A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients
Identifieur interne : 003452 ( PascalFrancis/Checkpoint ); précédent : 003451; suivant : 003453A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients
Auteurs : E. Van Cutsem [Belgique] ; C. Verslype [Belgique] ; P. Beale [Australie] ; S. Clarke [Australie] ; R. Bugat [France] ; A. Rakhit [États-Unis] ; S. H. Fettner [États-Unis] ; U. Brennscheidt [Suisse] ; A. Feyereislova [Suisse] ; J.-P. Delord [France]Source :
- Annals of oncology [ 0923-7534 ] ; 2008.
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- Pascal (Inist)
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
Abstract
Background: Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy. Patients and methods: Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1-14) and i.v. oxaliplatin (day 1 of a 21-day cycle). Results: The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m2 twice daily, oxaliplatin 130 mg/m2) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m2 twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients). Conclusion: The MTD for this combination in MCRC is capecitabine 825 mg/m2 twice daily days 1-14, oxaliplatin 130 mg/m2 day 1 and erlotinib 100 mg/day of a 21 -day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.
Affiliations:
- Australie, Belgique, France, Suisse, États-Unis
- Midi-Pyrénées, Nouvelle-Galles du Sud, Occitanie (région administrative)
- Sydney, Toulouse
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Delord</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Institut Claudius Regaud</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">08-0131158</idno><date when="2008">2008</date><idno type="stanalyst">PASCAL 08-0131158 INIST</idno><idno type="RBID">Pascal:08-0131158</idno><idno type="wicri:Area/PascalFrancis/Corpus">003716</idno><idno type="wicri:Area/PascalFrancis/Curation">002923</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">003452</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">003452</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients</title><author><name sortKey="Van Cutsem, E" sort="Van Cutsem, E" uniqKey="Van Cutsem E" first="E." last="Van Cutsem">E. Van Cutsem</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>University Hospital Gasthuisberg</s1><s2>Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></inist:fA14><country>Belgique</country><wicri:noRegion>University Hospital Gasthuisberg</wicri:noRegion></affiliation></author><author><name sortKey="Verslype, C" sort="Verslype, C" uniqKey="Verslype C" first="C." last="Verslype">C. Verslype</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>University Hospital Gasthuisberg</s1><s2>Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></inist:fA14><country>Belgique</country><wicri:noRegion>University Hospital Gasthuisberg</wicri:noRegion></affiliation></author><author><name sortKey="Beale, P" sort="Beale, P" uniqKey="Beale P" first="P." last="Beale">P. Beale</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Sydney Cancer Centre</s1><s2>Sydney</s2><s3>AUS</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Clarke, S" sort="Clarke, S" uniqKey="Clarke S" first="S." last="Clarke">S. Clarke</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Sydney Cancer Centre</s1><s2>Sydney</s2><s3>AUS</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Australie</country><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Bugat, R" sort="Bugat, R" uniqKey="Bugat R" first="R." last="Bugat">R. Bugat</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Institut Claudius Regaud</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name sortKey="Rakhit, A" sort="Rakhit, A" uniqKey="Rakhit A" first="A." last="Rakhit">A. Rakhit</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>F. Hoffmann-La Roche</s1><s2>Nutley, NJ</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>F. Hoffmann-La Roche</wicri:noRegion></affiliation></author><author><name sortKey="Fettner, S H" sort="Fettner, S H" uniqKey="Fettner S" first="S. H." last="Fettner">S. H. Fettner</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>F. Hoffmann-La Roche</s1><s2>Nutley, NJ</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>F. Hoffmann-La Roche</wicri:noRegion></affiliation></author><author><name sortKey="Brennscheidt, U" sort="Brennscheidt, U" uniqKey="Brennscheidt