Ryan et al. (2011): Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients

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Title	Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients
Topic	Ginger
Author	Ryan, JL, Heckler, CE, Roscoe, JA, Dakhil, SR, Kirshner, J, Flynn, PJ, Hickok, JT, Morrow, GR
Year	2011
Journal	Support Care Cancer
DOI	https://doi.org/10.1007/s00520-011-1236-3

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	4

Study characteristics

Inclusion criteria	Diagnosed with cancer, may have received ≥1 chemotherapy cycle, and were scheduled for at least three additional chemotherapy cycles, chemotherapy must have been given without concurrent radiation therapy or interferon and without planned interruption by radiation therapy or surgery, must have experienced nausea of any severity in any chemotherapy cycle before study enrollment, as well as scheduled to receive a 5-HT3 receptor antagonist (e.g., Zofran®, Kytril®, Navoban®, or Anzemet®) plus dexamathasone at all chemotherapy cycles
Exclusion criteria	Patients on coumadin or heparin for therapeutic anticoagulation, patients with a bleeding disorder, patients who hadn't had platelet count >100,000/μl before the baseline cycle
N randomized	744
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, NI
Specifications on analyses	Tukey–Kramer procedure for multiple comparisons; planned intention-to-treat analysis, but not all participants from the baseline cycle were included in the evaluation/ more participants were evaluated than those who completed cycle 2
Countries of data collection	United States
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: Day -3 to -1: before the chemotherapy T1: Day 1: first day of chemotherapy T2: Day 2 to 4: 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.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Lung Cancer, Hematologic Cancers, Gynecologic Cancers, Genitourinary Cancers, Gastrointestinal Cancers, 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	5-HT3 antiemetics plus dexamathasone
Previous cancer therapies	Surgery, Chemotherapy, Radiation therapy
Gender	Mixed
Gender specifications	93 % female
Age groups	Adults (18+)
Age groups specification	Mean: 53 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	187
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	66 Completed all assessments: 121 Sufficient data for analysis: 152
Drop-out reasons	Baseline: 1 - Began coumadin, 1 - Gastrointestinal, 1 - Low platelets, 1 - Treatment change, 1 - Other medical, 6 - Changed mind, 5 - Incomplete forms, 1 - Ineligible Study Cycle 2: 2 - Chemotoxicity, 9 - Gastrointestinal, 1 - Low platelets, 5 - Off chemotherapy, 7 - Treatment change, 1 - Treatment delay, 5 - Other medical, 13 - Changed mind, 1 - Lost medication, 5 - Incomplete forms
Intervention	Ginger capsules + all patients received 5-HT 3 receptor antagonist (e.g., Zofran®, Kytril®, Navoban®, or Anzemet®) plus dexamathasone
Dosage and regime	250mg 2x3 ginger capsules (liquid extract from ginger root in virgin olive oil + excipients, 1.5g ginger daily) 1.5g daily
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.	6
Side effects / Interactions	Overall associated with ginger: gastrointestinal symptoms, such as stage 2 heartburn, bruising/redness and skin rash

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	187
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	68 Completed all assessments: 119 Sufficient data for analysis: 141
Drop-out reasons	Baseline: 1 - Began coumadin, 2 - Chemotoxicity, 2 - Gastrointestinal, 1 - Low platelets, 3 - Off chemotherapy, 1 - Treatment delay, 1 - Other medical, 5 - Changed mind, 2 - Incomplete forms Study Cycle 2: 1 - Bleeding, 5 - Chemotoxicity, 7 - Gastrointestinal, 3 - Low platelets, 5 - Off chemotherapy, 3 - Treatment change, 5 - Treatment delay, 1 - Low WBC, 5 - Other medical, 10 - Changed mind, 4 - Incomplete forms, 1 - Deceased
Intervention	Ginger capsules + all patients received 5-HT 3 receptor antagonist (e.g., Zofran®, Kytril®, Navoban®, or Anzemet®) plus dexamathasone
Dosage and regime	2x1 placebo capsules 250mg 2x2 ginger capsules ((liquid extract from ginger root in virgin olive oil + excipients and placebo capsules, 1.0g ginger daily)
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.	6
Side effects / Interactions	Overall associated with ginger: gastrointestinal symptoms, such as stage 2 heartburn, bruising/redness and skin rash

