THESE t DOCTORAT TOULOUSE

Université Fédérale
t
THESE
Toulouse Midi-Pyrénées
En vue de
l'obtention du
DOCTORAT DE L,UNIVERSITÉ DE TOULOUSE
Délivré par:
Université Toulouse 3 Paul Sabatier (UT3 Paul Sabatier)
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Présentée et soutenue par
Thierry - Gwénaël FERRON
le vendredilg juin 20I5
s
Titre:
THERAPEUTIC METHODS FOR PERITONEAL CARCINOMATOSIS
STAN DARDIZATION OF HYPERTHERM IC INTRAPERITONEAL CHEMOTHERAPY
PHARMACOKI N ECTICS AN D PHARMACODYNAMIC STU DIES
Êcole doctorale et discipllne ou spécialité:
ED BSB : Biotechnologies, Cancérologie
Unité de recherche:
EA
4553 lndividualisation des traitements des cancers de l'ovaire (IUCT-O)
Directeur/trlce(s) de Thèse :
Pr BCttiNA COUDERC
PrJean Pierre DELORD
lury:
Pr Olivier GLEHEN (Rapporteur)
Pr Marc POCARD (Rapporteur)
Pr Etienne CHATELUT (Examinateur)
Pr Laurent POULAIN (Examinateur)
Pr Bettina COUDERC (Directeur de thèse)
Pr Jean Pierre DELORD
(Co-directeur de thèse)
!
!
REMERCIEMENTS)
!
Au)Pr)Oliver)GLEHEN,)Rapporteur)
Je!te!remercie!vivement!d’avoir!accepté!de!juger!ce!travail!de!thèse.!Nous!partageons!des!
points! communs,! année! de! naissance,! origine! géographique,! CHIPeur! Breton…! Mais!
sache!que!je!suis!admiratif!du!travail!que!tu!as!réalisé!en!France!pour!la!standardisation!
de!la!chimiohyperthermie!intraGpéritonéale.!Ton!équipe!est!extremement!active!dans!la!
domaine!de!la!PK.!J’espère!que!tu!trouveras!un!vif!intérêt!dans!ce!travail.!Avec!toute!ma!
reconnaissance.!
Au)Pr)Marc)POCARD,)Rapporteur)
Ta!présence!au!jury!de!ma!thèse!de!science,!à!fortiori!comme!rapporteur,!m’honore.!Tes!
connaissances! en! science! fondamentale! et! ton! esprit! “empécheur! de! tourner! en! rond”!
font!de!toi!un!leader!reconnu!en!recherche.!Ta!critique!ne!peut!être!que!positive!à!mes!
yeux.!!Avec!ma!profonde!gratitude.!
Au)Pr)Etienne)CHATELUT,)Examinateur)
Il!y!a!13!ans,!tu!m’as!interdit!de!mettre!de!la!chimiothérapie!dans!un!péritoine!sans!faire!
des!prélevements!de!PK…!Ce!travail!est!donc!aussi!le!tien!même!si!mes!connaissances!en!
pharmacocinétique! sont! toujours! aussi! mauvaises.! Ta! célérité! sur! excel! n’est! pas! une!
légende,!tout!comme!ton!esprit!de!synthèse.!Mille!mercis.!Avec!toute!mon!amitié!et!ma!
gratitude.!
Au)Pr)Laurent)POULAIN,)Examinateur)
Je! vous! remercie! de! votre!intérêt! pour! ce! travail.! C’est! toujours! un! immense! plaisir! de!
travailler!avec!les!équipes!de!Caen.!C’est!un!honneur!pour!moi!de!vous!avoir!parmi!les!
membres!de!mon!jury.!Veuillez!trouver!ici!l'expression!de!ma!sincère!reconnaissance.!
Au)Pr)Bettina)COUDERC,)Directeur)de)thèse)
Que!dire…!MERCI!de!tout!coeur!…!Sans!toi!cette!thèse!ne!serait!pas!là…!Après!m’avoir!
accueilli! dans! ton! laboratoire! au! quotidien,! tu! m’as! de! suite! considéré! comme! un!
membre! à! part! entière! de! ton! équipe…! et! que! de! fous! rires…! que! d’idées! folles…! mais!
aussi!que!de!soutiens!pendant!ces!derniers!mois!pénibles.!Avec!toute!mon!amitié!et!ma!
profonde!reconnaissance.!
Au)Pr)Jean)Pierre)DELORD,)Examinateur)
Mon!mentor!en!recherche!en!transfert…!Le!Wikipedia!de!la!médecine!moderne…!Notre!
amitié!professionnelle!et!personnelle!n’a!jamais!connue!de!faille.!Tes!conseils!nocturnes!
de! ces! derniers! mois! m’ont! permis! de! tenir.! Merci! pour! ton! soutien! et! ton! aide!
permanente.!A!notre!amitié…!
!
!
2!
A)tous)les)membres)de)l’équipe)EA4553)et)du)comité)d’oncoNgyneco,)
Un!grand!merci…!
Laurence,!à!notre!duo!et!notre!complicité!sans!égal…!
Eliane,!ma!reine!du!péritoine…!
Alejandra,!la!petite!qui!a!poussé!comme!une!flèche…!
Et!à!tous!les!autres…!
!
!
Aux)membres)du)bloc)opératoire)et)de)chirurgie,)
Aux!IBODES,!IADE,!aide!soignants,!brancardiers…!à!tous!ceux!que!j’ai!harcellé!avec!ces!
innombrables! prélevements! de! PK! depuis! 13! ans…! ce! travail! n’aurait! pu! être! fait! sans!
vous.!
Votre!soutien!m’a!profondement!touché…!
A!mes!ami(e)s!anesthesites…!sans!vous,!vous!savez,!nous!ne!sommes!rien…!
A!mes!ami(e)s!chirurgiens!de!l’Institut!
!
A)Denis,)
Tu!m’as!souvent!expliqué!que!l’on!peut!être!le!meilleur!chirurgien!du!monde,!mais!si!on!
ne!fait!pas!de!recherche…!on!fait!forcement!un!jour!fausse!route…!
Merci!de!ta!clairvoyance!et!de!ton!aide!constante.!
!
3!
A)Berenice,!
La!vie!sans!toi!serait!des!plus!fades!et!sans!intérêt.!
Tu! sais! rendre! positif! chaque! moment! de! la! vie…! même! les! plus! difficiles! comme! ces!
derniers!mois.!
Vivement!demain…!
Je!t’aime!
!
A)Ewen,)Klervi,)Ederna)et)Aodrenn)
Vous!êtes!toutes!quatre!ma!vie,!ma!fierté!…!
Vous!étes!l’équilibre!de!ma!vie.!
Je!vous!aime!tant…!
Je!vous!dédie!ce!travail.!
!
A)mon)père!
Ton!absence!est!toujours!aussi!difficile!malgré!les!années…!
)
A)Maman)
Pour!que!tu!sois!encore!plus!fière!de!moi…!
Je!t’embrasse!tendrement!
!
A)mes)soeurs,)frères)et)pieces)rapportées…)
Un!grand!merci!à!tous!pour!ce!bonheur!que!vous!m'apportez!au!quotidien.!Nous!avons!la!
chance!d'être!unis,!soudés,!ne!perdons!jamais!cette!chance.!
!
A)Chantal)et)Daniel,)
Un! grand! merci!pour!votre!présence!et!votre!gentillesse!sans!faille…!Puissent!les!filles!
vous!combler…!!
!
!
!
4!
CONTENTS)
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RESUME)))
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p.)5)
SUMMARY) )
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p.)8)
GLOSSARY) )
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p.)11)
1.)INTRODUCTION) )
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p.)13)
1.1!:!ROLE!OF!COMPLETE!CYTOREDUCTIVE!SURGERY! !
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p.)15)
1.2:!ROLE!OF!INTRAPERITONEAL!CHEMOTHERAPY!
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!
!
p.)16)
1.3:!ROLE!OF!HYPERTHERMIA!
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p.)18)
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1.4:! SYNERGY!
CHEMOTHERAPY! !
BETWEEN!
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HYPERTHERMIA!
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!
!
AND!
!
INTRAPERITONEAL!
!
!
p.)19)
1.5:!HYPERTHERMIC!INTRAPERITONEAL!CHEMOTHERAPY!(HIPEC)!!!
p.)21)
1.6:!PERSONNAL!RESEARCH!OVERVIEW! !
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p.)22)
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p.)27)
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2.)RESULTS)) )
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2.1:! DEMONSTRATION! OF! THE! FEASIBILITY! OF! LAPAROSCOPIC!
PERITONECTOMY! FOLLOWED! BY! OXALIPLATIN! BASED! INTRAPERITONEAL!
CHEMOTHERAPY!AND!ITS!PHARMACOKINETICS!CONSEQUENCES! !
!
p.)28)
2.1.1:! First! step:! To! demonstrate! the! feasibility! of! laparoscopic! peritonectomy!
and!HIPEC.!!
2.1.2:!Second!step:!to!compare,!in!an!experimental!study,!the!pharmacokinetics!of!
oxaliplatin!during!Open!versus!Laparoscopic!HIPEC.!
2.1.3:!Discussion!and!future!prospect!
!
2.2:! EVALUATION! OF! THE! PHARMACOKINETIC! INTERGPATIENT! VARIABILITY!
OF! OXALIPLATIN! BASED! OPEN! ABDOMEN! HIPEC! AND! COMPARISON! OF! THE! IMPACT!
OF! TWO! PROCEDURES! OF! DRUG’S! DELIVERY! ON! OXALIPLATIN! PK.! A! POPULATION!
PHARMACOKINETIC!APPROACH.! !
!
!
!
!
!
!
p.)33)
2.2.1:!To!develop!a!PK!model!and!to!compared!the!impact!of!two!procedures!of!
drug’s!delivery!
2.2.2:!Discussion!and!future!prospect!
!
!
5!
!
2.3:! EVALUATION! OF! THE! TOXICITY! FOR! PATIENTS! WHO! UNDERWENT!
COMPLETE!CYTOREDUCTIVE!SURGERY!ASSOCIATED!TO!CISPLATIN!AND!OXALIPLATIN!
BASED!HIPEC.!CLINICAL!AND!PHARMACODYNAMIC!STUDIES!!
!
!
p.)35)
2.3.1:!Cisplatin!based!HIPEC!related!toxicity!
2.3.2:!Oxaliplatin!based!HIPEC!related!toxicity!
2.3.3:!Discussion!and!future!prospect!
!
3.)CONCLUSION)
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p.)45)
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p.)48)
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REFERENCES)
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6!
RESUME))
La! carcinose! péritonéale! (CP)! correspond! le! plus! souvent! à! l’envahissement!
métastatique!de!la!cavité!péritonéale!survenant!dans!85!à!90%!des!cas!de!l’ovaire!et!5!à!
20%! des! cancers! colorectaux.! La! pauvreté! de! des! signes! cliniques! explique! que! le!
diagnostic!se!fasse!à!un!stade!souvent!avancé.!!
Jusque!récemment,!le!traitement!d’une!CP!était!exclusivement!palliatif!avec!une!
chirurgie! de! nécessité! incomplète! et! une! chimiothérapie! systémique,! et! une! survie!
médiocre.! La! cause! du! décès! est! dans! la! majorité! des! cas! la! carcinose! elleGmême.! Les!
avancées! en! matière! de! chirurgie! péritonéale! extensive! et! de! chimiothérapie!
intrapéritonéale! combinée! ou! non! à! une! hyperthermie! ont! fait! naître! de! nombreux!
espoirs!de!curabilité.!
La!chirurgie!de!cytoreduction!complète!représente!le!facteur!pronostic!essentiel,!
quelque! soit! l’origine! tumorale! primitive.! L’association! d’une! chirurgie! et! d’une!
chimiothérapie! intraperitonéale! a! été! développée! dans! le! cancer! de! l’ovaire! avec! des!
taux! de! survie! impressionnants.! L’hyperthermie! induit! une! destruction! sélective! des!
cellules!en!hypoxie,!dans!des!zones!tumorales!en!acidose,!tout!en!préservant!le!tissu!sain!
environnant.! Pour! les! patients! atteints! de! CP,! une! technique! nommée! CHIP! a! été!
developpée! permettant! de! délivrer! une! chimiothérapie! intrapéritonéale! en! condition!
d’hyperthermie.! Une! augmentation! importante! de! la! survie! de! patients! atteints! de! CP!
colorectal!ou!de!maladie!rare!du!péritoine!a!été!mise!en!évidence.!Des!essais!cliniques!
sont!en!cours!afin!de!vérifier!le!bénéfice!attendu!de!l’HIPEC!dans!différentes!pathologies.!
Premièrement,! compte! tenu! de! large! développement! de! la! laparoscopie,!
l’adressage!de!patients!avec!une!carcinose!localisée!est!fréquent.!Nous!avons!développé,!
sur! modèle! animal,! une! technique! de! péritonectomie! laparoscopique! avec! CHIP! à!
l’oxaliplatine.! Les! paramètres! pharmacocinétiques! (PK)! en! terme! d’absorption! de! la!
drogue!et!de!pénétration!intraGtissulaire!ont!été!analysés!avec!mise!en!évidence!du!rôle!
favorable! de! l’hyperpression! intraabdominale.! Ces! travaux! ont! été! publié! dans!
Gynecologic*Oncology,!dans!Annals*of*Surgical*Oncology!(2!articles)!et!inclus!dans!un!
chapitre*de*livre*international*(Humana*Press)*concernant!la!pharmacologie!et!la!PK!
des!sels!de!platine.!
Ensuite,! nous! avons! établi! un! nouveau! modèle! de! pharmacocinétique! des!
populations!que!nous!avons!appliqué!à!la!comparaison!de!deux!modes!d’administration!
de!la!chimiothérapie!lors!des!CHIP!à!l’oxaliplatine,!sur!24!patients.!Ce!travail!a!été!publié!
dans!Cancer*Chemotherapy*and*Pharmacology.!!
Enfin,!différentes!études!cliniques!et!pharmacodynamiques!(PD)!ont!été!réalisée!
afin! d’évaluer! et! de! prédire! la! toxicité! spécifique! des! CHIP! réalisées! au! Cisplatine! et! à!
l’Oxaliplatine.!
Trois! travaux! successifs! ont! été! réalisés! pour! évaluer! la! toxicité! rénale! liée! au!
Cisplatine.!Dans!une!étude!pilote!de!PK,!non!publiée,!de!désescalade!de!dose,!nous!avons!
montré!que!le!risque!d’insuffisance!rénale!n’est!pas!expliqué!par!la!PK!(présentation!au!
Congrès! de! PharmacoGOncologistes).! Cela! a! été! confirmé! dans! une! étude! rétrospective!
bicentrique! avec! mise! en! évidence! de! facteurs! de! risque.! Ce! travail! est! soumis! à!
publication! dans! European* Journal* of* Surgical* Oncology.! Enfin! une! étude! de! phase! I!
!
7!
d’escalade! de! dose! a! été! réalisée! permettant! de! déterminer! la! dose! optimale! de!
Cisplatine!en!CHIP!et!est!soumise!à!publication!dans!Journal*of*Clinical*Oncology.!!
Compte!tenu!de!la!toxicité!rénale!du!cisplatine,!une!étude!prospective!de!phase!II!
a!évalué!la!morbidité!de!l’oxaliplatine!en!CHIP!dans!le!cancer!de!l’ovaire.!Cet!essai!a!été!
clos!de!façon!anticipée!compte!tenu!du!taux!d’hémopéritoine!et!publié!dans!European*
Journal*of*Surgical*Oncology.!Afin! d’analyser!et!prédire!ce!risque,!une!étude!PKGPD!a!
été! conduite! sur! 75! patients! traités! par! CHIP! à! l’oxaliplatine! avec! une! corrélation! PK!
entre! ! l’absorption! et! la! survenue! de! thrombopénie! et! d’hémoperitoine.! Ce! travail! est!
publié!dans!Cancer*Chemotherapy*and*Pharmacology.!
!
!
8!
SUMMARY)
)
Peritoneal!carcinomatosis!(PC)!is!usually!caused!by!widespread!cancer!metastatic!cells!
within!the!peritoneal!cavity!and!occurred!in!85%!of!ovarian!cancer!patients!and!5–20%!
of! colorectal! carcinoma! patients.! Because! of! the! poverty! of! symptoms,! patients! are!
diagnosed!with!an!advanced!stage.!PC!will!be!the!leading!death!cause!of!these!patients.!
Recently,! the! treatment! was! limited! to! standard! palliative! surgery! and! intravenous!
chemotherapy! with! very! poor! results! in! term! of! survival.! The! development! of! new!
surgical!techniques!combined!with!intraperitoneal!chemotherapy!associated!or!not!with!
hyperthermia!provided!new!hope!of!a!potential!cure!for!patients!with!PC.!!
Indeed,! complete! cytoreductive! surgery! represents! the! most! important! prognostic!
factor!for!patients!with!PC!whatever!the!primary!cancer!locations.!Combined!treatment!
using! complete! cytoreductive! surgery! and! intraperitoneal! chemotherapy! has! been!
developed! leading! to! unprecedented! survival.! Hyperthermia! induces! a! selective!
destruction! of! tumor! cells! in! hypoxic! and! acidic! parts! of! tumors,! but! leaves! normal!
tissues! intact.! In! addition! heat! is! acting! for! synergy! with! the! cytotoxic! agent.! A! new!
technique! to! deliver! intraoperative! intraperitoneal! chemotherapy! associated! with!
hyperthermia,!called!HIPEC,!was!developed!for!patient!with!PC.!It!significantly!increases!
survival!in!patients!with!colic!cancer!PC,!peritoneal!mesothelioma!and!pseudomyxoma!
peritonei.!Several!ongoing!trails!have!been!designed!to!establish!the!real!role!of!HIPEC!
for!different!pathology.!!
First,! because! of! the! major! development! and! the! widespread! use! of! minimal! invasive!
surgery,! recruitment! of! patients! has! been! profoundly! changed! with! localized! PC.! We!
have! demonstrated! in! an! experimental! study! the! feasibility! and! reliability! of!
laparoscopic!peritonectomy!followed!by!oxaliplatin!based!intraperitoneal!chemotherapy!
and! its! pharmacokinetics! consequences! regarding! the! peritoneal! drug! absorption,! the!
increased!tissue!diffusion,!and!the!role!of!intraperitoneal!pressure.!Several!articles!were!
published! in! Gynecologic* Oncology! and! in! Annals* of* Surgical* Oncology) and! in! an!
international! book* chapter* (Humana* Press)! concerning! pharmacology! and!
pharmacokinetics!of!platinum!salts.!
Then,) to! establish! a! new! population! pharmacokinetic! model! and! to! compare! two!
procedures! of! drug’s! delivery! during! HIPEC,! data! from! 24! patients! treated! with!
oxaliplatin! based! HIPEC! were! collected! and! analyzed.! This! work! was! published! in)
Cancer*Chemotherapy*and*Pharmacology.!
Finally,!different!clinical!and!pharmacodynamic!studies!were!performed!to!evaluate!the!
toxicity! for! patients! who! underwent! complete! cytoreductive! surgery! associated! to!
Cisplatin!or!Oxaliplatin!based!HIPEC.!)
Three! different!works!were!performed!to!evaluate!the!renal!toxicity!of!cisplatin! based!
HIPEC.! An! unpublished! PK! study! regarding! acute! renal! failure! in! a! doseGdeescalation!
study!was!presented!at!a!PharmacoGoncologists!Meeting.!The!results!were!confirmed!in!
a! bicentric! retrospective! study! highlighting! some! risk! factors! (Submitted! to! the!
European* Journal* of* Surgical* Oncology).! Finally,! a! phase! I! study! dose! escalation! of!
hyperthermic! intraperitoneal! cisplatin! was! conducted! with! the! establishment! of! the!
!
9!
recommended! dose! of! cisplatin! for! HIPEC! (Submitted! to! the! Journal* of* Clinical*
Oncology).!
Because!of!renal!toxicity!related!to!cisplatin!based!HIPEC,!a!phase!II!prospective!study!
was!conducted!to!evaluate!the!morbidity!of!oxaliplatin!based!HIPEC.!As!a!result!of!this!
high!morbidity!rate!(hemoperitoneum),!this!trial!was!prematurely!closed!and!published!
in! the* European* Journal* of* Surgical* Oncology.! Finally,! to! evaluate! the! relationship!
between!oxaliplatin!exposure!and!observed!toxicity,!a!population!pharmacokinetics!was!
conducted! in! 75! patients! treated! with! CRS! and! oxaliplatin! based! HIPEC.! A! PK!
contribution,! relative! to! the! absorption! phenomenon,! on! the! severity! of! the!
thrombocytopenia! and! hemoperitoneum! was! shown.! This! work! was! published! in!
Cancer*Chemotherapy*and*Pharmacology.!
)
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!
10!
GLOSSARY)
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AUC)) )
)
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Area!Under!the!Curve!
AUCIP) )
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)
Intraperitoneal!Area!Under!the!Curve)
AUCP) )
)
)
Plasma!Area!Under!the!Curve)
AUCUF))
)
)
Plasma!Ultra!Filtrate!Area!Under!the!Curve)
CC)SCORE!
!
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Completeness!of!Cytoreduction!Score!
CRS) )
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Complete!Cytoreductive!Surgery!
HIPEC))
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Hyperthermic!IntraPeritoneal!Chemotherapy!
HSP) )
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Heat!Shock!Protein!
IP)
)
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Intraperitoneal)
IV)
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Intravenous)
PC)
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Peritoneal!Carcinomatosis!
PCI)
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)
Peritoneal!Cancer!index!
PD)
)
)
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Pharmacodynamics!
PK)
)
)
)
Pharmacokinetics)
)
)
French!Rare!Peritoneal!Disease!Netwok!
RENAPE)
RIFLE)
!
Risk,! Injury,! and! Failure;! and! Loss;! and! EndGstage! kidney!
disease!
11!
FIGURES)
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!
Fig.! 1! Molecular! weight! and! AUC! ratio! of! intraperitoneal! exposure! and! systemic!
exposure!of!drugs!used!to!treat!peritoneal!carcinomatosis!!
!
Fig.!2!Dedrick’s!biGcompartmental!model! !
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Fig.!3!ThreeGcompartmental!model!
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Fig.!4!The!antitumoral!effect!of!heat!
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Fig.!5!Overview!of!the!interactions!between!some!chemotherapeutic!agents!and!heat!
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Fig.!6!PKGPD!analysis!
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Fig.!7!An!illustrative!representation!of!differents!classes!of!third!generation!nanodrugs!
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12!
1.)INTRODUCTION)
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13!
!
Peritoneal!carcinomatosis!(PC)!is!usually!caused!by!widespread!cancer!metastatic!cells!
within!the!peritoneal!cavity.!PC!is!a!terrific!issue,!especially!in!ovarian!cancer!as!85G90%!
of! ovarian! cancer! patients! have! peritoneal! metastasis! at! diagnosis.! 5–10%! of! patients!
with! colorectal! carcinoma! present! with! synchronous! metastases! of! the! peritoneum! at!
the!time!of!initial!colon!resection!and!20–!50%!will!face!with!metachronous!peritenoal!
cancer! progression! [1].! Primary! cancers! of! the! peritoneum! including! mesothelioma!
represent!a!rare!disease!with!a!wide!extension!into!the!peritoneal!cavity.!
Because!of!the!poverty!of!symptoms,!patients!are!diagnosed!with!advanced!stage![2]!and!
the!PC!will!be!the!leading!cause!of!death!of!these!patients.!
The! physiological! mechanisms! associated! with! peritoneal! spreading! are! multiple:!
peritoneal! dissemination!of!free!cancer!cells!may!be!a!result!of!serosal!involvement! of!
the!primary!tumour,!adhesion!of!free!cancer!cells!and!presence!of!cancer!cells!in!lymph!
fluid!or!peritoneal!venous!blood.!
In! a! recent! past,! the! treatment! of! this! metastatic! disease! was! limited! to! standard!
palliative! surgery! and! intravenous! chemotherapy! with! very! poor! results! in! term! of!
survival.! Patients’! death! is! due! to! progression! of! PC,! and! distant! metastasis! are!
uncommon.! Finding! efficient! treatments! of! PC! is! the! major! concern! and! certainly! a!
crucial! part! of! clinical! research! in! PC.! The! rate! of! failure! and! the! dramatic! situation! of!
patients! encouraged! pushing! forward! direct! intraperitoneal! treatment! and! a! surgical!
effort.!
In!the!past!oncologists!have!assumed!that!PC!is!equal!to!distant!metastases!and!as!such!
regarded! it! as! an! incurable! component! of! intraabdominal! malignancy.! PC! has! been!
regarded! as! beyond! current! treatment! modalities.! Over! the! two! last! decades,! the!
development! of! new! surgical! techniques! combined! with! intraperitoneal! chemotherapy!
provided! new! hope! of! a! potential! cure! for! patients! with! PC.! Many! different! methods!
have! been! developed! to! deliver! intraperitoneal! chemotherapy! during! surgical! time!
period,! usually! associated! with! hyperthermia! (HIPEC:! hyperthermic! intraperitoneal!
chemotherapy)! or! with! high! pressure! (PIPAC:! pressurized! intraperitoneal! aerosol!
chemotherapy),! during! early! postoperative! period,! or! sequentially! with! a!
intraperitoneal!catheter.!
Curing! selected! patients! with! PC! is! a! realistic! goal.! PC! should! be! not! systematically!
considered! a! terminal! event.! The! term! “metastases”! may! be! replace! by! “implant”! to!
avoid! the! connotation! of! a! terminal! condition! and! death.! PC! has! to! be! considered! as! a!
localGregional! disease! warranting! localGregional! chemotherapy! to! treatment.! Indeed,! a!
10! years! median! overall! survival! is! achieved! with! complete! cytoreduction! and! IP!
chemotherapy!in!advanced!ovarian!cancer![3].!LongGterm!outcome!data!of!patients!with!
pseudomyxoma!peritonei!treated!by!complete!cytoreductive!surgery!and!HIPEC!shown!
a! 16! years! median! survival! rate! [4].! In! colorectal! PC,! 15%! of! patients! are! considered!
definitively!cured!after!a!combined!treatment:!IV!chemotherapy,!complete!cytoreductive!
surgery!with!or!without!HIPEC![5].!
!!
!
!
14!
1.1):)ROLE)OF)COMPLETE)CYTOREDUCTIVE)SURGERY)
!
Surgery! remains! the! mainstay! of! therapy! in! solid! cancer,! and! complete! resection!
represents! by! itself! the! most! important! determinant! to! cure.! Complete! surgery! allows!
removal! of! chemoresistant! clones! and! of! poorly! vascularized! tumors,! a! higher! growth!
fraction! in! better! perfused! small! residual! tumors! increasing! chemosensitivity,! and!
improval! of! host! immunocompetence! [6].! The! limitations! to! achieve! complete!
cytoreduction! are! surgical! experience,! the! performance! of! extensive! bowel! resections,!
and!poor!performance!status.!Considering!the!whole!peritoneum!as!an!organ!for!which!
metastatic! dissemination,! it! can! be! mainly! addressed! by! chemotherapy! and! complete!
surgery.!
Peritonectomy!and!cytoreductive!surgery!were!described!and!tailored!20!years!ago!as!
the!treatment!of!choice!for!selected!patients!with!evidence!of!peritoneal!carcinomatosis!
[7,!8].!The!clockwise!procedure!can!be!categorized!into:!!
G!right!subdiaphragmatic!and!parietal!peritonectomy,!!!
G!left!subdiaphragmatic!and!parietal!peritonectomy,!!
G!greater!omentectomy!with!splenectomy,!!
G!lesser!omentectomy!and!stripping!of!the!omental!bursa,!!
G!pelvic!peritonectomy!with!resection!of!involved!organs.!
Visceral! resections! such! as! uterus! and! ovaries,! gallbladder,! stomach,! distal! pancreas,!
colon!and!limited!small!bowel!should!be!performed!if!a!complete!cytoreduction!can!be!
achieved! as! a! result.! Completeness! of! Cytoreduction! Scoring! of! CC0,! G1! and! G2! is!
commonly!used!to!describe!residual!disease!of!<2.5!mm,!2.5!to!25mm!and!>25!mm![9].!
The! use! of! validated! scales,! such! as! the! PCI! (Peritoneal! Cancer! Index),! Gilly! score,!
laparoscopic! Fagotti! score,! and! CC! score! is! recommended! for! ovarian! cancer! [10]! and!
nonGgynaecological!PC![11,!12].!
The!quality!of!surgery!represents!the!most!important!prognostic!factor!for!patients!with!
PC!whatever!the!primary!cancer!locations,!confirmed!in!several!publications![13].!As!a!
consequence,!the!remaining!macroscopic!lesions!size!appears!every!time!as!the!weighty!
parameter!of!survival.!For!colorectal!or!gastric!PC,!longGterm!survival!was!obtained!only!
in!patients!who!underwent!complete!macroscopic!resection!(CC0)![5,!14G16].!According!
to! a! transversal! oncologic! point! of! view,! these! results! were! confirmed,! whatever! the!
primary! cancer! locations,! in! a! large! multicenter! cohort! study! of! 1290! patients! treated!
for! nonGgynecological! PC! [13].! For! advanced! ovarian! cancer,! the! largest! metaGanalysis!
performed!by!Bristow!et!al.![17]!which!included!81!studies!accounting!for!6885!patients,!
demonstrated!a!statistically!significant!positive!correlation!between!percent!of!maximal!
cytoreduction!and!median!survival!time.!!
The! use! of! these! scores! as! general! cutGoffs! represents! an! important! tool! to! exclude!
patients! from! this! morbid! procedure! [18].! Survival! analyses! studies! have! shown! that!
patients! with! PCI! scores! less! than! 19! (colorectal)! and! 10! (gastric)! benefit! most! from!
CRS!+!HIPEC![19].!
!
15!
Standardization! and! trained! teams! are! required! to! achieve! improved! completeness! of!
cytoreduction! [20].! In! high! volume! ovarian! cancer! centres,! complete! cytoreductive!
surgery!(CC0)!was!reported!in!70%!of!patients!in!advanced!ovarian!cancers!in!a!french!
multicentre! study! [21].! To! achieve! absence! of! remaining! disease,! specific! surgical!
training! is! mandatory,! including! colorectal! resection! and! diaphragm! stripping! and!
visceral!resection![10,!22].!
Quality!of!surgical!care!as!a!component!of!a!comprehensive!regimen!of!multidisciplinary!
management!has!been!shown!to!benefit!the!patient!in!many!types!of!malignancies![23,!
24].!
!
1.2:)ROLE)OF)INTRAPERITONEAL)CHEMOTHERAPY)
!
Over!the!last!decades,!combined!treatment!using!complete!cytoreductive!surgery!(CRS)!
and! intraperitoneal! chemotherapy! has! been! developed! especially! in! advanced! ovarian!
cancer.!The!advantage!of!intraperitoneal!chemotherapy!includes!the!ability!to!achieve!a!
significantly! higher! concentration! of! chemotherapy! in! the! locoregional! environment.!
Depending!on!their!molecular!weight,!their!affinity!to!lipids!and!clearance!by!the!liver,!
the!median!peak!peritoneal!concentration,!evaluated!by!the!area!under!the!curve!(AUC),!
is!20!to!1000!times!that!of!the!plasmatic!AUC![25]!(Fig.!1).!In!fact,!the!peritoneal!plasma!
barrier!provides!doseGintensive!therapy.!High!concentrations!of!anticancer!drugs!can!be!
in!direct!contact!with!tumor!cells,!with!lower!systemic!toxicity.!!Clinical!or!preGclinical!
results! support! the! favorable! impact! of! increasing! the! dose! or! durationGofGexposure!
(AUC)!on!the!cytotoxic!potential!of!drugs.!This!advantage!is!present!in!commonly!used!
agents! in! gynecological! and! GI! cancers! such! as! platinum! salts,! 5GFU,! taxanes,!
anthracyclin!or!mitomycin!C.!To!be!used!in!peritoneal!cavity,!the!agent!must!be!active!
against!the!tumor!being!treated,!should!not!have!vesicant!properties,!and!should!not!be!
a!prodrug!requiring!liver!activation.!Its!peritoneal!clearance!must!be!slow,!with!a!rapid!
clearance!from!the!systemic!circulation.!!
!
!
!
Fig.!1!Molecular!weight!and!AUC!ratio!of!
intraperitoneal!exposure!and!systemic!exposure!of!
drugs!used!to!treat!peritoneal!carcinomatosis!
(Van!der!Speeten!K!et!al.!Current!Drugs!Discovery!
Technologies!2009)![26]!
!
!
!
16!
An! additional! advantage! to! intraperitoneal! chemotherapy! administration! is! that! the!
blood! drainage! of! the! peritoneal! surface! provides! an! additional! intravenous!
chemotherapy! recently! designed! by! “bidirectional”! chemotherapy! regimens! consisting!
in! the! concurrent! intraperitoneal! and! intravenous! administration! of! the! drugs.! The!
pharmacokinetic!model!that!governs!this!phenomenon!goes!beyond!a!biGcompartmental!
model:!plasma!and!peritoneum.!This!“Dedrick!model”!suggested!it!should!be!possible!to!
expose! tumor! present! within! the! peritoneal! cavity! to! higher! drug! concentration!
compared!to!intravenous!delivery![27]!(Fig.!2).!But!this!biGcompartment!model!does!not!
provide! a! good! theoretical! model! of! the! penetration! of! intraoperative! intraperitoneal!
chemotherapy!in!the!space!between!the!peritoneal!membrane!and!the!tumor!nodules.!A!
triGcompartmental!model!is!more!frequently!used!associating!plasma,!peritoneal!cavity!
and! tumor! [26,! 28].! The! peritoneal! membrane! is! designed! as! an! independent!
compartment!with!its!own!ability!to!accumulate!the!drug!(Fig.!3).!!
!!!!
Fig.!2!Dedrick’s!biLcompartmental!model! !
!
!
Fig.!3!ThreeLcompartmental!model!
Experimental! studies! have! shown! that! drugs! penetration! is! limited! to! a! few! layers!
beneath! the! tumor! surface! [29,! 30].! Nevertheless,! the! penetration! depth! of! drugs! that!
are!intraperitoneally!delivered!was!probably!overGestimated!to!be!a!maximum!of!3!to!5!
mm.! This! is! the! reason! why! an! adequate! and! complete! cytoreductive! surgery! must!
precede!the!intraperitoneal!chemotherapy.!
Encouraging! results! of! randomized! trials! of! IP! adjuvant! chemotherapy! in! the!
management! of! advanced! ovarian! cancer! have! been! published,! with! superiority! to!
intravenous! adjuvant! chemotherapy! [25].! Three! phase! 3! intergroup! trials! have!
compared! intraperitoneal! with! intravenous! chemotherapy! in! advanced,! post! resection!
lowGvolume!remaining!disease!ovarian!cancer!patients.!!
The! first! trial! (GOG! 104! –! SWOG! 8501)! was! published! in! 1996! [31].! A! statistically!
significant! survival! advantage! among! patients! treated! with! intraperitoneal!
chemotherapy! was! demonstrated,! but! the! regimen! did! not! include! paclitaxel! which! is!
the!major!advanced!for!ovarian!cancer!during!the!90th.!!
The! second! trial! (GOG! 114),! published! in! 2001! [32]! showed! a! significant! difference! in!
progressionG! free! survival,! nevertheless! associated! with! increase! treatment! related!
toxicities.!Both!effects!were!related!to!the!addition!of!two!cycles!of!intensive!intravenous!
carboplatin!in!patients!treated!with!IP!regimen.!!
!
17!
The!third!trial!(GOG!172),!published!in!2006![33]!has!compared!intravenous!paclitaxel!
plus!cisplatin!with!intravenous!paclitaxel!plus!intraperitoneal!cisplatin!and!paclitaxel!in!
patients! with! stage! III! ovarian! cancer.! IP! regimen! improves! survival! in! optimally!
debulked! patients.! Results! were! updated! in! 2013! [3].! 110! months! of! median! overall!
survival! was! shown! for! patients! without! gross! residual! disease! treated! with! IP!
chemotherapy.! This! unprecedented! survival! improved! with! increasing! number! of! IP!
cycles! [34].! Risk! of! death! decreased! by! 12%! for! each! cycle! of! IP! chemotherapy!
completed.! Younger! patients! were! more! likely! to! complete! the! IP! regimen,! with! a! 5%!
decrease! in! probability! of! completion! with! each! year! of! age! [34].! It! should! promote!
further!investigation!of!novel!strategies!for!implementing!IP!chemotherapy!for!patients!
with!no!residual!disease.!
Using!IP!chemotherapy!at!the!same!time!to!a!cytoreductive!surgery!is!clearly!a!different!
situation! compared! to! adjuvant! sequential! treatment.! It! looks! crucial! then! to! describe!
the! impact! of! the! extent! of! peritoneal! resection! on! pharmacokinetics.! Several!
publications! have! shown! that! the! extent! of! parietal! peritoneal! resection! did! not! affect!
the! pharmacokinetics! of! intraoperative! intraperitoneal! Cisplatin! based! chemotherapy.!
The! pharmacological! barrier! between! the! abdominopelvic! cavity! and! plasma! could! be!
unrelated!to!the!surface!of!intact!peritoneum![35].!On!the!other!hand,!some!have!shown!
the!opposite.!The!extent!of!peritonectomy!increased!the!clearance!of!mitomycin!C!from!
the!peritoneal!space![36].!
!
1.3:)ROLE)OF)HYPERTHERMIA)
!
Cancer! cells! are! sensitive! to! heat.! Therapeutic! effects! of! hyperthermia! are! well! known!
since! the! beginning! of! the! 20th! century! [37].! The! direct! cytotoxicity! of! hyperthermic!
treatment! seems! to! be! based! on! the! denaturation! and! aggregation! of! cytoplasmic,!
nuclear! or! membrane! proteins.! The! chaotic! vasculature! inside! the! tumor! tissue! often!
leads! to! areas! of! acidosis,! hypoxia! and! energy! deprivation.! Because! of! low! perfusate!
area,!temperatures!between!40!and!44!°C!hyperthermia!induces!a!selective!destruction!
of!tumor!cells!in!hypoxic!and!acidic!parts!of!tumors,!but!leaves!normal!tissues!intact![38,!
39].!
In!a!metaGanalysis!published!in!1940,!Johnson!et!al.!has!shown!the!effect!of!exposure!to!
heat!in!several!cancer!line!cells:!breast!cancer,!sarcoma,!epithelioma.!Regarding!thermal!
death! time,! there! is! a! straightGline! correlation! between! exposure! time! and! level! of!
temperature.!In!fact,!a!similar!inGvivo!thermal!destruction!is!observed!after!exposure!of!
cancer!cells!during!50!hours!at!40°C!and!respectively!30!hours/41.5°C;!20!hours/42°C;!
8! hours/44°C;! and! 1! hour/45°C.! This! strict! timeGtemperature! relationship! was!
confirmed!in!several!studies!during!the!1970s!and!1980s.!The!thermal!energy!dose!for!
induction! of! cell! death! is! closely! related! to! the! amount! of! energy! required! for! cellular!
protein!denaturation.!But,!after!thermal!exposure,!a!mechanism!of!thermoGtolerance!is!
developed!with!an!upGregulation!of!specific!proteins!to!prevent!cell!lethal!damage.!In!the!
case!of!hyperthermia,!the!proteins!partly!involved!are!heatGshock!proteins!(HSP).![40].!
However,! following! more! prolonged! or! intense! thermal! exposure,! these! compensatory!
mechanisms!often!fail.!Above!this!“breakpoint!temperature”,!vascular!and!architectural!
!
18!
changes! increased! blood! flow,! enhanced! drug! delivery,! drug! extravasation!
(chemosensitisation)!and!higher!oxygenation!of!the!tissue!(radiosensitisation)[41].!
!
!
Fig.!4!The!antitumoral!effect!of!heat!(Issels!RD,!Eur!J!Cancer!2008)![40].!
To!be!effective!in!cancer!therapy,!as!demonstrated!in!animal!tumors,!hyperthermia!has!
to! be! uniform! within! the! tumor.! [42].! For! PC! patients,! hyperthermia! is! delivered! after!
complete! cytoreductive! surgery! without! persisting! macroscopic! disease.! In! open!
abdomen! HIPEC! technique,! because! of! the! surgical! approach! by! laparotomy! and! the!
manipulation!by!the!hand!of!the!surgeon,!a!uniform!distribution!of!heated!perfusate!is!
easily!achieved.!!
!
)1.4:) SYNERGY)
CHEMOTHERAPY)
BETWEEN)
HYPERTHERMIA)
AND)
INTRAPERITONEAL)
!
Heat! has! an! own! direct! cytotoxic! effect,! and! in! addition! is! acting! for! synergy! with! the!
cytotoxic! agent.! In! vivo! studies! have! demonstrated! that! the! thermal! enhancement! of!
cytotoxicity! is! maximized! at! temperatures! between! 40.5! and! 43! °C! for! many!
chemotherapeutic! agents.! In! that! model,! cytofluorometry! analysis! shows! that!
hyperthermia! increases! the! intracellular! adriamycin! accumulation! in! different! human!
epithelial! cancer! cell! lines! in! mucinous! as! well! as! serous! tumor! [43].! Many! in! vitro!
studies!demonstrated!that!heating!strongly!potentiate!the!cytotoxic!effects!of!cisplatin,!
by! increasing! the! intracellular! drug! penetration! and! drug! reaction! with! DNA,! and!!
inhibits! repair! of! drugGinduced! lethal! or! subGlethal! damage.! In! a! mouse! breast! tumor!
model,! cisplatin! and! heat! have! shown! to! be! active! alone,! but! the! combination! is! more!
active!than!each!one!alone![44].!In!a!model!of!rat’s!carcinomatosis,!the!pharmacokinetics!
data!are!favoring!the!combination!of!cisplatin!and!regional!hyperthermia![45].!!The!AUC!
in! the! peritoneal! cavity! for! both! total! and! ultrafiltered! platinum! is! larger! with!
hyperthermia,! but,! more! important,! the! AUC! in! the! plasma! is! 4! times! larger! for! rats!
receiving!regional!hyperthermia.!Enhanced!platinum!concentrations!are!observed!in!all!
!
