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La Chirurgia nell’esofago di Barrett
e nell’Adenocarcinoma
Carlo Castoro
USD Chirurgia Oncologica dell’Esofago
Istituto Oncologico Veneto
IOV-IRCCS
Padova
GASTRO-LEARNING 2014Secondo Modulo: Oncologia Gastrointestinale
Padova 16 giugno, 2014
The Natural History of Barrett’s Esophagus
Starts here…..
…..And ends here
Barrett’s esophagus Management
The management of patients with Barrett's esophagus involves three major components:
● Treatment of the associated GERD
● Endoscopic surveillance to detect dysplasia
● Treatment of dysplasia
The goal of therapy is to prevent cancer development
Meta-analysis of Incidence of AC in BE patients
Overall Incidence: 6.3/1000 pts year (95%c.i. 4.7-8.4)Heterogeneity: χ2= 238.2, p<.001)
Yousef F Am J Epidemiol 2008
Esofago di Barrett e Rischio di AdenocarcinomaE.B.R.A. Registry
• Standard endoscopic definition
• Standard pathologic report
• Definition of follow-up and outcomes
• Audit• Semestral meeting24 participant
centers
Prof G Zaninotto – Prof M Rugge
• Only index endoscopy: 439 pts (34%)
• Incident lesion at index endoscopy– 4 invasive cancer– 7 HG IEN
• Incident lesion (w/in 12 months) – 3 invasive cancer– 3 HG IEN
BE enrolled patients : 1297
Considered for
analysis:841
E.B.R.A. Registry. Results .1.
Median F-Up: 44.6 (24.7 – 60.5) months3083 Patient/years
23pts
Progression to HG-IEN/ACMultivariate Analysis
P-Value RR (95% CI)
Age 0.12 -
BE Length ( cm) 0.01 1.16 (1.03-1.30)
Hiatus Hernia(cm) 0.25 -
Nodularity/Ulceration (yes-no)
0.0002 7.60 (2.63-21.98)
LG –IEN (yes-no) 0.02 3.74 (1.22-11.43)
Barrett’s esophagus Dysplasia as a marker of
risk
— Endoscopic surveillance is performed primarily to detect dysplasia in Barrett's esophagus
- LGD ( LG NIN )
- HGD ( HG NIN )
The goal of therapy is to prevent cancer progression
Barrett’s esophagus Treatment of GERD
● Medical therapy: PPI
Reduces, does not eliminate, acid secretion and reflux
Eliminates symptoms
● Antireflux surgery
The goal of therapy is to prevent cancer development
Intervento Antireflusso
Barrett’s Esophagus:Medical vs. Antireflux Surgery
• 89 patients (71 M 18 F, median age 58 yrs) • 45 pts Laparoscopic Nissen • 44 PPI• Follow-up 34 months (minimum F-up 12
months)
G Zaninotto JOGS, 2012
Symptoms: surgery vs medical therapy
* p<0.001
Before treatment
After treatment
* **
I.M. 1-30%
I.M. 31-100%
I.M. 1-30%
I.M. 31-100%
SSBE
LSBE
PRE POST
I.M. Score before and after treatment
p<0.001
No I.M.27%
12/44
Zaninotto G JOGS 2011
I.M. 1-30%
I.M. 31-100%
I.M. 1-30%
I.M. 31-100%
SSBE
PRE POST
I.M. Score before and after treatment
SSBE
Surgery
Medical Therapy
No I.M.
No I.M.
