Progress in reducing anticipatory nausea and vomiting: a study of community practice.
Morrow GR. Roscoe JA. Hynes HE. Flynn PJ. Pierce HI. Burish T.
URCC CCOP Research Base, Behavioral Medicine Unit, University of Rochester Medical Center, NY 14642, USA.
Chemotherapy-related nausea and vomiting (NV) in 300 consecutive patients treated in community practices prior to the availability of 5-HT3 antiemetics (9/87 to 1/91) were compared with NV in a second sample of 300 patients treated after their commercial introduction (9/93 to 2/95). Eighty-six percent of the later patients received 5-HT3 antiemetics, and significantly fewer (43.3%) reported one or more episodes of posttreatment vomiting during their first four cycles of chemotherapy compared with those in the previous sample (55.0%: P < .01). Identical numbers of both groups (79.3%) reported at least one episode of posttreatment nausea. A significant increase in the average duration of both posttreatment nausea (from 28.1 h to 37.2 h; P = 0.001) and posttreatment vomiting (from 10.9 h-16.5 h, P = .02) was found; no significant differences were seen in the reported severity of either symptom. The proportion of patients experiencing at least one episode of anticipatory nausea (31.0% vs 32.0%) or anticipatory vomiting (7.7% vs 6.3%) did not differ significantly (P > 0.5) between groups, nor were there significant differences in the duration or severity of anticipatory symptoms (P > 0.4 for all comparisons). The reduction in the frequency of posttreatment vomiting supports research findings of efficacy. Findings of an increase in duration of posttreatment nausea and emesis and no change in the frequency of posttreatment nausea or in anticipatory symptoms show a continuing need for progress in control of posttreatment emesis and emphasize the need for further research on the control of chemotherapy-induced nausea.
Randomized, double-blind comparison of granisetron versus granisetron plus prednisolone as antiemetic prophylaxis during multiple-day cisplatin-based chemotherapy.
Handberg J. Wessel V. Larsen L. Herrstedt J. Hansen HH.
Finsen Center, Department of Oncology, Rigshospitalet, University of Copenhagen, Denmark.
Ninety chemotherapy-naive cancer patients receiving cisplatin-based (> or = 50 mg/m2) chemotherapy participated in a randomized, double-blind, cross-over study comparing the safety and efficacy of granisetron (GRA) versus granisetron plus prednisolone (GRA + PRE). All patients received i.v. granisetron 3 mg and were randomly allocated to oral prednisolone 50 mg or placebo prior to chemotherapy. At the subsequent cycle of chemotherapy, patients were crossed over to the other antiemetic treatment. A complete response, defined as no emetic episodes and no worse than mild nausea, was obtained in 63% in the GRA group and in 79% of the patients in the GRA + PRE group day 1 (P = 0.013). Complete response rates on days 1-3 were 16% vs 27% (P = 0.251). Significantly less nausea and vomiting was seen with the combination in the first 24 h after cisplatin (P = 0.001 and P = 0.0003) and during days 1-3 (P = 0.005 and 0.044). Patient preference was 51.5% for the combination and 26.5% for granisetron alone, whereas 22% had no preference (P = 0.0270). Adverse reactions were mild and comparable; headache and constipation were the ones most frequently reported. Prednisolone significantly improves the antiemetic effect of granisetron in patients receiving cisplatin-based chemotherapy, but the study also emphasizes the poor complete protection rate in patients receiving multiple-day cisplatin-based chemotherapy.
Neuropharmacology of emesis and its relevance to anti-emetic therapy. Consensus and controversies.
Andrews PL. Naylor RJ. Joss RA.
Department of Physiology, St. George's Hospital Medical School, Tooting, London, UK.
Recent great advances in the neuropharmacology of the emetic pathways have led to better therapy and improved insight into pathophysiological processes in patients undergoing chemo- and radiotherapy. This article gives an overview of the area, outlines current controversies and makes recommendations for future clinical studies.
Corticosteroids, dopamine antagonists and other drugs.
Herrstedt J. Aapro MS. Smyth JF. Del Favero A.
Department of Oncology R, Copenhagen University Hospital Herlev, Herlev Ringvej, Denmark.
