neo- andadjuvant treatment for gastric cancer and ge ......t 1–4 nodes ct+ ct-rt + ct 0, 1–3, >3...
TRANSCRIPT
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Neo- and Adjuvant treatment for Gastric cancer and GE junction Cancer
Andrés CervantesProfessor of Medicine
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DISCLOSURE SLIDE
Employment: None; Stock Ownership: None
Consultant or Advisory Role: Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas.
Research Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Sierra Oncology, Astra Zeneca, Medimmune, BMS, MSD
Speaking: Merck Serono, Roche, Angem, Bayer, Servier, Foundation Medicine. Grant support: Merck Serono, Roche.
Others: Executive Board member of ESMO, Chair of Education ESMO, General and Scientific Director INCLIVA, Associate Editor: Annals of Oncology and ESMO Open, Editor in chief: Cancer Treatment Reviews.
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Classical approach to localised gastric cancer
� Surgical resection
� Pathology assessment and estimation of risk
� Treatment based upon classical TNM stage
� Postoperative chemotherapy of limited value
� Postoperative chemoradiation in US
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The Gastric Group. JAMA 2010;303:1729–37
Meta-analysis of individual data of trials involving adjuvant chemotherapy versus surgery alone for gastric cancer
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Noh SH, et al. Lancet Oncol 2014;15:1389–1396, © (2014), with permission from Elsevier
Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy versus surgery alone: 5-year follow -up of a randomised phase III trial
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SURGERYNO TREATMENT
STRATIFICATION
T 1–4NODES CT+ CT-RT + CT0, 1–3, >3
MacDonald JS, et al. N Engl J Med 2001;345:725–730
The role of radiation in the postoperative setting: Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: A randomised Phase III Trial
Study design
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Smalley S, et al. J Clin Oncol 2012;30:2327–2333
Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: Long term data of a randomised Phase III Trial
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ARTIST: The role of Radiation in the Postoperative SettingAdjuvant Cisplatin and Capecitabine versus Chemoradiation forGastric Cancer after Surgery: A Randomized phase III Trial
Park SH, et al. J Clin Oncol 2015; 33: 3130-3136
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CRITICS TRIALDesign: 788 pts: 393 CT and 395 CRT
Tissuebanking
QoL
Chemoradiation
3x EC/OC q 3 wks
D1 + surgery
D1 + surgeryPreoperative chemotherapy3x EC/OC q 3 wks
Preoperative chemotherapy3x EC/OC q 3 wks
R
45 Gy/25 fx + / capecitabine
cisplatin-
Stratified for:- Center- Histological type- Localisation of tumor
Cats A, et al. Lancet Oncol 2018; 19:616-628
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Final Results from CRITICS
/
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Cats A, et al. Lancet Oncol 2018; 19:616-628
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Eligible patients:� Adenocarcinoma of the stomach
or lower third of the oesophagus (from 1999), suitable for curative resection
� Non-metastatic disease� Stage II or greater
Chemotherapy (ECF):Epirubicin 50 mg/m2, IV day 1Cisplatin 60 mg/m2, IV day 15-FU 200 mg/m2/day, continuous infusion, days 1-21(cycles repeated every 3 weeks)
PrimaryOverall survival
SecondaryProgression-free survivalSurgical resectabilityQuality of Life
Recruitment: July 1994-April 2002
Study entry and randomisation
S armN=253
CSC armN=250
3-6 weeks
6-12 weeks
