Data from this study support that American ginseng has activity against CRF but that clinically meaningful results may not be realized until 2 months after starting ginseng. Clinically meaningful was defined as a difference of at least 10 points on a 0 to 100 scale based on previously published work (41). Participants currently receiving radiation and/or chemotherapy had statistically significantly better general fatigue scores at both 4 and 8 weeks in the ginseng arm vs the placebo arm. Better results in those receiving cancer treatment may indicate that ginseng may be a better preventive agent than treatment intervention, despite the fact that all patients had to have a certain level of fatigue to enter the trial. This is based on the fact that although it would be expected for fatigue to increase throughout cancer treatment, fatigue scores actually decreased (improved) during treatment. However, this issue requires further study. These data also provide further support that vigor and fatigue are conceptually and experientially different constructs, as the vigor subscales in the MFSI-SF and POMS were not significantly improved, whereas the fatigue-inertia subscale in the POMS and general physical fatigue subscales in the MFSI-SI were positively impacted.
Strengths of this study include that it was a randomized, double-blind trial involving 40 different clinical sites, most of which are community cancer centers. In addition, based on the correlation coefficients between fatigue, sleep, and pain, enrollment effectively targeted fatigue and not fatigue secondary to sleep disturbance or pain. An important limitation of this study is that it evaluated the use of ginseng only out to 8 weeks. Long-term or continued efficacy is not known.
It is curious that two of the fatigue measures were sensitive to changes over the course of the study from the intervention (POMS fatigue-inertia and MFSI general subscale), whereas the BFI was not. We cannot know, with certainty, why this was. The BFI, however, does use a 0 to 10 scale with descriptive anchors at the beginning and end, whereas the POMS and MFSI use a response scale that is shorter and delineated with descriptors throughout. It may be that patients were not able to distinguish between such closely spaced numbers without descriptors.
The mechanism by which American ginseng may be able to moderate fatigue is evidenced by preclinical data. Several investigators have established a consistent link between CRF and inflammation and have provided data to support dysregulation of the hypothalamic pituitary adrenal axis (42–46). These data suggest that chronic fatigue in cancer is associated with an inability for the hypothalamic pituitary adrenal axis to regulate inflammatory processes and that concentrations of inflammatory cytokines remain elevated instead of reachieving homeostasis (42–46). Preclinical data evaluating the biologic activity of ginseng have demonstrated the ability of ginseng to downregulate inflammatory pathways (47), decrease inflammation (26–28), and modulate cortisol and the impact of chronic stress on the hypothalamic pituitary adrenal axis (27).
Based on the provider- and patient-reported toxicity data in this trial, there were no discernible side effects from ginseng. In addition, there are other data to corroborate ginseng’s safety. The first is a recent report investigating herbs for possible inhibition of the cytochrome P450 system. American ginseng (P. quinquefolius) was one of a few herbs found to be noninhibitory (48). Second, there have been contradictory reports of ginseng’s ability to proliferate breast cancer cells as well as the thought that it might be estrogenic. Preclinical research sheds insight into this contradiction. Characteristics and properties of ginsenosides depend on the processing; certain extraction methods can result in estrogenic properties. Specifically, ginseng derived from methanol extraction, as opposed to water extraction, does exhibit estrogenic properties and has been found to proliferate cancer cells in breast cell lines in vitro (49–51). Ginseng products not derived from methanol extraction methods, but instead from water extraction or pure ground root, do not have estrogenic properties (51). In fact, preclinical data have demonstrated breast cancer cell inhibition by water-extracted American ginseng in both estrogen-sensitive and -insensitive cell lines (50).
Does ginseng interfere with the activity of chemotherapeutic agents? There are preclinical data demonstrating that American ginseng does not interfere with tamoxifen, doxorubicin, cyclophosphamide, paclitaxel, 5-fluorouracil, and methotrexate; rather ginseng was synergistic with these agents against MCF-7 breast cancer cell lines, inhibiting growth (47,51,52). It must be noted, however, that this is not definitive proof because there have not been studies done in humans to answer this question.
Because ginseng is not a regulated drug by the Food and Drug Administration and is a plant that is subject to all of the variables relevant for any agricultural crop, the potency of important ginsenosides is variable (24), and standardization regarding manufacturing processes and quality are not well established or proactively enforced. The pilot ginseng trial was fortunate enough to get a crop that contained 5% ginsensosides (33), where our phase III trial only had 3% ginsenoside content. Despite some increase in dose to compensate, it is possible that the effect of ginseng on fatigue may have been more profound had our dose and/or potency been higher.
In summary, although this study provides support for the use of American ginseng to ameliorate CRF, more research is necessary to understand its role and how to maximize its positive effects. It would, however, be reasonable for a cancer survivor to try American ginseng for fatigue, taking into consideration that there are no other pharmacologic agents known to be effective. Attention should be paid to the type of ginseng purchased, as mentioned above. In addition, it will be important to further explore the biologic activity of American ginseng with respect to CRF and to work toward a safe, standardized, potent product that is accessible to all who wish to try it.