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Originally published as JCO Early Release 10.1200/JCO.2005.11.930 on February 22 2005 © 2005 American Society of Clinical Oncology.
Platinums in Lung Cancer: Sufficient or Necessary?University of Colorado Cancer Center, Denver, CO This issue of the Journal of Clinical Oncology presents two articles that address the role of cisplatin and carboplatin in the treatment of advanced non–small-cell lung cancer (NSCLC).1-2 The first of these studies is a meta-analysis of the published literature comparing platinum-based regimens to non–platinum-based regimens.1 The second is a randomized study comparing vinorelbine plus cisplatin to the non–platinum-containing regimen of docetaxel plus gemcitabine.2 These analyses support the current American Society of Clinical Oncology (ASCO) guidelines for the treatment of advanced NSCLC, which state, "First-line chemotherapy given to patients with advanced NSCLC should be a two-drug combination regimen. Non–platinum-containing chemotherapy regimens may be used as alternatives to platinum-based regimens in the first line."3 Cisplatin was shown to have activity in advanced NSCLC in studies from Memorial Sloan-Kettering Cancer Center and other institutions more than 20 years ago.4,5 When combined with a variety of other agents, these combinations were shown to prolong survival compared with best supportive care in randomized trials and in a meta-analysis of these randomized trials.6 These results led to the original 1997 ASCO guidelines for the treatment of advanced NSCLC, which stated, "In stage IV disease, chemotherapy prolongs survival and is most appropriate for individuals with good performance status. Chemotherapy given to NSCLC patients should be a platinum-based combination regimen."7 During the 1990s, several new agents were shown to be active in the treatment of advanced NSCLC, including paclitaxel, docetaxel, vinorelbine, and gemcitabine.8 In randomized trials comparing either paclitaxel or docetaxel with best supportive care, both were shown to produce a significant survival advantage.9,10 In the paclitaxel study, the hazard ratio (HR) was 0.68,9 which was somewhat better than the 0.73 HR reported with cisplatin regimens.6 Randomized trials showed that combinations of cisplatin plus gemcitabine and cisplatin plus vinorelbine were superior to cisplatin alone.11,12 Other randomized trials showed that the combination of vinorelbine and cisplatin was superior to vinorelbine,13 paclitaxel plus carboplatin was superior to paclitaxel,14 gemcitabine plus carboplatin was slightly superior to gemcitabine,15 and docetaxel plus cisplatin was slightly superior to docetaxel.16 Many randomized trials compared doublets containing these new agents plus either cisplatin or carboplatin.17 These randomized trials invariably found equivalent efficacy with somewhat differing toxicity profiles. A smaller number of randomized trials compared combinations of these new agents with the new agent plus either cisplatin or carboplatin.17 These trials also showed equivalent efficacy results. These randomized trials led to the current ASCO guidelines stating that platinum doublets or nonplatinum doublets are the standard for advanced NSCLC patients with good performance status.3 The study of D'Addario et al1 in this issue of the Journal of Clinical Oncology was a literature-based meta-analysis designed to compare the efficacy and toxicity of platinum-based to non–platinum-based chemotherapy in advanced NSCLC patients. However, the analysis did not use individual patient data. The primary efficacy end points were objective response rates and one-year survival rates. Overall survival could not be assessed because the authors did not collect individual data. The analysis included both randomized phase II and randomized phase III studies of varying designs. Many of these studies compared a platinum doublet with a nonplatinum single agent. No subset analysis was performed comparing these trials, though most favored the doublet. A subset analysis was performed in trials using third-generation agents. For the entire group of studies, the authors report that the platinum-based therapies had a significantly higher response rate and 1-year survival compared with the nonplatinum combinations. The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nephrotoxicity and nausea and vomiting. In the subset of trials with third-generation agents, there was no significant increase in survival compared with platinum combinations. These data are consistent with the current ASCO guidelines and can be used to support them. The report of Georgoulias et al2 