Cunningham D, et al. N Engl J Med 2006;355:11–20
MAGIC: Study design
Pre-operative chemotherapy:ECFx3
Post-operative chemotherapy:ECFx3
Surgery
Surgery
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MAGIC Trial results
Logrank p-value = 0.0001Hazard Ratio = 0.66
(95% CI 0.53 - 0.81)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from randomisation
0 12 24 36 48 60 72
163 250190 253
EventsTotalCSCS
Logrank p-value = 0.009Hazard Ratio = 0.75
(95% CI 0.60 - 0.93)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from randomisation
0 12 24 36 48 60 72
149 250170 253
EventsTotalCSCS
2 year survival
5 year survival
Median survival
CSC 50% 36% 24 mo
S 41% 23% 20 mo
Benefit to CSC arm
9% 13% 4 mo
PFS* Overall
� On multivariate analysis, treatment effect unchanged after adjustment for age, performance status, site of primary and gender
� Hazard ratio for death � Adjusted: 0.74 (95%CI: 0.59-0.93) � Unadjusted: 0.75
Cunningham D, et al, N Engl J Med 2006;355:11–20. Copyright © (2006) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
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Trial CTNo. pts control
No. ptsCT
5-year survival control
5-year survival CT
HR(CI at 95%)
CunninghamN Eng J Med 2006
ECF253
No CT250 23% 36 %
0.750.60-0.93p=0.009
YchouJ Clin Oncol 2011
CDDP5-FU
111No CT
113 24% 38%0.69
0.50-0.95p=0.021
AllumJ Clin Oncol 2009
CDDPFU
402No CT
40017,6% 25.5%
0.840.72-0.98P=0.03
Summary of trials of perioperative chemotherapy for localized Oesophago-gastric cancer with a surgical only controlled arm
1. Cunningham D, et al, N Engl J Med 2006;355:11–20.2. Ychou M, et al. J Clin Oncol 2011;29:1715-1726.3. Allum W, et al. J Clin Oncol 2009; 27:5062-5067. Only esophageal cancer
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Classification of gastric adenocarcinoma: Pathology
� Intestinal versus diffuse subtypes
Lauren P. et al. Acta Pathol Microbiol Scand 1965;64:31–49
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Cancer Genome Atlas Research Network. Nature 2014;513:202–209
9%
22%20%
50%
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No effect of Preoperative ECF in MSI-H Gastric Cancer Patients
Smyth EC, et al. JAMA Oncol 2017; 3:1197-2003.
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Preoperative ECF in Gastric and GE Junction Patients The role TRG.
Smyth EC, et al. J Clin Oncol 2016; 32:2721-2727.
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Preoperative ECF in Gastric and GE Junction Patients The role TRG and ypNstatus
Smyth EC, et al. J Clin Oncol 2016; 32:2721-2727.
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ECX versus CF
Alderson D, et al. Lancet Oncol 2017: 18:1249-1260.
CF vs EXC
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ECX versus CF
Alderson D, et al. Lancet Oncol 2017: 18:1249-1260.
mOS 23.4 months for CFmOS 26.1 months for ECXHR:0.90 (95% CI: 0.77-1.05; p:0.19)
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ECX versus BEV -ECX
Cunningham D, et al. Lancet Oncol 2017: 18:357-370.
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FLOT-4 Study
FLOT x4 - RESECTION - FLOT x4
ECF/ECX x3 - RESECTION - ECF/ECX x3
• Gastric or EGJ cancer typ I-III
• Medically and anatomically operable
• cT2-4/cN-any/cM0 or cT-any/cN+/cM0
R
n=716
STRATIFIKATION
FLOT: Docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1; Leucovorin 200 mg/m², d1; Oxaliplatin 85 mg/m², d1, q2w
ECF/ECX: Epirubicin 50 mg/m2, d1; Cisplatin 60 mg/m², d1; 5-FU 200 mg/m² (or Capecitabin 1250 mg/m² p.o.geteilt in 2 doses d1-d21), q2w
Stratification: ECOG (0 or 1 vs. 2), localization(GEJ Type I vs. Type II/III vs. Gastric), age (< 60 vs. 60-69 vs. ≥70 years) and nodal status (cN+ vs. cN-).
