esophageal and gastric cancer...esophageal and gastric cancer peter c. enzinger, md director, center...
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Esophageal and Gastric Cancer
Peter C. Enzinger, MD
Director, Center for Esophageal and Gastric Cancer
Dana-Farber Cancer Institute
Associate Professor, Harvard Medical School
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Disclosures:
• Consultant:
• Astellas
• Celgene
• Five Prime
• Lilly
• Loxo
• Merck
• Taiho
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Cancer Site Incidence Deaths
Esophagus
Stomach
16,940
28,000
15,690
10,960
Esophagogastric Cancer 2017
USA
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Males in USAFemales in USA
Incidence of Gastric Adenocarcinoma
CA Cancer J Clin ‘08
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Brown. J. Natl. Cancer Inst. 2008
Trends in Esophagogastric Cancer:
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++++ > 8-fold risk
+++ 4-8-fold risk
++ 2-4-fold risk
+ < 2-fold risk
+/- Conflicting studies
--- No proven risk
Risk Factor SCC ADC Tobacco +++ ++ ETOH +++ --- Barrett’s Esophagus --- ++++ Weekly Reflux Symptoms --- +++ Obesity --- ++ Poverty ++ --- Achalasia ++++ Caustic injury to esophagus ++++ --- Tylosis (NEPPK) ++++ --- Plummer-Vinson syndrome ++++ --- History of head & neck cancer ++++ --- H/o breast ca treated with radiotherapy +++ ++ Frequent consumption of hot beverages + --- HPV (China, Japan, South Africa) +/- --- Beta blocker --- +/- Anticholinergics --- +/- Aminophylines --- +/-
Risk Factors:
Esophageal CA
Enzinger & Mayer. N Engl J Med 2003
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0
2
4
6
8
10
12
14
16
18
0 20-29 30-39 40 + 0 3.5 11 14.5 25 28.5 36+
Adenocarcinoma
Squamous Cell Carcinoma
Adenocarcinoma
Squamous Cell Carcinoma
Cigarettes per Day Drinks per Week
Data from Takezaki 2000, Wu 2001 and Brown 2001
Tobacco/Alcohol and Esophageal Cancer
1-19
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Squamous
epitheliumMetaplasia
Low-
Grade
Dysplasia
High-
Grade
DysplasiaADC METS
Oxidative stress
Inflammation
G1&G2
COX-2
BCL-2
4%/yr
0.5%/yr
1%/yr
5%/yr10%
GERD1:7 Americans
0.005%/yr
Early Genetic Events:
17pLOH p53; 9pLOH p16
cyclin D1
2nd Tier Genetic Events:
p53 mutation; p16 mutation/methylation
EGF(R), telomerase RNA
Late Genetic Events:
4 N (G2) aneuploidy of 5q/13q
and LOH of 5q/13q(Rb)/18q
?
c-erbB2
E-cadherin-catenin
85+%
Neoplastic Progression of Barrett’s Esophagus
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Risk Factors
for
Gastric
Adenocarcinoma
• Nutritional
– Low fat or protein consumption
– Salted meat or fish
– High nitrate consumption
• Environmental
– Poor food preparation (smoked)
– Lack of refrigeration
– Poor drinking water (well water)
– Occupation (rubber, coal workers)
– Smoking (1.6x)
– Low social class
• Medical
– Prior gastric surgery
– Helicobacter pylori infection (2x)
– Gastric atrophy and gastritis
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Helicobacter pylori
N=0
mutagens
Higher pH
Bacterial growth + nitrate
Gastric
ascorbic acid
B-carotene
Proposed Cascade of
Pathologic Events in
Gastric Adenocarcinoma
Salt
Normal Superficial
gastritis
Atrophic
gastritisMetaplasia Dysplasia Carcinoma
Salt N-nitroso Chronic inflammation
carcinogens and reactive oxygen species
inhibition
promotion
Adapted from Correa
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Hereditary Gastric Cancer• 1-3% of all gastric cancers:
• Hereditary Diffuse Gastric Cancer (HDGC):
– E-cadherin/CDH1 Germline Mutation
– Autosomal dominant
• families with > 2 patients with gastric cancer at any age, one confirmed DGC
• individuals with DGC before the age of 40
• families with diagnoses of both DGC and LBC (one diagnosis < age 50)
– 70% risk of DGC; 40% risk of lobular breast cancer (LBC)
– Prophylactic total gastrectomy
• Li-Fraumeni syndrome Lynch syndrome
• Peutz-Jeghers syndrome Hereditary breast and ovarian cancer
• Familial adenomatous polyposis Juvenile polyposis syndrome
• MUTYH-associated adenomatous polyposis (MAP)
• PTEN hamartoma tumor syndrome (Cowden syndrome)
Van der Post, RS. J Med Genet. 2015 Jun; 52(6): 361–374.
