Drugs 43 (Suppl, 3): 1-5, 1992 00 12-6667/92/0300-0001/$2.50/0 © Adis International Limited. All rights reserved. DRSUP3389
Methodology of Antiemetic Trials J. Gordon McVie l and Karel M. de BruijnI Cancer Research Campaign, London, England 2 Department of Clinical Research, Sandoz Pharma Ltd, Basel, Switzerland
Summary
Progress in antiemetic research dictates that clinical trials of antiemetic agents be conducted according to guidelines for Good Clinical Practice, as follows. Studies must be of a prospective, parallel-group design in which the. new treatment is compared with the existing best available treatment, after optimal dosage schedules for each have been established. Ethically, placebo-controlled trials can only be justified when chemotherapy with a low emetogenic potential is used. All end-points (nausea, vomiting, adverse events and quality of life parameters) must be specified in detail before the trial is begun. Patient populations must be homogenous with respect to prior chemotherapy and other confounding variables. Finally, patients must actively participate in the evaluation of antiemetic therapy, since only they can provide reliable information regarding the impact of nausea and vomiting on their quality of life.
5-Hydroxytryptamine type 3 (serotoninj) [5HT 3]-receptor antagonists have revolutionised the treatment of emesis induced by cancer chemotherapy. They have also profoundly influenced the methodology of antiemetic trials. As a result, emesis is clearly distinguished from nausea, and the debilitating effect of nausea has become the major target for further improvements in antiemetic care. The increased efficacy of aggressive chemotherapeutic regimens, particularly those containing cisplatin, has been partly offset by the problems with nausea and vomiting that they provoke. Various antiemetic agents were employed with modest success until Gralla et al. (1981) introduced a successful treatment with somewhat toxic doses of metoclopramide. Metoclopramide became the mainstay of antiemetic treatment and was often combined with other agents to enhance efficacy or to diminish its adverse effects. A variety of antiemetic regimens were claimed to be efficacious on the basis of small and some-
times uncontrolled clinical trials. General guidelines began to emerge for antiemetic treatment. Firstly, it is easier to prevent chemotherapy-induced nausea and vomiting than to alleviate it; thus, most emetogenic chemotherapy schedules now begin with the prophylactic administration of antiemetic drugs. Secondly, antiemetic treatment must completely inhibit nausea and vomiting so that anticipatory vomiting in later chemotherapy courses is prevented, i.e. activation of a positive feedback mechanism is avoided. Thirdly, the choice of the antiemetic treatment should depend on the emetogenic potential of the chemotherapy. Thus, highly emetogenic chemotherapy may sometimes justify prolonged treatment with dosages or combinations of antiemetic drugs that are known to produce side effects, while less emetogenic chemotherapy regimens need not. As well as adhering to the general principles of antiemetic treatment mentioned above, the development of the 5-HT3-receptor antagonists con-
Drugs 43 (Suppl. 3) 1992
2
formed to the requirements laid down in the guidelines for 'Good Clinical Practice'. This is a set of standards that encompasses adherence to the human rights declaration (including the obligation to obtain informed consent and not withhold effective treatment from patients) and that governs the design and execution of clinical studies. Requirements include proper randomisation, on-site monitoring, definition of efficacy end-points in advance and comparison with existing treatment or placebo. Although the basic principles of 'Good Clinical Practice' apply to all clinical studies, they are most strictly enforced by regulatory authorities in order to ensure the proper conduct of clinical studies that support a registration dossier. Differences in interpretation of some of the guidelines gave rise to discrepancies between the development programmes of the 5-HT3-receptor antagonists.
