Traditional Herbal Medicine, Sipjeondaebo-Tang, for Cancer-Related
Fatigue: A Randomized, Placebo-Controlled, Preliminary Study
Cancer-related fatigue (CRF) is a distressing, persistent, subjective sense of
physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or
cancer treatment that is not proportional to recent activity and interferes with
usual functioning. It is also the most prevalent symptom experienced by patients
with cancer that affects quality of life. - CRF is estimated to occur in up
to 90% of patients during active cancer treatment and 27% to 82% of patients after treatment. Multidimensional factors of physical and psychosocial mechanisms can cause
CRF, which starts before diagnosis and persists for months or years after treatment
completion. , - CRF may also be a predictor of
shorter survival. The National Comprehensive Cancer Network guidelines recommend non-pharmacological and pharmacological interventions
for CRF after managing concurrent symptoms and treatable contributing factors
including pain, emotional distress, anemia, sleep disturbance, nutritional deficit,
and comorbidities. Despite a variety of interventions that have been beneficial to
patients with CRF, there is currently no gold standard in its treatment. Sipjeondaebo-tang (Juzentaihoto in Japanese, Shi-Quan-Da-Bu-Tang in Chinese, SDT) is
a traditional herbal medicine comprised of 10 herbs and has been widely used for
relieving fatigue in East Asia. In previous studies, SDT was shown to be an immune-augmentative drug that
induced natural killer cell activity and decreased regulatory T cells. , In human
study, SDT has an adjuvant effect on maintenance of antibody on influenza
vaccination in elderly. SDT has also been shown to improve chronic fatigue syndrome and the quality
of life and anorexia in patients with cancer. - To the best of our knowledge,
no double-blind, randomized, placebo-controlled study of the efficacy of SDT in CRF
has been published. With the high prevalence of CRF and the limited number of therapeutic options, the
purpose of this double-blind, randomized, placebo-controlled, preliminary trial was
to evaluate the efficacy and safety of SDT on CRF. 

