1. AATS/STS General Thoracic Surgery Symposium
Surgery for Squamous Cell Cancer of the Esophagus: Only for Salvage or as Part of Combined Modality Therapy?
Stephen G. Swisher, MD
AATS/STS General Thoracic Surgery Symposium
Seattle, WA
April 26, 2015
14:15- 14:30 Surgery for Squamous Cell Cancer of the Esophagus: Only for Salvage or as Part of Combined Modality Therapy?
*Stephen G. Swisher, MD Anderson Cancer Center
Stephen - Preferably, the presentation should start with a clinical case to then gradually work your way back to the take-home message which should be the last slide with 3/4 bullet pointed statements and the answer to the main question expressed in the title of your presentation. SPF
I plan to discuss today currrent approaches in the management of squamous and adenocarcinoma of the esophagus

2. Esophageal Resections Histology - MDACC
As you all know there has been a dramatic shift in North America and Europe in the histology of esophageal cancer from scca to adenocarcinoma.
Consistent with these reports, our institution has seen a dramatic increase in the proportion of adenocarcinoma from 40% to 90%
with a reduction in squamous cell carcinoma from 60% to 10%.
MDACC Thoracic Surgery Database

3. Esophageal Cancer Case #1
52 yo female who developed dysphagia and found to have middle SCCA esophagus.
EGD-EUS-T3N1, cm. CT-PET- no distant metastases. Bronchoscopy- No tracheal mucosa involvement
The indications for resection therefore include all patients with resectable esophageal cancer who are physiologically fit and do not have distant metastases or tracheoesophageal fistulae.

4. Esophageal Cancer Treatments Type of Esoph after Chemoradiation
Definitive Chemoradiation     Salvage Esophagectomy
RTOG 8501
FFCD 9102
Preoperative Chemoradiation  Planned Esophagectomy
CROSS - Trimodality
Chemoradiation  or    Selective Esophagectomy
RTOG 0246
Locoregional failure which was 60% in RTOG would be carefully evaluated with serial endoscopy and biopsy and CT scans.
Indication for salvage surgery would be bx positive disease, failure to epithelialize and non-dilatable strictures. Additionally CT evidence of increasing mass without systemic metastases would be criteria for salvage therapy according to the investigator. This would be up to the individual investigators but would include surgical salvage if appropriate.

5. Definitive Chemoradiation
Well what about the strategy of preoperative chemoradiation for GEJ adenocarcinoma.

6. 44% Locoregional Failure 7% Site of Recurrence Not Known
Definitive Chemoradiation
SCCA– RTOG – CRT vs RT alone
44% Locoregional Failure
7% Site of Recurrence Not Known
Definitive CRT
Did this improved locoregional control did not result in improved long-term survival with overlapping curves.
Increased benefit of trimodality balanced out perhaps by the increased treatment related mortality.
Herskovic et al., NEJM, 2001

7. 44% Locoregional Failure 7% Site of Recurrence Not Known
Definitive Chemoradiation
RTOG – Long-Term Results
44% Locoregional Failure
7% Site of Recurrence Not Known
Definitive CRT
129 pt randomized; 73 pts non-randomized arms
Cooper et al., JAMA, 1999

8. Preop CRT  Surg
Well what about the strategy of preoperative chemoradiation for GEJ adenocarcinoma.

9. Preoperative Chemoradiation
CROSS Trial
Did this improved locoregional control did not result in improved long-term survival with overlapping curves.
Increased benefit of trimodality balanced out perhaps by the increased treatment related mortality.
van Hagen et al., NEJM, 2012

10. Preoperative Chemoradiation
CROSS Trial
Path CR: 18/37 pts SCCA 47%; 28/121 pts (23%); p<0.008
van Hagen et al., NEJM, 2012

11. Preoperative Chemoradiation
CROSS Trial
Path CR
Adeno
SCCA p
CROSS
28/121 (23%)
18/37
(47%)
P<0.008
Path CR: 18/37 pts SCCA 47%; 28/121 pts (23%); p<0.008
van Hagen et al., NEJM, 2012

