Sufferers of obstructive sleep apnea are at increased risk of developing cancer and thrombosis


People who suffer from obstructive sleep apnea (OSA) are at an increased risk of cancer, according to a large study presented on Monday at the European Respiratory Society (ERS) International Congress in Barcelona, Spain.

A second study showed that OSA was also linked to a decline in processing powers in the elderly; in particular, those aged 74 years or more and men showed a steeper decline in certain cognitive tests.

A third study found that patients with more severe OSA were at greater risk of developing blood clots in their veins—a potentially life-threatening condition.

OSA is a common sleep disorder whereby people experience partial or complete obstruction of their airways during sleep and stop breathing several times a night. This can manifest as loud snoring, gasping, choking and daytime sleepiness. It is believed to affect at least 7-13% of the population. People who are overweight or obese, have diabetes, or who smoke or consume large amounts of alcohol are most at risk of OSA.

Dr. Andreas Palm, a researcher and senior consultant at Uppsala University, Sweden, who presented the first study, says that “it is known already that patients with obstructive sleep apnea have an increased risk of cancer but it has not been clear whether or not this is due to the OSA itself or to related risk factors for cancer, such as obesity, cardiometabolic disease and lifestyle factors. Our findings show that oxygen deprivation due to OSA is independently associated with cancer.”

Dr. Palm and colleagues looked at data from 62,811 patients five years prior to the start of treatment for OSA in Sweden. Between July 2010 and March 2018, patients were treated with continuous positive airway pressure (CPAP), which provides a positive pressure of air through a mask to keep the airways open during sleep.

The researchers linked these data with data from the Swedish National Cancer Registry and socio-economic data from Statistics Sweden.

The researchers took account of factors that could affect the results such as body size, other health problems and socio-economic status. They matched 2,093 patients with OSA and a diagnosis of cancer up to five years before OSA diagnosis with a control group of 2,093 patients with OSA but no cancer.

They measured the severity of OSA with the apnea hypopnea index (AHI), which measures the number of breathing disturbances during sleep, or the oxygen desaturation index (ODI), which measures how many times an hour levels of oxygen in the blood fall by at least 3% for ten seconds or longer.

“We found that patients with cancer had slightly more severe OSA, as measured by an apnea hypopnea index average of 32 versus 30, and an oxygen desaturation index of 28 versus 26,” he said. “In further analysis of subgroups, ODI was higher in patients with lung cancer (38 versus 27) prostate cancer (28 versus 24) and malignant melanoma (32 versus 25).”

“The findings in this study highlight the need to consider untreated sleep apnea as a risk factor for cancer and for doctors to be aware of the possibility of cancer when treating patients with OSA. However, extending screening for cancer to all OSA patients is not justified or recommended by our study results.”

The study only looked at data from one point in time and it cannot show that OSA causes cancer, only that it is associated with it. Some important lifestyle factors such as physical activity and food preferences were not captured on an individual basis in the study. The main strength of the study is its large size and the high quality of data on cancer diagnosis and OSA.

In the future, Dr. Palm and his colleagues plan to increase the number of patients and to follow the patients over time to study the potential influences of CPAP treatment on cancer incidence and survival.

“The association between OSA and cancer is less well established than the link with diseases of the heart and blood vessels, insulin resistance, diabetes and fatty liver disease,” he said. “Therefore, more research is needed, and we hope our study will encourage other researchers to research this important topic.”

In a second presentation, Professor Raphaël Heinzer, director of the Centre for Investigation and Research on Sleep (CIRS) at Lausanne University, Switzerland, told the congress that the study conducted by his colleague Dr. Nicola Marchi showed that OSA was linked to a greater decline in mental processing powers over a period of five years.

Professor Heinzer, Dr. Nicola Marchi, of Lausanne University Hospital, and colleagues studied people aged 65 years and over from the general population of Lausanne who were recruited to the CoLaus/PsyCoLaus and HypnoLaus studies between 2003 and 2008, and who were followed up every five years.

A total of 358 participants took a sleep test to examine the presence and severity of OSA when they joined the studies. During the first follow-up between 2009 and 2013, their mental processing abilities were also tested and another cognitive assessment took place during the second follow-up five years later.

