|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.17.2056 on May 27 2008 © 2008 American Society of Clinical Oncology.
First-Line Chemotherapy for Non–Small-Cell Lung Cancer: Is There a Superior Regimen Based on Histology?
Division of Hematology-Oncology, Indiana University Department of Medicine, Indianapolis, IN Lung cancer remains a formidable challenge. In the United States, death from lung cancer accounts for approximately 25% of all cancer deaths and exceeds the second, third, fourth, and fifth most common causes of cancer death combined. It is a leading cause of cancer morbidity and mortality worldwide, with an alarming increase in developing countries, largely as a result of export of tobacco. During the past quarter of a century, there has been definite progress in understanding the biology of lung cancer. Cisplatin-based adjuvant chemotherapy has significantly improved progression-free survival after surgery, which has translated to a 5% to 10% improvement in the cure rate.1 Concurrent chemoradiotherapy has improved median survival and long-term disease-free survival, especially compared with radiation alone as a single modality.2 However, progress in stage IV non–small-cell lung cancer (NSCLC) has been more elusive and has not been associated with realistic probability of disease-free survival beyond 5 years.3 Single clinical trials, as well as meta-analyses, have confirmed that platinum combination chemotherapy improves survival compared with best supportive care,4 single-agent cisplatin,5 or single-agent, second-generation cytolytic agents.6 However, these gains in survival have been modest, with a 2-month prolongation in median survival time and a 10% to 20% increased probability for survival at 1 year but few, if any, patients remaining progression free at 5 years. The addition of bevacizumab to platinum doublets has added an additional 2 months of survival time compared with chemotherapy alone.7 Second-, third-, and fourth-line therapy can now be realistically offered to patients, especially those retaining a favorable performance status and not experiencing progression during initial platinum-based chemotherapy.8-10 Unfortunately, once again, the gains in survival have been relatively meager, usually 6 to 8 weeks compared with the control arms. Nonsmokers have attained a more dramatic effect with erlotinib, more than doubling median survival time compared with best supportive care (12.2 v 5.6 months, respectively).10 Newer molecular-targeted agents such as sunitinib have demonstrated clinical activity,11 but its role in the numerical order of options in NSCLC remains to be determined. An often overlooked advance in management of stage IV NSCLC has been the development of effective antiemetics for chemotherapy-induced nausea and vomiting, thus making these modest gains in survival with platinum-based chemotherapy more tolerable for patients. Numerous studies have compared various platinum doublets; the great majority of these trials have concluded that all such regimens are comparable in their clinical efficacy.12,13 It is against this background that Scagliotti et al14 report yet another study, this time comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed. This study was sponsored and funded by Eli Lilly & Co (Indianapolis, IN) and was designed as a noninferiority study. As is often the case with industry-sponsored studies, large patient populations were entered in a relatively short time interval. From July 2004 to December 2005, 863 patients were randomly assigned to cisplatin plus gemcitabine, and 862 patients were randomly assigned to cisplatin plus pemetrexed. This represents the largest number of patients entered onto a single phase III study using either of these two regimens. Noninferiority was documented because the median survival time was an identical 10.3 months in each arm. Progression-free survival also demonstrated noninferiority (4.8 months in the pemetrexed arm v 5.1 months in the gemcitabine arm), and objective response rates were also comparable (30.6% in the pemetrexed arm v 28.2% in the gemcitabine arm). There was statistically significantly more grade 3 to 4 granulocytopenia, thrombocytopenia, and anemia and increased febrile neutropenia associated with the gemcitabine arm. Alopecia was also more common with gemcitabine. Emetic episodes were identical in both arms, but grade 3 to 4 nausea was observed in 7.2% of patients randomly assigned to pemetrexed compared with 3.9% of patients receiving gemcitabine. I personally doubt that any of these results (other than the increased nausea) were surprising to the authors, sponsors, or lung cancer cognoscenti. However, what was interesting was the relationship that histology had in predicting improved survival between the two arms. Patients were not randomly assigned according to histology, but it was a prespecified subset analysis. Eight hundred forty-seven patients with adenocarcinoma were randomly assigned. In these patients, there was improved survival for the cisplatin plus pemetrexed arm compared with the cisplatin plus gemcitabine arm (12.6 v 10.9 months, respectively; hazard ratio = 0.84; 95% CI, 0.71 to 0.99; P = .03). By contrast, the reverse was seen for the 473 patients with squamous cell carcinoma, with survival favoring the cisplatin plus gemcitabine arm compared with the cisplatin plus pemetrexed arm (10.8 v 9.4 months, respectively; hazard ratio = 1.23; 95% CI, 1.00 to 1.51; P = .05). Another important finding from this study was the relationship of smoking to survival. The median survival time for never-smokers was 15.6 months compared with 10.2 months for current or former smokers. Presumably, there was no disparity in incidence of nonsmokers in adenocarcinoma patients accounting for the improved survival on the pemetrexed arm. The overall incidence of never-smokers was 14.8% for the cisplatin