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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3458-3464 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.4685 5-Hydroxytryptamine-3 Receptor Antagonist With or Without Short-Course Dexamethasone in the Prophylaxis of Radiation Induced Emesis: A Placebo-Controlled Randomized Trial of the National Cancer Institute of Canada Clinical Trials Group (SC19)
From the National Cancer Institute of Canada Clinical Trials Group; Kingston Regional Cancer Centre, Queen's University, Kingston; Queen Elizabeth II Health Sciences Centre, Nova Scotia; Centre Hospitalier Universitaire de Sherbrooke Hopital Fluerimont, Sherbrooke; Centre Hospitalier Universitaire de Quebec Pavillon Hotel Dieu de Quebec, Hopital Maisonneuve Rosemont; McGill University, Department of Oncology; Centre Hospitalier de L'Universite de Montreal Hopital Notre-Dame, Quebec; Toronto Sunnybrook Regional Cancer Centre; University of Toronto; Princess Margaret Hospital, University Health Network, University of Toronto, Toronto; British Columbia Cancer Agency, Vancouver Centre; British Columbia Cancer Agency Fraser Valley Centre; British Columbia Cancer Agency Cancer Centre for the Southern Interior; British Columbia Cancer Agency Vancouver Island Cancer Centre, British Columbia, Canada; London Regional Cancer Centre, London; Northwestern Ontario Regional Cancer Centre, Sudbury; Cross Cancer Institute, Edmonton, Canada Address reprint requests to Rebecca K.S. Wong, MBChB MSc, Radiation Medicine Program, Princess Margaret Hospital, 610 University Avenue, Toronto M5G 2M9 Canada; e-mail: Rebecca.wong{at}rmp.uhn.on.ca
PURPOSE: To evaluate the effectiveness of prophylactic dexamethasone for the control of radiation induced emesis (RIE) when added to ondansetron during days 1 to 5 of fractionated radiotherapy. The study had two hypotheses: ondansetron and dexamethasone could provide superior control of RIE over ondansetron alone during the prophylactic period and; the combination could provide sustained control of RIE during subsequent fractions of radiotherapy.
PATIENTS AND METHODS: Between May 2001 to Jan 2004, 211 patients receiving radiotherapy ( RESULTS: During the prophylactic period there was a trend for improved complete control of nausea in the dexamethasone arm (50% v 38%; P = .06) while complete and partial control of emesis, average nausea score, and use of rescue medications were similar in the two groups. During the overall study period patients receiving dexamethasone had better complete control of emesis (23% v 12%; P = .02) and a lower average nausea score (0.28 v 0.39; P = .03); there was a trend towards less use of rescue medications with dexamethasone (70% v 80%; P = .09); other outcomes were similar on the two arms. Quality of life analysis showed a significant difference in appetite. CONCLUSION: The addition of dexamethasone to ondansetron as prophylaxis provides a modest improvement in protection against RIE during moderately emetogenic fractionated radiotherapy. It is a potentially useful addition to 5-hydroxytryptamine-3 receptor antagonists in this setting.
Radiation-induced emesis (RIE) was first described by Court-Brown in 19531and further characterized by Danjoux et al2 in 1979. Like chemotherapy-induced emesis, it is the result of multiple mechanisms.3,4 The main factors determining the intensity of the emetogenic stimuli in RIE are dose fractionation, volume of the radiotherapy, and organs exposed to radiation. In general, the emetogenic stimulus is proportional to the dose per fraction and the volume of the abdomen being treated. In contrast to the situation with chemotherapy-induced emesis, the impact of the use of different combinations of antiemetics, or different durations and doses of radiotherapy, are less well characterized. The effectiveness of dopamine receptor and 5-hydroxytryptamine-3 receptor antagonists (5-HT3) antagonists in the prophylaxis and treatment of RIE has been well established in randomized trials.5-14 The role of dexamethasone alone or in combination with these agents is not well defined. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) randomized trial SC12 demonstrated the efficacy of dexamethasone versus placebo in preventing RIE without any significant increase in toxicity.15 These results are similar in magnitude to those achievable with 5-HT3 antagonists.8,13 In SC12, most emetic episodes occurred during the initial phase of treatment (days 1 to 5) and tapered as the course progressed. This observation, coupled with analogous evidence from studies addressing the management of chemotherapy-induced emesis, led to the following hypotheses: could the combination of dexamethasone with a 5-HT3 antagonist provide superior control of radiation-induced nausea and vomiting? Could an intensive prophylaxis regimen at the onset of radiotherapy provide adequate control of RIE associated with a fractionated course?
