Download Esophageal Cancer

Cancers of the Esophagus and Stomach
A Decade in Review
Mitchell C. Posner M.D., FACS
Thomas D. Jones Professor and Vice Chairman
Chief, Section of General Surgery and Surgical Oncology
Medical Director, Clinical Cancer Programs
University of Chicago
Esophageal Adenocarcinoma
Relative 5 Year Survival Rates
Esophageal Cancer
1975-77
1987-89
5%
10%
2001-07
19%
Ca Cancer J Clin 2012; 62: ePub
Gastric Adenocarcinoma
Relative 5 Year Survival Rates
Stomach Cancer
1975-77
1987-89
15%
20%
2001-07
27%
Ca Cancer J Clin 2012; 62: ePub
Cancers of the Esophagus and Stomach
A Decade in Review
• Prevention/Screening
• Diagnosis/Imaging/Staging
• Treatment
 esophageal tumors
 gastric tumors
• Applied research
H. pylori
Esophageal vs. Gastric Cancer
Serologic test results†
Case subjects, N (%)
Control subjects, N (%)
Unadjusted OR (95% CI)
Adjusted OR (95% CI)‡
Noncardia gastric cancer
H. pylori negative
12 (7)
43 (25)
1.00 (referent)
1.00 (referent)
CagA-negative strains
51 (29)
44 (25)
5.05 (2.11 to 12.07)
6.55 (2.31 to 18.53)
CagA-positive strains
110 (64)
86 (50)
5.64 (2.47 to 12.88)
8.93 (3.27 to 24.40)
H. pylori positive
Gastric cardia cancer
H. pylori negative
25 (41)
15 (25)
1.00 (referent)
1.00 (referent)
CagA-negative strains
11 (18)
24 (39)
0.34 (0.14 to 0.85)
0.21 (0.06 to 0.81)
CaA-positive strains
25 (41)
22 (36)
0.81 (0.35 to 1.85)
0.43 (0.12 to 1.52
H. pylori positive
Kamangar F et al. J Natl Cancer Inst. 2006;
Innovative Endoscopic Techniques
Diagnosis
High Resolution Endoscopy
Chromoendoscopy
Narrow Band Imaging
Innovative Endoscopic Techniques
Diagnosis
Autofluorescence Imaging
Confocal Laser Endomicroscopy
Esophageal Malignancy
Depth of Invasion
Ortiz-Fernando-Sorto J et al. World J Gastrointest Endosc. 2011
Esophageal Malignancy
Histology Dictating Therapy
Konda VJ et al.Am J Gastroenterol. 2012
Endoscopic Mucosal Resection
Barrett’s Esophagus
Ortiz-Fernando-Sorto J et al. World J Gastrointest Endosc. 2011
Endoscopic Submucosal Dissection
Esophageal Cancer
Ortiz-Fernando-Sorto J et al. World J Gastrointest Endosc. 2011
“Early” Esophageal Cancer
Treatment Algorithm
Konda VJ et al.Am J Gastroenterol. 2012
Value of PET
Esophageal vs. Gastric Cancer
Primary
(sensitivity)
Esophageal
> 95%
Gastric
~ 65%
Metastases
(undetected)
20%
10%
Heeren PA et al. J Nucl Med. 2004
Smyth E et al. Cancer 2012
Study Design MUNICON-I
(Lordick et al. Lancet Oncol 2007)
Non-Responder
AEG
type I-II
Resect
CTx
PET d14
PET d0
CTx: 3 months
Responder
Resect
Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35%
Weber et al. J Clin Oncol 2001;19:3058-65 Ott et al. J Clin Oncol 2006;24:4692-8
AEG: adenocarcinoma of the esophago-gastric junction; C: cisplatinum; d: day
CTX: chemotherapy PET: positron emission tomography; SUV: standard uptake value
Results MUNICON-I
Median event-free survival
[95% CI] in months:
Metabolic Responder:
29.7 [23.6; 35.7]