The literature on corticosteroids, dopamine antagonists and other antiemetics, such as cannabinoids and benzodiazepines. was reviewed and presented at a consensus conference on antiemetics. Based on the reviews and the discussion during the conference, guidelines for the use of these agents are given.
Optimal selection of antiemetics in children receiving cancer chemotherapy.
Roila F. Aapro M. Stewart A.
Medical Oncology Division, Policlinico Hospital, Perugia, Italy.
Only a few studies have been carried out specifically on the prevention of nausea and vomiting in children receiving chemotherapy. In these patients older antiemetic drugs such as metoclopramide and phenothiazines had moderate efficacy and induced significant side effects, especially marked sedation and extrapyramidal reactions. In comparative trials the 5-HT3 receptor antagonists have shown better efficacy and tolerability than chlorpromazine or metoclopramide combined with dexamethasone. The combination of a 5-HT3 receptor antagonist plus dexamethasone is superior to a 5-HT3 receptor antagonist alone and should be the standard antiemetic prophylaxis in all paediatric patients receiving highly or moderately emetogenic chemotherapy. The optimal dose and scheduling of these antiemetic drugs need to be studied, as well as the antiemetic efficacy, in the prevention of chemotherapy-induced delayed and anticipatory emesis in children.
Methodology of antiemetic trials: response assessment, evaluation of new agents and definition of chemotherapy emetogenicity.
Hesketh PJ. Gralla RJ. du Bois A. Tonato M.
Section of Medical Oncology, St. Elizabeth's Medical Center, Boston, MA 02135, USA.
Establishing appropriate and practical methodology is a key to progress in the investigation of chemotherapy-induced nausea and vomiting. Critical issues include patient response assessment, proper trial design for evaluating new agents, and the definition of chemotherapy emetogenicity. In assessing antiemetic response, the primary end-point should be complete control of emesis and nausea. Emesis and nausea should be independently assessed with the period of observation defined (acute, delayed, anticipatory). Emesis can be evaluated by measuring the number of emetic episodes either by direct observation or by patient self-report using patient-completed diaries. Nausea should be measured by patient self-report with the standard parameters, including frequency and intensity. New antiemetic drug development should proceed in an orderly progression from open-label phase I-II trials defining tolerance and minimally fully effective dose to phase III comparative trials. A randomized, parallel, double-blind study is the preferred design for the latter, and the comparator arm should always include the current best available treatment. Antiemetic placebos are no longer acceptable with chemotherapy regimens known to produce emesis in a majority of patients. None of the emetogenic classifications proposed to date adequately accounts for all known important patient- and treatment-related prognostic variables. A modification of a recently reported schema is proposed for use in making antiemetic treatment recommendations and defining the emetogenic challenge in clinical trials.
Delayed emesis following anticancer chemotherapy.
Kris MG. Roila F. De Mulder PH. Marty M.
Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, New York, USA.
Delayed emesis is a distinct syndrome where vomiting begins or persists 24 or more hours after chemotherapy. It is more likely to occur when the stimulus for emesis is strong and/or acute vomiting is poorly controlled. The pathophysiology appears different than that which causes acute emesis. The literature reporting clinical trials to prevent delayed nausea and vomiting are presented. The best ways of preventing delayed emesis following anticancer chemotherapy are discussed.
Antiemetic strategies for high-dose chemoradiotherapy-induced nausea and vomiting.
Spitzer TR. Grunberg SM. Dicato MA.
Bone Marrow Transplant Program, Department of Medicine, Massachusetts General Hospital, Boston 02114, USA.
The treatment of nausea and vomiting in patients receiving high doses of irradiation and/or chemotherapeutic agents as preparation for hematopoietic stem cell transplantation is discussed. Such patients have very high rates of both early and delayed emesis. Based on the available evidence it is recommended that 5-HT3 receptor antagonists be used to combat emesis in this setting. Continued research is also required to define the optimal antiemetic strategy for these patients.
Consensus proposal for 5HT3 antagonists in the prevention of acute emesis related to highly emetogenic chemotherapy. Dose, schedule, and route of administration.
Gandara DR. Roila F. Warr D. Edelman MJ. Perez EA. Gralla RJ.
