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\begin{document}

\title{The efficacy and safety of silymarin in the treatment of
chemotherapy-induced peripheral neuropathy, a randomized double-blinded
clinical trial}



\author[1]{Ramin Shekarriz}%
\author[1]{Hojjat Ghorbani}%
\author[1]{Mahmoud Mousazadeh}%
\author[2]{Khatereh Vahedi}%
\author[3]{Ebrahim Salehifar}%
\affil[1]{Mazandaran University of Medical Sciences}%
\affil[2]{Isalmic Azad University}%
\affil[3]{Mazandaran University of Medical Sciences Faculty of Pharmacy}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Aim: The aim of this study was to evaluate the efficacy and side effects
of silymarin in the treatment of CIPN. Methods: Patients who referred to
outpatient oncology department of a referral educational hospital
affiliated to Mazandaran University of Medical Sciences and experienced
CIPN were randomized to receive silymarin or placebo. Intervention group
received 140 mg of the Silymarin twice daily accompanied and 300 mg/day
Gabapentin, whereas control group received 300 mg/day of Gabapentin and
placebo twice daily for 3 months. The grade of neuropathy was determined
according to the CTCAE criterion. The improvement of neuropathy was
defined as the reduction of at least one neuropathic score. The visual
analogue scale (VAS) was used to assess the severity of patients' pain
and the EORTC-QLQ-C30 criterion was used to assess the quality of life.
Patients were evaluated initially and at the follow up visit 3 months
after the enrollment. Results: A total of 80 patients were enrolled in
the study. There was no significant difference between the groups in
terms of severity of neuropathy at baseline. At the end of the study,
the number of people with improved neuropathy in the silymarin group was
82.8\% patients, which was significantly higher than 48.4\% observed in
the patients received placebo (P= 0.005). The silymarin-treated group
showed a significant reduction in pain compared with those receiving
placebo. Despite the improvement in quality of life in the intervention
group compared to the comparison group, this difference was not
statistically significant. Gastrointestinal symptoms were the only
reported side effects with a similar incidence in two groups.
Conclusion: The present data demonstrate the potential clinical use of
silymarin as an adjuvant therapy to reduce CIPN symptoms.%
\end{abstract}%



\sloppy


\textbf{The efficacy and safety of silymarin in the treatment of
chemotherapy-induced peripheral neuropathy, a randomized double-blinded
clinical trial}

Running Title: \textbf{Silymarin in neuropathy of chemotherapy}

\textbf{Abstract}

\textbf{Aim:} The aim of this study was to evaluate the efficacy and
side effects of silymarin in the treatment of chemotherapy-induced
peripheral neuropathy (CIPN).

\textbf{Methods:} Patients who referred to outpatient oncology
department of a referral educational hospital affiliated to Mazandaran
University of Medical Sciences and experienced CIPN were randomized to
receive silymarin or placebo. Intervention group received 140 mg of the
Silymarin twice daily accompanied and 300 mg/day Gabapentin, whereas
control group received 300 mg/day of Gabapentin and placebo twice daily
for 3 months. The grade of neuropathy was determined according to the
CTCAE criterion. The improvement of neuropathy was defined as the
reduction of at least one neuropathic score. The visual analogue scale
(VAS) was used to assess the severity of patients' pain and the
EORTC-QLQ-C30 criterion was used to assess the quality of life. Patients
were evaluated initially and at the follow up visit 3 months after the
enrollment.

\textbf{Results:} A total of 80 patients were enrolled in the study.
There was no significant difference between the groups in terms of
severity of neuropathy at baseline. At the end of the study, the number
of people with improved neuropathy in the silymarin group was 82.8\%
patients, which was significantly higher than 48.4\% observed in the
patients received placebo (P= 0.005). The silymarin-treated group showed
a significant reduction in pain compared with those receiving placebo.
Despite the improvement in quality of life in the intervention group
compared to the comparison group, this difference was not statistically
significant. Gastrointestinal symptoms were the only reported side
effects with a similar incidence in two groups.

