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© 2000 American Society for Clinical Oncology Dexamethasone for the Prophylaxis of Radiation-Induced Emesis: A National Cancer Institute of Canada Clinical Trials Group Phase III StudyFrom the National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada. Address reprint requests to Peter Kirkbride, MD, Weston Park Hospital, Whitham Rd, Sheffield, S10 2SJ, United Kingdom; email pkirkbride{at}WPH.TRENT.NHS.UK
PURPOSE: To investigate the efficacy of dexamethasone as a prophylactic antiemetic for patients receiving fractionated radiotherapy to the upper abdomen in a randomized controlled trial. PATIENTS AND METHODS: One hundred fifty-four patients planned to receive fractionated radiotherapy to fields involving the upper abdomen (minimum total dose, 20 Gy; minimum number of fractions, five) were randomized to receive prophylactic dexamethasone (2 mg orally three times a day [tid], starting in the morning of first treatment and continuing until after their fifth treatment) or placebo. The primary end point of the study was the proportion of patients free from emesis during the study period. Secondary end points included a quality-of-life assessment using the core questionnaire of the European Organization for Research and Treatment of Cancer and side effects of dexamethasone therapy in this population of patients. RESULTS: Fifty-four (70%) out of 75 patients receiving dexamethasone had complete protection versus 37 (49%) out of 75 patients on placebo (P = .025). Most emetic episodes occurred during the initial phase of treatment. Although there was no difference in global quality of life between the two sets of patients, patients receiving dexamethasone had less nausea and vomiting and less loss of appetite but more insomnia. CONCLUSION: Dexamethasone 2 mg tid seems to be an effective prophylactic antiemetic in this situation. Side effects were acceptable, but there seemed to be no overall effect on global quality of life.
AS A TREATMENT modality, radiotherapy is effective for a variety of malignancies, whether given alone or in combination with either surgery or chemotherapy. Although the side effects of nausea and vomiting are usually less severe and less frequent with radiotherapy than with chemotherapy, these important complications can be distressing for the significant proportion of patients undergoing this type of therapy and, occasionally, can even lead to unplanned interruptions in radiation treatment. The likelihood that a patient receiving radiation therapy will experience nausea and vomiting has been difficult to quantify. However, a recent proposal has defined levels of emetogenicity for the various types of radiation treatment, and this has been used by the American Society of Clinical Oncology in defining guidelines for prophylaxis and treatment of radiation-induced emesis.1 For patients deemed to be at moderate risk of emesis during a course of fractionated radiation treatment, standard treatment is not well-defined. Most clinicians would not routinely use prophylactic agents for patients undergoing fractionated treatment and would reserve these antiemetics for rescue. However, in circumstances where there is a 30% to 60% risk of emesis, this may be unacceptable. Even if antiemetics are being used to prevent nausea and vomiting, the data are insufficient on which are the most appropriate agents. 5-hydroxytryptamine-3 (5-HT3) antagonists have been studied and have shown efficacy,2,3 but there is concern about the potential expense of using these drugs routinely in this situation. Dexamethasone has been well studied as an antiemetic for chemotherapy-induced emesis, but there are only anecdotal reports of efficacy in both the prevention and treatment of radiation-induced emesis.4 Because corticosteroids were felt to be potentially useful agents in this situation, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) undertook a phase III randomized study to assess the efficacy of dexamethasone in the prophylaxis of radiation-induced emesis. The trial aimed (1) to compare the efficacy of dexamethasone versus placebo in the prevention of radiation-induced nausea and emesis, (2) to assess the safety and tolerance of dexamethasone in a group of patients, (3) to evaluate the extent to which nausea and emesis affect global quality of life during the first week of radiotherapy, and (4) to see whether prophylactic antiemetic therapy would have a significant effect on quality of life in this situation.
