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Support Care Cancer (2005) 13: 80–84 DOI 10.1007/s00520-004-0718-y Steven M. Grunberg David Osoba Paul J. Hesketh Richard J. Gralla Sussanne Borjeson Bernardo L. Rapoport Andreas du Bois Maurizio Tonato Received: 17 August 2004 Accepted: 26 August 2004 Published online: 14 December 2004 # Springer-Verlag 2004 S. M. Grunberg University of Vermont, Burlington, VT, USA REVIEW ARTICLE Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity—an update S. M. Grunberg (*) Division of Hematology/Oncology, Fletcher Allen Health Care, UHC Campus/St. Joseph 3400, 1 South Prospect Street, Burlington, Vermont, 05401, USA e-mail: [email protected] Tel.: +1-802-8470770 Fax: +1-802-8475946 D. Osoba QOL Consulting, West Vancouver, BC, Canada P. J. Hesketh St. Elizabeth’s Medical Center, Boston, MA, USA R. J. Gralla New York Lung Cancer Alliance, New York, NY, USA S. Borjeson Division of Nursing Science, Linkoping University, Linkoping, Sweden B. L. Rapoport The Medical Oncology Centre of Rosebank, Johannesburg, South Africa A. du Bois Dr Horst-Schmidt-Kliniken, Wiesbaden, Germany M. Tonato Policlinico Monteluce, Perugia, Italy Abstract Development of effective antiemetic therapy depends upon an understanding of both the antiemetic agents and the emetogenic challenges these agents are designed to address. New potential antiemetic agents should be studied in an orderly manner, proceeding from phase I to phase II open-label trials and then to randomized double-blind phase III trials comparing new agents and regimens to best standard therapy. Use of placebos in place of antiemetic therapy against highly or moderately emetogenic chemotherapy is unacceptable. Nausea and vomiting should be evaluated separately and for both the acute and delayed periods. Defining the emetogenicity of new antineoplastic agents is a challenge, since such data are often not reliably Evaluating new antiemetic agents New antiemetic drug development should follow an orderly and logical progression beginning with open-label phase I/II tolerance and dose-finding trials and progressing recorded during early drug development. A four-level classification system is proposed for emetogenicity of intravenous antineoplastic agents. A separate four-level classification system for emetogenicity of oral antineoplastic agents, which are often given over an extended period of time, is also proposed. Keywords Antiemetic . Emetogenicity . Emesis . Nausea . Classification through phase III comparative trials (Table 1). Appropriate candidates for phase I trials are normal volunteers or cancer patients for whom prior conventional antiemetic treatments have failed. In this type of trial efficacy parameters are important, but clearly secondary to toxicity assess- 81 Table 1 Recommendations on evaluation of new agents 1. Phase I/II trials should always precede phase III trials Level of consensus—High Confidence level—High 2. Phase I/II trials should define minimal fully effective dose Level of consensus—High Confidence level—High 3. Phase III trials should employ a double-blind, randomized parallel design Level of consensus—High Confidence level—High 4. Phase III trials should use best available treatment as comparator Level of consensus—High Confidence level—High 5. Placebo comparators are not appropriate for trials against acute or delayed emesis with chemotherapeutic agents for which there is a significant emetic risk Level of consensus—High Confidence level—High ments. After successful completion of phase I trials, phase II trials should be completed to confirm antiemetic efficacy and define minimal fully effective doses. If substantial efficacy has been noted in initial studies, then appropriate populations for study may include chemotherapy-naive patients receiving moderately to highly emetogenic chemotherapy. Phase III trials should be initiated only after completion of phase I/II trials. A prerandomization stratification for important prognostic variables such as gender and ethanol consumption should be considered unless a large sample population of patients is enrolled in the study and the impact of prognostic factors can be analyzed by a multifactorial analysis at the end of the study. Other patient characteristics such as increased fatigue, low social functioning, and pre-existing nausea may also be of importance [13]. A randomized, parallel double-blind study is the preferred design for comparative trials. The comparator arm should contain the current best available treatment. If efficacy results of phase II trials are sufficiently compelling, then the new agent can be compared as a single agent against the best available therapy. An acceptable alternative design is to combine the new agent with the current best standard and compare it with the current best standard combined with placebo. Treatment with antiemetic placebos alone is no longer acceptable with chemotherapies known to induce emesis in most patients. This includes the evaluation of acute or delayed emesis in patients receiving moderately or highly emetogenic