Although cardiovascular mortality and ailments have been associated with sleep -disordered breathing in multiple studies, the connection with cancer mortality is a new subject. As per the team headed by Dr. F. Javior Neito, Dr. Paul E. Peppard, Dr. Terry Young and others on the team at School of Medicine and Public Health, University of Wisconsin- Madison, used the 22-years data on mortality follow-up from the Wisconsin Sleep Cohort sample. This included the assessment of SDB at the baseline that included complete polysomnography.
What is Sleep Disordered Breathing?
Sleep disordered breathing shows episodes of partial or total obstruction in the upper airways during sleep. This is associated with repeated sleep disturbances, snoring, apnea and snoring. The aim of the study was to examine if SDB is related to mortality due to cancer in a large community-based sample.
Sleep-disordered breathing (SDB) was judged utilizing the hypoxemia index (wherein 90% oxygen saturation) and apnea-hypopnea index. Additionally, the mortality in cancer patients was compared across SDB levels, utilizing multivariate and crude analysis. Animals and in-vitro studies shows intermittent hypoxia does have an impact on the growth of cancer tumors.
Measurements And Results
For proper analysis, the case study took into account the sex, age, body mass index and smoking as the key criteria as SDB showed association and impact on the cancer mortality. This was done by the dose-response fashion.
As per the journal study “The occurrence of sleep-disordered breathing among middle-aged adults” published in the Journal of Medicine of N. England (1993), by Dr. T. Young, M. Palta, J Dempsey, and their team, they found that 6% of the US adults suffered with moderate to severe SDB while the impact of obesity has given an impetus to the ailment. SDB continues to afflict more people every year.
Additionally, SDB is associated with plenty of other disorders such as poor quality of life, depression and risk of occupational hazards, hypertension, cardiovascular diseases. Chronic hypoxia is one of the characteristics associated with solid tumor tissue. In 2007, G.O Ahn, M. Brown did a study and wrote a paper – “Targeting tumors with hypoxia-activated cytotoxins” in Front Biosci, which showed an association with sympathetic and profound metabolic system, that is connection with hypoxemic events. The common features are therapeutic resistance, metastatic potential and tumor progression. Most of the in-vitro studies have shown that cultured lung cancer cells, with intermittent hypoxia have higher resistance to apoptosis and radiation. These tumors become prone to metastasis.
Another study showed that utilized mice models for OSA, showed that cancer progression accelerated when there was intermittent hypoxia, as it affected the growth of tumors.
Methods Used in Wisconsin Sleep Cohort
Established in 1988, the Wisconsin Sleep Cohort was a community-based study about history of sleep related disorders and predictors. Of the 2940 people that were invited, which included both women and men, within the age group of 30 to 60 years who were living in Southern Wisconsin. All of the invited people were on state-agencies and ranged from unskilled to professional experts. Only 1,546 people agreed to participate in the study.
Variables in Data
All of the participants that consented to be in the study were put through an 18-channel PSG or polysomnography. This included electrooculography, electroencephalography, and electromyography. The thirty seconds recordings were analyzed by trained professionals using the standard measures for sleep stages, hypopnea and apnea.
As per standard measures, apnea is stopping of oral airflow for a minimum of 10 seconds, while Hypopnea is a reduction in breathing which includes lowering of oxyhemoglobin saturation of 4% or more. AHI or apnea-hypopnea index was assessed on the average number of episodes of hypopnea and apnea in 1 hour of sleep.
