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Antiemetic therapy

1. EMESIS INDUCED BY CONVENTIONAL-DOSE CHEMOTHERAPY

1.0 General strategy

The emetogenic potential of cancer chemotherapeutic agents varies. However, classification is arbitrary because the emetogenic characteristics of many chemotherapeutic agents, such as frequency, intensity, duration and the latency to feeling nausea or vomiting after drug administration are unknown. Furthermore, the emetogenic potential of a single agent can vary if it is given in combination with other chemotherapeutic agents, and emesis is also influenced by dosage of the chemotherapeutic drug the duration of its infusion and also patients’ individual characteristics, such as gender, age, a history of chronic alcohol intake, previous experience of emesis either during pregnancy or during earlier cancer treatment, susceptibility to motion sickness, etc. Generally, emetogenic potential of intravenously administered drugs is considered high (> 90% of incidence) for cisplatin, dacarbazine, carmustine, mechlorethamine, dactinomycin and cyclophosphamide ≥1500 mg/m2 and cyclophosphamide plus epirubicin and doxorubicin in breast cancer patients; moderate (30%-90%) for oxaliplatin, cyclophosphamide < 1500 mg/m2, ifosfamide, cytosine-arabinoside, anthracyclines, carboplatin, irinotecan, idarubicine, bendamustine, clofarabine, alemtuzumab and azacitidine; low (10%-30%) for paclitaxel, docetaxel, mitoxantrone, topotecan, gemcitabine, etoposide, teniposide, pemetrexed, methotrexate, mitomycin-C, fluorouracil, bortezomib, cetuximab, trastuzumab, temsirolimus, catumaxumab, ixabepilone and panitumumab and minimal (< 10%) for bleomycin, busulfan, fludarabine, vinca alkaloids, rituximab, bevacizumab.  Recently also oral antineoplastic agents have been classified accordingly (Grunberg 2005): hexamethylmelamine and procarbazine as highly emetogenic agents, cyclophosphamide, temozolomide, vinorelbine and imatinib as moderately, capecitabine, fludarabine, everolimus, lapatinib, sunitinib, lenalidomide and thalidomide as lowly and chlorambucil, hydroxyurea, l-phenylalanine mustard, 6-thioguanine, methotrexate, gefitinib, erlotinib, and sorafenib as minimally emetogenic chemotherapy. Since oral agents tend to be given daily for several days to several weeks, emetogenicity can only be judged for the entire period without a distinction between acute and delayed emesis, and antiemetic regimens will tend to differ from those recommended for single dose intravenous chemotherapeutic agents. Of the highly emetogenic agents cisplatin has been the most studied. An optimal antiemetic schedule is capable of preventing acute emesis induced by cisplatin in 70-80% of cases, can prevent delayed emesis due to cisplatin in 60% of cases and prevents acute emesis induced by moderately emetogenic agents in about 90% of cases. It is noteworthy that the incidence of delayed emesis is low in patients who do not experience acute vomiting, while it is substantial in patients who do. For this reason, the prevention of acute vomiting is very important. Few studies have been conducted in the field of the antiemetic prophylaxis required in special situations, such as high-dose chemotherapy and radiation therapy. Paediatric antiemetic therapy is similar to that employed in adults. Some differences in the pharmacokinetics as well as toxicity profiles of antiemetics in children have been demonstrated. Bearing these facts in mind it seems reasonable, at least until more studies are conducted in children, to use adult trial data for deciding upon suitable paediatric therapy.