U" first="U." last="Brennscheidt">U. Brennscheidt</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>F Hoffmann-La Roche Ltd</s1><s2>Basel</s2><s3>CHE</s3><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>F Hoffmann-La Roche Ltd</wicri:noRegion></affiliation></author><author><name sortKey="Feyereislova, A" sort="Feyereislova, A" uniqKey="Feyereislova A" first="A." last="Feyereislova">A. Feyereislova</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>F Hoffmann-La Roche Ltd</s1><s2>Basel</s2><s3>CHE</s3><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Suisse</country><wicri:noRegion>F Hoffmann-La Roche Ltd</wicri:noRegion></affiliation></author><author><name sortKey="Delord, J P" sort="Delord, J P" uniqKey="Delord J" first="J.-P." last="Delord">J.-P. Delord</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Institut Claudius Regaud</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author></analytic><series><title level="j" type="main">Annals of oncology</title><title level="j" type="abbreviated">Ann. oncol.</title><idno type="ISSN">0923-7534</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Annals of oncology</title><title level="j" type="abbreviated">Ann. oncol.</title><idno type="ISSN">0923-7534</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Advanced stage</term><term>Antineoplastic agent</term><term>Capecitabine</term><term>Colorectal cancer</term><term>Erlotinib</term><term>Human</term><term>Increasing dose</term><term>Metastasis</term><term>Oxaliplatin</term><term>Therapeutic protocol</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Dose croissante</term><term>Erlotinib</term><term>Capécitabine</term><term>Oxaliplatine</term><term>Stade avancé</term><term>Métastase</term><term>Cancer colorectal</term><term>Homme</term><term>Protocole thérapeutique</term><term>Anticancéreux</term><term>Protocole XELOX</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background: Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy. Patients and methods: Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1-14) and i.v. oxaliplatin (day 1 of a 21-day cycle). Results: The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m<sup>2</sup> twice daily, oxaliplatin 130 mg/m<sup>2</sup>) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m<sup>2</sup> twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients). Conclusion: The MTD for this combination in MCRC is capecitabine 825 mg/m<sup>2</sup> twice daily days 1-14, oxaliplatin 130 mg/m<sup>2</sup> day 1 and erlotinib 100 mg/day of a 21 -day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0923-7534</s0></fA01><fA03 i2="1"><s0>Ann. oncol.</s0></fA03><fA05><s2>19</s2></fA05><fA06><s2>2</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients</s1></fA08><fA11 i1="01" i2="1"><s1>VAN CUTSEM (E.)</s1></fA11><fA11 i1="02" i2="1"><s1>VERSLYPE (C.)</s1></fA11><fA11 i1="03" i2="1"><s1>BEALE (P.)</s1></fA11><fA11 i1="04" i2="1"><s1>CLARKE (S.)</s1></fA11><fA11 i1="05" i2="1"><s1>BUGAT (R.)</s1></fA11><fA11 i1="06" i2="1"><s1>RAKHIT (A.)</s1></fA11><fA11 i1="07" i2="1"><s1>FETTNER (S. H.)</s1></fA11><fA11 i1="08" i2="1"><s1>BRENNSCHEIDT (U.)</s1></fA11><fA11 i1="09" i2="1"><s1>FEYEREISLOVA (A.)</s1></fA11><fA11 i1="10" i2="1"><s1>DELORD (J.-P.)</s1></fA11><fA14 i1="01"><s1>University Hospital Gasthuisberg</s1><s2>Leuven</s2><s3>BEL</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></fA14><fA14 i1="02"><s1>Sydney Cancer Centre</s1><s2>Sydney</s2><s3>AUS</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></fA14><fA14 i1="03"><s1>Institut Claudius Regaud</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>5 aut.</sZ><sZ>10 aut.</sZ></fA14><fA14 i1="04"><s1>F. Hoffmann-La Roche</s1><s2>Nutley, NJ</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="05"><s1>F Hoffmann-La Roche Ltd</s1><s2>Basel</s2><s3>CHE</s3><sZ>8 aut.</sZ><sZ>9 aut.