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Small-Cell Lung Cancer: New Directions for Systemic Therapy.

The outcomes for patients with lung cancer have improved considerably over the past two decades. This has been due to the development of novel treatment approaches, a better understanding of disease biology, and, more recently, the emergence of immunotherapy as an effective option. However, for patients with small-cell lung cancer (SCLC), the treatment paradigms have largely remained the same for a long time. This status quo has not been for the lack of studying novel strategies but is mainly because several new therapies, combinations, and targeted agents have failed to demonstrate a benefit for patients with SCLC. Almquist and Ganti provided an excellent review on the treatment of limitedstage SCLC. Nearly one third of patients diagnosed with SCLC have limited-stage disease, which is potentially curable with definitive combined-modality therapy. Cisplatin-based chemotherapy administered concurrently with thoracic radiotherapy, followed by prophylactic cranial radiation, remains the standard practice for patients with good performance status. Although the use of hyperfractionated thoracic radiotherapy given in two fractions per day is considered the standard approach, its adoption has been challenged by practical and logistical realities for individual patients and care providers. Therefore, radiotherapy is given in conventional once-daily fractions at a comparable biologic dose. The use of higher-dose radiotherapy was not successful over conventional-dose radiotherapy in a phase III study of patients with locally advanced non–small-cell lung cancer (RTOG 0617). Based on these data, it appears that improvement of systemic therapy has the best potential to increase survival for patients with SCLC. For extensive-stage SCLC, systemic chemotherapy results in high response rates, but the duration of benefit is modest, and effective salvage therapies are unavailable. Administration of chemotherapy concurrently with molecularly targeted agents, such as antiangiogenic agents, hedgehog pathway inhibitors, and insulinlike growth factor receptor inhibitors, has failed to improve treatment outcomes. Consequently, more recent efforts to identify novel targets have focused on understanding the genomic landscape of SCLC, which is characterized by a high incidence of p53 mutation and RB1 loss. Because these are loss-of-function mutations, they are not amenable to conventional targeted strategies. For patients with certain driver mutations, interrupting the relevant molecular pathways is being pursued as a therapeutic strategy in ongoing studies. However, the high mutation burden observed in SCLC tumors renders modulation of any specific pathway less likely to result in meaningful clinical benefits. Novel combination approaches targeting multiple pathways are a potential way forward for certain dominant oncogenic events.