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Originally published as JCO Early Release 10.1200/JCO.2009.22.4345 on May 26 2009 © 2009 American Society of Clinical Oncology.
Re-Evaluating Duration of Therapy in Advanced Non–Small-Cell Lung Cancer: Is It Really Duration or Is It More About Timing and Exposure?Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC The optimal therapeutic approach for the individual patient diagnosed with advanced stage IV non–small-cell lung cancer (NSCLC) in 2009 is becoming increasingly difficult to define. Platinum-based doublets have been a mainstay of therapy in the first-line setting since a landmark meta-analysis clearly demonstrated a significant, yet modest, survival benefit compared to best supportive care.1 The development of several active drugs in patients previously treated with platinum-based doublets has lead to the approval of four agents in the second- and third-line setting: docetaxel, pemetrexed, gefitinib, and erlotinib. The validation of both the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways as therapeutic targets in advanced NSCLC has been an important step in modestly improving outcomes.2,3 Scagliotti et al4 recently showed a therapeutic advantage for pemetrexed and cisplatin compared to gemcitabine and cisplatin in nonsquamous NSCLC. This finding shattered the concept that all platinum-based doublets are created equal. Histology now matters both for the safety of bevacizumab and the efficacy of pemetrexed. Two major questions have been addressed over the past decade or so. One has been the optimal duration of first-line platinum-based therapy in advanced NSCLC.5 The initial trials addressing this issue were performed because of observations suggesting that responses occurred early (after the first two to three cycles) and because of cumulative toxicity to prolonged therapy. The message from these trials was that survival was not improved by prolonged therapy with platinum-based doublets led to most major guidelines recommending a brief duration (four cycles) in the first-line setting. These trials were done before the validation of both the EGFR and VEGF pathways with cetuximab3 and bevacizumab2 where the targeted agent was continued until disease progression. Whether this should be called prolonged therapy or maintenance therapy is a matter of debate. A second question addressed the continuation of therapy with a single agent (which had known activity in advanced, refractory NSCLC) following a defined duration of first-line platinum-based therapy.6 Many of these trials evaluated agents approved in the second- or third-line setting. Again, whether this is prolonged duration, sequential therapy, maintenance therapy, or early administration of second-line therapy remains a matter of debate. Interestingly, these trials seem to have had a much greater impact on both progression-free survival (PFS) as well as overall survival (OS) compared to the extended use of platinum-based doublets. In practice, first-line therapy with platinum-based doublets is typically delivered for four (maybe six in some cases) cycles. If bevacizumab or cetuximab was part of the original regimen, it would typically be continued until disease progression based on the design of the pivotal trials.2,3 There are virtually no data regarding the appropriate surveillance strategy for patients once they have completed first-line therapy (ie, what tests should be done and when, how often should patients be evaluated). There is also no information on the value of a treatment break. Many patients who have significant cumulative toxicities during the first four cycles of therapy often resolve these toxicities with a short break or time off therapy. Second-line therapy administered at the time of disease progression (presumably radiographic or symptomatic) has been demonstrated to improve survival and palliate symptoms. However, many patients never receive such therapy due to rapid disease progression or disease-related events which significantly compromises their performance status. Strategies which would identify disease progression earlier or routine administration of effective second-line therapy at a defined time point may increase the number of patients receiving subsequent lines of therapy. In this issue of Journal of Clinical Oncology, Soon et al7 provided a very timely and insightful meta-analysis addressing the duration of therapy in advanced NSCLC. They identified 13 randomized clinical trials (comprising 3,027 patients) of varying designs, none of which included bevacizumab or other targeted agents. The authors concluded that extending therapy, particularly with a third generation agent or regimen, substantially improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.69 to 0.81; P < .00001) but had a far less dramatic, but still statistically significant, effect on OS (HR, 0.92; 95% CI, 0.86 to 0.99; P = .03). Soon et al should be commended for completing this analysis, as it helps us to refocus the issue of treatment strategies in the era of multiple lines of therapy. Several issues with this meta-analysis deserve further consideration. Five of the 13 trials (1,369 patients or 45% of all the patients included in the meta-analysis) simply evaluated the duration of first-line therapy with platinum-based doublets comparing three to four cycles with six or more cycles. None of these trials were individually positive for OS. In almost all trials comparing various platinum-based doublets, the median number of cycles delivered is four, suggesting that the average patient either progresses within four cycles or has toxicity which leads to the cessation of therapy.6 The finding by Soon et al7 that toxicity was greater and quality of life was worse with prolonged therapy supports the prevailing opinion that a brief duration of treatment with a platinum-based doublet is best. A second issue worth considering are the trials in which the prolonged duration component of therapy included agents which are approved in the second-line setting and known (or believed) to improve survival. Two such trials stand out, both of which enriched the population by randomly assigning only patients who completed four cycles of therapy and had stable or responding disease.8,9 These two trials randomly assigned patients to either immediate or delayed docetaxel8 or pemetrexed maintenance versus placebo9; these represent 32% of the patients analyzed in the meta-analysis.7 In addition, when these trials were analyzed