Nausea is a frequent and debilitating side-effect of cancer. Protein and Ginger for the Treatment of Chemotherapy-Induced Delayed Nausea

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1 THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 14, Number 5, 2008, pp Mary Ann Liebert, Inc. DOI: /acm Protein and Ginger for the Treatment of Chemotherapy-Induced Delayed Nausea MAX E. LEVINE, Ph.D., 1 MARCUM G. GILLIS, B.S., 2 SARA YANCHIS KOCH, B.S., 3 ANNE C. VOSS, Ph.D., 4 ROBERT M. STERN, Ph.D., 5 and KENNETH L. KOCH, M.D. 3 ABSTRACT Background: Nausea that develops during the period that begins 24 hours after the administration of chemotherapy is called delayed nausea, and occurs in many patients with cancer. Meals high in protein decrease the nausea of motion sickness and pregnancy, possibly by reducing gastric dysrhythmias. Ginger also has antinausea properties. Objectives: To explore the use of protein meals with ginger for the treatment of the delayed nausea of chemotherapy. Design: Twenty-eight (28) patients with cancer receiving chemotherapy for the first time were assigned to 1 of 3 groups. For 3 days beginning the day after their chemotherapy, Control Group patients continued with their normal diet, Protein Group patients consumed a protein drink and ginger twice daily, and High Protein Group patients consumed a protein drink with additional protein and ginger twice daily. Outcome measures: Patients recorded in a diary each day whether they had experienced nausea, whether their nausea had been frequent, whether their nausea had been bothersome, and whether they had needed any antiemetic medication. Gastric myoelectrical activity was assessed in 5 patients before and after ingestion of a high protein meal and ginger. Results: Reports of nausea, frequent nausea, and bothersome nausea were significantly less common among High Protein Group patients than among Control and Protein Group patients. Furthermore, significantly fewer patients in the High Protein Group used antiemetic medication. Differences between the Protein and Control groups were not statistically significant. In the 5 patients who had tests of gastric myoelectrical activity performed, a significant decrease in gastric dysrhythmia occurred after ingestion of the protein and ginger. Conclusions: High protein meals with ginger reduced the delayed nausea of chemotherapy and reduced use of antiemetic medications. Protein with ginger holds the potential of representing a novel, nutritionally based treatment for the delayed nausea of chemotherapy. INTRODUCTION Nausea is a frequent and debilitating side-effect of cancer chemotherapy. Nausea and vomiting are reported by patients to be among the most bothersome side-effects of their chemotherapy, 1 and are sometimes intense enough to compel a patient to withdraw from treatment. 2 Despite efforts to reduce chemotherapy-induced nausea and vomiting through the administration of various antiemetic agents, nausea remains a significant problem. 3 The incidence of 1 Department of Psychology, Siena College, Loudonville, NY. 2 Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC. 3 Department of Internal Medicine, Section of Gastroenterology, Wake Forest University School of Medicine, Winston-Salem, NC. 4 Ross Products Division, Abbott Laboratories, Columbus, OH. 5 Department of Psychology, The Pennsylvania State University, University Park, PA. 545

2 546 LEVINE ET AL. vomiting has been significantly diminished in recent years with the introduction of serotonin and neurokinin-1 antagonist antiemetics, but patients continue to suffer from chemotherapy-induced nausea. 4 Protein meals and ginger represent potentially effective novel treatments for nausea. Jednak et al. 5 compared the effect of protein, carbohydrate, and fat meals on nausea experienced during the first trimester of pregnancy. Proteinpredominant meals reduced nausea significantly more than isocaloric carbohydrate and fat meals. Levine et al. 6 demonstrated that liquid protein meals reduced nausea and other motion sickness symptoms during exposure to provocative motion significantly more than liquid carbohydrate meals and when no meal was given. The physiologic mechanism by which protein offers protection against the development of nausea remains unclear, but the reduction of gastric dysrhythmias represents one possibility. Reports of nausea tend to be accompanied by abnormalities in gastric myoelectrical activity, as measured by electrogastrography. 