1.1 Prevention of acute emesis induced by cisplatin

1.1.1 Prevention of acute emesis induced by cisplatin

The combination of high-dose metoclopramide, plus steroids, plus diphenhydramine or lorazepam is able to achieve complete protection from acute emesis in about 60% of patients. Until about fifteen years ago this combination was regarded as the standard treatment (Del Favero 1993), but has been superseded by the 5HT3 receptor antagonists and more recently by the NK1 receptor antagonists. Since the introduction of the 5-HT3-receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron) many studies have been conducted into their efficacy. 5-HT3-receptor antagonists achieve complete protection from acute cisplatin-induced emesis in 40-60% of patients (Del Favero 1993). Several studies comparing the various 5-HT3 receptor antagonists, have shown equivalent efficacy and tolerability for ondansetron, granisetron, and dolasetron on a type 1 level of evidence (IGAR 1995b; Navari 1995a). The combination of 5-HT3-receptor antagonists plus dexamethasone is superior to 5-HT3-receptor antagonists alone since it is able to provide complete protection from acute emesis in about 70-90% of patients, on a type 1 level of evidence (Roila 1996). A combination of 5-HT3-receptor antagonists plus dexamethasone versus a combination of high-dose metoclopramide, plus dexamethasone, plus diphenhydramine or lorazepam was evaluated in two large double-blind, randomized studies in patients receiving single high dose (> 50 mg/m2) cisplatin (Cunningham 1996; IGAR 1992). Complete protection from both vomiting and nausea was significantly superior with ondansetron plus dexamethasone and this regimen was better tolerated. Furthermore, complete protection from vomiting was maintained from the first to third cycle of chemotherapy in the ondansetron group, although protection from nausea decreased significantly with this regimen (Cunningham 1996; IGAR 1993). Therefore an intravenous combination of 5-HT3 receptor antagonists plus single dose dexamethasone has been regarded as standard treatment on a type 1 level of evidence until recently.
No differences between the 5-HT3 receptor antagonists in terms of efficacy and/or tolerability has been demonstrated, so that the choice of drugs within this class should be based essentially on the cost in different countries, taking into account their optimal dose and scheduling (Warr 1997; Roila 1997).
Recently, two studies have compared palonosetron, a 5-HT3 receptor antagonist with a long half life (about 40 hours) with ondansetron and granisetron in the prevention of cisplatin-induced acute emesis. In the first study, two different doses (0.25 and 0.75mg iv) of palonosetron have been compared with 32 mg iv of ondansetron. Only 67% of patients was submitted to dexamethasone, as they should have been, in the first 24 hours. Complete response (no vomiting and no rescue treatment) was not significantly different among the three arms .  The second study, a double-blind study carried out in 1114 patients, compared palonosetron 0.75 mg iv with granisetron 40 μg/kg iv, both combined with dexamethasone 16 mg iv followed by 8 mg iv (cisplatin-treated patients) or 4 mg orally (anthracyclines + cycophosphamide treated patients) on day 2-3. The complete response was similar in the first 24 hours  (75.3% versus 73.3%, respectively) but significantly superior with palonosetron on day 2-5 (56.8% versus 44.5%) and on day 1-5 (51.5% versus 40.4%) (Saito 2009). Despite some shortcomings of this last study (i.e., cisplatin and non-cisplatin treated patients were combined, doses of dexamethasone were different from those generally used for acute and delayed emesis prophylaxis, etc.) the similar results achieved in the first 24 hours permit us to conclude that, due to its longer half-life, palonosetron induced more protection from delayed emesis that a single administration before chemotherapy of granisetron. This study does not address the issue of whether palonosetron is superior to other 5-HT3 antagonists when an NK1 antagonist is used as recommended by guidelines (see after). Therefore, considering the negative results achieved in one study, more studies are necessary before to recommend palonosetron as the 5-HT3 antagonist of choice to prevent cisplatin-induced acute emesis.
Interesting results with aprepitant, a neurokinin NK1 receptor antagonist, have been achieved in some phase II studies where this drug was combined with a 5-HT3 antagonist and dexamethasone (Hesketh 2001). Recently , two phase III double-blind studies have been published in which the standard treatment (ondansetron 32 mg iv plus oral dexamethasone 20 mg in the first 24 hours and oral dexamethasone 8 mg twice daily on days 2-4) was compared with an aprepitant regimen (oral aprepitant 125 mg plus ondansetron 32 mg iv and oral dexamethasone 12 mg in the first 24 hours; oral aprepitant 80 mg plus oral dexamethasone 8 mg on day 2 and 3 and oral dexamethasone 8 mg on day 4). In the aprepitant arm the dexamethasone dose was reduced due to a pharmacokinetic interaction with aprepitant that increases its plasma level more than two fold. In the first study 569 patients were enrolled (Poli-Bigelli 2003). The complete response (no vomiting and no rescue treatment) was significantly superior with aprepitant compared with the standard treatment (62.7% versus 43.3% on days 1-5, 82.8% versus 68.4% on day 1 and 67.7% versus 46.8% on days 2-5 respectively). Also complete protection from nausea was significantly superior with aprepitant. In the second study 530 patients were enrolled. Aprepitant induced a significantly superior complete response than standard treatment (72.7% versus 52.3% on days 1-5, 89.2% versus 78.1% on day 1 and 75.4% versus 55.8% on days 2-5) (Hesketh 2003). Complete response from nausea was not significantly different. In both studies adverse effects were mild and not significantly different between the two groups of patients.
Recently fosaprepitant has been approved, a water-soluble phosphoryl prodrug for aprepitant, that when administered intravenously is converted within 30 minutes to aprepitant. A dose of 115 mg of fosaprepitant was bioequivalent in its AUC to aprepitant 125 and can be used as parenteral alternative to oral aprepitant on day 1 of a 3-day oral aprepitant regimen (Navari 2007; Lasseter 2007). Clinical trials, still lacking, are necessary to evaluate the efficacy of intravenous fosaprepitant with respect to oral aprepitant.
Casopitant, a new neurokinin-1 receptor antagonist, has been first evaluated in a double-blind, dose ranging study in 493 patients receiving cisplatin chemotherapy. The addition of casopitant to ondansetron plus dexamethasone at doses of 50 mg, 100 mg and 150 mg administered orally on day 1-3, significantly reduced emesis on days 1-5 (complete responses in 76%, 86%, 77% of patients, respectively, versus 60% with ondansetron and dexamethasone alone (Roila 2009). In this study an exploratory arm using oral casopitant 150 mg only on day 1 obtained 75% complete responses. A subsequent phase III study evaluated in 810 patients submitted to cisplatin the addition of 150 mg single oral dose or of an intravenous dose on day 1, 90 mg, followed by oral casopitant 50 mg on day 2 and 3 to ondansetron plus dexamethasone with respect the two drugs without casopitant. Complete response was significantly superior with the addition of casopitant on day 1-5 (86%, 80% versus 66% respectively), on day 1 (95%, 94% versus 88%),  and on day 2-5 (86%, 80% versus 66%) (Grunberg 2009). Casopitant has not yet be approved by the regulatory agencies. In conclusion, an NK1 antagonist combined with a 5-HT3 antagonist and dexamethasone significantly increases antiemetic efficacy with respect to a 5-HT3 antagonist and dexamethasone and the triple combination should be considered the new standard option for the prevention of cisplatin-induced acute emesis on a type 1 evidence.
Complete protection from vomiting after low and repeated doses (20-40 mg/m2/day for 3-5 days) cisplatin was significantly superior with daily ondansetron (or dolasetron) plus dexamethasone (complete control around 55-80%) compared with high-dose metoclopramide plus dexamethasone (Rath 1993), with ondansetron (or dolasetron) alone (Fo x 1993) and with alizapride and dexamethasone (Nicolai 1993). The optimal scheduling remains to be clarified. The combination treatment is more effective than single agent used alone, even though its efficacy needs to be improved and total protection over the whole period of treatment is relatively poor. An interaction between acute and delayed emesis may be responsible for suboptimal results. Therefore, an intravenous combination of single dose 5-HT3-receptor antagonists plus dexamethasone (repeated every day of chemotherapy) may be regarded as the standard option for the prevention of emesis induced by low repeated doses of cisplatin (20-40 mg/m2/day for 3-5 days), on a type 1 level of evidence. Randomized clinical trials are needed to evaluate whether an NK1 antagonist can improve the control of emesis in this subgroup of patients.

