Oncologist. The. Chemotherapy-Induced Nausea and Vomiting: The Importance of Acute Antiemetic Control FREDERICK M.

Transcription

1 The Oncologist Chemotherapy-Induced Nausea and Vomiting: The Importance of Acute Antiemetic Control FREDERICK M. SCHNELL Central Georgia Hematology and Oncology Associates, Macon, Georgia, USA Key Words. Chemotherapy Nausea Vomiting 5-HT 3 -receptor antagonists ABSTRACT Nausea and vomiting are two of the most feared side effects of cancer chemotherapy and radiotherapy. Chemotherapy-induced nausea and vomiting can be broadly categorized as acute (occurring within 24 hours of therapy), delayed (persisting for 6-7 days after therapy), or anticipatory (occurring prior to chemotherapy administration). Breakthrough and refractory nausea and vomiting describe the symptoms of uncontrolled emesis. Evidence suggests that good control of nausea and vomiting during the acute period correlates with the control of delayed emesis. Conversely, protection failure during the first 24 hours has a high predictive value for delayed emesis in the same cycle. The 5-HT 3 -receptor antagonists, regarded as the gold standard in antiemetic therapy, are the first-line treatment for moderately and highly emetogenic chemotherapy and radiotherapy regimens in adults and children. Evidence suggests that the 5-HT 3 -receptor antagonists administered in combination with corticosteroids afford the best protection from symptoms of acute emesis and, by extrapolation, the most effective prevention of delayed emesis. Antiemetic therapeutic guidelines stress that the goal of therapy is to prevent cytostatic-induced nausea and vomiting. Therefore, the prophylactic use of the most effective antiemetic regimen taking into consideration the emetogenicity of the chemotherapy and individual patient characteristics must be adhered to in order to prevent acute, delayed, and anticipatory nausea and vomiting. The Oncologist 2003;8: INTRODUCTION Chemotherapy-induced nausea and vomiting (CINV) are two of the greatest fears of patients with cancer [1-4]. Inadequately controlled CINV and radiation-induced nausea and vomiting (RINV) can precipitate a number of medical complications that may prove life threatening, including dehydration and electrolyte imbalance, or cause physical damage, including Mallory-Weiss tears of the esophagus. These complications may lead to extended hospitalization, with the associated burden on nursing time and pharmacy resources and overall cost implications. The distressing symptoms of nausea and vomiting have a considerable impact on all aspects of the patients qualities of life, as well as those of their family and caregivers. The distress resulting from these symptoms can escalate over time [5, 6] and can potentially lead to a patient s refusal to continue with the most effective antitumor therapy [1, 7, 8]. Indeed, failure to control these side effects can lead to 25%- 50% of patients delaying or refusing possible lifesaving antineoplastic therapy [9]. Nausea and vomiting associated with chemotherapy can be classified as acute, delayed, or anticipatory. In addition, two further categories exist for uncontrolled symptoms breakthrough and refractory nausea and vomiting. Acute nausea and vomiting are defined as occurring within 24 hours after chemotherapy and can be further subdivided into acute (within 12 hours) and late-acute (12-24 hours). Delayed nausea and vomiting are usually defined as commencing more than 24 hours after administration of chemotherapy and may persist for 6-7 days [1, 10]. They Correspondence: Frederick M. Schnell, M.D., F.A.C.P., Central Georgia Hematology and Oncology Associates, 682 Hemlock Street, Suite 100, Macon, Georgia 31201, USA. Telephone: ; Fax: ; fmschnell@aol.com Received September 3, 2002; accepted for publication December 20, AlphaMed Press /2003/$12.00/0 The Oncologist 2003;8:

2 Schnell 188 commonly occur following the administration of cisplatin, carboplatin, cyclophosphamide, or doxorubicin [11]. Some reports also have suggested that delayed symptoms may begin sooner than 24 hours, perhaps as soon as 16 hours, postchemotherapy [12, 13]. Anticipatory nausea and vomiting occur before, during, or after (but before acute chemotherapy symptoms would be expected to occur) the administration of a subsequent course of treatment if previous emetic control has been poor [10, 11]. They are conditioned responses linked to visual, gustatory, olfactory, and environmental factors associated with previously administered chemotherapy [1]. Breakthrough nausea and vomiting refer to symptoms that occur despite antiemetic prophylaxis and/or necessitate the use of rescue medication. Refractory nausea and vomiting refer to symptoms that occur during subsequent treatment cycles when control was incomplete in earlier cycles [14]. This review focuses on the relationship between acute antiemetic control and the occurrence of delayed-onset and anticipatory nausea and vomiting. It highlights data supporting the concept that good acute control, with appropriate doses of prophylactic antiemetics with proven efficacy, has a positive impact on the incidence and control of delayed and anticipatory nausea and vomiting. The therapeutic benefits of the 5-HT 3 -receptor antagonists are discussed in this context. RISK FACTORS FOR THE DEVELOPMENT OF ACUTE NAUSEA AND VOMITING The incidence of acute emesis is determined by the emetogenic potential of the administered chemotherapy, patient variables, and the dosage and efficacy of the prescribed antiemetic regimen. The emetogenic potential of a chemotherapeutic regimen depends on a number of factors, including the chosen cytotoxic agent(s), the dose given, and the administration schedule (Table 1) [7, 15, 16]. Cisplatin is one of the most highly emetogenic agents, with doses of 50 mg/m 2 or more inducing nausea and vomiting within 24 hours in more than 90% of patients not administered antiemetic prophylaxis. Even in those patients receiving appropriate prophylaxis during multiple-cycle chemotherapy, the risk of vomiting associated with cisplatin is 20% greater than with non-cisplatin-containing regimens [17]. Agents with moderately high emetogenic potentials include methotrexate, doxorubicin, cyclophosphamide, and carboplatin, while vinblastine and bleomycin are considered to have low emetogenicity as monotherapy products [7]. The emetogenicity of radiotherapy is mainly Table 1. Relative emetogenic potential of antineoplastic drugs Emetogenic potential (% of patients) Agent Dosage Onset/duration of response (hours) High (>90%) Cisplatin >50 mg/m Cyclophosphamide >1,000 mg/m Dacarbazine 4-24 Mechlorethamine Moderately high (60%-90%) Cisplatin <50 mg/m Cyclophosphamide 750-1,000 mg/m Methotrexate >1,000 mg/m Carboplatin 6-46 Doxorubicin >60 mg/m Moderate (30%-60%) Cyclophosphamide <750 mg/m Methotrexate 250-1,000 mg/m Doxorubicin <60 mg/m Moderately low (10%-30%) Methotrexate <250 mg/m Fluorouracil 3-10 Etoposide Low (<10%) Hydroxyurea 8-48 Vinblastine Bleomycin Tamoxifen Chlorambucil Adapted with permission from Clin J Oncol Nurs 1999;3: [7]. Based on information from Bilgrami and Fallon [15] and Hesketh et al. [16].

