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Support Care CancerDOI 10.1007/s00520-008-0528-8 Phase II trial of encapsulated ginger as a treatmentfor chemotherapy-induced nausea and vomiting Suzanna M. Zick & Mack T. Ruffin & Julia Lee &Daniel P. Normolle & Rivka Siden & Sara Alrawi &Dean E. Brenner Received: 14 June 2008 / Accepted: 15 October 2008 daily, or matching placebo for 3 days. The primary outcome Goals of work Ginger has been used to treat numerous was change in the prevalence of delayed CINV. Secondary types of nausea and vomiting. Ginger has also been studied outcomes included acute prevalence of CINV, acute and for its efficacy for acute chemotherapy-induced nausea and delayed severity of CINV, and assessment of blinding.
vomiting (CINV). However, its efficacy for delayed CINV Main results There were no differences between groups in in a diverse oncology population is unknown.
the prevalence of delayed nausea or vomiting, prevalence of Materials and methods We performed a randomized, acute CINV, or severity of delayed vomiting or acute double-blind, placebo-controlled trial in 162 patients with nausea and vomiting. Participants who took both ginger and cancer who were receiving chemotherapy and had experi- aprepitant had more severe acute nausea than participants enced CINV during at least one previous round of who took only aprepitant. Participants were able to chemotherapy. All participants were receiving a 5-HT3 accurately guess which treatment they had received. Ginger receptor antagonists and/or aprepitant. Participants were appeared well tolerated, with no difference in all adverse randomized to receive either 1.0 g ginger, 2.0 g ginger events (AEs) and significantly less fatigue and miscella-neous AEs in the ginger group.
Conclusions Ginger provides no additional benefit for This trial is registered in ClinicalTrials.gov ID: NCT00065221.
reduction of the prevalence or severity of acute or delayedCINV when given with 5-HT3 receptor antagonists and/or Departments of Family Medicine, University of Michigan,Ann Arbor, MI, USA Biostatistics Unit of the Comprehensive Cancer Center,University of Michigan,Ann Arbor, MI, USA R. SidenDepartment of Pharmacy Services, University of Michigan, Chemotherapy-induced nausea, retching, and vomiting (CINV) has historically had significant negative impacts on the quality of life (QoL) and daily functioning of patients receiving chemotherapy CINV that occurs Department of Internal Medicine, University of Michigan, within the first 24 h of chemotherapy treatment is considered acute. Delayed CINV occurs at greater than 24 h post-treatment and can persist for several days. The negative impacts of CINV on QoL persist despite the introduction of newer treatments for nausea and vomiting, Ann Arbor, MI 48104, USAe-mail: szick@med.umich.edu such as serotonin (5-HT3) antagonists for acute CINV and aprepitant [neurokinin-1 (NK-1) antagonist] [for several doses, adequate sample size, and investigation into both acute and delayed CINV, we conducted a randomized, Several recent surveys have found that the prevalence of placebo-controlled, double-blind clinical trial to determine CINV after receiving conventional anti-emetic therapy the efficacy of a ginger extract for the treatment of CINV in ranged from 48% to 67% , , ]. In one survey adults with a histologically confirmed diagnosis of cancer conducted in ten community oncology clinics, only 33% of that were currently being treated with chemotherapy.
the patients did not have either delayed or acute CINV, andthe majority of patients who developed CINV experiencedboth delayed and acute CINV In a US national survey, only fatigue was a more prevalent side effect of chemo-therapy treatment compared to CINV [In particular, patients consistently reported significantly more delayednausea and vomiting compared to acute CINV, indicating The study protocol and all procedures were approved by the that delayed CINV continues to be difficult to control University of Michigan (UM) Medical School Institutional despite the introduction of anti-emetic agents targeted at Review Board and all participating clinical sites review this timeframe ]. Patients experiencing CINV reported boards. All participants provided written informed consent.
lower satisfaction with their care [missed work days The study took place between June 2003 and May 2006.