The SC19 study was a multicenter, placebo-controlled, double-blind, randomized trial. Stratification was performed for the degree of emetogenic stimulus using radiotherapy field description (whole abdomen and pelvis, partial abdomen and pelvis, and partial abdomen). Random assignment was performed through the NCIC CTG central office.
Eligibility criteria. Patients in the study arm received dexamethasone 4 mg once daily (fractions 1 to 5), while control arm patients received identical placebo during this period. All patients received ondansetron oral disintegrating tablet 8 mg twice-a-day fractions 1 to 5. All patients received a rescue pack consisting of prochloperazine 10 mg tid orally (fractions 1 to 5) and ondansetron 8 mg tid (fractions 6 to 15). Specific instructions were given to use the rescue pack only for persistent nausea and vomiting as necessary. The time between fractions 1 to 5 is referred to as the prophylactic period and between fractions 6 to 15 as the symptomatic treatment period. The entire time between fractions 1 to 15 is the study period (Fig 1).
Outcome information was collected through daily diaries completed by the patients between fractions 1 to 15. Nausea and vomiting, as well as other symptoms including food intake, nausea, indigestion, heartburn, anxiety, nervousness, headache, diarrhea, and constipation, were scored using a 4 point scale (0 = none, 4 = severe/quite a bit). The validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 16 was used to assess quality of life (QOL), as had been used in previous studies of the NCIC CTG addressing control of nausea and vomiting. The core instrument consists of questions addressing global QOL and five functional domains, three symptom domains, and single-item symptom scores. An additional trial-specific module of five questions addressing the impact of nausea on QOL was also included.15 The questionnaire was completed on days 1, 5, and 15, as well as at 1-month postcompletion of radiotherapy. The National Cancer Institute Common Toxicity Criteria version 2.0 were used to assess toxicity. A pill count was conducted at fractions 5 and 15 to confirm compliance.
Outcome definition. For the first study hypothesis (to evaluate whether the combination of ondansetron and dexamethasone would be more effective than ondansetron and placebo in controlling nausea and vomiting during the prophylactic period), complete control of nausea and complete control of vomiting during fractions 1 to 5 were defined as the relevant outcome variables and the primary end points of our study. For the second hypothesis (to evaluate whether this prophylactic strategy could provide sustained control of nausea and vomiting during the entire study period), complete control of nausea and complete control of vomiting during fractions 1 to 15 were defined as the relevant outcome variables. Other secondary end points defined a priori included average nausea score, use of rescue medications, toxicities, and QOL comparisons during the prophylactic and study periods.
Statistical and sample size considerations. The target sample size was based on the assumption of a 70% complete protection rate against RIE for the control arm for the first 5 fractions of radiotherapy. An enrollment of 200 patients provided 80% power, using a one sided 5% level test to detect a 15.5% improvement in complete protection rate for the study arm during the prophylactic period. This sample size also provided 85% power (using a one sided 5% level test) to detect a 20% improvement in the study arm versus a 40% complete protection rate between fractions 1 to 15 for the control arm. In terms of QOL comparisons, considering the five functional domains, with a standard deviation of each item of less than or equal to 25, a sample size of 200 patients has a 80.7% power to detect a 10-point difference, using a 5% level two-sided test. A 7 to 10 point difference in QOL scores is considered clinically significant.17-20 Ethics approval was obtained from each participating institution. GlaxoSmithKline provided study drug and funding to NCIC CTG to support the conduct of the study.