\textbf{Conclusion:} The present data demonstrate the potential clinical
use of silymarin as an adjuvant therapy to reduce CIPN symptoms.

\textbf{Keywords:} Silymarin, Chemotherapy-induced peripheral neuropathy
(CIPN), Inflammation, Platinum, Taxanes, Vinca alkaloids

\textbf{What is already known about this topic?}

\begin{itemize}
\tightlist
\item
  Chemotherapy-induces peripheral neuropathy is a common complication of
  chemotherapy agents with a significant impact on patients' quality of
  life.
\item
  Oxidative stress and inflammation has a critical role in the
  development of chemotherapy-induces peripheral neuropathy.
\item
  Silymarin was effective in reducing chemotherapy-induced neuropathic
  pain in animal studies.\textbf{What does this article add?}
\end{itemize}

\begin{itemize}
\tightlist
\item
  Silymarin significantly reduced the severity of chemotherapy-induces
  peripheral neuropathy as measured by Common Terminology Criteria for
  Adverse Events (P= 0.005).
\item
  The silymarin-treated group showed a significant reduction in pain
  compared with those receiving placebo (P= 0.001).
\item
  The frequency of adverse effects of silymarin was similar to placebo.
\end{itemize}

\textbf{1. Background}

Chemotherapy-induces peripheral neuropathy (CIPN) is a common
complication of chemotherapy agents with a significant impact on
patients' quality of life. The risk of developing CIPN is higher among
conventional chemotherapy drugs especially with platinum (e.g.,
cisplatin and oxaliplatin), taxanes, and vinca alkaloids {[}1, 2{]}.

The development of CIPN during antineoplastic therapy is one of the most
common cause of the termination or modification of cancer treatment
{[}3{]}. Peripheral neuropathy may present as sensory, motor, or
autonomic dysfunction. Clinical signs of neurological complications
include paresthesia, numbness of the fingers, gait disturbance, ataxia,
loss of deep tendon reflexes, wrist or foot drop, facial nerve palsy,
and optic neuropathy {[}4, 5{]}.

The functional impairment of neurons induced by chemotherapeutic drugs
may be mediated through oxidative stress, inflammation, apoptosis and
electrophysiological disturbances {[}6{]}. In oxidative stress, the
release of oxygen free radicals including hydrogen peroxide, superoxide
ions, and nitric oxide causes changes in cell components which may lead
to lipid peroxidation and subsequent cell death {[}7-9{]}. Silymarin is
a flavonoid mixture extracted from Silybum marianum seed, which consists
of a mixture of flavolignans including silibinin, isosilibinin,
silicristin, and silidianin {[}10{]}. Although silymarin has been mostly
known as its hepatoprotective properties {[}11{]}, growing evidence has
shown the neuroprotective effects of silymarin in neurodegenerative
diseases, such as Alzheimer's disease, Parkinson's disease, and cerebral
ischemia, via reducing reactive oxygen species (ROS), decreasing
inflammatory cytokines, and altering cellular apoptosis pathway
{[}12{]}. Beside the positive effect on CIPN, Laboratory data show that
silymarin and its compounds (especially silibinin) have strong
anticarcinogenic effect against cancer cells such as breast cancer and
human promyelocytic leukemia HL-60 cells {[}13, 14{]}.

It is acknowledged that the treatment of peripheral neuropathy is
difficult and completely relieve of peripheral neuropathy (especially
associated pain) may not occur with current therapies and complementary
therapies may help in better management of CIPN {[}4, 15, 16{]}.

The aim of this study was to evaluate the efficacy and side effects of
silymarin in the treatment of peripheral neuropathy caused by
chemotherapy drugs.

\textbf{2. Methods}

\textbf{2.1. Patients:}

In our study, 236 patients who referred to the outpatient oncology
department of Emam Hospital, affiliated to Mazandaran University of
Medical Sciences were screened for enrollment. Eighty patients were
eligible for the study. Inclusion criteria were a histologically
confirmed diagnosis of cancer, at least 18 years of age, and occurrence
of CIPN.