p<0.04
42%
16%
Effect of Antireflux Surgery on Barrett’s epithelium (Short and Long Segment)
Oelschlager 2001 30/54 (55%) 0/36 (0%) <0.001
Hofstetter 2001 8/20 (40%) 1/49 (2%) <0.001
Gurski 2003 11/32 (34%) 0/21 (0%) <0.001
Zaninotto 2005 6/11 (54%) 0/24 (0%) <0.001
Biertho 2006 23/59 (39%) 0/11 (0%) <0.001
Csendes* 2006 20/31 (64%) 26/42 (62%)
Author Year Regression
SSBE LSBEp
* Vagotomy, Partial Gastrectomy & Duodenal Diversion
Regression of LG NiN in BE: Multivariate Analysis
Medical 12/19 63.2 15.53 0.033
Surgery 15/16 93.8
< 60 13/16 77.2 1.02 0.407
> 60 14/19 76.9
Male 17/22 77.2 1.10 0.211
Female 10/13 76.9
SSBE 12/16 75 1.75 0.677
LSBE 15/19 78.9
Post-treatment regression (%) O.R. p
Rossi, Ann Surg 2006
Metanalysis: Probability of regression to lower grades of dysplasia, nondysplastic or non
metaplastic tissue between surgical and medical treated patients
Chang, Ann Surg 2007
Metanalysis: Probability of progression to more advanced grades of dysplasia between surgical
and medical treated patients
Chang, Ann Surg 2007
Comparison of pooled incidence rates of esophageal adenocarcinoma betwen surgically
and medically treated patients
Chang EY, Ann Surg 2007
Onset of HGD/Ca after medical (43 pts) or surgical therapy (58 pts) : long-term results
5% 3%
BE
Onset of HGD/Ca
Medical treatment Surgical treatment
No patients had cancer when surgery was effective!
Parrilla P et al. Ann Surg 2003
Participants 189 820
BMI 26.1 23.1 1.
s/p A.R Surgery 7 (3.7) 8 (1) 1
pts on antireflux medications 4 (57%) 0 0.026
Mean duration (years)of post-op A/R medications
10 = =
Esophageal Adenocarcinoma Control
sp
Barrett’s esophagus Treatment of GERD
Does aggressive treatment of reflux prevent progression to cancer?
— The primary goal of anti-reflux therapy for patients with Barrett's esophagus is to control their reflux symptoms
Available data suggest, but do not prove, that aggressive antireflux therapy might also prevent cancer in these patients.
The goal of therapy is to prevent cancer development
Does antireflux surgery prevent cancer?
Probably yes,....providing the dam can cope!
Barrett’s esophagus Treatment of LGD
ENDOSCOPIC ABLATION / MUCOSECTOMY AND ANTIREFLUX SURGERY ?
No Agreement
Barrett’s esophagus Treatment of LGD
● For most patients with verified low-grade dysplasia after extensive biopsy sampling, we suggest surveillance endoscopy at intervals of 6 to 12 months
(Grade 2C). Extensive biopsy sampling involves taking four-quadrant biopsies at intervals of no more than 1 cm throughout the columnar-lined esophagus
AGA guidelines
Barrett’s esophagus Treatment of LGD
● For most patients with verified low-grade dysplasia after extensive biopsy sampling, we suggest surveillance endoscopy at intervals of 6 to 12 months
(Grade 2C). Extensive biopsy sampling involves taking four-quadrant biopsies at intervals of no more than 1 cm throughout the columnar-lined esophagus
Radiofrequency ablation may be an appropriate therapy for verified low-grade dysplasia if an experienced provider is available
Antireflux surgery??AGA guidelines
No agreement
Barrett’s esophagus Treatment of HGD
TREATMENT OF HIGH-GRADE DYSPLASIA — For patients with verified high-grade dysplasia (also called intraepithelial neoplasia) in Barrett's esophagus, there are generally four proposed management options:
● Esophagectomy
● Endoscopic therapies that ablate the neoplastic tissue
● Endoscopic mucosal resection
● Intensive endoscopic surveillance in which invasive therapies are withheld until biopsy specimens reveal adenocarcinoma.???
No agreement
Barrett’s esophagus Treatment of HGD
TREATMENT OF HIGH-GRADE DYSPLASIA — For patients with verified high-grade dysplasia (also called intraepithelial neoplasia) in Barrett's esophagus, there are generally four proposed management options:
● Esophagectomy
● Endoscopic therapies that ablate the neoplastic tissue
● Endoscopic mucosal resection
● Intensive endoscopic surveillance in which invasive therapies are withheld until biopsy specimens reveal adenocarcinoma.???
No agreement
Barrett’s esophagus Treatment of HGD
TREATMENT OF HIGH-GRADE DYSPLASIA — For patients with verified high-grade dysplasia (also called intraepithelial neoplasia) in Barrett's esophagus, there are generally four proposed management options:
● Esophagectomy
● Endoscopic therapies that ablate the neoplastic tissue
● Endoscopic mucosal resection
● Intensive endoscopic surveillance in which invasive therapies are withheld until biopsy specimens reveal adenocarcinoma.???
