Extensive-stage small-cell lung cancer—moving beyond response rate?
Authors: R. Ferraldeschi, P. Lorigan
Journal: Annals of Oncology (2009)

With the notable exception of prophylactic cranial irradiation (PCI), there has been little real progress in the management of extensive-stage small-cell lung cancer (ED SCLC) over the last 20 years, despite the evaluation of a number of agents that have proven efficacy in other tumor types. This disappointing outcome has come at a significant cost, both in terms of number of patients enrolled in essentially negative trials and the expense of carrying out these studies. There are two obvious conclusions—we need new treatment approaches and we need to design studies capable of predicting at an earlier stage the likely outcome. Response rate has always been considered a key factor in outcome and is commonly reported as a secondary end point. There is certainly recent evidence for ED SCLC that regimens associated with a lower response rate have a worse outcome [1.Socinski M, Smit E, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin (PC) versus etoposide plus carboplatin (EC) in chemonaive patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC): interim results. 2008 Annual Meeting of the American Society of Clinical Oncology 2008 Annual Meeting of the American Society of Clinical OncologyMay 30–June 3, Chicago, IL. (Abstr NSA).Google Scholar]. For conventional chemotherapy drugs, there appears to be a clear relationship between objective response rates from phase I and phase II trials and subsequent regulatory approval of the drug for breast, non-small-cell lung, colorectal, ovarian and other solid tumors but not for melanoma or renal cell carcinoma [2.Goffin J. Baral S. Tu D. et al.Objective responses in patients with melanoma or renal cell cancer in early clinical studies do not predict regulatory approval.Clin Cancer Res. 2005; 11: 5928-5934Crossref PubMed Scopus (75) Google Scholar]. A review of phase II trial design used in studies of molecular targeted agents reached similar conclusions [3.El-Maraghi R.H. Eisenhauer E.A. Review of phase II trial design using studies of molecular targeted agents: outcomes and predictors of success in phase II.J Clin Oncol. 2008; 26: 1346-1354Crossref PubMed Scopus (115) Google Scholar]. For phase III studies of conventional chemotherapy, there is evidence that objective response can predict for survival in metastatic breast cancer [4.Bruzzi P. Del Mastro L. Sormani M.P. et al.Objective response to chemotherapy as a potential surrogate end point of survival in metastatic breast cancer patients.J Clin Oncol. 2005; 23: 5117-5125Crossref PubMed Scopus (107) Google Scholar], advanced colorectal cancer [5.Buyse M. Thirion P. Carlson R.W. et al.Relation between tumor response to first-line chemotherapy and survival in advanced colorectal cancer: meta-analysis. Meta-Analysis Group in Cancer.Lancet. 2000; 356: 373-378Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, 6.Johnson K.R. Ringland C. Stokes B.J. et al.Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis.Lancet Oncol. 2006; 7: 741-746Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar] and non-small-cell lung cancer (NSCLC) [6.Johnson K.R. Ringland C. Stokes B.J. et al.Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis.Lancet Oncol. 2006; 7: 741-746Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar]. But does a higher response rate predict for better survival in ED SCLC? In this edition of Annals of Oncology, Hotta et al. [7.Hotta K. Kiura K. Fujiwara Y. et al.Association between incremental gains in the objective response rate and survival improvement in phase III trials of first-line chemotherapy for extensive disease small-cell lung cancer.Ann Oncol. 2009; 20: 829-834Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar] assess the extent to which the overall response rate (ORR) is predictive of mortality, how much difference in ORR is needed to predict an obvious survival difference, and what factors could affect the association between the two parameters in the first-line treatment of ED SCLC. They found only a modest association between the ORR and median survival time differences in the trials (R2 = 0.3314). The association was stronger for trials in which PCI was given to those having an objective response to the initial chemotherapy (R2 = 0.6279). Large differences in ORR were needed to predict a survival advantage (1.2-day survival advantage per 2% increase in ORR). Despite the obvious limitations of such an analysis, carried out on studies conducted over a 15- to 20-year period, with different staging systems and response criteria, these are important data and highlight that even for regimens achieving significantly higher rates of response, any effect on survival is modest. The majority of responding patients relapse quickly and die of their disease. The combination of etoposide and platinum is the standard of care for patients with ED SCLC and a good performance status [8.Chute J.P. Chen T. Feigal E. et al.Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress.J Clin Oncol. 1999; 17: 1794-1801Crossref PubMed Google Scholar, 9.Pujol J.L. Carestia L. Daures J. Is there a case for cisplatin in the treatment of small cell lung cancer? A meta analysis of randomised trials of a cisplatin-containing regimen versus a regimen without this alkylating agent.Br J Cancer. 2000; 83: 8-15Crossref PubMed Scopus (258) Google Scholar]. A number of different approaches have been used to try to improve on this, including the addition of further agents to the existing regimen, dose intensification, and the use of maintenance treatment or alternating non-cross-resistant regimens. Most of these approaches failed to improve survival convincingly and their role remains uncertain [10.Ferraldeschi R. Baka S. Jyoti B. et al.Modern management of small-cell lung cancer.Drugs. 