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The Cancer Genome Atlas Research Network. Nature. 2014;513:202-209.
Genomic Characterization of Esophagogastric Cancer
CIN: chromosome instability
EBV: ebstein-barr virus
MSI: microsatellite instability
GS: genomically stable
Presented by: Peter C. Enzinger, MD
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The Cancer Genome Atlas Research Network. Nature. 2014;513:202-209.
Genomic Characterization of Esophagogastric Cancer
The Cancer Genome Atlas Research Network. Nature . 2017; 1–9
Presented by: Peter C. Enzinger, MD
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Mutations, copy #, & translocations across gastric molecular subtypes
The Cancer Genome Atlas Research Network. Nature. 2014;513:202-209.
Presented by: Peter C. Enzinger, MD
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Localized Esophageal Cancer
What Can Surgery
Accomplish?
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Localized Esophageal Cancer Treated With Surgery
Rice, Blackstone, Rusch. Ann Surg Oncol 2010
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Localized Esophageal Cancer
Does (Neo)Adjuvant
Chemotherapy
Improve Surgical Outcomes?
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Neoadjuvant Chemotherapy Compared with Surgery
Alone for Localized Esophageal Cancer
Sjoquist et al. Lancet Oncol 2011;12(7):681-92
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Localized Esophageal Cancer
Does Neoadjuvant
Chemoradiation
Therapy Improve
Surgery Outcomes?
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All-Cause Mortality Estimates for Neoadjuvant C/RT Compared with Surgery Alone
Sjoquist et al.
Lancet Oncol 2011;
12(7):681-92
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CROSS Study: Schema
• Chemoradiotherapy regimen: • Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29• Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy
• Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE)
Van Hagen et al. N Engl J Med 2012;366:2074-84.
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CROSS Study: Overall survival
Van Hagen et al. N Engl J Med 2012;366:2074-84.
HR, 0.657; 95% CI 0.495-0.871
24.0 mo 49.4 mo
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POET: Schema
Arm A
Week
Arm B
PLF I PLF III (3 weeks)
15 x 2 Gy in 3 weeks
PE (1 week)
Surgery
Surgery
1 1314 17 20-21
PLF: Cisplatin 50mg/m2, 1h, d 1,15,29. Leukovorin/5-FU 500mg/m2 2h / 2g/m2 24h, d1,8,15,22,29,36
PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5
PLF II
6 7
PLF I PLF II
Stahl M, et al. J Clin Oncol.2009;27:851-856.
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POET: Overall Survival (Long-term Results)
Stahl M, et al. J Clin Oncol.2009;27:851-856.
Stahl M, et al. Eur J Cancer.2017;183-190.
Median Survival:
C→C→S C→C/RT→S
21.1 mo 30.8 mo
3yr 5yr
47% 40%
26% 24%
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Can Surgery Improve
the Outcome of
Chemoradiation?
Localized Esophageal Cancer
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Schema
tumor size
histology
weight loss
2 x Cisplatin (75 mg/m2)
+
5-fluorouracil (1000 mg/m2/d CI x 4d)
+
radiation therapy (5000 cGy)
R
A
N
D
O
M
I
Z
E
radiation therapy (6400 cGy)
Herskovic A, et al. N Engl J Med. 1992;326:1593-1598.
al-Sarraf M, et al. J Clin Oncol. 1997;15:277-284.
