Over the past 30 years, thoracic oncologists have sought therapies for use in the adjuvant setting that might mimic the survival advantage offered by adjuvant chemotherapy in other solid tumors such as breast and colon cancers.[1,2] For decades, the mainstay of treatment for early-stage lung cancer has been resection. With increasing stage, though, escalating percentages of patients relapse with distant metastases. In the 1980s and 1990s, multiple regimens were tested in clinical trials as adjuvant therapy for lung cancer. None of these regimens in isolation provided convincing evidence that adjuvant chemotherapy would be beneficial in non-small-cell lung cancer (NSCLC).
In a 1995 meta-analysis, the British NSCLC Collaborative Group combined the results of many early trials, finding that cisplatin-based chemotherapy appeared to offer a 5% survival advantage at 5 years; however, the confidence intervals around that figure were not narrow enough for the result to be statistically significant (P = .08). This sparked interest in the next generation of clinical trials assessing the use of platinum-based therapy in the adjuvant setting in NSCLC. Looking back, we will never know if the P value sparked the current trials or if the time was finally right in the thoracic oncology community for serious trials on adjuvant chemotherapy.
IALT, BLT, and ALPI
In 2003, the International Adjuvant Lung Cancer Trial (IALT) Collaborative Group published the largest trial designed to address the question of the efficacy of cisplatinum-based chemotherapy in NSCLC. This study found a 4.5% improvement in overall 5-year survival, which was statistically significant and consistent with the magnitude of response seen in the meta-analysis. These results clearly were viewed with great enthusiasm from the thoracic oncology community.
The results of two other trials, the Big Lung Trial (BLT) and the Adjuvant Lung Project Italy (ALPI), were published shortly thereafter.[5,6] Several points must be taken into consideration when comparing these seemingly similar large simple randomized trials. ALPI was stopped after 5 years of accrual with only 1,088 evaluable patients, accounting for only 84% of the recruitment goal. The BLT only enrolled 381 patients (76% of their goal) and clearly stated in the methods section that the power to detect a 5% difference in 5-year survival based on this sample size was only 20%.
Other significant differences that appear in these studies are the treatment choices utilized (Table 1). First, ALPI included twice as many patients who received adjuvant radiation therapy (43% in both the experimental and control arms). The effects of radiation therapy on survival in adjuvant lung cancer have yet to be fully determined. Previous studies have shown detrimental effects using older radiation delivery techniques. Use of modern radiation equipment may not confer the detrimental effects previously seen, but modern studies such as the trial published in 2000 by the Eastern Cooperative Oncology Group (ECOG), which assessed the use of sequential adjuvant chemotherapy and radiation therapy as compared to radiation therapy alone, did not show a survival benefit. The patients in these studies who received radiation therapy may not be comparable to those in the studies who received either chemotherapy alone or best supportive care. The BLT did not have as many patients who received radiation therapy (14% in both arms), but they prescribed a lower targeted cisplatin cumulative dose (150-240 mg/m2 vs 300-400 mg/m2 in IALT) with a lower compliance.
Stating that either BLT or ALPI are negative studies when compared to IALT is an oversimplification of the data. Studies that have been reported as positive or negative may be wrong in their conclusions since a study may not have been appropriately designed to detect the difference that was proposed. The benefit of using point estimates and confidence intervals is that readers are able to determine the weight of evidence a study provides either in support of the experimental arm or in support of the standard. Taking a dichotomizing approach and deeming a study positive or negative misleads readers to assume that the study design was appropriate and the study result was definitive.
More Recent Trials
1. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators: Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 345:939-944, 1995.
2. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1-15, 1992.
3. Immerman SC, Vanecko RM, Fry WA, et al: Site of recurrence in patients with stages I and II carcinoma of the lung resected for cure. Ann Thorac Surg 32:23-27, 1981.
4. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-360, 2004.
5. Scagliotti GV, Fossati R, Torri V, et al: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 95:1453-1461, 2003.
6. Waller D, Peake MD, Stephens RJ, et al: Chemotherapy for patients with non-small cell lung cancer: The surgical setting of the Big Lung Trial. Eur J Cardiothorac Surg 26:173-182, 2004.
7. PORT Meta-analysis Trialists Group: Postoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet 352:257-263, 1998.
8. Keller SM, Adak S, Wagner H, et al: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 343:1217-1222, 2000.
9. Douillard JY, Rosell R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial. Lancet Oncology 7:719-727, 2006.
10. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-2597, 2005.
11. Strauss GM, Herndon JE II, Maddaus MA, et al, for the CALGB RTOG: Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633 (abstract 7007). J Clin Oncol 24(18S):365s, 2006.
12. Strauss G, Herndon J, Maddaus M, et al: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALBG) protocol 9633 (abstract 7019). J Clin Oncol 22(14S):621a, 2004.
13. Schiller JH, Harrington D, Belani CP, et al, for the Eastern Cooperative Oncology Group: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002.
14. Ardizzoni A, Tiseo M, Boni L, et al: CISCA (cisplatin vs. carboplatin) meta-analysis: An individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC) (abstract 7011). J Clin Oncol 24(18S):366s, 2006.
15. Zojwalla NJ, Raftopoulos H, Gralla RJ: Are cisplatin and carboplatin equivalent in the treatment of non-small cell lung carcinoma (NSCLC)? Results of a comprehensive review of randomized studies in over 2300 patients (abstract 7068). J Clin Oncol 22(14S), 2004.
16. Sedrakyan A, Van Der MJ, O'Byrne K, et al: Postoperative chemotherapy for non-small cell lung cancer: A systematic review and meta-analysis. J Thorac Cardiovasc Surg 128:414-419, 2004.
17. Hotta K, Matsuo K, Ueoka H, et al: Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22:3852-3859, 2004.
18. Pignon JP, Tribodet H, Scagliotti GV, et al, on behalf of the LACE Collaborative Group: Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients (abstract 7008). J Clin Oncol 24(18S):366s, 2006.