1. Evaluation of Efficacy When the clinical development of the 5-HT3receptor antagonists started, no uniform definitions existed for measuring the efficacy of antiemetic treatment. The term emesis is ambiguous, since it means either vomiting or the combination of vomiting and nausea, and the distinction between acute and delayed emesis was not always made. Consequently, terms like 'patient response' and 'control of emesis' can be misleading when used without further definition, since they do not unequivocally refer to vomiting alone, but may also include nausea. For example, the WHO scale for measuring nausea and vomiting ranges from 0 to 4, where 0 represents absence of emesis and 4 incapacitating emesis, but it does not distinguish between nausea and vomiting (WHO Handbook, 1979). So, during the development of all the 5-HT3receptor antagonists, control of vomiting was measured by counting the number of vomits. Control was then classified as total control (no vomits), major (l or 2 vomits), minor (up to 4 or 5 vomits) and failure (5 or more vomits). These criteria applied to the first 24 hours after the administration of the chemotherapy.
Owing to the subjective nature of nausea, its control cannot be graded as simply as can that of vomiting. Severity and duration are the parameters used to analyse nausea. The grading of intensity as mild, moderate or severe is often based on the degree of interference with normal daily activities. The limitations of this grading system become clear when trying to classify mild nausea that occurs at night and keeps the patient awake. Sometimes, the duration rather than the severity has been chosen as the criterion for classifying nausea. It has not always been specified whether acute or delayed nausea, or the combination of the 2 were considered when defining nausea control. When grading the severity of nausea, observers rely on reporting by patients. This method may be sufficient for evaluating nausea during a hospital stay, but it fails to represent accurately the patients' symptoms when they are at home. The retrospective collection of information can result in misrepresentations with regard to delayed nausea after highly emetogenic chemotherapy given on an outpatient or daycare basis. This is especiallytrue when a benzodiazepine with amnestic properties is part of the antiemetic treatment. In some studies, this problem has been remedied by asking the patients to record their symptoms in a diary or by contacting them daily at home. Such methods have highlighted how delayed nausea and vomiting adversely affect the quality of life of patients when they are no longer under direct observation. The ultimate aim of antiemetic treatment is to prevent all vomiting and all nausea in cancer patients treated with chemotherapy. Therefore, it would be useful to have a single outcome parameter for control of nausea and vomiting combined.
2. Study Design Randomised trials are important because they reduce the effects of investigator bias. A large sample size allows maximum power, minimum error and subset analysis. The selection of patients receiving highly emetogenic chemotherapy regimens
Methodology of Antiemetic Trials
meant that the 5-HT3-receptor antagonists had to be compared with the most effective antiemetic treatment available. Thus, the comparator treatment was based on high doses of metoclopramide, given either alone or in combination with corticosteroids, benzodiazepines or diphenhydramine, in order to enhance efficacy and mitigate the expected extrapyramidal side effects. If it is assumed that highly emetogenic chemotherapy regimens administered without antiemetic prophylaxis will produce nausea and vomiting in almost all patients, the efficacy of antiemetic therapy will be represented by the proportion of patients receiving that treatment who do not suffer from emesis after chemotherapy. This strategy has created some difficulties. The use of highly emetogenic chemotherapy virtually rules out the inclusion of placebo control groups, since in this situation it is unethical to withhold effective treatment. However, some regulatory authorities, notably the Food and Drug Administration, have not accepted this reasoning when evaluating new antiemetic drugs for registration and insist that placebo-controlled studies be done. They argue that it remains to be proven that, without antiemetic prophylaxis, the chemotherapy used in the studies does, indeed, produce emesis in almost all patients. Objections similar to those used against placebo-controlled studies are sometimes raised against dose-finding studies that aim to establish a partially effective or noneffective dose. Such objections are valid. Patients treated with a variety of cytotoxic drugs for their cancer should not be exposed to unnecessarily high doses of supportive treatment. For all new drugs, the optimal dose, i.e. the lowest dose that is fully effective and that does not produce intolerable adverse drug reactions, must be established. Dose-finding studies with the 5-HT3-receptor antagonists have included strict criteria for treatment failure, and rescue treatment has been given as soon as this has occurred. These studies have usually established a partially effective rather than a completely ineffective dose. The finding of a bell-shaped dose effect curve has been intriguing and if substantiated should be investigated further.