Patients at least 18 years of age who were planned to receive fractionated radiation therapy to a field at least partially encompassing the upper abdomen, defined as a field size of at least 80 cm2 between the upper border of T11 and lower border of L3, were eligible for the study. These entry criteria were used because they closely resemble those used in the previously published phase III trials that examined the value of ondansetron for prevention of radiation-induced emesis in patients undergoing fractionated radiotherapy.2,3 According to the American Society of Clinical Oncology guidelines, this group of patients would fit in the category of moderate to high risk of radiation-induced emesis, and the use of prophylactic antiemetics would be recommended. However, at the time this trial was initiated in 1995, no such guidelines were in existence, and standard practice was not to use prophylaxis for this group of patients. Indeed, many clinicians still reserve antiemetics for treatment of symptoms rather than prevention. Patients were excluded from the study if they received any cytotoxic chemotherapy in the week before commencement of radiation therapy or during the first 7 days after the start of radiation therapy, if they were currently using any corticosteroid medication other than topical or inhaled preparations, if they had medical contraindications to corticosteroids (eg, diabetes mellitus or active peptic ulcer), or if they had taken any medication with antiemetic intent within 2 days before start of radiation therapy. Patients were stratified by dose per fraction ( < 2 Gy v > 2 Gy) and by field volume ( < 150 cm2 v > 150 cm2). All patients were given the study medication as well as rescue antiemetics. In this trial, the rescue drug was chosen to be prochlorperazine 10 mg, 4 to 6 hourly orally or rectally, as needed. All participants gave full informed consent and were allowed to withdraw from the study at any time. All patients underwent a full history and physical examination, including performance status evaluation, before entry onto the study, but no other routine investigations were mandated. The trial was designed as a multicenter, national, double-blind, randomized study. Patients were randomized to receive either dexamethasone 2 mg orally three times a day (tid) or placebo one tablet orally tid. Both medications were enclosed in identical capsules to ensure blinding. Patients received their first dose of study medication on the morning of their first radiotherapy fraction and continued to take the capsules until after they had received their fifth radiation treatment. Therefore, depending on the day of the week the patients started treatment, study medication was taken for 5 to 7 days. All patients were given diaries that were used to evaluate response and toxicity. Before the start of radiotherapy and at 24-hour intervals until the end of the study period, patients recorded the number of times they vomited or retched, their food intake, their degree of indigestion or heartburn, the severity of their nausea, and their level of anxiety. Patients also determined their satisfaction with study medication at 24-hour intervals until the end of the study period. They recorded consumption of both study and rescue medication as well as any other upsetting symptoms. In addition, all patients completed quality-of-life assessments. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30+1)5 plus a trial-specific nausea and vomiting checklist were completed by each patient before randomization, on the day of the first fraction before treatment (if the prerandomization questionnaire was completed more than 5 days before), on the day of the fifth fraction before treatment, and on day 15. The primary end point of the study was the proportion of patients free from emesis (vomiting or retching) during the first 4 fraction days. These data, together with other end points including severity of nausea, food intake, degree of indigestion or heart burn, anxiety, satisfaction of study medication, consumption of additional antiemetics, and patient-reported side effects, were documented by a patient self-administered daily diary.
Statistical Methods
Patient Population A total of 154 patients were entered onto the study from 11 centers across Canada. All patients had a good performance status (Eastern Cooperative Oncology Group 0 to 3) and experienced no nausea or vomiting in the week before entry on the study. Three patients had withdrawn before randomization because one patient refused because of concern over treatment side effects, another patient was hospitalized for progression of high-grade lymphoma before the start of radiotherapy, and another was feeling nauseated at baseline before randomization. Among the 151 randomized patients, 75 were randomized to receive dexamethasone and 76 to receive placebo; one patient was ineligible because insufficient field lay within the required borders. Demographic characteristics, details of the tumor sites treated, and treatment parameters are listed in Tables 1, 2, and 3, respectively. The intention was to include patients receiving both radical and palliative courses of treatment (usually of 4 to 6 weeks and 1 to 2 weeks duration, respectively); however, only 14% of patients entered received daily fractions of more than 2 Gy. Radical treatments almost always use fractions of 2 Gy or less, and this result indicates that only a small proportion of palliatively treated patients was represented.