Between May 2001 and January 2004, 211 patients were randomly assigned and 204 patients (101 patients on the dexamethasone arm; 103 patients on placebo) were confirmed as eligible (Fig 2). All patients received the study intervention as planned. The two groups were well balanced for all important characteristics including age, sex, primary histology, and susceptibility to motion sickness. There were more patients with ECOG 0 in the study arm (P = .006; Table 1).
Patient Diary Data With respect to our primary hypotheses—to determine if the use of prophylactic ondansetron and dexamethasone during fractions 1 to 5 would provide better protection from nausea and vomiting during the prophylactic period—the proportion of patients with complete protection of nausea and vomiting in that period was the primary outcome measure. Only one patient on the control arm was unassessable due to the use of nabilone in error, mistakenly taken as an appetite stimulant. There was a trend in favor of the dexamethasone arm for the proportion of patients with complete control of nausea (50% v 38%; P = .06), but no significant differences in the proportions of patients with complete control of emesis (78% v 71%; P = .14), partial or better control of emesis (91% v 86%; P = .13), and average nausea scores (maximum = 4) across the prophylactic period (0.24 v 0.32; P = .08). There was no statistically significant difference in the proportion of patients who used rescue medications (prochloperazine) during this time (10% v 15%; P = .2; Table 2).
With regard to the second hypothesis—to determine if the use of prophylactic ondansetron and dexamethaseone during days 1 to 15 would provide sustained control of nausea and vomiting—the proportion of patients with complete protection of nausea and vomiting between fractions 1 to 15 was the primary outcome measure. Thirteen patients were unassessable (six patients on placebo; seven patients on dexamethaseone) as antiemetics were taken by mistake, without cause. We observed an apparent advantage to the dexamethasone arm over the study period, with better complete protection against emesis (23% v 12%; P = .02), lower average nausea score (0.28 v 0.39; P = .03), and a trend towards less use of rescue medications (71% v 82%; P = .09). There were no significant differences in partial or better control of emesis (70% v 65%; P = .19) and complete control of nausea (15% v 9%; P = .14; Table 2). As an exploratory analysis, a stratified logistic regression model was performed for preselected prognostic factors. To obtain a more parsimonious model, only factors that were significant at a .1 level were kept in the final model. This provided additional evidence in support of the effect of dexamethasone in improving nausea control during both the prophylactic period and the entire study duration. Treatment with dexamethasone was significant for complete control of nausea for fractions 1 to 5 (P = .04). Other factors that were significant include ECOG performance status for complete control of emesis for fractions 1 to 5 (P = .08), prior cancer therapy for complete control of nausea for fractions 1 to 5 (P = .095), and age for complete control of emesis for fractions 1 to 15 (P = .053). All the results remained unchanged after adjustment of the ECOG PS, prior cancer therapy and age. The combination of ondansetron and dexamethasone was well tolerated with a similar toxicity profile to ondansetron plus placebo. The proportion of patients with no adverse events was 50% versus 57%, respectively (Table 3). Proportions of patients with grade 2 or less toxicity of dyspepsia (16% v 17%), constipation (27% v 20%), and headache (18% v 12%) were similar in the two groups. One patient on the dexamethasone arm experienced grade 3 gastric ulcer (Table 3).
QOL Data Completion of QOL questionnaires was considered mandatory for all patients able to read English or French. Compliance rates were high, with 99% of expected forms received at baseline, and 97%, 93%, and 95% at fractions 5 and 15, and at 1-month follow-up, respectively. Average global QOL scores deteriorated in both groups, but returned to baseline in both arms by 1-month postcompletion of treatment (Fig 3). Figure 3 shows change in QOL scores from baseline for selected functional scales and symptom scales. Based on repeated measures analysis across time (fractions 5 to 15), there were significant benefits of dexamethasone in appetite (P = .005) and a trend favoring dexamethasone with respect to global QOL (P = .08) and nausea and vomiting (P = .06), but a detrimental effect on sleep (P = .013) and constipation (P = .07).
