Systemic Therapy for Gastric Cancer
Charles S. Fuchs, MDCharles S. Fuchs, MD
Dana-Farber Cancer InstituteDana-Farber Cancer Institute
Harvard Medical SchoolHarvard Medical School
Boston, MABoston, MA
GASTRIC CANCER 2009
#New Cases #New Cases (rank)(rank)
# Deaths (rank)# Deaths (rank)
United States (2008)*United States (2008)* 21,50021,500 (#14)(#14) 10,80010,800 (#13)(#13)
Worldwide (2002)Worldwide (2002)°° 934,000934,000 (#4)(#4) 700,000700,000 (#2)(#2)
* Jemal, et. al. CA Cancer J Clin 2008;58:71* Jemal, et. al. CA Cancer J Clin 2008;58:71
° Parkin, et. al. CA Cancer J Clin 2005;55:75° Parkin, et. al. CA Cancer J Clin 2005;55:75
Gastric Cancer Mortality:Regional Differences
Jemal et al. CA Cancer J Clin. 2006. 56:106.
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Gastric Cancer: Pathology
Intestinal typeIntestinal type
Cohesive cellsCohesive cells
Forms discrete massForms discrete mass
Distal stomachDistal stomach
EndemicEndemic
Better prognosisBetter prognosis
Diffuse typeDiffuse type
Lack cell cohesionLack cell cohesion
Infiltrates without discrete massInfiltrates without discrete mass
Proximal stomachProximal stomach
Not endemicNot endemic
Worse prognosisWorse prognosis
1. Adenocarcinomas (90%), lymphoma, leiomyosarcoma1. Adenocarcinomas (90%), lymphoma, leiomyosarcoma
2. Adenocarcinoma can be subdivided:2. Adenocarcinoma can be subdivided:
Gastric Cancer Survival by Stage
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 1 2 3 4 5
Time, years
Surv
ival
(%)
National Cancer Data Base 1985-1996
IA
IB
II
IIIA
IIIBIV
CASEA 62 yo man presents with new metastatic gastric adenocarcinoma
(liver mets). PS = 0 to 1. Your choice of front-line therapy:
A. Docetaxel, cisplatin, 5-FU (DCF)
B. Irinotecan, cisplatin or FOLFIRI
C. Epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)
D. Capecitabine/cisplatin (5-FU/cisplatin)
E. 5-FU, leucovorin, oxaliplatin (FOLFOX)
F. Single agent therapy
G. Other
Gastric Cancer: Single Agent Chemotherapy
18-31%18-31%IrinotecanIrinotecan
17-24%17-24%DocetaxelDocetaxel
5-21%5-21%PaclitaxelPaclitaxel
19%19%CisplatinCisplatin
17%17%DoxorubicinDoxorubicin
30%30%Mitomycin CMitomycin C
11%11%MethotrexateMethotrexate
21%21%5-Fluorouracil5-Fluorouracil
Response RateResponse RateDrugDrug
5-FU and Cisplatin in Advanced Gastroesophageal Adenocarcinoma Trials
Ohtsu et al. J Gastro 2007
JapanJapan EuropeEurope US/EuropeUS/Europe
NN 105105 134134 112112
RRRR 34%34% 20%20% 23%23%
Median PFSMedian PFS 3.9 mos.3.9 mos. 4.1 mos.4.1 mos. 3.7 mos.3.7 mos.
Median OSMedian OS 7.3 mos.7.3 mos. 7.2 mos.7.2 mos. 8.5 mos.8.5 mos.