1.1.2 Schedule

A single iv dose administration of a 5-HT3-receptor antagonists and dexamethasone 12 mg plus oral aprepitant is the standard option on a type 2 level of evidence.
The optimal dose of aprepitant is 125 mg orally 1 hour before the cisplatin administration (Chawla 2003). Effective single iv dose levels have been established for all the 5-HT3-receptor antagonists: Ondansetron 8 mg has been reported to be inferior to 32 mg in one randomised study (Beck 1992) even though in two other studies this difference was not observed (Ruff 1994; Seynaeve 1992), so that the standard dose is 8 mg. The optimal single dose of granisetron has been established to be 10 mcg/kg (1 mg) (Navari 1995a) on a type 1 level of evidence, even though in most studies granisetron has been employed at 40 mcg/kg (3 mg). The dose of tropisetron is 5 mg (Van Belle 1994) and that of dolasetron is 1.8 mg/kg (Hesketh 1996). The dose of palonosetron is 0.25 mg iv (Eisenberg 2003; Gralla 2003). Oral administration of 5-HT3 antagonists has been shown to have similar efficacy to intravenous administration (Gralla 1998; Krzakowski 1998).
The optimal iv dose of dexamethasone in the prevention of cisplatin-induced acute emesis has been identified in a dose finding study carried out in 531 patients in which dexamethasone was combined with ondansetron (IGAR 1998). A 20 mg single dose iv was shown to be significantly superior to 4 and 8 mg dexamethasone and superior, although not significantly, to 12 mg iv. Since adverse events were mild and not significantly different between the four doses, 20 mg iv dexamethasone should be considered the optimal dose when used with a 5-HT3 antagonist without aprepitant.