Study Design This randomized, double-blind, placebo-controlled, preliminary study was
conducted to investigate the efficacy of 3 weeks of SDT treatment on CRF. The
accrual occurred from May 2018 to June 2020 at Kyung Hee University Hospital in
Gangdong, Republic of Korea. Participants who met the eligibility criteria and
voluntarily signed the informed consent were randomly assigned in a 1:1 ratio
into the SDT and placebo groups. A permuted-block randomization sequence using a
2 × 2 block based on a computer-generated table of random digits was used for
group assignment. Random assignment was implemented via another statistician who
was not associated with the current study. Only pharmacies had access to the
randomization sequence. The random list ensured full allocation concealment,
which was concealed in an opaque envelope prior to the first visit of the
subject. The professional clinical research coordinator enrolled the
participants and recorded the case report form from every patient-reported
questionnaire. Both the researchers and the participants were blinded, and the
analysis was performed by a separate statistician, who belongs to the Kyung Hee
Medical Science Research Institute. This study was reviewed and approved by the Institutional Review Board of Kyung
Hee University Hospital at Gangdong (KHNMC-OH-IRB 2017-08-006). The protocol was
registered in the Clinical Research Information Service (KCT0003442). All
research adhered to the tenets of the Declaration of Helsinki, and the study was
performed according to the Good Clinical Practice guidelines. The study proposal
has not changed since the allocation started. Eligibility Patients were eligible to participate in the trial if they had a confirmed
malignant solid tumor, were older than 19 years; were at least 1 month past
their last major treatment (ie, surgery, radiotherapy, or chemotherapy);
complained of moderate or severe fatigue, defined as a Brief Fatigue Inventory
(BFI) score of 4 or more; had fatigue that started or got worse according to
cancer progression or cancer-related treatment and lasted more than 1 month; and
had an Eastern Cooperative Oncology Group (ECOG) performance status of below 2.
Patients were excluded if they had moderate to severe pain (Numeric Rating Scale
(NRS) of 4 or more); had at least one of the following: pleural effusion,
ascites, or edema on the extremities with a severity of grade 3 or more,
according to Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.03;
had anemia that required a transfusion (hemoglobin ≤ 7 g/dL); were diagnosed
with hypothyroidism, a psychological or mental disorder, nutritional dystrophy,
or paralytic or atrophic myopathy including myasthenia gravis; had a history of
alcoholic or psychotropic drug abuse; were pregnant or breast-feeding; planned
to receive surgery, chemotherapy, or radiotherapy during the study period; were
2 times higher or more than normal serum levels of aspartate transaminase (AST)
or alanine transferase (ALT); or were one and a half times higher or more for
their serum creatinine level. The eligibility criteria did not change from the
registration of the study proposal to the end of the study. All participants
signed an informed consent form before participating in the study. Any kind of concurrent use of medication or dietary supplements that could have
potentially affected fatigue was allowed only when the participants maintained
the same type and dosage of medication for more than 2 weeks before the study
initiation. At baseline, the following data were recorded: demographic data, information on
cancer and treatment history for cancer, comorbidities, BFI score, Hospital
Anxiety and Depression Scale (HADS), and European Organization for Research and
Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ-C30) score. Intervention Patients enrolled in the study were randomly assigned to receive either SDT (3 g)
or matched placebo orally 3 times per day for 3 weeks. All participants took
fatigue-relieving education by a professional nurse. SDT (Desiten, Hanpoong Pharm & Foods Co., Seoul, Korea) was an already
approved product for chronic fatigue or remnant fatigue after disease by the
Ministry of Food and Drug Safety (MFDS) in Korea. SDT granules were a dark brown
mixture of spray-dried hot water extracts of 10 medicinal plants consisting of
Astragali Radix (10.5%), Panax ginseng radix (10.5%), Atractylodes Rhizoma Alba
(10.5%), Poria sclerotium (10.5%), Rehmanniae Radix (10.5%), Angelicae Gigantis
Radix (10.5%), Paeonia Radix (10.5%), Cnidii Rhizoma (10.5%), Glycyrrhizae Radix
et Rhizoma (5.3%), and Cinnamomi Ramulus (10.5%). Each herb in SDT was quality
controlled from their places of origin to the final product by the manufacturing
company. A placebo consisting of lactose, corn starch, and caramel coloring was
prepared by the same pharmaceutical company, and it has a similar appearance,
dose, and scent as SDT. An education in fatigue relief consisted of 7 domains: knowing reasons for
fatigue, gaining insight into fatigue state, energy conservation, nutrition
coaching, sleep hygiene education, exercise coaching, and additional methods the
patient can try. Participants were educated by a professional nurse and
recommended to maintain the education throughout the study period. Participants in both groups were recommended to maintain the dosage of SDT or
placebo throughout the trial period. Dose modification was not scheduled. If
participants failed to take more than 70% of SDT or placebo during the trial,
the participant was dropped from the study out due to low compliance. If fatigue
was completely resolved within the study period, early cessation of the study
was also permitted. Outcome Measures The primary outcome measure was the BFI to evaluate the efficacy of 3 weeks of
SDT in improving CRF. Patients completed the BFI at baseline, and after week 1,
week 2, week 3 (treatment completion), and week 6. The BFI is a 9-item scale
validated in the cancer population for the assessment of fatigue severity and
impact on function. , The secondary outcome measures were depression and
anxiety using the HADS, quality of life using the EORTC QLQ-C30,
immunoregulatory tests of cytokines, including interleukin-6 (IL-6) and tumor
necrosis factor-α (TNF-α), and lymphocyte subsets (CD3 + ,
CD4 + , CD8 + , CD4 + /CD8 + , and
CD16 + 56 + ), and safety. The HADS consists of a 14-item
questionnaire measuring depression and anxiety validated in a number of clinical
situations and has been widely used for patients with advanced
diseases. , The EORTC QLQ-C30 is a 30-item measurement that
evaluates the overall quality of life in patients with cancer and consists of
functional, symptom, and global health status subscales. , Peripheral blood samples for lymphocyte subset and cytokine tests were taken
from each patient at baseline and after week 3. Cell preparation and assay
procedures were conducted by Green Cross Laboratories © . Safety Evaluation Any adverse events were assessed using the Common Terminology Criteria for
Adverse Events (CTCAE, version 4.1). Laboratory tests, including those for
hemoglobin, white blood cell count, platelet count, aspartate aminotransferase,
alanine aminotransferase, total bilirubin, blood urea nitrogen, and serum
creatinine, were performed at the baseline and end of the study. We also
followed the World Health Organization-Uppsala Monitoring Center (WHO-UMC)
causality assessment system. Sample Size As a reference study using the BFI score for SDT was absent when we built the
study structure, we calculated the sample size based on the study conducted by Chen which used a similar traditional herbal medicine, Bojungikki-tang, for
CRF. Both herbal medications share several major ingredients, especially Panax
ginseng Radix and Astragalli Radix, and are traditionally used for fatigue. The
standard deviation in the former study was 1.95. We estimated that a total of 50
evaluable participants were needed for the 0.05 alpha, 80% power, and 20%
dropout rate to detect a difference between groups of 1.8 score in this 1:1
study. Statistical Analysis An independent statistician performed the statistical analyses. The
intention-to-treat (ITT) principle was used with the
last-observation-carried-forward (LOCF) method. All values are presented as mean
and standard deviation or N  unless stated otherwise. Baseline variables were
compared between groups using the independent t -test,
chi-square test, Wilcoxon rank sum test, or Fisher’s exact test. The duration of
illness was analyzed using the Kaplan–Meier method. The primary outcome was
analyzed with the corresponding one-way analysis of covariance (ANCOVA),
considering the baseline scores as covariates. Repeated measures of ANOVA were
used to analyze the serial change of BFI to detect inter-group and inter-time
differences and group-by-time interactions for ITT analysis. An independent t -test was used to compare changes in scores after
performing the Shapiro-Wilk test to confirm the normality of the distribution.
If a normal distribution was not achieved, the Wilcoxon signed rank test was
used. All statistical analyses were 2-sided, and statistical significance was
set at 0.05. All statistical analyses were performed using Statistical Analysis
System (SAS), version 9.4 (SAS Institute, Cary, NC, USA). 