chemotherapy. If a placebo treatment is employed for other antiemetic trials, there should be zero tolerance for the development of breakthrough emesis or nausea, with immediate rescue of patients developing symptoms. A key element in new agent and new regimen evaluation is a careful assessment of the side effect profile. This includes objectively measurable side effects, such as changes in vital signs, blood chemistries, electrocardiograms or physical examination. In addition, subjectively measurable side effects, such as headache, akathisia, sedation, and diarrhea, should also be assessed. Typically these effects are measured by their presence or absence and then with a categorical rating by the patient (mild, moderate or severe effects). An ongoing challenge in the evaluation of the side effects of new agents is separating the adverse effects of the antiemetics from those of the chemotherapy, symptoms of malignancy, intercurrent illnesses or concomitant medications. Defining chemotherapy emetogenicity Defining the emetogenicity of chemotherapy agents is of value for at least two important reasons. First, such a classification can be used as a framework for defining antiemetic treatment guidelines. Second, it can provide a means for clinical investigators to attain a more precise definition of the emetogenic challenge that is being employed in an antiemetic trial. A useful schema would provide enough information to be utilized for both of these purposes. At present there is no commonly accepted schema for classifying the emetogenicity of cancer chemotherapy agents or combinations. A number of schemas have been proposed in which chemotherapy agents have been divided among three to five emetogenic levels [1, 4, 9, 10, 15]. The literature has been a very limited source of useful information in the development of these schemas, given the imprecise, inconsistent and extremely limited ways in which information on emesis and nausea has been recorded in most therapeutic trials. Most schemas have not differentiated between the various types of emesis, such as acute, delayed and anticipatory, and few have accounted for important treatment- and patient-related variables, such as chemotherapy dose, rate and route of administration, gender, age, and history of ethanol consumption [5, 7]. A new problem in emetic assessment is the growing use of extended oral administration of cytotoxic agents [11, 12, 14, 16] and targeted biologic agents [2, 3]. The distinction between acute and delayed emesis loses significance when an agent is given orally over a period of several days or weeks. The tendency of even experienced physicians and nurses to underestimate the incidence of emesis that occurs in the days after the patient has left the clinic and is no longer under direct observation [6] may also contribute to the erroneous assumption that such agents are only minimally emetogenic. Careful follow-up and careful observation of overall emetogenicity may therefore become the only valid method of assessment for such agents. 82 Hesketh et al. have proposed a classification system for acute emesis that accounts for chemotherapy dose and standardizes the rate and route of chemotherapy administration [8]. Chemotherapy agents were divided into five levels according to the expected frequency of emesis in the absence of effective antiemetic prophylaxis. Given the paucity of objective data in the literature, however, this schema, like others proposed earlier, reflects primarily the opinions of the authors and is thus potentially open to some of the criticisms that have been directed at prior schemas. At present, no single schema addresses all of the important issues that must be taken into account in creating a definitive emetogenic classification system, and further work should be carried out on this important issue (Table 2). Overall a system that emphasizes classification according to intrinsic emetogenicity (emetogenicity without concomitant antiemetic therapy) is favored, with the recognition of certain limitations. Some chemotherapeutic agents, such as the taxanes and pemetrexed, require concomitant use of corticosteroids for safe administration, and evaluation of baseline emetogenicity must take use of this necessary combination into account. It is also recognized that combination chemotherapy regimens may have a greater emetogenic potential than any single included agent. Cyclophosphamide and doxorubicin, for example, are each moderately emetogenic, but the combination of these agents is considered to be highly emetogenic. However, no prospectively validated or generally accepted algorithm has been devised for calculating the expected emetogenicity of combination regimens. One potential area in which new information can be obtained relates to the emetogenic potential of new antineoplastic agents. During the initial phase I and phase II evaluation process of a new antineoplastic agent, there is a Table 2 therapy unique opportunity to obtain definitive information on the emetogenic potential and pattern of emesis in the absence of routine