H pylori rx after gastric ca surgery increases survival

 A recent study found that in patients with gastric cancer who had had a radical gastrectomy and were H pylori positive but then were treated for the infection had significantly improved survival vs those not treated (see h pylori rx in survival gastric ca JAMA2024 in dropbox, or doi:10.1001/jamanetworkopen.2024.3812)

 

Details:

-- 1293 patients were found who had had a radical gastrectomy and were H. pylori positive in a retrospective cohort study in a single referral hospital in China from 2010 to 2019

    -- patients had gastric or esophagogastric junction adenocarcinoma and underwent curative gastrectomy with D2 lymphadenectomy

    -- patients were divided into two groups: 125 (10%) of the 1293 patients had H. pylori therapy during the perioperative period, and 1168 patients did not

-- median age 59, 67% male, BMI 22, smokers 35%, hypertension 13%, coronary heart disease 5%, diabetes 6%

-- histologic grade: G1/G2 38%; G3/G4 57%

-- TNM stage: I in 50%, II/III in 50%

-- tumor size: <4mm diameter in 80%, >4cm in 20%

-- distal gastrectomy in 70%/proximal in 11%

--  CEA <5 in 86%

-- 46% (600 patients) had TNM stage III disease

-- 63% (808 patients) received adjuvant chemotherapy

-- no statistically significant difference between the groups in terms of sex, age, BMI, smoking history, and comorbidities; but:

    -- those receiving H. pylori treatment: higher proportion had distal gastrectomies (82% versus 62%) and received less adjuvant chemotherapy (43% versus 65%)

    -- those not receiving H. pylori treatment: more advanced T-stage, N-stage and TNM stage, as well as larger tumor maximum diameter

 

--propensity score matching was performed in both groups of patients to equalize statistically the measured variables, resulting in a total of 124 patients who received treatment versus 364 who did not

-- H. pylori treatment was mostly 14 days of amoxicillin, clarithromycin, and omeprazole

 

-- Main outcomes: overall survival (OS) and disease-free survival (DFS)

  

Results:

-- three-year overall survival rates:

    -- H. pylori group: 95.9% (99.2%-99.5%

    -- untreated group: 81.4% (79.0%-83.8%)

 

-- five-year overall survival rates:

    -- H. pylori group: 94.1% (89.3%-99.2%)

    -- untreated group: 73.8% (70.7%-77.0%)

        -- 67% decrease with H. pylori treatment, HR 0.33 (0.18-0.60)

        -- after propensity score matching, 50% decrease, HR 0.50 (0.26-0.99), p=0.048

 

-- Disease-free survival at three years:

    -- H. pylori group: 94.5% (90.3%-98.9%)

    -- untreated group: 70.0% (67.1%-73.1%)

-- Disease-free survival at five years:

    -- H. pylori group: 84.9% (75.6%-95.4%)

    -- untreated group: 59.2% (55.4%-63.3%)

        -- overall, 71% decrease with H pylori treatment, HR 0.29 (0.17-0.50), p<0.001

        – after propensity score matching, 52% decrease, HR 0.48 (0.27-0.87), p=0.02

 

 

PSM=propensity score matching

  

-- Multivariable analysis (age >60, TNM stage, tumor max diameter, adjuvant chemotherapy, H pylori treatment):

    -- overall survival: 62% decrease with H pylori treatment, HR 0.38 (0.17-0.87), p=0.02

    -- disease-free survival: 52% decrease with H pylori treatment, HR 0.48 (0.28-0.83), p=0.008

        -- by subgroups, the following were significant prognosticators:

            -- independent factors for overall survival: >60 years old (1.47-fold decrease), TNM stage II/III (8.87-fold decrease), tumor maximum diameter >4cm (2.33-fold decrease), adjuvant chemotherapy (37% increase), and H. pylori treatment (62% increase)

            -- independent factors for disease-free survival: TNM stage II/III (4.61-fold decrease), tumor maximum diameter >4cm (2.37-fold decrease), and H. pylori treatment (52% increase)

 

-- patients with TNM stage II/III disease who received adjuvant chemotherapy

    -- overall survival: 51% decrease with H pylori treatment, HR 0.49 (0.24-0.99), p=0.046

