Li WQ, Zhang JY, Ma JL, et al. Effects of Helicobacter pylori treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: Follow-up of a randomized intervention trial. BMJ. 2019;366:l5016
Blinded, randomized, factorial, placebo-controlled trial (Shandong Intervention Trial)
To determine whether eradication of H pylori and/or garlic and/or vitamin (vitamin C, vitamin E, and selenium) supplementation affect gastric cancer incidence or mortality over a period of just over 2 decades (22.3 years)
The participants are those in the Shandong Intervention Trial. In 1994, 3,599 people volunteered for the trial, including undergoing gastroscopy with biopsies and providing blood samples for H pylori testing. All participants were from 13 villages in Linqu, China, a region with a high incidence of gastric cancer. After all exclusionary criteria were applied, a total of 3,365 participants (aged 35-64) were tracked and assessed.
Of the total 3,365 participants, 2,258 were seropositive for IgG antibodies toward H pylori and 1,107 were not. Each group received either sham treatment for H pylori or proper H pylori eradication treatment as well as a 2 x 2 assignment to vitamin and garlic supplement arms. The details of the groups are as follows:
- From September 15, 1995, to November 29, 1995, the seropositive group (n=2,258) received 1 g amoxicillin and 20 mg omeprazole (n=1,130) or a placebo equivalent (n=1,128) twice daily for 2 weeks. During this time, those who were seronegative (n=1,107) received a placebo to maintain the masking of all participants.
- From January to March 1996, 13C urea breath tests showed that 382 participants were still seropositive, and these participants received an additional 2-week treatment of amoxicillin and omeprazole. To maintain masking of participants, 383 participants were matched for sex, village, and age and given a placebo treatment.
- From November 30, 1995, to March 31, 2003, all participants (n=3,365) were randomized to receive either a vitamin capsule (n=1,677) or an identical-appearing placebo (n=1,688) twice daily. Each capsule of vitamin supplement contained 250 mg vitamin C, 100 IU vitamin E, and 37.5 µg of selenium.
- From November 30, 1995, to March 31, 2003, all participants (n=3,365) were randomly assigned to take 1 capsule twice daily of garlic supplementation or placebo. The garlic supplement (brand used: Waukanuga) contained 200 mg of aged garlic extract and 1 mg steam-distilled garlic oil per capsule. Placebo bottles contained minute quantities of garlic oil to mask assignment.
Compliance of patients was considered to be excellent, with tracking of supplement intake done through pill counts at monthly visits for 7.3 years of supplementation. All supplements and placebos concluded on March 31, 2003. Records of gastric cancer incidence, as well as causes of death for the study participants, continued throughout the 22.3-year follow-up period, ending on December 1, 2017.
The primary outcome measure was the incidence and mortality of gastric cancer over the course of the study (22.3 years). The authors surmised incidence from scheduled gastroscopies and active clinical follow-up. They ascertained gastric cancer–related mortality from official records, including death certificates and hospital records.
Secondary outcome measures included other causes of death, including other cancers and cardiovascular disease.
Primary outcome: From 1995 to 2017, there were 151 incident cases of gastric cancer and 94 deaths due to the disease.
All 3 interventions were associated with a significant reduction in gastric cancer mortality. Adjusted hazard ratios were 0.62 (95% CI; 0.39-0.99) for H pylori eradication, 0.48 (0.31-0.75) for vitamin supplementation, and 0.66 (0.43-1.00) for garlic supplementation.
At this analysis, 22.3 years post-randomization of participants, H pylori eradication led to reduced incidence, vitamin supplementation led to reduced incidence, and garlic supplementation did not reach any statistical significance regarding gastric cancer incidence.
Regarding the secondary outcomes, there were no measurable effects between any of the interventions and other cancers or cardiovascular disease in this study.
Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, following only lung and colorectal cancers.1 Around the world, incidence varies greatly by culture and region, with the highest incidence rates in Eastern and Central Asia and Latin America. In North America, incidence is relatively low, at 5.6/100,000 of the poplulation.1 Given the genetic predisposition of gastric cancer, higher clinical suspicion is warranted in those with gastric complaints who are of Asian or Latin descent.2
The overall incidence of gastric cancer has been declining, even before the introduction of H pylori eradication. Specifically, non-cardia gastric cancer, which involves the lower portion of the stomach, has been declining. This is thought to be attributable to changes in sanitation, food preservation techniques, and better availability of fresh fruits and vegetables.3 Most recently eradication of H pylori, which is associated with atrophic gastritis and higher risk of gastric cancer, has led to the further declines in the incidence of non-cardia gastric cancer.