antiemetic treatment. However, early clinical trials often do not restrict antiemetic use and reports of such trials of new cytotoxic and biologic agents seldom describe whether concomitant antiemetic agents were given. It is suggested that prophylactic antiemetic agents not be routinely used in initial trials of new agents unless Table 3 Emetogenic potential of single intravenous antineoplasticagents Degree of emetogenicity (incidence) Agent High (>90%) Cisplatin Mechlorethamine Streptozotocin Cyclophosphamide ≥1500 mg/m2 Carmustine Dacarbazine Oxaliplatin Cytarabine >1 g/m2 Carboplatin Ifosfamide Cyclophosphamide <1500 mg/m2 Doxorubicin Daunorubicin Epirubicin Idarubicin Irinotecan Paclitaxel Docetaxel Mitoxantrone Topotecan Etoposide Pemetrexed Methotrexate Mitomycin Gemcitabine Cytarabine ≤100 mg/m2 5-Fluorouracil Bortezomib Cetuximab Trastuzumab Bleomycin Busulfan 2-Chlorodeoxyadenosine Fludarabine Vinblastine Vincristine Vinorelbine Bevacizumab Moderate (30–90%) Low (10–30%) Recommendations on defining emetogenicity of chemo- 1. Emetic potential and pattern of emesis should be rigorously assessed during clinical development of new antineoplastic agents Level of consensus—High Confidence level—High 2. A comprehensive schema for classifying antineoplastic agent emetogenicity incorporating all important treatment and patient related prognostic variables should be developed Level of consensus—High Confidence level—High 3. Descriptive classifications based upon clinical databases of homogeneously treated patients should be developed and enhanced Level of consensus—High Confidence level—Moderate 4. Working schema for use in defining emetogenicity of intravenous and oral antineoplastic agents are proposed Level of consensus—Moderate Confidence level—Low Minimal (<10%) 83 Table 4 Emetogenic potential of single oral antineoplasticagents Degree of emetogenicity (incidence) Agent High (>90%) Hexamethylmelamine Procarbazine Cyclophosphamide Etoposide Temozolomide Vinorelbine Imatinib Capecitabine Fludarabine Chlorambucil Hydroxyurea L -Phenylalanine mustard 6-Thioguanine Methotrexate Gefitinib Moderate (30–90%) Low (10–30%) Minimal (<10%) the existence of significant emetic risk has been established through clinical experience with the investigational agent or through prior experience with similar standard agents. It is also suggested that the existence and intensity of nausea and vomiting be recorded using standard antiemetic methodology rather than the less informative Common Toxicity Criteria. Several other methods of defining chemotherapy emetogenicity have been proposed. Analysis of large databases in which information on emesis has been prospectively recorded and antiemetic prophylaxis was uniform could provide information on residual emetogenicity and potentially permit gender and other important prognostic variables to be taken into account. However, it is controversial whether emetogenicity of specific antineoplastic agents should be solely classified with, rather than without, the use of state-of-the-art antiemetic agents as a practical clinical guide. Such a classification schema would markedly change with the introduction of each new anti- emetic agent or antiemetic strategy and would not provide valuable information on intrinsic emetogenicity. The validity of such a schema for combination chemotherapy would be further compromised by the numerous doses and schedules under which the “same” combination regimen can be given and by the confounding effects on emetogenicity of the demographic characteristics of the specific patient populations for which different combination regimens are designed or used. Recognition of the common phase III clinical trial design in which established antineoplastic agents or combinations are administered with or without a new antineoplastic agent has also led to the concept of differential emetogenicity, by which the intrinsic emetogenicity of the new agent would be estimated as the difference between the observed emetogenicity of the two study arms. However, there is significant concern that such an estimate would be heavily dependent on the emetogenicity of the baseline standard regimen itself. For example, addition of a moderately emetogenic investigational agent to a regimen that is already highly emetogenic would add little to the overall emetogenicity of the combination and could lead to marked underestimation of the intrinsic emetogenicity of the new agent. Despite the limitations of the emetogenic classification schemas proposed to date, there is still a need to agree upon a working schema that can be employed for treatment recommendations and for defining the emetogenic challenge in clinical trials. For this purpose, a modification of the schema of Hesketh et al. [8] based on intrinsic emetogenicity of single agents is proposed. Intravenous chemotherapy agents are listed with division across four broad emetogenic groups: high, moderate, low, and minimal (Table 3). A separate listing of oral agents is also proposed (Table 4). 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