Steven E. Vogl, MD
In 2011 the American College of Radiology Imaging Network (ACRIN) group published its publicly funded study of three annual screening chest computed tomography (CT) scans among heavy smokers aged 55 to 74.1 The results remain the first and only screening study for any cancer demonstrating a significant reduction in death from any cause—7% at the time of publication. The reduction in all-cause mortality appeared just 2 years after the first screening CT and continued throughout the published follow-up.
The results probably underestimate the benefits of annual CT scanning, since the scanning stopped after just three scans, whereas the number of new lung cancers continued to grow each year. The major benefits of the CT scans probably are from the second and later scans, when new, tiny nodules can be identified and removed if they grow slowly, as lung cancers do. The first scan identifies many cancers that have grown for years, and may already have spread, so removing them may not delay death. Subsequent screens can detect nodules that are new or enlarging and so are very sensitive detectors of adenocarcinoma and squamous cell cancer of the lungs. The evaluation of new or enlarging nodules is difficult, requiring collaboration among radiologists, pulmonary physicians, and surgeons, but is now widely available.
A Missed Opportunity?
These very important National Lung Screening Trial results were ignored for 2 years, until several august societies, the U.S. Preventive Services Task Force (USPSTF), and the Medicare bureaucracy finally decided to approve screening chest CT scans for heavy smokers, but only for those who met precisely the eligibility criteria for the National Lung Screening Trial (with a 2-year extension to age 76 for Medicare and to age 80 for the USPSTF). An opportunity was missed to extend the results favoring screening to those with a comparable annual risk of lung cancer who did not meet the National Lung Screening Trial eligibility criteria (survivors of mantle radiation for Hodgkin lymphoma, survivors of a prior lung cancer, and those with sufficient carcinogen or radon exposure).
This failure is trivial when measured against what happened next: Nothing! Jemal and Fedewa, working for the American Cancer Society, recently published a short article reporting the results of a survey of 2,347 heavy smokers in 2015.2 A total of 3.9% reported having a screening chest CT scan in the previous year. Of an estimated 6.8 million persons at risk and eligible in the United States, this means about 263,000 were scanned.
Many of the remaining 6.5 million will die younger than they have to.— Steven E. Vogl, MD
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Many of the remaining 6.5 million will die younger than they have to. They include fathers and mothers, working people with steady jobs, children of living elderly parents, productive members of American society, most of whom acquired an eventually lethal tobacco addiction while still children. Perhaps society feels it should not intervene in a lethal process that is self-inflicted. Perhaps the tobacco companies do not want to emphasize the lethal risks of the habit they promote. Perhaps doctors are too busy clicking on boxes in electronic medical records to think about or emphasize lung cancer screening. Certainly, lung cancer screening lacks the committed constituency possessed by breast cancer: mammographers, breast surgeons, and breast radiation oncologists, all of whom are professionally dedicated to mammography and depend upon it for their livelihoods.
Perhaps middle-aged smokers feel threatened by the thought that their habit could lead to a lethal cancer. Perhaps insurance companies will do whatever they can to discourage the immediate expenditure of about $300 per CT scan to add to their immediate profits, knowing the eventual costs may well be borne by a different insurance company in 2 to 3 years, when the then metastatic lung cancer produces symptoms.
Skyrocketing Costs of Treating Lung Cancer
Before 2013, lung cancer treatment was surgery for a minority; radiation for a minority; bevacizumab (Avastin) with chemotherapy for some with metastatic disease (expensive but short term); and relatively short periods of chemotherapy for some. Most of the drugs used were then inexpensive, with the exception of pemetrexed (Alimta), which alone remained patented among the then-employed lung cancer chemotherapy drugs. Many elderly smokers presented very ill with lung cancer, too impaired to tolerate toxic systemic chemotherapy, and were referred for hospice care, with little treatment beyond narcotics and perhaps short courses of palliative radiation.
