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\begin{document}

\title{The prevalence and predictors of herb-drug interactions among Iranian
cancer patients during chemotherapy courses}



\author[1]{Maliheh Sadat Bazrafshani}%
\author[2]{Abbas Pardakhty}%
\author[2]{Behjat Kalantari Khandani}%
\author[2]{Haleh Tajadini}%
\author[2]{Sadra Ghazanfari Pour}%
\author[2]{Sara Hashemi}%
\author[2]{Shiva Amiri}%
\author[1]{Soheil Mehmandoost}%
\author[1]{Amin Beigzadeh}%
\author[2]{Samaneh Abbaszadeh}%
\author[1]{Hamid Sharifi}%
\affil[1]{Kerman University of Medical Sciences}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Abstract Background: The concurrent usage of herbal medicines with
conventional therapies is an important concern in cancer treatment which
can lead to unexpected consequences like herb-drug interactions. The aim
of this study was to determine the prevalence of potential herb-drug
interactions and to predict factors associated with herb-drug
interactions for cancer patients. Methods: This cross-sectional study
was conducted among a convenience sample of 315 cancer patients
referring to the oncology clinics of Kerman in 2018. Data were collected
via comprehensive face-to-face interviews and medical chart reviews. A
drug interaction checker was used to determine herb-drug interactions.
The information of patients was compared based on herb-drug interactions
by using bivariable logistic regression models and predictors were
determined by the multivariable logistic regression model. All analyses
were performed by Stata software version 16. Results: Of 262 patients
who used herbal medicines, 209 patients {[}79.8\% (95\% CI: 75.2 --
85.1){]} had potential herb-drug interactions. Chamomile was the most
popular herbal medicine (n=163, 78\%), and minor and moderate herb-drug
interactions were caused by green tea (n=34, 16.3\%) and peppermint
(n=78, 37.5\%). The number of chemotherapeutic agents (OR: 1.92, 95\%
CI: 1.43--2.58; P-value\textless{}0.0001) and the experience of pain
during chemotherapy courses (OR=2.22, 95\%CI:1.00--4.94; P-value=0.04)
were some of the predictors of herb-drug interactions among cancer
patients. Conclusion: The majority of cancer patients used herbal
medicines during chemotherapy courses and physicians could reduce the
odds of herb-drug interactions with proper education, monitor the side
effects of chemotherapy, and prevent patients from self-medication with
herbal medicines.%
\end{abstract}%



\sloppy


\textbf{The prevalence and predictors of herb-drug interactions among
Iranian cancer patients during chemotherapy courses}

Maliheh Sadat Bazrafshani\textsuperscript{1}, \emph{Abbas
Pardakhty\textsuperscript{2}} , Behjat Kalantari
Khandani\textsuperscript{3}, Haleh Tajadini\textsuperscript{4}, Sadra
Ghazanfari\textsuperscript{5}, Sara Hashemi\textsuperscript{6}, Shiva
Amiri\textsuperscript{7}, Soheil Mehmandoost\textsuperscript{1}, Amin
Beigzadeh\textsuperscript{8}, Samaneh Abbaszadeh\textsuperscript{1},

\emph{Hamid Sharifi\textsuperscript{1}}

\textsuperscript{1}HIV/STI Surveillance Research Center, and WHO
Collaborating Center for HIV Surveillance, Institute for Futures Studies
in Health, Kerman University of Medical Sciences, Kerman, Iran

\textsuperscript{2}Pharmaceutics Research Center, Neuropharmacology
Institute, Kerman University of Medical Sciences, Kerman, Iran

\textsuperscript{3}Hematology and Oncology Division, Department of
Internal Medicine, Kerman University of Medical Sciences, Kerman, Iran

\textsuperscript{4}Physiology Research Center, Institute of
Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

\textsuperscript{5}Student Research Committee, Kerman University of
Medical Sciences, Kerman, Iran

\textsuperscript{6}Departement of Medical Chemistry, Faculty of
Pharmacy, Kerman University of Medical Sciences, Kerman, Iran

\textsuperscript{7}Pharmaceutics Research Center, Institute of
Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran;
Department of Toxicology and Pharmacology, Faculty of Pharmacy, Kerman
University of Medical Sciences, Kerman, Iran

\textsuperscript{8}Sirjan School of Medical Sciences, Sirjan, Iran

\textbf{Corresponding authors: Hamid
Sharifi,}\emph{sharifihami@gmail.com,}\textbf{Abbas
Pardakhty,}apardakhty@yahoo.com