The cognitive tests assessed global cognitive function (knowledge and reasoning skills), processing speed (time taken to understand and react to information), executive function (ability to organize thoughts and activities, prioritize tasks and make decisions), verbal memory, language and visual perception of spatial relationships between objects (visuospatial function).

Speaking before the congress, Dr. Marchi says that they “found that OSA and, in particular, low oxygen levels during sleep due to OSA, was associated with a greater decline in global cognitive function, processing speed, executive function and verbal memory. We also found that people aged 74 and older and men were at higher risk of cognitive decline related to sleep apnea in some specific cognitive tests.”

For example, the Stroop test, which measures processing speed and executive function, showed a steeper decline in people aged 74 and older compared to younger participants, and the verbal fluency test showed a steeper decline in men only but not in women.

“This study demonstrates that the severity of sleep apnea and night-time oxygen deprivation contribute to cognitive decline in old age. It also shows that sleep apnea is related to a decline in specific cognitive functions, such as processing speed, executive function and verbal memory, but not to a decline in all cognitive functions; for instance, language and visuospatial function were not affected,” said Dr. Marchi.

“People with OSA and doctors should be aware that OSA may play a role in cognitive decline. However, to date, OSA treatment with continuous positive airway pressure (CPAP) has not been clearly demonstrated to prevent cognitive decline.

“Our study suggests that probably not all OSA patients have the same risk of cognitive decline; there is probably a subgroup of patients, particularly those with greater nocturnal oxygen deprivation but also older patients and men, who could be at greater risk of OSA-related cognitive decline,” he said.

The researchers plan to analyze data on the impact of OSA after ten years to find out more about who is at most risk of cognitive decline related to OSA. Dr. Marchi suggests that performing a randomized controlled trial with these patients in order to investigate the effect of CPAP on cognition should be the next step after that.

Strengths of the study include that it followed people over a five-year period, assessment of OSA was performed with the “gold standard” polysomnography test, and that several tests were used to evaluate a range of cognitive processes. Limitations include that the participants were relatively healthy, without severe cognitive impairment or dementia and that OSA was assessed only at the beginning of the study.

A third study, presented by Professor Wojciech Trzepizur, from Angers University Hospital, France, showed that patients with more severe OSA, as measured by AHI and markers of nocturnal oxygen deprivation, were more likely to develop venous thromboembolism (VTE). Out of 7,355 patients followed over more than six years, 104 developed VTEs.

“This is the first study to investigate the association between obstructive sleep apnea and the incidence of unprovoked venous thromboembolisms. We found that those who spent more than 6% of their night-time with levels of oxygen in their blood below 90% of normal had an almost two-fold risk of developing VTEs as compared to patients without oxygen deprivation,” said Professor Trzepizur.

“Further studies are required to see whether adequate treatment for OSA, for instance with CPAP treatment, might reduce the risk of VTEs in patients with marked nocturnal oxygen deprivation.”

Professor Winfried Randerath,of the Bethanien Hospital at the University of Cologne, Germany, is head of the ERS specialist group on sleep disordered breathing and was not involved in the three studies. He commented that “these three studies show worrying associations between obstructive sleep apnea and important diseases that affect survival and quality of life. The data support the relevance of sleep apnea on cancer, venous thromboembolisms and mental health.

“While they cannot prove that OSA causes any of these health problems, people should be made aware of these links and should try to make lifestyle changes in order to reduce their risk of OSA, for instance, by maintaining a healthy weight. However, if OSA is suspected, definite diagnosis and treatment should be initiated.

“We look forward to further research that may help to clarify whether OSA may be causing some of the health problems seen in these studies.”

In recent years, there has been reported that OSA played a negative role in cancer incidence. And the high prevalence of OSA epidemiologically linked to the increasing of cancer worldwide. Herein, we performed this study to further explore the overall incidence of cancer and OSA in the corresponding population, and provide some evidence on the association between the two entities. In this up-to-date meta-analysis, we found that more than half of the cancer patients also developed OSA. Additionally, OSA patients are 1.53 times more likely to suffer from cancer when compared to non-OSA patients.

