Chemotherapy-induced nausea and vomiting (CINV) are the main adverse effects suffered by cancer patients undergoing chemotherapy. In recent years, development of antiemetic drugs and treatments has continuously progressed. For example, pairing second-generation serotonin 5-hydroxytryptamine-3 (5-HT3) receptor antagonists with dexamethasone greatly reduces CINV.1 Despite advances, between 50% and 60% of patients receiving chemotherapy still experience nausea and vomiting,2,3 and if left unchecked, CINV increases physical discomfort, affects quality of life, and can cause metabolic imbalance, dehydration, fatigue, and moodiness.4,5 Chemotherapy may even be interrupted or delayed in severe cases, threatening patient survival.6,7 To establish an effective method of treatment for CINV, relevant institutions and associations have created care guidelines; however, even when cancer patients follow antiemetic drug guidelines and take conventional antiemetic drugs, the effects aimed at perturbing delayed nausea and vomiting (DNV) in adult cancer patients are still limited. In fact, CINV can at present be controlled in approximately only 20% of adult cancer patients.8 Thus, more research is needed on alternative, nondrug measures to control nausea and vomiting.
A traditional antiemetic remedy is the root of the ginger plant (Zingiber officinale), commonly known as ginger, which is found all over the world. The antiemetic mechanisms of ginger extract are still unclear. The extract contains 6-gingerol, 6-shogaol, 8-gingerol, and 10-gingerol, which have similar prokinetic effects to 5-HT3 antagonists, neurokinin 1 receptor antagonists, and antihistamines.7 Preclinical tests in animals have shown that ginger extract is effective against CINV9,10; however, the results from clinical trials have not been as conclusive.11–13
Chemotherapy-induced nausea and vomiting can be classified as acute or delayed in patients, depending on the time of onset. The former occurs within 24 hours of chemotherapy, whereas the latter takes place 24 hours or more after chemotherapy.14 In this study, we performed a meta-analysis to determine whether the oral administration of ginger could reduce CINV.
Materials and Methods
Search Strategies for Empirical Literature
We systematically searched the literature for studies in English published between 2000 and 2017. Using the PICOS (patient, problem/population, intervention, comparison, outcome, study) framework, we searched for relevant studies using the following keywords: for P: “cancer patient”; for I: “0.5–2.0 grams of Zingiberaceae,” “Zintoma, dry ginger,” “ginger capsules,” “powdered ginger root,” “Zingiber officinale Roscoe,” “ginger extract,” “powdered ginger,” “6-gingerol,” or “shogalos per day”; for C: “placebo” or “standard care”; for O: “chemotherapy-induced nausea and vomiting”; and for S: “randomized control trial.” Specifically, these searches were performed in databases that included the Cumulative Index to Nursing and Allied Health Literature database, PubMed, ProQuest, MEDLINE, and the Cochrane Library. The studies were then screened in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement, the details of which are shown in Figure 1.15 Our inclusion criteria included (1) research subjects 18 years or older diagnosed with cancer and treated with chemotherapy, (2) oral use of ginger as an intervention measure, (3) research performed in a hospital or at home, and (4) acute or delayed CINV as the primary outcome. The exclusion criteria included discourse analyses or retrospective studies, nonrandomized tests, and animal studies.
We used the Cochrane risk of bias tool to assess the risk of error in the research designs.16Table 1 presents the evaluation items, allocation methods, and evaluation results. For the consistency between 2 evaluators, we calculated the κ value using SPSS 20 (Chicago, Illinois); a higher κ value indicates greater consistency.
