Iago Rodríguez-Lago
Gastroenterologist at the Inflammatory Bowel Disease Unit, Digestive System Department
It is a well-designed and well-conceived study from the outset, but it is important to note that it does not include new patients nor does it constitute a clinical trial: it is a mathematical model that combines three previously published findings (the global prevalence of H. pylori, the risk of colorectal cancer observed in 43 studies, and the number of cases recorded by GLOBOCAN in 2022).
The methodology applied is robust and, in some respects, innovative: simulations to account for uncertainty in the estimates, multiple sensitivity analyses, and an assessment of publication bias. It is also worth noting that the authors acknowledge that their results are exploratory, precisely because causality cannot be proven with this study design.
Part of this limitation stems from the data source, as, of the 43 studies, 38 are case-control or cross-sectional studies, and only five are prospective cohorts. The disparity between them is very great, and the authors are barely able to explain 7 per cent of the differences (heterogeneity). In summary, the study presents a very interesting statistical model, but one based on somewhat weak evidence. Nevertheless, this approach allows for the inclusion of a very large number of patients, requires less time to obtain results, and serves to guide future research, although it does not appear likely to change our current clinical practice.
It is consistent with what we already know, as the association was described years ago with similar magnitudes; there is a certain degree of biological plausibility, because in animal models the infection alters gut immunity and the microbiota, and eradication prevents this effect. The key to interpreting the study is to distinguish between three things: ‘association’ does not mean ‘caused’, and ‘caused’ does not mean ‘preventable’. That 22 per cent risk would only translate into preventable cases if the relationship were causal and if eradicating the bacterium were to reverse the risk. The evidence on eradication cited in the article itself is limited: four studies, with an overall neutral result, and the only indication of a benefit appears only after 10 years. It is also worth putting these figures into perspective, as in colorectal cancer, lifestyle factors, diet, family history, etc., account for a significant proportion of cases; consequently, these are still currently regarded as the key areas for preventive action.
Although the study offers an interesting approach and a comprehensive overview of these issues, it does not provide any immediate practical implications for our patients or the general population. Nevertheless, it raises an interesting point, as there is therefore the possibility of a dual benefit in countries that already carry out active screening for the bacterium to prevent gastric cancer. In Spain, the priority remains increasing participation in colorectal screening, which does have a proven benefit.
[Regarding possible limitations] If we analyse the methods used in detail, it has been mathematically assumed that the relationship between the two factors (H. pylori and colorectal cancer) is causal. We must bear in mind that the infection is also a marker of socio-economic conditions and hygiene during childhood, which are in turn linked to diet, smoking, obesity, etc. As some of these factors are associated with both conditions, there may be some uncertainty regarding the nature of the relationship between them and the role played by exposure to the bacterium itself.
They also highlight a striking detail: if the bacterium were a more direct cause of the tumour, one would expect a higher risk with the more virulent strains, yet the opposite is true.
All estimates for strains carrying CagA, VacA and GroEL fall below the overall risk.
In conclusion, although one-fifth of cases are linked to the bacterium, this does not mean that one-fifth are preventable. Association does not imply causality, and causality does not imply preventability. The study shows that the higher the quality of the research from which the data are derived, the lower the observed effect. Taking all 14 studies into account, the figure drops from 22 per cent to 12 per cent, demonstrating that data quality is essential for drawing robust conclusions. Based on this evidence, we do not have sufficient grounds to screen for H. pylori with a view to reducing the risk of colorectal cancer. We do know that participation in colorectal cancer screening programmes is effective, and there is very solid evidence to support this. The most valuable aspect of this work is that it highlights where further research is needed, particularly in countries that already screen for the bacterium to prevent gastric cancer, as this could help us uncover the influence this might have on colorectal cancer.