19!
selected!tissues!after!regional!hyperthermia,!4!times!higher!in!the!tumor!and,!regarding!
its!specific!toxicity,!only!of!a!factor!2!in!the!kidney![45].!!
The!thermal!enhancement!ratio!varies!with!the!antineoplasic!agent![46].!Chemotherapy!
and! heat! ! interact! in! different! ways! (Fig.! 5).! A! linear! enhanced! cytotoxicity! when!
temperatures! are! raised! from! 37! to! 40.5! °C! is! demonstrated! with! platinum! salts! and!
alkylating!drugs.!Conversely,!antimetabolites!like!5’Fluorouracil!have!not!been!found!to!
interact!with!heat.!The!impact!of!hyperthermia!is!different!when!using!carboplatin.!The!
cellular!uptake!of!carboplatin!clearly!increases!at!43°C,!when!this!uptake!is!not!modified!
between!37!and!41.5°C![47].!However,!the!cytotoxic!effect!is!already!increased!at!40°C,!
suggesting! an! increased! activity! of! carboplatin! at! higher! temperatures.! And! the! fact! is!
that! the! CarboplatinGDNA! adduct! formation! increases! linearly! with! temperature,!
probably!because!more!carboplatin!is!transformed!into!adequate!metabolites!at!higher!
temperatures.! Using! the! same! model! of! rat’s! carcinomatosis,! Los! studied! the!
pharmacokinetics! of! Carboplatin! administered! alone! or! in! combination! with!
hyperthermia.! The! peritoneal! AUC! is! smaller! in! rats! receiving! hyperthermia,! while! the!
plasmatic! AUC! is! 3! times! larger! [48].! This! could! be! explained! by! the! fact! that!
hyperthermia!fasts!the!peritoneal!clearance!of!carboplatin,!and!slows!its!excretion!from!
plasma.!These!results!suggest!an!increase!in!tumor!exposure!via!the!systemic!circulation!
according!to!the!Dedrick’s!bicompartmental!model.!
The!chemical!structure!of!the!cytotoxic!agent!must!not!be!modified!by!hyperthermia.!!
Increasing! and! maintaining! temperature! above! 43°C! in! clinical! situation! during! a! long!
period!(60!minutes)!is!difficult!because!of!adverse!effects.!Between!41!and!43°C,!blood!
flow!and!vascular!permeability!represent!both!the!critical!factors!for!drug!uptake.!
!
Fig.!5!Overview!of!the!interactions!between!some!chemotherapeutic!agents!and!heat!(Issels!RD,!Eur!J!Cancer!
2008)![40].!
Clinical! effectiveness! of! the! association! of! locoregional! hyperthermia! with!
chemotherapy!was!demonstrated!in!patients!with!advanced!soft!tissue!sarcoma.!Phase!2!
studies! have! shown! that! chemotherapy! with! regional! hyperthermia! improves! local!
control!compared!with!chemotherapy!alone.!A!phase!3!randomized!study!was!published!
in! 2010! to! assess! the! safety! and! efficacy! of! regional! hyperthermia! with! chemotherapy!
for! localized! high! risk! sarcoma! [49].! 341! patients! were! enrolled.! They! were! randomly!
!
20!
assigned!to!receive!either!neoGadjuvant!chemotherapy!alone!or!combined!with!regional!
hyperthermia.! The! treatment! response! rate! in! the! group! that! received! regional!
hyperthermia! was! 28·8%,! compared! with! 12·7%! in! the! group! who! received!
chemotherapy! alone! with! a! moderate! toxicity.! An! impact! on! overall! survival! was!
reported.!For!the!authors,!this!randomized!trial!provides!the!first!evidence!that!regional!
hyperthermia!added!to!preoperative!and!postoperative!chemotherapy!is!clinically!more!
effective!than!chemotherapy!alone!in!a!specific!population!of!patients!with!highGrisk!soft!
tissue!sarcoma.!
!
)1.5:)HYPERTHERMIC)INTRAPERITONEAL)CHEMOTHERAPY)(HIPEC)))
!
For!patients!with!peritoneal!carcinomatosis,!delivering!of!intraoperative!intraperitoneal!
chemotherapy! associated! with! hyperthermia! was! developed! 30! years! ago.! Commonly!
called! HIPEC,! this! multimodal! therapeutic! approach! has! been! developed! especially! in!
rare!peritoneal!disease!expert!centers.!HIPEC!was!first!tested!in!canine!models!by!Spratt!
from!Louisville![50,!51].!There!has!been!a!growing!level!of!support!for!the!use!of!HIPEC!
in!peritoneal!surface!malignancies.!Sugarbaker!has!developed!and!refined!the!approach!
for!a!variety!of!malignancies!including!mesothelioma,!pseudomyxoma!peritonei,!ovarian!
cancer,! and! advanced! colorectal! cancer! [52].! HIPEC! is! delivered! in! only! one! session,!
under! direct! surgical! supervision,! after! complete! removal! of! PC! before! tumor! cell!
entrapment.! Indeed,! a! high! incidence! and! rapid! progression! of! peritoneal! surface!
implantation! to! fibrin! entrapment! of! remaining! free! tumor! cells! on! traumatized!
peritoneal!surfaces!occurred!during!the!early!postoperative!period,!promoted!by!growth!
factors!involved!in!the!wound!healing!process.!As!collagen!is!laid!down,!the!tumor!cells!
are!entrapped!within!scar!tissue,!which!is!dense!and!not!penetrated!by!intraperitoneal!
chemotherapy.! It! may! cause! a! high! incidence! of! locoGregional! treatment! failure.! To!
eradicate!the!reimplantation!of!malignant!cells!into!peritonectomized!surfaces,!it!seems!
logical!to!use!intracavitary!chemotherapy!in!a!large!volume!of!fluid!during!the!operation!
as!HIPEC!procedure.!An!other!way!is!to!prevent!adhesion!formation.!It!is!clear!therefore!
that!the!reduction!of!adhesive!disease!has!many!immediate!and!delayed!functional!and!
therapeutic!consequences!in!PC!management![53].!!
Several!phase!2!studies!and!case!series!have!been!published.!If!a!complete!cytoreductive!
surgery!is!achieved,!all!phases!2!studies!reported!a!median!survival!longer!than!2!years.!!
A! randomized! Dutch! trial! was! conducted! comparing! HIPEC! with! mitomycin! C! and!
cytoreductive! surgery! to! intravenous! chemotherapy! alone! (5Gfluorouracil,! leucovorin)!
for!treatment!of!carcinomatosis!from!colorectal!origin!showed!that!2Gyear!survival!was!
43%!in!the!HIPEC!group!versus!16%!in!the!control!(p=0·014)![54].!Those!results!were!
confirmed!after!8!years!of!followGup,!with!45%!of!5!yearGsurvival![55].!
In!a!multiGinstitutional!study!of!1290!patients!who!underwent!CRS!and!HIPEC!for!nonG
ovarian!PC,!Glehen!has!reported!longGterm!survival!in!a!selected!group!of!patients!with!
an!acceptable!morbidity![13].!A!case!control!study!was!conducted!by!Elias!to!compare!
the!longGterm!survival!of!patients!with!isolated!and!resectable!PC!in!comparable!groups!
of! patients! treated! with! CRS! plus! HIPEC! and! systemic! chemotherapy! versus! systemic!
chemotherapy!alone![56].!FiveGyear!overall!survival!was!51%!(95%!CI,!36%!to!65%)!for!
the!HIPEC!group!and!13%!for!the!palliative!chemotherapy!alone.!
!
21!
A! recent! metaGanalysis! has! shown! that! CRS! followed! by! HIPEC! significantly! increases!
survival!in!patients!with!advanced!peritoneal!colic!cancer![57].!HIPEC!is!also!proposed!
as!a!standard!treatment!for!peritoneal!mesothelioma!and!pseudomyxoma!peritonei.!!
Several! ongoing! trails! have! been! designed! to! establish! the! real! role! of! HIPEC! in!
recurrent!ovarian!cancer!(CHIPOR!trial),!colorectal!cancer!(Prodige!7)!as!well!as!several!
phase!I/II!trials!in!gastric!cancer.!
!!
1.6:)PERSONNAL)RESEARCH)OVERVIEW)
!
Over! the! two! last! decades,! recruitment! of! patients! has! been! profoundly! changed.!
Patients! are! currently! referred! at! the! time! of! primary! treatment,! with! localized!
peritoneal! carcinomatosis! and! a! low! peritoneal! cancer! index.! A! major! development! is!
the! widespread! use! of! minimal! invasive! surgery,! which! is! a! result! of! the! technological!
advancement!made!in!laparoscopic!surgery.!Patients!are!usually!treated!by!laparoscopy.!
The!first!part!of!this!present!project!was!developed!in!this!context.!!
!
In! an! experimental! study,! we! first! demonstrated! the! feasibility! and! reliability! of!
laparoscopic!peritonectomy!followed!by!oxaliplatin!based!intraperitoneal!chemotherapy!
and! its! pharmacokinetics! consequences! regarding! the! peritoneal! drug! absorption,! the!
increased!tissue!diffusion,!and!the!role!of!intraperitoneal!pressure.!
Several! articles! were! published! in! Gynecologic! Oncology! and! in! Annals! of! Surgical!
Oncology! and! in! a! book! chapter! concerning! pharmacology! and! pharmacokinetics! of!
platinum!salts:!
Feasibility) of) laparoscopic) peritonectomy) followed) by) intraNperitoneal)
chemohyperthermia:)an)experimental)study.!Ferron!G,!GessonGPaute!A,!Classe!
JM,!Querleu!D.!Gynecol!Oncol.!2005!Nov;99(2):358G61.!!
Pharmacokinetics) of) oxaliplatin) during) open) versus) laparoscopically)
assisted) heated) intraoperative) intraperitoneal) chemotherapy) (HIPEC):) an)
experimental)study.!GessonGPaute!A,!Ferron!G,!Thomas!F,!de!Lara!EC,!Chatelut!
E,!Querleu!D.!Ann!Surg!Oncol.!2008!Jan;15(1):339G44.!!
Increased) tissue) diffusion) of) oxaliplatin) during) laparoscopically) assisted)
versus) open) heated) intraoperative) intraperitoneal) chemotherapy) (HIPEC).!
Thomas!F,!Ferron!G,!GessonGPaute!A,!Hristova!M,!Lochon!I,!Chatelut!E.!!Ann!Surg!
Oncol.!2008!Dec;15(12):3623G4.!
Laparoscopically) assisted) Heated) IntraNoperative) Intraperitoneal)
Chemotherapy) (HIPEC):) Technical) aspect) and) pharmacokinetics) data.!
Ferron! G,! GessonGPaute! A,! Gladieff! L,! Thomas! F,! Chatelut! E,! Querleu! D.! In!
Platinum!and!Other!Heavy!Metal!Compounds!in!Cancer!Chemotherapy.!Bonetti!A!
et!al.!Humana!Press!2008.!
!
!
22!
Then,!we!established!a!new!population!pharmacokinetic!model!and!we!compared!two!
procedures!of!drug’s!delivery!during!HIPEC.!!
In!fact,!there!is!no!standardized!method!for!HIPEC!delivery.!Technical!parameters,!such!
as! open! or! closed! abdomen,! differ! from! institution! to! institution,! still! based! on! the!
surgeon’s! personal! preference! and! linked! to! the! “school”! of! HIPEC.! The! marketing! in!
France! of! new! European! Community! approved! reheaters! the! method! has! modified!
deliver! drug! during! HIPEC! procedure.! Therefore,! there! is! a! need! to! evaluated! new!
procedure! using! new! PK! model.! Data! from! 24! patients! treated! with! oxaliplatin! based!
HIPEC!were!collected!and!analyzed!
This!work!was!published!in!Cancer!Chemotherapy!and!Pharmacology.!
Pharmacokinetics) of) heated) intraperitoneal) oxaliplatin.! Ferron! G,! Dattez! S,!
Gladieff!L,!Delord!JP,!Pierre!S,!Lafont!T,!Lochon!I,!Chatelut!E.!!Cancer!Chemother!
Pharmacol.!2008!Sep;62(4):679G83.!
!
Finally,!different!clinical!and!pharmacodynamic!studies!were!performed!to!evaluate!the!
toxicity! for! patients! who! underwent! complete! cytoreductive! surgery! associated! to!
Cisplatin! or! Oxaliplatin! based! HIPEC.! Indeed,! different! drugs! are! used! for! HIPEC!
depending!on!the!origin!of!the!tumor.!Two!drugs!are!predominantly!used!in!France:!!
!
G!Cisplatin,!for!ovarian!cancer!and!rare!peritoneal!disease!
!
G!Oxaliplatin,!for!colorectal!cancer,!rare!peritoneal!disease.!
!
Regarding!Cisplatin!HIPEC!related!toxicity;!a!three!steps!study!was!performed:!
1G! PK! data! from! 12! patients! who! underwent! a! CRS! and! Cisplatin! based! HIPEC!
were! recorded! according! to! the! renal! function! in! a! retrospective! dose! deGescalation!
study! using! a! three! compartmental! model.! Acute! renal! failure! was! reported! in! a! high!
rate!of!patient.!Occurrence!of!renal!failure!is!not!dose!dependant,!and!due!to!a!different!
mechanism!as!known!with!using!intravenous!cisplatin.!!
This! unpublished! work! was! presented! at! the! “13ème! journées! du! Groupe! de!
Pharmacologie!Clinique!Oncologique”!–!Nîmes!2010.!
Chimiohyperthermie)
Intraperitoneale)
à)
base)
de)
Cisplatine:)
Pharmacocinétique)et)tolerance)rénale.!Civade!E,!Ferron!G,!Pierre!S,!Lochon!I,!
Rouge!P,!Gladieff!L,!Chatelut!E.!–!Poster!presentation!at!the!“13ème!journées!du!
Groupe!de!Pharmacologie!Clinique!Oncologique”!–!Nîmes!2010.!
!
!
2G! As! we! reported! an! high! frequency! of! renal! toxicity,! a! large! bicentric!
retrospective! study! was! performed.! Data! from! 66! patients! treated! with! CRS! and!
Cisplatin! based! HIPEC! have! been! recorded! in! two! cancer! centers:! Institut! Claudius!
Regaud!GToulouse!and!Institut!du!Cancer!–!Montpellier.!This!work!was!presented!at!the!
!
23!
French!Society!Of!Gynecologic!Oncology!(SFOG)!Annual!Meeting!!and!is!currently!under!
review!at!the!European!Journal!of!Surgical!Oncology.!
Predictive) factors) of) acute) kidney) injury) after) cytoreduction) surgery) and)
cisplatin) based) hyperthermic) intraperitoneal) chemotherapy) for) ovarian)
peritoneal) carcinomatosis:) a) retrospective) bicentric) study.! Vieille! P,! Quenet!
F,! Gladieff! L,! Rougé! P,! Chaltiel! L,! Querleu! D,! MD,! Saint! Aubert! B,! Martinez! A,!
Carrere!S,!Ferron!G.!!(Under!review!at!the!European!Journal!of!Surgical!Oncology)!
–! Poster! presentation! at! the! French! Society! of! Gynecologic! Oncology! Annual!
Meeting!–!Toulouse!–!Nov!2014!
!
!
3G! to! identify! the! recommended! dose! of! cisplatin! for! HIPEC! after! cytoreductive!
surgery!after!neoadjuvant!chemotherapy,!a!multicentric!phase!I!study!dose!escalation!of!
hyperthermic! intraperitoneal! cisplatin! was! then! conducted.! This! work! is! currently!
under!reviewat!the!Journal!of!Clinical!Oncology!
Results) of) a) multicenter) phase) I) doseNfinding) trial) of) hyperthermic)
intraperitoneal) cisplatin) after) neoadjuvant) chemotherapy) and) complete)
cytoreductive) surgery) and) followed) by) maintenance) bevacizumab) in)
initially)unresectable)ovarian)cancer.!Gouy!S,!Ferron!G,!Glehen!O,!Le!Deley!MC,!
Marchal!F,!Pomel!C,!Quenet!F,!Bereder!JM,!Bayar!A,!Kockler!L,!Morice!P.!(Under!
review!at!the!Journal!of!Clinical!Oncology)!
!
Regarding!Oxaliplatin!HIPEC!related!toxicity;!a!two!steps!study!was!performed:!
1G! to! evaluate! the! morbidity! of! oxaliplatin! based! HIPEC,! a! phase! II! prospective!
study! was! conducted.! This! work! was! published! in! the! European! Journal! of! Surgical!
Oncology!
Hyperthermic) intraNperitoneal) chemotherapy) using) Oxaliplatin) as)
consolidation)therapy)for)advanced)epithelial)ovarian)carcinoma.)Results)of)
a)phase)II)prospective)multicentre)trial.)CHIPOVAC)study.)Pomel!C,!Ferron!G,!
Lorimier!G,!Rey!A,!Lhomme!C,!Classe!JM,!Bereder!JM,!Quenet!F,!Meeus!P,!Marchal!
F,!Morice!P,!Elias!D.!Eur!J!Surg!Oncol.!2010;36(6):589G93!
!
!
2G! to! evaluate! the! relationship! between! oxaliplatin! exposure! and! observed!
toxicity,! a! population! pharmacokinetics! concerning! oxaliplatin! based! HIPEC! was!
conducted!and!published!in!Cancer!Chemotherapy!and!Phamacology!
Population) pharmacokinetics) of) peritoneal,) plasma) ultrafiltrated) and)
proteinNbound) oxaliplatin) concentrations) in) patients) with) disseminated)
peritoneal) cancer) after) intraperitoneal) hyperthermic) chemoperfusion) of)
oxaliplatin) following) cytoreductive) surgery:) correlation) between)
oxaliplatin)exposure)and)thrombocytopenia.!Chalret!du!Rieu!Q,!WhiteGKoning!
M,! Picaud! L,! Lochon! I,! Marsili! S,! Gladieff! L,! Chatelut! E,! Ferron! G.! Cancer!
Chemother!Pharmacol.!2014;74(3):571G82.!
!
24!
!
In) addition,! we! participated! to! several! publications! regarding! different! aspects! of!
HIPEC:!!
G! two! articles! were! published! regarding! prevention! of! occupational! exposure! for!
operating!room!personnel.!!
[Hyperthermic) intraoperative) intraperitoneal) chemotherapy) (HIPEC):)
evaluation,) prevention) and) policies) to) avoid) occupational) exposure) for)
operating)room)personnel].!Simon!L,!Halilou!MC,!Gladieff!L,!Gadiou!M,!Herin!F,!
Hennebelle!I,!Chatelut!E,!Ferron!G.!Bull!Cancer.!2009!Oct;96(10):971G7.!!
Professional) risks) when) carrying) out) peritoneal) carcinomatosis) surgery)
with) Hyperthermic) Intraperitoneal) Chemotherapy) (HIPEC):) a) French)
multicentric) survey.! Ferron! G,! Simon! L,! Guyon! F,! et! al.! (Under! review! at! the!
Annals!of!Surgical!Oncology)!!
!
G! two! review! articles! were! published! in! the! French! peerGreview! “Bulletin! du! cancer”!
concerning!HIPEC!and!intraperitoneal!chemotherapy!:!
[Importance) of) hyperthermic) intraperitoneal) chemotherapy) (HIPEC)) in)
ovarian)cancer]!Ferron!G,!Martinez!A,!Mery!E,!Querleu!D,!Thomas!F,!Chatelut!E,!
Gladieff!L.!Bull!Cancer.!2009;96(12):1243G52.!!
[Pharmacological) bases) of) intraperitoneal) chemotherapy]) Gladieff! L,!
Chatelut!E,!Dalenc!F,!Ferron!G.!Bull!Cancer.!2009;96(12):1235G42.!!
!
G!and!we!have!also!participated!to!several!case!series!about!HIPEC!and!to!guidelines!for!
PC!treatment;!that!are!mentioned!above:!
Survival) Benefit) of) Hyperthermic) Intraperitoneal) Chemotherapy) for)
Recurrent)Ovarian)Cancer:)A)MultiNinstitutional)Case)Control)Study.))Le!Brun!
JF,!Campion!L,!BertonGRigaud!D,!Lorimier!G,!Marchal!F,!Ferron!G,!Oger!AS,!Dravet!
F,!Jaffre!I,!Classe!JM.!Ann!Surg!Oncol.!2014;21(11):3621G7!
Peritoneal) carcinomatosis) treated) with) cytoreductive) surgery) and)
Hyperthermic)Intraperitoneal)Chemotherapy)(HIPEC))for)advanced)ovarian)
carcinoma:)a)French)multicentre)retrospective)cohort)study)of)566)patients.!
Bakrin! N,! Bereder! JM,! Decullier! E,! Classe! JM,! Msika! S,! Lorimier! G,! Abboud! K,!
Meeus! P,! Ferron! G,! Quenet! F,! Marchal! F,! Gouy! S,! Morice! P,! Pomel! C,! Pocard! M,!
Guyon! F,! Porcheron! J,! Glehen! O;! FROGHI! (FRench! Oncologic! and! Gynecologic!
HIPEC)!Group.!Eur!J!Surg!Oncol.!2013!Dec;39(12):1435G43.!
Complete) Cytoreductive) Surgery) Plus) Intraperitoneal) Chemohyperthermia)
With)Oxaliplatin)for)Peritoneal)Carcinomatosis)of)Colorectal)Origin.)Elias!D,!
Lefevre! JH,! Chevalier! J,! Brouquet! A,! Marchal! F,! Classe! JM,! Ferron! G,! Guilloit! JM,!
Meeus!P,!Goéré!D,!Bonastre!J.!J!Clin!Oncol.!2009!Feb!10;27(5):681G5.!!
!
25!
OxaliplatinNbased) hyperthermic) intraperitoneal) chemotherapy) in) primary)
or)recurrent)epithelial)ovarian)cancer:)A)pilot)study)of)31)patients.!Frenel!JS,!
Leux! C,! Pouplin! L,! Ferron! G,! Berton! Rigaud! D,! Bourbouloux! E,! Dravet! F,! Jaffre! I,!
Classe!JM.!J!Surg!Oncol.!2011!Jan!1;103(1):10G6.!
Coeliac) lymph) node) resection) and) porta) hepatis) disease) resection) in)
advanced) or) recurrent) epithélial) ovarian,) fallopian) tube,) and) primary)
peritoneal)cancer.!Martinez!A,!Pomel!C,!Mery!E,!Querleu!D,!Gladieff!L,!Ferron!G.!
Gynecol!Oncol!2011!May!1;121(2):258G63.!
Adherence)to)guidelines)in)gynecologic)cancer)surgery.)Ferron!G,!Martinez!A,!
Gladieff! L,! Mery! E,! David! I,! Delannes! M,! Montastruc! M,! Balagué! G,! Picaud! L,!
Querleu!D.)Int!J!Gynecol!Cancer.!2014!Nov;24(9):1675G8.!!
!
!
!
!
!
!
26!
!
2.)RESULTS))
!
!
!
27!
2.1:)DEMONSTRATION)OF)THE)FEASIBILITY)OF)LAPAROSCOPIC)PERITONECTOMY)
FOLLOWED) BY) OXALIPLATIN) BASED) INTRAPERITONEAL) CHEMOTHERAPY) AND)
ITS)PHARMACOKINETICS)CONSEQUENCES!
!!
Since! 30! years,! after! its! introduction! especially! in! France,! laparoscopic! approach! for!
cancer!gained!wide!acceptance.!This!approach!represents!the!first!choice!for!both!early!
colic!and!suspected!ovarian!mass!at!the!time!to!diagnostic!but!also!for!resection![58,!59].!
It!has!been!shown!to!be!effective!in!selected!cases!in!excluding!unnecessary!laparotomy!
associated! with! specific! morbidity.! Laparoscopy! is! considered! as! a! good! diagnostic!
modality! in! patients! with! ascites! seen! on! radiologic! studies! who! need! a! definitive!
diagnosis! to! determine! the! primary! sites.! It! allows! evaluation! of! tumor! dissemination,!
and! histological! diagnosis.! Diagnostic! laparoscopy! provides! a! wide! view! of! the! whole!
abdominal! cavity! without! a! large! incision.! 30°! or! flexible! endoscope! improve! the!
abdominal!exploration![60].!Endoscopy!is!a!key!tool!in!the!diagnosis!and!management!
planning!of!peritoneal!carcinomatosis.!Several!studies!have!shown!the!accuracy!and!the!
reproducibility!for!the!PCI!score!in!laparoscopy![61].!Specific!endoscopic!score!has!been!
published!and!routinely!used!like!the!Fagotti!score![62].!
Because!of!long!term!survival!obtained!in!patients!with!low!PCI,!and!the!development!of!
specific! phase! II! trials! in! highGrisk! patients! for! PC! (ProphyloGCHIP),! recruitment! of!
patients! has! been! profoundly! changed.! Furthermore,! most! of! the! medical! and! surgical!
oncologists! are! convinced! that! complete! cytoreduction! associated! to! HIPEC! represent!
the! optimal! treatment! for! patients! with! PC.! Patients! are! currently! referred! to! HIPEC!
centers!at!the!time!to!primary!treatment,!with!localized!peritoneal!carcinomatosis.!
It! seems! logical! to! evaluate! the! possibility! to! perform! the! cytoreductive! surgery! and!
HIPEC!by!laparoscopy.!
This!work!was!performed!in!two!successive!steps:!
2.1.1:! First! step:! To! demonstrate! the! feasibility! of! laparoscopic! peritonectomy! and!
HIPEC.!!
An! experimental! study! was! performed! in! five! adults! pigs.! Four! trocars! in! each!
abdominal!quadrants!were!placed!in!order!to!perform!a!complete!peritonectomy!and!to!
place! the! inGflow! and! outGflow! drains.! When! the! reached! temperature! was! obtained!
(43°C),!HIPEC!was!delivered!during!30!minutes.!Manipulation!of!the!bowel!to!obtain!a!
adequate!distribution!of!heat!was!performed!by!the!replacement!of!the!umbilical!trocar!
by!the!surgeon!hand.!All!the!procedures!were!successfully!completed!with!an!adequate!
intraabdominal!temperature!and!distribution.!!
It!was!published!in!Gynecologic!Oncology:!
Ferron!G,!GessonGPaute!A,!Classe!JM,!Querleu!D.!!
Feasibility) of) laparoscopic) peritonectomy) followed) by) intraNperitoneal)
chemohyperthermia:)an)experimental)study.)
Gynecol!Oncol.!2005!Nov;99(2):358G61.!!
!
28!
Gynecologic Oncology 99 (2005) 358 – 361
www.elsevier.com/locate/ygyno
Feasibility of laparoscopic peritonectomy followed by intra-peritoneal
chemohyperthermia: An experimental study
Gwénaël Ferron*, Amélie Gesson-Paute, Jean-Marc Classe, Denis Querleu
Department of Surgical Oncology, Institut Claudius Regaud Cancer Center, 20-24 Rue du Pont Street Pierre, 31052 Toulouse Cedex, France
Received 16 March 2005
Available online 19 August 2005
Abstract
Objective. Hyperthermic intraperitoneal chemotherapy (HIPEC) is being evaluated for patients with minimal residual or no residual
disease after primary surgery and chemotherapy for stage III ovarian carcinoma. The use of operative laparoscopy to perform peritonectomy
and HIPEC is reported.
Methods. Five adult pigs were used. The placement of trocars in the four quadrants was planned in order to complete a total
peritonectomy and then to place the HIPEC drains. The umbilical trocar was then replaced manually by the surgeon through a LapdiscR to
manipulate the bowel loops. The abdominal cavity was filled with heated saline (43-C), and the pumps were activated for 30 min.
Results. The procedure was successfully completed with an adequate intraabdominal temperature and distribution.
Conclusion. These preliminary data suggest the technical feasibility of the laparoscopic approach for HIPEC, in an animal model without
carcinomatosis. Our ongoing research is designed to gather pharmacokinetic data in an experimental controlled randomized fashion to
compare a laparoscopic to a laparotomy approach on the same model.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Ovarian cancer; Intraperitoneal chemotherapy; Hyperthermia; Laparoscopy
Introduction
Ovarian carcinoma is the leading cause of mortality
among gynecologic cancer patients. Most present with
advanced disease and are treated with a combination of
primary, interval, or secondary cytoreductive surgery and
chemotherapy. In a significant number of patients, complete clinical response is achieved. However, approximately 50% of patients who achieve a complete remission
eventually recur, justifying further attempts to define
additional therapy regimens, including intraperitoneal
chemotherapy [1]. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed as a therapeutic tool
in the management of digestive tract cancer patients with
peritoneal carcinomatosis [2,3] and more recently in
* Corresponding author. Fax: +33 56142411 7.
E-mail address: [email protected] (G. Ferron).
0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2005.06.043
ovarian cancer patients [4 – 7]. HIPEC is currently being
evaluated in a French multi-centre phase I– II trial where
only patients with minimal residual or no residual disease
are included. We believe that HIPEC could be applied
without performing a laparotomy, particularly considering
that laparoscopic surgery is adapted for adhesiolysis and
comprehensive examination of the peritoneal cavity with
acceptable accuracy and morbidity [8].
From the experience of others [9], the prerequisites for a
satisfactory exposition of the diseased peritoneum are
known. Two closed circuits, one in the lower the other
one in the upper abdomen, are needed. A temperature of 42
to 43-C must be maintained for 30 min. Continuous
mobilization of the bowel and high flow of the dialysate
are required. The goal of this study was to verify that all
these criteria could be met using a laparoscopic approach. In
addition, we wanted to assess the feasibility of peritonectomy procedure that usually precedes HIPEC in clinical
practice.
G. Ferron et al. / Gynecologic Oncology 99 (2005) 358 – 361
359
This study was supported by the research program of the
Institut Claudius Regaud Cancer Center and by Karl Storz
Inc., who provided the laparoscopic equipment. All the
experiments were carried out in the surgery laboratory of the
Rangueil university hospital in Toulouse, France.
Material and methods
Five adult (20 kg) pigs were used in the experimental
laboratory. The Helsinki rules for the use of animals in
experimentation were met. All procedures were performed
under general anesthesia. The animals were placed in supine
position. A 12 mm trocar was placed in the umbilical area
to accommodate the endoscope. Four additional 12 mm
VersastepR (Tyco Healthcare Group LP, Norwalk, Connecticut USA) trocars were placed in each quadrant of the
abdomen (Fig. 1). The design of the reducer of the VerstasepR
was chosen to accommodate large diameter (22 Fr) drains
without leakage of CO2 and perfusate. The positioning of
trocars in the four quadrants was planned in order to perform a
complete peritonectomy and then to place the HIPEC drains.
During HIPEC, the trocars were maintained vertically in order
to prevent fluid leakage. Filters were adapted to the tip of the
drains in order to avoid sticking to the visceral surface and
obstructing the lumen.
Extended peritonectomy of the parietal and pelvic
peritoneum was performed using laparoscopic techniques.
Gas pressure was helpful to find the point of dissection of
the peritoneum and its underlying tissues. Peritoneum of the
anterior abdominal wall, paracolic gutters, undersurface of
both hemidiaphragms, and lateral pelvis was completely
removed. To perform the peritonectomies, the peritoneum
was progressively stripped off the posterior rectus sheath
and the diaphragm. Broad traction must be exerted on the
specimen with electrosurgical dissection allowing separation
of peritoneum and the abdominal wall. Stripping the visceral
peritoneum from the surface of the bladder was impossible
because of the anatomy of the pig’s bladder. The umbilical
trocar was then replaced by a device allowing the placement
Fig. 2. Positioning of HIPEC drains with the right surgeon’s hand through
the LapdiscR.
of the hand and forearm in the abdomen without any gas or
liquid leak (LapdiscR, Ethicon Endo Surgery Inc, Cincinnati, USA). Silicon drains, 22 French, were used to create
the abdominal irrigation circuit. Temperature probes were
placed at the tip of each drain.
The four drains corresponding to the two circuits (one
inflow and one outflow drain for each of them) were
positioned under laparoscopic guidance. One retrohepatic
drain was used as an inflow drain in the upper abdomen.
The outflow drain from the upper abdomen was placed in
the left upper quadrant. The outflow drain from the lower
abdomen was placed in the pelvis. The inflow drain of the
lower abdomen, which was manipulated by the hand of the
surgeon, was used to distribute the flow in all areas of the
abdomen.
The abdominal cavity was then filled with heated (43-C)
saline. In this pilot experiment, no anticancer drug was used.
The pumps were then activated, the bowel loops were hand
mobilized by the surgeon through the LapdiscR for 30 min
(Fig. 2). Temperature of the irrigation fluid was constantly
monitored. At the end of the procedure, methylene blue was
injected in order to check the completeness of peritoneal
exposure to the heated fluid. The animal was then sacrificed,
and a laparotomy was performed. Correct placement of the
drains, diffusion of the dye into the subperitoneum, and
remaining peritoneal surfaces were checked.
Results
Fig. 1. Positioning of trocars to complete peritonectomy.
The peritonectomy procedure was successfully completed in all five animals. Average duration of the operation
was 20 min. Parameters of intraperitoneal heated flow
360
G. Ferron et al. / Gynecologic Oncology 99 (2005) 358 – 361
infusion were then assessed. Knowing that the therapeutic
index is optimal at 41– 43-C [2 3], the goal of achieving the
adequate intraabdominal temperature was fulfilled using a
perfusate heated at 46-C with a 1500 ml/min flow that
resulted in inflow temperatures at 43– 45-C and outflow
temperatures at 41– 42-C. Target temperature was reached
after 8 to 12 min. Active permanent manipulation of the
bowel and viscera, and the manual adaptation of the
direction of the inflow from drain number 4 as well,
allowed us to obtain a homogeneous intraabdominal
temperature. The distribution of blue dye was even in the
abdominal cavity in all animals. Exposure of all peritoneal
surfaces to heated perfusate, including the root of the
mesentery and the omental bursa, was achieved.
Discussion
There is currently no evidence that additional therapy is
able to improve the outcome of ovarian cancer patients in
apparent complete remission. Second-look surgeries are no
longer standard in the management of advanced ovarian
cancers, which results in a lack of information about the
actual status of the peritoneal surface at the time of
completion of chemotherapy. The development of intraperitoneal drug therapy is one of the main topics of
investigation in an effort to improve the long-term results
in the case of peritoneal spread of ovarian carcinomas.
Randomized controlled studies have demonstrated a significant improvement in progression-free survival after
intraperitoneal versus systemic chemotherapy [10]. However, many drawbacks and morbidity related to sequential
punctures or the use of indwelling catheters have impeded
the spread of intraperitoneal chemotherapy use. Repeated
cycles of intraperitoneal chemotherapy are necessary,
thereby with the risk of possible complications of repeat
abdominal punctures or obstruction of permanent catheters
[11]. The frequent occurrence of intraperitoneal adhesions
may impair the actual exposition of potentially diseased
sites to local drug therapy.
On the other hand, encouraging results have been
obtained by HIPEC in the management of otherwise
inevitable lethal conditions, including peritoneal carcinomatosis from colorectal cancer, mesothelioma, and pseudomyxoma peritonei [2,9]. The complication rate of
extensive peritonectomy procedures followed by HIPEC
is a major limitation to the use of this combined management in ovarian cancers. It is assumed that the morbidity
of HIPEC after relatively minor peritonectomy procedures
in patients with minimal residual disease only is more
acceptable. This point is being explored in a French
collaborative phase I– II study. Inherent morbidity related
to completing cytoreduction and chemohyperthermia during the same session might be reduced in the context of
minimal residual disease, which is the major potential
indication in ovarian carcinomas. Comprehensive assess-
ment of the peritoneal cavity, although long and tedious in
patients with a history of major cytoreductive surgery, may
be successfully achieved using laparoscopic techniques
with acceptable morbidity [12]. Complete adhesiolysis
immediately before exposure to chemotherapy ensures an
adequate repartition of the drug throughout the abdominal
cavity. HIPEC is administered in only one session, under
direct surgical monitoring, which overcomes the problems
encountered with permanent catheters and repeat intraperitoneal chemotherapy administration.
The ‘‘closed’’ and the ‘‘coliseum’’ laparotomy techniques
currently used for HIPEC have complementary advantages
and disadvantages [13]. The main disadvantage of the
closed technique is the lack of uniform distribution of the
heated perfusate. On the other hand, the closed technique
allows one to rapidly obtain and maintain hyperthermia,
avoiding exposure of the operating room staff to toxic
drugs. Laparoscopic techniques may prove to be an optimal
route to administer intraperitoneal chemotherapy [14]. The
possibility of using a closed technique, while manipulating
the viscera using the hand-assisted technique and/or laparoscopic instruments, combines the advantages of both
laparotomy techniques. In addition, experimental studies
demonstrated that raised intraabdominal pressure might
facilitate drug penetration into tumoral tissue [15].
Conclusion
It is clear that debulking of gross disease is not feasible
laparoscopically and that secondary HIPEC should not be in
the future a substitute for inadequate primary surgery. In
addition, chemoresistant patients are likely not to be good
candidates for HIPEC. It is assumed that hyperthermic
intraperitoneal chemotherapy will be proposed, in the
setting of phase I– II trials, as a consolidation therapy to
patients showing a complete or optimal response to primary
surgery and systemic chemotherapy. Clinical investigation is
needed in this subgroup of patients [10]. The complication
rate of extensive peritonectomy procedures followed by
HIPEC is a major limitation to the use of this combined
management in ovarian cancers. It is assumed that the
morbidity of HIPEC after relatively minor peritonectomy
procedures in patients with minimal residual disease only is
more acceptable. This point is being explored in a French
collaborative phase I– II study. As a consequence, HIPEC
should be first evaluated in a selected group of patients
presenting with (1) a high risk of recurrence, (2) a
demonstrated chemosensitive disease, (3) an acceptable
potential complication rate. All criteria must at this moment
be met, which means that phase I– II studies and further
phase III studies assessing HIPEC are acceptable only in the
setting of consolidation therapy. In this context, the bulk of
the disease has been removed or medically reduced,
supporting the rationale for a laparoscopic approach,
knowing that the requirement for extensive peritonectomy
G. Ferron et al. / Gynecologic Oncology 99 (2005) 358 – 361
may be a limitation to the use of the laparoscopic approach.
However, these preliminary data suggest the technical
feasibility of the laparoscopic approach for HIPEC applied
to ovarian cancer patients with no or minimal residual
disease. Physical parameters including pressure, flow, and
temperature can be controlled, and prerequisites are met.
However, we have not administered chemotherapy in this
preliminary experiment. Our ongoing research is designed
to gather pharmacokinetic data and study drug metabolism
in an experimental controlled randomized study comparing
laparoscopic and laparotomy approaches.
[7]
[8]
[9]
[10]
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Howell SB. Intraperitoneal therapy for stage III ovarian cancer: a
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[3] Verwall VJ, van Ruth S, de Bree E, van Slooten GW, van Tinteren H,
Boot H, et al. Randomized trial of cytoreduction and hyperthermic
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[4] Ryu KS, Kim HS, Kim JW, Ahn WS, Park YG, Kim SJ, et al. Effects
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[5] Friberg G, Fleming G. Intraperitoneal chemotherapy for ovarian
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Makhija S, Leitao M, Sabbatini P, Bellin N, Almadrones L, Leon L,
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Childers JM, Lang J, Surwit EA, Hatch KD. Laparoscopic surgical
staging of ovarian cancer. Gynecol Oncol 1995;59(1):25 – 33.
Sarnaik AA, Sussman JJ, Ahmad SA, Lowy AM. Technology of
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Chang E, Alexander HR, Libutti SK, Hurst R, Zhai S, Figg WD, et al.
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!
2.1.2:! Second! step:! to! compare,! in! an! experimental! study,! the! pharmacokinetics! of!
oxaliplatin!during!Open!versus!Laparoscopic!HIPEC.!
The!HIPEC!procedure!was!based!on!460!mg/m2!of!oxaliplatin!over!30!minutes!at!41°C!
to!43°C,!identical!to!the!drug!schema!used!for!patient.!
Two!groups!of!10!pigs!were!studied.!All!the!procedures!were!successfully!completed.!
This! study! has! confirmed! the! technical! feasibility! and! reliability! of! the! laparoscopic!
approach! for! HIPEC,! and! it! has! extended! knowledge! concerning! peritoneal! drug!
absorption.! The! results! have! reported! that! the! mean! half! time! of! IP! oxaliplatin! was!
significantly!shorter!in!the!laparoscopic!group!than!in!the!laparotomy!group.!Absorption!
and! diffusion! of! oxaliplatin! in! tissue! were! also! better! in! the! laparoscopic! group!
suggesting!the!role!of!intraGabdominal!pressure.!This!increased!penetration!of!drug!into!
the!tumor!should!enhance!the!antitumor!effect.!!
This!second!step!was!published!in!Annals!of!Surgical!Oncology!(2!articles)!and!in!a!book!
chapter!concerning!pharmacology!and!pharmacokinetics!of!platinum!salts:!
GessonGPaute!A,!Ferron!G,!Thomas!F,!de!Lara!EC,!Chatelut!E,!Querleu!D.!
Pharmacokinetics) of) oxaliplatin) during) open) versus) laparoscopically)
assisted) heated) intraoperative) intraperitoneal) chemotherapy) (HIPEC):) an)
experimental)study.))
Ann!Surg!Oncol.!2008!Jan;15(1):339G44.!!
!
Thomas!F,!Ferron!G,!GessonGPaute!A,!Hristova!M,!Lochon!I,!Chatelut!E.!!
Increased) tissue) diffusion) of) oxaliplatin) during) laparoscopically) assisted)
versus)open)heated)intraoperative)intraperitoneal)chemotherapy)(HIPEC).))
Ann!Surg!Oncol.!2008!Dec;15(12):3623G4.!
!
Ferron!G,!GessonGPaute!A,!Gladieff!L,!Thomas!F,!Chatelut!E,!Querleu!D.!
!Laparoscopically) assisted) Heated) IntraNoperative) Intraperitoneal)
Chemotherapy)(HIPEC):)Technical)aspect)and)pharmacokinetics)data.))
In!Platinum!and!Other!Heavy!Metal!Compounds!in!Cancer!Chemotherapy.!Bonetti!
A!et!al.!Humana!Press!2008.!
!
!
29!