\textbf{Address:} HIV/STI Surveillance Research Center, and WHO
Collaborating Center for HIV Surveillance, Institute for Futures Studies
in Health, Kerman University of Medical Sciences, Kerman, Iran

\textbf{Postal Code:} 7616914111, Kerman, Iran

\textbf{Tel:} +98 3431325422

\textbf{Fax:} +98 3433222047

\textbf{Cell Phone:} +98 9133485812

\textbf{E-mail:}sharifihami@gmail.com

\textbf{Abstract}

\textbf{Background:} The concurrent usage of herbal medicines with
conventional therapies is an important concern in cancer treatment which
can lead to unexpected consequences like herb-drug interactions. The aim
of this study was to determine the prevalence of potential herb-drug
interactions and to predict factors associated with herb-drug
interactions for cancer patients.

\textbf{Methods:} This cross-sectional study was conducted among a
convenience sample of 315 cancer patients referring to the oncology
clinics of Kerman in 2018. Data were collected via comprehensive
face-to-face interviews and medical chart reviews. A drug interaction
checker was used to determine herb-drug interactions. The information of
patients was compared based on herb-drug interactions using bivariable
logistic regression models and predictors were determined by the
multivariable logistic regression model. All analyses were performed by
Stata software version 16.

\textbf{Results:} Of 262 patients who used herbal medicines, 209
patients {[}79.8\% (95\% CI: 75.2 -- 85.1){]} had potential herb-drug
interactions. Chamomile was the most popular herbal medicine (n=163,
78\%), and minor and moderate herb-drug interactions were caused by
green tea (n=34, 16.3\%) and peppermint (n=78, 37.5\%). The number of
chemotherapeutic agents (OR: 1.92, 95\% CI: 1.43--2.58;
P-value\textless{}0.0001) and the experience of pain during chemotherapy
courses (OR=2.22, 95\%CI:1.00--4.94; P-value=0.04) were some of the
predictors of herb-drug interactions among cancer patients.

\textbf{Conclusion:} The majority of cancer patients used herbal
medicines during chemotherapy courses and physicians could reduce the
odds of herb-drug interactions with proper education, monitor the side
effects of chemotherapy, and prevent patients from self-medication with
herbal medicines.

\textbf{Keywords: Cancer, Chemotherapy, Herbal medicine, Food/Herbal
drug interactions}

\emph{}

1. Introduction

Cancer is one of the major leading causes of death worldwide (1).
According to World Health Organization (WHO) reports, breast,
colorectal, lung, and liver cancers had the highest incidence and
mortality rate in the Eastern Mediterranean Region (EMR) in 2020 (2).
These types of cancers with similar incidence and mortality are also
observed in Iran and there is an increment trend in incidence and
mortality rate for most cancers (3). Surgery, radiation therapy, and
systemic treatment are the main cancer treatment protocols that are
applied separately or in combination for cancer patients (4).
Chemotherapy, as a systemic treatment of cancer, has many side effects
(5) such as nausea and vomiting, diarrhea, mucositis, fatigue, and hair
loss (6, 7).

For reducing the short-term and long-lasting side effects of
chemotherapy, a great proportion of cancer patients used the
Complementary and Alternative Medicines (CAM) (8-10); this usage is
commonly without the consultation provided by physicians and health care
workers (11). Among CAM therapies, herbal medicines are more popular
among patients. Current reports show a remarkable and variable
prevalence of using herbal medicine by cancer patients from 14\% to
66.7\% (12-15), especially during conventional treatments or palliative
care and chemotherapy (37\% -38\%) (16, 17). In fact, the concurrent
usage of herbal medicines with conventional therapies is one of the most
important concerns in cancer treatment which can lead to unexpected
consequences (18, 19).

In the pharmacokinetic interactions, herbal medicines due to their
pharmacokinetic properties interact with chemical agents and affect the
absorption, distribution, metabolism, and excretion of chemotherapeutic
agents when orally used. The pharmacodynamics interactions often are
lower clinically significant than pharmacokinetic interactions (20-22).
The herb-drug interactions in cancer patients are more important,
however, the prevalence of this event among cancer patients is not known
and limited studies reported only a proportion of patients who were at
risk for herb-drug interactions (19, 23, 24). Along with the unclear
prevalence of herb-drug interactions in cancer patients, the
epidemiological predictors of it are also unknown and several studies
have only reported the mechanisms of some herb-drug interactions (19,
25, 26). As regards a great proportion of Iranian cancer patients use
herbal medicine in combination with a chemotherapeutic agent (27), and
according to the lack of updated studies on this issue, the aim of this
study was to determine the prevalence of potential herb-drug
interactions among these patients and also identify the epidemiological
predicting factors of herb-drug interactions for Iranian cancer
patients.