7 Interventions that have been effective for the reduction of the severity of nausea have tended to diminish the dysrhythmic stomach activity that accompanies nausea (e.g., Muth et al. 8 ). Indeed, the antinausea effects referred to earlier of protein meals in the context of pregnancy and motion sickness were accompanied by significant reductions in gastric dysrhythmias. 5,6 Lien et al. 9 showed that ginger reduces nausea, gastric dysrhythmia, and plasma vasopressin, a hormone that has been shown to increase along with nausea. Ginger also prolonged latency before nausea onset and shortened recovery time after exposure to a rotating optokinetic drum, a stimulus that often induces symptoms of motion sickness. Gonlachanvit et al. 10 reported that one gram of ginger reduced the gastric dysrhythmia and nausea resulting from the infusion of dextrose to produce hyperglycemia in healthy humans. In addition, it has been shown that ginger reduces postoperative nausea and vomiting. 11 The aim of the present study was to determine the extent to which protein meals with ginger, used as adjuvant therapies for standard antiemetic treatment, would reduce the de- TABLE 1. DEMOGRAPHIC VARIABLES, CANCER TYPES, CYTOTOXIC AGENTS, AND ANTIEMETIC MEDICATIONS AS A FUNCTION OF EXPERIMENTAL GROUP Experimental Group Control Protein High Protein Demographics Patients (n) Sex (no. female) Age (mean years) Cancer type Breast Hodgkin s lymphoma Non-Hodgkin s lymphoma Bladder Lung Gastric Prostate Cytotoxic agent Cyclophosphamide/doxorubicin Cyclophosphamide/epirubicin Cyclophosphamide/doxorubicin/rituximab Doxorubicin/dacarbazine Doxorubicin/docetaxel Doxorubicin Paclitaxel/gemcitabine Paclitaxel Gemcitabine/navalbine Etoposide (VP-16) Cisplatin Oxaliplatin Carboplatin Antiemetic medication Promethazine Prochlorperazine Lorazepam Ondansetron Dexamethasone Aprepitant Note: None of the group differences in any of the variables displayed was statistically significant.

3 PROTEIN, GINGER, AND NAUSEA OF CHEMOTHERAPY 547 layed nausea that often develops at least 24 hours after the administration of chemotherapy, and can continue for several days. In addition, electrogastrograms (EGGs) were recorded from a small sample of the patients to examine the effects of the test meal on gastric myoelectrical activity. MATERIALS AND METHODS Participants Twenty-eight (28) patients with cancer (19 women) aged years (mean age 54.3 years) scheduled for their first chemotherapy treatment with a moderately or highly nauseogenic cytotoxic drug completed the study. To be considered eligible, patients must also have been at least 18 years old at the time of their enrollment, and must not have had a history of gastrointestinal disorders involving nausea, undergone gastrointestinal surgery, or been diagnosed with gastrointestinal obstruction. A history of adverse reactions to any proteins or ginger also excluded patients from the study. The characteristics of the patients in each experimental group are displayed in Table 1. The table highlights the great variability among the study sample in terms of the type of cancer that had been diagnosed, the cytotoxic agent that was administered, and the antiemetic drug that was prescribed. However, no difference between groups on any of these characteristics was statistically significant, nor were there significant correlations between these characteristics and any outcome measure. All patients provided written informed consent prior to their participation in the study. Procedure Recruitment and assignment to test meal groups. Patients with cancer scheduled for their first chemotherapy treatment were invited to participate. Patients were told that the protein meals with ginger were test products that may or may not relieve delayed nausea with any more success than standard antiemetic treatment would alone. As patients were enrolled in the study, they were randomly assigned to 1 of 3 experimental groups: Protein Group, High Protein Group, or Control Group. This was not a blinded study; both the investigators and the patient were aware of the group to which the patient had been assigned, but not until after the patient had provided consent to participate. There was no systematic bias in group membership in terms of sex, age, cancer type, cytotoxic agent administered, or antiemetic medication prescribed (Table 1). The Protein and High Protein Groups received test meals of varying protein content and ginger in the form of dried powdered ginger root in addition to standard antiemetic medication; the Control Group received only standard antiemetic medication. Patients assigned to the Protein and