Intermittent hypoxia and sleep fragmentation are highly prevalent conditions and hallmarks of sleep apnea, which have been proposed as the main causes of most of the commodities associated with OSA.[31] It has been demonstrated that intermittent hypoxia can stimulate the production of reactive oxygen species (ROS), which led to oxidative stress and systemic inflammation.[32] Increased activity of the hypoxia-inducible factor-1 (HIF-1) and reduction in antioxidant promoted by intermittent hypoxia could accelerate ROS production, thus contributing to oxidative stress.[6] Increased activity of HIF-1 also contributed to tumor growth by increasing expression of vascular endothelial growth factor (VEGF) and angiogenesis. In the meanwhile, Hakim and colleagues illustrated that sleep fragmentation can accelerate tumor growth and progression through tumor-associated macrophages recruitment and proinflammatory TLR4 signaling pathways in animal models.[33] From the perspective of tumor biology, hypoxia is a frequent phenomenon in solid tumor, and it enhanced the malignant properties in proliferation, invasion, metastasis and angiogenesis of cancer, however, the mechanisms varies from different tumors.[34] Hence, we inferred that OSA could not only increase the incidence of cancer in population, but also enhanced malignancy of cancer. Katarzyna et al investigated the association between telomere length (TL) and risk of cancer in OSA patients. In this study, the authors digged a considerable effect size of TL on the risk of cancer. Moderate-to-severe OSA individuals, who had longer telomeres on average, showed a higher risk of cancer than non-OSA individuals. On the other hand, longer telomeres kept a sustained capacity of cell proliferation to increase the possibility of attaining a critical number of genetic mutations. It speculated that the combination of OSA-mediated telomere elongation and a higher rate of genetic mutation accumulation may represent a survival advantage of precancerous cells, and thus predispose OSA patients to a higher risk of cancer.

Clinical studies did not achieve a unified consensus on the relationship between OSA and the incidence of tumors from earlier literatures.[35] The first clinical cohort investigation on OSA and cancer incidence was performed in Spanish by Campos-Rodriguez et al.[15] A total of 4910 patients from seven teaching hospitals were included and followed up for an average of 4.5 years. Percent nighttime with oxygen saturation < 90% (Tsat90) and AHI were used to evaluate the severity of OSA. The result showed the cancer incidence in Tsat90 > 12% was 2.33 times higher than Tsat90 < 1.2% category. In stratified analyses, together with Tsat90, AHI was associated with cancer incidence in patients younger than 65 years. In the same year, a prospective study from Copenhagen was published by Christensen et al, however, no clear association was observed between the incidence of cancer and the presence of symptoms related to sleep-disordered breathing.[36] This negative result may be attributed to the inclusion of patients who were not diagnosed by polysomnography, but by questionnaires, which led to some non-OSA patients being calculated in this study. For further examine the higher prevalence of OSA among patients with solid tumors, a longitudinal nationwide-based cohort study base on more than 5.6 million individuals was reported. Sleep apnea appeared to increase the risk for only certain types of solid malignancies, including pancreatic and kidney cancer and melanoma, nevertheless, it did not increase the risk of colorectal, breast, and prostate cancers.[30] There was also evidence that the severity of OSA was linked to the aggressiveness of breast cancer and melanoma.[14,27] Because different tumor types have different biological behaviors, heterogeneity still existed in the current published data.

