Support Care Cancer (2002) 10:88–95
`DOI 10.1007/s005200100295
`
`R E V I E W A RT I C L E
`
`Fausto Roila
`Donatella Donati
`Stefano Tamberi
`Guido Margutti
`
`Delayed emesis: incidence, pattern, prognostic
`factors and optimal treatment
`
`Published online: 23 August 2001
`© Springer-Verlag 2001
`
`Presented as an invited lecture at the sym-
`posium “Supportive Care in Cancer”
`Copenhagen, Denmark, June 14–16, 2001
`
`F. Roila (✉) · D. Donati · S. Tamberi
`G. Margutti
`Medical Oncology Division,
`Arcispedale S. Anna, Ferrara, Italy
`e-mail: roila fausto@libero.it
`Tel.: +39-075-5783968
`Fax: +39-075-57209990
`F. Roila
`Policlinico Hospital, Via Brunamonti,
`06122 Perugia, Italy
`
`Introduction
`
`cyclophosphamide, carboplatin,
`doxorubicin and epirubicin, should
`also receive antiemetic prophylaxis
`with oral dexamethasone to prevent
`delayed emesis.
`
`Keywords Delayed emesis ·
`Antiemetic prophylaxis ·
`5-HT3 antagonists · Dexamethasone ·
`Metoclopramide
`
`Abstract Delayed emesis has been
`arbitrarily defined as vomiting
`and/or nausea beginning, or persist-
`ing for, more than 24 h after chemo-
`therapy administration. Acute emesis
`is the most important prognostic fac-
`tor for delayed emesis. Owing to the
`relatively high incidence and severi-
`ty all patients treated with cisplatin
`≥50 mg/m2 should receive antiemetic
`prophylaxis. In these patients a com-
`bination of dexamethasone plus me-
`toclopramide or a 5-HT3 antagonist
`is the most efficacious regimen. All
`patients submitted to moderately
`emetogenic chemotherapy, such as
`
`In the last 20 years important progress has been achieved
`in the prevention and treatment of chemotherapy-induced
`nausea and vomiting. Factors contributing to the im-
`proved control of emesis include: enhanced knowledge of
`the pathophysiology of emesis; the completion of large
`methodologically sound clinical studies on antiemetics;
`and the discovery of new and more efficacious antiemetic
`drugs, in particular the 5-HT3 receptor antagonists.
`While our understanding of chemotherapy-induced
`emesis was improving, it soon became clear that we
`were confronted with two types of emesis: acute and de-
`layed. Delayed emesis has been arbitrarily defined as
`emesis that begins or persists more than 24 h after che-
`motherapy.
`Until the last decade little attention had been ad-
`dressed to the delayed emesis phenomenon. There are
`various reasons for this:
`G Primarily it is a less severe event than acute emesis.
`
`G Delayed emesis occurs when the patients are at home
`and away from direct observation by the oncologists.
`G An animal model for the study of this condition has
`not been available until recently [33, 43].
`The inevitable consequence has been that only a few, and
`often not well-conducted, studies have been published on
`this topic.
`
`Pathophysiology
`
`The pathophysiology of delayed emesis is unknown.
`Though not proven, various mechanisms have been pos-
`tulated:
`1. Disruption of the blood–brain barrier. Antineoplastic
`agents, especially cisplatin, can disrupt the blood–
`brain barrier, determining a mild and reversible cere-
`bral oedema. The increased intracranial pressure may
`potentiate other emetic inputs. This has been demon-
`strated in the dog after cisplatin administration via the
`
`Helsinn Healthcare Exhibit 2045
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
`
`Page 1 of 8
`
`

`
`carotid artery [37]. When the drug was intravenously
`administered instead there was no neurotoxicity; but
`if the blood–brain barrier was opened using mannitol
`then intravenous cisplatin also induced significant
`neurotoxicity. The documented activity of corticoste-
`roids in the treatment of cerebral oedema and delayed
`emesis gives some support to this hypothesis.
`2. Disruption of gastrointestinal motility and/or perme-
`ability. Chemotherapeutic agents, in particular cis-
`platin, can cause temporary disturbances of gastroin-
`testinal tract function, such as hypomotility and gas-
`troparesis, that are capable of inducing protracted
`nausea and vomiting [3, 6].