</sZ></fA14><fA20><s1>332-339</s1></fA20><fA21><s1>2008</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>22429</s2><s5>354000161905310210</s5></fA43><fA44><s0>0000</s0><s1>© 2008 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>37 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>08-0131158</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Annals of oncology</s0></fA64><fA66 i1="01"><s0>GBR</s0></fA66><fC01 i1="01" l="ENG"><s0>Background: Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy. Patients and methods: Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1-14) and i.v. oxaliplatin (day 1 of a 21-day cycle). Results: The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m<sup>2</sup> twice daily, oxaliplatin 130 mg/m<sup>2</sup>) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m<sup>2</sup> twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients). Conclusion: The MTD for this combination in MCRC is capecitabine 825 mg/m<sup>2</sup> twice daily days 1-14, oxaliplatin 130 mg/m<sup>2</sup> day 1 and erlotinib 100 mg/day of a 21 -day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02R</s0></fC02><fC02 i1="02" i2="X"><s0>002B13B01</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Dose croissante</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Increasing dose</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Dosis creciente</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Erlotinib</s0><s2>FR</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Erlotinib</s0><s2>FR</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Erlotinib</s0><s2>FR</s2><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Capécitabine</s0><s2>NK</s2><s2>FR</s2><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Capecitabine</s0><s2>NK</s2><s2>FR</s2><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Capecitabina</s0><s2>NK</s2><s2>FR</s2><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Oxaliplatine</s0><s2>NK</s2><s2>FR</s2><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Oxaliplatin</s0><s2>NK</s2><s2>FR</s2><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Oxaliplatino</s0><s2>NK</s2><s2>FR</s2><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Stade avancé</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Advanced stage</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Estadio avanzado</s0><s5>05</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Métastase</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Metastasis</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Metástasis</s0><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Cancer colorectal</s0><s2>NM</s2><s5>07</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Colorectal cancer</s0><s2>NM</s2><s5>07</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Cancer de colon y recto</s0><s2>NM</s2><s5>07</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Homme</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Human</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Hombre</s0><s5>08</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Protocole thérapeutique</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Therapeutic protocol</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Protocolo terapéutico</s0><s5>09</s5></fC03><fC03 i1="10" i2="X" l="FRE"><s0>Anticancéreux</s0><s5>23</s5></fC03><fC03 i1="10" i2="X" l="ENG"><s0>Antineoplastic agent</s0><s5>23</s5></fC03><fC03 i1="10" i2="X" l="SPA"><s0>Anticanceroso</s0><s5>23</s5></fC03><fC03 i1="11" i2="X" l="FRE"><s0>Protocole XELOX</s0><s4>INC</s4><s5>86</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Inhibiteur enzyme</s0><s5>37</s5></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Enzyme inhibitor</s0><s5>37</s5></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Inhibidor enzima</s0><s5>37</s5></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Dérivé de la quinazoline</s0><s2>FR</s2><s5>38</s5></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Quinazoline derivatives</s0><s2>FR</s2><s5>38</s5></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Protein-tyrosine kinase</s0><s2>FE</s2><s5>39</s5></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Protein-tyrosine kinase</s0><s2>FE</s2><s5>39</s5></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Protein-tyrosine kinase</s0><s2>FE</s2><s5>39</s5></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Transferases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Transferases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Transferases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Enzima</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Inhibiteur de la tyrosine kinase</s0><s5>40</s5></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Tyrosine