A BALANCED APPROACH TO THE TREATMENT OF ESOPHAGEAL CANCER

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A BALANCED APPROACH TO THE TREATMENT OF
ESOPHAGEAL CANCER
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DEFINITIONS
?PREOPERATIVE THERAPY INDUCTION THERAPY
NEOADJUVANT THERAPY ? POSTOPERATIVE THERAPY
ADJUVANT THERAPY ? COMBINED MODALITY gt 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)
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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
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SUMMARY
?PRE-OP (Neoadj) CONCOMITANT CHEMO-RADIOTHERAPY
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
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With a Balanced Approach to Rx, Is There a Role
for Surgery AfterPreop Chemotherapyfor Esophageal
Cancer?
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Preop (Induction or Neoadjv) Chemotherapy ?Surgery
Series Histology Rx regimen pts Med Surv
OS RTOG8911 SCCA Preop/Postop 213 15 mos 20
INT-0113 Adenoca-54 Cisplatin/5FU (5-yr) Kels
en Surgery alone 227 16 mos 20 MRC SCCA Pr
eop 400 17 mos 43 Adenoca-66 Cisplatin/5FU (
2-yr) Surgery alone 402 13 mos 34 MAGIC Adenoc
a Preop/Postop 253 24 mos 36 Cunningham
Epirub/Cis/5FU (5-yr) Surgery alone 250 20
mos23 France Adenoca Preop/Postop
113 NS 38 Boige Cisplatin/5FU (5-yr)
Surgery alone 111 NS 24
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META-ANALYSIS OF PREOP CHEMOTHERAPY (Thirion et
al, ASCO 2007)
?4 BENEFIT WITH PREOP CHEMOTHERAPY _at_ 5 YRS ? 7
SURVIVAL BENEFIT FOR ADENOCA WITH PREOP
CHEMOTHERAPY ? 4 SURVIVAL BENEFIT FOR SCCA WITH
PREOP CHEMOTHERAPY
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With a Balanced Approach to Rx, Is There a Role
for Surgery AfterPreop Chemoradiotherapyfor
Esophageal Cancer?
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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
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RTOG 85-01
Week 1 5 8 11 5-FU
1000 mg/m2 x 4 d???? CDDP 75 mg/m2 d 1 ????
RT 50 Gy RT 64 Gy
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RTOG 85-01
RTChemoRT Pts 62 61 5-year 0 28 Surviv
al Local 66 47 Failure JAMA 1999
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INT 0123 - Schema
5-FU/CDDP X 4 64.8 Gy
5-FU/CDDP X 4 50.4 Gy
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INT 0123
MEDIAN
2-YR
50.4 Gy 17.6 M 38
64.8 Gy 12.9 M 29
p0.14 (log-rank)
50.4 Gy
64.8 Gy
50.4 Gy
109
59
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64.8 Gy
107
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6
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INT 0123 - First Failure ()
64.8 Gy50.4 Gy 107 109 Total LR
61 60 LR persistence 44 42
LR failure 17 18 Distant failure
10 15
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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 LN- 75 67 LN 26
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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
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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 Preop 4.5
M 39 26 Surg 1.8 M 16
(p 0.02)
(p 0.005)
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Preop CMT Randomized Trials
TRIAL SURVIVALCOMMENTS U Michigan No 15 not
S.S. Walsh Yes 6 survival for
surgery EORTC No (DFS) Unconventional des
ign Australasian No Only 35 Gy Seoul No - CAL
GB 9781 Yes 56/500 pts.
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Preop CMTMeta-analysis
Am J Surg 2002
9 trials, 1116 pts Preop CMT vs. Surgery
3-Yr Survival (odds ratio) - all patients 2.50
(p0.038) - concurrent CMT 0.45 (p0.005)
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With a Balanced Approach to Rx, Is There a Role
for Adjuvant Treatment Following Surgery for
Esophageal Cancer?
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Does Postop CMT Improve Surgery?
INT 0116, NEJM 2001
5-FU/LV x 4 45 Gy
T3 and/or N1-2 (85)
Surgery alone
603 entered, 556 eligible Stages IB- IV
(non-M1) 20 GE Junction
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INT 0116 Adjuvant Gastric Trial
3-Yr Local Grade IV SurvFail Toxicity Surgery
30 29 32 RT/Chemo 40 19 41
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German Oesophageal Cancer Study Group
172 pts SCC
FU/LV/VP16/ VP16/CDDP CDDP X 3 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
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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 232310-2317 2005
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German Oesophageal Cancer Study Group
()Preop CT?CT-RT?OR Defin. Preop
CT?CT-RT pCR 33 - Mortality13 4
(p0.03) 2-yr LF 36 58 (p0.003) Med Surv 16
m 15 m 3-Yr Surv 31 24
Stahl et al JCO 2005
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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 232310-2317 2005
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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 gt 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)
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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 251160-1168 2007
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Fig 1. Treatment Design of the Federation
Francophone de Cancerologie Digestive 9102 trial
Bedenne, L. et al. J Clin Oncol 251160-1168 2007
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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?
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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 Downstaging5-Yr
Surv None 76 15 Stage I 13 34 pCR 42 48

p0.02
p0.015
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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 133 166 No 34
p 0.002
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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 33 13 positi
ve 7
p 0.44
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Does Post-CMT EUS Predict pCR?
Kalha et al, MDACC, Cancer 2004
? 83 pts. with adenocarcinoma ? T stage 29
accurate ? N stage 50 accurate ? 22 had EUS
but had pCR at surgery
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Does Post-CMT PET Predict Response?

• MSKCC (Downey)Leuven (Flamen)
• 40 Pts 38 Pts
• 20 undetected M1 ? SUV? Path
• 23 restaged after CMT gt 80 78
• ? SUV? Path
• gt 65 100 ? Major resp 16 vs.
• lt 65 30 6 m median surv

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Does Post-CMT PET Predict Survival?
Br?cher et al, 2006 GI
? 105 pts, SCC ? Preop CMT restage 3-4 wks
surgery ? MVA for survival Pathology (p
0.0001) 18-FDG-PET (p 0.015)
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Planned vs. Salvage Surgery
Swisher et al, MDACC J ThoracCardiovasc Surg 2002
? 1987-2000 retrospective review ? lt2
ofesophagectomies at MDACC were for salvage
Cervical Op 5-Yr AnastomosisMortalityS
urvival Planned 99 37 6 25 Salvage 13 61 15
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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
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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)
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CMT /- Surgery New Regimens

• ? Taxol/CDDP RTOG
• ? Irinotecan/CDDP MSKCC, CALGB
• ? Irinotecan/CDDP platform
• - Bevacizumab MSKCC
• - Cetuximab DFCI
• ? Irinotecan/CDDP vs. Taxol/CDDP ECOG
• ? Oxaliplatin/5-FU SWOG, ACOSOG

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Minskys 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
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ACKNOWLEDGMENTS
? BA JOBE ? JG HUNTER ? L LEICHMEN ? BD
MINSKY ? XX