Cooperative Group Research Endeavors in Small-cell Lung Cancer: Current and Future Directions

Current and Future Directions

Randeep Sangha; Primo N. Lara, Jr.; Alex A. Adjei; Paul Baas; Hak Choy; Laurie E. Gaspar; Glenwood Goss; Nagahiro Saijo; Joan H. Schiller; Everett E. Vokes; David R. Gandara


Clin Lung Cancer. 2009;10(5) 

In This Article

Abstract and Introduction


The International Lung Cancer Congress (ILCC), now in its ninth year, is a key forum for representatives of cooperative groups in North America, Europe, and Japan to discuss ongoing and planned clinical trials in lung cancer. Many of the significant strides in lung cancer treatment often originate from investigations designed within the cooperative group system and were a feature of the 2008 ILCC. Small-cell lung cancer (SCLC) represents 15% of all lung cancers diagnosed annually and is characterized by rapid growth kinetics, disseminated metastases, and development of chemotherapy resistance. Many questions remain regarding the optimal use of radiation therapy and approaches for enhancing the effects of chemotherapy to improve clinical outcomes. Herein, we explore and outline the scientific vision of each cooperative group's SCLC research portfolio, as presented at the 2008 ILCC. Highlights include an ongoing Intergroup phase III study exploring differing radiation therapy schemes for limited-stage SCLC and a Southwest Oncology Group 0124 trial establishing platinum/etoposide as the standard of care for untreated extensive-stage SCLC in North America. Continued research efforts sponsored by these groups will represent the future of SCLC diagnosis and management.


Lung cancer is a strikingly prevalent malignancy and is the leading cause of cancer-related death in worldwide. Small-cell lung cancer (SCLC) represents 15% of all lung cancers, and in 2009, an estimated 32,000 new cases will be diagnosed in the United States.[1] Small-cell lung cancer is characterized by aggressive growth kinetics and disseminated metastases, with 60%-70% of patients presenting with advanced- (or "extensive-") stage disease. Despite high initial tumor response rates following platinum-based chemotherapy, SCLC rapidly develops drug resistance, subsequently leading to tumor progression and patient death. Unfortunately, progress in SCLC management has been agonizingly slow, with a glaring lack of therapeutic advances, despite a wealth of new chemotherapeutic drug classes and targeted agents. With median survivals of 7–11 months and a 2-year survival rate of < 5% for patients with extensive-stage disease, the need to improve outcomes is apparent.[2]

The US cooperative groups, sponsored by the taxpayer-supported National Cancer Institute, as well as cooperative groups from Canada, Europe, and Asia, all play a critical role in overcoming the slow progress in SCLC drug development by incorporating SCLC-specific clinical trials into their respective research portfolios. Within the United States, there are 4 general oncology cooperative groups active in lung cancer research: the Cancer and Leukemia Group B (CALGB), Eastern Cooperative Oncology Group (ECOG), North Central Cancer Treatment Group (NCCTG), and the Southwest Oncology Group (SWOG).[3] The CALGB, ECOG, and SWOG include member institutions from throughout the country, whereas NCCTG is a regional cooperative group centered at the Mayo Clinic. Within Canada, the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) oversees cooperative oncology efforts. In addition, a focused cooperative oncology group that plays a pivotal role and crosses the US/Canadian border is the Radiation Therapy Oncology Group (RTOG). The 2008 International Lung Cancer Congress (ILCC), now in its ninth year, provides a unique forum to gather representatives from the North American cooperative groups as well as international groups such as the European Organization for Research and Treatment of Cancer (EORTC) and the Japan Clinical Oncology Group (JCOG). This article, the fourth in a series that outlines the scientific vision of each group, will focus on clinical research in SCLC.

