Pseudomyxoma Peritonei Where are we in 2014?
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1 Pseudomyxoma Peritonei Where are we in 2014? Santiago González-Moreno, MD, PhD Head, Department of GI Surgical Oncology Peritoneal Surface Oncology Program Medical Director
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3 French Organization Courtesy of Olivier Glehen, MD, PhD 3 LEVELS OF EXPERIENCE Expert Center (3) Competence Center (6) Specialized Center (21) BIG-RENAPE
4 1. Background: Some scientific contributions 1.! Management of Colorectal Carcinomatosis. a.! Pivotal Dutch trial (Verwaal, Zoetmulder et al) b.! Use of Oxaliplatin / Irinotecan in HIPEC (Elias et al) c.! HIPEC vs no HIPEC (PRODIGE 7) (PI F Quenet) 2.! Management of advanced ovarian cancer a.! b.! CHIPOR (PI Bereder) Dutch trial (PI van Driel) 3.! Prophylaxis and Early Detection of Peritoneal Disease a.! b.! Prophylochip (PI D Elias) Gastrichip (PI O Glehen) 4.! French registry studies (gastric, mesothelioma, colorectal, PMP, ovarian...)
5 1. Background: Some scientific contributions 1.! Management of Colorectal Carcinomatosis. a.! Pivotal Dutch trial (Verwaal, Zoetmulder et al) b.! Use of Oxaliplatin / Irinotecan in HIPEC (Elias et al) c.! HIPEC vs no HIPEC (PRODIGE 7) (PI F Quenet) 2.! Management of advanced ovarian cancer a.! b.! CHIPOR (PI Bereder) Dutch trial (PI van Driel) 3.! Prophylaxis and Early Detection of Peritoneal Disease a.! b.! Prophylochip (PI D Elias) Gastrichip (PI O Glehen) 4.! French registry studies (gastric, mesothelioma, colorectal, PMP, ovarian...)
6 GRUPO ESPA OL DE CIRUGê A ONCOLî Treatment Centers in Spain (16) GICA PERITONEAL (GECOP) * * * * ** * * * * * * * *
7 Collaborative efforts in Peritoneal Surface Oncology
8 Pseudomyxoma peritonei: issues What is not that new (but important)?: Standard knowledge and practice Definition. Site of origin. Histopathology. Therapeutic Management: primary tumor /peritoneal disease What is new? Consensus on PMP classification / terminology (ongoing) What is next? PSOGI Congress. Amsterdam October 2014
9 Pseudomyxoma peritonei: issues What is not that new (but important)? Standard knowledge and practice Definition. Site of origin. Histopathology. Therapeutic Management: primary tumor /peritoneal disease What is new? Consensus on PMP classification / terminology (ongoing) What is next? PSOGI Congress. Amsterdam October 2014
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14 Pseudomyxoma peritonei: definition
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17 Pseudomyxoma peritonei: definition CLINICAL descriptive term, NOT A PATHOLOGICAL DIAGNOSIS Mucinous peritoneal implants and/or mucinous ascites originating from a ruptured appendiceal neoplasm (= mucinous appendiceal neoplasm with peritoneal metastases) Predictable pattern of intraperitoneal dissemination on the basis of a redistribution phenomenon Represents different diseases with varied histopathological appearances
18 Pseudomyxoma peritonei: natural history Courtesy P Sugarbaker (WCI, USA) Regional Lymph node involvement 4.2 % Distant metastases 6 % Protracted clinical course, slow growth, indolent behaviour Rare disease : 1 / Gonz lez-moreno S. Ph D thesis, n= 501