Metabolic Non-Responder:
14.1 [7.5; 20.6]
Hazard ratio 2.18 [1.32; 3.62]
Log-rank p-value: p<0.002
Median follow-up: 28.0 months
Lordick et al. Lancet Oncol 2007; 8: 797-805
Study Design MUNICON-II
Non-Responder
AEG
type I-II
Radio-Ctx
Cispl. + 32 Gy
Resect
CTx
PET d14
PET d0
CTx: 3 months
Resect
Responder
Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35%
Weber et al. J Clin Oncol 2001;19:3058-65
Lordick et al. Lancet Oncol 2007;8:797-85
AEG: adenocarcinoma of the esophago-gastric junction; C: cisplatinum; d: day
CTX: chemotherapy PET: positron emission tomography; SUV: standard uptake value
CALGB 80803 Schema
Induction Chemo:
modified FOLFOX6
days 1,15, 29
T3/4 or N1
Esophageal
Adenoca
PET Scan
pre-treatment
PET-responders: ≥ 35% SUV decrease:
continue initial chemo + concurrent RT
(5040cGy in 180cGy fx)
PET Scan day
36-42
Randomize
Induction Chemo:
Carboplatin/
Paclitaxel days
1,8,22,29
Surgical resection 6
weeks post-RT
PET- nonresponders: < 35% SUV
decrease: cross-over to alternative
chemo + concurrent RT
(5040cGy in 180cGy fx)
Esophageal Cancer
Surgical Approach
•
•
•
•
Transhiatal Esophagectomy
Transthoracic Esophagectomy
Minimally Invasive Esophagectomy
Robotic-Assisted Esophagectomy
Esophageal Cancer
Transhiatal vs Transthoracic Resection
Population-based study: SEER 1992-2002
Outcome Variables
Transthoracic (n = 643)
Transhiatal (n = 225)
p Value
Thirty-day mortality (%)
13.1
6.7
0.009
Hospital length of stay (days)
20.7
21.4
0.65
Need for anastomotic dilatation
(%)
34.5
43.1
0.02
1 year
55.5
57.3
0.64
3 years
29.4
40.0
0.003
5 years
22.7
30.5
0.02
Overall survival (%)
Chang AC et al. Ann Thorac Surg 85(2): 424-9, 2008
GI Cancer Resections
24
Mortality (%)
20
V Low
Low
Med
High
V High
16
12
8
4
0
Colon
Stomach
Esophagus
Pancreas
Birkmeyer J SSO 2011
Proportion of population-wide extirpative
procedures performed at low volume centers
50%
40%
30%
0.329650092
0.299474606
20%
0.181882022
0.165512465
10%
0%
1999
2000
2001
Esophagus
1-3/yr
2002
2003
Pancreas
1-6/yr
2004
Colon
1-43/yr
2005
2006
2007
Rectum
1-15/yr
Birkmeyer J SSO 2011
Esophageal Cancer – Resection
Trends in Operative Mortality
Finks JF et al. N Engl J Med. 2011
Esophageal Cancer – Squamous Cell CA
Role of Surgery
CRT + Surgery
CRT alone
Bedenne, L. et al. J Clin Oncol; 25:1160-1168 2007
Esophageal Cancer – Squamous Cell CA
Role of Surgery
6 month mortality
16% SGY vs. 6% CRT
Bedenne, L. et al. J Clin Oncol; 25:1160-1168 2007
Esophageal Cancer – Squamous Cell CA
Role of Surgery
Stahl, M. et al. J Clin Oncol; 23:2310-2317 2005
Esophageal Cancer – Squamous Cell CA
Role of Surgery
postop mortality = 11%
CRT + Surgery
CRT
CRT + Surgery
CRT
Stahl, M. et al. J Clin Oncol; 23:2310-2317 2005
ESOPHAGEAL CANCER
Preoperative Chemoradiotherapy
• multicenter phase III trial
• n= 363 pts. EUS T2-3,N0-1(74% adeno, 67% N+)
• carboplatin/paclitaxel/41.4 Gy
Results:
median surv.
