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© 2002 American Society for Clinical Oncology
Treatment of Advanced Non–Small-Cell Lung Cancer With Two-Drug CombinationsUniversity of Colorado Cancer Center, Denver, CO CISPLATIN-BASED combination chemotherapy was shown to improve survival and quality of life in patients with advanced non–small-cell lung cancer (NSCLC) during the 1990s.1-3 Randomized studies also showed that medical costs per life-year gained were similar to those of other effective medical therapies.4 For these reasons, the American Society of Clinical Oncology (ASCO) guidelines recommended cisplatin-based chemotherapy regimens for selected patients with good performance status with advanced NSCLC.1 Many NSCLC patients with advanced age (> 70 years), poor performance status (PS; 2), and comorbid disease are still not offered therapy because of questions about clinical benefit. In addition, the severe toxicities and inconvenience associated with cisplatin-based therapy, including the need for prolonged intravenous hydration, nausea, vomiting, malaise, hearing loss, neuropathy, and nephrotoxicity, limit the usefulness of the drug in this patient population. Where do we stand in 2002? In this issue of the Journal of Clinical Oncology, Kosmidis et al5 present the results of a randomized trial comparing a nonplatinum doublet of paclitaxel and gemcitabine (P/G) to a platinum-containing combination of carboplatin and paclitaxel (P/Cb). The authors wanted to know whether the nonplatinum combination would be more effective or less toxic than their standard paclitaxel/carboplatin combination. The study included 509 patients with advanced stage IIIB and IV NSCLC who had a PS of 0 to 2 and who were not limited by age. The patient characteristics were well balanced between the study arms. There were no significant or clinically relevant differences in any efficacy parameter. The objective response rates (28% for P/G v 35% for P/Cb), time to progression, and survival (median 10.4 months and 41.7% 1-year survival for P/G v 9.8 months and 41.4% for P/Cb) were similar. The rates of severe toxicities were remarkably low in both arms. The rates of grade 3 or 4 neutropenia were 15% in each arm, and grade 3 or 4 thrombocytopenia and anemia were reported in less than 2% of patients in each arm. There were no toxic deaths in either arm. Not surprisingly, the patients with stage IIIB disease had a superior survival outcome compared with those with stage IV (P = .002), and patients with a PS of 0 or 1 had a significantly superior survival compared with PS 2 patients (P < .0001). There were no differences in survival between the two arms for patients with PS 2. Despite the fact that PS 2 patients had a worse survival outcome, their survival was superior (median 5.9 months and 12- and 18-month survival rates of 15%) to that of historical controls with PS 0 or 1 or PS 2 treated with best supportive care (BSC). Additionally, in the study by Kosmidis et al there was no increase in toxicity in PS 2 patients compared with PS 0 or 1 patients, and there were no toxic deaths. What does this study tell us about the routine treatment of advanced NSCLC patients, and how do the results compare with the results of other studies? There are now ample data to show that many different two-drug combinations that include cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and vinorelbine provide equivalent efficacy results, whether or not the combination contains a platinum.6-11 There are also evolving data to suggest that these two-drug combinations are superior to a single drug, no matter which of these six single drugs is used.12-16 There are randomized trials suggesting that these two-drug combinations are equivalent to both old17-19 and new20-22 three-drug combinations, with less toxicity. How should a specific two-drug combination be selected for PS 0 or 1 patients? Certainly, toxicity, convenience, cost, and experience should be considered, and the selection of the optimal combination may, therefore, differ in different regions of the world. The study by Kosmidis et al5 showed toxicity rates in both arms that are among the lowest reported. These low toxicity rates were even lower than the rates reported for the paclitaxel/carboplatin combination reported in the recent Southwest Oncology Group (SWOG) and Eastern Cooperative Oncology Group (ECOG) randomized trials. The lower rates may be attributed in part to a lower dose of paclitaxel (200 mg/m2 compared with 225 mg/m2). In both the SWOG and ECOG studies, the paclitaxel/carboplatin arm had lower rates of most severe toxicities except neuropathy, compared with the cisplatin-containing comparitors.10,11 In the study by Kosmidis et al, the paclitaxel/carboplatin arm had significantly fewer outpatient