In this study, we found OSA is significantly related to the rising incidence of tumors, and subgroup analysis for severity of OSA disclosed that the incidence of cancers did not linearly increase according to the severity of OSA defined by AHI, from a group to group aspect, moderate to severe group presented a higher incidence than mild group, and severe group was higher than moderate group. Nevertheless, if we only analyzed the studies grouped by mild, moderate, and severe, mild OSA group has the lowest risk rate of 38 (95%CI, 36–41)% for cancer, moderate for 44 (95%CI, 40–48)%, severe for 49 (95%CI, 44–54)% (see Fig. S6, Supplemental Digital Content). This inconsistent may be caused by the different grouping comparison methods of the original literature. However, the high-risk cancer in OSA still not proved OSA directly participant the carcinogenesis, even growing evidences had demonstrated the pathophysiological of OSA related to immune response and biological pathways of cancers. To explore the causality of cancer and OSA, a genome-wide association study (GWAS) was reported in breast cancer to determine the causal effect of risk of OSA on breast cancer.[20] The authors conducted a two-sample study, one from real-world research, another from the Breast Cancer Association Consortium (BCAC), and provided the evidence that rs11588454 and rs11897825 were associated with increased risk of breast cancer. Then, the Mendelian randomization analyses found evidence of a detrimental causal effect of OSA on breast cancer risk was similar to the results of the real-world study. In lung cancer, OSA has also been confirmed to have a higher incidence than healthy control. In addition, the stage of lung cancer in OSA was more advanced, and the mortality, recurrence rate, and metastasis rate increased compared to healthy control in a 1-year follow-up.[24] Besides tumors located in the chest region, OSA also linked to the aggressiveness of cutaneous malignancy. By screening 443 patients who diagnosed with melanoma, 65% of OSA patients were sorted out by respiratory polygraphy, and results found intermittent nighttime oxyhemoglobin desaturation (DI4%) and AHI were independently associated with greater aggressiveness of cutaneous melanoma by detecting some clinical markers.[27]

In sensitivity analysis, we found that the two included studies had some influence on the prevalence of cancer in OSA individuals. Jara et al’s study was a retrospective matched cohort study on all veterans diagnosed with OSA from October 1992 to September 2013. The result showed a nearly 2-fold higher hazard of developing any tumor in OSA compared to non-OSA individuals.[10] Such high ratio might related to certain reasons: the subjects included in the study are veterans, rather than the regular community population. As it mentioned in the original text, “the diagnosis of OSA could get disability benefits since 2004, which provided veterans with a financial incentive to receive an OSA diagnosis.”[10] This may be the cause of OSA overdiagnosis in this study. A nationwide population survey based health insurance database conducted by Gozal et al identified that OSA only increased the risk of a very selective number of cancers.[21] Individuals with OSA only increased the risk of pancreatic and kidney cancer and melanoma by adjusted data. The prevalence of cancers in OSA patients reached 1.37 (95%CI, 0.91–20.7) times higher than non-OSA individuals. However, the national insurance data used in this epidemiological survey ignored the uninsured people, who happen to be low-income and relatively poor people. These people lack primary health services and are at higher risk of cancerous diseases. Therefore, the prevalence of tumors with OSA obtained in this study was slightly lower (Supplemental Figure 4).

Some limitations still existed in this meta-analysis. Firstly, in this meta-analysis, there were still two studies diagnosed OSA by questionnaires, which will overdiagnose some healthy individuals, thus, strengthen the association between OSA and cancer. Secondly, in the studies of colorectal cancer, only Chen et al’s study included malignant neoplasm. And in Lee et al’s study, carcinoma in situ and intramucosal carcinoma were included for incidence statistics of colorectal neoplasia, meanwhile, Thompson et al’s study screened colorectal adenoma by colonoscopy. These abnormal growths of glandular tissue in the gastrointestinal tract mentioned above could all attributed to precancerous lesions and included the two studies that might increase the incidence of cancer in this meta-analysis. Thirdly, besides some large epidemiologic studies, a part of the published studies included in our study has a small sample size, which may skew the results. Fourth, not all the studies included for calculating cancer incidence in OSA when compared to the control group were adjusted by age, gender, obesity, smoking, or alcohol intake. This inter-study heterogeneity might have some influence on our results. Lastly, publication bias existed in our study, because only published literatures in English were included.

In this study, despite these limitations, we deliberately focused on relationships between cancer and OSA, and currently available data suggested individuals with OSA were more likely to develop tumors, and the incidence was related to the severity of OSA. In the meantime, there was a high prevalence of OSA in cancer patients. Whether OSA potentially promoted the tumor malignancy, and how did it increase tumorigenesis or progression, need further studies to delineate.

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Original Research: The findings will be presented at European Respiratory Society (ERS) International Congress



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