kinase inhibitor</s0><s5>40</s5></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Inhibidor tyrosine kinase</s0><s5>40</s5></fC07><fC07 i1="07" i2="X" l="FRE"><s0>Dérivé de la fluoropyrimidine</s0><s5>41</s5></fC07><fC07 i1="07" i2="X" l="ENG"><s0>Fluoropyrimidine derivatives</s0><s5>41</s5></fC07><fC07 i1="07" i2="X" l="SPA"><s0>Fluoropirimidina derivado</s0><s5>41</s5></fC07><fC07 i1="08" i2="X" l="FRE"><s0>Pyrimidine nucléoside</s0><s5>42</s5></fC07><fC07 i1="08" i2="X" l="ENG"><s0>Pyrimidine nucleoside</s0><s5>42</s5></fC07><fC07 i1="08" i2="X" l="SPA"><s0>Pirimidina nucleósido</s0><s5>42</s5></fC07><fC07 i1="09" i2="X" l="FRE"><s0>Agent alkylant</s0><s5>43</s5></fC07><fC07 i1="09" i2="X" l="ENG"><s0>Alkylating agent</s0><s5>43</s5></fC07><fC07 i1="09" i2="X" l="SPA"><s0>Agente alquilante</s0><s5>43</s5></fC07><fC07 i1="10" i2="X" l="FRE"><s0>Platine II Complexe</s0><s2>NC</s2><s2>NA</s2><s5>44</s5></fC07><fC07 i1="10" i2="X" l="ENG"><s0>Platinum II Complexes</s0><s2>NC</s2><s2>NA</s2><s5>44</s5></fC07><fC07 i1="10" i2="X" l="SPA"><s0>Platino II Complejo</s0><s2>NC</s2><s2>NA</s2><s5>44</s5></fC07><fC07 i1="11" i2="X" l="FRE"><s0>Tumeur maligne</s0><s2>NM</s2><s5>45</s5></fC07><fC07 i1="11" i2="X" l="ENG"><s0>Malignant tumor</s0><s2>NM</s2><s5>45</s5></fC07><fC07 i1="11" i2="X" l="SPA"><s0>Tumor maligno</s0><s2>NM</s2><s5>45</s5></fC07><fC07 i1="12" i2="X" l="FRE"><s0>Cancer</s0><s2>NM</s2></fC07><fC07 i1="12" i2="X" l="ENG"><s0>Cancer</s0><s2>NM</s2></fC07><fC07 i1="12" i2="X" l="SPA"><s0>Cáncer</s0><s2>NM</s2></fC07><fC07 i1="13" i2="X" l="FRE"><s0>Pathologie de l'appareil digestif</s0><s5>46</s5></fC07><fC07 i1="13" i2="X" l="ENG"><s0>Digestive diseases</s0><s5>46</s5></fC07><fC07 i1="13" i2="X" l="SPA"><s0>Aparato digestivo patología</s0><s5>46</s5></fC07><fC07 i1="14" i2="X" l="FRE"><s0>Pathologie du côlon</s0><s5>47</s5></fC07><fC07 i1="14" i2="X" l="ENG"><s0>Colonic disease</s0><s5>47</s5></fC07><fC07 i1="14" i2="X" l="SPA"><s0>Colón patología</s0><s5>47</s5></fC07><fC07 i1="15" i2="X" l="FRE"><s0>Pathologie de l'intestin</s0><s5>48</s5></fC07><fC07 i1="15" i2="X" l="ENG"><s0>Intestinal disease</s0><s5>48</s5></fC07><fC07 i1="15" i2="X" l="SPA"><s0>Intestino patología</s0><s5>48</s5></fC07><fC07 i1="16" i2="X" l="FRE"><s0>Pathologie du rectum</s0><s5>49</s5></fC07><fC07 i1="16" i2="X" l="ENG"><s0>Rectal disease</s0><s5>49</s5></fC07><fC07 i1="16" i2="X" l="SPA"><s0>Recto patología</s0><s5>49</s5></fC07><fN21><s1>077</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist><affiliations><list><country><li>Australie</li><li>Belgique</li><li>France</li><li>Suisse</li><li>États-Unis</li></country><region><li>Midi-Pyrénées</li><li>Nouvelle-Galles du Sud</li><li>Occitanie (région administrative)</li></region><settlement><li>Sydney</li><li>Toulouse</li></settlement></list><tree><country name="Belgique"><noRegion><name sortKey="Van Cutsem, E" sort="Van Cutsem, E" uniqKey="Van Cutsem E" first="E." last="Van Cutsem">E. Van Cutsem</name></noRegion><name sortKey="Verslype, C" sort="Verslype, C" uniqKey="Verslype C" first="C." last="Verslype">C. Verslype</name></country><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Beale, P" sort="Beale, P" uniqKey="Beale P" first="P." last="Beale">P. Beale</name></region><name sortKey="Clarke, S" sort="Clarke, S" uniqKey="Clarke S" first="S." last="Clarke">S. Clarke</name></country><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Bugat, R" sort="Bugat, R" uniqKey="Bugat R" first="R." last="Bugat">R. Bugat</name></region><name sortKey="Delord, J P" sort="Delord, J P" uniqKey="Delord J" first="J.-P." last="Delord">J.-P. Delord</name></country><country name="États-Unis"><noRegion><name sortKey="Rakhit, A" sort="Rakhit, A" uniqKey="Rakhit A" first="A." last="Rakhit">A. Rakhit</name></noRegion><name sortKey="Fettner, S H" sort="Fettner, S H" uniqKey="Fettner S" first="S. H." last="Fettner">S. H. Fettner</name></country><country name="Suisse"><noRegion><name sortKey="Brennscheidt, U" sort="Brennscheidt, U" uniqKey="Brennscheidt U" first="U." last="Brennscheidt">U. Brennscheidt</name></noRegion><name sortKey="Feyereislova, A" sort="Feyereislova, A" uniqKey="Feyereislova A" first="A." last="Feyereislova">A. Feyereislova</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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