2. Material and methods

2.1 subject and setting

The present cross-sectional study was conducted among 315 cancer
patients who referred to the oncology clinics of Kerman (one private and
two governmental clinics) during February to June 2018. These patients
were selected via convenience sampling method and sampling was not
restricted to sex, cancer site and clinical stage of cancer. The
inclusion criteria were age above 18 years and receiving at least one
chemotherapy courses through infusion, injection or oral route. Patients
who had completed the chemotherapy course one month before the survey
were also eligible for the study.

2.2 Data collection

In this study data were collected via comprehensive face to face
interviews and also medical chart reviews. For interview, we designed an
interview form consisting of three separated parts. In the first part
age, sex, marital status, place of residence and educational level of
patients were collected as demographic information. The second part
included the common name of herbal medicines which patients used them in
oral route during chemotherapy courses. In the last part of the
interview form, common side effects of chemotherapy such as constipation
and diarrhea, nausea and vomiting, pain, skin and oral lesions were
asked. In this part, the status of other comorbidity illnesses was
recorded. The first author interviewed all patients in waiting rooms of
clinics before the start of chemotherapy course or after its completion.
Other clinical information was obtained through medical chart review.
The cancer site, clinical stage, metastatic status and recurrence status
were in clinical information category. To protect patients' privacy,
this part of the data collection was done by the staff of the oncology
clinics.

2.3 herb-drug interaction assessment

For checking herb-drug interactions, we used a drug interaction checker
supported by natural medicine collaboration (URL:
https://naturalmedicines.therapeuticresearch.com/). The scientific names
of herbal medicines and the generic name of chemotherapeutic agents as
pair of herb-drug check together. In this part, the scientific name of
herbal medicines was determined and approved by two herbalists.
According to the results, interactions were stratified in three levels:
minor, moderate and major based on the evidence (anecdotal evidence,
theoretically based on pharmacology, vitro studies, randomized and
non-randomized clinical trials).

2.4 Ethical approval

The protocol of the study was reviewed and approved by the Ethics
Committee of Kerman University of Medical Sciences (ethics no:
IR.KMU.REC.1396.1278). In this study, oral informed consent was obtained
prior to interviews by the first author of the study.

2.5 Data analysis

Data were described using mean \selectlanguage{ngerman}± Standard Deviation (SD), frequency, its
percentage and 95\% Confidence Intervals (CIs). Demographic and clinical
information of patients were compared based on herb-drug interactions by
bivariable logistic regression models. Every variable with a
P-value\textless{}0.2 in bivariable models was selected and entered into
the multivariable logistic regression model using backward elimination.
In every step of multivariable models, variables with great P-value were
continuously removed from the model set until all remaining variables in
the model were significant (P-value\textless{}0.05). All descriptive and
analytical analyses were performed by using Stata software version 16.

3. Results

3.1 Demographic and clinical information of cancer patients with herbal
medicines

Of 315 cancer patients recruited for the study, 262 patients (83.2\%;
95\% CI: 78.6, 87.1) used at least one herbal medicine during
chemotherapy courses and were included in this analysis. The mean ± SD
age of cancer patients who used herbal medicines was 51.1±14.0 years
(age range: 18 to 92). More than 70\% of the patients were females
(n=188, 71.8\%) and urban residents (n=204, 77.9\%). The majority of
cancer patients were married (n=248, 94.7\%). More than half of the
patients were under diploma (n=152, 58.0\%). Breast was the most
prevalent cancer site among patients (n=98, 37.4\%). Almost nearly half
of the patients had metastatic cancers (n=117, 44.7\%), but recurrence
was not frequent among them (n=45, 17.2\%). More than half of the
patients suffered from comorbidities (n=138, 52.7\%). Common
complications among patients were nausea and vomiting (n=186, 71.0\%),
constipation and diarrhea (n=169, 64.5\%) and pain (n=160, 61.1\%)
(Table 1).

3.2 Prevalence of herb-drug interactions

Of 262 patients with herbal medicine, 209 patients {[}79.8\% (95\% CI:
75.2 -- 85.1){]} had potential herb-drug interaction. The prevalence of
herb-drug interactions based on demographic and clinical information is
shown in Table 1.