3 189 CINV: Acute Antiemetic Control dependent upon the treatment field. For example, almost 100% of patients undergoing total body irradiation (TBI) experience symptoms of emesis, while radiation of the cranium only is considered low risk (about 10%-30% of patients experience emesis) [11]. The dose of radiation administered per fraction and the pattern of fractionation are also risk factors for RINV [11]. For example, a patient s risk of developing RINV is greater if the radiation is delivered as a single high dose than if it is fractionated [18]. Fractionated irradiation can cause considerable distress to the patient, since treatment can comprise up to 40 sessions given over a period of 6-8 weeks [18]. Chemotherapeutic agents also differ in the time-to-onset of symptoms and duration of the emetic response. For example, cyclophosphamide has a latency period of about 10 hours before the onset of symptoms, which then continue for up to 3 days [19], while mechlorethamine can stimulate emesis within 30 minutes of administration [7]. Antiemetic therapeutic efficacy is also influenced by a number of patient characteristics, and each individual should be treated according to his or her unique risk factor profile (Table 2) [7, 13, 20]. The risk associated with the presence of multiple risk factors is likely to be cumulative. Indeed, in an investigation of over 800 chemotherapy-naïve patients, the incidence of postchemotherapy nausea was 20% in patients having no risk factors and 76% in those with four risk factors [20]. Moreover, a significant interaction between age and gender has been shown, with younger women being at greatest risk [21]. Pharmacogenetics an area of research that makes use of genetic variations to optimize drug discovery and development and patient treatment will inevitably impact on future drug selection in certain groups of patients requiring therapy [22]. Recently, a genetic polymorphism has been identified that affects patients responses to antiemetic therapy following moderate to highly emetogenic chemotherapy [23]. The 5-HT 3 -receptor antagonists are metabolized by the cytochrome P450 (CYP) enzymes, and patients who have been identified as ultrarapid metabolizers of the isoenzyme CYP2D6 have a significantly higher frequency of vomiting within the first 24 hours after chemotherapy following administration of ondansetron or tropisetron (which is licensed outside of the U.S.). The results of this small study suggest that effective acute control may be compromised in patients with this genetic polymorphism who are offered these antiemetics as supportive care agents since both 5-HT 3 -receptor antagonists are metabolized by CYP2D6; tropisetron is metabolized principally by CYP2D6, whereas ondansetron is also partially metabolized by CYP3A, CYP1A2, and, to a small degree, CYP1A1 [24]. This is in contrast with granisetron, which is metabolized exclusively by the CYP3A subfamily [24], and may thus be the antiemetic of choice in patients suspected of being ultrarapid metabolizers of CYP2D6. IMPACT OF ACUTE CONTROL ON DELAYED AND ANTICIPATORY NAUSEA AND VOMITING Evidence suggests that good control of acute nausea and vomiting, particularly during the initial treatment received by chemotherapy-naïve patients, correlates with the control of delayed and, by extrapolation, anticipatory symptoms as well as acute- and delayed-onset emesis associated with subsequent cycles of treatment [25-27]. Correlation Between Acute and Delayed Control of CINV Although the neuropharmacologic mechanism of delayed CINV is not well understood, these symptoms occur more frequently with highly emetogenic chemotherapy and are more difficult to treat than acute nausea and vomiting [28, 29]. Because delayed symptoms are less responsive to treatment than prevention, optimal prophylactic control is imperative to minimize their occurrence. Patients who do not vomit in the first 24 hours posttreatment have shown high rates of complete protection from delayed emesis. Conversely, failure during the acute period has a high negative predictive value for delayed Table 2. Risk factors associated with the development of chemotherapy-induced nausea and vomiting Risk factor Gender Age Alcohol consumption Motion sickness Pregnancy-induced emesis Anxiety Previous cycles of chemotherapy Change in risk Greater risk in females Lower incidence at <6 or >50 years Lower incidence in individuals consuming >10 alcohol units/week Prior history leads to greater risk Prior history leads to greater risk High anxiety levels correlated with greater risk Poorly controlled nausea and vomiting in previous cycles increases likelihood of CINV and anticipatory nausea and vomiting

4 Schnell 190 emesis in the same cycle [12]. Furthermore, patients who experience delayed symptoms during their initial cycle of chemotherapy are more likely to suffer recurrent delayed symptoms during subsequent cycles [13] as well as reduced acute antiemetic protection in the next cycle [30]. Thus, any patient characteristic that predisposes an individual to acute symptoms (such as female sex, low prior alcohol intake history, and emesis with prior cycles of chemotherapy) should also be considered as a predictive factor for delayed nausea and vomiting [11]. Of these predictors, poor control of acute CINV (often defined as three or more vomiting episodes associated with a particular treatment) constitutes an important risk factor for the occurrence of delayed symptoms [31]. For example, Mantovani et al. observed poor control of acute emesis to predict for symptoms of delayed emesis following cisplatin therapy, the incidence and severity of which were greatest during the period from hours following treatment [12]. In that study, good control of delayed emesis was achieved in patients who had complete protection from acute symptoms (75% and 72.2%, respectively). Similarly, in a study of 267 evaluable patients who received cisplatin ( 50 mg/m 2 ), antiemetic prophylaxis resulted in the control of vomiting in 79% of patients with comparable control rates being maintained through to day 5 (range, 84%-86%; Fig. 1) [27]. The degree of nausea control achieved on day 1 (77%) was also comparable with the rates reported on days 2 to 5 (range, 69%-77%; Fig. 1). A further study of 532 patients receiving granisetron plus dexamethasone as antiemetic