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 ISREQUIRED FOR pT3 N1 TUMORS

● DEFINITIVE CHEMORADIOTHERAPY FORSCCA IS AN ACCEPTABLE STANDARD

● PREOP (Neoadjuvant) & POSTOP (Adjuvant)COMBINATION CHEMOTHERAPY FORRESECTABLE ESOPHAGUS or GEJ ADENOCA IS AN ACCEPTABLE APPROACH

SUMMARY●PRE-OP (Neoadj) CONCOMITANT CHEMO-RADIOTHERAPY FOR RESECTABLE ADENOCA OF ESOPHAGUS OR GEJ IS A DE-FACTOACCEPTABLE 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 Rx regimen # pts Med Surv OSRTOG8911 SCCA Preop/Postop 213 15 mos 20% INT-0113 Adenoca-54% Cisplatin/5FU (5-yr)Kelsen Surgery alone 227 16 mos 20%

MRC 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 (5-yr)

Surgery alone 250 20 mos23%

France Adenoca Preop/Postop 113 NS 38%Boige Cisplatin/5FU (5-yr) Surgery alone 111 NS 24%

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 1000 mg/m2 x 4 dCDDP 75 mg/m2 d 1

RT 50 Gy

RT 64 Gy

RTOG 85-01

RTChemoRT

# Pts 62 61

% 5-year 0 28Survival

% Local 66 47Failure JAMA 1999

INT 0123 - Schema

S

T

R

A

T

I

F

Y

Weight loss> or < 10%

Tumor size< or > 5 cm

HistologyAdenoSquamous

R

A

N

D

O

M

I

Z

E

5-FU/CDDP X 4+ 64.8 Gy

5-FU/CDDP X 4 + 50.4 Gy

%

A L

I V

E

0

25

50

75

100

MONTHS FROM RANDOMIZATION0 6 12 18 24 30 36

///// // / //////

/ ////

/ / /// // / /

/ / //// // / /

/ ///// / /////

// //

//// / / / / /

//// / // / /////// // / /

INT 0123

64.8 Gy

50.4 Gy

MEDIAN 2-YR50.4 Gy 17.6 M 38%64.8 Gy 12.9 M 29%

p=0.14 (log-rank)

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 61 60 LR persistence 44 42 LR failure 17 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 4044 LN- 7567 LN+ 26

Surgeryvs. CMTSurgery 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 ptsEntered: 56 pts, stages I-IIIMedian F/U: 6 Yr

% Survival#ArmMedian5-Yr30 Preop 4.5 M 3926 Surg 1.8 M 16

(p = 0.02) (p = 0.005)

Preop CMT Randomized Trials

TRIAL SURVIVALCOMMENTSU Michigan No 15% not S.S.Walsh Yes 6% survival

for surgeryEORTC No (+DFS) Unconventional

designAustralasian No Only 35 GySeoul No -CALGB 9781 Yes 56/500 pts.

Preop CMTMeta-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?

T3 and/orN1-2 (85%)

5-FU/LV x 4 + 45 Gy

Surgery alone

INT 0116, NEJM 2001

• 603 entered, 556 eligible• Stages IB- IV (non-M1)• 20% GE Junction

INT 0116 Adjuvant Gastric Trial

3-Yr Local Grade IVSurvFailToxicity

Surgery 30%** 29% 32%

RT/Chemo 40% 19% 41%

German Oesophageal Cancer Study Group

172 pts SCC

FU/LV/VP16/ VP16/CDDPCDDP X 3 40 Gy Surg

FU/LV/VP16/ VP16/CDDPCDDP x 3 T4 or T3 obst: 65 GyT3: 60Gy + 4 Gy brachy

Stahl et al JCO 2005

Copyright © American Society of Clinical Oncology

Stahl, M. et al. J Clin Oncol; 23:2310-2317 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)

German Oesophageal Cancer Study Group

(%)Preop CTCT-RTOR Defin. Preop CTCT-RTpCR 33% -Mortality13 4 (p=0.03)2-yr LF 36 58 (p=0.003)Med Surv 16 m 15 m3-Yr Surv 31 24

Stahl et al JCO 2005

Copyright © American Society of Clinical Oncology

Stahl, M. et al. J Clin Oncol; 23:2310-2317 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)

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%)

Copyright © American Society of Clinical Oncology

Bedenne, L. et al. J Clin Oncol; 25:1160-1168 2007

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)

Copyright © American Society of Clinical Oncology

Bedenne, L. et al. J Clin Oncol; 25:1160-1168 2007

Fig 1. Treatment Design of the Federation Francophone de Cancerologie Digestive 9102 trial

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 SurvNone 76 15Stage I 13 34pCR 42 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 133 166 No 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% pCR52 negative 3313 positive 7

p = 0.44

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

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 surgery

● MVA + for survival Pathology (p = 0.0001) 18-FDG-PET (p = 0.015)

Planned vs. Salvage Surgery

Swisher et al, MDACCJ ThoracCardiovasc Surg 2002

● 1987-2000 retrospective review● <2% ofesophagectomies at MDACC were for salvage

% Cervical % Op % 5-Yr#AnastomosisMortalitySurvivalPlanned 99 37 6 25

Salvage 13 61 15 25

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 RTOG● Irinotecan/CDDP MSKCC, CALGB

● Irinotecan/CDDP platform + - Bevacizumab MSKCC - Cetuximab 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