Intermittent Hypoxia May Signal Lung Cancer Recurrence and Mortality

Could undiagnosed obstructive sleep apnea (OSA) impact lung cancer outcomes? In this interview, Timothy I. Morgenthaler, MD, Center for Sleep Medicine, Mayo Clinic, discusses new findings linking intermittent hypoxia to higher recurrence and mortality in early-stage non–small cell lung cancer (NSCLC). Learn how oxygen desaturation index (ODI) may serve as a practical risk marker, why routine OSA screening could improve outcomes, and what future studies may reveal about treating sleep-disordered breathing in oncology patients.

Interested readers can find the full study, "Lung cancer reoccurrence and mortality is accelerated with episodic hypoxemia," published in Respiratory Medicine, here.

Read the Transcript

Timothy I. Morgenthaler, MD: Hello, I'm Dr Tim Morgenthaler. I'm a professor of medicine at Mayo Clinic in Rochester, Minnesota. I work in the Center for Sleep Disorders, and I'm a sleep medicine specialist, a pulmonologist, and in the past, a critical care medicine specialist as well.

Pulmonology Learning Network (PLM): What prompt you to investigate intermittent hypoxia as a predictor of early recurrence and mortality in surgically treated stage I-II non-small cell lung cancer (NSCLC)? Were there specific biologic or clinical signal that led you to focus on oxygen desaturation index (ODI) rather than markers of nocturnal hypoxemia?

Dr Morgenthaler: Well, so first of all, ideally, for this question, I think we would have conducted a large prospective study directly evaluating an association between obstructive sleep apnea, which is known to cause intermittent hypoxemia and lung cancer outcomes. I've been interested in how obstructive sleep apnea affects a wide variety of outcomes. For lung cancer or cancer in general, as a natural candidate, there are articles that have been published already about these associations. So, like I said, we would have liked to have done a large prospective study, but we really didn't have access to a comprehensive database of sleep studies or the funding needed for such a trial.

What we did have at Mayo Clinic was a very rich resource of thousands of overnight oximetry studies that have been performed over the recent years as really sort of part of routine clinical care. Oftentimes clinicians here will order overnight oximetry to screen for significant obstructive sleep apnea. So, you know, we realized as we thought about this project—and when I say we, it was a sleep fellow who brought this up as a potential project—we realized that many patients who underwent curative surgery for early stage non-small cell lung cancer were likely to have had overnight oximetries as part of their preoperative or general medical evaluations. So, we thought this was kind of a unique opportunity for a retrospective study to just see if exposure to those high frequencies of intermittent hypoxemia, which is a fair surrogate for obstructive sleep apnea, ended up being associated with cancer recurrence or mortality.

So, we leveraged the data that we had to answer what we thought was an important clinical question or at least see if there was a signal there that we should pursue further. We thought that might be a good first step.

Why did we focus on the oxygen desaturation index? Well, the ODI is a practical and validated measure for intermittent hypoxia, obviously, but it's closely linked to the severity of obstructive sleep apnea. It's not a perfect test, but it's not a bad surrogate to tell you if somebody has an ODI that's, you know, greater than 15, you very likely have some degree of obstructive sleep apnea. So, we chose to focus on that because it was easily obtained from the overnight oximetry that we had. It's commonly used in clinical practice, and it's not infrequently used as a screening tool for significant obstructive sleep apnea. But the other important reason is that we did think that sleep apnea might play a key role in lung cancer outcomes. And if that were true, like everywhere else in medicine, obstructive sleep apnea often is undiagnosed. In contrast, it's quite rare for patients with lung cancer who are going to undergo treatment to have nothing known about their oxygen status or sustained hypoxemia, because they’re typically quite thoroughly evaluated for their lung and cardiac function. So, we though that by focusing on that ODI, which we had available, that we’d be able to use that as a marker that would reflect not only intermittent hypoxia, but maybe be a fair surrogate for undiagnosed obstructive sleep apnea.

PLM: You found a more than 6-fold higher risk of recurrence or death among patients with ODI greater than or equal to 15. What mechanisms might explain this strong association between intermittent hypoxia and tumor biology or the tumor microenvironment?

Dr Morgenthaler: Honestly, the association of intermittent hypoxemia with cancer risk was brought to my attention by a very bright Mayo Clinic sleep medicine fellow, the first author on our paper, Dr Fernando Figuero, who's now on staff at Vanderbilt. He brought this to my attention as we were thinking about what project we might want to work on together. It turns out that intermittent hypoxia triggers cycles of this low oxygen and reoxygenation that end up driving inflammation, oxidative stress, activation of pathways like hypoxia-inducible factor 1 (HIF-1). This is not my area of expertise, I've just read about it, but there are animal studies that show intermittent hypoxia can make cancer cells more aggressive, help them evade the immune system. The literature as regards humans and cancer risk is a bit more complex, but in general, it does appear that there's a fairly strong association. So, we thought we would investigate that.

