dissertation (2007) (use of antiemetics in radiotherapy)
TRANSCRIPT
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Should patients who receive radiotherapy treatment
to moderate or lower emetogenic areas , according to current
antiemetic guidelines , be given antiemetics prophylactically ?
Martin J M Hogg
Candidate number: 29929
Module Code: !"H#$$!
Course %itle: &Sc 'Hons( in )adiotherapy * +ncology
Submitted in partial ulilment o the &Sc 'Hons(
in )adiotherapy * +ncology
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"bstract
As many as 40-80% of patients who receive radiotherapy as part of their
treatment will experience nausea and/or emesis , depending on the area
of irradiation (eyer et al !00"a#$ hese symptoms can represent a
therapeutic challenge and if these symptoms are not controlla&le with
antiemetic treatment , the rate of mortality , mor&idity , and health care
costs may increase (Aapro, !004#$ 't can &e said that there are few studies
comparing antiemetics for the prevention of nausea and emesis in patients
receiving fractionated radiotherapy (ranen et al )**+# , however ,
fractionated radiotherapy may involve periods of up to + or 8 wees , and
prolonged symptoms of nausea and emesis could affect treatment
outcome and patients uality of life (eyer et al !00"a#$ .ence a detailed
discussion of relevant trials is part of this dissertation$ arious antiemetics
exist to relieve the symptoms of nausea and emesis , and ". receptor
antagonists have &ecome the first choice of most oncologists (1oodin and
2unningham, !00!#$ 2urrent antiemetic guidelines recommend the use of
this class of antiemetics as prophylaxis for moderate or lower emetogenic
radiotherapy (eyer et al !00" , therefore , a discussion of whether the
evidence from trials supports these recommendations will &e part of this
dissertation$ A ris exists that waiting for symptoms of nausea and emesis
to emerge in patients rather than prescri&ing prophylactic antiemetic
treatment may lead to increased suffering and poorer disease control ,
and in this dissertation it will &e investigated whether prophylactic
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management offers a &etter treatment option for at-ris patients (.oriot,
!004#$
.owever , the researcher has concluded that , even though current
antiemetic guidelines and the proposal of prophylactic treatment are
3ustified , individual ris-factors of patients should &e included in antiemetic
therapy and , therefore , further studies are needed to investigate this
and , importantly , the duration of prophylactic treatment$
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C+-%.-%S
)$ 'ntroduction pp"-)0
)$) hysiology of emesis and pharmacology
of "-. antiemetics in radiotherapy patients pp+-*
)$! 5verview of trials with antiemetics in radiotherapy patients p*
)$ 2urrent antiemetic guidelines for radiotherapy patients pp*-)0a&le ) current antiemetic guidelines (A625 and 7A622# p)0
!$ 6earch strategy pp))-)
a&le ! a&ulated literature search p)4
$ iscussion pp)"-4!
$) 5ndansetron versus metoclopramide pp)"-)8
$! 5ndansetron versus place&o pp)8-!0
$ prophylactic tropisetron or metoclopramide pp!0-!!
$4 prophylactic ondansetron vs expectant metoclopramide pp!-!4
$" prophylactic ondansetron vs chlorpromaine,dexamethasone pp!"-!+
$+ a multicenter 'talian trial pp!+-!*
$9 prophylactic dexamethasone pp!*-0
$8 granisetron and its clinical use pp0-!
$* prophlactic tropisetron pp!-4
$)0 6ummary and further discussion of evidence pp4-8
$)) current antiemetic guidelines and their use pp8-4!
4$2onclusion pp4!-4
:eference list pp44-48
Appendix (literature reviewed ta&ulated# pp4*-")
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/0 1ntroduction
his dissertation will discuss whether patients receiving radiotherapy
treatment to emetogenic areas should receive antiemetics prophylactically$
As stated &y .oriot (!004# nausea and vomiting are two of the most
distressing side-effects of radiotherapy and inadeuate control of nausea
and/or vomiting may result in significant patient suffering and therefore a
decrease in the patients; uality of life$ hese pro&lems may also have an
impact on the patients compliance to a potentially cura&le treatment with
the outcome of treatment therefore &eing decreased , essentially an
unfavoura&le outcome (.oriot, !004 < eyer et al)**8#$ Also , untreated
emesis which persists during the patients; course of radiotherapy may
cause further physiologic changes such as dehydration , electrolyte
im&alance and malnutrition , which in turn can impact on uality of life and
final outcome of the patients; treatment (eyer et al )**8#$
herefore , the aims and o&3ectives of this dissertation will &e to critically
analyse and guide the reader through the current evidence as to whether
patients undergoing radiotherapy to certain emetogenic areas of the &ody
should &e given antiemetics prophylactically$ his will include an overview
and discussion of current antiemetic guidelines and their
recommendations , as well as a detailed discussion of trials with
antiemetics in radiotherapy patients and their conclusions and
recommendations for future practice$
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=ut first , this introduction will explain some of the &acground needed ,
such as physiology of emesis , to further the reader;s understanding of the
topic$
/0/ #hysiology o emesis and pharmacology o 3H%! antiemetics in
radiotherapy patients
he mechanism of emesis after irradiation is a complex multifactorial
clinical event defined &y different factors (site of irradiation , dose per
fraction , field sie# , as well as &y psychological and physiological
varia&les (eyer and itl&ach )**8#$ :esearch suggest that the critical
organs responsi&le for radiation-induced emesis are in the upper
a&domen , and the underlying mechanism may &e related to a toxin
released &y degradation of tumour proteins and the production of a
second messenger resulting from radiation-associated cellular damage
has &een considered (eyer and itl&ach )**8#$ 2urrently , much is
nown a&out the lethal effects of radiation on cells and tissues , however ,
the pathological mechanism of radiation-induced emesis remains only
partially understood (eyer et al )**8#$ As stated &y eyer and itl&ach
()**8# vomiting can &e seen as a hierarchically organied toxin defence
system in which the irradiated patient responds in a certain way to a
perceived toxin and in this way tries to protect him- or herself from
damage$ here are two primary phases involved in emesis , the
prodromal phase , which occurs prior to vomiting , and the vomiting
phase , the final outcome &eing the propulsion of gut contents through the
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mouth (A&raham et al !000#$ omiting is an important post-irradiation
symptom , however , the relationship &etween radiation and cell death and
vomiting does not prove that cell death is the ma3or acute emetic stimulus
(eyer and itl&ach )**8#$ he irritation of the gastrointestinal mucosa is a
strong emetic stimulus and , importantly , the gastrointestinal tract
contains nearly 80% of serotonin ( "-. # present in the &ody , which is
stored in the enterochromaffin cells , which line the gastrointestinal tract
( A&raham et al !000#$ hat serotonin was involved in the process of
radiation-induced emesis was hypothesied when it was o&served that
increased urinary excretion of the main meta&olite of serotonin ( "-.'AA #
was associated with it ( A&raham et al !000 #$ he theory that irradiation
leads to damage of enterochromaffin cells and the release of serotonin
from these cells , which activate the serotonergic receptors on visceral
afferent fi&res to induce emesis is now widely accepted (A&raham et al
!000#$ hese nerve impulses reach the area postrema , in which lies the
chemoreceptor trigger one (2># , a richly vascularied circumventricular
structure (A&raham et al !000#$ he &lood-&rain &arrier is poorly
developed in the area postrema allowing su&stances , such as serotonin ,
to &e accessi&le to the 2> , which then &inds to this su&stance (via "-
.-receptors# and activates the vomiting centre to induce emesis as a
response to this (A&raham et al !000#$ As stated &y eyer and itl&ach
()**8# there are various neurotransmitter systems localied in the area
postrema and different receptor &locing su&stances have &een
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investigated that may result in an antiemetic effect through inhi&ition of
these systems$ he largest concentration of "-.-receptors in the 2?6 is
in the region where the 2> is located and most vagal afferents enter the
&rain from the gastrointestinal tract (A&raham et al !000# , thus it is
possi&le that this region , the area postrema , acts as a relay &etween
visceral afferents and the vomiting centre , which could &e inhi&ited &y "-
. antagonists (A&raham et al !000#$ :esearch studies have proven that
"-. receptor antagonists are very effective in treating nausea and
vomiting associated with radiotherapy in cancer patients and there are
highly selective "-. receptor antagonists, such as ondansetron and
granisetron , availa&le in radiotherapy (.oriot, !004#$
he "-. receptor antagonists specifically &loc the &inding of serotonin
to receptors on the vagal afferent nerves or the 2> , there&y minimising
the emetic response (.oriot, !004# , although there is conflicting evidence
as to whether a central or peripheral mechanism plays a more important
role in radiation-induced emesis (A&raham et al !000#$ As stated &y
6eegenschmiedt (!004# physicians may argue that differences in
pharmacology are not important , however small differences in
pharmacology may mae a huge difference in therapeutic efficacy to one
treatment or another$ =oth ondansetron and granisetron demonstrate a
high affinity for the "-. receptors (6eegenschmiedt, !004# , however
granisetron has demonstrated an insurmounta&le antagonism of "-.
