Defining the Emetogenicity of Cancer Chemotherapy Regimens: Relevance to Clinical Practice

Defining the Emetogenicity of Cancer Chemotherapy Regimens: Relevance to Clinical Practice PAUL J. HESKETH St. Elizabeth s Medical Center, Boston, Massachusetts, USA Key Words. Chemotherapy Emesis Emetogenicity ABSTRACT Significant progress has been made in recent years in developing more effective and better tolerated means to prevent nausea and vomiting induced by cancer chemotherapy. The most significant development has been the introduction of a new class of antiemetic agents, the selective antagonists of the type 3 serotonin receptor. With the new antiemetic therapeutic options and their attendant higher costs has come a need to define evidence-based guidelines to assist in their judicious and cost-effective use. A number of predictive factors for antiemetic risk have been defined. Some of these factors relate to the patient INTRODUCTION Nausea and vomiting have consistently ranked high on the list of factors most feared by patients receiving chemotherapy [1, 2]. Inadequately controlled emesis significantly impairs quality of life and increases the risk of patient non-compliance with therapy. Substantial progress has been made over the last decade in developing more effective and better tolerated means to prevent chemotherapy-induced emesis [3]. Several factors have contributed to the therapeutic advances in this area, including new insights into the pathophysiology of emesis, recognition of the value of combination antiemetic therapy, tailoring therapy for both acute emesis ( 24 h after chemotherapy), and delayed emesis (>24 h after chemotherapy) and the development of new antiemetic agents, particularly the selective antagonists of the type 3 serotonin (5-hydroxytyptamine [5-HT 3 ]) receptor. There are currently three 5-HT 3 receptor antagonists (dolasetron, granisetron, and ondansetron) approved for use in the United States. As with other new supportive care agents, however, the availability of new antiemetic agents with their attendant higher acquisition costs compared with older antiemetics has created a need to develop practice population (age, gender, history of ethanol consumption, and prior experience with chemotherapy), and some relate to the treatments administered. Clearly, the most important of all these factors in predicting risk of emesis is the intrinsic emetogenicity of the chemotherapy. Although an ideal emetogenic classification schema for chemotherapy has yet to be realized, recent developments in this area have allowed a more precise estimation of emetogenic risks and have provided antiemetic guideline groups with a useful foundation on which to base their treatment recommendations. The Oncologist 1999;4:191-196 guidelines to help ensure their rational and cost-effective use. A reliable method of predicting the risk of emesis following cancer chemotherapy would provide a solid foundation for the development of treatment guidelines for the appropriate use of the 5-HT 3 receptor antagonists and other antiemetics in patients receiving chemotherapy. Over the last 15 years, there has been growing recognition of a number of factors that are important in predicting the risk of emesis following antineoplastic chemotherapy [4-6]. Some of these factors are related to the treatment, including the specific agent(s), chemotherapy dose, route and rate of administration, and antiemetic regimen employed. With many chemotherapy agents, emetic risk is directly proportional to chemotherapy dose. In addition, in general, short i.v. infusions induce more emesis than protracted i.v. infusions or administration by the oral route. Other factors relate to the patient population, including patient age, gender, history of ethanol consumption, and history of prior chemotherapy. Factors associated with decreased risk of emesis include older age, male gender, history of heavy ethanol consumption, and no emesis with prior chemotherapy. Of all these predictive factors, the Correspondence: Paul J. Hesketh, M.D., Division of Hematology/Oncology, St. Elizabeth s Medical Center, 736 Cambridge Street, Boston, Massachusetts 02135, USA. Telephone: 617-789-2317; Fax: 617-789-2959; e-mail phesketh@aol.com Accepted for publication March 31, 1999. AlphaMed Press 1083-7159/99/$5.00/0 The Oncologist 1999;4:191-196

