Uthaipaisanwong et al. (2020): Effects of ginger adjunct to the standard prophylaxis on reducing carboplatin and paclitaxel-induced nausea vomiting: a randomized controlled study

Reference ↗
Title	Effects of ginger adjunct to the standard prophylaxis on reducing carboplatin and paclitaxel-induced nausea vomiting: a randomized controlled study
Topic	Ginger
Author	Uthaipaisanwong, A, Oranratanaphan, S, Musigavong, N
Year	2020
Journal	Supportive Care in Cancer
DOI	https://doi.org/10.1007/s00520-019-05201-5

Brief summary

In this study, 48 patients with gynecological cancer were randomly divided into two groups. One group received a capsule containing 500mg of ginger powder four times a day from the first to the fifth day of chemotherapy, while the other group received a placebo. Both groups also received standard anti-nausea/anti-vomiting medication. The groups were switched for the next chemotherapy cycle. The intake of ginger led to a decrease in the severity of acute nausea after chemotherapy compared to placebo (day 1). No differences were found for day 2-5. In terms of frequency of vomiting, degree of nausea and side effects such as diarrhea, constipation and heartburn, there were no benefits of ginger intake. The study is characterized by a clear and comprehensible presentation of the results. Missing effects could have been influenced by a generally low incidence of vomiting and nausea.

In dieser Studie wurden 48 Patientinnen mit gynäkologischen Krebserkrankungen zufällig in zwei Gruppen aufgeteilt. Die eine Gruppe erhielt vom ersten bis zum fünften Tag der Chemotherapie viermal täglich eine Kapsel mit 500mg Ingwerpulver, die andere Gruppe erhielt ein Placebo. Beide Gruppen erhielten zusätzlich Standardmedikamente gegen Übelkeit/Erbrechen. Für den nächsten Chemotherapie-Zyklus wurden die Gruppen getauscht. Die Einnahme von Ingwer hat im Vergleich zu Placebo zu einer Abnahme der Schwere der akuten Übelkeit nach Chemotherapie geführt (1. Tag). Es wurden keine Unterschiede für Tag 2-5 gefunden. In Bezug auf Häufigkeit von Erbrechen, Grad der Übelkeit und Nebenwirkungen wie Durchfall, Verstopfung und Sodbrennen zeigte sich keine Vorteile durch Ingwereinnahme. Die Studie zeichnet sich durch eine übersichtliche und verständliche Darstellung der Ergebnisse aus. Fehlende Effekte könnten durch ein allgemein geringes Auftreten von Erbrechen und Übelkeit beeinflusst worden sein.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	Yes
Number of arms	2

Study characteristics

Inclusion criteria	Patients with gynecological cancers (ovarian, cervical, endometrial, vulvar carcinoma; stage 1-4, recurrence), ECOG status 0-2, carboplatin-paclitaxel chemotherapy
Exclusion criteria	Patients using other gingers or the other antiemetic medication such as NK1 receptor antagonist or long-acting 5HT3 receptor antagonists to current study treatment; patients with gut obstruction or brain or bowel metastasis, patients using anticoagulant medication, and patients with allergy to ginger
N randomized	48
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis
Specifications on analyses	All statistical analyses were performed using STATA version 15.1. P values less than 0.05 were considered significant. Demographic data of all participants were analyzed by using mean, 95%CI, and percentage. Nausea score from day 1 to day 5 was showed in mean, and analysis of variance (ANOVA) for a 2 × 2 crossover study was analyzed comparing treatment, sequence, and period effect. Nausea grading for each day was compared using proportion f grading between treatment after adjusted sequence and period by using random-effects ordered logistic regression. Vomiting and side effects were analyzed by comparing percentages between groups using random-effects logistic regression.
Countries of data collection	Thailand
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: Baseline T1: Day 1 of chemotherapy T2: Day 2-5 of chemotherapy