], and negative effects on QoL [, , ]. Agents that Individuals 18 years and older who had a histologically could safely further decrease the rates of CINV, and confirmed diagnosis of cancer currently being treated with especially delayed CINV, are needed.
chemotherapy (for adjuvant, neoadjuvant, curative, or Ginger root (Zingiber officinale Roscoe, Zingiberaceae) palliative means) were eligible. Patients must also have was first cultivated in Asia and has been used as a medicinal received at least one previous chemotherapy treatment with herb for at least 2,000 years ]. In Chinese, Indian, Middle the same chemotherapeutic agent and have experienced Eastern, and western herbal medicine, ginger is used nausea or vomiting of any severity as a result of that primarily as a remedy for digestive disorders including treatment. Patients were recruited from the UM Health dyspepsia, nausea, vomiting, and diarrhea ].
System oncology clinics and from ten other sites that were Ginger root contains approximately 1.5% to 2.0% of a part of the National Cancer Institute’s (NCI’s) Community number of pungent compounds Gingerols are the most Clinic Oncology Program (CCOP). Patients were ineligible abundant pungent compounds in fresh roots, and several if they: (a) were receiving multiple-day chemotherapy; (b) gingerols of various chain lengths (n6 to n10) are present, were receiving concurrent radiotherapy that was classified with the most plentiful being 6-gingerol. Shogaols, the as high or intermediate risk of causing emesis (i.e., total dehydrated form of gingerols, are mainly found in the dried body irradiation, hemi-body, upper abdomen, abdominal– and thermally treated roots, with 6-shogaol being the most pelvic mantle, cranium, or craniospinal irradiation); (c) abundant ]. Gingerols and shogaols appear to be the were taking therapeutic doses of coumadin (individuals on compounds that confer most of the medicinal properties to low-dose coumadin to maintain peripheral or central venous catheters were allowed), aspirin (individuals taking low- Ginger demonstrates numerous properties that may be dose 81 mg aspirin were allowed), or heparin; (d) had a beneficial in treating CINV, including reversing the inhib- history of a bleeding disorder(s) and those experiencing itory effect of cisplatin on gastric emptying in rats , ], clinically significant thrombocytopenia; (e) had an allergy as a 5-HT3 receptor antagonist , , ], and as an to ginger or had taken ginger in the last week; or (f) were nursing mothers, pregnant women, or planning a pregnancy Previous clinical trials have examined the effect of ginger during the study period. Patients were eligible to participate on CINV with mixed results, with one study showing no if they were scheduled to have a single-day chemotherapy effect ], another with mixed results ], and two others regime and to receive a 5-HT3 receptor antagonist antie- with positive outcomes , of ginger compared to metic and/or the antiemetic aprepitant.
placebo or metoclopramide. Apart from their mixed out- All potentially eligible participants were approached by comes, it is difficult to assess these studies as they are a research assistant or nurse after their visit at various limited by their small sample sizes, no clear identification oncology clinics, and interested patients were scheduled for or quality control of the ginger product used, unclear or their screening visit. The screening visit was within 28 days limited patient population, and no examination of appro- of when the study medication was administered and could priate ginger dose. Further, only one study ] investigated be replaced with a pre-chemotherapy visit if all study delayed nausea and vomiting. Using a well-defined and procedures were conducted. Written and verbal informed broad patient sample, a well-characterized ginger product at consent were obtained at the beginning of the screening visit. Patients then had a physical exam, medical history, a asked whether they experienced nausea or vomiting during list of concomitant medications collected, a complete blood or after their chemotherapy treatment, are also asked how count (with platelets and differentials), a comprehensive long in minutes or hours their nausea lasted and how they chemistry screen, and a prothrombin time/international ratio would describe their nausea or vomiting “at its worst” using test. Participants were also given a questionnaire to assess a six-point Likert scale (very mild to intolerable) as well as the amount of ginger in their typical diet. Those participants the time period when the “nausea or vomiting was the who had acceptable physical exams, laboratory values, and worst”, e.g., 4–8 h after treatment ]. Delayed chemo- were not eating a significant amount of ginger were deemed therapy-induced nausea or vomiting was defined as any eligible and were scheduled to receive their study medica- nausea or vomiting that occurred greater than 24 h after tion during their next round of chemotherapy.
