The National Cancer Act of 1971 established a national priority to address the widely shared dread of a cancer diagnosis. The goal of the National Cancer Act was to strengthen the National Cancer Institute (NCI) to more effectively carry out the national effort against cancer.
James L. Mulshine, MD
Fred R. Hirsch, MD, PhD, FASCO
After the Act was signed into law by then-President Richard Nixon, the budget of the agency was increased fourfold by the end of that decade. As a result of that enhanced funding, the National Cancer Act’s most notable impact was significant progress in the exploration of viral carcinogenesis and treatment of established cancers.1 However, from the inception of the NCI, there was a notion that it should also evaluate the potential of prevention and early detection measures, as outlined by President Franklin Roosevelt during the first NCI building dedication in 1940.2 A success story that has not been widely appreciated is the NCI’s impact in providing an effective early detection approach to lung cancer, which has quietly evolved into a well-validated cancer screening method despite formidable speed bumps along the way. We will briefly outline this story.
Collaborative Efforts in Early Screening Options
After time in the laboratory of the renowned cervical cancer cytologist Georgios Papanikolaou, MD, PhD, Geno Saccomanno, MD, PhD, adapted that cytologic approach to a sputum test to diagnose early lung cancer from the examination of exfoliated cells of the respiratory epithelium.3,4 Dr. Saccomanno established a research institute in Grand Junction, Colorado, which was the transportation hub for uranium mining that was conducted in the second half of the 20th century in southwest Colorado. A large number of workers involved in uranium mining developed lung cancer, which fueled enormous interest in improving the diagnostic efficiency for this cancer.5
Initial studies failed to show a significant benefit of using chest x-ray alone to detect early lung cancer. So, when Dr. Saccomanno developed a promising new sputum cytology evaluation, there was interest in combining chest x-ray with sputum cytology to more routinely detect early and more curable lung cancer.4,5
The benefit of combining chest x-ray and sputum cytology to improve the early detection of lung cancer emerged just as the National Cancer Act was signed into law. This allowed the NCI to use funding and administrative structures to more deeply investigate promising cancer research opportunities, as vividly related by then-Director of the Division of Cancer Biology and Diagnosis Nathaniel I. Berlin, MD, PhD.6
Dr. Berlin led the conduct of the early lung cancer trial by assembling a structure called the Cooperative Early Lung Cancer Detection Program. This organization arose in response to a conversation between Dr. Berlin and a renowned lung cancer pathologist from Johns Hopkins, John Frost, MD. Dr. Frost proposed that the cytologic approach developed by Dr. Saccomanno could be added to chest x-ray to enable more effective early detection of lung cancer with corresponding improvement in patient outcomes. The four-university consortium was assembled to conduct this trial through a then-innovative contracting mechanism, which largely anticipated the eventual structure that has now evolved into the National Clinical Trials Network.
The consortium institutions included John Hopkins, Memorial Sloan Kettering, and Mayo Clinic, Rochester, Minnesota, for patient accrual; and the University of Cincinnati for data management and analysis of the trial data. The Diagnosis Research Advisory Group of the NCI organized periodic site visits to monitor the work of the group. To rigorously conduct the trial, a multidisciplinary team including statisticians, radiologists, pathologists, bronchoscopists, surgeons, and clinical trial specialists was assembled.
Early Efforts Lead to Debate, Important Lessons Learned
What is evident from considering these accommodations is that the NCI effort was a careful attempt designed to ask the right question in the right fashion at a scale that was not previously feasible. The three sites performing the screening each accrued 10,000 male smokers. They had separate screening protocols but evaluated the same trial endpoint, which was the number of deaths due to lung cancer. For example, the Mayo Clinic site conducted a baseline round of screening to allow the prevalence of lung cancer to be excluded from the trial.6
Even 50 years ago, there was considerable controversy about the design of the trial, with one camp believing in the inherent value of early detection without performing the trial, and others passionate in asserting that the proposed 30,000-person trial was not sufficient to address the magnitude of the problem.6 The results of this large effort were published in a series of final site reports and conclusively proved that the addition of sputum cytology to annual chest x-ray failed to significantly reduce the number of deaths due to lung cancer.7-10
“With radiomic analysis, images such as thoracic CTs obtained for one reason can be reanalyzed using advanced image-processing techniques to reveal other major disease processes.”— James L. Mulshine, MD, and Fred R. Hirsch, MD, PhD, FASCO
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The inherent value of lung cancer screening was debated over the next 2 decades, but many important lessons emerged from that experience and were outlined in a vast number of subsequent research publications. These topics included the logistics of running a large trial, the integration of fiber optic bronchoscopy into early lung cancer management, and deeper analysis of the biology of the early natural history of lung cancer.6 Of note, a published critique of the study by the lead investigator at the Mayo Clinic provided a cogent analysis of the limitations of that trial design, which still is foundational in prospective screening trial design today.11
Finally, clinical specimens (sputum cytology) were systematically accrued during the conduct of the Johns Hopkins component of the trial and were stored in conjunction with the data from all trial participants’ clinical outcomes. This archive provided invaluable material for subsequent biomarker validation in a fashion that was to be scaled widely in many subsequent NCI research efforts.6,12
In the wake of this trial, lung cancer remained a dominant factor in global cancer mortality. Then-NCI Director Samuel Broder, MD, pointed out on a number of occasions that all roads to success in the war on cancer must go through lung cancer. The NCI’s continued investment in early lung cancer detection research, fueled by the resources of the National Cancer Act, played an indispensable role in enabling the next breakthrough for successful early lung cancer detection.
