H pylori rx, vitamins, and dec gastric cancer

A recent Chinese study found that H pylori treatment, as well as long-term vitamin or garlic supplementation, reduced the risk of death from gastric cancer (see hpylori rx vitamins gastric cancer decrease bmj2019 in dropbox, or doi.org/10.1136/bmj.l5016)

Details:

-- 3365 residents in a high risk region for gastric cancer (Shandong province): 2258 were seropositive for H pylori antibodies and randomized to H pylori treatment, vitamin supplementation, garlic supplementation, or their placebos

-- the remaining 1107 H pylori seronegative participants were randomized to the same vitamin supplementation, garlic supplementation, or their placebos

-- those with H pylori treatment were given amoxicillin 1 g BID and omeprazole 20 mg BID for 2 weeks; the vitamin groups received vitamin C 250 mg, vitamin E 100IU, and selenium 37.5 µg (all BID); and the garlic groups received garlic extract 200 mg BID and steam-distilled garlic oil 1 mg BID. The vitamin and garlic groups received therapy for 7.3 years (1995-2003)

-- primary outcome: cumulative incidence of gastric cancer identified by scheduled gastroscopies, with follow-up in 2017

Results:

-- 151 incident cases gastric cancer and 94 gastric cancer deaths were identified from 1995-2017; 79% of the gastric cancers and 81% of the gastric cancer deaths occurred in people who were baseline H pylori positive. Most were non-cardia types (as seen with H pylori)

-- gastric cancer incidence (results adjusted for age, sex, smoking and alcohol intake)

    -- H pylori treatment: 52% decrease in gastric cancer incidence which persisted 22 years post-intervention, OR 0.48 (0.32-0.71)

    -- vitamin supplementation: 36% decreased risk, OR 0.64 (0.46-0.91)

    -- garlic supplementation: not statistically significant difference, OR 0.81 (0.57-1.13)

-- gastric cancer mortality:

    -- H pylori treatment: 38% decreased risk, aHR 0.62 (0.39-0.99), the effect appeared after about 8 years

    -- vitamin supplementation: 52% decreased risk, aHR 0.48 (0.31-0.75), the effect appeared after about 8 years

    -- garlic supplementation: 34% decreased risk, aHR 0.66 (0.43-1.00), the effect appeared after about 12 years

-- secondary analysis: vitamin supplementation was marginally associated with decreased all-cause mortality, HR 0.87 (0.76-1.01)

-- no differences in these interventions with other cancers (including esophageal cancer) or cardiovascular disease, though there was a trend to decreased risk of colorectal cancer mortality with H pylori treatment, HR 0.30 (0.08 - 1.10), p= 0.07  [though there were only 10 cases in the placebo group and 3 in the treatment]; and a non-statistically significant increase in liver cancer mortality, adjusted HR 1.78

-- the protective effect of vitamin supplementation was greater in those with favorable histology and younger than 45yo

Commentary:

-- gastric cancer is the 3^rd leading cause of death from cancer globally

-- in 2018, about half of the estimated deaths from gastric cancer occurred in China

    -- in 1980-82 the area in China (Shandong province) in the above study has one of the highest mortality rates from gastric cancer worldwide, with age-adjusted rates of 55 per 100K in men and 19 per 100K in women

-- epidemiologic studies suggest a strong link between H pylori infection to the progression of precancerous gastric lesions and the development of gastric cancer, specifically noncardia gastric adenocarcinomas

-- epidemiologic studies also show that diets rich in vitamin A and garlic might protect against gastric cancer in high risk people with insufficient vitamin intake

-- the Shandong Intervention Trial began in this area in 1995 to evaluate these 3 potentially protective interventions. After 14.7 years of follow-up, the trial reported a significant reduction in gastric cancer and not statistically significant reduction in gastric cancer deaths associated with H pylori treatment. The garlic and vitamin supplementation arms showed favorable trends, not statistically significant. the current study provides the 22 year follow-up

-- another study finding that H Pylori eradication was associated with decreased gastric cancer risk was done in Korea: see http://gmodestmedblogs.blogspot.com/2019/06/h-pylori-eradication-and-decreased.html . This blog has reference to many other studies documenting efficacy of H pylori eradication (even in asymptomatic people) in decreasing gastric cancer

-- in terms of other cancers:

    -- there is concern that eradication of H Pylori might be associated with increased esophageal cancer, esp adenocarcinoma. In Shandong province there was no evident increased risk, though esophageal adenoca is uncommon there. however, several other studies have found that H pylori infection might be protective from esophageal cancer (and specifically some H pylori subtypes: eg CagA-positive ones), though it does seem that the incidence of esophageal cancers pales in relationship to gastric cancers 

    -- there are studies also finding decreased colon cancer in those treated for H Pylori (see  http://gmodestmedblogs.blogspot.com/2018/11/h-pylori-colorectal-cancer-and-general.html: some genetic variants of H pylori (eg VacA) are associated with colon cancer); this study also found a pretty impressive statistical trend to a decrease in colorectal cancer

--one other important finding was that a one-time treatment of H Pylori had long-lasting effects, with an effect at 22 years exceeding that of the original 14.7 year analysis

    --so, one issue raised is when to test and treat, since gastric cancer typically is in older people. This trial found that even those with intestinal metaplasia and dysplasia at baseline did well, as well as those 51-71 years old (see see http://gmodestmedblogs.blogspot.com/2019/06/h-pylori-eradication-and-decreased.html for some of the other studies, showing some inconsistency in results).  Other studies have found better effectiveness if treatment is done earlier.

