Marx et al. (2017): The Effect of a Standardized Ginger Extract on Chemotherapy-Induced Nausea-Related Quality of Life in Patients Undergoing Moderately or Highly Emetogenic Chemotherapy: A Double Blind, Randomized, Placebo Controlled Trial

Reference ↗
Title	The Effect of a Standardized Ginger Extract on Chemotherapy-Induced Nausea-Related Quality of Life in Patients Undergoing Moderately or Highly Emetogenic Chemotherapy: A Double Blind, Randomized, Placebo Controlled Trial
Topic	Ginger
Author	Marx, W, McCarthy, A, Ried, K, McKavanagh, D, Viletta, L, Sali, A, Lohning, A, Isenring, E
Year	2017
Journal	Nutrients
DOI	https://doi.org/10.3390/nu9080867

Brief summary

51 cancer patients suffering from nausea were randomly divided into two arms during 3 chemotherapy cycles: One arm received an additional 1.2 g of standardized ginger extract in capsule form daily, while the other arm received a placebo. All participants also received anti-nausea/anti-vomiting medication. The majority of participants received chemotherapy, which leads to moderate vomiting/nausea, 18 participants also received the relatively new drug aprepitant. The ginger arm experienced significantly less nausea/vomiting, less fatigue and a higher quality of life in the first chemotherapy cycle compared to the placebo arm. In the 2nd cycle there were no arm differences, in the 3rd cycle the quality of life and fatigue in the ginger arm was again significantly better than in the control arm with placebo. The 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 solid.

51 Krebspatienten, die unter Übelkeit litten, wurden während 3 Chemotherapiezyklen zufällig in zwei Gruppen geteilt: Die eine Gruppe erhielt zusätzlich täglich 1.2 g standardisiert hergestellten Ingwerextrakt in Kapselform, die andere Gruppe ein Plazebo. Alle Teilnehmer erhielten zusätzlich Medikamente gegen Übelkeit/Erbrechen. Die Mehrheit der Teilnehmer erhielt eine Chemotherapie, die zu moderatem Erbrechen /Übelkeit führt, 18 Teilnehmer erhielten zusätzlich das relativ neue Medikament Aprepitant. Die Ingwergruppe erlebte im ersten Chemotherapiezyklus im Vergleich zur Plazebogruppe bedeutsam weniger Übelkeit/Erbrechen, geringere Fatigue und eine höhere Lebensqualität. Im 2. Zyklus gab es keine Gruppenunterschiede, im 3. Zyklus war die Lebensqualität und Fatigue in der Ingwergruppe wieder bedeutsam besser als in der Kontrollgruppe mit Plazebo. Die unerwünschten Ereignisse waren in beiden Gruppen gleich häufig, i.e. Ingwer rief nicht mehr Nebenwirkungen hervor wie das Plazebo. 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	No
Number of arms	2

Study characteristics

Inclusion criteria	Patients who were chemotherapy-naïve, were due to receive a moderately- or highly-emetogenic chemotherapy regimen, were at least 18 years old, had a baseline Karnofsky score >60, had no known concurrent neoplasms or illnesses that induced nausea independent of chemotherapy, and did not self-prescribe therapies or complementary products used for nausea.
Exclusion criteria	Patients who were scheduled to receive radiotherapy during the study period, were pregnant or lactating, concurrently used other ginger-containing supplements or ingested large quantities of ginger, had a history of adverse reactions to ginger, and/or thrombocytopenia.
N randomized	51
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	Mann-Whitney U test
Countries of data collection	Australia
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T1: 1st cycle of chemotherapy (assessment from 3 days before to 4 days after) T2: 2nd cycle of chemotherapy (assessment from 3 days before to 4 days after) T3: 3rd cycle of chemotherapy (assessment from 3 days before to 4 days after)

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.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Colorectal Cancer - Colon Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Other Cancers
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	NI
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Intervention arm: 16 % woman; Placebo arm: 16 % woman
Age groups	Adults (18+)
Age groups specification	Mean (SD) intervention vs. placebo: 57 (14) vs. 59 (11) 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	24
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	9
Drop-out reasons	Due to side effects: n = 1, consent withdrawn: n = 5, difficulty swallowing capsule: n = 2, contact lost: n = 1
Intervention	Ginger capsules
Dosage and regime	Daily dose 4x300mg ginger capsules (standardized extract), with meals, per cycle for 5 days, starting on the day of chemotherapy over 3 cycles + Antiemetics (for 3 chemotherapy cycles, duration: day of chemo to 5 days post chemo)
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.	-999
Side effects / Interactions	N=2: constipation; N=4: reflux