visits compared with the paclitaxel/gemcitabine arm, although there were no differences in costs.5 There could be future differences in costs as the patents on paclitaxel and carboplatin expire. These data can be used to conclude that there are now less toxic and more convenient two-drug combinations that provide equivalent survival and improved quality of life compared with older cisplatin-based combinations for PS 0 or 1 advanced NSCLC patients. Although a platinum compound is not necessary, several combinations with carboplatin are among the most effective and least toxic. What about PS 2 and elderly patients? There are data to suggest that most of the current two-drug combinations containing cisplatin (eg, paclitaxel/cisplatin, docetaxel/cisplatin, and gemcitabine/cisplatin) are too toxic for use in PS 2 patients.23 In a randomized trial of single-agent paclitaxel versus BSC, the median survival of the PS 2 subset randomized to BSC was only 2.2 months, with a 1-year survival rate of 5%.24 The PS 2 patients randomized to paclitaxel had a superior survival, but the differences were not significant in this small subset analysis. In a randomized trial conducted by Cancer and Leukemia Group B, the two-drug combination of paclitaxel/carboplatin provided a significantly superior survival compared with single-agent paclitaxel in the PS 2 subset analysis.12 The median survival was 4.7 months, compared with 2.4 months, and the 1-year survival rate was 18% versus 10% (P < .01), favoring the combination.12 There were no toxic deaths, and the rate of grade 3 or 4 neutropenia was an acceptable 47%. Similar results were obtained in the paclitaxel/carboplatin arm of the ECOG randomized trial. The trial of Kosmidis et al5 reported similar survival (median, 5.9 months; 1-year, 15%) in both arms. The reported rates of grade 3 or 4 neutropenia were even lower, at 15% in both arms. Although these studies were too small to prove that some two-drug combinations are preferred over a single agent in PS 2 patients, they suggest that several two-drug combinations (paclitaxel/carboplatin and paclitaxel/gemcitabine) can be given safely to PS 2 patients. Additional randomized trials in this subset are needed, and are in progress. The data from multiple randomized trials that have entered elderly patients have shown that this subset does not have a significantly worse outcome compared with younger patients, and that the two-drug combinations described above were adequately tolerated.12,15,16,25,26 In most trials comparing a single agent to a two-drug combination, the combination resulted in superior survival compared with single-agent therapy, but the differences were not always significant in these subset analyses.12,15,16 Randomized trials restricted to elderly patients have shown that single-agent vinorelbine was superior to BSC, but there are conflicting data as to whether two-drug combinations are superior to a single agent in this patient population.27-29 We have learned much about the treatment of advanced NSCLC since the ASCO guidelines were published in 1997. The report of Kosmidis et al5 solidifies the role of two-drug chemotherapy for patients with good PS. It also raises the possibility of using one of these two combinations for selected PS 2 patients. We look forward to the results of randomized trials adding new targeted therapies to these two-drug combinations. REFERENCES 1. Clinical practice guidelines for the treatment of unresectable non–small-cell lung cancer. J Clin Oncol 15:2996-3018, 1997
2. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 311: 899-890, 1995
3. Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non-small cell lung cancer: Effects on survival and quality of life. J Clin Oncol 17: 3188-3194, 1999 4. Evans WK, Will BP, Berthelot JM, et al: The economics of lung cancer management in Canada. Lung Cancer 14: 19-29, 1996[CrossRef][Medline]
5. Kosmidis P, Mylonakis N, Nicolades C, et al: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small cell lung cancer: A randomized phase III trial. J Clin Oncol 20: 3578-3585, 2002 6. Van Meerbeeck JP, Smit EF, Lianes P, et al: A EORTC randomized phase III trial of three chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 20: 308a, 2001 (abstr 1228) 7. Georgoulias V, Papadakis E, Alexopoulos A, et al: Docetaxel plus cisplatin versus docetaxel plus gemcitabine chemotherapy in advanced non-small cell lung cancer: A preliminary analysis of a multicenter randomized phase II trial. Proc Am Soc Clin Oncol 18: 461a, 1999 (abstr 1778)
8. Bonomi P, Kim K, Fairclough D, et al: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide and cisplatin: Results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18: 623-631, 2000 9. Giaccone G, Splinter TA, Debruyne C, et al: Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non–small-cell lung cancer: The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 16: 2133-2141, 1998[Abstract]
