Post on 29-Dec-2021
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