1.2 Prevention of delayed emesis induced by cisplatin

1.2.1 Prevention of delayed emesis induced by cisplatin

Delayed emesis has arbitrarily been defined as nausea and vomiting starting around 16-24 hours after administration of cisplatin. Mechanisms mediating delayed emesis may differ from acute emesis, since the specific serotonin antagonist antiemetics are much less effective during the delayed period. It is noteworthy that the incidence of delayed emesis is low in patients who did not have acute vomiting while it is substantial in patients who did. For this reason prevention of acute vomiting is very important. The combination of orally administered metoclopramide (0.5 mg/kg four times daily on days 2-5) plus dexamethasone (8 mg twice daily on days 2-3 and 4 mg twice daily on days 4-5) provides complete protection from delayed vomiting in around 50% of patients and it is superior to either dexamethasone or placebo on a type 2 level of evidence (Kris 1989). The 5-HT3 receptor antagonists used alone showed, at best, only a moderate activity against delayed emesis, on a type 2 level of evidence (Navari 1995b). The combination of granisetron or ondansetron plus dexamethasone is equivalent to dexamethasone alone, on a type 2 level of evidence (Latreille 1998). There is some evidence that the combination of a 5-HT3 receptor antagonist and steroids is superior to 5-HT3 receptor antagonist alone, on a type 2 level of evidence (Gebbia 1995; Gridelli 1996). A recent randomized study demonstrated equivalent prevention of delayed emesis by oral metoclopramide combined with intramuscular dexamethasone and oral ondansetron combined with intramuscular dexamethasone: complete protection from delayed vomiting was around 60% and complete protection from delayed nausea around 45-50% (IGAR 1997a). Due to its lower costs, metoclopramide plus dexamethasone is considered the standard option for the prevention of delayed emesis on a type C basis. In patients who do not tolerate metoclopramide the standard option is regarded as ondansetron in combination with dexamethasone on a type R basis. In the phase II double-blind trials aprepitant produced some interesting activity against cisplatin-induced delayed emesis (Navari 1999). In two phase III trials the complete response on days 2-5 was significantly superior with aprepitant (80 mg orally on days 2 and 3) plus dexamethasone than with dexamethasone alone (Hesketh 2003 ; Poli-Bigelli 2003). Therefore, two recently published guidelines for the prevention of cisplatin-induced delayed emesis, recommended a combination of aprepitant plus dexamethasone in patients treated with a combination of aprepitant, a 5-HT3 antagonist and dexamethasone to prevent acute nausea and vomiting, on the basis of its superiority to dexamethasone alone (Kris 2006; Roila 2006). Unfortunately, in both studies the treatment of choice for cisplatin-induced delayed emesis was not used. Therefore, to define the role of aprepitant in the prophylaxis of cisplatin-induced delayed emesis it is necessary to carry out further studies in which all patients receive the same standard combination of aprepitant plus a 5-HT3 antagonist plus dexamethasone for the prevention of cisplatin-induced acute emesis, and, starting from 24 hours after cisplatin administration, patients should be randomized to receive dexamethasone plus metoclopramide (or ondansetron) or dexamethasone plus metoclopramide (or ondansetron) plus aprepitant.

1.2.2 Schedule

The recommended antiemetic schedules are: – oral aprepitant 80 mg on day 2 and 3 + oral dexamethasone 8 mg on day 2-4; – oral metoclopramide 20 mg or 0.5mg/kg every 6 hours days 2 through 4 + dexamethasone po or im 8 mg twice on days 2 and 3, and 4 mg twice on day 4 or as: oral ondansetron 8 mg twice days 2 through 4 + dexamethasone po or im 8 mg twice on days 2 and 3, and 4 mg twice on day 4.