Comparison of the change scores at individual time points provided additional details on the impact on QOL at individual time points. Significant differences were observed favoring the use of dexamethasone in nausea and vomiting (P = .03; Fig 3) and appetite (P = .005) at day 5. In addition, emotional functioning at day 15 significantly favored the dexamethasone arm. However, dexamethasone has a detrimental effect on sleep (P = .002) and constipation (0.003) for day 5.
These results are in support of an effect from a short course of dexamethasone (4 mg once daily for 5 days) when added to a 5-HT3 antagonist is more effective in providing sustained protection against radiation-induced nausea during a fractionated course of radiotherapy than is the 5-HT3 antagonist alone. In absolute terms, there was an 11% benefit (12% v 23%) in complete control of vomiting and 6% (9% v 15%) in complete control of nausea for the study period of radiotherapy (15 days), with no significant change in the toxicity profile. QOL data show a significant difference for the study period for appetite. The observed differences were sufficient in magnitude to be considered clinically significant.18 Lastly, stratified logistic regression analysis identified dexamethasone as a significant factor in complete control of nausea for the prophylactic period. Although our study did not demonstrate a statistically significant benefit for the primary end point, (defined as the proportion of patients with complete control of emesis and nausea between days 1 through 5), results on several secondary end points, as well as QOL data, would suggest that benefits do exist with the addition of dexamethasone. Can a trial be positive when the primary end point is negative? In many intervention trials, the primary end point carries significantly greater importance relative to its secondary end points. For example, a trial that sets out to identify a survival benefit (using overall or cause-specific survival as the primary end point) is unlikely to conclude that the results are positive if the primary end point is negative. However, in symptom control trials, outcome measures are by nature multidimensional. The relative importance of the primary versus secondary end points can be similar, with the choice being made driven by methodological properties. The complex nature of choosing a primary response variable can be observed in other clinical areas where symptom outcome is of greatest importance.21-24 The interpretation of what is clinically significant is further complicated by the fact that symptom measures can be analyzed in several ways, and definition for response or change can directly affect the outcome of the comparisons.25 While conceptually, statistical adjustment for multiple end points or comparisons requires consideration, the optimal way of accomplishing this across multidimensional outcomes is not well established. The design and interpretation of symptom control trials and their multidimensional end points therefore present unique challenges. When there is explicit reporting of which end points were planned a priori, with clear definitions for response or change, and attention to accounting for all randomly assigned patients for each of the secondary end points, a carefully selected panel of end points can provide multidimensional evaluation that support effectiveness when unidimensional primary end point(s) alone cannot, as in the case of this trial. In the absence of established methodology to adjust for the appropriate selection of multiple end points, interpretation of the P values of the individual outcomes should be made with caution. Similarly, it is possible, therefore, that some of the observed changes in QOL scores that reached statistical significance were due to chance alone. In this study, irrespective of the study intervention, for the patients who did experience nausea or vomiting and thus were counted as failures, the strategy of using a 5-HT3 antagonist for rescue (fractions 6 to 15) as necessary was used in this trial. What is the residual burden of nausea and vomiting for those who did not achieve complete control of nausea and vomiting? The nausea and vomiting profile between fraction days 6 to 15 provides some insight into this. We observed that