From the AGA Journals

Smoking and alcohol raise risk of second cancer in squamous cell carcinoma

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Tobacco and alcohol cessation decrease risk

In this large, prospective, multicenter Japanese study published in the December 2021 issue of Gastro Hep Advances, alcohol and/or smoking cessation for 5 or more years was found to reduce the risk of field cancerization in patients with superficial esophageal squamous cell carcinoma (ESCC). Multiple lesions that are identified by lack of staining of squamous epithelium of the esophagus with Lugol iodine (Lugol-voiding lesion) are known as field cancerization effect. The investigators found that, following endoscopic resection of first primary ESCC (n = 331), alcohol cessation (adjusted hazard-ratio, 0.47; 95% confidence interval, 0.26-0.85) and cigarette smoking cessation (AHR 0.49, 95% CI, 0.26-0.91) reduced the rate of development of second primary ESCC.

Anand Jain, MD, is with the division of digestive diseases at Emory University

Dr. Anand Jain

This study highlights the magnitude of impact that known environmental exposures can have on the development and prognosis in ESCC. The investigators found that heavy drinking was almost 6.6 times, and heavy smoking was 2.1 times, as prevalent in individuals with high-grade esophageal epithelial dysplasia identified on Lugol iodine staining. In a mouse model, they showed that acetaldehyde, an established carcinogen produced during ethanol metabolism, which is also a compound found in cigarette smoke, induces DNA damage in the esophageal epithelium. According to this study, individuals with superficial ESCC and an inactive aldehyde dehydrogenase 2 enzyme are at higher risk for expansion and progression of esophageal dysplastic epithelium. A flushing reaction following ethanol ingestion is a marker of inactive aldehyde dehydrogenase in humans.

The take-home message from this study is that alcohol and tobacco cessation for 5 years can significantly reduce the risk of second primary ESCC. Practitioners should be vigilant in counseling patients, particularly those with Lugol-voiding lesions grades B or C or those who have a flushing reaction.

Anand Jain, MD, is with the division of digestive diseases at Emory University, Atlanta. Ravinder Mittal, MD, is with the division of digestive diseases at University of California, San Diego. They declared having no relevant conflicts of interest.



Field cancerization and subsequent second cancer in squamous cell carcinoma (SCC) patients was significantly associated with cigarette and alcohol use, based on data from more than 300 individuals.

Cigarette and alcohol use are established risk factors for SCCs of the esophagus, head, and neck, Manabu Moto, MD, of Kyoto University and colleagues wrote. “In addition, squamous cell carcinoma and squamous dysplastic epithelium develop multifocally in these organs,” in a phenomenon known as field cancerization, but the interaction of multiple dysplastic epithelium with other factors, notably whether cessation of cigarette and alcohol use would reduce risk of SCC, has not been well studied.

In a study published in Gastro Hep Advances, the researchers identified 331 adults with newly diagnosed superficial esophageal SCC who underwent endoscopic resection, and 1,022 healthy controls. Field cancerization was based on the number of Lugol-voiding lesions (LVLs) per endoscopic view according to three groups: grade A, 0 LVLs; grade B, 1-9; or grade C, at least 10. The primary study outcome was a measure of risk factors for the development of LVLs.

“Multiple LVLs are closely associated with inactive aldehyde dehydrogenase 2 (ALDH2) and field cancerization,” the researchers wrote. Before assessing their human subjects, they used a mouse model to investigate whether alcohol intake and abstinence would affect acetaldehyde-induced DNA damage to the esophageal epithelium among individuals with ALDH2 dysfunction.

The researchers found that DNA damage, measured by acetaldehyde-derived DNA adduct levels (via N2-ethylidene-dG), accumulated with alcohol consumption over time, but decreased with alcohol cessation in the mouse model.

For the human part of the study, participants completed a lifestyle survey at entry, with questions about alcohol consumption history, alcohol flushing response, smoking, consumption of high-temperature foods, and consumption of green and yellow vegetables and fruit. Drinking status was divided into five groups: never/rarely (of less than 1 unit/week), light (1-8.9 units/week), moderate (9-17.9 units/week), heavy (18 or more units/week), and ex-drinker, with 1 unit defined as 22 g of ethanol. Smoking was divided into three groups: never (0 pack-years), light (less than 30 pack-years), and heavy (30 or more pack-years). Patients were given educational materials at study entry about the importance of alcohol and smoking cessation, as well as verbal advice to cease these behaviors.

Participants underwent endoscopic surveillance at 3-month intervals for up to 6 months following endoscopic resection.

Overall, increased alcohol consumption was associated with increased risk in development of LVL across all LVL grades; higher grades of LVLs were positively associated with high-intensity alcohol consumption, smoking, flushing, and high-temperature foods, and negatively associated with eating vegetables and fruit.

The risk of LVL grade progression was most strongly associated with increased alcohol consumption and with reported flushing. “The greatest risk was observed in the patients with flushing reactions who consumed an average of 30 units per week in grade C LVL,” with an odds ratio of 534, compared with healthy controls. “Since flushing reaction is caused by accumulation of acetaldehyde due to ALDH2 deficient, our result also means that acetaldehyde is a strong carcinogen in field cancerization.”

Secondary outcomes included the incidence of second primary esophageal SCC and head/neck SCC; these were significantly more prevalent in patients with grade C LVL (cumulative 5-year incidence of 47.1% for ESCC and 13.3% for head and neck SCC). However, alcohol and smoking cessation significantly reduced the development of second primary esophageal SCC (adjusted hazard ratios, 0.47 for alcohol and 0.49 for smoking).

The study findings were limited by several factors including the lack of randomization to noncessation and cessation groups and the inclusion of cancer patients, but not long-term cancer survivors, the researchers noted.

“We believe that our data will be useful to establish a prevention and surveillance strategy for cancer survivors, because the overall prognosis of esophageal cancer and head and neck cancer is still poor,” with a 5-year survival rate of less than 20%, and the results highlight the need to educate cancer survivors on the value of smoking and alcohol cessation, they added.

The study was supported by the National Cancer Center Research and Development Fund 36 by the Ministry of Health, Labour, and Welfare of Japan. The researchers had no financial conflicts to disclose.

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