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	183
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	74 Completed all assessments: 109 Sufficient data for analysis: 134
Drop-out reasons	Baseline: 1 - Began coumadin, 2 - Chemotoxicity, 2 - Gastrointestinal, 1 - Off chemotherapy, 5 - Other medical, 11- Changed mind, 3 - Incomplete forms Study Cycle 2: 3 - Chemotoxicity, 5 - Gastrointestinal, 1 - Low platelets, 3 - Off chemotherapy, 1 - Radiation therapy, 1 - Treatment change, 2 - Treatment delay, 1 - Disease progression, 5 - Other medical, 15 - Changed mind, 1 - Drug incorrectly given, 1 - Lost medication, 10 -Incomplete forms
Intervention	Ginger capsules + all patients received 5-HT 3 receptor antagonist (e.g., Zofran®, Kytril®, Navoban®, or Anzemet®) plus dexamathasone
Dosage and regime	2x2 placebo capsules 250mg 2x1 ginger capsules (liquid extract from ginger root in virgin olive oil + excipients and placebo capsules, 0.5g ginger daily)
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.	6
Side effects / Interactions	Gastrointestinal symptoms, such as stage 2 heartburn, bruising/redness and skin rash

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	188
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	66 Completed all assessments: 122 Sufficient data for analysis: 149
Drop-out reasons	Baseline: 1 - Bleeding, 1 - Chemotoxicity, 1 - Gastrointestinal, 3 - Off chemotherapy, 2 - Other medical, 14 - Changed mind, 1 - Incomplete forms Study Cycle 2: 1 - Bleeding, 4 - Chemotoxicity, 5 - Gastrointestinal, 2 - Low platelets, 2 - Off chemotherapy, 5 - Treatment change, 1 - Treatment delay, 1- Disease progression, 7 - Other medical, 7 - Changed mind, 2 - Drug incorrectly given, 6 - Incomplete forms
Intervention	Placebo capsules + all patients received 5-HT 3 receptor antagonist (e.g., Zofran®, Kytril®, Navoban®, or Anzemet®) plus dexamathasone
Dosage and regime	2x3 placebo capsules
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.	6
Side effects / Interactions	???

Outcomes

Nausea

Outcome type As specificed by the authors	Primary
Outcome specification	Reducing acute nausea severity on day 1 of chemotherapy
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".	On day 1 of chemotherapy, acute average nausea: intervention arms vs. placebo (change, SE): -0.350, -0.140 (p=0.013) sign. single difference placebo vs. intervention arm 0.5g, p=0.046, no sign. differences for other individual comparisons (1g vs. 0.5g, p=0.076; placebo vs. 1.5g, p=0.738) Maximum: intervention arms vs. placebo (change, SE): -0.470, 0.160 (p=0.003) sign. single difference placebo vs. 1.0g (p=0.036), placebo vs. 0.5g (p=0.017) no sign. difference for placebo vs. 1.5g (p=0.431)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

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

Nausea

Outcome type As specificed by the authors	Secondary
Outcome specification	Delayed, anticipatory nausea
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".	Day 2, day 3 and follow-up nausea on day 4: delayed nausea: no significant differences between arms.
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	NA
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".	No significant differences between the arms.
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

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

Vomiting

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
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".	No significant differences between the arms, majority of patients did not report episodes of vomiting (mean incidence = 0.5)
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	Funded by the National Cancer Institute's Community Clinical Oncology Program (CCOP)
Conflicts of Interest	No conflicts of interests have been reported.

Further points for assessing the study

Sample

Power analysis performed	No
- Sample size corresponds to power analysis	NA
- Reasons for insufficient sample size based on power analysis	su
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	Yes
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	Yes
Measurement of compliance	Yes
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

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