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Ginger for chemotherapy-related nausea in cancer patients: A URCC CCOP randomized, double-blind, placebo-controlled clinical trial of 644 cancer patients
Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 1 de junio del 2009
Presenter: J. L. Ryan, PhD, MPH
Presenter's Affiliation: URCC CCOP
Type of Session: Scientific
- It is well known that the #1 severe side effect reported among patients receiving chemotherapy is nausea.
- Nausea is a symptom which is very subjective and manifested by a link between the digestive system and nervous system. It is thought to be regulated by neurotransmitters such as serotonin (5HT3), dopamine, or neurokonin.
- The gold standards for measurement of nausea are self-assessment tools.
- Despite the widespread use of antiemetics, 73% of patients receiving chemotherapy are reported to have acute nausea onset within 24 hours or late onset of nausea after 24 hours but up to 5 days post-chemotherapy.
- This demonstrates a need to find additional therapies to treat chemotherapy-induced nausea.
- Ginger is an ancient spice that has been previously used by healthcare providers worldwide for headaches, nausea and vomiting, diarrhea, and joint pain.
- It is thought to work as an anti-inflammatory and anti-spasmodic agent. It has also been shown in previous reports to be effective for morning sickness in pregnancy and motion sickness.
- A recent randomized, double-blind, placebo-controlled trial published by Zick et. al. in 2008 from the U. of Michigan suggests that ginger given after the start of chemotherapy along with a 5-HT3 receptor antagonist and/or aprepitant did NOT improve nausea.
- Their study included 162 patients with cancer who were receiving chemotherapy and had experienced chemo-induced nausea and vomiting during at least one previous round of chemotherapy, and subjects were randomized to receive either 1.0 g ginger daily, 2.0 g ginger daily, or matching placebo for 3 days.
- They found that there were no differences between groups in the prevalence of delayed nausea or vomiting, prevalence of acute nausea/vomiting, or severity of delayed symptoms.
- A study by Pace et al. performed in 1986 showed that the use of ginger did reduce the severity of chemotherapy related nausea in patients with gynecologic cancers. Another recent study performed by Levine et. al. in 2008 showed that high protein meals with ginger reduced the delayed nausea of chemotherapy and reduced use of antiemetic medications in 28 patients.
- Although these studies did suggest positive effects of ginger on reducing nausea, the small sample sizes and design inadequacies of these studies limit their generalizability and power of the results.
- In addition, the Levine study did not test ginger alone, and it is unclear if the results may be biased due to the addition of protein with the ginger.
- The purpose of this study was to conduct a multi-site, phase II/III randomized, placebo-controlled, double-blind clinical trial to assess the efficacy of ginger for chemotherapy-related nausea in cancer patients at the University of Rochester-affiliated Community Clinical Oncology Program (CCOP) member sites.
Materials and Methods
- The primary objective of this study was to determine whether ginger is more effective than placebo in controlled chemotherapy-induced nausea when added to a 5-HT3 receptor antagonist + dexamethasone on day 1 of chemotherapy. The secondary objective was to determine the most effective dose of ginger.
- Eligibility criteria:
- Cancer patients who experienced nausea in a previous cycle of chemotherapy and were scheduled to receive at least 3 more cycles of chemotherapy were included.
- All patients had to be on 5-HT3 receptor antagonist on Day 1 of chemotherapy. Both moderately and highly emetic chemotherapy treatments were used.
- Patients taking Coumadin or other blood-thinners were NOT eligible for this study due to the drug-drug interactions between Coumadin and ginger.
- This study is a randomized placebo-controlled, double blind clinical trial where patients were randomized (in a ratio of 1:1:1:1) to one of four treatment arms: placebo group, 0.5 g ginger daily, 1 g ginger daily, and 1.5 g ginger daily.
- Ginger was given in the form of capsules. All patients took 3 capsules of 250 mg ginger or placebo by mouth twice daily for 6 days starting 3 days before the initiation of chemotherapy.
- Nausea was assessed at baseline and for the 2 following chemotherapy cycles. Patients reported the severity of nausea during the morning, afternoon, evening, and night daily on a 7-point semantic rating scale ('1' = 'Not at all Nauseated' and '7' = "Extremely Nauseated") for Days 1-4 of each cycle.
- A total of 644 patients were accrued in this study and randomized to the 4 treatment arms. 90% of patients were female, 92 were white, and the mean age of patients was 53.
- Breast (66%), alimentary (6.5%), and lung (6.1%) cancers were the most common cancer types.
- 86% of patients had previous surgery, 56% of patients had previous chemotherapy, and 7% of patients had previous radiation.
- 71% of patients completed all chemotherapy cycles.
- The investigators used an analysis of covariance (ANCOVA) method to examine the change in nausea between the four study arms on Day 1 of cycles 2 and 3, and found that all doses of ginger significantly reduced nausea (p=0.003) compared to baseline.
- The largest reduction in nausea occurred with 0.5g and 1.0g of ginger.
- Furthermore, there was a significant linear decrease in nausea over a 24 hour time period for patients using ginger suggesting that time of day also had a significant effect on nausea (p<0.001).
- There was no significant effect of ginger seen on vomiting.
- This study demonstrated that there are positive effects of ginger supplementation on the reduction of chemotherapy induced nausea during Day 1 of chemotherapy.
- The most effective daily dose of ginger found to be effective was 0.5 g-1.0 g.
- Despite having very effective pharmacologic options for treating chemotherapy induced nausea, over 70% of patients continue to report nausea as the number one side effect of chemotherapy. Therefore, alternative or additional treatment strategies are needed.
- This trial is a well-designed study in that it was randomized, double-blinded and placebo-controlled. The arms were well-balanced.
- This study provides promising data regarding the use of ginger in conjunction with 5-HT3 receptor antagonists such as Zofran or Kytril for the treatment of chemotherapy-induced nausea.
- The results of this study did differ from the results of the recent study by Zick et. al. mentioned above. However the major difference between the 2 studies is that in the current study, ginger was started 3 days before chemotherapy, whereas Zick et. al. started ginger treatment after chemotherapy initiation. The current study also had a much larger study population which may have contributed to the difference in results.
- Ginger is a cheap natural product with a low toxicity profile, and may be very beneficial to patients who may not be able to afford expensive anti-nausea agents.
- Although this data is promising, this study does have some limitations.
- A point scale questionnaire was used to assess the severity of nausea at 4 times during the day. Patient reporting is a very subjective measure which is not standardized, and introduces bias. Slightly more objective measures to observe nausea severity that could have been used are ECOG toxicity criteria scoring or examination of the need for breakthrough medication usage.
- Additionally, there were no data provided on potential toxicities associated with ginger in these patients.
- Patients were not stratified according to age, types of cancer, or potency of anti-emetic agents. These analyses may have a potential impact on targeting this therapy to subgroups that may benefit more than others.
- Some remaining questions from this study are:
- 1) Will all forms of ginger supplements help patients with nausea?
- 2) How many days of treatment with ginger are necessary?
- 3) Is there an effect of ginger on chemotherapy efficacy? This will be an important area for future research as our first goal is to treat the patientÕs cancer.
- In conclusion, the data presented in this study is very promising. Nausea is a major side effect of chemotherapy that hinders patientÕs quality of life and better treatments need to be found. The combination of complementary therapies with current pharmacologic treatments for chemotherapy-induced nausea is an area that is exciting and warrants further investigation to address the questions mentioned above.
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