Exclusion criteria were 1) any underlying diseases with manifestation of
neuropathy symptoms including diabetes, neuromuscular disease, vitamin
B12 deficiency, amyloidosis, and connective tissue disease, 2) patients
with a history of neurological diseases such as hereditary and acquired
neuropathies, 3) taking any antioxidant supplement in the last two
months, 4) pregnancy or breastfeeding, 4) known hypersensitivity to
silymarin. All participants gave their written informed consent.
Eligible patients were randomly~assigned to treatment arms on a~1:1
basis.

The study was approved by the ethics committee of Mazandaran University
of Medical Sciences (IR.MAZUMS.IMAMHOSPITAL.REC.1398.6176) and
registered in Iranian Registry of Clinical Trials
(IRCT20201128049515N1). The trial was conducted according to the
guidelines of the Declaration of Helsinki for Research on Human Subjects
1989. Considering the effect size of 0.6, 95\% confidence level and test
power of 80\%, sample size was calculated 80 patients (40 cases in each
group) by G-Power software.

\textbf{Figure 1: Here}

\textbf{2.2. Study Design:}

This was a randomized, double-blind, placebo-controlled study. Patients
treated with chemotherapy regimens consist of taxanes, platinum
derivatives, vincristine or thalidomide and experienced symptoms of
peripheral neuropathy were screened for enrollment. Block randomization
with the size of four in each block was used to allocate patients in
treatment or control arms. Each patient was assigned a computer-based
unique five-digit randomization code. The codes was held by a third
party and handed over for statistical analyses after the complement of
data collection. Both Silymarin and placebo were manufactured by an
authorized pharmaceutical company (Goldaru, Isfahan, Iran). The placebo
and silymarin were indistinguishable in size, weight, and their
appearance. The treatment regimens was carried out according to the
following scheme: Intervention group received 140 mg of the silymarin in
two daily doses with 300 mg/day Gabapentin as a usual treatment of
peripheral neuropathy, while the comparison group received 300 mg/day of
Gabapentin and placebo (filled by microcrystalline cellulose). The
schedule of administration of placebo was equal to silymarin (twice
daily). Duration of trial was 3 months. Patients were evaluated at
baseline and 3 months after entering the study.

The primary objective was to evaluate the efficacy of the drug.
Demographic and clinical characteristics of patients were recorded.
Possible side effects of silymarin were recorded.

The CTCAE criterion (Common Terminology~Criteria~for Adverse Events) was
used to assess the severity of neuropathy {[}17{]}. The grading of
neuropathy was carried out based on the presence of paresthesia,
peripheral motor neuropathy or peripheral sensory neuropathy and the
level of limiting impact on activity of daily living (ADL) or self-care
ADL. Improvement of neuropathy was defined as the reduction of at least
one neuropathic score.

According to this criterion, a score of zero is equivalent to the
absence of neuropathy, a score of 1 is equivalent to mild neuropathy, a
score of 2 is equivalent to moderate neuropathy which limits
instrumental ADL, a score of 3 is equivalent to severe neuropathy
correspond which limits the self-care ADL, a score of 4 is equivalent to
life-threatening neuropathy.

The visual analogue scale (VAS) was also used to assess the severity of
patients' pain. The visual analogue scale was rated from 0 (no pain) to
10 (the most severe pain the patient has ever experienced). The
EORTC-QLQ-C30 (European Organization for Research and Treatment of
Cancer - quality of life - questionnaires ) criterion was used to assess
the improvement of patients' quality of life {[}18{]}.

\textbf{2.3. Statistical Analysis:}

Mean and standard deviation were used to describe quantitative data and
frequency and percentage were used to describe categorical data. ANCOVA
test was used to evaluate the effect of silymarin on quantitative
variables (EORTC QLQ and VAS) so that the final EORTC QLQ and VAS scores
were used as the main factor and adjusted based on the initial score.
Chi-square test was used to describe the qualitative outcomes (e.g.,
severity of neuropathy and number of patients improved). All tests were
calculated at 95\% significance level using SPSS software version 21.