receptors , therefore it is not easily displaced &y endogenous serotonin ,
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whereas ondansetron is a competitive antagonist and can &e easily
dissociated from its cognate receptor (6eegenschmiedt, !004#$
't can &e said that "-. receptor antagonists either &loc the &inding of
serotonin at the vagal afferents and there&y suppress the trigger to the
2> or &loc serotonin &inding directly in the 2> , again reducing the
emetic response of the individual$
/02 +verview o trials with antiemetics in radiotherapy patients
ata on the incidence of and ris factors for radiation-induced emesis are
&ased on clinical studies or trials of patients undergoing radiotherapy
(rameret al )**8#$ All these data suggest that "-. receptor
antagonists may &e &eneficial in treating nausea and/or emesis in
radiotherapy patients (ramer et al )**8#$ he researcher has used the
data of several trials to critically evaluate whether prophylactic treatment of
radiotherapy patients with antiemetics conforms with current evidence$
hese trials were chosen on the &asis that they studied the use of
prophylactic antiemetics in patients receiving either single-fraction or
fractionated radiotherapy and these trials will &e discussed in the
appropriate section$
/0! Current antiemetic guidelines or radiotherapy patients
he two current antiemetic guidelines used for this dissertation will &e
those of the American 6ociety of 2linical 5ncology (A625# and the
7ultinational Association of 6upportive 2are in 2ancer (7A622#$ ractice
guidelines help in selecting appropriate antiemetic care (1ralla et al !00"#$
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Antiemetic guidelines from various organiations have &een availa&le for
some time , although it is unclear how often these guidelines are used and
data indicates that practitioners do not treat patients according to the
recommendations (@oeller et al !00!# and this will &e critically evaluated in
more detail in the discussion section$ 'n !004 , therefore , a new guideline
process was initiated and conducted &y representatives from nine
oncology organiations including A625 and 7A622$
2urrent guidelines are summarised in a&le )(he Antiemetic
6u&committee of the 7A622, !00+ < @ris et al !00+#$
%"&4. / : Current "ntiemetic 5uidelines '"SC+ and M"SCC(
:is evel 'rradiated area Antiemetic 1uidelines
.igh (B*0%# =' rophylactic treatmentwith "-. receptorantagonist Cdexamethasone
7oderate (+0-*0%# Dpper A&domen rophylactic treatment
with "-. receptorantagonist
'ntermediate '"SC+ only( .emi&ody , uppera&domen , a&do-pelvic ,mantle , craniospinalirradiation
(not stated#
ow (0-"*%# ower thorax region andpelvis , cranium(radiosurgery# ,
craniospinal irradiation
rophylactic treatment orrescue treatment with "-. receptor antagonist
7inimal (E0%# .eadF?ec , =reast ,2ranium, Gxtremities
:escue treatment withdopamine or "-.
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20 Search strategy
A literature search is a systematic , explicit and reproduci&le method for
identifying the existing &ody of wor produced &y researchers (in, )**8#$
ata&ases used for this literature search were Hu&7ed; and the
H2ochrane i&rary; , &oth of which allow a search for 3ournal articles , such
as reviews , research studies or trials and meta-analysis of a given topic$
he researcher;s topic was &roen down into separate elements , which
were used as eywords and offered a precise terminology$ 't was
determined that alternative eywords for each important element would &e
used , such as synonyms and plurals , to increase the amount of potential
articles that could &e retrieved$ @eywords were formed into groups and
=oolean operators were used to com&ine search terms$ A Hfree text
search; and a H7e6.; search were used for &oth data&ases , as these
methods would indicate more references$ @eywords are found in titles ,
a&stracts and su&3ect headings of the article$ 5nce the researcher had
identified one or more articles that suited the research needs , the
eywords of these articles were also used to help guide future searches$
he first group of eywords were Hantiemetic; and Hantiemetics; , retrieving
a large amount of articles and were com&ined with the =oolean operator
H5:; , which resulted in search I$ he second group of eywords
consisted of Hradiotherapy; , Hradiation therapy; and Honcology; and this
group was also com&ined with the =oolean operator H5:; , which resulted
in search I9$ he third group of eywords consisted of Hemesis; , Hvomiting;
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, Hnausea; , Hradiation-induced emesis; , radiation-induced nausea; ,
Hradiation-induced vomiting; , Hradiotherapy-induced emesis; ,
Hradiotherapy-induced nausea; , Hradiotherapy-induced vomiting; , H:'?;
and H:'G; , the latter two eywords &eing common a&&reviations$ he
eywords of this last group were also com&ined with the =oolean operator
H5:; , which resulted in search I)*$ hen searches I , I9 and I)* were
com&ined with the =oolean operator HA?; , which resulted in search I!0$
his last search was then com&ined with a =oolean operator H?5; to
exclude articles with Hchemotherapy; as a eyword , as these articles were
deemed not relevant to the dissertation topic , resulting in )!4 articles in
Hu&7ed; and +8 articles in the H2ochrane i&rary;$ o support the
lielihood of relevant material &eing found , the search was refined &y
Hsearch limits;$ hese included only searching for articles in Henglish; ,
however , this may lead to valua&le articles in other languages &eing
excluded (in, )**8#$ he date range for the accessed articles was left
open , even though 1reenhalgh (!00)# states that a limit of " years is
deemed the norm , as there has &een little research into antiemetics and
radiotherapy and the researcher felt that this would have excluded
valua&le material , such as early trials$ he articles were further limited to
Hhuman su&3ects; , excluding research into animals , as this was found to
&e irrelevant to the topic$ hese articles were then downloaded or
manually searched for in the li&rary , and the a&stract was read to
determine the value of the article in respect to the dissertations topic$
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5nce the ey articles for this dissertation were found through this
process , other search strategies were employed$ 5ne of these strategies
was Hcross-referencing; , where the references in the ey articles are
searched for potentially valua&le articles that may not have &een found in
the original search$ Authors , that may &e experts in the field of
antiemetics and radiotherapy , were extracted from ey articles and their
names were used as additional search eywords$ he last additional
search strategy was a manual search of 3ournals which had &een identified
through the original search as having more articles on the chosen topic
than others$ herefore a comprehensive literature search reuires a
com&ination of eywords , su&3ect headings and searching &y specifics in
relevant data&ases (in, )**8# , in this case medical data&ases$
a&le ! (page )4 # shows the ta&ulated search strategy$
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%able 2 : %abulated 4iterature Search
6earch eywords :etrieved articles
in u&7ed
:etrieved articles
in 2ochranei&rary
I) antiemetic ))80 )""+
I! antiemetics ))80)" )+"!