19 Pseudomyxoma peritonei: a disease model!#$%&$'()*+$,*&#$%-(*.$/,+-00$)-./1*. &%*)/2+*)-.*#$,3-'#%-)/%4.$*#,/0)0 (5/(6-,,*.,4$7'$#1*./,,4)$(/0(/0-8$ *9(0-+$(5$#$%-(*.$/,'/3-(4!+-0$/0$0(/(90/)$./2,$(* '9%/13$:-.($.(#$%-(*.$/,,*'*%$;-*./,(5$%/#4 #$%-(*.$/,'/%'-.*)/(*0-0 González-Moreno S. Pseudomyxoma peritonei: a are disease and a disease model in peritoneal surface oncology. Clin Transl Oncol 2011; 13:211-2
20 Pseudomyxoma peritonei: a disease model Glehen O et al. Cancer 2010; 116:
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22 Pseudomyxoma peritonei: natural history
23 Appendiceal Neoplasms with Peritoneal Metastases Prognostic Implications of Histopathology Histopathology is the driver of prognosis and therapy
24 Epithelial Appendiceal Neoplasms: Subclassification!!GH=BIJH?!! B.($01./,*%'*,*.-' Histopathological criterion (50 %) Uihlein A, McDonald JR. Primary carcinoma of the appendix resembling carcinoma of the colon Surg Gynecol Obstet 1943; 76:
25 Epithelial Appendiceal Neoplasms: Subclassification!#$%&'( $%)*')$%+,( -./ ( K*6;%/+$!/+$.*'/L'*,*. 8943:.1;<( I*.-.3/0-3$ B.3/0-3$ A$%-(*.$/, K4)#5/1'MD$)/(*;$.L ';<69<7(!##$.+$'(*)4 D$)-'*,$'(*)4 A<16?1/./( G*%$&/3*%/2,$ K$00&/3*%/2,$
26 p<0.001 (log-rak) p<0.258 (Cox prop haz) n = 501
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32 Epithelial Appendiceal Neoplasms: SURGICAL MANAGEMENT Epithelial Appendiceal Neoplasm GH=BIJH? BINE?NBI!K K*6;%/+$!#$%&' D-;5;%/+$!$#(#&' Cecal involvement Biopsy positive Regional LN Ò '$'$'(*)4*% -,$*:'$'$'(*)4 >-;5(=*,$'(*)4 Mesoappendiceal LN positive
33 Pseudomyxoma peritonei: histopathology
34 Appendiceal Mucinous Neoplasms with Peritoneal Dissemination Prognostic Implications of Histopathology The pathology of the peritoneal lesion is the key factor that determines prognosis over the pathology of the primary tumor Ronnett et al., 1995 Bradley et al., 2006 Carr et al., 2012
35 Pseudomyxoma peritonei: standard of care
36 Pseudomyxoma peritonei: treatments Traditional: Palliative Serial debulking Ip chemotherapy Aggressive: Curative - intent Cytoreductive surgery Perioperative Ip chemotherapy Gough et al., 1994 (n=56) Miner et al, 2005 (n=97) Sugarbaker, 2009 (n= 801) Youssef et al., 2010 (n= 411) Chua et al, 2010, 2012 (n=2298) Elias et al., 2011 (n=301) No role for systemic chemotherapy except for high-grade cases and/or recurrent disease with no further surgical options
37 Pseudomyxoma peritonei: Comparative Treatment Results 70 % at 20 years CC - 0/1 Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncology 2006; 7(1):69-76
38 Pseudomyxoma peritonei: available evidence!9(5*% =*9.(%4. O409%3 CPF?9;/%2/S$% =/.'$%TURRV H? CQ'$.($%F WRQ QR409%3 CPF UR:4$/%&*,,*6:9#24#( '/($;*%-$0 E,-/0$(/,L ET?JURQR X%/.'$ C)9,1'$.(%-'F YRQ ZY[CW\F ]X?O^P O\[C^QF _*900$&$(/,L ]=>URQR H< CQ'$.($%F \\Q ^V[CWZF OZ[CZ\F * Overall (complete CR)
39 2298 patients over 18 years 16 treatment centers (Europe, North America, Australia) Median survival 16.3 years Median PFS 8.2 years 10-year survival 63 % 15-year survival 59 %
40 Pseudomyxoma peritonei: available evidence `=4(*%$+9'13$09%;$%4'*)2-.$+6-(5#$%-*#$%/13$ -.(%/#$%-(*.$/,'5$)*(5$%/#4-09.a9$01*./2,4 '*.0-+$%$+(5$0(/.+/%+*&'/%$&*%)9'-.*90 /##$.+-'$/,(9)*%06-(5#$%-(*.$/,0#%$/+/((5$ #%$0$.(1)$b A81'B'281<';+:*.'CDDEF'GC!E&>'HIG0E'!