High Protein groups were asked to consume 2 test meals each day: 1 at breakfast (8:00 AM) and 1 in the late afternoon before dinner (4:00 PM) for 3 days beginning 24 hours after their first chemotherapy session had ended; patients in the Control Group were asked to continue with their normal diet. The composition of the test meals for each group is denoted in Table 2. Patients in all groups were asked not to modify their intake of protein and ginger during the study period unless dictated by the study protocol. Symptom diary. At the end of each day of the 3-day study period, patients completed a Symptom Diary before bedtime to indicate whether or not they had experienced symptoms of nausea that day. Reports of the incidence of nausea, of nausea being a frequent occurrence, and of nausea being bothersome were made in the diary. All patients had been prescribed antiemetic medication to take as needed over the 3-day period; they also recorded in the diary the use of any such medication each day. Patients were instructed not to refer in their diaries to their nausea or use of antiemetic medication during the first 24 hours after the administration of their chemotherapy. Adverse event monitoring. Patients were instructed to contact the investigators in the event of any adverse incident related to their participation in the study. Patients also received a phone call each evening during the 3-day study period from 1 of the investigators to monitor the occurrence of any adverse events. The phone call also represented an opportunity to remind patients to continue with their test TABLE 2. TEST MEAL COMPOSITION Protein Group meal: One 237-mL ProSure beverage a kcal (23% whey protein (17 g), 21% fat, 57% carbohydrates) Four 250-mg capsules of dried powdered ginger root (Zintona ) b High Protein Group meal: One 237-mL ProSure beverage kcal (23% whey protein (17 g), 21% fat, 57% carbohydrates) Three 6.6-g scoops of ProMod protein powder a (added to ProSure) - 84 calories (71% whey protein (15 g), 19% fat, 10% carbohydrate) Four 250-mg capsules of dried powdered ginger root (Zintona) a Abbott Laboratories, Abbott Park, IL. b Herbalist & Ooc GmbH, Berlin, Germany.

4 548 meals and diaries, and to answer any questions patients may have had. Electrogastrography Electrogastrograms (EGGs) were collected from 5 of the High Protein Group patients in a manner identical to that described in Levine et al. 12 For 15 minutes before and 30 minutes after ingestion of their test meal, estimates of the percentage of EGG power within the normal range ( cpm) and within the gastric tachyarrhythmia frequency bandwidth ( cpm) were obtained by dividing power in those frequency ranges by estimates of total EGG power. Data analysis Chi-square analyses were performed to determine whether the percentage of reports of the incidence of nausea differed among the three groups. Similar analyses were conducted for the percentage of reports of nausea being frequent, the percentage of reports of nausea being bothersome, and the number of patients in each group who used antiemetic medication at any time during the 3-day study period. Alpha levels were set at 0.05 for each of these tests. The percentage of normal EGG activity before the test meal was compared to the percentage after the meal by paired t- tests with the level set at Similarly, the percentage of gastric tachyarrhythmia was compared before and after the test meal. Preprandial and postprandial ratings of nausea that corresponded to those changes were also assessed. RESULTS LEVINE ET AL. Of 178 screened patients, 50 were deemed eligible to participate, and 36 were enrolled. Most of the screen failures were based on the administration of chemotherapy that was only mildly, if at all, nauseogenic. Eight (8) of the enrolled A B C D FIG. 1. Nausea data obtained from the symptom diaries of patients assigned to the Control, Protein, and High Protein Groups. (A) Reports of nausea were significantly less common among High Protein Group patients (p 0.01). (B) Reports of nausea being frequent were significantly less common among High Protein Group patients (p 0.01). (C) Reports of nausea being bothersome were significantly less common among High Protein Group patients (p 0.01). (D) The use of prescribed antiemetic medication was significantly less common among High Protein Group patients (p 0.05). Asterisks represent significant differences between the High Protein Group and the other 2 groups; none of the differences between the Protein Group and Control Group were statistically significant.