Hesketh 192 intrinsic emetogenicity of the chemotherapy has consistently emerged as the most important. EMETOGENICITY CLASSIFICATION SCHEMAS An ideal emetogenic classification schema would take into account a number of key factors, including: A) derivation from objective data rather than opinion; B) ability to account for the different types of emesis with an ability to predict the likelihood of acute and delayed emesis; C) ability to account for important patient- and treatment-related predictive factors; D) ability to account for the emetogenic potential of combinations, and E) simplicity of use. Several efforts have been made in the past to devise classification schemas for chemotherapy emetogenicity [7-11]. None of these systems have achieved widespread acceptance as a standard schema. Most have significant limitations, including: failure to account for important treatment-related factors, such as chemotherapy dose and rate and route of administration; failure to account for combinations or different patterns of emesis, and reliance on opinion rather than objective data in stratifying chemotherapy agents. In addition, none attempted to account for important patient-related variables. A NEW PROPOSAL FOR DEFINING ACUTE EMETOGENICITY OF CANCER CHEMOTHERAPY Recently, a number of individuals with a longstanding interest in the antiemetic field have proposed a new classification schema for acute emesis [12]. This schema builds upon the system proposed by Lindley et al. [10]. It standardizes chemotherapy rate and route of administration (short i.v. infusion) and patient age (adults), attempts to account for the importance of chemotherapy dose where clinically relevant, includes newer chemotherapy agents, and also proposes an algorithm to predict the emetogenicity of combination regimens. A few oral agents were also classified using customary administration schedules. On the basis of a comprehensive literature search and the consensus of the authors, individual chemotherapy agents were assigned to one of five emetogenic levels. The five levels define the risk of acute emesis in the absence of effective antiemetic prophylaxis. Table 1 lists individual chemotherapy agents by emetogenic level. Since the publication of this schema, a number of additional chemotherapeutic agents have received regulatory approval in the United States and are now incorporated into clinical practice. These include the camptothecin analogs irinotecan and topotecan, and the oral fluoropyrimidine carbamate capecitabine. Review of the clinical experience with these agents to date in phase I and II trials would suggest that capecitabine [13] and topotecan [14, 15] are level 2 agents and that irinotecan is a level 3 agent [16-18]. Table 1. Emetogenic potential of chemotherapy agents Frequency of Level emesis (%)* Agent 5 >90 Carmustine > 250 mg/m 2 Cisplatin 50 mg/m 2 Cyclophosphamide > 1,500 mg/m 2 Dacarbazine Mechlorethamine Streptozocin 4 60-90 Carboplatin Carmustine 250 mg/m 2 Cisplatin < 50 mg/m 2 Cyclophosphamide > 750 mg/m 2 1,500 mg/m 2 Cytarabine > 1 g/m 2 Doxorubicin > 60 mg/m 2 Methotrexate > 1,000 mg/m 2 Procarbazine (oral) 3 30-60 Cyclophosphamide 750 mg/m 2 Cyclophosphamide (oral) Doxorubicin 20-60 mg/m 2 Epirubicin 90 mg/m 2 Hexamethylmelamine (oral) Idarubicin Ifosfamide Irinotecan Methotrexate 250-1,000 mg/m 2 Mitoxantrone < 15 mg/m 2 2 10-30 Capecitabine Docetaxel Etoposide 5-Fluorouracil < 1,000 mg/m 2 Gemcitabine Methotrexate > 50 mg/m 2 < 250 mg/m 2 Mitomycin Paclitaxel Topotecan 1 <10 Bleomycin Busulfan Chlorambucil (oral) 2-Chlorodeoxyadenosine Fludarabine Hydroxyurea Methotrexate 50 mg/m 2 L-phenylalanine mustard (oral) Thioguanine (oral) Vinblastine Vincristine Vinorelbine *Proportion of patients who experience emesis in the absence of effective antiemetic prophylaxis. Adapted with permission from [12]. EMETOGENICITY OF CHEMOTHERAPY COMBINATIONS None of the older emetogenic classification schemas adequately accounted for the impact on emetogenicity of administering chemotherapy agents in combination. Recognizing that most chemotherapy agents are administered