Prospective Randomized Intergroup Study:Radiation Therapy vs Chemotherapy + Radiation Therapy for Localized SCC or ADC of the Esophagus
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Herskovic A, et al. N Engl J Med. 1992;326:1593-1598. al-Sarraf M, et al. J Clin Oncol. 1997;15:277-284.
Intergroup Study
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Stratification :
• adenocarcinoma vs squamous cell vs adenosquamous
• pretreatment weight loss < 10% vs ≥ 10%
• performance status: 0 vs 1 vs 2
• center
Inoperable
esophageal
cancer
R
A
N
D
O
M
I
Z
E
50 Gy/5 weeks
+ Folfox, 3 cycles
50 Gy/5 weeks +
5FU/cisplatin, 2 cy.
Folfox, 3
cycles
5FU/cisplatin, 2
cycles
Conroy et al. Lancet Oncol. 2014 Mar;15(3):305-14.
Prodige 5 - ACCORD 17 - Schema
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FOLFOX: more gr. 1-2 PN, fewer toxic & sudden deaths, less mucositis, less alopecia,
decreased renal toxicity, shorter chemotherapy (12 days vs 16-20 days) in an outpatient
setting. Conroy et al. Lancet Oncol. 2014 Mar;15(3):305-14.
Prodige 5 - ACCORD 17 - Survival
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• A total of 455 patients with localized esophageal cancer were given 2 courses of 5-FU/cisplatin plus radiation therapy.
• 259/455 patients experienced a “partial response”, were considered operative candidates, and entered the randomized component of the trial.
Bedenne. J Clin Oncol. 2007;25:1160-1168.
Chemoradiation Therapy With or Without Surgery: French Phase III Trial
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Survival
3-month mortality median 2-year
5-FU/CDDP x 3
+
1%
Radiation therapy
19.3
months
40%
P=0.56
Surgery 9% 17.7 months
34%
Partial Response
R
A
N
D
O
M
I
Z
E
(259 pts)
Bedenne. J Clin Oncol. 2007;25:1160-1168.
Chemoradiation Therapy With or Without Surgery: French Phase III Trial
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Patients:
(N = 177)
uT3-4,N0-1, M0
with SCC
R
A
N
D
O
M
I
Z
E
3 cycles:
5-FU/LV +
Cisplatin +
Etoposide
Chemoradiation:
Cisplatin + Etoposide
+ 40 Gy RT
→ Surgery
Chemoradiation:
Cisplatin + Etoposide
+ > 60 Gy RT
Stahl. J Clin Oncol. 2005;23:2310-2317.
Chemoradiation Therapy With or Without Surgery:German Phase III Trial - Schema
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Arm Completed
Treatment
Treatment
Mortality
3-yr Local
Recurrence
Median
Survival
3-Year Survival
Induction Chemo
All Responder
Arm A:
C/RT →S 62% 12.8% 41% 16 mo. 31% 54%
Arm B:
C/RT 85% 3.5%
(P = 0.03)
64%
(P = 0.004)
15 mo. 24%
(P = 0.02)
54%
Stahl. J Clin Oncol. 2005;23:2310-2317.
Chemoradiation Therapy With or Without Surgery:German Phase III Trial - Results
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Stahl. J Clin Oncol. 2005;23:2310-2317.
Median survival (N = 172):
Arm A (C/RT →S) -16.4 months
Arm B (C/RT only)-14.9 months
31.3% (P = 0.02)
24.4%
Chemoradiation Therapy With or Without Surgery:German Phase III Trial - Survival
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Localized Esophageal
Pre-operative cisplatin/5-FU chemotherapy offers a
small survival advantage in distal esophageal and GE
junction cancer.
Neoadjuvant platinum-based chemoradiation (esp. w.
carbo/tax) offers a greater survival advantage with
better local control but increased surgical morbidity.
