Giuseppe Maria Ettorre - Il ruolo della chirurgia oncologica nell'era delle terapie target nella neoplasia colorettale metastatica: ...
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Il ruolo della chirurgia oncologica nell’era delle
terapie target nella neoplasia colorettale
metastatica: massimizzazione dell’integrazione,
il concetto di
“prognostic surgery” e “biological surgery”
Giuseppe Maria EttorreChirurgia Generale e Trapianti d’Organo Polo Ospedaliero Interaziendale Trapianti S. Camillo–Forlanini INMI “L. Spallanzani”
over time
1400
1200
1000 139
800
600
400
966
139
200
295
0Accademia Lancisiana
Simposio
Moderatore: D. Manfredi“Vi era un atteggiamento rinunciatario
fino agli anni 80…poi con il contributo di
Couinaud, Ton That Tung, Gans, Pettinari
si è ridotta la mortalita operatoria”
“era tramontata l’epoca in cui il fegato
era considerato la terra di nessuno per il
chirurgo”
Atti Acc. Lanc 198424 gennaio 1984
Moderatore: D. Manfredi
Casistica Personale 187 resezioni
Periodo dal 1960 al 1974:
74 resezioni “a la demande”
Tumori maligni secondari 27,3% di mortalità
Periodo dal 1975 al 1983
113 resezioni con tecnica della“digitoclasia”
Tumori maligni secondari 11,1% di mortalitàSimposio dell’11 dicembre 1990
Le metastasi: biologia, diagnosi e
possibilità terapeutiche
Moderatore: D. Manfredi
Casistica Personale 176 resezioni
Mortalità 8,3%
Complicanze maggiori:
emorragia postoperatoria
ascessi sub freniciLortat-Jacob 1952: •Toracofrenolaparotomia • Perdite importanti • Clampaggio vascolare • Diagnosi incerta pre op
Hepp, Couinaud,
Lortat-Jacob,Fekete,
Bismuth, Belghiti,
Gayet
60 anni dopoPresent result
Inchiesta AFC, 1997
Fattori prognostici sfavorevoli
Tumore Primitivo - Infiltrazione Sierosa
- Dukes C (N+)
Metastasi- - Numero > 4
- Diametro > 5 cm
- Margine resezione < 1cmOne or Two Stage Heptectomy Combined with
Portal Vein Embolization for Initially
Nonresectable Colorectal Cancer Liver
Metastases
• No post-operative
mortality
• Long-Term Survival
comparable to
patients with initially
resectable CRLM
Jaeck Am J Surg 2003Colorectal liver metastases
Paul Brousse Hospital - 1400 patients (1988 - 2000)
Non resectable
Initially non resectable
CHEMO : 1105 (79%)
1400 Resectable
13%
1200
1000 139 RESECTION : 434
800
87% 32%
600
400
966 68%
139
200
295
0Overall survival after resection of multiple liver
metastases according to chemotherapy response
(%)
100 Im
po
ssi
95% Responding : 58
Im
po
ssi
92% Stabilization : 39
Im
po
ssi
80
I
m
p
Progression : 34
Im
po
ssi
bil
I
m
p
Im
po
ssi
bil
Im
po
ssi
bil
I
m
p
60 55%
I
m
p
63%
Im Im
po po
ssi ssi
bil bil
Im
po
ssi
bil
I
m
p
Im
po
ssi
Im
po
ssi
bil
44%
Im
po
40
ssi
37%
Im
po
ssi
bil
I
m
p
Im
po
ssi
Im
po
ssi
bil
Im
po
ssi
30%
Im
pos
20
si…
I I
m m
p p
Im
po
ssi
bil
12%
Log Rank: p< 0.0001 Im
po
ssi
bil
I
m
p
Im
po
ssi
8%
0 1 2 3 4 5
Years
Update: Adam R et al. Ann Surg 2004; 240:644–658Novel therapies
8
Relative no. of pts treateda 7 Irinotecan
Oxaliplatin
6 Bevacizumab
5 Erbitux
4
3
2
1
0
Year
The increase in OS in non-resected patients corresponds
with the use of currently available targeted therapies:
cetuximab and bevacizumab
aCompared with irinotecan use in 1998 Kopetz S, et al. J Clin Oncol 2009;27:3677–3683The impact of multidisciplinary management
2012 chemotherapy
100 Median survival >30 months
5-year survival 15 %
2012 overall (surgery + chemo)
Median survival >40 months
5-year survival 30 %
Surviving %
50 2022
>50%?