Randomized, multicenter, Phase II/III Study
23% had Siewert type I33% had Siewert type II/III
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FLOT Regimen
Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting
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Chemo Related Toxicity 1
Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting
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Chemo Related Toxicity 2
Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting
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Survival ECF/ECX versus FLOT
Al-Batran et al. J Clin Oncol 2017; 35(suppl): #4004
ECF/ECX FLOT
mOS 35 months 50 months[27-46] [38-na]
HR 0.77 [0,63 – 0,94] p=0.012 (log rank)
2y. 59% 68% 3y. 48% 57% 5y. 36% 45%
OS rate* ECF/ECX FLOT
*projected OS-rates
Median follow-up time: 43 months
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Trial CTNo. pts control
No. ptsCT
5-year survival control
5-year survival CT
HR(CI at 95%)
CunninghamN Eng J Med 2006
ECF253
No CT250 23% 36 %
0.750.60-0.93p=0.009
YchouJ Clin Oncol 2011
CDDP5-FU
111No CT
113 24% 38%0.69
0.50-0.95p=0.021
AllumJ Clin Oncol 2009
CDDPFU
402No CT
40017,6% 25.5%
0.840.72-0.98P=0.03
Al-BatranASCO 2017
FLOT360ECF
356FLOT
36% 45%0.77
0.63-0.94P=0.012
Summary of trials of perioperative chemotherapy for localized Oesophago-gastric cancer
1. Cunningham D, et al, N Engl J Med 2006;355:11–20.2. Ychou M, et al. J Clin Oncol 2011;29:1715-1726.3. Allum W, et al. J Clin Oncol 2009; 27:5062-5067. Only esophageal cancer4. Al-Batran SA, et al 2017; 35(suppl): #4004
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ESMO MAGNITUDE OF THE CLINICAL BENEFIT SCALE
FLOT vs ECF trial: GRADE A
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�Absolute increase in 5-year survival 9%
Cheny NI et al. Ann Oncol 2015; 27:1547-1573
X
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TrialCT
ExperimentalNo. pts
pCRControl vs
Experimental
5-year survival
Control vsExp
HR(CI at 95%)
CunninghamN Eng J Med 2006
ECF 503 0% vs 8% 23% vs 36 %0.75
0.60-0.93p=0.009
Al-BatranASCO 2017
FLOT 716 5,8% vs 15,6% 36% vs 45%0.77
0.63-0.94P=0.012
Alderson +Lancet Oncol 2017
ECX 897 3% vs 11% 39% vs 42%*0.90
0.77-1.050.19
CunninghamLancet Oncol 2017
BEV-ECX 1063 8% vs 11% 50% vs 48%*1.09
0.91-1.290.36
Perioperative chemotherapy for localized Oesophago-gastric cancer: a new standard
1. Cunningham D, et al, N Engl J Med 2006;355:11–20.2. Al-Batran SA, et al 2017; 35(suppl): #40043. Alderson D. et al Lancet Oncol 2017 on line +Only Esophageal, *3 year OS4. Cunningham D, et. Lancet Oncology 2017; 18:357-370
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Neoadjuvant chemotherapy in gastric cancer: Conclusions
� Perioperative chemotherapy:� Induces downstaging� May increase the R0 resection rate� Prolongs disease free survival� Improves overall survival
� Evidence level I based upon 2 well designed and properly conducted randomised trials.
� FLOT is current standard of care� Preoperative therapy is better tolerated than postoperative� Localised gastric cancer requires a multidisciplinary team approach� Further research on biological predictive factors is needed
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Currently recommended approach to localised gastric cancer
� Clinical assessment and staging
� Multidisciplinary team discussion
� FLOT preoperative treatment in clinical stage II and III patients
� Surgical resection after FLOT chemotherapy
� Pathology assessment and estimation of risk
� Postoperative chemotherapy if tolerated
� Radiotherapy still experimental
� No biological agents (Bevacizumab) to be used in this setting
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Treatment for localised gastric cancer: What is standard of care? ESMO guidelines
Gastric Cancer (Adenocarcinoma)
Operable Stage > T1N0
Preoperativechemotherapy
Consider endoscopic /
limited resection
Operable Stage T1N0
SurgeryAdjuvant
chemotherapyAdjuvant
chemoradiation
Surgery
Post-operative chemotherapy
Preferred pathway