-- patients with TNM stage II/III disease not receiving adjuvant chemotherapy

    -- overall survival: no statistical difference

-- no difference in those who were TNM stage I

 

 Commentary:

-- H. pylori is the most common chronic bacterial infection worldwide: 4.4 billion people are infected 

-- H. pylori is a documented human carcinogen, associated with 80% to 90% of gastric cancers globally (it is the single most significant risk factor for developing gastric cancer, conferring a 3-fold risk)

    -- H. pylori is considered a carcinogen per the NIH and WHO: http://gmodestmedblogs.blogspot.com/2022/03/carcinogen-update-now-including-h-pylori.html  

-- H. pylori eradication reduces the risk of gastric cancer even in those who are asymptomatic, as well as reducing the complications of peptic ulcer disease 

-- H. pylori infections are largely asymptomatic or minimally symptomatic, suggesting that routine testing needs to be done to eliminate the burden of H. pylori infections 

-- a meta-analysis covering the years 1970-2016 found the highest pooled rate of H. pylori positivity was in Africa (79%), with lower rates being in North America (37%), Western Europe (34%), and Oceania (24%). A more recent meta-analysis found that these numbers largely persisted, with North America having 36% positivity

    -- it should be noted that the quality and rigor of epidemiologic studies in resource-limited countries is often more limited 

-- one large US study with 16,144 people in 4 Hispanic/Latino communities found an H pylori seroprevalence of 57%

-- an NHANES study of 7465 people from 1988-1991 in the US found a 32.5% seropositivity (see https://academic.oup.com/jid/article/181/4/1359/856832 ) 

 

 --gastric cancer is the fifth most common cancer globally and the 4^th leading cause of death, with 1.08 million new cases and 0.76 million deaths in 2020

-- in the US, the American Cancer Society estimates that in 2024 there will be about 26,890 new cases of gastric cancer (16,160 men and 10,730 women), with about 10,880 deaths (6,490 men and 4,390 women)

    -- though the average age for gastric cancer is 68, about 2%-8% are diagnosed in people under 40yo

-- the incidence of gastric cancer in the US has been decreasing by about 1.5% per year over the last 10 years

-- the prevalence of H pylori in the US from 2016-2019 was about 36% of the population, but also has been decreasing. Not clear why??

    – perhaps due to improved refrigeration of food storage and decreased consumption of salted and smoked foods (risk factors for gastric cancer)

    – perhaps it is related to the decreasing number of people infected with H pylori (and the curves below suggest parallel declines of both H pylori and gastric cancer)

        -- would be interesting to know how much of the decrease in H pylori is from more treatment over time….

 

--this graph is from a global prevalence of H Pylori assessment ( https://www.gastrojournal.org/article/S0016-5085(23)05687-1/fulltext )

 

 

 

hard to read the writing here, but this graph documents the changes in the US from 1980 to 2022

--there have been a few studies done in the VA healthcare system in the US:

   -- 913,328 individuals had H pylori testing during their routine care, finding a 40% positivity rate in study from 1999-2018: https://gmodestmedblogs.blogspot.com/2023/06/h-pylori-common-in-us-veterans.html

       -- H. pylori positivity declined over the 20-year time period of the study, from 35.9% in 1999-2006 to 18.4% in 2013-2018 

    --another large retrospective VA study of 371,813 patients with H pylori infection from 1994-2019 found that 2024 of them developed gastric cancer after 7 yr followup, and those treated for H Pylori had a 76% decreased gastric cancer risk (limited to those with documented H Pylori eradication) but those not treated or without confirmed H pylori eradication had no change in gastric cancer: https://gmodestmedblogs.blogspot.com/2019/12/h-pylori-in-us-veterans.html

 

Prior blogs on H. pylori/gastric cancer: 

    -- for the many prior blogs, see http://gmodestmedblogs.blogspot.com/search?q=H+pylori