1.3 Prevention of acute emesis induced by moderately emetogenic chemotherapy

1.3.1 Prevention of acute emesis induced by moderately emetogenic chemotherapy
High and repeated doses of dexamethasone (8 mg iv before chemotherapy plus 4 mg orally every 6 hours for four doses, starting at the time of chemotherapy) or methylprednisolone (40-125 mg iv or im every six hours for three doses, starting half an hour before chemotherapy) achieve around 60-80% complete protection from acute vomiting induced by moderately emetogenic chemotherapy (cyclophosphamide, doxorubicin, epirubicin, carboplatin used alone or in combination) (Del Favero 1993). However, even single dose dexamethasone (20 mg) has been associated with a complete protection rate of 74% (Parry 1991). Corticosteroids are equivalent or superior in terms of efficacy to repeated low doses of metoclopramide, but they are better tolerated (Del Favero 1993). Various 5-HT3 receptor antagonists have shown to be superior to metoclopramide, alizapride or phenothiazines on a type 1 level of evidence. When used alone, the percentage of complete protection from vomiting varies from 50% to 70%. In two randomized, double-blind studies ondansetron or granisetron were compared with dexamethasone used at high and repeated doses. Both 5-HT3 receptor antagonists and dexamethasone were found to be equally effective in the control of acute nausea and vomiting (complete control around 70%), but dexamethasone achieved better control of delayed nausea and vomiting (IGAR 1995a; Jones 1991). In another study, complete protection from acute vomiting was shown to be superior in patients treated with combination of dexamethasone plus granisetron (93%) compared with dexamethasone or granisetron alone (around 70%), (IGAR 1995a). The protective effect of the combination persists during three consecutive cycles (IGAR 1995c). Finally, ondansetron 8 mg iv plus dexamethasone 16 mg iv single-dose achieved over 90% complete control from acute emesis in a study (Soukop 1992).
Therefore, before the introduction of the NK1 receptor antagonists, the standard option for the prevention of acute emesis induced by moderately emetogenic chemotherapy was the combination of dexamethasone plus a 5-HT3 receptor antagonists, on a type 1 level of evidence (IGAR 1995a; Soukop 1992).
Two different doses (0.25 and 0.75mg iv) of palonosetron have been compared, in two double-blind studies, with ondansetron and dolasetron. In these studies 0.25 mg of palonosetron induced superior  complete protection from acute and delayed emesis (Eisenberg 2003; Gralla 2003). Unfortunately, in these studies the 5-HT3 antagonists were often not given – as they should have been – with dexamethasone for the prophylaxis of acute emesis and no prophylaxis for delayed emesis was administered. Additionally, several patients were pretreated and may have had mild nausea in previous courses, and although the distribution of pretreated patients was similar among the three arms, it was not known if the distribution among the three arms of patients with mild nausea was also similar. More recently, these results have been confirmed by another study comparing palonosetron with granisetron, both combined with dexamethasone for the prevention of acute and delayed emesis (Saito 2009). Therefore, to prevent acute emesis induced by moderately emetogenic chemotherapy different from a combination of an antracycline plus cyclophosfamide for breast cancer patients, a combination of palonosetron plus dexamethasone is the standard prophylaxis on a type 1 evidence.
A double-blind study comparing orally aprepitant (125 mg) plus dexamethasone (12 mg) plus ondansetron (8 mg before and 8 mg 8 hours after the chemotherapy) on day 1 and aprepitant 80 mg on day 2 and 3, with orally ondansetron (8 mg before and 8 mg 8 hours after) plus dexamethasone (20 mg) on day 1 and ondansetron 8 mg twice on day 2 and 3 in 866 patients with breast cancer receiving cyclophosphamide ± doxorubicin or epirubicin has been published (Warr 2005). Overall complete response was significantly superior with the aprepitant regimen than with the control regimen (50.8% versus 42.5%). Complete response on day 1 and on days 2-5 was also statistically superior with aprepitant (76% versus 69% and 55% versus 49%, respectively). Adverse events were not significantly different between the two regimens.
Recently, casopitant has been evaluated in a double-blind, dose ranging study in 719 patients submitted to moderately emetogenic chemotherapy. The addition of casopitant to ondansetron plus dexamethasone at doses of 50 mg, 100 mg and 150 mg administered orally on day 1-3, significantly reduced emesis on days 1-5 (complete responses in 81%, 79%, 85% of patients, respectively, versus 70% with ondansetron and dexamethasone alone (Airpornwirat 2006). In this study an exploratory arm using oral casopitant 150 mg only on day 1 obtained 80% complete responses. A subsequent phase III study, published only as an abstract, carried out in 1933 breast cancer patients submitted to an anthracycline plus cyclophosphamide-based chemotherapy compared the addition of 150 mg single oral dose or of oral 150 mg on day 1 and 50 mg on day 2-3 or of an intravenous dose on day 1, 90 mg, followed by oral casopitant 50 mg on day 2 and 3 to ondansetron plus dexamethasone with respect the two drugs without casopitant. In the first 24 hours the complete response was similar with or without the addition of casopitant 88%, 89%, and 86%, respectively versus 85% with dexametasone and ondansetron alone, while was significantly superior with the addition of casopitant on day 2-5 (73%, 73% and 74% versus 59%) (Grunberg 2008; Aziz 2008). Therefore, the combination of a NK1 receptor antagonist plus a 5-HT3 receptor antagonist and dexamethasone is the standard prophylaxis for the prevention of acute emesis induced by an anthracycline plus cyclophosphamide in women with breast cancer on a type 1 level of vidence.

1.3.2 Schedule

For patients with breast cancer submitted to a combination of an anthracycline plus cyclophosphamide the optimal scheduling is oral aprepitant 125 mg + dexamethasone + a 5-HT3 antagonist.
In patients submitted to moderately emetogenic chemotherapy different from an anthracycline plus cyclophosphamide combination the optimal scheduling is intravenous palonosetron 0.25 mg + dexamethasone.
The optimal dose and schedule of dexamethasone has been recently identified by a double-blind randomized study which compared: – 8 mg iv followed by 4 mg orally every 6 hours for 4 doses starting concomitantly with the chemotherapy administration with – 24 mg single dose iv and – 8 mg single dose iv immediately before chemotherapy (IGAR 2004). In this study all patients received 8 mg ondansetron iv on day 1 and oral dexamethasone 4 mg twice daily on days 2-5 after chemotherapy. The complete protection from acute vomiting/nausea was not significantly different among the three antiemetic regimens: 84.6% / 66.7% with 8 mg iv plus 16 mg orally, 83.6% / 56.9% with 24 mg iv and 89.2% / 61.0% with 8 mg iv, respectively. Also the complete protection from delayed vomiting and nausea was not significantly different neither were the adverse events. Therefore, a single iv dose of 8 mg dexamethasone is the standard dose on a type 1 level of evidence .

1.3.3 Prevention of acute emesis by oral CMF

In the prevention of emesis induced by oral CMF, a combination of single-dose dexamethasone on days 1 and 8 (10 mg iv), plus 14 days of oral metoclopramide (10 mg, 3 times daily) or ondansetron alone (8 mg, 3 times daily) for 15 days are able to achieve complete protection from vomiting in over 70% of patients, and its use is suitable for individual clinical use on a type 1 level of evidence (Buser 1993; Levitt 1993). The comparison showed that patients receiving the metoclopramide combination regimen experienced significantly less nausea during the first 24 hours after chemotherapy (Levitt 1993).