plus pemetrexed arm versus 14.1% for the cisplatin plus gemcitabine arm. How should these results be interpreted in the face of numerous equivalent studies of various chemotherapy regimens? Is there a molecular rationale to explain these disparate results? Most prior phase III studies evaluating different chemotherapy regimens in NSCLC have failed to document a difference based on histology. However, few recent studies have evaluated survival according to histology because it was assumed that this was an insignificant variable. An older Eastern Cooperative Oncology Group study demonstrated improved response rate but no difference in survival in a phase III study comparing four different regimens.15 The authors propose a molecular rational for these results. Pemetrexed inhibits thymidylate synthetase (TS). Baseline expression of TS gene is significantly higher in squamous cell carcinoma compared with adenocarcinoma. Preclinical data suggest that there is reduced activity of pemetrexed with high expression of TS.16 This hypothesis would be more convincing if molecular correlates evaluating TS levels were available to substantiate these improved results with pemetrexed in adenocarcinoma. RRM1 is the predominant determinant of the efficacy of gemcitabine.17 It would be of interest to see whether there was a difference in RRM1 expression based on histology accounting for the superior results with gemcitabine in squamous cell carcinoma and inferior results in adenocarcinoma. The authors state that tumor samples were collected when possible for biomarkers. These data will be awaited with great interest. We continue to strive to achieve personalized medicine for our patients with NSCLC.18 Genomic, proteomic, and pharmacogenomic19 differences may allow this to be a reality, especially for adjuvant chemotherapy.20 Treatment decisions based on light microscopy have only rarely been recommended, perhaps because this is a pathologic tool of a century ago compared with these more modern techniques. In the United States, for appropriately eligible patients including those with adenocarcinoma, a standard regimen has been carboplatin, paclitaxel, and bevacizumab.7 It is impossible to know the impact of carboplatin as opposed to cisplatin or whether bevacizumab would further improve survival with a platinum plus pemetrexed regimen for adenocarcinoma. In a small phase II study in 39 patients treated with carboplatin, pemetrexed, and bevacizumab, there was an impressive 55% objective response rate with a 58% 1-year survival. The question posed by this editorial was whether there is a superior regimen based on histology. Is cisplatin plus pemetrexed a superior regimen for adenocarcinoma? Is it inferior in squamous cell carcinoma? These questions will continue to be debated. However, I do feel that, for adenocarcinoma of the lung, cisplatin plus pemetrexed is a preferred regimen compared with cisplatin plus gemcitabine based on noninferiority and decreased toxicity. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on May 27, 2008. REFERENCES 1. Pignon JP, Tribodet H, Scagliotti GU, et al: Lung adjuvant cisplatin evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients. J Clin Oncol 24:366s, 2006 (suppl, abstr 7008) 2. Curran WJ, Scott CB, Langer CJ, et al: Long-term benefit is observed in a phase III comparison of sequential vs. concurrent chemo-radiation for patients with unresected NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 22:621, 2003 (abstr 2499) 3. Breathnach OS, Freidlin B, Conley B, et al: Twenty-two years of phase III trials for patients with advanced non–small-cell lung cancer: Sobering results. J Clin Oncol 19:1734-1742, 2001 4. Souquet 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] 5. Sandler AB, Nemunaitis C, Denham J, 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 6. Sederholm C, Gillerdal G, Lamberg K, et al: Phase III trial of gemcitabine plus carboplatin versus single-agent gemcitabine in the treatment of locally advanced or metastatic non–small-cell lung cancer: The Swedish Lung Cancer Study Group. J Clin Oncol 23:8380-8388, 2005 7. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006 8. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non–small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000 9. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597, 2004 10. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 11. Socinski MA, Novello S, Brahmer JR, et al: Multicenter, phase II trial of sunitinib in previously treated, advanced non–small-cell lung cancer. J Clin Oncol 26:650-656, 2008 12. Scagliotti GV, De Marinis F, Rinaldi M, et al: Phase III randomized trial comparing three platinum-based doublets in advanced non–small-cell lung cancer. J Clin Oncol 20:4285-4291, 2002 13. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 356:92-98, 2002 14. Scagliotti GV, Parikh P, von Pawel J, et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. J Clin Oncol 26:3543-3551, 2008 15. Ruckdeschel JC, Finkelstein DM, Ettinger DS, et al: A randomized trial of the four most active regimens for metastatic non–small-cell lung cancer. J Clin Oncol 4:14-22, 1986[Abstract] 16. Giovannetti E, Mey V, Nannizzi S, et al: Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small cell lung cancer cells. Mol Pharmacol 68:110-118, 2005 17. Zheng Z, Chen T, Li X, et al: DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med 356:800-808, 2007 18. Einhorn LH: Will we ever have personalized medicine for non-small cell lung cancer? J Thorac Oncol 1:737-739, 2006[Medline] 19. Hsu DS, Bala S, Balakumaran, et al: Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer. J Clin Oncol 25:4350-4357, 2007 20. Potti A, Mukherjee S, Petersen R, et al: A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 355:570-580, 2006
Related Articles
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