--elimination of H Pylori seems to significantly reduce gastric cancers, though clearly not eliminate them. perhaps there would be added benefit with some combination of H Pylori eradication along with the above vitamin supplementation in those deficient plus garlic. Other studies have suggested that potentially adding allium vegetables (eg onions, garlic, chives, leeks, shallots and scallions) or even the synthetic diallyl trisulfide (allitridum, eg see https://www.ncbi.nlm.nih.gov/pubmed/15361287) which has shown some protective effect, might be effective.

    -- some limitations of the Shandong study might also explain the persistence of gastric cancers despite H Pylori therapy (and, of course, there may just be several other causes of gastric cancer which are not being addressed by H pylori treatment), eg:

        --we do not know the H pylori status after treatment. how often did it not work?  They did use therapy that is no longer considered adequate (they used just PPI and amoxacillin). And, though it seems that reinfection is not common, adding some reinfections to perhaps inadequate therapy might increase the rate of continued infection and continued gastric cancer risk. see http://gmodestmedblogs.blogspot.com/2019/06/h-pylori-eradication-and-decreased.html for info on this, noting a systematic review of reinfection being 3.1%

        --we do not know if vitamin/garlic supplementation was continued after the initial study stopped in 2003. Likely did not continue at the same level, though also likely that changes in their consumption would affect all groups. But, given the benefits found (which may have been much greater if they continued the supplementations), this could explain some of the residual gastric cancer risk. 

    --And, of course, over the length of a study like this one, many changes happen. Dietary changes?? (eg potential role of salt, nitrites in the diet). Smoking/alcohol (though the studies are pretty inconsistent on their role)?? other, unknown factor??, perhaps lifestyle changes ?? (eg see http://gmodestmedblogs.blogspot.com/2016/08/normal-bmiexercise-lower-cancer-risk-2.html  which reviews the positive effects of lifestyle on cancer)

--other limitations to this study include:

    -- there were too few cancers to have adequate secondary analyses/subgroup analyses

    -- they had scheduled gastroscopies during the trial period and later mostly in those with more advanced gastric lesions during the study period (therefore, there could be ascertainment biases in the long-term followup)

    -- this was a particular rural Chinese population with documented nutritional deficiencies, so may not be generalizable to other populations (though, the relation between H pylori and gastric cancer has been found in many countries. Prior blogs note the world-wide overlap of countries with high H pylori prevalence with high rates of gastric cancer). And H pylori is the largest known human bacterial infection, with >50% of the world’s population infected and is the strongest known risk factor: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952980/

So, this study adds to the quite large literature that H pylori infection (even asymptomatic) is associated with gastric cancer (and is the most common of the known risk factors) and that treatment seems to lower the risk across many studies and countries. I should add the following observations:

-- H pylori infection is really common in the US in people coming from high-risk countries (which is much of the world, it seems). see http://gmodestmedblogs.blogspot.com/2018/01/h-pylori-ppi-use-and-gastric-cancer.html , which documents the high incidence of H pylori and gastric cancer in several countries, including the Dominican Republic, Haita, Jamaica, Guatemala. also,  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444111/ for worldwide global prevalence in gastric cancer and h pylori global incidence gastro2017 in dropbox, or doi.org/10.1053/j.gastro.2017.04.022  for H pylori global prevalence

-- even in the US, H pylori is quite common, with suggestions that up to 40% are infected (see http://gmodestmedblogs.blogspot.com/2018/11/h-pylori-colorectal-cancer-and-general.html , which has data of colorectal cancer cases but found that 40% of the control patients in 10 prospective cohort studies were sero-positive for H pylori). 

-- there are some H  pylori strain that are more highly associated with gastric cancer (eg cagA-positive ones), and perhaps in the future we might be able to narrow our treatment approach to these high-risk strains, but we do not have the ability to decipher these strains easily, or the studies suggesting that this is an effective strategy…

I have personally been testing patients pretty regularly and treating H pylori infections when found, based on the plethora of studies, several documented in prior blogs: see http://gmodestmedblogs.blogspot.com/search?q=h+pylori , and this started because I have seen a seemingly high number of patients from countries with high prevalence of H pylori who have died from gastric cancer in the past. And my experience confirmed H pylori in several US patients who have never traveled outside the US do have H pylori, including a person with refractory ITP and another with refractory pruritis who had complete resolution with H pylori therapy

geoff​

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