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Neo-adjuvant, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Endometrial Cancer, Gynecologic Cancers - Vulvar Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage, Advanced Stage
Specifications on cancer stages	Cancer stage, n (%) Stage 1: 13 (27.7), stage 2: 2 (4.3), stage 3: 16 (34.0), stage 4: 3 (6.4), recurrent: 13 (27.7)
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Carboplatin-paclitaxel chemotherapy Types of chemotherapy, n (%) neoadjuvant: 4 (8.5), adjuvant: 43 (91.5)
Previous cancer therapies	NI
Gender	Female
Gender specifications	Female n (%): 48 (100)
Age groups	Adults (18+)
Age groups specification	Age in years, mean (SD): 53.9 (13.8)

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	24
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	1
Drop-out reasons	Excluded due to changing chemotherapy (n=1)
Intervention	Ginger powder capsules (certified quality) + all participants received standard antiemetic medication including dexamethasone, ondansetron, and ranitidine; if necessary dimenhydrinate
Dosage and regime	Daily dose 4x500mg before meals and one in the evening from day 1 to day 5 of chemotherapy + standard antiemetic medication included 20 mg of dexamethasone, 8 mg of ondansetron, and 50 mg of ranitidine which were injected 30 min before chemotherapy administration; if necessary 50mg dimenhydrinate before chemotherapy and 5 days at home
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	5
Side effects / Interactions	According to data, no serious side effects in ginger-group or differences to placebo (p>0.05, not significant)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	24
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Placebo in corn starch capsules + all participants received standard antiemetic medication including dexamethasone, ondansetron, and ranitidine; if necessary dimenhydrinate
Dosage and regime	Daily dose before meals and one in the evening from day 1 to day 5 of chemotherapy + standard antiemetic medication included 20 mg of dexamethasone, 8 mg of ondansetron, and 50 mg of ranitidine which were injected 30 min before chemotherapy administration; if necessary 50mg dimenhydrinate before chemotherapy and 5 days at home
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	5
Side effects / Interactions	According to data, no serious side effects in placebo-group or differences to ginger (p>0.05, not significant)

Outcomes

Nausea

Outcome type As specificed by the authors	NI
Outcome specification	Severity of nausea at T1 (acute) and T2 (delayed) (0-10, 0 = none, 10 = strongest possible nausea) Nausea was defined a disorder characterized by a queasy sensation and/or the urge to vomit
Type of measurement	NRS (Numeric Rating Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Significant difference between ginger vs. placebo (mean): 0.96 vs. 1.49 (p=0.03) on day 1 of chemotherapy No significant group differences (p=0.39-0.94) on day 2-5 of chemotherapy
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Nausea

Outcome type As specificed by the authors	NI
Outcome specification	Degree of nausea Grade 0 defined as normal appetite; Grade 1 defined as loss of appetite without alteration in eating habits; Grade 2 defined as decreased oral intake without significant weight loss, dehydration, or malnutrition; Grade 3 defined as inadequate oral caloric or fluid intake
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant differences p>0.05 on day 1-5 of chemotherapy
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Vomiting

Outcome type As specificed by the authors	NI
Outcome specification	Frequency of vomiting Vomiting was defined a disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant difference ginger vs. placebo: 10.6% vs. 8.5% (p=0.78) on day 1 of chemotherapy No significant group differences (p>0.05) on day 2-5 of chemotherapy
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Toxicity

Outcome type As specificed by the authors	NI
Outcome specification	Side effects included diarrhea, constipation, heartburn.
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Diarrhea: ginger vs. placebo: 27.7% vs. 36.2% (p=0.34), no significant difference Heartburn: ginger vs. placebo: 8.5% vs. 12.8% (p=0.38), no significant difference Constipation: ginger vs. placebo: 14.9% vs. 4.3% (p=0.09), no significant difference
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	The authors thank the Ratchadapisek Sompotch Fund, Faculty of Medicine, Chulalongkorn University (grant number RA61/019) which provided funding support.
Conflicts of Interest	According to authors no conflict of interest.

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	erh
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?