R0 resection
pCR rate
op mortality
CRT+ surgery
49mo
90%
33%
3.8%
surgery alone
26mo
p=0.011
65%
-3.7%
Van Gaast A et al. ASCO 2010
Esophageal Cancer
Neoadjuvant Chemotherapy vs. Surgery Alone
Mortality
p = 0.05
Gebski V et al. Lancet Oncol 8: 226-34, 2007
Esophageal Cancer
Preoperative Chemotherapy
Comparison of MRC and Intergroup Study
MRC
Intergroup
Chemotherapy
(all cycles)
90%
71%
Surgical resection
92%
80%
Esophageal Cancer
Preoperative Chemotherapy - MRC OEO2
Allum W H et al. JCO 2009;27:5062-5067
©2009 by American Society of Clinical Oncology
Esophageal Cancer
Preoperative Chemotherapy - MRC OEO2
Allum W H et al. JCO 2009;27:5062-5067
©2009 by American Society of Clinical Oncology
Esophageal Cancer
Preoperative Chemotherapy – INT 0113
Kelsen D P et al. JCO 2007;25:3719-3725
©2007 by American Society of Clinical Oncology
Esophageal Cancer
Preoperative Chemotherapy – INT 0113
Kelsen D P et al. JCO 2007;25:3719-3725
©2007 by American Society of Clinical Oncology
Esophageal Cancer
Neoadjuvant Chemoradiotherapy vs. Surgery Alone
Mortality
P=0.002
Gebski V et al. Lancet Oncol 8: 226-34, 2007
Preoperative Chemoradiotherapy
CROSS Trial
Van Hagen P et al. N Engl J Med. 2012
Methods
Data Source
Patients
• The National Cancer Data
Base (NCDB)
• Esophageal Cancer
– 1450 Commission on Cancer
(CoC) hospitals
– >70% of all new cancers
– Standardized definitions
– 8,562 patients (1998-2007)
– Clinical Stage I-III
– Middle & lower third tumors
– Adenocarcinoma and
squamous cell carcinoma
Esophageal Cancer - Neoadjuvant Therapy
Trends in Utilization
Neoadjuvant
+
surgery
Merkow RP et al. Ann Surg Oncol. 2012
Results: Margins, Nodes, Mortality
Unadjusted Rate
(%)
Adjusted Odds
Ratio (95% CI)
Surgery alone
13.3
1.0 (referent)
Neoadjuvant
5.7
0.60 (0.47-0.76)
Surgery alone
52.3
1.0 (referent)
Neoadjuvant
37.4
0.24 (0.17-0.33)
Surgery alone
5.4
1.0 (referent)
Neoadjuvant
3.1
0.93 (0.67-1.28)
P-value
Positive Margins
P<0.001
Positive Lymph Nodes
P<0.001
30-day Mortality
P=0.651
Molecular Targets: Esophagogastric
Cancer
 KRAS mutation: < 5-10%
 BRAF mutation: < 5%
 EGFr over expression: 50-80%
 EGFr mutation: < 5%
 CMET: < 10%
 HER2 over expression: 10-25%
Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee
Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006
HER2 and trastuzumab
mechanism of action
HER2 receptor
trastuzumab
Trastuzumab

Inhibits HER2-mediated signalling in HER2-positive tumors

Prevents HER2 activation by blocking extracellular
domain cleavage

Activates antibody-dependent cellular cytotoxicity
ToGA trial design
Phase III, randomized, open-label, international, multicenter study
3807 patients screened1
810 HER2-positive (22.1%)
HER2-positive
advanced GC
(n=584)
5-FU or capecitabinea
+ cisplatin
(n=290)
R
5-FU or capecitabinea
+ cisplatin
+ trastuzumab
(n=294)
 Stratification factors
−
−
−
−
−
advanced vs metastatic
GC vs GEJ
measurable vs non-measurable
ECOG PS 0-1 vs 2
