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Abstract

Objective:

evaluate the efficacy of Zingiber Officinale in the management of nausea and vomiting induced by treatment with cisplatin associated with radiotherapy in patients with uterine cervical neoplasms.

Methods:

a triple-blind, randomized, placebo-controlled trial. Interventions: Comparing the effects of ginger with institutional antiemetic therapy (ondansetron with dexamethasone). Patients with cervical cancer who started treatment with cisplatin with an indication of 40 mg/m² associated with radiotherapy, aged over 18 years, and with the ability to tolerate swallowing a capsule were recruited and equally allocated (1:1:1) into 3 groups of 16 patients each (the ginger capsules 250 mg group, ginger capsules 500 mg group, and placebo group). Nausea and vomiting were measured on baseline, 7 days after the first dose of medication and every seven consecutive days during a treatment break.

Results:

The 250 mg ginger group had an 8.0% greater chance of experiencing nausea within 24 h after the chemotherapy infusion than the placebo group, although there is no statistical significance (P = .92986). The 500 mg ginger group showed a 63.9% reduction in nausea under the same conditions (P = .40460). No change was detected in the occurrence of nausea episodes during the 6 weeks (P = .8664) or between the groups (P = .2817). No change was detected in acute or late vomiting during the 6 weeks (P = .3510) or between the groups (P = .8500 and P = .5389, respectively).

Conclusion:

Ginger supplementation does not reduce the intensity of acute and late nausea and vomiting. REBEC (RBR-47yx6p9).

Keywords

uterine cervical neoplasms chemotherapy radiotherapy ginger nausea vomiting

Introduction

Cervical cancer is the fourth most common cancer in the female population globally, with approximately 600 000 new cases and 340 000 deaths in 2020, with middle- and low-income countries being the most affected.¹ Among the treatment strategies for advanced cervical cancer, systemic chemotherapy is used to allow the possibility of remission, long-term survival, comfort, and control of symptoms caused by incurable diseases. Cisplatin, in combination with radiotherapy, is a therapeutic modality that is well tolerated by patients and has a great tumor response. However, its side effects interfere with the quality of life.²

Chemotherapy-induced nausea and vomiting (CINV) and radiation-induced nausea and vomiting (RINV) is the most common side effect of anticancer treatment, occurring in up 70% to 80% of patients.^3,4 In recent years, the literature has made explicit the growing relevance of herbal agents as therapies to offer a complementary alternative.^5,6 For example, ginger (Zingiber officinale), which acts on the gastrointestinal tract, significantly influences gastric emptying, optimizes intestinal motor activity and indigestion, and potentiates the reduction of nausea and vomiting when combined with antiemetic drugs.⁷

Thus, the relationship between the medicinal properties of ginger and the management of nausea and vomiting caused by cisplatin can be observed in experimental studies that confirm the safe use of ginger root and its effectiveness in the prevention and treatment of CINV.^8
-10 In addition, one can also mention a meta-analysis involving 9 randomized clinical trials, which verified the effectiveness of using ginger in reducing CINV and described statistically significant results in the experimental group about the control of acute nausea and vomiting (OR: 0.60; IC 95%: 0.42-0.86; P: .006).¹¹

This study aimed to evaluate the efficacy of Zingiber Officinale in the management of nausea and vomiting induced by treatment with cisplatin associated with radiotherapy in patients with uterine cervical neoplasms.

Methods

Study Design

This was a triple-blind, randomized, placebo-controlled trial comparing the effects of adding 2 different concentrations of ginger to institutional antiemetic therapy (ondansetron with dexamethasone).¹² Institutional antiemetic therapy was applied to all participants included in the study. It is based on protocols previously published and on formal statements and randomized protocol items (SPIRIT) and Consolidated Assay Reports (CONSORT).¹³ This clinical trial was conducted at the Liga Norte Riograndense Contra o Câncer (LIGA).

Ethical Approval

All procedures performed in this study involving human subjects followed the ethical standards of the Declaration of Helsinki of 1964 and its subsequent amendments, the Madrid Declaration of the World Psychiatric Association respecting all required good clinical practices. This protocol was approved by the local division ethics committee (nº 40602320.0.0000.5293). All participants included in the study guaranteed their participation by signing the Free and Informed Consent Form. This study was also registered in REBEC (RBR-47yx6p9).

Participants

Patients with a diagnosed uterine cervical neoplasm, starting treatment with cisplatin with an indication of 40 mg/m² associated with radiotherapy, aged over 18 years, and able to tolerate swallowing a capsule were recruited.

