A Double-Blind, Randomized, Placebo-Controlled Trial of Panax Ginseng for Cancer-Related Fatigue in Patients With Advanced Cancer

Background: Despite the high frequency, severity, and effects of cancer-related fatigue (CRF) on the quality of life (QoL) of patients with cancer, limited treatment options are available. The primary objective of this study was to compare the effects of oral Panax ginseng extract (PG) and placebo on CRF. Secondary objectives were to determine the effects of PG on QoL, mood, and function. Methods: In this randomized, double-blind, placebo-controlled study, patients with CRF ≥4/10 on the Edmonton Symptom Assessment System (ESAS) were eligible. Based on a pilot study, we randomized patients to receive either 400 mg of standardized PG twice daily or a matching placebo for 28 days. The primary end point was change in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale from baseline to day 29. Results: Of 127 patients, 112 (88.2%) were evaluable. The mean (SD) FACIT-F subscale scores at baseline, day 15, and day 29 were 22.4 (10.1), 29.9 (10.6), and 30.1 (11.6) for PG (P<.001), and 24.0 (9.4), 30.0 (10.1), and 30.4 (11.5) for placebo (P<.001). Mean (SD) improvement in the FACIT-F subscale at day 29 was not significantly different in the PG than in the placebo group (7.5 [12.7] vs 6.5 [9.9]; P=.67). QoL, anxiety, depression, symptoms, and functional scores were not significantly different between the PG and placebo groups. Improvement in the FACIT-F subscale correlated with baseline scores (P=.0005), Hospital Anxiety and Depression Scale results (P=.032), and sex (P=.023). There were fewer any-grade toxicities in the PG versus placebo group (28/63 vs 33/64; P=.024). Conclusions: Both PG and placebo result in significant improvement in CRF. PG was not significantly superior to placebo after 4 weeks of treatment. There is no justification to recommend the use of PG for CRF. Further studies are needed. Trial Registration: ClinicalTrials.gov identifier: NCT01375114.

Abstract

Background: Despite the high frequency, severity, and effects of cancer-related fatigue (CRF) on the quality of life (QoL) of patients with cancer, limited treatment options are available. The primary objective of this study was to compare the effects of oral Panax ginseng extract (PG) and placebo on CRF. Secondary objectives were to determine the effects of PG on QoL, mood, and function. Methods: In this randomized, double-blind, placebo-controlled study, patients with CRF ≥4/10 on the Edmonton Symptom Assessment System (ESAS) were eligible. Based on a pilot study, we randomized patients to receive either 400 mg of standardized PG twice daily or a matching placebo for 28 days. The primary end point was change in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale from baseline to day 29. Results: Of 127 patients, 112 (88.2%) were evaluable. The mean (SD) FACIT-F subscale scores at baseline, day 15, and day 29 were 22.4 (10.1), 29.9 (10.6), and 30.1 (11.6) for PG (P<.001), and 24.0 (9.4), 30.0 (10.1), and 30.4 (11.5) for placebo (P<.001). Mean (SD) improvement in the FACIT-F subscale at day 29 was not significantly different in the PG than in the placebo group (7.5 [12.7] vs 6.5 [9.9]; P=.67). QoL, anxiety, depression, symptoms, and functional scores were not significantly different between the PG and placebo groups. Improvement in the FACIT-F subscale correlated with baseline scores (P=.0005), Hospital Anxiety and Depression Scale results (P=.032), and sex (P=.023). There were fewer any-grade toxicities in the PG versus placebo group (28/63 vs 33/64; P=.024). Conclusions: Both PG and placebo result in significant improvement in CRF. PG was not significantly superior to placebo after 4 weeks of treatment. There is no justification to recommend the use of PG for CRF. Further studies are needed. Trial Registration: ClinicalTrials.gov identifier: NCT01375114.

Background

Cancer-related fatigue (CRF) is the most common symptom in patients with cancer.1,2 Despite the high frequency, severity, and effects of CRF on quality of life (QoL), limited treatment options are available.1,3 Prior pharmacologic studies for CRF in patients with cancer have shown mixed results.1,4,5 Panax ginseng extract (PG) is widely used in the United States and other countries, including Korea and China,6,7 under the belief that it will improve overall QoL, including energy and vitality, particularly during times of fatigue or stress.810 PG has been found to have direct action on the central nervous system (CNS), including cognition, sleep disturbance, depression, pain, and the ability to modulate inflammatory cytokines.9,1117 Despite its frequent use, there are no well-powered, placebo-controlled trials using validated CRF outcome measures to investigate the effects of PG in patients with cancer.18 A prospective, open-label, pilot study by our group in 30 patients with CRF (≥4/10 measured by the Edmonton Symptom Assessment System [ESAS]) found that 400 mg twice daily of oral PG (prepared from Panax ginseng C.A. Meyer root) for 30 days was safe and well tolerated, with good adherence and no major toxicity.19 There was significant improvement of Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale scores (mean difference [SD], 14.2 (17.4); P=.0006). Further, there was a significant mean (SD) improvement in ESAS feeling of well-being score from 4.67 (2.04) to 3.50 (2.34) (P=.01374) and ESAS appetite score from 4.29 (2.79) to 2.96 (2.46) (P=.001).

The primary objective of the current study was to examine the effects of oral PG at 400 mg twice daily compared with placebo on CRF as determined by FACIT-F subscale at the end of 4 weeks. Secondary objectives were to determine the effects of PG on QoL domains (FACIT-F), mood (Hospital Anxiety and Depression Scale [HADS]), patient-reported treatment benefit (Global Symptom Evaluation [GSE]), and physical function as measured by both the 6-minute walk test (6MWT) and hand grip strength (HGS; via Jamar hydraulic hand dynamometer [Lafayette Instrument, Lafayette, IN]). We also determined the side effects and tolerability of PG in these patients.

We hypothesized that patients who received PG would have greater average improvement in FACIT-F subscale scores from baseline to day 29 compared with those who received placebo.

Methods

Patients

The University of Texas MD Anderson Cancer Center Institutional Review Board approved this study, and all patients provided written, informed consent to participate in this prospective trial (ClinicalTrials.org identifier: NCT01375114). Eligible patients were enrolled from outpatient oncology centers and supportive care clinics at MD Anderson Cancer Center.

Eligibility criteria were the same as for our prior pilot study.19 Briefly, we included patients diagnosed with cancer and CRF with an average intensity of ≥4/10 on the ESAS (scale, 0–10) during the 24 hours before study enrollment. CRF also had to be present every day for most of the day for a minimum of 2 weeks. Other important eligibility criteria were normal cognition; no infections; hemoglobin level ≥8 g/L within 2 weeks of enrollment; ECOG performance status (PS) ≤2; no current uncontrolled pain or depressive symptoms; no history of psychiatric illness, such as major depression, obsessive compulsive disorder, or schizophrenia; no uncontrolled diabetes or treatment with anticoagulants or systemic steroids; no history of hepatitis A, B, or C; no significant history of uncontrolled19 hypertension or symptomatic tachycardia; and no current use of the following medications: ginseng, methylphenidate, modafinil, phenobarbital, diphenylhydantoin, primidone, phenylbutazone, monoamine oxidase inhibitors, clonidine, and tricyclic antidepressants.