1.4 Prevention of delayed emesis induced by moderately emetogenic chemotherapy

1.4.1 Prevention of delayed emesis induced by moderately emetogenic chemotherapy

The incidence of delayed vomiting/moderate-severe nausea is low (delayed vomiting 12%/ delayed nausea 14%) in patients who did not have acute vomiting or acute moderate-severe nausea, while it increases (delayed vomiting 55%, delayed nausea 75%) in patients who did (IGAR 1997b). Three comparative studies have been published, in which oral ondansetron (8 mg twice daily on days 2-5), or dolasetron (200 mg orally), or oral dexamethasone (4 mg twice daily on days 2-5) were better than placebo or no treatment (Kaizer 1994; Koo 1996; Pater 1997). Unfortunately, for all of these studies some methodological criticisms can be made. The results of a double-blind randomized study carried out in patients receiving moderately emetogenic chemotherapy for the first time have been recently published (IGAR 2000). In this study all patients received ondansetron combined with dexamethasone (the treatment of choice) for prophylaxis of acute emesis. Patients were then divided into two groups: those who did not have either acute vomiting or moderate-to-severe nausea (the low risk group) and patients who had one or both (the high risk group). Patients in the low risk group were then randomly assigned to one of the following regimens, given on days 2-5 after the start of chemotherapy: – oral placebo, – 4 mg of dexamethasone given orally twice daily, or – 8 mg of ondansetron in combination with 4 mg of dexamethasone, given orally twice daily. Patients in the high risk group were randomly assigned to receive oral dexamethasone alone or in combination with ondansetron at the same doses as those used in the low risk group. Among the 618 patients in the low-risk group there was a significantly more complete protection from delayed vomiting and moderate-to-severe nausea in patients who received ondansetron plus dexamethasone (91.8%) and dexamethasone alone (87.4%) than in those who received placebo (76.8%). In these patients ondansetron significantly increased the incidence of constipation. Of the 87 patients in the high-risk group complete protection was achieved in 40.9% of those treated with ondansetron plus dexamethasone and in 23.3% treated with dexamethasone alone, a not statistically significant difference. In conclusion all patients submitted to moderately emetogenic chemotherapy should receive prophylactic antiemetics for delayed emesis. The standard option is dexamethasone 4 mg orally two times daily on days 2-4 on a type 1 level of evidence.
In the phase III study (Warr 2005) aprepitant has been shown superior to a 5-HT3 antagonist in the prevention of delayed emesis induced by moderately emetogenic chemotherapy in breast cancer patients receiving a combination of an anthracycline plus cyclophosphamide and treated with a combination of aprepitant, a 5-HT3 antagonist and dexamethasone to prevent acute nausea and vomiting. On this basis, aprepitant can be recommended on day 2 and 3 in these patients even if no superiority with respect to dexamethasone has been until now demonstrated. Therefore, randomized, double-blind studies comparing aprepitant with dexamethasone for the prevention of delayed emesis induced by moderately emetogenic chemotherapy are needed. The optimal duration and dose of dexamethasone have not been defined.

1.5 Prevention of anticipatory emesis

1.5.1 Prevention of anticipatory emesis

Anticipatory nausea and vomiting develops in around 30% of patients by the fourth treatment cycle. These figures refer to the pre-5HT3 receptor antagonists era. Anticipatory nausea and vomiting develop only in patients who experienced post-treatment nausea and vomiting at least once. Some degree of anxiety may facilitate this conditioning process. Once they develop, anticipatory nausea and vomiting cannot be controlled by antiemetics, including 5-HT3 receptor antagonists. Optimal treatment of anticipatory emesis is first of all optimal treatment of acute/delayed nausea and vomiting on a type 3 level of evidence (Morrow 1998). A preventive treatment with low-dose alprazolam (0.5 m to 2 mg daily) is suitable for individual clinical use on a type 2 level of evidence (Razavi 1993). Behavioural interventions such as desensitization, counterconditioning and hypnosis are suitable for individual clinical use on a type 2 level of evidence.

1.6 Rescue of antiemetic treatment failure

1.6.1 Definition of treatment failure

A strict definition of treatment failure is lacking. It is defined by different authors as the presence of any vomiting, or vomiting more than 3 times, or 5 times, with or without nausea.