2007; 67: 2135-2152Crossref PubMed Scopus (45) Google Scholar]. Newer drugs such as topotecan, irinotecan, pemetrexed, and paclitaxel have recently been added to platinum and etoposide. Despite encouraging early results, randomized clinical trials have failed to show superiority of the newer regimens over etoposide and platinum in terms of overall survival (OS) [1.Socinski M, Smit E, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin (PC) versus etoposide plus carboplatin (EC) in chemonaive patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC): interim results. 2008 Annual Meeting of the American Society of Clinical Oncology 2008 Annual Meeting of the American Society of Clinical OncologyMay 30–June 3, Chicago, IL. (Abstr NSA).Google Scholar, 11.Heigener D. Freitag L. Eschbach C. et al.Topotecan/cisplatin (TP) compared to cisplatin/etoposide (PE) for patients with extensive disease-small cell lung cancer (ED-SCLC): final results of a randomised phase III trial.J Clin Oncol (Meeting Abstracts). 2008; 26 (Abstr 7513)Google Scholar, 12.Natale R. Lara P. Chansky K. et al.S0124: a randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated extensive stage small cell lung cancer (E-SCLC).J Clin Oncol (Meeting Abstracts). 2008; 26 (Abstr 7512)Google Scholar, 13.Niell H.B. Herndon II, J.E. Miller A.A. et al.Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732.J Clin Oncol. 2005; 23: 3752-3759Crossref PubMed Scopus (161) Google Scholar]. The combination of pemetrexed and carboplatin resulted in a significantly lower response rate (40.5% versus 24.9%) and shorter median OS (9.6 versus 7.3 months) compared with etoposide and carboplation, a greater difference than that predicted using the Hotta formula [1.Socinski M, Smit E, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin (PC) versus etoposide plus carboplatin (EC) in chemonaive patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC): interim results. 2008 Annual Meeting of the American Society of Clinical Oncology 2008 Annual Meeting of the American Society of Clinical OncologyMay 30–June 3, Chicago, IL. (Abstr NSA).Google Scholar]. PCI, previously recommended for patients with limited-stage disease, has recently been shown to benefit those with ED SCLC who had a response to initial chemotherapy, with a doubling of the 1-year survival rate (27% versus 13%) [14.Slotman B. Faivre-Finn C. Kramer G. et al.Prophylactic cranial irradiation in extensive small-cell lung cancer.N Engl J Med. 2007; 357: 664-672Crossref PubMed Scopus (850) Google Scholar]. In light of the improved survival with distant disease control with PCI, the role of consolidation radiotherapy to the primary site is worth considering. A single-center randomized trial published in 1999 demonstrated an improvement of 5-year OS for complete responders (at least at distant level) receiving additional thoracic chemoradiotherapy compared with chemotherapy alone (9.1% versus 3.7%) [15.Jeremic B. Shibamoto Y. Nikolic N. et al.Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study.J Clin Oncol. 1999; 17: 2092-2099Crossref PubMed Google Scholar]. The Dutch Lung Cancer Study Group has recently initiated a randomized trial (CREST) to evaluate this approach. The survival benefit seen with PCI in ED SCLC would indicate that strategies to consolidate or maintain a response may be beneficial. The role of cytotoxic agents as maintenance therapy has been looked at in a number of trials; the analysis by Hotta et al. specifically excluded these studies. These studies were heterogeneous in design, making it difficult to draw clear conclusions. A meta-analysis of 14 published randomized clinical trials encompassing 2550 patients indicated that maintenance chemotherapy decreased the 1- and 2-year risk of death or disease progression in small-cell lung cancer (SCLC) and improved 1- and 2-year OS by 9% and 4%, respectively [16.Bozcuk H. Artac M. Ozdogan M. Savas B. Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A metaanalysis of the published randomized controlled trials.Cancer. 2005; 104: 2650-2657Crossref PubMed Scopus (64) Google Scholar]. A therapeutic plateau has been reached with conventional cytotoxic chemotherapy in ED SCLC. The evaluation of targeted therapies for SCLC has lagged behind that for NSCLC and other common cancers, and results from initial phase III studies have not been encouraging [17.Lee S, Woll P, James L, et al. A phase III randomised, double blind, placebo controlled trial of etoposide/carboplatin with or without thalidomide in advanced small cell lung cancer. 12th World Conference on Lung Cancer, Seoul, Korea, September 2–6, 2007. (Abstr PRS-04).Google Scholar, 18.Shepherd F.A. Giaccone G. Seymour L. et al.Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer.J Clin Oncol. 2002; 20: 4434-4439Crossref PubMed Scopus (235) Google Scholar]. A number of newer targeted agents are under evaluation. The usual challenges exist, related to the heterogeneity, complexity and redundancies in the systems that influence tumor proliferation and metastasis in SCLC, in addition to study design and the lack of validated predictive biomarkers to individualize therapy. Efforts over the next 5–10 years will be concentrated on defining the roles of these newer agents and how best to combine them with standard chemotherapy and radiotherapy. However, there remains a real concern, supported by the study from Hotta et al., that simply improving response rates will not have a major impact on survival. Maintenance therapy in responding patients, ideally guided by validated predictive factors, is a logical strategy to study, and a number of such studies are open or in conception.