This randomized, double-blind, placebo-controlled, preliminary study was
conducted to investigate the efficacy of 3 weeks of SDT treatment on CRF. The
accrual occurred from May 2018 to June 2020 at Kyung Hee University Hospital in
Gangdong, Republic of Korea. Participants who met the eligibility criteria and
voluntarily signed the informed consent were randomly assigned in a 1:1 ratio
into the SDT and placebo groups. A permuted-block randomization sequence using a
2 × 2 block based on a computer-generated table of random digits was used for
group assignment. Random assignment was implemented via another statistician who
was not associated with the current study. Only pharmacies had access to the
randomization sequence. The random list ensured full allocation concealment,
which was concealed in an opaque envelope prior to the first visit of the
subject. The professional clinical research coordinator enrolled the
participants and recorded the case report form from every patient-reported
questionnaire. Both the researchers and the participants were blinded, and the
analysis was performed by a separate statistician, who belongs to the Kyung Hee
Medical Science Research Institute. This study was reviewed and approved by the Institutional Review Board of Kyung
Hee University Hospital at Gangdong (KHNMC-OH-IRB 2017-08-006). The protocol was
registered in the Clinical Research Information Service (KCT0003442). All
research adhered to the tenets of the Declaration of Helsinki, and the study was
performed according to the Good Clinical Practice guidelines. The study proposal
has not changed since the allocation started. 

Patients were eligible to participate in the trial if they had a confirmed
malignant solid tumor, were older than 19 years; were at least 1 month past
their last major treatment (ie, surgery, radiotherapy, or chemotherapy);
complained of moderate or severe fatigue, defined as a Brief Fatigue Inventory
(BFI) score of 4 or more; had fatigue that started or got worse according to
cancer progression or cancer-related treatment and lasted more than 1 month; and
had an Eastern Cooperative Oncology Group (ECOG) performance status of below 2.
Patients were excluded if they had moderate to severe pain (Numeric Rating Scale
(NRS) of 4 or more); had at least one of the following: pleural effusion,
ascites, or edema on the extremities with a severity of grade 3 or more,
according to Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.03;
had anemia that required a transfusion (hemoglobin ≤ 7 g/dL); were diagnosed
with hypothyroidism, a psychological or mental disorder, nutritional dystrophy,
or paralytic or atrophic myopathy including myasthenia gravis; had a history of
alcoholic or psychotropic drug abuse; were pregnant or breast-feeding; planned
to receive surgery, chemotherapy, or radiotherapy during the study period; were
2 times higher or more than normal serum levels of aspartate transaminase (AST)
or alanine transferase (ALT); or were one and a half times higher or more for
their serum creatinine level. The eligibility criteria did not change from the
registration of the study proposal to the end of the study. All participants
signed an informed consent form before participating in the study. Any kind of concurrent use of medication or dietary supplements that could have
potentially affected fatigue was allowed only when the participants maintained
the same type and dosage of medication for more than 2 weeks before the study
initiation. At baseline, the following data were recorded: demographic data, information on
cancer and treatment history for cancer, comorbidities, BFI score, Hospital
Anxiety and Depression Scale (HADS), and European Organization for Research and
Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ-C30) score. 

