Sleep disordered breathing is associated with an increased risk of cancer mortality

Sleep disordered breathing (SDB), which is associated with an increased risk of adverse cardiovascular events and psychopathological outcomes, is also associated with an increased risk of cancer mortality, according to a new study.

“Recent in vitro and animal studies have shown that repeated episodes of hypoxia (an inadequate supply of oxygen) are associated with accelerated cancer progression,” said F. Javier Nieto, MD, PhD, chair of the Department of Population Health Sciences at the University of Wisconsin School of Medicine and Public Health. “Our results are the first to suggest that SDB is also associated with an increased risk of cancer mortality in humans.”

The results will be presented at the ATS 2012 International Conference in San Francisco.

The researchers examined 22-year mortality data on 1,522 subjects from the Wisconsin Sleep Cohort, a prospective, community-based study of the predictors and natural history of sleep disorders. SDB was assessed by polysomnography at baseline.

After adjustment for age, sex, body mass index, smoking and other factors, both all-cause and cancer mortality were associated with the presence and severity of SDB in a dose-response fashion. Compared to subjects without SDB, the adjusted relative hazards of cancer mortality were 1.1 for study participants with mild SDB, 2.0 for those with moderate SDB, and 4.8 for those with severe SDB.

The team of University of Wisconsin investigators led by Dr. Nieto conducted this research in collaboration with Ramon Farre, PhD, professor of Physiology at the Unit of Biophysics and Bioengineering at University of Barcelona, Spain. In a separate study which will also be presented at the ATS 2012 conference, Dr. Farre’s group and colleagues at the Hospital Clinic-IDIBAPS in Barcelona follow up on their earlier mouse experimental model showing that the effect of intermittent hypoxia on cancer growth is considerably stronger in lean mice than in obese mice.

Overview of Sleep-Disordered Breathing
Upper airway obstruction occurring during sleep—that is, sleep-disordered breathing (SDB)—was first demonstrated in the 1960s. SDB represents a group of physiopathologic conditions that are characterized by an abnormal respiratory pattern during sleep that can be isolated or can coexist with other respiratory, nervous, cardiovascular, or endocrine diseases. SDB is now known to be widely prevalent in the general population, and it is responsible for or contributes to numerous problems, ranging from fragmented sleep patterns to hypertension to traffic accidents.

SDB includes obstructive sleep apnea (OSA), which consists of breathing cessations of at least 10 seconds occurring in the presence of inspiratory efforts during sleep. Central sleep apnea consists of similar apneas, but these instead take place in the absence of inspiratory efforts.

The obstructive sleep apnea syndrome (OSAS) is a potentially disabling condition characterized by excessive daytime sleepiness, disruptive snoring, repeated episodes of upper airway obstruction during sleep, and nocturnal hypoxemia. It is defined by an apnea-hypopnea index (the total number of episodes of apnea and hypopnea per hour of sleep), or respiratory disturbance index, of 5 or higher in association with excessive daytime somnolence.

Risk factors for sleep apnea include obesity, increased neck circumference, craniofacial abnormalities, hypothyroidism, and acromegaly. Daytime consequences include not only excessive sleepiness but also impaired cognitive performance and disturbed moods with a reduced quality of life. Excessive daytime sleepiness is reported to be associated with a higher risk of motor vehicle accidents and work place injuries or poor work performance .

In general, everyone with SDB snores, but not everyone who snores has SDB. Snoring in the absence of SDB is termed primary or simple snoring. However, some evidence indicates that snoring is one end of a clinical continuum with an opposite extreme of severe OSA. Some health problems may be associated even with primary snoring.

Upper airway resistance syndrome (UARS) is characterized by snoring with increased resistance in the upper airway, resulting in arousals during sleep. This can disturb sleep architecture to the point of causing daytime somnolence. No distinct diagnostic criteria exist for this entity. Patients with UARS can be treated with nasal continuous positive airway pressure (n-CPAP).

Treatment involves elimination of contributing factors and provision of n-CPAP. n-CPAP is effective in improving sleep quality and reducing daytime sleepiness. Long-term treatment with n-CPAP reduces both mortality and the acute blood pressure elevation that occurs with SDB. Over time, a trend develops toward baseline blood pressure reduction in hypertensive patients with SDB. Medical and surgical interventions may also be indicated.

“The consistency of the evidence from the animal experiments and this new epidemiologic evidence in humans is highly compelling,” said Dr. Nieto. “In vitro and animal studies suggest that intermittent hypoxia promotes angiogenesis and tumor growth, which can explain these observations.”