At the same time that non-cardia gastric cancer incidence has been falling, cardia gastric cancer, which is similar to esophageal cancer, has increased sevenfold. The reasons for this are unclear, but central obesity, with ensuing hiatal hernia and reflux, are implicated.4 In addition, cardia gastric cancer is often not H pylori–related.
The Shandong Intervention Trial began in 1994 and has been an ongoing study with several time points of follow-up to assess temporal effects of the interventions.5 This trial is also a seminal study within oncology, showing for the first time that eradiation of H pylori infection lowers the incidence of gastric cancer.6,7 The eradication of H pylori is now an accepted strategy for lowering the risk of gastric cancer worldwide.8 Ongoing studies continue to determine the best ways to create community-wide programs to lower incident gastric cancer through H pylori eradication.9,10
Two earlier time points used for data analysis of the Shandong trial included 7.3 years post-randomization and 14.7 years post randomization. The current study took place 22.3 years after randomization. The data from all of these have created a temporal perspective of the interventions used in the trial. A central finding of this study is confirmation that eradication of H pylori with a treatment lasting only 2-4 weeks significantly lowers both the incidence and mortality of gastric cancer over the ensuing 20-plus years.
Vitamin supplementation trended toward lower gastric cancer incidence and mortality, but did not reach statistically significant lowering of incidence and mortality until 22.3 years. Garlic supplementation did not reach statistically significant reduction of gastric cancer incidence at any time points, but at 22.3 years garlic led to a statistically significant reduction in gastric cancer mortality. This suggests that a limited time course of treatment with vitamins or garlic (7.3 years, from 1995-2003) influenced the incidence and mortality of gastric cancer more than 2 decades later.
Data on self-prescribed or medically prescribed treatments, including H pylori–directed therapies, were not tracked after 2003. Lifestyle, diet, and supplement use were also no longer tracked after 2003. The authors admit these shortcomings and contend that masking and randomization used during the study led to an unbiased adoption of these confounders, making them unlikely to change the results.
This population was known to be nutritionally deficient, specifically in vitamin C and selenium, 2 of the nutrients in the vitamin supplement. However, more than the daily requirements were given as supplements, so it is unclear whether it is repletion or dose-dependent effects of the vitamins that played a role in their reduction of incidence and mortality of gastric cancer. It is also not possible to ascertain whether adding these nutrients would benefit those who are not deficient.
As is often the case, the authors conclude with the proposal that further studies must be done before adopting any of the therapeutic interventions into community medicine. However, it is difficult clinically to justify patients not replete of vitamin C, selenium, and vitamin E while enjoying garlic in their diets as well. Once again, we have reason to promote the adoption of a highly plant-based diet, with another study suggesting benefit from the allium garlic in particular. While further studies are conducted, we can be confident that this overall healthful advice will serve patients well and, perhaps, even lessen their risk of developing or dying of gastric cancer.
- Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
- Loh M, Koh KX, Yeo BH, et al. Meta-analysis of genetic polymorphisms and gastric cancer risk: Variability in associations according to race. Eur J Cancer. 2009;45(14):2562-2568.
- Balakrishnan M, George R, Sharma A, Graham DY. Changing trends in stomach cancer throughout the world. Curr Gastroenterol Rep. 2017;19(8):36.
- Mukaisho K, Nakayama T, Hagiwara T, Hattori T, Sugihara H. Two distinct etiologies of gastric cardia adenocarcinoma: Interactions among pH, Helicobacter pylori, and bile acids. Front Microbiol. 2015;6:412.
- Gail MH, You W, Chang Y, et al. Factorial trial of three interventions to reduce the progression of precancerous gastric lesions in Shandong, China: Design issues and initial data. Control Clin Trials. 1998;19(4):352-369.
- Ma J-L, Zhang L, Brown LM, et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst. 2012;104(6):488-492.
- Herrero R, Parsonnet J, Greenberg ER. Prevention of gastric cancer. JAMA. 2014;312(12):1197-1198.
- Herrero R, Park JY, Forman D. The fight against gastric cancer–the IARC Working Group report. Best Pract Res Clin Gastroenterol. 2014;28(6):1107-1114.
- Pan K, Zhang L, Gerhard M, et al. A large randomised controlled intervention trial to prevent gastric cancer by eradication of Helicobacter pylori in Linqu County, China: Baseline results and factors affecting the eradication. Gut. 2016;65(1):9-18.
- Sugano K. Screening of gastric cancer in Asia. Best Pract Res Clin Gastroenterol. 2015;29(6):895-905.