1.6.2 Rescue medication after optimal prevention of acute and delayed emesis

It is likely that the majority of treatment failures are mediated through non-5-HT3-induced mechanisms (Herrstedt 1996). Research data are insufficient to enable any standard treatment to be recommended.
– In patients experiencing emesis after an appropriate preventive treatment, either a repeated dose of the same 5HT3 antagonist, or another compound of the same class, or the addition of a dopamine antagonist with or without steroids, or the addition of sedatives are suitable for individual clinical use on a type R basis.
– In patients failing at previous cycle with ondansetron plus methylprednisolone, the addition of metopimazine at the subsequent cycle induced significantly better complete control of emesis over the whole course of chemotherapy (53% vs 33%) and this triple drug combination is suitable for individual clinical use on a type 1 level of evidence (Lebeau 1997).
–  2 vomits, severe nausea or nausea > Patients failing (> 4 hours) at previous cycle within 24 hours after cisplatin or cyclophosphamide while they received an antiemetic prophylaxis with ondansetron 8 mg iv and dexamethasone 10 mg iv have been randomized at subsequent cycle between continued treatment with ondansetron plus dexamethasone and granisetron 3 mg iv plus dexamethasone 10 mg iv (de Wit 2001). In a double-blind study in 40 patients a significant benefit from crossing-over to granisetron after failure on ondansetron was found (9/19 versus 1/21 patients achieved complete protection). Considering the very low number of patients evaluated with possible different risk of emesis at the subsequent cycle of chemotherapy these results should be confirmed in a large double-blind study.

1.6.3 Rescue medication after suboptimal treatment

Suboptimal treatment means either an insufficient dose of 5-HT3 receptor antagonists, or its use without corticosteroids and aprepitant. The dosages defined in the optimal treatment schedule are recommended for use as standard rescue medication, on a type R basis.

1.7 Selected Reviews

1. The Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC). Prevention of chemotherapy- and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol 2006; 17: 20-28.
2. Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24: 2932-2947.

2. PREVENTION OF EMESIS INDUCED BY RADIOTHERAPY

2.0 General data

Emesis due to radiation treatment has an unclear origin. Emetogenic risk is related to the treatment field and could be classified as high (>90%) for total body irradiation and total nodal irradiation, moderate (60%-90%) for upper abdomen, half body irradiation and upper body irradiation, low (30-60%) for lower thoracic region and pelvic irradiation, cranium and craniospinal irradiation and for radiotherapy to the head and neck and minimal (< 30%) for radiotherapy, to the extremities and breast (Feyer 2005). Emesis induced by radiation is an acute event appearing from 30 minutes to 4 hours following irradiation. Psychological attitude to treatment may be important for emetic susceptibility. No data on the incidence and prevention of delayed emesis induced by radiation therapy are available.

2.1 Prevention of emesis during concomitant radiochemotherapy

In patients undergoing concomitant radiochemotherapy the antiemetic prophylaxis is according to the guidelines of chemotherapy induced nausea and vomiting choosing the risk category of the used chemotherapeutic regimen. However, in the case the risk category of radiotherapy is higher than the concomitant applied chemotherapy  the risk category of radiotherapy has to be chosen to tailor the antiemetic treatment.

2.2 Prevention of emesis in high risk patients

Studies on this topic are scanty. Evidence is in favour of a treatment with 5-HT3 receptor antagonists with respect to placebo, metoclopramide and chlorpromazine (Tyley 1992, Spitzer 1994, Prentice 1995, Sykes 1997). No randomized comparative studies adding dexamethasone to a 5-HT3 antagonists with respect to a 5-HT3 antagonist alone have been carried out.
TBI is associated with a high risk of radiotherapy-induced emesis. In this patients a prophylaxis with a 5-HT3 antagonist in combination with dexamethasone is the standard treatment on a type R basis.

2.3 Prevention of emesis in moderate risk patients

Evidence is in favour of a treatment with 5-HT3 receptor antagonists versus placebo or metoclopramide or prochlorperazine (Priestman 1990; Priestman 1993; Franzen 1996; Lanciano 2001)  on a type 1 level of evidence.
The role of corticosteroids in this indication has been recently defined in two double-blind studies on patients submitted to fractionated radiotherapy to the upper abdomen. In the first, 154 patients were randomized to receive prophylactic oral dexamethasone (2 mg orally three times daily, starting in the morning of first treatment and continuing until after the end of treatment) or placebo (Kirkbride 2000). Dexamethasone was statistically superior to placebo (complete protection 70% versus 37%). In the second, 211 patients received ondansetron 8 mg bid with either dexamethasone 4 mg daily or placebo during fractions 1 to 5 of at least 15 fractions of radiotherapy (Wong 2006). Dexamethasone improved the complete control of nausea during the prophylactic period (50% vs 38%) and the complete control of emesis during the overall study period (23% vs 12%).
In patients receiving radiotherapy with moderate emetogenic risk a prophylaxis with a 5-HT3 antagonist and optional in combination with short course (day 1-5) dexamethasone is the standard prophylaxis on a type 2 evidence.

2.4 Prevention of emesis in low risk patients

In patients receiving radiotherapy with low emetogenic risk a prophylaxis / a rescue (LeBurgeois 1999) with a 5-HT3 receptor antagonist is the standard on a type 2 evidence / type 3 level of evidence.

2.5 Prevention of emesis in minimal risk patients

In  patients receiving radiotherapy of minimal emetogenic risk a rescue with a dopamine receptor antagonist or prophylaxis with a 5-HT3 receptor antagonist is the standard on a type 3 evidence.