`On the other hand, the gut mucosa normally provides
`an effective barrier against the entry of macromole-
`cules into the bloodstream, but it has been postulated
`that the cytotoxic effects of cisplatin on the gut muco-
`sa can stimulate the release of hormones, many of
`which can induce emesis when given in high doses
`[3, 6].
`3. Role of endogenous or exogenous adrenal hormones.
`Corticosteroids and noradrenaline (but not adrenaline)
`may have a role in chemotherapy-induced delayed
`emesis. In fact, urinary cortisol excretion was inverse-
`ly related and noradrenaline excretion was directly re-
`lated to the intensity of chemotherapy-induced de-
`layed nausea [7, 8]. The anti-inflammatory properties
`of cortisol may act as an antiemetic by preventing the
`release of serotonin in the gut or preventing the acti-
`vation of 5-HT3 receptors in the gastrointestinal
`system [7]. Noradrenaline, however, may have an
`emetogenic effect promoting the release of serotonin
`in the gut or alternatively affecting 5-HT3 receptor
`sensitivity [8].
`Moreover, corticosteroids (dexamethasone) are fre-
`quently used for the prevention of acute emesis, and it
`has been suggested that their abrupt discontinuation
`can bring about adrenal failure, which may be respon-
`sible for the occurrence of the delayed emesis [2]. On
`the other hand, two recent studies showed that dexa-
`methasone administration before chemotherapy led to
`a significant decline in endogenous cortisol levels in
`24 h and to a subsequent, rapid, significant recovery
`in the next 24 h [30, 41].
`4. Accumulation of emetogenic metabolites from che-
`motherapeutic agents. Others have postulated that de-
`layed emesis may be the result of an accumulation of
`metabolites of chemotherapy agents (those of cis-
`platin have been identified in the body fluid and tis-
`sues over 24 h after its administration) or of the hy-
`pomagnesaemia induced by cisplatin.
`It is likely that delayed emesis is a multifactorial phe-
`nomenon with relative contributions from each of the
`above factors or others not yet determined.
`
`89
`
`Incidence and pattern of delayed emesis
`
`Delayed emesis has been studied mainly in cisplatin-
`treated patients, but it also occurs with moderately
`emetogenic chemotherapy, especially carboplatin and cy-
`clophosphamide. The incidence and characteristics of
`delayed emesis differ between patients receiving cis-
`platin-based and those receiving moderately emetogenic
`chemotherapy, and we will therefore describe the two
`phenomena separately.
`
`Cisplatin
`
`Cisplatin induces a biphasic pattern of emesis. In one
`study, all patients not receiving antiemetic prophylaxis
`following cisplatin, 120 mg/m2, experienced nausea and
`vomiting within the first 24 h after chemotherapy [11].
`Symptoms begin with a short latency period of 2–3 h and
`peak around 6–8 h after cisplatin administration. This
`acute phase lasts for 10–18 h before subsiding. It is fol-
`lowed by a separate phase occurring more than 24 h later.
`Recently, a new definition of cisplatin-induced de-
`layed emesis has been proposed [28]). In fact, in patients
`treated with cisplatin and receiving placebo, metoclopra-
`mide or ondansetron as antiemetics, there appear to be
`two vomiting peaks: one at approximately 4 h and one at
`18 h, with a period of virtually no vomiting between
`them, even in patients receiving placebo. While both me-
`toclopramide and ondansetron attenuate the first peak
`significantly, neither eliminates or attenuates the second
`peak at 18 h. These observations suggest that the phe-
`nomenon of delayed emesis may begin at 16 h rather
`than 24 h after cisplatin [28]. However, this pattern of
`emesis induced by cisplatin was not confirmed in 196
`cisplatin-treated patients who had acute emesis despite
`prophylaxis with ondansetron or granisetron combined
`with dexamethasone. In this study the start of vomiting
`was uniformly distributed during the first 24 h [17].