To provide a foundation for discussion, one must first consider current treatment perspectives in SCLC. The standard therapeutic approach for patients with limited-stage SCLC (LS-SCLC) who are not candidates for a clinical protocol is 4 cycles of chemotherapy with concurrent thoracic irradiation. Based on its preclinical synergy and superiority in efficacy and tolerability with concomitant irradiation, cisplatin and etoposide chemotherapy has supplanted alkylator/anthracycline–based regimens as the chemotherapy backbone.[4] Thoracic irradiation results in local control and a survival benefit; however, the timing of radiation appears critical.[5,6] For example, early concurrent chemoradiation yields a small, but significant, survival advantage when compared with late concurrent or sequential thoracic irradiation; yet, the optimal radiation dose and fractionation regimen remains controversial.[7,8] For patients with excellent performance status and an adequate baseline pulmonary reserve, administration of twice-daily thoracic irradiation to 45 Gy with cisplatin/etoposide has shown encouraging long-term survival results.[9] However, in practice, this schedule is logistically difficult to administer and yet unknown to be superior to a biologically equivalent dose of a once-daily thoracic irradiation regimen. Patients with LS-SCLC who attain a complete response (CR) after concurrent chemoradiation are offered prophylactic cranial irradiation (PCI) based on a meta-analysis reporting a 5.4% improvement in 3-year overall survival (OS; 20.7% PCI-treated vs. 15.3% control) and a 25% reduction in the incidence of brain metastases (33.1% PCItreated vs. 58.6% control).[10]

In North America and Europe, the cornerstone of treatment for extensive-stage SCLC (ES-SCLC) consists of platinum (cisplatin or carboplatin) and etoposide chemotherapy. The primary role of radiation therapy is for palliating symptomatic sites of disease. Recently, PCI has been incorporated into the treatment algorithm on the basis of results from a phase III clinical trial randomizing 286 patients with ES-SCLC with any response to initial chemotherapy to either PCI or observation.[11] At 1 year, PCI significantly reduced the incidence of symptomatic brain metastases (14.4% PCI-treated vs. 40.4% control; hazard ratio [HR], 0.27; P < .001) and increased OS (27.1% PCI-treated vs. 13.3% control; [HR], 0.68; P = .003). Indeed, this has led to the recommendation that PCI be offered for patients with ES-SCLC who respond to first-line chemotherapy, after a thorough discussion of the potential risks and benefits.

Unfortunately, the disease recurs in the majority of patients shortly after initial treatment. Although second-line chemotherapy can result in tumor regression, responses are short-lived, and median survival is often < 6 months.[2] A key factor guiding the selection of future therapy, and its possible efficacy, is the type of response gained after exposure to a first-line platinum-based regimen. Historically, patients are classified into 1 of 3 groups of relapsed disease: platinum sensitive, platinum resistant, or refractory. Platinum sensitivity is arbitrarily defined as a chemotherapy-free interval > 90 days, whereas patients with platinum-resistant disease have recurrent disease within 90 days of completing chemotherapy.[2] Refractory SCLC refers to those who do not respond to, or progress during, first-line chemotherapy. Patients with platinum-resistant and refractory disease are often grouped together and generally have poor responses to subsequent chemotherapy (≤ 10%) and shorter median survivals than patients with platinum-sensitive disease. Although there is no standard second-line treatment option, a number of agents have shown single-agent activity, such as the camptothecin analogues (topotecan, irinotecan), paclitaxel, vinorelbine, and gemcitabine.[2] Multiple-agent regimens, such as retreatment with platinum/etoposide, are also a common treatment choice for platinum-sensitive tumors. In the late 1990s, a randomized phase III trial for patients with recurrent SCLC compared single-agent topotecan with cyclophosphamide, doxorubicin, and vincristine (CAV) and found topotecan to be equally efficacious but with greater palliative effects on common lung cancer symptoms.[12] Topotecan, as a result of its US Food and Drug Administration (FDA) approval for second-line SCLC therapy in platinum-sensitive relapsed disease, has emerged as the standard of comparison in most phase III clinical trials.[13]

These perspectives highlight the current state of SCLC management, which has not changed significantly in the past decade. We will now explore the scientific progress and research endeavors pursued by the large multi-institutional cooperative groups.


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