41 Pseudomyxoma peritonei: available evidence `>$'$.($3-+$.'$09;;$0(0(5/(*#1)/,09%;-'/, %$0$'1*.C'*)#,$($'4(*%$+9'1*.c-&#*00-2,$F '*)2-.$+6-(5DBAE=-0(5$)*0(&9.+/)$.(/,,4 2/0$+0(%/($;4&*%AGAb ' B'281<';+:*.'CDDQF'IQ>'CRR0CQC'
42 Pseudomyxoma peritonei: available evidence!2 systematic reviews of literature (Bryant 2005, Yan 2006)!Comparison with historical controls (Sugarbaker 2004)!Large retrospective patient series, uniform treatment, prolonged follow up (> 10 y) Sugarbaker 2009, personal experience, n=801 Elias et al. 2010, French multicentric, n=301 Youssef et al. 2010, monocentric UK, n=441 Chua et, multicentric worldwide, n= 2298!Several smaller monoinstitutional patient series (n<100)!expert consensus meeting (Madrid 2004, Milan 2006) Is this enough evidence to accept CRS + PIC as the standard of care for PMP? Is a randomized trial needed? Can a randomized trial be carried out in PMP?
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58 Pseudomyxoma peritonei: some HIPEC regimens Center / Country HIPEC Drug(s) and doses HIPEC Duration (minutes) Concomitant Intravenous Chemotherapy EPIC Washington Hospital Center Washington, DC (USA) Mitomycin C, 15 mg/m 2 Doxorubicin, 15 mg/m FU, 400 mg/m 2 LV, 20 mg/m 2 5-FU 4 days Washington Hospital Center Washington, DC (USA) Gustave Roussy Institute Villejuif (France) Oxaliplatin, 130 mg/m FU, 400 mg/m 2 LV, 20 mg/m 2 Oxaliplatin, 460 mg/m FU, 400 mg/m 2 LV, 20 mg/m 2 5-FU 4 days No National Cancer Institute Amsterdam (Netherlands) National Cancer Institute Milan (Italy) Centre Hospitalo-Universitaire Lyon-Sud Lyon (France) Mitomycin C, 35 mg/m 2 90 No No MitomycinC,3.3mg/m 2 /L Cisplatin, 25 mg/m 2 /L 90 No No Mitomycin C, 10 mg/ ml of perfusate 90 No No
59 Pseudomyxoma peritonei: Prognostic factors! =*)#,$($.$00*& '4(*%$+9'1*. Sugarbaker et al. Lancet Oncol 2006! D-0(*#/(5*,*;4 Ronnett et al. Am J Surg Pathol 1995
60 Pseudomyxoma peritonei: Prognostic factors! A$%-(*.$/,+-0$/0$ 29%+$.CA=BF PCI < 20 PCI > 20 Sugarbaker PH. Cancer J 2009
61 Pseudomyxoma peritonei: issues What is not that new (but important)? Definition. Site of origin. Histopathology. Therapeutic Management: primary tumor /peritoneal disease What is new? Consensus on PMP classification / terminology (ongoing) What is next? PSOGI Congress. Amsterdam October 2014
62 Pseudomyxoma peritonei: issues What is new? Consensus on PMP classification / terminology (ongoing) In my own mind it is clear that the newest thing in PMP is that pathologists and clinicians are working together under PSOGI auspices in trying to achieve a consensus in terminology, to be announced in Amsterdam in October 2014
63 The Ronnett Classification Histopathological Characterization of PMP All patients treated by a uniform treatment strategy, by the same surgeon
64 The Ronnett Classification: Histopathological Characterization of PMP Before Ronnett After Ronnett Low-grade mucinous adenocarcinoma of the appendix with PMP Mucinous adenoma or adenocarcinoma with peritoneal dissemination (3 tier) Histopathological Characterization of the Clinical syndrome PMP, showing its diversity PIVOTAL STUDY
65 Appendiceal Mucinous Neoplasms with Peritoneal Dissemination Prognostic Implications of Histopathology The pathology of the peritoneal lesion is the key factor that determines prognosis over the pathology of the primary tumor Ronnett et al., 1995 Bradley et al., 2006 Carr et al., 2012
66 APÉNDICE
