A BALANCED
APPROACH TO THE
TREATMENT OF
ESOPHAGEAL
CANCER
DEFINITIONS
●PREOPERATIVE THERAPY = INDUCTION
THERAPY = NEOADJUVANT THERAPY
● POSTOPERATIVE THERAPY = ADJUVANT
THERAPY
● COMBINED MODALITY = > 1 TREATMENT
MODALITY
-i.e. a bi-modality approach:
-preop chemotherapy followed by surgery
-i.e. a tri-modality approach:
-initial surgery followed by postop
(adjuvant) chemoradiotherapy; or other
multimodality combinations)
SUMMARY
●SURGERY + ADDITIONAL MODALITY IS
REQUIRED FOR pT3 N1 TUMORS
● DEFINITIVE CHEMORADIOTHERAPY FOR
SCCA IS AN ACCEPTABLE STANDARD
● PREOP (Neoadjuvant) & POSTOP (Adjuvant)
COMBINATION CHEMOTHERAPY FOR
RESECTABLE ESOPHAGUS or GEJ ADENOCA IS
AN ACCEPTABLE APPROACH
SUMMARY
●PRE-OP (Neoadj) CONCOMITANT CHEMORADIOTHERAPY FOR RESECTABLE ADENOCA
OF ESOPHAGUS OR GEJ IS A DE-FACTO
ACCEPTABLE STANDARD FOR
● ROLE OF PREOP CHEMOTHERAPY (WITHOUT
XRT) FOR RESECTABLE SCCA IS POORLY
DEFINED AND NOT RECOMMENDED
● EARLY RESPONSE TO FDG-PET MAY PREDICT
RESPONSE FROM PREOP THERAPY
With a Balanced
Approach to Rx, Is
There a Role for
Surgery AfterPreop
Chemotherapyfor
Esophageal Cancer?
Preop (Induction or Neoadjv)
Chemotherapy Surgery
Series
Histology
RTOG8911
INT-0113
yr)
Kelsen
SCCA
Preop/Postop 213
Adenoca-54% Cisplatin/5FU
15 mos
20%
(5-
Surgery alone 227
16 mos
20%
MRC
Rx regimen # pts Med Surv
OS
SCCA
Preop 400
17 mos 43%
Adenoca-66% Cisplatin/5FU
(2-yr)
Surgery alone 402
13 mos 34%
MAGIC
Adenoca
Preop/Postop 253
24 mos 36%
Cunningham
Epirub/Cis/5FU
yr)
Surgery alone 250
20 mos23%
France Adenoca
Preop/Postop 113
Boige
Cisplatin/5FU
NS
38%
(5-yr)
(5-
META-ANALYSIS OF PREOP
CHEMOTHERAPY (Thirion et
al, ASCO 2007)
●4% BENEFIT WITH PREOP CHEMOTHERAPY @
5 YRS
● 7% SURVIVAL BENEFIT FOR ADENOCA WITH
PREOP CHEMOTHERAPY
● 4% SURVIVAL BENEFIT FOR SCCA WITH
PREOP CHEMOTHERAPY
With a Balanced
Approach to Rx, Is
There a Role for
Surgery AfterPreop
Chemoradiotherapyfor
Esophageal Cancer?
Questions
● What is the standard of care?
● Is more (intensification) better?
● Does any approach (pre/postop CMT) help?
● Can we identify responders preop?
● Lastly, what do you do when……
RTOG 85-01
Week
1 5 8 11
5-FU
RT
1000 mg/m2 x 4 d
CDDP 75 mg/m2 d 1
RT
50 Gy
64 Gy

RTOG 85-01
RTChemoRT
# Pts
62
61
% 5-year
Survival
0
28
% Local
Failure
66
47
JAMA 1999
INT 0123 - Schema
R
S
T
Weight loss
> or < 10%
A
N
R
D
A
T
Tumor size
< or > 5 cm
O
M
I
F
Y
Histology
Adeno
Squamous
5-FU/CDDP X 4
+
64.8 Gy
I
Z
E
5-FU/CDDP X 4
+
50.4 Gy
INT 0123
100
/ //
/////
/
% AL I VE
75
50
// //
//// ////
/ /
//
/ //
//
/
//
MEDIAN 2-YR
50.4 Gy 17.6 M
38%
64.8 Gy 12.9 M
29%
p=0.14 (log-rank)
//
/
//
// /
/ // /
/
//
25
50.4 Gy
/
/
//// / //
/
/ /// /// /
/ //// / /
/ //
/
64.8 Gy
0
0
6
12
18
24
30
36
MONTHS FROM RANDOMIZATION
50.4 Gy
64.8 Gy
109
107
59
42
24
17
6
6
INT 0123 - First Failure (%)
64.8 Gy50.4 Gy
#
107
109
Total LR
LR persistence
LR failure
61
44
17
60
42
18
Distant failure
10
15
En Bloc Esophagectomy
Altorki and Skinner Ann Surg 2001
• 111 patients (10% had preop therapy)
• Mortality (%):
5
• Local Fail (%):
8
#Group5-Yr Surv (%)
111
Total
40
44
LN75
67
LN+
26
Surgeryvs. CMT
Surgery
CMT
(INT 0133)(RTOG 85-01)
Median survival
18 months
14 months
5-year survival
20%
27%
Rx-related death
6%
2%
Local Failure
31% + 30%*
45%
* 30% had R1-2 resection
Does Preop CMT Improve
Surgery?