3.3 Properties of chemotherapy regimens of cancer patients with
interaction

Thirty-three different chemotherapeutic agents were prescribed for
cancer patients. The mean ± SD of prescribed medications was 4.0±1.8 per
patient (medication range: 1 to 10). Cyclophosphamide was the most
frequent chemotherapeutic agent (n=105, 50.2\%). Arsenic Trioxide,
Flutamide, Nivolumab, and Thalidomide (n=1, 0.48\%) were the least
prescribed chemotherapeutic agents. The common chemotherapeutic agents
are presented in Fig 1.

3.4 Properties of herbal medicines used by cancer patients with
potential interaction

Cancer patients with potential herb-drug interaction reported 78
different herbal medicines used during chemotherapy courses. The mean ±
SD number of herbal medicines among these patients was 12.6 ± 5.5 per
patient (range: 2 to 29). The \emph{Matricaria chamomilla L.}(chamomile)
was the most popular herbal medicine among cancer patients. The most
frequent herbal medicines used by a significant percentage of cancer
patients are depicted in Fig 1.

3.5 Frequency and types of herb-drug interactions

Based on the findings, 128 pairs of herbs and drugs can lead to
potential herb-drug interactions. Of them, 19 and 116 pairs of herbs and
drugs caused potential minor and moderate herb-drug interactions among
cancer patients. In this study no major herb-drug interaction was found.
Potential moderate herb-drug interactions occurred in all patients
(n=209, 100\%), while potential minor herb-drug interactions happened in
less than a third of the patients (n=67, 32.1\%). The frequent potential
minor and moderate herb-drug interaction was caused by \emph{Camellia
sinensis L\textbf{.}} (green tea) (n=34, 16.3\%) and \emph{Mentha
piperita L} . (peppermint) (n=78, 37.5\%), respectively when used in
combination with Cyclophosphamide. Among herbal medicines,\emph{Camellia
sinensis L.} (green tea), \emph{Matricaria chamomilla L.}(chamomile),
\emph{Curcuma longa L.} (Turmeric) and \emph{Silybum marianum L.Gaertn}
(milk thistle) caused both potential minor and moderate herb-drug
interactions. Potential minor and moderate herb-drug interactions are
detailed in Appendix A.

3.6 Frequency of confirmed evidence for herb-drug interactions

In this study, the considerable number of herb-drug interactions was
determined or confirmed with vitro (66 studies) and clinical studies (46
studies, randomized and non-randomized clinical trials) and only 4
herb-drug interactions were based on anecdotal evidence (Fig 2). All
herb-drug interactions were confirmed by one evidence except nine
herb-drug interactions which were confirmed by two evidences. These
pairs were ``Cyclophosphamide and \emph{Mentha piperita L} .'' (Vitro
and randomized clinical trial), ``Cyclophosphamide and \emph{Glycyrrhiza
glabra L.''} (Vitro and randomized clinical trial), ``Docetaxel
and\emph{Glycyrrhiza glabra L.''} (Vitro and randomized clinical trial),
``Doxorubicin and \emph{Valeriana officinalis L.''} (Vitro and
non-randomized clinical trial), ``Paclitaxel and \emph{Glycyrrhiza
glabra L.''} (Vitro and randomized clinical trial), ``Tamoxifen
and\emph{Mentha piperita L} .'' (Vitro and randomized clinical trial),
``Tamoxifen and \emph{Foeniculum vulgare Mill''} (Vitro and
theoretically based on pharmacology), ``Tamoxifen and \emph{Valeriana
officinalis L.''} (Vitro and non-randomized clinical trial) and
``Tamoxifen and \emph{Glycyrrhiza glabra L.''} (Vitro and randomized
clinical trial). The type of evidence for other herb-drug interactions
is presented in Appendix A.

3.7 Mechanisms of actions of herb-drug interactions

Based on the reported evidences, in the most drug interactions,
induction or inhibition of hepatic and intestinal Cytochrome P450 3A4
(CYP3A4) were occurred (139 cases; 69.8\%). Results showed that the
first phase of metabolism of chemotherapeutic agents which mostly depend
on CYP3A4 was impaired. Other frequent mechanisms of herb-drug
interactions were the dip of GI transit time (11 cases) and the plunge
of hepatotoxicity of chemotherapeutic agents (8 cases) (table 2).