12. Preoperative Chemoradiation
CROSS Trial
Path CR
Adeno
SCCA p
CROSS
28/121 (23%)
18/37
(47%)
P<0.008
MDACC
55/193
(29%)
13/42
(31%) NS
Path CR: 18/37 pts SCCA 47%; 28/121 pts (23%); p<0.008
van Hagen et al., NEJM, 2012
Rohatgi et al., Cancer 2005

13. Definitive CRT vs Preop CRT Surg
Because of this increased toxicity, it was elected to eliminate the induction chemotherapy and compare a higher dose of radiation therapy with the standard 50.4 gy utilized in RTOG

14. dCRT vs CRTPlanned Eso
Squam Responders– FFCD 9102
Surgery
N=129
Multi-center
Eso: SCCA
T3-4,N0-3,M0
N=455
Responders
N=259
20Gy
5FU/CDDP x 3
N=130
Another randomized study which was recently reported was FFCD The French multi-center trial which treated 455 predominantly squamous cell carcinoma with
Concurrent 46gy 5fu and cis responders were then randomized to surgery or additional radiation and chemotherapy.
46Gy
5-FU/CDDP x 2
Bedenne et al., JCO, 2007

15. 1.63 HR Locoregional Relapse
dCRT vs CRTPlanned Eso
Squam Responders– FFCD 9102
1.63 HR Locoregional Relapse
CRT Alone (p=0.03)
Did this improved locoregional control did not result in improved long-term survival with overlapping curves.
Increased benefit of trimodality balanced out perhaps by the increased treatment related mortality. Palliative intervention for
dysphagia
.0002
No. of patients 31 60 %
Dilatation
No. of patients 24 18 %
Stent
No. of patients 7 42 %
Dysphagia grade 3‡ at last
follow-up before death§
.04
No. of patients/No. of dead
patients
38/60 36/79 %
2-year recurrence probability, % .23
Rate SE
Locoregional probability, % .0014
Rate SE
Metastatic probability, % .24
Rate SE
Bedenne et al., JCO, 2007

16. Def CRT vs Preop CRTSurg
Squam – German Trial R A N D O M I Z E
Chem/RT
(Cis, Etop
+ 50 gy HF
or 60 gy HDR)
Chemo
FLEP
N=86
Surgery
T1-4a N0-3 M0
SCCA
Multi-Center
Chemo/RT
(Cis, Etop
gy)
Chemo
FLEP
N=86
Stahl and his colleagues randomized predominantly squamous cell carcinoma patients to FLEP chemotherapy followed by concurrent chemoradiation (with hyperfractionated 50 gy and cis and 5-FU) followed by surgery or
Or concurrent chemoradiation alone with (cisplatinum and etoposide and 64.8 gy)
Stahl et al., JCO,2005

17. Chemo/RT +/- Surgery: Phase III Esophageal Cancer: German Trial
Overall Survival
p = ns
172 patients randomized per arm (86 pts per arm). SCCA – FLEP then EP + 65 Gy CRT or FLEP then 45 Gy + EP CRT and Surgery.
Rx related mortality 12.8% in surgery arm vs 3.5% CRT arm. Locoregional control at 2 years significantly better with surgery.
No statistical difference in overall survival at 2 years but
Trial underpowered, time point to look for difference is prior to split so this trial may actually be positive at different timepoint with less treatment related mortality.
Stahl et al., JCO, 2005

18. Definitive CRT and Salvage Esophagectomy
Investigators were still frustrated, however, by the high locoregional failure rates of 40 to 60% and strategies to improve this were evaluated.
Investigators decided to try adding additional induction chemotherapy prior to the concurrent chemoradiation and to increase the dose of radiation therapy to 64.8 gy.