3
The natural course of chemotherapy-induced emesis is to worsen progressively with successive chemotherapy courses. Therefore, one cannot compare antiemetic efficacy in patients receiving de novo chemotherapy with results in patients who have been previously exposed to chemotherapy. Chemotherapy-naive patients may have better antiemetic control than those who have previously received chemotherapy. As a result of the progressive course of chemotherapy-induced emesis and the occasional development of psychosomatic anticipatory vomiting, antiemetic trials with a crossover design are particularly open to carryover effects and tend to favour the first antiemetic treatment of the sequence. In addition, studies involving patients with cancer are characterised by a high rate of premature discontinuation because of changes in the chemotherapy as a result of adverse effects or deterioration in the patients' condition during the course of cancer treatment. The choice ofa double-blind study design sometimes necessitates the use of a complicated dosage schedule for the 5-HT3-receptor antagonist in order to match the dosage, schedule of the comparator treatment. Thus, the schedules of 5-HT3-receptor antagonist administration in comparative treatment studies could vary from I to 4 doses a day to continuous infusion for 8 to 24 hours, matching the dosage schedule for metoclopramide. Metoclopramide monotherapy, however, is not the most effective treatment for chemotherapy-induced emesis, and during highly emetogenic chemotherapy antiemetic cocktails should be used. Matching an antiemetic treatment that needs to be given once a day [e.g. granisetron or tropisetron (Navoban'P, Novaban'Pj] with a cocktail requires such treatment to be supplemented with placebo injections and dummy drugs. This is very demanding for patients who are already undergoing aggressive chemotherapy, and the risk to immunocompromised patients of infections from multiple placebo injections is difficult to justify. In addition, it may be possible to identify the patients who have received an antiemetic cocktail because of the adverse effects that are often produced (such as sleepiness from benzodiazepines, restlessness and mus-
Drugs 43 (Suppl. 3) 1992
4
cular rigidity from metoclopramide, and facial flushing from corticosteroids), thus preventing the study from being truly double-blind. As a consequence, tropisetron has been compared with antiemetic cocktails in nonblind studies. Interestingly, some of the tropisetron studies show the efficacy of the antiemetic cocktails to be much better than expected on the basis of the published results to date, but the incidence of extrapyramidal side effects remains as described in the earlier reports (Gralla et al. 1981; Kris et al. 1983). The unexpectedly good efficacy of the standard treatment regimen underscores the value of prospective controlled trials for the evaluation of new drugs, even when a double-blind study design is impractical or impossible.
3. Recommendations for the Conduct of Antiemetic Clinical Trials On the basis of the experience described above, the following guidelines for the conduct of studies of antiemetic treatments would be appropriate: • The end-points of antiemetic studies should be clearly stated in advance and the definition of emesis control specified in detail. For efficacy testing, not only vomiting but also nausea should be considered. It needs to be clear whether the duration or the intensity of nausea, or the combination of both is to be examined. It no longer suffices to study only acute nausea and/or vomiting, and antiemetic treatment must be followed for more than 1 chemotherapy treatment course. Quality of life end-points are excellent if they are clearly defined and differentiated from side effects or symptoms of disease (Klein Poelhuis et al. 1987). • Antiemetic treatment is best evaluated in prospective parallel-group studies. A crossover design is unsuitable for the evaluation of antiemetic treatment. • For ethical reasons, no placebo-controlled studies can be performed in patients receiving highly emetogenic chemotherapy. • Metoclopramide monotherapy is insufficient
when highly emetogenic chemotherapy is given. Instead, antiemetic cocktails should be used as comparative treatment or the 5-HT3-receptor antagonists should be directly compared with each other. • Double-blind studies should only be performed after establishing the optimal dosage schedule of all treatments to be compared. • The prevention of chemotherapy-induced emesis needs to be studied separately from the treatment of patients who have previously experienced emesis. In view of the progressive course of chemotherapy-induced emesis, the best way of studying antiemetic treatment is to follow up patients who are new to chemotherapy for several courses, preferably without altering the chemotherapy dose. • Treatment groups in antiemetic studies should be balanced for confounding variables, such as cancer type, sex, age and emetogenicity of chemotherapy. • Patients should participate in evaluating the efficacy of the antiemetic treatment they receive. Ultimately, only patients can provide reliable information regarding the impact of nausea and vomiting on their quality of life.
