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Originally published as JCO Early Release 10.1200/JCO.2009.22.9955 on May 26 2009 © 2009 American Society of Clinical Oncology.
Duration of Chemotherapy for Metastatic Non–Small-Cell Lung Cancer: More May Be Better After AllThe University of Texas Southwestern Medical Center, Dallas, TX
Emory University, Atlanta, GA Non–small-cell lung cancer (NSCLC) is one of the few diseases for which numerous randomized clinical trials have compared best supportive care with chemotherapy.1,2 These studies have shown that compared with best supportive care, platin-based chemotherapy improves survival in patients with good performance status. Since these studies were performed, we have seen the impact of systemic therapy on survival, both in second-line (docetaxel, erlotinib, and pemetrexed) and third-line (erlotinib) recurrent disease settings. Despite the survival advantage observed with first- and second-line chemotherapy, most randomized studies to date have failed to show a definitive improvement in survival with the administration of additional first-line chemotherapy, although most have shown an improvement in progression-free survival (PFS), more often than not with a higher incidence of adverse events. As pointed out by Soon et al3 in this issue of Journal of Clinical Oncology, there are several ways to administer additional chemotherapy to patients who have responded or stabilized after four to six cycles of first-line chemotherapy. These include: first, continuing first-line chemotherapy until disease progression; second, continuing first-line chemotherapy, but limiting it to a specified number of cycles; and third, switching to a different regimen after a defined number of cycles of first-line chemotherapy. Various terms have been used to describe to these different scenarios. Some call the first and second approaches maintenance therapy and the third early second-line therapy, whereas others call the first and second approaches prolonged chemotherapy and the third induction chemotherapy followed by consolidation. Although there is no uniform consensus regarding terminology, early second-line therapy implies interval progression, and maintenance therapy implies continuation of original regimen, whereas consolidation implies switching to a different treatment. We prefer the terminology of maintenance for the first and second approaches and consolidation for the third. Regardless of the terminology, before the administration of additional chemotherapy can be adopted as part of routine practice, it is critically important to show a survival benefit, given the toxicities associated with chemotherapy in diseases with poor prognoses, such as lung cancer. Presumably, an improvement in PFS without an improvement in overall survival suggests that both the first and second regimens are active, and it does not matter when the second regimen is administered—at progression or immediately after the first regimen. Although this question of sequence has only been formally tested in one advanced NSCLC trial,4 it has been tested extensively in other malignancies, such as colorectal carcinoma and breast cancer.5,6 In reports of these studies, it has been argued that if PFS is improved without corresponding improvement in survival, the timing of administration of consolidation or second therapy does not matter; the second regimen could be delayed until progression. Regardless of the underlying mechanism, what is most important is that an approach works (ie, that it improves survival). In the absence of a clearcut survival advantage, it is hard to justify added expense or toxicity. However, several recent studies have suggested that there may be benefit in administering additional chemotherapy after four to six cycles of a front-line regimen. In the clinical trial in advanced NSCLC reported by Fidias et al,4 patients received gemcitabine and carboplatin as first-line therapy. Those without progression after four cycles of chemotherapy were randomly assigned to immediately receive an additional six cycles of docetaxel or to follow the standard of care, which was defined as no additional therapy until disease progression, at which point they received docetaxel. Median PFS with immediate docetaxel (5.7 months) was significantly longer (P = .0001) than that with delayed docetaxel (2.7 months). Although there was a trend toward improved survival with immediate docetaxel (12.3 months) compared with delayed docetaxel (9.7 months), it did not quite reach statistical significance (P = .0853). One reason for poorer survival in the delayed arm of the trial reported by Fidias et al4 may have been because many patients randomly assigned to receive delayed docetaxel at progression never received it. Whereas 145 (95%) of 153 patients randomly assigned to receive immediate docetaxel received at least one cycle of additional chemotherapy, only 98 (63%) of 156 patients randomly assigned to the delayed arm actually went on to receive docetaxel at progression. Thirty of the remaining 58 patients did not receive delayed docetaxel because of disease progression or death. Survival for the 98 patients in the delayed arm who actually received docetaxel was 12.5 months—identical to the 12.5-month survival of the 145 patients in the immediate arm. This discrepancy suggests that the trend toward improved survival in the immediate arm as a whole was simply a result of more patients being able to receive an active drug. Thus, early treatment may be better, not because it does a better job of killing cancer cells in the first-line setting, but because it can be administered before other complications of the disease render patients unable to receive it. Another study suggesting that there may be a window of opportunity immediately after first-line chemotherapy in which to administer an effective second regimen was reported in abstract form by Ciuleanu et al.7 This phase III study compared pemetrexed with placebo in the consolidation setting. Although the difference in survival again did not reach statistical significance (preliminary median survival, 13.0 months with pemetrexed v 10.2 months with placebo; hazard ratio [HR], 0.798; 95% CI, 0.63 to 1.01; P = .060), there was an almost 5-month improvement in survival for nonsquamous histology. Once again, the fact that only 50% of patients who were administered the placebo received any form of salvage therapy probably