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71 Pseudomixoma Peritonei: Characterization of the primary appendiceal tumor The absence or presence of mucus or epithelium in the peritoneum determines the primary tumor diagnosis, irespective of its histological appearance The presence of mucus outside the appendix, even if it is acellular, is not compatible with a diagnosis of adenoma (a lesion curable by complete excision). (Carr, Sobin, WHO Classification of digestive tumors 2010 ) The question of whether these tumors are ruptured adenomas or invasive carcinomas is not easily answered. (Misdraji, 2010): INTERMEDIATE TERMS: MUCINOUS APPENDICEAL NEOPLASM, LAMN borderline tumor of the appendix, mucinous tumors of low malignant potential, mucinous tumors of uncertain malignant potential The nomenclature of peritoneal lesions and primary tumor should reflect its histological appearance A ruptured adenoma with associated DPAM is still an adenoma; its prognosis is certainly different from an intact adenoma without peritoneal dissemination; the adjectives specify this detail
72 Pseudomixoma Peritonei: Characterization of the primary appendiceal tumor LOW-GRADE APPENDICEAL MUCINOUS NEOPLASMS (LAMN) MUCINOUS ADENOCARCINOMA (MACA) DISCORDANT FEATURES
73 PMP: nomenclature histopathological classification >*..$d$(/,lc QVVO ed=c.qrvf G-0+%/f-$(/,Lc URRY GgDC.QRZF h%/+,$4$(/,lc URRO exhc.qrqf ]A!G K!GI AG=!iBM] ( AG=! C,*6c-.($%)c5-;5F G!=! G=A:,*6 G=A:5-;5
74 PMP: Histopathological Classifications ( #5.?.DEA30415F( *G29<0(#9?09<(H(?.I1<>()<930>9?0( J1??9K(90(35FL(MNNO( P-#(Q?(R(MSNT( AGA',-.-'/,04.+%*)$ _E? _E?!./V<3C.(90(35FL(WSSX(!Y-(Q?(R(MSZT( ',/00-&4)9'-.*90.$*#,/0)0*&(5$ /##$.+-7 _E? IJ 8<3V597(90(35FL(WSS\( P](Q?(R(MSMT( '*.(%*3$%0-$0-.',/00-j'/1*.*& AGA/.+)9'-.*90.$*#,/0)0*&(5$ /##$.+-7 _E? _E? #3<<(90(35FL(WSMW( 83/.?6/01^9(Q?(R(WZNT( _35.V309(eDJ=,/00-j'/1*.*&AGAc URQR _E? _E?
75 PMP: Histopathological Classifications Ronnett WHO 3rd Misdraji Bradley WHO 4th
76 confusion information
77 The Ronnett Classification: Common language across the world +;041<( #1;?0<7(?( ';63<B3^9<(((((((((((((((((((( #3?D9<(`(WSSN( H?! CQ'$.($%F WRQ >*..$d *5.3/(90(35F((((((((((((((((((( *`'&(WSMS( X%/.'$ C)9,1'$.(%-'F YRQ >*..$d #4;3(90(35F((((((((((((((( `#&(WSMW( B.($%./1*./, C)9,1'$.(%-'F UUVW >*..$d
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79 Adenocarcinoma of the appendix (WHO) NJ Carr, MJ Arends, GT Deans, LH Sobin It has been suggested that appendix adenomas may cause disseminated pseudomixoma peritonei with a terminal outcome, and some authors use the term adenomucinosis for the spread of these lesiones within the abdomen. It is considered that with higher probability these cases are examples of well-differentiated adenocarcinoma 3 rd Ed., 2000
80 Adenocarcinoma of the appendix (WHO) NJ Carr, LH Sobin The term disseminated peritoneal adenomucinosis (DPAM) should be avoided, since low and high grade lesions represent a continous spectrum and the concept of ruptured adenoma does not reflect the clinical course that ofentimes result in death from abdominal visceral obstruction Primary tumor: Misdraji PMP: Bradley Descriptive terms, with no diagnostic nor prognostic value: 4ª Ed, 2010 Cyst Mucocele
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82 The Ronnett Classification for PMP: a valid tool for patient management 17 years later Santiago González-Moreno, MD, PhD Department of Surgical Oncology Peritoneal Surface Oncology Program Need for a consensus on terminology