4. Conclusion Progress in antiemetic treatment, especially that with the 5-HT3-receptorantagonists, combined with a systematic approach and definition of chemotherapy-induced emesis, should eradicate nausea and vomiting in patients treated with mildly or moderately emetogenic chemotherapy. Antiemetic research now faces the ultimate challenge: to prevent any chemotherapy regimen from inducing vomiting and nausea, in order to give the increasing numbers of patients with cancer an optimal quality of life.
References Gralla RJ, Itri LM, Pisko SE, Squillante AE, Kelsen DP, et al. Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and chlorproma-
Methodology of Antiemetic Trials
zine in patients with chemotherapy induced nausea and vomiting. New England Journal of Medicine 305: 905909, 1981 Klein Poelhuis EH, Hart AAM, Burgers JMV, Hermus RJJ, Bruning PF. Assessment of quality of life: scoring performance status in cancer patients. In Aaronson NK, Beckman J (Eds) The quality oflife in cancer patients, pp. 93-99, Raven Press, New York, 1987 Kris MG, Tyson LB, Gralla RJ, Clark RA, Allen JC, et aI. Extrapyramidal reactions with high-dose metoclo-
5
pramide. New England Journal of Medicine 309: 433434, 1983 WHO handbook for reporting results of cancer treatment. World Health Organization, Geneva, 1979
Correspondence and reprints: Prof. J. G. Mcvie, Scientific Director, Cancer Research Campaign, 2 Carlton House Terrace, London SWIY 5AR, England.
Methodology of Antiemetic Trials J. Gordon McVie l and Karel M. de BruijnI Cancer Research Campaign, London, England 2 Department of Clinical Research, Sandoz Pharma Ltd, Basel, Switzerland
Summary
Progress in antiemetic research dictates that clinical trials of antiemetic agents be conducted according to guidelines for Good Clinical Practice, as follows. Studies must be of a prospective, parallel-group design in which the. new treatment is compared with the existing best available treatment, after optimal dosage schedules for each have been established. Ethically, placebo-controlled trials can only be justified when chemotherapy with a low emetogenic potential is used. All end-points (nausea, vomiting, adverse events and quality of life parameters) must be specified in detail before the trial is begun. Patient populations must be homogenous with respect to prior chemotherapy and other confounding variables. Finally, patients must actively participate in the evaluation of antiemetic therapy, since only they can provide reliable information regarding the impact of nausea and vomiting on their quality of life.