compared the vinorelbine plus cisplatin combination (VC) with a combination of docetaxel plus gemcitabine (DG). All patients received prophylactic recombinant human granulocyte colony-stimulating factor (rhG-CSF) because of the high rate of neutropenia. Response rates and survival results slightly favored the VC arm, but were not significantly different. Patients treated with VC had significantly higher rates of grade 2 to 4 anemia, grade 3 to 4 neutropenia, febrile neutropenia, and nausea and vomiting. The authors concluded that the nonplatinum DG regimen had a more favorable safety profile compared with VC, and therefore should be considered a front-line alternative for patients with comorbidities or who cannot otherwise tolerate cisplatin. This study is also consistent with current ASCO guidelines and with the results of the meta-analysis described above in the subset of studies evaluating non–platinum-containing third-generation regimens. By no means do this study and the meta-analysis indicate that non–platinum-containing regimens are preferred for most patients. None of the randomized studies showed a significant survival advantage for the nonplatinum combinations, and in many the survival was slightly inferior in the nonplatinum arm. Noninferiority analyses were not conducted in these trials. The study regimens in the Georgoulias study cannot be considered as routine regimens for patients with NSCLC because they required prophylactic G-CSF and had higher toxicity rates than other reported combinations not requiring G-CSF. It seems unlikely that additional randomized trials comparing doublets or triplets of these active agents will change current practice guidelines. In the near future, the discovery of new therapeutic targets, novel agents that target these proteins, and ways to identify subjects most and least likely to benefit from the agents alone or in combination are more likely to change practice. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Paul A. Bunn Jr, Aventis, Eli Lilly, Bristol-Myers Squibb, Genentech. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue. REFERENCES
1. D'Addario G, Pintilie M, Leighl N, et al: Platinum-based versus non–platinum-based chemotherapy in advanced non–small-cell lung cancer: A meta-analysis of the published literature. J Clin Oncol 23:2926-2936, 2005
2. Georgoulias V, Ardavanis A, Tsiafaki X, et al: Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non–small-cell lung cancer: A phase III randomized trial. J Clin Oncol 23:2937-2945, 2005
3. Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology: Treatment of unresectable non–small-cell lung cancer guideline: Update 2003. J Clin Oncol 22:330-353, 2004 4. Gralla RJ, Cvitkovic E, Golbey RB: Cis-Dichlorodiammineplatinum (II) in non-small cell carcinoma of the lung. Cancer Treat Rep 63:1585-1588, 1979[Medline] 5. Bunn PA Jr, The expanding role of cisplatin in the treatment of non-small cell lung cancer. Semin Oncol 16:10-21, 1989 (4 suppl 6)
6. 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. BMJ 311:899-909, 1995 7. American Society of Clinical Oncology: Clinical practice guidelines for the treatment of unresectable non–small-cell lung cancer. J Clin Oncol 15:2996-3018, 1997[Abstract] 8. Bunn PA Jr, Kelly K: New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: A review of the literature and future directions. Clin Cancer Res 4:1087-1100, 1998[Abstract]
9. Ranson M, Davidson N, Nicolson 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 10. Roszkowski K, Pluzanska A, Krazakowski M, et al: A multicenter, randomized phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naïve patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer 27:145-157, 2000[CrossRef][Medline]
11. Sandler AB, Nemunaitis J, Denham C, et al: Phase II 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 12. 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, 1998[Abstract] 13. Le Chevalier T, Brisgand D, Douillard JY, et al: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non–small-cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol 12:360-367, 1994[Abstract] 14. Lilenbaum RC, 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 21:1, 2002 (abstr 2) 15. 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 (SLCSG). Proc Am Soc Clin Oncol 21:291a, 2002 (abstr 1162) 16. Georgoulias V, Ardavanis A, Agellidou 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)
17. Bunn PA Jr: Chemotherapy for advanced non-small cell lung cancer: Who, What, When, Why? J Clin Oncol 20:23s-33s, 2002 (suppl 18)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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