The secondary objectives included: (1) comparing the effect of a low-dose (1.0 g) and a high-dose (2.0 g)powdered ginger root extract versus placebo for reducing Eligible participants were randomly assigned to receive a the prevalence and severity of acute (within 24 h of ginger extract, manufactured by Pure Encapsulations® receiving chemotherapy) nausea and vomiting (assessed (Sudbury, MA, USA), 1.0 g (four capsules ginger and four with the MANE); (2) assessing the safety of different doses capsules placebo daily), 2.0 g (eight capsules daily), or a (low versus high) of oral powdered ginger root; and (3) matching placebo (eight capsules daily). These doses were determining if study participants are blinded to study chosen based on the manufacturer’s recommendations and assignment, as well as determining which variables may on doses used in previous clinical studies using this extract.
unblind participants (taste, smell, and decrease in nausea Each capsule contained 250 mg dry extract of ginger root and emesis) during the 3-day study period.
[10:1 (v/v) extraction solvent (ethanol 50%)/root] standard- We assessed safety by querying participants verbally ized to 15 mg (5%) of total gingerols. The University of about any hospitalizations or adverse events that occurred Michigan Investigational Drug Service placed 250 mg of during any of the 3 days of the study. We also reviewed the Pure Encapsulations® ginger or lactose powder in size hospital records to assess the cause of hospitalizations and “0” red animal gelatin capsules made by Gallipot®. Based gather information about laboratory abnormalities. Toxic- on high-performance liquid chromatography (HPLC) anal- ities were graded based on National Cancer Institute ysis, a 250-mg capsule of ginger extract contained 5.38 mg Common Toxicity Criteria version 3.0 for Adverse Events (2.15%) 6-gingerol, 1.80 mg (0.72%) 8-gingerol, 4.19 mg All study participants had access to 24-h nursing (1.78%) 10-gingerol, and 0.92 mg (0.37%) 6-shogaol.
support at their local institution. Any adverse events Content of gingerols and 6-shogaol in the study medication reported by the participants to their local health care were independently verified using appropriate HPLC providers or CCOP research staff were promptly reported methods (Integrated Biomolecule; Tuscon, AZ, USA) [].
to UM study personnel and followed up by a direct query to Participants were told to take the study medication twice the CCOP research site for additional information.
per day with water and to bring all unused capsules to thefinal (72 h) study visit. The first study drug dose was taken within 1 h of the completion of chemotherapy. Patientswere seen at the study clinic at the time of their Eligible participants were randomized equally to one of chemotherapy treatment and 3 days after the end of their three groups: placebo, ginger extract 1.0 g, or ginger extract 2.0 g. The randomization code blocked by research site wascomputer-generated by the study biostatistician. Study par- ticipants were also stratified at randomization into one of twostrata [strata 1=5-HT3 antagonist; strata 2=aprepitant (NK1 Our primary objective was to compare the effect of a low- antagonist)]. Participants who received a 5-HT3 antagonist dose (1.0 g) and a high-dose (2.0 g) powdered ginger root plus aprepitant were placed into the aprepitant strata, while extract versus placebo for reducing the prevalence and those participants that received only a 5-HT3 antagonist severity of delayed nausea and vomiting using a 2-day were placed in the 5-HT3 strata. The stratification allowed patient diary based on a modified “Morrow Assessment of for an equal distribution of the NK1 antagonist (aprepitant) Nausea and Emesis” (MANE; we replicated questions for to be distributed equally between the treatment arms.
days 2 and 3, not just the first 24 h after chemotherapy All study participants as well as all study personnel who treatment). The MANE is a validated questionnaire used to assessed outcomes, worked with study data, or adminis- assess the prevalence and severity of vomiting and nausea tered tests or questionnaires were unaware of the random- in a given time period, i.e. 24 h. Patients, along with being ization list or treatment assignment.
Baseline characteristics were reported, stratified by treat- ment group, using means and SDs for continuous variablesand counts and percentages for categorical variables.
We screened 4,244 patients, of whom 162 met all eligibility Balance between treatment groups on baseline character- criteria and were randomized: 57 to the placebo, 53 to the istics was tested using Kruskal–Wallis statistics for contin- 1.0-g ginger dose, and 52- to the 2.0-g ginger dose. Figure uous variables and Pearson’s chi-square and Fisher exact documents sources of recruitment for potential participants, tests, as appropriate, for categorical variables.
