Trattamento chirurgico dell'esofago di Barrett - Gastrolearning®

La Chirurgia nell’esofago di Barrett
e nell’Adenocarcinoma
Carlo Castoro
USD Chirurgia Oncologica dell’Esofago
Istituto Oncologico Veneto
IOV-IRCCS
Padova
GASTRO-LEARNING 2014
Secondo 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 Adenocarcinoma
E.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) months
3083 Patient/years
23pts

Progression to HG-IEN/AC
Multivariate 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/Ulcerati
on (yes-no)
0.0002 7.60 (2.63-
21.98)
LG –IEN (yes-no) 0.02 3.74 (1.22-
11.43)

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

Treatment of GERD
● Medical therapy: PPI
Reduces, does not eliminate, acid secretion and reflux
Eliminates symptoms
● Antireflux surgery

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
0
5
10
15
20
25
Total Surgery 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 LSBE
p
* 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 Controls p

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.

Does antireflux surgery prevent cancer?
Probably yes,....providing
the dam can cope!

Treatment of LGD
ENDOSCOPIC ABLATION / MUCOSECTOMY AND ANTIREFLUX
SURGERY ?
No Agreement

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

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
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.???

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, 2000
Macey, 2001 Shand, 2001
Wolfsen, 2002 Overholt, 2003)
Courtesy E Ancona

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

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

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
0
20
40
60
80
100
0
6
12
18
24
30
36
42
48
54
60
mos.
%
pStage 0 - Ia pStage I b
pStage II pStage III-IV

Barrett’s adenocarcinoma
Influence of surveillance on survival
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 6 12 18 24 30 36 42 48 54 60
months
Occasional finding Unsurveilled Barrett's Surveilled Barrett's
N=10 pts
N=49 pts
N=14 pts
G Zaninotto, E Ancona JOGS, 2012

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 Carcinoma
1980-2011: 4179 pz

Esophageal and EG Junction Carcinoma
1980-2011: 4179 pz
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

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
?

Trends in Management and
Prognosis for Esophageal cancer
Surgery
Twenty-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

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
0
2
4
6
8
10
1980-1987 1988-1995 1996-2004
%
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

0
25
50
75
100
12 24 36 48 60
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%

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

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

Sjoquist Lancet Oncol 2011

Surgery
(n=188)
N+ or T2/T3 oesophageal
cancer
41.4Gy in 5 wks
paclitaxel 50 mg/m2 q wk
Carboplatin AUC 2 q wk
Surgery
(n=178)
CROSS: randomized phase III study
Van Hagen NEJM 2012

Van Hagen NEJM 2012

Neoadjuvant chemoradiation treatment of choice for oesphageal
adenocarcinoma
How to make another substantial step forward?

Target therapy

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