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.