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Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5155-5157 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.4015
Duration of First-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer: Less Is More in the Era of Effective Subsequent TherapiesMultidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC The treatment of advanced, metastatic stage IIIB/IV non–small-cell lung cancer (NSCLC) has come a long way. Fifteen to 20 years ago, debate existed as to whether these stages should be treated at all.1,2 In 1995, the NSCLC Collaborative Group published a meta-analysis based on individual patient data, exploring the survival benefit of cisplatin-based chemotherapy (CBC) in this disease.3 The trials evaluated in this meta-analysis used agents typically referred to as first- or second-generation agents, and included drugs such as mitomycin, etoposide, and the vinca alkaloids; most of these are not commonly used in the modern day treatment of advanced NSCLC. In advanced disease, CBC improved survival compared with best supportive care (BSC). The absolute survival benefit was modest (2-month improvement in median survival time; 4 months for BSC and 6 months for CBC) and a 10% improvement in the 1-year survival rate (10% for BSC and 20% for CBC). This benefit of CBC was associated with a hazard ratio of 0.73, translating to a 27% risk reduction in death over the course of the disease. In 1997, the American Society of Clinical Oncology (ASCO) endorsed treatment of patients with stages IIIB/IV NSCLC who had a good performance status (PS) at the time of diagnosis.4 Around the turn of the century, a plethora of phase III trials evaluated the new third-generation agents (paclitaxel, docetaxel, vinorelbine, irinotecan, and gemcitabine) in combination with either a platinum, or in novel nonplatinum-based doublets.5 These new drugs modestly improved the therapeutic index of therapy, but no combination seemed superior. Two-drug combinations seemed to optimize the balance between the survival and palliative benefits of treatment and the risk of toxicity commonly seen with platinum-based regimens.6 In 1999, the first demonstration that second- or third-line treatment could improve survival and palliate symptoms lead to the approval of docetaxel for second-line treatment.7 Since then, three additional agents (gefitinib, pemetrexed, and erlotinib) have been approved for the treatment of refractory disease.8-10 Recently, two important biologic pathways (the epidermal growth factor receptor [EGFR] and vascular endothelial growth factor [VEGF] pathways) have recently been validated as therapeutic targets in advanced NSCLC.9,11 Lastly, the recent discovery of EGFR activating mutations12,13 has created optimism that continued insights into the biology of lung cancer will lead to further therapeutic gains. Although we have much work ahead, it is important to recognize that substantial progress has been made in the therapeutic options currently available for patients with advanced NSCLC. Despite these advances, the overall survival profile remains poor for most patients, and platinum-based doublets remain the cornerstone of treatment. Although these doublets improve survival, they are not curative options and are associated with substantial toxicity, much of which is cumulative. The goal of therapy in this setting is to maximize the impact platinum-based therapy has on survival, and the palliation of disease-related symptoms without undue toxicity. The original ASCO guidelines4 addressed the appropriate duration of therapy in this setting and cited a single trial that randomly assigned 74 patients to two to three cycles of a non–platinum-based combination regimen compared with continuous treatment. This trial did not show a significant difference in survival. Based on this trial, ASCO recommended that no more than eight cycles be delivered to patients with stages IIIB/IV NSCLC. However, in most clinical trials evaluating various strategies in this population, the median number of cycles delivered was typically three to four, suggesting that either the disease was refractory to treatment or the patient could not tolerate the toxicities of treatment beyond three to four cycles. Likewise, when reported, objective responses and palliation of symptoms typically occurred within the first two to three cycles.5 With this in mind, Smith and colleagues14 were the first to address the question of the duration of therapy in advanced NSCLC by random assignment of 308 patients to three, compared with six cycles of mitomycin, vinblastine, and cisplatin. They could not demonstrate an advantage from six cycles, as the response rate, time to disease progression, and overall survival were identical between the two arms. A second trial randomly assigned 230 patients with stage IIIB/IV disease to four cycles of carboplatin plus paclitaxel (CbP), compared with treatment until