The treatment of these smoking-related cancers has just improved dramatically, and will likely improve further, but at great financial cost to society.— Steven E. Vogl, MD
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Antibodies blocking the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) process of immune cell blockade have led to enormous drug company investment and explosive growth in drug indication, clinical value, and drug sales. One of them (durvalumab [Imfinzi]) has just demonstrated a major decrease in time to disease progression with likely survival improvement after definitive chemoradiation for regionally advanced non–small cell lung cancer (NCSLC).3 One (pembrolizumab [Keytruda]) has been approved by the U.S. Food and Drug Administration (FDA) as initial therapy by itself if more than 50% of the cancer cells express the marker PD-L1, because survival is superior with it compared to chemotherapy in this group.4 The FDA has also approved this drug with initial chemotherapy for lung cancer that is not small cell or squamous cell regardless of PD-L1 expression.5
Three of these drugs (pembrolizumab, atezolizu-mab [Tecentriq], and nivolumab [Opdivo]) have already supplanted chemotherapy as “second-line” treatments for metastatic lung cancer that is not small cell. At least five studies are underway looking at the value of these drugs after resection of lung cancer.
It seems clear that virtually no one should die of NSCLC without a trial of one of these drugs. Although not yet subjected to formal study, the frail and the elderly, who were until recently excluded from chemotherapy for advanced lung cancer, can probably safely receive trials of PD-1–blocking agents, which are considerably less toxic than chemotherapy for most of the patients treated. If these drugs prove active as surgical adjuvant therapy, they could be deployed two or three times in the course of a single patient’s illness. Enhancers of their activity (such as epacadostat, ipilimumab [Yervoy], and tremelimumab) may improve the benefit and also add to the toxicity and the cost.
Two years of pembrolizumab costs just about $300,000 for the drug alone. Costs of administration, monitoring for toxicity, and managing toxicity are additional. None of the competitor drugs have tried to undercut the price. Very few people in the United States with lung cancer will die without receiving these drugs. It seems possible in short order that not only the 156,000 people who die of lung cancer in the United States annually will receive these drugs, but also many of the additional 60,000 who survive lung cancer will receive them as well (based on 2014 U.S. government numbers for lung cancer diagnoses and deaths).
Exactly how these costs play out will depend on study results and insurance determinations not yet fully available. What is clear is that the treatment of these smoking-related cancers has just improved dramatically, and will likely improve further, but at great financial cost to society.
The costs of allowing heavy smokers to die of undetected lung cancer remains great to them, their families, and their employers. Because PD-1 antagonists are both very effective and very expensive, the cost to society of not detecting lung cancer when tiny and not metastatic has just skyrocketed.
That physicians should act in the interest of those under their care and push for CT screening of heavy smokers has been clear since 2011. It remains to be seen whether evolving systems of care in hospitals and large groups, now manipulated primarily to improve immediate -institutional income, can somehow be induced to provide incentives to busy primary care practices to screen heavy smokers. It is their public duty to establish and effectively advertise CT screening programs for lung cancer in high-risk populations. Given the gridlock in Washington, we need voluntary agencies such as the American Cancer Society and the American Lung Association to mount broad advertising campaigns to induce smokers to present for screening. Their efforts to date have been laudable but inadequate. ■
Dr. Vogl is an oncologist who works in the community oncology setting. He is affiliated with Montefiore Medical Center in New York City and White Plains Hospital.
DISCLOSURE: Dr. Vogl reported no conflicts of interest.
1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365:395-409, 2011.
2. Jemal A, Fedewa SA: Lung cancer screening with low-dose computed tomography in the United States-2010 to 2015. JAMA Oncol 3:1278-1281, 2017.
3. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919-1929, 2017.
4. Reck M, Rodriguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823-1833, 2016.
5. Langer CJ, Gadgeel SM, Borghaei H, et al: Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: A randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17:1497-1508, 2016.
Disclaimer: The opinions expressed in this column reflect those of the author and do not necessarily reflect the opinions of ASCO or The ASCO Post.
At Microphone 1 is an occasional column written by Steven E. Vogl, MD, of the Bronx, New York. When he is not in his clinic, he can generally be found at major oncology meetings and often at the microphone, where he stands ready with critical questions for presenters of new data.
The opinions expressed in this column are those of the author. If you would like to share your opinion on this or another topic, please write to editor@ASCOPost.com.