    -- for a blog of studies showing that H. pylori eradication decreased gastric cancer, see http://gmodestmedblogs.blogspot.com/2019/06/h-pylori-eradication-and-decreased.html , which reviews several studies including those done in asymptomatic patients, as well as some less typical presentations for H. pylori, including ITP, an array of dermatologic manifestations including chronic pruritus/chronic urticaria, and an association with colon cancer (colon cancer seems to be associated with the the more virulent of the strains with  VacA  toxin. Is the current trend of earlier age for gastric cancer as well as colorectal cancer associated with the H pylori strains with VacA (or possibly CagA strains)?? I could find no studies tracking changes in expression of either CagA or VacA strains over time, though for more information into the genetics: https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-023-02838-9

    -- there are also many blogs on different therapies for H. pylori, as well as some insight into drug resistance patterns in the US: http://gmodestmedblogs.blogspot.com/2023/01/h-pylori-antimicrobial-resistance-in.html

 

-- this current study provided evidence that even in those with higher risk gastric cancer who had H pylori infection, there were significantly better survival outcomes if they had H pylori treatment

    – these results applied to various subgroups, including whose with the most advanced disease and those with TNM stage II/III having adjuvant chemotherapy (though no benefit in the group not treated for H pylori)

-- prior to this study there were a couple of similar observational ones done in Korea but with conflicting results; this current study is the largest one done.

    – one of these Korean studies found a 50% decreased subsequent incidence of metachronous gastric cancers in people with early gastric cancer who were treated for their H pylori infection: https://gmodestmedblogs.blogspot.com/2018/04/h-pylori-eradication-decreases.html

 

Limitations:

-- there are clear differences in the patients who received versus did not receive H. pylori therapy: in particular those not receiving therapy did have more advanced tumors, suggesting a significant selection bias in comparing these groups.

    -- propensity score matching does help equalize the groups, but this is a statistical process which does not necessarily equalize the groups appropriately: for example see https://gmodestmedblogs.blogspot.com/2020/03/tramadol-fo-oa-inc-mortalityprobs-with.html

    -- there were also some subgroup analyses that also seemed to equalized the patients, such as comparing patients with the same TNM stage or whether they had or did not have adjuvant chemotherapy

-- this was a retrospective study and therefore can only confer an association and not causality, since there were very likely unmeasured confounders

-- the study was done in one institution in China, which might limit its generalizability to other areas of the world (different variants of H pylori there?)

-- the study was also done over a 9-year period, and there might have been changes over time in the surgeries and other treatments done, which might also confound the results

-- the VA blogs noted above are certainly a specific subgroup of the US population (basically males who were physically fit when they were recruited into the armed services and many were likely affected psychologically and medically by being in wars). the VA system provides lots of information on its patients since it is a cohesive system of care with lots of accessible data. it would be great if we in the US had the coherent systems of other resource-rich countries and many less-rich ones, with lots of accessible data on the population (demographics, psychosocial variables, meds, lab tests, diagnoses, outcomes, etc) providing us with the ability to assess our clinical outcomes systematically (and hugely benefit our ability to understand our own public health needs and target necessary interventions)

-- though we can assume that on the order of 80-90% of the patients treated for H pylori in this study has successful eradication of the H pylori, we do not have tests-of-cure to validate the adequacy of the H pylori treatment and see if the results tracked with elimination of the H pylori (as the VA study did)

-- it should be noted that patients with H pylori-negative gastric cancers seem to have a worse prognosis in some studies

 

so, bottom line to me:

-- we should routinely be testing and treating H pylori at one time in pretty much all patients, and best done before one gets gastric cancer… (though there seems to be benefit even if they have gastric cancer)

    -- H pylori is the most common chronic bacterial infection in the world: 50% are infected, and it seems that 20-30% or so are currently infected in the US

    -- it is a documented carcinogen and the most prominent risk factor for gastric cancer, and it may play a role in colon cancer

    -- it also plays a role in other non-GI cancers, such as ITP and a variety of dermatologic problems

    -- it increases the risk 3-fold for severe GI bleeds in those taking NSAIDs (and NSAIDs, unfortunately, are taken all the time, with their myriad of bad potential effects on many major organ systems)

    --and this comes from a strong advocate (ie, me) for doing all we can to assure a healthy gut microbiome, and avoiding antibiotics as much as possible…

 

geoff

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