Annals of Surgical Oncology 15(1):339–344
DOI: 10.1245/s10434-007-9571-9
Pharmacokinetics of Oxaliplatin During Open
Versus Laparoscopically Assisted Heated
Intraoperative Intraperitoneal Chemotherapy (HIPEC):
An Experimental Study
Amélie Gesson-Paute, MD,1 Gwenael Ferron, MD,1,3 Fabienne Thomas, MD,2,3
Emanuelle Cohen de Lara, MD,2,3 Etienne Chatelut, MD, PhD,2,3 and Denis Querleu, MD1,3
1
Department of Surgical Oncology, Institut Claudius Regaud, 20-24 Rue du Pont Pierre, 31052 Toulouse Cedex, France
2
EA3035, Institut Claudius Regaud, 20-24 Rue du Pont Pierre, 31052 Toulouse Cedex, France
3
Paul Sabatier University, University of Toulouse, Toulouse, France
Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is being evaluated for
patients with minimal residual or no residual disease after primary surgery and chemotherapy
for stage III ovarian carcinoma. The technical feasibility of the laparoscopic approach for
HIPEC has been demonstrated in a previous study. An experimental study on the porcine
model was carried out to compare oxaliplatin pharmacokinetics during a laparoscopic-assisted
procedure versus the coliseum technique for HIPEC.
Methods: Adult pigs received an HIPEC procedure that was based on 460 mg/m2 of oxaliplatin over 30 minutes with a perfusate heated at 41!C to 43!C. The HIPEC drains were
placed in the upper and lower quadrants of the abdomen. Peritoneal fluid and blood samples
were collected every 10 minutes during the procedure, and the pharmacokinetics of oxaliplatin
was studied.
Results: Two groups of 10 adult pigs were studied. All the procedures were successfully
completed with an adequate intra-abdominal temperature and distribution. No major technical problems were encountered. At the end of the HIPEC, 41.5% of the molecule was
absorbed in the laparoscopic group compared with 33.4% in the laparotomy group
(P = .0543). Peritoneal oxaliplatin half-life (T½) was significantly faster in the laparoscopic
procedure (median, 37.5 vs. 59.3 minutes, P = .02). The area under the curve ratio of peritoneal to plasma reflects a more important oxaliplatin crossing through the peritoneal barrier
in the laparoscopic procedure (ratio, 16.4 in the closed procedure vs. 28.1 in the open one;
P = .03).
Conclusions: This study confirms the technical feasibility and reliability of the laparoscopic
approach for HIPEC, and it extends knowledge concerning peritoneal drug absorption. Oxaliplatin absorption is far higher with laparoscopy in terms of time course in peritoneal
perfusion. Clinical application in selected patients may be expected after further experimental
investigation designed to define the adequate drug dosage.
Key Words: Hyperthermia—Intraperitoneal chemotherapy—laparoscopy—oxaliplatin—pharmacokinetics.
Received March 20, 2007; accepted June 11, 2007; published
online: October 18, 2007.
Address correspondence and reprint requests to: Gwenael
Ferron, MD; E-mail: [email protected]
Ovarian cancer is the leading cause of mortality
among gynecological cancers. However, an
increasing number of patients experience complete
response after a combination of surgery and
Published by Springer Science+Business Media, LLC " 2007 The Society of
Surgical Oncology, Inc.
339
340
A. GESSON-PAUTE ET AL.
chemotherapy. Despite complete remission at the
end of managing the primary tumor, recurring
disease is observed in approximately 50% of stage
III patients.1 This justifies the investigation on
additional therapies, including intraperitoneal chemotherapy applied to digestive tract cancers with
peritoneal dissemination.2,3
Previous experimental data from our laboratory
demonstrated the feasibility of laparoscopic peritonectomy and heated intraperitoneal chemohyperthermia (HIPEC).4 HIPEC is an accepted option in the
management of digestive tract cancers with peritoneal
carcinomatosis. More recently, HIPEC has been
proposed in selected ovarian cancer patients with
encouraging results5 in an effort to improve the
outcome of stage III ovarian cancer. A French multicenter phase I–II trial actually includes patients with
minimal residual disease or no residual disease with
ovarian cancer.
We assume that HIPEC could be applied without
performing a laparotomy, particularly when no bulky
disease is present. In addition, laparoscopic surgery is
adapted for adhesiolysis and comprehensive examination of the peritoneal cavity with acceptable accuracy and morbidity.6,7 Here, we report the results of
an experimental study
MATERIALS AND METHODS
This experimental study was performed on adult
pigs. This study was conducted in accordance with
the Declaration of Helsinki rules for the use of animals in experimentation.
Surgical Procedure
Twenty adult pigs were needed. The study was
conducted in an experimental laboratory. All procedures were performed while the animals were under
general anesthesia and in a supine position.
Half of the group of pigs underwent an HIPEC
performed by laparotomy, and the procedures were
conducted as previously described by Elias et al. 8
with the coliseum technique. Oxaliplatin was
delivered at the dose of 460 or 360 mg/m2 and
heated in the abdominal cavity with a fixed volume
(dextrose 5%—2 L/m2).9 Four drains were placed in
four regions of the abdomen: in the right and left
upper quadrants with, respectively, an inflow and
an outflow circuit. For the lower abdomen, the
outflow drain was placed in the pelvis. The sur-
Ann. Surg. Oncol. Vol. 15, No. 1, 2008
geon!s hand manipulated the inflow drain to evenly
distribute the flow in the abdominal cavity.
The other group of pigs underwent a laparoscopically assisted HIPEC that used the same dosage and
physical parameters. A 12-mm trocar was placed in the
umbilical area to accommodate the endoscope. Four
additional 12-mm Versastep trocars (Tyco Healthcare
Group, Norwalk, CT) were placed in each quadrant of
the abdomen (Fig. 1).4,8 The umbilical one was replaced by a Lapdisc (Ethicon Endo Surgery, Cincinnati, OH), which allowed the placement of the hand
and forearm in the abdomen without any gas or liquid
leak. During HIPEC, the trocars were maintaining
vertically to prevent leakage. Temperature probes were
placed at the tip of each exit drains. Knowing that the
therapeutic index is optimal at 41!C to 43!C,2,10 the
goal for achieving adequate intra-abdominal temperature was fulfilled by using a perfusate heated between
46!C to 52!C, with a 1360 mL/min flow that resulted in
outflow temperature at 41!C to 43!C. Active permanent manipulation of viscera and manual adaptation
of the inflow drain (no. 3) allowed us to obtain a
homogeneous intra-abdominal temperature.
Peritonectomy was not performed in this study.
Peritoneal fluid temperature was constantly monitored in all experiments. Intra-abdominal pressure
was not measured.
Animals were kept under general anesthesia until
their last blood sample was drawn, and then they
were killed. The fluid containing chemotherapy was
destroyed according to regulations after complete
suction of the fluid in the abdomen.
Blood Sampling
Nine blood samples were collected for each animal
at different times: before HIPEC, at time 0 (T0) when
the peritoneal fluid reached 43!C, and every 10 minutes during the procedure. Blood samples were then
collected after the HIPEC at 45 minutes and at 1, 1.5,
and 2 hours after T0. Samples were immediately
centrifuged at +4!C, for 10 minutes at 1500 · g. For
samples collected at the end of the procedure (i.e., 30
minutes after T0), at 1 and 2 hours after initiation of
HIPEC, an aliquot of plasma was ultrafiltered by
centrifugation at +4!C for 20 minutes at 2000 · g
through a Amicon MPS1 micropartition system with
YMT membranes (cutoff 30,000 Da).
In the laparotomy group, one of three animals had
additional blood samples drawn at 6 and 7 hours. In
the second group, six animals were kept under general anesthesia for the same protocol.
341
PHARMACOKINETICS OF OXALIPLATIN
Statistical Analysis
Pharmacokinetic results were carried out with
Statview software, version 4.55. The AUC and concentration data were compared by a t-test. Tmax (the
time to reach the target temperature) and T½ data
were analyzed with the Mann-Whitney test. Differences were considered significant at P < .05.
RESULTS
FIG. 1. Positioning of hyperthermic intraperitoneal chemotherapy
drains with the surgeon!s hand through the Lapdisc.
A total of 20 adult pigs were used in this experimental study. The procedure was successfully completed in all 20 HIPEC procedures: 10 pigs underwent
an HIPEC performed by laparotomy, and 10 other
pigs underwent an HIPEC that was laparoscopically
hand-assisted.
Peritoneal Fluid Sample Preparation
Five 5-mL samples of peritoneal fluid were collected for each animal at different time points: before
the temperature reached 43!C, at the beginning of the
HIPEC procedure, and then every 10 minutes during
the procedure.
All samples were frozen at )20!C until assay.
Platinum Determination
Platinum levels in the plasma and in the plasma
ultrafiltrate were measured by means of flameless
atomic absorption spectrophotometric analysis
according to a previously described method.11
Nominal values of platinum controls were 21, 105,
and 210 ng/mL for plasma ultrafiltrate and 20.9,
104.7, and 209.3 ng/mL for plasma samples. Platinum
determination in samples was validated when measured control values were within 10% of the mediumand high-level controls and 20% for the low-level
control. Results were expressed in nanograms per
milliliter of oxaliplatin.
Pharmacokinetic Study
Pharmacokinetics data were analyzed by 4.1 Kinetica software (Innaphase, Philadelphia, PA) with a
noncompartmental method. The area under the oxaliplatin concentration-time curve was determined
from T0 to 2 hours (AUC2h) with a mixed log-linear
rule. Pharmacokinetic parameters calculated included
Tmax, Cmax, and elimination half-life T½. The peritoneal T½ was calculated by using 4 time points (T0
and 10, 20, and 30 minutes) in each peritoneal fluid
profile.
Intraoperative Parameters
No noticeable technical problems were encountered in the laparotomy group as a result of our
experience in human clinical practice.
The most frequently encountered complication
during laparoscopic procedures was circuit obstruction by the contact of small bowel and omentum with
the tips of the drains. The first procedure was performed with Gamida drains, which were not well
adapted to the level of suction negative pressure
(Fig. 2). The following procedures were thus performed with the hair curlers routinely used during open
procedures, which allowed easier manual separation of
the bowel from the drains, thanks to the surgeon!s hand
in the abdominal cavity. Overall, technical problems,
which were eventually solved, occurred in three procedures of the laparoscopic group. As a result, target
temperature was reached after 8 minutes (median value) in the laparotomy group versus 12.5 minutes for
the laparoscopic group (P = .03). If we excluded
experiments for which technical problems occurred,
the time to reach optimal temperature decreased (7 vs.
12 minutes, P = .03). Fig. 3 shows the temperature
curve of optimal procedure in each group.
Pharmacokinetic Study
Pharmacokinetics of Heated Intraoperative
Intraperitoneal Oxaliplatin
A decrease in platinum concentration was observed
in the peritoneal perfusion during HIPEC in both
groups (Fig. 4). Analysis of T½ of the drug revealed a
significant difference that reflected faster tissular
Ann. Surg. Oncol. Vol. 15, No. 1, 2008
342
A. GESSON-PAUTE ET AL.
FIG. 2. First laparoscopic procedure performed with special Gamida drains; the circuit!s obstruction results from strong aspiration.
absorption of oxaliplatin in the laparoscopic group
(median value, 37.5 minutes vs. 59.3 minutes;
P = .02), giving evidence that the closed technique
seems to influence and raise the platinum absorption
through the peritoneal barrier. At the time of completion of HIPEC, 41.5% of the molecule was absorbed in the laparoscopic group, compared with
33.4% in the laparotomy group (P = .05).
Time Course of Oxaliplatin in the Peripheral Blood
Peak plasma concentration of platinum was observed on average 30 minutes after starting HIPEC in
the laparotomy group, whereas the peak plasma concentration was obtained after 46.4 minutes (P = .87)
in the laparoscopic group (Fig. 5). Then platinum
concentration dropped rapidly in both groups, resulting in a limited systemic AUC. The AUC2h is higher for
the laparoscopic procedure, as is plasma concentrations at time 2 hours (C2h) in ultrafiltrate (Table 1).
The AUC ratio of peritoneal to plasma (at 30 minutes)
was larger in the laparotomy group (28.1 vs. 16.4,
P = .03), reflecting the fact that the molecule is kept in
the abdominal cavity with less penetration through the
peritoneal barrier in the blood compartment compared
with the laparoscopic group. During HIPEC, oxaliplatin was more rapidly absorbed in the laparoscopic
group: 41.5% of oxaliplatin was absorbed in the laparoscopic group, compared with 33.4% in the laparotomy group at the end of the HIPEC (P = .0543).
DISCUSSION
This experimental study is part of current clinical
investigation aimed at improving the outcome of
Ann. Surg. Oncol. Vol. 15, No. 1, 2008
ovarian cancer patients whose disease is in apparent
complete remission. The standard primary initial
management of such cancers combines maximal cytoreductive surgery with systemic chemotherapy.
Second-look surgeries are no longer standard in the
management of advanced ovarian cancers, which results in a lack of information concerning the actual
status of the peritoneal surface at the time of completion chemotherapy. Encouraging results of a randomized, controlled study of HIPEC in the
management of peritoneal carcinomatosis in colorectal cancer patients have been published.2 HIPEC
has also been proposed in ovarian cancers, mesothelioma, and pseudomyxoma peritonei.3,12
HIPEC administered in only one session, under
direct surgical monitoring, might be more applicable
in clinical practice than sequential intraperitoneal
chemotherapy that uses permanent catheters.5 Evidence of a high complication rate of extensive peritonectomy procedures followed by HIPEC is a major
potential limitation. However, it is assumed that the
morbidity of HIPEC alone or after minor peritonectomy procedures in patients with minimal residual
disease only or with a negative second-look surgery is
more acceptable. This point is being explored in an
ongoing French collaborative phase I/II study. In
addition, complete adhesiolysis and comprehensive
assessment of the peritoneal cavity can be completed
laparoscopically with acceptable morbidity.6
In this experiment, we developed tips to overcome
the limitations of a closed HIPEC technique in
terms of intra-abdominal temperature homogeneity
and complete exposure of all peritoneal surfaces,
including the root of the mesentery and the omental
bursa, to heated perfusate. Considering that manual
mobilization of the bowel by the surgeon!s hand is
an essential component of even distribution of the
drug and complete exposure of the bowel,8 the use
of a hand-assisted technique has proved to be useful.
Xiphopubic laparotomy is no longer required. In
this regard, the laparoscopic hand-assisted HIPEC is
superior to the standard closed HIPEC procedure
that has been proposed for palliation of debilitating
malignant ascites in a series of 14 patients.13 Handassisted surgery mimics the Sugarbaker modification
of the coliseum technique in that it uses an impermeable disposable drape covering the entire operative field with a cruciate cut in its central portion to
permit access for the surgeon!s arm.14 In addition,
the laparoscopic technique avoids exposure of the
operative room staff from droplets of chemotherapy
and aerosols that may escape into the environment.15
PHARMACOKINETICS OF OXALIPLATIN
343
FIG. 3. Temperature curve for optimal procedure in the (a) laparotomy and (b) laparoscopy groups.
FIG. 4. Decrease in oxaliplatin concentrations in heated peritoneal instillation (460 mg/m2). The first point (t = 0 minutes) corresponds to
the concentration in the peritoneal fluid before the hyperthermic intraperitoneal chemotherapy (i.e., before the temperature of 43!C was
reached). (a) Laparotomy group. (b) Laparoscopy group.
FIG. 5. Oxaliplatin pharmacokinetics in plasma after heated intraperitoneal chemotherapy
(460 mg/m2).
This experiment provides evidence that laparoscopic
HIPEC is feasible and was successfully completed in all
animals after resolution of minor technical problems.
The minimal additional time to reach the target temperature is likely to disappear with experience.
From the pharmacokinetic point of view, we
demonstrated that laparoscopic HIPEC provides
equivalent exposure of the peritoneum compared
with an open one. Evidence is given that intraabdominal hyperpressure facilitates drug penetration
Ann. Surg. Oncol. Vol. 15, No. 1, 2008
344
A. GESSON-PAUTE ET AL.
TABLE 1. Oxaliplatin concentrations after heated intraperitoneal chemotherapy (460 mg/m2)
Variable
Mean UF C2h (ng/mL)
Mean plasma AUC2h
(ng/mL · min)
Median peritoneal T½ (min)
Laparotomy Laparoscopy P value
2295.26
1102.01
2994.17
1292.65
.04
.23
59.3
37.5
.02
UF, ultrafiltrate; AUC, area under the curve; T½, half-life
elimination.
into the blood compartment. A massive crossing of
the molecule through the peritoneal barrier has been
observed, but these results must be interpreted with
caution because they are important only for ultrafiltrate values. Tissue platinum concentration (ongoing
experiment) would confirm other experimental studies.16,17 Indeed, it has been proved that intraperitoneal chemotherapy with increased intra-abdominal
pressure improved the tumor accumulation and the
antitumor effect of cisplatin in rats. The tolerance of
sustained intra-abdominal pressure was manageable
in ventilated pigs.
Further experimental studies are required to
investigate the tissue concentration of platinum in
peritoneum, liver, and omentum; to assess the role of
peritoneal pressure; and to define the appropriate
dosage of drug, taking into account the higher blood
concentrations of drug during laparoscopic procedures.
Our group is planning an additional experimental
program in small animals with induced peritoneal
carcinomatosis.
In conclusion, this experimental study on adult
pigs provides further evidence of the feasibility and
reliability of a HIPEC laparoscopic approach. We
obtained optimal conditions in terms of temperature
and agent diffusion. The revolutionary hand-assisted
concept matches the requirements of the open approach from a technical point of view. In addition,
the closed procedure avoids staff members! exposure
to drugs during surgery. The results of this study
indicate that further investigation is warranted of the
place of laparoscopy in HIPEC as an innovative
application of laparoscopic surgery in gynecological
cancer, with the aim of reducing surgical trauma and
improving patient quality of life.
ACKNOWLEDGMENTS
Supported by the research program of the Institut
Claudius Regaud Cancer Center; by Sanofi-Aventis,
which provided the drug; and Karl Storz Inc., which
provided the laparoscopic equipment. All the experAnn. Surg. Oncol. Vol. 15, No. 1, 2008
iments were carried out in the surgery laboratory of
Rangueil University Hospital, Toulouse, France.
REFERENCES
1. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL,
Montz FJ. Survival effect of maximal cytoreductive surgery for
advanced ovarian carcinoma during the platinum area: a metaanalysis. J Clin Oncol 2002; 20:1248–59.
2. Verwall VJ, van Ruth S, de Bree E, et al. Randomised trial of
cytoreduction and hyperthermic intraperitoneal chemotherapy
versus systemic chemotherapy and palliative surgery in patients
with peritoneal carcinomatosis of colorectal cancer. J Clin
Oncol 2003; 21:3737–43.
3. Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome?.
Lancet Oncol 2006; 1:69–76.
4. Ferron G, Gesson Paute A, Classe JM, Querleu D. Feasibility
of laparoscopic peritonectomy followed by intra-peritoneal
chemohyperthermia: an experimental study. Gynecol Oncol
2005; 99:358–61.
5. Armstrong DK, Bundy BN, Wenzel L, et al. Intraperitoneal
cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;
354:34–43.
6. Leblanc E, Querleu D, Narducci F, Occelli B, Papageorgiou T,
Sonoda Y. Laparoscopic restaging of early stage invasive adnexal tumors : a 10-year experience. Gynecol Oncol 2004;
94:624–9.
7. Paraskeva PA, Purkayastha S, Darzi A. Laparoscopy for
malignancy: current status. Semin Laparosc Surg 2004; 11:27–36.
8. Elias D, Bonnay M, Puizillou M, et al. Heated intra-operative
intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution.
Ann Oncol 2002; 13:267–72.
9. Elias D, Antoun S, Raynard B, et al. Treatment of treatment of
peritoneal carcinomatosis using complete excision and intraperitoneal chemohyperthermia. A phase I–II study defining the
best technical procedures. Chirurgie 1999; 124:380–9.
10. Sugarbaker PH, Landy D, Pascal R, Jaffe G. Histologic
changes induced by intraperitoneal chemotherapy in patients
with peritoneal carcinomatosis from cystadenocarcinoma of
the large bowel. Cancer 1990; 11:1–14.
11. el-Yazigi A, Al-Saleh I. Rapid determination of platinum by
flameless atomic absorption spectrophotometry following the
administration of cisplatin to cancer patients. Ther Drug Monit
1986; 8:318–20.
12. Elias D, Blot F, Otmany A, et al. Curative treatment of peritoneal
carcinomatosis arising from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer 2001; 92:71–6.
13. Garofalo A, Valle M, Garcia J, Sugarbaker PH. Laparoscopic
intraperitoneal hyperthermic chemotherapy for palliation of
debilitating malignant ascites. Eur J Surg Oncol 2006.
14. Sugarbaker PH. An instrument to provide containment of intraoperative intraperitoneal chemotherapy with optimized
distribution. J Surg Oncol 2005; 92:142–6.
15. Stuart OA, Stephens AD, Welch L, Sugarbaker PH. Safety
monitoring of the coliseum technique for heated intraoperative
intraperitoneal chemotherapy with mitomycin C. Ann Surg
Oncol 2002; 9:186–91.
16. Jacquet P, Stuart A, Chang D, Sugarbaker PH. Effects of intra
abdominal pressure on pharmacokinetics and tissue distribution of doxorubicin after intra peritoneal administration. Anti
Cancer Drugs 1996; 7:596–603.
17. Esquis P, Consolo D, Magnin G, et al. High intra-abdominal
pressure enhances the penetration and antitumor effect of
intraperitoneal cisplatin on experimental peritoneal carcinomatosis. Ann Surg 2006; 244:106–12.
Annals of Surgical Oncology
Published by Springer Science+Business Media, LLC " 2008 The Society of Surgical Oncology, Inc.
Letter to the Editor
Increased Tissue Diffusion of Oxaliplatin During
Laparoscopically Assisted Versus Open Heated
Intraoperative Intraperitoneal Chemotherapy
(HIPEC)
To the Editor:
In the January 15, 2008 issue of the Annals of Surgical
Oncology we reported the results of an experimental study
comparing heated intraoperative intraperitoneal chemotherapy (HIPEC) performed by laparotomy versus laparoscopically hand-assisted.1 The technical feasibility of the
closed technique (laparoscopic) was explored in a previous
work2 and the major purpose of this second experimental
study was to compare the pharmacokinetics of oxaliplatin
with both techniques in adult pigs. The dose of oxaliplatin
administered was 460 mg/m2, heated in the abdominal
cavity for 30 min. The results supported the laparoscopic
approach since the mean half-life (T1/2) of oxaliplatin in
peritoneal perfusion was significantly shorter in the laparoscopic group than in the laparotomy group (median
37.5 min versus 59.3 min, respectively), suggesting faster
tissue absorption of oxaliplatin. Since that time, the tissue
oxaliplatin concentration has been determined.
This present work brings new results of platinum determination in tissue samples from the pigs used in the previous study. Indeed, liver, peritoneum, and omentum
biopsies were realized 30 min after T0 (i.e., the start of
HIPEC when the peritoneal fluid reached 43!C), which
corresponds to the end of the procedure. Tissues were kept
frozen at -20!C until analysis. Biopsies were desiccated by
low-pressure centrifugation using a Speed Vac at 60!C for
few hours, until constant weight was reached. Tissue was
then digested in 65% nitric acid at 95!C and evaporated to
dryness. The solid residue was dissolved in 1 ml of a mixture of Triton X100 (0.1%) and nitric acid (0.2%). Platinum levels were measured by means of flameless atomic
absorption spectrophotometric analysis according to a
previously described method.3 Oxaliplatin concentration
was determined in liver, omentum, and peritoneum of
20 pigs (i.e., 10 pigs in the laparotomy group and 10 pigs in
the laparoscopy group). The mean oxaliplatin level was
higher in the three types of tissues from the laparoscopy
group compared with the laparotomy group, as shown in
Fig. 1. This difference was significant in the liver
(P = 0.001, bilateral t-test). We previously showed that, at
the time of completion of HIPEC, 41.5% of the molecule
was ‘‘absorbed’’ in the laparoscopic group, compared with
33.4% in the laparotomy group, based on the disappearance of the drug in peritoneal perfusion, which arises from
FIG. 1. Oxaliplatin concentration in liver, omentum, and peritoneum in the laparotomy and laparoscopy groups. Each point is the
average of ten determinations; bars indicate standard deviations.
both better absorption and diffusion of oxaliplatin in tissues.
These results confirm our previous hypothesis that the
‘‘closed’’ HIPEC technique (i.e., laparoscopy) allows better
penetration of the drug in tissues and, thus, probably in
tumors. Esquis et al.4 published results of platinum concentration in intra- and extraperitoneal organs after intraperitoneal (IP) cisplatin with high intra-abdominal pressure
(IAP). They observed higher levels of platinum in peritoneal tumors and diaphragm but not in liver, kidney, and
heart with the IAP technique compared with intravenous or
classical IP. In this work, increased penetration in tumors
produced a better antitumor effect with increased survival
in rats treated with IAP. The next step would be to validate
the superiority of laparoscopic HIPEC in animals with induced peritoneal carcinomatosis to determine platinum
levels in tumors and evaluate the clinical benefit in terms of
survival.
These results might stimulate us to investigate tissue drug
concentrations in patients that benefit from both techniques
in common practice to confirm our observations and evaluate the consequences in term of therapeutic effect and
toxic side effects.
Fabienne Thomas, PhD1
Gwenaël Ferron, MD2
Amélie Gesson-Paute, MD3
Maria Hristova1
Isabelle Lochon1
Etienne Chatelut, PhD1
1
EA3035, Institut Claudius Regaud
20–24 Rue du Pont Pierre, 31052 Toulouse Cedex, France
E-mail: [email protected]
LETTER TO THE EDITOR
2
Department of Surgical Oncology, Institut Claudius Regaud
20–24 Rue du Pont Pierre, 31052 Toulouse Cedex, France
3
Department of General and Gynecological Surgery, Hôpital
Rangueil
1 Avenue Jean Poulhe`s, 31059 Toulouse Cedex, France
REFERENCES
1. Gesson-Paute A, Ferron G, Thomas F, et al. Pharmacokinetics
of oxaliplatin during open versus laparoscopically assisted heated intraoperative intraperitoneal chemotherapy (HIPEC): an
experimental study. Ann Surg Oncol 2008; 15:339–44.
Ann. Surg. Oncol.
2. Ferron G, Gesson-Paute A, Classe JM, et al. Feasibility of
laparoscopic peritonectomy followed by intra-peritoneal
chemohyperthermia: an experimental study. Gynecol Oncol
2005; 99:358–61.
3. el Yazigi A, Al Saleh I. Rapid determination of platinum by
flameless atomic absorption spectrophotometry following the
administration of cisplatin to cancer patients. Ther Drug Monit
1986; 8:318–20.
4. Esquis P, Consolo D, Magnin G, et al. High intra-abdominal
pressure enhances the penetration and antitumor effect of
intraperitoneal cisplatin on experimental peritoneal carcinomatosis. Ann Surg 2006; 244:106–12.
DOI: 10.1245/s10434-008-0115-8
Laparoscopically Assisted Heated
Intra-Operative Intraperitoneal
Chemotherapy (HIPEC): Technical
Aspect and Pharmacokinetics Data
Gwenaël Ferron, Amélie Gesson-Paute, Laurence Gladieff,
Fabienne Thomas, Etienne Chatelut, and Denis Querleu
Abstract Hyperthermic intraperitoneal chemotherapy (HIPEC) is being evaluated
for patients with minimal residual or no residual disease after complete cytoreductive
surgery. An experimental study on the porcine model was carried out to demonstrate
the feasibility of the laparoscopic approach and to compare oxaliplatin pharmacokinetics during a laparoscopic assisted vs. the “coliseum” technique for HIPEC.
In the first step, feasibility of the peritonectomy procedure followed by HIPEC
was evaluated in five adult pigs. In the second step, ten adult pigs were selected
to receive laparoscopic assisted HIPEC procedure and ten pigs were selected for
standard HIPEC in laparotomy. The HIPEC procedure was based on 460 mg/m2
of oxaliplatin for 30 min with a heated perfusate at 41–43 °C. HIPEC drains were
placed in the upper and lower quadrants of the abdomen. Peritoneal fluid and blood
samples were collected every 10 min during the procedure and the pharmacokinetics
of oxaliplatin was studied.
For the first step, the procedure was successfully completed with an adequate
intrabdominal temperature and distribution. For the second step, no major technical
problems were encountered. At the end of the HIPEC, 41.5% of the chemotherapy
was absorbed in the laparoscopic group compared to 33.4% in the laparotomy group
(p = 0.0543). The peritoneal oxaliplatin half-life (T1/2) was significantly shorter in
the laparoscopic procedure (median value of 37.5 min vs. 59.3 min, p = 0.02). The
area under the curve ratio for peritoneal/plasma reflects a faster oxaliplatin absorption through the peritoneal barrier in the laparoscopic procedure (ratio: 16.4 in the
laparoscopic group vs. 28.1 in the laparotomy group, p = 0.03).
This study confirms the technical feasibility and reliability of the laparoscopic
approach for HIPEC, and improves understanding of peritoneal drug absorption.
Oxaliplatin absorption is significantly higher with laparoscopy, regarding time course
in the peritoneal perfusion. Clinical application in selected patients may be expected
after further experimental investigation designed to define adequate drug dosage.
G. Ferrron(!), A. Gesson-Paute, L. Gladieff, F. Thomes, E. Chatelut, and D. Querleu
Department of Surgical Oncology, Institut Claudius Regaud, 20-24 Rue du Pont Pierre,
31052 Toulouse Cedex, France
e-mail: [email protected]
A. Bonetti et al. (eds.), Platinum and Other Heavy Metal Compounds
in Cancer Chemotherapy,
© Humana Press, a part of Springer Science + Business Media, LLC 2009
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G. Ferron et al.
Keywords Hyperthermia; Intraperitoneal chemotherapy; Laparoscopy; Oxaliplatin;
Pharmacokinetics
Introduction
Hyperthermic intraperitoneal chemotherapy (HIPEC) based on platinum compounds
administration is being evaluated in patients with peritoneal carcinomatosis and
sometimes in patients with previous intravenous chemotherapy. HIPEC has been
proposed following advantage of IP vs. IV in randomized trials in patients with
colorectal, gastric, peritoneal and ovarian cancer (1). We assume that HIPEC can
be applied without performing a laparotomy, particularly when no bulky disease is
present especially as a consolidation treatment after standard adjuvant chemotherapy
or in cases of high risk of peritoneal recurrence. This may be applicable during a
second look laparoscopy in high risk cases. In addition, laparoscwopic surgery is
adapted for adhesiolysis and comprehensive examination of the peritoneal cavity
with acceptable accuracy and morbidity (2, 3).
To reinforce this approach, we performed a two step experimental study on the
porcine model. The first step demonstrates the feasibility of laparoscopic peritonectomy and heated intraperitoneal chemohyperthermia (HIPEC) (4). The second step
compares the pharmacokinetics of oxaliplatin between an open vs. a laparoscopically assisted intraperitoneal hyperthermic chemotherapy (5).
Materials and Methods
A total of twenty five adult pigs were used. During the first step we performed
five laparoscopic procedures to evalue the feasibility of peritonectomy followed
by HIPEC. A 12 mm trocar was placed in the umbilical area to accommodate
the endoscope. Four additional 12 mm Versastep® (Tyco Healthcare Group LP,
Norwalk, Connecticut USA) trocars were placed in each quadrant of the abdomen
(Fig. 1). The positioning of trocars in the four quadrants was planned to perform a
complete peritonectomy and later to place the HIPEC drains. The umbilical trocar
was then replaced by a Lapdisc® (Ethicon Endo Surgery Inc, Cincinnati, USA)
allowing placement of the hand and forearm in the abdomen without any gas or
liquid leakage. Four drains were placed under laparoscopic guidance: in the right
and left upper quadrants with an inflow and an outflow circuit respectively. For
the lower abdomen, the outflow drain was placed in the pelvis. The hand of the
surgeon manipulated the inflow drain in order to evenly distribute the flow within
the abdominal cavity. For the first step, no anticancer drug was used. At the end of
the procedure, methylene blue was injected in order to check the completeness of
peritoneal exposure to the heated fluid.
Twenty adult pigs were used for the second step. Half of the group underwent HIPEC via laparotomy as previously described by Elias et al. (6) using the
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345
Fig. 1 Positioning of HIPEC drains with the surgeon’s right hand through the Lapdisc®
“coliseum” technique. The other group of pigs underwent laparoscopically assisted
HIPEC featuring the same dosage and physical parameters. Oxaliplatin was delivered at a dose of 460 mg/m2 filled heated (43 °C) in the abdominal cavity with a fixed
volume (dextrose 5%–2L/m2) during 30 min (7). Knowing that the therapeutic index is
optimal at 41–43 °C, the goal for achieving the adequate intraabdominal temperature
was fullfilled using a perfusate heated at 46–52 °C, with a 1,360 mL/min flow that
resulted in outflow temperature at 41–43 °C.
Blood and Peritoneal Fluid Sampling
Nine blood samples were collected from each animal at different times: before
HIPEC, at time zero (T0) when the peritoneal fluid reached 43 °C, and every
10 min during the procedure. Blood samples were then collected after the HIPEC
at 45 min, 1 h, 1.5 h and 2 h after T0. Samples were immediately centrifuged at
+4 °C, for 10 min at 1,500 g. For samples collected at the end of the procedure
(i.e. 30 min after T0), at 1 and 2 h after the HIPEC beginning, an aliquot of plasma
was ultrafiltered by centrifugation at +4 °C for 20 min at 2,000 × g through a
Amicon MPS1 micropartition system with YMT membranes (cut-off 30,000 Da).
Five 5 ml samples of peritoneal fluid were collected from each animal at different
time points: before the temperature reached 43 °C, at the beginning of the HIPEC and
then every 10 min during the procedure. All samples were frozen at –20 °C until assay.
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G. Ferron et al.
Platinum Determination
Platinum levels in the plasma and in the plasma ultrafiltrate were measured by
means of flameless atomic absorption spectrophotometric analysis according to
a previously described method. Nominal values of platinum controls were 21,
105 and 210 ng/mL for plasma ultrafiltrate and 20.9, 104.7 and 209.3 ng/mL for
plasma samples. Platinum determination in samples was validated when measured
control values were comprised within 10% for the medium and high level control
and 20% for the low level control.
Results
In the first step, the peritonectomy procedure was successfully completed in all
five animals. Active permanent manipulation of the bowel and viscera, and manual
adaptation of the direction of the inflow by the surgeon’s hand, allowed us to obtain
a homogeneous intraabdominal temperature. The distribution of blue dye was even
in the abdominal cavity in all the pigs. Exposure of all peritoneal surfaces to heated
perfusate, including the root of the mesentery and the omental bursa, was achieved.
In the second step, no noticeable technical problems were encountered in the
laparotomy group as a result of our experience in human clinical practice. The
most frequently encountered complication during laparoscopic procedures was
circuit obstruction by the contact of small bowel and omentum with the tips of the
drains in three procedures. As a result, target temperature was reached after 8 min
(median value) in the laparotomy group vs. 12.5 min in the laparoscopic group
(p = 0.03) (Fig. 2).
Pharmacokinetics of Heated Intraoperative
Intraperitoneal Oxaliplatin
A decrease in platinum concentration was observed in the peritoneal perfusion during
HIPEC in both groups (Fig. 3). Analysis of T1/2 of the drug showed a significantly
faster tissue absorption of oxaliplatin in the laparoscopic group (median value:
37.5 min vs. 59.3 min, p = 0.02), giving evidence that the “closed” technique seemed
to influence and raise platinum absorption through the peritoneal barrier. At the time
of completion of HIPEC, 41.5% of the chemotherapy was absorbed in the laparoscopic group, compared to 33.4% in the laparatomy group (p = 0.05).
Time Course of Oxaliplatin in the Peripheral Blood
Peak plasma concentration of platinum was observed on average 30 min after
starting HIPEC in the laparotomy group whereas peak plasma concentration was
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347
Fig. 2 Temperature curve of optimal procedure in each group
obtained after 46.4 min (p = 0.87) in the laparoscopic group (Fig. 4). Platinum
concentration then dropped rapidly in both groups, resulting in a limited systemic
area under the curve (AUC). The AUC2h was higher for the laparoscopic procedure,
as was C2h in ultrafiltrat (Table 1). The AUC ratio peritoneal/plasma (at 30 min)
was larger in the laparotomy group (28.1 vs. 16.4, p = 0.03), reflecting the fact
that oxaliplatin was kept in the abdominal cavity with less penetration through the
peritoneal barrier to the blood compartment compared to the laparoscopic group.
During HIPEC, oxaliplatin was more rapidly absorbed in the laparoscopic group:
41.5% of oxaliplatin was absorbed in the laparoscopic group, compared to 33.4%
in the laparotomy group at the end of the HIPEC procedure (p = 0.0543).
Discussion
Development of intraperitoneal drug therapy is one of the main areas of research
to improve the long-term survival for patients with peritoneal carcinomatosis.
Encouraging results of a randomized controlled study of HIPEC in the management of peritoneal carcinomatosis in colorectal cancer patients have been published
(8). HIPEC has also been proposed in ovarian cancers, mesothelioma and pseudomyxoma peritonei (9, 10). Laparoscopic techniques may prove to be an optimal route
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G. Ferron et al.
Fig. 3 Decrease in oxaliplatin concentrations in heated peritoneal instillation (460 mg/m2). First
point (t = 0 min) corresponds to concentration in the peritoneal fluid before the HIPEC (i.e. before
the temperature of 43 °C was reached)
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349
Fig. 4 Oxaliplatin pharmacokinetics in plasma after heated intraperitoneal chemotherapy (460 mg/m2)
Table 1 Oxaliplatin concentrations after heated intraperitoneal chemotherapy (460 mg/m2)
Laparotomy
Laparoscopy
p
Mean ultrafiltrate C2h (ng/ml)
2295.26
2994.17
Mean plasma AUC2h (ng/ml × min)
1102.01
1292.65
Median peritoneal T1/2 (min)
59.3
37.5
AUC Area under the plasma concentration-time curve; T1/2 Half life elimination
0.04
0.23
0.02
to administer intraperitoneal chemotherapy especially after complete cytoreductive
surgery and adjuvant chemotherapy as a consolidation treatment. This approach can
also be utilised in cases at high risk of peritoneal recurrence in patients with colorectal cancer or gastric cancer. HIPEC administered in only one session, under direct
surgical monitoring, might be more applicable in clinical practice than sequential
intraperitoneal chemotherapy using permanent catheters.
The possibility of using a closed technique, while manipulating the viscera using
the hand-assisted technique and/or laparoscopic instruments, combines advantages
of both laparotomy techniques.
In this study, we developed techniques to overcome the limitations of a “closed”
HIPEC procedure in terms of intraabdominal temperature homogeneity and complete
exposure of all peritoneal surfaces, including the root of the mesentery and the omental bursa, to heated perfusate. Considering that manual mobilisation of the bowel by
the surgeon’s hand is an essential component of even distribution of the drug and
complete exposure of the bowel (6), the use of hand-assisted technique has proved to
be useful. Xiphopubic laparotomy is no longer required. In this regard, the laparoscopic
hand-assisted HIPEC is superior to standard “closed” HIPEC procedure that has been
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G. Ferron et al.
proposed for palliation of debilitating malignant ascites in a series of 14 patients
(11). Hand-assisted surgery mimicks the Sugarbaker modification of the “coliseum”
technique using an impermeable disposable drape covering the entire operative field
with a cruciate cut in its central portion to open the access site to the surgeon’s arm
(12). In addition, the laparoscopic technique avoids exposure of the operative room
staff from droplets of chemotherapy and aerosols that may escape into the environment (13). This study provides evidence that laparoscopic HIPEC is feasible, and was
successfully completed in all animals after resolution of minor technical problems
(15 cases with a laparoscopic approach). The minimal additional time to reach target
temperature is likely to disappear with experience.
From the pharmacokinetic point of view we demonstrated that laparoscopic
HIPEC provides equivalent exposure of the peritoneum compared to an open one.
Evidence is given that high intraabdominal pressure facilitates drug penetration into
the blood compartment. A massive crossing of the molecule through the peritoneal
barrier has been observed, but these results must be interpreted with caution, as they
are significant only for ultrafiltrat values. Further experimental studies are required,
to investigate tissue concentrations of platinum in the peritoneum, liver and omentum,
assess the role of peritoneal pressure, and define appropriate dosage of drug, taking
into account higher blood concentrations of drug during laparoscopic procedures.
Conclusions
This experimental study provides further evidence of the feasibility and reliability
of HIPEC laparoscopic approach. We obtained optimal conditions in terms of temperature and agent distribution in the laparoscopy group as well as the laparotomy
group. The hand-assisted concept is revolutionary compared to classic “closed”
techniques and matched the requirements of the open approach from the technical
point of view. In addition, the “closed” procedure avoids drug exposure to the staff
present in the operative room. The results of this study favours further investigation of the role of laparoscopic HIPEC as an innovative application of laparoscopic
surgery in surgical oncology, with the aim of reducing surgical morbidity and hopefully improving the quality of life of patients.
Acknowledgments This study was supported by the research program of the Institut Claudius
Regaud Cancer Centre, by Sanofi-Aventis who provided the drug and Karl Storz INC. who
provided the laparoscopic equipment. All experiments were carried out in the surgery laboratory
of the Rangueil university Hospital in Toulouse, France.
References
1. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian
cancer. N Engl J Med 2006;354:34–43.
2. Leblanc E, Querleu D, Narducci F, Occelli B, Papageorgiou T, Sonoda Y. Laparoscopic restaging
of early stage invasive adnexal tumors: a 10-year experience. Gynecol Oncol ;94:624–9.
Bonetti_Ch37.indd 350
10/12/2008 1:00:39 AM
Laparoscopically Assisted Heated Intra-Operative Intraperitoneal Chemotherapy
351
3. Paraskeva PA, Purkayastha S, Darzi A. Laparoscopy for malignancy: current status. Semin
Laparosc Surg 2004;11:27–36.
4. Ferron G, Gesson-Paute A, Classe JM, Querleu D. Feasibility of laparoscopic peritonectomy
followed by intra-peritoneal chemohyperthermia: an experimental study. Gynecol Oncol
2005;99:358–61.
