Selective Surgery as an Option in the Treatment of Locally Advanced

Esophageal Carcinoma

Wayne Hofstetter, MD

Salvage Esophagectomy

Disclosures………..

Cured

Incurable

Need Surgery

Selective approach

Organ Preservation: Why Not?

Death from local-regional disease is the ultimate failure of therapy

…Death from therapy isn’t so well tolerated either

J Gastrointest Surg (2013) 17:1359–1369 DOI 10.1007/s11605-013-2223-4 ORIGINAL ARTICLE

Surgery Is an Essential Component of Multimodality Therapy for Patients with Locally Advanced Esophageal Adenocarcinoma Caitlin C. Murphy & Arlene M. Correa & Jaffer A. Ajani & Ritsuko U. Komaki & James W. Welsh &Stephen G. Swisher & Wayne L. Hofstetter

• Background Experience with neoadjuvant chemoradiation (CXRT) has raised questions regarding the additional benefit of surgery after locally advanced esophageal adenocarcinoma patients achieve a clinical response to CXRT. We sought to quantify the value of surgery by comparing the overall (OS) and disease-free survival (DFS) of trimodality-eligible patients treated with definitive CXRT vs. CXRT followed by esophagectomy.

• Methods We identified 143 clinical stage III esophageal adenocarcinoma patients that were eligible for trimodality therapy. All patients successfully completed neoadjuvant CXRT and were considered appropriate candidates for resection. Patients that were medically inoperable were excluded. Cox regression models were used to identify significant predictors of survival.Results Among the 143 patients eligible for surgery after completing CXRT, 114 underwent resection and 29 did not. Poorly differentiated tumors (HR=2.041, 95% CI=1.235–3.373) and surgical resection (HR=0.504, 95% CI=0.283–0.899) were the only independent predictors of OS. Patients treated with surgery had a 50 and 54 % risk reduction in overall and cancer-specific mortality, respectively. Median OS (41.2 vs. 20.3 months, p=0.012) and DFS (21.5 vs. 11.4 months, p=0.007) were significantly improved with the addition of surgery compared to definitive CXRT.

• Conclusions Surgery provides a significant survival benefit to trimodality-eligible esophageal adenocarcinoma patients with locally advanced disease.

Poor PS after CXRT

Choice*

Planned dCXRT

Definitive CXRT

Salvage EsophagectomyAfter Failed Definitive

Chemoradiation For Esophageal Adenocarcinoma

Jenifer L. Marks, Wayne Hofstetter, Arlene Correa, Reza Mehran, David Rice, Jack Roth, Garrett Walsh, Ara Vaporciyan, Jeremy Erasmus, Joe Chang, Dipen Maru,

Jeffrey Lee, Jared Lee, Jaffer Ajani, Stephen Swisher

January 30th, 2012

Definitions

• Salvage esophagectomy defined as resection after chemoradiotherapy delivered with curative intent

• >90 days from completion of treatment to resection

• Leak defined as any radiographic or clinically apparent leak

Results

Chemoradiotherapy → Surgery

n = 586

Planned

CRT → Surgery

n = 521

Salvage

dCRT→ Surgery

n = 65

Matched pair, n=65

Results: Time to surgery

Salvage

n=65

Planned

n=521

p value

Time to surgery

(mean # days)304 ± 237 58 ± 27 <.001

95% CI (days) 244-362 55-59

Salvage Indication

Recurrence

Persistence

56 (86%)

9 (14%)

Results: Surgical outcomes

Salvage

n=65

Planned

n=521

p value

Surgery time (min) 392 ± 118 395 ± 109 NS

EBL (cc) 473 ± 286 515 ± 351 NS

# nodes harvested 17 ± 8 20 ± 10 0.013

# nodes positive 1 ± 2.2 1.2 ± 2.6 NS

Extent of Resection

R0

R1

R2

59 (90.8%)

3 (4.6%)

3 (4.6%)

493 (94.6%)

26 (5%)

2 (0.4%)