Surgery may not be needed in patients who have a
clinical response to chemoradiation. FOLFOX may
be the best choice for these patients.
Conclusions from these Studies
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What Can Surgery
Accomplish?
Localized Gastric Cancer
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Survival for Resected Localized Gastric Cancer
Survival for 10,601 patients with resected gastric cancer
using SEER data 1973-2005 and AJCC 7th ed.Washington. Ann Surg Oncol 2010
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What are Proven Strategies to
Enhance Outcomes for
Surgical Resection?
Localized Gastric Cancer
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Stratify
depth of tumor
penetration 5-FU/leucovorin x 1
5-FU/leucovorin
+
4500 cGy
radiation
5-FU/leucovorin x 2
number involved
nodes
location of tumor observation
extent of surgery
R
A
N
D
O
M I
Z
E
Macdonald JS, et al. N Engl J Med. 2001;345(10):725-730.
Intergroup Protocol 0116Adjuvant Therapy for Gastric Cancer
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Macdonald JS, et al. N Engl J Med. 2001;345:725-730.
Smalley SR, et al. J Clin Oncol. 2012; 30:2327-2333
Chemoradiotherapy
Surgery Only
50%
41%
3 years
Intergroup Protocol 0116
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ECF x 3 q3/52
3-6 weeks
Resection
ECF x 3 q3/52
6-12 weeks
CSC S
Follow-up
Within 6 weeks
Resection
Cunningham D, et al. N Engl J Med. 2006;355:11-20. 503 Patients:
15% Lower Third12% GE Junction
MAGIC Trial: Schema
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MAGIC: Survival
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FLOT4 Study Design
FLOT x4 - RESECTION - FLOT x4
ECF/ECX x3 - RESECTION - ECF/ECX
x3
• Gastric cancer or
adenocarcinoma of
the gastro-esophageal
junction type I-III
• Medically and
technically operable
• cT2-4/cN-any/cM0 or
cT-any/cN+/cM0
R
n=716
S
T
RA
T
I
F
I
CA
T
I
O
N
FLOT: docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1;
leucovorin 200 mg/m², d1; oxaliplatin 85 mg/m², d1, every
two weeks
ECF/ECX: Epirubicin 50 mg/m2, d1; cisplatin 60 mg/m², d1;
5-FU 200 mg/m² (or capecitabine 1250 mg/m² p.o. divided
into two doses d1-d21), every three weeks
Stratification: ECOG (0 or 1 vs. 2), location of primary (GEJ type I vs.
type II/III vs. stomach), age (< 60 vs. 60-69 vs. ≥70 years) and nodal
status (cN+ vs. cN-).
Presented by: Salah-Eddin Al-Batran
Randomized, multicenter, investigator-initiated, phase II/III study
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FLOT4: Progression-Free Survival
ECF/ECX FLOT
mPFS 18 months 30 months
[15-22] [21-41]
HR 0.75 [0.62-0.91]
p=0.004 (log rank)
2y 43% 53% 3y 37% 46% 5y 31% 41%
PFS rate* ECF/ECX FLOT
*projected PFS rates
Presented by: Salah-Eddin Al-Batran
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FLOT4: Overall Survival
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
Presented by: Salah-Eddin Al-Batran
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FLOT 4: Toxicity
Grade 3-4 >5% ECF/ECX (N=354) FLOT (N=354) P-value (Chi-Square)
Diarrhea 13 (4%) 34 (10%) 0.002
Vomiting 27 (8%) 7 (2%)
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Localized Gastric:
Post-operative 5-FU-based chemoradiation therapy remains
one standard of care for muscle-invasive or LN positive
disease.
The peri-operative FLOT4 regimen appears to be an
improvement over MAGIC/ECF and should be considered
for patients of better performance status.
Conclusions from these Results
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What are the Active Agents and
Combinations for this Disease?