prophylaxis for cisplatin chemotherapy found that a comparable percentage of patients who were complete responders (defined as no vomiting, no worse than mild nausea, no use of rescue medication, and no withdrawal from the study over the 3-day treatment period) on the day of chemotherapy (day 0, 79%) maintained a complete response over the following 3 days (range, 75%-81%) [8]. Rates of total control (i.e., absolute absence from nausea and vomiting, no use of rescue medication, and no study withdrawal) over the study period were also comparable (day 0, 72%; days 1-3, 65%-83%). Delayed CINV seems to be less prevalent in children than in adults [32], which may be reflected by the lower incidence of chemotherapy-induced emesis in children under the age of 6 years [7] (Table 2). Nevertheless, platinum-based and cyclophosphamide chemotherapeutic regimens, which are accompanied by vomiting during the acute phase, are associated with a significantly higher incidence of delayed vomiting [32]. These findings confirm the paramount importance of achieving effective control of acute CINV in order to reduce the development of delayed symptoms [4], which presents physicians with a clinical challenge. It is important that physicians take a full medical history to identify patients at greatest risk of developing nausea and vomiting and ensure that the most effective currently available antiemetic agents are administered prophylactically at optimum doses to control symptoms during the acute phase. Nevertheless, it must be stressed that good acute control must be coupled with the administration of regular antiemetic medication throughout the posttreatment period to maximize the control of delayed CINV. Protection Against Anticipatory Nausea and Vomiting Anticipatory nausea and vomiting are conditioned responses and, therefore, typically only occur after a previous negative experience with chemotherapy [11]. Although individual risk profiles (e.g., a history of motion sickness, anxious personalities; Table 2) are indirect predictors for the development of anticipatory nausea and vomiting, the most important risk factor is the occurrence of acute or delayed symptoms with prior chemotherapy [9, 11, 33]. A conditioning response may ensue, such that these symptoms then occur spontaneously hours or even days before the next series of treatments [34]. Therefore, aggressive prophylaxis against both acute and delayed symptoms particularly during the first cycle of chemotherapy confers the most effective prevention against anticipatory CINV [11, 13]. OPTIMAL CONTROL OF THE ACUTE PHASE The aim of antiemetic treatment is the total prevention of nausea and vomiting for each individual, thereby conferring the best patient outcome [11]. Total control (i.e., no nausea, no vomiting or retching, and no use of antiemetic rescue medication) during the postchemotherapy period Patients (%) No retching/vomiting No nausea Day 1 Day 2 Day 3 Day 4 Figure 1. Rates of complete protection against retching/vomiting and nausea from days 1-5 following the administration of cisplatin ( 50 mg/m 2 ). Antiemetic prophylaxis comprised three doses of intravenous ondansetron, 0.15 mg/kg, plus intravenous dexamethasone, 20 mg. Reprinted with permission from Oncology 1993;50: [27].

5 191 CINV: Acute Antiemetic Control will maximize patients quality of life, including their ability to sustain their normal daily activities after such treatment, thereby reducing associated symptom management costs. Thus, optimum control will be associated with considerable socio- and pharmacoeconomic, as well as clinical, benefits. As discussed above, effective acute prophylaxis in conjunction with the administration of regular and adequate prophylaxis post-treatment is an important determinant of the control of both delayed and anticipatory CINV. Hence, maximizing the number of patients who experience total control of nausea and vomiting during the acute phase of the first cycle of treatment is an important goal of antiemetic therapy [7]. Effective acute prophylaxis is achieved by tailoring antiemetic therapy to the individual at the outset of cancer treatment. The Role of 5-HT 3 -Receptor Antagonists The Accepted Gold Standard Since the mid-1980s, major progress has occurred in antiemetic drug development. Prior to that time, high doses of metoclopramide were used to combat cisplatin-induced nausea and vomiting. However, while these partially suppressed symptoms, as many as 30%-60% of patients continued to suffer nausea and vomiting, and extrapyramidal effects associated with dopamine (D 2 ) antagonism occurred in up to 5% of patients [35]. A greater understanding of the pathophysiology of emesis disclosed the importance of serotonin (5-HT) in the mediation of the emetic response. Release of serotonin from enterochromaffin cells in the small intestinal mucosa contributes to the acute nausea and vomiting associated with chemotherapy. Serotonin activates receptors on vagal afferent fibers in the intestinal mucosa, which relay sensory information to discrete brain areas involved in the genesis of nausea and vomiting [36]. However, the precise mechanism underlying the development of CINV remains unclear and is likely to involve additional pathways to those mediated by serotonin or dopamine [28]. The 5-HT 3 -receptor antagonists specifically block the binding of serotonin to the receptors on the vagal nerves that trigger the emetic response [7]. This specificity obviates the severe and distressing extrapyramidal side effects sometimes associated with conventional antiemetics [17]. The introduction of the 5-HT 3 -receptor antagonists has represented a significant clinical advance in the prevention of CINV, particularly for patients receiving highly emetogenic cisplatin-containing chemotherapy, in whom the 5-HT 3 -receptor antagonists generally produce superior efficacy to high-dose metoclopramide [1]. Three of these agents are licensed for use in the U.S.: granisetron, ondansetron, and dolasetron. A further agent in this class, tropisetron, is available in Europe and selected other countries. All three agents licensed for use in the U.S. are available in both injectable and oral formulations; however, only granisetron and ondansetron are indicated for use with highly emetogenic chemotherapy by the oral route. Data from animal studies have shown that the oral formulation reaches the gut directly, is absorbed across the proximal gut mucosa, and is immediately available to bind with 5-HT 3 receptors on the vagal afferent neurons [37, 38]. Oral antiemetics can be more convenient for patients and may allow reductions in nursing time, in contrast with intravenous administration of the same agents [39]. A Comparable Pharmacologic Profile? Although the chemical structures of all drugs in this class are similar, the individual 5-HT 3 -receptor antagonists exhibit notable pharmacologic differences in their selectivity, potency, dose-response profiles, and half-lives [1, 40, 41] that may affect their activities as antiemetic agents in certain individuals. For example, pharmacologic potencies of these agents differ; the rank order of the U.S.