From Pages to Practice

By James O’Connell, MB MSc

Published September 30, 2020


Lung cancer is the second most common type of cancer and the most common cause of cancer-related mortality in the United States. In 2020, the National Cancer Institute estimates 228,000 new cases of lung cancer and 135,000 deaths due to the disease. The association between smoking and lung cancer has been recognized as a major public health problem since the 1964 report of the Surgeon General on smoking and health. What followed was decades of increased lung cancer incidence. Not until the early 1990s did the incidence of lung cancer begin to decline and the benefits of public health measures to change smoking behavior become apparent. Lung cancer incidence has continued to decline in the past two decades. However, less is known about changes in lung cancer mortality, and in particular, mortality by histologic subtype.

In a recent study published in NEJM, Howlader and colleagues reported that the incidence-based mortality from non–small-cell lung cancer (NSCLC) declined annually between 2001 and 2016 in both men and women. However, a greater decline was seen in the more recent period from 2013 to 2016 than from 2001 to 2013. In addition, the 2-year survival rate among NSCLC patients improved by 9% in both men and women from 2001 to 2014

The faster decline in annual incidence-based mortality and the improvement in 2-year survival in more recent years corresponded with the approval of targeted therapy for NSCLCs. In the past decade, we have seen improved recognition and targeted treatment of epidermal-growth-factor-receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene mutations in NSCLC. We should continue to see improvements in survival as more targeted therapies that involve the identification and inhibition of other upregulated pathways by either small molecule inhibitors or receptor monoclonal antibodies are developed.

A decline in mortality from small-cell lung cancer (SCLC) during this period corresponded with declining incidence, with no improvement in survival owing to limited treatment options. However, some promising immunotherapy strategies for SCLC are emerging.

In the last few decades, the change in smoking behavior has been key to preventing lung cancer. In the decades ahead, improved targeted and personalized therapies will be key in reducing lung cancer mortality.

The following NEJM Journal Watch summary provides more details of the study:


Trends in Population-Level Lung Cancer Mortality

Anne S. Tsao, MD reviewing Howlader N et al. N Engl J Med 2020 Aug 13

Population mortality trends according to cancer subtypes are lacking. To evaluate recent trends in population-level U.S. mortality attributable to non–small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), investigators linked mortality records from the National Center for Health Statistics with incident histologic tumor types reported to Surveillance, Epidemiology, and End Results (SEER) registries from 2001 through 2016. The researchers calculated population-level, incidence-based mortality by dividing the number of cancer-specific deaths among persons with a particular cancer diagnosis by the general population at risk at the time of death in the SEER areas.

Results were as follows:

  • NSCLC incidence in men decreased annually by 1.9% from 2001 to 2008 and by 3.1% from 2008 to 2016.

  • NSCLC incidence-based mortality in men decreased annually by 3.2% from 2006 to 2013 and by 6.3% from 2013 to 2016; 2-year NSCLC-specific relative survival improved from 26% in 2001 to 35% in 2014.

  • NSCLC incidence in women was steady from 2001 to 2006 and then decreased annually by 1.5% from 2006 to 2016.

  • NSCLC incidence-based mortality in women decreased annually by 2.3% from 2006 to 2014 and by 5.9% from 2014 to 2016; 2-year NSCLC-specific relative survival improved from 35% in 2001 to 44% in 2014.

  • NSCLC survival improvements were consistent in both men and women across all ethnicities.

  • SCLC-specific relative survival curves were flat in men and women, as SCLC mortality declined almost exclusively as a result of declining incidence.

Comment: These optimistic findings demonstrating the decline in NSCLC mortality are the result of decreasing incidence and improved therapies. Reductions in NSCLC deaths accelerated following the establishment of routine testing for molecular alterations, such as EGFR and ALK, and the availability of targeted therapies. We will likely continue to see further survival improvements in the next few years, given that immunotherapies became commercially available in 2015. This study demonstrates a more accurate method of evaluating lung cancer mortality with the incidence-based mortality calculation, which can be used to further evaluate mortality rates by histologic subtypes, treatment, and stage.

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James is a 2020-2021 NEJM Editorial Fellow and a graduate of the National University of Ireland, Galway. He has a Masters of Science in Evidence-Based Healthcare from University College London and completed Basic Specialist Training in general internal medicine with the Royal College of Physicians in Ireland.