the median cumulative number of emetic episodes during fractions 6 to 15 was modest at 2.5 for both the study and control arm (study arm range, 1 to 20; control arm range, 1 to 52). The median number of rescue ondansetron tablets taken was 61-15 and 7.1-18 These data would suggest that residual nausea and vomiting is modest in severity when a short, intensive prophylactic regimen of 5-HT3 antagonist (± dexamethasone) is employed, followed by symptomatic use of the 5-HT3 antagonist alone for the remainder of the radiotherapy. A recent study reported by Marazano et al26 lends support to this assertion. Their crossover, randomized trial between prophylactic versus symptomatic use of a 5-HT3 antagonist showed similar efficacy for both approaches, suggesting that symptomatic treatment may be reasonable. This hypothesis would require confirmation through future trials. What does the SC19 study add to the current standard management for RIE? Several guidelines have been published calling for the use of prophylactic management of RIE, including the use of a 5-HT3 antagonist.27-30 For patients receiving moderate- to highly-emetogenic radiotherapy, it is generally recommended that prophylactic therapy be considered. The use of a 5-HT3 antagonist is uniformly recommended in this setting, while a dopamine receptor antagonist is also advocated. A recent update by Feyer et al31 suggests the addition of dexamethasone to upper abdominal irradiation on the basis of our previous trial (SC12).15 Results of the SC19 study provide evidence of a modest benefit with this short prophylactic regimen for patients receiving moderately emetogenic radiotherapy: it is a potentially useful addition to 5-HT3 antagonists in this setting.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported by GlaxoSmithKline. Presented in part at the Annual Meeting of the European Society of Therapeutic Radiation Oncology, Amsterdam, 2004; and the Annual Meeting of the Multinational Association of Supportive Care in Cancer, Geneva, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Court-Brown W: Symptomatic disturbance of the single therapeutic dose of X-rays. BMJ 1:802-804, 1953[Medline] 2. Danjoux C, Rider W, Fitzpatrick P: The acute radiation syndrome. Clin Radiol 30:581-584, 1979[CrossRef][Medline] 3. Sagar S: The current role of anti-emetic drug in oncology: A recent revolution in patient symptom control. Cancer Treatment Rev 18:95-135, 1991[Medline] 4. Young R: Mechanisms and treatment of radiation induced nausea and vomiting, in Davis C, Lake-Bahrr G, Grahame-Smith D (eds): Nausea and Vomiting: Mechanisms and treatment. Berlin Heidelberg, Germany, Springer-Verlag, 1986 5. Tramer MR, Reynolds DJ, Stoner NS, et al: Efficacy of 5-HT3 receptor antagonists in radiotherapy-induced nausea and vomiting: A quantitative systematic review. Eur J Cancer 34:1836-1844, 1998[CrossRef][Medline] 6. Bey P, Wilkinson PM, Resbeut M, et al: A double-blind, placebo-controlled trial of IV dolasetron mesilate in the prevention of radiotherapy-induced nausea and vomiting in cancer patients. Support Care Cancer 4:378-383, 1996[CrossRef][Medline] 7. Spitzer TR, Bryson JC, Cirenza E, et al: Randomized double-blind, placebo-controlled evaluation of oral ondansetron in the prevention of nausea and vomiting associated with fractionated total-body irradiation. J Clin Oncol 12:2432-2438, 1994 8. Franzen L, Nyman J, Hagberg H, et al: A randomised placebo controlled study with ondansetron in patients undergoing fractionated radiotherapy. Ann Oncol 7:587-592, 1996 9. Khoo VS, Rainford K, Horwich A, et al: The effect of antiemetics and reduced radiation fields on acute gastrointestinal morbidity of adjuvant radiotherapy in stage I seminoma of the testis: A randomized pilot study. Clin Oncol (Royal College of Radiologists) 9:252-257, 1997 10. Emesis Study Group for the Ondansetron Orally Disintegrating Tablet in Radiotherapy Treatment, LeBourgeois JP, McKenna CJ, Coster B, et al: Efficacy of an ondansetron orally disintegrating tablet: A novel oral formulation of this 5-HT(3) receptor antagonist in the treatment of fractionated radiotherapy-induced nausea and emesis. Clin Oncol (Royal College of Radiologists) 11:340-347, 1999 11. Priestman TJ, Roberts JT, Lucraft H, et al: Results of a randomized, double-blind