I I) 5: I! ))89!4 !*8
I4 radiotherapy )84)9" *48
I" radiation therapy )9!0*" "4
I+ oncology )4+* )")8
I9 I4 5: I" 5: I+ 09*! !)48
I8 emesis !!098 )4)I* vomiting 4)8)8 *!8
I)0 nausea !)08 ))8!)
I)) radiation-inducedemesis
)0 !"
I)! radiation-inducednausea
*+ )0+
I) radiation-inducedvomiting
44!9* *0
I)4 radiotherapy-induced emesis !*9 !
I)" radiotherapy-induced nausea
49 )!*
I)+ radiotherapy-induced vomiting
44!9+ ))4
I)9 :'? " 0
I)8 :'G "!* 4!
I)* I8 5: I*J5: I)8 **4" )4!4
I!0 I A? I9 A?
I)*
*+ 40+
I!) I!0 ?5chemotherapy
)!4 +8
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!0 6iscussion
he discussion section will consist of a critical analysis of trials , although
the researcher is aware of Hpu&lication &ias; , where it is often felt that only
exciting studies are pu&lished , hence invalid conclusions inevita&ly result
&ecause less provocative studies with negative or contrary findings are not
pu&lished (1reenhalgh, !00)#$ .owever , the researcher felt that the trials
discussed here offer a good selection$ he discussion of trials will &e
followed &y a summary and an analysis of whether , &ased on the
evidence of trials , current antiemetic guidelines reflect good practice and
how they are and should &e used in a clinical environment$
!0/0 +ndansetron versus Metoclopramide '#riestman et al /99$(
his was an early study ()**0# , &ut is included as it is referenced &y
many other authors as one of the first important trials with a ". receptor
antagonist used in radiotherapy patients$ his study compared the efficacy
and safety of ondansetron and metoclopramide in preventing emesis after
a single fraction of radiotherapy to the upper a&domen$ he authors state
that at the time of this study ondansetron , a ". receptor antagonist ,
had shown some effectiveness in the prevention of chemotherapy-induced
vomiting , whereas metoclopramide was still &eing widely used for
radiation-induced emesis$ his study was a multicenter comparative study
using a randomied dou&le-&lind , parallel-group design$ :andomly
allocating patients to the different groups of a clinical trial attempts to
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ensure that any unnown prognostic factors are eually distri&uted , so
that their effects can &e allowed for in tests of statistical significance
(5lver, )**8#$ 't therefore ensures that these significant differences are
due to true treatment effects and also avoids &ias (5lver, )**8#$ .owever ,
the authors of this study do not state how patients were randomied ,
hence it is difficult to &e certain that the a&ove points are valid in this case$
ou&le-&linding assumes that neither patients nor investigators now
which arm of the study has &een randomly assigned to which drug and
this serves to eliminate any effects due to expectation or suggestion &y
investigators or patients (5lver, )**8#$ arallel-group design was used to
determine which patients were to receive either the study drug
(ondansetron# or the control drug (metoclopramide# and these two groups
are then compared (5lver, )**8#$ he authors planned to recruit )+0
patients , however , at the point of interim analysis *9 patients had &een
randomied of which )" patients were withdrawn$ he design of the study
allowed for an interim analysis when 80 or more evalua&le patients had
&een recruited and this was calculated &y a two-sided test (Hpower;
calculation# , which lets the authors of this study wor out how large a
sample they will need in order to detect a true difference &etween the
groups (1reenhalgh, !00)#$ :easons for the patients; withdrawal were K
patients receiving steroids which have a proven antiemetic effect
(@ir&ride et al !000# or patients receiving antiemetics as part of their
medication prior to the start of this study$ 5verall , the differences &etween
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to clarify the duration of antiemetic therapy reuired after single fraction
radiotherapy$
!02 +ndansetron versus #lacebo '7ran8en et al /99(
his was a multicenter , dou&le-&lind , randomised , parallel-group study
design , which can &e said to &e standard practice in trials with antiemetics
(5lver, )**8#$ he authors state that there are few randomised studies
comparing antiemetic drugs for prophylaxis of nausea and/or emesis in
patients treated with fractionated radiotherapy$ herefore , the aim of this
study was to compare the efficacy of prophylactic ondansetron with that of
a place&o$ A total of ))) patients were recruited , all of which would have
a course of )0 or more fractions to parts of the a&domen$ he patients
consisted of two different groups , those with non-gynaecological
malignancies and a group with gynaecological malignancies$ Gach group
was randomised depending on area treated and previous medical history
of nausea and/or emesis$ atients were excluded if they had concurrent
chemotherapy , severe other illnesses , gastrointestinal o&structions , 2?6
metastases , previous antiemetic treatment in the last !4 hrs and
administration of &enodiaepines or steroids , &oth of which can have an
antiemetic effect$ 't may &e argued that although these exclusions of
patients may facilitate the data analysis , it does mean that the included
patients may not necessarily represent a typical cancer patient , there&y
maing it difficult to use the results of this study for a general population
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(.oriot and Aapro, !004#$ 5ndansetron or place&o were given twice daily
from the first day of irradiation until up to ! days following last treatment$
?o other antiemetic was allowed , however , each patient was provided
with rescue medication (metoclopramide# if they experienced severe
nausea and/or emesis on one day , although patients were considered
treatment failure for each day the rescue medication was taen$ he
patients in the study groups were similar in respect to total irradiation field
sie , dose per fraction and total num&er of fractions and the study period
included up to " wees of treatment , the mean num&er of fractions for
&oth groups &eing )8$ atients results were recorded with diary cards
including num&er of vomits , retches and grade of nausea and the patients
were given a uestionnaire once a wee to determine impact on glo&al
health and uality of life and 5lver ()**8# states that the assessment of an
antiemetic should reflects its a&ility to control nausea and emesis , the
toxicities of the antiemetic , and an assessment &y the patients of their
overall rating of the antiemetic , &alancing efficacy with toxicity$ 5f the
patients receiving prophylactic ondansetron +9% experienced complete
control compared with 4"% of patients receiving place&o over the total
time of treatment$ .owever , 4% of patients receiving ondansetron
suffered from emesis throughout , compared to !)% in the place&o group
and it was noted that there was no difference &etween the two groups
regarding the use of rescue medication$ atients who suffered severe
adverse effects were withdrawn earlier from the place&o group than from
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the ondansetron group , however , several patients in the ondansetron
group suffered from repeated headaches$ 1oodin and 2unningham (!00!#
state that headache can &e a conseuence of ". receptor antagonist
therapy , &ut it is rarely of clinical significance and can usually &e easily
controlled , however , severe headache may lead to discontinuation of the
antiemetic regimen , although no correlation with a history of recurrent or