-licensed agents is granisetron > ondansetron > dolasetron. Although both granisetron and ondansetron exhibit high binding affinities for the 5-HT 3 receptor (pk i values, 8.42 and 8.07, respectively), granisetron is specific for this receptor, whereas ondansetron also possesses weak affinity for 5- HT 1B, 5-HT 1C, α 1 -adrenergic, and µ-opioid receptors [42]. The affinities ondansetron has for receptors other than the target 5-HT 3 receptor may confound antiemetic therapy, potentially producing more adverse drug reactions in patients than a drug that does not possess affinities for other receptors (e.g., granisetron). In addition, dolasetron and granisetron possess significantly longer elimination halflives than ondansetron, that is, the time a drug is present and active in the body. The shorter elimination half-life of ondansetron may account for the dosing variability associated with this drug [1]. For example, when used as monotherapy, to produce satisfactory control of emesis in patients undergoing chemotherapy, it is necessary to administer ondansetron as a single high dose (32 mg i.v.) or as part of a multiple dosing regimen (0.15 mg/kg three times daily) [43]. This is in contrast with granisetron, which is effective as a single-dose monotherapy agent (10 µg/kg i.v. or 2 mg orally once daily) [44]. Of interest, the duration of action of granisetron has been shown to be at least 24 hours, considerably longer than that predicted by its halflife [45], and is a possible consequence of its noncompetitive antagonism of the 5-HT 3 receptor [46]. However, while such pharmacologic differences may be expected to translate into clinical relevance, the full significance of these variations remains thus far equivocal [1, 47]. Nevertheless,

6 Schnell 192 these differences may differentiate individuals responses to their given antiemetic therapies, impacting on acute control of nausea and vomiting and the overall success of treatment. Optimizing Efficacy Comparative trials with high-dose metoclopramide have demonstrated that dolasetron, ondansetron, and granisetron are more effective in preventing acute emesis, are better tolerated, and are preferred by more patients [1, 19, 48-50]. 5-HT 3 -receptor antagonists have become the agents of choice in preventing acute CINV following both moderately and highly emetogenic chemotherapy [11, 51]. Complete response and total control rates seen with specific drugs range from 60%-80% for moderately emetogenic chemotherapy [4, 52-54], 40%-60% for cisplatin-containing therapy [4, 33, 55, 56], and 25%-60% for high-dose cisplatin regimens [33, 35, 47, 57, 58]. The efficacies of the 5-HT 3 -receptor antagonists are dependent on their appropriate use, including the administration of adequate doses. However, due to cost considerations, many of these agents are often used at lower than optimal doses. In the U.S., the approved dose of intravenous ondansetron is 32 mg; however, ondansetron is frequently given at doses as low as 8 mg when administered as part of a combination treatment approach for moderately or highly emetogenic chemotherapy [59-62]. The impact of such a practice on symptom control may jeopardize effective patient management. In contrast, oral dolasetron is approved in the U.S. for use with moderately emetogenic chemotherapy at a dose of 100 mg administered within 1 hour before chemotherapy [63]. However, a dose-related response for oral dolasetron has been shown to occur at doses between 25 and 200 mg [64, 65]. Indeed, a significant linear dose-response relationship was observed in 399 cancer patients receiving moderately emetogenic chemotherapy over the entire dolasetron dose range of mg (p < 0.001), with complete response rates of 60.5% and 76.3% achieved with the 100 mg and 200 mg doses, respectively [64]. Consideration of the consequences of potentially worse acute control, with its associated adverse clinical, humanistic, and economic effects, is therefore essential before administering lower-than-indicated doses of any approved agent. Administration of lower doses of agents with lower potency and/or shorter half-lives in those patients receiving carboplatin or cyclophosphamide agents (in whom nausea and vomiting typically peak about hours after administration) may be particularly detrimental [7]. Bone Marrow Transplantation Conditioning treatments for patients undergoing bone marrow transplantation (BMT) TBI and high-dose chemotherapy are both highly emetogenic procedures. Cancer patients undergoing these procedures often suffer from acute nausea and vomiting, which can extend for prolonged periods of days or weeks after high-dose chemotherapy [66]. It is especially imperative that acute nausea and vomiting are adequately controlled to minimize the occurrence of delayed emesis in these patients. 