19. The resultant single arm trial (INT 0122) evaluated this strategy with 45 patients who were treated with 3 months of cisplatinum and 5-FU followed by concurrent chemoradiation with cisplatinum, 5FU and radiation to 64.8 gy.
Swisher et al., JTCVS, 123:175-83, 2002

20. 1.63 HR Locoregional Relapse
Salvage Esophagectomy
Literature Review
1.63 HR Locoregional Relapse
CRT Alone (p=0.03)
Kyushu University, Japan
Did this improved locoregional control did not result in improved long-term survival with overlapping curves.
Increased benefit of trimodality balanced out perhaps by the increased treatment related mortality. Palliative intervention for
dysphagia
.0002
No. of patients 31 60 %
Dilatation
No. of patients 24 18 %
Stent
No. of patients 7 42 %
Dysphagia grade 3‡ at last
follow-up before death§
.04
No. of patients/No. of dead
patients
38/60 36/79 %
2-year recurrence probability, % .23
Rate SE
Locoregional probability, % .0014
Rate SE
Metastatic probability, % .24
Rate SE
Thorpe et al., Br J Surg, 2007

21. Salvage Esophagectomy in Modern Era
Investigators were still frustrated, however, by the high locoregional failure rates of 40 to 60% and strategies to improve this were evaluated.
Investigators decided to try adding additional induction chemotherapy prior to the concurrent chemoradiation and to increase the dose of radiation therapy to 64.8 gy.

22. Salvage Esophagectomy 2 Stage Procedure
Two-Stage Operation for High-Risk Patients with Thoracic
Esophageal Cancer: An Old Operation Revisited
Masaru Morita, MD, PhD, FACS, Tomonori Nakanoko, MD, Nobuhide Kubo, MD, Yoshihiko Fujinaka, MD,
Keisuke Ikeda, MD, Akinori Egashira, MD, PhD, Hiroshi Saeki, MD, PhD, Hideaki Uchiyama, MD, PhD, FACS,
Takefumi Ohga, MD, PhD, Yoshihiro Kakeji, MD, PhD, FACS, Ken Shirabe, MD, PhD, FACS, Tetsuo Ikeda, MD,
PhD, Shunichi Tsujitani, MD, PhD, FACS, and Yoshihiko Maehara, MD, PhD, FACS
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
ABSTRACT
Purpose. An esophagectomy followed by reconstruction
for esophageal cancer is a highly aggressive operation. The
purpose of this study was to justify a two-stage operation
for high-risk patients with esophageal cancer.
Methods. The clinical results of 27 patients who underwent
two-stage operation were compared with 118 patients
who underwent a simultaneous resection and reconstruction
(control subjects). The reasons for the selection of the
two-stage operation were underlying general disease in 13
patients (liver dysfunction, n = 6; pulmonary disease,
n = 3; poor performance status, n = 2; diabetes and renal
failure, n = 1 each) and high-risk operation in 14 other
patients (colon interposition, n = 7; salvage operation after
definitive chemoradiotherapy, n = 4; and intraoperative
events, n = 3). The patients initially underwent an esophagectomy
and a cervical esophagostomy. Reconstruction
was usually performed 2–3 weeks later.
Results. The patients in the two-stage group were older
than the control patients (mean 67.8 vs years old).
The morbidity rate of the two-stage operation was 29.6%,
which was not statistically different than control patients
(32.2%). Postoperative complications in the two-stage
operation were anastomotic leakage in 5 patients, and
pneumonia and wound infection in 1 patient each. No
patient experienced in-hospital death. The survival rates
were not statistically different between the two groups.
Conclusion. A two-stage operation is a safe operation
that prevents the occurrence of critical postoperative
First Stage
Second Stage
27 High Risk Pts (7 Salvage)
No Increased Morbidity vs 118 Low Risk Pts
Morita et al, Ann Surg Onc, 2011