3.8 Demographic and clinical correlates of herb-drug interaction among
cancer patients

The bivariable logistic regression models showed that herb-drug
interactions were related to sex, cancer site, recurrence status,
experience pain as chemotherapy complication, and the number of
chemotherapeutic agents and herbal medicines. Based on the results,
females (OR: 2.28, 95\% CI: 1.22--4.26; P-value=0.01), and patients with
the experience of pain during chemotherapy (OR: 3.16, 95\% CI:
1.70--5.87; P-value\textless{}0.0001) had greater odds of herb-drug
interactions. By increasing the number of chemotherapeutic agents (OR:
1.75, 95\% CI: 1.40--2.19; P-value\textless{}0.0001) and herbal
medicines (OR: 1.12, 95\% CI: 1.05--1.20, P-value\textless{}0.0001) the
odds of herb-drug interactions increased for cancer patients. In
contrast, patients with gastrointestinal cancers (OR: 0.09, 95\% CI:
0.03--0.24, P-value\textless{}0.0001) and other types pf cancers (OR:
0.20, 95\% CI: 0.04--0.95, P-value=0.04) versus patients with breast
cancer had a lower odd of herb-drug interactions. Also, cancer patients
with unclear recurrence status had lower odds of herb-drug interaction
in comparison to patients with negative recurrence status (OR: 0.19,
95\% CI: 0.04--0.89, P-value: 0.03) (Table 3).

3.9 Predictors of herb-drug interactions

According to the results of the multivariable logistic regression model,
the number of chemotherapeutic agents (OR: 1.92, 95\% CI: 1.43--2.58;
P-value\textless{}0.0001), number of herbal medicines (OR: 1.15, 95\%
CI: 1.06--1.24, P-value\textless{}0.0001), gastrointestinal cancers (OR:
0.08, 95\% CI: 0.02--0.30, P-value\textless{}0.0001), thorax cancers
(OR: 0.10, 95\% CI: 0.01--0.61, P-value= 0.01), IV clinical stage (OR:
8.42, 95\% CI: 1.10--64.04, P-value= 0.04), unclear recurrence status
(OR: 0.06, 95\% CI: 0.005--0.67, P-value= 0.02) and the experience of
pain during chemotherapy (OR=2.22, 95\%CI:1.00--4.94; P-value=0.04) were
determined as the predictors of herb-drug interactions among cancer
patients (Table 4).

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.

\textbf{Limitations}

The main limitation in this study was related to determining scientific
names of herbal medicines because some of the herbal medicines with one
common name have several scientific names which are different in
therapeutic properties. For this issue, the herbalists selected the
prevalent species of herbal medicines in our country (Iran). The other
limitation was underestimation of herbal medicines which patients used.
Because they used some herbal medicines but did not remember the name of
them due to recall bias. The other limitation of this study is related
to the design of the study. As this was a cross-sectional study, we
could not confirm the causation of the predictor variables with the
potential herb-drug interaction as the outcome.

4.1 Conclusion

The results of our study revealed that the majority of cancer patients
used herbal medicines during chemotherapy courses and all of them who
used herbal medicines had potential herb-drug interactions. As regards,
the consequences of herb-drug interactions may be life-threating or
change the treatment process of cancer patients. In addition, as the
interactions of many herbal medicines with chemotherapeutic agents are
not clear, physicians and health care workers should pay more attention
to these patients and avoid them to take herbal medicines in combination
with chemotherapeutic agents. The risk of herb-drug interactions will
remarkably decrease with proper patient education and the training of
their families, monitoring the side effects of chemotherapy in patients
and consulting patients to prevent them from self-medication with herbal
medicines by involving traditional medicine specialists in the treatment
process of cancer patients. Extensive studies are recommended to
determine the interactions between herbal medicines and chemotherapeutic
agents.

Acknowledgement

We thank cancer patients and their families for their participation in
this study and also, we are particularly grateful to the staff of
oncology clinics for helping us in data collection. We greatly
appreciate Professor Mir Tajadini, Sharifi Far and Rameshk for all the
helpful advice in identifying medicinal plant species used as herbal
medicines.

Conflicts of interest

None

Funding

This study was funded by the research deputy of Kerman University of
Medical Sciences. (Grant number, 95000567).

Availability of Data

``Data sharing not applicable''

Author contribution

All authors contributed to the conceptualization of the study and its
methodology. H.S., A.B., S.A., B.K.K. and H.T. was responsible for data
curation. Formal analysis and validation were conducted M.S.B, S.M. and
A.P. also validated the study. H.S. was the project administrator and
wrote the original draft. S.A., S.G.P. and S.H supervised the project.
All authors reviews and edited the final version.

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