CALGB 9781
Accrual goal: 500 pts
Entered:
56 pts, stages I-III
Median F/U: 6 Yr
% Survival
#ArmMedian5-Yr
30
26
Preop
Surg
4.5 M
1.8 M
(p = 0.02)
39
16
(p = 0.005)
Preop CMT
Randomized Trials
TRIAL
SURVIVALCOMMENTS
U Michigan
No
15% not S.S.
Walsh
Yes
6% survival
for surgery
EORTC
No (+DFS)
Unconventional
design
Australasian
No
Only 35 Gy
Seoul
No
CALGB 9781
Yes
56/500 pts.
Preop CMT
Meta-analysis
Am J Surg 2002
• 9 trials, 1116 pts
• Preop CMT vs. Surgery
• 3-Yr Survival (odds ratio)
- all patients
2.50 (p=0.038)
- concurrent CMT 0.45 (p=0.005)
With a Balanced
Approach to Rx, Is
There a Role for
Adjuvant Treatment
Following Surgery for
Esophageal Cancer?
Does Postop CMT
Improve Surgery?
INT 0116, NEJM 2001
T3 and/or
N1-2 (85%)
5-FU/LV x 4 + 45 Gy
Surgery alone
• 603 entered, 556 eligible
• Stages IB- IV (non-M1)
• 20% GE Junction
INT 0116 Adjuvant Gastric
Trial
3-Yr
Local Grade IV
SurvFailToxicity
Surgery
30%**
29%
32%
RT/Chemo
40%
19%
41%
German Oesophageal
Cancer Study Group
172 pts SCC
FU/LV/VP16/
CDDP X 3
VP16/CDDP
40 Gy
Surg
FU/LV/VP16/
VP16/CDDP
CDDP x 3
T4 or T3 obst: 65 Gy
T3: 60Gy + 4 Gy brachy
Stahl et al JCO 2005
Fig 3. Kaplan-Meier plots showing (A) overall survival from the date of randomization among patients
allocated to preoperative chemoradiation and surgery (arm A, n = 86) or chemoradiation without surgery
(arm B, n = 86) and (B) survival as randomized among patients treated according to their treatment arm
excluding cross-over patients (arm A, n = 75; arm B, n = 81)
Stahl, M. et al. J Clin Oncol; 23:2310-2317 2005
Copyright © American Society of Clinical Oncology
German Oesophageal
Cancer Study Group
(%)Preop CTCT-RTOR
Defin. Preop CTCT-RT
pCR
33%
Mortality13
4 (p=0.03)
2-yr LF
36
58 (p=0.003)
Med Surv
16 m
15 m
3-Yr Surv
31
24
Stahl et al JCO 2005
Fig 4. Kaplan-Meier plots showing the freedom from locoregional progression among patients allocated
to preoperative chemoradiation and surgery (arm A) or chemoradiation without surgery (arm B)
Stahl, M. et al. J Clin Oncol; 23:2310-2317 2005
Copyright © American Society of Clinical Oncology
FFCD 9102
• 445 pts (cT3 N0-1) SCCA: Pre-op (Neoadjuvant or
Induction) 5-FU/CDDP/RT x 2
(46 Gy or 30 Gy split course)
Surgery
•259 pts > PR
5-FU/CDDP/RT x 2 x 3
(20 Gy or 15 Gy split course)
• Median (18 vs. 19 m) and 2-yr surv (34% vs. 40%)
Fig 3. Overall survival of the patients with esophageal cancer responding to induction chemoradiation
who were randomly assigned to either surgery (arm A) or continuation of chemoradiation (arm B)
Bedenne, L. et al. J Clin Oncol; 25:1160-1168 2007
Copyright © American Society of Clinical Oncology
Fig 1. Treatment Design of the Federation Francophone de Cancerologie Digestive 9102 trial
Bedenne, L. et al. J Clin Oncol; 25:1160-1168 2007
Copyright © American Society of Clinical Oncology
FFCD 9102
● 9% operative mortality (1% with CMT)
● Only responders were randomized
● Bias against surgery: it may be most
helpful in pts. with residual disease
● Does pCR predict outcome and can
responders be accurately identified?