There was only one protocol violation affecting the major end point (one patient with an inappropriate field size mentioned previously), and the analysis was performed on an intent-to-treat basis. There were four other protocol violations, but all of those were a result of the baseline quality-of-life questionnaires being completed after randomization but before treatment. Fifty-four (72%) out of 75 of the patients who received dexamethasone had complete protection against emesis compared with 37 (49.3%) out of 75 patients who received placebo (P = .025, adjusted for multiple testing using the method of the triangular test). If patients who experienced two episodes or less of radiotherapy-induced emesis are counted as having partial protection, then the rate of success in patients who received dexamethasone was 63 (84%) out of 75 compared with 53 (70.7%) out of 75 (P = .078). For the nausea and vomiting end point, we have only one missing data point from the placebo arm. We have performed analyses assuming missing data as success and failure, and both analyses have similar results. Only results assuming missing data as failure are reported here. Most of the emetic episodes occurred during the initial phases of treatment; the total number of emetic episodes on day 1 was 107 (43 in the dexamethasone arm and 64 in the placebo), whereas the average daily number of episodes over the remainder of the study period was 18.3 (13.2 in dexamethasone arm and 23.4 in placebo arm). All patients were issued with rescue medication, prochlorperazine 10 mg every 6 hours orally or rectally, with instructions to take it if they developed nausea and vomiting. Twenty-two patients took rescue medication after the first fraction, but only one patient took it after the fifth fraction. Fifty-three patients (71%) on the dexamethasone arm never required rescue medication compared with 43 patients (57%) on the placebo arm (P = .125).
Quality of Life
Of interest, in the 112 patients who received more than 10 fractions of radiotherapy (ie, over 2 weeks of treatment) and who completed quality-of-life questionnaires on day 15, there was no significant difference in any of the parameters between the two arms. Although there was no change in the nausea and vomiting scores of the quality-of-life assessments for patients in the dexamethasone arm from fifth fraction (mean score of 17.8) to day 15 (mean score of 18.5), there was a decrease in nausea and vomiting scores from the fifth fraction (mean score of 24.5) to day 15 (mean score of 19.5) for patients in the placebo arm who received 10 or more fractions of radiotherapy, although it was not statistically significant (P = .104).
Side Effects of Treatment Specific effects thought to be likely to occur as a result of administration of corticosteroids were included in the patient dairy and were recorded by the patient each day. Analysis of these data showed no significant differences between the two groups in terms of indigestion or heartburn, anxiety or nervousness, and satisfaction with antiemetic therapy. However, food intake on days 2 to 5 of the study period was significantly increased in the dexamethasone arm compared with the placebo arm (P = .02). There were no differences between other toxicities that were reported by patients, and, apart from one patient on the placebo arm who described grade 3 abdominal pain, there were no other toxicities greater than grade 2. All patients were asked on a daily basis about how satisfied they were with the medication given to prevent nausea and vomiting. There was no difference between the two groups. The mean satisfaction score for patients on the dexamethasone arm and placebo arm varied between 79% and 85% and between 73% and 79%, respectively, over days 1 to 5.
Most published information on the prophylaxis and treatment of radiation-induced emesis concerns patients receiving large single fractions for palliation or in situations using highly emetogenic radiotherapy, such as total-body irradiation. The vast majority of patients undergoing radiation treatment receive fractionated radiotherapy, often over several weeks. Although the overall risks of nausea and vomiting are less if radiation-induced emesis occurs in this situation, its effect can be prolonged and, if severe, can lead to breaks in treatment.6 Because there is evidence that prolongation of treatment times in radical radiation schemes may have a deleterious effect by allowing proliferation of the tumor during the treatment time,7 more effective control of this problem could represent a major step forward in the management of those patients at risk for this side effect. A number of medications are used both alone and in combination to prevent and treat radiation-induced emesis, and a survey of Canadian radiation oncologists performed before the initiation of this trial indicated that at least eight different drugs, used either alone or in combination, were being used as standard (Table 5). There has been recent interest in the effect of the 5-HT3 receptor antagonist drugs, such an ondansetron, in this setting, but other antiemetics have not been well-studied. The mechanism of action of corticosteroids such as dexamethasone in the prevention and treatment of radiation-induced emesis is not well-understood. However, corticosteroids seem to be highly effective in the treatment of both acute and delayed onset chemotherapy-induced nausea and vomiting,8 and several radiation oncologists use them for radiation-induced emesis (Table 5).
