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Originally published as JCO Early Release 10.1200/JCO.2006.06.1432 on May 8 2006 © 2006 American Society of Clinical Oncology.
Oral Second-Line Chemotherapy for Advanced Non–Small-Cell Lung Cancer: The Bottom LineUniversity of California Davis Cancer Center, Sacramento, CA In this issue of the Journal of Clinical Oncology, Ramlau et al1 describe the results of a phase III trial comparing oral topotecan versus intravenous docetaxel in patients with previously treated advanced stage non–small-cell lung cancer (NSCLC). The study was large (more than 800 patients), employed a noninferiority design, and was performed by an experienced international group of lung cancer investigators. The authors report that oral topotecan is active in this clinical setting, and that the study met predefined criteria for noninferiority with regard to survival. What do these results mean for the practicing oncologist, and will they alter our second-line management of NSCLC patients? To put these data into perspective, we must first ask how this study stacks up against previously reported trials of second-line therapy. In the current study, for example, efficacy parameters of response rate and overall survival were not statistically different between docetaxel and topotecan (5% in each arm, and 31.7 v 27.9 weeks, respectively; P = .057), whereas time to progression was superior in the docetaxel arm (13.1 v 11.3 weeks, respectively; P = .02). Although both agents were reported to be relatively well tolerated, the hematologic toxicity profile favored docetaxel, as did the overall quality-of-life assessment (P < .0001). In fact, despite a significant expansion of the therapeutic armamentarium, there appears to be no clear winner among the agents tested in randomized trials of second-line therapy, at least in terms of efficacy parameters (Table 1). This conclusion seems particularly well justified when one looks at the results from study to study with docetaxel at 75 mg/m2, which served as a study arm in five of the seven trials listed. Most likely, variability in eligibility criteria and patient characteristics account for differences between studies. In addition to measures of efficacy and toxicity, docetaxel is reported to convey quality-of-life benefits in this clinical setting, and to be cost effective.9,10
So where do we go from here? With the exception of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, for which patient characteristics such as sex (female), histology (adenocarcinoma or bronchioloalveolar carcinoma), smoking status (never-smoking), or tumor biomarkers (EGFR gene copy number or mutation status) portend a greater likelihood of benefit, there are no clear-cut clinical features, and as yet no generally accepted predictive biomarkers, to guide physicians in selecting from among the remaining available options for second-line therapy for the majority of patients with NSCLC. An obvious question is whether combinations of these second-line therapies are likely to be better than single agents in achieving the palliative goals of second-line therapy. Once again, there are no definitive results to suggest that combinations are superior, although many clinical trials are ongoing investigating the possibilities. Two potential considerations worthy of discussion are combinations of the chemotherapeutic agents listed above with EGFR TKIs or with antiangiogenic agents such as bevacizumab. With regard to the former, the possibility of antagonism between concurrently administered chemotherapy and EGFR TKIs has led to a series of studies evaluating the concept of pharmacodynamic separation, such as intermittent dosing of the EGFR TKI together with chemotherapy.11,12 At the same time, combinations of bevacizumab with chemotherapy, recently shown to improve survival in first-line therapy, are also of interest in second-line therapy, as exemplified by a joint North Central Cancer Treatment Group/Southwest Oncology Group trial investigating pemetrexed plus bevacizumab.13 Last, we return to our original question: how does oral topotecan stack up against its competitors for second-line therapy? One distinction is that it is oral chemotherapy. Whether that is deemed a positive or negative feature may be in the eyes of the beholder, when considering issues such as patient convenience, cost, and recent changes in reimbursement policies. Although an oral drug can be appealing and offer flexibility to some patients, the myelosuppression associated with topotecan may be a limiting factor in its use. Finally, the bottom line, and the last sentence in the conclusion states that "Topotecan may provide an option for patients who desire an orally available treatment after relapse." It is difficult to argue with that. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, 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 in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Author Contributions
REFERENCES
1. Ramlau R, Gervais R, Krzakowski M, et al: Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non–small-cell lung cancer. J Clin Oncol 24:2800-2807, 2006 2. Dancey J, Shepherd FA, Gralla RJ, et al: Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: Results of a prospective, randomized phase III trial. Lung Cancer 43:183-194, 2004[CrossRef][Medline] 3. Leighl NB, Shepherd FA, Kwong R, et al: Economic analysis of the TAX 317 trial: Docetaxel versus best supportive care as second-line therapy of advanced non-small-cell lung cancer. J Clin Oncol 20:1344-1352, 2002 4. 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 5. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 18:2354-2362, 2000 6. 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 7. Ramlau R, Gervais R, Krzakowski M, et al: Oral topotecan demonstrates clinical activity in relapsed non-small cell lung cancer: Results from an open-label, phase III study (387) comparing oral topotecan to intravenous docetaxel. J Clin Oncol 23:625s, 2005 (suppl; abstr 7017) 8. Bonomi P, Paz-Ares L, Langer C, et al: Xyotax versus docetaxel for the second line treatment of non small cell lung cancer (NSCLC): The STELLAR 2 phase III study. Lung Cancer 49:S35, 2005 9. 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 10. Thatcher N, Chang A, Parikh P, et al: ISEL: A phase III survival study comparing gefitinib (Iressa) plus best supportive care (BSC) with placebo plus BSC in patients with advanced non small cell lung cancer (NSCLC) who had received one or two prior chemotherapy regimens. Lung Cancer 49:S4, 2005 11. Davies AM, Lara PN, Lau D, et al: Intermittent erlotinib in combination with docetaxel (DOC): Phase I schedules designed to achieve pharmacodynamic separation. J Clin Oncol 24:630s, 2005 (suppl, abstr 7038) 12. Gandara DR, Gumerlock PH: Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: Case closed or is the jury still out? J Clin Oncol 23:5856-5858, 2005 13. Sandler AB, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial E4599. J Clin Oncol 23:2s, 2005 (suppl; abstr LBA4)
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