Metastatic Esophagogastric Cancer
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Evolution of Therapy in Advanced Esophagogastric Cancer
FAM < FAMTX
CF = ELF = FAMTX > EAP
5-FU < FAM
PELF = FAMTX < ECF
ECF > MCF
ECF = ECX = EOF = EOX
DCF > CF CF = FOLFIRIFOL = CFFOX
DC < DCF IP < FOLFIRI
Randomized Phase III
Randomized Phase II
Multi-center Phase II
FOLFOX
FOLFIRI = EOXmDCFFOL =ECFFOX
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CALGB 80403 / ECOG E1206: Schema
Stratification:
ECOG 0-1 vs 2
ADC vs. SCC
ARM A: (ECF + cetuximab); 1 cycle = 21 days
Cetuximab 400 → 250mg/m2 IV, weekly
Epirubicin 50 mg/m2 IV, day 1
Cisplatin 60mg/m2 IV, day 1
Fluorouracil 200mg/m2/day, days 1-21
ARM B: (IC + cetuximab); 1 cycle = 21 days
Cetuximab 400 → 250mg/m2 IV, weekly
Cisplatin 30 mg/m2 IV, days 1 and 8
Irinotecan 65 mg/m2 IV, days 1 and 8
ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days
Cetuximab 400 → 250mg/m2 IV, weekly
Oxaliplatin 85 mg/m2 IV, day 1
Leucovorin 400 mg/m2, day 1
Fluorouracil 400 mg/m2 IV bolus, day 1
Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)
Enzinger. J Clin Oncol 2016
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CALGB 80403 / E1206: Survival
FOLFOX-C has similar efficacy to ECF-C in Esophageal and GEJ Cancer
Progression-Free Survival Overall Survival
0 5 10 15 20 25 30
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y O
vera
ll S
urv
ival
67 55 38 23 14 10 473 56 33 21 13 10 5
73 61 41 24 14 6 5
Number of Patients at Risk
ECF-CIC-C
FOLFOX-C
Events n/N (%)
Median months
95% CI
ECF-C 63/67 (94.0%) 11.6 8.1-13.4
IC-C 68/73 (93.2%) 8.6 6.0-12.4 FOLFOX-C 65/73 (89.0%) 11.8 8.8-13.9
Log-rank test p=0.61
0 5 10 15 20 25 30
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bil
ity
Pro
gre
ss
ion
-fre
e S
urv
iva
l
67 41 17 7 5 5 3
73 35 11 5 4 1 073 47 22 8 8 3 2
Number of Patients at Risk ECF-C
IC-CFOLFOX-C
Events n/N (%)
Median months
95% CI
ECF-C 65/67 (97.0%) 7.1 4.5-8.4
IC-C 72/73 (98.6%) 4.9 3.9-6.0 FOLFOX-C 70/73 (95.9%) 6.8 5.4-8.1
Log-rank test p=0.09
Treatment modifications:
FOLFOX-C (73%) vs IC-C (85%) vs ECF-C (91%) (χ2, p=0.013).
Discontinued treatment for adverse event or treatment-related death:
FOLFOX-C (11%) vs. ECF-C (19%) vs IC-C (26%) (χ2, p=0.17).Enzinger. J Clin Oncol 2016
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Time to Progression Overall Survival
Grade 3-4 Toxicity DCF CF
Neutropenia 82% 57%
Febrile Neutropenia 29% 12%
Stomatitis 21% 27%
Diarrhea 19% 8%
Vomiting 14% 17%
Van Cutsem et al.
