Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic
capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although
the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors
lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost
universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation
burden. Because of early metastasis, only a small fraction of patients are amenable
to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide
chemotherapy. Therefore, the vast majority of patients are currently being treated
with chemoradiation with or without immunotherapy. In patients with disease confined
to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide
chemotherapy. Patients with metastatic (extensive-stage) disease are treated with
a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed
death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to
platinum-based chemotherapy, these responses are transient because of the development
of drug resistance. In recent years, the authors have witnessed an accelerating pace
of biologic insights into the disease, leading to the redefinition of the SCLC classification
scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define
unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current
knowledge of SCLC biology and clinical management may lead to unprecedented advances
in SCLC patient care. Here, the authors present an overview of multimodal clinical
approaches in SCLC, with a special focus on illuminating how recent advancements in
SCLC research could accelerate clinical development.
