Use of Melatonin Is Associated With Lower Risk of Colorectal Cancer in Older Adults

Globally, colorectal cancer (CRC) remains the third most diagnosed cancer and the second leading cause of death through cancer. According to statistics from the International Agency for Research on Cancer, there were approximately 1.8 million new CRC cases and 900,000 deaths in 2018, accounting for about one-tenth of cancer cases and deaths. The incidence and mortality of CRC increase rapidly after age 50 years, leading to an increasing global burden in the foreseeable future because of population aging. Considering the relatively high risk of developing CRC in older adults, effective preventive strategies are highly needed among older adults. Chemoprevention, using medications to block the pathogenetic pathways of disease, has become an attractive strategy for cancer prevention. Over recent decades, several non-anti-cancer medications were found to have potential benefits regarding CRC prevention. Low-dose aspirin was recommended by the US Preventive Services Task Force for the primary prevention of CRC. However, the positive net benefit was obvious only in adults aged 50–59 years, whereas the harms (gastrointestinal bleeding as an example) may exceed the benefits for the older adults. Therefore, effective and safe chemoprevention is critical for reducing the incidence rate of CRC in older adults.

Melatonin is a natural indolic compound mainly secreted by the pineal gland of humans and mammals, which regulates the circadian rhythm. Clinically, melatonin is used orally for the short-term treatment of insomnia, such as jet lag or during shift work. Because circadian rhythm disruption was found to be a contributing factor in cancer development, melatonin has attracted great attention in cancer prevention and adjuvant cancer treatment. Besides the important role in regulating the circadian rhythms, melatonin is also acknowledged for its antioxidant, anti-inflammatory, immune-modulating, and oncostatic activities. Several epidemiological studies support a protective role of melatonin in breast, prostate, and ovarian cancers, yet other studies yielded controversial conclusions. However, population-based evidence for the association of melatonin with CRC remains lacking. Furthermore, previous epidemiologic studies mainly concerned body melatonin levels, such as urinary melatonin exertion or serum melatonin levels; none focused on its chemopreventive effect as oral medication.

Therefore, the objective of this study was to investigate whether the use of melatonin was associated with a reduced CRC incidence in the elder Swedish population (age 50+ years). Scientists hypothesized that melatonin might have a protective effect regarding the development of CRC.

This retrospective nationwide cohort study was approved on February 6, 2013, by the Ethics Committee at Lund University (Dnr 2012/795), Sweden. They used information on individuals from Swedish population-based registers with national coverage. These registers were linked using each persons unique identification number replaced by a serial number to preserve confidentiality.

They further linked these individuals to the Swedish Cancer Registry to identify patients who had been diagnosed with CRC from July 1, 2007, through December 31, 2016, by using the International Classification of Diseases, Tenth Revision, Clinical Modification codes C18, C19, and C20. The Swedish Cancer Registry contains data on the TNM staging system, including the size of the tumor (T), nodal status (N), and presence of metastatic disease (M). By combining the T, N, and M categories, we can determine the stage at diagnosis of CRC, ranging from stage I (the least advanced) to stage IV (the most advanced) as follows: stage I (T1 or T2, N0, and M0), stage II (T3 or T4, N0, and M0), stage III (any T, N1 or N2, and M0), and stage IV (any M1). By further linking to the Cause of Death Register, we could identify individuals who had died during the follow-up period.

The follow-up was started on the date of the first prescription of melatonin for melatonin users or the index date for their comparisons (the same date as the corresponding melatonin user), ended at the first date of diagnosis of cancer, date of death from any cause, and the end of the study period (December 31, 2016), whichever came first.

The incidence rate of CRC was 10.40 per 10,000 person-years for melatonin users, whereas the rate was 12.82 per 10,000 person-years in the nonusers. They found a significant negative association between melatonin use and risk of CRC (adjusted hazard ratio, 0.82; 95% confidence interval, 0.72–0.92). A test for trend showed a significant dose-response correlation (P < 0.001). The decrease of CRC risk was independent of tumor location and stage at diagnosis. When stratified by age groups, the inverse association was significant only among individuals aged 60 years and older.

 

Sherry