`The incidence and pattern of delayed emesis have
`been described in one study on 86 patients receiving cis-
`platin, 120 mg/m2, and treated for the prevention of
`acute emesis with metoclopramide, dexamethasone and
`diphenhydramine or lorazepam, who were monitored for
`5 days after the chemotherapy without receiving any
`antiemetic treatment other than that received for acute
`emesis [26]. During the first 24 h, 38% of patients had
`vomiting. Over the next 4 days, 93% of patients experi-
`enced some degree of delayed nausea and vomiting. The
`incidence and intensity of symptoms peaked during the
`48- to 72-h period following chemotherapy administra-
`tion, when 61% of patients had vomiting and 78% had
`nausea. The incidence and intensity of the phenomenon
`decreased during the subsequent days. In any case, the
`symptoms experienced during the delayed phase were
`less severe than those during the acute phase.
`
`Page 2 of 8
`
`

`
`90
`
`Moderately emetogenic chemotherapy
`
`Less information is available on the incidence and char-
`acteristics of delayed emesis induced by moderately
`emetogenic chemotherapy. One difference is that the
`emetic symptoms follow a monophasic pattern after
`moderately emetogenic chemotherapy. The onset of eme-
`sis after carboplatin and cyclophosphamide occurs with a
`latency period of 6–12 h, which is longer than that ob-
`served with cisplatin. Symptoms are most intense in the
`first 24 h, but nausea and vomiting can persist over a 24-
`to 36-h period [31]. In a study in which 31 breast cancer
`patients treated with 5-fluorouracil, doxorubicin and cy-
`clophosphamide were observed for 4 consecutive days
`without receiving any antiemetic prophylaxis, most of
`them had vomiting for 2 or more days [31].
`In another study, performed in 28 patients treated with
`carboplatin (300–400 mg/m2), the peak intensity of eme-
`sis occurred between 8 and 12 h after chemotherapy and,
`although symptoms subsided significantly by 24 h, some
`patients (11%) continued to have emesis 48 h after this
`[31].
`On the basis of these observations, Martin has sug-
`gested the opportunity of distinguishing the two patterns
`of delayed emesis by reserving the term ‘delayed emesis’
`for the biphasic pattern of symptoms which follow cis-
`platin treatment and using the term ‘prolonged emesis’
`for the late emesis following non-cisplatin chemotherapy
`[31].
`Moreover, Morrow has proposed considering delayed
`emesis as only that occurring after an initial 24 h free of
`nausea and vomiting and considering ‘persistent emesis’
`as emesis that continues beyond the day of chemothera-
`py administration [35].
`Data on the incidence of delayed emesis in patients
`treated with moderately emetogenic chemotherapy are
`scanty. In a large study by the Italian Group for Antieme-
`tic Research, evaluating patients treated with cyclophos-
`phamide, doxorubicin, epirubicin and carboplatin, on
`days 2–5, when patients were monitored without receiv-
`ing any antiemetic prophylaxis, the incidence of moderate
`to severe vomiting and nausea was approximately 20%
`and 25%, respectively [19]. However, studies often differ
`in the incidence of delayed emesis observed, and the dif-
`ferences can sometimes be explained by patient/treatment
`characteristics that represent important prognostic factors.
`
`Prognostic factors in delayed emesis
`
`Few studies have evaluated the prognostic factors predis-
`posing patients to delayed emesis, and almost all of them
`have been performed in cisplatin-treated patients.
`G The most important prognostic factor to emerge from
`these studies is obtaining complete protection from
`
`nausea and vomiting during the first 24 h [16, 26, 27,
`42]. This factor is independent of the type of anti-
`emetic treatment received for acute or delayed eme-
`sis.
`In patients followed for more than one cycle of chemo-
`therapy the incidence of delayed vomiting in the
`second/third cycles was dependent on the results ob-
`tained in the first 24 h of the same cycles of chemothera-
`py. Not only that, but the incidence of delayed vomiting
`in the second/third cycles was also dependent on the in-
`cidence of delayed vomiting in the first/second cycles
`[16]. Furthermore, the study showed that delayed vomit-
`ing was a prognostic factor for acute emesis in the subse-
`quent cycles [16].