Barrett’s esophagus Treatment of HGD
● For most patients with Barrett's esophagus and high-grade dysplasia who are fit to undergo endoscopy, we suggest endoscopic eradication therapy rather than esophagectomy or intensive endoscopic surveillance
(Grade 2C). Endoscopic eradication therapy includes endoscopic mucosal resection for the removal and staging of visible lesions (if present), followed by radiofrequency ablation to ablate the remaining metaplastic epithelium.
AGA guidelines
IS THE PRESENCE OF BURIED BE A CLINICALLY RELEVANT ISSUE ?
Several cases of invasive adenocarcinoma developing from “buried” Barrett’s epithelium have already been reported after Barrett mucosal ablation
(Bonavina, 1999 Van Laethem, 2000Macey, 2001 Shand, 2001Wolfsen, 2002 Overholt, 2003)
Courtesy E Ancona
EUS Stadiazione
Prophylactic esophagectomy in Barrett’s esophagus with HGD
• Incidence of occult invasive adenocarcinoma:
Tseng, 2003 30% 1982-1994: 43% ( 61% pStage I )1994-2001: 17% ( 100% pStage I )
Fernando, 2002 39% Headrick, 2002 36% Zaninotto, 2000 33% Patti, 1999 36% Ferguson, 1997 53% Edwards, 1996 41% Peters, 1994 55% Rice, 1993 38% Pera, 1992 50% Altorki, 1991 45%
range: 30-55%
pT1a: 5% pN+ pT1b: 18-31% pN+
Courtesy E Ancona
No agreement
Barrett’s esophagus Treatment of HGD
TREATMENT OF HIGH-GRADE DYSPLASIA — For patients with verified high-grade dysplasia (also called intraepithelial neoplasia) in Barrett's esophagus, there are generally four proposed management options:
● Esophagectomy
● Endoscopic therapies that ablate the neoplastic tissue
● Endoscopic mucosal resection
● Intensive endoscopic surveillance in which invasive therapies are withheld until biopsy specimens reveal adenocarcinoma.???
Barrett’s esophagus Treatment of HGD
● Esophagectomy is the only therapy for high-grade dysplasia that clearly removes all of the neoplastic epithelium,
● rates of procedure-related mortality and long-term morbidity
● post-op quality of life impairment
Endoscopic eradication therapy is available, has proven efficacy (although long-term data are not yet available), and is relatively safe
DIVERTICOLO FARINGO-ESOFAGEO?
Attività 2010-2013 Chirurgia Oncologia dell’Esofago
INTERVENTI RESEZIONE ESOFAGEA: 216
Mortalità Postoperatoria: 2/216 (0.9%)
Fistole Anastomotiche: 6/216 (3.6%)
Open questions in surgical resection for HGD or Early Cancer in Barrett’s
Esophagus• The role of minimal resection (idest
Merendino jejunal interposition)
Courtesy E Ancona
Merendino jejunal interposition
Barrett’s esophagus The case for
esophagectomy
Multifocal HGD, not amenable of eradication with endoscopic mucosectomies
Confirmed diagnosis, 2 expert pathologists, repeated biopsies
Surgical risks acceptable
Lack of patient compliance to endoscopic follow up
The goal of therapy is to prevent cancer progression
No agreement
EGJ Adenocarcinoma Survival after R0 resection
Barrett’s adenocarcinomaInfluence of surveillance on survival
N=10 pts
N=49 pts
N=14 pts
G Zaninotto, E Ancona JOGS, 2012
Barrett’s esophagus Summary and Recommendations
Barrett’s – IM no dysplasia
- Treat GERD- Antireflux surgery in non responders to medical therapy
LGD
- Endoscopic ablation and antireflux surgery- Strict endoscopic followup
HGD
- Endoscopic mucosectomy and/or ablation and antireflux surgery- Esophagectomy if eradication fails or multifocal HGD
Oesophagectomy for cancer:
techniques and results
K Esofago Toracico (n = 2992)
K Esofago Cervicale (n = 717)K Cardias (n = 972)
Periodo: 1980 / 1994 - Pazienti: 3020
13%
65%
22%
Tecnica di esofagectomia per cancro
Esophageal and EG Junction Carcinoma1980-2011: 4179 pz
Tecnica di esofagectomia per cancro
Esophageal and EG Junction Carcinoma1980-2011: 4179 pz
80-8
485
-89
90-9
495
-99
00-0
405
-11
0
20
40
60
80
100
SCC
Adeno
Altro
Achieving R0 resection should be the goal of surgery
(it is the most significant independent prognostic factor)
Key points
• surgical approach • esophageal resection• gastric resection
• extent of lymphadenectomy
Tecnica di esofagectomia per cancro
Type II: Distal esophagectomy and proximal gastrectomy with paraesophageal and upper abdominal lymphadenectomy; resection extended to subtotal esophagectomy with proximal gastrectomy or total gastrectomy, or esophago-gastrectomy.