Implications for Future Research
With funding from an NCI R01 grant, Claudia Henschke, MD, reported a cohort study that compared the sensitivity of low-dose spiral computed tomography (CT) compared with chest x-ray and found that spiral CT was more sensitive in detecting early-stage lung cancer.13 This unexpected result roiled the oncology field, but then-Director of the NCI Richard Klausner, MD, directed that feasibility studies to validate the utility of low-dose CT in reducing lung cancer mortality should be conducted expeditiously.14
In 2002, the randomized National Lung Screening Trial (NLST) was initiated by the next NCI Director, Andrew von Eschenbach, MD. Per design, the trial accrued more than 53,000 patients to address the ability of low-dose CT detection to reduce lung cancer mortality compared with chest x-ray, at an eventual cost of $250 million.15 Even given the lethality of lung cancer, this is a level of research investment in early cancer detection enabled by the National Cancer Act that no other nation to this day has committed to this critical issue.
The NLST was completed on schedule and reported a lung cancer mortality reduction of 20%, as was predetermined to be the critical threshold for screening success.16 Long-term follow-up and publication of a large European randomized trial have confirmed this finding.17,18 The robustness of the low-dose CT detection of earlier lung cancer allows a responsible transition of lung cancer screening from research findings to an implementable cancer screening service. This transition was reflected in the Centers for Medicare and Medicaid Services’ issuance of a National Coverage Determination outlining provisions for federal reimbursement of this cancer screening service.19 Thus, the lung cancer screening advancement completed the arc of addressing a seemingly unapproachable health goal, as envisioned with the launch of the war on cancer 50 years earlier.
However, in keeping with the research spirit of the first NCI chest x-ray screening trial, the NLST effort included provisions to systematically collect not only the clinical specimens for molecular biomarker development, but also, in breaking new ground, thoracic CT images in a fashion to enable critical 21st century open digital imaging research.20 In this regard, the National Cancer Act, as intended by Congress, not only benefited patients with cancer, but also now can spawn innovative new approaches that will have a broader impact, affecting more than just cancer and enabling progress in other major chronic diseases as well.
As recently reported, there is a burgeoning new field of radiomic research. With radiomic analysis, images such as thoracic CTs obtained for one reason can be reanalyzed using advanced image-processing techniques to reveal other major disease processes. This approach is relevant, as heavy smoking results in increased rates of coronary artery disease and chronic obstructive pulmonary disease in addition to lung cancer. Collectively, these three diseases are three of the four leading causes of premature deaths in our society. Low-dose CT scan used for lung cancer detection can routinely visualize all three of these major diseases, typically well in advance of the appearance of any clinical symptoms, so that preemptive measures may be administered. Therefore, advanced imaging could provide a critical new tool to prevent the progression to fatal disease for many individuals and, in the process, provide a major validation of the wisdom of sustained National Cancer Act investments.21
DISCLOSURE: Dr. Mulshine reported no conflicts of interest. Dr. Hirsch has been paid for a consulting or advisory role by AstraZeneca, Genentech, Lilly, Merck, Bristol Myers Squibb, Novartis, Amgen, Oncocyte, Regeneron/Sanofi, and Daiichi Sankyo/UCB Japan; his institution has received research funding from Amgen, Merck, AbbVie, Biodesix, Mersana, and Rain Therapeutics; his institution holds patents, has patents pending, receives royalties, participates in royalty-sharing agreements, or holds other intellectual property interests from EGFR FISH, and IHC for prediction of outcome in patients treated with EGFR inhibitors.
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17. National Lung Screening Trial Research Team: Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial. J Thorac Oncol 14:1732-1742, 2019.
18. de Koning HJ, van der Aalst CM, de Jong PA, et al: Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med 382:503-513, 2020.
19. Centers for Medicare and Medicaid Services: Decision memo for screening for lung cancer with low-dose computed tomography. Published February 5, 2015. Available at https://www.cms.gov/newsroom/press-releases/national-coverage-determination-ncd-screening-lung-cancer-low-dose-computed-tomography-ldct. Accessed September 22, 2021.
20. Clark KW, Gierada DS, Marquez G, et al: Collecting 48,000 CT exams for the lung screening study of the National Lung Screening Trial. J Digit Imaging 22:667-680, 2009.
21. Yip R, Jirapatnakul A, Hu M, et al: Added benefits of early detection of other diseases on low-dose CT screening. Transl Lung Cancer Res 10:1141-1153, 2021.
This commentary was originally published in ASCO Daily News (September 15, 2021). It is reprinted here with permission of the American Society of Clinical Oncology (ASCO). © 2021, ASCO.
Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO or The ASCO Post.
Dr. Mulshine is Professor in the Department of Internal Medicine at Rush Medical College, Chicago. He is also Scientific Director and Vice Chair of the Prevent Cancer Foundation. Dr. Hirsch is Executive Director of the Center for Thoracic Oncology at The Tisch Cancer Institute at Mount Sinai, New York. He is also the Joe Lowe and Louis Price Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Associate Director of the Tisch Cancer Institute.