chemotherapy (one of six regimens: cisplatin/mitomycin/vinblastine, cisplatin/mitomycin/ifosfamide, cisplatin/vinorelbine, cisplatin/gemcitabine, carboplatin/paclitaxel, or carboplatin/docetaxel) followed by surgery.²¹ This trial, referred to as MRC LU22, was stopped early after compelling evidence supporting adjuvant chemotherapy emerged, establishing a new standard of care for resectable NSCLC. Most patients in LU22 had clinical stage I disease (61%), with 31% stage II and only 7% of patients with stage III NSCLC. Postoperative complications were similar between the two groups. No overall survival benefit was seen with neoadjuvant chemotherapy (HR = 1.02; 95% CI, 0.80 to 1.31; p = 0.86). Similar to the MRC LU22 trial, the North American S9900 trial closed prematurely after accruing 354 of 600 planned patients. This randomized phase III study evaluated the benefit of three cycles of preoperative carboplatin/paclitaxel followed by surgery with surgery alone in patients with clinical stage IB–IIIA NSCLC (excluding N2 disease).²² After a median follow-up of 64 months, there was a nonsignificant trend in survival benefit in favor of preoperative chemotherapy (HR = 0.79; 95% CI, 0.60 to 1.06; p = 0.11), equivalent to an absolute gain of 9% at 5 years (50% vs. 41%). This magnitude of benefit is similar to that seen with adjuvant chemotherapy administered after the surgical resection. No interaction between treatment and stage was found in this study.

Meta-Analyses

The efficacy of neoadjuvant chemotherapy in resectable NSCLC has also been examined in large meta-analyses.^23–25 Two of the three published meta-analyses were based on pooled data from manuscripts and abstracts, a method considered inferior to a meta-analysis of individual patient data.^23,24 The NSCLCCG recently reported a systematic review and meta-analysis combining individual patient data from fifteen randomized controlled trials, involving 2385 patients, that evaluated the addition of preoperative chemotherapy to surgery versus surgery alone.²⁵ Seven of the fifteen trials used cisplatin-based chemotherapy, four carboplatin-based combinations, and three either cisplatin or carboplatin-based chemotherapy; the remaining trial employed docetaxel alone. Although all trials randomly assigned patients to neoadjuvant chemotherapy followed by surgery versus surgery alone, there was heterogeneity in the treatments given postoperatively, including five trials that used postoperative chemotherapy in the preoperative arm, usually in responders. Most patients had clinical stage IB-IIIA disease (IB, 44%; II, 27%; IIIA, 22%). The meta-analysis found a significant survival benefit to chemotherapy given before surgery over surgery alone, with a HR of 0.87 (95% CI, 0.78 to 0.96; p = 0.007), equivalent to an absolute improvement in survival of 5% at 5 years, similar to the magnitude of benefit observed for adjuvant chemotherapy administered after surgical resection. There was no evidence of a difference in the effect on survival by chemotherapy regimen, platinum agent used, or clinical stage.

The adjuvant and neoadjuvant approaches were compared in the Neoadjuvant/Adjuvant Taxol Carboplatin Hope (NATCH) study, the first randomized controlled trial of preoperative versus postoperative chemotherapy in early-stage NSCLC. This three-arm trial, which accrued 624 patients, compared disease-free survival with surgery alone versus three cycles of preoperative or postoperative carboplatin and paclitaxel chemotherapy in resectable clinical stage I (tumor size > 2 cm), II, and T3N1 NSCLC.²⁶ Ninety percent of the patients in the neoadjuvant arm received their planned chemotherapy versus 66% in the adjuvant chemotherapy arm. Complete resection rates, surgical procedures, and postoperative mortality were similar across the three arms. After a median follow-up of 51 months, no significant differences in 5-year disease-free or overall survival were detected when preoperative or adjuvant chemotherapy was added to surgery. The study has been criticized for lacking statistical power to detect clinically meaningful differences about the outcome of patients treated with chemotherapy before or after surgery with only 200 patients per group. The numbers of patients needed to observe a 5% difference would need to be similar to the 400 to 900 patients on each arm of the IALT and ANITA studies. Further, despite broad stage eligibility, 75% of the patients had clinical stage I disease, a group in whom the benefit of systemic therapy is not firmly established. Finally, a meta-analysis comparing the efficacy of adjuvant versus neoadjuvant chemotherapy for early-stage NSCLC in 32 randomized trials (22 postoperative and 10 preoperative) involving over 10,000 patients has been published.²⁷ No significant differences in overall and disease-free survival were observed between the two groups.

Thus, the available evidence suggests that the relative effects of neoadjuvant and adjuvant systemic therapy are likely similar, with comparable hazard ratios for death in published meta-analyses: 0.89 for the adjuvant individual patient data (IPD) LACE meta-analysis, 0.86 for the updated adjuvant IPD NSCLCCG meta-analysis, and 0.87 for the IPD NSCLCCG meta-analysis of neoadjuvant chemotherapy. However, a more convincing body of evidence exists overall from large randomized controlled trials and meta-analyses for the efficacy and tolerability of postoperative chemotherapy than for preoperative chemotherapy. Thus, it is generally recommended that surgery, the most important treatment modality for early-stage NSCLC, not be delayed and that systemic treatment, if indicated, be administered postoperatively.

The treatment of early-stage NSCLC has undergone a paradigm shift over the past 7 to 8 years with the addition of systemic therapy to local therapy. Several large randomized controlled trials and two meta-analyses have demonstrated a survival advantage for patients with stage II and IIIA NSCLC treated with adjuvant chemotherapy compared with those who underwent observation. Adjuvant platinum-based chemotherapy is now considered the standard of care for patients with stage II to IIIA NSCLC and may be considered an option for select stage IB patients with adverse prognostic factors (primary tumor greater than 4 cm, T2 tumor with visceral pleural invasion). The efficacy of preoperative chemotherapy in patients with early-stage NSCLC has also been analyzed in randomized trials and meta-analyses. Although meta-analyses suggest survival benefits comparable to those seen with postoperative chemotherapy, the majority of individual trials have found no statistically significant differences. However, the recruitment of a high percentage of patients with stage I disease, for whom the benefit of systemic therapy is not yet firmly established, variability of the chemotherapy regimens used, and early trial closure might be responsible for the negative results of individual studies. Further, an important limitation of neoadjuvant trials lies in the challenge to properly stage patients prior to surgical resection, especially stage II patients. Thus, based on clinical trials data, stronger evidence exists supporting the use of postoperative chemotherapy in patients with resectable NSCLC. In this era of personalized targeted therapy, research is ongoing to individualize systemic therapy in early-stage NSCLC and to integrate novel biological therapeutics into the treatment paradigm.

This chapter provides a comprehensive update on the role of adjuvant therapy for NSCLC. Although there are some proponents of neoadjuvant chemotherapy for early stage disease, this treatment is mostly reserved for advanced stage IIA disease followed by surgical resection. There is a general consensus that chemotherapy with or without targeted therapy, for example, tyrosine kinase inhibitors (TKIs), should be used after stage T1-2, N1, and, of course, Tx N2 disease. The role in stage T3 disease is less clear with the group from New England Medical Center advocating use of a neoadjuvant chemotherapy regimen, which I advocate as well. Likewise, the use of neoadjuvant chemotherapy or chemoradiation therapy for stage T3 N1 is gaining popularity. The main area of controversy is whether patients with T2 N0 disease should also get routine chemotherapy after surgery. The preliminary data from the CALGB 9633 would suggest that this is the case, at least for stage T2 >4 cm lesions.