5. Gesson-Paute A, Ferron G, Thomas F, de Lara EC, Chatelut E, Querleu D. Pharmacokinetics
of oxaliplatin durin open versus laparoscopically assisted heated intraoperative intraperitoneal
chemotherapy (HIPEC): an experimental study. Ann Surg Oncol 2008;15:339–44.
6. Elias D, Bonnay M, Puizillou JM, et al. Heated intra-operative intraperitoneal oxaliplatin after
complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution.
Ann Oncol 2002;13:267–72.
7. Elias D, Antoun S, Raynard B et al. Treatment of peritoneal carcinomatosis using complete excision and intraperitoneal chemohyperthermia. A phase I-II study defining the best
technical procedures. Chirurgie 1999;124:380–9.
8. Verwall VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic
intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients
with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737–43.
9. Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma
peritonei syndrome? Lancet Oncol 2006;1:69–76.
10. Elias D, Blot F, Otmany A, et al. Curative treatement of peritoneal carcinomatosis arising
from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer
2001;92:71–6.
11. Garofalo A, Valle M, Garcia J, Sugarbaker PH. Laparoscopic intraperitoneal hyperthermic chemotherapy for palliation of debilitating malignant ascites. Eur J Surg Oncol 2006;32:682–5.
12. Sugarbaker PH. An instrument to provide containement of intraoperative intraperitoneal
chemotherapy with optimized distribution. J Surg Oncol 2005;92:142–6.
13. Stuart OA, Stephens AD, Welch L, Sugarbaker PH. Safety monitoring of the coliseum
technique for heated intraoperative intraperitoneal chemotherapy with mitomycin C. Ann
Surg Oncol 2002;9:186–91.
Bonetti_Ch37.indd 351
10/12/2008 1:00:39 AM
!
2.1.3:!Discussion!and!future!prospect!
!
Knowledge! has! profoundly! changed! during! the! two! last! decades! about! peritoneal!
carcinomatosis.! Initially! palliative! treatment! was! the! only! one! issue! for! patients,!
associated! with! a! shortGterm! survival! and! a! bad! quality! of! life,! resulting! in! intestinal!
obstruction! over! months! and! a! fatal! outcome! with! progression! of! intraperitoneal!
disease.! The! new! approach! combining! cytoreductive! surgery! and! intraperitoneal!
carcinomatosis!offers!hope!for!longGterm!survival!in!selected!patients.!
Peritoneal! carcinomatosis! can! be! quantified! using! a! recommended! score,! with! the!
extend! directly! correlating! with! treatment! success.! Limited! carcinomatosis,! with! a! low!
PCI! (Peritoneal! Cancer! Index)! represents! a! therapeutic! challenge! regarding! to! the! real!
possibility!to!cure!these!patients.!
As! previously! described,! the! introduction! of! minimal! invasive! surgery! has! completely!
modified! the! recruitment! of! patients.! Currently,! patients! are! referred! with! limited!
peritoneal! extension! after! a! laparoscopic! evaluation! and! sometime! a! laparoscopic!
resection!of!the!tumor.!Laparoscopy!represents!the!recommended!surgical!approach!for!
exploration! of! adnexal! mass,! ascitis! or! for! resection! of! early! colorectal! cancer.!
Prophylactic!HIPEC!for!patient!with!a!high!risk!of!developing!PC!from!colorectal!cancer!
is!currently!on!evaluation!in!France!(ProphyloCHIP!trial).!Using!laparoscopic!represents!
the! best! way! to! deliver! HIPEC! without! the! need! to! extensive! peritonectomy.! The!
necessity! of! adhesiolysis! determines! the! complexity! of! the! procedure! and! requires! an!
operating!team!with!experience!in!minimally!invasive!abdominal!surgery.!
We!described!the!first!application!of!laparoscopy!for!peritonectomy!and!HIPEC.!PK!data!
published,! with! a! favorable! modification! of! the! ratio! between! peritoneal! AUC! and!!
plasma! ultrafiltrated! AUC,! has! confirmed! the! difference! observed! between! open! and!
close! abdomen! technique.! According! to! these! results,! a! 30%! decreasing! dose! rate! is!
recommended! when! using! a! close! abdomen! technique! compared! to! its! open!
counterpart.!This!difference!was!confirmed!by!OrtegaGDebalon!in!an!experimental!study!
[63].!
Our!hypothesis!concerning!the!increased!tissue!diffusion!during!laparoscopic!HIPEC!was!
the! role! of! intraGabdominal! pressure.! It! was! confirmed! in! two! consecutive! works!
published! by! Facy! [64].! The! authors! shown! that! the! association! of! hyperthermia! and!
highGpressure!(25!cm!H2O)!increased!tissue!penetration!of!oxaliplatin!better!than!either!
of! them! alone! and! did! not! significantly! increase! systemic! absorption.! The! interest! to!
enhance!the!intraGabdominal!pressure!up!to!40!cm!H2O!was!also!evaluated.!Despite!an!
enhancing! effect! on! the! concentration! of! drug! in! the! peritoneum,! very! high! intraG
abdominal! pressure! (40! cm! H2O)! does! not! improve! the! depth! of! penetration! into! the!
tissue! [65].! Increasing! the! pressure! to! the! maximal! tolerated! pressure! in! the! closed!
procedures!seems!to!be!without!benefit,!because!the!drug!concentrations!at!25!and!40!
cm! H2O! were! not! different.! IntraGabdominal! highGpressure! was! well! tolerated! in! this!
experimental!model.!In!human!application,!highGpressure!pneumoperitoneum!caused!a!
significant! decrease! in! static! respiratory! system! compliance! and! an! increase! in!
inspiratory!resistance,!and!represents!a!limitation!for!obese!patients.!!
!
30!
On!the!other!hand,!adverse!impact!on!the!surgical!peritoneal!environment!during!a!CO2!
pneumoperitoneum! has! been! described! [66],! with! an! increased! expression! levels! of!
connective! tissue! growth! factor,! matrix! metalloproteinaseG9,! EGselectin,! chemokine!
ligand! 2! (CXCLG2),! HyalG1! and! HyalG2.! HighGpressure! laparoscopy! has! a! negative!
oncologic! impact! increasing! postoperative! tumor! growth! and! dissemination! [67],! and!
facilitated!implantation!of!malignant!cells!and!port!site!metastases![68].!
After!we!reported!the!feasibility!of!laparoscopic!peritonectomy!and!HIPEC,!Facchiano!et!
al! [69]! reported! the! first! human! application,! in! palliative! care,! for! treatment! of!
malignant! ascites! secondary! to! unresectable! peritoneal! carcinomatosis! from! advanced!
gastric! cancer.! Esquivel! et! al! [70]! reported! in! 2009! the! first! case! of! combined!
laparoscopic! cytoreductive! surgery! and! HIPEC! with! curative! intent! in! a! patient! with!
limited! peritoneal! mesothelioma! using! our! published! technique.! The! same! team!
published![71]!a!10!cases!consecutive!!series!and!demonstrated!the!feasibility!and!safety!
of!cytoreductive!surgery!and!HIPEC!via!the!laparoscopic!route!in!selected!patients!with!
lowGtumor! volume! and! no! small! bowel! involvement! mainly! from! appendiceal!
malignancies.! Fagotti! et! al! [72]! confirmed! the! feasibility! of! this! technique! in! selected!
platinumGsensitive!single!recurrent!ovarian!cancer!patients.!Rettenmaier!et!al.![73]!has!
used! laparoscopic! carboplatin! based! HIPEC! as! a! consolidation! treatment! for! ovarian!
cancer! patient! with! a! complete! response! after! neoadjuvant! chemotherapy.! Its!
reproducibility! and! safety! were! confirmed! by! Passot! ! [74]! and! Esquivel! [75].! Patients!
with!low!grade!pseudomyxoma!peritonei!and!limited!peritoneal!disease!(PCI!less!than!
10)! underwent! a! laparoscopic! cytoreductive! surgery! and! HIPEC.! The! authors! have!
concluded!that!laparoscopic!CRS!combined!with!HIPEC!is!feasible!and!safe!for!curative!
treatment! of! strictly! selected! patients! with! peritoneal! surface! malignancy! and! might!
reduce! postoperative! complications! and! length! of! hospital! stay.! As! prophylaxis! for!
patients! with! high! risk! of! developing! peritoneal! carcinomatosis,! Sloothaak! et! al! has!
confirmed! the! safety! and! the! short! hospital! stay! in! a! monocentric! pilot! study! by! using!
laparoscopic! mitomycin! C! based! HIPEC! [76].! In! 2012,! a! review! was! published!
concerning!laparoscopic!HIPEC![77].!Eight!studies!encompassing!a!total!of!183!patients!
were! reported.! Indication! for! laparoscopic! HIPEC! was! neoadjuvant! in! 5! patients,!
adjuvant!in!102!patients,!and!palliative!in!76!patients.!
Using! nebulizers,! the! pneumoperitoneum! may! become! a! new! way! to! administer!
intraoperative! treatments! [78].! It! have! been! developed! by! a! german! team! and! called!
PIPAC! (Pressurized! intraperitoneal! aerosol! chemotherapy).! The! principle! is! to! apply!
chemotherapy! as! a! pressurized! aerosol! within! the! abdominal! cavity! allowing! a!
homogeneous!repartition!of!the!cytotoxic!agent.!For!the!authors,!it!generates!a!pressure!
gradien,! which! counterbalances! tumoral! interstitial! fluid! pressure.! Ten! studies,!
including! 2! ex! vivo! and! in! vitro! studies,! 6! clinical! studies,! and! 2! ongoing! clinical! trials!
using! PIPAC! in! women! with! recurrent! ovarian! cancer! have! been! identified.! PIPAC! has!
demonstrated! antitumor! activity! based! on! histological,! radiological,! and! clinical!
evidence![79].!The!toxicity!of!PIPAC!is!manageable.!The!ongoing!development!of!PIPAC!
is! currently! dedicated! to! recurrent! disease! and! palliative! intent.! Using! neoadjuvant!
PIPAC!will!be!the!next!step,!with!an!evaluation!of!the!postoperative!morbidity.!
Effective! precautions! have! to! be! taken! in! order! to! minimize! workers! exposure.! The!
members!of!the!operating!room!staff!are!usually!familiar!with!the!risks!of!exposure!to!
various!infectious!agents,!to!various!solvents,!to!the!anesthetic!gases!and!to!XGrays.!The!
management! of! PC! adds! exposure! to! surgical! smokes! and! to! cytotoxic! drugs.! A! few!
!
31!
publications! have! confirmed! a! possible! drug! contamination! of! surface’s! workplace,!
especially! around! the! operating! table! [80].! Risk! of! exposure! is! minimized! in! Close!
Abdomen! HIPEC! than! in! Open! abdomen.! ! Several! reports! have! documented! identified!
drugs!in!the!urine!of!health!care!workers,!and!measured!genotoxic!responses!in!workers!
[81].!No!detectable!levels!of!the!cytotoxic!agent!were!present!in!any!of!the!samples![82].!
A!residual!risk!is!mainly!due!to!the!possibility!of!direct!or!indirect!skin!exposure!and!can!
be! prevented! by! the! correct! use! of! personal! protective! equipment! [83].! The! failure! to!
detect! chemotherapy! residues! depends! on! the! measuring! techniques! used,! taking! on!
board!the!chosen!detection!threshold![84].!Many!of!the!antineoplasic!agents!are!known!
or!suspected!human!carcinogens,!effects!on!fertility!and!reproduction!are!documented!
[85,! 86].! Chromosomal! aberrations,! micronuclei! induction,! DNA! damage! represent! the!
most! frequent! abnormities! for! occupational! exposure.! Although! limited,! some!
publications!exist!on!the!relationship!of!occupational!exposure!to!cytotoxic!agents!with!
cancer! in! health! care! workers! [87].! Data! are! missing! concerning! the! real! impact! to!
HIPEC!exposure.!There!are!not!currently!any!formal!European!Guidelines!about!the!type!
of! PPE! to! be! used! for! the! HIPEC! procedure.! Some! teams! follow! the! recommendations!
made!by!the!National!Institute!for!Occupational!Safety!and!Health![88].!!
After! a! first! article! concerning! either! environmental! contamination! risk! management,!
personal! protective! equipment,! or! occupational! health! supervision! [89],! a! practices!
survey! was! carried! out! in! France,! via! the! RENAPE! Network.! This! publication! was!
recently!submitted!to!the!Annals!of!Surgical!Oncology.!!
!Considering!the!advantages!of!close!abdomen!HIPEC!on!safety!environmental!aspects,!
the!laparoscopic!technique!avoids!exposure!of!the!operative!room!staff!from!droplets!of!
chemotherapy!and!aerosols.!!
!
!
!
!
32!
!
2.2:) EVALUATION) OF) THE) PHARMACOKINETIC) INTERNPATIENT) VARIABILITY) OF)
OXALIPLATIN) BASED) OPEN) ABDOMEN) HIPEC) AND) COMPARISON) OF) THE) IMPACT)
OF)TWO)PROCEDURES)OF)DRUG’S)DELIVERY)ON)OXALIPLATIN)PK.)A)POPULATION)
PHARMACOKINETIC)APPROACH.)
!!
Pharmacokinetics! (PK)! of! heated! intraperitoneal! oxaliplatin! was! previously! published!
by!the!Gustave!Roussy!PK!team![90].!However,!no!model!was!used!to!analyze!the!data.!
The! aim! of! this! study! was! to! develop! a! PK! model,! which! is! able! to! simultaneously!
describe!peritoneal!and!plasma!oxaliplatin!concentrations!versus!time!in!order!to!obtain!
mean!PK!parameters!and!their!interGindividual!variability.!!
2.2.1:To! develop! a! PK! model! and! to! compared! the! impact! of! two! procedures! of! drug’s!
delivery!
This! model! was! applied! to! compare! the! impact! of! two! procedures! of! drug’s! delivery!
during! HIPEC! on! oxaliplatin! PK.! Indeed,! European! Community! approved! reheaters! –!
recirculators! have! been! marketed.! Two! different! procedures! for! drug’s! delivery! were!
also!used,!depending!to!the!“school”!of!HIPEC!training,!related!to!the!marketing!of!new!
European!Community!approved!reheaters:!
!
G!for!the!first!procedure!(12!patients):!the!solution!instilled!within!the!peritoneal!
cavity! contained! oxaliplatin,! and! a! delay! of! 8G10! minutes! was! necessary! to! reach! the!
targeted!temperature!(42G43°C)!
!
G!for!the!second!procedure!(12!patients):!the!cavity!was!initially!filled!only!with!
the!carrier!solution.!Oxaliplatin!was!added!to!the!peritoneal!instillate!when!the!targeted!
temperature!was!reached.!
Plasma! and! peritoneal! fluid! oxaliplatin! concentrations! were! analyzed! according! to! a!
population!PK!approach!using!NONMEM!according!to!a!threeGcompartment!model.!
An! interGindividual! variability! was! reported,! larger! for! plasma! PK! parameters! than! for!
peritoneal! parameters.! The! percentage! of! oxaliplatin! dose! absorbed! during! the! HIPEC!
procedure!may!vary!from!40!to!68%.!
The!heated!intraGoperative!procedure!did!not!have!any!impact!on!oxaliplatin!PK.!
This!PK!model!is!useful!to!implement!PK!evaluation!of!further!oxaliplatin!based!HIPEC!
clinical!trails.!
This!work!was!published!in!Cancer!Chemotherapy!and!Pharmacology.!
Ferron!G,!Dattez!S,!Gladieff!L,!Delord!JP,!Pierre!S,!Lafont!T,!Lochon!I,!Chatelut!E.!!
Pharmacokinetics)of)heated)intraperitoneal)oxaliplatin.)
Cancer!Chemother!Pharmacol.!2008!Sep;62(4):679G83.!
!
33!
Cancer Chemother Pharmacol
DOI 10.1007/s00280-007-0654-x
ORIGINAL AR T I CL E
Pharmacokinetics of heated intraperitoneal oxaliplatin
G. Ferron · S. Dattez · L. GladieV · J.-P. Delord ·
S. Pierre · T. Lafont · I. Lochon · E. Chatelut
Received: 13 November 2007 / Accepted: 26 November 2007
© Springer-Verlag 2007
Abstract
Objective To evaluate the pharmacokinetic inter-patient
variability of 30-min hyperthermic intraperitoneal oxaliplatin chemotherapy.
Patients and methods Data were obtained from 24
patients who were treated according to two procedures of
heated intra-operative intraperitoneal oxaliplatin. For the
Wrst procedure (12 patients), the solution instilled within the
peritoneal cavity contained oxaliplatin, and a delay of 8–
10 min was necessary to reach a temperature of 42–43°C.
For the second procedure (12 patients), the cavity was initially Wlled only with the dextrose solution, and oxaliplatin
was added to the peritoneal instillate when temperature
reached 42–43°C. Plasma and peritoneal Xuid oxaliplatin
concentrations were analyzed according to a population
pharmacokinetic approach using NONMEM.
Results Peritoneal and total plasma data were simultaneously analyzed according to a three-compartment pharmacokinetic model. The peritoneal half-life ranged between
18 and 42 min. The mean peritoneal clearance was 5.47 L/h
(§21%), and the mean plasma clearance was 3.71 L/h
(§47%). The heated intra-operative procedure did not have
any impact on oxaliplatin pharmacokinetics.
G. Ferron · S. Pierre
Department of Surgical Oncology and Anesthaesiology,
Institut Claudius-Regaud, Toulouse, France
L. GladieV · J.-P. Delord
Department of Medical Oncology,
Institut Claudius-Regaud, Toulouse, France
S. Dattez · J.-P. Delord · T. Lafont · I. Lochon · E. Chatelut (&)
EA3035, Institut Claudius-Regaud and Université de Toulouse,
20-24 rue du Pont Saint-Pierre, 31052 Toulouse, France
e-mail: [email protected]
Conclusion The inter-individual variability was larger for
plasma pharmacokinetic parameters than that for peritoneal
parameters. However, the percentage of oxaliplatin dose
absorbed during a 30-min hyperthermic intraperitoneal
chemotherapy may vary from 40 to 68%. The present
pharmacokinetic model will be useful to implement pharmacokinetic evaluation of further clinical trials of hyperthermic intraperitoneal chemotherapy based on platinum
compounds’ administration.
Keywords Population pharmacokinetics ·
Intraperitoneal chemotherapy · Oxaliplatin · HIPEC ·
Carcinomatosis
Introduction
In the past two decades, the evolution of loco regional therapy has changed the management of peritoneal surface
malignancies. Encouraging results of a randomized controlled study of hyperthermic intraperitoneal chemotherapy
(HIPEC) in the management of peritoneal carcinomatosis
in colorectal cancer patients have been published [10].
HIPEC has also been proposed in ovarian cancers, peritoneal mesothelioma and pseudomyxoma peritonei [9].
HIPEC administered in only one session, after complete
cytoreduction under direct surgical monitoring, might be
more applicable in clinical practice than in sequential intraperitoneal chemotherapy using permanent catheters [7].
Pharmacokinetics (PK) of heated intraperitoneal oxaliplatin have been previously reported [2–4]. However, no
model has been used to analyze the data. The aim of the
current study was to develop a PK model which is able to
simultaneously describe peritoneal and plasma oxaliplatin
concentrations versus time in order to obtain mean PK
123
Cancer Chemother Pharmacol
parameters and their interindividual variability. This model
has been applied to compare the impact of two procedures
of HIPEC on oxaliplatin PK.
Patients and methods
Patients and oxaliplatin administration
Data were obtained from 24 patients who were treated from
June 2005 to January 2007 for primary or recurrent peritoneal carcinomatosis with debulking surgery and HIPEC.
Their primitive tumor type was ovarian (n = 17), colorectal
(n = 5), mesothelioma (n = 1), or pseudomyxoma (n = 1). All
except the two patients with mesothelioma, or pseudomyxoma, were previously treated by intravenous chemotherapy.
All patients provided written informed consent before
study enrolment. The main patient characteristics are
shown in Table 1. HIPEC procedures were conducted as
previously described by Elias et al. [4] with the “coliseum”
technique. Oxaliplatin was administered in a 5% dextrose
solution (2 L/m2) at a dose of 460 (n = 17) or 360 mg/m2
(n = 7). The initial dose (i.e., 460 mg/m2) was reduced for
the Wnal seven patients treated due to toxicity. The Wrst 12
patients were treated according to the Wrst HIPEC procedure (group 1), and the following 12 patients to the second
procedure (group 2). For the Wrst procedure, the solution
instilled within the peritoneal cavity contained oxaliplatin,
and a delay of 8–10 min was necessary to reach a temperature of 42–43°C. For the second procedure, the cavity was
initially Wlled only with the dextrose solution, and oxaliplatin was added to the peritoneal instillate when the temperature reached 42–43°C. The extracorporeal circulation of the
Xuid was realized using the Performer LRT® System
(Medolla, MO, Italy). Perfusion duration was exactly
30 min from the time when optimum temperature (42–
43°C) was reached.
Sampling and platinum assay
Seven peritoneal Xuid samples were collected (every 5 min
during the 30-min HIPEC) per patient. An additional peritoneal sample was obtained just before the warm-up period
for the Wrst 12 patients (HIPEC procedure 1). Eleven blood
samples (5 mL) were collected: before the HIPEC, 0.167,
0.333, 0.5, 0.75, 1, 2, 4, 6, and 8 after the beginning of the
HIPEC. Blood samples were immediately centrifuged at
2,000£g for 10 min at 4°C. One milliliter of plasma was
ultraWltered using an Amicon MPS1 micro partition system
with YMT membranes (30,000 MW cut-oV) at 4°C for
20 min at 2,000£g.
Peritoneal Xuid samples were collected: at the beginning
of the perfusion (for the 12 Wrst patients only), at the beginning of HIPEC, and every 5 minutes during HIPEC.
Samples were kept at ¡20°C until analysis by Xameless
atomic absorption spectrophotometry, according to a previously described method [8]. The limit of quantiWcation was
10 ng/mL for both peritoneal Xuid and ultraWltrate, and
20 ng/mL for plasma.
Pharmacokinetic analysis
Peritoneal and total plasma data
Peritoneal and plasma data from the 24 patients were
simultaneously analyzed using NONMEM (version V,
level 1.1 running on Pentium 200 pro) [1] according to a
three-compartment pharmacokinetic model (Fig. 1) and a
Wrst-order conditional estimation (FOCE) method. A proportional error model was used for residual and interpatient variability. Individual pharmacokinetic parameters
were obtained by Bayesian estimation using the POSTHOC
option. The impact of the HIPEC technique (TECH = 0,
or = 1 for the Wrst or the second procedure, respectively) on
absorption rate from peritoneal compartment to plasma,
Ka, was tested according to the following equation:
TVKa = !5 £ (1 ¡ !7 £ TECH) where !5 is the typical
value of Ka (TVKa) of patients for whom TECH = 0, and
!5 £ (1 ¡ !7) that of patients for whom TECH = 1. A Wrst
analysis was done by allocating a constant value of TECH
(either 0 or 1) for all samples during the HIPEC procedure.
A second analysis was done by coding TECH = 1 only for
samples during the warm-up period and then TECH = 0.
The two models with the covariate TECH were compared
to that without covariate by the "2 test of diVerence
between the respective objective function values (OBJs);
OBJ equal to minus twice the log likelihood of the data. A
change of at least 3.84 (P < 0.05, one degree of freedom)
was required to consider Ka as signiWcantly dependent of
the covariate TECH.
Table 1 Characteristics of the 24 patients
Characteristics
Mean
Gender (male/female)
2/22
Age (years)
53
32–68
Body weight (kg)
65
50–90
Dose of oxaliplatin (mg)
711
460–880
123
Range
UltraWltrate plasma data
Since ultraWltrate (uf) plasma concentrations observed at
time 6 and/or 8 h were higher than those observed at previous sampling time for 12/24 patients, no attempt was made
to obtain a structural pharmacokinetic model to describe the
Peritoneal
compartment
Ka
Central
compartment
K12
Peripheral
compartment
K21
Peritoneal concentrations (ng/mL)
Cancer Chemother Pharmacol
250000
mean observed concencentrations
model predicted concentrations
200000
150000
100000
50000
0
0
0.1
0.2
0.3
K10
observed uf plasma data. The pharmacokinetic parameters
corresponding to uf plasma concentrations were obtained
by model independent method using Kinetica software
(version 4.1, InnaPhase, Waltham, MA, USA). Mixed linear and logarithmic trapezoidal rule was used to calculate
the area under the curve of the uf plasma concentrations
versus time from time 0 to 8 h after the beginning of the
HIPEC (AUC0-8 h).
0.4
0.5
0.6
0.7
Time (hours)
Plasma concentrations (ng/mL)
Fig. 1 Pharmacokinetic model with Ka = 0 when time > duration of
the peritoneal infusion, and peritoneal and plasma concentrations
corresponding to the peritoneal and central compartment, respectively
a
18000
b
mean observed concentrations
model predicted concentrations
16000
14000
12000
10000
8000
6000
4000
2000
0
0
1
2
3
4
5
6
7
8
9
Time (hours)
Fig. 2 Mean (§SD) observed peritoneal (a) and total plasma (b)
oxaliplatin concentrations, and curve of concentrations versus time
corresponding to the mean pharmacokinetic parameters
Results
2.5
Pharmacokinetics
2.3
2.1
Peritoneal and total plasma data
1.9
Ka (h-1)
The structural pharmacokinetic model was found to
describe the data very accurately with a residual variability
of 8 and 13% for peritoneal and plasma concentrations,
respectively. Figure 2 shows the mean observed peritoneal
(Fig. 2a) and total plasma (Fig. 2b) concentrations versus
time, and concentrations corresponding to mean pharmacokinetic parameters obtained by the model. The mean pharmacokinetic parameters and their interindividual variability
are shown in Table 2. The inter-individual variability was
larger for plasma pharmacokinetic parameters than that for
peritoneal parameters. Figure 3 shows that the absorption
rate (Ka) of oxaliplatin from peritoneal compartment to
plasma was not dependent on the administered dose. The
mean peritoneal half-life (=ln 2/Ka) ranged between 18 and
42 min.
By considering the covariate TECH during either the
whole HIPEC procedure or only during the warm-up
period, no signiWcant decrease of the OBJ was observed
indicating that there was no change in Ka due to the HIPEC
technique. Figure 3 conWrms that individual values of Ka
were not dependent on the procedure.
TECH=1
TECH=0
1.7
1.5
1.3
1.1
0.9
0.7
0.5
400
500
600
700
800
900
1000
Oxaliplatin dose (mg)
Fig. 3 Absorption rate (Ka) of oxaliplatin from peritoneal compartment to plasma versus oxaliplatin dose; TECH = 0, or = 1 in case of a
delay, or not to reach the temperature of 42–43°C
UltraWltrate plasma data
The mean uf plasma AUC0-8 h was 13.7 !g/mL £ h (range:
8.0–20.0 !g/mL £ h). As previously stated to justify the
model-independent method to analyze these data, the mean
uf concentration (Fig. 4) at T + 8 h was slightly higher than
that at T + 6 h.
123
Cancer Chemother Pharmacol
Table 2 Mean peritoneal and plasma oxaliplatin pharmacokinetic
parameters
Parameter
Mean
CV (%)
Peritoneal
Volume of distribution (L)
3.95
Clearance (L/h)
5.47
17
21
Ka (h¡1)
1.40
22
T1/2 (h)
0.49*
0.30–0.70**
Plasma
Central volume of distribution (L)
15.3
Clearance (L/h)
27
3.71
T1/2!((h)
47
0.21*
T1/2"((h)
0.18–0.22**
12.9*
5.33–38.08**
Uf plasma concentration (ng/mL)
CV coeYcient of variation
* Harmonic mean
** Extreme values
12000
10000
8000
6000
4000
2000
0
0
1
2
3
4
5
6
7
8
9
Time (hours)
Fig. 4 Mean (§SD) observed ultraWltered plasma oxaliplatin concentrations
Toxicity
Major morbidity (grade 3 and 4) occurred in eight patients in
group 1 (Wrst HIPEC procedure), and in four patients in
group 2 (second HIPEC procedure). The most signiWcant
morbidities were abdominal bleeding, anastomotic leaks,
sensory alteration or paresthesia, infection complications,
systemic inXammatory response syndrome, and thrombocytopenia. Eight patients in group 1 and one patient in group 2
developed abdominal bleeding. Grade 3–4 thrombocytopenia
occurred in ten patients in group 1, and one patient in group
2. Systemic inXammatory response syndrome associated
with clinical peritonitis and a high level of C reactive protein
was seen in nine patients in group 1, and none in group 2.
Discussion
Pharmacokinetics of oxaliplatin given by HIPEC has been
previously reported, but this study was the Wrst based on a
123
population approach allowing to analyze all peritoneal and
plasma data from 24 patients simultaneously. The mean
value of 29 min (range 18–42 min) obtained for the peritoneal half-life was consistent with those previously reported
(i.e., 30 min [2] or 40 min [3]). The absorption process was
not dependent on the dose (Fig. 3). The NONMEM methodology also allowed us to evaluate if the procedure had an
impact on the absorption speciWcally during the warm-up
period: Ka was not signiWcantly diVerent during this period
in comparison with the period with peritoneal liquid at 42–
43°C. Since the pharmacokinetic model well described the
peritoneal data it is possible to estimate the mean absorbed
dose of oxaliplatin according to the mean Ka and the duration of the HIPEC procedure: half of the dose is absorbed
after 30 min of HIPEC. However, although the interindividual variability on Ka was limited (i.e., coeYcient of variation of 22%), there was a ratio of 2 between the extreme
values indicating that for some patients the percentage of
dose absorbed during a 30-min HIPEC may vary between
40 and 68%. This diVerence contributed to the variability of
the plasma oxaliplatin concentrations that was also the consequence of the interindividual variability in plasma pharmacokinetic parameters (i.e., 47% for plasma clearance).
The proWle of ultraWltered plasma oxaliplatin concentrations was unexpected. For most of the patients, concentrations at time 6 or 8 h were higher than those at previous
sampling time. This was also observed in the experimental
model of HIPEC in pigs [5]. We can make the hypothesis
that platinum compounds are released from the peritoneal
membranes lately after the end of the HIPEC. This fraction
does not necessarily correspond to unchanged oxaliplatin.
Indeed, we could make the hypothesis that oxaliplatin may
be conjugated with glutathione by the glutathione-S-transferase within the cells constituting the peritoneal membranes and then transported out of the cells to the plasma
compartment by the MRP transporters. Since platinum glutathione S-conjugates are relatively small molecules [6],
they would contribute to this rebound of the uf plasma concentrations.
A signiWcant correlation was observed between uf
plasma AUC and platelet count at nadir (r = ¡0.58,
P < 0.01, data not shown). However, the diVerence in
hematologic toxicity may be explained by considering only
the oxaliplatin dose: mean (§SD) nadir count of platelets
was signiWcantly lower (P < 0.001) after 460 mg/m2 of oxaliplatin than after 360 mg/m2: 86,900 (§69,600)/mm3 and
198,400 (§29,700)/mm3, respectively. The previous
hypothesis relative to platinum glutathione S-conjugates
could explain why pharmacokinetic–pharmacodynamic
relationship is not stronger than that between dose and toxicity. Moreover, thrombopenia was also the consequence of
post-operative hemorrhage that was more frequent for
patients for whom the Wrst HIPEC procedure was
Cancer Chemother Pharmacol
performed. Since all of them received 460 mg/m2 of
oxaliplatin, whereas 7 of 12 patients with second HIPEC
procedure received 360 mg/m2, HIPEC procedure probably
contributed as much as the oxaliplatin doses or plasma concentrations to this hematological toxicity. Besides the pharmacokinetic results, this study showed the impact of the
HIPEC procedure on toxicity. Detailed clinical (both toxicity and eYcacy) results will be reported elsewhere.
In conclusion, the present pharmacokinetic model
allowed us to quantify the respective interindividual variability to peritoneal and systemic processes. It will be useful to implement pharmacokinetic evaluation of further
clinical trials of HIPEC based on oxaliplatin administration
that is planned.
Acknowledgment We thank Miss Tracy Chapman for editorial
assistance with the English.
References
1. Beal SL, Sheiner LB (1982) Estimating population kinetics. Crit
Rev Biomed Eng 8:195–222
2. Elias D, Bonnay M, Puizillou JM, Antoun S, Demirdjian S, El OA,
Pignon JP, Drouard-Troalen L, Ouellet JF, Ducreux M (2002)
Heated intra-operative intraperitoneal oxaliplatin after complete
resection of peritoneal carcinomatosis: pharmacokinetics and
tissue distribution. Ann Oncol 13:267–272
3. Elias D, Matsuhisa T, Sideris L, Liberale G, Drouard-Troalen L,
Raynard B, Pocard M, Puizillou JM, Billard V, Bourget P,
Ducreux M (2004) Heated intra-operative intraperitoneal oxaliplatin plus irinotecan after complete resection of peritoneal carcinomatosis: pharmacokinetics, tissue distribution and tolerance. Ann
Oncol 15:1558–1565
4. Elias D, Raynard B, Bonnay M, Pocard M (2006) Heated intraoperative intraperitoneal oxaliplatin alone and in combination with
intraperitoneal irinotecan: pharmacologic studies. Eur J Surg
Oncol 32:607–613
5. Gesson-Paute A, Ferron G, Thomas F, de Lara EC, Chatelut E,
Querleu D (2007) Pharmacokinetics of oxaliplatin during open
versus laparoscopically assisted Heated Intraoperative Intraperitoneal Chemotherapy (HIPEC): an experimental study. Ann Surg
Oncol (available online)
6. Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas
M, Gamelin E (2000) Clinical pharmacokinetics of oxaliplatin:
a critical review. Clin Cancer Res 6:1205–1218
7. Jaaback K, Johnson N (2006) Intraperitoneal chemotherapy for the
initial management of primary epithelial ovarian cancer. Cochrane
Database Syst Rev CD005340
8. LeRoy AF, Wehling ML, Sponseller HL, Friauf WS, Solomon RE,
Dedrick RL, Litterst CL, Gram TE, Guarino AM, Becker DA
(1977) Analysis of platinum in biological materials by Xameless
atomic absorption spectrophotometry. Biochem Med 18:184–191
9. Sugarbaker PH (2007) Adjuvant intraperitoneal chemotherapy:
a review. Recent Results Cancer Res 169:83–89
10. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren
H, Boot H, Zoetmulder FA (2003) Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic
chemotherapy and palliative surgery in patients with peritoneal
carcinomatosis of colorectal cancer. J Clin Oncol 21:3737–3743
123
!
!
2.2.2:!Discussion!and!future!prospect!
Standardization! of! HIPEC! technique! represents! an! important! challenge! in! order! to!
conduct! multiGinstitutional! and! international! trials.! According! to! the! results! to! our!
practices!survey,!a!relative!homogeneity!of!the!practices!was!shown!in!France,!linked!to!
the!“schools”!of!HIPEC,!with!more!than!half!of!the!teams!having!been!in!practice!for!over!
10! years.! Whatever! an! open! or! closed! method! for! HIPEC! is! used,! is! still! based! on! the!
surgeon’s! preference! and! training.! The! most! frequently! performed! open! abdomen!
procedure! was! established! by! Sugarbaker,! and! soGcalled! “Coliseum! technique”.! Open!
HIPEC! technique! allows! a! manual! distribution! of! the! perfusate.! Two! European!
Community! approved! reheaters! –! recirculators! are! commonly! used! in! France! for! open!
abdomen! technique,! with! two! different! ways! to! deliver! hyperthermia! and! IP!
chemotherapy:!!
G!First,!by!using!the!SunCHIP!reheater:!increasing!of!temperature!occurred!quickly,!the!
solution!instilled!within!the!peritoneal!cavity!contain!immediately!oxaliplatin.!!
G! Second,! by! using! the! Performer! LRT! reheater:! increasing! of! temperature! occurred!
slowly,!8!to!10!minutes!are!necessary!to!reach!42G43°C.!When!the!targeted!temperature!
is!reached,!oxaliplatin!is!instilled.!!
We! have! demonstrated! that! the! heated! intraGoperative! procedure! did! not! have! any!
impact!on!oxaliplatin!PK.!!
Our! work! has! contributed! to! improve! the! homogeneity! of! technique.! For! clinical! trial!
enrollment,! data! of! patients! and! PK! studies! may! be! substantially! similar! whatever! the!
device!and!the!technique!used.!!
!!
!
!
34!
!
2.3:)EVALUATION)OF)THE)TOXICITY)FOR)PATIENTS)WHO)UNDERWENT)COMPLETE)
CYTOREDUCTIVE)SURGERY)ASSOCIATED)TO)CISPLATIN)AND)OXALIPLATIN)BASED)
HIPEC.)CLINICAL)AND)PHARMACODYNAMIC)STUDIES)
!
!
The!use!of!HIPEC!was!initially!developed!as!a!treatment!for!rare!peritoneal!disease!and!
has! continuously! gain! interest.! But! at! the! beginning! of! our! experience,! 13! years! ago,!
there!was!an!important!lack!of!data!regarding!toxicity!and!PKGPD!studies.!First!reported!
experiences! were! focused! on! reproducibility! in! small! sample! size.! Moreover,! these!
series! were! retrospective! with! heterogeneous! patients! cohorts! and! technique.! For!
example,!the!dose!of!IP!cisplatin!ranged!from!25!mg/m2!to!150!mg/m2.!!
Now,! numbers! of! case! series! publications! are! available! in! ovarian! cancer,!
gastrointestinal!cancer!and!rare!peritoneal!disease!reporting!an!acceptable!morbidity!
While! waiting! for! results! from! some! prospective! phase! III! clinical! trials,! a! HIPEC!
program! was! developed! at! the! Institut! Claudius! Regaud,! with! a! strong! interest! for!
clinical!trail!involvement!and!PKGPD!studies.!
Paradoxically,! data! regarding! drug! dose! rate,! volume! and! type! of! carrier! solution,! and!
duration! of! hyperthermia! were! missing! at! the! beginning! of! our! experience.! Our! HIPEC!
program! has! started! with! the! application! of! early! experience! published! by! some!
pioneers.!Refinements!have!been!secondarily!applied!explicating!that!dose!escalation!PK!
studies!were!usually!available!after!the!first!toxicity!related!publications.!!
Toxicity! varies,! depending! to! the! drug! used.! In! our! center,! two! cytotoxic! agents! are!
predominantly! used! for! HIPEC:! cisplatin! and! oxaliplatin,! with! different! side! effects,!
respectively,!renal!toxicity!and!abdominal!bleeding.!
2.3.1:!Cisplatin!based!HIPEC!related!toxicity!
Three! different!works!were!performed!to!evaluate!the!renal!toxicity!of!cisplatin!based!
HIPEC.! Cisplatin! represents! the! cornerstone! of! chemotherapy! for! ovarian! cancer.! As!
previously!described,!in!patients!with!minimal!residual!disease!after!surgery,!sequential!
adjuvant! intraperitoneal! cisplatin! based! chemotherapy! has! been! to! produce! the! best!
results! thus! far! observed! in! terms! of! survival! phase! III! clinical! trials.! A! number! of!
institutions!around!the!world!have!begun!to!offer!cisplatin!HIPEC!for!ovarian!cancer.!
Evaluation! of! the! renal! toxicity! represents! a! crucial! point! because! it! limits! the!
therapeutic! option! for! recurrences! and! had! an! important! impact! on! patient! quality! of!
life.!
!
2.3.1.1:!First!step!
PK! data! from! 12! patients! who! underwent! a! CRS! and! Cisplatin! based! HIPEC! were!
recorded! according! to! the! renal! function! in! a! retrospective! dose! deGescalation! study!
!
35!
using!a!three!compartmental!model.!Three!different!dose!levels!were!used:!100,!80!and!
70! mg/m2,! with! 2! l/m2! NaCl! 0.9%! solution,! heated! during! 60! min! at! 42G43°C.!
Postoperative!acute!renal!failure!was!evaluated!according!to!the!RIFLE!score.!!The!mean!
maximum!fraction!of!the!dose!absorbed!was!69%!with!an!interGindividual!variability!at!
7%.! The! mean! ratio! AUCIP/AUCUF! was! 4.3,! confirming! the! pharmacokinetics! advantage!
of! the! procedure.! Acute! renal! failure! was! reported! in! 83%! of! patients,! 58%! of! which!
with!high!grade!(failure,!loss!or!endGstage).!!
Occurrence!of!renal!failure!is!not!dose!dependant,!and!due!to!a!different!mechanism!as!
known!with!using!intravenous!cisplatin.!!
This! unpublished! work! was! presented! at! the! “13ème! journées! du! Groupe! de!
Pharmacologie!Clinique!Oncologique”!–!Nîmes!2010!and!represents!the!base!for!the!next!
step.!
!Civade!E,!Ferron!G,!Pierre!S,!Lochon!I,!Rouge!P,!Gladieff!L,!Chatelut!E.!!
Chimiohyperthermie!Intraperitoneale!à!base!de!Cisplatine:!Pharmacocinétique!et!
tolerance!rénale.!!
!
2.3.1.2:!Second!step!
Based! to! this! first! report! of! high! frequency! of! renal! toxicity,! a! large! bicentric!
retrospective! study! was! performed.! Data! from! 66! patients! treated! with! CRS! and!
Cisplatin! based! HIPEC! have! been! recorded! in! two! cancer! centers:! Institut! Claudius!
Regaud! GToulouse! and! Institut! du! Cancer! –! Montpellier.! Decrease! glomerular! filtration!
rate!more!than!25%!at!day!7!postoperative!was!reported!for!48%!of!patients:!1/3!were!
classified!in!the!Risk!group,!1/3!in!the!Injury!group!and!1/3!in!the!Failure!group.!!
Variables! significantly! associated! with! renal! failure! occurrence! were! treatment! by!
angiotensin!converting!enzyme!inhibitors!and!preGexisting!hypertension.!Intraoperative!
diuresis!represents!a!important!factor!for!acute!renal!injury!in!multivariate!analysis.!
This!work!was!presented!at!the!French!Society!of!Gynecologic!Oncology!Annual!Meeting!
–!Toulouse!–!Nov!2014!–!and!is!actually!submitted!at!the!European!Journal!of!Surgical!
Oncology.!