FAMtx vs. ELF vs. 5FU/CDDP in FAMtx vs. ELF vs. 5FU/CDDP in Advanced Gastric CancerAdvanced Gastric Cancer
399 patients399 patients
with advancedwith advanced
diseasedisease
ResponseResponse Median Median
RateRate SurvivalSurvival
FAMtxFAMtx 12%12% 9 mos9 mos
ELFELF 9%9% 7 mos7 mos
5-FU+CDDP5-FU+CDDP 20%20% 9 mos9 mos
Gastric Cancer: Chemotherapy Versus Supportive Care
AuthorAuthor RegimenRegimen No. No. of of Pts.Pts. Median SurvivalMedian Survival((mos)mos)
PyrhonenPyrhonen FEMTXFEMTXBSCBSC
17171919
121233
MuradMurad FAMTXFAMTXBSCBSC
30301010
101033
GlimeliusGlimelius ELFELFBSCBSC
101088
101044
ScheithauerScheithauer ELFELFBSCBSC
18181919
>7.5>7.544
5-FU/CDDP vs. Capecitabine/CDDP in Advanced Gastric Cancer
Kang et al. ASCO 2006
NN RR%RR%
MedianMedian
TTP,TTP,
mosmos
MedianMedian
OS,OS,
mosmos
5-FU/CDDP5-FU/CDDP 137137 2929 5.05.0 9.39.3
Capecitabine/CDDPCapecitabine/CDDP 139139 4141 5.6*5.6* 10.5*10.5*
*P = N.S.*P = N.S.
S-1
Oral fluoropyrimidine: tegafur, CDHP, OXOOral fluoropyrimidine: tegafur, CDHP, OXO
Tegafur converted to 5-FUTegafur converted to 5-FU
CDHP inhibits DPD in gut (prevents degradation)CDHP inhibits DPD in gut (prevents degradation)
OXO inhibits phosphorylation of 5-FU in gut (reduces OXO inhibits phosphorylation of 5-FU in gut (reduces diarrhea)diarrhea)
Asian and Caucasian population have different rates of Asian and Caucasian population have different rates of activation of tegafur to 5-FUactivation of tegafur to 5-FU
CYP2A6CYP2A6
Different polymorphisms for Asians vs. CaucasiansDifferent polymorphisms for Asians vs. Caucasians
S-1/CDDP in First-Line Advanced Gastric Cancer (FLAGS)
RR
AA
NN
DD
OO
MM
II
ZZ
EE
S-1S-1
CisplatinCisplatin
5-FU5-FU
CisplatinCisplatin
1,000 patients worldwide:1,000 patients worldwide:
FLAGS: Results
Ajani et. al. GI ASCO 2009Ajani et. al. GI ASCO 2009
OutcomeOutcome
# pts# pts response rateresponse rate median PFSmedian PFSmedian median
OSOS
S-1S-1
++
CisplatinCisplatin
521521 29.1%29.1% 4.8 mos4.8 mos 8.6 mos8.6 mos
p=0.40p=0.40 p=0.92p=0.92 p=0.20p=0.20
5-FU5-FU
++
CisplatinCisplatin
508508 31.9%31.9% 5.5 mos5.5 mos 7.9 mos7.9 mos
ECF Versus FAMtx in Advanced Esophagogastric Cancer J Clin Oncol 1997; Br J Cancer 1999
ECF:ECF: Epirubicin 50 mg/mEpirubicin 50 mg/m22 q 3 wksq 3 wks CDDP 60 mg/mCDDP 60 mg/m22 q 3 wksq 3 wks
55--FU 200 mg/mFU 200 mg/m22 /d C.I./d C.I.