The rationale for including various tumor types is multifold. First, CRF is a syndrome that results from increased production of inflammatory cytokines and tumor byproducts irrespective of tumor types. This pathophysiology of CRF is more related to the interaction between cancer and the host rather than to any specific histology, as demonstrated by similar rates of frequency and severity of fatigue across patients with various tumor types.20,21 Second, the frequency and severity of CRF in patients who have various tumor types are largely the same, as seen in clinical trials of methylphenidate,22 donepezil,23 fish oil,24 and dexamethasone25 in the treatment of CRF. Third, by including patients with various tumor types, we will obtain a more representative distribution in terms of age, sex, and behavior than we would in a study of patients with a single tumor type.

Intervention

In this double-blind, randomized, placebo-controlled trial, patients took 400 mg of PG capsules twice daily or a matching placebo (an inactive excipient methylcellulose) twice daily. The matching placebo was compounded by the same investigational pharmacy as the study drug. The placebo was prepared as colored capsules for similar appearance and we included an inactive excipient methylcellulose as an ingredient for the placebo. Timing of administration was specified as every morning and every afternoon before 3:00 pm for 28 days.

PG, which is commercially available, was supplied by Indena S.p.A. (Milan, Italy). It was prepared from Panax ginseng C.A. Meyer root (drug extract ratio 1:3–5) and standardized26 to contain ≥7.0% of ginsenosides and malonyl ginsenosides (≥0.9% Rg1 ≤1.4%; ≥1.7% Rb1 ≤3.0%). The manufacturing percentage range (mean ± standard error of the mean) of ginsenosides was 12% ± 3%. The extract was prepared through hydroalcoholic extraction (EtOH 70%). Certificate of analysis (CofA) using high-performance liquid chromatography identification was obtained for each batch to ensure standardized contents of ginsenosides, pH, alcohol content, loss on drying, and total residual organic solvents. The CofA also complied with the standards of no heavy metals and no microbials, assessed based on microbial counts, total combined yeasts/molds, and presence of bile-tolerant gram-negative bacteria, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, aflatoxins, and pesticides. The same process was used in studies involving animal models27 and in our preliminary study using PG, which was found to be beneficial in reducing CRF.19

The decision to use an oral dose of PG at 400 mg twice daily for a duration of 4 weeks was based on the successful results of our preliminary study examining the safety and efficacy of PG in significantly improving CRF.19 Our dosage of PG at 400 mg twice daily, containing ≥7.0% of ginsenosides and malonyl ginsenosides, is higher compared with that used in other clinical studies and monographs from the WHO and German Commission E,8,2842 which used PG for symptoms in patients without cancer. In these various studies, the dose ranged from 40 to 800 mg of ginseng extract.19

Outcomes

Demographic information was recorded at baseline (at randomization and before treatment), and included age, sex, race, religion, marital status, education, occupation, cancer stage, cancer type, and ECOG PS.

A research nurse supervised the completion of symptom assessment tools, including the FACIT-F, ESAS, and HADS, at baseline, day 15, and day 29. The GSE questionnaire was assessed on day 29. FACIT-F subscale is a QoL instrument commonly used in cancer clinical trials.43 It consists of 27 general QoL questions divided into 4 domains (physical, social, emotional, and functional) and has a 13-item fatigue subscale; the latter of which was the primary outcome of our study. Using the subscale, patients rate the intensity of their fatigue and its related symptoms on a scale of 0 to 4. The total score ranges between 0 and 52, with higher scores denoting less fatigue. Test–retest reliability coefficients for the fatigue subscale range from 0.84 to 0.90. The FACT-F subscale has also demonstrated strong internal consistency (α, 0.93–0.95).37 The FACIT-F subscale was used as the primary outcome measure because it is the most widely used, validated tool for assessing treatment response in CRF trials.4447

The ESAS evaluates 10 commonly experienced symptoms, including pain, fatigue, nausea, depression, anxiety, drowsiness, dyspnea, anorexia, sleep disturbance, and impaired feelings of well-being. The severity of each symptom was rated on a numerical scale of 0 to 10 (0 = no symptom, 10 = worst possible severity). The ESAS is both valid and reliable in patients with cancer.48 The ESAS fatigue item was used to identify patients with clinically significant fatigue and as a secondary outcome measure for our study.

Patients' depression and anxiety were assessed using HADS. This 14-item assessment instrument has been validated in a number of clinical situations and has been widely used in patients with cancer.49

In the GSE, patients were asked rate their CRF (eg, worse, about the same, or better) after treatment with the study medication. If their response was “better,” they were asked to rate how much better (eg, hardly any better at all, a little better, somewhat better, moderately better, a good deal better, a great deal better, a very great deal better).50

A research nurse supervised the completion of 2 objective measurements, the 6MWT and HGS, at baseline and day 29. The 6MWT was used to assess physical function, and has been recommended by the American Thoracic Society as an objective measure of functional capacity.51 HGS was used to measure the maximum isometric strength of the hand and forearm muscles.52

Toxicity and safety was assessed by the research nurse using the NCI's CTCAE, version 4.0 (CT-CAE v4.0). Questionnaire and medication review occurred at baseline (before treatment initiation); treatment days 8, 15, and 29; and 1 month after the study medication was stopped.

Statistical Analysis

The primary objective was to determine whether the average improvement in CRF from baseline to day 29 in patients who received PG was greater than in those who received placebo as measured by FACIT-F subscale scores. The primary end point, therefore, was the change in these scores from baseline to day 29. Differences in group means of the sample showed a normal distribution and were therefore analyzed using the 2-sample t test. Using similar methods, we analyzed differences between groups in scores at baseline and on days 15 and 29 for FACIT-F, HADS, ESAS symptoms, ESAS symptom distress scores, 6MWT, and HGS.

Our sample size estimation for this study was based on previous fatigue treatment trials.5355 Assuming a standard deviation of 5.8 in difference scores, with at least 50 evaluable patients per group, we planned to detect differences as small as 3.3 or larger with a 2-sided significance level of 0.05 and 80% power. To account for a dropout rate of 20% based on prior trials, we planned to recruit 64 patients into each group, for a total of 128 patients.

Baseline patient characteristics between the PG and placebo groups were compared using the chi-square test (or Fisher exact test for variables with expected cell frequencies ≤5). The number of patients experiencing adverse events (AEs) was compared between groups using the chi-square test; multiple linear model analysis was used in ad hoc analysis to determine the factors associated with FACIT-F subscale score improvement with PG. We analyzed all data at each time point (symptoms and AEs) for all patients who received at least one dose of study medication. All results reported in this study are based on 2-sided tests. The normality assumption was tested using the Shapiro-Wilk W statistic.56 A P value ≤0.05 was considered statistically significant.