progression.15 No benefit was seen for those patients treated beyond four cycles. In a subset analysis, those patients who could have received more cycles but stopped at four fared as well as those patients continuing on CbP until progression. A third trial randomly assigned 297 patients with advanced NSCLC to either three or six cycles of carboplatin plus vinorelbine; no response, survival, or quality-of-life differences were demonstrated.16 A consistent theme in all these trials was the increasing risk of cumulative toxicity characteristic of the regimen used when longer durations were delivered. For example, in the trial using CbP,15 after four cycles, the rate of grade 2 to 4 neuropathy was 19.9%; at cycle 8, 43% of patients continuing on treatment had developed grade 2 to 4 neuropathy. These data lead ASCO in 2003 to change the recommendation regarding the duration of therapy in this setting.17 The new guidelines stated that treatment should be stopped at four cycles for patients not responding to treatment, and no more than six cycles should be administered for any patient. In this issue of the Journal, Park et al, representing the Korean Cancer Study Group,18 report a trial addressing whether four or six total cycles of CBC is optimal in those patients who have nonprogressing disease following their initial two cycles of CBC. Nonprogression at 2 months, also known as the disease control rate, has recently been shown to be a powerful predictor of survival with CBC based on trials from the Southwest Oncology Group.19 The trial by Park et al investigated the duration of therapy in a patient population whose disease had demonstrated sensitivity to CBC before random assignment, arguably representing the patient population with the highest probability of benefiting from extended duration of therapy. Park and colleagues failed to demonstrate any benefit in response rates or survival using a noninferiority design for six compared with four total cycles, despite demonstrating a significant improvement in the time to disease progression (TDP). Interestingly, patients randomly assigned to four cycles were more likely to receive second-line treatment, had less toxicity (including financial), and regained their functional status more rapidly than those patents randomly assigned to six cycles. The overall survival profile of the study population was quite impressive (> 50% 1-year survival on both arms), but the findings are completely consistent with previous trials addressing the question of treatment duration. The authors should be commended for completing this trial, addressing this issue in an innovative manner. The treatment of advanced-stages IIIB/IV NSCLC is becoming increasingly complex. We have several first-line chemotherapy regimens, including bevacizumab in selected patients, with three agents approved for second-line treatment. One of these, erlotinib, is also approved for treatment in the third-line setting. Medical oncologists must now approach advanced NSCLC like our great national past-time, baseball, in which players get three strikes before they are retired. Our patients deserve a treatment strategy in which they are likely to be exposed to three lines of therapy as a survival and palliative advantage to treatment, compared with placebo or BSC, has been established. In this context, the duration of therapy with cytotoxic agents, particularly in the first-line setting, is important, as none of our available treatment options is devoid of toxicity. Prolonging the duration of first-line chemotherapy without a clear signal of a survival benefit in the era of effective subsequent therapies is not justified. It seems prudent to limit our first-line cytotoxic therapies to four cycles, as the message is clear from the multiple trials briefly reviewed here. Some may argue that the benefit in the TDP seen by Park et al18 could be an argument for continuing chemotherapy for six cycles. We believe that the additional toxicity seen is not justified, and the minimal TDP benefit is meaningless in the context of the available subsequent therapies that are known to prolong survival in this setting. This is particularly true if a more prolonged course of first-line therapy reduces the likelihood of receiving subsequent therapy as suggested in the Korean trial. An important issue in the overall management strategy of advanced NSCLC is the timing of second-line therapy, which, if delivered immediately following the initial four cycles, is commonly called maintenance or sequential therapy. An initial trial of maintenance vinorelbine20 did not show any survival benefit. Brodowicz and colleagues21 evaluated maintenance gemcitabine following cisplatin plus gemcitabine and showed a significant prolongation of progression-free survival but no overall survival advantage. Recent data from a phase III trial evaluating the timing of docetaxel following four cycles of first-line carboplatin plus gemcitabine suggested an