Vieille!P,!Quenet!F,!Gladieff!L,!Rougé!P,!Chaltiel!L,!Querleu!D,!MD,!Saint!Aubert!B,!
Martinez!A,!Carrere!S,!Ferron!G.!!
Predictive) factors) of) acute) kidney) injury) after) cytoreduction) surgery) and)
cisplatin) based) hyperthermic) intraperitoneal) chemotherapy) for) ovarian)
peritoneal)carcinomatosis:)a)retrospective)bicentric)study!(Submitted)!!
!
36!
Predictive factors of acure kidney injury
Predictive factors of acute kidney injury after cytoreduction surgery and
cisplatin based hyperthermic intraperitoneal chemotherapy for ovarian
peritoneal carcinomatosis: a retrospective bicentric study
Pierre Vieillea, MD, François Quenetb, MD, Laurence Gladieffc ,MD, Pierre Rougéc ,MD,
Leonor Chaltielc, PhD, Denis Querleuc, MD, PhD, Bernard Saint Aubertb , MD, PhD, Alejandra
Martinezc, MD , Sébastien Carrereb, MD ,Gwenaël Ferronc, MD.
a
Service de gynécologie obstétrique, CHU Carémeau de Nîmes
Institut du cancer de Montpellier
c
Institut Claudius Regaud – IUCT Oncopole
b
Short title :
Predictive factors of acute kidney injury after cisplatin based HIPEC
1
Predictive factors of acure kidney injury
Abstract
Introduction:
Hyperthermic intraperitoneal Chemotherapy (HIPEC) is the standard treatment for some
peritoneal disease such as pseudomyxoma peritonei, peritoneal mesothelioma advanced colon
cancer. Cisplatine bsed CHIP seems to improve the treatment of peritoneal carcinomatosis from
ovarian cancer and can have a significant impact on the patient’s survival. One of the important
adverse effects of cisplatin administration is nephrotoxicity.
Design of the study:
Bicentric retrospective study.
Patient and method:
Data from patients treated with cytoreduction surgery (CRS) plus HIPEC have been recorded in
two French centres. Patients characteristics were noted such as data concerning cytoreductive
surgery and HIPEC and pre-, intra and postoperative management. Patients were divided into
two groups according to the occurrence of a postoperative acute kidney injury. A univariate and
a multivariate analysis were performed.
Results:
This study included 66 patients with a median age of 57, 43,9% underwent a first-line treatment
and 56,1% were treated for recurrent disease.. A decrease in glomerular filtration rate (GFR)
>25% at day-7 postoperative compared to day-0 was reported for 48,4%. Variables significantly
associated with AKI occurrence were treatment by angiotensin converting enzyme inhibitors
(ACEI) and/or angiotensin receptors blockers (ARBs), pre-existing high blood pressure.
Intraoperative crystalloid volume and diuresis were statistically lower in the AKI group. The
multivariate analysis identified high blood pressure and intraoperative diuresis as significant
factors for acute renal injury.
Conclusion:
Cisplatin based HIPEC is possible with a low AKI rate if hydration is adequate in order to
maintain a high diuresis level. Largest prospective study should be leaded to confirm these
results.
Keywords: Peritoneal carcinomatosis, Ovarian cancer, HIPEC, Cisplatin, nephrotoxicity, acute
kidney injury, hydration
2
Predictive factors of acure kidney injury
INTRODUCTION
patient undergoing uncomplete surgery (7). Di
Ovarian cancer represents 22,240 new cases in 2013
Giorgio et al. in 2013 showed that CC score
in united states which represent 3 % of new cases of
(p<0.002) and degree of colorectal-wall involvement
all sites cancer (1). In France, a 2013 cancer
(p<0.037) are the most important predictive factors of
incidence and mortality assessment reported 4615
long-term (five-year) survival, these results were
annual new cases of ovarian cancer with 3140 deaths
confirmed by multivariate analysis (8). A Cochrane
in 2012 (2). Ovarian cancer generally affects older
review in 2013, showed a direct correlation between
women, and reduced life expectancy observed in the
degree of cytoreduction and overall survival (9).
developing countries explains that the incidence rates
Platinum anticancer drugs introduction into the
range from over 11 cases out of 100,000 in Europe to
clinical treatment of cancer has resulted in dramatic
less than 3 cases out of 100,000 in Africa (3).
improvements in ovarian carcinoma. (10). The intra
Ovarian cancer is the fifth leading cause of cancer-
peritoneal (IP) drug administration in advanced
related deaths after lung, breast, colon and pancreas
ovarian cancer has been demonstrated to be efficient
(United States, 2013) (1).
but cisplatin seems to be superior to carboplatin in IP
Because of the poverty of symptoms, around 75% of
delivery (11–13). The combination of hyperthermia
women
with IP drugs administration improve the anti tumoral
are diagnosed with an extension of the
disease outside the pelvis (FIGO stage III/IV) (4).
effect of chemotherapy and hyperthermia has also an
The standard treatment for these advanced stages is
anti tumoral effect, which acts in synergy with the
laparotomy with primary complete cytoreductive
pharmacological action of drugs(14,15).
surgery followed by platinum-based chemotherapy.
Hyperthermic intraperitoneal Chemotherapy (HIPEC)
The principles of surgical management of peritoneal
is the standard treatment for rare peritoneal disease
surface malignancies have been widely described and
(pseudomyxoma
the
the
mesothelioma) but has also an interest in the
completeness of cytoreduction (CC) score established
management of peritoneal carcinomatosis from
depending on the remaining macroscopic lesions size
colorectal tumor.
(5,6).
Intraperitoneal
The completeness of cytoreduction is one of the most
intravenous therapy seems to improve the survival
important factors influencing recurrence of epithelial
rate in advanced ovarian cancer compared to
ovarian
surgery
intravenous chemotherapy alone among the patient
treatment,
with and without residual disease after surgical
quality
of
cancer
debulking,
surgery
(EOC).
irrespective
is
A
of
evaluated
complete
primary
by
significantly improves overall survival compared to
peritonei
chemotherapy
and
peritoneal
combined
to
debulking (16,17).
3
Predictive factors of acure kidney injury
One of the most important adverse effect of cisplatin
advanced or recurrent EOC were collected. The
systemic
is
patients were treated in two French centres: Institut
nephrotoxicity by activation of multiple cell death
Claudius Regaud, Toulouse and ICM Val d’Aurelle,
and survival pathways and initiation of a robust
Montpellier.
inflammatory response in renal tubular epithelial
Microsoft® Access database management system.
cells, which is responsible for acute renal injury
A computer generated search of two institional
(AKI) (18). Kusamura et al. found cisplatin dose for
patient database was performed to retroscpectively
HIPEC of 240 mg or more as having a significant
identify all patients who was treated with CRS plus
correlation with an increase of serum creatinine high
platinum based HIPEC
or equal to 3,0 x ULN (upper limit normal) (> grade
fallopian or primary peritoneal cancer between 2007
3 systemic toxicity) during the postoperative period,
and 2013 at two Comprehensive Cancer Centers:
but they did not find any independent risk factor
Institut Claudius Regaud (Toulouse – France) and
during the postoperative period (19). AKI rate
Institut du Cancer de Montpellier (Montpellier –
reported is variable in literature(17–19).
France)
and
intraperitoneal
administration
The
A
patient’s
database
was
created
using
from advanced ovarian,
characteristics
noted
were
the
The aim of this study is to highlight risk factors to
following: age, size, weight, comorbidities (diabetes,
develop a postoperative AKI for women undergoing
hypertension), treatment by angiotensin converting
cytoreductive surgery (CRS) followed by HIPEC.
enzyme
Patient’s
receptors blockers (ARBs) and ASA score. The type
characteristics
information
on
surgery
have
and
been
pre-,
registred;
intra-
inhibitors
(ACEI)
and/or
angiotensin
and
of treatment was noted: recurrence or first line and
immediately postoperative management of patient to
the previous treatments (surgery, chemotherapy or
determine which elements could influence or reduce
both). The extent of peritoneal carcinomatosis was
the risk to develop acute kidney injury.
assessed
intraoperatively
with
Sugarbaker’s
Peritoneal Cancer Index (PCI) (20). The preoperative
amount of crystalloid administrated was recorded.
The principle of surgical procedures in the two
PATIENTS AND METHODS
centers were the same, consisting in a complete CRS
This bicentric study is a retrospective analysis from a
(CC0 or CC1) followed by Platinum based HIPEC,
prospective database. Data from patients treated with
heated between 41 and 43°C for 60 minutes using the
CRS plus HIPEC based on cisplatin between 2007
“coliseum” open technique. The CRS was evaluated
and
by
2013
for
peritoneal
carcinomatosis
from
the
number
of
visceral
resections
and
4
Predictive factors of acure kidney injury
by
or >75%, respectively). GFR was calculated using
Sugarbaker (5) with into three levels according to the
MDRD (Modification of Diet in Renal Disease)
number of procedures performed: level I, 1 or 2
equation. The aim was to determine which factor(s)
procedures; level II, 3 or 4 procedures; level III, 5 or
among
6 procedures (21). The completeness of the cancer
postoperative acute kidney injury occurrence.
peritonectomy
procedures,
as
described
the
data
recorded
could
influence
resection was evaluated with the CC-score: CC-0
correspond to no macroscopic residual disease, CC-1
Data is summarized by frequency and percentage for
to residual tumour nodules less than 2.5 mm, and CC-
categorical variables and by median and range for
2 to residual tumour nodules more than 2.5 mm (20).
continuous variables. Differences between groups
Datas recorded for HIPEC were dose, body
were analysed using χ2 test or Fisher’s exact test for
temperature 5 to 30 minutes before and after the
qualitative variables and Mann Whitney test for
intraperitoneal
perfusion.
continuous variable. Multivariate logistic regression
epidural
with backward variable selection was performed to
analgesia, diuresis, fluid loss (blood and ascites),
determine variables significantly associated with the
continued intravenous noradrenalin administration
outcome, the renal failure. All factors considered
and seven first postoperative days management and
significant at the P<0.10 level were included in the
treatment (red blood cell units (RBCU), albumin,
logistic model. P-values <0.05 were considered as
crystalloid
statistically significative. All statistical analyses were
chemotherapy
Intraoperatives
data
were
and
aminoglycosides
collected:
colloid,
and
inflammatories (NSAIs)).
noradrenalin,
non-steroidal
anti-
conducted using the STATA 13.0 software.
Pre operative (day-0)
blood sampling, at 24 hours, at day-7 and at the end
of hospitalization was noticed. The postoperative
complications
identified
were
hemoperitoneum,
ascites, sepsis, septic shock and the necessity of
reintervention or dialysis.
Patients were divided into two groups according to
normal renal function or acute kidney injury at day 7
but they were also compared too, according to their
renal failure degree using RIFLE classification of
decrease of glomerular filtration rate (GFR) (22) :
Risk, Injury or Failure (GFR decrease >25%, >50%
5
Predictive factors of acure kidney injury
RESULTS
treatment with ACEI and/or ARBs were statistically
Sixty-six patients undergoing CRS and HIPEC based
significant in the AKI group.
on cisplatin for an EOC during this period were
crystalloid volume perfusated and diuresis were
identified. The characteristics of the patients are
significantly higher in the NRF group. Even if
listed in table 1. None included of the patients died in
preoperative crystalloid volume perfused was more
the 30 postoperative days.
important in the NRF group, the difference was not
The median Follow-up was 35.9 months (95%CI:
statistically significant.
[28.2; 43.2]). The 3 year-survival rate
is 69.17%
Intraoperative noradrenalin administration was not
(95%CI: [54.0; 80.21]). Recurrence occurred for 47
significantly different, but it must be noted that
patients (74,2%), with a median relapse free survival
among the patients without epidural analgesia, none
of 12.8 months (95%CI : [7.6 ; 18.4]) and a Relapse
of
Free Survival (RFS) rate at 3 years of 22.85%
(p<0.0001).
(95%CI: [12.98; 34.41]).
Regarding biologic datas, patients with AKI at day-7
A decrease in GFR >25% at day-7 postoperative
seemed to have a higher preoperative plasmatic urea
compared to day-0 was reported for 48,4% of patients
level but it was not significant. At day-1 a plasmatic
(n=30), data were missing for four patients.
urea increase as a GFR decrease was correlated with
According to RIFLE classification, 32 patients
AKI occurrence at day 7 (table 3).
(51.6%) were considered with no kidney injury, 11
None of the identified postoperative complications
(17.7%) were classified in the Risk group, 10
was significantly associated with acute kidney injury:
(16.1%) in the Injury group and 9 (14.5%) in the
no patient needed a reintervention, one case of
Failure group. Among patients with GFR decrease
hemoperitoneum occurred in AKI group (p=0.48),
>25% at day-7, 14 (60.9%) suffer from chronic
one case of postoperative ascites in NRF group and
kidney
(GFR
two in AKI group (p=0.61), one case of sepsis in
<60mL/min/m2) (data were missing for seven
each group (p=1.00) and one septic shock in NRF
patients) and among these patients, 4 (28.6%)
group (p=0.49).
required dialysis.
No
A univariate analysis was performed between the two
treatments between the two groups (NRF vs. AKI):
groups: NRF group (normal renal function) and AKI
red blood cells units; 0.0(0.0: 6.0) vs. 0.0(0.0: 4.0) (p
group
corresponding
= 0.39), albumin (dose: 20%, 100mL); 4.0(0.0: 10.0)
respectively to a GFR decrease ≤ 25% and > 25% at
vs. 5.0(0.0: 12.0) (p = 0.93), Aminoglycosides; 1
day-7 (table 2). A high blood pressure and a
(3.1%) vs. 0 (p = 1.00), NSAIs; 9 (29%) vs. 6
disease
(acute
six
kidney
months
injury)
later
them
needed
difference
was
intraoperative
found
for
Intraoperative
noradrenalin
postoperative
6
Predictive factors of acure kidney injury
(22.2%) (p = 0.55), diuretics; 14 (43.8%) vs. 16
DISCUSSION
(57.1%) (p = 0.30) and 4 patients (12.5%) received
CRS associated with HIPEC is getting an important
noradrenalin in the NRF group vs. 5 (18.5%) in the
role in the treatment of recurrent EOC, its place must
AKI group (p = 0.72).
be most clearly defined in the case of advanced EOC
The comparison of the different variables according
frontline treatment. Most studies reporting the use of
to RIFLE classification (table 4) did not allow to
HIPEC for EOC are retrospectives and concern small
demonstrate significant differences because of the
samples with relatively low levels of evidence, no
small sampling in each group, but it suggests that
randomized controlled trial is available. Cisplatin acts
acute kidney injury severity increases with the
by binding DNA and generating lesions causing
reduction of pre and intraoperative amount of
cancer cells death (14). The combination of
crystalloids. Similar results are observed for diuresis:
hyperthermia with IP drugs administration improve
low intraoperative urine volume seems to be linked to
the anti tumoral effect of chemotherapy, this has been
more severe renal function degradation. The number
shown in rats models. Higher intratumour platinum
of peritonectomies seems to be important too:
concentrations are available with drug heat
43.7% of the patients in the NRF group, 54.6% in the
combination than with cisplatin at 37°C (15,23,24)
Risk group, 70% in the Injury group and 77.7% in the
Hyperthermia has also an anti tumoral effect, which
failure group underwent level 2 or 3 procedures
acts in synergy with the pharmacological action of
(more than three procedures). The median cisplatin
drugs. These effects of hyperthermia are known for a
doses in the same groups were respectively 75, 75, 60
long time. The study of supranormal temperatures
and 80 mg/m2.
upon normal human cells (derived from normal adult
Two significant factors for acute renal injury were
and embryonic tissues) and neoplastic human cells
identified in the multivariate analysis: high blood
(derived from biopsies of malignant tumors) exposed
pressure (OR=18.59; 95%CI [1.90-182.31]; p=0.012)
to temperatures of 42.5-43°C, shows an highest
and intraoperative diuresis (OR=0.54; 95%CI [0.37thermo sensitivity of neoplastic cells compared to
0.77]; p=0.001). Variables used for this test were
normal cells with an higher cells died rate in tumoral
high blood pressure, preoperative crystalloid volume,
cultures (15,25).
intraoperative
diuresis
and
number
peritonectomy
crystalloid
volume,
Hyperthermic intraperitoneal Chemotherapy (HIPEC)
of
procedure,
body
is
temperature
before
HIPEC
and
the
standard
treatment
for
pseudomyxoma
preoperative
peritonei and peritoneal mesothelioma. The overall
plasmatic urea level.
survival rate is more important in pseudomyxoma
peritonei and peritoneal mesothelioma than in other
7
Predictive factors of acure kidney injury
histology (26,27).
A review published in 2014, exposed several results
Several drugs are used in HIPEC for treatment of
concerning chemotherapy in frontline for stage III or
EOC, cisplatin is the most widely used. Oxaliplatin
IV EOC: overall survival was 22.8 months vs 24.5
have an interesting pharmacokinetic in HIPEC but
months respectively in the PS group (primary surgery
variability in peritoneal and systemic oxaliplatin
followed
exposures are observed between patients (28). A
chemotherapy) and in the NACT group (Neoadjuvant
potential benefit of Oxalipaltin based HIPEC for the
chemotherapy) and the median progression-free
treatment of peritoneal carcinomatosis from
survival (PFS) time was respectively 10.2 vs. 11.7
colorectal origin had been shown, an effective
months with no difference between the two groups.
antitumor activity and a favorable toxicity profile in
In case of platinum resistant recurrent ovarian cancer,
EOC seems to exist. Oxaliplatin at the dose of 460
the
mg/m2 during 30 min with a 42-44°C of temperature
chemotherapy (CT) significantly improves RFS from
had not shown any survival benefit and was
3.4 vs. 6.7 months (p<0.001), but the overall survival
responsible for an high rate of intraperitoneal
was respectively 13.3 vs. 16.6 months (33). In a
bleeding (29). HIPEC with cisplatin seems logical as
recent study, 566 patients underwent CRS and
the standard chemotherapy used in EOC but no study
HIPEC, the median overall survival was 35,4 months
with high level of evidence justified the use of
for patients with peritoneal carcinomatosis from
cisplatin and the widely used dose of 75 mg/m2 (30).
advanced EOC treated with CRS and HIPEC as
HIPEC seems to be interesting treatment of ovarian
front-line therapy and for recurrent EOC, the median
cancer and can have a significant impact on patient
overall survival was 45.7 months. They did not find
survival when the appropriate patients are selected
any difference between patients with chemoresistant
(31). In 2013, the FROGHI (French Oncologic and
and chemosensitive recurrence, suggesting HIPEC
Gynecologic HIPEC) Group, in a retrospective study,
may increase the potential effect of intraperitoneal
identified several prognostic factors being significant
cisplatin in platinum-resistant patients. Median
for overall survival in patients treated by HIPEC for
recurrence-free survival was 11.8 months for
advanced EOC (front line therapy) and for recurrent
advanced EOC (32). Another study in 2007, on 81
EOC: the period of treatment, the age, the PCI, the
patients
CC-score, the performans status, and the number of
abdominal closure technique for chemoresistant and
HIPEC drugs The multivariate analysis identified 2
recurrent advanced EOC reported median overall and
significant factors: the performans status and the
disease-free survivals of 28.4 and 19.2 months,
Peritoneal Cancer Index (PCI)> 8 (32).
respectively
by
six
adjunction
cycles
of
undergoing
(34).
of
platinum
bevacizumab
CRS
These
and
results
based
(BEV)
HIPEC
to
using
suggest
an
8
Predictive factors of acure kidney injury
improvement of survival with this treatment but must
of 75 to 150 mg/m2. Only one case of grade 3/4
be confirmed by larger studies. We reported in this
toxicity occurred in this study, but they reported a
study a survival rates at 3 years of 69.17% with a
low overall morbidity rate of 34% while their
median Follow-up of 35.9 months. Recurrence
literature review exposed rates from 27 to 65 % (35).
occurred for 47 patients (74,2%), and RFS rate at 3
Di Giorgio et al., in a prospective single center study
years was 22.85% (95%CI: [12.98; 34.41]). Similar
of
results are observed in the literature, but the doses of
followed by HIPEC based on cisplatin at the dose of
chemotherapy are variable.
75 mg/m2, reported 24 patients (51,1%) presented
A postoperative acute kidney injury was observed for
grade 1 complication, 10 patients (21,3%) grade 2, 10
48.4% of patients with 14.5% in the Failure group
patients (21,3%) grade 3 and 2 (4,2%) grade 4. No
(GFR
RIFLE
renal function alteration was reported (36). A part
classification, which corresponds to grade 3 and
from extracellular expansion using at least 1 liter of
higher of NCI CTCAE V4.0 (National Cancer
normal saline with 3 g of magnesium sulfate and 40 g
Institute, Common Terminology Criteria for Adverse
of mannitol intravenously (17), authors, in these
Events; Version 4.0, May 2009). In 2007, a study was
study, did not report sodium thiosulfate or other
reporting systemic toxicity after peritonectomy and
nephroprotectant.
HIPEC,
247
increased doses of cisplatin by reducing toxicity (37)
procedures for pseudomyxoma peritonei, colorectal
but a potential reduction antitumor activity is unclear
and gastric carcinomatosis, peritoneal mesothelioma,
(38,39). Acute renal injury rate post Cisplatin-HIPEC
ovarian carcinomatosis and abdominal sarcomatosis.
is difficult to assess because of the very varied data
All HIPEC regimens used cisplatin associated either
given in the literature. A very few articles had
with doxorubicin or mitomycin, the median dose of
especially study this complication.
cisplatin was 204 mg (100-300). Ten (4%) cases of
The only patient characteristics, which appear to be
grade 3 and 4 (1,6%) cases of grade 4 serum
risk factors in our study, are high blood pressure and
creatinine alteration were observed with an onset on
treatment by ACEI and/or ARBs. Renin Angiotensin
day 3 (1-6) and a maximum on day 8 (3-15) (19).
system (RAS) blockers, ACEI and ARBs, have been
Bakrin et al. observed 51 renal insufficiency (8%)
evaluated as risk factors of adverse events after
with 15 (2%) developping chronic renal insufficiency
cardiothoracic surgery, preoperative RAS-blocker use
and 6 patients (1%) requiring long-term dialysis (25).
was associated with increased odds, for both,
Schmidt et al, reported a study of 67 patients among
postoperative AKI (OR, 1.17; 95% CI, 1.01-1.36; P =
which 51 underwent HIPEC with cisplatin at the dose
0.04) (40). Furthermore, the same assessment has
decrease>
242
75%)
patients
according
were
to
undergoing
47
patients
undergoing
Sodium
surgical
thiosulfate
procedure
allows
9
Predictive factors of acure kidney injury
been done on patient developing a septic shock:
seems to be higher in the Failure group (median: 80
patients who developed AKI were more likely to
mg; range: 70; 100).
have been on ACEIs or ARBs and to have a pre-
Patient with AKI at day-7 seemed to have received
existing high blood pressure. It is interesting in this
less pre and intraoperative crystalloid volume, the
study to notice that platinum-based chemotherapy
only
was
AKI.
intraoperative perfusion. Preoperative perfusion of
Aminoglycosides and NSAIs use, as in our study,
crystalloid seemed different between the two groups
were not significantly associated with AKI but the
but was at the border of significance. This is
data for which our results differ are important BMI,
correlated with the difference in urine output, more
lower baseline GFR which are associated with an
important in the NRF group. Kadji et al., in a
increased risk of AKI (41). These results are in
retrospective study on 54 patients undergoing 57
agreement with ours, the difference could be
CRS + HIPEC with various types of chemotherapy
explained by the low number of sepsis (n=2; 33%)
including cisplatin, did not find any negative effects
and of septic shock (n=1; 1,5%) that we reported and
of crystalloids on renal function but the amount of
which could be added on factors of AKI. Concerning
hydroxyl-ethyl starch (HES) given had a significant
high blood pressure, a recent study on cisplatin and
negative effect on postoperative GFR in patients
mannitol used as nephroprotectant, has shown that
younger than 60 (p <0.001). Intraoperative blood
patients who had a history of hypertension had a
loss and urine output had no significant impact on
higher likelihood of developing nephrotoxicity: (OR
postoperative GFR, in their study (43). There was a
= 3.219 (95% CI = 1.228, 8.439; P = 0.017)) (42).
disparity in our population because of different pre-
The doses of cisplatin more likely to be responsible
and intraoperative management of patients between
for AKI reported are 100 mg/m2 intravenous and
the two centers: either preoperative hyperhydration
>240 mg intraperitoneal (19,42). We did not find any
(4000 to 6000 mL perfused 48 hours before
significant difference between the two groups (NRF
procedure) and intraoperative hyperhydration with
and AKI) for the median cisplatin dose. The highest
furosemide administration to maintain a diuresis
dose use in our study was 100 mg/m2 intraperitoneal,
during HIPEC phase at least of 250mL per 15
but the dose of 240 mg would correspond to 150
minutes or lower hydration with largest noradrenalin
mg/m2 if we consider the median BSA (body surface
use to maintain a correct hemodynamic variables.
area) of 1,6m2 (1.4; 2.1) in our population and no
Noradrenalin use did not appear like a significant
patient received such an important dose. However,
factor of acute kidney injury but hyperhydration
according to RIFLE classification, cisplatin dose
seemed to improve postoperative renal function, as a
not
a
risk
factor
to
develop
difference
appearing
significant
was
10
Predictive factors of acure kidney injury
high level of urine output. Pili-Floury et al. describe
a very large 95% confidence interval for high blood
postoperative alteration of renal function after
pressure, and the non-significance of variables like
reductive surgery associated with cisplatin-based IPC
intra- and preoperative crystalloid volume.
intraperitoneal chemotherapy) and risk factors for
Despite a GFR decrease persistence at 6 months, a
moderate to severe acute renal failure using two
low number of patient needed dialysis. This suggests
strategies according to the absence or presence of
that most of renal function degradations are moderate
epinephrine in the IPC baths. They reported that the
and not responsible for important decrease of quality
absence of epinephrine in the IPC bath, is
of life. Cisplatin based HIPEC seems possible with
significantly associated with the occurrence of acute
low morbidity rates but antitumor activity needs to be
renal injury as a higher duration of severe
proved. In tumor samples surgically removed from
hypotension, a lower blood protein level on arrival in
human donors diagnosed with colorectal or ovarian
ICU (intensive care unit) and a lower volume of
peritoneal carcinomatosis before and after HIPEC
intraoperative diuresis (44). Vasopressive drugs use,
treatment, it was not possible to detect any known
systemic or intraperitoneal, must be studied to clarify
cisplatin-related molecule by MALDI MS (Matrix-
their influence on chemotherapy pharmacokinetic, in
Assisted
terms of anti tumoral effect but also in term of
Spectrometry).
toxicity.
Plasma- Mass Spectrometry) allowed detecting
Preoperative hypoalbuminemia did not appear as a
cisplatin in tumor samples but oxaliplatin response
significant risk factor in this work, this could be due
was twice higher (45).
Laser
Desorption
ICS
MS
Ionization-Mass
(Inductively
Coupled
to a lack of subject in our population to evidence this
variable, because a low plasmatic albumin level has
CONCLUSION
been found to associate with increased risk of
In this study, risk and protective factors for renal
cisplatin nephrotoxicity, like pre-existing renal
function degradation were identified and others as
insufficiency (18), but none of the patients we
potential
included present a preoperative renal function
retrospective data collection raises an issue in terms
degradation.
of missing data. Despite that, it is worth mentioning
After multivariate analysis, the only significant risk
that adjustable variables could affect postoperative
factors for AKI due to cisplatin were pre-existing
renal function, like crystalloid volume perfused.
high blood pressure and intraoperative diuresis.
Larger prospective multicentric studies should be
These results are linked to literature data, but this
performed, and could lead to established standardized
analysis suffers from a lack of data, which explained
protocol of pre and intraoperative management of
risk
factors
were
supposed.
The
11
Predictive factors of acure kidney injury
patient undergoing CRS + HIPEC. Indeed, even if
advanced or recurrent EOC, there is still much to do
this treatment increases the patient’s survival with
concerning its morbidity rate.
12
Predictive factors of acure kidney injury
Tables
Table 1: Patient’s characteristics
Characteristics
Age: median (Range)
Body mass index
Data
57.0 (20.0: 75.0)
<18
[18-25[
[25-30[
>=30
2 (3.0%)
43 (65.2%)
14 (21.2%)
7 (10.6%)
1
2
3
4
23 (35.4%)
39 (60.0%)
2 (3.1%)
1 (1.5%)
1(-)
Score ASA
Type of treatment
First line
29 (43.9%)
Recurrence
37 (56.1%)
Comorbidities and treatment
Diabetes
3 (4.5%)
High blood pressure
11 (16.7%)
IEC/ARA II
4 (6.1%)
Intraoperative parameters
PCI: median (range)
8 (0.0: 33.0)
Visceral resections
0
26 (39.4%)
1-2
32 (48.5%)
>3
8 (12.1%)
Peritonectomy procedures
0
8 (12.1%)
Level 1
22 (33.3%)
Level 2
25 (37.9%)
Level 3
11 (16.7%)
Completeness of cytoreduction
CC0
63 (95.5%)
CC1
3 (4.5%)
Median operating time (min) (range)
320
(147.0: 720.0)
1(-)
Cisplatin (dose in mg/m2)
median (range)
75 (34.0: 100.0)
1(-)
Epidural analgesia
29 (45.3%)
2(-)
13
Predictive factors of acure kidney injury
Table 2: Univariate analysis for risk factors of acute kidney injury (GFR decrease > 25%) at
day-7 postoperative.
Variables
Age
BMI
ASA Score
1-2
3-4
NRF (n=32)
58 (20.0: 75.0)
21.3 (17.8: 38.1)
AKI (n=30)
57 (41.0: 65.0)
22 .6 (18.2: 33.3)
30 (96.8%)
1 (3.2%)
1(-)
29 (96.7%)
1 (3.3%)
0(-)
15 (51.7%)
14 (48.3%)
3(-)
0 (0.0%)
1 (3.1%)
2 (6.3%)
14 (50.0%)
14 (50.0%)
2(-)
4 (13.3%)
2 (6.7%)
8 (26.7%)
45,8 (5.3: 109.1)
4(-)
14.8 (0.0: 38.5)
66.6 (16.3: 147.4)
0.0 (0.0: 3.0)
0.0598
Intraoperative colloids (mL/kg)
Intraoperative crystalloids (mL/kg)
RBCU
Input
67.8 (0.0: 127.7)
1(-)
15.6 (0.0: 216.7)
92.1 (49.0: 186.4)
0.0 (0.0: 3.0)
Albumin (20%; 100mL)
0
1
2
28 (87.5%)
2 (6.3%)
2 (6.3%)
28 (93.3%)
1 (3.3%)
1 (3.3%)
1.0000
Blood loss
Diuresis (ml/kg/h)
Output
787.5 (100.0: 3650.0)
5,8 (1.6: 27.3)
700.0 (100.0: 3300.0)
2.8 (1.2: 9.7)
0.7675
< 0.001
PCI
>8
≤8
0.8964
ACEI/ ARBs
Diabetes
HBP
Preoperative crystalloids (mL/kg)
Peritonectomy procedures
Visceral resections
0
1-2
>3
Cisplatin dose (mg/m2)
Cytoreduction score
CC0
CC1
Median operating time (min)
p-values
0.3005
0.1831
1.0000
Surgical and HIPEC procedures
2.0 (0.0: 6.0)
3.0 (0.0: 6.0)
0.0491
0.6066
0.0400
0.4769
< 0.001
0.8769
0.0681
14 (43.8%)
14 (43.8%)
4 (2.5%)
75.0 (34.0: 100.0)
1(-)
11 (36.7%)
15 (50.0%)
4 (13.3%)
75.0 (34.5: 100.0)
0(-)
0.8826
31 (96.9%)
1 (3.1%)
337.5 (147.0: 690.0)
28 (93.3%)
2 (6.7%)
317.5 (228.0: 720.0)
0.6066
35.0 (32.0: 37.6)
0 (-)
37.9 (35.8: 39.4)
0 (-)
5 (15.6%)
0.1 (0.0: 0.2)
35.8 (34.5: 37.6)
5(-)
37.8 (35.6: 39.3)
1(-)
9 (30.0%)
0.1 (0.0: 0.2)
0.0162
1 (3.1%)
13 (40.6%)
12 (37.5%)
0(-)
2 (6.7%)
8 (26.7%)
16 (55.2%)
1(-)
0.6066
0.2458
0.1666
0.1392
0.1449
Intraoperative data
Body temperature
PreHIPEC
PostHIPEC
Noradrenalin (qualitative)
Dose (µg/kg/min)
Aminoglycosides
NSAI
Epidural analgesia
0.5962
0.1761
0.5708
14
Predictive factors of acure kidney injury
Table 3: Univariate analysis for biologic data according to acute kidney injury (GFR decrease >
25%) at day-7 postoperative.
Biologic data
Albumin (g/L)
GFR (mL/min/1.73m2)
Urea (mmol/L)
C-reactive protein (mg/L)
NRF (n=32)
AKI (n=30)
p-values
Day-0
40.0 (21.0: 46.0)
7(-)
87.6 (58.5: 155.9)
4.5 (1.3: 8.8)
8(-)
1.4 (0.0: 37.0)
18(-)
40.0 (19.4: 49.0)
3(-)
88.0 (57.3: 137.8)
5.7 (3.1: 46.0)
3(-)
3.0 (0.0: 23.0)
17(-)
0.3272
Day-1
27.0 (12.0: 40.0)
24.5 (13.0: 35.0)
1(-)
0(-)
GFR (mL/min/1.73m2)
97.3 (49.2: 174.3)
85.4 (36.2: 177.6)
Urea (mmol/L)
2.5 (0.7: 28.0)
4.0 (1.6: 8.0)
C-reactive protein (mg/L)
94.0(36.0: 231.0)
85.0 (23.0: 194.6)
9(-)
9(-)
ΔHb D-0 /Hb D-1 (g/dL)
1.6 (-3.7: 6.0)
2.1 (-2.5: 6.2)
2(-)
3(-)
ΔHb D-0 /Hb D-1 : difference in haemoglobin rate between Day-0 and Day-1
Albumin (g/L)
0.6370
0.0508
0.7895
0.2698
0.0285
0.0070
0.2262
0.2499
15
Predictive factors of acure kidney injury
Table 4 : Variable distribution according RIFLE classification.
Variables
Age
BMI
NRF (n=32)
58 (20.0: 75.0)
21.3 (17.8:
38.1)
Risk (n=11)
56 (41.0: 65.0)
22.3 (19.5:
29.0)
Injury (n=10)
58.5 (46.0: 64.0)
27.4 (19.7:
33.3)
Failure (n=9)
57 (41.0: 61.0)
21.6 (18.2:
30.5)
ASA Score
2.0(1.0: 4.0)
1(-)
2.0 (1.0: 3.0)
0(-)
2.0 (1.0: 2.0)
0(-)
2.0 (1.0: 2.0)
0(-)
15 (51.7%)
14 (48.3%)
3(-)
5 (55.6%)
4 (44.4%)
2(-)
6 (60.0%)
4 (40.0%)
0(-)
3 (33.3%)
6 (66.7%)
0(-)
0 (0.0%)
1 (3.1%)
2 (6.3%)
1 (9.1%)
1 (9.1%)
3 (27.3%)
1 (10.0%)
1 (10.0%)
3 (30.0%)
2 (22.2%)
0 (0.0%)
2 (22.2%)
Input
67.8
37.9
(0.0: 127.7)
(7.4: 81.6)
1(-)
1(-)
15.6 (0.0: 216.7) 18.2 (0.0: 38.5)
54.4
(5.3: 109.1)
0(-)
9.4 (0.0: 21.7)
16.5
(6.8: 66.7)
3(-)
13.7 (0.0: 36.4)
92.1
(49.0: 186.4)
73.5
(42.0: 147.4)
45.0
(24.0: 130.4)
61.2
(16.3: 88.3)
25 (78.1%)
1 (3.1%)
4 (12.5%)
2 (6.3%)
8 (72.7%)
1 (9.1%)
2 (18.2%)
0 (0.0%)
7 (70.0%)
1 (10.0%)
0 (0.0%)
2 (20.0%)
9 (100.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
28 (87.5%)
2 (6.3%)
2 (6.3%)
11 (100.0%)
0 (0.0%)
0 (0.0%)
8 (80.0%)
1 (10.0%)
1 (10.0%)
9 (100.0%)
0 (0.0%)
0 (0.0%)
702.5
(100.0: 2240.0)
0(-)
3.0
(1.2: 6.7)
0 (-)
617.0
(100.0: 2090.0)
1(-)
1.8
(1.5: 4.7)
1(-)
PCI
>8
≤8
ACEI/AA-2R
Diabetes
HBP
Preoperative crystalloids (mL/kg)
Intraoperative colloids (mL/kg)
Intraoperative crystalloids
(mL/kg)
RBCU
0
1
2
3
Albumin (20%; 100mL)
0
1
2
Blood loss
Diuresis (ml/kg/h)
Output
787.5
950.0
(100.0: 3650.0)
(200.0: 3300.0)
2(-)
1(-)
5.8
2.8
(1.6: 27.3)
(1.7: 9.7)
0(-)
0(-)
Surgical and HIPEC procedures
Peritonectomy procedures
0
Level 1
Level 2
Level 3
Visceral resections
0
1-2
>3
Cisplatin dose (mg/m2)
5 (15.6%)
13 (40.6%)
9 (28.1%)
5 (15.6%)
3 (27.3%)
2 (8.2%)
4 (36.4%)
2 (8.2%)
0 (0.0%)
3 (30.0%)
6 (60.0%)
1 (10.0%)
0 (0.0%)
2 (22.2%)
4 (44.4%)
3 (33.3%)
14 (43.8%)
14 (43.8%)
4 (12.5%)
75.0
(34.0: 100.0)
4 (36.4%)
4 (36.4%)
3 (27.3%)
75.0
(35.2: 100.0)
4 (40.0%)
6 (60.0%)
0 (0.0%)
60.0
(34.5: 100.0)
3 (33.3%)
5 (55.6%)
1 (11.1%)
80.0
(70.0: 100.0)
16
Predictive factors of acure kidney injury
1(-)
0(-)
0(-)
0(-)
35.5
(34.5: 36.9)
2(-)
37.8
(37.4: 38.8)
2(-)
1 (10.0%)
0.1 (0.1: 0.1)
0(-)
0 (0.0%)
4 (40.0%)
35.5
(35.0: 36.3)
3(-)
38.3
(36.3: 39.0)
3(-)
5 (55.6%)
0.1 (0.1: 0.2)
1(-)
1 (11.1%)
2 (22.2%)
Intraoperative data
Body temperature
preHIPEC
PostHIPEC
Noradrenalin (qualitative)
dose (μg/kg/min)
Aminoglycosides
NSAI
35.0
(32.0: 37.6)
0(-)
37.9
(35.8: 39.4)
0(-)
5 (15.6%)
0.1 (0.0: 0.2)
1(-)
1 (3.1%)
13 (40.6%)
36.0
(34.8: 37.6)
0(-)
37.5
(35.6: 39.3)
1(-)
3 (27.3%)
0.0 (0.0: 0.0)
1(-)
1 (9.1%)
2 (18.2%)
17
Predictive factors of acure kidney injury
FIGURES
Figure 1: Overall survival rate of patients at 3 years
Figure 2: Relapse Free Survival rate of patients a 3 years.
18
Predictive factors of acure kidney injury
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21
!
2.3.1.3:!Third!step!!
To! identify! the! recommended! dose! of! cisplatin! for! HIPEC! after! cytoreductive! surgery!
after! neoadjuvant! chemotherapy,! a! multicentric! phase! I! study! dose! escalation! of!
hyperthermic!intraperitoneal!cisplatin!was!conducted.!Four!doses!were!planned:!50,!60,!
70!and!80!mg/m2!according!to!a!dose!escalation!method.!The!endGpoint!of!this!trial!was!
doseGlimiting! toxicity.! Compared! to! the! clearance! measured! before! HIPEC,! creatinine!
clearance!decrease!by!30!ml/mn!or!more!in!50%!of!patients.!!
The!recommended!dose!of!cisplatin!for!HIPEC!established!by!this!study!is!70!mg/m2.!
This!work!is!currently!under!review!in!the!Journal!of!Clinical!Oncology.!
Gouy!S,!Ferron!G,!Glehen!O,!Le!Deley!MC,!Marchal!F,!Pomel!C,!Quenet!F,!Bereder!
JM,!Bayar!A,!Kockler!L,!Morice!P!
Results) of) a) multicenter) phase) I) doseNfinding) trial) of) hyperthermic)
intraperitoneal) cisplatin) after) neoadjuvant) chemotherapy) and) complete)
cytoreductive) surgery) and) followed) by) maintenance) bevacizumab) in)
initially)unresectable)ovarian)cancer!(Under!review)!
!
37!
Results of a multicenter phase I dose-finding trial of hyperthermic
intraperitoneal cisplatin after neoadjuvant chemotherapy and
complete cytoreductive surgery and followed by maintenance
bevacizumab in initially unresectable ovarian cancer
Gouy S1, Ferron G2, Glehen O3, Le Deley MC4, Marchal F5, Pomel C6, Quenet F7,
Bereder JM8, Bayar A4, Kockler L9, Morice P1.
1
Department of Surgery, Gustave Roussy and University Paris Sud,Villejuif, France;
2
Department of Surgery, Institut Claudius Regaud, Toulouse, France;
3
Department of Surgery, Hôpital Lyon Sud, Bénite, France;
4
Department of Statistic, Institut Gustave Roussy and University Paris Sud, Villejuif,
France;
5
Department of Surgery, Centre Alexis Vautrin, Nancy, France;
6
Department of Surgery, Centre Jean Perrin, Clermont -Ferrand, France;
7
Department of Surgery, Centre Val d’Aurelle, Montpellier, France
8
Department of Surgery, Centre Hospitalier l’Archet II, Nice, France
9………………………………………………..
Running head: phase I dose finding trial of hyperthermic intraperitoneal cisplatin
No competing interests declared/ No conflicts of interest to declare
Presented in ESGO (Liverpool, UK, October 2013) and ESMO (Amsterdam,
Netherlands, September 2013)
Address correspondence to:
Sébastien GOUY, M.D, Service de Chirurgie, Institut Gustave Roussy,
114 rue Edouard Vaillant, 94805 Villejuif Cedex, France.
