Chapter 116: Small Cell Lung Cancer: Diagnosis, Treatment, and Natural History

INTRODUCTION

Small-cell lung cancer (SCLC) is, in many ways, a unique tumor. Untreated, it is a highly virulent malignancy, with a life expectancy best measured in weeks. Conversely, it displays exquisite chemosensitivity, resulting in partial or complete responses in the majority of cases. For the first time in more than 30 years, the standard of care for advanced SCLC has changed with the addition of immune checkpoint inhibitor therapy to standard chemotherapy. Unfortunately, even with this advance, durable tumor responses are rare, and as a result, more than 95% of SCLC patients die from their disease. This chapter reviews the biology, epidemiology, diagnosis, clinical presentation, staging, and current management of this difficult disease.

EPIDEMIOLOGY

Lung cancer remains the leading cause of cancer death in men and women in the United States. In 2021, estimates call for 235,760 cases of newly diagnosed lung cancer (119,100 men and 116,660 women) and 131,880 deaths (69,410 in men and 62,470 in women).¹ Smoking tobacco products is the leading cause of lung cancer, conferring a 20-fold increase in risk and accounting for approximately 90% of all cases,² and smoking cessation reduces this risk substantially.³ The prevalence of smoking in the United States peaked in 1964 at 42.7% with the landmark surgeon general’s report on Smoking and Health. Since that report, the percentage of ever-smokers who have successfully quit smoking, or “quit ratio,” has steadily increased to 61.7% in 2017, meaning that are currently more former smokers than current smokers, and the prevalence of smoking has declined below 18%.⁴ The incidence of lung cancer lagged behind smoking cessation by just under three decades, but it has steadily declined by nearly 30% from its peak in 1982.⁵ One study predicts that continued decline in smoking prevalence will reduce lung cancer deaths to 50,000 annually by 2065, a 60% reduction, despite increasing population and life expectancy.⁶

SCLC is more tightly associated with smoking than any other histologic subtype of lung cancer, with only 2% of cases occurring in never-smokers^7–9 and a relative risk that increases sharply with duration and intensity of exposure.¹⁰ COPD is an independent risk factor for SCLC and mediates a small proportion of the smoking risk effect.¹¹ Other proposed risk factors include exposure to bis(chloromethyl) ether, nickel, vinyl chloride, asbestos, cadmium, radon, arsenic, and radiation, but the impact of each of these agents is not well quantified.¹² Due to the tight association between SCLC and tobacco use, smoking cessation had a greater impact on SCLC than other types of lung cancer, decreasing proportional incidence from a peak of 17% of all lung cancer in 1986 to 13% in 2002, where it has remained as of 2017.^5,13 SCLC mortality has declined in parallel with incidence and can be attributed almost entirely to smoking cessation, as survival following diagnosis has remained brief. In contrast, non–small-cell ...