Patients enrolled in the study were randomly assigned to receive either SDT (3 g)
or matched placebo orally 3 times per day for 3 weeks. All participants took
fatigue-relieving education by a professional nurse. SDT (Desiten, Hanpoong Pharm & Foods Co., Seoul, Korea) was an already
approved product for chronic fatigue or remnant fatigue after disease by the
Ministry of Food and Drug Safety (MFDS) in Korea. SDT granules were a dark brown
mixture of spray-dried hot water extracts of 10 medicinal plants consisting of
Astragali Radix (10.5%), Panax ginseng radix (10.5%), Atractylodes Rhizoma Alba
(10.5%), Poria sclerotium (10.5%), Rehmanniae Radix (10.5%), Angelicae Gigantis
Radix (10.5%), Paeonia Radix (10.5%), Cnidii Rhizoma (10.5%), Glycyrrhizae Radix
et Rhizoma (5.3%), and Cinnamomi Ramulus (10.5%). Each herb in SDT was quality
controlled from their places of origin to the final product by the manufacturing
company. A placebo consisting of lactose, corn starch, and caramel coloring was
prepared by the same pharmaceutical company, and it has a similar appearance,
dose, and scent as SDT. An education in fatigue relief consisted of 7 domains: knowing reasons for
fatigue, gaining insight into fatigue state, energy conservation, nutrition
coaching, sleep hygiene education, exercise coaching, and additional methods the
patient can try. Participants were educated by a professional nurse and
recommended to maintain the education throughout the study period. Participants in both groups were recommended to maintain the dosage of SDT or
placebo throughout the trial period. Dose modification was not scheduled. If
participants failed to take more than 70% of SDT or placebo during the trial,
the participant was dropped from the study out due to low compliance. If fatigue
was completely resolved within the study period, early cessation of the study
was also permitted. 

The primary outcome measure was the BFI to evaluate the efficacy of 3 weeks of
SDT in improving CRF. Patients completed the BFI at baseline, and after week 1,
week 2, week 3 (treatment completion), and week 6. The BFI is a 9-item scale
validated in the cancer population for the assessment of fatigue severity and
impact on function. , The secondary outcome measures were depression and
anxiety using the HADS, quality of life using the EORTC QLQ-C30,
immunoregulatory tests of cytokines, including interleukin-6 (IL-6) and tumor
necrosis factor-α (TNF-α), and lymphocyte subsets (CD3 + ,
CD4 + , CD8 + , CD4 + /CD8 + , and
CD16 + 56 + ), and safety. The HADS consists of a 14-item
questionnaire measuring depression and anxiety validated in a number of clinical
situations and has been widely used for patients with advanced
diseases. , The EORTC QLQ-C30 is a 30-item measurement that
evaluates the overall quality of life in patients with cancer and consists of
functional, symptom, and global health status subscales. , Peripheral blood samples for lymphocyte subset and cytokine tests were taken
from each patient at baseline and after week 3. Cell preparation and assay
procedures were conducted by Green Cross Laboratories © . 

Any adverse events were assessed using the Common Terminology Criteria for
Adverse Events (CTCAE, version 4.1). Laboratory tests, including those for
hemoglobin, white blood cell count, platelet count, aspartate aminotransferase,
alanine aminotransferase, total bilirubin, blood urea nitrogen, and serum
creatinine, were performed at the baseline and end of the study. We also
followed the World Health Organization-Uppsala Monitoring Center (WHO-UMC)
causality assessment system. 