Adenocarcinoma of the esophagus & esophago-gastric junction
• Type I Esophago-gastric resection
& gastric pull-up
• Type II Esophago-gastric resection& gastric pull-up
Extended gastrectomy & esophago-jejunostomy
Limited resection for early cancer :short esophageal resection + proximal gastrectomy & Merendino jejunal interposition
• Type III Extended gastrectomy (D2)& esophago-jejunostomy
?
Tecnica di esofagectomia per cancro
Trends in Management and Prognosis for Esophageal cancer
SurgeryTwenty-five Years of Experience at a Single Institution
Objective: To investigate trends in results of esophagectomies for carcinoma at a single
high-volume institution
Ruol A, Castoro C, et al. Arch Surg 2009; 144(3):247-254
Tecnica di esofagectomia per cancro
1980-2004: 3493 carcinoma of the thoracic esophagus & EG-J type I-II
1978 consecutive surgical resections
years 1980-1987 1988-1995 1996-2004
N. patients % resections
p = 0.01
785/1438 54.6%
659/1178 55.9%
534/877 60.9%
R0 complete
resections p <
0.0001
585 74.5%
502 76%
481 90%
Ruol, Castoro et al. Arch Surg 2009;144(3):247-54
1978 esophagectomies for Cancer of the thoracic esophagus & EG-J - postoperative deaths
%
1.4% (7/495) after
gastric pull-up
64/785 8.2%
42/659 6.4%
14/534 2.6%
in-hospital deaths p < 0.0001
Ruol, Castoro et al. Arch Surg 2009;144(3):247-54
Tecnica di esofagectomia per cancro
1980-1987 (n=785) 1988-1995 (n=659)1996-2004 (n=534)
Survival after resection surgery (R0-2), including postop. deaths
months
%
p<0.0001
43%
19%23%
Ruol, Castoro et al. Arch Surg 2009;144(3):247-54
Tecnica di esofagectomia per cancro
Tecnica di esofagectomia per cancro
New standards
• Early cancer T1a: endoscopic mucosectomy
• Neoadjuvant chemo-radiation (CROSS Trial)
• Minimally invasive oesophagectomy
• High volume centers multidisciplinary team
- Stadio potenzialmente operabile: CT, CT-RT,
Chirurgia?
- Terapia neoadiuvante: quando? quale ?
- Terapia definitiva: quando? quale CT-RT?
Carcinoma dell’esofago e del cardias:percorsi diagnostico-terapeutici
Padova, 9 Maggio 2014
Linee Guida: NCCN, ESMO, AIRO, AIOM
Courtesy H. van Laarhoven
To treat or not to treat neoadjuvantly?
That is not the question (anymore)
Courtesy H. van Laarhoven Ronellenfitch, Eur J Cancer 2013, 3149
Courtesy H. van LaarhovenSjoquist Lancet Oncol 2011
BJS 2014; 101: 321
Courtesy H. van Laarhoven
Surgery(n=188)
N+ or T2/T3 oesophageal cancer
41.4Gy in 5 wkspaclitaxel 50 mg/m2 q wkCarboplatin AUC 2 q wk
Surgery(n=178)
CROSS: randomized phase III study
Van Hagen NEJM 2012
Courtesy H. van LaarhovenVan Hagen NEJM 2012
Courtesy H. van LaarhovenVan Hagen NEJM 2012
Courtesy H. van Laarhoven
Neoadjuvant chemoradiation treatment of choice for oesphageal adenocarcinoma
How to make another substantial step forward?
Courtesy H. van Laarhoven
Target therapy