capecitabine vs 5-FU
aChosen
at investigator’s discretion
GEJ, gastroesophageal junction
1Bang
et al; Abstract 4556, ASCO 2009
Secondary end point:
tumor response rate
Intent to treat
p=0.0017
Patients (%)
p=0.0145
47.3%
41.8%
p=0.0599
32.1%
34.5%
5.4%
2.4%
CR
ORR= CR + PR
CR, complete response; PR, partial response
PR
ORR
F+C + trastuzumab
F+C
RTOG 1010: Phase II Study of Neoadjuvant
Trastuzumab and Chemoradiation for Esophageal
Adenocarcinoma (Siewert I, II)
CHEMORADIATION
SURGERY
HER-2 (+)
(FISH)
TRASTUZUMAB
+
CHEMORADIATION
HER-2 (-)
(FISH)
SURGERY
+
TRASTUZUMAB (1 YR)
ALTERNATIVE
STUDIES
Chemoradiation: Carbo + Paclitaxel, RT 5040 cGy  Surgery
Maintenance trastuzumab post op
Sample Size = 130 Her-2 (+) Pts, Increase
3-Yr Survival from 30% to 50%. 520+ pts to be screened
Gastric Cancer Surgery
Extent of LND
Gastric Cancer Resection
Tumor Control
Songun I et al. Lancet Oncol 2010
Gastric Cancer Resection
Tumor Control
D1=41% D2=25%
Songun I et al. Lancet Oncol 2010
Gastric Cancer Resection
Tumor Control
D1=41% D2=25%
INT 0116
LR = 24%
DGCT
LR = 25%
Songun I et al. Lancet Oncol 2010
Gastric Cancer Resection
Value of Adequate Surgery
DGCT
INT 0116
Appropriate Extent of Resection
Gastric Cancer
NCCN v2.2011 guidelines:
Gastric resection should include the regional
lymphatics: perigastric lymph nodes (D1) and those
along the named vessels of the celiac axis (D2) with a
goal of examining at least 15 or greater lymph nodes.
Surgical experience & hospital volume matter!
Post-operative Chemoradiation:
SWOG 9008/Intergroup 0116 Trial
Resected stage Ib-IV (M0)
gastric or OGJ adenocarcinoma
n=556 (<D1 resection 54%
D1 = 36%, D2 = 10%)
Observation n=275
Randomised
5-FU/LV Chemoradiation
(4500Gy) n=281
Median OS: 27 v 36m
HR for death 1.32; p=0.0046
Smalley SR et al., J Clin Oncol. 2012
•Highly selected population (All had
R0 resection + recovered from
surgery) yet only 64% completed
treatment.
•Significant treatment-related
toxicity:
1% toxic death
73% grade 3/4 AEs
Peri-operative Chemotherapy:
The MRC MAGIC Trial
Resectable
adenocarcinoma of
the stomach, OGJ or
lower oesophagus
n=503
Pre-operative
ECFx3
Randomised
Surgical
resection
within 3-6/52
Postoperative
ECF x3
within 612/52
Surgical
resection within
6/52
Median OS: 24 v 20 months
5 yr OS: 36% v 23%
13% OS benefit for ECF
HR for death 0.75, p=0.009
Pre-op chemo well tolerated (5% did not
complete pre-op treatment due to toxicity)
No increase in post-op complications
Cunningham et al., NEJM 2006
Adjuvant Chemotherapy for
Resectable Gastric Cancer
CLASSIC Trial
Bang y et al. Lancet 2012
Adjuvant Chemotherapy: ACTSGT1
Observation n=530
Stage II-III gastric cancer treated
with curative gastrectomy; all with at
least D2 dissection n=1059
Randomised
Adjuvant S-1 80mg/m2/day x28
days q 6 weeks x 12 months
n=529
Screening programme in Japan
allows detection of disease at an
earlier stage
S1 efficacy not proven in non-Asian
population