In this trial, a greater proportion of patients who received prophylactic dexamethasone had complete protection from radiation-induced emesis over the study period compared with patients receiving placebo. The complete protection rate of 72% is comparable with the 61% and 67% rates in patients who were receiving similar radiotherapy and were prescribed prophylactic ondansetron in the trials published by Priestman et al2 in 1993 and Franzen et al3 in 1996. However, it should be noticed that 49.3% of patients receiving placebo in this study also had complete protection, which compared with 35% of patients in the Priestman et al2 study who were given prophylactic prochlorperazine. This may suggest that the emetogenic potential of the radiation therapy in this trial was somewhat less than that of the British study, although the only difference was in allowing patients with a smaller field size to be entered. Nevertheless, the use of small field sizes was unusual, and 83% of all patients had a field area of more than 150 cms in diameter. In the Danish study,3 patients on the standard arm were given placebo as in this trial, and the complete protection rate for those patients was 45%. Although it is not possible to make direct comparisons between the efficacy of corticosteroids and 5-HT3 receptor antagonists in this situation, these results suggest that their efficacy may be similar. Although a formalized comparison of these agents could be undertaken, an alternative would be to see if they could act synergistically in combination. This approach has been used in patients receiving moderately emetogenic chemotherapy, where the two drugs seem to have similar responses when used alone9 but are more effective when used in combination.10,11 In this study, the trial intervention was used only for the first week of radiotherapy, even though some patients were receiving courses of up to 6 weeks duration. Despite this, it seems that there was little evidence of any rebound phenomenon after cessation of the study medication because the quality-of-life analysis performed on day 15 showed no increase in nausea or vomiting for patients who received dexamethasone but improved scores for those who had only received placebo. This and the fact that the majority of emetic episodes and consumption of rescue antiemetics occurred on the first day of treatment or shortly thereafter suggest that the main emetogenic stimulus in fractionated radiotherapy occurs early in treatment. Accordingly, prophylactic antiemetics may not need to be prescribed for a full course of radical treatment but only for the first week, or even less. There were concerns during the design of the study that the potential side effects from dexamethasone might outweigh any benefits seen in reducing emesis. This contributed to the use of a dosage scheduling of 2 mg tid rather than the higher doses used for chemotherapy. Nevertheless, there was no difference in the levels of anxiety, indigestion, nausea, and overall satisfaction between the two groups; in fact, food intake from days 2 to 5 was significantly better in the patients who received dexamethasone than in those who received placebo. The quality-of-life results indicate that, although there was no difference in global quality of life between the two arms, there was significantly more insomnia in patients who received corticosteroids. This should be kept in mind when prescribing dexamethasone as an antiemetic in this situation, and the use of night sedation should be considered. However, there seems to be little published literature in the benefits of this on patients with corticosteroid-induced sleep disturbance. However, the well-known side effect of increased appetite seemed to translate into an improvement in this domain of quality of life and may make the use of dexamethasone particularly applicable to patients receiving fractionated palliative radiotherapy who may have anorexia as a result of advanced or metastatic cancer. The results of this trial suggest that dexamethasone in the dose of 2 mg tid is an effective prophylactic antiemetic for patients receiving fractionated radiotherapy at moderate to high risk of radiation-induced emesis. In this study, the drug was only used for 1 week, and effects were only recorded for the first week of radiotherapy. Therefore, it is not possible to comment on whether the benefit of corticosteroids would be maintained over longer periods of time to patients receiving more protracted courses. It is also possible that the administration of significant doses of corticosteroids for several weeks would cause a high incidence of side effects directly related to the drugs. Therefore, one must be cautious about recommending the use of prophylactic dexamethasone for several weeks. However, these results suggest that most of the emesis in patients receiving fractionated radiotherapy to the abdomen occurs early on in treatment and that it may only be necessary to administer antiemetic prophylaxis for the initial few fractions (the nausea and vomiting scores of patients receiving placebo spontaneously improved between the fifth and fifteenth fractions of treatment). In addition, in the one published study looking at the prolonged administration of 5-HT3 receptor antagonists in this situation, the effectiveness of the antiemetic decreased after the first week of treatment.3 Therefore, we would recommend that the prevention and treatment of radiation-induced emesis for patients receiving protracted courses of radiotherapy needs further study. However, with the benefits demonstrated in this study, with no observed increase in significant side effects or adverse effects on overall quality of life, and with the known beneficial effects of corticosteroids on appetite and sense of well-being,12 dexamethasone might be the ideal prophylactic antiemetic in patients receiving fractionated palliative radiotherapy of moderate to high emetogenic potential. Examples of this would be patients receiving 5 or 10 fractions to the thoracolumbar spine for bone metastasis or patients receiving palliative radiotherapy for metastasis to paraaortic nodes. Both these populations were well-represented in the population studied in the current trial. Nevertheless, it is imperative that more studies need to be carried out in this area, particularly in evaluating the efficacy of corticosteroids, 5-HT3 receptor antagonists, or a combination of both. The recently proposed classification of levels of emetogenicity for various radiation treatment techniques should facilitate such studies by allowing trials to be performed on patients at similar levels of risk for radiation-induced emesis.