5-HT 3 -receptor antagonists have been shown to be highly effective in controlling emesis after conditioning treatments [67-70] and are the first-line treatment for both adults and pediatric patients undergoing such therapies [11, 13]. Granisetron was found to be significantly more effective for prophylaxis of emesis induced by conditioning chemotherapy prior to BMT than older, conventional antiemetic therapies [71]. Ninety-four percent of patients who were administered granisetron experienced complete control of acute emesis, while only 7.6% of patients treated with conventional antiemetics had the same degree of control. As a consequence, granisetron was more effective at preventing delayed nausea and vomiting than the standard antiemetics (control of emesis on days 5-6 for patients receiving granisetron or standard antiemetics was 66.7% and 20.0%, respectively) [71]. Potential for Corticosteroid Combination All current evidence suggests that prophylactic administration of the 5-HT 3 -receptor antagonists affords the best protection from acute CINV and, by extrapolation, the most effective prevention of delayed and anticipatory symptoms. However, despite their proven efficacies, a significant proportion of patients still experience symptoms of CINV during the first 24 hours, depending on the chemotherapy regimen administered [29]. The synergistic effect of conventional antiemetics in combination with corticosteroids is well established, and, prior to the introduction of the 5-HT 3 -receptor antagonists, combination antiemetic therapy, such as metoclopramide plus dexamethasone and diphenhydramine or lorazepam, was generally regarded as the most effective treatment in this setting. The addition of corticosteroids to 5-HT 3 -receptor antagonists has also been shown to be significantly more effective than the combination of a steroid with conventional antiemetics. For example, complete protection from retching and vomiting was achieved in 79% of patients who received a 5-HT 3 -receptor antagonist plus steroid, compared with 59% of patients who received a steroid as part of a non-setron antiemetic regimen (p < 0.002) [26, 27]. Similarly, in a comparative trial of 357 patients receiving cisplatin therapy, total control (defined as no vomiting, no nausea, and no use of rescue medication) occurred in 65% of patients receiving oral granisetron, 1 mg twice daily plus intravenous dexamethasone, compared with only 45% of

7 193 CINV: Acute Antiemetic Control metoclopramide plus dexamethasone-treated patients (p = 0.007) [29]. In directly comparative, single-agent studies of 5-HT 3 - receptor antagonists that permitted concomitant corticosteroid use [39, 52], the addition of the steroid improved total control rates by 9.8%-13.4% at 24 hours and by 4.7%- 8.7% at 48 hours postchemotherapy. Results from a study investigating optimum corticosteroid doses suggest that a dexamethasone dose of 20 mg be used as standard prophylaxis in combination with 5-HT 3 -receptor antagonists [72] (Table 3). As previously noted, patients most at risk for CINV are younger, female patients and patients who have received either high doses of cisplatin or additional emetogenic chemotherapy. The benefit of adding dexamethasone to a 5-HT 3 -receptor antagonist antiemetic in these higher risk groups suggests that women and younger patients may attain a particular advantage from this combination regimen [29]. Pediatric patients have also been shown to benefit from the addition of a corticosteroid to a 5-HT 3 -receptor antagonist. Sixty-one percent of children aged 3-18 years receiving ondansetron, 0.15 mg/kg i.v. three times daily, supplemented with dexamethasone, 8 mg/m 2 i.v. plus 16 mg/m 2 in divided doses, experienced a complete emetic response, compared with only 23% of patients administered ondansetron alone [73]. Similarly, a number of studies have shown that corticosteroids can enhance the safety and efficacy of antiemetic regimens in BMT patients [66]. The regular administration of a steroid, as the minimum treatment regimen, throughout the posttreatment period is also recommended to protect against the occurrence of delayed emesis [11, 13]. Multiple-Cycle Chemotherapy An important aspect of prophylactic antiemetic therapy is control of nausea and vomiting over repeated cycles of chemotherapy. A decline in antiemetic effect has been shown during successive treatment cycles with standard antiemetic regimens, including high-dose metoclopramide plus dexamethasone or methylprednisolone [74] and combination prophylaxis with methylprednisolone, thiethylperazine, and amitriptyline [75]. In contrast, combination therapy with a 5- HT 3 -receptor antagonist plus dexamethasone has been shown to be effective in the majority of patients over successive courses of carboplatin-based chemotherapy [76]. Unlike metoclopramide, antiemetic efficacy of ondansetron plus dexamethasone was retained in patients who completed second and third cycles of cisplatin chemotherapy [27]. In addition, the antiemetic efficacy of granisetron has been shown to be maintained for up to eight repeated chemotherapy cycles [9, 77]. Good control of acute nausea and vomiting during first-cycle chemotherapy is thus crucial, as emesis in prior chemotherapy cycles is a predictor for emesis in subsequent cycles (Table 2) [7, 13]. Breakthrough Emesis and Treatment Failure Patients who fail on antiemetics during initial chemotherapy cycles (i.e., those experiencing three or more vomiting episodes) are at high risk of experiencing all types of nausea and vomiting during subsequent treatments. It is of extreme importance that a critical reevaluation of the antiemetic regimen is performed and control is maximized in subsequent cycles by administration of proven antiemetic agents that afford the best acute control of nausea and vomiting, thereby limiting future breakthrough emesis. In an evaluation of granisetron in patients refractory to previous antiemetics, some of whom had received ondansetron, a complete response was achieved in 53%-60% of patients in cycles 1-6, with the proportion of complete responders remaining constant throughout successive treatment cycles (Fig. 2) [17]. However, patients receiving doses of cisplatin in excess of 50 mg/m 2 had lower complete response rates (25.0%-57.1%) than those receiving other cytostatic agents (59.3%-67.9%). Furthermore, in a small, randomized, double-blind study of patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy, granisetron plus dexamethasone was compared with continued ondansetron treatment [78, 79]. Of the 40 eligible patients, significant benefit was achieved by switching patients to granisetron after failure with ondansetron (p = 0.005) (Fig. 3). The authors stated that this effect is Table 3. 5-HT 3 -receptor antagonists plus varying dexamethasone doses in a randomized trial with 531 patients Dexamethasone dose Complete control: vomitingcomplete control: nausea 4 mg 69%* 61% 8 mg 69%* 61% 12 mg 78%* 66% 20 mg 83%* 71% *p < 0.01 compared with dexamethasone, 4 mg and 8 mg. Reprinted with permission from J Clin Oncol 1998;16: [72].

