Introduction
Non-Hodgkin lymphomas (NHL) constitute a diverse group of disorders, the incidence of which has been steadily rising until the mid-1990s in developed nations. In laboratory and animal studies, statins exhibit potential anti-tumor effects via various pathways, including cholesterol-dependent and independent mechanisms, which lead to apoptosis (cell death), inhibition of proliferation, and anti-inflammatory and anti-angiogenic effects.
Despite promising laboratory findings, epidemiological studies have not consistently supported the preventive effect of statins against lymphomas. While some studies suggest a reduced risk of lymphoma among statin users, others found no such association, and in some cases, statin usage was linked to an increased risk of NHL. Furthermore, laboratory investigations suggest that statins may enhance or impair the effectiveness of treatments like radiation, chemotherapy, or biological agents such as Rituximab on lymphoma cell growth.
The concurrent use of statins and chemoimmunotherapy for NHL treatment is a matter of concern, as conflicting results have been reported in clinical studies regarding their combined efficacy. Some studies show no impact of statin use on chemotherapy effectiveness, while others suggest an improvement in event-free survival, particularly for follicular lymphomas. This article explains the studies examining the risk and survival of NHL among statin users.
How Do Statins Work in Non-hodgkins Lymphoma?
Statins, commonly prescribed for hypercholesterolemia in the Western world, are extensively utilized medications. Statins inhibit the mevalonate pathway responsible for cholesterol synthesis by blocking the enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase. These drugs are increasingly prescribed to prevent heart disease, particularly among individuals aged 45 and older, as evidenced by a rise in their usage from 2 to 16 percent in Manitoba, Canada, between 1996 and 2005.
In Sweden, approximately 31 percent of individuals aged 60 and above used statins in 2018, while in the United States of America (USA), the usage among adults aged 40 and above was around 26 percent in 2012. These drugs work by inhibiting the key enzyme in the mevalonate pathway, which reduces the production of cholesterol and isoprenoids, impacting the function of various oncogenic proteins such as Ras family proteins.
Moreover, statins have demonstrated pro-apoptotic, anti-angiogenic, and immunomodulatory effects in laboratory studies, along with the ability to modulate BCL2 proteins involved in cell survival, potentially affecting multiple cancer types, including lymphoproliferative malignancies like multiple myeloma.
While epidemiological studies have supported the in vitro findings, indicating potential anticancer effects of statins across various cancers, including lymphoma, research on the relationship between statin use and lymphoma prognosis has yielded mixed results. These outcomes are influenced by factors such as lymphoma subtype and treatment regimen, particularly for common subtypes like chronic lymphocytic leukemia (CLL).
In CLL, in vitro studies suggest mechanisms through which statins could inhibit disease progression, such as amplifying cytokine signaling or reversing doxorubicin resistance. However, laboratory studies also indicate that statins might interfere with the CD20 receptor of lymphatic cells, potentially hindering the efficacy of Rituximab, a key component in B-cell lymphoma treatment.
Understanding the potential benefits and drawbacks of statin use in lymphoma treatment is crucial. While their positive effects could offer a cost-effective addition to lymphoma therapy, any negative impact on Rituximab treatment could have significant implications, given the widespread use of statins.
Existing epidemiological studies on this topic have limitations, such as small sample sizes or focusing on selected patients from specialized centers. In studies article aimed to address these gaps by examining statin use in different NHL subtypes or CLL within a population-based setting in Sweden and specifically evaluating its implications for rituximab-treated patients, particularly those with follicular lymphoma and analyzing them separately based on treatment strategies.
What Factors Should Be Considered When Using Statins in Non-hodgkins Lymphoma?
Previous studies have primarily examined the relationships between statin usage and the risk of overall cancer, as well as specific types like prostate and breast cancer. In contrast, the current analysis focused on the connection between statin use before diagnosis and the risk of non-Hodgkin lymphoma (NHL).
Our findings align with recent studies, indicating a reverse relationship between statin usage and NHL risk. However, when considering NHL subtypes, statin use was only associated with a reduced risk of developing marginal zone lymphoma (MZL), not other subtypes. Limited data were available regarding the association between statin use and survival rates. Several factors must be considered when interpreting these findings.
The following are the factors associated with the use of statins in non-Hodgkin lymphoma:
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Firstly, there may be selection bias, as preclinical cancers could lower cholesterol levels, and NHL patients typically have lower cholesterol levels at diagnosis. This might make NHL patients less likely to take statins than controls, potentially biasing the results.
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However, the analysis suggested that this bias had minimal influence on risk estimation. Additionally, hospital-based case-control studies might overestimate the protective effect of statins due to the generally poorer health of hospital controls. Yet, similar results were obtained when excluding hospital-based studies, suggesting minimal bias from this source.
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Secondly, the time-dependent nature of statin use could introduce bias. For instance, in cohort studies, patients might be classified as exposed even if they had stopped using statins for a short period during follow-up.
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Moreover, differences in the lengths of follow-up periods for exposure assessment between cases and controls could lead to bias. Although the studies included in the analysis did not provide sufficient information to determine the existence of this bias, it remains a possibility.
Furthermore, despite generally high agreement between data collected from interviews and prescription databases regarding statin usage, recall bias might still occur in case-control and cohort studies. This could explain the inverse association between interview-based studies and administrative data-based studies.
Conclusion
In conclusion, statin use is inversely associated with the risk of non-Hodgkin lymphoma. Future research examines the effect of non-Hodgkin lymphoma. Some studies suggest statin use does not affect the survival of NHL patients, but more research is needed. The main drawback of this statin use is limited data on statin use in NHL patients due to the lack of time to progression of the disease. More research and studies are required for the use of statins in NHL patients.