.018

Results: Major morbidity

Per

cen

tage

0

5

10

15

20

25

30

35

40

Major Event Any Leak Conduit Loss

Salvage, n=65

Planned, n=521

Matched pair, n=65

p=.192

p=.098

p=.067

Results: Conduit Loss with Leak

0

5

10

15

20

25

30

Salvage, 3/12 (n=65)

Planned, 5/59 (n=521)

Matched pair, 2/11 (n=65)

p=NS%

condu

it l

oss

/ l

eak

Results: Mortality

Salvage

n=65

Planned

n=521

p value

LOS (days) 19 (4-153) 14 (0-88) NS

30d Mortality 2 (3.1%) 15 (2.9%) NS

90d Mortality 3 (4.6%) 27 (5.2%) NS

Time (months)

Cu

mu

lati

ve

surv

ival

pro

bab

ilit

y p=0.2221.0

0.8

0.6

0.4

0.2

0

0 4836 6012 24

521

65

374

38

255

19

188

12

134

10

101

5

Planned, n=521

Salvage, n=65

Number at risk

Results: Median Survival

32 months

48 months

p=0.449

Planned

Salvage

Number at risk

34

19

65

65

8

5

21

12

13

10

42

38

0 48 6024 3612Time (months)

Cu

mu

lati

ve

surv

ival

pro

bab

ilit

y

1.0

0.2

0

0.6

0.4

0.8

32 months

40 months

Results: Matched pair median survival

Salvage EsophagectomyModern Era-Multi-Center Europe

Markar et al., JCO, 2015

Results: MVA for predictors of Major Event, n=586

n HR Lower Upper p value

Type of resection <.005

ILE 409 1.0

Transhiatal 63 1.058 0.570 1.963 NS

3 Field 53 3.643 1.997 6.646 0.000

MIE 61 2.030 1.145 3.599 0.015

Results: MV analysis

•Salvage strategy and time to surgery are not predictors of death or major event on multivariate analysis for all patients or salvage patients alone

Stage IIB-III SCCA upper-mid esoph

C+CXRT

Accrued from 1994-2002

34% refused surgery in arm A (10 mets/7 response)

Treatment related death 12.8% vs 3.5%

pCR = 35%

P=0.02 P=0.003

Accrual 1993-2000 Median F/U 47.4 months

pCR 23% / Adeno 11% of study population

Treatment related mortality: 12.4% vs 3.8%

The CROSS Trial

RANDOMI Z E

Carbo-Taxol + 41.4 Gy XRT SurgeryN=178

SurgeryN=188

Van Hagen et al., NEJM 2012

cT1N1 or T2-3N0-1 carcinoma (adeno

75%) of esophagus, no cervical or Type III

GEJ

Recruitment: March 2004 Dec 2008

Cross Trial: NEJM

Van Hagen et al., NEJM 2012

pCR 18/37 (49%)

pCR

Incurable

Need Surgery

Selective approach

49%

20%

30%

Salvage versus planned esophagectomy after chemoradiotherapy for ESCC:

Perioperative and oncologic outcomes

Kyle G. Mitchell, MD

PI: Hofstetter

Background• ESCC: uncertain benefit with surgery if

clinical response to CXRT1,2

• Selective approach to surgery3

• MSKCC (n=232)4

• Resection: n=108

• Surgery = “time-dependent”• BMT: censored at time of salvage (n=17)

• TMT > BMT

• Knowledge gap: Small reports, conflicting results

1. Bedenne JCO 2007 2. Stahl JCO 20053. Swisher JTO 2017 4. Barbetta JTCVS 2018

BackgroundAuthor Journal, year Location Population n Note

Barbetta JTCVS 2018 MSKCC

ESCC TMT vs dCXRT

2000-2016

TMT n=108

Salvage n=17

Elimova Oncology 2018 MDACC

EAC, ESCC iso LRR p

BMT/TMT

Excluded surgery ≤6m p BMT

Iso LRR n=127

ESCC n=27

Swisher (RTOG 0246)