23. Salvage Esophagectomy Free Jejunal Interposition
Long-segment, supercharged, pedicled jejunal flap for total
esophageal reconstruction
Anthony J. Ascioti, MD, a
Wayne L. Hofstetter, MD,
Michael J. Miller, MD, b
David C. Rice, MD,
Stephen G. Swisher, MD,
Ara A. Vaporciyan, MD,
Jack A. Roth, MD,
J. B. Putnam, MD, d
W. Roy Smythe, MD, e
Barry W. Feig, MD, c
Paul F. Mansfield, MD,
Peter W. T. Pisters, MD,
Marla T. Torres, BS,
and Garrett L. Walsh, MDa
Objective: Many patients with cancer have limited esophageal reconstruction options
when the stomach is unavailable as a replacement conduit or when longsegment
discontinuity exists. Jejunum has been used as an alternative conduit, both
as a pedicled or free flap interposition; however, reports of this are usually limited
to short-segment repairs. Microvascular augmentation of a pedicled jejunal flap
allows creation of a longer conduit, making it possible to replace the entire
esophagus with jejunum. Few reports describe this technique in patients with cancer.
We report our initial experience with “supercharged” pedicled jejunum as an
alternative conduit for total esophageal reconstruction.
Methods: Review of a prospectively collected departmental database was performed
to identify those patients who underwent total esophageal reconstruction with
supercharged pedicled jejunum. Data regarding their perioperative course and
postoperative function were gathered from the prospectively collected clinical data,
review of hospital records, and patient interviews.
Results: Total esophageal reconstruction with supercharged pedicled jejunum was
attempted in 26 patients (age range, years) between March 2000 and April
2004. Twenty-four of 26 patients were ultimately discharged with an intact supercharged
pedicled jejunum flap, for an overall success rate of 92.3%. One patient
experienced intraoperative flap loss caused by technical difficulties harvesting the
flap and never had the flap interposed. One other flap loss occurred in the early
postoperative period in a patient who had multisystem organ failure after a prolonged
reconstruction. Cervical anastomotic leaks occurred in 19.2% (5/26) of the
patients. Two midconduit leaks occurred that were suspicious for iatrogenic perforation
from nasogastric tube placement; one required reoperation. One additional
early reoperation was performed for cecal ischemia. There were no mortalities.
Functional results were available in 95.4% (21/22) of the patients receiving supercharged
pedicled jejunum who survived at least 6 months after reconstruction. At
the time of follow-up, 95% (20/21) of the patients were tolerating regular diet, and
76.2% (16/21) did not require any supplemental alimentation. Ninety-five percent
(20/21) of the patients were free from reflux symptoms, and 80.9% (17/21) had no
dumping symptoms. Only 1 patient required dilation of a midconduit stricture. One
patient required late reoperation for conduit redundancy.
Conclusions: Supercharged pedicled jejunum is a suitable alternative conduit for
total esophageal replacement in patients with cancer with otherwise limited reconstructive
options. Functional outcomes are excellent, despite the severity of disease
and technical challenges in this patient population.
by D. RIce
Jejunal Free Graft
Ascioti et al, Ann Thor Surg, 2005

24. Salvage Esophagectomy Omental Transposition
And a somewhat worrisome, but statistically in-significant trend in the peri-operative mortality.
To note, none of the 3 deaths in the salvage group were attributed to leak
(arlene, let’s look up afib rate in both groups)
Courtesy of David Rice MD

25. Salvage Esophagectomy Omental Transposition
And a somewhat worrisome, but statistically in-significant trend in the peri-operative mortality.
To note, none of the 3 deaths in the salvage group were attributed to leak
(arlene, let’s look up afib rate in both groups)
Courtesy of David Rice MD