severe headache has &een found according to the authors of this study$
he patients weely grading of symptoms showed that the ondansetron
group experienced significantly less inconvenience than the place&o group
, however , after the first three wees of treatment no significant difference
could &e o&served , raising the uestion whether prophylactic antiemetics
should &e given for a complete treatment course or 3ust for a limited
amount of time , even though the authors admit that there was a trend
towards worsening of symptoms with an increasing num&er of fractions$
.owever , these results do show a &eneficial prophylactic antiemetic effect
of ondansetron , when compared to place&o, on prevention of nausea and
emesis , and also on improvements in the patients; uality of life$
!0! prophylactic %ropisetron or Metoclopramide '"ass et al /99(
his study was a prospective , randomised , open trial in ! patients with
seminoma stage ' , who received fractionated radiotherapy to the
a&dominal region (para-aortic nodes or Hdog-leg; fields#$ he authors state
that even mild gastrointestinal adverse effects due to radiotherapy often
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lead to significant interruption of the patients; lifestyle and uality of life ,
therefore prophylactic treatment with effective antiemetics may &e
warranted$ Antiemetics , such as metoclopramide , have &een used &y
radiotherapists , &ut are not always effective and have the disadvantage of
leading to extrapyramidal side effects , such as tremors , general anxiety
and involuntary muscle contractions (Aass et al )**9#$ he sample sie of
this trial is very small , hence one should &e careful to draw firm
conclusions from this study , a fact the authors admit themselves$ atients
were included if they were &etween )8 and 90 years of age , had an
a&sence of nausea and/or emesis prior to radiotherapy , had no use of
drugs which could influence emesis and had given written consent$ he
patients were treated daily over wees with a target dose of 01y ,
excluding weeends or &an holidays$ All patients were seen at least once
a wee &y their radiotherapist or more often if there was sufficient clinical
need and the patients also completed diary cards on a daily &asis$
atients were randomised to tae either tropisetron ("mg , once daily# or
metoclopramide ()0mg , times daily# and received these antiemetics
throughout the treatment period$ here were )) patients in the tropisetron
group and )! patients in the metoclopramide group , all of which were
compara&le regarding age , haematological status and liver and idney
function , and none of the patients had a previous history of
gastrointestinal disorders$ he authors state that experience of nausea
and emetic events were significantly lower in the tropisetron group when
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compared with the metoclopramide group$ hat a patient from the
metoclopramide group , who due to lac of control of emesis , received
rescue tropisetron and two patients from the tropisetron group who
received rescue metoclopramide , in all three cases with satisfactory
results , shows that an individual assessment , including individual ris
factors , may &e more suita&le than relying solely on ". receptor
antagonists as stated in current guidelines (eyer, !004#$ Apart from these
patients either drug was well tolerated $ Although constipation seemed to
&e an adverse event in some patients receiving tropisetron and 1oodin
and 2unningham (!00!# state that this effect has &een reported in patients
receiving ". receptor antagonists however , during a&dominal
radiotherapy this may act in a positive way against radiation-induced
diarrhoea$ he results of this study confirm that nausea and vomiting
represent freuent clinical pro&lems during radiotherapy treatment in
patients with seminoma stage ' and as nausea and/or emesis is difficult to
foresee , the authors suggest that prophylactic antiemetics should &e part
of the management policy$ As was also seen in previously discussed
studies , the effect of ". antagonists , in this case tropisetron , did
weaen over the treatment period , again maing the optimal duration of
antiemetic regimen difficult to decide$ inally , it should &e noted that the
cost of tropisetron was approximately !0 times higher than that of
metoclopramide at the time of this study , which may have cost
implications for the health service provider$
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!00 prophylactic +ndansetron vs e;pectant metoclopramide '
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ondansetron group when compared to the various metoclopramide groups
, however , there was no correlation &etween severity of nausea and
incidence of vomiting , although there appeared to &e a trend for less
emetic episodes within the ondansetron group and this group reuired no
additional antiemetic treatment$ here appeared to &e less diarrhoea in
patients treated with ondansetron and a para-aortic field and this group
had the lowest incidence of a&dominal discomfort , however , there
seemed to &e no correlation &etween the level of a&dominal discomfort
and the presence of diarrhoea$ 'nterestingly , the ondansetron group
suffered from fewer headaches than the other groups , whereas anorexia
was similar &etween all groups and all patients complained of lethargy
towards the end of the treatment$ he authors state that in this study the
use of prophylactic ondansetron was associated with a lower incidence of
nausea and emesis , &ut reduced field sie showed no significant
difference , however , the antiemetics were compared using different
schedules , possi&ly introducing a &ias towards prophylactic ondansetron$
he authors conclude that metoclopramide was effective in 80% of
patients involved , hence they suggest this drug to &e used
prophylactically and ondansetron to &e used as rescue treatment only ,
however , the choice of the optimal prophylactic antiemetic and its
schedule will remain unclear until larger studies , including studies on cost-
effectiveness , have &een undertaen$
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!0 prophylactic ondansetron vs chlorproma8ine and de;amethasone
'Sy=es et al /99 (
his study has investigated clinical efficacy and safety profile of
ondansetron and compared it to an antiemetic com&ination of
chlorpromaine and dexamethasone$ his study was a prospective ,
randomised study and was comprised of ++ patients who received single
fraction radiotherapy to the lower pelvis or to the upper lum&ar spine$
Gxclusion criteria for patients were concurrent chemotherapy , concurrent
antiemetic treatment , severe concurrent illness , gastrointestinal
o&struction , 2?6 metastases , vomiting in the !4hrs prior to the study and
administration of &enodiaepines$ All these exclusions may &e valid in
ensuring that the study results are not influenced &y data other than the
actual study data , however , it must &e stated that these exclusions may
mae it difficult to transfer results to a typical cancer patient population
(.oriot and Aapro, !004#$ All patients were given the antiemetic prior to
radiotherapy and for a further three days$ 5verall , ondansetron was found
to &e effective in *% of patients , with complete or ma3or control of
emesis , compared to 4% of patients treated with a com&ination of
chlorpromaine and dexamethasone$ he success rate for delayed emesis
(days !-4# for ondansetron treatment was also more favoura&le$ 'n the
cost-&enefit analysis , the costs of the study drugs and any rescue
medication , as well as the time for additional nursing care and cost of
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materials were evaluated per patient$ his resulted in ondansetron &eing
not unduly expensive when compared with the antiemetic com&ination
used in this study , when complete control of emesis is the aim$ his study
has shown that ondansetron is superior to chlorpromaine and
dexamethasone in preventing radiotherapy-induced nausea and vomiting ,
&oth as prophylactic and as maintenance antiemetic treatment , however ,
the authors do state that it may not &e necessary to provide antiemetic
therapy for the full 4-day period$
!00 a multicenter 1talian trial 'the 1talian 5roup or "ntiemetic
)esearch in )adiotherapy, /999(
his was an important study , which was carried out to assess the
incidence , pattern and prognostic factors of radiation-induced emesis ,
and evaluate the use of antiemetic drugs in clinical practice$ As many as
") italian radiation oncology centers too part in this trial , which included
*4 patients entering the trial , of which *)4 were evaluated$ his large
num&er of patients included various sites of irradiationK &reast (!))# ,
pelvis (!)0# , head and nec ()+# , thorax ()!*# , &rain ("!# , upper
a&domen (4!# , sin and/or extremities (9# and other sites (*9#$ atients
were excluded if they were under the age of )8 years and/or had
concomitant chemotherapy$ he authors state that there have &een
studies on irradiated site , dose and fractionation , together with patient
characteristics , however , these data come from selected patient
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studies were generally limited to patients receiving a&dominal radiotherapy
and most had a small sample sie , maing the evaluation of ris factors
for radiation-induced emesis controversial$ 'n this 'talian multicenter trial it
was found that the overall cumulative incidence of nausea and vomiting
occurred in a&out 40% of patients , a percentage which is lower than
found in other studies , however , this is not unexpected , as this study
involved a wide range of patients and not only those at a moderate or high
ris of radiation-induced emesis$ An unexpected fact in this study was the
high incidence of radiation-induced emesis in patients receiving
radiotherapy to the head and nec region and the &reast , especially as
these groups of patients are classed as at minimal ris in current
antiemetic guidelines (see a&le ) page LL#$ he authors state that
although ". receptor antagonists offer &etter control of radiation-
induced emesis in most cases , there is no information a&out the utiliation
of these drugs in daily practice &y oncologists$ he authors further state
that this may &e due to an under evaluation of the clinical relevance of
radiation-induced emesis and even though there is evidence that
prophylactic treatment is warranted in many cases , a Hwait and see;
approach seems to &e preferred &y oncologists$ 5verall , from this studies;
data there is evidence that despite antiemetic treatment 4+% of patients
suffered from vomiting and "8% suffered from nausea$ he authors
suggest that this may have &een due to su&optimal dosage of the
antiemetics and &ecause of the fact that preventative treatment was only
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offered to patients at high ris of radiation-induced emesis$ he authors
conclude that there is a need to reinforce an evidence-&ased approach to
identify the &est antiemetic treatment for patients receiving radiotherapy$
!00 prophylactic de;amethasone '
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compared with 9 (4*$%# out of 9" who received place&o$ 'nterestingly ,
most emetic episodes occurred during the initial phases of treatment ,
again raising the issue of whether prolonged prophylactic treatment over a
longer period is necessary$ 5f the))! patients who received more than )0
fractions of radiotherapy , there was no significant difference in any of the
parameters in &oth groups after fraction )" , including nausea and
vomiting scores$ he authors suggest that a greater proportion of patients
who received prophylactic dexamethasone had complete protection
compared with the place&o group , however , it is not possi&le to mae
direct comparisons to ". receptor antagonists , &ut the results could
suggest a similar efficacy$
!0>0 5ranisetron and its clinical use
he specific efficacy of granisetron in achieving control of emesis in acute
radiation-induced nausea and emesis has &een demonstrated in a num&er
of studies (eyer et al !00"a# , one of these &eing a trial to compare a
daily dose of granisetron with a place&o (anciano et al !00)#$ his latter
trial was a multicenter , randomised , dou&le-&lind study using granisetron
as a prophylactic antiemetic in patients receiving fractionated upper
a&dominal radiotherapy$ atients were included if they were over )8 years
of age , had radiation fields of at least )00cm! , would receive at least )0
fractions and at most 0 fractions of treatment and this included !+4
patients &efore the start of the trial$ atients were excluded if they had
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participated in prior drug trials within the last 0 days , had an unsta&le
medical disorder , a poor performance status , treatment with any
medication with a nown effect on emesis , &rain tumours , a nown
hypersensitivity to ". receptor antagonists , concurrent chemotherapy ,
previous a&dominal radiotherapy or emesis within !4hrs &efore the
administration of the study medication$ atients were assessed via daily
worsheets which were evaluated weely$ 1ranisetron or place&o was
given as two )mg ta&lets )hr prior to the start of radiotherapy on each day
of treatment and also on non-treatment days , such as weeends , at
approximately the same time and patients were randomised to receive
either of the study drugs$ he patient data was compared at !4hrs and at
)0 and !0 fractions$ 5ut of the total of patients included in this study , all
patients who received a minimum of 80% of the prescri&ed study
medication over a !-4 wee period and who returned the worsheets were
considered to have completed the study$ his left 8+ (+4$!%# patients in
the granisetron group and "9 (4$8%# patients in the place&o group$ or
patients treated with granisetron the median time to first emesis was "
days compared to * days in patients treated with place&o , hence there
was a significant difference &etween treatment groups with the granisetron
group at a lower ris of emesis$ .owever , the difference &etween groups
when evaluated at !0 fractions of treatment showed no statistical
significance , again raising the uestion of how long patients should
receive antiemetics prophylactically$ he most common side effects
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reported &y patients receiving granisetron were diarrhoea , asthenia and
constipation , however , this is a nown fact (Aapro, !004# , &ut there are
no nown reports of extrapyramidal side effects , as seen with older
antiemetics (1oodin and 2unningham, !00!#$ his large study shows that
!mg of granisetron , administered once daily , is significantly more
effective than place&o for the prevention of nausea and/or emesis in
patients receiving fractionated radiotherapy to the upper a&domen ,
however , it is difficult to assess granisetron when compared to other
". receptor antagonists , e$g$ ondansetron , due to a lac of trials
comparing these$ 1ranisetron is a potent and highly selective ".
receptor antagonist that has little or no affinity for other receptors , e$g$
dopaminergic , opioid (Aapro, !004# , and this contrasts with the
competitive antagonism shown &y ondansetron with its detecta&le affinity
for other receptors (eyer et al !00" and the irreversi&le &inding of
granisetron may &e the cause for its longer duration at receptor sites
(=lower and Aapro, !00!#$
!090 prophylactic tropisetron
Although not approved for the prevention and treatment of radiation-
induced nausea and vomiting , tropisetron has &een investigated in recent
trials (eyer et al !00" , one of which (7ystaidou et al !00+# will &e
discussed in this section$ he study was a prospective, randomised open
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la&el study which was carried out to evaluate the efficacy of prophylactic
tropisetron or rescue tropisetron in patients receiving palliative or radical
fractionated radiotherapy$ 5verall , !88 patients were included and the
criteria for inclusion were age over )8 years , a diagnosis of malignant
disease reuiring fractionated radiotherapy and that the radiotherapy was
given to moderate or high emetogenic areas , however , according to
current antiemetic guidelines , some of the studies patients did not actually
fall into these categories (e$g$ &reast cancer patients#$ atients were
randomised into either a group receiving tropisetron as prophylaxis or into
a group receiving tropisetron as rescue medication$ he prophylactic
group received "mg of tropisetron ) day &efore start of treatment , )-! hrs
&efore each radiotherapy fraction and then once daily for 9 days after
completion of treatment , whereas the rescue group received tropisetron
on an as-needed &asis as soon as nausea and/or vomiting developed$ or
a &aseline assessment involved physicians recorded patient
characteristics , type of radiotherapy , patients; medical history and
performed a physical examination$ atients were given diary cards to
record their use of medication and any adverse effects$ he authors state
that ris factors found to &e associated with radiation-induced vomiting
were site of primary cancer , presence of metastasis , type of therapy and
dose fraction$ he incidence of vomiting was higher in patients receiving
treatment to lung , &owel , liver , uterine system and &reast cancer and it
should &e reiterated that not all of these patients would &e expected to &e
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su&seuent days after initial irradiation represents an acute response to
that days; radiotherapy , a delayed response to previous days;
radiotherapy , a com&ination of &oth , or even a completely new
mechanism$ 5ndansetron has also &een shown to &e superior , when
used prophylactically , to a com&ination of chlorpromaine and
dexamethasone (6yes et al )**9# , however , dexamethasone on its own
has &een shown to &e a cost-effective alternative when compared with a
place&o (@ir&ride et al !000#$ 5ther ". receptor antagonists have
&een found to &e as effective as ondansetron , such as granisetron
(anciano et al !00)# and tropisetron (7ystaidou et al !00+ < Aass et al
)**9# , additionally , these antiemetics may only need a once daily
administration compared to multiple doses of ondansetron , hence they
may &e &etter suited for patients with regards to treatment compliance$
Although =arra3on et al (!00)# state that there is no difference &etween
ondansetron , granisetron and tropisetron , the researcher is unaware of
trials which compare different ". receptor antagonists in the same trial ,
hence it is uestiona&le whether comparing separate trials allows to infer
that these antiemetics show no difference$ Another fact that has to &e
taen into account when investigating whether antiemetics should &e
given as prophylaxis to patients receiving single or fractionated
radiotherapy , is that of the side effects profile and 1oodin and
2unningham (!00!# state that treatments used to control nausea and
vomiting form a crucial part of the supportive care regimen of cancer
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patients and should not add to the patients side effects &urden , therefore ,
safety and tolerance of antiemetics should form part of the considerations
in their selection and use$ 'mportantly , ". receptor antagonists do not
in general show extrapyramidal reactions in patients when compared with
older antiemetics and this is pro&a&ly a conseuence of their relative
selectivity for ". receptors over dopamine receptors (1oodin and
2unningham, !00!#$ .owever , &oth ondansetron and granisetron can
lead to moderate or severe headaches in the ma3ority of patients and to
a&normal vision and diiness in a minority of patients (1oodin and
2unningham, !00!#$ he most common side-effects of ". receptor
antagonists , other than headache , are constipation , diarrhoea , asthenia
and somnolence (1oodin and 2unningham, !00!#$ urthermore , the
development of significant electrocardiograph changes with some ".
receptor antagonists may indicate a potential for significant cardiac effects
in patients , especially in those patients who may &e predisposed to
cardiac complications (e$g$ the elderly# (@eefe, !00!#$ he elderly are
more liely to suffer from the adverse effects of irradiation , may have
declining organ function , and are more liely to suffer some degree of
cognitive impairment (1ridelli and Aapro, !004#$ he expansion of this age
group is important for cancer treatment , &ecause cancer incidence and
mortality are highest in the elderly (1ridelli and Aapro, !004#$ herefore ,
the elderly are liely to suffer from several radiotherapy related side effects
and may reuire antiemetic treatment , however , elderly patients are often
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evidence is valid enough to support current antiemetic guidelines and if
the evidence is sufficient , should antiemetic guidelines &e enforced more
rigorously in clinical practice$
!0//0 Current antiemetic guidelines and their use
1ralla et al ()***# state that practice guidelines are systematically
developed statements to help the practitioner and patient decisions a&out
appropriate care for specific clinical circumstances , such as the use of
antiemetics , and that good clinical guidelines should include
considerations of validity , relia&ility , reproduci&ility , clinical applica&ility ,
clarity , multidisciplinary process , review of evidence and documentation$
.owever , guidelines pu&lished &y different groups differ in their definitions
and recommendations , which can lead to confusion when used &y various
different radiation oncologists (eyer, !004#$ Additionally , even though
each of the antiemetic guidelines used for this dissertation mentions
patient ris factors , none of the guidelines actually incorporate these
factors into their system for determining the overall patient ris of
radiation-induced vomiting (eyer, !004#$ 'n order , therefore , to achieve
an optimal treatment strategy to prevent nausea and/or emesis , it would
&e useful to develop a ris-ad3usted treatment where the individual ris of
the patient is taen into consideration as well as the emetogenicity of the
radiotherapy regimen (eyer et al !00"a#$ 7arananoet al(!00"# state
that the diversity of recommendations reflect the limited amount of high
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uality evidence , the use of a small num&er of ris categories and the
different composition and insufficient relationship &etween A625 and
7A622 committees , guidelines from which have &een used for this
dissertation$ ?evertheless , current antiemetic guidelines have &een
streamlined and will &e discussed in more detail K
$))$) high ris K otal =ody 'rradiation (='#
atients receiving =' are at high ris and should &e given ". receptor
antagonists as prophylaxis &efore each fraction of treatment and for at
least !4hrs after , and &ecause of the high ris of emesis dexamethasone
as additional treatment is recommended (7arananoet al!00"#$ 1i&&s
and 2assoni ()**+# state that granisetron and ondansetron have &een
shown to &e highly effective as an antiemetic when administered prior to
total &ody irradiation delivered as a single fraction treatment and
=elacemi et al ()**+# state that single fraction =' seems to &e more
emetogenic than fractionated regimens$
$))$! moderate ris K upper a&domen
Gvidence suggests that prophylactic treatment is superior than intervention
on an as-needed &asis in this group and that ". receptor antagonists
are more effective than older antiemetics (@ris et al !00+#$ he A625
guidelines include an intermediate ris group in this category , however ,
@ris et al (!00+# state that due to differences &etween antiemetic agents ,
dopamine receptor antagonists may &e more appropriate for the
intermediate ris group , &ut this is not as clearly stated as may &e wished
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for$ 7aranano et al(!00"# state that patients in the moderate ris group
should receive prophylactic antiemetics &efore each fraction for the entire
treatment cycle and that a rescue antiemetic was not suggested due to a
high percentage of patients experiencing nausea and/or emesis in this
group$
$))$ low ris K lower thorax region , pelvis , cranium (radiosurgery# ,
craniospinal
A625 recommend a ". receptor antagonist &efore each fraction of
treatment (@ris et al !00+# , whereas 7A622 suggest that patients in this
group should receive prophylaxis or rescue treatment with a ".