influenced the outcome. Final results have yet to be reported. Does it matter why patients who receive extended chemotherapy live longer? Probably not. Those who live longer do not care why they are living longer—whether it is because of the addition of a new cross-resistant drug, extended duration of chemotherapy, or other factors—as long as they do live longer, particularly if their quality of life is not significantly impaired, and there are no cumulative toxicities of agents or regimens administered. With either approach (ie, early initiation of a second therapy or prolonged duration of the first one), patients have the opportunity to receive more effective therapy. In this edition of JCO, Soon et al3 report a meta-analysis of 13 randomized controlled trials involving more than 3,000 patients, in which patients received extended or additional chemotherapy beyond a standard number of cycles. In their meta-analysis, they found extension of chemotherapy improved PFS substantially (HR, 0.75; 95% CI, 0.69 to 0.81; P < .001), particularly when third-generation regimens were used rather than older regimens (HR, 0.70 v 0.92; interaction P = .003). To our knowledge, for the first time, a small but statistically significant benefit in survival (HR, 0.92; 95% CI, 0.86 to 0.99; P = .03) was also observed. However, the survival benefit only became significant when the phase III trial7 evaluating the role of pemetrexed versus placebo in this setting was added to the meta-analysis. Though the data from the meta-analysis by Soon et al suggest that initiation of maintenance or consolidation systemic therapy prolongs survival, it will be of utmost importance to see an absolute survival benefit in the pemetrexed study. Toxicities associated with chemotherapy administered in a noncurative setting in a disease with poor prognosis are always of concern. However, of the seven trials included in the meta-analysis by Soon et al3 that reported on quality of life, five noted no major differences between treatment and control groups. Thus, although extended chemotherapy may not have improved quality of life, it did not appear to have a negative impact on it. It is not clear from the meta-analysis by Soon et al3 whether one particular trial design was better than another. Although PFS was affected most by trial design on the basis of the first and second maintenance therapy approaches we have described, this did not hold true for overall survival. It may be that one trial design is more effective than others, although with too few types in each category, this is difficult to prove. It is also unclear whether trial design should be different for different targeted agents. This is becoming particularly important as a number of new drugs and new extended therapy trials are emerging. Many of these trials will involve targeted therapies with fewer adverse effects, some of which can be ingested orally, making it significantly easier to administer treatment for an extended period of time. Although one could argue that the benefit of maintenance or consolidation therapy is modest, we are reminded of the stark reality that lung cancer continues to be a lethal disease with poor outcomes for most people. The addition of a targeted agent to combination therapy represents a new approach to improving survival in patients with advanced NSCLC. Similarly, molecular selection to identify patients for first-line therapy with an inhibitor of the epidermal growth factor receptor is emerging as a promising strategy. It is reasonable to add the use of extended or prolonged therapy to this list as another way of extending patient survival in NSCLC. Oncologists have long argued that the goal of cancer treatment is to make cancer a chronic disease. This implies the need for chronic therapy. Chronic treatment for cancer is not a new concept. Continuing chemotherapy until progression is a common practice in many types of advanced cancer, although there is not much supporting level-one evidence for it. For example, chronic hormonal therapy is the standard of care in breast and prostate cancers. In the past, toxicities have limited extended administration of chemotherapy for NSCLC patients. With the advent of more tolerable drugs, targeted or cytotoxic, this may no longer be the case, and patients with lung cancer may now have the opportunity to receive more of an effective therapy. The survival benefit reported in the meta-analysis by Soon et al3 is modest at best. However, if additional trials substantiate the survival benefit, particularly if they do so without major toxicities, we will have a paradigm change in the management of advanced NSCLC. Although we hope that the emerging scientific and biologic discoveries regarding the pathophysiology of cancer will result in more effective, less toxic targeted drugs, we should continue to use any weapon in our arsenal to make cancer a chronic disease. Extended chemotherapy for NSCLC may be a small step toward getting there. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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. Employment or Leadership Position: None Consultant or Advisory Role: Joan H. Schiller, Eli Lilly (C), Genentech (C), AstraZeneca (C), Pfizer (C); Suresh S. Ramalingam, Genentech (C), Eli Lilly (C), Roche (C) Stock Ownership: None Honoraria: Suresh S. Ramalingam, Genentech, Eli Lilly Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Joan H. Schiller Administrative support: Joan H. Schiller Manuscript writing: Joan H. Schiller, Suresh S. Ramalingam Final approval of manuscript: Joan H. Schiller, Suresh S. Ramalingam 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. Spiro SG, Rudd RM, Souhami RL, et al: Chemotherapy versus supportive care in advanced non-small cell lung cancer: Improved survival without detriment to quality of life. Thorax 59:828–836, 2004. 3. Soon YY, Stockler MR, Askie LM, 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. 4. 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. 5. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209–1214, 2004. 6. Sledge GW, Neuberg D, Bernardo P, et al: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An intergroup trial (E1193). J Clin Oncol 21:588–592, 2003. 7. 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.
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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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