The following exclusion criteria were considered: a history of hypersensitivity to ginger; pregnancy or breastfeeding; having another primary neoplasm; ongoing chemotherapy treatment; having undergone previous antineoplastic and/or radiotherapy treatment; radiotherapy treatment in the epigastric region of the abdomen; surgery scheduled during the study period; having any feeding device (gastroenteric tube, gastrostomy, or jejunostomy); simultaneous use of a supplement or ginger-based foods; use of anticoagulants; history of bleeding disorders (severe thrombocytopenia), hyperthyroidism, or heart disease; and a pre-existing condition causing nausea and vomiting.

Sample Size

The sample size calculation was established using G Power Software version 3.1.9.2(https://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower), considering a Cohen f effect size of 0.17, a test power of 0.80, and a significance level of 5% (P value < .05). The sample was estimated to be 39 patients with a potential addition of 20%, totaling 48 participants, which were equally allocated (1:1:1) into 3 groups of 16 patients each (the ginger capsules 250 mg group, ginger capsules 500 mg group, and placebo group).

Groups

The placebo group (PG) ingested capsules containing 1.000 mg of placebo (77.80% pharmaceutical starch + 10.10% pharmaceutical talc + 10.10% microcrystalline cellulose + 1% magnesium stearate + 1% colloidal silicon magnesium dioxide, contained in size 00 white/blue gelatin capsules). Placebo capsules were taken with approximately 250 ml of water every 12 h, for a total of 1.000 mg per day, according to the previously published protocol.¹²

The ginger 500 mg group consisted of patients who received capsules containing 250 mg of ginger extract in white/blue gelatin capsules nº 00. The capsules were swallowed with approximately 250 ml of water every 12 h, totaling 500 mg daily. Ginger was dehydrated and ground into a powder without any chemical additives.

Finally, the ginger 1.000 mg group received capsules containing 500 mg of the ginger extract contained in white/blue gelatin capsules nº 00 and were swallowed with an average of 250 ml of water every 12 hours, totaling 1.000 mg per day. The ginger was dehydrated and ground into a powder without any chemical additives.

Allocation Randomization and Hiding

Upon providing informed consent, eligible participants were randomized using the Software Research Randomizer program with a block design (1:1:1; 1.000mg; 500 mg; placebo group).¹² In addition, patients were randomized into 3 intervention groups.

To ensure blind allocation, an off-site randomization schedule was followed. This schedule was prepared by a researcher from the Instituto de Ensino, Pesquisa e Inovação (LIGA), who had no contact with any participants during the entire trial and was not involved in the recruitment, screening, evaluation, enrollment, or treatment process. To enroll a participant, the principal investigator e-mailed the name of the participant who consented to the investigator at LIGA. These details were entered into the allocation worksheet, and the corresponding treatment allocation and participant identification numbers were emailed to the researcher.

Blindness

Survey participants, group researchers, and individuals who evaluated the results were not given access to details of the group assignments. This ensured the impossibility of bias for or against the treatments tested.

Questionnaire and Recruitment

On the first day of chemotherapy, a nursing consultation was conducted with patients and caregivers individually, and upon consent to participate in the study, the Registration Form containing sociodemographic information, including age, marital status, profession, education, socioeconomic classification, and risk factors (alcoholism, smoking, HPV, use of oral contraceptives, and regular Pap smear) was administered. Subsequently, the pharmacist dispensed a bottle of capsules corresponding to the group allocation previously determined by the participant.¹²

Adverse effects were assessed by completing the follow-up sheet by assessing the control of nausea and vomiting according to the Common Terminology Criteria for Adverse Events or CTCAE (nausea/vomiting).¹⁴ The CTCAE for nausea was classified as Grade 1 (loss of appetite with no change in eating habits), Grade 2 (decreased oral intake without significant weight loss, dehydration, or malnutrition), or Grade 3 (inadequate intake of calories or fluids by mouth; tube feeding, parenteral nutrition (TPN) or indication for hospitalization). Vomiting was classified as grade 1 (intervention not indicated), grade 2 (outpatient IV hydration; medical intervention indicated), grade 3 (tube feeding, TPN, or indication for hospitalization), grade 4 (life-threatening consequences), or grade 5 (death).

Evaluation

Seven relevant time points were considered to assess outcomes based on the cisplatin chemotherapy plus radiotherapy protocol: baseline (P0) and 7 days after the first dose of medication (P1), and every seven consecutive days during a treatment break (P2, P3, P4, P5, and P6).¹²

Data Management and Analysis

Initially, an experienced team member (RLMS) was trained to collect the data according to the study protocol. Data were collected using the REDCap website. Data management included baseline characteristics (demographics, lifestyle, comorbidities, history of HPV treatment, history of long-term oral contraceptive use, tumor characteristics, FIGO staging, and inclusion and exclusion criteria), potential confounders, and results of the CTCAE questionnaire. Participants who withdrew from our study were followed up, and the data were analyzed according to the intent-to-treat principle.