8 Schnell 194 Patients (%) n = 512 n = 333 n = 227 n = 149 n = 102 n = 48 Patients (%) Ondansetron (n = 21) Granisetron (n = 19) Cycle of treatment Complete protection Partial protection Failure Figure 2. Proportion of patients showing a complete response following administration of antiemetic prophylaxis with granisetron prior to administration of chemotherapy. Data from later cycles were not analyzed due to low patient numbers. Reprinted with permission from Anticancer Drugs 1998;9: [17]. unlikely to be explained by efficacy differences in the administered doses. Thus, treatment failure with one 5-HT 3 -receptor antagonist does not predict subsequent failure with all setrons, or at least not in patients who receive granisetron following treatment failure with ondansetron. Therapeutic Recommendations The importance of the prophylactic administration of antiemetics is recognized by various evidenced-based U.S. guidelines, including those compiled by the American Society of Clinical Oncology (ASCO), the American Society of Health-System Pharmacists (ASHP), and the Multinational Association of Supportive Care in Cancer (MASCC). All these guidelines recommend antiemetic prophylaxis with a 5- HT 3 -receptor antagonist in combination with a steroid in patients receiving moderately to highly emetogenic chemotherapy or radiotherapy. These guidelines emphasize that prevention of delayed and anticipatory nausea and vomiting is predominantly dependent on ensuring optimum acute symptom control. In all patients receiving cisplatin, a corticosteroid plus a 5-HT 3 -receptor antagonist is recommended for the prevention of delayed and anticipatory CINV. In patients receiving high-risk, non-cisplatin regimens, a prophylactic corticosteroid with or without either a 5-HT 3 -receptor antagonist or metoclopramide is suggested [11, 51]. Overall, the prophylactic use of the most effective antiemetic regimen appropriate to the chemotherapy employed is suggested to prevent acute, delayed, and anticipatory nausea and vomiting. Such regimens must be used with the initial chemotherapy in order to prevent the occurrence of symptoms, rather than waiting to assess the patient s emetic response with less effective treatment. Treatment should be individualized by considering the important individual patient risk factors. In the outpatient Figure 3. Effect of switching antiemetic treatment to granisetron after failure with ondansetron, compared with continuous ondansetron treatment [78, 79]. setting, patients must be encouraged to continue with prophylactic antiemetics. This is highlighted following a recent survey that suggested that nurses and physicians often underestimate the occurrence of nausea and vomiting in cancer patients [80]. This may be due to underreporting of these symptoms by patients while they are in hospital or because of delayed symptoms that patients experience once discharged from hospital without provision of adequate antiemetic prophylaxis. All patients at risk of delayed emesis require sustained prophylaxis throughout the posttreatment period. The prescription of antiemetics during the delayed phase should be accompanied by patient counsel emphasizing the importance of prevention over treatment and thus the need for regular self-administration. Effective preventative measures serve to enhance patients quality of life and lead to improved patient compliance with subsequent chemotherapy cycles. Administration of appropriate antiemetic prophylaxis should be accompanied by close monitoring of the success of therapy. The success of symptomatic control should not be assumed and must be established by direct communication with, and assessment by, the patient. DISCUSSION Prevention of nausea and vomiting induced by cytotoxic agents is critical in the management of the patient with cancer. The 5-HT 3 -receptor antagonists are currently perceived as the gold standard antiemetic treatment, providing effective control of acute nausea and vomiting, while offering a substantial tolerability benefit over older conventional antiemetics. Three agents are currently licensed in the U.S.: ondansetron, granisetron, and dolasetron. All are available as oral and i.v. formulations, but only oral granisetron and ondansetron are currently indicated for use with highly emetogenic agents. Efficacy of the 5-HT 3 -receptor antagonists is further increased with the concurrent use of corticosteroids, and U.S. guidelines

9 195 CINV: Acute Antiemetic Control now recommend the concomitant use of these agents in moderately/highly emetogenic settings [11, 13]. Successful prevention and control of acute CINV considerably reduces the risk of delayed symptoms in the same cycle, which are inherently more difficult to treat. The challenge of treating delayed symptoms may be due in part to the underlying physiological mechanism, which has not been fully elucidated and is likely to involve transmitters other than serotonin. Indeed, recent clinical trials have examined the antiemetic effect of neurokinin-1 (NK1)-receptor antagonists in cancer patients undergoing highly emetogenic chemotherapy, suggesting a partial involvement of substance P [81]. During the delayed phase, an NK1-receptor antagonist in combination with granisetron and dexamethasone provided significantly better control of emesis than placebo during days 2-5. This combination was also more effective during the acute phase than granisetron plus dexamethasone alone, though the NK1-receptor antagonist plus dexamethasone combination without granisetron was significantly less effective than the triple combination. This suggests that, during the acute phase, 5-HT and substance P may be acting together to produce emesis and that antagonists for both transmitters are necessary to confer good overall protection from emesis. However, no NK1-receptor antagonists are currently licensed, and until they are commercially available, health care professionals should use the best available and most suitable agents during the acute and delayed phases. This choice should accommodate patient factors as well as pharmacologic consideration of the 5-HT 3 -receptor antagonists. Effective control of CINV during a patient s initial treatment reduces the incidence of symptoms, including anticipatory CINV, associated with subsequent cycles. As a result, patients are more likely to retain their quality of life, have a more positive attitude toward chemotherapy, and opt to continue receiving treatment over multiple cycles as a consequence. In addition, pharmacoeconomic benefits are also attained, with reduced hospital stays per patient leading to lower hospital costs and lower resource consumption [13]. Thus, complete protection against nausea and vomiting during the acute phase of the first cycle of treatment is imperative during antiemetic therapy. However, there is the risk that not all patients will respond to antiemetic therapy. In conclusion, in controlling CINV, the strategy should always focus on prevention rather than treatment. Health care professionals can optimize their patients outcomes by ensuring that therapy is tailored according to each patient s individual risk profile. Consideration of the chemotherapeutic regimen and patient characteristics must be coupled with the provision of antiemetic therapy with proven efficacy at fully effective doses. In this way, effective acute control with its attendant advantages can be maximized during a patient s initial treatment, in adherence with the right first time ethic. ACKNOWLEDGMENT This manuscript was supported by Roche. F.M.S. has received honoraria and is a consultant for Roche. REFERENCES 1 Hesketh PJ. Comparative review of 5-HT 3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Invest 2000;18: Coates A, Abraham S, Kaye SB et al. On the receiving end patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol 1983;19: Cooper S, Georgiou V. The impact of cytotoxic chemotherapy perspectives from patients, specialists and nurses. Eur J Cancer 1992;28A(suppl 1):S36-S38. 