`Even in patients treated with moderately emetogenic
`drugs the most important prognostic factor is obtaining
`complete protection in the first 24 h after chemotherapy
`administration [19, 21]. The incidence of delayed vomit-
`ing/moderate to severe nausea is low (<15%/<15%) in
`patients who did not have acute vomiting/moderate-
`severe nausea, but is high (55%/75%) in patients who
`did [19, 21].
`G Another important prognostic factor for delayed eme-
`sis is the dose of cisplatin administered. In fact, two
`studies have shown that doses ≤90 mg/m2 induced de-
`layed emesis less frequently than doses >90 mg/m2
`(22% versus 43% in one study [42] and 19.4% versus
`46.9% in another [16]).
`G Sex is also a significant prognostic factor, indepen-
`dent of the antiemetic treatment received. In one
`study 76% of females versus 39% of males had de-
`layed vomiting after cisplatin chemotherapy [42].
`G In patients treated with cisplatin, age, tumour burden
`and tumour localisation also seem to be important. In
`fact, patients with ovarian cancer with diameter of the
`greatest residual tumour <2 cm had less delayed
`nausea than those with diameter ≥2 cm [15], patients
`with supradiaphragmatic localisation less than those
`with infradiaphragmatic localisation, and older pa-
`tients less than younger ones [5]. However, these re-
`sults require confirmation in larger studies.
`
`Treatment of delayed emesis
`
`Owing to its relatively high incidence and severity, at
`least in some high-risk patients, delayed emesis causes
`distress and discomfort to many patients and can contrib-
`ute to reducing the compliance in subsequent cycles of
`chemotherapy. For these reasons it is important to know
`and utilize the best available preventive treatment.
`The objectives of treatment for delayed emesis should
`be: (1) to provide patients with the best treatment able to
`obtain complete protection from acute emesis starting
`from the first cycle of chemotherapy; (2) to use regimens
`
`Page 3 of 8
`
`

`
`Table 1 Cisplatin-induced delayed emesis: comparative studies
`without 5-HT3 antagonists (O open, SB single blind, DB double-
`blind, PL placebo, ALZ alizapride, MTC metoclopramide, DEX
`
`dexamethasone, PCP prochlorperazine, C.P. complete protection
`from delayed vomiting, N.S. not specified)
`
`Type of No. of
`study
`patients
`
`Cisplatin Antiemetics
`dose
`(mg/m2)
`
`C.P. Results
`(%)
`
`Vomiting
`
`Nausea
`
`Reference
`
`91
`
`DB
`
`SB
`
`SB
`
`O
`
`O
`
`DB
`
`DB
`
`91
`
`120
`
`63
`
`70
`
`42
`
`60
`
`152
`
`120
`
`≥50
`
`80
`
`≥60
`
`MTC+DEX and DEX>PL
`
`MTC and DEX>PL
`
`[27]
`
`[42]
`
`MTC+DEX=ALZ+DEX=DEX [34]
`
`DEX+PCP≥No therapy
`
`MTC+DEX>PL
`
`ACTH=PL
`
`[32]
`
`[44]
`
`[38]
`
`52.0 MTC+DEX>DEX>PL
`MTC+DEX
`35.0
`DEX
`11.0
`PL
`69.0 MTC=DEX=PL
`MTC
`65.4
`DEX
`56.7
`PL
`44.0 MTC+DEX>ALZ+DEX
`60–120 DEX
`30.0 and DEX
`ALZ+DEX
`70.0
`MTC+DEX
`28.6 DEX+PCP≥No therapy
`80 or 100 DEX+PCP
`20.0
`No therapy
`75.0 MTC+DEX>PL
`MTC+DEX
`50.0
`PL
`67.0 ACTH >PL
`ACTH
`43.0
`PL
`62.0 ACTH 2 mg≥ACTH 1 mg>PL ACTH 2 mg≥ACTH 1 mg>PL [39]
`60–120 ACTH 1 mg
`ACTH 2 mg+1 mg 71.4
`after 72 h
`PL
`
`35.3
`
`that consist of oral agents, facilitating easy outpatient
`use; (3) to use regimens that contain agents proven to be
`efficacious and tolerable in this setting; (4) to use treat-
`ments that take account of cost factors whenever possi-
`ble.
