AbstractDespite significant advances in anti-emetic therapy, chemotherapy-induced nausea and vomiting (CINV) remains a significant burden to cancer patients. Ginger (Zingiber officinale) has shown promise as an adjuvant to standard anti-emetic therapy to allay CINV. It contains several bioactive compounds that could interact beneficially with the multiple pathways involved in this adverse outcome of treatment. However, the results of previous clinical trials testing ginger are equivocal and the extant literature has multiple limitations that require further investigation.
The primary purpose of this Thesis by Publication is to determine the efficacy, safety, and feasibility of ginger in clinical practice through a systematic program of literature reviews, and clinical, survey, and laboratory studies that account for the limitations of the extant literature, and current gaps in the knowledge.
The aim of the first study undertaken in this thesis was to investigate the potential mechanisms of action exerted by ginger on CINV. Certain active compounds in ginger act via antagonism of the 5-HT3 receptors within the gastrointestinal tract leading to a possible reduction in CINV. Whether these compounds act directly at the serotonin binding site or act allosterically to modulate receptor activity has not been fully elucidated. Interactions between the principle compounds of ginger on the recently solved crystal structure of the murine 5-HT3 receptor were investigated using in silico techniques, in order to characterise the sites and determine if a preference in binding affinity is evident within the two distinct binding sites (Chapter 6). The results of this study demonstrated the investigated ginger compounds exhibited high binding affinity at both sites. We postulated that these compounds may potentially act at both sites – as seen with other serotonin modulators. The observed binding promiscuity of these compounds is likely due to their high degree of non-covalent interaction potential
The second study included in this thesis investigated the concentration of the primary bioactive compounds within 20 widely-available ginger products (including dietary supplements, beverages, and confectionary) using Reverse-Phase High-Performance Liquid Chromatography analysis (Chapter 7). This study addressed the efficacy and safety component of the projects aims by providing the following results. First, of the six dietary supplements analysed, standardized ginger extracts provided the most potent and consistent concentration of analysed ginger compounds, providing support for the use of standardized extracts in clinical trials. Second, when the concentration of compounds was presented by the approximate concentration that would be consumed in one serving, there were products from each product category that contained concentrations of the analysed compounds equal to, or exceeding, dietary supplements. This demonstrates that cancer patients could consume therapeutic concentrations of the active compounds within ginger through dietary intake alone. This has important implications for future clinical trials that aim to investigate the use of ginger supplementation. Furthermore, due to the potential effect ginger supplementation might exert on platelet aggregation, these results suggest that a high dietary intake of ginger products during chemotherapy could have safety implications. By analysing the concentration of primary compounds in a wide-range of commercially available ginger products, the information provided by this study will be able to inform Australian clinicians interested in these products for their adjuvant medicinal properties.
In the third and main study (Chapter 9), the efficacy and safety of ginger supplementation in humans was investigated in a clinical setting by way of a double-blind, randomized, placebo-controlled trial (N=51). This trial addressed the methodological limitations of the extant literature through the introduction of multiple robust features to the study design. These include following patients over an extended number of chemotherapy cycles, controlling for CINV-specific prognostic factors by recruiting only chemotherapy-naïve patients, implementing a dosing schedule consistent with the pharmacokinetics of oral ginger supplements, and independently analysing ginger supplements before and after the recruitment phase in order to ensure potency. The primary outcome was chemotherapy-induced nausea-related quality of life. Secondary outcomes included the severity, prevalence, and frequency of nausea, vomiting, and retching. This was also the first trial to assess the effect of ginger supplementation on cancer-related fatigue and nutritional status. The results of this study demonstrated a significant association between CINV- and nausea-related quality of life (p=0.043 and 0.029, respectively), global cancer-related quality of life (p=0.015), and cancer-related fatigue (p=0.007) in patients receiving the ginger intervention during the first cycle of chemotherapy. However, ginger supplementation did not reduce the prevalence or severity of CINV overall. There was no significant difference in reported adverse effects in the intervention group compared to the placebo group. By cycle 3 of chemotherapy, there was also significant attrition (33%). This suggests that the trial protocol could have been overly burdensome for participants and that the trial might not have been sufficiently powered to detect difference in CINV prevalence and severity. These results support previous studies, which indicate that ginger is well-tolerated; however, despite significant associations between ginger supplementation and CINV-related quality of life (QoL), cancer-related QoL, and cancer-related fatigue, the use of ginger supplementation as an effective treatment for CINV is not supported by this trial.
The final study provided information regarding the feasibility of introducing dietary supplements such as ginger as a complement to routine clinical practice (Chapter 10). Healthcare professionals (N=370) responded to this survey, which assessed their current level of confidence, usage, and barriers with respect to recommending dietary supplements. The findings indicate mixed levels of confidence in recommending dietary supplements for their patients; nonetheless, there is strong interest in further training in this area despite the multiple barriers articulated, including concerns regarding drug-nutrient interactions.
In summary, the results of this thesis demonstrate that ginger supplementation is generally safe and feasible, and has several viable mechanisms of action related to CINV. While no reduction in the severity or prevalence of CINV were reported in our trial, ginger supplementation could be an effective and well-tolerated adjuvant intervention to enhance CINV-related QoL and reduce fatigue. Currently, healthcare professionals are interested in dietary supplements; however, further professional training in this area would improve the integration of dietary supplements into standard clinical practice. Future studies that explore the efficacy and the safety-profile of ginger are warranted in larger clinical trials.
|Date of Award||2015|
|Supervisor||Elizabeth Isenring (Supervisor), Karin Ried (Supervisor) & Anna Lohning (Supervisor)|