Thamlikitkul et al. (2017): Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin–cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study

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Title	Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin–cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study
Topic	Ginger
Author	Thamlikitkul, L, Srimuninnimit, V, Akewanlop, C, Ithimakin, S, Techawathanawanna, S, Korphaisarn, K, Chantharasamee, J, Danchaivijitr, P, Soparattanapaisarn, N
Year	2017
Journal	Support Care Center
DOI	https://doi.org/10.1007/s00520-016-3423-8

Brief summary

34 breast cancer patients undergoing chemotherapy were recruited and randomly divided into two arms. One arm received 1000mg ginger (capsule) per day for 5 days after the start of the 2nd chemo cycle and switched to placebo in the 3rd cycle and vice versa. All participants also received anti-nausea/anti-vomiting medication. The intake of ginger did not lead to any improvement. Adverse events were equally frequent in both arms, i.e. ginger did not cause more side effects than the placebo. The study is well reported, so the data are robust.

34 Brustkrebspatientinnen während Chemotherapie wurden rekrutiert und zufällig in zwei Gruppen unterteilt. Die eine Gruppe erhielt nach Beginn des 2. Chemozyklus 5 Tage lang 1000mg Ingwer (Kapsel) pro Tag und wechselte im 3. Zyklus zu Placebo und umgekehrt. Alle Teilnehmer erhielten zusätzlich Medikamente gegen Übelkeit/Erbrechen. Die Einnahme von Ingwer hat zu keiner Verbesserung geführt. Die unerwünschten Ereignisse waren in beiden Gruppen gleich häufig, d.h. Ingwer rief nicht mehr Nebenwirkungen hervor wie das Placebo. Die Studie ist gut berichtet, die Daten sind daher solide.

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	Women aged 18 years or older with documented breast cancer who had received a first cycle of AC chemotherapy and who experienced vomiting or moderate to severe nausea, defined as a nausea score of ≥40 on a visual analog scale of 0 (no nausea) to 100 (unbearable nausea). Their treatment plan included at least two more cycles of AC
Exclusion criteria	Pregnancy or lactation, nausea or vomiting prior to chemotherapy administration, presence of conditions that may cause nausea or vomiting (e.g., brain metastasis, bowel obstruction, hepatitis, or recent abdominal or pelvic irradiation within 1 week), bleeding diathesis, allergy to ginger, or concomitant treatment with other chemotherapy.
N randomized	34
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.	ITT Analysis
Specifications on analyses	ANOVA
Countries of data collection	Thailand
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: during first chemotherapy cycle T1: 0-24h (within 24h after chemotherapy) T2: >24h (after 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.	Palliative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast 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	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	First cycle of AC chemotherapy
Previous cancer therapies	NI
Gender	Female
Gender specifications	100 % female
Age groups	Adults (18+)
Age groups specification	Mean: 49 years Range: 32-68 years

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	19
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	Ginger capsules
Dosage and regime	Daily dose 2x500mg ginger capsule (dried ginger powder) for 5 days, starting 30min before second chemotherapy cycle; Antiemetics: Ondansetron + Dexamethason; Crossover in cycle 3
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	No significant difference in the incidence of adverse events between subjects receiving ginger and placebo. No study-treatment-related adverse events were observed.

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	15
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 capsules
Dosage and regime	500-mg placebo twice a day for 5 days starting on the first day of the second chemotherapy cycle; Antiemetics: Ondansetron + Dexamethason; Crossover in cycle 3
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	No significant difference in the incidence of adverse events between subjects receiving ginger and placebo. No study-treatment-related adverse events were observed.

Outcomes

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Primary
Outcome specification	Reduction of the nausea score
Type of measurement	VAS (Visual Analogue 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".	Nausea score max: T0 (during first chemotherapy) (Mean (range)): 58 (40-90), T1 (0-24h) intervention vs. placebo Mean(SD): p=0.64, T2 (>24h) intervention vs. placebo Mean(SD: p=0.21, total intervention vs. placebo Mean(SD): p=0.30 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	?

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Secondary
Outcome specification	Scoring of vomitting
Type of measurement	VAS (Visual Analogue 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".	Vomiting intervention vs. placebo: p=0.5 Vomiting grade 3 intervention vs. placebo: 3% vs. 3% 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	?

Additional medication

Outcome type As specificed by the authors	Secondary
Outcome specification	Emergency medication
Type of measurement	Observation
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".	Number of tablets Mean(SD Intervention vs. placebo: Ondansetron: p=0.99, Domperidone / metoclopramide: p=0.4 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	?

Interaction with cancer treatment

Outcome type As specificed by the authors	Secondary
Outcome specification	Dose reduction/Delay of chemotherapy
Type of measurement	Observation
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".	NA
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".	Chemotherapy intervention vs. placebo: Dose reduction: 3% vs. 3% Delay: 9% vs. 6% No p-values have been reported.

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	Secondary
Outcome specification	Side effects
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".	NA
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".	No study-treatment-related adverse events were observed; No significant difference in the incidence of adverse events between subjects receiving ginger and placebo. Side effects - Intervention in n: Fever: n = 4, Fatigue: n = 25, Muscosites: n = 5, Diarrhea: n = 2, Constipation: n = 14, Neutropenia: n = 6, Thrombcytopenia: n = 14 Side effects - Placebo in n: Fever: n = 3, Fatigue: n = 21, Mucositis: n = 4, Constipation: n = 12, Neutropenia: n = 4, Thrombcytopenia: n = 12, Febrile neutropenia: n = 1 no significant differences

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 Government Pharmaceutical Organization for providing ginger capsules and placebo, Siriraj Cancer Center for providing funding support.
Conflicts of Interest	No information.

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	?
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	?