they were both published in abstract format only, which was a significant treatment interaction factor for OS in the meta-analysis. Both docetaxel and pemetrexed are approved agents in the second-line setting and were considered third generation agents by Soon et al.7 The results of these two trials are strikingly similar with regard to their impact on PFS as well as OS. In these two trials, 37% to 50% of patients randomly assigned to the shorter duration arm (delayed docetaxel or placebo) never received subsequent therapy. The duration of therapy was clearly brief for these patients but they were also not exposed to agents known to be active in the second-line setting, unlike the patients on the extended arm. One might interpret these finding more as a test of the timing and whether or not patients received effective second-line therapy rather than arguing that an extended duration of first-line therapy provided the benefit observed. In fact, in the trial by Fidias et al,8 the survival of patients randomly assigned to delayed docetaxel who actually received it was identical to the survival of patients on the immediate docetaxel arm. This observation strongly suggests that it not the duration of first-line therapy or the timing of second-line therapy but the exposure of patients to active agents that drives OS. In these two trials, the extended duration arms may have actually once again proven that second-line therapy is effective and not necessarily convinced everyone that longer durations of therapy in the first-line setting are best. It does focus the issue of how patients should be optimally evaluated over time once a brief duration of first-line therapy is delivered. Strategies that implement earlier administration of second-line therapy perhaps at a defined time point may expose greater numbers of patients to effective therapy without extending the duration of first-line therapy and risking greater toxicity. It should also be noted that an extended duration of chemotherapy did not benefit patients with squamous cell histology in the trial by Ciuleanu et al.9 Another issue centers on the most appropriate end point of interest in such an analysis. Although there is continuing controversy over the most appropriate end point is in advanced NSCLC, we have generally demanded that new treatment and/or treatment paradigms improve OS in this disease.10 In the Soon et al meta-analysis, the impact of extended duration was greatest on PFS, which was a secondary end point. Not all the trials reported this end point, which may be useful in evaluating new treatments by negating the impact of therapies delivered after progression has been documented.11 In the modern era of treating advanced NSCLC, exposure to multiple lines of approved agents may be most important and may not be accurately reflected in PFS evaluations. The unfortunate weaknesses of this meta-analysis were the inability to draw firm conclusions about the impact of extended durations of therapy on toxicity, health-related quality of life, and the likelihood of receiving subsequent therapies. In addition, this meta-analysis included trials of cytotoxic agents only. How we should use this information in the targeted therapy era is an open question. In advanced NSCLC, the goal of therapy is not to cure but to maximize the effect of multiple lines of therapy on OS and control of disease-related symptoms with an acceptable toxicity profile. What Soon et al7 suggest is that extended first-line therapy was associated with increased toxicity, some risk of fewer patients receiving subsequent therapy and no hint that it impacted favorably on quality of life. This again raises the issue of treatment breaks and how they could favorably influence quality of life by giving patients time free of toxicity and the relative inconvenience of adhering to a treatment schedule. So where do we go from here? We need more information on the appropriate strategies that expose more patients to agents currently approved by the US Food and Drug Administration for the treatment of advanced NSCLC.6 Extending the duration of first-line therapy by sequencing to effective second-line therapy is one such strategy. However, extended therapy risks increased toxicity and perhaps a negative impact on the individual patient's quality of life. We need to understand both patient preferences as well as the value of time off therapy in this setting. The optimal manner in which to evaluate patients between lines of therapy is also poorly defined both clinically and with regard to imaging studies. Several clinical trial designs could be explored in this setting and could provide insight into many questions currently outstanding. Until then, we should be cautious about extending the duration of first-line therapy. It may be that it is more about the timing and exposure to multiple active agents than it is about duration. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials: Non-small Cell Lung Cancer Collaborative Group. BMJ 311:899–909, 1995. 2. 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. 3. Pirker R, Szczesna A, von Pawel J, et al: FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 26:6s; 2008 (suppl) abstr 3.[CrossRef] 4. 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. 5. Socinski MA, Stinchcombe TE: Duration of first-line chemotherapy in advanced non small-cell lung cancer: Less is more in the era of effective subsequent therapies. J Clin Oncol 25:5155–5157, 2007. 6. Stinchcombe TE, Socinski MA: Treatment paradigms for advanced stage non-small cell lung cancer in the era of multiple lines of therapy. J Thorac Oncol 4:243–250, 2009.[CrossRef][Medline] 7. Soon Y, Stockler MR, Askie L, et al: Duration of chemotherapy for advanced non–small-cell lung cancer: A systematic review and meta-analysis of randomized trials. J Clin Oncol 27:3277–3283, 2009. 8. Fidias PM, Dakhil SR, Lyss AP, et al: Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 27:591–598, 2009. 9. Ciuleanu TE, Brodowicz T, Belani CP, et al: Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: A phase III study. J Clin Oncol 26:426s; 2008 (suppl) abstr 8011. 10. Pazdur R: Endpoints for assessing drug activity in clinical trials. Oncologist 13:19–21, 2008 (suppl 2. 11. Dancey JE, Dodd LE, Ford R, et al: Recommendations for the assessment of progression in randomised cancer treatment trials. Eur J Cancer 45:281–289, 2009.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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