Real-world data on herb-drug interactions in oncology: A scoping review of pharmacoepidemiological studies
Graphical abstract
Introduction
The proportion of patients with cancer who seek benefits from complementary medicines has increased significantly, from approximately 25% prior to 1990 to an average of 51% from 2009 to 2018 worldwide (Horneber et al., 2012). Herbal medicines are the most commonly used type of complementary medicine (Bautista et al., 2011; Molassiotis et al., 2005). Herbal medicines refer to “herbs, herbal materials, herbal preparations and finished herbal products that contain, as active ingredients, parts of plants, other plant materials or combinations thereof” (WHO, 2019). In some countries, herbal medicines may also contain natural ingredients derived from animals or minerals. A recent systematic review of 155 studies showed that the pooled prevalence of herbal medicine use is 22% among patients with cancer, with the highest prevalence reported in Africa and Asia (Asiimwe et al., 2021).
While patients with cancer take herbs to improve their general health or reduce the side effects of cancer treatment, many use them concomitantly with conventional drugs (Alsanad et al., 2014). However, this usage can cause herb-drug interactions (HDI) that increase or decrease the pharmacological or toxicological effects of either component (Fugh-Berman, 2000). These interactions can lead to both beneficial and harmful health outcomes. For example, the combination of Yunzhi or Lingzhi with cytotoxic drugs may lead to improved survival and the alleviation of chemotherapy-related side effects (Lam et al., 2020). However, for patients with cancer, concerns about negative interactions may be significant, considering the narrow therapeutic windows of oncologic drugs. One example is the use of the cytochrome inducer, St. John's wort, which may lower the plasma concentrations of anticancer drugs, such as docetaxel and irinotecan (Meijerman et al., 2006). A previous review of five studies found that 13.9% of patients with cancer are at risk of herb/food supplement-drug interactions (Alsanad et al., 2014).
Due to methodological and cost considerations, randomized controlled trials (RCTs) often do not have sufficient sample size and follow-up duration in investigating herb-drug interactions. Moreover, the usefulness of RCTs may be particularly limited as they are carried out using selected populations under carefully controlled conditions. Therefore, the results are often less generalizable to a broader population (Garrison Jr et al., 2007). Consequently, pharmacoepidemiological studies are often the principal method used to study drug interactions (Hennessy et al., 2016). Pharmacoepidemiology is “the study of the use of and the effects of drugs in large numbers of people” (Strom, 2019a). These studies aim to collect real-world data, which is commonly defined as data used for decision-making that are not collected in conventional randomized controlled trials (Garrison Jr et al., 2007).
Although regulatory authorities have issued guidelines for methods to evaluate the risk of drug-drug interactions, less attention has been given to HDI (EMA, 2012; FDA, 2020). There is less data on HDI compared with conventional drug-drug interactions (DDIs), and often the data on a specific herb cannot be extrapolated to other herbs (EMA, 2012). A previous review of HDI focused on summarizing the proportion of patients with cancer at risk of HDIs, but it did not provide a critical appraisal of the methods used to study the interactions (Alsanad et al., 2014). The goal of this review was to provide an overview of how existing pharmacoepidemiological research on HDI has been conducted (including study designs, data sources, and interaction analyses); and to identify gaps to be addressed in future research initiatives.
Section snippets
Overall approach
Given the nascent state of the field, we conducted a scoping review to address the main exploratory question: What pharmacoepidemiological methods are used to study HDI in patients with cancer using real-world data? A scoping review method with a narrative synthesis approach was chosen as it was deemed to be more appropriate to summarize studies that vary in methodological approaches and map the limited existing evidence to address the research questions (Peters et al., 2020b).
There is
Study selection
In total, 11,081 records were retrieved. After removing duplicated articles (n = 4,590) and ineligible articles based on title and abstract screening (n = 6,539), 52 full-text manuscripts were assessed for eligibility. Finally, 29 articles were selected for data extraction (Ali-Shtayeh et al., 2016; Alsanad et al., 2016; Ben-Arye et al., 2016; Block et al., 2012; Clairet et al., 2019; Drozdoff et al., 2019; Engdal et al., 2009; Fahim et al., 2019; Firkins et al., 2018; Hsu et al., 2015;
Discussion
As integrative oncology is gaining popularity among patients with cancer, the assessment of HDI is a crucial step in its development, as both clinicians and patients may be concerned about the safety of concurrent usage of herbs and drugs in addition to the efficacy of the herbs. To our knowledge, this is the first review to summarize the methods used by existing pharmacoepidemiological studies on HDI and propose suggestions to improve these studies. In this scoping review, 28
Limited sample size
As addressed by some researchers, one important limitation of existing pharmacoepidemiological studies of HDI was a small sample size (Jermini et al., 2019; Schad et al., 2018; Thronicke et al., 2017; Wu et al., 2014). Notably, clinically observable interaction outcomes were often rare. Moreover, as patients took diverse combinations of herbs and drugs, it was difficult for both prospective and retrospective studies that focused on actual clinical outcomes to balance the characteristics of
Conclusions
In this scoping review, we summarized the methods used in pharmacoepidemiological studies of HDI using real-world data. Among the studies reviewed, most clinical interaction outcomes identified did not lead to negative consequences. Based on the study limitations, several recommendations to enrich the data sources and optimize the study designs were proposed. Pharmacoepidemiological studies are the mainstay for generating evidence on HDI risks, given the difficulty in conducting trials. Future
CRediT authorship contribution statement
Chun Sing Lam: Conceptualization, Funding acquisition, Data curation, Formal analysis, Writing – original draft. Ho Kee Koon: Conceptualization. Chung Tin Ma: Conceptualization, Funding acquisition, Data curation, Formal analysis. Kwok Yin Au: Conceptualization. Zhong Zuo: Conceptualization. Vincent Chi-Ho Chung: Conceptualization, Writing – review & editing. Yin Ting Cheung: Conceptualization, Data curation, Formal analysis, Writing – review & editing, Supervision.
Conflicts of Interest
On behalf of all authors, the corresponding author states that there is no conflict of interest associated with this publication
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