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