reasons for exclusions, and reasons for discontinuing the Prevalence of delayed and acute nausea or vomiting intervention. The low proportion of recruited patients was calculated as a binary variable, i.e., “yes” if the patient reflects the broad screening of unselected patients presenting had nausea or vomiting (of any severity) or “no” if the to oncology clinics at all CCOP sites. Forty-six participants patient had no nausea or vomiting. If participants vomited in the placebo group, 43 participants in the 1.0-g ginger and/or retched at least once, it was counted as a “yes” for dose, and 40 participants in the 2.0-g ginger dose arm vomiting for that time period. The prevalence of nausea and completed all study visits. Adherence to study medications vomiting was compared separately by treatment arm using was moderate to high, with 79% of all participants taking Cochran Mantel–Haenszel tests stratified for aprepitant greater than 80% of all study medication and with no (“yes” or “no”). Logistic regression was also used to model significant differences between groups (p=0.80).
the effect of treatment while controlling for covariates,including: emetogenicity of chemotherapeutic agent (high, Sociodemographic and clinical characteristics moderate, low); aprepitant (“yes” or “no”); and presence orabsence of baseline nausea or vomiting (“yes” or “no”) as In Table , we present the sociodemographic and clinical appropriate for delayed values and presence or absence of characteristics of participants by treatment group. There acute nausea or vomiting (“yes” or “no”). Analyses of was no significant difference between treatment groups for severity of delayed and acute nausea and vomiting were any demographic or clinical characteristics.
examined as an ordinal outcome. Severity of nausea and All participants received a 5-HT3 receptor antagonist.
vomiting and/or retching was graded on a six-point scale, Fifty-two participants (32.1%) received aprepitant. Of the where 1 equaled very mild and 6 equaled intolerable. These 52 participants given aprepitant, 49 (94.2%) were receiving severity analyses were only performed on participants who moderate or high emetic risk antineoplastic compared to had experienced nausea or vomiting. Analyses of severity only three (5.8%) who were being administered low emetic were performed using Cochran Mantel–Haenszel tests between treatment groups (placebo, ginger =1.0 g andginger=2.0 g) and stratified by aprepitant (yes/no). Anal- Prevalence and severity of acute and delayed nausea yses were conducted according to the intention-to-treat principle; however, no imputation was performed formissing values at day 1, 2, or 3. Data were entered into a Fifty-eight percent (n=94) of study participants reported central database located at Dartmouth College (Hanover, experiencing both acute and delayed nausea, while 30.9% NH, USA). For all analyses, two-sided tests and a (n =50) of participants reported acute vomiting and/or significance level of 0.05 were used. The experiment-wise retching and 24.7% (n=40) reported delayed vomiting type I error rate was protected only for the principal outcome measure. No adjustments were made for multiple- There was no significant difference between either of the hypothesis testing, as the secondary outcomes were viewed ginger doses compared to placebo in the prevalence of acute or delayed nausea or vomiting. This observation was The sample size was justified in terms of the analysis of consistent when participants were stratified by whether or between-treatment differences in delayed nausea. The not aprepitant was prescribed as part of their treatment for prevalence of delayed nausea in patients taking standard CINV (Table Although not significant, participants who antiemetic therapy was assumed to be 51% for lower dose received aprepitant and either dose of ginger had more chemotherapy and 74% for higher dose chemotherapy. If treatment failures compared to those who received aprepi- the highest ginger dose caused a 30% relative reduction tant in addition to placebo for both acute and delayed from placebo in the prevalence of delayed nausea, the study had 75% power to reject the null hypothesis of no treatment When not stratified by use of aprepitant, there was no significant difference in severity between either the low 4082 Excluded 53 - Unwilling to sign consent 314 – Receiving multi-day chemotherapy 102 – Not receiving a 5-HT3 agonist 82 – Receiving anti-coagulation 2806 – Denies nausea or vomiting 725 - Miscellaneous 3 – Unknown 0 - Misunderstood directions dose or the high dose of ginger and placebo, except for 2.0 g, or placebo) the patient received. Outcome assessors delayed nausea. Participants who received the high dose of were not able to correctly identify which treatment the ginger (2.0 g) reported having significantly more severe patient received (p=0.27). Patients, however, were signif- episode of delayed nausea compared to both placebo and icantly (p = 0.01) more likely to correctly guess the low-dose ginger (1.0 g; mean ± SD: placebo = 2.8 ± 1.2, treatment they were given. Patients indicated that it was ginger 1.0 g=2.9±1.1, ginger 2.0 g=3.4±1.1; p=0.03).
the “the way the capsule worked” (16%placebo, 51%1.0 g, Table presents results of the severity of both acute and 33%2.0 g for each treatment group; p=0.12) as the most delayed nausea and vomiting stratified by the use of common reason for knowing which treatment they were aprepitant. For those participants who did not receive taking. The taste of the capsule was the second most likely aprepitant, we observed no significant difference in severity reason given for being able to know what treatment a of nausea or vomiting between either dose of ginger or participant received (9%placebo, 25%1.0 g, 33%2.0 g for each placebo (Table However, participants who were pre- scribed aprepitant and either dose of ginger had signifi-cantly more severe delayed nausea (Table ).