J Clin Oncol 2006
Phase III: DCF vs CF for Esophagogastric Cancer
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Shah et al. JCO 2015;33:3874-3879
Grade 3-4 Toxicity mDCF DCF
Neutropenia w GCSF 56% 45%
Febrile Neutropenia 9% 16%
Stomatitis 0 13%
Diarrhea 6% 3%
Vomiting 2% 19%
Randomized PII: Modified DCF vs. DCF for Met Gastric
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Guimbaud. J Clin Oncol 2014
Phase 3: FOLFIRI vs ECX for Met Gastric/GEJ
-
Previously
untreated patients
with locally
advanced or
metastatic
oesophago-
gastric cancer
R
A
N
D
O
M
I
S
A
T
I
O
N
Epirubicin
Cisplatin
Fluorouracil
Epirubicin
Cisplatin
Xeloda (capecitabine)
Epirubicin
Oxaliplatin
Fluorouracil
Epirubicin
Oxaliplatin
Xeloda (capecitabine)Stratified for:
- Center (63 centers, mainly UK, 2 Aus)
- Locally advanced vs metastatic
- PS 0/1 vs 2
2 x 2 design
Cunningham D, et al. N Engl J Med. 2008;358:36-46.
REAL-2: Schema
-
0
20
40
60
80
100
0 1 2 3Time since randomisation (years)
Pro
bab
ilit
y of
su
rviv
al (
%)
ECF EOF ECX EOX
Arm OS (m) 1-year survival
(95% CI)
P-value HR
(95% CI)
ECF
EOF
ECX
EOX
9.9
9.3
9.9
11.2
37.7 (31.8-43.6)
40.4 (34.2-46.5)
40.8 (34.7-46.9)
46.8 (40.4-52.9)
0.612
0.389
0.020
1
0.96 (0.79-1.15)
0.92 (0.76-1.11)
0.80 (0.66-0.97)
Cunningham D, et al. N Engl J Med. 2008;358:36-46.
EOX
ECF
REAL-2: Survival (ITT)
-
IntelliDose chemotherapy order entry (COE) platform:Trends in metastatic gastric cancer chemotherapy treatment* (2005-2016 )
Year of initiation of first-line therapy
N=4,333
Year of initiation of second-line therapy
N=1,822
2005-09 2010-12 2013-14 2015-16 2005-09 2010-12 2013-14 2015-16
N 1,073 1,357 948 883 N 465 604 424 329
FOLFOX (%) 12.0 21.2 35.1 41.0 FOLFOX (%) 13.3 13.1 17.2 16.4
ECF/EOX (%) 13.8 23.0 11.6 10.2 ECF/EOX (%) 11.2 7.9 5.4 3.0
DCF (%) 22.9 14.3 11.8 8.4 DCF (%) 15.7 9.3 7.3 2.1
CF (%) 12.6 10.8 7.9 7.2 CF (%) 4.3 4.6 3.3 3.3
TAX (%) 4.8 4.1 3.8 6.3 TAX (%) 11.8 11.4 21.0 22.8
C+Irinotecan (%) 9.0 2.8 1.1 1.5 FOLFIRI (%) 11.2 9.1 12.0 9.7
C+TAX (%) 9.8 12.2 15.6 14.6 C+TAX (%) 7.1 19.7 7.5 7.6
FU mono (%) 9.2 7.5 8.1 6.5 FU mono (%) 9.2 112.1 13.0 22.2
Other (%) 5.9 4.1 5.0 4.3 Other (%) 14.8 11.9 13.0 11.9
FOLFOX=fluoropyrimidine (FU) + oxaliplatin ; ECF/EOX=epirubicin + platinum + FU ; DCF=docetaxel (D) + cis/carboplatin (C) + FU ;
CF=C + FU; TAX=taxane; DF = D + FU* With or without biologic agents
Abrams T et al. GI Cancers Symposium 2018
-
HER2-positive
advanced GC
(n = 584)
5-FU or capecitabine
+ cisplatin
(n = 290)
R
aChosen at investigator’s discretion
GEJ, gastroesophageal junction
5-FU or capecitabinea
+ cisplatin
+ trastuzumab
(n = 294)⚫ Stratification factors
− Advanced vs metastatic
− GC vs GEJ
− Measurable vs non-measurable
− ECOG PS 0-1 vs 2
− Capecitabine vs 5-FU
Phase III, randomized, open-label, international, multicenter study
Bang, Y-J et al. Lancet 2010; 376:687
3807 patients screened1
810 HER2-positive (22.1%)
ToGA - Schema
-
(HER2 3+ or 2+/FISH+)
ToGA: Overall Survival
2.7 mo.