5-Hydroxytryptamine type 3 (serotoninj) [5HT 3]-receptor antagonists have revolutionised the treatment of emesis induced by cancer chemotherapy. They have also profoundly influenced the methodology of antiemetic trials. As a result, emesis is clearly distinguished from nausea, and the debilitating effect of nausea has become the major target for further improvements in antiemetic care. The increased efficacy of aggressive chemotherapeutic regimens, particularly those containing cisplatin, has been partly offset by the problems with nausea and vomiting that they provoke. Various antiemetic agents were employed with modest success until Gralla et al. (1981) introduced a successful treatment with somewhat toxic doses of metoclopramide. Metoclopramide became the mainstay of antiemetic treatment and was often combined with other agents to enhance efficacy or to diminish its adverse effects. A variety of antiemetic regimens were claimed to be efficacious on the basis of small and some-
times uncontrolled clinical trials. General guidelines began to emerge for antiemetic treatment. Firstly, it is easier to prevent chemotherapy-induced nausea and vomiting than to alleviate it; thus, most emetogenic chemotherapy schedules now begin with the prophylactic administration of antiemetic drugs. Secondly, antiemetic treatment must completely inhibit nausea and vomiting so that anticipatory vomiting in later chemotherapy courses is prevented, i.e. activation of a positive feedback mechanism is avoided. Thirdly, the choice of the antiemetic treatment should depend on the emetogenic potential of the chemotherapy. Thus, highly emetogenic chemotherapy may sometimes justify prolonged treatment with dosages or combinations of antiemetic drugs that are known to produce side effects, while less emetogenic chemotherapy regimens need not. As well as adhering to the general principles of antiemetic treatment mentioned above, the development of the 5-HT3-receptor antagonists con-
Drugs 43 (Suppl. 3) 1992
2
formed to the requirements laid down in the guidelines for 'Good Clinical Practice'. This is a set of standards that encompasses adherence to the human rights declaration (including the obligation to obtain informed consent and not withhold effective treatment from patients) and that governs the design and execution of clinical studies. Requirements include proper randomisation, on-site monitoring, definition of efficacy end-points in advance and comparison with existing treatment or placebo. Although the basic principles of 'Good Clinical Practice' apply to all clinical studies, they are most strictly enforced by regulatory authorities in order to ensure the proper conduct of clinical studies that support a registration dossier. Differences in interpretation of some of the guidelines gave rise to discrepancies between the development programmes of the 5-HT3-receptor antagonists.
1. Evaluation of Efficacy When the clinical development of the 5-HT3receptor antagonists started, no uniform definitions existed for measuring the efficacy of antiemetic treatment. The term emesis is ambiguous, since it means either vomiting or the combination of vomiting and nausea, and the distinction between acute and delayed emesis was not always made. Consequently, terms like 'patient response' and 'control of emesis' can be misleading when used without further definition, since they do not unequivocally refer to vomiting alone, but may also include nausea. For example, the WHO scale for measuring nausea and vomiting ranges from 0 to 4, where 0 represents absence of emesis and 4 incapacitating emesis, but it does not distinguish between nausea and vomiting (WHO Handbook, 1979). So, during the development of all the 5-HT3receptor antagonists, control of vomiting was measured by counting the number of vomits. Control was then classified as total control (no vomits), major (l or 2 vomits), minor (up to 4 or 5 vomits) and failure (5 or more vomits). These criteria applied to the first 24 hours after the administration of the chemotherapy.
Owing to the subjective nature of nausea, its control cannot be graded as simply as can that of vomiting. Severity and duration are the parameters used to analyse nausea. The grading of intensity as mild, moderate or severe is often based on the degree of interference with normal daily activities. The limitations of this grading system become clear when trying to classify mild nausea that occurs at night and keeps the patient awake. Sometimes, the duration rather than the severity has been chosen as the criterion for classifying nausea. It has not always been specified whether acute or delayed nausea, or the combination of the 2 were considered when defining nausea control. When grading the severity of nausea, observers rely on reporting by patients. This method may be sufficient for evaluating nausea during a hospital stay, but it fails to represent accurately the patients' symptoms when they are at home. The retrospective collection of information can result in misrepresentations with regard to delayed nausea after highly emetogenic chemotherapy given on an outpatient or daycare basis. This is especiallytrue when a benzodiazepine with amnestic properties is part of the antiemetic treatment. In some studies, this problem has been remedied by asking the patients to record their symptoms in a diary or by contacting them daily at home. Such methods have highlighted how delayed nausea and vomiting adversely affect the quality of life of patients when they are no longer under direct observation. The ultimate aim of antiemetic treatment is to prevent all vomiting and all nausea in cancer patients treated with chemotherapy. Therefore, it would be useful to have a single outcome parameter for control of nausea and vomiting combined.