This study was coordinated by the Clinical Trials Group of the National Cancer Institute of Canada and participating investigators included: P.K. Ganguly, K.E. Hong, D. Panjwani (Dr H. Bliss Murphy Cancer Centre, St John’s, Newfoundland); P.K. Joseph, L.A. Mulroy, R.D.H. Rutledge, A. Sun (Nova Scotia Cancer Centre, Halifax, Nova Scotia); J. Carson, S.E. Kumar, M.Z. Abd-El-Malek (Saint John Regional Hospital, Saint John, New Brunswick); P. Cross, L. Eapen (Ottawa Regional Cancer Centre, Civic Division, Ottawa, Ontario); I. Ackerman, G. Morton, G. Thomas, R. Wong (Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario); A. Bezjak, J.D. Brierley, A. Fyles, M. Gospodarowicz, P. Kirkbride, W. Levin, L.A. Manchul, M. Milosevic, R. Tsang, P. Warde, W.A. Wells (Princess Margaret Hospital, Toronto, Ontario); A.R. Dar (London Regional Cancer Centre, London, Ontario); S. Gulavita (Thunder Bay Regional Cancer Centre, Thunder Bay, Ontario); A.D. Chowdhury, A.L. Cooke, P. Hahn, K. Jones, A.S. Leylek, S. El Sayed, K. Vijay (Manitoba Cancer Treatment and Research Foundation, Winnipeg, Manitoba); G. Dundas, R. Pearcey (Cross Cancer Institute, Edmonton, Ontario); P.A. Blood, H. Joe, and J. Lim (Vancouver Island Cancer Centre, Victoria, British Columbia, Canada).
1. Gralla RJ, Osoba D, Kris MG, et al: Recommendations for the use of antiemetics: Evidence-based, clinical practice guidelines. J Clin Oncol 17:2971-2994, 1999 2. 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. J Clin Oncol 5:358-363, 1993
3.
Franzen L, Nyman J, Hagberg H, et al: A randomized placebo controlled study with ondansetron in patients undergoing fractionated radiotherapy. Ann Oncol 7:587-592, 1996 4. Sagar SM: The current role of anti-emetic drugs in oncology: A recent revolution in patient symptom control. Rev 18:95-135, 1991
5.
Aaronson N: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 6. Fyles AW, Dembo AJ, Bush RS, et al: Analysis of complications in patients treated with abdomino-pelvic radiation therapy for ovarian carcinoma. Int J Radiat Oncol Biol Phys 22:847-851, 1992[Medline] 7. Withers HR, Taylor JMG, Maciejewski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27:98-113, 1988 8. Markman M, Scheider V, Ettinger DS: Antiemetic efficacy of dexamethasone. N Engl J Med 311:549-552, 1991[Abstract] 9. Jones AL, Hill AS, Soukop M, et al: Comparison of dexamethasone and ondansetron in the prophylaxis of emesis induced by moderately emetogenic chemotherapy. Lancet 338:483-487, 1991[Medline]
10.
The Italian Group: The Italian Group for Antiemetic Research: Dexamethasone, granisetron, or both for the prevention of nausea and vomiting during chemotherapy for cancer. N Engl J Med 332:1-5, 1995 11. Roila F, Tonato M, Cognetti F, et al: Prevention of cisplatin-induced emesis: A double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 9:675-678, 1991[Abstract] 12. Bruera E, Roca E, Cedaro L, et al: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep 69:751-754, 1985[Medline] Submitted January 6, 1999; accepted January 5, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