\textbf{3. Results:}

In this trial, 236 patients were screened for eligibility and 80
patients enrolled (Figure 1).

The silymarin and placebo groups were similar in terms of sex, age and
the frequency of each class of chemotherapy drugs used for patients
(Table 1).

\textbf{Table 1: Here}

The mean score of EORTC QLQ of patients allocated to silymarin treatment
was 94.07 \selectlanguage{ngerman}± 6.65, whereas it was 93.02 ± 7.16 in the placebo group. The
mean final EORTC QLQ was 94.47 ±7.32 in the intervention group and 92.42
±8.39 in the comparison group. In the present study, analysis of
covariance showed that the mean differences of EORTC QLQ in the
intervention group improved 1.06 times more than the comparison group,
but this difference was not statistically significant (p-value = 0.4)
(Table 2).

\textbf{Table 2: Here}

The mean score of VAS in the Silymarin group and placebo group were
5.77± 1.79 and 5.73± 1.98, respectively. The mean of final VAS was
2.13±1.45 in the silymarin group and 4.2±1.85 in the placebo group.
Analysis of covariance showed that VAS in the intervention group
decreased 1.99 times (95\% CI: 1.001-2.975) more than the comparison
group and this difference was statistically significant (p-value
\textless{}0.0001) (Figure 2).

\textbf{Figure 2: Here}

The severity of CIPN was measured using the CTCAE criterion. There was
no significant difference between the two groups in the severity of
neuropathy at the beginning of the study (Table 3).

\textbf{Table 3: Here}

Improvement of neuropathy was defined as the reduction of at least one
neuropathic score. The number of people with improved neuropathy was
significantly higher in the silymarin group compared to placebo group
(Table 4).

\textbf{Table 4: Here}

Six patients in placebo group and 7 patients in silymarin group
experienced gastrointestinal symptoms (e.g., epigastric pain, nausea and
vomiting). Three patients in silymarin group and 2 patients in placebo
group discontinued the trial due to side effects. Overall, the side
effects were tolerable and were managed with advising patients to
receive the study drug after meal.

\textbf{4. Discussion}

To our knowledge, this is the first randomized, double-blind,
placebo-controlled clinical trial to evaluate the efficacy and safety of
silymarin in the treatment of CIPN. The silymarin-treated group showed a
significant reduction in pain (measured by the VAS criterion) compared
with those receiving placebo. Silymarin also significantly reduced the
severity of peripheral neuropathy and more people in the
silymarin-treated group showed improvement in peripheral neuropathy
compared to the comparison group. But despite the improvement in quality
of life in the intervention group compared to the comparison group, this
difference was not statistically significant.

The development of CIPN during chemotherapy adversely affects the
outcome of the disease and the patient's quality of life {[}19{]}.
Cumulative doses of chemotherapy drugs, prior or concomitant
administration of other neurotoxic drugs (such as cisplatin plus
paclitaxel combination therapy), pre-existing neuropathy, co-morbidities
and finally the short injection time of the drug are the most important
risk factor for CIPN {[}2{]}.

More than 40 randomized trials have evaluated a variety of pharmacologic
interventions for the treatment of CIPN, only limited agents such as
duloxetine and in some trials gabapentin were effective {[}20-22{]}. Due
to the side effects of synthetic drugs following long-term use for
painful and inflammatory conditions, many studies have tested different
plant extracts and their active compounds for their analgesic and
anti-inflammatory properties {[}23{]}. Oxidative stress and increased
free radicals have been suggested as an important cause of CIPN.
Silymarin, due to its antioxidant activity, may have protective effect
against neuropathy {[}24{]}. Silymarin is a free radical scavenger that
affects various stages of the arachidonic acid cascade via the
cyclogenase and lipoxygenase pathways {[}7{]}.