2. Study Design Randomised trials are important because they reduce the effects of investigator bias. A large sample size allows maximum power, minimum error and subset analysis. The selection of patients receiving highly emetogenic chemotherapy regimens
Methodology of Antiemetic Trials
meant that the 5-HT3-receptor antagonists had to be compared with the most effective antiemetic treatment available. Thus, the comparator treatment was based on high doses of metoclopramide, given either alone or in combination with corticosteroids, benzodiazepines or diphenhydramine, in order to enhance efficacy and mitigate the expected extrapyramidal side effects. If it is assumed that highly emetogenic chemotherapy regimens administered without antiemetic prophylaxis will produce nausea and vomiting in almost all patients, the efficacy of antiemetic therapy will be represented by the proportion of patients receiving that treatment who do not suffer from emesis after chemotherapy. This strategy has created some difficulties. The use of highly emetogenic chemotherapy virtually rules out the inclusion of placebo control groups, since in this situation it is unethical to withhold effective treatment. However, some regulatory authorities, notably the Food and Drug Administration, have not accepted this reasoning when evaluating new antiemetic drugs for registration and insist that placebo-controlled studies be done. They argue that it remains to be proven that, without antiemetic prophylaxis, the chemotherapy used in the studies does, indeed, produce emesis in almost all patients. Objections similar to those used against placebo-controlled studies are sometimes raised against dose-finding studies that aim to establish a partially effective or noneffective dose. Such objections are valid. Patients treated with a variety of cytotoxic drugs for their cancer should not be exposed to unnecessarily high doses of supportive treatment. For all new drugs, the optimal dose, i.e. the lowest dose that is fully effective and that does not produce intolerable adverse drug reactions, must be established. Dose-finding studies with the 5-HT3-receptor antagonists have included strict criteria for treatment failure, and rescue treatment has been given as soon as this has occurred. These studies have usually established a partially effective rather than a completely ineffective dose. The finding of a bell-shaped dose effect curve has been intriguing and if substantiated should be investigated further.
3
The natural course of chemotherapy-induced emesis is to worsen progressively with successive chemotherapy courses. Therefore, one cannot compare antiemetic efficacy in patients receiving de novo chemotherapy with results in patients who have been previously exposed to chemotherapy. Chemotherapy-naive patients may have better antiemetic control than those who have previously received chemotherapy. As a result of the progressive course of chemotherapy-induced emesis and the occasional development of psychosomatic anticipatory vomiting, antiemetic trials with a crossover design are particularly open to carryover effects and tend to favour the first antiemetic treatment of the sequence. In addition, studies involving patients with cancer are characterised by a high rate of premature discontinuation because of changes in the chemotherapy as a result of adverse effects or deterioration in the patients' condition during the course of cancer treatment. The choice ofa double-blind study design sometimes necessitates the use of a complicated dosage schedule for the 5-HT3-receptor antagonist in order to match the dosage, schedule of the comparator treatment. Thus, the schedules of 5-HT3-receptor antagonist administration in comparative treatment studies could vary from I to 4 doses a day to continuous infusion for 8 to 24 hours, matching the dosage schedule for metoclopramide. Metoclopramide monotherapy, however, is not the most effective treatment for chemotherapy-induced emesis, and during highly emetogenic chemotherapy antiemetic cocktails should be used. Matching an antiemetic treatment that needs to be given once a day [e.g. granisetron or tropisetron (Navoban'P, Novaban'Pj] with a cocktail requires such treatment to be supplemented with placebo injections and dummy drugs. This is very demanding for patients who are already undergoing aggressive chemotherapy, and the risk to immunocompromised patients of infections from multiple placebo injections is difficult to justify. In addition, it may be possible to identify the patients who have received an antiemetic cocktail because of the adverse effects that are often produced (such as sleepiness from benzodiazepines, restlessness and mus-
Drugs 43 (Suppl. 3) 1992
4
cular rigidity from metoclopramide, and facial flushing from corticosteroids), thus preventing the study from being truly double-blind. As a consequence, tropisetron has been compared with antiemetic cocktails in nonblind studies. Interestingly, some of the tropisetron studies show the efficacy of the antiemetic cocktails to be much better than expected on the basis of the published results to date, but the incidence of extrapyramidal side effects remains as described in the earlier reports (Gralla et al. 1981; Kris et al. 1983). The unexpectedly good efficacy of the standard treatment regimen underscores the value of prospective controlled trials for the evaluation of new drugs, even when a double-blind study design is impractical or impossible.