`In this section the results of comparative studies spe-
`cifically planned to evaluate different antiemetic treat-
`ments in the prevention of delayed emesis will be pre-
`sented. Studies with the primary objective of evaluating
`different antiemetic drugs in the prevention of acute
`emesis, and in which the same drugs were continued in
`the following days, will not be reported. This is because
`in such studies the superiority of one drug with respect
`to another in the prophylaxis of delayed emesis could
`mean either that the drug is superior or that the superiori-
`ty of a drug is due to better results obtained with this
`drug in the first 24 h that persist in the following days
`and, therefore, to a dependence effect. To distinguish
`these two results a multifactorial analysis comparing the
`results obtained in the prevention of delayed emesis bal-
`ancing those obtained in the prophylaxis of acute emesis
`should be carried out. Unfortunately, no such analysis
`was performed in these studies.
`In evaluating antiemetic efficacy against delayed
`emesis, considering the differing incidence and charac-
`teristics of the phenomenon, it is necessary to plan stud-
`ies in which patients subjected to cisplatin chemotherapy
`are clearly separated from those subjected to moderately
`emetogenic chemotherapy. Instead, two recently pub-
`
`lished studies enrolled both types of patients [1, 23]. In
`these studies, from day 2 to day 5 all patients received
`dexamethasone (4 mg or 10 mg orally) and were ran-
`domised to receive granisetron (1 mg or 2 mg orally) or
`metoclopramide (10 mg or 20 mg three times a day). The
`proportion of patients who achieved complete protection
`from delayed emesis was similar with both regimens
`(68% versus 55% and 81% versus 84%, respectively
`with granisetron and metoclopramide).
`
`Following cisplatin
`
`Antiemetic activity of drugs other than 5-HT3
`receptor antagonists
`
`In Table 1 the comparative studies between different an-
`tiemetics (used alone or in combination) or with respect
`to placebo in the prevention of delayed emesis are sum-
`marized [27, 32, 34, 38, 39, 42, 44].
`From these data it appears clear that the efficacy
`shown by metoclopramide, dexamethasone or ACTH,
`when used alone, although superior to placebo in the pre-
`vention of delayed nausea or vomiting, is often of limited
`clinical significance. A combination of oral metoclopra-
`mide (0.5 mg/kg, or 20 mg, every 6 h on days 2–5) plus
`dexamethasone (8 mg every 12 h on days 2 and 3 after
`cisplatin and 4 mg every 12 h on days 4 and 5) is the
`most efficacious antiemetic treatment for the prevention
`
`Page 4 of 8
`
`

`
`92
`
`Table 2 Cisplatin-induced delayed emesis: comparative studies with 5-HT3 antagonists (OND ondansetron, GRAN granisetron)
`
`Type of
`study
`
`No. of
`patients
`
`DB
`
`DB
`
`DB
`
`DB
`
`DB
`
`DB
`
`DB
`
`48
`
`538
`
`434
`
`619
`
`527
`
`236
`
`322
`
`Cisplatin
`dose
`(mg/m2)
`
`≥100
`
`≥70
`
`≥50
`
`≥69
`
`≥50
`
`≥50
`
`≥50
`
`Antiemetics
`
`OND
`PL
`OND
`PL
`DEX+PL
`DEX+GRAN
`DEX+PL
`DEX+GRAN
`GRAN+PL
`GRAN+DEX
`OND+PL
`OND+DEX
`MTC+DEX
`OND+DEX
`
`C.P.