U.C. Davis Cancer Center, Sacramento, CA 95817, USA.
Selective antagonists to the Type 3 serotonin receptor (5HT3) in combination with corticosteroids are now considered the standard of care for the prevention of emesis from moderately to highly emetogenic chemotherapy. Here we address issues of optimal dose, schedule and route of administration of four currently available selectable 5HT3 antagonists. This paper utilizes an evidence based medicine approach to the literature regarding this class of drugs, emphasizing the results large, randomized, controlled trials to make formal recommendations concerning optimal use of this important new class of anti-emetic agents. We conclude that for each drug there is a plateau in therapeutic efficacy at a definable dose level above which further dose escalation does not improve outcome. Furthermore, a single dose is as effective as multiple doses or continuous infusion, and finally, emerging data demonstrate that the oral route is equally efficacious as the intravenous route of administration, even with highly emetogenic chemotherapy.
Consensus regarding multiple day and rescue antiemetic therapy.
De Mulder PH. Roila F. Kris MG. Marty MM.
Department of Medical Oncology, University Hospital Nijmegen, The Netherlands.
Different forms of moderately and highly emetogenic cancer chemotherapy that are administered over several days per cycle are discussed with reference to the most efficacious antiemetic therapy. Both preventive and rescue antiemetic therapy are considered.
Aetiology and prevention of emesis induced by radiotherapy.
Feyer PC. Stewart AL. Titlbach OJ.
Department of Radiotherapy, Medical School Charite, Humboldt University Berlin, Germany. Petra.Feyer@rz.hu-berlin.de
The introduction of new antiemetics has resulted in renewed interest in the aetiology and control of radiation induced emesis. Studies both with fractionated treatment and with high-dose single exposures have clearly demonstrated the value of the 5HT3 receptor antagonist antiemetics. This paper reviews the selection of optimal antiemetics.
Statistical considerations in the design, conduct and analyses of antiemetic clinical trials. An emerging consensus.
Morrow GR. Ballatori E. Groshen S. Olver I.
University of Rochester Cancer Center, NY, USA.
Various aspects of trial design and planning for clinical testing of antiemetic therapies administered to cancer patients are considered. It is generally felt that a randomized double-blind parallel-arm design is the best. Ways of achieving adequate power of such studies are discussed briefly, as is the need for previous identification of primary and secondary end-points. Finally, summary recommendations are given.
The antiemetic efficacy of granisetron plus dexamethasone, haloperidol and loracepam in breast cancer patients treated with high-dose chemotherapy with peripheral blood stem-cell support.
Climent MA. Palau J. Ruiz A. Soriano V. Aznar E. Olmos T. Guillem V.
Servicio Oncologia Medica, Instituto Valenciano de Oncologia, Valencia, Spain.
There has recently been a marked trend to increasing dose intensity in cancer chemotherapy, with or without peripheral blood stem-cell support, which has been associated with a higher frequency of nausea and vomiting. Antiemetic treatment in this setting has not been extensively analysed. From October 1995 to January 1997, prevention of emesis with granisetron 3 mg/12 h i.v., dexamethasone 12 mg/24 h i.v., haloperidol 0.5 mg/12 h p.o., and loracepam I mg/24 h p.o. was instituted in 30 breast cancer patients treated with high-dose chemotherapy (a 4-day intravenous continuous infusion of cyclophosphamide 1500 mg/m2 per day, thio-TEPA 125 mg/m2 per day and carboplatin 200 mg/m2 per day).A total of 30% of the patients (9/30) obtained complete or major protection on the 4 days of chemotherapy treatment (96.7% (29/30) on day 1, 86.7% (26/30) on day 2, 70% (21/30) on day 3, and 50% (15/30) on day 4). On the days following chemotherapy, 46.7% (14/30) presented fewer than two emetic episodes on day 5, 70% (21/30) on day 6, 83.4% (25/30) on day 7 and, 93.3% (28/30) on day 8. This energic antiemetic combination treatment has hardly any effect in the prevention of emesis, providing complete or major protection of 30% for the 4 days of chemotherapy treatment. Further investigation aimed at improving antiemetic treatment results is necessary.