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	27
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	8
Drop-out reasons	Due to side effects: n=3, consent withdrawn: n= 4, severe nausea / vomiting: n=1
Intervention	Placebo capsules
Dosage and regime	Placebo capsules with meals, per cycle for 5 days, starting on the day of chemotherapy over 3 cycles + Antiemetics (for 3 chemotherapy cycles, duration: day of chemo to 5 days post chemo)
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.	-999
Side effects / Interactions	NI

Outcomes

Quality of life

Outcome type As specificed by the authors	Primary
Outcome specification	CINV-dependent quality of life (QoL) at T0 (baseline), T6 (4th day after chemotherapy)
Type of measurement	FLIE (Functional Living Index for Emesis)
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".	Cycle 1: Intervention significantly superior to placebo, clinical relevance minimal Nausea-related QoL (median (25th, 75th percentile)) intervention vs. placebo: 124.5 (113.2, 126) vs. 111 (99, 126) (p=0.029) CINV-related QoL (median (25th, 75th percentile)) intervention vs. placebo: 124.5 (113.2, 126) vs. 111 (99, 126) (p=0.043) Cycle 2, cycle 3: no significant differences
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	CINV symptoms: Nausea, retching, vomiting. To T1-T6 (1 day before chemotherapy - 4th day after chemotherapy)
Type of measurement	Rhodes Inventory of Nausea
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".	CINV symptoms: No significant differences in prevalence and severity of CINV in all cycles Subgroup analysis: there was no significant arm difference between participants with and without aprepitant Anticipatory CINV score: cycle 1: p=0.44; cycle 2: p=0.61; cycle 3: p=0.76 Delayed CINV score: cycle 1: p=0.75; cycle 2: p=0.26; cycle 3: p= 0.86
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	?

Nutrition status

Outcome type As specificed by the authors	Secondary
Outcome specification	Nutrition status at T2 (at the day of chemotherapy)
Type of measurement	PG-SGA (Patient-Generated Subjective Global Assessment)
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 in all cycles (p>0.05)
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	?

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	Global cancer-associated quality of life (FACT-G). For T0 (Baseline) and T6 (4th day after chemotherapy)
Type of measurement	FACT (Functional Assessment of Cancer Therapy)
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".	Cycle 1: mean(SD) intervention vs. placebo: 85.1 (18.9) vs. 71.9 (18.3), p=0.015 Cycle 3: mean(SD) intervention vs. placebo: 83.6 (15.0) vs. 75.1 (13.9), p=0.040 Intervention arm significantly superior, clinically relevant
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	?

Fatigue

Outcome type As specificed by the authors	Secondary
Outcome specification	At baseline and T6 (Day 4 after chemotherapy)
Type of measurement	FACIT (Functional Assessment of Chronic Illness Therapy)
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".	Cycle 1: mean(SD) intervention vs. placebo: 41.8 (13) vs. 32.2 (10.8), p=0.006 Cycle 3: mean(SD) intervention vs. placebo: 42.4 (10.2) vs. 36.1 (7.2), p=0.013 Intervention arm significantly superior, clinically relevant
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	Prognostic factors (age, gender, anticipated CINV, chemotherapy emetogenicity)
Type of measurement	Unspecified questionnaire
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 associations (p>0.05)
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	Secondary
Outcome specification	Adverse events
Type of measurement	ESAS (Edmonton Symptom Assessment 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".	Side effects: serious adverse effects intervention vs. placebo: 1 vs. 3 participants, none assigned to intervention Four patients in this trial experienced significant adverse events, none of which could reasonably be attributed to the ginger intervention. N=1: lung collapsed; N=1: allergic reaction to pegfilgrastim; N=2: neutropenic fever
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	This study was partially funded by the Health Practitioners Research Scheme (Queensland Health) and the Vice Chancellor’s Seeding Grant (Bond University).
Conflicts of Interest	Luis Vitetta, Karin Ried, and Avni Sali have received previous government and/or industry funding for nutraceutical research. All authors declare no conflict of interest related to their involvement in the current study.

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	?

Additional Notes

Aherence (Number of capsules consumed each day during the study period, min. 3 capsules/day): 71% of all participants, intervention: 67%, placebo: 74%

Quality of patient blinding (success of blinding after 3rd chemotherapy cycle): allocation correctly estimated intervention (63%) vs. placebo (30%)