comparative study of ondansetron and metoclopramide in the prevention of nausea and vomiting following high-dose upper abdominal irradiation. Clin Oncol (Royal College of Radiologists) 2:71-75, 1990 12. Sykes AJ, Kiltie AE, Stewart AL: Ondansetron versus a chlorpromazine and dexamethasone combination for the prevention of nausea and vomiting: A prospective, randomised study to assess efficacy, cost effectiveness and quality of life following single-fraction radiotherapy. Support Care Cancer 5:500-503, 1997[CrossRef][Medline] 13. Priestman TJ, Roberts JT, Upadhyaya BK: A prospective randomized double-blind trial comparing ondansetron versus prochlorperazine for the prevention of nausea and vomiting in patients undergoing fractionated radiotherapy. Clin Oncol (Royal College of Radiologists) 5:358-363, 1993 14. Prentice HG, Cunningham S, Gandhi L, et al: Granisetron in the prevention of irradiation-induced emesis. Bone Marrow Transplant 15:445-448, 1995[Medline] 15. Kirkbride P, Bezjak A, Pater J, et al: Dexamethasone for the prophylaxis of radiation-induced emesis: A National Cancer Institute of Canada Clinical Trials Group phase III study. J Clin Oncol 18:1960-1966, 2000 16. EORTC Quality of Life Group: European Organisation for Research in Cancer Quality of Life. http://www.eortc.be/home/qol/ 17. Osoba D, Bezjak A, Brundage M, et al: Analysis and interpretation of health-related quality-of-life data from clinical trials: Basic approach of the National Cancer Institute of Canada Clinical Trials Group. Eur J Cancer 41:280-287, 2005[CrossRef][Medline] 18. Norman GR, Sloan JA, Wyrwich KW: Interpretation of changes in health-related quality of life: The remarkable universality of half a standard deviation. Med Care 41:582-592, 2003[CrossRef][Medline] 19. Wyrwich KW, Fihn SD, Tierney WM, et al: Clinically important changes in health-related quality of life for patients with chronic obstructive pulmonary disease: An expert consensus panel report. J Gen Intern Med 18:196-202, 2003[CrossRef][Medline] 20. Norman GR, Sridhar FG, Guyatt GH, et al: Relation of distribution- and anchor-based approaches in interpretation of changes in health-related quality of life. Med Care 39:1039-1047, 2001[CrossRef][Medline] 21. Zanolla L, Zardini P: Selection of endpoints for heart failure clinical trials. European Journal of Heart Failure 5:717-723, 2003[Medline] 22. Hauptman PJ: Measurement of end points in heart failure trials: Jousting at windmills? Mt Sinai J Med 71:298-304, 2004[Medline] 23. Legro RS, Myers E: Surrogate end-points or primary outcomes in clinical trials in women with polycystic ovary syndrome? Hum Reprod 19:1697-1704, 2004 24. Breitfeld PP: Assessing the overall impact of therapy: It's not so simple. J Pediatr Hematol Oncol 24:518-520, 2002[CrossRef][Medline] 25. Twisk J, Proper K: Evaluation of the results of a randomized controlled trial: How to define changes between baseline and follow-up. J Clin Epidemiol 57:223-228, 2004[CrossRef][Medline] 26. Maranzano E, Bellavita R, DeAngelis V, et al: Double-blind randomized clinical trial comparing prophylaxis vs. rescue treatment in patients undergoing fractionated upper abdomen radiotherapy, ESTRO. Amsterdam, the Netherlands, Elsevier, 2004, pp S386 27. ASHP: Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health Syst Pharm 56:729-764, 1999 28. NCCN: NCCN antiemesis practice guidelines. Oncology (Huntington) 11:57-89, 1997 29. Anonymous: Prevention of chemotherapy- and radiotherapy-induced emesis: Results of Perugia Consensus Conference. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC) 811-819, 1998 30. Gralla RJ, Osoba D, Kris MG, et al: Recommendations for the use of antiemetics: Evidence-based, clinical practice guidelines. [erratum appears in J Clin Oncol 17:3860, 1999]. J Clin Oncol 17:2971-2994, 1999 31. Feyer P, Maranzano E, Molassiotis A, et al: Radiotherapy-induced nausea and vomiting (RINV): Antiemetic guidelines. Support Care Cancer 13:122-128, 2005[CrossRef][Medline] Submitted October 20, 2005; accepted May 4, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
15 fractions) to the upper abdomen were randomly assigned to receive ondanstron 8 mg bid with either dexamethasone 4 mg daily or placebo during fractions 1 to 5. Rescue antiemetics were provided. 