Results

A total of 112 patients were evaluable; 56 received PG and 56 received placebo. Figure 1 shows the details of a CONSORT diagram including patient enrollment, randomization, follow-up, and patients in analysis. Adherence to study medication was assessed by the percentage of prescribed pills taken during the study period. Pill count was assessed using a pill diary completed by the study patients. Of the 127 patients who participated in the study, 112 (88.2%) had an adherence rate of 100%; 15 (11.8%) had an adherence rate ranging from 2 (3.4%) to 42(72.4%) pills. There was no significant difference in the adherence rates between the PG and placebo groups (P=.81).

No significant group differences were seen in baseline characteristics except cancer type (Table 1). There were also no significant group differences in baseline FACIT, ESAS, HADS, 6MWT, and HGS scores. Of 112 patients, 110 (98.2%) had advanced cancer. There was significant improvement in mean change of the FACIT-F subscale (Figure 2) and ESAS fatigue scores in the PG and placebo groups at days 15 and 29. The mean (SD) FACIT-F subscale scores at baseline, day 15, and day 29, respectively, were 22.4 (10.1), 29.9 (10.6), and 30.1 (11.6) for PG (P<.001) and 24.0 (9.4), 30.0 (10.1), and 30.4 (11.5) for placebo (P<.001). Mean (SD) improvement in the FACIT-F subscale at day 29 (primary outcome) was not significantly different in the PG and placebo groups (7.5 [12.7] vs 6.5 [9.9], respectively; P=.67). Clinically meaningful improvement in change for the FACIT-F subscale was seen in 35 of 63 patients (55.5%) in the PG group versus 35 of 64 (54.6%) in the placebo group (P>.2). Mean (SD) improvements in the ESAS fatigue item, FACIT-F, HADS, ESAS, 6MWT, and HGS scores at day 29 were not significantly different in the PG and placebo groups (Table 2), and the frequency of GSE score of “better” was not significantly different between the groups (PG group, 21/54 [39%] vs placebo, 20/53 [38%]; P=.93).

Figure 1.
Figure 1.

CONSORT diagram.

Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase.

aUnrelated to study drug.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 9; 10.6004/jnccn.2017.0149

In a multiple linear model analysis, improvement in the FACIT-F subscale score from day 0 to 29 was significantly correlated with baseline FACIT-F subscale score (P=.0005), HADS score (P=.032), and male sex (P=.023), such that higher fatigue, depression, and male sex were associated with greater improvement in CRF. Age, race, marital status, employment status, education, primary site, ECOG PS, or baseline HADS anxiety were not associated with change in CRF. There were fewer any-grade toxicities in the PG versus placebo group (28/63 vs 33/64, respectively; P=.024; Table 3). Table 4 summarizes the type of grade 3 to 5 AEs in both groups.

Discussion

Our study is the first randomized, double-blind, placebo-controlled control study to successfully evaluate the effects of PG on CRF using validated tools. In this study, we found that PG intake was associated with a significant reduction in the severity of CRF in patients with advanced cancer (Figure 2). However, PG was not significantly better than placebo in improving CRF at day 29 as measured by the FACIT-F subscale. We also found that PG did not significantly improve QoL, anxiety, depression, cancer-related symptoms, patient-reported benefit of treatment on CRF, and physical function scores compared with placebo according to FACIT-F, HADS, ESAS, GSE, 6MWT, and HGS, respectively. There were, however, significantly fewer AEs in the PG group than the placebo group.

Our results confirm the data from our preliminary study that the use of PG is safe and tolerable. Although well tolerated at the current dose of 400 mg twice daily, PG use is not recommended for CRF treatment in the clinical setting, because its effect was no different from that of placebo. In contrast to other pharmaceutical and nutraceutical randomized controlled trials to treat CRF, which have been negative, the use of PG in our study was found to be safe in patients with cancer and was associated with clinically meaningful benefit in >55% of patients.57 The study had a strong placebo response, which is common in fatigue studies and a major barrier for the study of new interventions.58 The exact reason for placebo response in our study is unclear. However, the history of PG use to improve overall QoL, including energy and vitality, may have resulted in a high expectation of benefit.18,59,60 Strategies to

Table 1.

Patient Demographics and Clinical Characteristics at Baseline

Table 1.
Figure 2.
Figure 2.

Change in mean (SD) fatigue score (FACIT-F) for PG (red) and placebo (blue) groups.

Error bars indicate SDs of the groups.

Abbreviations: FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue subscale; PG, Panax ginseng extract.

aP<.001 for baseline and day 15 scores and for baseline and day 29 scores in both groups.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 9; 10.6004/jnccn.2017.0149

account for a placebo response include recruiting a larger number of patients and increasing study duration, both of which escalate study costs. Although longer study duration could potentially eliminate the placebo response, it is not always feasible due to the increased risk of attrition in patients with advanced cancer.61 Therefore, potential future clinical trials might consider a placebo run-in before starting the study drug to eliminate placebo responders and allow for shorter studies.

In our study, the frequency of grade 3 to 5 AEs (Table 4) was significantly less in the PG group (1.6%) compared with the placebo group (14%), suggesting the potential role of PG in modulating the toxicities of cancer and its treatments. Further studies are needed.

Barton et al62 recently published a multicenter, double-blind, placebo-controlled, randomized control study for the treatment of CRF using a different ginseng preparation, Panax quinquefolius, also known as American or Wisconsin ginseng. However, there were several notable differences in the results between

Table 2.

Change in Symptom Scores at Days 15 and 29

Table 2.
Table 3.

Adverse Events in Placebo and Ginseng Groups

Table 3.
that study and ours. Barton et al's study found that CRF, as assessed by the Multidimensional Fatigue Symptom Inventory (MFSI) general scale, was not significantly better in the P quinquefolius group than the placebo group at the end of 4 weeks of treatment (primary end point). However, MFSI scores were significantly improved at the end of 8 weeks and in the subgroup of patients receiving chemotherapy at the end of 4 weeks.

Minimal clinically important difference (MCID) helps us evaluate the clinical meaningfulness of any observed treatment or intervention-related differences using a validated instrument for fatigue. It is difficult to compare the effects of P ginseng and P quinquefolius on CRF, because different instruments were used to assess CRF in the Barton et al62 study compared with ours. One alternate measure is to compare these studies using MCID. Both studies found clinically meaningful improvement of fatigue at the primary end point; however, Barton et al's study found lower placebo response, which was slightly below the threshold of MCID on the MFSI general scale.63 In our study, the placebo response was more robust and exceeded the threshold of MCID (3.5) by 3 points on the FAC-IT-F subscale. The reasons for the different placebo

Table 4.

Summary of Adverse Events Experienced by Patientsa

Table 4.
response in these 2 studies are not known, and this requires further research.

One important difference in our study from that of Barton et al is a higher ginsenosides ratio of Rg1 to Rb1 in the PG preparation than in P quinquefolius.6466 Prior studies suggest that the higher contents of Rg1 in P ginseng is associated with CNS stimulant action, whereas the Rb1 contents of P quinquefolius are mainly calming to the CNS. Our study results did not suggest better antifatigue effects with a higher ginsenoside concentration compared with those of Barton et al.62 However, the species of ginseng used to prepare the ginseng extract capsules by Barton et al was P quinquefolius compared with P ginseng used in our study. Further studies are needed to evaluate whether the antifatigue effects differ between P ginseng and P quinquefolius.