4 Goedhals L, Heron JF, Kleisbauer JP et al. Control of delayed nausea and vomiting with granisetron plus dexamethasone or dexamethasone alone in patients receiving highly emetogenic chemotherapy: a double-blind, placebo-controlled, comparative study. Ann Oncol 1998;9: Rhodes VA, McDaniel RW. Nausea, vomiting, and retching: complex problems in palliative care. CA Cancer J Clin 2001;51: Rhodes VA, Watson PM. Symptom distress the concept: past and present. Semin Oncol Nurs 1987;3: Doherty KM. Closing the gap in prophylactic antiemetic therapy: patient factors in calculating the emetogenic potential of chemotherapy. Clin J Oncol Nurs 1999;3: The Italian Multicenter Study Group. A double-blind randomized study comparing intramuscular (i.m.) granisetron with i.m. granisetron plus dexamethasone in the prevention of delayed emesis induced by cisplatin. Anticancer Drugs 1999;10: Ritter Jr HL, Gralla RJ, Hall SW et al. Efficacy of intravenous granisetron to control nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. Cancer Invest 1998;16: Yalcin S, Tekuzman G, Baltali E et al. Serotonin receptor antagonists in prophylaxis of acute and delayed emesis induced by moderately emetogenic, single-day chemotherapy: a randomized study. Am J Clin Oncol 1999;22: Gralla RJ, Osoba D, Kris MG et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol 1999;17:

10 Schnell Mantovani G, Maccio A, Curreli L et al. Comparison of oral 5- HT 3 -receptor antagonists and low-dose oral metoclopramide plus i.m. dexamethasone for the prevention of delayed emesis in head and neck cancer patients receiving high-dose cisplatin. Oncol Rep 1998;5: ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm 1999;56: Sigsgaard T, Herrstedt J, Christensen P et al. Antiemetic efficacy of combination therapy with granisetron plus prednisolone plus the dopamine D 2 antagonist metopimazine during multiple cycles of moderately emetogenic chemotherapy in patients refractory to previous antiemetic therapy. Support Care Cancer 2000;8: Bilgrami S, Fallon BG. Chemotherapy-induced nausea and vomiting. Easing patients fear and discomfort with effective antiemetic regimens. Postgrad Med 1993;94:55-58, Hesketh PJ, Kris MG, Grunberg SM et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997;15: Carmichael J, Keizer HJ, Cupissol D et al. Use of granisetron in patients refractory to previous treatment with antiemetics. Anticancer Drugs 1998;9: Feyer PC, Stewart AL, Titlbach OJ. Aetiology and prevention of emesis induced by radiotherapy. Support Care Cancer 1998;6: De Mulder PH, Seynaeve C, Vermorken JB et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting: a multicenter, randomized, double-blind, crossover study. Ann Intern Med 1990;113: Osoba D, Zee B, Pater J et al. Determinants of postchemotherapy nausea and vomiting in patients with cancer. Quality of Life and Symptom Control committees of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1997;15: Roila F, Tonato M, Basurto C et al. Antiemetic activity of high doses of metoclopramide combined with methylprednisolone versus metoclopramide alone in cisplatin-treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research. J Clin Oncol 1987;5: The new word in designer drugs. BMJ 1998;316: Kaiser R, Sezer O, Papies A et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 2002;20: Blower P, Aapro M. Granisetron vs ondansetron: is it a question of duration of 5-HT 3 receptor blockade? Br J Cancer 2002;86: ; author reply Roila F, Boschetti E, Tonato M et al. Predictive factors of delayed emesis in cisplatin-treated patients and antiemetic activity and tolerability of metoclopramide or dexamethasone. A randomized single-blind study. Am J Clin Oncol 1991;14: Italian Group for Antiemetic Research. Ondansetron + dexamethasone vs metoclopramide + dexamethasone + diphenhydramine in prevention of cisplatin-induced emesis. Lancet 1992;340: Roila F. Ondansetron plus dexamethasone compared to the standard metoclopramide combination. Oncology 1993;50: Gralla RJ. Antiemetic treatment for cancer chemotherapy: problems and progress. Support Care Cancer 1994;2: Heron JF. Single-agent oral granisetron for the prevention of acute cisplatin-induced emesis: a double-blind, randomized comparison with granisetron plus dexamethasone and highdose metoclopramide plus dexamethasone. Semin Oncol 1995;22(suppl 10): de Wit R, van den Berg H, Burghouts J et al. Initial high antiemetic efficacy of granisetron with dexamethasone is not maintained over repeated cycles. Br J Cancer 1998;77: Italian Group for Antiemetic Research. Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of cisplatin-induced emesis. Ann Oncol 1995;6: Dupuis LL, Lau R, Greenberg ML. Delayed nausea and vomiting in children receiving antineoplastics. Med Pediatr Oncol 2001;37: Navari R, Gandara D, Hesketh P et al. Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. The Granisetron Study Group. J Clin Oncol 1995;13: Sussman N. Reactions of patients to the diagnosis and treatment of cancer. Anticancer Drugs 1995;6(suppl 1): Marty M, Kleisbauer JP, Fournel P et al. Is Navoban (tropisetron) as effective as Zofran (ondansetron) in cisplatininduced emesis? The French Navoban Study Group. Anticancer Drugs 1995;6(suppl 1): Anastasia PJ. Effectiveness of oral 5-HT 3 receptor antagonists for emetogenic chemotherapy. Oncol Nurs Forum 2000;27: Endo T, Minami M, Kitamura N et al. Effects of various 5-HT 3 receptor antagonists, granisetron, ondansetron, ramosetron and azasetron on serotonin (5-HT) release from the ferret isolated ileum. Res Commun Mol Pathol Pharmacol 1999;104: Andrews PL, Davis CJ, Bingham S et al. The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J Physiol Pharmacol 1990;68: Gralla RJ, Navari RM, Hesketh PJ et al. Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy. J Clin Oncol 1998;16: Del Favero A, Roila F, Tonato M. Reducing chemotherapyinduced nausea and vomiting. Current perspectives and future possibilities. Drug Saf 1993;9: Andrews PL, Bhandari P, Davey PT et al. Are all 5-HT 3 receptor antagonists the same? Eur J Cancer 1992;28A(suppl 1):S2-S6.