ResponseResponseRateRate
MedianMedianSurvivalSurvival
1 Yr1 YrSurvivalSurvival
Grade 3/4Grade 3/4NeutropeniaNeutropenia
ECFECF 45%45% 8.7 mos8.7 mos 36%36% 36%36%274274 patientspatientswithwithadenoadeno --carcinomacarcinoma FAMtxFAMtx 21%21% 5.7 mos5.7 mos 21%21% 58%58%
REAL-2 Trial Design for Advanced and Metastatic Gastro-Esophageal Cancer
REAL-2 Trial Design for Advanced and Metastatic Gastro-Esophageal Cancer
ECFECF EEFEEF
EEXEEXECXECX
2x2 multifactorial design2x2 multifactorial design
X: Xeloda 1250 mg/m2
daily
E: Eloxatin 130 mg/m2
every 3 weeks
1,000 patients randomized to:1,000 patients randomized to: N Eng J Med 2008
5FU 484 178 37 8 2Capecitabine480 206 52 12 3 1
Number at risk
0
20
40
60
80
100
0 1 2 3 4 5 6Time since randomisation (years)
Pro
bab
ilit
y of
su
rviv
al (
%)
5FU
Capecitabine
Overall Survival (Per-protocol): Fluoropyrimidine comparison
N Median 1 year 95% CI
5FU 484 9.6 39.4% 35.0 - 44.0
Capecitabine 480 10.9 44.6% 40.1 – 49.0
HR 0.86 (0.8 – 0.99)HR 0.86 (0.8 – 0.99)
HR for ITT population = 0.88 (0.77 – 1.00) p= 0.058N Eng J Med 2008
11041187490Cisplatin141048198474Oxaliplatin
Number at risk
0
20
40
60
80
100
0 1 2 3 4 5 6Time since randomisation (years)
Pro
bab
ilit
y of
su
rviv
al (
%)
Cisplatin
Oxaliplatin
Overall Survival (Per-protocol): Platinum comparison
NN MedianMedian 1 year1 year 95% CI95% CI
Cisplatin 490 10.0 40.1% 35.7 - 48.4
Oxaliplatin 474 10.4 43.9% 39.4 – 49.0
HR 0.92 (0.8 – 1.10)HR 0.92 (0.8 – 1.10)
HR for ITT population = 0.91 (0.79-1.04) p=0.159N Eng J Med 2008
0
20
40
60
80
100
0 1 2 3Time since randomisation (years)
Pro
bab
ilit
y of
su
rviv
al (
%)
ECF EOX
Survival by Regimen ECF vs EOX (ITT)
ArmArm OS (m) OS (m) 1 year survival 1 year survival (95% CI)(95% CI)
p-valuep-value HRHR(95% CI)(95% CI)
ECFEOX
9.911.2
37.7 (31.8-43.6)
46.8 (40.4-52.9)
0.02010.80 (0.66-0.97)
Phase II Studies of 5-FU/Oxaliplatin in Advanced Gastroesophageal Adenocarcinoma
Study Regimen NORR(%)
TTP(months)
Median OS(months)
Louvet et al1 FOLFOX-6 41 45 6.2 8.6
Al-Batran et al2 FOLFOX-6 41 43 5.6 9.6
Chao et al3 FLOX 55 56 5.2 10.0
DeVita et al4 FOLFOX-4 61 38 7.1 11.2
Lordick et al5 FUFOX 48 54 6.5 11.4
Cavanna et al7 FOLFOX-4 56 43 6.0 10.0
1. Louvet et al. J Clin Oncol. 2002. 20:4543. 2. Al-Batran et al. J Clin Oncol. 2004. 22:658.3. Chao et al. Br J Cancer. 2004. 91:453. 4. De Vita et al. Br J Cancer. 2005. 92:1644.5. Lordick et al. Br J Cancer. 2005. 93:190. 6. Jatoi et al. ASCO, 2005. Abstract 4059.7. Cavanna et al. Am J Clin Oncol. 2006. 29:371.
NCCTG = North Central Cancer Treatment Group;
5-FU, LV, Oxaliplatin vs. 5-FU, LV, Cisplatin in Advanced Gastroesophageal Adenocardinoma
Al-Batran et al, J Clin Oncol 2008
RR
AA
NN
DD
OO
MM
II
ZZ
EE
5-FU 2,600mg/m5-FU 2,600mg/m22/24hr/24hrLeucovorin 200mg/mLeucovorin 200mg/m22
Oxaliplatin 85mg/mOxaliplatin 85mg/m22
5-FU 2,000mg/m5-FU 2,000mg/m22/24hr/24hrLeucovorin 200mg/mLeucovorin 200mg/m22
Cisplatin 50mg/mCisplatin 50mg/m22
220 patients with advanced gastric cancer:220 patients with advanced gastric cancer:
Q 2 weeksQ 2 weeks
Q 2 weeksQ 2 weeks
FLO vs FLP in Advanced Gastroesophageal CancerAl-Batran et al.
