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Originally published as JCO Early Release 10.1200/JCO.2003.76.018 on July 1 2003 © 2003 American Society for Clinical Oncology
Platin or No Platin? That Is the QuestionDepartment of Medicine, University of Wisconsin Comprehensive Cancer Center, Madison, WI LUNG CANCER is notoriously difficult to treat. So difficult, in fact, that several meta-analyses were required in the 1990s to convince many clinicians that chemotherapy does have a small, but statistically significant, impact on survival when compared with best supportive care1–3 These studies did show, however, that the benefit of chemotherapy was limited to cisplatin-based chemotherapy, whereas regimens that are based on alkylating agents were detrimental.1 Cisplatin-based regimens resulted in a hazard ratio of 0.73 for survival compared with best supportive care, with an absolute improvement in survival at 1 year of 10%, whereas long-term alkylating agents resulted in a hazard ratio of 1.26, and a 6% decrease in 1-year survival. On the basis of these data, the American Society of Clinical Oncology treatment guidelines in 1997 for unresectable disease concluded: "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 platin-based regimen."4 Cisplatin, however, has been associated with a significant number of side effects, most notably nausea and vomiting. Although this toxicity has become much more manageable with the advent of the HT3 antiemetics, concerns remain regarding renal toxicity, neuropathy, ototoxicity, and generalized fatigue and asthenia. To alleviate some of these side effects, clinicians have turned toward the platin analog carboplatin. Although carboplatin has a relatively low single-agent response rate,5 data from most, but not all, randomized trials support equivalent clinical benefit between cisplatin and carboplatin in advanced non–small-cell lung cancer (NSCLC). A European Organization for Research and Treatment of Cancer study from the late 1980s demonstrated similar survival for cisplatin and carboplatin when each drug was combined with etoposide.6 Another more recent study comparing carboplatin plus gemcitabine with cisplatin plus gemcitabine showed a similar survival advantage compared with treatment with cisplatin- and carboplatin-based regimens.7 In an Eastern Cooperative Oncology Group study (E1594), four different chemotherapy doublets were compared with each other8; the comparator arm involved cisplatin plus paclitaxel, whereas one of the experimental arms included carboplatin plus paclitaxel. Although the dose and infusion rate of the paclitaxel differed between the two arms (135 mg/m2 over 24 hours in the cisplatin arm, and 225 mg/m2 over 3 hours in the carboplatin arm), the overall response and median survival did not differ significantly (22% and 7.8 months in the cisplatin plus paclitaxel arm, and 17% and 8.1 months in the carboplatin plus paclitaxel arm, respectively). However, a phase III trial by a Yugoslavian group found an improved survival by log-rank analysis when carboplatin was substituted for cisplatin in combination with vindesine and mitomycin.9 Conversely, a European trial comparing cisplatin plus paclitaxel with carboplatin plus paclitaxel, in which the dose and schedule of paclitaxel was identical between the two arms, found a statistically significant improvement in median survival (9.8 months) in the cisplatin arm, compared with 8.5 months in the carboplatin arm.10 Another study, reported by Rodriguez et al,11 compared docetaxel plus cisplatin and docetaxel plus carboplatin with vinorelbine plus cisplatin; 75 mg/m2 of docetaxel was given in both arms. Although the study was not designed to compare the two docetaxel arms with each other, but with the comparator vinorelbine plus cisplatin arm, the investigators reported a trend toward improved survival in the docetaxel plus cisplatin arm (10.9 months) compared with the docetaxel plus carboplatin arm (9.1 months). Essentially all of these studies found decreased toxicity in the carboplatin arm. Thus, although it could be debated whether carboplatin produces exactly the same outcome as cisplatin in advanced NSCLC overall, results seem to be similar and tolerability is improved. Another strategy to avoid cisplatin side effects is to not administer it at all. In this issue of the Journal of Clinical Oncology, Gridelli et al12 report the result of their randomized trial comparing a non–platin-based doublet, gemcitabine and vinorelbine, with two cisplatin-based regimens. The two comparator arms in this study, cisplatin plus vinorelbine or cisplatin plus gemcitabine, were chosen because they were the two most commonly used regimens in Italy and Canada at the time the study was planned. Patients were randomly assigned to the gemcitabine plus vinorelbine and two cisplatin-based arms on a 2:1:1 ratio, and the two cisplatin arms were combined for analysis. The hypothesis of the study was that patients receiving the non–cisplatin-based regimen would experience similar efficacy, with quality of life as the primary end point. Did the authors succeed? They clearly demonstrated a difference in toxicity; patients receiving the cisplatin-based therapies had more myelosuppression, vomiting, renal toxicity, hair loss, ototoxicity, and fatigue than patients receiving gemcitabine plus vinorelbine. Perhaps somewhat surprisingly (at least for the nonexperts among us in the area of quality of life), they did not achieve their major end point: Even though the non–cisplatin-containing arms were significantly less toxic than the gemcitabine plus vinorelbine arm, it did not improve global quality of life. A discussion regarding the pros and cons of the quality-of-life analysis, symptom improvement, or toxicity impact is perhaps best left for another day (and another editorialist!). For many patients, however, the real issue is outcome: Was this new regimen as efficacious? Technically, yes. There was no difference in response rates (30% for the cisplatin regimens, 25% for the gemcitabine plus vinorelbine regimen) or survival (38 v 32 