-
Is 2nd line therapy of benefit?
Metastatic Esophagogastric Cancer
-
R
A
N
D
O
M
I
Z
E
Docetaxel 75
mg/m2 q 3 weeks
Best supportive
care
168 patients :
Primary Endpoint:
Overall
Survival
Ford et al. Lancet Oncol. 2014 Jan;15(1):78-86.
Cougar-02: Randomized Trial of Docetaxel vs. BSC in
Relapsed Esophagogastric Adenocarcinoma
-
3.6 mo 5.2mo
HR: 0.67, 95% CI 0.49–0.92;
p=0.01
Ford et al. Lancet Oncol. 2014 Jan;15(1):78-86.
Cougar – 02: 2nd line Docetaxel vs. BSC: Overall Survival
-
Ramucirumab 8 mg/kg
q2wk
+
BSC (n = 238)
R
A
N
D
O
M
I
Z
E
Placebo q2wk
+
BSC (n = 117)
S
C
R
E
E
N
Treatment until disease progression
or intolerable
toxicity
Tumor assessment, survival, and safety follow-
up
N = 355
• Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial
• Gastric or GEJ adenocarcinoma
• Stratification factors: region, weight loss (≥10% vs.
-
Months
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28
Overa
ll S
urv
ival
0.0
0.2
0.4
0.6
0.8
1.0
Ramucirumab
Placebo
Censored
Censored
Ram 238 154 92 49 17 7 3 0 0
Plcb 117 66 34 20 7 4 2 1 0
No. at Risk
HR (95% CI) = 0.776 (0.603, 0.998)
Log rank P-value (stratified) = 0.0473
Ramucirumab Placebo
Patients / Events 238 / 179 117 / 99
Median (mos) (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7)
6-month OS 42% 32%
12-month OS 18% 11%
REGARD: Overall Survival
Δ mOS = 1.4 months
Fuchs et al. Lancet. 2014 Jan 4;383(9911):31-9.
-
Treat until
disease
progression
or intolerable
toxicity
• Important inclusion criteria:- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma- Progression after 1st line platinum/fluoropyrimidine based chemotherapy
•Stratification factors:- Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)
Ramucirumab 8 mg/kg day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycle
N = 330
Placebo day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
Survival and
safety follow-
up
RAINBOW: Study Design
* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC
1:1
Wilke et al. Lancet 2014; 15: 1224-35
-
RAINBOW: Overall Survival
RAM + PTX 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0
PBO + PTX 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0
No. at risk
Wilke et al. Lancet 2014; 15: 1224-35
HR (95% CI) = 0.807 (0.678, 0.962)
Stratified log rank p-value = 0.0169
RAM + PTX PBO + PTX
Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38)
6-month OS 72% 57%
12-month OS 40% 30%
Major Response Rate 28% 16%
Duration of Response 4.4mo 2.8mo
Δ mOS = 2.3 months
Censored
-
No benefit for angiogenesis inhibitors in frontline:
AVAGAST: Bevacizumab AVATAR: Bevacizumab
RAINFALL: Ramucirumab ZAMEGA: Ziv-Aflibercept
-
ONO-4538-12 (Attraction-2): Phase 3 Study of Nivolumabvs Placebo in Patients With Refractory GC
Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471.
Study Design and Endpoints
Key eligibility criteria:•Age ≥20 years•Unresectable advanced or recurrent GC or GJC•Histologically confirmed adenocarcinoma•Prior treatment with ≥2 regimens and refractory to/intolerant of standard therapy•ECOG PS of 0 or 1
Nivolumab3 mg/kg IV Q2W
R
2:1
• Stratification based on:– Country (Japan vs Korea vs Taiwan)– ECOG PS (0 vs 1)– Number of organs with metastases (
-
ONO-4538-12 (Attraction-2): Response & Survival
Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471.
