Are There Sex Differences in the Association of Alcohol Consumption With the Risk of Soft Tissue Sarcoma? A Nationwide Population-based Study in Korea.

Background: In most patients, a soft tissue sarcoma is sporadic and not related to a specific known cause; however, demographic, environmental, and lifestyle factors may be linked to its development. Alcohol consumption, a major risk factor for oncogenesis, has increased, particularly among females, and it might be a risk factor for soft tissue sarcoma, with potential differences in the association based on the biological differences between males and females. Nevertheless, there is a lack of research data to determine the association between alcohol consumption and soft tissue sarcoma. Because soft tissue sarcoma often has poor oncologic and functional outcomes once it develops, identifying controllable factors for prevention would be beneficial.

Questions/purposes: (1) Is there a dose-response association between overall alcohol consumption and the incidence of soft tissue sarcoma? (2) Are there associations between the amount of alcohol consumption per occasion and drinking frequency with the incidence of soft tissue sarcomas?

Methods: This was a retrospective, population-based comparative study using the National Health Insurance Service database, which offers large-scale data from a relatively ethnically homogeneous Korean population, along with comprehensive health information. The database includes demographic, socioeconomic, health checkups, social behavior surveys, and claims data. We screened 4,234,415 people 20 years or older who underwent health checkups in 2009. Soft tissue sarcoma was defined as ICD-10 codes C47 or C49 and the registration code for cancer (V193), with at least two outpatient claims or more than one inpatient claim per year. Among the screened individuals, we excluded 7% (286,384) because of incomplete data, and we excluded 0.02% (198) with soft tissue sarcoma diagnosed before the index year. To better explore the association, we excluded 0.2% (10,088) of patients who died or developed soft tissue sarcoma in the index year. Finally, we included 3,937,745 participants (2,148,348 males and 1,789,397 females) and followed them until December 31, 2020 (mean follow-up 10 ± 1 years). The mean daily alcohol consumption was calculated using the drinking frequency (number of days per week) and the mean amount consumed on each occasion (the number of glasses [8 grams of ethanol per glass]), based on the concept of a standard drink in Korea. Based on the ethanol consumption, alcohol drinking levels were divided into three categories: individuals who did not drink, those who drank < 30 grams per day of ethanol, and those who drank ≥ 30 grams per day of ethanol. The soft tissue sarcoma incidence was calculated by dividing the number of events by the total person-years of follow-up. To address our primary study question, which was about the association of soft tissue sarcoma incidence and overall alcohol consumption, the analysis model was adjusted for age (years), smoking status (nonsmoker, past smoker, and current smoker), regular exercise (yes versus no), and metabolic syndrome (yes versus no). To address our secondary outcome, which was about associations between the amount of alcohol consumption per occasion and drinking frequency with the incidence of soft tissue sarcomas, alcohol consumption was divided into drinking frequency and amount of alcohol intake per occasion. Among the participants, 969 (males n = 550, females n = 419) were diagnosed with soft tissue sarcoma during the follow-up period, resulting in an incidence of 2.43 (males 2.55, females 2.30) per 100,000 person-years. To identify a monotonic dose-response association, we considered not only the statistical significance for individual exposure groups, but also the overall consistent directional trend in association across all groups.

Results: Compared with the individuals who did not drink (reference), alcohol consumption was not associated with an increased incidence of soft tissue sarcoma in overall participants who drank < 30 grams per day and those who drank ≥ 30 grams per day of ethanol (adjusted HR 1.05 [95% confidence interval (CI) 0.9 to 1.22] and adjusted HR 0.92 [95% CI 0.70 to 1.21], respectively; p = 0.58 among three groups) or in males who drank < 30 grams per day and those who drank ≥ 30 grams per day of ethanol (adjusted HR 0.84 [95% CI 0.70 to 1.01] and adjusted HR 0.75 [95% CI 0.56 to 1.00], respectively; p = 0.17 among three groups). In females, compared with individuals who did not drink (reference), soft tissue sarcoma incidence increased in those who drank < 30 grams per day and those who drank ≥ 30 grams per day of ethanol (adjusted HR 1.51 [95% CI 1.20 to 1.9]; p = 0.01 and adjusted HR 2.48 [95% CI 1.17 to 5.27]; p = 0.06, respectively). Although a drinking frequency of 1 to 2 days per week was associated with increased risk of developing a soft tissue sarcoma (adjusted HR 1.61 [95% CI 1.27 to 2.04]; p = 0.003), the HR did not increase with higher drinking frequency across all four groups (adjusted HR 1.21 [95% CI 0.66 to 2.200; p = 0.88 for 3 to 5 days and adjusted HR 1.46 [95% CI 0.47 to 4.56]; p = 0.60 for 6 to 7 days, respectively). However, for females consuming 3 to 4, 5 to 7, and ≥ 14 glasses per occasion, the adjusted HRs were 1.51 (95% CI 1.07 to 2.13; p = 0.09), 1.73 (95% CI 1.16 to 2.58; p = 0.06), and 3.70 (95% CI 1.37 to 9.98; p = 0.03), respectively, and the HR tended to increase with higher consumption levels per occasion across all six groups (adjusted HR 1.30 [95% CI 0.94 to 1.81]; p = 0.09 for 1 to 2 glasses and adjusted HR 1.73 [95% CI 0.81 to 3.68]; p = 0.38 for 8 to 13 glasses).

Conclusion: This nationwide population-based study demonstrated a tendency toward a dose-response relationship between the level of alcohol consumption and the incidence of soft tissue sarcoma among females. These findings suggest that strategies for individuals vulnerable to alcohol-related complications could be considered. These strategies might include campaigns, education programs, and policy interventions; social guidelines to reduce alcohol consumption may be warranted, and alcohol consumption may be considered as a screening factor for soft tissue sarcoma. To clarify whether there is a causal relationship, further research is required on the mechanisms through which alcohol consumption and drinking patterns may contribute to the development of soft tissue sarcoma.

Level of evidence: Level III, prognostic study.