We divided adverse events into those that most commonlyoccurred in the trial, e.g., laboratory abnormalities events, Both patients and research personnel who were responsible and side effects most often associated with ginger con- for collecting study endpoints from patients (outcome sumption, e.g., GI events. There were no significant assessors) were asked to evaluate which treatment (1.0 g, differences in total adverse events, non-serious adverse Table 1 Baseline characteristics of the randomization groups Concomitant 5-HT3 receptor antagonists and NK-1, n (%) 5-HT3 5-hydroxytryptamine type 3, NK-1 neurokinin-1 receptor antagonista Emetic risk of intravenously administered antineoplastic agents based on the American Society of Clinical Oncology (ASCO) guidelines forantiemetics in 2006 When patients received more than one antineoplastic agent, only the agent that possessed the highest emetic risk islisted. If more than one antineoplastic agent of the same emetic risk was administered, then both antineoplastic agents are listed.
events, dyspnea, gastrointestinal events, or laboratory thrombosis, another patient was hospitalized after experienc- abnormalities between treatment groups, although labora- ing severe diarrhea and abdominal pain, and another patient tory abnormalities were close to being significantly higher hospitalized for anemia, low platelets, and white blood cells.
in the placebo and 1.0-g dose (8placebo vs. 81.0-g dose vs.
We found no significant difference in serious adverse events 12.0-g dose; p=0.06) compared to the 2.0-g dose. There were significantly more fatigue (5placebo vs. 11.0-g dose vs. 02.0-g dose;p=0.03) and miscellaneous adverse events (8placebo vs.
31.0-g dose vs. 12.0-g dose; p=0.02) in the placebo group compared to either ginger dose. Nearly all of the adverseevents were non-serious and graded as either a 1 or a 2 on We found no benefit of a ginger extract, in the doses and the NCI toxicity version 3. Out of the 42 patients who formulation used, on our primary end point, the prevalence experienced an adverse event, only three were serious: One of delayed nausea and vomiting, when added to contem- patient was hospitalized with an upper extremity deep vein porary standard antiemetic therapy in cancer patients Table 2 Prevalence of acute and delayed nausea and vomiting a P values were calculated using Cochran Mantel–Haenszel tests stratified by apripetant (yes or no) b P values are Pearson chi-squares calculated using logistic regression adjusting for emetic risk of the chemotherapeutic agent (high, moderate,low), apripetant, presence or absence of baseline nausea or vomiting (yes or no) as appropriate for delayed values and presence or absence of acutenausea or vomiting (yes or no) as appropriate for acute measures receiving chemotherapy. These results are consistent severity of delayed nausea (p = 0.03), although when whether evaluated in unadjusted analyses or in analyses stratifying by use of aprepitant, severity of delayed nausea that adjusted for presence or absence of acute nausea, or was only increased when the 2.0-g dose of ginger was taken vomiting, emetogenicity of chemotherapeutic agent, and with aprepitant (p=0.01) and not when taken without use of aprepitant. Likewise, ginger extract caused no decrease in the severity of delayed nausea or vomiting.
Similar to delayed CINV, we found that ginger extract The 2.0-g dose of ginger extract, however, did increase the did not decrease the prevalence of acute nausea or vomiting Table 3 Severity of acute and delayed nausea and vomiting a Severity of nausea and vomiting graded on a six-point Likert scale graded as 1=very mild, 2=mild, 3=moderate, 4=severe, 5=very severe, and6=intolerableb P values were calculated using Cochran Mantel–Haenszel tests stratified by apripetant (yes or no) compared to placebo. Further, ginger extract at both doses The third study that found results in contrast to ours was did not affect the severity of acute nausea or vomiting.