Does pCR Predict
Outcome?
Berger et al, FCCC, JCO 2005
● 131 pts (78% adeno)
● Preop 45 Gy + 5-FU based CT
● 14 months median F/U
Downstaging#%5-Yr Surv
None
76
Stage I
13
pCR
42
15
34
48
p=0.02
p=0.015
Does pCR Predict
Outcome?
Rohatgi et al, MDACC, Cancer 2005, 2006
● 45-50.4 Gy + CT (+/- induction), 86% Adeno
● 69/235 (29%) had pCR
● pCR Adeno vs. SCC: 29% vs 31%
● Median F/U 37 M
Median
#pCRSurv (m)
69 Yes
166 No
133
34
p = 0.002
Does Post-CMT Biopsy
Predict pCR?
Yang et al, MDACC, Dis Eso 2004
● 65 pts, GE junction
● 40-45 Gy + 5-FU based CT
● Post-treatment Bx within 30 days before surgery
#Biopsy% pCR
52 negative
13 positive
33
7
p = 0.44
Does Post-CMT EUS
Predict pCR?
Kalha et al, MDACC, Cancer 2004
● 83 pts. with adenocarcinoma
● T stage:
● N stage:
29% accurate
50% accurate
● 22 had EUS+ but had pCR at surgery
Does Post-CMT PET
Predict Response?
MSKCC (Downey)Leuven (Flamen)
• 40 Pts
• 38 Pts
• 20% undetected M1
• SUV Path
• 23 restaged after CMT
> 80% 78%
• SUV Path
> 65%
100%
● Major resp: 16 vs.
< 65%
30%
6 m median surv
Does Post-CMT PET
Predict Survival?
Brϋcher et al, 2006 GI
● 105 pts, SCC
● Preop CMT restage 3-4 wks
● MVA + for survival
Pathology
(p = 0.0001)
18-FDG-PET
(p = 0.015)
surgery
Planned vs. Salvage Surgery
Swisher et al, MDACC
J ThoracCardiovasc Surg 2002
● 1987-2000 retrospective review
● <2% ofesophagectomies at MDACC were for salvage
% Cervical
#AnastomosisMortalitySurvival
Planned
99
37
% Op
% 5-Yr
6
25
Salvage
15
25
13
61
RTOG 0241 – Phase II
Taxol/CDDP/5-FU/50.4 Gy (RTOG E-0113)
“Selective” surgery
● At least T1N0, all histologies
● Accrual 31/42 patients
Do Markers Predict
Outcome After CMT?
● COX-2 mRNA
(Xi, Clin Cancer Res, 2005)
● Microvessel Density
(Hironaka, Clin Cancer Res 2002)
● p53, CDC25B, MT
(Kishi, Br J Surg 2003)
● Serum proteomic spectra
(Hayashida, Clin Cancer Res 2005)
CMT +/- Surgery:
New Regimens
● Taxol/CDDP
● Irinotecan/CDDP
RTOG
MSKCC, CALGB
● Irinotecan/CDDP platform +
- Bevacizumab
- Cetuximab
MSKCC
DFCI
● Irinotecan/CDDP vs. Taxol/CDDP
ECOG
● Oxaliplatin/5-FU
SWOG, ACOSOG
Minsky’s Answers
● ChemoRT or surgery is standard – 25% 5-yr survival
● Advantage oftrimodality therapy is 5-10%
● If T2-4N+: CMT then restage with PET, CT, EUS, Bx
● Squamous Cell:
- cCR by all criteria
observe
- non-responding or any residual
surgery
● Adenocarcinoma: less data but surgery for all
● Improve imaging/markers to identify pCR and new CMT
ACKNOWLEDGMENTS
● BA JOBE
● JG HUNTER
● L LEICHMEN
● BD MINSKY
● XX