26. MDACC: Omental Transpostion Salvage Esophageal Anastomotic Leak
Objective: An uncontained thoracic anastomotic leak may cause severe morbidity or mortality. Thoracic
transposition of an omental flap along with the gastric conduit may decrease leak incidence, severity, or need
for reoperations after esophagectomy.
Methods: We identified 607 patients who underwent esophagectomy with thoracic anastomosis between January
2001 and August All patients were studied for leak postoperatively. Four leak grades were defined,
ranging from radiographic leak to conduit loss. Univariate and multivariate analyses were performed to identify
variables associated with anastomotic leak.
Results: Omental reinforcement was used in 215 of 607 patients (35%). Anastomotic leak occurred in 51 of 607
patients (8.4%). Patients with omentumhad a significantly lower (odds ratio [OR], 0.4; P¼.014) anastomotic leak
rate (4.7%) compared with patients without omentum (10.5%). Salvage resections were performed in 69
patients and 23 (32%) received omentum; the leak rate with omentum was 4.6% compared with 15% without
(OR, 0.27; P ¼ .24). Patients undergoing planned esophagectomy with omentum had a significantly lower leak
rate than patients without omentum (4.7%vs 9.8%) (OR, 0.43; P ¼ .04). Reoperations to rescue an anastomotic
leak (Grade 3) was less common with omentum (OR, 0.26; P¼ .024). Multivariate analysis identified omental reinforcement
(OR, 0.45; P ¼ .034) and surgeon (OR, 3.4; P ¼ .001) as variables predictive of an anastomotic leak.
Conclusions: Omental reinforcement of thoracic esophagogastric anastomoses decreases overall leak rate
and need for reoperation. We recommend pedicled omental transposition to reinforce all thoracic anastomoses.
Endoscopic evaluation of significant anastomotic leaks is still warranted. (J Thorac Cardiovasc Surg
2012;144: )
There was a significantly lower overall leak rate in the group with omental reinforcement of the thoracic anastomosis compared to patients without omentum.
Sepesi et al., JTCVS,144: ; 2012

27. Salvage Esophagectomy Op Mortality – Modern Era
Planned
n=521
p value
LOS (days)
12 (4-153)
11 (0-88) NS
30d Mortality
2 (3.1%)
15 (2.9%)
90d Mortality
3 (4.6%)
27 (5.2%)
Marks et al., AATS, 2012

28. CRT and Selective Esophagectomy
Investigators were still frustrated, however, by the high locoregional failure rates of 40 to 60% and strategies to improve this were evaluated.
Investigators decided to try adding additional induction chemotherapy prior to the concurrent chemoradiation and to increase the dose of radiation therapy to 64.8 gy.

29. 63% 3YR; 37% 5 YR SURVIVAL
Enrollment requirements included resectable esophageal cancer patients who were without metastases and whose clinical stage by EUS was greater than T1N0
Eligible patients were then treated initially with 2 cycles of 5-FU, cisplatinum and paclitaxel (5-FU (650 mg/m2/d), Cisplatin (15 mg/m2/d), Paclitaxel (200 mg/m2/d)
followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fx) and Daily 5-FU (300 mg/m2/d), and Cisplatin (15 mg/m2/d)
Patients were then restaged 4 to 6 weeks after chemoradiation and if there was no evidence of residual cancer they were followed with serial endoscopies, CTs, PETs.
If residual or recurrent locoregional cancer was identified without evidence of metastatic disease patients were evaluated for salvage esophagectomy

30. 21/41 pts esoph preservation
51%
SCCA-CROSS-25 %;CALGB %; RTO ; SCOPE1 71%-cetux; rtog %

31. Esophageal Cancer Case #1
Treated with Definitive Chemoradiation: Oxaliplatin and 5-fluoruracil and RT to 54.4 Gy.
EGD – ulcer, NED – refused surgery.
The indications for resection therefore include all patients with resectable esophageal cancer who are physiologically fit and do not have distant metastases or tracheoesophageal fistulae.

32. Esophageal Cancer Case #1
16 months later dysphagia CT-PET –Increase FDG (SUV 17) circum middle eso; EGD revealed necrotic SCCA in middle eso Bronch: Necrotic ulcer R BI with fragments of Squamous Cell Carinoma
The indications for resection therefore include all patients with resectable esophageal cancer who are physiologically fit and do not have distant metastases or tracheoesophageal fistulae.