RRRR
MedianMedian
PFSPFS
MedianMedian
OSOS
FLOFLO 35%35% 5.8 mos5.8 mos 10.7 mos10.7 mos
FLPFLP 25%25% 3.9 mos3.9 mos 8.8 mos8.8 mos
P-valueP-value 0.0770.077 NSNS
FLO vs FLP in Advanced Gastroesophageal Cancer
Al-Batran et al.
Grade Grade 3 Toxicity3 Toxicity
FLOFLO
N=112N=112
FLPFLP
N=102N=102 P-valueP-value
Nausea (%)Nausea (%) 4.54.5 8.88.8 0.0030.003
Vomiting (%)Vomiting (%) 2.72.7 5.95.9 0.0020.002
Fatigue (%)Fatigue (%) 3.63.6 6.96.9 0.030.03
Neurosensory (%)Neurosensory (%) 14.314.3 2.02.0 <0.001<0.001
Any grade renal (%)Any grade renal (%) 10.710.7 34.334.3 0.030.03
FLO vs FLP: Patients >65 years (N=94)Al-Batran et al.
RRRR Median PFSMedian PFS Median OSMedian OS
FLOFLO 41%41% 6.0 mos6.0 mos 13.9 mos13.9 mos
FLPFLP 17%17% 3.1 mos3.1 mos 7.2 mos7.2 mos
P-valueP-value 0.0120.012 0.0290.029 0.0830.083
Irinotecan, 5-FU, LV vs. Cisplatin, 5-FU, LV in Advanced Gastroesophageal Adenocarcinoma
Dank et al. Ann Oncol 2008
NN RRRR
MedianMedian
TTPTTP
MedianMedian
OSOS
FU/LV/IRIFU/LV/IRI 170170 32%32% 5.0 mos5.0 mos 9.0 mos9.0 mos
FU/LV/CDDPFU/LV/CDDP 163163 26%26% 4.2 mos4.2 mos 8.7 mos8.7 mos
P-valueP-value 0.230.23 0.0880.088 0.530.53
CPT-11 and Cisplatin in Advanced Gastric Cancer
AuthorAuthor No. of PtsNo. of Pts RRRR G3-4 DiarrheaG3-4 Diarrhea G4 Neutropenia G4 Neutropenia
Boku*Boku* 4444 48%48% 20%20% 57%57%
TakinckiTakincki 1919 38%38% ---- ----
AjaniAjani 3636 58%58% 22%22% 15%15%
* Median survival = 9 mos.* Median survival = 9 mos.
Taxanes in Advanced Gastric Cancer
AgentAgent AuthorAuthor No. No. of of Pts.Pts. RR (%)RR (%)
TaxolTaxol OhtsuOhtsu 1616 2020
TaxolTaxol AjaniAjani 3333 1717
TaxolTaxol CascinuCascinu 3636 2222
TaxotereTaxotere MavroudisMavroudis 3030 2020
TaxotereTaxotere MaiMai 6363 2424
TaxotereTaxotere ECOGECOG 4141 1717
TaxotereTaxotere EORTCEORTC 3737 2424
Docetaxel 75 mg/mDocetaxel 75 mg/m22 + +
Cisplatin 75 mg/mCisplatin 75 mg/m22 + +
5-FU 750 mg/m5-FU 750 mg/m22/d CI days 1-5/d CI days 1-5
every 3 weeksevery 3 weeks
n=221n=221
n=224n=224
RRAANNDDOOMMII
Z Z AATTIIOON N
V325: Phase III Study of DCFV325: Phase III Study of DCFJ Clin Oncol 2006J Clin Oncol 2006
Cisplatin 100 mg/mCisplatin 100 mg/m22 + +
5-FU 1000 mg/m5-FU 1000 mg/m22/d CI days 1-5/d CI days 1-5
every 4 weeksevery 4 weeks
V325: DCF in Gastric Cancer
DCFDCF
N=221N=221
CFCF
N=224N=224 P-valueP-value
Response RateResponse Rate 37%37% 25%25% 0.010.01
Median TTP (months)Median TTP (months) 5.65.6 3.73.7 0.0010.001
Median OS (months)Median OS (months) 9.29.2 8.68.6 0.020.02
J Clin Oncol 2006J Clin Oncol 2006
V325: DCF in Gastric CancerJ Clin Oncol 2006J Clin Oncol 2006
33%33%46%46%Early treatment discontinuationEarly treatment discontinuation