Phone: 33.1.42.11.44.39. Fax: 33.1.42.11.52.13.
Email: [email protected]
1
Abstract
Purpose: Hyperthermic intraperitoneal chemotherapy (HIPEC) can improve the
outcome of patients with initially inoperable ovarian cancer who are offered complete
cytoreductive surgery (CCRS) after responding to neoadjuvant chemotherapy. The
aim of this multicenter phase I study was to identify the recommended dose of
cisplatin for HIPEC at CCRS after neoadjuvant carboplatin and paclitaxel (CP).
Methods: Patients were treated with 6 cycles of CP followed by CCRS and HIPEC
using cisplatin heated for one hour at 42°C+/-1°C. Four cisplatin dose levels were
evaluated, between 50 to 80 mg/m². Dose-limiting toxicities (DLTs) were defined as a
grade ≥IIIb adverse event (Dindo classification). The Continual Reassessment
Method was used for this dose-finding study, with a target percentage of DLT set at
20%. Twenty-two cycles (15 mg/kg/cycle) of maintenance bevacizumab therapy were
planned after surgery.
Results: From 08/11 to 10/12, 30 patients were recruited. No DLT occurred at the
first three dose levels (4, 4 and 5 patients at 50, 60 and 70 mg/m² respectively). At
dose level 4 (80 mg/m², 17 patients), four DLTs occurred: renal failure (n=2),
peritonitis (n=1) and hemorrhage (n=1). Eight weeks after surgery, creatinine
clearance was reduced to <30 ml/min in 3 patients treated at 80 mg/m², and between
30 and 60 ml/min in 6 patients (2, 1, 1 and 2 at the four dose levels respectively).
Twenty patients started maintenance bevacizumab, and 7 received 22 courses.
Conclusions: Based on the DLT observed and prolonged impairment of renal
function, we recommend a dose of 70 mg/m² of cisplatin for HIPEC.
2
Introduction
In most cases, ovarian cancer is discovered at an advanced and initially unresectable
stage. The standard of care in advanced stage ovarian cancer (ASOC) combines
complete cytoreductive surgery (CCRS) and systemic chemotherapy with a platinum
agent. Unfortunately, progression-free survival is usually short, with an estimated
median duration of 17 months in a French multicenter study.1 To improve the
prognosis of ASOC, three therapies were considered promising: intra-peritoneal
chemotherapy,
hyperthermic
intraperitoneal
chemotherapy
(HIPEC)
and
bevacizumab. HIPEC is an attractive therapy against peritoneal carcinomatosis from
ovarian cancer: after CCRS resecting the macroscopic peritoneal implants, HIPEC
treats the remaining microscopic peritoneal implants. However, the exact place and
modalities of HIPEC in ASOC remain to be defined. Intraperitoneal cisplatin
chemotherapy has been shown to be significantly efficient as frontline treatment for
ASOC in three large randomized studies.2-4 Those three studies used intraperitoneal
cisplatin capitalizing on its favorable peritoneal plasma gradient. Cisplatin is currently
the reference agent for the treatment of ovarian cancer, as demonstrated in the metaanalysis reported by Aabo et al.5 Adding hyperthermia to intraperitoneal cisplatin
yielded direct cytotoxic and synergistic effects.6,7 However, the dose of cisplatin
ranged from 25 mg/m2 to 150 mg/m2 in the series which used HIPEC to treat ASOC.
Moreover, these series were retrospective with heterogeneous patient cohorts.8
Bevacizumab administered as maintenance adjuvant therapy significantly increased
the progression-free survival of patients with peritoneal carcinomatosis from ovarian
cancer, as shown by two international randomized phase III trials (GOG0218 and
ICON 7).9,10
3
Considering the therapeutic impact of adding maintenance bevacizumab and the
interest of HIPEC, the CHIPASTIN trial proposed a new therapeutic approach for
ovarian cancer with initially unresectable peritoneal carcinomatosis. This new
strategy combines CCRS with HIPEC, followed by bevacizumab maintenance
therapy over 15 months (22 courses, 15 mg/kg/course). The CHIPASTIN trial
included a dose-finding study for cisplatin administered in HIPEC.
Patients and methods
The study is an investigator-driven trial conducted in seven French comprehensive
cancer centers for initially unresectable ASOC. The trial comprised two parts: a
dose-finding study of cisplatin for HIPEC (phase I), and evaluation of the efficacy of
the entire strategy combining CCRS+HIPEC followed by maintenance bevacizumab.
The protocol was approved by the Ethics Committee and by the Competent Health
Authority, and was registered in the ClinicalTrials.gov registry (NCT02217956).
Written informed consent from the patient was mandatory before surgery. This trial
was sponsored by the Gustave Roussy Institute.
Patient eligibility
Patients aged between 18 and 65 with a confirmed histologic diagnosis of epithelial
ovarian cancer were screened for the study if their disease was deemed
unresectable at diagnosis (stage IIIC according to the International Federation of
Gynecology and Obstetrics).11 After 6 cycles of neoadjuvant chemotherapy, they
were included in the study if macroscopically complete CCRS was considered
feasible, providing all eligibility criteria were fulfilled. The main criteria were: 1)
4
adequate renal function (creatinine <140 μmol/L, clearance >60 mL/min), bone
marrow function (neutrophil count >1,500/μL, platelets 150,000/μL), hepatic function
(bilirubin <1.5xULN, AST/ALT <1.5xULN) and nutritional status (albumin >25 G/l); 2)
No grade >1 neuropathy (CTC-AE v4.0 classification); 3) No contraindication to
bevacizumab administration.
Treatment plan
All patients were treated with 6 cycles of neoadjuvant chemotherapy combining
carboplatin (area under the curve, 5) and paclitaxel (175 mg/m2 every three weeks or
80 mg/m2 weekly). CCRS+HIPEC had to be performed within 10 weeks after the last
injection of carboplatin. Cisplatin was administered as HIPEC, heated for one hour at
42°C+/-1°C. The dose of cisplatin was defined according to the dose escalation
method. Four dose levels were planned: 50, 60, 70, and 80 mg/m2. Maintenance
bevacizumab (15mg/kg every 3 weeks ×22 cycles) was started 10 to 14 weeks after
CCRS+HIPEC, for a total duration of maintenance therapy of 15 months.
Study endpoints
The primary endpoint of the trial was dose-limiting toxicity (DLT) within 30 days
following CCRS+HIPEC. The following adverse events were classified as DLT:
1) Death; 2) Grade IV toxicity according to the Dindo classification; 3) Digestive,
hepato-biliary or a pancreatic fistula requiring resurgery; 4) Severe bleeding (>30%
blood mass) requiring resurgery; 5) an adverse event deemed life-threatening or
resulting in a permanent disability.12
The safety of CCRS+HIPEC was evaluated during hospitalization and at the visit
planned at week 8 after CCRS+HIPEC, and included clinical assessment and
5
biological tests on days 1, 3 and 5, then twice a week during hospitalization, then at
week 8 (+/-2 weeks). The safety of maintenance bevacizumab was evaluated before
each new cycle and 4 weeks after the last administration. Creatinine clearance
computed with the Cockroft formula was monitored over the whole study duration
according to the same schedule.
Toxicity occurring after CCRS+HIPEC was graded using the Dindo classification and
adverse events that occurred later were graded using the CTC-AE v4.0
classification.13
To monitor the disease status, a clinical follow-up was performed at week 8, then
every 3 weeks during maintenance therapy and every 4 months after the end of
treatment until disease progression or death. CA125 and CA19.9 biomarkers were
measured at week 8, at cycle 11, at the end of treatment, and every 4 months
thereafter. A thoraco-abdominal CT scan was performed at the end of treatment and
12 months later, or when progression was suspected. Disease-free survival (DFS),
defined as the time to relapse or death from any cause, and overall survival (OS),
computed from the date of CCRS+HIPEC, were used as efficacy endpoints.
Statistical considerations
The dose-finding study was performed using the Continual Reassessment Method
(CRM), with a one-parameter logistic model in a Bayesian framework.14 After each
new observation, the model was reassessed using all data previously collected. The
dose level recommended for the next patient was the one nearest to the 20% target
percentile. Patients were included at the best ongoing estimate of the recommended
dose (RD). Additional allocation rules were applied to ensure patient safety. The
technical details are available in the appendix.
6
Based on the literature on the CRM and considering the number of levels to be
explored, the targeted number of patients was set at 30, allowing for acceptable
accuracy of the toxicity probability estimate at the dose identified as the
recommended dose.
Descriptive statistics were used to describe the patient population and outcomes.
DFS and OS curves were estimated with the Kaplan-Meier method. An exploratory
prognostic factor study was conducted to identify risk factors for renal impairment,
given the level of creatinine clearance observed at week 8, reflecting the stabilized
value. We first performed a covariance analysis (ANCOVA) of creatinine clearance
over the covariables using the SAS proc glm procedure. We then modeled the risk of
grade II-IV toxicity (clearance<60 mL/mn) using logistic regression. The dose level
was forced into the models. All p values are two-sided and estimates are provided
with their 95% confidence intervals (95%CI). Analyses were performed using SAS
9.3 and R software programs.
Results
From June 2011 to September 2012, 30 of the 39 patients screened for the study
were enrolled in the trial (Figure 1). All eligible patients were included at the date they
were considered eligible for CCRS+HIPEC, regardless of the number of patients still
under evaluation at the time of study entry, because the dose-escalation method
allowed continuous recruitment. All patients included were evaluable for DLT
assessment.
7
Patient baseline characteristics
The median age and body mass index of the 30 patients were respectively 58 years
(range, 26-65) and 22 kg/m2 (range, 16-40). Twenty-six patients (87%) had an
ovarian carcinoma and 4 patients, a primary peritoneal carcinoma. The histologic
subtype was serous in 29 and undetermined in one patient. The tumor was grade 1
in 2 cases (7%), grade 2 in 10 (33%), grade 3 in 12 cases (40%), and undetermined
in 6 cases (20%). All patients received 6 cycles of a weekly regimen of neoadjuvant
carboplatin-paclitaxel chemotherapy (N=19, 63%) or a standard every-three-week
regimen (N=10, 33%). One patient received three cycles of each regimen. The
median time interval between the diagnosis and start of neoadjuvant chemotherapy
was 24 days (range, 7-58). In most cases, patients had preoperative immunonutrition
with oral impact® (3 bags/day) over 7 days (87%), bowel preparation (97%) and
preoperative hydration (87%). The median preoperative plasma albumin level was 41
g/L (range, 27–44). The median interval between the last carboplatin injection and
CCRS+HIPEC was 41 days (range, 24-81).
Surgical procedures
All study patients underwent exploration of the abdominal cavity and a
macroscopically complete resection of their disease. Surgical procedures and HIPEC
are detailed in Table 1. The dose of cisplatin was adhered to in all cases. The median
operative time was 360 min (range, 214-780) and the median hospital stay was 19
days (range, 10-69). Pathological reports of surgical specimens indicated tumor
sterilization in 5 patients (17%), persistence of active cells but with major sterilization
in 15 patients (50%), and a considerable portion of persistently active disease in 10
patients (33%). Fifteen patients (50%) had retroperitoneal lymph node involvement,
8
with capsular rupture in 4 patients. Among the 16 patients (53%) with at least one
bowel resection, 8 had mesocolon and/or mesorectum lymph node involvement,
including one patient with capsular rupture.
Dose escalation and safety of CCRS+HIPEC
As illustrated in Figure 2, the dose was escalated from the first level (50 mg/m2) to
the highest dose level (80 mg/m2), with 4, 4, 5 and 13 patients at the four dose levels
respectively.
Overall, four patients experienced a toxic event considered as a DLT during the 30
days after CCRS+HIPEC (Figure 2). All DLTs were observed at the 80 mg/m2 dose
level. Two patients experienced HIPEC-related renal failure requiring dialysis (gradeIV in the Dindo classification, as well as in the CTC-AE v4.0 classification). In one
case, creatinine clearance was evaluated at 101 mL/mn before CCRS+HIPEC,
19 mL/mn at day 3 after CCRS+HIPEC, 9 mL/mn at day 7, and 13 mL/mn a year
later. In the second case, creatinine clearance was evaluated at 61 mL/mn at the
screening visit, 57 mL/mn just before CCRS+HIPEC, 13 mL/mn at day 6 after
CCRS+HIPEC, 10 mL/mn at day 7. A partial recovery was observed at week 10 with
creatinine clearance at 24 mL/mn, but the patient then relapsed and died of cancer.
The other two DLTs were surgical complications requiring further surgery (Dindo
grade IIIb): one patient sustained small bowel perforation with peritonitis related to
both CCRS and HIPEC. Another patient with two anastomoses (colorectal and
ileocolic) experienced active bleeding of the ileocolic anastomosis, related to CCRS,
and required a transient stoma. In addition to the four DLTs, 23 adverse events
occurred in 14 patients during the first 8 weeks after CCRS+HIPEC (Table 2).
9
Regarding the evaluation of renal function (Table 3), we observed wide variations in
creatinine clearance during the post-HIPEC days, in both directions. Compared to the
clearance measured before HIPEC, creatinine clearance decreased by 30 mL/mn or
more in 15 out of the 30 patients, leading to grade II renal insufficiency in 10 patients
(30≤clearance<60
mL/mn),
grade
III
renal
insufficiency
in
2
patients
(15≤clearance<30 mL/mn) and grade IV renal failure in 2 patients (clearance<15
mL/mn). Levels stabilized at week 8 in most cases. At that point in time, creatinine
clearance was lower than the initial value (30 mL/mn) in 6 patients. Three of them,
experienced grade III renal insufficiency: in addition to the two patients with a DLT
previously described, one patient did not require dialysis and partially recovered, but
had persistent grade II renal insufficiency (clearance=35 mL/mn).
In the model adjusted on the dose level, the creatinine level at week 8 was
significantly correlated with the baseline value (p=0.001) and diuresis before HIPEC
(p=0.001). The trend towards lower clearance with an increasing cisplatin dose
(-5.0/10 mg/m2) was not significant (p=0.20). No significant association was
observed between the creatinine level and body mass index (p=0.62), Sugarbaker’s
peritoneal cancer index (p=0.24), maintenance fluid requirement and blood loss
during surgery (p=0.82 and 0.88, respectively). The results are shown in Figure 3.
In the logistic regression analysis, the risk of grade II-IV renal failure (creatinine
clearance <60 mL/mn, N=9) was exclusively associated with low diuresis before
HIPEC (p=0.026). No significant association was observed with the cisplatin dose
level (p=0.39).
Based on all these observations, the estimated probability of DLT associated with a
cisplatin dose of 80 mg/m2 was 19% (95%CI, 7-38%) which is the closest to the
target probability set at 20%. However, considering both the DLT observations and
10
prolonged impairment of renal function in several patients, we recommend a cisplatin
dose of 70 mg/m2.
Maintenance treatment with bevacizumab
Among the 30 patients who underwent CCRS+HIPEC, 20 patients started
maintenance bevacizumab. The median interval between CCRS+HIPEC and the first
bevacizumab injection was 78 days (range, 52-93). Overall, 10 patients did not start
bevacizumab due to DLT (N=4), pulmonary embolism (N=1), early recurrence (N=2),
the patient’s choice (N=2) and the physician’s decision (N=1).
Among the 20 patients who started maintenance bevacizumab, 7 completed the
treatment (22 cycles) and 13 stopped before completing the 22 cycles. The reasons
for early stopping were progression in 6 cases, adverse events in 6 cases (enterocutaneous fistula requiring hospitalization for medical treatment after 3 cycles, grade
III arthralgia after 4 cycles, eventration complicated by a small bowel fistula after 9
cycles requiring immediate surgery, grade II diarrhea after 11 cycles, subocclusion
after 12 cycles, grade II renal insufficiency after 20 cycles) and the physician’s
decision after 19 cycles in one case. The adverse events documented during
maintenance bevacizumab are detailed in Table 4. The median change in creatinine
clearance during maintenance bevacizumab was -9 mL/mn (range, -38 to + 58).
Survival analysis and recurrence
With a median follow-up of 29.3 months since the diagnosis (range, 23–37) and 23
months after CCRS+HIPEC (range, 17-31), disease progression or a relapse has
occurred in 23 patients, leading to death in 9. Among the 23 patients, 12 had a
recurrence exclusively in the abdominal cavity, 6 had a metastatic recurrence (nodes,
11
n=3; nodes and liver n=1; pleura, n=1; lung, n=1) and 5 patients had a combined
recurrence (peritoneal associated with nodes, n=3; liver, n=1; and lung, n=1). Among
the 21 patients alive at the last follow-up visit, 7 were in first continuous complete
remission more than 26 months since the diagnosis. Median DFS since
CCRS+HIPEC was 16.7 months (95%, 10.6-21.0) and after CCRS+HIPEC, 2-year
DFS and OS were 27% (95% CI, 14–46) and 71% (95%, 51–85), respectively.
12
Discussion
The CHIPASTIN trial comprised 30 homogeneous patients (stage IIIC serous
carcinoma and a macroscopically complete resection of the disease) over a short
period of time (18 months versus the 24 months initially planned), which demonstrate
the interest of this trial. To our knowledge, CHIPASTIN is the first phase I dose
escalation trial of front-line hyperthermic intraperitoneal cisplatin after neoadjuvant
chemotherapy and CCRS in initially unresectable ovarian cancer. CHIPASTIN
provided crucial information. Firstly, considering the prolonged renal function
impairment observed, we recommend a dose of 70 mg/m2. Indeed, compared to the
clearance measured before HIPEC, creatinine clearance decreased by 30 mL/mn or
more in 15 of the 30 patients. Furthermore, three patients experienced grade III renal
insufficiency, 8 weeks after CCRS+HIPEC. Among them, 2 required dialysis and did
not recover normal renal function and the third patient did not require dialysis but
experienced persistent grade II renal insufficiency. In addition, another patient
stopped maintenance bevacizumab after 20 cycles due to grade II renal insufficiency.
This point is crucial because renal insufficiency limits the therapeutic options if a
recurrence occurs and has an impact on patient quality of life. In the largest series of
CCRS+HIPEC published to date, comprising 566 patients with ASOC, 92 for frontline treatment and 474 for treatment of a recurrence, renal insufficiency was reported
in 51 patients (8%) including 15 patients (2%) who developed chronic renal
insufficiency, requiring long-term dialysis in 6 patients. However, in that series,
various drugs were used during HIPEC : cisplatin in 76% of cases, alone or in
combination, with doses ranging from 30 to 100 (median=50 mg/m²).15 Hakeam and
al. recently estimated the incidence of cisplatin nephrotoxicity after CCRS+HIPEC
13
combining cisplatin 50mg/m2 and doxorubicin 15mg/m2. In that retrospective cohort
of 53 patients, comprising 40 with ASOC, two patients with an ovarian cancer
experienced postoperative renal insufficiency (5%). Both of them recovered a normal
glomerular filtration rate at one and three months respectively, but serum creatinine
failed to normalize in one patient.16 Royer et al., showed that an intraperitoneal
concentration above 10 mg/L eradicated 100% of platinum resistant ovarian cells in a
clonogenic assay.17 As 70 mg/m2 is deemed sufficient for maximum efficacy and is
considered acceptable in terms of renal toxicity, we recommend a 70 mg/m2 dose of
cisplatin during HIPEC for one hour at 42°C. In addition, our data suggest that
pronounced diuresis should be maintained before HIPEC to reduce the risk of renal
impairment.
Regarding other toxicities after CCRS+HIPEC, we observed a low incidence of major
morbidities: resurgery in 2 patients (6%, versus 8 % in the series reported by Bakrin
et al.) and radiologic drainage of lymphoceles in 6 (20%, versus 27% in the largest
series in the literature focused on this topic).15,18
Concerning maintenance bevacizumab therapy, the percentage of patients who
completed the 22 cycles of bevacizumab was consistent with that published in both
phase 3 trials, GOG-0218 and INCON 7 (24% received 22 cycles and 42% received
18 cycles, respectively).9,10 An increased risk of fistula related to bevacizumab after
surgery has previously been reported by Burger et al.19 In CHIPASTIN, two patients
developed a fistula during bevacizumab, requiring surgery in one case. Bevacizumab
appears to be feasible after CCRS+HIPEC provided that patients with bowel
resection are carefully screened. In addition, we observed a median reduction in
creatinine clearance of 9 mL/mn during maintenance bevacizumab. An equivalent
reduction in creatinine clearance (9.8 to 11.6 mL/min/1.73 m2) was also observed by
14
Levy et al., in a series of 72 patients with solid tumors who had been included in four
Phase I trials testing antiangiogenics.20
With the CHIPASTIN strategy, median PFS was 16.7 months (95%, 10.6-21.0) after
surgery. Costa-Miranda et al. reported median chemotherapy-free survival attaining
16 months with a similar strategy (six cycles of neoadjuvant chemotherapy followed
by cytoreductive surgery and without adjuvant chemotherapy) but without HIPEC.21
However, the populations differ between the two studies, with more advanced
disease in our trial (no bowel resection in Costa-Miranda’s study). The relatively
similar results with and without HIPEC as well as the cisplatin-related renal toxicity
raise two questions : the interest of adding HIPEC in this setting for all patients and
the choice of cisplatin for HIPEC. In order to achieve progress in this setting, further
prospective trials are warranted to evaluate other drugs intraperitoneally such as
paclitaxel and targeted treatments, and to better define patients who may benefit
from HIPEC.
15
Acknowledgments
We thank the women who participated in the trial and their families.
We would like to thank the study teams, Katty Malkekzadeh for data management
and Dorota Gajda for the statistical analyses.
We thank Lorna Saint Ange for editing.
Funding
CHIPASTIN was supported by Roche
16
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20
Tables
21
Table 1: Characteristics of cytoreductive surgery and HIPEC
Characteristics
PCI (Peritoneal Cancer Index), median (range)
Number of affected regions (/ 13 ), median (range)
N=30
10.5 (1-35)
7 (1-13)
Standard procedures, N (%)
Lymphadenectomy pelvic and para-aortic
30 (100%)
Supracolic omentectomy
30 (100%)
Extensive procedures, N (%)
Splenectomy
12 (40%)
Cholecystectomy
14 (47%)
Diaphragmatic peritoneal surgery
23 (77%)
Bowel resection
16 (53%)
Details of the bowel resection, N (%)
Small bowel resection
5
Hemicolectomy
9
Total colectomy
1
Low anterior resection
11
Number of intestinal anastomoses
1
11
2
5
Transient stoma
Complete macroscopic resection, N (%)
2
30 (100%)
HIPEC procedure, N (%)
Open wall
24 (80%)
Closed wall
6 (20%)
Average intraperitoneal temperature, °C, median (range)
42 (40-43)
Cisplatin dose adhered to
30 (100%)
Epidural anesthesia, N (%)
24 (80%)
Operative time, minutes, median (range)
410 (256–780)
Blood loss, mL, median (range)
950 (200-2720)
Hospital stay, days, median (range)
Intensive care unit stay, days, median (range)
18.5 (10-69)
10 (1-25)
* CC0 according to Sugarbaker’s classification1
22
Table 2: Grade II-IV adverse events (AE) during the 8 weeks after CCRS+HIPEC
according to the Dindo classification
II
Dose level
IIIa
60 mg/m2
70 mg/m2
80 mg/m2
IV
Toxicity
N=14 N=9
50 mg/m2
IIIb
N=2 N=2
2 AE in 2/4 patients
1
1
0
0
Renal insufficiency
1
0
0
0
Lymphocele
0
1
0
0
3 AE in 2/4 patients
1
2
0
0
Urinary infection
1
0
0
0
Lymphocele
0
1
0
0
Necrotizing enterocolitis
0
1
0
0
7 AE in 4/5 patients
4
3
0
0
Renal insufficiency
2
0
0
0
Pulmonary embolism
1
0
0
0
Urinary infection
1
0
0
0
Lymphocele
0
3
0
0
15 AE in 10/17 patients
8
3
2
2
Anemia
1
0
0
0
Klebsiella Pneumonia infection
1
0
0
0
Urinary infection
2
0
0
0
Septicemia
1
0
0
0
Wall collection
0
1
0
0
Lymphocele
0
2
0
0
Small bowel perforation with peritonitis
0
0
1
0
Rectal bleeding
0
0
1
0
Renal insufficiency
3
0
0
2
23
Table 3: Distribution of creatinine clearance at different time points
Time
Creatinine clearance (mL/mn)
Median (Range)
<15
15-30 30-60 60-90
> 90
Baseline
93.5 (55 - 179)
0
0
0
14
16
Minimal value
63.5 ( 8 - 138)
2
2
10
10
6
At week 8
75.5 (17 - 146)
0
3
6
10
11
54 (13 – 96)
1
1
4
3
1
- At start of bevacizumab
87.5 (39 - 166)
0
0
5
7
8
- Latest measure after the
70 (41 - 170)
0
0
6
9
5
No bevacizumab (N=10)
- Latest measure
(median time after
CCRS+HIPEC, 83 days)
Bevacizumab (N=20)
end of bevacizumab
(median time after
CCRS+HIPEC, 460 days)
24
Table 4: Adverse events (AE) reported during bevacizumab treatment
CTC AE
No. cycle when AE occurred / total
Grade
number of cycles administered
III
6 & 7/20
III
11/19
III
14/21
Eventration
I
3/20
Enterocutaneous fistula
III
3/3
Eventration complicated by a
IV
9/9
Diarrhea
II
11/11
Epigastralgia & subocclusion
III
12/12
Arthralgia
III
4/4
Osteomuscular pain
III
9/22
II
20/20
Hypertension (N=3)
Gastrointestinal AE (N=2)
small bowel fistula
Pain (N=2)
Renal AE (N=1)
Renal insufficiency
25
Figures
Figure 1: Participant flow diagram
Figure 2: Dose-limiting toxicities and dose escalation
Figure 3: Observed and predicted creatinine clearance level at week 8, according to
the baseline value and main covariables
The dots represent the observed values. The lines represent the values
predicted by the model including the dose level, creatinine clearance before
HIPEC and hourly diuresis during anesthesia before HIPEC.
The diuresis before HIPEC was dichotomized at the median value, 143 mL/h,
defining high diuresis if >143 mL/h versus low diuresis if <143 mL/mn.
The coefficient of determination of the final model, R², was 0.64.
Details are given in the appendix.
26
Screened for study entry
N=39
Not eligible at the time of surgery
- Incomplete cytoreductive surgery, N=8
- Adenocarcinoma stage IV, N=1
Registered in the study
N=30
CCRS + HIPEC performed
N=30
Evaluable for the dose-finding study
N=30
Did not start Bevacizumab maintenance
- DLT, N=4
- Toxicity other than DLT, N=1
- Progression, N=2
- Patient choice, N=2
- Physician choice, N=1
Bevacizumab maintenance started
N=20
Early stop of Bevacizumab, N=13
- Toxicity, N=6
- Progression, N=6
- Physician choice, N=1
Bevacizumab maintenance completed
as per protocol, N=7
27
Dose Level mg/m
2
80
DLT
70
No
60
#
Dindo Gr.
Description
1
#22
IIIb
Bowel Perforation
2
#27
IV
Renal Failure
3
#37
IV
Renal Failure
4
#38
IIIb
Rectal Bleeding
Yes
50
3
4
5
6
8
9
10 11 12 13 19 20 21 22 23 24 26 27 28 29 30 31 32 33 34 35 36 37 38 39
Patient study number
28
High diuresis
Low diuresis
29
Appendix
Dose-finding method
Based on a preliminary simulation study, we used a one-parameter logistic model
with a fixed intercept equal to 3, and a slope equal to exp(Beta) to be estimated in a
Bayesian framework. The prior distribution of the Beta parameter to be estimated
was a normal distribution with a mean of zero and variance of 1.34. The working
model was set using the getprior function from the dfcrm R package, with a prior
guess of recommended dose equal to 80 mg/m² and the indifference interval
parameter set at 0.07, leading to a vector of initial guesses of the probability of DLT
at the four dose levels of {0.01, 0.03, 0.08, 0.20}.
This model was reassessed after each new observation, using all previous collected
data, in order to predict the probability of experiencing a DLT at each level, and to
define the current recommended dose. The target percentage of DLT was set at
20%.
In order to ensure patient safety, the following restrictions were applied:
1. Skipping doses was not allowed.
2. When the model recommended dose escalation, at least two patients fully
evaluated for toxicity at the current dose level were required before allocating
patients at the next higher dose level.
3. When a new dose level was opened, if a new patient could be included within 15
days after the start of treatment of a patient at a new dose level, she could not be
enrolled at this new dose level but at the previous lower dose level.
30
A target accrual of 30 patients was set. A stopping rule was considered if the lowest
dose was deemed too toxic. The trial would then have been stopped without a dose
recommendation.
Prognostic factor analysis of creatinine clearance
Table 5: Prognostic factor analysis of creatinine clearance at week 8
Final model*
Coefficient
SE
-5.0
3.8
0.20
64Creatinine clearance before HIPEC
+0.50
0.14
0.001
Diuresis before HIPEC > 143 mL/h
-33.3
8.9
0.001
Dose level
p
p to enter
Body Mass Index>22 kg/m²
-
0.62
Sugarbaker’s Peritoneal Cancer Index>10.5
-
0.24
Maintenance fluid requirement > 904 mL/h
-
0.82
Blood loss > 900 mL
-
0.88
*In this covariance analysis, the final model comprised the following three variables:
dose level, creatinine clearance before HIPEC, and diuresis before HIPEC. The
coefficient of determination of the final model, R², was 0.64. The variables in italics in
the lower part of the table correspond to the covariables that were not retained in the
final model. For these latter covariables, the “p to enter” was computed for each
covariable separately, adjusted on the final model. Except for the dose level and
creatinine clearance before HIPEC that were entered as continuous variables in the
covariance analysis, the covariables were dichotomized considering their median
value.
SE: Standard Error
31
!
2.3.2:!Oxaliplatin!based!HIPEC!related!toxicity!
!
Because!of!renal!toxicity!related!to!cisplatin!based!HIPEC,!it!was!logical!to!use!an!other!
platinum! compound! for! HIPEC! treatment! for! ovarian! cancer.! Oxaliplatin,! a! thirdG
generation! platinum! compound,! represents! a! logical! choice! for! IP! therapy! of! PC! of!
gastrointestinal! or! ovarian! origin.! As! previously! described,! the! pharmacodynamic!
aspects! of! oxaliplatin! administration! have! been! adequately! studied.! Oxaliplatin! is! the!
cornerstone! of! HIPEC! for! colorectal! cancer,! and! has! also! shown! promising! activity! in!
recurrent! and! platinumGresistant! ovarian! cancer,! mesothelioma! and! gastric! cancer.!
However,! specific! toxicity! of! highGdose! heated! IP! oxaliplatin! following! cytoreduction!
have!been!few!reported.!
!
2.3.2.1:!First!step!!
To! evaluate! the! morbidity! of! oxaliplatin! based! HIPEC! in! ovarian! cancer,! a! phase! II!
prospective!study!was!conducted.!Oxaliplatin!based!HIPEC!was!used!as!a!consolidation!
treatment!for!initially!unresecable!ovarian!cancer,!after!6!courses!of!IV!chemotherapy.!!
Grade!III!complications!occurred!in!29%!of!patients!with!a!high!rate!of!intraperitoneal!
bleeding.!As!a!result!of!this!high!morbidity!rate,!the!trial!was!prematurely!closed.!
This!work!was!published!in!the!European!journal!of!Surgical!Oncology!
Pomel!C,!Ferron!G,!Lorimier!G,!Rey!A,!Lhomme!C,!Classe!JM,!Bereder!JM,!Quenet!F,!
Meeus!P,!Marchal!F,!Morice!P,!Elias!D.!!
Hyperthermic) intraNperitoneal) chemotherapy) using) Oxaliplatin) as)
consolidation)therapy)for)advanced)epithelial)ovarian)carcinoma.)Results)of)
a)phase)II)prospective)multicentre)trial.)CHIPOVAC)study.)
Eur!J!Surg!Oncol.!2010;36(6):589G93!
!
38!
Available online at www.sciencedirect.com
EJSO 36 (2010) 589e593
www.ejso.com
Hyperthermic intra-peritoneal chemotherapy using Oxaliplatin as consolidation
therapy for advanced epithelial ovarian carcinoma. Results of a phase II prospective
multicentre trial. CHIPOVAC study*,**
C. Pomel a,*, G. Ferron b, G. Lorimier c, A. Rey d, C. Lhomme d, J.M. Classe e, J.M. Bereder f,
F. Quenet g, P. Meeus h, F. Marchal i, P. Morice d, D. Elias d
a
Centre Jean Perrin, 58 rue Montalembert, 63000 Clermont-Ferrand, France
b
Centre Claudius Regaud, Toulouse, France
c
Centre Paul Papin, Angers, France
d
Institut Gustave Roussy, Villejuif, France
e
Centre Ren!e Gauducheau, Nantes, France
f
Centre Antoine- Lacassagne et Centre Hospitalo-universitaire, Nice, France
g
Centre Val d’Aurelle, Montpellier, France
h
Centre Leon Berard, Lyon, France
i
Centre Alexis Vautrin, Nancy, France
Accepted 12 April 2010
Available online 13 May 2010
Abstract
Introduction: The aim of the present study was to prospectively evaluate morbidity of intra-peritoneal hyperthermic chemotherapy (HIPEC)
using Oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma and, secondly, to study peritoneal recurrence.
Methods: Between 2004 and 2007, 31 patients from 18 to 65 years with FIGO stage IIIC epithelial ovarian carcinoma were treated by surgery and a total of 6 cycles of platinum based chemotherapy. Those patients were eligible for consolidation therapy. We performed a second
look laparotomy operation with intra-peritoneal hyperthermic chemotherapy. We used Oxaliplatin 460 mg/m2 with 2 l/m2 of dextrose in an
open medial laparotomy for a total of 30 min at a temperature of 42e44 ! C.
Results: The grade 3 morbidity rate was 29% (95 CI: 14e45%). Nine patients experienced a total of 13 exploratory laparotomies for intraabdominal bleeding after HIPEC. Two-year disease free and overall survival were 27% and 67% respectively. As a result of this high level
of morbidity the trial was closed.
Conclusion: Using intra-peritoneal Oxaliplatin associated with hyperthermia as consolidation therapy for advanced ovarian cancer results in
a high risk of grade 3 morbidities with only a small benefit on survival.
! 2010 Elsevier Ltd. All rights reserved.
Keywords: HIPEC; Ovarian epithelial carcinomatosis
Introduction
Epithelial ovarian cancer (EOC) is usually discovered at
an advanced stage resulting in an overall poor prognosis for
this condition. Modern first line treatment with debulking
*
This trial was supported by the Gustave Roussy Institute, Villejuif,
France.
**
Presented at the 16th International Meeting of the European Society
for Gynaecological Oncology (ESGO 16) Belgrade, Serbia, October
11e14, 2009.
* Corresponding author. Tel.: þ33 473278080.
E-mail address: [email protected] (C. Pomel).
0748-7983/$ - see front matter ! 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejso.2010.04.005
surgery which is as complete as possible and an intravenous
combination of Paclitaxel and Platinum chemotherapy can
result in remission in a majority of cases. Unfortunately,
50% of optimally debulked patients will recurre after a negative second look following 6 cycles of platinum based chemotherapy.1 Thus, overall survival will depend upon on 2
conditions: first, chemosensitivity and secondly, quality of
cytoreductive surgery. Systemic treatment alone never
results in cure, and so optimising surgery continues to be
the best way to improve survival.2 Intra-peritoneal chemotherapy (IPC) after optimal debulking surgery has been
demonstrated as being beneficial in terms of overall and
590
C. Pomel et al. / EJSO 36 (2010) 589e593
disease free survival with acceptable quality of life.3e5 At
this time a search for an effective consolidation treatment
is required in order to control residual microscopic disease.
So far none of the intravenous consolidation treatments
have showed any survival benefits.6 The use of IPC as consolidation therapy is suggestive of a treatment benefit but
does not support a change in clinical practice.7 On the other
hand, IPC seems a very interesting and logical approach for
a disease involving the peritoneal cavity. A consensus has
emerged to support the potential benefit of hyperthermia
associated with intra-peritoneal chemotherapy (HIPEC)
for the treatment of peritoneal carcinomatosis from colorectal origin.8 Recent studies suggest some interest for the use
of HIPEC in EOC patient.9 Standard HIPEC is used at the
time of debulking surgery. We have designed a study aimed
to evaluate the HIPEC related morbidity as consolidation
therapy for EOC patients.
a complete immersion of the entire peritoneal cavity with
HIPEC. The peritoneal extent was scored with the Peritoneal
Cancer Index (PCI). At this stage a secondary cytoreductive
surgery including peritonectomies according to Sugarbaker’s techniques was accepted.11 If no disease remained
or disease not exceeding one mm in the greatest diameter
(volume) then an intra-peritoneal hyperthermic chemotherapy was achieved. Four intra-peritoneal temperature detectors were placed in the abdominal cavity, one in the right
hypochondrium, one in the left hypochondrium, one in the
pelvis and one in contact with the small bowel. We were
using Oxaliplatin 460 mg/m2 with 2 l/m2 of dextrose in
a open medial laparotomy for a total of 30 min with
a 42e44 ! C of temperature. Anticoagulants such as fractionated heparin were used as thrombotic prophylaxis.
Methods
Patients underwent surgery in eight different institutions.
After 13 inclusions, 6 patients developed intra-abdominal
bleeding. Therefore the dose of Oxaliplatin was reduced
from 460 mg/M2 to 350 mg/M2. Analysis after 28 inclusions
demonstrated that 13 emergency procedures were performed
on 9 patients. The clinical trial was then closed. At the same
time 3 more patients were registered before we closed the
trial. Therefore our results involved 31 patients. Patient characteristics are summarized on Table 1. Nine patients had
optimal debulking at first look laparotomy. Twenty two
patients had suboptimal debulking (more than 1 cm residual
tumour) at first look laparotomy. Thirty patients had 6 cycles
of platinum and paclitaxel chemotherapy prior to the HIPEC
and one patient had 8 cycles. PCI analysis observed at the beginning of the HIPEC laparotomy are reported on Table 2.
Twenty two patients had persistent disease at the time of
the procedure. Nine patients had negative cytology with no
residual disease. Limited cyto reduction without bowel
resections performed at the time of the HIPEC could be completed for 16 patients. Six patients had less than 1 mm residual tumour. Median operative time before the HIPEC started
was 210 mn (70-700 mn). Six patients received a blood transfusion at the time of the surgery.
Between September 2004 and January 2007, we conducted a prospective non randomized multicentre phase 2
trial using hyperthermia and intra-peritoneal chemotherapy
as consolidation therapy for advanced EOC. The trial was
accepted by the local ethics committee. Informed consent
was obtained from all patients. Oxaliplatin was used as
a single agent. The main goal of the study was to examine
the morbidity of this process, the secondary goal was to examine the overall survival and recurrence free survival. The
design of the study was to enrol 67 patients for 2 years of
inclusion and 5 years of follow-up. Statistical analysis was
a Simon multistep “optimum design”. The expected 20%
grade 3 morbidity was considered to be acceptable. 40%
was considered unacceptable. Morbidity was defined by
Dindo classification.10 The study was planned in two steps
with a minimum of 67 patients. Twenty eight at the first
step and 39 at the second step. If the morbidity exceeded
ten patients after inclusion and evaluation of the first 28
patients, then the study would be stopped. To be eligible
for the study patients had Stage IIIC peritoneal carcinomatosis from ovarian, tubal or primary serous peritoneal adenocarcinoma including the following criteria:
-Patients aged from 18 to 65 years
-Patients that could not be optimally debulked at first look
laparotomy and/or patients with positive second look after 6 cycles of cisplatin/carboplatin based chemotherapy.
Exclusion criteria was limited to patients of ASA 3.
All the patients presented normal preoperative coagulation state, normal preoperative platelets counts and no
patients was taking antiaggregant therapy before the surgery. A laparotomy was performed after 6 cycles of platinum based chemotherapy. This procedure required a full
abdominal adhesiolysis including small bowel, large bowel,
posterior aspect of the liver and finally lesser sac to allow
Results
Postoperative course
The grade 3 morbidity rate was 29% (95 CI: 14e45%).
Thirteen emergency laparotomies were performed on 9
Table 1
Patients characteristics.
Epithelial ovarian cancer
Primary peritoneal cancer
Median age
Median weight (kilos)
ASA score
28
3
57 (36e64)
60 (49e95)
0:
1:
2:
7
10
14
591
C. Pomel et al. / EJSO 36 (2010) 589e593
Table 2
Peritoneal cancer index analysis observed at the beginning of the
laparotomy.
Index
Nb pts
0
1e5
6e10
11e20
>20
9
10
7
4
1
100%
93%
79%
80%
67%
60%
Overall Survival
61%
40%
41%
20%
27%
Recurrence Free Survival
0%
patients for active intra-abdominal bleeding (IAB). Surgical
characteristics of all patients with IAB are summarized on
Table 3. These surgeries were performed between postoperative day 3 and day 12 (with a median of 8 day). Six
patients had one exploratory laparotomy. Two patients
had two exploratory laparotomies. One patient had three
exploratory laparotomies. Among those 9 patients with
IAB, median platelet levels were 88,500 (54,000 to
191,000) This was not statistically different from the rest
of the group study (42,000e245,000). No active bleeding
was observed at the time of the exploratory laparotomies
and one patient developed disseminated intravascular coagulapathy. One patient developed a coma with neurologic
disorders and needed a tracheostomy. Five patients developped pulmonary infections. Median post op stay was 18
days range from 9 to 46 days. There was no difference of
morbidity between 460 mg/M2 (13 patients) and
350 mg/m2 (18 patients) dose of Oxaliplatin. All patients
recovered completely. Overall and recurrence free survival
are summarized on Fig. 1. To date 24 patients have developed a recurrence.
Discussion
This trial assessing cytoreductive surgery plus HIPEC
with Oxaliplatin was prematurely closed as there had
0
6
12
Patients at risk
31
26
31
31
27
18
18
21
12
24
18
8
30
Months
8
2
Figure 1. Overall and recurrence free survival.
been an unacceptably high rate of re-surgery for peritoneal
haemorrhage. To test this combined treatment for EOC was
logical when considering that HIPEC using Oxaliplatin and
surgical resection cured approximately 25% of patients
with peritoneal carcinomatosis from colorectal origin.