5 PROTEIN, GINGER, AND NAUSEA OF CHEMOTHERAPY 549 patients failed to return their symptom diaries to the investigators; 3 of these patients had been assigned to the Protein Group, 2 to the High Protein Group, and 3 to the Control Group. No adverse events were reported by patients who had either completed or not completed the study. Among the 28 patients who completed the study, significantly fewer reports of nausea were made by patients in the High Protein Group than by patients in the other 2 groups, 2 (2) 12.7, p The difference between the Protein and Control Groups was not statistically significant. Only 6 of 24 ratings made by High Protein Group patients indicated that nausea had been experienced during the preceding day, while 15 of 25 ratings made by Control Group patients and 20 of 27 ratings made by Protein Group patients indicated the incidence of nausea (Fig. 1A). Significantly fewer reports of nausea being a frequent symptom were made by patients in the High Protein Group than by patients in the other 2 groups, 2 (2) 19.9, p The difference between the Protein and Control Groups was not statistically significant. Only 3 of 23 ratings made by High Protein Group patients indicated that frequent nausea had been experienced during the preceding day, while 15 of 25 ratings made by Control Group patients and 20 of 27 ratings made by Protein Group patients indicated frequent bouts of nausea (Fig. 1B). Significantly fewer reports of nausea being bothersome were made by patients in the High Protein Group than by patients in the other 2 groups, 2 (2) 14.0, p The difference between the Protein and Control Groups was not statistically significant. Only 6 of 23 ratings made by High Protein Group patients indicated that nausea had been bothersome during the preceding day, while 11 of 25 ratings made by Control Group patients and 21 of 27 ratings made by Protein Group patients indicated that their nausea had been bothersome (Fig. 1C). Significantly fewer patients in the High Protein Group elected to use antiemetic medication than patients in the other 2 groups, 2 (2) 6.4, p The difference between the Protein and Control Groups was not statistically significant. Only 5 of 10 patients in the High Protein Group used a prescribed antiemetic drug at any time during the 3- day test period, while all 9 patients in the Control Group and 7 of 9 patients in the Protein Group used an antiemetic drug (Fig. 1D). For the 5 High Protein Group patients who had their EGGs recorded before and after ingestion of their first test meal, their mean baseline nausea rating was 8.0 (out of 10). The rating decreased to 4.6 after the test meals, but the difference was not statistically significant for this small group of patients. Gastric tachyarrhythmia decreased significantly from before to after ingestion of the test meal, t(4) 3.13, p 0.05 (Fig. 2A). Normal gastric activity increased significantly over this same time period, t(4) 2.70, p 0.05 (Fig. 2B). A B FIG. 2. Gastric myoelectrical activity before and after the test meals in 5 patients. (A). Gastric tachyarrhythmia decreased significantly from before to 20 minutes after ingestion of the test meal (p 0.05). (B) Normal gastric activity increased significantly from before to 20 minutes after the test meal (p 0.05). Error bars represent standard errors of the means.

6 550 DISCUSSION Reports of nausea were significantly less common among patients treated with high protein meals with ginger for 3 days following their initial chemotherapy treatment. Furthermore, the use of antiemetic medication among the same patients was significantly reduced, and indicates that the use of protein and ginger holds the potential for being an effective alternative for managing delayed nausea. That the ingestion of high protein meals with ginger was associated with fewer reports of frequent nausea and fewer reports of nausea being bothersome reinforces the notion that these nutritional supplements can provide relief for patients as they recover from a chemotherapy treatment. Five (5) nauseated patients, all of whom had been assigned to the High Protein Group, consumed their first test meal as their gastric myoelectrical activity was monitored. Though the physiologic mechanism responsible for any purported beneficial effect of this nutritional intervention remains unknown, it is noteworthy that a consistent decrease in gastric dysrhythmia and a concurrent increase in normal, rhythmic gastric activity were evident after ingestion of the test meal. Each of the patients reported a relief from nausea with the meal s ingestion. The ability of protein meals to reduce the nausea of pregnancy 5 and the nausea of motion sickness 6 has been attributed to their reduction of gastric dysrhythmias. The suggestion that protein s value is based upon its ability to reduce gastric dysrhythmia and/or enhance normal gastric activity should be regarded only as conjecture at this point, given that these data reflect the responses of only 5 patients, but more research in this area seems warranted. Ginger has been used in Asian countries for hundreds of years to relieve nausea, and many studies have demonstrated the potential value of ginger in preventing or reducing the nausea of pregnancy, 13 postoperative nausea, 11 and the nausea of motion sickness. 