Locally Advanced Esophageal Adenocarcinoma:

Chemotherapy is the best treatment

Lorenzo Ferri MD PhD

McGill University

Adenocarcinoma of the Distal Esophagus

Resection Provides the Greatest Chance for a Cure

Goal = Local Control Metrics for Success = High R0 and Low LR Recurrence

The majority of patients die of

DISTANT metastasis

Neo-adjuvant Treatment is Standard of Care For Locally Advanced Cancer

2 Viable Options for Locally Advanced Esophageal Adenocarcinoma

GOAL = IMPROVED SYSTEMIC CONTROL Metric for success = high Overall Survival

GOAL = IMPROVED LOCAL CONTROL Metrics for Success

pCR/ High R0 and reduced LR recurrence

Chemo as a radio-sensitizer

NEOADJUVANT CHEMOTHERAPY NEOADJUVANT CHEMO-RADIOTHERAPY

Debate: Chemotherapy>>Chemoradiotherapy Adenocarcinoma of the Esophagus

• Strong Data in support for Chemotherapy vs Surgery alone in EAC

• Data (weak as it may be) in support for CRT vs Surgery Alone in EAC

• ESCC and EAC are DIFFERENT diseases

• Data Chemotherapy vs Chemoradiation for Esoph CA

• We’ve been down this road before! – • RT doesn’t work for Gastric ADC

• Radiation Makes up for Bad Surgery

• Do the Right Surgery – Don’t need radiation

• Radiation Increases Post-Operative Complications

Data in Support of Neoadjuvant Chemotherapy

IMPROVED SYSTEMIC CONTROL Overall Survival IMPROVED SYSTEMIC CONTROL

NEOADJUVANT CHEMOTHERAPY

MAGIC Trial Peri-op Epirubicin/Cisplatin/5FU

Cunningham NEJM 2006

ADC mixed location

FFCD –Trial Neo-adj Cisplatin/5FU

Ychou JCO 2011

ADC mixed location Lancet 2002

OES2 – MRC Trial Neo-adj Cisplatin/5FU

Esophagus Mixed histology

• Locally Advanced Adenocarcinoma

• cT3 = 85%

• cN+ = 80%

Esoph/EGJ = 83%

Annals of Oncology 2011, and Sudarshan et al, Ann Surgical Oncol 2014

21-day cycle

Taxotere 75 mg/m2 IV day 1

Cisplatin 75 mg/m2 IV day 1

5-fluorouracil 750 mg/m2 CIV day 1-5

(prophylactic G-CSF in first 7-10 days of each cycle)

LN+ = 5 Local/Regional Recurrence 5%

• ECF/X Surgery ECF/X Epirubicin 50mg/m2 Day1

Cisplatin 60 mg/m2 Day1

5FU – 200 mg/m2 CIV x 9 weeks

Capecitabine 1250mg/m2 Daily

• FLOT Surgery FLOT Docetaxel 50 mg/m2

Oxaliplatin 85mg/m2

Leucovorin 200 mg/m2

5FU 2600 mg/m2 CIV x 24 hours

716 pts Adenocarcinoma

Stomach and EGJ (I,II,III)

ECF/ECX 360

FLOT 356

2010 - 2015

OS, PFS, pCR, R0

Lancet Oncol 2019

cT3/4 = 81%

cN+ = 80%

Location Stomach = 44%

Esoph+EGJ = 56%

Taxotere (Docetaxel) Based Triplets – now the standard of care for neoadjuvant chemotherapy of Esophago-Gastric Adenocarcinoma

Data in Support of Neoadjuvant Chemo Radiotherapy

GOAL = IMPROVED LOCAL CONTROL pCR/R0, reduced LR recurrence

Chemo as a radio-sensitizer

NEOADJUVANT CHEMO-RADIOTHERAPY

Walsh, NEJM 1996

Irish Trial ADC only

Cis/5FU + 40 Gy

7 Negative Trials!

Poor Surgical Control?