As per the analysis done by team headed by Dr. F. Javior Neito, Dr. Paul E. Peppard, Dr. Terry Young and others, there were cut-points namely –
- Normal sleep with AHI score of 5 or lower
- Mild sleep disordered breathing with AHI score of 5 to 14.9
- Moderate sleep disordered breathing with AHI score of 15 to 29.9
- Severe Sleep disordered breathing with AHI score > 30
In the current study, participants that used CPAP devices during the PSG study were categorized in the Severe SDB section. The use of CPAP is an assumption that the participants are in the severe SDB category. To further examine the risk of cancer with oxygen saturation, the team used a set of 1306 participants from which the Hypoxemia Index could be calculated. Using the AHI cut-points, the results showed:
- 73% of people with AHI below 5 episodes/hour (0.8 percentile on Hypoxemia Index)
- 90% of the people with AHI below 15 episodes/hour (3.6 percentile on Hypoxemia Index)
- 97% of the people with AHI below 30 episodes/hour (11.2% percentile on Hypoxemia Index)
Factors for the analysis
All standardizations were followed and tests were performed by trained professionals while considering these parameters:
- Use of alcohol (drinks per week)
- Level of education (less than high school/more)
- Smoking (never, occasionally, currently, heavy smoking)
- Self-assessed general health (excellent, very good, good, fair, poor),
- Level of daytime sleepiness/ drowsiness
- Diabetes, sleep apnea and other medical conditions diagnosed by a doctor
- BMI and circumference of the waist
- Age of the individual
A total of 1, 522 participants gave all the information on the above-mentioned key variables for analysis. 11th November 2011 was considered as the baseline for the study. All cause and cancer deaths/mortality rates were calculated with the 95% confidence intervals. For comparing survival for SDB categories, Kaplan- Meier techniques were used.
Cox regression models were based on age and this was considered as caner risk depends upon age factor. The research team analyzed the data based on AHI, ran hazard models that will predict death due to cancer using Hypoxemia Index in 1, 306 participants for information, as a linear term.
Results of the Study
Of the 1522 participants, 24% or 365 people had mild sleep disordered breathing issues and 4% or 59 people were diagnosed with severe sleep apnea. Those with higher severity of SDB were lower educated, higher BMI, mostly male and had reported poor health and increased daytime drowsiness.
Of the 112 deaths in the study cohort, cancer was the cause of 50 deaths. To be precise, lung cancer, colorectal, ovary and endometrial, brain, breast, bladder, and liver cancer were the leading cause. It was seen that cancer mortality increased with the severity of SDB. When compared to those without any SDB, people with SDB had a much higher risk of mortality with cancer. The Kaplan-Meier analysis suggested that the dose-response lowered the chance of survival that was free of cancer as the SDB increased. The factors that affected the increase of SDB were BMI, sex, smoking and age and all of these factors increased the hazards of mortality.
The hypoxemia index had a deep association with cancer mortality in a dose–response fashion. When used as a continuous variable, an increase in the hypoxemia index was associated with adjusted ratio of mortality with cancer as 1.9. As per the stratified analyses, a dose–response connection of SDB and cancer mortality was seen to be more significantly among people that were not obese as compared with obese participants. Thus, results gave a deeper insight into the connection of sleep disorders and their affect on health and diseases.
Results And Discussion
This is one of few community-based cohort studies that has documented a connection between cancer mortality and sleep disordered breathing over a period of 22 years. There is significant association after adjusting to possible variables including sex, age, BMI, physical activity, sleep duration, waist circumference, and diabetes.
However, there was significant association when SDB was studied with solid cancers and still persisted when the participants on CPAP were not considered during analysis. As cancer patients lose weight before, they die, it improves their breathing and reduces SDB.
However, their observations were consistent with the hypothesis which had evidence from the study on in-vitro animal studies about the strong affect of hypoxia in progression of cancer. When cancer cells were subjected to intermittent/chronic hypoxia, it showed higher resistance to radiation and progression of malignancy was more.
In the European Respiratory Journal, the paper “Intermittent Hypoxia Enhances Cancer Progression In A Mouse Model Of Sleep Apnoea” by Dr. I. Almendros, J.M. Montserrat, J. Ramirez J, M. Torres showed that melanoma injected mice showed that intermittent hypoxia was similar to sleep apnea in human beings and increases the growth of tumors. It is due to the enhanced angiogenesis that is related to hypoxemia of the tissues.
This study was able to prove that cancer mortality had a higher association with SDB using the hypoxemia index than with AHI. Hypoxemia Index is sleep time that has lower than 90% oxygen saturation. Although the study group was limited, the results show that it needs to be probed further and studied in a wider range of age groups. As SBD is associated with obesity, it might be one of the factors that may be factored in for cancer mortality.