Clinical Efficacy of the Modified Helicobacter pylori Eradication Therapy for Helicobacter pylori-Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma: A Meta-Analysis
Helicobacter pylori (HP) has been recognized as a primary cause of gastric mucosa-associated lymphoid tissue (MALT) lymphoma since 1993. While HP eradication therapy is widely used for low-grade gastric MALT lymphoma in HP-positive patients, there is growing evidence that modified HP eradication therapy may also be effective for HP-negative gastric MALT lymphoma. This meta-analysis aims to evaluate the clinical efficacy of modified HP eradication therapy in HP-negative gastric MALT lymphoma patients.
Background
Gastric MALT lymphoma is a type of extra-nodal lymphoma, with the stomach being the most common site. HP, a common infectious agent, has been implicated in the pathogenesis of gastric MALT lymphoma. HP eradication therapy is the preferred treatment for low-grade HP-positive gastric MALT lymphoma. However, the treatment of HP-negative gastric MALT lymphoma presents unique challenges, as these cases are more likely to invade the submucosal layer and have a higher non-response rate to HP eradication therapy. Radiotherapy or rituximab is typically recommended for HP-negative cases, but these treatments can lead to significant complications. Given the minimal side effects associated with HP eradication therapy, there is interest in exploring its efficacy in HP-negative cases.
Methods
A comprehensive search of PubMed, Medline, and Ebsco databases was conducted from January 1971 to February 2019. The search terms included “gastric mucosa-associated lymphoid tissue lymphoma,” “gastric MALT lymphoma and HP,” “Gastric MALT lymphoma,” and “Helicobacter pylori.” Studies were included if they reported the response rate of modified HP eradication therapy in HP-negative gastric MALT lymphoma patients, were published in English, provided full-text access, and included concrete data. Case reports, review articles, letters, and studies with insufficient data were excluded.
Data extraction and quality assessment were performed independently by two authors using a standardized form. The Newcastle-Ottawa quality assessment scale (NOS) was used to evaluate study quality, with a score of ≥6 indicating high quality. Statistical analyses were conducted using R 3.5.3, with the pooled response rate expressed as a decimal. Heterogeneity was assessed using the I-squared (I2) statistic, and sub-group analyses were performed to identify sources of heterogeneity. Publication bias was evaluated using the Egger test.
Results
A total of 14 studies involving 148 patients with HP-negative gastric MALT lymphoma were included in the meta-analysis. The overall pooled response rate for modified HP eradication therapy was 0.38 (95% confidence interval [CI]: 0.29–0.47), with significant heterogeneity observed (I2 = 57%; P < 0.01). Sub-group analyses based on geographic regions revealed varying response rates: Korea (0.63; 95% CI: 0.50–0.76), Japan (0.16; 95% CI: 0.05–0.30), China (0.38; 95% CI: 0.20–0.55), and Western countries (0.57; 95% CI: 0.08–1.00). The Egger test indicated no significant publication bias (P = 0.69).
Discussion
The meta-analysis findings suggest that modified HP eradication therapy is effective for low-grade HP-negative gastric MALT lymphoma, particularly in Korea and Western countries. The pooled response rate of 0.38 indicates that a significant proportion of patients benefit from this treatment. The sub-group analysis highlighted regional differences in response rates, with Korea and Western countries showing higher efficacy compared to Japan.
Several factors may contribute to the efficacy of modified HP eradication therapy in HP-negative cases. False negatives in HP detection methods, the immunosuppressive effects of antibiotics, the presence of other pathogens, gene translocations, and the state of chemokine receptors are all potential mechanisms. Clarithromycin, a common antibiotic in HP eradication regimens, has been shown to induce apoptosis in activated lymphocytes and inhibit cellular proliferation, which may contribute to its anti-tumor effects. Additionally, other Helicobacter species, such as Helicobacter heilmannii and Helicobacter suis, may play a role in the pathogenesis of HP-negative gastric MALT lymphoma and respond to similar eradication therapies.
Gene translocations, particularly t(11;18)(q21;q21), have been associated with resistance to antibiotic therapy. However, some studies have shown that HP-negative gastric MALT lymphoma with this translocation can still respond to modified HP eradication therapy. The expression of chemokine receptors, such as CXCR3, also influences treatment response, with CXCR3-negative tumors being more sensitive to HP eradication therapy.
Implications
The findings of this meta-analysis have important implications for the management of HP-negative gastric MALT lymphoma. Modified HP eradication therapy offers a conservative treatment option with fewer side effects compared to radiotherapy or chemotherapy. The allowable follow-up time for achieving histological remission may be extended to one year, allowing for a more comprehensive assessment of treatment efficacy. The use of clarithromycin or azithromycin, along with other antibiotics, may enhance the efficacy of the treatment. Additionally, genetic testing for gene translocations and chemokine receptor status may provide valuable insights for personalized treatment strategies.
Limitations
The meta-analysis has several limitations, including the small sample size of included studies, potential selection bias, varying diagnostic and evaluation criteria, and high heterogeneity in some sub-group analyses. The influence of patient age, lesion depth, and antibiotic type was not fully explored. These limitations highlight the need for further research to validate the findings and optimize treatment protocols.
Conclusion
This meta-analysis demonstrates that modified HP eradication therapy is a viable treatment option for low-grade HP-negative gastric MALT lymphoma, particularly in Korea and Western countries. The therapy’s efficacy, combined with its minimal side effects, makes it a valuable alternative to more aggressive treatments. However, the heterogeneity of the included studies and the need for further research underscore the importance of continued investigation into the mechanisms and optimization of HP eradication therapy for HP-negative gastric MALT lymphoma.
doi.org/10.1097/CM9.0000000000000813
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