83 Pathological Characterization of Pseudomixoma Peritonei: Objectives :N*+$0'%-2$(5$5-0(*#/(5*,*;-'/,0#$'(%9)*&(5$+-0$/0$ :N*+$3$,*#/.*)$.',/(9%$(5/(k! >$l$'(0-(0#$'9,-/%2-*,*;-'/,2$5/3-*9%! D/0#%*;.*01'-)#,-'/1*.0! B090$&9,&*%(5$%/#$91'+$'-00-*.:)/S-.;! A%*3-+$0/'*))*.,/.;9/;$&*%',-.-'-/.0/.+ #/(5*,*;-0(0
84 Pathological Characterization of Pseudomixoma Peritonei: Methodology :! G*+-j$+]$,#5-#%*'$00k :! =,-.-'-/.+06-(5$7#$%-$.'$-.(5$j$,+(5%*9;5/00*'-/1*.6-(5A?JgB :! E7#$%(#/(5*,*;-0(0 :! X$2%9/%4URQYLX-%0(>*9.+*&a9$01*.0C\F24$)/-,C^O F :! G/4URQYLG$$1.;-.h/0-.;0(*S$L]-0'900-*.*&/.06$%0L :! =-%'9,/1*.*&09))/%4*&+-0'900-*.0/.+/.06$%0 :! J'(*2$%URQYL?$'*.+%*9.+*&a9$01*.0CWFC+$/+,-.$QUMQYF :! G/4URQ\L=-%'9,/1*.*&/.06$%0(*0$'*.+%*9.+ /.+N5-%+%*9.+*&QVa9$01*.0C+$/+,-.$R^MQ\F
85 May 2013
86 Pathological Characterization of Pseudomixoma Peritonei: ISSUES :! ]$j.-1*./.+90$*&(5$($%)`agabl :! G/,-;./.(30L2$.-;../(9%$L :! h-./%4*%($%./%4',/00-j'/1*.l :!?4.*.-)0*%/j7$+.*)$.',/(9%$L :! G$/.-.;*&?-;.$(:%-.;'$,,0/.+(5$-%%$,/13$a9/.1(4L :! G$/.-.;*&$7(%//##$.+-'$/,/'$,,9,/%)9'-.L :! I*)$.',/(9%$*&#%-)/%4/##$.+-'$/,(9)*%0 :! =,-.-'/,'*%%$,/1*./.+/##,-'/2-,-(4L
87 Consensus on Pseudomixoma Peritonei: DELIVERABLES :! B.($%./1*./,=*.0$.090*.I*)$.',/(9%$ :! G*+-j'/1*.*&'9%%$.(NIG',/00-j'/1*. :! K$d$%(*A%*&Le5-($S-.+CHB==F :! =%$/1*.*&/6*%S-.;;%*9#*&#/(5*,*;-0(0(*$7#,*%$ +-/;.*01''%-($%-//.+0/)#,-.;-009$0c-.3*,3-.;'-%'9,/1*.*& 0,-+$0 :! A%*&*%)/&*%%$#*%1.;C'5$'S,-0(F :! K/%;$%%$0$/%'5+/(/2/0$6-(5#/(5*,*;-'/,M0(/;-.;&$/(9%$0
88 I*)$.',/(9%$ HIIC Heated Intraoperative Intraperitoneal Chemotherapy HIPEC Hyperthermic IntraPeritoneal Chemotherapy IPCH IntraPeritoneal ChemoHyperthermia IPHC IntraPeritoneal Hyperthermic Chemotherapy CHPP Continuous Hyperthermic Peritoneal Perfusion
89 I*)$.',/(9%$ HIIC Heated Intraoperative Intraperitoneal Chemotherapy HIPEC Hyperthermic IntraPeritoneal Chemotherapy IPCH IntraPeritoneal ChemoHyperthermia IPHC IntraPeritoneal Hyperthermic Chemotherapy CHPP Continuous Hyperthermic Peritoneal Perfusion
90 PMP: Histopathological Classifications Ronnett WHO 3rd Misdraji Bradley WHO 4th
91 PMP: Histopathological Classifications Ronnett WHO 3rd Misdraji Bradley WHO 4th PSOGI consensus
92 Pseudomyxoma peritonei: issues What is not that new (but important)? Definition. Site of origin. Histopathology. Therapeutic Management: primary tumor /peritoneal disease What is new? Consensus on PMP classification / terminology (ongoing) What is next? PSOGI Congress. Amsterdam October 2014
93 Pseudomyxoma peritonei: What is next?
94 Pseudomyxoma Peritonei: Take-home Messages 1.! PMP, although a rare disease, has served as a model disease in the development of Peritoneal Surface Oncology. 2.! The clinical and scientific knowledge about PMP as well as its therapeutic approach has developed over the last 2-3 decades and it is very well established at this point. 3.! The main pending issue in PMP has to do with nomenclature associated with its histopathological classification and characterization. Consensus work among expert surgical oncologist and pathologist is underway, another historical landmark for this rare disease.
95 Radiology Medical Oncology Clinical Nutrition Pathology Anesthesiology ( ( Peritoneal Surface Oncology Program Surgical Oncology Intensive Care Hospitalization Nursing O.R. Nursing
96 Merci!
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