Small Cell Carcinoma of the Lung

Abstract

Small cell lung cancer (SCLC) is a malignant epithelial tumor that occurs almost exclusively in smokers. It accounts for approximately 13% of lung cancer diagnoses in the United States annually. For treatment planning, SCLC is divided into either limited stage disease (LS-SCLC- that is, disease is confined to the chest and can be encompassed within a tolerable radiation field)- or extensive stage disease (ES-SCLC). Approximately 60-70% of patients with SCLC have extensive stage disease (ES-SCLC) at diagnosis. With treatment, the median survival times are about 18-30 months in LS-SCLC and 8-12 months in ES-SCLC.

ES-SCLC is treated with systemic chemotherapy with palliative intent. LS-SCLC is treated with concurrent chemotherapy and thoracic radiation therapy (TRT) with curative intent. The standard-of-care chemotherapy regimen is an etoposide-platinum doublet, largely due to a more favorable toxicity profile than older alkylating-agent and anthracycline-based regimens, particularly when administered with TRT. Cisplatin is the platinum of choice in LS-SCLC as it may be more efficacious. In ES-SCLC, carboplatin is often used because of its greater tolerability and ease of administration. Although about 80% of patients respond to initial chemotherapy or chemoradiation, most relapse and die of their disease within 2 years. Many attempts to improve on the outcomes with conventional chemotherapy over the past 30 years have been unsuccessful, including dose dense, dose intense and maintenance chemotherapy, the addition of other cytotoxins to the etoposide-platinum base, and the replacement of etoposide with other cytotoxins in a platinum-doublet.

The advances with the greatest impact on patient outcome in the first-line treatment of SCLC over the past decade have been in the field of radiation oncology. Considerable clinical evidence has been accumulated through phase III trials and meta-analyses that the earlier initiation of TRT in combination with cisplatin-based chemotherapy, particularly during cycle 1, improves survival in LS-SCLC. Although clinical trials continue to evaluate the optimal dose and schedule of concurrent TRT in LS-SCLC, the current gold standard is accelerated hyperfractionated TRT, with 45 Gy administered twice daily (1.5 Gy per fraction) over a period of 3 weeks. While the administration of prophylactic cranial irradiation (PCI) to patients with LS-SCLC who responded to first-line treatment has been long-accepted, it has only recently been shown that PCI also improves survival in patients with ES-SCLC who have responded to chemotherapy.

Patients with relapsed SCLC generally have a very poor prognosis. Patients who respond to first-line chemotherapy and have a treatment free interval of at least 3 months before progression are considered to have “sensitive disease,” and they are most likely to benefit from second-line chemotherapy. There is no accepted standard regimen for relapsed SCLC. Commonly employed approaches include reinduction with the regimen that was used first-line, the use of a “non-cross resistant” multi-drug regimen (such as CAV: cyclophosphamide, doxorubicin, and vincristine), or single-agent topotecan. Topotecan is the only drug with an FDA indication for treatment of relapsed SCLC.

Amrubicin and picoplatin are new cytotoxic agents in phase III clinical trials for SCLC. Although the data from phase II studies of these agents are encouraging, significantly improving the survival rate of patients with SCLC will require the development of more novel therapeutic agents based on our increasing understanding of the molecular biology of SCLC. The most promising therapeutic targets at present include regulators of apoptosis (such as BCL-2) and angiogenesis (such as VEGF and its receptors), and the c-Met/HGF, IGF-1/IGF-1R, and PI3K/Akt/mTOR pathways. Patient participation in clinical trials of agents targeting these pathways will be crucial.