JTO 2017

Int J Rad Oncol B Phys

2012 Mult USA

EAC, ESCC 2003-2008

Selective surgery

n=43

Surgery n=21

Farinella JSO 2016 France EAC, ESCC 2006-2014 Salvage n=16

Markar JCO 2015 Mult Europe EAC, ESCC TMT 2000-2010

Planned n=540

Salvage n=308

Juloori JTO 2014 MDACC EAC, ESCC TMT 2000-2011

n=285

Salvage n=40

Rad onc

XRT field -->

Leak

Marks Ann Thorac Surg 2012 MDACC EAC 1997-2010 salvage Salvage n=65

Morita J Gastroenterol 2011 Japan EAC, ESCC 1994-2009 Salvage n=27

Morita ASO 2011 Japan EAC, ESCC 2-stage 2005-2010

n=27

Salvage n=4

Morita J Gastroenterol 2011 Japan EAC, ESCC 1994-2009 Salvage n=27

Miyata JSO 2009 Japan ESCC TMT 1994-2007 Salvage n=33

Oki Dis Esophagus 2007 Japan ESCC 1994-2005 Salvage n=14

Tomimaru J Surg Oncol 2006 Japan ESCC 1985-2004 Salvage n=24

MethodsInclusion:

• ESCC MDACC 2004-2016

• CXRT → Surgery

Exclusion:

• Cervical (<20cm)

• Emergent

Definitions:

• Salvage: for failure (recurrent/persistent dz) after documented dCXRT, or delay ≥ 90d after CXRT

• Planned: All else

2004-2016ESCC

n=121

ESCC p CXRTN=78

No CXRT: 30Cervical: 12No resection: 6Emergent for perf: 1

PlannedN=36

Salvagen=42

Variable

Planned

n=36

Salvage

n=42 p

Sex

M

F

24 (66.7)

12 (33.3)

26 (61.9)

16 (38.1)

0.662

Age, median (IQR) (years) 63.5 (54.5-67.0) 65.5 (57.5-70.0) 0.150

Race

W

AA

H

Asian

31 (86.1)

1 (2.8)

2 (5.6)

2 (5.6)

28 (66.7)

5 (11.9)

5 (11.9)

4 (9.5)

0.252

BMI, median (IQR) 21.9 (19.9-24.8)24.3 (20.9-27.0) 0.024

Smoking

Never

Former/Current

12 (33.3)

24 (66.7)

10 (23.8)

32 (76.2)

0.351

Zubrod at surgery

0

1

17 (47.2)

19 (52.8)

16 (38.1)

26 (61.9)

0.416

Major comorbidities

DM

CAD

COPD

0 (0.0)

3 (8.3)

3 (8.3)

9 (21.4)

8 (19.0)

1 (2.4)

0.003

0.175

0.330

Differentiation

Well/moderate

Poor

15 (41.7)

21 (58.3)

22 (52.4)

20 (47.6)

0.345

Tumor location

Upper/middle thoracic

Lower thoracic/GEJ

13 (31.1)

23 (63.9)

25 (59.5)

17 (40.5)

0.039

Results: Cohort characteristics (unmatched)Variable

Planned

n=36

Salvage

n=42 p

Tumor size, median (IQR)(cm) 5.0 (4.0-7.0) 5.0 (3.0-6.0) 0.356

cT

cT1

cT2

cT3

cT4

0 (0.0)

3 (8.3)

32 (88.9)

1 (2.8)

1 (2.4)

6 (14.3)

32 (76.2)

3 (7.1) 0.547

cN

cN0

cN+

12 (33.3)

24 (66.7)

21 (50.0)

21 (50.0) 0.137

SUVmax, median (IQR)

Pre tx*

Post tx**

14.0 (9.1-19.9)

4.5 (3.1-7.0)

12.8 (11.5-16.9)

5.1 (4.0-8.1)

0.828

0.225

XRT dose, Gy***

<50.4

≥50.4

4 (11.4)

31 (88.6)

7 (18.9)