As a reference study using the BFI score for SDT was absent when we built the
study structure, we calculated the sample size based on the study conducted by Chen which used a similar traditional herbal medicine, Bojungikki-tang, for
CRF. Both herbal medications share several major ingredients, especially Panax
ginseng Radix and Astragalli Radix, and are traditionally used for fatigue. The
standard deviation in the former study was 1.95. We estimated that a total of 50
evaluable participants were needed for the 0.05 alpha, 80% power, and 20%
dropout rate to detect a difference between groups of 1.8 score in this 1:1
study. 

An independent statistician performed the statistical analyses. The
intention-to-treat (ITT) principle was used with the
last-observation-carried-forward (LOCF) method. All values are presented as mean
and standard deviation or N  unless stated otherwise. Baseline variables were
compared between groups using the independent t -test,
chi-square test, Wilcoxon rank sum test, or Fisher’s exact test. The duration of
illness was analyzed using the Kaplan–Meier method. The primary outcome was
analyzed with the corresponding one-way analysis of covariance (ANCOVA),
considering the baseline scores as covariates. Repeated measures of ANOVA were
used to analyze the serial change of BFI to detect inter-group and inter-time
differences and group-by-time interactions for ITT analysis. An independent t -test was used to compare changes in scores after
performing the Shapiro-Wilk test to confirm the normality of the distribution.
If a normal distribution was not achieved, the Wilcoxon signed rank test was
used. All statistical analyses were 2-sided, and statistical significance was
set at 0.05. All statistical analyses were performed using Statistical Analysis
System (SAS), version 9.4 (SAS Institute, Cary, NC, USA). 

Patient Characteristics A total of 50 patients were recruited for the study and randomly allocated to the
SDT and placebo groups in a 1:1 ratio. Three participants in the placebo group
discontinued the intervention, as detailed in . In total, 47 patients
completed the trial and 50 were included in the ITT analysis for the primary
endpoint. Baseline patient characteristics are provided in , illustrating
that there were no statistically significant differences between the arms in
baseline assessed variables. Efficacy After 3 weeks of treatment, mean BFI scores decreased significantly in both arms
compared with the baseline, and decreased significantly in the SDT arm compared
with the placebo arm adjusted for baseline fatigue ( P = .04; ).
Anxiety and depression did not improve significantly in both arms compared with
the baseline, and there was no significant difference between the arms. Patient
quality of life, as assessed through the EORTC QLC-C30, improved significantly
in both arms compared with the baseline in terms of the functional and symptom
scales, but there was no significant difference between the arms. The global
health status scale improved significantly only in the SDT arm compared with the
baseline, and showed a significant difference between the arms
( P = .02). The fatigue level in both arms gradually decreased from the baseline and was at a
minimum after week 3, and then rebounded after week 6 . After performing a repeated
measures ANOVA, inter-group and inter-time differences of the BFI score from the
baseline to week 6 showed significant differences ( P = .007 and P < .001, respectively). However, the group-by-time
interaction difference did not show a significant difference
( P = .487). Lymphocyte subset and cytokine tests showed no significant differences in both
arms compared with the baseline, and between the arms adjusted for baseline, as
shown in . Safety No serious adverse events related to SDT or placebo administration occurred
during the study period. All laboratory results, including liver and renal
function, were normal after SDT administration. However, 1 participant in the
SDT group experienced grade 1 dyspepsia, which subsided within 3 days without
any rescue treatment. One participant in the placebo group complained of
pruritus, assessed as grade 1 according to the CTCAE. Although this was the
reason why the participant in the placebo group ended the clinical trial, the
pruritus also subsided within 3 days. 

A total of 50 patients were recruited for the study and randomly allocated to the
SDT and placebo groups in a 1:1 ratio. Three participants in the placebo group
discontinued the intervention, as detailed in . In total, 47 patients
completed the trial and 50 were included in the ITT analysis for the primary
endpoint. Baseline patient characteristics are provided in , illustrating
that there were no statistically significant differences between the arms in
baseline assessed variables. 