`(%)
`
`40.0
`33.0
`36.0
`26.0
`35.0
`38.0
`58.4
`57.2
`58.0
`78.9
`50.0
`63.0
`60.0
`62.0
`
`Results
`
`Vomiting
`
`OND≥PL
`
`OND≥PL
`
`Nausea
`
`OND=PL
`
`OND≥PL
`
`GRAN+DEX=DEX
`
`GRAN+DEX=DEX
`
`GRAN+DEX=DEX
`
`GRAN+DEX=DEX
`
`GRAN+DEX>GRAN
`
`GRAN+DEX>GRAN
`
`OND+DEX≥OND
`
`OND+DEX≥OND
`
`MTC+DEX=OND+DEX MTC+DEX=OND+DEX
`
`Reference
`
`[9]
`
`[36]
`
`[29]
`
`[10]
`
`[22]
`
`[13]
`
`[18]
`
`of delayed emesis. Nonetheless, as shown in two large
`studies in 249 and in 522 patients, therapy of this phe-
`nomenon is far from being optimal: about 40–60% of pa-
`tients had delayed nausea and/or vomiting despite treat-
`ment with metoclopramide plus dexamethasone [16, 20].
`
`Antiemetic activity of 5-HT3 receptor antagonists
`
`Only recently has the role of the 5-HT3 receptor antago-
`nists in the prevention of cisplatin-induced delayed eme-
`sis been clarified. In Table 2 the results of the most im-
`portant comparative studies performed with the 5-HT3
`receptor antagonists are reported [9, 10, 13, 18, 22, 29,
`36]. The analysis of all these studies suggests that 5-HT3
`receptor antagonist activity in the prevention of delayed
`emesis is probably not as good as it is in the prevention
`of acute emesis and that their efficacy, when used alone,
`is only moderate. Furthermore, in two studies the addi-
`tion of a 5-HT3 antagonist to dexamethasone did not re-
`sult in more cases of complete protection from delayed
`vomiting and nausea than were achieved with dexameth-
`asone alone [10, 29]. On the other hand, the addition of
`dexamethasone to a 5-HT3 antagonist decreased the inci-
`dence of delayed emesis to a lower level than was seen
`with a 5-HT3 antagonist alone [13, 22].
`Finally, in a double-blind randomised study, oral on-
`dansetron (8 mg every 12 h on days 2–4) combined with
`dexamethasone showed similar antiemetic activity as
`standard metoclopramide plus dexamethasone in the pre-
`vention of cisplatin-induced delayed emesis, and these
`two regimens should be considered the antiemetic pro-
`phylaxis of choice for delayed emesis [18]. Considering
`the higher cost, metoclopramide remains the standard
`treatment, but, according to the results of this study,
`preference should be given to ondansetron in patients
`
`who do not tolerate metoclopramide or who had emesis
`in the first 24 h [18].
`
`Following moderately emetogenic chemotherapy
`
`Until recently the problem of delayed emesis due to
`moderately emetogenic chemotherapy has received little
`attention. At present, three comparative studies on the
`prevention of delayed emesis induced by moderately
`emetogenic drugs show ondansetron, granisetron and
`dexamethasone to be superior to placebo [14, 24, 25]
`(Table 3). In none of these three studies did patients re-
`ceive the optimal antiemetic prevention of acute emesis
`(a combination of dexamethasone plus a 5-HT3 receptor
`antagonist) in the first 24 h [4, 12], and this increased the
`incidence of delayed emesis. In another open study the
`addition of a 5-HT3 antagonist (ondansetron or dolaset-
`ron) to dexamethasone did not increase the proportion of
`patients with complete protection from delayed emesis
`over that achieved with dexamethasone alone [40].
`Finally, the Italian Group for Antiemetic Research
`carried out a double-blind study in which, 24 h after che-
`motherapy, patients were divided into two groups: pa-
`tients who did not have either vomiting or moderate to
`severe nausea (the low-risk group) and patients who had
`one or both (the high-risk group) [21]. Patients in the
`low-risk group were then randomly assigned to receive
`one of the following from day 2 to day 5 after chemo-
`therapy: oral placebo, 4 mg of dexamethasone given
`orally twice daily, or 8 mg of ondansetron in combina-
`tion with 4 mg of dexamethasone, given orally twice dai-
`ly. Patients in the high-risk group were randomly as-
`signed to receive oral dexamethasone alone or in combi-
`nation with ondansetron at the same doses as were used
`in the low-risk group.