30%
2002 1,000%
15% in
10 yrs
3%
0
0 1 2 3 4 5
Years after diagnosis of colorectal metastases
Poston G, et al. J Clin Oncol 2008;26:4828–33; Kopetz S, et al. J Clin Oncol 2009;27:3677–3683; data on fileLiver Resection of Colorectal Metastases : 15895 patients
Pre-operative chemotherapyLiver Resection of Colorectal Metastases : 8051 patients
Pre-operative chemotherapyLiver Resection of Colorectal Metastases : 8051 patients
Pre-operative chemotherapy
25% of the patients
receive a targeted
therapyWhy are we getting better? • Multi-modal therapy • No one medical specialty is dominant • All are required: - hepatobilary surgery - medical oncology - radiology - anesthesiology - gastroenterology • MULTI-DISCIPLINARY TEAM WORKING
European Colorectal Metastases
Treatment Group recommendations
1. Van Cutsem E, et al. Eur J Cancer 2006;42:2212–2221; 2. Nordlinger B, et al. Eur J Cancer 2007;43:2037–2045
• “There needs to be an insistence on a
multidisciplinary approach to the treatment of
patients [with mCRC] with an improved appraisal of
their status and improved work-up”1
• “All cases involving resection should be discussed in
multidisciplinary team meetings”2Comparison of process and liver resection rates in
Erbitux trials in liver-limited KRAS wt studies
Who % RR Who determined Liver resection
Study recruited? Erbitux arm liver resectability? rate Erbitux arm
Treatment Decision on liver
General
CRYSTAL oncologist
with Erbitux
RR 71%
resection by
general
oncologist
13%
Treatment Decision on liver
General
OPUS oncologist
with Erbitux
RR 76%
resection by
general
oncologist
16%
Treatment Decision on liver
CELIM MDT with
liver surgeon
with Erbitux
RR 70%
resection by
MDT with liver
surgeon
33%
Treatment Decision on liver
POCHER MDT with
liver surgeon
with Erbitux
RR 79%
resection by
MDT with liver
surgeon
60%
Liver surgeons MUST work with medical oncologists from
the outset if these outcomes are to be reproduced
Köhne C-H, et al. ASCO 2011 (Abstract No. 3576);
Folprecht G, et al. EMCC 2011 (Abstract 6009); Garufi C, et al. Br J Cancer 2010;103:1542–1547Definition of resectability
– All liver metastases that can be completely
removed while leaving at least 30% of
remnant liver
– Absence of extrahepatic disease
Adam R, Bismuth H, Ann Surg 2004New definition of resectability
‘Practical’ rather than ‘dogmatic’
– All liver metastases that can be completely removed while
leaving at least 30% of remnant liver
– With resectable extrahepatic disease
In practice: three categories of patients
Easily resectable • Complete resection with good margins
• No margins, small liver remnant
Marginally resectable
• Concomitant extrahepatic (resectable)
• Widespread hepatic disease
Definitely non-resectable • Non-resectable extrahepatic
• Multiple metastatic sites
Adam R, et al. Gastrointest Cancer Res 2009;3:S15–22Criteri Nordlinger Gruppo B: “non optimally resectable”: Motivi Oncologici ( almeno 2 fattori) • >4 metastasi • Dimensioni >5 cm • Metastasi sincrone • Stadio III (N+) sul tumore primitivo • Marker tumorali (CEA e CA19-9 aumentati) Gruppo B: “non optimally resectable”: Motivi Chirurgici “tecnicamente difficile” • vicino alle vene sovraepatiche • vicino ad entrambi i rami portali • Necessità di eseguire una resezione epatica che risparmi
Optimal approach for surgery
Possono essere
inizialmente non
resecabili tuttavia…Optimal approach Transplantation
for surgery
PVE
PVL
Lap PVL
Two step
Left wedge
Lap left wedgeOptimal approach for surgery
Hanging Anterior
maneuver approach
Pringle No Pringle
Intermittent
Pringle
Robotic approach
Laparoscopic approach
ALPPSSurgery and Targeted Therapies
Pathological response
• Histological tumour response corresponds to