For quantitative data analysis, repeated-measures ANOVA based on the linear mixed-effects model was used. A binary variable was also created to indicate the occurrence of nausea within 24 hours after the infusion for at least one of the 6 weeks. In this case, a logistic regression model was used, and the odds ratio for the occurrence of nausea was calculated for the 3 groups. The association between groups and the Common Terminology Criteria for Adverse Events (CTCAE) and sociodemographic variables was tested using Fisher’s exact test. Data presented in the text and tables are reported as means and SDs, means, absolute values, and percentages (%). Statistical significance was set at P < .05. The software used is R Project for Statistical Computing for Windows, version 4.0.2.

Thus, we authors authorize the publication of data from this research. All data generated or analyzed during this study are included in this published article and the Supplemental document provided.

Results

Between March and August 2021, 48 patients were selected for eligibility and randomly assigned to PG, EG1, or EG2 (Figure 1). Among the patients interviewed at recruitment for the research, 2 did not meet the criteria because they had cardiac comorbidities associated with acetylsalicylic acid. In addition, 4 patients discontinued the study due to loss of follow-up (n = 3) and dropout (n = 1). Thus, 44 patients completed the experiment.

Figure 1.

CONSORT 2010 flow diagram.

Regarding sociodemographic data, 31.8% of the participants were between 38 and 51 years old, 47.7% were brown, 50% had a family income of up to 1 minimum wage, and 63.6% did not perform preventive (pap smear) regularly. All patient characteristics were well-balanced between the groups.

Regarding stay in the study, of the 48 patients recruited, 91.7% completed week 1, 79.2% completed week 2, 70.8% completed week 3, 66.7% completed week 4, 52.1% completed week 5, and finally, 41.7% week 6.

Adverse Effects

Given the statistical analysis performed with the placebo group as a reference, it can be said that the Ginger 250 mg group had an 8.0% higher chance of experiencing acute nausea (within 24 hours after the infusion). In contrast, that administered 500 mg of ginger had a 63.9% lower chance of feeling nauseous than the placebo group. However, the results presented were not statistically significant (Table 1).

Table 1.

Chances of Nausea at Least Once in the 24 Hours After Chemotherapy Infusion in the 6 Weeks of Treatment.

Group	OR	CI-95%	P-value
Ginger 250 mg	1.0833	0.1708-6.8795	.92986
Ginger 500 mg	0.3611	0.0165-3.2692	.40460

There is no statistical evidence of an association between the participant’s group and having felt nausea within 24 hours after the chemotherapy infusion. Furthermore, regarding the number of nausea episodes 4 days after the chemotherapy infusion (delayed nausea), no significant change was detected over the 6 weeks between the 3 groups (Table 2).

Table 2.

Acute and Delayed Nausea and Vomiting Throughout the 6 Weeks of Treatment.

ANOVA	F	(CI-95%)	P-value
Number of vomiting 24 h after infusion
Time	1.1239	0.04 (0-0.09)	.3510
Group	0.1633	0.01 (0-0.10)	.8500
Time*Group	0.9030	0.07 (0-0.08)	.5326
Number of vomiting in the 4 d after the infusion
Time	0.8180	0.03 (0-0.06)	.5389
Group	0.5959	0.04 (0-0.17	.5571
Time*Group	1.2189	0.08 (0-0.11)	.2843
Number of nausea in the 4 d after the infusion
Time	0.3732	0.02 (0-0.05)	.8664
Group	1.3064	0.10 (0-0.28)	.2817
Time*Group	1.3474	0.08 (0-0.10)	.2112

No change in the number of acute or late vomiting episodes was detected between the groups over the 6 weeks.

Regarding the severity of symptoms, statistical analyses showed an association between the groups and the Common Terminology Criteria for Adverse Events (CTCAE) in the second week of treatment, thus rejecting the evidence of association in the remaining weeks. Regarding nausea, 49.3% of the participants in the Ginger 500 mg group, 48.2% in the Ginger 1.000 mg group, and 23.5% in the placebo group were classified as grade zero for at least 1 week during treatment. As for grade 1, 33.3% of the participants were in the Ginger 500 mg group and 39.3% in the Ginger 1.000 mg group, compared to 58.8% in the placebo group. Finally, 17.4% of participants in the Ginger 500 mg group, 12.5% in the Ginger 1.000 mg group, and 17.6% in the placebo group were classified as grade 2 for at least 1 week during treatment (Figure 2).