Sakuramoto et al., NEJM 2007
Adjuvant Chemotherapy for
Resectable Gastric Cancer
Meta- analysis
The GASTRIC Group JAMA 2010
Adjuvant Radiation Therapy
Resectable Gastric Cancer
Snyder RA et al. Int J Surg Oncol. 2012
Adjuvant Chemotherapy vs. CRT
ARTIST Trial
capecitabine + cisplatin (XP)
6 cycles (n = 228)
Stage II-III gastric cancer treated
with curative gastrectomy; all D2
dissection n=458
Randomised
XP 2 cycles
capecitabine + 45GY XRT
XP 2 cycles (n = 230)
Chemotherapy vs. Chemoradiotherapy
for Resectable Gastric Cancer
ARTIST Trial: all patients
Lee J et al. JCO 2012
Chemotherapy vs. Chemoradiotherapy
for Resectable Gastric Cancer
ARTIST Trial: node + patients
3 yr DFS
77.5% vs. 72.3%
Treat 20 patients to prevent recurrence in 1 patient
Lee J et al. JCO 2012
Chemotherapy vs. Chemoradiotherapy
for Resectable Gastric Cancer
ARTIST Trial
Lee J et al. JCO 2012
Gastric Cancer
Targeted Agents – ToGA Trial
Bang YJ et al. Lancet. 2010
GIST
• >90% tumors  KIT or PDGFRα mutation
• >80% metastatic GIST patients benefit from
imatinib mesylate
• Resected primary GIST: 5-yr survival = 54%
CP1271510-62
GIST – Adjuvant
Z9001
A phase III randomized double-blind study of
adjuvant imatinib vs placebo in patients following
resection of primary GIST
Primary
GIST 3
cm
Complete
gross
resection
tumor KIT +
R
a
n
d
o
m
i
z
e
Placebo
x
1 year
lmatinib
x
1 year
F
O
L
L
O
W
U
P
PI: Ron DeMatteo
3048365-63
GIST – Adjuvant
Z9001
Recurrence-free and
alive (%)
Recurrence free survival
100
80
60
40
Imatinib
Placebo
Total
359
354
Events
30
70
20
HR 0.35 (95% CI 0.22-0.53); P<0.0001
0
0
12
6
24
18
30
36
Months
Placebo
Imatinib
359
354
207
188
105
89
33
34
Lancet. 2009 Mar 28;373(9669):1097-104
3048365-64
GIST – Adjuvant
Z9001
Multivariate Analyses For Recurrence: Placebo Group
Tumor location
Stomach
Small bowel
Rectum
Tumor size
<5 cm
5-10 cm
10 cm
Mitotic rate
<5
5
Genotype
Exon 9
Exon 11
Exon 13
PDGFRA
WT
0
2
4
6
8
10
12
Hazard ratio
14
16
18
20
ASCO 2010
3048365-65
GIST – Adjuvant
Z9001
Recurrence-free and
alive (%)
RFS For Exon 11- Mutant
Cases by Arm
RFS For Wildtype Cases
by Arm
100
100
80
80
60
60
40
40
Imatinib (n=173)
Imatinib (n=32)
Placebo (n=173)
Placebo (n=32)
20
20
Treatment
Treatment
P<0.0001 at 24 months
HR 3.42 (95% CI 1.93-6.06)
P=0.6123 at 24 months
0
0
0
6
12
18
24
30
36
0
6
12
18
24
30
36
Months
ASCO 2010
3048365-66
SSGXVIII: Study design
An open-label Phase III study
Random
assignment
1:1
Imatinib for
12 months
Follow-up
Stratification:
1) R0 resection, no
tumor rupture
2) R1 resection or
tumor rupture
Imatinib for 36 months
Follow-up
GIST – Adjuvant Imatinib
One vs. Three Years
Joensuu H et al. JAMA 2012
Advanced GIST
Sunitinib in Imatinib Resistant GIST
Advanced GIST
Sunitinib in Imatinib Resistant GIST
Esophageal/Gastric Cancer
Incidence / Mortality 2012
Esophageal Cancer
Stomach Cancer
24000
20000
17,460
16000
15,070
21,320
12000
8000
10,540
4000
0
new cases
deaths
Ca Cancer J Clin 2012; 62: epub