This strategy was mainly applicable to patients with limited
intra-peritoneal cancer volume and no extraperitoneal involvement.12 Platinum remains the most active drug class
in ovarian cancer treatment. However, Oxaliplatin,
a third-generation platinum derivative, has shown effective
antitumour activity and a favorable toxicity profile in epithelial ovarian cancer.13 Consolidation/maintenance therapy in the standard management of EOC remains
controversial, primarily due to the unknown impact of
this strategy on overall survival. The use of HIPEC after
6 cycles of chemotherapy may represent an interesting approach as the peritoneal cavity has been previously treated
both surgically and medically. Therefore this could minimize the amount of intra-peritoneal disease. This is extremely important as it has been demonstrated that the
effect of HIPEC reaches the centre of tumour deposits
Table 3
Characteristics of all 9 patients with intra-abdominal bleeding.
Patients
Bigest deposit
(cm)
PCI
Surgical procedure
Residual deposit
Experience of the
Centre in HIPEC
(years)
1
5
30
0
10
2
3
4
5
6
7
1
0
0
0
0
2
2
0
0
0
0
19
0
0
0
0
0
0
4
15
15
15
10
4
8
9
0
1
0
4
Peritonectomies, Diaphragmatic
stripping, cholecystectomy,
appendicectomy, infragastric
omentecomy, pelvic and PA
lymphadenectomy
Infragastric omentectomy
Adhesiolysis
Adhesiolysis
Adhesiolysis
Adhesiolysis
Peritonectomies, diaphragmatic
stripping, appendicectomy,
completion of omentectomy,
pelvic lymphadenectomy
Adhesiolysis
Infragastric omentectomy
0
0
4
8
592
C. Pomel et al. / EJSO 36 (2010) 589e593
less than 3 mm.14 Extensive surgery associated with HIPEC
usually impacts on morbidity. Therefore, our results reflect
the side effects of HIPEC alone. 5 of the 8 centres involved
in this study using HIPEC had more than 10 years of experience in this field. Unfortunately, in our series, surgical
morbidity was a major issue. 9 patients developed postoperative intra-abdominal bleeding (IAB) which was not incidentally associated with a less than 50,000/ml platelets
level. Other studies using Oxaliplatin for HIPEC in colon
cancer patient regimen did not show such a dramatic risk
of IAB. In the Gustave Roussy Institute, 90 patients were
treated for peritoneal pseudomyxoma with intra-peritoneal
Oxaliplatin alone (460 mg/m2 in 2 l/m2 of iso-osmotic 5
per cent dextrose; 27 patients) or intra-peritoneal Oxaliplatin (360 mg/m2) plus intra-peritoneal irinotecan
(360 mg/m2) (63 patients), at a homogeneous intra-peritoneal temperature of 43 ! C for 30 min. These 90 patients received an intravenous perfusion of 5-fluorouracil (5-FU)
(400 mg/m2) with leucovorin (20 mg/m2) before starting
HIPEC. Less than 5% of the patients developed postoperative bleeding.15 Nevertheless, in a recent publication, Marcotte et al. observed an 18% risk of haemorrhage in
a consecutive series of 38 patients treated by HIPEC with
Oxaliplatin at the same dose.16 Furthermore, Ceelin et al.
observed the case of one patient who developed unexplained repeated episodes of hemoperitoneum.17 This phenomenum occured in three patients in our current series.
Recently, Fagotty et al. used the same dose of Oxaliplatinum. After complete CRS they were submitted to intraperitoneal perfusion of Oxaplatinum (460 mg/m2) heated
to 41.5 ! C for 30 min. The population of recurrent ovarian
cancer patients with a platinum-free interval of at least 6
months were prospectively enrolled. Interestingly they observed 7 postoperative haemorrhage.18 Should we consider
that 6 cycles of paclitaxel-platinum based chemotherapy
prior to HIPEC may affect platelets toxicity? Does ovarian
peritoneal carcinomatosis alter the coagulation system? We
were unable to clearly answer to these questions. Unfortunately, the choice of Oxaliplatin with HIPEC does not appear to be a good option for EOC patients. Gori et al.
investigated the effect of intra-peritoneal hyperthermic perfusion chemotherapy as consolidation therapy in stage
IIIBeIIIC epithelial ovarian cancer, following cytoreductive surgery and systemic chemotherapy (cisplatinecyclophosphamide e six cycles). In a multicentre
prospective trial, 29 patients with complete or optimal cytoreductive surgery and systemic treatment were included
in the consolidation group and received HIPEC using cisplatin 100 mg/m2, for 60 min. The consolidation therapy
group showed a better 5-year survival rate and lower recurrent disease rate, but differences were not statistically significant.19 Furthermore, Kim JH et al. reported the study
of 19 patients with stage IceIIIc EOC who received consolidation intra-operative HIPEC using 6 L of lactated
Ringer’s solution containing paclitaxel 175 mg/m,2 for
90 min in hyperthermic phase. The survival rates were
compared with 24 patients treated with conventional therapy. The 8-year overall survival rates were 84.21% in the
HIPEC-paclitaxel group and 25.00% in the control group
with a significant P value.20
Our inclusion criteria included patients with poor prognostic factors: suboptimal (incomplete) debulking at first
time laparotomy or positive second look. This could explain
that overall and disease free survival rates are disappointing
in this trial. Unfortunately HIPEC did not decrease the risk
of peritoneal recurrence as 80% of our patients developed
intra-abdominal recurrence. As claimed in the recent paper
of Helm et al. we still believe that HIPEC may be a future
option in the management of advanced epithelial ovarian
cancer. The choice of appropriate drugs will be the key point.
In conclusion, this phase II trial showed a dramatic rate
of morbidity that fortunately did not affect perioperative
mortality. We were unable to demonstrate any survival benefit following this therapy. Physicians should be aware of
the possibility of acute intra-abdominal hematological
emergencies following intra-peritoneal Oxaliplatin administration associated with hyperthermia in epithelial ovarian
cancer patients. Therefore we would not recommend the
use of Oxaliplatin in this indication.
Conflict of interest
The authors declare that there are no conflicts of interest.
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intravenous cyclophosphamide versus intravenous cisplatin plus inrtavenous cyclophosphamide for stage III ovarian cancer. N Engl J Med
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7. Piccart MJ, Floquet A, Scarfone G, et al. Intraperitoneal cisplatin versus no further treatment: 8-year results of EORTC 55875, a randomized phase III study in ovarian cancer patients with a pathologically
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15. Elias D, Honor!e C, Ciuchend!ea R, et al. Peritoneal pseudomyxoma: results
of a systematic policy of complete cytoreductive surgery and hyperthermic
intraperitoneal chemotherapy. Br J Surg 2008 Sep;95(9):1164–71.
16. Marcotte E, Sideris L, Drolet P, et al. Hyperthermic intraperitoneal
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from appendix: preliminary results of a survival analysis. Ann Surg
Oncol 2008 Oct;15(10):2701–8. [Epub 2008 Jul 25].
17. Ceelen WP, Peeters M, Houtmeyers P, Breusegem C, De Somer F,
Pattyn P. Safety and efficacy of hyperthermic intraperitoneal chemoperfusion with high-dose oxaliplatin in patients with peritoneal carcinomatosis. Ann Surg Oncol 2008 Feb;15(2):535–41.
18. Fagotti A, Paris I, Grimolizzi F, et al. Secondary cytoreduction plus
oxaliplatin-based HIPEC in platinum-sensitive recurrent ovarian cancer patients: a pilot study. Gynecol Oncol 2009 Jun;113(3):335–40.
19. Gori J, Castaño R, Toziano M, et al. Intraperitoneal hyperthermic chemotherapy in ovarian cancer. Int J Gynecol Cancer 2005 MareApr;15
(2):233–9.
20. Kim JH, Lee JM, Ryu KS, et al. Consolidation hyperthermic intraperitoneal chemotherapy using paclitaxel in patients with epithelial ovarian cancer. J Surg Oncol 2010 Feb 1;101(2):149–55.
!
2.3.2.2:!Second!step!
To! evaluate! the! relationship! between! oxaliplatin! exposure! and! observed! toxicity,! a!
population! pharmacokinetics! of! peritoneal,! plasma! ultrafiltrated! and! proteinGbound!
oxaliplatin! was! conducted! in! 75! patients! treated! at! the! Institut! Claudius! Regaud! with!
CRS!and!oxaliplatin!based!HIPEC.!
1866! PK! data! were! simultaneously! analyzed! in! a! five! compartmental! model! and!
compared!to!the!most!frequently!observed!toxicities!in!treated!patients.!
An! important! variability! in! peritoneal! and! systemic! oxaliplatin! exposure! has! been!
observed.! No! statistically! significant! associations! were! found! between! oxaliplatin!
related! toxicity! and! previous! treatment! with! oxaliplatin! or! importance! of! surgery!
(number!of!peritonectomy!procedures,!duration!of!surgery).!
!Thrombocytopenia! was! observed! in! 14%! of! patients! and! seems! to! be! related! to! PK!
variability! observed! both! in! the! peritoneum! and! systemic! compartment,! which! is!
correlated!to!perioperative!abdominal!bleeding.!
This!work!was!published!in!Cancer!Chemotherapy!and!Pharmacology.!
Chalret! du! Rieu! Q,! WhiteGKoning! M,! Picaud! L,! Lochon! I,! Marsili! S,! Gladieff! L,!
Chatelut!E,!Ferron!G.!
Population) pharmacokinetics) of) peritoneal,) plasma) ultrafiltrated) and)
proteinNbound) oxaliplatin) concentrations) in) patients) with) disseminated)
peritoneal) cancer) after) intraperitoneal) hyperthermic) chemoperfusion) of)
oxaliplatin) following) cytoreductive) surgery:) correlation) between)
oxaliplatin)exposure)and)thrombocytopenia.)
Cancer!Chemother!Pharmacol.!2014;74(3):571G82.!
!
39!
Cancer Chemother Pharmacol (2014) 74:571–582
DOI 10.1007/s00280-014-2525-6
ORIGINAL ARTICLE
Population pharmacokinetics of peritoneal, plasma ultrafiltrated
and protein-bound oxaliplatin concentrations in patients
with disseminated peritoneal cancer after intraperitoneal hyperthermic
chemoperfusion of oxaliplatin following cytoreductive surgery:
correlation between oxaliplatin exposure and thrombocytopenia
Quentin Chalret du Rieu · Mélanie White-Koning · Laetitia Picaud · Isabelle Lochon ·
Sabrina Marsili · Laurence Gladieff · Etienne Chatelut · Gwenaël Ferron
Received: 9 April 2014 / Accepted: 6 July 2014 / Published online: 23 July 2014
© Springer-Verlag Berlin Heidelberg 2014
Abstract
Purpose First, to evaluate the peritoneal (IP), plasma
ultrafiltrated (UF) and protein-bound (B) pharmacokinetics (PK) of oxaliplatin after intraperitoneal hyperthermic
chemoperfusion (HIPEC) following cytoreductive surgery.
Second, to evaluate the relationship between oxaliplatin
exposure and observed toxicity.
Methods IP, UF, and B concentrations from 75 patients
treated by 30-min oxaliplatin-based HIPEC procedures
were analysed according to a pharmacokinetic modelling
approach using NONMEM. Oxaliplatin was administered
in a 5 % dextrose solution (2 L/m2) at 360 (n = 58) or
460 mg/m2 (n = 17). The most frequently observed toxicities were related to the peritoneal, systemic exposures and
to the parameters corresponding to the oxaliplatin absorption from peritoneal cavity into plasma.
Results IP (n = 536), UF (n = 669) and B (n = 661) concentrations were simultaneously described according to a
Q. Chalret du Rieu · M. White-Koning · I. Lochon · S. Marsili ·
E. Chatelut · G. Ferron
EA4553, Univ. Toulouse III Paul Sabatier, 31000 Toulouse,
France
Q. Chalret du Rieu · M. White-Koning · I. Lochon · S. Marsili ·
E. Chatelut (*) · G. Ferron
Institut Claudius Regaud, IUCT-O, Laboratoire de
Pharmacologie, 1 avenue Irène Joliot-Curie, 31059 Toulouse,
France
e-mail: [email protected]
L. Picaud · G. Ferron
Institut Claudius Regaud, IUCT-O, Département de Chirurgie
Oncologique, 31059 Toulouse, France
L. Gladieff
Institut Claudius Regaud, IUCT-O, Département d’Oncologie
Médicale, 31059 Toulouse, France
five-compartment PK model with irreversible nonlinear
binding from UF to B according to a Michaelis–Menten
equation. The mean (±SD) maximum fraction of dose
absorbed and elimination half-life from the peritoneum was
53.7 % (±8.5) and 0.49 h (±0.1), respectively. The mean
(±SD) ratio AUCIP/AUCUF was 5.3 (±2) confirming the
pharmacokinetic advantage of the procedure. Haemoperitoneum (22.7 %), neuropathy (18.7 %), grade 3/4 thrombocytopenia (13.3 %) were the most frequently reported
toxicities. AUCUF accounts for approximately 12 % of the
variation in the maximum percentage of platelet decrease
(r = 0.35, p = 0.002). Thrombocytopenia was correlated
with higher AUCUF, partly dependent on the extent and rate
of oxaliplatin absorption.
Conclusions Despite a common dose administered, variability in peritoneal and systemic oxaliplatin exposures are
observed, leading to differences in haematological toxicity
between patients.
Keywords Oxaliplatin · HIPEC · Population
pharmacokinetic · Thrombocytopenia · NONMEM
Introduction
Peritoneal carcinomatosis is caused by widespread metastases in the peritoneal cavity. Until recently, the treatment
of this terminal condition was limited to standard palliative
surgery and chemotherapy with mediocre results in terms
of survival. However, a recent meta-analysis has shown that
the use of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) significantly increases survival in patients with colorectal cancer
[1]. Experimental studies have shown that drug penetration
is limited to a few cell layers beneath the tumour surface
13
572
[2] and consequently HIPEC must be administered immediately after the CRS in order to achieve maximal cytotoxic
activity on residual tumour cells before they are trapped in
the post-operative fibrin adhesions [3]. This combination is
the standard treatment for both pseudomyxoma peritonei
and peritoneal mesothelioma [4]. There are ongoing clinical trials in colorectal cancer [5] and advanced ovarian cancer [6, 7] as well as several phase I/II trials in gastric cancer
[8].
Although other drugs such as cisplatin [9], carboplatin
[10], paclitaxel [11], mitomycin C [12] or doxorubicin [13]
have been used, the antineoplastic platinum-compound
oxaliplatin is currently frequently employed because its
cytotoxic activity is substantially improved by hyperthermia [14] and its intratumoural penetration is optimal [15].
However, these therapeutic advantages have to be put into
balance with the associated risk of peripheral sensory neuropathy and haematological toxicity which are the doselimiting toxicities of oxaliplatin administered intravenously
[16]. Votanopoulos et al. [12] reported a 14.5 % incidence
of grade 3–4 neutrophil toxicity and a 10.9 % incidence
of grade 3–4 platelet toxicity among patients treated with
oxaliplatin-based HIPEC. On the other hand, Elias et al.
[17] found a grade 3–4 haematological toxicity rate of 58,
41 % of grade 4 neutropenia and 26 % of grade 3 thrombocytopenia, in 39 patients with peritoneal carcinomatosis of
either gastro-intestinal or peritoneal origin who underwent
CRS followed by HIPEC with oxaliplatin and irinotecan.
Several authors have examined the pharmacokinetics (PK) of oxaliplatin during HIPEC [18–21] and found
that oxaliplatin was linearly absorbed from peritoneum to
plasma and linearly eliminated from a central compartment.
On the other hand, Elias et al. [15] showed that intratumoural oxaliplatin penetration was high, similar to absorption at the peritoneal surface and 18 times higher than
that in non-bathed tissues. In a previous study, we showed
that inter-individual variability was larger for plasma PK
parameters than for peritoneal parameters [18].
Two recent studies [20, 22] used semi-mechanistic population pharmacokinetic and pharmacodynamic (PK/PD)
Friberg-type models to characterize the oxaliplatin PK
in peritoneum and plasma (only total equal to ultrafiltrable plus protein-bound concentrations were determined)
in relation to absolute neutrophil counts over time on,
respectively, 30 and 66 patients treated with CRS and
oxaliplatin-based HIPEC. Valenzuela et al. [20] found that
a peritoneum oxaliplatin exposure was associated with the
incidence of severe neutropenia, which suggested that the
use of primary prophylaxis with G-CSF to counterbalance
the neutropenia should be considered when peritoneal concentrations of oxaliplatin administered in dextrose 5 %
during 30–60 min are expected to be higher than 900 and
660 mg/L [22].
13
Cancer Chemother Pharmacol (2014) 74:571–582
In the present study, we simultaneously evaluated the
pharmacokinetics of peritoneal (IP), plasma ultrafiltrated
(UF) and protein-bound (B) oxaliplatin concentrations
in 75 patients treated by HIPEC following CRS. We also
related the most frequently observed toxicities to the peritoneal and systemic oxaliplatin exposures and to the parameters reflecting absorption into plasma.
Patients and methods
Patients and oxaliplatin administration
Seventy-five patients were treated by 30-min oxaliplatin-based HIPEC procedures conducted as previously
described by Elias et al. [23] with the “coliseum” technique (open abdomen, closed circuit). Primary tumour type
was colorectal carcinomatosis (n = 25), advanced ovarian
cancer (n = 18), peritoneal mesothelioma (n = 9), pseudomyxoma peritonei (n = 20), and other (CUP, cervical
cancer, n = 3). Oxaliplatin was administered in a 5 % dextrose solution (2 L/m2) at a dose of 460 mg/m2 (n = 17)
or 360 mg/m2 (n = 58): the initial dose of 460 mg/m2 was
reduced to 360 mg/m2 due to toxicity. The first twelve
patients were treated according to the first HIPEC procedures (group 1) and the following (n = 63) to the second
procedure (group 2) [18]. For the first procedure, the solution was instilled within the peritoneal cavity contained
oxaliplatin and a delay of 8–10 min was necessary to reach
a temperature of 42–43 °C. For the second procedure, the
cavity was initially filled only with the dextrose solution
and oxaliplatin was added to the peritoneal instillate when
the temperature reached 42–43 °C. We previously showed
from the data of the 24 first included patients that the procedure did not impact on oxaliplatin pharmacokinetics
[18]. The extracorporeal circulation of the fluid was realized using the Performer LRT® system (Rand, Medolla,
MO, Italy). Perfusion duration was exactly 30 min from the
time when optimum temperature (42–43 °C) was reached.
The study was approved by the institutional review board
from our institution and performed in accordance with the
ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All patients provided written informed consent before study enrolment. Their main
characteristics are shown in Table 1.
Pharmacokinetic data
Seven peritoneal fluid samples were collected (every 5 min
during the 30-min HIPEC) per patient. One additional
peritoneal sample was obtained just before the warm-up
period for the first 12 patients who had undergone a different warm-up procedure [18]. Oxaliplatin was added to the
Cancer Chemother Pharmacol (2014) 74:571–582
573
Table 1 Characteristics of the 75 patients studied
Pharmacodynamic data
Characteristics
Mean
SD
Median (min–max)
Weight (kg)
Height (m)
Age (years)
BSA (m2)
ALB (g/L)
PROT (g/L)
SCr (µmol/L)
CLCr (mL/min)
BMI (kg/m2)
PLATINCL (×109/L)
PCI (n)
67.5
1.647
55.83
1.72
20.67
40.87
79.79
85.1
24.90
293.21
11.49
14.4
5.18
9.65
0.18
5.48
8.62
28.61
31.84
5.18
90.62
8.71
65 (37–106)
1.65 (1.5–1.85)
57.02 (32.6–73.27)
1.69 (1.32–2.09)
21 (10–34)
42 (19–58)
75 (35–155)
82.3 (23.3–199.6)
23.88 (14.45–42.46)
289 (94–635)
9 (0–39)
REG (n)
6.6
4.3
6 (0–13)
BSA body surface area, BMI body mass index, ALB serum albumin
concentration, PLATINCL platelet count before surgery, PROT serum
total protein concentration, PCI Sugarbaker’s peritoneal index, SCr
serum creatinine concentration, REG number of impacted regions,
CLCr Cockcroft–Gault creatinine clearance
peritoneal instillate before (first twelve patients) or when
the temperature reached 42–43 °C (all the other patients).
Ten blood samples (5 mL) were collected before HIPEC,
0.167, 0.333, 0.5, 0.75, 1, 2, 4, 6, and 8 h after HIPEC.
Blood samples were immediately transferred from the surgical unit to the laboratory and then immediately centrifuged at 2,000×g for 10 min at 4 °C. One mL of plasma
was immediately ultrafiltered using Amicon MPS1 micropartition system with YMT membranes (30,000 MW cutoff) at 4 °C for 20 min at 2,000×g.
Samples were kept at −20 °C until analysis. Total
platinum in peritoneum, plasma and ultrafiltrated plasma
was measured immediately after thawing of samples by
flameless atomic absorption spectrophotometry according to a previously described method [24]. Specific
matrix and calibration were used for standard and quality control (QCs) samples: water for peritoneal or ultrafiltrated plasma, and plasma for total plasma analysis,
respectively. The limit of quantification was 5.25 ng/mL
for both peritoneal fluid and plasma ultrafiltrated platinum concentrations, and 10.5 ng/mL for plasma platinum concentrations. Accuracy ranged between 95.2 and
109.9 % for water QCs, and 87.1 and 109.5 % for plasma
QCs. Precision within and between runs was lower than
10 % for the 6 QCs (low, medium and high QCs in each
matrix). Before conducting the pharmacokinetic analysis,
platinum concentrations measured were converted into
oxaliplatin concentrations according to their molecular
weights. Consequently, all the results were expressed as
oxaliplatin concentrations in nanograms per millilitre (ng/
mL), corresponding to the sum of unchanged oxaliplatin
and all its platinum metabolites.
The onset of toxicity (haemoperitoneum, ascites, neuropathy and haematotoxicity) was monitored by the clinical team until the patients were discharged from hospital. Haematotoxicity was evaluated by the neutrophil or
platelet counts obtained once a day until the patients were
discharged.
Pharmacokinetic analysis
A population pharmacokinetic approach was applied to
simultaneously link up intra-peritoneal (IP) to plasma
ultrafiltrate (UF) and to protein-bound (B) oxaliplatin concentrations. The protein-bound concentrations (PtB) were
obtained by subtracting the ultrafiltrated plasma oxaliplatin
concentrations (PtUF) to the total plasma (PtT) ones [25], at
the same sampling time, as follows:
PtB = PtT − PtUF
For each type of data, the structural PK model was
selected between 1-, 2- or 3-compartment models. The
intra-peritoneal oxaliplatin was assumed to be absorbed
into the plasma through a first-order process. To model the
irreversible binding of ultrafiltrated plasma oxaliplatin to
plasmatic proteins, a first-order process [26] or a nonlinear
binding through a Michaelis–Menten equation [25] model
were tested. A first-order elimination was assumed for both
ultrafiltrated and protein-bound oxaliplatin concentrations.
Inter-individual variability (IIV) in the pharmacokinetic
parameters was assumed to follow a log-normal distribution, and consequently, an exponential error model was
used. Different error models (i.e. additive, proportional and
combined) were tested to describe the three IP, UF and B
residuals errors.
Model selection
The likelihood ratio test was used to discriminate two
nested models. A difference greater than 3.84 for one
additional parameter, corresponding to a significance
level of 5 %, was used. Non-nested models were discriminated by computing the Bayesian Information Criterion
(BIC = OFV + k × Ln(n), with n, the number of observations; k, the number of estimated parameters; and OFV, the
objective function value). The model with the lowest BIC
value was selected. Model development was guided by precision in parameter estimates [i.e. relative standard error
(RSE)], visual inspection of the classic goodness-of-fit
plots (GOFs) and normalized prediction discrepancy errors
(NPDE) [27, 28]. One thousand simulations of the building dataset based on the dose regimen and sampling timepoints of each patient were performed using the parameter
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574
estimates in order to compute NPDE. These were plotted
versus time and versus population prediction concentrations (PRED) for each type of data (UF, IP and B) in order
to identify a possible bias in the structural model. The best
model according to the LRT, acceptable parameter precision supported by the goodness-of-fit plot and NPDE, was
finally selected.
Covariate analysis
In order to explain part of the IIV, a covariate analysis was
performed. Only covariates with a biologically plausible
effect were tested. The empirical Bayesian estimates (EBE)
obtained using the POSTHOC option in NONMEM were
used to screen the influence of covariates on PK parameter
estimates. Nonparametric statistical tests were first applied
to discriminate the covariate statistically correlated (i.e.
Wilcoxon, Spearman or Kruskal–Wallis tests for, respectively, binary, continuous or categorical covariates) only on
PK parameters with an η-shrinkage lower than 30 % [29].
Only covariates with a statistically significant association
(p < 0.05) with a model parameter were further tested in
NONMEM in order to be incorporated into the population
model. For parameters with an η-shrinkage higher than
30 %, all the covariates were tested in NONMEM. A stepwise analysis was performed with sequentially a forward
inclusion (p < 0.05, leading to a drop of 3.84 in OFV after
addition of one covariate parameter) and backward elimination (p < 0.01, leading to an increase of 6.63 in OFV
after removal of one parameter covariate). Continuous
covariates were evaluated using power equations after centring on the median of the covariate; categorical covariates
were incorporated into the model as indicator variables.
The covariates tested included body surface area, age, sex,
serum total protein concentration, creatinine clearance (calculated according to Cockcroft and Gault equation), first
treatment or relapse and the primary tumour site. The latter was divided into four categories according to the global
therapeutic management strategy: (1) colorectal cancer; (2)
advanced ovarian cancer; (3) peritoneal mesothelioma; and
(4) pseudomyxoma peritonei or other. The extent of peritoneal carcinomatosis was assessed by intraoperative exploration, using Sugarbaker’s peritoneal cancer index [30], and
the distribution of implant throughout the abdomen regions.
The surgical procedure was evaluated with the number of
peritonectomy procedures required to achieve a complete
cytoreductive surgery and the duration of the surgery.
Model evaluation
NPDE versus time and NPDE versus PRED were computed, according to the same procedure as described
above, to evaluate the final model including covariates.
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Cancer Chemother Pharmacol (2014) 74:571–582
By construction, the NPDE should follow a standard
normal distribution, and consequently, a Kolmogorov–
Smirnov test was performed to check normality [27, 28].
Visual predictive checks (VPC) were also used to evaluate the final model. For each type of data (IP, UF and B),
one thousand simulations, based on the dose regimen and
sampling timepoints of each patient, were performed with
the final parameter estimates. The 5th, 50th and 95th percentiles of the observed concentrations were calculated at
each theoretical sampling time and plotted versus theoretical sampling time. The 5th, 50th and 95th percentiles of
the predicted concentrations were calculated at each theoretical sampling time and for each of the 1,000 simulations.
Therefore, the 5th, 50th and 95th percentiles for the 1,000
model-based predicted percentiles were calculated at each
theoretical sampling time and plotted versus theoretical
sampling time. The observed concentrations were added on
the respective plots to evaluate the ability of the model to
describe peritoneal, plasma ultrafiltrate and plasma proteinbound oxaliplatin concentrations.
Secondary pharmacokinetic parameters
The peritoneal half-life was calculated as t1/2(IP) = ln 2/ka.
The oxaliplatin maximum bioavailability (MB), corresponding to the maximum fraction of absorbed dose, was calcu−Conct=last )
× 100,
lated for each patient as MB = (Conct=0
Conct=0
with Conct=0 and Conct=last the individual prediction of peri
toneal concentrations (IPRED in NONMEM), respectively,
at the beginning and at the end of the CHIP.
The areas under the curve (AUC) for concentration versus time values were computed with the trapezoidal rule for
both the intra-peritoneal (AUCIP) and plasma ultrafiltrated
compartments (AUCUF) considering the individual Bayesian predictions concentrations (Conc) over time. Indeed,
thanks to the final model, Conc were computed after adding
numerous lines into the dataset (EVID = 2 in NONMEM
dataset) with time from t = 0 to t = last, respectively, every
0.1 h for the IP compartment, and every 0.5 h until 48 h for
the UF compartment.
Pharmacokinetic–pharmacodynamic (PKPD) analysis
The pharmacodynamics of oxaliplatin were evaluated by
the toxicity. Different variables reflecting the most frequently observed toxicities in treated patients (onset of
haemoperitoneum, ascites, sepsis, neuropathy and depth
of thrombocytopenia) were related to the peritoneal (i.e.
AUCIP and individual prediction of initial peritoneal concentrations Conct=0) exposures, systemic (i.e. AUCUF)
exposures and to the parameters reflecting the absorption into the plasma (i.e. ka, MB). Thrombocytopenia was
described by the maximum percentage of platelet decrease
Cancer Chemother Pharmacol (2014) 74:571–582
(relative percentage between the value determined before
the surgery and the observed nadir). Statistical tests were
applied to identify relationships between PK and toxicity. For the qualitative binary toxicity variables, Student’s t tests or Wilcoxon comparison of mean tests were
performed, whereas for the quantitative toxicity variables,
Pearson’s or Spearman’s correlation coefficients and corresponding significance tests were used. Logistic and linear
regressions were then performed to aid the clinical interpretation of the observed associations.
Software
Concentration–time profiles of these three types of concentration were analysed using nonlinear mixed effects models with NONMEM version 7.2. The subroutine ADVAN13
and the first-order conditional estimation method with
interaction (FOCE-I) was used. Pirana 2.7.1 was used as an
interface for NONMEM procedure. Graphical evaluation
was performed using plots produced by R 2.14.0.
Results
The data from 75 patients are integrated in the present dataset. Overall, 1,866 data were simultaneously analysed with,
respectively, 536 intraperitoneal, 669 plasma ultrafiltrated
and 661 plasma protein-bound oxaliplatin concentrations.
Clinical results
Patients had a mean Sugarbaker’s peritoneal cancer index
of 11.5 [median (min–max): 9 (0–39)] for an average
of 6.6 affected regions [median (min–max): 6 (0–13)].
Fig. 1 Pharmacokinetic compartment model linking intra-peritoneal
(IP) oxaliplatin concentrations to plasma ultrafiltrated (UF) and protein-bound (B) oxaliplatin concentrations. Oxaliplatin was administered in the peritoneal compartment. UF oxaliplatin was transferred
to the central compartment according to the absorption constant rate
ka. UF oxaliplatin can bind irreversibly to plasma proteins according
575
Twenty-one per cent of patients were previously treated
by a protocol of chemotherapy containing oxaliplatin
(e.g. FOLFOX). A complete cytoreductive surgery was
reached in all patients: 70 patients exhibited no residual
disease (cytoreductive score of CC0), and 5 had a remaining disease <1 mm (cytoreductive score of CC1), respectively. The mean duration of surgery and number of procedures of peritonectomy were, respectively, 4.71 h [median
(min–max): 4.25 (2.32–9)], and 3.4 [median (min–max): 4
(0–10)]. Mean perioperative total insensitive losses (including blood loss) was 1,057 mL [median (min–max): 732.5
(87–5, 131)] based on 52 patients. The mean hospital stay
was 21.7 days [median (min–max): 17 (6–90)] based on
73 patients. Haemoperitoneum (22.7 % of patients), neuropathy (18.7 %), thrombocytopenia [13.3 % of grade 3
(n = 5) and 4 (n = 5)] and ascites (4 %) were the most
frequently reported toxicities. Patients who exhibited grade
3–4 thrombocytopenia had a mean nadir of 27.2 × 109
platelets per litre [median (min–max): 26 (7–47)] and a
mean maximum percentage of platelet decrease of 89.4 %
[median (min–max): 91.8 (76.5–98.2)]. The observed nadir
appeared on average 7 days after the end of the treatment
[median (min–max): 7 (3–10)]. Interestingly, neutropenia
were rarely observed (only two patients exhibited grade 3
neutropenia) which is why we decided not to include them
in the current PKPD analysis.
Pharmacokinetic model
The structural pharmacokinetic model included five different compartments (Fig. 1): the three compartments corresponding to the available concentrations (i.e. VIP, VUF and
VB), and two additional compartments corresponding to
peripheral compartments of distribution of either UF or B
to a nonlinear Michaelis–Menten equation (Km, Vm). Both UF and B
oxaliplatin can change between the central and peripheral compartments (QUF and QB, respectively) or be eliminated according to a
first-order process from the central compartment (kEL-UF and kEL-B,
respectively)
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Table 2 Population pharmacokinetic parameter estimates with their
inter-individual variability (IIV) and associated relative standard error
(RSE)
Parameters
Population median
estimates (RSE %)
IIV (%)
[RSE (%)]
ka (h−1)
1.42 (4.3)
24.1 (12.7)
VIP (L)
3.73 (3.7) × (BSA/1.69)1.24 (21)
16.6 (11)
22.1 (7.6)
VUF (L)
−1
26.9 (17.1)
kEL-UF (h )
0.191 (28)
70.4 (34.8)
QUF (h−1)
44.4 (7.2)
36.1 (14.2)
VPeri-UF (L)
163 (9)
26 (19.5)
Vm (ng/h)
124 (12.3)
27.9 (13.7)
Km (ng/mL)
5,980 (14.1)
–
kEL-B (h−1)
4.58 (8.3) × (PROT/42)−0.75 (34.1)
17.3 (53.7)
19.4 (14.3)
62.1 (14.8)
17.5 (9.9)
25.4 (49.5)
−1
QB (h )
VPeri-B(L)
ERRIP (%)
ERRUF (%)
ERRB (%)
ε-Shrinkage IP (%)
ε-Shrinkage UF (%)
10.9 (5.8)
19 (4.8)
22.8 (4.1)
10.1
15.1
ε-Shrinkage B (%)
10.9
ERR refers to the respective residual errors for the intra-peritoneal
(IP) oxaliplatin concentrations, plasma ultrafiltrated (UF) and proteinbound (B) oxaliplatin concentrations
RSE (%) = (standard error/final parameter estimate) × 100
IIV (%) = (ωIIV) × 100
BSA (m2) body surface area, PROT (g/L) serum total protein concentration
oxaliplatin (VPeri-UF and VPeri-B). Absorption from peritoneum to UF compartment as well as elimination from UF
and B compartments were better described by first-order
processes according to ka, kEL-UF and kEL-B, respectively.
Binding of oxaliplatin to plasma proteins was described
according to a nonlinear Michaelis–Menten equation
parameterized in Vm (the maximum rate of drug transport),
and Km (the ultrafiltrated oxaliplatin concentration at which
the rate is half maximum). Proportional residual error models best fitted each of the three types of data with 10.9, 19
and 22.8 % for the IP, UF and B oxaliplatin concentrations,
respectively. As VB is not identifiable, we decided to fix it
to 1. IIV were estimated on all parameters except on Km.
The median population pharmacokinetic parameter estimates and their inter-individual variability were reported
in the Table 2. Goodness-of-fit plots, VPCs and NPDEs for
the each type of data were depicted on the Figs. 2 and 3.
The mean [95 % confidence interval (95 % CI)] and standard deviation (95 % CI) of the NPDE for peritoneal concentrations were −0.004 (−0.082; 0.075) and 0.931 (0.874;
0.985), respectively; 0.088 (0.017; 0.158) and 0.924
(0.873; 0.973) for the plasma ultrafiltrated concentrations,
13
respectively; and 0.089 (0.021; 0.158) and 0.889 (0.84;
0.936) for the plasma protein-bound concentrations,
respectively.
Forward inclusion followed by backward elimination of
covariates within the population pharmacokinetic model
identified two significant covariates: body surface area
(BSA) on both VIP (IIV decreases from 20.9 to 16.6 %)
and serum total protein concentration (PROT) on kEL-B (IIV
decreases from 24.2 to 17.3 %). The covariate parameters
and their precision of estimation were reported on Table 2.
Secondary pharmacokinetic parameters
The mean maximum bioavailability (MB) was 53.7 %
[median (min–max): 53.6 (30.7–73.4)], and the mean elimination half-life from the peritoneum was 0.49 h [median
(min–max): 0.5 (0.3–0.9)]. The mean AUCIP and AUCUF
was 84.8 µg.h/mL [median (min–max): 81.6 (51.9–136.7)]
and 17.7 µg.h/mL [median (min–max): 16.4 (6.5–30.1)],
respectively. The mean pharmacokinetic advantage (i.e.
ratio AUCIP/AUCUF) was 5.3 [median (min–max): 4.9
(2.6–12.7)].
Pharmacokinetic–pharmacodynamic analysis
The results of the statistical tests examining the association
between the peritoneal or systemic exposure of oxaliplatin
and the various toxicity variables are reported in Table 3.
AUCUF accounts for approximately 12 % of the variation
in the maximum percentage of platelet decrease [p = 0.002
with a Pearson’s coefficient of correlation (r) of 0.35].
Furthermore, statistically significant correlations were
found between MB and AUCUF (p = 1 × 10−7, r = 0.57),
ka (p = 2.2 × 10−16, r = 0.83) and Conct=0 (p = 0.004,
r = 0.32). Furthermore, Conct=0 was statistically correlated with AUCIP (p < 2 × 10−16, r = 0.82) and AUCUF
(p = 0.016, r = 0.28). No statistically significant associations were found between the onset of ascites or neuropathy and oxaliplatin exposures (neither IP nor UF, results not
shown). No statistically significant associations were found
between a previous treatment with oxaliplatin and any toxicity (results not shown). No statistically significant associations were found between the surgery (duration of surgery
or number of peritonectomy procedures) and oxaliplatin
exposure (neither IP nor UF, results not shown).
Discussion
In the literature, publications reporting population
PK models of oxaliplatin after HIPEC procedure in
patients who underwent cytoreductive surgery are few.
Here, we present the first population PK model able to
Cancer Chemother Pharmacol (2014) 74:571–582
Fig. 2 Evaluation of the pharmacokinetic model by visual predictive check (VPC) and goodness-of-fit plots [observations (DV) versus
individual predictions concentrations (IPRED)] for intra-peritoneal
(IP) oxaliplatin concentrations (a, b), plasma ultrafiltrated (UF) oxaliplatin concentrations (c, d) and plasma protein-bound (B) oxalipl-
577
atin concentrations (e, f). In the VPC plots, open circles represent
the observed data, the dotted lines the 5th, 50th and 95th percentiles
of the observed data associated with their 90 % prediction intervals
(shaded areas). In DV versus IPRED plots, the solid lines represent
the identity line (y = x)
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Cancer Chemother Pharmacol (2014) 74:571–582
Fig. 3 Evaluation of the PK model by normalized prediction discrepancy errors (NPDE) versus time and versus population predictions
concentrations (PRED), for intra-peritoneal (IP) oxaliplatin concentrations (a, b), plasma ultrafiltrated (UF) oxaliplatin concentrations
(c, d) and plasma protein-bound (B) oxaliplatin concentrations (e, f).
The dashed lines represent the 95 % prediction interval of the 1,000
simulations
simultaneously describe peritoneal, plasma ultrafiltrated
and protein-bound oxaliplatin concentrations after administration of oxaliplatin in the peritoneum. Moreover, this
is, to our knowledge, the first population PK analysis
of plasma ultrafiltrated oxaliplatin concentrations after
HIPEC procedure, which is considered to be the pharmacologically active compound [31]. This PK model was
built based on data from 75 patients (with a total of 1,866
oxaliplatin concentrations), which is, to our knowledge,
the largest HIPEC-treated patient population database
to have been analysed using a pharmacokinetic modelling approach. Although the recent study by Pérez-Ruixo
et al. [21] included 107 patients treated by oxaliplatin,
only 57 of these underwent oxaliplatin-based HIPEC after
CRS, while the remaining 50 patients received oxaliplatin
intravenously.
The whole PK model comprised five different compartments (Fig. 1). The ultrafiltrated oxaliplatin was eliminated
from the systemic compartment by both a linear process
and a nonlinear process corresponding to irreversible protein binding; the latter mimicking the binding of the free
oxaliplatin to plasmatic proteins described by a nonlinear
Michaelis–Menten equation [25]. As in Royer et al., the
protein binding was only applied to the plasma UF concentration as IP oxaliplatin binding was shown to be very
low [25, 32, 33]. Moreover, as the lost fraction corresponding to this phenomenon is not identifiable, this could lead
to an overestimation of the central volume (VUF) of plasma
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579
Table 3 Pharmacokinetic–pharmacodynamic analysis. Pharmacokinetics was evaluated by the peritoneal exposure (Conct=0 and AUCIP),
systemic exposure (AUCUF) and the rate (ka) and extent [maximum
bioavailability (MB)] of the systemic absorption of oxaliplatin from
peritoneum. Pharmacodynamics was evaluated by the toxicity (onset
of haemoperitoneum and sepsis and depth of thrombocytopenia).
Variables
Haemoperitoneum
No
AUCUF (ng.h/mL)
AUCIP (ng.h/mL)
MB (%)
ka (h−1)
Conct=0 (ng/mL)
Mean values (standard deviation) for each group as well Student’s or
Wilcoxon’s test p values are given for haematoperitoneum and sepsis.