Lastly, our study enrolled mostly patients with advanced cancer (98.2%) compared with the Barton et al study, which enrolled those with early-stage cancer and cancer survivors. It is very likely that the mechanisms of CRF associated with advanced cancer differ from those of early cancer and cancer survivors due to the presence of tumor byproducts, increased inflammatory response, higher brain exposure to toxic effects of cancer therapy, higher frequency of cancer cachexia, and other CRF-related symptoms.20,6769 More research is needed to characterize the mechanistic differences in fatigue subtypes.

Our study has various strengths and limitations. In addition to being the first successfully completed randomized controlled trial of PG in patients with cancer using validated measures, the results also suggest PG feasibility and safety in advanced cancer. Our study results suggest a potential role of PG in managing toxicities due to its significant modulation of AEs with respect to placebo (Table 3). The main limitation of this study is that the effect of PG on CRF was measured for only 29 days. However, under ideal circumstances, treatments that act promptly are best for the management of an acute and debilitating condition such as CRF in the advanced cancer setting. Additionally, further studies are needed to understand the mediating mechanisms of action of PG on CRF, including the role of inflammatory cytokines.70

There are no pharmacokinetic studies of PG in patients with cancer that show the difference or similarity between the 800-mg daily dose and the 400-mg twice-daily dose. The use of an oral 400-mg twice-daily dose (last dose before 3:00 pm) was intended to distribute the ginseng dose according to diurnal variation of CRF, and to avoid insomnia due its CNS action as a result of nighttime dosing.7176 However, further studies are needed to determine the ideal frequency of PG administration. Our sample size calculation for this study was based on a standard deviation of 5.8 on the FACIT-F subscale score in an exercise intervention study for CRF. The change in FACIT-F subscale score is the most commonly used primary outcome measure in CRF treatment trials. This includes pharmacologic CRF trials in advanced cancer by our group,4547 in addition to those used by other groups in CRF and treatment trials using exercise intervention.77 However, it may be possible that the exercise interventions may have an effect on biobehavioral factors associated with CRF and are quite different from that for ginseng, and therefore further studies are necessary.

Conclusions

Our results show that oral PG at a dose of 400 mg twice daily and a matching placebo resulted in significant improvement in CRF with minimal side effects. However, PG was not significantly superior to placebo after 4 weeks of treatment for the management of CRF and other accompanying symptoms. Based on these findings, there is no justification to recommend PG for managing fatigue in patients with advanced cancer. Further studies are needed.

Acknowledgments

The authors wish to thank Vicki Gayle, BA, BSN, RN, OCN; Rama Aashraya, MD; Julio A. Allo, MPH; and Jill Delsigne-Russell, PhD, ELS, for patient accrual, data support, and manuscript review.

Dr. Yennurajalingam has disclosed that he has received research funding from Genentech. Dr. Tannir has disclosed that he has received honoraria from Pfizer, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, Exelixes, and Nektar; has held a consulting or advisory role with Novartis, GlaxoSmithKline, Bristol-Myers Squibb, Exelixes, and Nektar; and has received research funding from Novartis, GlaxoSmithKline, Bristol-Myers Squibb, and Epizyme. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.The study drug was supplied by Indena S.p.A. (Milan, Italy).

References

  • 1.

    BergerAMMooneyKBanerjooC. NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue version 1.2016. Accessed July 27 2017. To view the most recent version of these guidelines visit NCCN.org.

    • Search Google Scholar
    • Export Citation
  • 2.

    de RaafPJde KlerkCTimmanR. Differences in fatigue experiences among patients with advanced cancer, cancer survivors, and the general population. J Pain Symptom Manage2012;44:823830.

    • Search Google Scholar
    • Export Citation
  • 3.

    BowerJEBakKBergerA. Screening, assessment, and management of fatigue in adult survivors of cancer: an American Society of Clinical Oncology clinical practice guideline adaptation. J Clin Oncol2014;32:18401850.

    • Search Google Scholar
    • Export Citation
  • 4.

    PeuckmannVElsnerFKrummN. Pharmacological treatments for fatigue associated with palliative care. Cochrane Database Syst Rev2010:CD006788.

    • Search Google Scholar
    • Export Citation
  • 5.

    MintonOStonePRichardsonA. Drug therapy for the management of cancer related fatigue. Cochrane Database Syst Rev2008:CD006704.

  • 6.

    VolmerDRaalAKalleRSoukandR. The use of Panax ginseng and its analogues among pharmacy customers in Estonia: a cross-sectional study. Acta Pol Pharm2016;73:795802.

    • Search Google Scholar
    • Export Citation
  • 7.

    BaegIHSoSH. The world ginseng market and the ginseng (Korea). J Ginseng Res2013;37:17.

  • 8.

    EllisJMReddyP. Effects of Panax ginseng on quality of life. Ann Pharmacother2002;36:375379.

  • 9.

    ColemanCIHebertJHReddyP. The effects of Panax ginseng on quality of life. J Clin Pharm Ther2003;28:515.

  • 10.

    LeeNLeeSHYooHRYooHS. Anti-fatigue effects of enzyme-modified ginseng extract: a randomized, double-blind, placebo-controlled trial. J Altern Complement Med2016;22:859864.

    • Search Google Scholar
    • Export Citation
  • 11.

    ParkHJShimHSKimJY. Ginseng purified dry extract, BST204, improved cancer chemotherapy-related fatigue and toxicity in mice. Evid Based Complement Alternat Med2015;2015:197459.

    • Search Google Scholar
    • Export Citation
  • 12.

    EtemadifarMSayahiFAbtahiSH. Ginseng in the treatment of fatigue in multiple sclerosis: a randomized, placebo-controlled, double-blind pilot study. Int J Neurosci2013;123:480486.

    • Search Google Scholar
    • Export Citation
  • 13.

    ReayJLScholeyABKennedyDO. Panax ginseng (G115) improves aspects of working memory performance and subjective ratings of calmness in healthy young adults. Hum Psychopharmacol2010;25:462471.

    • Search Google Scholar
    • Export Citation
  • 14.

    KennedyDOScholeyAB. Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol Biochem Behav2003;75:687700.

    • Search Google Scholar
    • Export Citation
  • 15.

    ChoiKT. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer. Acta Pharmacol Sin2008;29:11091118.

    • Search Google Scholar
    • Export Citation
  • 16.

    KimHGChoJHYooSR. Antifatigue effects of Panax ginseng C.A. Meyer: a randomised, double-blind, placebo-controlled trial. PLoS One2013;8:e61271.

    • Search Google Scholar
    • Export Citation
  • 17.

    DharmanandaS. The nature of ginseng: traditional use, modern research, and the question of dosage. Herbalgram2002:3451.

  • 18.