The present study showed significantly better improvement of CIPN
following use of silymarin compared to placebo (82.8\% vs. 48.4\%). The
initial evidence of efficacy of silymarin in CIPN comes from
experimental studies. Mannelli et al evaluated the efficacy of
silybinin, an structural component of silymarin {[}25{]}, in reducing
oxaliplatin-induced neuropathic pain in a rat model. They reported that
repeated administration of silybinin reduces oxaliplatin-induced pain.
Silybinin was introduced as a valid treatment option for
chemotherapy-induced neuropathy {[}26{]}.

The effects of topical administration of silymarin in prevention of
capecitabine-induced Hand--Foot Syndrome (HFS) were evaluated in a
randomized, double-blinded, placebo controlled clinical trial. The trial
concluded that prophylactic administration of topical silymarin could
significantly reduce the severity of capecitabine-induced HFS and delay
its occurrence in patients with gastrointestinal cancer after 9 weeks of
application {[}27{]}. Choi et al. showed that oxaliplatin-induced
neuropathy was inhibited by silymarin through combined mechanisms of
combating oxidative stress, p38-mediated mitogen-activated protein
kinase apoptosis, and decreased brain derived neurotrophic factor
expression {[}28{]}.

Following exposure to platinum agents, several morphological changes in
DNA including damage to cell bodies, nuclei, nucleoli, neuronal atrophy
in dorsal root ganglion cells and cell death may occur. In addition to
platinum agents, ROS may have a role in the pathophysiology of CIPN
following other chemotherapy agents such as taxane derivatives.
Paclitaxel enhances the formation of ROS through alterations in
mitochondria and subsequent pain caused by neurological and inflammatory
damage through transient receptor potential ankyrin 1 (TRPA1) channels.
It also leads to the production of Interleukin-1 \selectlanguage{greek}β \selectlanguage{english}(IL-1\selectlanguage{greek}β\selectlanguage{english}) and other
proinflammatory cytokines secreted from microglia {[}26, 28{]}. Vinca
alkaloids, including vincristine cause inflammatory reactions in
peripheral tissues and make changes in spinal afferent fiber. Increased
C fiber degradation, calcium channel modulation, production of free
radicals are mechanisms proposed for neuropathic pain following taxan
derivatives. Also, they increase TNF-\selectlanguage{greek}α \selectlanguage{english}and IL-6 in the sciatic nerve
following oxidative stress {[}29, 30{]}. Based on the aforementioned
evidences, it seems that oxidative stress is the main cause of
neuropathic pain by nearly all types of chemotherapy agents. So the
beneficial effect of silymarin in CIPN could be contributed to its
proven antioxidant properties {[}31{]}.

Growing evidences suggest that different immune cells and subsequently
inflammation are involved in the development of neuropathic pain.
Activation of mast cells and secretion of inflammatory mediators
(histamine and Tumor Necrosis Factor {[}TNF{]}-\selectlanguage{greek}α\selectlanguage{english}) may lead to peripheral
nerve damage. Silymarin modulates the immune system by inhibiting
neutrophil migration and immobilization of mast cells. It also inhibits
TNF-\selectlanguage{greek}α \selectlanguage{english}mediated production of reactive oxygen species, lipid peroxidation
and modulates T cell function {[}32-34{]}.

For an anti-neuropathic agent to be desirable in CIPN, it is necessary
that the agent does not interfere with the cytotoxicity effect of the
chemotherapy agent {[}35{]}.

It was shown that silymarin poses a dual action as a chemopreventive
agent and a chemosensitizer. Silymarin inhibits organic anion
transporters (OAT) and ATP-binding cassettes (ABC) transporters which
are helpful in overcoming the resistance to chemotherapy {[}36{]}. It
may has a protective role against cancer in vivo and in vitro by
inducing an imbalance between cell survival and apoptosis by disrupting
the expression of cell cycle regulators and proteins involved in
apoptosis {[}37{]}. Also anti-metastatic activity has been reported for
silybinin {[}28{]}.