CROSS Trial Mixed Histology

Carbo/Taxol+ 41.4 Gy

van Hagen, NEJM 2012

McGill University

Department of Surgery

CROSS Trial

• SCC – HR 0.42 (95%CI 0.22-0.78) P=0.007

• ADC – HR 0.74 (95%CI 0.53-1.02) p=0.07

van Hagen, NEJM 2012

Pathologic Complete Response • Overall = 29%

• SCC = 49%

• ADC = 23%

Response to Radiotherapy

Esophageal Adenocarcinoma and Squamous Cell Carcinoma are DIFFERENT Diseases

McGill University

Department of Surgery Lancet Oncology 2016

• SCC – aHR 0.46 (95%CI 0.26-0.79) P=0.005

• ADC – aHR 0.75 (95%CI 0.56-1.01) p=0.059

Esophageal Adenocarcinoma and Squamous Cell Carcinoma are DIFFERENT Diseases

• Different response to radiotherapy

• EAC – 20-25% pCR

• ESCC – 35-50% pCR

• Metastatic diseases is treated differently – why are we treated them similarly in the neo-adjuvant setting?

Perfect Separation of EAC and ESCC ESCC = Head and Neck Cancer

EAC= Gastric Adenocarcinoma(CIN)

Adam Bass et al, Nature Jan 2017

Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas.…... Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity [and treated similarly].

Few Prospective Data with Direct Comparison of Chemo vs Chemorads

• Both suffered from very low accrual

• Greatly underpowered

• No improvement in R0 rate

• Outdated chemotherapy (CF)

• No en-bloc esophagectomy

POET Trial Stahl, 2009

Burmeister, 2011

Annals Oncology 2016

Cisplatin 75 mg/M2 day 1 5FU 1000 mg/M2 CIV day 1-5

RT 40Gy in 20 with Cycle 2-3

Randomized Phase II (pCR endpoint) 181 Pts – cT1N1, cT2-3N0-1 Mixed Histology Squamous = 50 (27%) ADC = 131 (73%)

NEO-Res Trial

nCT nCTRT

pCR 9% 28%*

ADC 7% 22%*

SCC 16% 42%*

R0 74% 87%*

ADC 71% 89%*

SCC 76% 96%*

Local Recurrence 19% 16% NS

ADC 22% 16% NS

SCC 10% 17% NS

OVERALL SURVIVAL

OS by HISTOLOGY

3 YR Survival nCT nCTRT 49% 47%

ADC 48% 43% SCC 52% 56%

Chemotherapy vs Chemoradiation Where are the other Trials?

• Neo-Aegis (Trinity College – John Reynolds) • MAGIC vs CROSS – Adenocarcinoma (recently added FLOT)

• Ireland/UK/Denmark

• 345/540 pts as of October 15th 2019

• TOP GEAR • ECF/X then surgery vs CTRT+surgery then ECF/X - Adenocarcinoma

• Australia, Canada

• ESOPEC – (University Hospital Freiburg - Jens Hoeppner) • FLOT vs CROSS – Adenocarcinoma (stomach and EGJ)

• Across Germany

• Accrued over 300

• NeXT – JCOG1109 (Keio University - Yuko Kitagawa) • CF vs DCF vs CF+RT – Squamous only

• Across Japan

• Accrual completed (600) analysis in 2021

EAC

ESCC

Courtesy of John Reynolds, Trinity College Dublin

Ann Oncol 2017

Esophageal and Gastric Adenocarcinoma Are Biologically Similar

What about the data on Radiation for Gastric Adenocarcinoma? We’ve been down this road before!

Lancet Oncology 2018

Chemotherapy

ECX or EOX x3

Gastrectomy

≥D1

Chemotherapy

ECX or EOX x3

Chemotherapy

ECX or EOX x3

Gastrectomy

≥D1

Chemoradiotherapy

CX + 45Gy

N=393

N=395

788 pts - Adenocarcinoma 83 % Body/Antrum

17% Cardia/EGJ

Both Arms Very Well Matched

Lancet Oncology 2018

Chemotherapy

ECX or EOX x3

Gastrectomy

≥D1

Chemotherapy

ECX or EOX x3

Chemotherapy

ECX or EOX x3

Gastrectomy

≥D1

Chemoradiotherapy

CX + 45Gy

N=393

N=395

788 pts - Adenocarcinoma 83 % Body/Antrum

17% Cardia/EGJ

Progression Free Survival

Survival Curves ALSO

Very Well Matched! ASCO 2016

4d 4sb

1

63

57

8a 11p 12a 9

Distalgastrectomy

D1

D1+

D2 4d 4sb

1

63

57

8a 11p 12a 9

Distalgastrectomy

D1

D1+

D2

Radiotherapy makes up for bad surgery...

