Vaughan T L, Farrow D C, Hansten P D, Chow W H, Gammon M D, Risch H A, Stanford J L, Schoenberg J B, Mayne S T, Rotterdam H, Dubrow R, Ahsan H, West A B, Blot W J, Fraumeni J F
Fred Hutchinson Cancer Research Center, and Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle 98109, USA.
Cancer Epidemiol Biomarkers Prev. 1998 Sep;7(9):749-56.
Incidence of adenocarcinomas of the esophagus and gastric cardia has risen dramatically over the past 2 decades in the U. S., for reasons that are not yet clear. A number of common medications (e.g., calcium channel blockers, tricyclic antidepressants, and certain asthma medications) promote gastroesophageal reflux by relaxing the lower esophageal sphincter (LES). Reflux is thought to increase cancer risk by promoting cellular proliferation, and by exposing the esophageal epithelium to potentially genotoxic gastric and intestinal contents. Recent studies have suggested that calcium channel blockers may also increase cancer risk by inhibiting apoptosis. Using personal interview data from a multicenter, population-based case-control study conducted between 1993 and 1995 in three areas of the U. S., we evaluated whether the use of LES-relaxing drugs was associated with increased risk of adenocarcinomas of the esophagus and gastric cardia. Cases of esophageal adenocarcinoma (n = 293) and gastric cardia adenocarcinoma (n = 261) were compared with general population controls (n = 695). Information on additional case groups of esophageal squamous cell carcinoma (n = 221) and noncardia gastric cancer (n = 368) were also available for comparison. Overall, 27.4% of controls had used one or more of these drugs for at least 6 months, compared with 30.2% of esophageal adenocarcinoma and 23.8% of gastric cardia adenocarcinoma cases. The adjusted odds ratios (ORs) for ever use were 1.0 [95% confidence interval (CI) = 0.7-1.5] and 0.8 (95% CI = 0.5-1.1), respectively. There was little evidence of increasing risk with increasing duration of use of all LES-relaxing drugs together. We found an increased risk of esophageal adenocarcinoma among persons reporting use of asthma drugs containing theophylline (OR = 2.5; 95% CI = 1.1-5.6) or beta agonists (OR = 1.7; 95% CI = 0.8-3.8). Risks were higher among long-term users (>5 years) of these drugs (OR = 3.1; 95% CI = 0.9-10.3 and OR = 2.3; 95% CI = 0.8-7.0, respectively). In contrast, there was no evidence that the use of calcium channel blockers or other specific groups of drugs increased the risk of any of the cancers studied. These results provide reassuring evidence that the increases in incidence of adenocarcinomas of the esophagus and gastric cardia are not likely to be related to the use of LES-relaxing drugs as a group, or calcium channel blockers in particular, but they do suggest that persons treated for long-standing asthma may be at increased risk of esophageal adenocarcinoma.
过去20年里，美国食管腺癌和贲门腺癌的发病率急剧上升，原因尚不清楚。一些常用药物（如钙通道阻滞剂、三环类抗抑郁药和某些哮喘药物）通过松弛食管下括约肌（LES）促进胃食管反流。反流被认为通过促进细胞增殖以及使食管上皮暴露于可能具有基因毒性的胃和肠内容物而增加癌症风险。最近的研究表明，钙通道阻滞剂还可能通过抑制细胞凋亡增加癌症风险。利用1993年至1995年在美国三个地区进行的一项基于人群的多中心病例对照研究的个人访谈数据，我们评估了使用LES松弛药物是否与食管腺癌和贲门腺癌风险增加有关。将食管腺癌病例（n = 293）和贲门腺癌病例（n = 261）与普通人群对照（n = 695）进行比较。还可获得关于另外两组病例的信息，即食管鳞状细胞癌（n = 221）和非贲门胃癌（n = 368），以供比较。总体而言，27.4%的对照至少使用过一种此类药物达6个月以上，相比之下，食管腺癌病例中有30.2%，贲门腺癌病例中有23.8%。曾经使用过药物的调整后比值比（OR）分别为1.0 [95%置信区间（CI）= 0.7 - 1.5]和0.8（95% CI = 0.5 - 1.1）。几乎没有证据表明同时使用所有LES松弛药物的时间越长风险越高。我们发现，报告使用含茶碱的哮喘药物（OR = 2.5；95% CI = 1.1 - 5.6）或β受体激动剂（OR = 1.7；95% CI = 0.8 - 3.8）的人患食管腺癌的风险增加。这些药物的长期使用者（>5年）风险更高（OR分别为3.1；95% CI = 0.9 - 10.3和OR = 2.3；95% CI = 0.8 - 7.0）。相比之下，没有证据表明使用钙通道阻滞剂或其他特定药物组会增加所研究的任何一种癌症的风险。这些结果提供了令人安心的证据，即食管腺癌和贲门腺癌发病率的增加不太可能与作为一个整体的LES松弛药物的使用有关，特别是与钙通道阻滞剂无关，但它们确实表明，接受长期哮喘治疗的人患食管腺癌的风险可能会增加。