Our study suffers from this limitation that it was not powered enough
for subgroup analysis based on CIPN associated with different
chemotherapeutic agents. Considering the positive findings of this
trial, we recommend conducting future clinical trials to have a better
understanding of usefulness of silymarin in treatment of CIPN induced by
a given chemotherapeutic class.

\textbf{Conclusion:}

The results of this clinical trial demonstrate the potential clinical
use of silymarin as an adjuvant therapy to reduce CIPN symptoms.

\textbf{Declarations}

\textbf{Ethics approval and consent to participate}

All procedures performed in study involving human participants were in
accordance with the ethical standards of the institutional and/or
national research committee and with the 1964 Helsinki declaration and
its later amendments or comparable ethical standards. Also ethics
committee of Mazandaran University of Medical Sciences, Iran approved
this study (Code no: IR.MAZUMS.IMAMHOSPITAL.Rec.1398.6176).

\textbf{Consent for publication}

Not applicable

\textbf{Availability of data and materials}

The datasets used and/or analysed during the current study are available
from the corresponding author on reasonable request.

\textbf{Competing interests}

The authors declare that they have no competing interests.

\textbf{Funding}

This study was funded by an academic grant from Mazandaran medical
University.

\textbf{Authors' contributions}

R.Sh. and E.S. were involved in planning and supervised the work. H.Gh.
and Kh.V. collected the data. M.M. performed the statistical analysis
and aided in interpreting the results. R.Sh., H.Gh. and E.S. wrote the
manuscript in consultation with M.M. All authors discussed the results
and approved the final manuscript.

\textbf{Acknowledgements}

We would like to acknowledge the Research and Technology Deputy of
Mazandaran University of Medical Sciences for financial support of the
trial. Also we appreciate the Goldaru Company for free providing of the
silymarin and placebo.

\textbf{Authors' information (optional)}

\textbf{List of abbreviations:}

ABC transporters: ATP-binding cassettes transporters

ADL: Activity of daily living

CIPN: Chemotherapy induced peripheral neuropathy

CTCAE\textbf{:} Common Terminology Criteria for Adverse Events

EORTC-QLQ-C30: European Organization for the Research and Treatment of
Cancer Quality of Life Questionnaire

HFS: Hand--Foot Syndrome

IL: Interleukin

OAT: Organic anion transporters

ROS: Reactive oxygen species

TNF-\selectlanguage{greek}α: \selectlanguage{english}Tumor necrosis factor-alpha

TRPA: Transient receptor potential ankyrin

VAS: Visual analog scale

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\verb`Table 1.docx`  available at \url{https://authorea.com/users/429582/articles/533264-the-efficacy-and-safety-of-silymarin-in-the-treatment-of-chemotherapy-induced-peripheral-neuropathy-a-randomized-double-blinded-clinical-trial}

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\verb`Table 2.docx`  available at \url{https://authorea.com/users/429582/articles/533264-the-efficacy-and-safety-of-silymarin-in-the-treatment-of-chemotherapy-induced-peripheral-neuropathy-a-randomized-double-blinded-clinical-trial}

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\verb`Table 3.docx`  available at \url{https://authorea.com/users/429582/articles/533264-the-efficacy-and-safety-of-silymarin-in-the-treatment-of-chemotherapy-induced-peripheral-neuropathy-a-randomized-double-blinded-clinical-trial}

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\verb`Table 4.docx`  available at \url{https://authorea.com/users/429582/articles/533264-the-efficacy-and-safety-of-silymarin-in-the-treatment-of-chemotherapy-induced-peripheral-neuropathy-a-randomized-double-blinded-clinical-trial}

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\verb`Fig 2.docx`  available at \url{https://authorea.com/users/429582/articles/533264-the-efficacy-and-safety-of-silymarin-in-the-treatment-of-chemotherapy-induced-peripheral-neuropathy-a-randomized-double-blinded-clinical-trial}

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