fibrosis and not to increase necrosis
• Pathological response is related to prognosis
• Tumour regression was more evident in patients
treated with oxaliplatine
Rubbia-Brandt Ann Oncol 2007Surgery and Targeted Therapies
Pathological response
• The tumour response can be evaluated
assessing the presence of viable tumour cells
• This method is relevant in patients with
targeted therapies because the changes in
tumour size can underestimate the pathological
response
Goh BK Eur J Surg Oncol 2006Surgery and Targeted Therapies
Pathological response
Patients treated with:
• 5FU + Oxaliplatine 45% of viable tumour cells
• 5FU + Oxaliplatine + BEVA 33% of viable
tumour cells
Ribero Cancer 2007Surgery and Targeted Therapies
Safety and Bevacizumab
• No risk of morbidity if stopped 6-8 weeks
before surgery
• Other studies report 4-6 weeks
• The risk of tumour regrowth after stopping
Bevacizumab can be reduced with infusion of
conventional chemotherapy
Kesmodel SB J Clin Oncol 2008Surgery and Targeted Therapies
Safety and Bevacizumab
Pre-operative Bevacizumab is associated to
decreased post-operative hepatic
insufficiency
Mahfud M World J Surg 2010Surgery and Targeted Therapies
Safety and Bevacizumab
Pre-operative Bevacizumab is associated to
increased post-operative hepatic
insufficiency
Kishi Y Ann Surg Oncol 2010Surgery and Targeted Therapies
Safety and Cetuximab
• Cetuximab does not interfere with surgery
• Patients treated with Cetuxiamb have the same
rates of post-operative complications compared
to conventional chemotherapy
Pessaux P Eur J Surg Oncol 2010Surgery and Targeted Therapies
Safety
No confirmed data that
Bevacizumab and Cetuximab
interfere with liver function and
regeneration
Nordlinger B Clin Oncol 2012Surgery and Targeted Therapies
Targeted therapies and Liver Injury
• It’s well known that 5FU + Oxaliplatine or
Irinotecan are associated to liver injury
• Bevacizumab could reduce the liver injury
Kishi Y Ann Surg Oncol 2010Surgery and Targeted Therapies
Targeted therapies and Liver Injury
• Cetuximab also reduces the risk of liver injury
• Bevacizumab reduces the post-operative
steatohepatitis
Pessaux P Eur J Surg Oncol 2010Surgery and Targeted Therapies
It should be considered the use of
targeted therapies to have the same
or better result of conventional
chemotherapy with reduced number
of cycles and hepatic injury
Nordlinger B Clin Oncol 2012Vascularity of liver metastases Colorectal metastases: Classical criteria – Hypovascular on arterial phase – Peripheral halo – Fibrous stroma
Radiology and Liver Metastases
Colorectal liver metastases are
no longer hypovascular!
High-resolution optical imaging
of liver metastatic nodule in mice Tanaka, J Oncol. 2012Colorectal liver metastases are
no longer hypovascular!
Investigative Radiology 2004Colorectal liver metastases are
no longer hypovascular!
• 29 pts with untreated liver metastases
• 11/29 colorectal liver metastases
• All liver mets showed an early arterial
enhancementRadiology and Targeted Therapies
• RECIST response rates are a weak parameter for the
complex benefit of a preoperative treatment
• Do not include other metric aspects (e.g. the amount
of tumour reduction etc)
• Could help prevent unnecessary extensions to
treatment duration
• Do not consider changes in morphology of disease
presentation (e.g. cystic transformation)
Chun YS, JAMA 2009CONCLUSIONS • Multidisciplinary approach is recomended • High volume centers • Targeted Therapies have changed the approach • Debate on surgical approach in patients receiving targeted therapies • Further evaluation for radiological and pathological response
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