    BachHVKimJMyungSKChoYA. Efficacy of Ginseng supplements on fatigue and physical performance: a meta-analysis. J Korean Med Sci2016;31:18791886.

    • Search Google Scholar
    • Export Citation
  • 19.

    YennurajalingamSReddyATannirNM. High-dose Asian ginseng (Panax ginseng) for cancer-related fatigue: a preliminary report. Integr Cancer Ther2015;14:419427.

    • Search Google Scholar
    • Export Citation
  • 20.

    YennuSUrbauerDBrueraE. Factors associated with the severity and improvement of fatigue in patients with advanced cancer presenting to an outpatient palliative care clinic. BMC Palliat Care2012;11:16.

    • Search Google Scholar
    • Export Citation
  • 21.

    YennurajalingamSPalmerJZhangT. Association between fatigue and other cancer-related symptoms in patients with advanced cancer. Support Care Cancer2008;16:11251130.

    • Search Google Scholar
    • Export Citation
  • 22.

    HanksGWTruemanTTwycrossRG. Corticosteroids in terminal cancer—a prospective analysis of current practice. Postgrad Med J1983;59:702706.

    • Search Google Scholar
    • Export Citation
  • 23.

    BrueraERocaECedaroL. Action of oral methylprednisolone in terminal cancer patients. Cancer Treat Rep1985;69:751754.

  • 24.

    BrueraEStrasserFPalmerJL. Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study. J Clin Oncol2003;21:129134.

    • Search Google Scholar
    • Export Citation
  • 25.

    YennurajalingamSFrisbee-HumeSPalmerJL. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol2013;31:30763082.

    • Search Google Scholar
    • Export Citation
  • 26.

    NCCAM Interim Policy: Biologically Active Agents Used in Complementary and Alternative Medicine (CAM) and Placebo Materials. Available at: grants.nih.gov/grants/guide/notice-files/NOT-AT-05-003.html. Accessed July 27 2017.

    • Search Google Scholar
    • Export Citation
  • 27.

    LobinaCCaraiMALoiB. Protective effect of Panax ginseng in cisplatin-induced cachexia in rats. Future Oncol2014;10:12031214.

  • 28.

    de AndradeEde MesquitaAAClaro JdeA. Study of the efficacy of Korean red ginseng in the treatment of erectile dysfunction. Asian J Androl2007;9:241244.

    • Search Google Scholar
    • Export Citation
  • 29.

    HongBJiYHHongJH. A double-blind crossover study evaluating the efficacy of Korean red ginseng in patients with erectile dysfunction: a preliminary report. J Urol2002;168:20702073.

    • Search Google Scholar
    • Export Citation
  • 30.

    HanKHChoeSCKimHS. Effect of red ginseng on blood pressure in patients with essential hypertension and white coat hypertension. Am J Chin Med1998;26:199209.

    • Search Google Scholar
    • Export Citation
  • 31.

    Le GalMCathebrasPStrubyK. Pharmaton capsules in the treatment of functional fatigue: a double-blind study versus placebo evaluated by a new methodology. Phytother Res1996;10:4953.

    • Search Google Scholar
    • Export Citation
  • 32.

    KennedyDOScholeyAB. Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol Biochem Behav2003;75:687700.

    • Search Google Scholar
    • Export Citation
  • 33.

    KennedyDOScholeyABWesnesKA. Differential, dose dependent changes in cognitive performance following acute administration of a Ginkgo biloba/Panax ginseng combination to healthy young volunteers. Nutr Neurosci2001;4:399412.

    • Search Google Scholar
    • Export Citation
  • 34.

    D'AngeloLGrimaldiRCaravaggiM. A double-blind, placebo-controlled clinical study on the effect of a standardized ginseng extract on psychomotor performance in healthy volunteers. J Ethnopharmacol1986;16:1522.

    • Search Google Scholar
    • Export Citation
  • 35.

    ReayJLKennedyDOScholeyAB. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained ‘mentally demanding’ tasks. J Psychopharmacol2006;20:771781.

    • Search Google Scholar
    • Export Citation
  • 36.

    ReayJLKennedyDOScholeyAB. Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. J Psychopharmacol2005;19:357365.

    • Search Google Scholar
    • Export Citation
  • 37.

    SievenpiperJLSungMKDi BuonoM. Korean red ginseng rootlets decrease acute postprandial glycemia: results from sequential preparation- and dose-finding studies. J Am Coll Nutr2006;25:100107.

    • Search Google Scholar
    • Export Citation
  • 38.

    GrossDShenkmanZBleibergB. Ginseng improves pulmonary functions and exercise capacity in patients with COPD. Monaldi Arch Chest Dis2002;57:242246.

    • Search Google Scholar
    • Export Citation
  • 39.

    CaronMFHotskoALRobertsonS. Electrocardiographic and hemodynamic effects of Panax ginseng. Ann Pharmacother2002;36:758763.

  • 40.

    ScaglioneFCattaneoGAlessandriaMCogoR. Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected]. Drugs Exp Clin Res1996;22:6572.

    • Search Google Scholar
    • Export Citation
  • 41.

    BlumenthalMWernerRBGoldbergA. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin, TX: American Botanical Council; 1998.

    • Search Google Scholar
    • Export Citation
  • 42.

    AtteleASWuJAYuanCS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol1999;58:16851693.

  • 43.

    WebsterKCellaDYostK. The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system: properties, applications, and interpretation. Health Qual Life Outcomes2003;1:17.

    • Search Google Scholar
    • Export Citation
  • 44.

    MintonORichardsonASharpeM. A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue. J Natl Cancer Inst2008;100:11551166.

    • Search Google Scholar
    • Export Citation
  • 45.

    BrueraEValeroVDriverL. Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol2006;24:20732078.

    • Search Google Scholar
    • Export Citation
  • 46.

    BrueraEEl OstaBValeroV. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol2007;25:34753481.

    • Search Google Scholar
    • Export Citation
  • 47.

    YennurajalingamSFrisbee-HumeSPalmerJL. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol2013;31:30763082.

    • Search Google Scholar
    • Export Citation
  • 48.

    BrueraEKuehnNMillerMJ. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care1991;7:69.

    • Search Google Scholar
    • Export Citation
  • 49.

    JohnstonMPollardBHennesseyP. Construct validation of the hospital anxiety and depression scale with clinical populations. J Psychosom Res2000;48:579584.

    • Search Google Scholar
    • Export Citation
  • 50.

    GuyattGHFeenyDHPatrickDL. Measuring health-related quality of life. Ann Intern Med1993;118:622629.

  • 51.

    ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med2002;166:111117.

  • 52.

    InnesE. Handgrip strength testing: a review of the literature. Aust Occup Ther J1999;46:120140.

  • 53.

    SegalRReidRCourneyaK. Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer. J Clin Oncol2009;27:344350.

    • Search Google Scholar
    • Export Citation
  • 54.

    SegalRJReidRDCourneyaKS. Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol2003;21:16531659.

    • Search Google Scholar
    • Export Citation
  • 55.