`
`Page 5 of 8
`
`

`
`93
`
`Table 3 Delayed emesis induced by moderately emetogenic chemotherapy: comparative studies (D ondansetron, GRAN granisetron,
`DOL dolasetron)
`
`Type of
`study
`
`No. of
`patients
`
`Antiemetics
`
`DB
`
`O
`
`DB
`
`O
`
`DB
`
`48
`
`98
`
`139
`
`407
`
`618
`
`87
`
`OND
`PL
`DEX
`No Therapy
`GRAN
`PL
`DEX+OND or DOL
`DEX
`DEX+ONDb
`DEX
`PL
`DEX+ONDc
`DEX
`
`C.P.
`(%)
`
`60.0
`42.0
`57.0
`33.0
`67.1a
`49.3a
`47.0
`41.0
`91.8
`87.4
`76.8
`40.9
`23.3
`
`Results
`
`Vomiting
`
`OND>PL
`
`DEX>No therapy
`
`GRAN>PL
`
`Nausea
`
`OND>PL
`
`N.S.
`
`DEX+OND or DOL=DEX
`
`DEX+OND or DOL=DEX
`
`DEX+OND and DEX>PL
`
`DEX+OND and DEX>PL
`
`DEX+OND=DEX
`
`DEX+OND=DEX
`
`Reference
`
`[9]
`
`[25]
`
`[14]
`
`[40]
`
`[21]
`
`a No vomiting and no nausea at day 2
`
`b Patients without acute emesis
`
`c Patients with acute emesis
`
`Among the 618 patients in the low-risk group the
`level of complete protection from both delayed vomit-
`ing and moderate to severe nausea was significantly
`better in those who received ondansetron plus dexa-
`methasone (91.8%) and in those who received dexa-
`methasone (87.4%) than in those who received placebo
`(76.8%). In the 87 patients in the high-risk group, com-
`plete protection achieved with ondansetron plus dexa-
`methasone (40.9%) was superior to those achieved with
`dexamethasone alone (23.3%), but the difference was
`not statistically significant. In conclusion, the best way
`to prevent delayed emesis in patients receiving moder-
`ately emetogenic chemotherapy is to control acute eme-
`sis after chemotherapy administration. Prophylaxis
`against delayed emesis is warranted in both low- and
`high-risk patients, although fewer than half the patients
`at high risk will be protected and a remarkable number
`of patients at low risk would be protected without ac-
`tive treatment. In the low-risk group dexamethasone
`alone seems preferable to the combination of dexa-
`methasone plus ondansetron, because its efficacy is
`similar to that of the combination. It is better tolerated
`(it causes less constipation) and it is less costly. In the
`high-risk group the best antiemetic prophylaxis remains
`to be identified.
`
`In fact, in the prevention of cisplatin-induced delayed
`emesis with the two most efficacious treatments, (a com-
`bination of oral dexamethasone with metoclopramide or
`ondansetron), about 40–60% of patients continue to pres-
`ent delayed nausea and vomiting.
`In the prevention of delayed emesis induced by mod-
`erately emetogenic chemotherapy an antiemetic prophy-
`laxis with dexamethasone should be recommended for
`all patients even if only one fourth of those having acute
`vomiting or moderate-severe nausea achieved complete
`protection from delayed emesis.
`In the coming years better control of delayed emesis
`may be possible with the development of new and more
`efficacious antiemetic drugs for delayed emesis. From
`this point of view a possible neurotransmitter of delayed
`emesis has recently been identified: substance P, a neuro-
`peptide found within the central and peripheral nervous
`system. When substance P is released as a result of
`emetogenic stimuli, it binds to a specific NK1 receptor,
`and mediates nausea and vomiting. In the ferret, selec-
`tive antagonists of NK1 receptors have been shown to
`block chemotherapy-induced emesis. These antagonists
`are still being evaluated as antiemetics for the prophy-
`laxis of chemotherapy-induced acute and delayed eme-
`sis.
`
`Conclusions
`
`Despite the achievement of important results in the pre-
`vention of chemotherapy-induced nausea and vomiting,
`delayed emesis remains a challenge for antiemetic re-
`search, as the results obtained with the most efficacious
`regimens available are still unsatisfactory, particularly in
`cisplatin-treated patients.
`
`Page 6 of 8
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`

`
`94
`
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