After 3 weeks of treatment, mean BFI scores decreased significantly in both arms
compared with the baseline, and decreased significantly in the SDT arm compared
with the placebo arm adjusted for baseline fatigue ( P = .04; ).
Anxiety and depression did not improve significantly in both arms compared with
the baseline, and there was no significant difference between the arms. Patient
quality of life, as assessed through the EORTC QLC-C30, improved significantly
in both arms compared with the baseline in terms of the functional and symptom
scales, but there was no significant difference between the arms. The global
health status scale improved significantly only in the SDT arm compared with the
baseline, and showed a significant difference between the arms
( P = .02). The fatigue level in both arms gradually decreased from the baseline and was at a
minimum after week 3, and then rebounded after week 6 . After performing a repeated
measures ANOVA, inter-group and inter-time differences of the BFI score from the
baseline to week 6 showed significant differences ( P = .007 and P < .001, respectively). However, the group-by-time
interaction difference did not show a significant difference
( P = .487). Lymphocyte subset and cytokine tests showed no significant differences in both
arms compared with the baseline, and between the arms adjusted for baseline, as
shown in . 

No serious adverse events related to SDT or placebo administration occurred
during the study period. All laboratory results, including liver and renal
function, were normal after SDT administration. However, 1 participant in the
SDT group experienced grade 1 dyspepsia, which subsided within 3 days without
any rescue treatment. One participant in the placebo group complained of
pruritus, assessed as grade 1 according to the CTCAE. Although this was the
reason why the participant in the placebo group ended the clinical trial, the
pruritus also subsided within 3 days. 

In this randomized, double-blinded, placebo-controlled, preliminary study, we found
that SDT administration for 3 weeks improved CRF as measured by the BFI scale. Every
participant in the SDT group ended the trial successfully without any serious
adverse events. Fatigue is the most common cancer-related symptom, and persistent fatigue can present
in cancer survivors, patients with geriatric cancer, patients with cancer who
received surgery or chemotherapy, and patients in an advanced stage, regardless of
tumor type. As cancer progresses, the incidence of CRF typically increases. At the end of
life, it is estimated that 90% of patients with cancer experience fatigue. As pharmacological interventions for CRF, erythropoietin and methylphenidate
have shown some efficacy in fatigue reduction; however, concerns about the safety of
these agents, including tumor progression, sleep disruption, and decreased appetite,
might limit their usefulness. - SDT has been used to improve the following conditions; poor physical strength,
fatigue/malaise, loss of appetite, night sweats, coldness of hands and feet, and anemia. SDT alleviated hematotoxicity in patients with breast cancer receiving
chemotherapy without counteracting the effect of their treatment, and improved the progression-free survival of patients with postoperative
recurrence of non-small cell lung cancer by preventing nutritional deterioration
induced by adverse effects of anti-cancer drugs. Our results support the findings of another clinical study that showed SDT to be
effective in improving CRF in patients with lung cancer after chemotherapy. However, in contrast to this prior study, in which the control group was
patients that received the usual care, our study was conducted as a
placebo-controlled study with validated measures for CRF assessment. Other prior studies showed that SDT augmented immune function by inducing natural
killer cell activity, decreasing regulatory T cells, and enhancing quality of
life. - However, our results showed
that SDT did not improve quality of life as measured by the EORTC QLQ-C30, except
for the global health status scale, and did not affect lymphocyte or cytokine
levels. The median duration from cancer treatment including surgery, chemotherapy,
and radiotherapy in all participants in this study was 32.5 months, which implied
that fatigue was not related to cancer treatment, and the participants had good
performance status with ECOG 0-1. Future studies should address the potential
effects of SDT on quality of life or immune function as primary outcome
measurements. Panax ginseng and Astragalus included in SDT are considered the main herbs for
alleviating CRF. The systematic review and meta-analysis of randomized controlled
trials indicate that ginseng is safe and efficacious in reducing fatigue , ; however, the
efficacy of ginseng against CRF is controversial and requires further research. Moreover, Astragalus polysaccharide injections relieve CRF among patients
with advanced cancer, , and have been reported as a promising edible immunomodulatory
herbal medicine. Additionally, Astragalus-based herbal medicines combined with platinum-based
chemotherapies may improve survival, increase tumor response, and reduce
chemotherapy toxicity compared to platinum-based chemotherapies alone. There are some limitations to this study. First, the enrolled patients had
heterogeneity in their cancer type. Although CRF is a common cancer-related symptom
regardless of cancer type, the refining criteria for eligibility should be addressed
in future research. Second, the duration of SDT administration and the follow-up
period in this study were short owing to concerns about low compliance. In conclusion, we found that SDT can be an effective therapeutic option in reducing
CRF in patients with cancer. Larger long-term efficacy and safety studies should be
conducted in the future. 

