| Reference ↗
|
| Title
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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
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| Topic
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Ginger
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| Author
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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
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| Year
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2017
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| Journal
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Annals of Oncology
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| DOI
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https://doi.org/10.1093/annonc/mdx315
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Study Note
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
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Prospective
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| Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals
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Multicentric
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| 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
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Double
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| Is randomized
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Yes
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| Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control
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No
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| Number of arms
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2
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Study characteristics
| Inclusion criteria
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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)
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| Exclusion criteria
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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.
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| N randomized
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244
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| 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.
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PP Analysis
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| Specifications on analyses
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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.
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| Countries of data collection
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Italy
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| LoE Level of evidence
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2b Oxford 2009
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| Outcome timeline Data collection times
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T1: Cycle 1 (day 2 to day 21 or 28
T2: Cycle 2 (day 23 or 30 to day 42 or 56)
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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.
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Curative
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| Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included
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Genitourinary Cancers - Bladder Cancer, Head and Neck Cancers, Lung Cancer, Other Cancers
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| 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
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NI
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| Specifications on cancer stages
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NI
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| Comorbidities
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NI
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| Current cancer therapies
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Chemotherapy
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| Specifications on cancer therapies
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HEC with cisplatin (single dose >50 mg/m2 every 21 or 28 day
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| Previous cancer therapies
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NI
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| Gender
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Mixed
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| Gender specifications
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Female: Intervention vs. Placebo: 31.4 % vs. 37.4 %
Female: n = 84
Male: n = 160
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| Age groups
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Adults (18+)
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| Age groups specification
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Intervention vs. Placebo: 58.8±10.4 vs. 59.5±10.0 years
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Arms
| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Intervention
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| Number of participants (arm) N randomized
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121
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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42,4 %
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| Drop-out reasons
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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).
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| Intervention
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Ginger capsules
+ Antiemetic treatment (NK-1 receptor antagonist, 5-HT3 receptor antagonist, dexamethasone)
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| Dosage and regime
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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)
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| One-time application
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No
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| 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.
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-999
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| Side effects / Interactions
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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.
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| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Placebo
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| Number of participants (arm) N randomized
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123
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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34.9 %
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| Drop-out reasons
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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).
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| Intervention
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Placebo capsules
+ Antiemetic treatment (NK-1 receptor antagonist, 5-HT3 receptor antagonist, dexamethasone)
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| Dosage and regime
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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)
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| One-time application
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No
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| 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.
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-999
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| Side effects / Interactions
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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.
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Outcomes
CINV (Chemotherapy-Induced Nausea and Vomiting)
| Outcome type As specificed by the authors
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Primary
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| Outcome specification
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Incidence of delayed nausea (day 2-5) (VAS score>5mm), incidence of significant delayed nausea (VAS score>25mm)
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| Type of measurement
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Diary questionnaire, VAS (Visual Analogue Scale)
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| 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".
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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)
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| 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".
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NA
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
|
?
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| Bias due to deviation from intended intervention (assignment to intervention)
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?
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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?
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| Bias in measurement of the outcome
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?
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| Bias in selection of the reported result
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?
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| Other sources of bias
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?
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| Overall RoB judgment
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?
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CINV (Chemotherapy-Induced Nausea and Vomiting)
| Outcome type As specificed by the authors
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Primary
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| Outcome specification
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Incidence of intercyclic nausea (day 6-20/27) (VAS score>5mm), incidence of significant intercyclic nausea (VAS score>25mm)
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| Type of measurement
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Diary questionnaire, VAS (Visual Analogue Scale)
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| 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".
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NA
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
|
| Bias arising from the randomization process
|
?
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| Bias due to deviation from intended intervention (assignment to intervention)
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?
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
|
?
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| Bias in measurement of the outcome
|
?
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| Bias in selection of the reported result
|
?
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| Other sources of bias
|
?
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| Overall RoB judgment
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?
|
CINV (Chemotherapy-Induced Nausea and Vomiting)
| Outcome type As specificed by the authors
|
Primary
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| Outcome specification
|
Incidence of anticipatory nausea (day 21/27) (VAS score>5mm), incidence of significant anticipatory nausea (VAS score>25mm)
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| Type of measurement
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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
|
?
|
Additional Notes