12%12%22%22%Withdrawal of ConsentWithdrawal of Consent
21%21%24%24%Discontinuation due to adverse eventDiscontinuation due to adverse event
12%12%29%29%Febrile NeutropeniaFebrile Neutropenia
57%57%82%82%Grade 3/4 NeutropeniaGrade 3/4 Neutropenia
CFCFDCFDCF
Phase II Study of Taxotere, Cisplatin, CPT-11 (TPC) in Metastatic Esophagogastric Adenocarcinoma
Taxotere 30 mg/mTaxotere 30 mg/m22
Cisplatin 25 mg/mCisplatin 25 mg/m22
CPT-11 50 mg/mCPT-11 50 mg/m22
weekly x 2 then one week restweekly x 2 then one week rest
56 patients56 patients Response rate = 54%Response rate = 54% Median progression-free survival = 7.1 monthsMedian progression-free survival = 7.1 months Median overall survival = 12 monthsMedian overall survival = 12 months
Grade 3/4 neutropenia = 21%Grade 3/4 neutropenia = 21%
Enzinger et al. Ann Oncol. 2009
Do you use any of the following “biologic” therapies in advanced gastric cancer study?
A. Bevacizumab
B. Cetuximab
C. Panitumumab
D. Erlotinib
E. Sunitinib
F. Sorafenib
G. None
Phase II Study of Irinotecan, Cisplatin, Bevacizumab in Metastatic Gastroesophageal Adenocarcinoma
Shah et al. J Clin Oncol. 2006
Irinotecan 65mg/m2 d1,8Irinotecan 65mg/m2 d1,8
Cisplatin 30mg/m2 d1,8Cisplatin 30mg/m2 d1,8
Bevacizumab 15mg/kg d1Bevacizumab 15mg/kg d1
47 patients47 patients
RR = 65%RR = 65%
Median TTP = 8.3 mosMedian TTP = 8.3 mos
Median OS = 12.3 mosMedian OS = 12.3 mos
Grade 3/4 HTN = 28%Grade 3/4 HTN = 28%
Two patients had gastric perforationTwo patients had gastric perforation
One patient had significant UGI bleedOne patient had significant UGI bleed
Q 21 daysQ 21 days
Phase II Study of mDCF and Bevacizumab in Metastatic Gastroesophageal Adenocarcinoma
Jhawer et al. GI ASCO 2009
Docetaxel 40 mg/m2 d1Docetaxel 40 mg/m2 d1
5-FU 400 mg/m25-FU 400 mg/m2
5-FU 1000 mg/m2/d d 1,25-FU 1000 mg/m2/d d 1,2
Bevacizumab 15mg/kg d1Bevacizumab 15mg/kg d1
Cisplatin 40 mg/m2 d3Cisplatin 40 mg/m2 d3
44 patients44 patients
RR = 67%RR = 67%
Median TTP = 12 mosMedian TTP = 12 mos
Median OS = 16 mosMedian OS = 16 mos
grade 3/4 neutropenia 51% vs. 82%grade 3/4 neutropenia 51% vs. 82%
Q 14 daysQ 14 days
Taxotere, Cisplatin, CPT-11, Bevacizumab (TPCA) in Metastatic Esophagogastric Adenocarcinoma
Taxotere 30 mg/mTaxotere 30 mg/m2 2 d1, 8 d1, 8Cisplatin 25 mg/mCisplatin 25 mg/m2 2 d1, 8 d1, 8CPT-11 50 mg/mCPT-11 50 mg/m2 2 d1, 8 d1, 8Bevacizumab 10 mg/kg d1Bevacizumab 10 mg/kg d1
q 3 weeksq 3 weeks
33 patients33 patients Response rate = 63%Response rate = 63%
Enzinger et al. GI ASCO 2008
Weekly Docetaxel and Bevacizumab (AvaTax) in Previously Treated Metastatic Esophagogastric Cancer
Enzinger et al.