Figure 2.

Nausea and vomiting According to the Common Terminology Criteria for Adverse Events (CTCAE).

The occurrence of grade 0 vomiting corresponds to 59.4% of patients in the 250 mg group, 75% in the ginger 500 mg Group, and 54.4% in the placebo group, respectively. There was an incidence of 36.2% in the ginger 500 mg group, 21.4% in the ginger 1.000 mg group, and 44.1% in the placebo group of grade 1 severity. Those considered grade 2 had an incidence of 4.3% and 3.6% in the ginger 500 mg and 1.000 mg groups, compared to 1.5% in the placebo group. Notably, none of the participants experienced a higher degree of nausea and vomiting.

When questioning the patients about the reason related to the symptoms of nausea and vomiting, 57.1% of the participants in the placebo group received anticancer treatment, while only 37.5% and 40% of the patients in the ginger 500 mg and ginger group 1.000 mg, respectively, had the same response: received anticancer treatment.

Among the findings associated with dehydration, dry mouth had a 0.0% incidence in at least 1 week during treatment compared to placebo, which had an incidence of the symptom in all weeks, reaching 31.2% as the highest value. In addition, the placebo group had a higher incidence of dry mouth (31.2%) in at least one of the weeks compared to the ginger 1.000 mg group, which had a lower incidence (Figure 3).

Figure 3.

Incidence of dry mouth, feebleness, thirst, dizziness, and dark urine of the study population.

Discussion

Despite the progress in antiemetic therapy, CINV still poses a significant concern to patients undergoing chemotherapy. Commonly used for gastrointestinal complaints, ginger has been suggested as a viable adjuvant treatment for nausea and vomiting in cancer patients.

Based on data from the follow-up form, the dosage of ginger used in this study proved to be safe and well-tolerated without associations with serious toxicities, with previous studies confirming this assertion.^9,10,15
-18 In addition, a previous randomized study affirms the safety and applicability of herbal supplementation not only for adults but also for children.^9,15,18
-20

Studies show that the ginger intake of 0.5 g to 1.5 g offers some gastrointestinal benefits as well as an influence on CINV, either in lowering the incidence of nausea and vomiting or their severity. Maintaining a continuous daily dosage was an important strategy for the analysis of the effectiveness of ginger.^{9,10,17,18,21} This is due to the influence of this root on gastrointestinal motricity and reduction of gastric emptying, directly implying the decrease of nausea and vomiting.⁷ However, an experiment highlighted that higher doses become less effective due to the possible saturation of receptors modulating these symptoms, followed by less effective signaling.¹⁰

In this study, ginger’s use in managing acute nausea had a significant impact compared to a placebo. Although not statistically significant, the benefit of the root in the digestive tract can be observed, an effect confirmed in studies with similar methodological designs.¹⁰ In contrast to a phase II study^9,15 that followed the response of the ginger group in the reduction of late motion sickness, our research did not show any difference between the groups in terms of the reduction of nausea episodes during the 4 days after the infusion of the antineoplastic drug. It is also worth noting that in a comparative study with chamomile, ginger was more effective in reducing the number of nausea episodes.²¹

On the other hand, although the literature is still scarce, a randomized controlled and double-blind clinical trial describes the effectiveness of using ginger, 2 g per day, in reducing acute nausea in patients with gynecological tumors, presenting statistically significant results (P = .03).²² Similar to the above, a quasi-experimental study also described the effectiveness of using ginger in reducing nausea in patients with gynecological cancer undergoing chemotherapy with cisplatin.²³

According to NCCN Guidelines,⁶ the treatment for advanced cervical cancer is given through the association between brachytherapy, radiotherapy and cisplatin, in order to potentiate the effect of the treatment. Thus, the reduction in the frequency of nausea and vomiting with the use of ginger occurs with the association between the aforementioned therapies.

Ginger has also been shown to be effective in reducing nausea and vomiting in other contexts. As an example, a randomized clinical trial, carried out with children from 1 to 10 years old with acute gastroenteritis, described the effectiveness of using ginger in reducing vomiting in this public.²⁴ Similarly, a systematic review sought to assess the safety and efficacy of using non-pharmacological methods to reduce nausea and vomiting in pregnant women. In this context, most of the methods used, especially ginger, are considered effective and reliable in reducing the signs and symptoms described.²⁵

As for the number of vomiting episodes, as in published studies, there was no beneficial effect for acute or late vomiting, showing the difficulty in controlling this adverse effect.^8,10,16,18