    CellaDEtonDTLaiJS. Combining anchor and distribution based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales. J Pain Symptom Manage2002;24:547561.

    • Search Google Scholar
    • Export Citation
  • 56.

    ShapiroSSWilkMB. An analysis of variance test for normality (complete samples). Biometrika1965;52:591611.

  • 57.

    YennurajalingamSBrueraE. Review of clinical trials of pharmacologic interventions for cancer-related fatigue: focus on psychostimulants and steroids. Cancer J2014;20:319324.

    • Search Google Scholar
    • Export Citation
  • 58.

    de la CruzMHuiDParsonsHABrueraE. Placebo and nocebo effects in randomized double-blind clinical trials of agents for the therapy for fatigue in patients with advanced cancer. Cancer2010;116:766774.

    • Search Google Scholar
    • Export Citation
  • 59.

    SandersonCHardyJSpruytOCurrowDC. Placebo and nocebo effects in randomized controlled trials: the implications for research and practice. J Pain Symptom Manage2013;46:722730.

    • Search Google Scholar
    • Export Citation
  • 60.

    MurrayDStoesslAJ. Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions. Pharmacol Ther2013;140:306318.

    • Search Google Scholar
    • Export Citation
  • 61.

    HuiDGlitzaIChisholmG. Attrition rates, reasons, and predictive factors in supportive care and palliative oncology clinical trials. Cancer2013;119:10981105.

    • Search Google Scholar
    • Export Citation
  • 62.

    BartonDLLiuHDakhilSR. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst2013;105:12301238.

    • Search Google Scholar
    • Export Citation
  • 63.

    SloanJAFrostMHBerzonR. The clinical significance of quality of life assessments in oncology: a summary for clinicians. Support Care Cancer2006;14:988998.

    • Search Google Scholar
    • Export Citation
  • 64.

    ChenSWangZHuangY. Ginseng and anticancer drug combination to improve cancer chemotherapy: a critical review. Evid Based Complement Alternat Med2014;2014:168940.

    • Search Google Scholar
    • Export Citation
  • 65.

    HarkeyMRHendersonGLGershwinME. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr2001;73:11011106.

    • Search Google Scholar
    • Export Citation
  • 66.

    ChenCFChiouWFZhangJT. Comparison of the pharmacological effects of Panax ginseng and Panax quinquefolium. Acta Pharmacol Sin2008;29:11031108.

    • Search Google Scholar
    • Export Citation
  • 67.

    StonePHardyJBroadleyK. Fatigue in advanced cancer: a prospective controlled cross-sectional study. Br J Cancer1999;79:14791486.

  • 68.

    SolanoJPGomesBHigginsonIJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage2006;31:5869.

    • Search Google Scholar
    • Export Citation
  • 69.

    TeunissenSCWeskerWKruitwagenC. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain Symptom Manage2007;34:94104.

    • Search Google Scholar
    • Export Citation
  • 70.

    SaliganLOlsonKFillerK. The biology of cancer-related fatigue: a review of the literature. Support Care Cancer2015;23:24612478.

  • 71.

    DhruvaADoddMPaulSM. Trajectories of fatigue in patients with breast cancer before, during, and after radiation therapy. Cancer Nurs2010;33:201212.

    • Search Google Scholar
    • Export Citation
  • 72.

    WrightFD'Eramo MelkusGHammerM. Predictors and trajectories of morning fatigue are distinct from evening fatigue. J Pain Symptom Manage2015;50:176189.

    • Search Google Scholar
    • Export Citation
  • 73.

    MiaskowskiCPaulSMCooperBA. Trajectories of fatigue in men with prostate cancer before, during, and after radiation therapy. J Pain Symptom Manage2008;35:632643.

    • Search Google Scholar
    • Export Citation
  • 74.

    MiaskowskiCDoddMLeeK. Preliminary evidence of an association between a functional interleukin-6 polymorphism and fatigue and sleep disturbance in oncology patients and their family caregivers. J Pain Symptom Manage2010;40:531544.

    • Search Google Scholar
    • Export Citation
  • 75.

    RadadKMoldzioRRauschWD. Ginsenosides and their CNS targets. CNS Neurosci Ther2011;17:761768.

  • 76.

    KennedyDOScholeyABWesnesKA. Dose dependent changes in cognitive performance and mood following acute administration of Ginseng to healthy young volunteers. Nutr Neurosci2001;4:295310.

    • Search Google Scholar
    • Export Citation
  • 77.

    MintonOStoneP. A systematic review of the scales used for the measurement of cancer-related fatigue (CRF). Ann Oncol2009;20:1725.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Author contributions: Study concept and design: Yennnurajalingam, Bruera. Data acquisition: Bruera, Tannir, Williams, Lu, Hess, Frisbee-Hume, House, Dubauskas, Lim, Lopez, Reddy, Azhar, Wong, Patel, Kuban, Kaseb, Cohen. Data analysis and interpretation: Yennnurajalingam, Bruera, Hess. Manuscript preparation: all authors. Critical revision: Yennnurajalingam, Bruera. Statistical analysis: Hess. Obtained funding: Yennurajalingam. Administrative, technical, or material support: Yennurajalingam, Bruera, Frisbee-Hume. Study supervision: Yennurajalingam, Bruera, Frisbee-Hume. Final approval of the manuscript: all authors. Dr. Yennurajalingam had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Correspondence: Sriram Yennurajalingam, MD, MS, The University of Texas MD Anderson Cancer Center, Department of Palliative Care and Rehabilitation Medicine, 1515 Holcombe Boulevard, Unit 1414, Houston, TX 77030. E-mail: syennu@mdanderson.org
  • View in gallery

    CONSORT diagram.

    Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase.

    aUnrelated to study drug.

  • View in gallery

    Change in mean (SD) fatigue score (FACIT-F) for PG (red) and placebo (blue) groups.

    Error bars indicate SDs of the groups.

    Abbreviations: FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue subscale; PG, Panax ginseng extract.

    aP<.001 for baseline and day 15 scores and for baseline and day 29 scores in both groups.

  • 1.

    BergerAMMooneyKBanerjooC. NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue version 1.2016. Accessed July 27 2017. To view the most recent version of these guidelines visit NCCN.org.

    • Search Google Scholar
    • Export Citation
  • 2.

    de RaafPJde KlerkCTimmanR. Differences in fatigue experiences among patients with advanced cancer, cancer survivors, and the general population. J Pain Symptom Manage2012;44:823830.

    • Search Google Scholar
    • Export Citation
  • 3.

    BowerJEBakKBergerA. Screening, assessment, and management of fatigue in adult survivors of cancer: an American Society of Clinical Oncology clinical practice guideline adaptation. J Clin Oncol2014;32:18401850.

    • Search Google Scholar
    • Export Citation
  • 4.

    PeuckmannVElsnerFKrummN. Pharmacological treatments for fatigue associated with palliative care. Cochrane Database Syst Rev2010:CD006788.

    • Search Google Scholar
    • Export Citation
  • 5.

