Bossi et al. (2017): A randomized, double-blind, placebo-controlled, multicenter study of a ginger extract in the management of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high-dose cisplatin

Reference ↗
Title	A randomized, double-blind, placebo-controlled, multicenter study of a ginger extract in the management of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high-dose cisplatin
Topic	Ginger
Author	Bossi, P, Cortinovis, D, Fatigoni, S, Cossu Rocca, M, Fabi, A, Seminara, P, Ripamonti, C, Alfieri, S, Granata, R, Bergamini, C, Agustoni, F, Bidoli, P, Nolè, F, Pessi, MA, Macchi, F, Michellini, L, Montanaro, F, Roila, F
Year	2017
Journal	Annals of Oncology
DOI	https://doi.org/10.1093/annonc/mdx315

Brief summary

244 cancer patients undergoing chemotherapy were randomly divided into two arms. One group received 160mg ginger (capsule) over 2 chemo cycles, the other arm received placebo. All participants also received additional medication for vomiting/nausea. The intake of ginger did not lead to an overall reduction in nausea or vomiting. However, significant differences were found in subarms: women had benefited significantly more from ginger than men, patients with head and neck tumors had experienced a significant improvement with ginger, and patients with lung cancer had also experienced significantly less vomiting between chemo cycles. The side effects of ginger were the same as those from the placebo arm. The study is not well reported, suggesting that the study was not methodologically well conducted and the results must be interpreted with caution.

244 Krebspatienten wurden unter Chemotherapie wurden zufällig in zwei Gruppen geteilt. Die ein Gruppe erhielt über 2 Chemozyklen 160mg Ingwer (Kapsel), die andere Gruppe erhielt Plazebo. Alle TeilnehmerInnen erhielten zusätzlich weitere Medikamente gegen Erbrechen/Übelkeit. Die Einnahme von Ingwer hat insgesamt zu keiner Verminderung von Übelkeit oder Erbrechen geführt. Allerdings zeigte sich in Untergruppen bedeutsame Unterschiede: Frauen hatten von Ingwer bedeutsam mehr profitiert als Männer, Patienten mit Kopf-Hals Tumoren hatten mit Ingwer eine bedeutsame Verbesserung erlebt, auch die Patienten mit Lungenkrebs hatten signifikant weniger Erbrechen zwischen den Chemozyklen verzeichnet. Die Nebenwirkungen von Ingwer waren mit denen aus der Plazebogruppe gleich. Die Studie ist nicht gut berichtet, so dass die Vermutung nahe liegt, dass die Studie methodisch nicht gut durchgeführt worden ist und die Ergebnisse mit Vorsicht interpretiert werden müssen.

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	Multicentric
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	Adult (>18years) patients of either gender with solid tumors and chemotherapy-naive who were planned to receive more than 2 cycles of HEC with cisplatin (single dose >50 mg/m2 every 21 or 28 days)
Exclusion criteria	Patients with symptomatic brain metastases; - scheduled to receive or having received, in the past 4 weeks, radiotherapy to upper abdomen or craniospinal region; - emesis or significant nausea within 24h before the first HEC cycle; - coagulation disorders or current therapy with oral anticoagulants; - planned surgery during the study period or within 2 weeks after its conclusion; - prior seizures; - cannabinoids or current/past drug or alcohol abuse; - use of other investigational drug(s) within 30 days before study entry or during the study; - any relevant condition potentially interfering with study evaluation; - known hypersensitivity to ginger or any components of the product.
N randomized	244
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	Logistic regression was used to estimate odds ratios for the incidence of nausea; ANOVA used to investigate differences in mean delayed, inter-cycle and anticipatory nausea between treatment arms and compliance to treatment.
Countries of data collection	Italy
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T1: Cycle 1 (day 2 to day 21 or 28) T2: Cycle 2 (day 23 or 30 to day 42 or 56)

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	Genitourinary Cancers - Bladder Cancer, Head and Neck Cancers, Lung Cancer, 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	HEC with cisplatin (single dose >50 mg/m2 every 21 or 28 day
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Female: Intervention vs. Placebo: 31.4 % vs. 37.4 % Female: n = 84 Male: n = 160
Age groups	Adults (18+)
Age groups specification	Mean (SD) intervention vs. placebo: 58.8 (10.4) vs. 59.5 (10.0) 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	121
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	42,4 %
Drop-out reasons	Not arm specified: Adverse effects (n = 25, 13 with ginger and 12 with placebo), withdrawal consent (n = 24), lost to follow-up (n = 1); protocol violations (n = 2), and other (n = 45; namely, changes to chemotherapy regimen (n = 5 for ginger versus n = 6 for placebo), patient’s decision (14 versus 7), concomitant medications (n = 1 for ginger), logistical problems (n = 2 for each group), health status (n = 3 for ginger), intolerance (n = 5 for ginger).
Intervention	Ginger capsules + Antiemetic treatment (NK-1 receptor antagonist, 5-HT3 receptor antagonist, dexamethasone)
Dosage and regime	Daily dose 4x40mg ginger capsule (“Ginger CO2 supercritical extract”), i.e. 2 capsules in the morning and 2 capsules in the late afternoon, starting the day after chemotherapy for 42-56 days (depending on duration of chemotherapy)
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	No significant arm difference. With regard to intervention-related side effects, intervention reported significantly more side effects than placebo (intervention: 63 vs. placebo: 35). Intervention reported more gastrointestinal side effects than placebo.

