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
Table 89-1Overview of the Adjuvant Chemotherapy Trials Enrolling More Than 300 Patients, Published After the 1995 Non–Small-Cell Lung Cancer Meta-Analysis ||Download (.pdf) Table 89-1Overview of the Adjuvant Chemotherapy Trials Enrolling More Than 300 Patients, Published After the 1995 Non–Small-Cell Lung Cancer Meta-Analysis
| ||ALPI3 ||IALT4 ||BLT5 ||JBR.106 ||CALGB 96337 ||ANITA8 |
|Study dates ||1994–1999 ||1995–2000 ||1995–2001 ||1994—2001 ||1996–2003 ||1994–2000 |
|No. of patients ||1088 ||1867 ||381 ||482 ||344 ||840 |
|Stage eligibility ||I–IIIA ||I–III ||I–III ||IB–II ||IB ||IB–IIIA |
|Chemotherapy regimen ||Mitomycin, vindesine and cisplatin ||Cisplatin plus a vinca alkaloid or etoposide ||Cisplatin-baseda ||Cisplatin and vinorelbine ||Carboplatin and paclitaxel ||Cisplatin and vinorelbine |
|No. of cycles planned ||3 ||3 or 4 ||3 ||4 ||4 ||4 |
|Pneumonectomy, no. (%) ||274 (25%) ||648 (35%) ||NA ||114 (24%) ||37 (11%) ||310 (37%) |
|Postoperative radiotherapy ||Optional ||Optional ||Optional ||None ||None ||Optional |
|Median follow-up, years ||5.4 ||4.7 ||NA ||5.1 ||6.2 ||6.3 |
|Hazard ratio for death ||0.96 ||0.86 ||1.02 ||0.69 ||0.83 ||0.8 |
|95% confidence interval ||0.81–1.13 ||0.76–0.98 ||0.77–1.35 ||0.52–0.91 ||0.64–1.08 ||0.66–0.96 |
|p-value ||0.589 ||<0.03 ||0.9 ||0.04 ||0.125 ||0.017 |
|Absolute difference in 5-year survival ||1% ||4.1% ||NA ||15% ||2% ||8.6% |
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.