As you pointed out in the question, the risk ratio of 6 really was quite stronger of a signal than we anticipated. I think that strong association probably reflects those biological effects of the tumor microenvironment influenced by cyclic hypoxemia. But it probably could also just represent some increased general health risks associated with obstructive sleep apnea, but that's speculation on my part.

PLM: You note that intermittent hypoxia often reflects undiagnosed or undertreated OSA. Based on your data, should routine OSA screening be considered before lung cancer surgery—even in the absence of classic sleep-disordered breathing symptoms?

Dr Morgenthaler: I don't want to overextend our findings. They were related to episodic hypoxemia, and overnight oximetry would be needed to actually detect that because it's the only tool that we have that measures that. But I think our findings do suggest that routine screening for obstructive sleep apnea, either using overnight oximetry or maybe just more classic screening tools for obstructive sleep apnea would be a good idea. Intermittent hypoxia is common in patients with obstructive sleep apnea—I think our listeners all know that—and sleep apnea often goes undetected, and yet it may have a real impact on cancer outcomes. In our study it was quite remarkable how many patients had significant elevations of oxygen desaturation index and were not diagnosed prior to the oximetry, or sometimes even after the oximetry, formally diagnosed with obstructive sleep apnea, meaning that it's a risk factor that I think often goes undetected.

So, I guess since sleep apnea is common, it's treatable, it's frequently undiagnosed, I think at the minimum, patients who are going to undergo further evaluation for their cancers should be screened for obstructive sleep apnea. If that means overnight oximetry, that might be a good idea. I do note that, quite apart from our findings, obstructive sleep apnea has been found to be quite common amongst cancer patients and survivors, and it's associated with reduced quality of life in that patient population, increased symptom burden, worse cancer outcomes, and that the National Comprehensive Cancer Network does recommend routine screening for sleep disorders and treatment of obstructive sleep apnea, primarily with CPAP, but I think that may just be because that's the most common well-established treatment. But they recommend that because it improves sleep quality. It proves related symptoms in this population. I think there are some studies, perhaps ours being one, that suggests that untreated sleep apnea may not be good for your cancer recurrence or your survival.

PLM: If OSA treatment could potentially modify risk, what kind of interventional studies do you believe are most urgently needed to test whether CPAP or other therapies can reduce recurrence?

Dr Morgenthaler: I think the first most important thing to do would be to replicate the findings from our study in a larger, preferably multi-center study, to confirm that that association between intermittent hypoxia and cancer recurrence is real, significant, and consistent across different populations and clinical settings. I think a study like that could be done perhaps in something like the Mayo Clinic platform, which is now a very large database of de-identified patient information of 20 million patients or so.  I think a study like that would be very important to do first because, if confirmed and if the signal is that strong, it almost calls out for a prospective randomized trial to test whether diagnosing and treating obstructive sleep apnea can actually reduce the risk of recurrence and improve survival after lung cancer surgery. That would be kind of a low-hanging fruit because we know how to diagnose sleep apnea and we know how to treat it. So boy, if we could make that kind of difference in patients' lives, we should be doing that. But, you know, that is an expensive study to do and requires a lot of work. So, I think maybe doing the larger retrospective study would be a good first step.

PLM: For practicing pulmonologists and thoracic surgeons, what is your main take-home message?

Dr Morgenthaler: Well, I think the main message—not to overextend—is intermittent hypoxia I think is a powerful independent predictive of early recurrence and mortality and surgically treated non-small cell lung cancer. It probably represents untreated sleep apnea that was prevalent and present even prior to the patient's cancer evaluation. Incorporating something like overnight oximetry or sleep screening really could make a big difference to patients' quality of life and their outcomes. So given how common and treatable OSA is, I think this is a practical step that we could really make even before all the studies are out, and it would probably make a big difference in patients’ lives.

Timothy I. Morgenthaler, MD,  is a Professor of Medicine in the Division of Pulmonary, Critical Care, and Sleep Medicine at Mayo Clinic. He holds degrees from the Massachusetts Institute of Technology and Dartmouth College.  After serving in the US Navy as a Diving Medical Officer, training at Mayo Clinic, and working in private practice, he joined the staff at Mayo Clinic in 2000 in the Division of Pulmonary and Critical Care Medicine. He served as the Director of the Center for Sleep Medicine at Mayo Clinic from 2016 to 2024. He is a past President of the American Academy of Sleep Medicine and has received the Academy’s Nathaniel Kleitman Distinguished Service Award for contributions to the field of sleep medicine. Dr Morgenthaler also has held roles in healthcare quality leadership, including Associate Chair for Quality in the Department of Medicine, Mayo Clinic Chief Patient Safety Officer, and he is currently serving as Vice-Chair for Quality at Mayo Clinic with a focus on Global Quality Consulting.

© 2025 HMP Global. All Rights Reserved.

Any views and opinions expressed above are those of the author(s) and do not necessarily reflect the views, policy, or position of the Psych Congress Network or HMP Global, their employees, and affiliates.