    MintonOStonePRichardsonA. Drug therapy for the management of cancer related fatigue. Cochrane Database Syst Rev2008:CD006704.

  • 6.

    VolmerDRaalAKalleRSoukandR. The use of Panax ginseng and its analogues among pharmacy customers in Estonia: a cross-sectional study. Acta Pol Pharm2016;73:795802.

    • Search Google Scholar
    • Export Citation
  • 7.

    BaegIHSoSH. The world ginseng market and the ginseng (Korea). J Ginseng Res2013;37:17.

  • 8.

    EllisJMReddyP. Effects of Panax ginseng on quality of life. Ann Pharmacother2002;36:375379.

  • 9.

    ColemanCIHebertJHReddyP. The effects of Panax ginseng on quality of life. J Clin Pharm Ther2003;28:515.

  • 10.

    LeeNLeeSHYooHRYooHS. Anti-fatigue effects of enzyme-modified ginseng extract: a randomized, double-blind, placebo-controlled trial. J Altern Complement Med2016;22:859864.

    • Search Google Scholar
    • Export Citation
  • 11.

    ParkHJShimHSKimJY. Ginseng purified dry extract, BST204, improved cancer chemotherapy-related fatigue and toxicity in mice. Evid Based Complement Alternat Med2015;2015:197459.

    • Search Google Scholar
    • Export Citation
  • 12.

    EtemadifarMSayahiFAbtahiSH. Ginseng in the treatment of fatigue in multiple sclerosis: a randomized, placebo-controlled, double-blind pilot study. Int J Neurosci2013;123:480486.

    • Search Google Scholar
    • Export Citation
  • 13.

    ReayJLScholeyABKennedyDO. Panax ginseng (G115) improves aspects of working memory performance and subjective ratings of calmness in healthy young adults. Hum Psychopharmacol2010;25:462471.

    • Search Google Scholar
    • Export Citation
  • 14.

    KennedyDOScholeyAB. Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol Biochem Behav2003;75:687700.

    • Search Google Scholar
    • Export Citation
  • 15.

    ChoiKT. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer. Acta Pharmacol Sin2008;29:11091118.

    • Search Google Scholar
    • Export Citation
  • 16.

    KimHGChoJHYooSR. Antifatigue effects of Panax ginseng C.A. Meyer: a randomised, double-blind, placebo-controlled trial. PLoS One2013;8:e61271.

    • Search Google Scholar
    • Export Citation
  • 17.

    DharmanandaS. The nature of ginseng: traditional use, modern research, and the question of dosage. Herbalgram2002:3451.

  • 18.

    BachHVKimJMyungSKChoYA. Efficacy of Ginseng supplements on fatigue and physical performance: a meta-analysis. J Korean Med Sci2016;31:18791886.

    • Search Google Scholar
    • Export Citation
  • 19.

    YennurajalingamSReddyATannirNM. High-dose Asian ginseng (Panax ginseng) for cancer-related fatigue: a preliminary report. Integr Cancer Ther2015;14:419427.

    • Search Google Scholar
    • Export Citation
  • 20.

    YennuSUrbauerDBrueraE. Factors associated with the severity and improvement of fatigue in patients with advanced cancer presenting to an outpatient palliative care clinic. BMC Palliat Care2012;11:16.

    • Search Google Scholar
    • Export Citation
  • 21.

    YennurajalingamSPalmerJZhangT. Association between fatigue and other cancer-related symptoms in patients with advanced cancer. Support Care Cancer2008;16:11251130.

    • Search Google Scholar
    • Export Citation
  • 22.

    HanksGWTruemanTTwycrossRG. Corticosteroids in terminal cancer—a prospective analysis of current practice. Postgrad Med J1983;59:702706.

    • Search Google Scholar
    • Export Citation
  • 23.

    BrueraERocaECedaroL. Action of oral methylprednisolone in terminal cancer patients. Cancer Treat Rep1985;69:751754.

  • 24.

    BrueraEStrasserFPalmerJL. Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study. J Clin Oncol2003;21:129134.

    • Search Google Scholar
    • Export Citation
  • 25.

    YennurajalingamSFrisbee-HumeSPalmerJL. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol2013;31:30763082.

    • Search Google Scholar
    • Export Citation
  • 26.

    NCCAM Interim Policy: Biologically Active Agents Used in Complementary and Alternative Medicine (CAM) and Placebo Materials. Available at: grants.nih.gov/grants/guide/notice-files/NOT-AT-05-003.html. Accessed July 27 2017.

    • Search Google Scholar
    • Export Citation
  • 27.

    LobinaCCaraiMALoiB. Protective effect of Panax ginseng in cisplatin-induced cachexia in rats. Future Oncol2014;10:12031214.

  • 28.

    de AndradeEde MesquitaAAClaro JdeA. Study of the efficacy of Korean red ginseng in the treatment of erectile dysfunction. Asian J Androl2007;9:241244.

    • Search Google Scholar
    • Export Citation
  • 29.

    HongBJiYHHongJH. A double-blind crossover study evaluating the efficacy of Korean red ginseng in patients with erectile dysfunction: a preliminary report. J Urol2002;168:20702073.

    • Search Google Scholar
    • Export Citation
  • 30.

    HanKHChoeSCKimHS. Effect of red ginseng on blood pressure in patients with essential hypertension and white coat hypertension. Am J Chin Med1998;26:199209.

    • Search Google Scholar
    • Export Citation
  • 31.

    Le GalMCathebrasPStrubyK. Pharmaton capsules in the treatment of functional fatigue: a double-blind study versus placebo evaluated by a new methodology. Phytother Res1996;10:4953.

    • Search Google Scholar
    • Export Citation
  • 32.

    KennedyDOScholeyAB. Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol Biochem Behav2003;75:687700.

    • Search Google Scholar
    • Export Citation
  • 33.

    KennedyDOScholeyABWesnesKA. Differential, dose dependent changes in cognitive performance following acute administration of a Ginkgo biloba/Panax ginseng combination to healthy young volunteers. Nutr Neurosci2001;4:399412.

    • Search Google Scholar
    • Export Citation
  • 34.

    D'AngeloLGrimaldiRCaravaggiM. A double-blind, placebo-controlled clinical study on the effect of a standardized ginseng extract on psychomotor performance in healthy volunteers. J Ethnopharmacol1986;16:1522.

    • Search Google Scholar
    • Export Citation
  • 35.

    ReayJLKennedyDOScholeyAB. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained ‘mentally demanding’ tasks. J Psychopharmacol2006;20:771781.

    • Search Google Scholar
    • Export Citation
  • 36.

    ReayJLKennedyDOScholeyAB. Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. J Psychopharmacol2005;19:357365.

    • Search Google Scholar
    • Export Citation
  • 37.

    SievenpiperJLSungMKDi BuonoM. Korean red ginseng rootlets decrease acute postprandial glycemia: results from sequential preparation- and dose-finding studies. J Am Coll Nutr2006;25:100107.

    • Search Google Scholar
    • Export Citation
  • 38.

    GrossDShenkmanZBleibergB. Ginseng improves pulmonary functions and exercise capacity in patients with COPD. Monaldi Arch Chest Dis2002;57:242246.