a crossover RCT comparing ginger to metoclopramide and However, when ginger was taken with aprepitant, there was ondansetron for controlling the incidence of CINV for 24 h an increase in the prevalence of delayed vomiting, although after treatment. Ginger powder was found to be as this did not reach statistical significance (p=0.07). Other- successful as metoclopramide in complete control of CINV, wise, these results were consistent whether or not a but ondansetron was found to be superior to both of the participant had been prescribed aprepitant.
other two treatments (complete control of nausea was 62% Ginger appeared to be well tolerated. There was no in ginger, 58% in metoclopramide, and 86% with ondanse- difference between placebo and ginger for all adverse tron) ]. Unlike our study, the 1.0-g dose of ginger events, for common AE categories including dypsnea and powder was not co-administered with antiemetics, e.g., gastrointestinal complaints, or serious adverse events.
5-HT3 receptor antagonists, but instead was given instead Despite the lack of statistical significance difference in serious AEs, all of the serious AEs did occur in the low- In contrast, another RCT crossover study in gynecologic dose ginger group and approached statistical significance oncology patients receiving cisplatin comparing 1.0 g (p=0.07). There were significantly fewer complaints of ginger to placebo and metoclopramide (placebo during the fatigue (p=0.03) and miscellaneous other adverse events first 24 h and metoclopramide during the next 4days) found (p=0.02) in the ginger treatment groups versus placebo, and there were borderline significantly fewer laboratory There was evidence in this study that ginger, when co- abnormalities in the high-dose ginger arm (p=0.06). The administered with aprepitant, increased the severity of occurrence of all serious adverse events in the low-dose delayed nausea. In addition, while not statistically signifi- ginger group should be viewed with caution, but given the cant, participants prescribed aprepitant and ginger (either small number of serious events (three), this result could be dose) had consistently higher prevalence of both acute and due to chance alone. Similarly, the positive effects of ginger delayed nausea and delayed vomiting compared to those on fatigue could also be attributed to chance due to the participants who received only aprepitant. It is possible that small number of events. The wide variety of events in the ginger root, similar to other of food and beverages, can alter miscellaneous other and laboratory AE groups appear the rate and extent of drug absorption. Ginger could unlikely to be explicable by a pharmacologic effect of decrease the absorption of aprepitant by increasing gastric ginger. However, possible pharmacological effects such as emptying time and intestinal motility and thus decreasing ginger root’s anti-inflammatory [, , , ] and aprepitant’s anti-nausea effects. Ginger extracts and their antioxidant effects could be responsible for constituents can shorten food transit time enhance some of the decreased AEs. As a consequence, future gastrointestinal motility [], and reverse pyrogallol-induced studies could be considered to examine the protective effect delay in gastric emptying in rats [].
of ginger on fatigue and laboratory abnormalities experi- Our study had several limitations. First, we were limited by inadequate power to detect small effect sizes for Our results are in contrast to three other randomized secondary outcomes. Second, we lacked adequate sample controlled trials (RCTs) [, examining the safety sizes to detect differences in the primary and secondary and efficacy of ginger root extracts or powder for acute outcomes by treatment with or without aprepitant. Third, CINV. Two of these studies [] are only available in we found that participants were able to determine if they abstract form, allowing for no more than limited compar- were randomized to either of the ginger treatment arms, isons with our study. Pace [] found that ginger indicating that how the capsule tasted allowed them to significantly decreased an acute nausea symptom score, determine which treatment they had received. Three meta- and Pecoraro et al. ] determined that participants who analyses of clinical trials found that when participants are received ginger compared to placebo appeared to have a not blinded, there tends to be a moderate overestimate of greater complete treatment response of acute CINV, the effect of the new treatment Lack of blinding although no statistical analysis is provided for the later is of particular concern when the outcomes are subjective or study. The results of these studies could differ from ours “soft”, such as with severity of nausea where ascertainment for numerous reasons, including overestimation of treat- bias can play a large role. Fourth, we also had a very ment effects owing to the studies’ small sample sizes (41 heterogeneous patient sample. The variability in our patient and 12 participants, respectively), lack of blinding, use of sample was beneficial, making the results more generaliz- different and non-validated outcome measures to assess able to a wide variety of oncology patients. However, our the prevalence and severity of CINV, different doses and sample heterogeneity also made it more difficult to detect ginger formulations, and lack of examination of delayed any effects of ginger in any subset of cancer patients or chemotherapy treatment combinations.
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