30 (81.1)

0.377

Delay from therapy to surgery,

median (IQR)(days) 60.5 (50.5-78.0) 160.5 (108.5-278.5) <0.001

Resection type

ILE

THE

Three-field

23 (63.9)

2 (5.6)

11 (30.6)

19 (45.2)

0 (0.0)

23 (54.8)

0.035

Minimally-invasive component

Y

N

6 (16.7)

30 (80.3)

7 (16.7)

35 (83.3) 1.000

*Available in 64 (82.1)

**Available in 62 (79.5)

***Available in 72 (92.3)

Results: Perioperative (unmatched)

Variable

Planned

n=36

Salvage

n=42 p

Operative time, median (IQR)(minutes) 351.0 (314.0-395.8) 411.0 (343.0-495.3) 0.013

Estimated blood loss, median (IQR)(mL) 325.0 (250.0-500.0) 400.0 (250.0-500.0) 0.980

Intraoperative transfusion 6 (16.7) 11 (26.2) 0.310

Postoperative transfusion 4 (11.1) 16 (38.1) 0.007

Major pulmonary event* 7 (19.4) 16 (38.1) 0.072

Major CV event** 8 (22.2) 18 (42.9) 0.054

Anastomotic leak 6 (16.7) 3 (7.1) 0.288

Recurrent injury 1 (2.8) 2 (4.8) 1.000

Chylothorax req surg intervention 0 (0.0) 4 (9.5) 0.120

ICU readmission 4 (11.1) 9 (21.4) 0.223

LOS, median (IQR)(days) 8.5 (7.0-30.5) 12.0 (8.0-22.3) 0.242

30-day readmission 0 (0.0) 4 (9.5) 0.120

30-day mortality 0 (0.0) 2 (4.8) 0.497

90-day mortality 5 (13.9) 6 (14.3) 0.960

Table 2: Operative and perioperative outcomes among unmatched cohort

*MPE: ARDS, pneumonia, reintubation, tracheostomy

**MCVE: atrial arrhythmia req tx, MI, arrest, PE

Results: Perioperative (unmatched)

Variable

Planned

n=36

Salvage

n=42 p

Operative time, median (IQR)(minutes) 351.0 (314.0-395.8) 411.0 (343.0-495.3) 0.013

Estimated blood loss, median (IQR)(mL) 325.0 (250.0-500.0) 400.0 (250.0-500.0) 0.980

Intraoperative transfusion 6 (16.7) 11 (26.2) 0.310

Postoperative transfusion 4 (11.1) 16 (38.1) 0.007

Major pulmonary event* 7 (19.4) 16 (38.1) 0.072

Major CV event** 8 (22.2) 18 (42.9) 0.054

Anastomotic leak 6 (16.7) 3 (7.1) 0.288

Recurrent injury 1 (2.8) 2 (4.8) 1.000

Chylothorax req surg intervention 0 (0.0) 4 (9.5) 0.120

ICU readmission 4 (11.1) 9 (21.4) 0.223

LOS, median (IQR)(days) 8.5 (7.0-30.5) 12.0 (8.0-22.3) 0.242

30-day readmission 0 (0.0) 4 (9.5) 0.120

30-day mortality 0 (0.0) 2 (4.8) 0.497

90-day mortality 5 (13.9) 6 (14.3) 0.960

Table 2: Operative and perioperative outcomes among unmatched cohort

*MPE: ARDS, pneumonia, reintubation, tracheostomy

**MCVE: atrial arrhythmia req tx, MI, arrest, PE

All TMT Salvage All TMT Salvage

Median delay, months 3.0 5.3 2.9 8.7

Pulmonary complication* 30.3 38.1 68.0 29.0

Cardiac complication* 33.3 42.9 1.0 0.0

Leak (Gr 3) 3.8 2.4 8.6 18.0

30d mortality 2.6 4.8 4.8 18.0

MDACC MSKCC

*MSKCC definition ≥ grade 3

Results: Pathologic (unmatched)