In the present study, the severity of symptoms reported by the patients was also evaluated. Greater grade 0 clinical responses in the ginger groups were obtained than in the placebo group. There were a greater number of participants who felt symptoms classified as grade 1 in the placebo group than in the ginger group. Finally, the 500 mg ginger and placebo groups were equivalent in grade 2; however, the 500 mg ginger group had a lower rate of histologically proven more severe neoplastic lesions. This corroborates studies showing that the beneficial effects of ginger reduce the severity of nausea with continued use.^9,15,26

In this context, the literature describes the antiemetic action of ginger through the action of different phytochemicals of this medicinal plant, with 2 main ones to highlight: 6-gingerol and 6-shogaol. The first is responsible for acting on the activation of 5-HT3 receptors of enteric neurons in a non-competitive manner. In addition to this, both act to suppress NK-1 receptors, central and peripheral dopamine, in addition to also suppressing substance P.¹⁵

Regarding the severity of vomiting and nausea, the groups assigned to use ginger had a higher number of patients in grade 0 than the placebo group. The placebo group included more patients with grade 1 symptoms than the intervention groups. However, the number of people who were in grade 2 (with greater severity), although low, was higher in the intervention group than in the placebo group. These findings are supported by studies that have also observed this effect on the severity of vomiting.^9,15,21

Clinical and Research Implications

This study was performed only on women with cervical cancer undergoing chemotherapy (cisplatin) and radiotherapy. This study has advantages and limitations. The most important limitation of this study was that our results only apply to patients with cervical cancer and are not generalizable to other types of cancer. Therefore, broader studies on ginger’s effect on different cancer types are suggested. Further research evaluating the effect of ginger on patients subjected to several days of chemotherapy and radiotherapy is merited. In addition, this study was conducted during the Covid-19 pandemic, resulting in a reduced sample size.

Although the use of ginger was not effective for this population, in this context, it is suggested the elaboration and conduction of new research with a high level of evidence and methodological rigor, with this same object of study and population, so that they can corroborate or refute and discuss these results.

Conclusion

Ginger supplementation does not show statistical significance in reducing the intensity of acute and late nausea and vomiting. However, it shows a reduction in the clinical frequency of acute nausea and vomiting with the use of ginger in higher concentrations, as well as a reduction in these late signs and symptoms with the use of ginger in higher concentrations. In addition, it also presents a reduction in the frequency of nausea and vomiting late, when compared to the presence of these acute signs and symptoms.

Therefore, although the use of ginger appears promising, this study did not show statistically significant results. However, the observed clinical findings encourage further studies to better investigate the action of ginger on the gastrointestinal tract during anticancer treatment.

Supplemental Material

sj-docx-1-ict-10.1177_15347354231220608 – Supplemental material for Effect of Zingiber Officinale in the Management of Nausea and Vomiting Induced by Treatment With Cisplatin Associated With Radiotherapy: A Randomized Controlled Trial

Supplemental material, sj-docx-1-ict-10.1177_15347354231220608 for Effect of Zingiber Officinale in the Management of Nausea and Vomiting Induced by Treatment With Cisplatin Associated With Radiotherapy: A Randomized Controlled Trial by Kauanny Vitoria Gurgel dos Santos, Romeika Lorena Mendes da Silva, Ayane Cristine Alves Sarmento, Kleyton Santos de Medeiros, Renata Lima Pessoa, Daniele Vieira Dantas and Rodrigo Assis Neves Dantas in Integrative Cancer Therapies

Footnotes

Acknowledgements

We thank the Federal University of Rio Grande do Norte and Liga Norte Riograndense Contra o Câncer for their support. Furthermore, we would like to thank the statisticians Silva, JB, and Nascimento, AMA of the Instituto de Ensino, Pesquisa e Inovação da Liga Norte Riograndense Contra o Câncer for their contribution to the elaboration of this clinical trial.

Author Contributions

Conceptualization: ACAS, DVD, KVGS, KSM, RLP, RAND, RLMS; Investigation: RLMS. Methodology: ACAS, KVGS, KSM, RLP, RAND, RLMS; Project administration: RLP, RAND; Orientation: KSM, RAND; Validation: RAND; Visualization: KSM, RAND; Writing—original draft: ACAS, DVD, KVGS, KSM, RLP, RAND, RLMS; Writing—proofreading and editing: DVD, KSM, RLP, RAND. All authors approved the final version to be submitted.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Coordination for the Improvement of Higher Education Personnel.

ORCID iDs

Kauanny Vitoria Gurgel dos Santos

Romeika Lorena Mendes da Silva

Ayane Cristine Alves Sarmento

Kleyton Santos de Medeiros

Daniele Vieira Dantas

Rodrigo Assis Neves Dantas

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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