Sleep-Disordered Breathing Is Common but Hard to Detect in Pediatric Patients

According to new research presented on June 5, at the 19th Annual Meeting of the American Academy of Dental Sleep Medicine, an estimated 18 percent of pediatric patients in a University of North Carolina-based study were at risk for sleep-related breathing disorders (SRBD). Importantly, pediatric risk was not associated with any demographic or craniofacial characteristics, as it is in adults, making it difficult to detect.

The study included 100 children between seven and 17 years of age, of which 43 percent were male and 57 percent were female. The group was 73 percent Caucasian, 10 percent Hispanic, nine percent African American, five percent Asian, and two percent American Indian.

Researchers used a previously validated survey, the Pediatric Sleep Questionnaire (PSQ), to estimate the risk of SRBD. Each patient’s parent or guardian completed the PSQ for his or her child. A score of 0.33 suggested risk for SRBD. Results indicated that 18 percent of the participants were at risk for sleep-disordered breathing.

Orthodontic records including information on craniofacial characteristics were obtained for each patient. The researchers looked for an association between risk for SRBD and craniofacial features. They also examined the effect of gender, race, age, and body mass index on SRBD risk. No significant associations were found for either demographic or craniofacial characteristics.

“We were surprised that our findings suggested that the risk for pediatric sleep disordered breathing was as high as it was, since our review of the literature suggested that the prevalence of pediatric obstructive sleep apnea was one to three percent. We speculate that either our sample size was too small, or that additional factors contribute to the condition in children,” said principle investigator Kristen Fritz.

Early diagnosis of pediatric SRBD is critical because signs and symptoms often lead to misdiagnosis of sleep disorders as other clinical conditions such as attention deficit disorder or attention deficit hyperactivity disorder.

“Ours is the first study to show an association between SDB and an elevated risk of cancer mortality in a population-based sample. If the relationship between SDB and cancer mortality is validated in further studies, the diagnosis and treatment of SDB in patients with cancer might be indicated to prolong survival,” Dr. Nieto concluded. “Additional studies are needed to replicate our results and to examine the relationships between SBD, obesity, and cancer mortality.”

“Obstructive Sleep Apnea And Cancer Mortality: Results From The Wisconsin Sleep Cohort Study” (Session A18, Sunday, May 20, 2012: 8:15 a.m., Room 3001-3003, Moscone Center; Abstract 30627)

* Please note that numbers in this release may differ slightly from those in the abstract. Many of these investigations are ongoing; the release represents the most up-to-date data available at press time.

Abstract 30627
Obstructive Sleep Apnea And Cancer Mortality: Results From The Wisconsin Sleep Cohort Study
Type: Scientific Abstract
Category: 16.04 - Sleep Disordered Breathing: Epidemiology, Genetics and Outcomes (SRN)
Authors: F.J. Nieto1, P.E. Peppard1, T. Young1, L. Finn2, K.M. Hla1, R. Farre3; 1University of Wisconsin - Madison, WI/US, 2University of Wisconsin - Madison/US,
3Universitat of Barcelona / - Barcelona/ES; Wisconsin Sleep Cohort Study

Abstract Body

Recent studies in a melanoma mice model have demonstrated that intermittent hypoxia promotes tumor growth. Even though previous data have shown that obstructive sleep apnea (OSA) is associated with total and cardiovascular mortality, the association between OSA and cancer incidence or mortality has not been studied. The goal of the present study was to examine the hypothesis that OSA is associated with increased cancer mortality in a population-based sample.

We used 20-year mortality follow-up data from the Wisconsin Sleep Cohort sample (n=1522). OSA was assessed with full polysomnography at baseline in all participants. The apnea-hypopnea index (AHI) was defined as the mean number of apnea and hypopnea events per hour of sleep, and categorized as normal (AHI <5); mild OSA (AHI 5-14.9); moderate OSA (AHI 15-29.9); and severe OSA (AHI ?30 or use of CPAP). Non-parametric Kaplan-Meier analyses were used to compare cumulative mortality and Cox proportional hazards regression was used to estimate total and cancer mortality adjusted relative hazards associated with OSA severity levels.

Both Kaplan-Meier analyses and Cox regression analyses adjusting for age, sex, body mass index (BMI), and smoking showed that both all-cause and cancer mortality were associated with the presence and severity of OSA in a dose-response fashion.

After excluding persons who had used CPAP treatment (n = 126), the associations were similar. In stratified analyses according to obesity status, the association was stronger among non-obese (BMI<30 kg/m2) than among obese participants (relative hazard comparing severe vs. non-OSA, 6.3 and 3.1, respectively).

Our study suggests that OSA is associated with an increased risk of cancer mortality in humans. These results are consistent with animal studies showing that intermittent hypoxia promotes increased angiogenesis and tumor growth. These results need to be replicated in studies looking at the association between OSA and survival after cancer diagnosis.


Nathaniel Dunford
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American Thoracic Society

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