10. Kelly K, Crowley J, Bunn PA Jr, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non–small-cell lung cancer: A Southwest Oncology Group trial. J Clin Oncol 19: 3210-3218, 2001
11. Schiller JH, Harrington D, Belani C, et al: Comparison of four chemotherapy regimens for advance non-small-cell lung cancer. N Engl J Med 346: 92-98, 2002 12. Lillenbaum R, Herndon J, List M, et al: Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): A CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 21: 1a, 2002 (abstr 2) 13. Sederholm C: Gemcitabine (G) compared with gemcitabine plus carboplatin (GC) in advanced non-small cell lung cancer (NSCLC): A phase III study by the Swedish Lung Cancer Study Group (SLUSG). Proc Am Soc Clin Oncol 21: 291a, 2002 (abstr 1162) 14. Georgoulias V, Ardavanis A, Agelidou M, et al: Preliminary analysis of a multicenter phase III trial comparing docetaxel (D) versus docetaxel/cisplatin (DC) in patients with inoperable advanced and metastatic non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21: 291a, 2002 (abstr 1163)
15. Sandler AB, Nemunaitis J, Denham C, et al: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol 18: 122-130, 2000 16. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non–small-cell lung cancer: A Southwest Oncology Group study. J Clin Oncol 16: 2459-2465, 1999[Abstract]
17. Crino L, Scagliotti GV, Ricci S, et al: Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non–small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 17: 3522-3530, 1999 18. Melo MJ, Barradas P, Costa A, et al: Results of a randomized phase III trial comparing 4 cisplatin (P)-based regimens in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC): Mitomycin/vinblastine/cisplatin (MVP) is no longer a therapeutic option. Proc Am Soc Clin Oncol 21: 302a, 2002 (abstr 1205) 19. Rudd RM, Gower NH, James LE, et al: Phase III randomised comparison of gemcitabine and carboplatin (GC) with mitomycin, ifosfamide and cisplatin (MIP) in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21: 292a, 2002 (abstr 1164) 20. Tan E, Souquet P, Pereira J, et al: Glob 1: Final results of a prospective randomized phase III trial comparing vinorelbine and cisplatin (NP) versus vinorelbine, ifosfamide, and cisplatin (NIP) in metastatic non small cell lung cancer (NSCLC) patients (pts). Proc Am Soc Clin Oncol 20: 326a, 2001 (abstr 1299) 21. Alberola V, Camps C, Provencia M, et al: Cisplatin/gemcitabine (CG) vs cisplatin/gemcitabine/vinorelbine (CGV) vs sequential doublets of gemcitabine/vinorelbine followed by ifosfamide/vinorelbine (GV/IV) in advanced non-small cell lung cancer (NSCLC): Results of a Spanish Lung Cancer Group phase III trial (GEPC/98-02). Proc Am Soc Clin Oncol 20: 308a, 2001 (abstr 1229) 22. Thompson D, Hainsworth J, Burris H III, et al: Prospective randomized study of four third generation chemotherapy regimens in patients (pts) with advanced non-small cell lung cancer: A Minnie Pearl Cancer Research Network Trial. Proc Am Soc Clin Oncol 20: 314a, 2001 (abstr 1253) 23. Sweeney CJ, Zhu J, Sandler AB, et al: Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: A phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 92: 2639-2647, 2001[CrossRef][Medline]
24. Ranson M, Davidson N, Nicholson M, et al: Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 92: 1074-1080, 2000 25. Kelly K, Giarritta S, Hayes S, et al: Should older patients (pts) receive combination chemotherapy for advanced stage non-small cell lung cancer (NSCLC)? An analysis of Southwest Oncology Trials 9509 and 9308. Proc Am Soc Clin Oncol 20: 329a, 2001 (abstr 1313)
26. Langer CJ, Manola J, Bernardo P, et al: Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: Implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94: 173-181, 2002
27. Gridelli C: The ELVIS trial: A phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer—Elderly Lung Cancer Vinorelbine Italian Study. Oncologist 6: 4-7, 2001 (suppl 1) 28. Frasci G, Lorusso V, Panza N, et al: Gemcitabine + vinorelbine (GV) yields better survival than vinorelbine (V) alone in elderly non-small cell lung cancer (NSCLC) patients: Final analysis of a Southern Italy Cooperative Oncology Group (SICOG) phase III trial. Proc Am Soc Clin Oncol 19: 485a, 2000 (abstr 1895) 29. Gridelli C, Cigolari S, Gallo C, et al: Activity and toxicity of gemcitabine and gemcitabine + vinorelbine in advanced non-small-cell lung cancer elderly patients: Phase II data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) randomized trial. Lung Cancer 31: 277-284, 2001[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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