3. PREVENTION OF EMESIS INDUCED BY HIGH-DOSE CHEMOTHERAPY

3.1 Prevention of acute emesis induced by high-dose chemotherapy

High-dose chemotherapy is associated with a more severe acute nausea and vomiting than conventional dose chemotherapy. Several phase II trials have demonstrated that 5-HT3 receptor antagonists have significant activity in the prevention of acute nausea and vomiting due to high-dose chemotherapy (Barbounis 1995; Or 1994). Few randomised trials which only include a small number of patients are available (Agura 1995; Bosi 1993). Ondansetron was superior to metoclopramide and droperidol. Higher doses of ondansetron were not correlated with more antiemetic efficacy, and a continuous infusion of chlorpromazine was comparable to a continuous infusion of ondansetron. Continuous infusion of ondansetron was less frequently associated with sedation and extrapyramidal reactions. 5-HT3 receptor antagonists are the s tandard option, on a type C basis , for the prevention of acute emesis from high dose chemotherapy, even if the optimal schedule remains to be determined. Similar to the antiemetic therapy for conventional chemotherapy, combination-drug schedules with steroids may be more effective than 5-HT3 antagonists alone and such combination, considering that complete protection from nausea and vomiting is achieved in only a small proportion of patients receiving a 5-HT antagonist alone, is recommended on a type 3 level of evidence . Recently, a double-blind study in 102 patients showed the similar efficacy of oral ondansetron 8 mg every 8 hours, oral granisetron 1 mg every 12 hours and iv ondansetron 32 mg every 24 hours when combined with 10 mg iv dexamethasone daily during and 1 day after various preparative regimens (complete response was 48%, 47% and 49%, respectively) (Fox-Geiman 2001). In 104 breast cancer patients receiving high-dose chemotherapy and the same antiemetic prophylaxis with prochlorperazine, lorazepam and diphenhydramine the efficacy of electroacupuncture once daily for 5 days has been compared with minimal needling and mock electrical stimulation or antiemetic medication alone (Shen 2000). Electroacupuncture was more effective in controlling emesis than minimal needling or antiemetic pharmacotherapy alone (median number of emetic episodes occurring during 5 days was 5, 10 and 15, respectively). Unfortunately, in this study patients did not receive an optimal antiemetic treatment which could influence the study results.

3.2 Prevention of delayed emesis induced by high-dose chemotherapy

Very little is known about the prevention of delayed emesis, which is a frequent side effect of high dose chemotherapy. Some specific problems may influence the optimal choice of antiemetic therapy in this group of patients, such as the use of metoclopramide in the presence of diarrhoea and a possible pharmacokinetic interaction between dexamethasone and cyclophosphamide. Moreover it has been reported that gastroparesis could be responsible of nausea and vomiting in these patients (Brand 1998; Nordesjo-Haglund 1999).

4. EMESIS PREVENTION IN CHILDREN

4.1 Prevention of acute emesis in children

5-HT3 receptor antagonists have been employed alone in several open studies of acute emesis in children (Benoit 1995; Hewitt 1993). Control rates for moderately emetogenic chemotherapy may reach 80%, falling to 50-60% in case of highly emetogenic treatments. In all studies there is a consistent report of lack of significant side-effects and of a better efficacy in comparison with older antiemetic combinations, including metoclopramide, dexamethasone, benztropine and lorazepam (Dick 1995; Hahlen 1995). In one study the addition of methylprednisolone (10 mg/kg) to granisetron induced a significant reduction of acute emesis (95% vs 85%) this was also seen with the addition of dexamethasone (8mg/m2 iv followed by 8 mg/m2 iv every 4-6 hrs) to ondansetron (Alvarez 1995; Hirota 1993). For these reasons the standard option for antiemetic therapy for highly and moderately emetogenic chemotherapy is regarded as the combination of a 5-HT3 receptor antagonist and steroids on a type C basis, provided that there is no contraindication to the use of corticosteroids. The optimal dose and scheduling of the 5-HT3 receptor antagonists has been evaluated in nine trials, but, unfortunately, these studies are insufficient to identify their optimal oral and intravenous dose (Roila 2005). In clinical practice, typically used doses follow the adult mg/kg regimens (i.e. ondansetron 0.15 mg/kg and granisetron 0.01 mg/kg).

4.2 Prevention of delayed emesis in childrenDelayed emesis has not been studied in children.

4.3 Emesis prevention in children

For paediatric antiemetic therapy, the drugs and scheduling have been derived empirically from experience in adults. This is the case, even though some differences have been reported in parameters such as side effects incidence and pharmacokinetic drug profile. Moreover, dystonic reactions after metoclopramide or phenothiazines are more frequent in children than in adults. For this reason the administration of these drugs to the young population as first-line treatment is not recommended.

INDEX

 

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Dr. Lisa Licitra (Editor)
Start Clinical Editor – Istituto Nazionale Tumori – Milan, Italy
mail: lisa.licitra@istitutotumori.mi.it

Dr. Fausto Roila (Reviewer)
Ospedale Policlinico Monteluce – Perugia, Italy
mail: faroila@unipg.it