193 Chemotherapy Emetogenicity Table 2. Algorithm for defining the emetogenicity of combination regimens 1. Identify the most emetogenic agent in the combination. 2. Determine the relative contribution of other agents to the emetogenicity of the combination. When considering other agents, the following rules apply: (A) Level 1 agents do not contribute to the emetogenicity of a given regimen. (B) Adding one or more level 2 agents increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination. (C) Adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent. Adapted with permission from [12]. as part of various combinations and not as single agents, it would be useful in predicting antiemetic risk to have an appropriate means of predicting the effect of combination regimens. Table 2 illustrates an algorithm to help predict the emetogenicity of chemotherapy combinations. The algorithm begins with the identification of the most emetogenic agent in the combination. The relative contribution of other chemotherapy agents to the overall emetogenicity of the combination is then assessed. When considering other agents, the following rules were suggested: A) Level 1 agents do not contribute to the emetogenicity of a given regimen; B) adding one or more level 2 agents increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination, and C) adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent. The algorithm was validated in part using a database of 197 patients assigned to receive a placebo antiemetic as part of four clinical trials comparing the 5-HT 3 receptor antagonist ondansetron with placebo [19-22]. The predicted incidence of emesis with a variety of chemotherapy regimens based upon the algorithm was compared with the actual observed frequency of emesis. For example, 44 patients received a combination of cyclophosphamide (<750 mg/m 2 ) and doxorubicin (20-60 mg/m 2 ) ± vincristine. The predicted emetogenic potential of this combination by the algorithm is level 4 (60%-90% frequency of emesis). Eighty-two percent (36/44) of patients receiving these regimens developed acute emesis when they received a placebo as antiemetic prophylaxis. Similar close correlations were noted between the predicted and observed frequency of emesis with a number of other chemotherapy regimens. A number of potential limitations of this algorithm should be kept in mind, however, The majority of patients from the latter database were women (88%) with breast cancer (79%) receiving primarily cyclophosphamide- and/or anthracycline-based chemotherapy. Few had a history of significant ethanol consumption. Therefore, based upon our knowledge of important patient-related factors, this group has to be considered somewhat high risk for the development of emesis. In addition, the algorithm attempts to predict only acute emesis risk. There is no accounting for the potential for delayed emesis. Clinicians are therefore advised to be cautious in attempting to generalize this algorithm to more diverse populations receiving other chemotherapy regimens. Further studies will be needed to determine the relevance of this algorithm to other patient populations. DEFINING RISK OF DELAYED EMESIS All efforts to date to define emetogenic schemas for chemotherapy agents have concentrated on the potential for emesis within the first 24 h (acute emesis). This is appropriate given the potential severity of uncontrolled acute emesis and the observation that emesis induced by many chemotherapy agents will resolve within 24 h. For a classification schema to be most relevant and serve as a basis for treatment recommendations, however, it must also account for the ability of certain chemotherapy agents to produce emesis beyond the 24-h period following chemotherapy, so-called delayed emesis. Cisplatin is the classic agent by which delayed emesis has been defined. In the absence of appropriate antiemetic prophylaxis, there is an approximate 65%-90% likelihood of delayed emesis following administration of cisplatin [23-25]. A number of other agents, including cyclophosphamide, carboplatin, and doxorubicin, also have the potential to induce delayed emesis. Although the risk of delayed emesis is less than with cisplatin, up to one-third of patients receiving these agents will experience delayed emesis in the absence of delayed antiemetic prophylaxis [26]. RELEVANCE OF CHEMOTHERAPY EMETOGENICITY TO CURRENT ANTIEMETIC USE AND CLINICAL RESEARCH At present, no comprehensive emetogenic classification schema that fulfills all the criteria of the ideal schema has been devised. However, given the pressing need to define rational evidence-based guidelines to help guide antiemetic use, the recently proposed schema [12] has been used as a framework for such recommendations. The National Comprehensive Cancer Network (NCCN) has used this classification schema as the basis for their recently released antiemetic guidelines [27]. For acute antiemetic prophylaxis in patients receiving chemotherapy with level 3-5 emetogenic potential, they recommended the use of an oral 5-HT 3 receptor antagonist