-
KEYNOTE-059: Phase 2 Study of Pembrolizumab for Advanced Gastric or GEJ Adenocarcinoma
Primary end point: ORR per RECIST v1.1 by central review
aThe first 40 patients enrolled regardless of PD-L1 expression. Enrollment after the first 40 patients will be determined based on the results of an interim analysis. b20 patients from Asian sites and 20 patients from non-Asian sites will be enrolled. Analysis cut-off date: Nov. 10, 2014.
Pembrolizumab 200 mg + Cisplatin + 5FU, all Q3W
Pembrolizumab200 mg Q3W
Pembrolizumab200 mg Q3W
COHORT 2
• PD-L1+ or PD-L1–
• No prior systemic therapy
N = 40b
COHORT 1
• PD-L1+ or PD-L1–
• ≥2 prior systemic treatments
N = 180a
COHORT 3
• PD-L1+ only• No prior systemic therapy
N = 50
Fuchs CS et al. JAMA Oncol 2018 [Epub ahead of print]
-
Cohort 1: Response by PD-L1 & MSI Expression
ResponseaPD-L1 Positive
(n = 148)
PD-L1 Negative
(n = 109)
% 95% CI % 95% CI
ORR (CR + PR) 15.5 10.1–22.4 6.4 2.6–12.8
CR 2.0 0.4–5.8 2.8 0.6–7.8
PR 13.5 8.5–20.1 3.7 1.0–9.1
DCRb 33.1 25.6–41.3 19.3 12.3–27.9
ResponseaMSI-High
(n = 7)
Not MSI-High
(n = 167)
% 95% CI % 95% CI
ORR (CR + PR) 57.1 18.4–90.1 9.0 5.1–14.4
CR 14.3 0.4–57.9 2.4 0.7–6.0
PR 42.9 9.9–81.6 6.6 3.3–11.5
DCRb 71.4 29.0–96.3 22.2 16.1–29.2Fuchs CS et al. JAMA Oncol 2018 [Epub ahead of print]
-
Cohort 1: Treatment Exposurea and Duration of Response
Median DoR
mos (95% CI)
All patients 8.4 (1.6+b to 17.3+)
PD-L1 positive 16.3 (1.6+ to 17.3+)
PD-L1 negative 6.9 (2.4 to 7.0+)
Con
firm
ed r
esp
on
der
s (n
= 3
0)
Time since first dose (months)
CR
PR
Progressive disease
Death
Ongoing pembrolizumab treatment
0 2 4 6 8 10 12 14 16 18 20 22 24
aPatients with measurable disease per RECIST v1.1 by central review at baseline who had ≥1 post-baseline assessment
were included (n = 30). Bar length indicates time to last imaging assessment. bNo progressive disease at last disease
assessment.
Data cutoff on January 16, 2017.Fuchs CS et al. JAMA Oncol 2018 [Epub ahead of print]
-
Conclusions from these Results
Metastatic Esophagogastric:
The most active single agents are the fluoropyrimidines, platinum
analogues, taxanes, and irinotecan.
1st Line: Fluoropyrimidine & platinum combos are standard.
Trastuzumab should be added for HER2/neu 3+ or FISH+ tumors.
Pts should receive at least 2-3 lines of therapy for their dz.
2nd Line: Paclitaxel + Ramucirumab is probably the best choice for
most patients. Checkpoint inhibitors should be given for MSI-H.
Checkpoint inhibitors should be offered to all PD-L1 positive pts.
-
References:
• Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003; 349 (23): 2241-52. PMID: 14657432
• Enzinger PC et al. CALGB 80403 (Alliance) /E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancer. J Clin Oncol. 2016 Aug 10;34(23):2736-42. PMID: 27382098
• Van Hagen P et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. PMID: 22646630
• Bang YJ et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. The Lancet , Volume 376 , Issue 9742 , 687 – 697 PMID: 20728210
• Fuchs CS et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018 Mar 15. doi: 10.1001/jamaoncol.2018.0013. [Epub ahead of print] PMID: 29543932
PMID:
20728210
https://www.ncbi.nlm.nih.gov/pubmed/29543932