9 Many of the studies have tried to determine the mechanism by which ginger relieves nausea. For example, Sharma and Gupta 14 demonstrated in a rat study that ginger reversed a cisplatin-induced delay in gastric emptying. That the Protein Group was not different from the Control Group in terms of the symptoms reported in the diary while the High Protein Group reported less nausea suggests that ginger was not critical to the high protein meal s beneficial effects. However, the present study s design does not allow for such a conclusion to be firmly drawn. For instance, there may have been a unique interaction effect of high doses of protein and ginger on nausea. CONCLUSIONS Additional studies are needed to confirm the present results. There are several limitations of the study. The sample of patients was small and widely variable in terms of cancer types, the cytotoxic agents administered, and the antiemetic medications prescribed. There was not an adequate control group for the ginger component of the test meals. In addition, a placebo meal that contained neither protein nor ginger was not included in the design. Future studies using randomized designs should aim to reduce the impact of these limitations. Nevertheless, the present results do suggest a therapeutic effect of this nutritionally based intervention for the delayed nausea of cancer chemotherapy. ACKNOWLEDGMENTS This study was sponsored by Ross Products Division of Abbott Laboratories, Columbus, OH. The authors wish to thank the patients who participated in the study, and Drs. Denise Levitan, Mebea Aklilu, Istvan Molnar, and Susan Melin of the Comprehensive Cancer Center at Wake Forest University Health Sciences for their assistance with the completion of this study. REFERENCES LEVINE ET AL. 1. Cull A. Psychological effects of anti-cancer therapy. In: Andrews PLR, Sanger GJ, eds. Emesis in Anti-Cancer Therapy: Mechanisms and Treatment. London: Chapman and Hall, 1993: Stewart DJ. Cancer therapy, vomiting, and antiemetics. Can J Physiol Pharmacol 1990;68: Morrow GR, Hickok JT, Rosenthal SN. Progress in reducing nausea and emesis: Comparison of ondansetron (Zofran), granisetron (Kytril), and tropisetron (Navoban). Cancer 1995;76: Roscoe JA, Morrow GR, Hickok JT, Stern RM. Nausea and vomiting remain a significant clinical problem: Trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage 2000;20: Jednak MA, Shadigian EM, Kim MS, et al. Protein meals reduce nausea and gastric slow wave dysrhythmic activity in first trimester pregnancy. Am J Physiol 1999;277:G855 G Levine ME, Muth ER, Williamson MJ, Stern RM. Protein-predominant meals inhibit the development of gastric tachyarrhythmia, nausea, and the symptoms of motion sickness. Aliment Pharmacol Ther 2004;19: Koch KL, Stern RM. Handbook of Electrogastrography. New York, NY: Oxford University Press, Muth ER, Jokerst MD, Stern RM, Koch KL. Effects of dimenhydrinate on gastric tachyarrhythmia and symptoms of vection-induced motion sickness. Aviat Space Environ Med 1995;66: Lien HC, Sun WM, Chen YH, et al. Effects of ginger on motion sickness and gastric slow wave dysrhythmias induced by circular vection. Am J Physiol 2003;284:G481 G Gonlachanvit S, Chen YH, Hasler WL, et al. Ginger reduces hyperglycemia-evoked gastric dysrhythmias in health humans:

7 PROTEIN, GINGER, AND NAUSEA OF CHEMOTHERAPY 551 Possible role of endogenous prostaglandins. J Pharmacol Exp Ther 2003;307: Chaiyakunapruk N, Kitikannakorn N, Nathisuwan S, et al. The efficacy of ginger for the prevention of postoperative nausea and vomiting: A meta-analysis. Am J Obstet Gynecol 2006;194: Levine ME, Chillas JC, Stern RM, Knox GW. The effects of serotonin (5-HT 3 ) receptor antagonists on gastric tachyarrhythmia and the symptoms of motion sickness. Aviat Space Environ Med 2000;71: Smith C, Crowther C, Willson K, et al. A randomized controlled trial of ginger to treat nausea and vomiting in pregnancy. Obstet Gynecol 2004;103: Sharma SS, Gupta YK. Reversal of cisplatin-induced delay in gastric emptying in rats by ginger (Zingiber officinale). J Ethnopharmacol 1998;62: Address reprint requests to: Max E. Levine, Ph.D. Department of Psychology Siena College 224 Roger Bacon Science Center Loudonville, NY mlevine@siena.edu

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