Pearson’s or Spearman’s correlation coefficient and corresponding p
value are given for depth of thrombocytopenia (maximum percentage
of platelet decrease)
Sepsis
Yes
p value
No
Maximum %
of platelet
decrease
Yes
p value
r
p value
16,729 (5,526)
83,488 (17,124)
52.3 (8.3)
1.44 (0.3)
20,917 (4,506)
89,303 (24,727)
58.3 (7.8)
1.58 (0.3)
0.003
0.50
0.01
0.09
16,860 (5,394)
84,291 (18,637)
52.3 (8.5)
1.42 (0.3)
19,221 (5,673)
85,776 (20,231)
56.3 (8.2)
1.57 (0.3)
0.06
0.76
0.05
0.04
0.35
0.36
0.41
0.14
0.002
0.001
0.0003
0.22
171,558 (26,470)
175,747 (31,478)
0.47
171,729 (29,047)
173,974 (24,850)
0.53
0.26
0.02
Bold refers to the associations statistically significant
Conct=0: individual peritoneal concentration predictions at t = 0
ultrafiltrated oxaliplatin. A covariate analysis was performed leading to the addition of two covariates in the population model (BSA on VIP and PROT on KEL-B). The ratio
between extreme predicted VIP corresponding to extreme
BSA observed values was 1.8 which may have a clinical
impact regarding the AUCIP—thrombocytopenia relationship discussed below. For kEL-B, the ratio corresponding
to extreme PROT values was even larger (i.e. 2.3), but no
major clinical impact is expected as it refers to the elimination of biologically inactive compounds. All the PK parameters were correctly estimated with a maximum RSE of
34.1 and 53.7 % for the fixed and random effects, respectively (Table 2). Although, IIVs on IP were lower than IIVs
on UF parameters, IIVs on IP were not negligible with
24.1 % on ka and 16.6 % on VIP. According to the respective residual errors (10.9, 19 and 22.8 % for the IP, UF
and B oxaliplatin concentrations, respectively), GOFs and
VPCs (Fig. 2), the model adequately described each type
of concentration and their associated variability in treated
patients. NPDE (Fig. 3) versus time and versus PRED did
not show any trend that evidences model inadequacy [27,
28]. Although the Kolmogorov–Smirnov test was statistically significant (p < 0.05), implying the rejection of the
normality of the NPDEs, the whole PK model showed
good descriptive features. Furthermore, Comets et al. [34]
suggested that a visual inspection of the aforementioned
NPDE graphs was appropriate to evaluate the ability of the
model to describe data.
The absorption parameters were close to the previously
published parameters. The mean value of apparent oxaliplatin elimination half-life from the peritoneum to plasma
was 29.6 min in the current study compared to 29.5 min
[35], 30 min [15], 40 min [17] or 29 min in our previous
analysis [18]. The mean maximum bioavailability was
53.7 %. However, this value corresponds to the maximum
fraction of absorbed dose from peritoneum to plasma, since
a fraction of the oxaliplatin may irreversibly bind to proteins in the peritoneal walls [15]. Pérez-Ruixo et al. [21]
estimated an absolute bioavailability of oxaliplatin administered in peritoneum of 38 % using data from patients
treated with oxaliplatin administered intravenously. Consequently, the difference could be partly explained by a high
uptake of oxaliplatin in local tissues [15].
Blood sampling was only conducted over an 8-h period,
which results in an imprecise estimate of the terminal
elimination phase (i.e. overestimation of the constant rate
of elimination leading to an underestimation of the mean
elimination half-life). However, even if a longer terminal
half-life was expected, this terminal elimination phase consists almost entirely of pharmacologically inactive platinum conjugates (e.g. albumin-bound platinum) [31]. Cotte
et al. [36] studying HIPEC with cisplatin thought that the
aggressiveness of the surgical procedure could influence
the systemic transfer of the cytotoxic drug administered
in the peritoneum during HIPEC. However, in the present
study, no correlations were found between either AUCIP,
AUCUF, ka, MB and the surgery (duration, number of peritonectomy) or the PCI.
By comparing the median population Km estimated of
5,980 ng/mL (Table 2) with the distribution of the observed
ultrafiltrated oxaliplatin concentrations (mean ± SD:
3,480 ± 3,084 ng/mL), there is no evidence of a complete
saturable binding of oxaliplatin proteins, as previously
mentioned by Graham et al. [31]. The protein binding process seems to be principally located in the linear range of
the Michaelis–Menten curve.
Peripheral sensory neuropathy and haematological
toxicity are known to be the dose-limiting toxicities of
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oxaliplatin after intravenous treatment [16]. In the present
study, neuropathy and grade 3–4 thrombocytopenia were
observed in approximately 19 and 14 % of treated patients,
respectively. The systemic exposure of oxaliplatin (AUCUF)
was found to be linked with the severity of the observed
thrombocytopenia, and more precisely with the maximum
percentage of platelet decrease since inclusion (p = 0.002,
r = 0.35). Linear regressions with observed platelet nadir
as dependent variable and AUCUF (respectively AUCIP) as
independent variable demonstrated a decrease of approximately 16 × 109 (respectively 19 × 109) platelets per litre
for an increase of approximately 20 % of the mean AUCUF
(i.e. 3,500 ng.h/mL) (respectively AUCIP; i.e. 17,000 ng.h/
mL). Moreover, a significant association was found
between AUCUF and the occurrence of haemoperitoneum:
logistic regression showed that for an increase of 20 % of
the mean AUCUF (i.e. 3,500 ng.h/mL), we expect to see an
increase of approximately 66 % in the odds of having haemoperitoneum. Three different mechanisms of action leading to oxaliplatin-related thrombocytopenia were reported
[37]: a splenic sequestration of platelets related to oxaliplatin-induced liver damage, an immune thrombocytopenia,
and a myelosuppression probably due to its direct toxicity
on megakaryocytic progenitors leading to their apoptosis.
Considering the kinetics of thrombocytopenia (mean time
to nadir of 7 days), as well as the absence of statistical
association between the depth of thrombocytopenia and
a previous administration of oxaliplatin, chemotherapyinduced myelosuppression seems to be the main cause of
observed thrombocytopenia in these patients.
In our study, 17 and 58 patients received a dose of
460 and 360 mg/m2, respectively. As the volume of solution (2 L/m2) and these doses were based on the body surface area, the drug concentrations observed in the peritoneum at t = 0 should be the same in all patients treated in
each group of doses. However, surprisingly, an important
inter-individual variability was observed [mean ± SD:
189.6 ± 34.6 and 176.1 ± 53.4 µg/mL for the 460 mg/m2
doses (n = 16) and 360 (n = 56), respectively]. A possible explanation for this variability is that two patients with
an identical body surface area might have very different
intraperitoneal volumes. The advantage of the Performer®
LRT system is that it adapts the infused intraperitoneal
volume according to the patient’s anatomy. However, this
means that the oxaliplatin dose to which the patient is
exposed will vary depending on the volume remaining in
the device. This initial variability in concentration coupled to that of ka and MB parameters lead to an important
variability not only on AUCIP [mean ± SD: 108.6 ± 17.1
and 77.8 ± 13.1 µg.h/mL(p = 9.6 × 10−8) for 460 and
360 mg/m2, respectively] but also contribute to variability
on AUCUF [mean ± SD: 22.9 ± 4.7 and 16.1 ± 4.9 µg.h/
mL(p = 3.4 × 10−5) for 460 and 360 mg/m2, respectively];
13
Cancer Chemother Pharmacol (2014) 74:571–582
AUCUF is itself associated with haematological toxicity.
Despite the lack of significant association between the
depth of thrombocytopenia and the surgery (duration, number of peritonectomies), we cannot exclude perioperative
haemorrhage as a factor of haematological toxicity. Indeed,
a statistically significant correlation was found between the
total perioperative insensitive losses and the maximum percentage of platelet decrease (p = 0.01, r = 0.35, n = 52).
Conclusions
In summary, the current work presents the first PK model
of oxaliplatin after HIPEC procedure in patients who
underwent cytoreductive surgery, which simultaneously
describes the kinetics of peritoneal, plasma ultrafiltrated
and protein-bound oxaliplatin concentrations. Thrombocytopenia was observed in approximately 14 % of patients.
On the one hand, they seem to be related to the PK variability observed both in the peritoneum and in the systemic compartment, depending on both the pharmacokinetic parameters of absorption from the peritoneum and
the initial concentrations in the peritoneum. The higher the
absorbed dose from the peritoneum, which is very dependent on the initial concentration in the peritoneum and ka,
the deeper the resultant thrombocytopenia. On the other
hand, we cannot exclude perioperative haemorrhage as a
factor of thrombocytopenia. A simple measure of the initial concentration in the peritoneum could dictate the prophylactic administration of platelet concentrates, after the
definition of a threshold. However, further prospective
studies are necessary to confirm and better understand this
observed variability in oxaliplatin exposure. In the future,
the PKPD relationship between oxaliplatin exposure and
the total platelet count over time could be investigated, as
already done by others for neutrophils [20] in order to optimize the peritoneal administration of oxaliplatin in such
HIPEC procedures.
Acknowledgments This work was integrated in a Ph.D. project
(Quentin Chalret du Rieu), granted by Institut de Recherches Internationales Servier.
Conflict of interest
None.
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!
2.3.3:!Discussion!and!future!prospect!
!
Accumulation!and!analysis!of!data!from!patients!treated!with!approved!drugs!are!crucial!
to!improve!therapeutic!management.!Despite!the!number!of!publications!about!HIPEC,!
data! are! missing! regarding! drug! toxicities! and! related! morbidity,! which! have! been!
probably! underGevaluated! at! the! beginning! of! the! experience.! Enrolment! of! patients! in!
phase! I! or! phase! II! clinical! trial! is! required.! Important! information! to! improve!
therapeutic!management!would!be!obtained!through!a!better!understanding!and!control!
of! the! relationship! between! the! drug! exposition! and! the! observed! toxicities,! but! also!
with!the!accumulation!and!analysis!of!data!from!patients!treated!with!approved!drugs.!
Regarding! specific! toxicity! of! cisplatin! based! HIPEC,! risk! of! acute! renal! failure! was!
difficult! to! assess! in! some! small! sample! size! heterogeneous! studies,! and! with! lack! of!
standardization! of! HIPEC! technique.! Comparison! of! published! HIPEC! regimens! was!
impossible! regarding! the! variability! of! volumes! and! concentrations! used,! the! different!
modalities!of!HIPEC,!the!different!time!to!exposure,!the!different!optimal!temperature,!
and! the! different! carrier! solutions.! A! consensus! on! technical! aspects! of! cytoreductive!
surgery! and! HIPEC! was! obtained! through! the! Delphi! process! in! 2006! at! the! Fifth!
International!Workshop!on!Peritoneal!Surface!Malignancy![91],!which!has!facilitate!data!
and!publications!analysis.!!
At! the! beginning! of! our! experience,! cisplatin! dose! rate! was! determinate! according! to!
intraperitonal! treatment! without! concurrent! surgery! and! hyperthermia.! In! our!
unpublished! deGescalation! study,! acute! renal! failure! according! to! RIFLE! score! was!
reported!in!83%!of!patients,!58%!of!which!with!high!grade!(failure,!loss!or!endGstage)!
after! CRS! and! cisplatin! based! HIPEC.! Because! of! low! plasma! dose! exposure,! we! have!
concluded!that!occurrence!of!renal!failure!is!not!dose!dependant,!and!due!to!a!different!
mechanism!as!known!with!using!intravenous!cisplatin.!!
High!rate!of!renal!toxicity!was!described!in!different!retrospective!studies,!ranged!from!
27%!to!65%![92],!depending!to!the!dose!of!cisplatin!used.!Hakeam!has!estimated!a!5%!
of! acute! renal! failure! rate! after! CRS! and! HIPEC! combining! cisplatin! 50mg/m2! and!
doxorubicin! 15! mg/m2! [93].! The! development! of! perioperative! acute! renal! failure! is!
associated! with! a! high! incidence! of! morbidity! and! mortality.! In! a! population! PKGPD!
study,!Cotte!has!reported!a!renal!toxicity!in!29%!of!patients!which!is!correlated!to!AUCp!
[94].!Acute!renal!failure!seems!to!have!been!more!frequent!in!patients!who!received!IP!
cisplatin!only!compared!to!IP!association!of!drugs.!But!in!this!study,!these!patients!who!
received!cisplatin!only!have!received!the!greatest!dose!of!cisplatin.!Royer!has!reported!a!
threshold! of! 25! mg·h/l! for! the! AUCp! of! total! platinum,! above! which! the! risk! of! renal!
toxicity! increases! [95].! Evaluation! of! renal! toxicity! is! more! effective! in! a! doseGfinding!
prospective! study.! In! our! dose! escalation! study,! all! DLT! were! observed! at! the! highest!
dose! level! (80! mg/m2)! with! HIPEC! related! renal! failure! requiring! dialysis.! A! wide!
variation! in! creatinin! clearance! was! observed! during! post! HIPEC! days.! In! a! model!
adjusted! on! the! dose! level,! the! creatinine! level! at! week! 8! was! significantly! correlated!
with!the!baseline!value!and!diuresis!before!HIPEC.!In!our!retroscpective!bicentric!study,!
we!have!shown!that!previous!hypertension,!renin!angiotensin!system!blockers!and!low!
intraoperative! diuresis! represent! the! main! risk! factor! of! renal! failure.! For! Cotte,! [94]!
!
40!
renal! toxicity! may! be! due! to! multiple! factors,! such! as! surgical! complications! (sepsis,!
hemodynamic!shock,!digestive!tract!occlusion)!and!medical!complications!(dehydration!
and!comedication!toxicity).!
How!to!prevent!acute!renal!failure?!!
2.3.3.1:!By!using!sodium!thiosulfate:!
It!allows!to!reduce!the!renal!toxicity!of!cisplatin!administered!locally!by!either!the!intraG
arterial,!intraGperitoneal!or!intraGthoracic!routes.!However,!controversies!still!exist!as!to!
the! effect! of! sodium! thiosulphate! on! cisplatin! antitumor! activity.! Sodium! thiosulfate! is!
currently! not! available! in! France.! Thus! sodium! thiosulphate! may! be! most! useful! in!
combination! with! intraperitoneal! cisplatin! where! it! confers! renal! protection! without!
altering!local!effects!of!cisplatin!
2.3.3.2:!By!using!low!dose!of!cisplatin:!
Early!in!the!development!of!cisplatin,!more!than!70%!of!patients!developed!acute!renal!
failure! that! appeared! to! be! cisplatin! doseGrelated.! Royer! [95]! has! shown! that! an!
intraperitoneal! concentration! above! 10! mg/l! eradicated! 100%! of! platinum! resistant!
ovarian!cells!in!a!clonogenic!assay.!Regarding!our!DLT!observed!at!the!level!80!mg/m2,!
a!70!mg/m2!dose!of!ciplatin!for!HIPEC!is!recommended.!
2.3.3.3:!By!maintaining!a!pronounced!diuresis!before!starting!cisplatin!based!HIPEC:!
!The!clinical!use!of!cisplatin!is!hampered!by!nephrotoxicity,!expressed!by!a!reduction!in!
glomerular! filtration! rate.! Despite! aggressive! hydration,! especially! with! normal! saline!
solutions,! which! are! routinely! applied! in! the! clinical! setting! to! prevent! nephrotoxicity,!
renal!failure!still!occurs.!For!intravenous!cisplatin!used,!some!authors!suggest!a!regimen!
consisting!of!prehydration!using!100!ml/h!of!normal!saline!solution!for!the!12!h!prior!to!
the! administration! of! the! compound! and! continuous! infusion! of! saline! during! and! at!
least!1!day!after!cisplatin!treatment![96].!In!some!clinical!trial,!to!prevent!renal!toxicity,!
a! hyperhydration! (≈12! ml/kg/h)! and! forced! diuresis! (≈2! ml/Kg/h)! during! HIPEC! are!
required! (CHORINE! trial,! CHIPOR).! Several! experimental! reports! have! suggested! that!
diuretics!(mannitol!and!furosemide)!decrease!cisplatin!nephrotoxicity.!But!others!have!
shown!that!they!may!aggravate!it.!During!cytoreductive!surgery,!objective!of!euvolemia!
is!mandatory!in!order!to!maintain!organ!perfusion,!which!represents!the!main!factor!to!
prevent! related! cisplatin! renal! toxicity.! Perioperative! fluid! losses! can! be! recorded! in!
terms! of! blood! and! intravascular! fluid! losses,! insensible! losses.! There! is! a! need! to!
replace!both!blood!and!extracellular!fluid!losses,!as!well!as!to!maintain!the!normal!water!
requirement.! According! to! the! extent! of! the! peritoneal! carcinomatosis! surgery,!
preoperative! hydratation! up! to! 10G15! ml/kg/h! is! required! [97].! Furthermore,! most!
anaesthetics! cause! peripheral! vasodilatation.! Either! vasoconstrictors! or! fluid!
replacement!is!needed.!In!the!case!of!the!kidney,!under!control!of!angiotensin,!adequate!
efferent! arteriolar! vasoconstriction! is! maintained,! which! is! responsible! for! the!
development! of! the! glomerular! filtration! pressure.! Patient! receiving! renin! angiotensin!
system! blockers! treatment! who! undergoes! anaesthesia! may! develop! a! significant!
decrease!in!the!perfusion!pressure!with!decreased!urine!production.!As!suggested!in!our!
study,!treatment!by!renin!angiotensin!system!blockers!may!be!replace!before!a!surgery!
when!a!cisplatin!based!HIPEC!is!planned.!Careful!use!of!preoperative!osmotic!laxatives!is!
mandatory!because!it!can!affect!renal!function!by!increasing!risk!of!dehydratation.!!
!
41!
Prospective!investigations!are!needed!to!decrease!drastically!the!risk!of!renal!failure!for!
patients!treated!by!cisplatin!based!HIPEC!and!to!select!to!highGrisk!population.!!
2.3.3.4:!By!using!taxane!based!HIPEC!
Because!paclitaxel!and!docetaxel!have!a!high!molecular!weight!and!hepatic!metabolism,!
high! intraperitoneal! to! systemic! drug! concentration! and! exposure! ratios! might! be!
achievable! after! intraperitoneal! delivery.! Based! to! the! results! of! the! two! GOG!
randomized! trials! for! ovarian! cancer! (GOGG114,! GOGG172)! [32G34]! comparing! IV!
carboplatin!plus!taxane!to!IP!instillation,!taxanes!are!routinely!used!intraperitonealy!in!
association!with!IP!cisplatin.!!
The! favorable! pharmacokinetics! of! taxanes! during! intraperitoneal! instillation!
chemotherapy! and! HIPEC! have! been! confirmed! in! several! animal! and! clinical! studies,!
with! a! highly! ratio! AUCIP/AUCp! ratio,! more! than! 1000! [98].! After! intraperitoneal!
administration! of! taxanes,! highly! cytotoxic! concentration! of! the! agents! persists! within!
the! peritoneal! cavity! for! several! days.! In! vitro,! synergistic! effect! in! a! timeGdependant!
manner! has! been! demonstrated! between! paclitaxel! and! hyperthermia.! Cell! death!
mechanism! seems! to! be! different! under! hyperthermic! conditions! comparing! to!
normothermic! conditions:! cell! necrosis! is! significantly! higher! than! apoptosis! with!
hyperthermia.! But! in! vivo,! necrosis! increases! local! inflammation! and! recruits! immune!
system![99].!
Clinical! experiences! with! taxane! based! HIPEC! are! limited! to! few! teams,! essentially! for!
ovarian!cancer![100,!101].!The!dose!used!is!very!different.!!A!phase!II!prospective!study!
was!recently!published!about!a!combined!cisplatin!and!paclitaxel!based!HIPEC!with!the!
same!dose!used!in!conventional!sequential!IP![102].!44!patients!were!included.!Systemic!
chemotherapyGrelated! complications! as! hematological! toxicity! and! renal! insufficiency!
range!from!0%!to!28%!and!0%!to!7%,!respectively.!Largest!studies!with!a!homogenous!
population!are!needed.!
2.3.3.5:!By!using!Carboplatin!based!HIPEC:!
!Carboplatin,!which!has!largely!supplanted!cisplatin!in!intravenous!regimens!because!of!
a! more! favorable! toxicity! profile,! has! undergone! limited! study! in! the! intraperitoneal!
setting! especially! with! hyperthermia.! As! previously! described,! hyperthermia! increases!
the! tumor! concentration! of! carboplatin! significantly,! yielding! an! increase! in! adduct!
formation! within! tumor! DNA! and! potentially! further! increasing! efficacy! [103].! Two!
phase! I! studies! was! conducted! regarding! HIPEC! carboplatin! doses.! Doses! up! to! 800–
1000! mg/m2! were! tolerable.! Argenta! [104]! has! published! a! monocentric! prospective,!
pilot! study! about! 10! patients! who! underwent! secondary! cytoreductive! surgery! for!
recurrent! platinum! sensitive! ovarian! cancer! followed! by! HIPECGcarboplatin! at! 1000!
mg/m2,! with! a! low! rate! of! side! effects.! In! a! retrospective! study,! Shetty! [105]! has!
compared!the!outcome!of!patients!treated!with!either!mitomycin!or!carboplatin!based!
HIPEC! for! malignant! peritoneal! mesothelioma.! Despite! absence! of! randomization! and!
matching,!the!authors!have!concluded!that!HIPEC!with!carboplatin!in!diffuse!malignant!
peritoneal! mesothelioma! is! associated! with! improved! overall! survival! and! shorter!
hospital! stay! compared! with! HIPEC! with! mitomycin.! Rettenmaier! has! published! his!
experience! about! advanced! stage! ovarian! cancer! patients! who! were! treated! with!
consolidation!HIPEC!with!carboplatin!at!varying!doses!(AUC!6,!8!or!10)!after!a!complete!
response! to! neoadjuvant! chemotherapy! and! surgery.! He! suggested! that! carboplatin!
!
42!
based! HIPEC! is! wellGtolerated,! even! at! an! AUC! of! 10! [106,! 107].! Dose! escalation! study!
and!phase!IGII!trials!are!needed!to!evaluate!the!real!role!of!carboplatin!for!HIPEC!
2.3.3.6:!By!using!Oxaliplatin!based!HIPEC:!
Because! it! induces! no! renal! or! hepatic! toxicity! and! its! efficacy! in! colorectal! cancer,!
oxaliplatin! is! the! widely! used! for! HIPEC! in! France.! Gustave! Roussy! team! has! reported!
several! prospective! trials! of! Oxaliplatin! based! HIPEC! following! complete! cytoreductive!
surgery!for!colorectal!peritoneal!carcinomatosis![90,!108,!109].!
According!to!these!results!and!the!rate!of!renal!failure!after!cisplatin!based!HIPEC,!we!
have!conducted!in!France!a!multiinstitutional!phase!II!prospective!study,!evaluating!the!
safety!of!an!oxaliplatin!based!HIPEC!in!ovarian!cancer!after!an!incomplete!surgery!and!6!
courses! of! chemotherapy.! Regarding! to! a! 29%! severe! morbidity! rate,! this! trail! was!
premature! closed! at! the! first! step! (31! patients).! Complications! were! mainly! related! to!
intraGabdominal! bleeding,! sometimes! with! unexplained! repeated! episodes! of!
hemoperitoneum.! This! specific! complication! was! not! related! to! the! importance! of! the!
surgery.! Indeed,! limited! cytoreduction! without! bowel! resections! was! required! for!
inclusion.!!
In!our!PKGPD!study,!concerning!75!patients!treated!by!oxaliplatin!based!HIPEC!either!for!
colorectal! PC! (n=25),! or! rare! peritoneal! disease! (n=29),! or! ovarian! cancer! (n=18)! or!
other! (n=3),! hemoperitoneum! occurred! in! 27%! of! patient.! Neuropathy! and! grade! 3G4!
thrombocytopenia! were! observed! in! approximately! 19! and! 14%! of! patients,!
respectively.! No! statistically! significant! associations! were! found! between! toxicity! and!
surgery! (duration! of! surgery,! extend! of! peritonectomy)! or! previous! treatment! with!
oxaliplatin.! An! interGindividual! variability! was! reported! regarding! the! bioavaibility! of!
oxaliplatin! (percentage! of! dose! absorbed! during! the! HIPEC)! with! a! statistically!
significant! correlation! with! hemoperitoneum.! The! systemic! exposure! of! oxaliplatin!
(AUCUF)!was!found!to!be!correlate!to!the!severity!of!the!observed!thrombocytopenia!and!
the! occurrence! of! abdominal! bleeding! (Fig.! 6).! With! an! increase! of! 20%! of! the! mean!
AUCUF,! we! expect! to! observe! an! increase! of! 66%! in! the! odds! to! developing!
hemoperitoneum.! A! statistically! significant! correlation! was! found! between! the! total!
perioperative!fluid!losses!and!thrombopenia.!
!
Fig.!6!PKLPD!analysis!
This! specific! complication! has! been! noted! at! a! rate! of! 5! to! 18%! after! surgery! for!
pseudomyxoma! peritonei! [110],! colorectal! cancer! [111],! and! ovarian! cancer! [112].!!
Incidence! of! bleeding! varies! with! the! origin! of! cancer.! Highest! rate! of! bleeding! was!
!
43!
observed! in! patients! treated! for! appendical/pseudomyxoma! peritonei! and! for! ovarian!
cancer.! One! way! to! explain! the! increasing! risk! of! hemoperitoneum! depending! to! the!
pathology! is! the! pathology! itself.! Indeed,! a! ten! time! higher! level! of! fibrin! degradation!
products!was!reported!in!ovarian!cancer!ascitis!than!in!colorectal!PC!and!cirrhosis.!This!
finding! suggests! a! catabolism! of! fibrinogen! in! ascitis! fluid! via! coagulation! and!
fibrinolysis.!It’s!the!reason!of!high!rate!of!hemorrhagic!ascitis,!and!probably!a!cause!of!
high!risk!of!abdominal!bleeding!after!oxaliplatin!HIPEC.!
Hypotonic! solutions! may! lead! to! diffuse! bleeding.! Because! intraperitoneal! hypotonic!
solutions!increase!platinum!accumulation!in!tumors!cells!and!enhance!its!cytotoxicity!in!
vitro! [113],! a! phase! I! clinical! study! of! oxaliplatin! based! HIPEC! with! dose! escalation! of!
hypotonic! solution! was! carried! out! [114].! A! high! incidence! of! unexplained! abdominal!
bleeding!and!thrombopenia!was!reported!using!hypotonic!solutions.!Moreover,!contrary!
to! the! experimental! studies! finding,! oxaliplatin’s! penetration! in! tumor! was! not!
increased.!
Careful! using! of! oxaliplatin! for! HIPEC! is! mandatory! especially! for! ovarian! cancer! and!
pseudomyxoma! peritonei.! According! to! our! results,! postGoperative! monitoring! of!
kinetics! of! thrombopenia! especially! for! patient! with! an! important! perioperative! fluid!
losses! could! be! helpful.! Indeed,! a! simple! measure! of! the! initial! concentration! into! the!
peritoneum! could! dictate! a! potential! prophylactic! administration! of! platelet!
concentrates.!In!the!future,!the!PKGPD!relationship!between!oxaliplatin!exposure!and!the!
platelet!count!over!time!could!be!investigated!in!order!to!optimize!the!IP!administration!
of!oxaliplatin!during!HIPEC!procedure.!
!
44!
!
3.)CONCLUSION)
!
45!
)
After! more! than! 20! years! of! research,! knowledge! has! changed! regarding! PC!
management,!and!the!importance!of!complete!cytoreductive!surgery!and!intraperitoneal!
chemotherapy.! At! the! beginning! of! the! experience,! PKGPD! data! were! rare! and! clinical!
practices!strongly!heterogeneous.!!
We!contributed,!thanks!to!our!research’s!results,!to!develop!a!PK!model,!which!is!able!to!
simultaneously! describe! peritoneal! and! plasma! exposure! and! proteinGbound!
concentration! versus! time.! This! model! allowed! to! confirm! the! PK! advantage! to! deliver!
HIPEC! laparoscopically! which! represents! probably! the! best! approach! for! patients!
previously! treated! by! minimal! invasive! surgery! for! high! risk! cancer.! ! This! model! also!
allowed!to!investigate!the!PKGPD!relationship!between!drug!exposure!and!toxicity.!
It’s! crucial! that! each! new! step! of! development! will! be! early! evaluated! using! PKGPD!
models.!Today,!new!and!major!developments!of!intraperitoneal!treatment!are!expected!
using!differents!ways:!
First,! by! intraperitoneal! using! of! targeted! therapy.! Indeed,! key! biologic! targets! of! IP!
therapy! in! terms! of! direct! tumor! cytotoxicity,! alterations! in! the! peritoneal! stomal!
microenvironment! (such! as! a! reduction! in! angiogenesis! or! growth! factors),! or!
enhancement!of!the!host!immune!response!have!not!already!been!completely!described.!
Furthermore,! it! is! obvious! that! each! of! these! pathways! could! drive! targeted!
interventions! that! might! further! improve! clinical! outcomes.! Intraperitoneal!
administration!of!combined!targeted!therapy!and!cytotoxic!agents!have!to!be!evaluating!
using!PK!model.!!!
Then,! different! methods! have! been! recently! developed! to! modifie! the! PK! of!
intraperitoneal! drug! delivery,! in! order! to! enhance! the! AUC! ratio! with! a! decreasing! of!
related! complication! rate.! Most! research! regarding! antiGcancer! drugs! with! liposomes,!
polymeric!micelles,!and!microspheres!(Fig.!7)!have!designed!the!drug!delivery!based!on!
the! enhanced! permeability! retention! effect! using! intravenous! or! intraperitoneal!
administration! to! target! the! cancer! [115].! Experimentally,! nanoparticles! included! in! a!
biodegradable! hydrogel! (gelatine! like)! are! frequently! used! for! intraperitoneal!
administration! [116].! Some! preliminary! studies! regarding! intraperitoneal!
administration! of! linked! cisplatin! microspheres! reported! favorable! AUC! ratio! between!
the! peritoneal! and! the! serum! [117].! Moreover,! the! microspheres! were! seen!
macroscopically! along! the! greater! omentum,! subphrenic! area,! pouch! of! Douglas,! and!
hepatic! portal! region! where! tumor! metastases! are! commonly! observed,! suggesting! a!
high! concentration! of! cisplatin! near! the! peritoneal! lesions.! Similar! results! have! been!
reported!using!Camptotecine![118],!Paclitaxel![119G122].!Intraperitoneal!administration!
of!Cisplatin!crossGlinked!with!hyaluronic!acid!based!hydrogel!was!described!by!Emoto!in!
2013![121].!Because!of!hyaluronic!acid!implication!in!ovarian!tumor!progression![123],!
we! have! demonstrated! the! oncologic! safety! for! using! ! hyaluronic! acid! barriers! in!
peritoneal!carcinomatosis![124].!These!results!will!give!us!the!opportunity!to!join!two!
important! research! programs! in! our! team:! microenvironment! and! PKGPD! analysis! for!
intraperitoneal!treatment.!
Finally,! different! modalities! have! been! published! to! deliver! hyperthermia! into! the!
peritoneal! cavity:! external! RadioGFrequency! devices;! hyperthermic! perfusion;! injection!
of! magnetic! and! ferroelectric! particles;! injection! of! magnetic! nanoparticles! that! may!
!
46!
carry!a!pharmacological!active!drug![125].!Although!the!description!of!specific!renal!and!
liver!adverse!effects!related!to!intraperitoneal!injection!of!silver!nanoparticles![126],!the!
use! of! magnetic! nanoparticles! is! a! very! promising! treatment! approach! since! it! may! be!
used! for! diagnostic! and! treatment.! An! ideal! magnetic! nanoparticle! would! be! able! to!
detect! and! diagnose! the! tumor,! carry! a! pharmacological! active! drug! to! be! delivered! in!
the! tumor! site,! apply! hyperthermia! through! an! external! magnetic! field! and! allow!
treatment!monitoring!by!magnetic!resonance!imaging.!!
An!important!field!of!research!is!still!open!regarding!PKGPD!studies!using!our!model!to!
investigate!IP!chemotherapy!linked!to!different!particles,!with!the!possibility!to!deliver!
hyperthermia!during!each!sequential!IP!injection.!!
!
!
Fig.!7!An!illustrative!representation!of!differents!classes!of!third!generation!nanodrugs!(Markman!JL.!Adv!
Drug!Deliv!Rev.!2013)![127].!
!
47!
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55!
Author:!ThierryGGwénaël!FERRON!
Title:! Therapeutic! methods! for! peritoneal! carcinomatosis.! Standardization! of!
hyperthermic!intraperitoneal!chemotherapy!–!Pharmacokinetics!and!Pharmacodynamic!
Studies!
Summary!
Peritoneal! carcinomatosis! (PC)! is! usually! caused! by! widespread! cancer! metastatic! cells! within! the!
peritoneal! cavity! and! occurred! in! 85%! of! ovarian! cancer! patients! and! 5–20%! of! colorectal! carcinoma!
patients.!Because!of!the!poverty!of!symptoms,!patients!are!diagnosed!with!an!advanced!stage.!PC!will!be!
the!leading!death!cause!of!these!patients.!
Recently,! the! treatment! was! limited! to! standard! palliative! surgery! and! intravenous! chemotherapy! with!
very! poor! results! in! term! of! survival.! The! development! of! new! surgical! techniques! combined! with!
intraperitoneal!chemotherapy!associated!or!not!with!hyperthermia!provided!new!hope!of!a!potential!cure!
for! patients! with! PC.! Indeed,! complete! cytoreductive! surgery! represents! the! most! important! prognostic!
factor! for! patients! with! PC! whatever! the! primary! cancer! locations.! Combined! treatment! using! complete!
cytoreductive! surgery! and! intraperitoneal! chemotherapy! has! been! developed! leading! to! unprecedented!
survival.! Hyperthermia! induces! a! selective! destruction! of! tumor! cells! in! hypoxic! and! acidic! parts! of!
tumors,!but!leaves!normal!tissues!intact.!In!addition!heat!is!acting!for!synergy!with!the!cytotoxic!agent.!A!
new! technique! to! deliver! intraoperative! intraperitoneal! chemotherapy! associated! with! hyperthermia,!
called!HIPEC,!was!developed!for!patient!with!PC.!It!significantly!increases!survival!in!patients!with!colic!
cancer! PC,! peritoneal! mesothelioma! and! pseudomyxoma! peritonei.! Several! ongoing! trails! have! been!
designed!to!establish!the!real!role!of!HIPEC!for!different!pathology.!!
First,!because!of!the!major!development!and!the!widespread!use!of!minimal!invasive!surgery,!recruitment!
of! patients! has! been! profoundly! changed! with! localized! PC.! We! have! demonstrated! in! an! experimental!
study! the! feasibility! and! reliability! of! laparoscopic! peritonectomy! followed! by! oxaliplatin! based!
intraperitoneal! chemotherapy! and! its! pharmacokinetics! consequences! regarding! the! peritoneal! drug!
absorption,!the!increased!tissue!diffusion,!and!the!role!of!intraperitoneal!pressure.!Several!articles!were!
published! in! Gynecologic* Oncology! and! in! Annals* of* Surgical* Oncology) and! in! an! international! book*
chapter*(Humana*Press)!concerning!pharmacology!and!pharmacokinetics!of!platinum!salts.!
Then,) to! establish! a! new! population! pharmacokinetic! model! and! to! compare! two! procedures! of! drug’s!
delivery! during! HIPEC,! data! from! 24! patients! treated! with! oxaliplatin! based! HIPEC! were! collected! and!
analyzed.!This!work!was!published!in)Cancer*Chemotherapy*and*Pharmacology.!
Finally,! different! clinical! and! pharmacodynamic! studies! were! performed! to! evaluate! the! toxicity! for!
patients! who! underwent! complete! cytoreductive! surgery! associated! to! Cisplatin! or! Oxaliplatin! based!
HIPEC.!)
Three! different! works! were! performed! to! evaluate! the! renal! toxicity! of! cisplatin! based! HIPEC.! An!
unpublished! PK! study! regarding! acute! renal! failure! in! a! doseGdeescalation! study! was! presented! at! a!
PharmacoGoncologists!Meeting.!The!results!were!confirmed!in!a!bicentric!retrospective!study!highlighting!
some! risk! factors! (Submitted! to! the! European* Journal* of* Surgical* Oncology).! Finally,! a! phase! I! study!
dose! escalation! of! hyperthermic! intraperitoneal! cisplatin! was! conducted! with! the! establishment! of! the!
recommended!dose!of!cisplatin!for!HIPEC!(Submitted!to!the!Journal*of*Clinical*Oncology).!
Because!of!renal!toxicity!related!to!cisplatin!based!HIPEC,!a!phase!II!prospective!study!was!conducted!to!
evaluate! the! morbidity! of! oxaliplatin! based! HIPEC.! As! a! result! of! this! high! morbidity! rate!
(hemoperitoneum),!this!trial!was!prematurely!closed!and!published!in!the*European*Journal*of*Surgical*
Oncology.! Finally,! to! evaluate! the! relationship! between! oxaliplatin! exposure! and! observed! toxicity,! a!
population!pharmacokinetics!was!conducted!in!75!patients!treated!with!CRS!and!oxaliplatin!based!HIPEC.!
A!PK!contribution,!relative!to!the!absorption!phenomenon,!on!the!severity!of!the!thrombocytopenia!and!
hemoperitoneum!was!shown.!This!work!was!published!in!Cancer*Chemotherapy*and*Pharmacology.!
!
56!
Auteur:!ThierryGGwénaël!FERRON!
Titre:! Modalités! thérapeutiques! de! la! carcinose! peritoneale.! Role! de! la!
chimiohyperthermie!
intraperitoneale!
–!
Etudes!
pharmacocinétiques!
et!
pharmacodynamiques!
Mots! clefs:! ! Intraperitoneal,! chimiotherapie,! carcinose,! pharmacocinetique,!
hyperthermie,!
Résumé:!!
La! carcinose! péritonéale! (CP)! correspond! le! plus! souvent! à! l’envahissement! métastatique! de! la! cavité!
péritonéale!survenant!dans!85!à!90%!des!cas!de!l’ovaire!et!5!à!20%!des!cancers!colorectaux.!La!pauvreté!
de!des!signes!cliniques!explique!que!le!diagnostic!se!fasse!à!un!stade!souvent!avancé.!!
Jusque! récemment,! le! traitement! d’une! CP! était! exclusivement! palliatif! avec! une! chirurgie! de!
nécessité! incomplète! et! une! chimiothérapie! systémique,! et! une! survie! médiocre.! La! cause! du! décès! est!
dans! la! majorité! des! cas! la! carcinose! elleGmême.! Les! avancées! en! matière! de! chirurgie! péritonéale!
extensive! et! de! chimiothérapie! intrapéritonéale! combinée! ou! non! à! une! hyperthermie! ont! fait! naître! de!
nombreux! espoirs! de! curabilité.! La! chirurgie! de! cytoreduction! complète! représente! le! facteur! pronostic!
essentiel,!quelque!soit!l’origine!tumorale!primitive.!L’association!d’une!chirurgie!et!d’une!chimiothérapie!
intraperitonéale! a! été! développée! dans! le! cancer! de! l’ovaire! avec! des! taux! de! survie! impressionnants.!
L’hyperthermie! induit! une! destruction! sélective! des! cellules! en! hypoxie,! dans! des! zones! tumorales! en!
acidose,! tout! en! préservant! le! tissu! sain! environnant.! Pour! les! patients! atteints! de! CP,! une! technique!
nommée!CHIP!a!été!developpée!permettant!de!délivrer!une!chimiothérapie!intrapéritonéale!en!condition!
d’hyperthermie.! Une! augmentation! importante! de! la! survie! de! patients! atteints! de! CP! colorectal! ou! de!
maladie! rare! du! péritoine! a! été! mise! en! évidence.! Des! essais! cliniques! sont! en! cours! afin! de! vérifier! le!
bénéfice!attendu!de!l’HIPEC!dans!différentes!pathologies.!
Premièrement,!compte!tenu!de!large!développement!de!la!laparoscopie,!l’adressage!de!patients!
avec! une! carcinose! localisée! est! fréquent.! Nous! avons! développé,! sur! modèle! animal,! une! technique! de!
péritonectomie! laparoscopique! avec! CHIP! à! l’oxaliplatine.! Les! paramètres! pharmacocinétiques! (PK)! en!
terme!d’absorption!de!la!drogue!et!de!pénétration!intraGtissulaire!ont!été!analysés!avec!mise!en!évidence!
du! rôle! favorable! de! l’hyperpression! intraabdominale.! Ces! travaux! ont! été! publié! dans! Gynecologic*
Oncology,!dans!Annals*of*Surgical*Oncology!(2!articles)!et!inclus!dans!un!chapitre*de*livre*international*
(Humana*Press)*concernant!la!pharmacologie!et!la!PK!des!sels!de!platine.!
Ensuite,!nous!avons!établi!un!nouveau!modèle!de!pharmacocinétique!des!populations!que!nous!
avons! appliqué! à! la! comparaison! de! deux! modes! d’administration! de! la! chimiothérapie! lors! des! CHIP! à!
l’oxaliplatine,!sur!24!patients.!Ce!travail!a!été!publié!dans!Cancer*Chemotherapy*and*Pharmacology.!!
Enfin,!différentes!études!cliniques!et!pharmacodynamiques!(PD)!ont!été!réalisée!afin!d’évaluer!et!
de!prédire!la!toxicité!spécifique!des!CHIP!réalisées!au!Cisplatine!et!à!l’Oxaliplatine.!
Trois!travaux!successifs!ont!été!réalisés!pour!évaluer!la!toxicité!rénale!liée!au!Cisplatine.!Dans!une!
étude!pilote!de!PK,!non!publiée,!de!désescalade!de!dose,!nous!avons!montré!que!le!risque!d’insuffisance!
rénale! n’est! pas! expliqué! par! la! PK! (présentation! au! Congrès! de! PharmacoGOncologistes).! Cela! a! été!
confirmé!dans!une!étude!rétrospective!bicentrique!avec!mise!en!évidence!de!facteurs!de!risque.!Ce!travail!
est! soumis! à! publication! dans! European* Journal* of* Surgical* Oncology.! Enfin! une! étude! de! phase! I!
d’escalade!de!dose!a!été!réalisée!permettant!de!déterminer!la!dose!optimale!de!Cisplatine!en!CHIP!et!est!
soumise!à!publication!dans!Journal*of*Clinical*Oncology.!!
Compte! tenu! de! la! toxicité! rénale! du! cisplatine,! une! étude! prospective! de! phase! II! a! évalué! la!
morbidité! de! l’oxaliplatine! en! CHIP! dans! le! cancer! de! l’ovaire.! Cet! essai! a! été! clos! de! façon! anticipée!
compte! tenu! du! taux! d’hémopéritoine! et! publié! dans! European* Journal* of* Surgical* Oncology.! Afin!
d’analyser! et! prédire! ce! risque,! une! étude! PKGPD! a! été! conduite! sur! 75! patients! traités! par! CHIP! à!
l’oxaliplatine! avec! une! corrélation! PK! entre! ! l’absorption! et! la! survenue! de! thrombopénie! et!
d’hémoperitoine.!Ce!travail!est!publié!dans!Cancer*Chemotherapy*and*Pharmacology.!
!
57!