Montazeri et al. (2013): Effect of Herbal Therapy to Intensity Chemotherapy-Induced Nausea and Vomiting in Cancer Patients

Reference ↗
Title	Effect of Herbal Therapy to Intensity Chemotherapy-Induced Nausea and Vomiting in Cancer Patients.
Topic	Ginger
Author	Montazeri, AS, Raei, M, Ghanbari, A, Dadgari, A, Montazeri, AS, Hamidzadeh, A
Year	2013
Journal	Iranian Red Crescent Medical Journal
DOI	https://doi.org/10.5812/ircmj.4392

Brief summary

This is a so-called cross-over study, i.e. the 44 cancer patients (different types of cancer) were randomly divided into two groups. One received 1000mg ginger daily (not standardized), the other a placebo. The treatment was started 30 minutes before the first chemo treatment. Observations were made over two cycles. At the end of the first cycle, the groups were switched. The chemotherapy regimen of the participants was highly emetic. Additional anti-nausea medication was also given. There were significant improvements in the ginger group compared to the placebo group. Side effects were not reported. The study is not well reported, suggesting that the study was not methodologically well conducted and the results must be interpreted with caution.

Dies ist eine sog. Cross-over Studie, i.e. die 44 Krebspatienten (verschieden Krebsarten) wurden per Zufallsgenerator in zwei Gruppen geteilt. Die eine erhielt täglich 1000mg Ingwer (nicht standardisiert), die andere ein Plazebo. Begonnen wurde 30 Minuten vor dem ersten Chemo-Beginn. Beobachtet wurde über zwei Zyklen. Nach Ende des ersten Zyklus wurden die Gruppen getauscht. Das Chemoregime der TeilnehmerInnen war hoch brechreizauslösend. Es wurden zusätzlich weitere brechreizlindernde Medikamente gegeben. In der jeweiligen Ingwergruppe ergaben sich signifikante Verbesserungen im Vergleich zur Plazeboeinnahme. Nebenwirkungen sind nicht berichtet. Die Studie ist nicht gut berichtet, so dass die Vermutung naheliegt, 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	Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	Yes
Number of arms	2

Study characteristics

Inclusion criteria	Age over 18, having the experience of chemotherapy with nausea and vomiting, having at least two chemotherapy episodes. Consists of 50-100 mg Cisplatin, with or without other chemotherapy agents with similar amount and prescription in two chemotherapy cycles without having any plans for radiotherapy among cycles, presence in ward for 24 hours ( in order to investigate the PRN), having no nausea and vomiting experiences for some reasons except for chemotherapy, lack of receiving PRN in 24 past hours, lack of treatment with corticosteroid drugs during considered cycles, lack of afflictions to hepatitis, digestion system block-age, brain malignancy and cerebral metastasis and clotting disorder on the basis of recorded information in files, lack of using the anti-clot drug
Exclusion criteria	Corticosteroids, digestive problems, anticoagulation, radiotherapy
N randomized	44
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	Kolmogorov-Smirnov Test
Countries of data collection	Iran
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T1: 1h after last capsule T2: after 2h T3: after 3h T4: after 4h T5: 24h after chemotherapy

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	NI
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	In: ≥2 cycles of cisplatin chemotherapy Chemoregime: 50-100 mg Cisplatin +/- andere Antiemetika: Granisetron 3 mg + Dexamethazon 8mg
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Female: 40.9 %
Age groups	Adults (18+)
Age groups specification	Mean(SD): 50.3±13.1 years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention, Placebo
Number of participants (arm) N randomized	22
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not arm specified: n = 13
Drop-out reasons	Not arm specified: death (n=3); change of drug regime (n=2), vomiting/capsule excretion/swallowing problems (n=2), radiotherapy between the cycles of chemotherapy (n=5), further participation refused (n=1)
Intervention	Ginger and placebo as cross-over intervention after 23 days + Antiemetics: Granisetron, dexamethazone
Dosage and regime	4x 250mg ginger capsule (production not standardized) Start: 2 capsules 30 minutes before the start of chemo, 2 capsules 6 hours after the end cross-over after cycle
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.	56
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention, Placebo
Number of participants (arm) N randomized	22
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not arm specified: n = 13
Drop-out reasons	Not arm specified: death (n=3); change of drug regime (n=2), vomiting/capsule excretion/swallowing problems (n=2), radiotherapy between the cycles of chemotherapy (n=5), further participation refused (n=1)
Intervention	Placebo and ginger as cross-over intervention after 23 days + Antiemetics: Granisetron, dexamethazone
Dosage and regime	4x 250mg ginger capsule (production not standardized) Start: 2 capsules 30 minutes before the start of chemo, 2 capsules 6 hours after the end cross-over after cycle
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.	56
Side effects / Interactions	NI

Outcomes

CINV (Chemotherapy-Induced Nausea and Vomiting)

Outcome type As specificed by the authors	Primary
Outcome specification	Frequency and severity of nausea and vomiting
Type of measurement	VAS (Visual Analogue Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Severity of the nausea in the first, second, third, fourth and the end of 24 hours in intervention vs. placebo arm reduced %9, %18.2, %13.7, %22.7, %13.7, %27.3 respectively In the second cycle these values were %7.2, %8 (in regime "routine anti emesis regime and placebo")) %5.3 , %14.1 (in regime "routine anti emesis regime and placebo")) and %24.1 24h after chemotherapy: Significant treatment effect in favor of A (routine anti – emesis regime and ginger): MD regime "routine anti–emesis regime and ginger" vs. regime "routine anti emesis regime and placebo": -0.93±3.39 vs. 1.80±2.33; p=0.01 Frequency of nausea: no significant differences between the arms at all time points in both cycles Vomiting / retching (frequency, severity): 1h after last capsule - 24h after chemotherapy: no significant difference between arms __ Raei Over both cycles: 1. nausea score after 24 hours 2. nausea score 3 hours after first dose Sign. Treatment effect in favor of ginger after 3 or 24 hours: Within-group comparison between cycles 1-2: Arm 1 Verum-placebo MD - 0.93±3.39 Arm 2 Placebo - verum MD 1.80±2.33 Then t-test inter-group comparison with above values: Ta = -2.571, df = 28, p = 0.01 Comparison of the cross-over regimes and the comparison between the two cycles showed no differences, i.e. ginger was superior to placebo in both cycles, irrespective of cycle and arm
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	None declared.
Conflicts of Interest	NI

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	?