Reference
Barton DL, Liu H, Dakhil SR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial. J Natl Cancer Inst. 2013 Aug 21;105(16):1230-1238.
Design
A double-blind trial randomized cancer patients to receive 2,000 mg of Panax quinquefolius (American or Wisconsin ginseng) versus placebo for cancer-related fatigue (CRF).
Participants
Adult patients with cancer undergoing or having completed curative intent treatment and experiencing fatigue, rated at least 4 on a numeric analogue fatigue scale (1–10) for ≥1 month, were eligible. Exclusion criteria included any brain malignancies, prior use of ginseng, or chronic use of systemic steroids or opioids. Other etiologies for fatigue, such as pain and insomnia, were also assessed and excluded. All participants were diagnosed within 2 years of study enrollment. Three hundred sixty-four participants (183 in ginseng group, 181 in placebo) were enrolled from 40 institutions, and 200 participants were available for primary endpoint analysis (147 in ginseng group, 153 in placebo group).
Study Medication and Dosage
Participants ingested two 500-mg capsules BID of pure Panax quinquefolius ground root from one production lot or a matching placebo containing rice powder. The ginseng contained 3% ginsenoside and was evaluated for quality and potency by an independent company.
Outcome Measures
The primary endpoint was change in the general subscale of the Multidimensional Fatigue Symptom Inventory (MFSI) from baseline to 4 weeks. Other MFSI subscales and the fatigue-inertia subscale of the Profile of Mood States (POMS) were also analyzed. Data were transformed to a 0–100 scale and evaluated at 4 and 8 weeks. A subset analysis was analyzed of those currently undergoing treatment versus those who were not. Toxicities were evaluated by self-report and the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) provider grading.
Key Findings
Overall, there was no statistically significant difference in MFSI scores at 4 weeks, but there was a statistically significant difference seen at 8 weeks for the ginseng group (P=0.003). Participants undergoing active treatment had statistically significant improvement in fatigue at both 4 and 8 weeks. Toxicities per self-report and CTCAE grading did not differ significantly between arms.
Practice Implications
There has been increasing interest in the use of ginseng for CRF since this research was first presented at the American Society of Clinical Oncology annual conference in 2012. Such attention is warranted, considering the persistent and debilitating nature of CRF and the lack of effective pharmacological interventions available.
In accordance with tolle causum (Latin for “remove the cause”), the unique nature of CRF relative to common fatigue is worth clarifying. CRF is not relieved by sleep or rest,1 and patients with CRF report being “unusually or overwhelmingly tired.”2 Chronic posttreatment fatigue tends to be stable over time, whereas treatment-related fatigue tends to worsen during therapy and improve during the month or two after the completion of therapy.3 The prevalence of fatigue is reported to be between 59% and 96% in patients undergoing chemotherapy, 65% to 100% in patients receiving radiation therapy, and 30% in long-term survivors.4 Several pharmacologic agents, such as methylphenidate, corticosteroids, anabolic steroids, antidepressants, and modafanil, as well as L-carnitine and coenzyme Q10 currently are being used as remedies. However, few of these agents have been studied in large placebo-controlled trials and, based on pre-clinical data, of those that have been studied, none has been proven to be significantly helpful. In my experience working in an integrative care setting, I would largely agree that little to no change in energy is seen using these treatments.
The positive results of this trial are compelling, especially considering the broad cross-section of cancer patients.
One complicating factor is that the etiology of CRF is multifactorial and largely misunderstood. Proposed mechanisms include pro-inflammatory cytokines,5 hypothalamic-pituitary-adrenal (HPA) axis dysregulation,6 circadian rhythm desynchronization,7 skeletal muscle wasting,8 and genetic dysregulation.9 The benefit of using botanicals with this type of symptom is that they contain a variety of constituents with different actions, and many, such as Panax spp, are immunomodulators. Thus, P quinquefolius may be able to positively affect individual cases of CRF with different combinations of causative factors. Much of the research using Panax spp cites total ginsenoside amount as well as ginsenoside subtypes as being important determinants of outcome. The current trial was designed to use 2,000 mg/day based on a 2010 pilot study for CRF that used escalating doses of P quinquefolius. In the pilot study (n=290), the crop used contained 5% ginsenoside, and both the 1,000-mg and 2,000-mg/day dosing showed significantly improved fatigue versus 750 mg/day over an 8-week period.10 In that study, 40% of the intervention group perceived a moderate to “very much better” benefit versus 17% on placebo. In the study being reviewed, the crop contained 3% ginsenoside.
The positive results of this trial are compelling, especially considering the broad cross-section of cancer patients from 40 different sites who participated, with 78% of the participants completing all study interventions. Of special note is the finding that those under current treatment not only benefited from the ginseng at 4 weeks but continued to improve over the 8-week period. As mentioned previously, patients with CRF undergoing treatment typically experience worsening of this condition throughout therapy. Therefore, one might consider using P quinquefolius at the onset of therapy to prevent the symptom from appearing, or at least lessening its intensity.
This calls into question the safety of using American ginseng while patients are undergoing treatment. Literature exists surrounding the possible estrogen-potentiating effect of P quinquefolius leading to proliferation of hormone-sensitive cancers.11 Whether this is a valid action of P quinquefolius is not clear. A 2006 study purports to explain this finding as a result of how the ginseng is extracted. The researchers found that ginseng products not derived from methanol extraction methods, but instead from water extraction or pure ground root, do not have estrogenic properties.12 Furthermore, preclinical data exists showing inhibition of breast cancer cell lines by water-extracted American ginseng in both estrogen sensitive and insensitive cell lines.13
Another safety concern is how the herb is metabolized through the liver. We would not want an intervention to possibly decrease or increase the rate of metabolism of any chemotherapeutic agent. To that point, in vitro data indicate a non-inhibitory affect of American ginseng on CP450 3A4,14 CYP2B1, CYP3A23, and CYP1A2 gene expression.15 Of course, in vitro data is not the same as clinical data, and until there is human data, we run the risk of drug underdosing or overdosing. This is a significant risk given that the therapeutic window of chemotherapeutic agents tends to be very narrow.
As an herbalist at heart, I must offer the greatest respect to P quinquefolius as a wild, native plant traditionally used as a nervous system tonic by both the Eclectics and Native Americans. It grows wild from Canada to Georgia and is considered endangered.16 The future viability of wild American ginseng is at risk for several reasons, including overharvesting, the fact that it takes at least 5 years for the roots to grow before being harvested, and increased economic incentives as the price of wild roots continues to rise. As a consequence, commercial farms are cultivating crops. Moving forward, researchers should always mention their crop source and what the specific subtypes of ginsenoside are in the plant used, as there is variance among crops produced in different bioregions.17
Using American ginseng as a potential preventive and treatment for CRF looks promising, but more research is warranted, with human trials proving its safety with use of various chemotherapeutic agents. It would also be worth exploring the efficacy of American ginseng versus other adaptogenic plants, such as Eleutherococcus (Siberian ginseng) or Panax ginseng (Asian ginseng) in separate arms to evaluate efficacy and safety for treating patients with CRF.