Hesketh 194 National Comprehensive Cancer Network (NCCN) Antiemesis Practice Guidelines Acute Primary treatment (Day 1) emetogenic potential PO tolerated:* Granisetron, 2 mg PO qd or 1 mg bid or Ondansetron, 8 mg PO bid (for high: category 2) or Dolasetron, 100 mg PO qd (for high: category 2) High to + Dexamethasone, 10-20 mg PO moderate ± Lorazepam, 0.5-2.0 mg PO (levels 5 + 4 + 3) Start before chemotherapy Repeat daily for fractionated doses of chemotherapy PO not tolerated:* Ondansetron, 8 mg (maximum, 32 mg) i.v. or Granisetron, 10 µg/kg (maximum, 1 mg ) i.v. or Dolasetron, 1.8 mg/kg i.v. or 100 mg i.v. + Dexamethasone, 10-20 mg i.v. ± Lorazepam, 0.5-2.0 mg i.v. Categories of acceptability for guideline recommendations Category 1: Recommendations that are uncontested and generally accepted by all authorities in that particular cancer. Category 2: Recommendations that are somewhat controversial. Category 3: Recommendations that caused real disagreements among members of the NCCN panel. Figure 1. Recommended antiemetic prophylaxis for patients receiving chemotherapy with level 3-5 acute emetogenic potential. *Order of listed antiemetics does not reflect preference. Reproduced with permission from [27]. The NCCN guidelines are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN guideline is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. combined with oral dexamethasone prior to chemotherapy (Fig. 1). For patients receiving level 2 chemotherapy, they recommended an oral dose of a dopaminergic antagonist or oral dexamethasone alone. For level 1 chemotherapy, no routine antiemetic prophylaxis was recommended (Fig. 2). Recognizing the potential of certain agents to induce delayed emesis, they also offered specific recommendations in this setting as well (Fig. 3). A simple-to-use, comprehensive emetogenic classification schema would also have potential relevance to antiemetic research. Efforts to develop additional useful antiemetic agents to address unmet needs (delayed emesis, high-dose chemotherapy, and multi-day chemotherapy) are continuing. Cisplatin has traditionally served as the gold standard emetogenic challenge in new agent development. As cisplatin use declines, however, the ability to evaluate new agents in a National Comprehensive Cancer Network (NCCN) Antiemesis Practice Guidelines Acute Primary treatment (Day 1) emetogenic potential PO tolerated:* Dexamethasone, 10-20 mg PO or Prochlorperazine, 10 mg PO q4-6h or 15mg spansule PO q8-12h Low or Thiethylperazine, 10 mg PO q4-6h (level 2) or Metoclopramide, 20 mg PO q4-6h + diphenhydramine, 25 mg PO q4-6h PRN ± Lorazepam, 0.5-1.0 mg PO q4-6h Start 30 min before chemotherapy Repeat daily for fractionated doses of chemotherapy Unlikely (level 1) PO not tolerated:* Dexamethasone, 20 mg i.v. or Prochlorperazine, 10 mg i.v. q4-6h or Metoclopramide, 0.5 mg/kg i.v. q3-4h + diphenhydramine, 25-50 mg i.v. PRN ± Lorazepam, 0.5-1.0 mg i.v., q4-6h No prophylactic treatment Figure 2. Recommended antiemetic prophylaxis for patients receiving chemotherapy with level 1-2 acute emetogenic potential. *Order of listed antiemetics does not reflect preference. Reproduced with permission from [27]. The NCCN guidelines are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN guideline is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. timely manner has become an increasing challenge. An emetogenic classification schema that allows more precision in defining emetic risk, particularly in high-risk patient categories, could potentially facilitate new antiemetic agent development. SUMMARY Substantial progress has been realized over the last 15 years in predicting the risk of emesis following cancer chemotherapy. Of the known predictive factors, the intrinsic emetogenicity and pattern of emesis have emerged as the most clinically relevant. A better understanding of the latter factors has allowed the development of rational guidelines to help assist the clinician in using antiemetic agents in the most rational and cost effective manner possible. Efforts should continue to develop more comprehensive emetogenic schemas that attempt to take into account all of the known patient- and treatment-related factors.

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