Thirty Years Later: We've Only Just Begun

November 17, 2006

By Rosalyn A. Juergens, MD
David S. Ettinger, MD, FACP

Article

The standard of care with regard to adjuvant chemotherapy of lung cancer has changed remarkably over the past 3 years. Until the initial report of the International Adjuvant Lung Trial in 2003, there was no real evidence from any individual randomized clinical trial (RCT) that adjuvant chemotherapy improves survival in resectable non-small-cell lung cancer. However, five RCTs that have now been reported indicate that adjuvant chemotherapy is effective, at least in certain subgroups of resectable patients. Moreover, numerous meta-analyses have also reported a positive effect from adjuvant treatment. Nonetheless, because of methodologic issues and conflicting results, the question of who should be treated and what constitutes optimal adjuvant therapy remains controversial. This article reviews the recent randomized trials that have contributed to a change in the state of the art, as well as some of the methodologic problems that may have confounded their proper interpretation. It also considers newer approaches to adjuvant therapy, with a particular focus on strategies that incorporate our growing knowledge of molecular medicine and predictive factors to the field of adjuvant chemotherapy of lung cancer.

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.[3] 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 (

= .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

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.[4] 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.[7] 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.[8] 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

Several studies have been published since IALT, BLT, and ALPI that had more rigorous designs. The two most recent studies published both used vinorelbine and cisplatin. The Intergroup trial (JBR-10) focused on stage IB and II patients, whereas the Adjuvant Navelbine International Trialist Association (ANITA) allowed a wider range of stages to enroll.[9,10] Both of these studies had statistically significant results. When synthesizing the data from these trials, one notable difference is the cumulative dose of cisplatin that the investigators planned to deliver. Targeting 400 mg/m² of cisplatin led to a higher cumulative achieved dose of cisplatin in these studies. This may, in part, explain the improved survival seen in both these studies.

At the 2006 American Society of Clinical Oncology (ASCO) meeting, the results of the Cancer and Leukemia Group B (CALGB) study 9633 were updated.[11,12] Disappointingly, the survival curves have come together with 2 additional years of follow-up. Several questions come to mind when assessing what may have made the difference in this study. Should the study have been stopped early? We will likely never know if carboplatin and paclitaxel would have been shown to be effective in stage IB lung cancer. Clearly, stopping rules are important in clinical trials to prevent patients on standard arms from receiving inferior therapy, but if we do not set the cutoff for stopping the study at a very high point, studies will be stopped early, as was the case with CALGB 9633.

If we follow the example of our colleagues who study adjuvant breast cancer, clearly large numbers of patients are required to be enrolled on study to answer the question of the utility of adjuvant treatment. Several hundred patients are likely not enough to adequately assess a 5% improvement in overall survival at 5 years. The thoracic oncology community needs to seriously commit to enrolling patients on trials of adjuvant treatment if incremental benefits in survival are to be detected.

The second question created by the updated results of CALGB 9633 is whether carboplatin is inferior to cisplatin in the adjuvant setting. No studies in the literature have successfully used carboplatin in the adjuvant setting. In metastatic lung cancer, ECOG 1594 demonstrated that a carboplatin-based regimen produced similar response and survival compared to three cisplatin-containing regimens.[13] Recent meta-analyses looking further at this question, however, showed that cisplatin did produce superior responses and possibly improved survival.[14,15] In treatments aimed at cure rather than palliation, a small difference between the efficacy of cisplatin and that of carboplatin could not only make a difference in achieving a statistically significant result but also save thousands of lives (and millions of dollars) worldwide.

Based on all these data, cisplatin is used preferentially at our institution in the adjuvant setting for the appropriate patient. Obviously, the greater toxicity associated with cisplatin treatment (as compared with carboplatin) is taken into consideration for any individual patient.

Meta-analyses and Moving Forward

When looking at the cumulative body of literature on adjuvant chemotherapy in NSCLC, the most persuasive data does not come from any particular trial but from a compilation of trials. Several meta-analyses have been conducted since the 1995 British meta-analysis supporting the use of cisplatin-based chemotherapy for adjuvant lung cancer.[16,17] As Dr. Strauss notes, due to the heterogeneity of adjuvant trials, simple extraction methods that are typically used in meta-analyses are not definitive.

The Lung Adjuvant Cisplatin Evaluation (LACE) was presented at the 2006 ASCO meeting.[18] LACE is an example of how research on adjuvant treatments will move forward, given its use of individualized patient data. The use of individual subset analyses in already underpowered trials is bound to lead us astray. The tables provided by Dr. Strauss may lead readers to believe that the benefit in different subgroups waxes and wanes. Subset analyses should be used for hypothesis generation, rather than to help clinicians make treatment decisions. When clinicians approach an individual patient, we realize subset analyses may be a factor, but this type of analysis should be taken with a grain of salt.

Conclusions

The results of LACE strongly support the use of adjuvant chemotherapy for stage II and III chemotherapy. The point estimate for the effect of adjuvant chemotherapy in stage IB NSCLC shows a benefit, but even with the current sample size of almost 1,400 patients, the confidence intervals are still wide. The concept of number needed to treat comes into play with stage IB NSCLC. Dozens of patients will be treated for every patient who benefits. The data currently being generated on profiling tumors will lead to the future of adjuvant treatment, especially in early-stage disease. Testing for cisplatin sensitivity with ERCC1, analysis of methylation patterns, and determining gene profiles will, hopefully in the near future, improve the current risk-benefit ratio for administering adjuvant lung cancer therapy. The completion of these trials will only be possible through international collaborative efforts. The work in adjuvant lung cancer research has only begun.

Rosalyn Juergens, MD
David Ettinger, MD, FACP, FCCP

Disclosures:

Dr. Ettinger has received grant support from Bristol-Myers Squibb and speaker's honoraria from Eli Lilly.

References:

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.