    • Search Google Scholar
    • Export Citation
  • 39.

    CaronMFHotskoALRobertsonS. Electrocardiographic and hemodynamic effects of Panax ginseng. Ann Pharmacother2002;36:758763.

  • 40.

    ScaglioneFCattaneoGAlessandriaMCogoR. Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected]. Drugs Exp Clin Res1996;22:6572.

    • Search Google Scholar
    • Export Citation
  • 41.

    BlumenthalMWernerRBGoldbergA. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin, TX: American Botanical Council; 1998.

    • Search Google Scholar
    • Export Citation
  • 42.

    AtteleASWuJAYuanCS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol1999;58:16851693.

  • 43.

    WebsterKCellaDYostK. The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system: properties, applications, and interpretation. Health Qual Life Outcomes2003;1:17.

    • Search Google Scholar
    • Export Citation
  • 44.

    MintonORichardsonASharpeM. A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue. J Natl Cancer Inst2008;100:11551166.

    • Search Google Scholar
    • Export Citation
  • 45.

    BrueraEValeroVDriverL. Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol2006;24:20732078.

    • Search Google Scholar
    • Export Citation
  • 46.

    BrueraEEl OstaBValeroV. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol2007;25:34753481.

    • Search Google Scholar
    • Export Citation
  • 47.

    YennurajalingamSFrisbee-HumeSPalmerJL. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol2013;31:30763082.

    • Search Google Scholar
    • Export Citation
  • 48.

    BrueraEKuehnNMillerMJ. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care1991;7:69.

    • Search Google Scholar
    • Export Citation
  • 49.

    JohnstonMPollardBHennesseyP. Construct validation of the hospital anxiety and depression scale with clinical populations. J Psychosom Res2000;48:579584.

    • Search Google Scholar
    • Export Citation
  • 50.

    GuyattGHFeenyDHPatrickDL. Measuring health-related quality of life. Ann Intern Med1993;118:622629.

  • 51.

    ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med2002;166:111117.

  • 52.

    InnesE. Handgrip strength testing: a review of the literature. Aust Occup Ther J1999;46:120140.

  • 53.

    SegalRReidRCourneyaK. Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer. J Clin Oncol2009;27:344350.

    • Search Google Scholar
    • Export Citation
  • 54.

    SegalRJReidRDCourneyaKS. Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol2003;21:16531659.

    • Search Google Scholar
    • Export Citation
  • 55.

    CellaDEtonDTLaiJS. Combining anchor and distribution based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales. J Pain Symptom Manage2002;24:547561.

    • Search Google Scholar
    • Export Citation
  • 56.

    ShapiroSSWilkMB. An analysis of variance test for normality (complete samples). Biometrika1965;52:591611.

  • 57.

    YennurajalingamSBrueraE. Review of clinical trials of pharmacologic interventions for cancer-related fatigue: focus on psychostimulants and steroids. Cancer J2014;20:319324.

    • Search Google Scholar
    • Export Citation
  • 58.

    de la CruzMHuiDParsonsHABrueraE. Placebo and nocebo effects in randomized double-blind clinical trials of agents for the therapy for fatigue in patients with advanced cancer. Cancer2010;116:766774.

    • Search Google Scholar
    • Export Citation
  • 59.

    SandersonCHardyJSpruytOCurrowDC. Placebo and nocebo effects in randomized controlled trials: the implications for research and practice. J Pain Symptom Manage2013;46:722730.

    • Search Google Scholar
    • Export Citation
  • 60.

    MurrayDStoesslAJ. Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions. Pharmacol Ther2013;140:306318.

    • Search Google Scholar
    • Export Citation
  • 61.

    HuiDGlitzaIChisholmG. Attrition rates, reasons, and predictive factors in supportive care and palliative oncology clinical trials. Cancer2013;119:10981105.

    • Search Google Scholar
    • Export Citation
  • 62.

    BartonDLLiuHDakhilSR. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst2013;105:12301238.

    • Search Google Scholar
    • Export Citation
  • 63.

    SloanJAFrostMHBerzonR. The clinical significance of quality of life assessments in oncology: a summary for clinicians. Support Care Cancer2006;14:988998.

    • Search Google Scholar
    • Export Citation
  • 64.

    ChenSWangZHuangY. Ginseng and anticancer drug combination to improve cancer chemotherapy: a critical review. Evid Based Complement Alternat Med2014;2014:168940.

    • Search Google Scholar
    • Export Citation
  • 65.

    HarkeyMRHendersonGLGershwinME. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr2001;73:11011106.

    • Search Google Scholar
    • Export Citation
  • 66.

    ChenCFChiouWFZhangJT. Comparison of the pharmacological effects of Panax ginseng and Panax quinquefolium. Acta Pharmacol Sin2008;29:11031108.

    • Search Google Scholar
    • Export Citation
  • 67.

    StonePHardyJBroadleyK. Fatigue in advanced cancer: a prospective controlled cross-sectional study. Br J Cancer1999;79:14791486.

  • 68.

    SolanoJPGomesBHigginsonIJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage2006;31:5869.

    • Search Google Scholar
    • Export Citation
  • 69.

    TeunissenSCWeskerWKruitwagenC. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain Symptom Manage2007;34:94104.

    • Search Google Scholar
    • Export Citation
  • 70.

    SaliganLOlsonKFillerK. The biology of cancer-related fatigue: a review of the literature. Support Care Cancer2015;23:24612478.

  • 71.

    DhruvaADoddMPaulSM. Trajectories of fatigue in patients with breast cancer before, during, and after radiation therapy. Cancer Nurs2010;33:201212.

    • Search Google Scholar
    • Export Citation
  • 72.

    WrightFD'Eramo MelkusGHammerM. Predictors and trajectories of morning fatigue are distinct from evening fatigue. J Pain Symptom Manage2015;50:176189.

    • Search Google Scholar
    • Export Citation
  • 73.

    MiaskowskiCPaulSMCooperBA. Trajectories of fatigue in men with prostate cancer before, during, and after radiation therapy. J Pain Symptom Manage2008;35:632643.

    • Search Google Scholar
    • Export Citation
  • 74.

    MiaskowskiCDoddMLeeK. Preliminary evidence of an association between a functional interleukin-6 polymorphism and fatigue and sleep disturbance in oncology patients and their family caregivers. J Pain Symptom Manage2010;40:531544.

    • Search Google Scholar
    • Export Citation
  • 75.

    RadadKMoldzioRRauschWD. Ginsenosides and their CNS targets. CNS Neurosci Ther2011;17:761768.

  • 76.

    KennedyDOScholeyABWesnesKA. Dose dependent changes in cognitive performance and mood following acute administration of Ginseng to healthy young volunteers. Nutr Neurosci2001;4:295310.

    • Search Google Scholar
    • Export Citation
  • 77.

    MintonOStoneP. A systematic review of the scales used for the measurement of cancer-related fatigue (CRF). Ann Oncol2009;20:1725.

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