Docetaxel 35mg/m2 d1, 8, 15Docetaxel 35mg/m2 d1, 8, 15
Bevacizumab 5mg/kg d1, 15Bevacizumab 5mg/kg d1, 15
40 pts – previously treated40 pts – previously treated
RR = 20%RR = 20%
Median PFS = 3.5 mos.Median PFS = 3.5 mos.
Median OS = 9.3 mos.Median OS = 9.3 mos.
Grade 3/4 bleeding = 18%Grade 3/4 bleeding = 18%
One patient (2.5%) had gastric perforationOne patient (2.5%) had gastric perforation
Q 28 daysQ 28 days
Bezacizumab in First-Line Advanced Gastric Cancer (AVAGAST)
RR
AA
NN
DD
OO
MM
II
ZZ
EE
CapecitabineCapecitabine
CisplatinCisplatin
PlaceboPlacebo
CapecitabineCapecitabine
CisplatinCisplatin
BevacizumabBevacizumab
760 patients with previously untreated disease:760 patients with previously untreated disease:
Primary Endpoint: Primary Endpoint: Overall Overall SurvivalSurvival
Phase III Study of IMC-1121B in Second-Line Gastric Cancer
RR
AA
NN
DD
OO
MM
II
ZZ
EE
IMC-1121BIMC-1121B
PlaceboPlacebo
615 patients who failed FU or CDDP-based therapy615 patients who failed FU or CDDP-based therapy
Primary Endpoint: Primary Endpoint: Overall Overall SurvivalSurvival
Phase II Study of Erlotinib in Gastroesophageal Adenocarcinoma SWOG 0127
Dragovich et al. J Clin Oncol. 2006
GE jxn (N=43)GE jxn (N=43) Gastric (N=25)Gastric (N=25)
Response RateResponse Rate 9%9% 0%0%
Median TTFMedian TTF 2 mos.2 mos. 1.6 mos.1.6 mos.
Median OSMedian OS 6.7 mos.6.7 mos. 3.5 mos.3.5 mos.
68 pts with previously untreated disease:68 pts with previously untreated disease:
Phase II Study of FOLFIRI-Cetuximab in Advanced Gastroesophageal Adenocarcinoma
Pinto et al. Ann Onc 2007
38 patients38 patients OR = 44%OR = 44% Median TTP = 8 mos.Median TTP = 8 mos. Median expected OS = 16 mos.Median expected OS = 16 mos.
Grade 3/4 neutropenia = 42%Grade 3/4 neutropenia = 42% Grade 3/4 diarrhea = 8%Grade 3/4 diarrhea = 8%
Cetuximab in Advanced Gastroesophageal Adenocarcinoma: EXPAND Trial
RR
AA
NN
DD
OO
MM
II
ZZ
EE
CapecitabineCapecitabine
CisplatinCisplatin
CapecitabineCapecitabine
CisplatinCisplatin
CetuximabCetuximab
870 patients with previously untreated disease:870 patients with previously untreated disease:
Primary Endpoint: Primary Endpoint: Progression-Free Progression-Free SurvivalSurvival
Trastuzumab in Gastric Cancer
RR
AA
NN
DD
OO
MM
II
ZZ
EE
CapecitabineCapecitabine
CisplatinCisplatin
CapecitabineCapecitabine
CisplatinCisplatin
TrastuzumabTrastuzumab
584 patients with HER-2 positive, previously untreated 584 patients with HER-2 positive, previously untreated advanced gastric cancer:advanced gastric cancer:
Primary endpoint:Primary endpoint:
Overall SurvivalOverall Survival
Paclitaxel vs. Placlitaxel/Lapatinib in Second-line ErbB2 Amplified Gastric Cancer
RR
AA
NN
DD
OO
MM
II
ZZ
EE
Weekly PaclitaxelWeekly Paclitaxel
Weekly PaclitaxelWeekly Paclitaxel
++
LapatinibLapatinib
314 patients following first-line therapy:314 patients following first-line therapy:
Primary endpoint:Primary endpoint:
Overall SurvivalOverall Survival
c-Met Pathway in Human Cancer
MET Amplification as a Predictor of Drug Sensitivity in Gastric and Esophageal Adenocarcinoma
Smollen et al PNAS, 2006
CASE56 yo man presents with new resectable distal gastric
adenocarcinoma. CT scan demonstrates gastric wall thickening without metastatic disease.