We conducted a meta-analysis using Comprehensive Meta-analysis 2. Prior to combining the literature and analyzing the results, we created funnel plots and calculated the odds ratios (ORs). We used the Cochran Q test and the I2 test to test heterogeneity and homogeneity in the literature.24 A P of Q value less than 0.05 confirms heterogeneity among the articles, whereby subgroup analysis was subsequently performed to identify the variables of nausea and vomiting. I2 presents the degree of heterogeneity; following confirmation of heterogeneity, the random-effects model was adopted for analysis. We then used forest plots to display the effect size and the 95% confidence interval (CI). Funnel plots and Egger regression were used to determine whether publication bias existed.25
Attributes and Quality of Study Samples
We obtained 223 studies associated with our research subject from the designated databases in English that met our research strategies. Ten randomized controlled trials were included for our meta-analysis with quality scores ranging from 6 to 9 points (Table 1). Ginger capsules were made in 9 of the 10 studies for easier swallowing, whereas the last study mixed ginger powder in yogurt. In terms of dosage, 6 studies used a daily dosage of 1.0 g, another experimented with daily dosages of 1.0 and 2.0 g, and the other studies used daily dosages of 0.7, 1.5, and 1.6 g, respectively. The cancer types being treated and the chemotherapy drugs that were used varied, but all of the studies also administered appropriate antiemetic drugs to patients who took ginger and patients in the control group (Table 2). The κ value of the 2 evaluators was 0.915 (P < .001), indicating extremely high consistency and correlation. Figure 1 details the process and results of the literature search.
Overall Efficacy of Ginger in Controlling CINV
We analyzed a total of 10 studies. The funnel plot presented symmetric conditions (Figure 2A) and Egger regression indicated no significant differences (P = .530). Heterogeneity existed among the study samples (Q(42) = 150.84, P < .001, I2 = 72.16%). The overall effect indicates that taking ginger can significantly reduce CINV in cancer patients. The OR was 0.71 (95% CI, 0.54–0.94; P = .015); however, as heterogeneity existed among the samples, we proceeded with a subgroup analysis and divided nausea and vomiting into acute or delayed.
Overall Efficacy of Ginger in Controlling Acute CINV
The meta-analysis of research on the efficacy of taking ginger on acute CINV involved 9 studies. The funnel plot and Egger regression (P = .931) indicated no publication bias (Figure 2B). The intake of ginger was significantly more effective than treatment with placebo in the control of acute CINV (OR, 0.60; 95% CI, 0.42–0.86; P = .006) (Figure 3). We then performed a meta-analysis on the subgroups of acute nausea and acute vomiting. The analysis on acute nausea included 7 studies. The results indicated no significant differences in alleviating acute nausea between participants who took ginger and the participants in the control group (OR, 0.62; 95% CI, 0.35–1.10; P = .104) (Figure 3). The analysis on acute vomiting also included 7 studies, and the results presented a significant reduction of acute vomiting in patients in the group who took ginger compared with those in the control group (OR, 0.58; 95% CI, 0.37–0.94; P = .025) (Figure 3).
Overall Efficacy of Ginger in Controlling Delayed CINV
The meta-analysis of research on the efficacy of taking ginger on delayed CINV involved 9 studies. The funnel plot and Egger regression (P = .645) indicated no publication bias (Figure 2B). In the control of delayed CINV, the results revealed no significant difference between the participants who took ginger and the participants in the control group (OR, 0.79; 95% CI, 0.54–1.15; P = .210) (Figure 4). We then performed a meta-analysis on the delayed nausea and delayed vomiting subgroups. The analysis on delayed nausea included 7 studies, and we found no significant difference in delayed nausea between participants who took ginger and the participants in the control group (OR, 0.97; 95% CI, 0.57–1.63; P = .895) (Figure 4). The analysis on delayed vomiting also included 7 studies. Similarly, no significant difference was found in delayed vomiting between the participants who took ginger and the participants in the control group (OR, 0.63; 95% CI, 0.37–1.08; P = .095) (Figure 4).
We conducted a systematic literature review and obtained effect sizes from 43 valid samples. The results demonstrated that the intake of ginger could control CINV, particularly acute vomiting.