advantage to "early"compared with "late or delayed" docetaxel—an agent with known activity and survival impact in this setting.22 Ongoing trials evaluating the timing of administering known effective second- or third-line therapies will help clarify the optimal management strategy. It may well be that the most important aspect of the management of stage IIIB/IV NSCLC is assuring that patients are exposed to additional agents with activity rather than prolonged exposure to a first-line platinum-based doublet. Limiting the duration of therapy with the new targeted therapies given with treatment in the second- or third-line setting has not been addressed. Although of no less importance, the paradigm in the second- or third-line setting has been the use of monotherapy with agents with much more favorable toxicity profiles than platinum-based doublets reducing cumulative toxicities. We should move beyond the duration question and address much more important issues for our patients afflicted with this disease: Can we predict which patients receive the greatest benefit from treatment? How do we maximize the therapeutic benefit of anti-EGFR and anti-VEGF therapies? Which biologic pathways are critical to an individual's cancer and can we target these pathways effectively? Can we customize therapy by genomic or proteomic analysis of tumor specimens and transition from nonspecific therapies in unselected patients to targeted therapies in targeted patients? Optimism should be our partner, as we have validated both the VEGF and EGFR pathways as biologically important in this disease and have launched adjuvant trials in early-stage NSCLC, with agents targeting these pathways. It is of interest that we have endorsed the concept of limiting treatment to four cycles in the adjuvant setting. We should let the evidence also guide us in the advanced setting, administering four cycles of first-line therapy and moving on to subsequent therapies when appropriate. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Mark A. Socinski, Thomas E. Stinchcombe REFERENCES 1. Haskell CM: Chemotherapy and survival of patients with non-small cell lung cancer: A contrary view. Chest 99:1325-1326, 1991[CrossRef][Medline] 2. Vokes EE, Bitran JD, Vogelzang NJ: Chemotherapy for non-small cell lung cancer: The continuing challenge. Chest 99:1326-1328, 1991[CrossRef][Medline] 3. 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 4. 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] 5. Socinski MA, Morris DE, Masters GA, et al: Chemotherapeutic management of stage IV non-small cell lung cancer. Chest 123:226S-243S, 2003[CrossRef][Medline] 6. Delbaldo C, Michiels S, Syz N, et al: Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: A meta-analysis. JAMA 292:470-484, 2004 7. 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 8. 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 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: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527-1537, 2005[CrossRef][Medline] 11. 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 12. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 13. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 14. Smith IE, O'Brien ME, Talbot DC, et al: Duration of chemotherapy in advanced non-small-cell lung cancer: A randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 19:1336-1343, 2001 15. Socinski MA, Schell MJ, Peterman A, et al: Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 20:1335-1343, 2002 16. von Plessen C, Bergman B, Andresen O, et al: Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer. Br J Cancer 95:966-973, 2006[CrossRef][Medline] 17. 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 18. Park JO, Kim S-W, Ahn JS, et al: Two versus four additional cycles in patients who are non-progressive after two cycles of platinum-based chemotherapy and its clinical implications for future management of non-small cell lung cancer: A prospective randomized phase III trial by the Korean Cancer Study Group. J Clin Oncol 25:5233-5239, 2007 19. Lara PN Jr, Redman MW, Kelly K, et al: Alternative measures predicting clinical benefit in advanced non-small cell lung cancer (NSCLC) from Southwest Oncology Group (SWOG) randomized trials: Implications for clinical trial design. J Clin Oncol 24, 2006 (abstr 7006) 20. Westeel V, Quoix E, Moro-Sibilot D, et al: Randomized study of maintenance vinorelbine in responders with advanced non-small-cell lung cancer. J Natl Cancer Inst 97:499-506, 2005 21. Brodowicz T, Krzakowski M, Zwitter M, et al: Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: A phase III trial. Lung Cancer 52:155-163, 2006[CrossRef][Medline] 22. Fidias P, Dakhil S, Lyss A, et al: Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small cell lung cancer: Updated report with survival. J Clin Oncol 25, 2007 (abstr 7516)
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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