weeks, respectively) between the two regimens. However, the gemcitabine plus vinorelbine regimen had an inferior progression-free survival (32 compared with 38 weeks in the cisplatin-based arms, P = .004), and the survival differences, although not statistically inferior, showed a trend toward inferiority for the non–cisplatin-based arm (P = .08). Other investigators have examined nonplatin doublets with mixed results. The Hellenic Cooperative Oncology Group randomly assigned patients to receive paclitaxel with either carboplatin or gemcitabine.13 Median and 1-year survival were 10.4 months and 41.7% for the carboplatin plus paclitaxel arm, and 9.8 months and 41.4% for the gemcitabine plus paclitaxel arm, respectively. Both regimens were well tolerated. The Greek Oncology Cooperative Group compared docetaxel plus cisplatin with gemcitabine plus docetaxel.14 Median survival was 10 months in the cisplatin plus docetaxel arm and 9.5 months in the gemcitabine plus docetaxel arm; 1-year survival was 42% and 39%, respectively. The gemcitabine plus docetaxel arm had the more favorable toxicity profile. Other studies, however, have reported a trend toward inferior survival with non–platin-based regimens. The Greek Cooperative Group for Lung Cancer compared docetaxel plus gemcitabine with vinorelbine plus cisplatin.15 Although not statistically significant, the median survival between the two groups was 9 months for docetaxel plus gemcitabine and 11.5 months for vinorelbine plus cisplatin. Toxicity, however, was lower in the docetaxel plus gemcitabine arm. The European Organization for Research and Treatment of Cancer conducted a clinical trial in which paclitaxel plus gemcitabine was compared with cisplatin plus paclitaxel and cisplatin plus gemcitabine.16 Again, although not statistically significant (P = .08), there was a trend toward inferior median and 1-year survival in the paclitaxel plus gemcitabine arm. What can we conclude from all of this information? Taken together, these trials indicate that third-generation nonplatin doublets, if not equivalent to cisplatin-containing doublets, are probably close. Clearly, toxicity is improved, particularly when compared with cisplatin-based regimens, making these regimens particularly appropriate for frail patients who are unlikely to tolerate the toxicity of cisplatin. Is there a clinically significant difference between carboplatin-based regimens and nonplatin doublets? Probably not. Finally, the outcome of patients with metastatic NSCLC—regardless of whether they are treated with platin-based doublets—is unacceptably poor. It seems unlikely that different combinations of drugs using different schedules will make a significant difference in survival. We need to continue to take advantage of the recent advances we have made in the understanding of the basic biology of cancer to produce better treatment options for our patients by continuing to develop drugs aimed at targeting pathways specific for cancer cells. REFERENCES
1. Anonymous: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials—Non-Small Cell Lung Cancer Collaborative Group. BMJ 311:899–909, 1995
2. Marino P, Pampallona S, Preatoni A, et al: Chemotherapy vs. supportive care in advanced non-small cell lung cancer: Results of a meta-analysis of the literature. Chest 106:861–865, 1994 3. Soquet PJ, Chauvin F, Boissel JP, et al: Polychemotherapy in advanced non-small cell lung cancer: A meta-analysis. Lancet 342:19–21, 1993[CrossRef][Medline] 4. American Society of Clinical Oncology: Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer: Adopted on May 16, 1997 by the American Society of Clinical Oncology. J Clin Oncol 15:2996–3018, 1997[Abstract] 5. Bonomi P, Finkelstein D, Ruckdeschel J, et al: Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: A study of the Eastern Cooperative Oncology Group. J Clin Oncol 7:1602–1613, 1989[Abstract] 6. Klastersky J, Sculier J, Lacroix J, et al: A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer protocol 07861. J Clin Oncol 8:1556–1562, 1990[Abstract] 7. Zatloukal P, Novakova L, Petruzelka L, et al: Gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with stage IIIB and IV non-small cell lung cancer (NSCLC): Final results of Czech Lung Cancer Cooperative Group phase III randomized trial. Proc Am Soc Clin Oncol 21:307a, 2002 (abstr 1225)
8. Schiller J, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 346:92–98, 2002 9. Jelic S, Mitrovic L, Radosavljevic D, et al: Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: A randomized phase III study. Lung Cancer 34:1–13, 2001[Medline]
10. Rosell R, Gatzemeier U, Betticher DC, et al: Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: A cooperative multinational trial. Ann Oncol 13:1539–1549, 2002 11. Rodriguez J, Pawel JV, Pluzanska A, et al: A multicenter, randomized phase III study of docetaxel + cisplatin (DC) and docetaxel + carboplatin (DCB) vs. vinorelbine + cisplatin (VC) in chemotherapy-naive patients with advanced and metastatic non-small cell lung cancer. Proc Am Soc Clin Oncol 20:314a, 2001 (abstr 1252)
12. Gridelli C, Gallo C, Shepherd FA, et al: Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: A phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:3025–3034, 2003
13. Kosmidis P, Mylonakis N, Nicolaides C, et al: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small cell lung cancer: A phase III randomized trial. J Clin Oncol 20:3578–3585, 2002 14. Georgoulias V, Papadakis E, Alexopoulos A, et al: Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: A randomised multicentre trial. Lancet 357:1478–1484, 2001[CrossRef][Medline] 15. Kakolyris S, Tsiafaki X, Agelidou A, et al: Preliminary results of a multicenter randomized phase III trial of docetaxel plus gemcitabine (DG) versus vinorelbine plus cisplatin (VC) in patients with advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 21:296a, 2002 (abstr 1182) 16. Van Meerbeeck JP, Smit E, Lianes P: 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)
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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