33. Esophageal Cancer Case #2
EUS: cm, recurrent squamous cell carcinoma
CT-PET: proximal eso FDG avid lesion (SUV-8.9), no distant metastases
Bronchoscopy: fistulous communication 8 cm proximal to carina
The indications for resection therefore include all patients with resectable esophageal cancer who are physiologically fit and do not have distant metastases or tracheoesophageal fistulae.

34. SCCA Esophageal Cancer MDACC Combined Modality Approach
ChemoRT
(50.4 Gy)
Low Risk
Surgery
and
Mid/Dist Location
Planned
Esophagectomy
Loco-
Regionally
SCCA Eso
Cancer
ChemoRT
(50.4 Gy)
Purpose: The strategy of definitive chemoradiation with selective surgical salvage in locoregionally advanced
esophageal cancer was evaluated in a Phase II trial in Radiation Therapy Oncology Group (RTOG)-affiliated sites.
Methods and Materials: The study was designed to detect an improvement in 1-year survival from 60% to 77.5%
(a = 0.05; power = 80%). Definitive chemoradiation involved induction chemotherapy with 5-fluorouracil (5-FU)
(650 mg/mg2/day), cisplatin (15 mg/mg2/day), and paclitaxel (200 mg/mg2/day) for two cycles, followed by concurrent
chemoradiation with 50.4 Gy (1.8 Gy/fraction) and daily 5-FU (300 mg/mg2/day) with cisplatin (15 mg/mg2/
day) over the first 5 days. Salvage surgical resection was considered for patients with residual or recurrent esophageal
cancer who did not have systemic disease.
Results: Forty-three patients with nonmetastatic resectable esophageal cancer were entered from Sept 2003 to
March Forty-one patients were eligible for analysis. Clinical stage was $T3 in 31 patients (76%) and N1 in
29 patients (71%), with adenocarcinoma histology in 30 patients (73%). Thirty-seven patients (90%) completed induction
chemotherapy followed by concurrent chemoradiation. Twenty-eight patients (68%) experienced Grade 3+
nonhematologic toxicity. Four treatment-related deaths were noted. Twenty-one patients underwent surgery following
definitive chemoradiation because of residual (17 patients) or recurrent (3 patients) esophageal cancer,and 1 patient
because of choice. Median follow-up of live patients was 22 months, with an estimated 1-year survival of 71%.
Conclusions: In this Phase II trial (RTOG 0246) evaluating selective surgical salvage after definitive chemoradiation
in locoregionally advanced esophageal cancer, the hypothesized 1-year RTOG survival
High Risk
Surgery Or
Cerv Location
Selective
Esophagectomy

35. Summary SCCA Eso Cancer-Combined Modality Approach
Upper Eso Location – laryngopharygectomy
Definitive Chemoradation
Salvage Esophagectomy for Recurrent Local Disease
Middle/Lower Eso Location – Good Risk
Preop CRT  Planned Esophagectomy
Middle/Lower Eso Location – Poor Risk
CRT  Clin CR  Selective Esophagect for Recurrent Local Disease
CRT  Clin non-CR  Consider Selective Esophagect
In summary then:
Chemoradiation alone with concurrent chemoradiation in SCCA appears to lead to improved survival and local control compared to radiation therapy.
The optimal regimen appears to be concurrent chemoradiation with RT to 50.4 gy.
The randomized trials in SCCA demostrate that surgery add improved locoregional control but no statistical improvement in survival perhaps because of high treatment related mortalit, targeting responders and looking at low numbers.
In adenocarcinoma the role of chemoradiation alone is still under evaluation and selective surgery will be reported in RTOG 0246 this fall at ASTRO
Alternative strategies to improve chemoradiation alone is to add novel therapeutics to improve the subset of patients who undergo pathologic response following chemoradiation.