3. Recommendations for the Conduct of Antiemetic Clinical Trials On the basis of the experience described above, the following guidelines for the conduct of studies of antiemetic treatments would be appropriate: • The end-points of antiemetic studies should be clearly stated in advance and the definition of emesis control specified in detail. For efficacy testing, not only vomiting but also nausea should be considered. It needs to be clear whether the duration or the intensity of nausea, or the combination of both is to be examined. It no longer suffices to study only acute nausea and/or vomiting, and antiemetic treatment must be followed for more than 1 chemotherapy treatment course. Quality of life end-points are excellent if they are clearly defined and differentiated from side effects or symptoms of disease (Klein Poelhuis et al. 1987). • Antiemetic treatment is best evaluated in prospective parallel-group studies. A crossover design is unsuitable for the evaluation of antiemetic treatment. • For ethical reasons, no placebo-controlled studies can be performed in patients receiving highly emetogenic chemotherapy. • Metoclopramide monotherapy is insufficient
when highly emetogenic chemotherapy is given. Instead, antiemetic cocktails should be used as comparative treatment or the 5-HT3-receptor antagonists should be directly compared with each other. • Double-blind studies should only be performed after establishing the optimal dosage schedule of all treatments to be compared. • The prevention of chemotherapy-induced emesis needs to be studied separately from the treatment of patients who have previously experienced emesis. In view of the progressive course of chemotherapy-induced emesis, the best way of studying antiemetic treatment is to follow up patients who are new to chemotherapy for several courses, preferably without altering the chemotherapy dose. • Treatment groups in antiemetic studies should be balanced for confounding variables, such as cancer type, sex, age and emetogenicity of chemotherapy. • Patients should participate in evaluating the efficacy of the antiemetic treatment they receive. Ultimately, only patients can provide reliable information regarding the impact of nausea and vomiting on their quality of life.
4. Conclusion Progress in antiemetic treatment, especially that with the 5-HT3-receptorantagonists, combined with a systematic approach and definition of chemotherapy-induced emesis, should eradicate nausea and vomiting in patients treated with mildly or moderately emetogenic chemotherapy. Antiemetic research now faces the ultimate challenge: to prevent any chemotherapy regimen from inducing vomiting and nausea, in order to give the increasing numbers of patients with cancer an optimal quality of life.
References Gralla RJ, Itri LM, Pisko SE, Squillante AE, Kelsen DP, et al. Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and chlorproma-
Methodology of Antiemetic Trials
zine in patients with chemotherapy induced nausea and vomiting. New England Journal of Medicine 305: 905909, 1981 Klein Poelhuis EH, Hart AAM, Burgers JMV, Hermus RJJ, Bruning PF. Assessment of quality of life: scoring performance status in cancer patients. In Aaronson NK, Beckman J (Eds) The quality oflife in cancer patients, pp. 93-99, Raven Press, New York, 1987 Kris MG, Tyson LB, Gralla RJ, Clark RA, Allen JC, et aI. Extrapyramidal reactions with high-dose metoclo-
5
pramide. New England Journal of Medicine 309: 433434, 1983 WHO handbook for reporting results of cancer treatment. World Health Organization, Geneva, 1979
Correspondence and reprints: Prof. J. G. Mcvie, Scientific Director, Cancer Research Campaign, 2 Carlton House Terrace, London SWIY 5AR, England.