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	123
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	34.9 %
Drop-out reasons	Not arm specified: Adverse effects (n = 25, 13 with ginger and 12 with placebo), withdrawal consent (n = 24), lost to follow-up (n = 1); protocol violations (n = 2), and other (n = 45; namely, changes to chemotherapy regimen (n = 5 for ginger versus n = 6 for placebo), patient’s decision (14 versus 7), concomitant medications (n = 1 for ginger), logistical problems (n = 2 for each group), health status (n = 3 for ginger), intolerance (n = 5 for ginger).
Intervention	Placebo capsules + Antiemetic treatment (NK-1 receptor antagonist, 5-HT3 receptor antagonist, dexamethasone)
Dosage and regime	Daily dose 4 Placebo capsule, i.e. 2 capsules in the morning and 2 capsules in the late afternoon, starting the day after chemotherapy for 42-56 days (depending on duration of chemotherapy)
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	No significant arm difference. With regard to intervention-related side effects, intervention reported significantly more side effects than placebo (A: 63; B: 35). Intervention reported more gastrointestinal side effects than placebo.

Outcomes

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Primary
Outcome specification	Incidence of delayed nausea (day 2-5) (VAS score>5mm), incidence of significant delayed nausea (VAS score>25mm)
Type of measurement	Diary questionnaire, 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".	Incidence of delayed nausea: no significant differences overall Cycle 1: (intervention vs. placebo: p=0.851 Cycle 2: intervention vs. placebo: p=0.379 Subgroup analysis : in the 2nd cycle lung cancer patients in intervention significantly higher than in placebo (OR 2.67 95%CI 1.03/6.87; p=0.042) Significant delayed nausea: overall no significant differences Cycle 1: intervention vs. placebo: p=0.163 Cycle 2: intervention vs. placebo: p=0.239 Subgroup analysis: men in intervention significantly higher than in placebo (OR 2.74 95% CI 1.28/5.85; 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	?

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Primary
Outcome specification	Incidence of intercyclic nausea (day 6-20/27) (VAS score>5mm), incidence of significant intercyclic nausea (VAS score>25mm)
Type of measurement	Diary questionnaire, 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".	Incidence of inter-cycle nausea: no significant differences overall Cycle 1: intervention vs. placebo:p=0.367 Cycle 2: intervention vs. placebo: p=0.417 Subgroup analysis: overall and in the first cycle lung cancer patients in intervention higher than in placebo (OR 2.77 95% CI 1.16/6.64; OR 4.27 95% CI 1.60/11.37) Significant inter-cycle nausea: no significant differences overall Cycle 1: intervention vs. placebo: p=0.074 Cycle 2: intervention vs. placebo: p=0.361 Subgroup analysis: Men significantly higher in intervention than in placebo (OR 2.38 95% CI 1.04/5.44; 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	?

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Primary
Outcome specification	Incidence of anticipatory nausea (day 21/27) (VAS score>5mm), incidence of significant anticipatory nausea (VAS score>25mm)
Type of measurement	Diary questionnaire, 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".	Incidence of anticipatory nausea: no significant differences Cycle 1: intervention vs. placebo: p=0.823 Cycle 2:intervention vs. placebo: p=0.629 Significant anticipatory nausea: no significant differences Cycle 1: intervention vs. placebo: p=0.666 Cycle 2: intervention vs. placebo: p=0.536
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	Intensity of vomiting, Questionnaires were completed at days 1 and 6 of the first and second cycle
Type of measurement	Diary 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".	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 significant arm difference (p=0.414-0.959)

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	?

Well-being

Outcome type As specificed by the authors	Secondary
Outcome specification	Influence of nausea on daily life (FLIE)
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".	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".	Overall no significant arm difference Subgroup analysis: Women and patients with head and neck tumors significantly higher in intervention than in placebo (7.31; 95% CI 14.56/0.06, p=0.048 and 7.43; 95% CI 14.42/0.43, p=0.038, respectively)

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	NA
Type of measurement	BFI (Brief Fatigue Inventory)
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 between arms. At cycle 1: worsening of the BFI score was smaller with ginger than placebo (treatment difference -0.23, 95% CI: -0.97 to 0.51). At cycle 2: the situation was different: worsening with ginger was slightly higher than with placebo (treatment difference 0.09, 95% CI –0.71 to 0.89). During both cycles, differences in BFI scores were negligible.
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	Helsinn Healthcare SA
Conflicts of Interest	The authors have no conflict of interest to declare. F. Macci is a full-time employee of Helsinn. L. Michellini and F. Montanaro received financial support from Helsinn for the conduct of the 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	?