4. Discussion
In this study, more than eight among ten of cancer patients used herbal
medicines during chemotherapy courses and eight patients out of ten
patients with the history of herbal medicine consumption had potential
herb-drug interactions. Potential moderate herb-drug interactions
occurred in all patients, while potential minor herb-drug interactions
happened in a third of patients. Based on the findings, chamomile is the
most popular herbal medicine and green tea leads to frequent potential
minor and moderate herb-drug interactions. The number of
chemotherapeutic agents, number of herbal medicines, gastrointestinal
cancers, thorax cancers, IV clinical stage, unclear recurrence status
and the experience of pain during chemotherapy courses were determined
as the predictors of herb-drug interactions among cancer patients.
High prevalence of using herbal medicines in combination with
conventional treatments is an important issue which has been addressed
in many studies with different population (28-31), a finding that has
also been discussed in our study. The majority of cancer patients used
herbal medicines during chemotherapy courses and according to our
previous study, this consumption was also hidden from physicians’ view
(32). Patients, regardless of current treatments, use herbal medicines
for a variety of reasons. For example, patients believe that they can
use herbal medicines without trouble, because they are natural,
effective in treating diseases and they can reduce cancer symptoms, and
they have no side effects (33, 34). These patients have mistaken beliefs
about herbal medicines, because herbs when used in combination with
drugs have an influence on induction and inhibition of metabolic enzymes
and finally on drug absorption (35). Herb-drug interaction is the
consequence of this combination and may lead to unexpected adverse
clinical outcomes (36, 37) such as hepatotoxicity (38). According to
related studies, the prevalence of herb-drug interactions among cancer
patients is considerable (39) and it varies from 2.3% (40) to 25% (41)
and 46% (42). The findings of our study showed that more than three
quarters of cancer patients had herb-drug interactions and this
prevalence was higher in comparison to other studies. Some of the
reasons for this discrepancy was related to more consumption of herbal
medicines by our patients, consumption herbal medicines which lead to
herb-drug interaction such as garlic, green tea (43) and chamomile (44)
and identification of new pairs of herb and drugs which resulted to
interactions over time.
An important issue in Drug Related Problems (RDPs) such as drug
interactions is related to Narrow Therapeutic Window (NTW) of some drugs
such as chemotherapeutic agents (45, 46). These drugs with a small
difference between the minimum effective range and the minimum toxic
range have steep dose-response relationship and they must be monitored
carefully (47, 48), because small changes in their dose or plasma
concentration can lead to life-threating toxicity or sub-optimal therapy
and under treatment of cancer (48, 49). But how dose herbal medicines
interact with these drugs? The drug clearance is the key point in this
story and the metabolic modification of some enzymes such as CYP and UGT
and drug uptake and efflux transporter are involved in this cycle (50,
51). The clearance of 70% of drugs depend on CYP enzyme and the most
important drug interactions caused by inhibition and induction of this
enzyme as well as UGT in the first and second phases of drug metabolism
especially chemotherapeutic agents (52, 53). The results of our study
are consistent with similar related studies (54, 55) indicating that
most of herb-drug interactions are caused by inhibition or induction of
CYP3A4 enzyme. As regards, the metabolized of many drugs depend on this
enzyme, induction or inhibition of it can lead to unexpected toxicity
and under treatment of cancer. In this regard, physicians and other
health workers must pay more attention and had better prevent patients
from using herbal medicines in combination with other drugs.
We also found that the number of herbal medicines and also
chemotherapeutic agents as predictors increased the odds of herb-drug
interactions among cancer patients. This result is in line with the
study conducted by Levy et al. (2017) on hospitalized patients (56) and
the study by Chi et al. (2020) on community-dwelling older adults (57).
The reason for this event is clear and by increasing the number of each
drug (herbal or chemotherapy), the odds of herb-drug interaction
subsequently increased. Another predicting factor was experiencing pain
during chemotherapy which was associated with increased odds of
herb-drug interactions. The results of related studies show that
considerable proportion of patients with chronic pain used CAM (58, 59).
Licorice (60), chamomile (61) and peppermint (62) as analgesic, are
popular herbal medicines and interact with chemotherapeutic agents. As a
result, the experience of pain causes the use of herbal medicines and
the herb-drug interaction is the potential outcome of this usage.
Type of cancer and advanced cancers were the other predictors of
herb-drug interactions in this study. According to the results, patients
with gastrointestinal cancers and thorax cancers had lower odds of
herb-drug interactions versus patients with breast cancer. This
difference can be justified by two reasons. First, the majority of
patients with breast cancers are females and females are more likely to
use herbal medicines in combination with other drugs (63, 64).
Therefore, the odds of herb-drug interactions for females are more than
males which was confirmed by results of bivariable logistic regression
in our study. The second reason was related to the type of drugs used
for patients with breast cancers. Tamoxifen, Letrozole and Exemestane
are common drugs which are usually prescribed for postmenopausal breast
cancer patients. These patients used specific herbal medicines to reduce
complications of menopause such as licorice, fennel and valerian, the
supplement estrogenic activity which interact with chemotherapeutic
agents (65, 66). In contrast, patients with advanced cancers had greater
odds of herb-drug interaction versus other patients. The results of one
study showed that patients with advanced cancers were inclined to use
CAM and the prevalence of using herbal medicines among these patients
were considerable (67). There are several reasons for these patients to
use herbal medicines. They look for a way to reduce severe symptoms of
cancer and also side effects of chemotherapy courses. Also, they hope to
live longer.