11 197 CINV: Acute Antiemetic Control 42 van Wijngaarden I, Tulp MT, Soudijn W. The concept of selectivity in 5-HT receptor research. Eur J Pharmacol 1990;188: Zofran (ondansetron hydrochloride) Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline, Kytril (granisetron hydrochloride) Prescribing Information. Nutley, NJ: Roche Laboratories Inc., Upward JW, Arnold BDC, Hideyukiu A et al. The clinical pharmacology of granisetron (BRL 43694): a novel specific 5-HT 3 -receptor antagonist. Jpn J Cancer Chem 1990;23: Lindley C, Blower P. Oral serotonin type 3-receptor antagonists for prevention of chemotherapy-induced emesis. Am J Health Syst Pharm 2000;57: Hesketh P, Navari R, Grote T et al. Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. J Clin Oncol 1996;14: Fauser AA, Bleiberg H, Chevallier B et al. A double-blind, randomized, parallel study of IV dolasetron mesilate versus IV metoclopramide in patients receiving moderately emetogenic chemotherapy. Cancer J 1996;9: Chevallier B. Efficacy and safety of granisetron compared with high-dose metoclopramide plus dexamethasone in patients receiving high-dose cisplatin in a single-blind study. The Granisetron Study Group. Eur J Cancer 1990;26(suppl 1):S33-S Marty M, Pouillart P, Scholl S et al. Comparison of the 5- hydroxytryptamine3 (serotonin) antagonist ondansetron (GR38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990;322: Koeller JM, Aapro MS, Gralla RJ et al. Antiemetic guidelines: creating a more practical treatment approach. Support Care Cancer 2002;10: Perez EA, Hesketh P, Sandbach J et al. Comparison of singledose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randomized parallel study. J Clin Oncol 1998;16: Jantunen IT, Flander MK, Heikkinen MI et al. Comparison of ondansetron with customary treatment in the prophylaxis of nausea and emesis induced by non-cisplatin containing chemotherapy. Acta Oncol 1993;32: Bleiberg HH, Spielman M, Falkson G et al. Antiemetic treatment with oral granisetron in patients receiving moderately emetogenic chemotherapy: a dose-ranging study. Clin Ther 1995;17: Roila F, Bracarda S, Tonato M et al. Ondansetron (GR38032) in the prophylaxis of acute and delayed cisplatin-induced emesis. Clin Oncol (R Coll Radiol) 1990;2: Ruff P, Paska W, Goedhals L et al. Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomised, parallel-group study. Oncology 1994;51: Audhuy B, Cappelaere P, Martin M et al. A double-blind, randomised comparison of the anti-emetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy. Eur J Cancer 1996;32A: Beck TM, Hesketh PJ, Madajewicz S et al. Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two singledose regimens in the prevention of cisplatin-induced nausea and vomiting. J Clin Oncol 1992;10: Sanchez LA, Holdsworth M, Bartel SB. Stratified administration of serotonin 5-HT 3 receptor antagonists (setrons) for chemotherapy-induced emesis. Economic implications. Pharmacoeconomics 2000;18: Seynaeve C, Schuller J, Buser K et al. Comparison of the anti-emetic efficacy of different doses of ondansetron, given as either a continuous infusion or a single intravenous dose, in acute cisplatin-induced emesis. A multicentre, doubleblind, randomised, parallel group study. Ondansetron Study Group. Br J Cancer 1992;66: Olver I, Paska W, Depierre A et al. A multicentre, doubleblind study comparing placebo, ondansetron and ondansetron plus dexamethasone for the control of cisplatin-induced delayed emesis. Ondansetron Delayed Emesis Study Group. Ann Oncol 1996;7: Hesketh PJ, Beck T, Uhlenhopp M et al. Adjusting the dose of intravenous ondansetron plus dexamethasone to the emetogenic potential of the chemotherapy regimen. J Clin Oncol 1995;13: Anzemet Tablets (dolasetron mesylate) Prescribing Information. Kansas City, MO: Hoechst Marion Roussel Inc., Fauser AA, Duclos B, Chemaissani A et al. Therapeutic equivalence of single oral doses of dolasetron mesilate and multiple doses of ondansetron for the prevention of emesis after moderately emetogenic chemotherapy. European Dolasetron Comparative Study Group. Eur J Cancer 1996;32A: Rubenstein EB, Gralla RJ, Hainsworth JD et al. Randomized, double blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy. Oral Dolasetron Dose-Response Study Group. Cancer 1997;79: Perez EA, Tiemeier T, Solberg LA. Antiemetic therapy for high-dose chemotherapy with transplantation: report of a retrospective analysis of a 5-HT 3 regimen and literature review. Support Care Cancer 1999;7: Abbott B, Ippoliti C, Bruton J et al. Antiemetic efficacy of granisetron plus dexamethasone in bone marrow transplant patients receiving chemotherapy and total body irradiation. Bone Marrow Transplant 1999;23: Fauser AA, Russ W, Bischoff M. Oral dolasetron mesilate (MDL 73,147EF) for the control of emesis during fractionated total-body irradiation and high-dose cyclophosphamide in patients undergoing allogeneic bone marrow transplantation. Support Care Cancer 1997;5: