dissertation (2007) (use of antiemetics in radiotherapy)

8/13/2019 DISSERTATION (2007) (Use of Antiemetics in Radiotherapy)

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Candidate number 299297

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$

24


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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

25


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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

26


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28/51


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

28


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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 '


30/51


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

33


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35/51


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

35


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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

36


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38/51


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

38


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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

39


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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#$

40


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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$

41


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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

42


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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#$

43


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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

44


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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

45


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47/51


48/51


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

48


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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 /

49


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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

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dissertation (2007) (use of antiemetics in radiotherapy)

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