receptor antagonist and , as prophylaxis , the antiemetic should &e given
&efore each fraction for the entire treatment , and , as rescue , it should &e
continued for each remaining day of radiotherapy treatment once the
rescue medication has &een given (7arananoet al!00"#$
$))$4 minimal ris K head and nec , extremities , cranium , &reast
=oth A625 and 7A622 suggest the use of antiemetics (dopamine or
". receptor antagonists# on an as-needed &asis as rescue medication
(@ris et al !00+ < 7aranano et al!00"#$ he incidence of vomiting in this
group is relatively low according to the guidelines and treatment should &e
reserved for patients who develop radiation-induced vomiting (7aranano
et al!00"#$
.owever , there is a need to investigate the importance of individual ris
factors in respect to incidence of nausea and vomiting (eyer et al !00"a#$
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eyer (!004# suggests an added ris profile that is determined &y the five
patient related factors (age , gender , alcohol intae , previous experience
of nausea and vomiting , psychological state# and the ris profile is then
calculated as a sum of the points accumulated$ A score of 4 or less would
&e seen as a normal-ris patient , whereas a score of " or higher would &e
seen as a high-ris patient , for example , a young female patient with low
alcohol intae , who has previous experience of nausea or vomiting and is
anxious a&out her therapy would have a ris score of + , therefore &eing
seen as a high-ris patient (eyer, !004#$ 'f this patient were a female
receiving radiotherapy to the &reast after having had chemotherapy , even
though current antiemetic guidelines categorise her as at minimal ris ,
this patient could still &e at a high ris and may therefore receive
su&optimal antiemetic treatment$ Another method of individual or patient-
tailored antiemetic treatment with ". receptor antagonists is that of
using the patients; cytochrome 4"0 !+ genotype , as all ". receptor
antagonists are meta&olied &y the cytochrome 4"0 enymes (@aiser et
al !00!#$ he results of a study (@aiser et al !00!# showed that antiemetic
treatment could &e improved &y the identification of non- , low- , or high-
responders on a pharmaco-genetic &asis , and if ultrarapid meta&oliers
were identified &efore treatment starts , the necessary antiemetic
treatment could &e adapted to the individuals needs , there&y possi&ly
preventing severe nausea or vomiting$
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:egarding antiemetic guidelines in general , the implementation of these
seem to &e difficult and structural difficulties , patient characteristics , and
other &arriers , such as acceptance of guidelines and education of medical
staff , can &e crucial factors for successful implementation (@aiser, !00"#$
=efore an antiemetic guideline can impact on a patients; outcome , it must
change the nowledge of the doctor , then attitudes towards or acceptance
of the guidelines and then the clinical &ehaviour that could lead to a &etter
outcome for the patient (@aiser, !00"#$
0 Conclusion
?ausea and vomiting in patients receiving radiotherapy to emetogenic
areas are common complaints and can &e distressing if these symptoms
last for days or wees , however , radiation oncologists tend to
underestimate this pro&lem (7ystaidou et al !00+#$ herefore ,
inadeuate control of nausea and vomiting may lead to significant
decrease in the patients; uality of life , which has &een shown to
decrease patients; compliance to treatment with a potential impact on
disease outcome (.oriot, !004#$ he choice of antiemetic and the optimal
dosage for radiation-induced nausea and/or vomiting are still su&3ects of
de&ate , however , the introduction of ". receptor antagonists has
resulted in a dramatic improvement in controlling these symptoms (eyer
et al )**8# , even though the num&er of randomised trials that have
compared ". receptor antagonists with conventional antiemetics is
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relatively small , those that exist demonstrate their efficacy and safety
(.oriot and Aapro, !004#$ .owever , there is evidence that in fractionated
radiotherapy the efficacy of ". receptor antagonists may decrease after
the first wee of treatment (@ris et al !00+#$ Gven then the
recommendations for the use of antiemetics in radiotherapy are for
prophylaxis over a whole treatment course in some patients groups (eyer
et al !00"a#$ .owever , only the irradiated site is considered the ris factor
in these recommendations and the researcher agrees with 7arananoet
al(!00"# who state that there is a need to investigate the importance of
the patients; individual ris factors and the duration of antiemetic treatment
, &efore any final conclusions on this su&3ect can &e made$ .owever ,
@aiser (!00"# states that 0-"0% of patients do not receive appropriate
antiemetic treatment , leading to the conclusion that current antiemetic
guidelines should &e &etter implemented in current clinical practice$ he
researcher concludes that further studies on this su&3ect are warranted
and that the most appropriate antiemetic treatment , for the present time ,
should com&ine proven efficacy with simple administration and convenient
dosing in order to improve patient compliance and uality of life (.oriot
and Aapro, !004#$
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)eerence 4ist
Aapro,7$ (!004#$ 1ranisetronK an update on its clinical use in the management ofnausea and vomiting The Oncologist,9,+9-+8+
Aass,?$,.atun,$G$,horesen,7$ and ossa,6$$ ()**9#$ rophylactic use oftropisetron or metoclopramide during ad3uvant a&dominal radiotherapy ofseminoma stage 'K a randomised , open trial in ! patients Radiotherapy andOncology,45 ,)!"-)!8
A&raham,A$,6ridhar,?$ and eeran3aneyulu,A$ (!000#$ 2ancer chemotherapy andradiation induced emesis (2:'G#K current and future therapeutic approaches
Indian Journal of Pharmacology,32 ,!"+-!+8
=elacemi,N$,5sahin,7$,ene,$,:io,=$,6utton,$,aporte,O$$,ou&oul,G$,1orin,?-2$ and augier,A$ ()**+#$ otal &ody irradiation prior to &one marrowtransplantationK efficacy and safety of granisetron in the prophylaxis and controlof radiation-induced emesis International Journal of Radiation Oncology , iology, Physics,3!"#$ ,99-8!