Adjuvant Chemoradiotherapy RTOG Intergroup 0116

MacDonald NEJM 2001

FU/LEU x 1 XRT45Gy/25 +FU/LEU FU/LEU x 2

MacDonald ASCO 2004

SURVIVAL BY EXTENT OF LYMPHADENECTOMY D0 RESECTION

D0

MacDonald ASCO 2004

SURVIVAL BY EXTENT OF LYMPHADENECTOMY D2 RESECTION

D2

JCO 2012

1-8 + LN

Omloo 2007

Transthoracic has BETTER Disease Control than Transhiatal

BACK to the CROSS TRIAL

Ann Surg 2018

SURGERY ALONE Transthoracic Esophagectomy >> Transhiatal Esophagectomy

(HR 0.62, 95% CI 0.43–0.90, P . 0.01

NEOADJUVANT CHEMORADIATION Transthoracic Esophagectomy = Transhiatal Esophagectomy

(HR 1.00, 95% CI 0.61–1.68, P . 0.98)

Radiotherapy makes up for bad surgery...

• Standard vs En Bloc Resection

Standard

En Bloc

Courtesy of Brendon Stiles, Cornell

Why don’t we just do the right surgery? Local Control

Metrics for Success = High R0 and Low LR Recurrence

Less Likely to have Local/Regional Recurrence

N Technique Local

Recurrence

Dresner 2000 176 Standard 21%

Law 1997 108 Standard 25%

Van Lanschot 1994 94 Standard 30%

Hulscher 2000 137 Standard 35%

CROSS 2016

(surgery alone)

188 Standard 38%

Hagen 2001 100 En-bloc 1%

Altorki 2001 111 En-bloc 8%

Ferri 2014 86 En-bloc 5%

Omloo et al., Ann. Surg, 2007

Long Term Survival Dictated by

SYSTEMIC CONTROL A Case for CHEMO

En Bloc Resection = High R0 and Low LR Recurrence

Radiotherapy increases post-operative complications

Mariette, JCO 2014

FFCD 9901

Stage 1 and 2 only

Mixed histology

Surgery Alone – 43.8 month survival

(1% operative mortality)

CTRT + Surgery – 31.8 month survival

(7% operative mortality)

Sheraz Markar 2017

Radiotherapy increases post-operative complications

Courtesy of John Reynolds, Trinity College Dublin

DLCO %predicted

98 % 82%

p<0.001

Chemoradiation The gift that keeps on giving!

Also has long term impact

on Pulmonary Function

BJS 2019

Courtesy of John Reynolds, Trinity College Dublin

Debate: Chemotherapy>>Chemoradiotherapy Adenocarcinoma of the Esophagus

• Strong Data in support for Chemotherapy vs Surgery alone in EAC

• Data (weak as it may be) in support for CRT vs Surgery Alone in EAC

• ESCC and EAC are DIFFERENT diseases

• Data Chemotherapy vs Chemoradiation for Esoph CA

• We’ve been down this road before! – • RT doesn’t work for Gastric ADC

• Radiation Makes up for Bad Surgery

• Do the Right Surgery – Don’t need radiation

• Radiation Increases Post-Operative Complications

Summary

PERI-OPERATIVE CHEMOTHERAPY NEOADJUVANT CHEMO-RADIOTHERAPY

DOCETAXEL(TAXOTERE) BASED TRIPLET CARBOPLATIN/TAXOL + 41.4 Gy

BOTH ARE ACCEPTABLE STANDARDS OF CARE

RADIATION DOES NOT ADDRESS THE ISSUE WITH EAC

Why have two forms of local therapy when, if the right surgery is performed, where we fail is systemically, not locally?

Annals of Thoracic Surgery April 2016

McGill Cornell

• Chemoradiotherapy

• MD Anderson • Cis/Carbo

• 5FU/Taxan

• 50.4 Gy

• Chemotherapy

• McGill • Docetaxel

• Cisplatin

• 5Fu

• Cornell • Cisplatin

• 5Fu

2002 - 2012

En Bloc Resection 2 or 3 Field

OS DFS

cT3N1 Adenocarcinoma

Overall survival RESULTS RESULTS

Time to recurrence

The Addition of Radiation Does NOT Improve Oncologic Outcomes After En Bloc Esophagectomy