Our finding that ginger can mitigate acute CINV is consistent with other studies that demonstrated ginger as an effective prophylaxis and treatment for nausea and vomiting; those studies observed positive effects of ginger in motion sickness, seasickness, surgical anesthesia, and pregnancy.26–29 The mechanisms of acute and DNV are, however, different. When cancer patients undergo chemotherapy, the toxicity of drugs damages the enterochromaffin cells on the gastrointestinal mucosa, which generates free radicals that stimulate the enterochromaffin cells in the gastrointestinal tract to release an excessive amount of serotonin.30 As the concentration of serotonin in the blood rises, the serotonin binds with 5-HT3 receptors located on vagal nerve endings,31 producing chemical stimuli that travel to the brain and induce nausea and vomiting. Such a result is called acute CINV. In contrast, vagal nerve activation causes enterochromaffin cells to produce other neurotransmitters, such as substance P. Apoptosis of enterochromaffin cells also generates substance P. These conditions may lead to DNV.32,33 The meta-analysis in this study only indicated that ginger is effective in controlling acute CINV. More support for future relevant research is needed; however, our study does provide a reference for clinical applications.
In most of the studies that we analyzed, the research design involved the production of ginger capsules for the oral intake of the primary components of ginger.11–13,18–23 Extracts were mainly derived from ginger root,11–13,17,18,22,23 and not all of the study results above proved that ginger root would be effective. It is currently known that fresh ginger root contains more gingerols, whereas dried ginger root contains more shogaols, particularly 6-shogaol.34 Whether the efficacy of ginger is associated with its freshness or physical state warrants further investigation. In terms of dosage, the studies included in our analysis administered 0.7 to 2.0 g of ginger daily; the 5 studies that found significant efficacy administered ~1.0 g/d.17,21,23 Ryan et al35 further observed that daily intake of 1.5 g of ginger was not as effective as 0.5 or 1.0 g of ginger in relieving nausea. Thus, the efficacy of ginger may be associated with the dose, but this, too, requires further investigation.
Some of the studies encompassed in our analysis also indicated that because ginger has a unique smell, participants knew that they were taking ginger from the smell of the capsules even if a double-blind research design was adopted, so the effects of the ginger treatment may be overestimated.23 In another aspect, 4 of the 10 studies focused on breast cancer patients,12,17,22,23 whereas the other studies did not focus on any single type of cancer (Table 2). This may have resulted in greater heterogeneity among the samples in the meta-analysis.
Based on our findings and the other relevant studies, ginger is not a complete alternative for antiemetic drugs; however, a suitable dosage could collaborate to alleviate nausea and vomiting without the adverse effects of antiemetic drugs. For example, metoclopramide causes focal dystonia and restlessness, and antihistamines can cause dry mouth, fatigue, and drowsiness.11 Thus, clinical applications could be feasible, but more empirical research is required. Furthermore, the studies included in our analysis administered other antiemetic drugs at the same time as ginger, so whether the efficacy of ginger is augmented by other antiemetic drugs is unknown.
Some research has indicated that ginger can bring about symptoms including diarrhea, dizziness, heartburn, or even allergy-like symptoms, such as rash or flushing.23,35 In the study by Ryan et al,35 24 of the cancer patients displayed adverse reactions, and 9 of those patients withdrew from the trial as a result of these adverse reactions. In the study by Yekta et al,23 5 of the 40 cancer patients experienced heartburn within a day of taking ginger, and another 2 patients experienced heartburn the following day. The remaining studies in our meta-analysis did not specifically document any adverse reactions. Nonetheless, the adverse effects of taking ginger likely limited its capacity for controlling CINV or affected a patient's willingness to participate in the trial, both of which may have contributed to the heterogeneity in our analysis.
This study focused on studies written in English, so other literature that could have met our inclusion criteria were not included. Furthermore, most of the studies examined small sample pools that also had differing daily doses of ginger, which must be taken into consideration. Because of the limited amount of ginger in each capsule, the participants in many of the studies were required to take 4 capsules a day.11,18–23 Some of the participants in the study conducted by Zick et al13 even had to take 8 capsules every day; only the participants in the study conducted by Thamlikitkul et al12 took 2 capsules per day. These high numbers of capsules may have led to low compliance and higher rates of participant loss. The smaller sample pools and the limitations mentioned may have affected the power of the actual differences between experimental and control groups; we suggest a follow-up to this study when more relevant research will have been conducted.
The results of this study indicate that ginger is significantly effective in controlling acute CINV but not effective in controlling DNV. Further support from more clinical trials would facilitate the establishment of relevant guidelines to give patients receiving chemotherapy a better quality of life.
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