Variable

Planned

n=36

Salvage

n=42 p

ypT

ypT0

ypT1

ypT2

ypT3

ypT4

16 (44.4)

2 (5.6)

8 (22.2)

8 (22.2)

2 (5.6)

13 (31.0)

7 (16.7)

4 (9.5)

14 (33.3)

4 (9.5)

0.191

ypN

ypN0

ypN1

ypN2

25 (69.4)

9 (25.0)

2 (5.6)

29 (69.0)

10 (23.8)

3 (7.1)

1.000

Lymph nodes examined, median (IQR) 21.5 (14.0-35.5) 17.0 (10.0-26.3) 0.109

Lymphovascular invasion 10 (27.5) 15 (35.7) 0.454

Pathologic margin

R0

R1

R2

32 (88.9)

2 (5.6)

2 (5.6)

38 (90.5)

2 (4.8)

2 (4.8)

1.000

Table 3: Pathologic characteristics among unmatched cohort

Results: Pathologic (unmatched)

Variable

Planned

n=36

Salvage

n=42 p

ypT

ypT0

ypT1

ypT2

ypT3

ypT4

16 (44.4)

2 (5.6)

8 (22.2)

8 (22.2)

2 (5.6)

13 (31.0)

7 (16.7)

4 (9.5)

14 (33.3)

4 (9.5)

0.191

ypN

ypN0

ypN1

ypN2

25 (69.4)

9 (25.0)

2 (5.6)

29 (69.0)

10 (23.8)

3 (7.1)

1.000

Lymph nodes examined, median (IQR) 21.5 (14.0-35.5) 17.0 (10.0-26.3) 0.109

Lymphovascular invasion 10 (27.5) 15 (35.7) 0.454

Pathologic margin

R0

R1

R2

32 (88.9)

2 (5.6)

2 (5.6)

38 (90.5)

2 (4.8)

2 (4.8)

1.000

Table 3: Pathologic characteristics among unmatched cohort

pCR (ypT0-isN0):• Planned: 41.7%• Salvage: 23.8%

Results: Survival (Unmatched; t0 = last day CXRT)

Results: Survival (Unmatched; t0 = last day CXRT)

MST 95% CI log-rank p

Planned 134.6 52.5-217.7 0.054

Salvage 35.4 23.3-47.5

MDFST 95% CI log-rank p

Planned 75.3 29.1-121.5 0.061

Salvage 28.3 18.1-38.4

MLocoregDFST 95% CI log-rank p

Planned 75.3 28.6-122.1 0.17

Salvage 29.6 17.8-41.3

Results: Survival (OS; by location)

Results: Survival (DFS; by location)

Summary

Relatively large ESCC salvage series

Among unmatched cohort, salvage: • BMI, DM, CAD

• Proximal tumors → 3 field

• Longer operations, periop transfusions/morbidity

• Poor OS/DFS/LRDFS

Depends on what the Definition of “Salvage” is:

• Regarding previous definitions:

• - Marks: Salvage = persistence or recurrence 90+ days after dCXRT; delays for decline in PS during chemo were counted as planned

• - Markar JCO 2015: Salvage = for persistent or recurrent disease after dCXRT, with subanalysis performed of those with recurrence vs perisistence

• - Barbetta JTCVS 2018: Salvage = dCXRT followed by surgery for recurrence

• - Farinella JSO 2016: Salvage = dCXRT followed by surgery for biopsy-proven local failure

• - Morita J Gastroenterol 2011: Salvage = residual tumor 1+ month after dCXRT

Is any of this scientific?

t0 = surgery

t0 = completion of CXRT

Planned: OS = 6m

Salvage: OS = 6m

Planned: OS = 12m

Salvage: OS = 18m

Death, progression

Death, progression

A)

B)

CXRT

CXRT

Immortality time bias

Conclusions

• Must acknowledge unavoidable bias

• Studies that are randomized are the only way to decipher the overall results

• Methods of detecting residual disease will help to individualize therapy

• Better systemic control may make LRC more important