=lower,$ and Aapro,7$ (!00!#$ 1ranisetron vs ondansetronK is it a uestion ofduration of "-. receptor &locadeLritish Journal of %ancer,&!"#'$ ,)++)-)++4
2urrow,$2$,2oughlan,7$,ardell,=$ and 2ooney,?$O$ ()**9#$ Dse ofondansetron in palliative medicine Journal of Pain and (ymptom)anagement,#3"5$ ,0!-09
eyer,$2$,6tewart,A$$ and itl&ach,5$O$ ()**8#$ Aetiology and prevention ofemesis induced &y radiotherapy (upporti*e %are in %ancer,! ,!"-!+0
eyer,$ (!004#$ he importance of simple , easy-to-follow antiemetic guidelines+cta Oncologica,43"suppl#5$,6"-68
eyer,$2$,7aranano,G$,7olassiotis,A$,2lar-6now,:$A$,:oila,$,Marr,$ and5lver,'$ (!00"a#$ :adiotherapy-induced nausea and vomiting (:'?#K antiemeticguidelines (upporti*e %are in %ancer,#3 ,)!!-)!8
eyer,$,6eegenschmiedt,7$.$ and 6teingrae&er,7$ (!00"$ 1ranisetron in thecontrol of radiotherapy-induced nausea and vomitingK a comparison with otherantiemetic therapies (upporti*e %are in %ancer,#3,+9)-+98
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eyer,$ and itl&ach,5$O$ ()**8#$ reatment of radiotherapy-induced nauseaand vomiting$ 'n 7$A$icato (Gd$#, )edical management of cancer treatmentinduced emesis$ (pp)0-)!*#$ondonK 7artin unit
in,A$ ()**8#$ %onducting research literature re*ie-s. from paper to the internet$
ondonK 6age u&lications
ranen,$,?yman,O$,.ag&erg,.$,Oao&sson,7$,6or&e,=$,?yth$A$$ andom&erg,.$ ()**+#$ A randomised place&o controlled study with ondansetron inpatients undergoing fractionated radiotherapy+nnals of Oncology,/ ,"89-"*!
1i&&s,6$O$ and 2assoni,A$7$ ()**+#$ A pilot study to evaluate the cost-effectiveness of ondansetron and granisetron in fractionated total &ody irradiation%linical Oncology,& ,)8!-)84
1oodin,6$ and 2unningham,:$ (!00!#$ ". receptor antagonists for the
treatment of nausea and vomitingK a reappraisal of their side-effect profileThe Oncologist,/,4!4-4+
1ralla,:$O$,5so&a,$,@ris,7$1$,@ir&ride,$,.eseth,$O$,2hinnery,$M$,2lar-6now,:$,1ill,$$,1roshen,6$,1run&erg,6$,@oeller,O$7$,7orrow,1$:$,ere,G$A$,6il&er,O$.$ and fister,$1$ ()***#$ :ecommendations for the use of antiemeticsKevidence-&ased , clinical practice guidelines Journal of %linical Oncology,##/"9$ ,!*9)-!**4
1ralla,:$O$,:oila,$ and onato,7$ (!00"#$ he !004 perugia antiemeticconsensus guideline processK methods , procedures and participants (upporti*e%are in %ancer,#3
,99-9*
1reenhalgh,$ (!00)#$ 0o- to read a paper$(!nded$#$ondonK =7O u&lishing1roup
1ridelli,2$ and Aapro,7$ (!004#$ actors influencing the choice of ". receptorantagonist antiemeticsK focus on elderly patients (upporti*e %are in %ancer,#2 ,489-4*+
.oriot,O-2$ (!004#$ rophylaxis versus treatmentK is there a &etter way to manageradiotherapy-induced nausea and vomitingL International Journal of RadiationOncology , iology , Physics,!'"4$ ,)0)8-)0!"
.oriot,O-2$ and Aapro,7$ (!004#$ reatment implications for radiation-inducednausea and vomiting in specific patient groups 1uropean Journal of %ancer,4'"/$,*9*-*89
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ramer,7$:$,:eynolds$$O$7$,6toner$?$6$,7oore,:$A$ and 7cPuay,.$O$ ()**8#$Gfficacy of "-. receptor antagonists in radiotherapy-induced nausea andvomitingK a uantitative systematic review 1uropean Journal of %ancer,34"#2$ ,)8+-)844
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"ppendi;
Author Near ype of article :esults /2omments
Aapro !004 :eview Dse of granisetron
in management ofnausea andemesis
Aass et al )**9 rial Dse of antiemeticsin radiotherapypatients
A&raham et al !000 :eview hysiology ofemesis andpharmacology ofantiemetics
=elacemi et al )**+ rial Dse of
prophylacticgranisetron in ='
=lower and Aapro !00! etter to editor Antiemetics andreceptor &locade
2urrow et al )**9 :etrospectiveanalysis
Dse ofondansetron inpalliative medicine
eyer et al )**8 :eview Aetiology andprevention ofemesis induced &yradiotherapy
eyer !004 6upplement Dse of antiemeticguidelines
eyer et al !00"a :eview Antiemeticguidelines for:'?
eyer et al !00"& :eview 1ranisetron incomparison withother antiemetics
eyer and itl&ach )**8 2hapter in =oo reatment of :'?
in )**8 =oo 5n literatureresearch
ranen et al )**+ rial/study 5ndansetron vsplace&o infractionated :
1i&&s )**+ ilot study 2ost-effectivenessof antiemetics in='
Author Near ype of article :esults /
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2omments
1oodin and2unningham
!00! :eview 6ide-effects profileof antiemetics
1ralla et al )*** 6pecial article Antiemeticguidelines
1ralla et al !00" 5riginal 6ummary ofmeeting onantiemeticguidelines
1reenhalgh !00) =oo .ow to read apaper
1ridelli and Aapro !004 :eview Antiemetics andelderly patients
.oriot !004 :eview rophylaxisversus treatment
.oriot and Aapro !004 :eview reatment
implications for:'? in specificpatient groups
@aiser et al !00! 6tudy atient-tailoredantiemetictreatment using4"0 cytochromes
@aiser !00" :eview Are antiemeticguidelines &eingused
@eefe !00! :eview 2ardiotoxic side
effects ofantiemetics
@hoo et al )**9 rial/study Gffect ofantiemetics andradiation field sieon 1' mor&idity
@ir&ride et al !000 rial/phase '''study
examethasoneas antiemetic in: patients
@oeller et al !00! 6pecial article Antiemeticguidelines and
treatmentapproach
@ris et al !00+ 6pecial article A625 antiemeticguidelines
anciano et al !00) rial/study 1ranisetron asprophylaxis in :
Author Near ype of article :esults /
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2omments
e=ourgeois et al )*** rial/study 5ndansetron fortreatment ofpatients receivingfractionated :
7aranano et al !00" :eport :eport onevidence-&asedrecommendationsfor antiemetics in:
7ystaidou et al )**8 rial Antiemetics inpatients with faradvanced cancer
7ystaidou et al !00+ 6tudy rophylactictropisetron infractionated :
5lver )**8 2hapter in &oo 7ethodology oftrials for treatingnausea andvomiting
riestman et al )**0 rial/study 5ndansetron andmetoclopramide inupper a&do :
riestman et al )** rial/study 5ndansetron andprochlorperainein fractionated :
6eegenschmiedt !004 6upplement 'n search of the
ideal antiemetic6yes et al )**9 6tudy Assess efficacy ,
cost-effectivenessand uality of life
Antiemetic6u&committee
!00+ :eview :esults ofantiemeticconference
'talian group forantiemeticresearch in :
)*** rial 7ulticenter trial forvarious : patientgroups
ramer et al )**8 Puantitative
systematic review
Antiemetics in
:'?