You recommend:
A. Surgery alone
B. Pre-operative ECF (ECX, EOX)
C. Pre-operative 5-FU/CDDP
D. Surgery followed chemotherapy
E. Surgery followed by 5-FU-based chemotherapy plus external beam radiotherapy
Adjuvant Therapy for Gastric Cancer: Meta-analysis
Earle, 1999
Adjuvant S-1 in Stage II/III Gastric CancerSakuvamoto et al, NEJM 2007
RR
AA
NN
DD
OO
MM
II
ZZ
EE
S-1 80 mg/m2 qd x 4 weeks followed S-1 80 mg/m2 qd x 4 weeks followed by 2 week rest x 1 yearby 2 week rest x 1 year
observationobservation
1,059 patients following resection of stage II/III gastric cancer1,059 patients following resection of stage II/III gastric cancer
Adjuvant S-1 in Gastric CancerSakuvamoto et al.
3-year3-year
Relapse-free SurvivalRelapse-free Survival
3-year3-year
Overall SurvivalOverall Survival
S-1S-1 72%72% 80%80%
ObservationObservation 60%60% 70%70%
P-valueP-value <0.001<0.001 0.0030.003
Hazard Ratio (95% CI)Hazard Ratio (95% CI) 0.62 (0.50-0.77)0.62 (0.50-0.77) 0.68 (0.52-0.87)0.68 (0.52-0.87)
Adjuvant Radiotherapy in Resectable Gastric Cancer
Hallissey et al, 1994
LocoregionalLocoregionalRelapse (%)Relapse (%)
5-Year5-YearSurvivalSurvival
ObservationObservation 57%57% 20%20%
Radiation (45 Radiation (45 Gy)Gy) 34%34% 12%12%
FAM chemotherapyFAM chemotherapy 41%41% 19%19%
436 patients following gastrectomy randomized to:436 patients following gastrectomy randomized to:
Intergroup 0116
RESECTEDRESECTED
STAGE IB-IV (MO)STAGE IB-IV (MO)
GASTRICGASTRIC
ADENOCARCINOMAADENOCARCINOMA
RR
AA
NN
DD
OO
MM
OBSERVATIONOBSERVATION
5-FU/LV 5-FU/LV5-FU/LV 5-FU/LV
5-FU/LV RADIATION 5-FU/LV x25-FU/LV RADIATION 5-FU/LV x2
4,500 cGy4,500 cGy
3-Year RFS (%)3-Year RFS (%)
Surgery aloneSurgery alone 3030
Post-op 5-FU/RTPost-op 5-FU/RT 4848
P<0.0001P<0.0001
•54% improvement in relapse-free survival54% improvement in relapse-free survival
3-Year OS (%)3-Year OS (%)
Surgery aloneSurgery alone 4040
Post-op 5-FU/RTPost-op 5-FU/RT 5050
P=0.01P=0.01
32% improvement in overall survival32% improvement in overall survival
Intergroup 0116
ObservationObservation TreatmentTreatment
LocalLocal 5151 2121
RegionalRegional 126126 7676
DistantDistant 3232 3636
Sites of RecurrenceSites of Recurrence
Conclusions from Intergroup 0116
Post-op. chemo-RT is a potential standard in Post-op. chemo-RT is a potential standard in therapy of resectable gastric cancer.therapy of resectable gastric cancer.
Toxicity of post-op. chemo-RT is acceptable.Toxicity of post-op. chemo-RT is acceptable.
Post-op. chemo-RT improved locoregional Post-op. chemo-RT improved locoregional recurrence > distant recurrence.recurrence > distant recurrence.
Pre -RT Chemo
(1 cycle) Chemo with RT
(45 Gy)Post --RT Chemo
(2 cycles)
EpirubicinEpirubicin 50 mg/m50 mg/m22 d1 d1
A Pilot Study of Adjuvant Chemoradiation After Resection of Gastric or Gastroesophageal Adenocarcinoma
CisplatinCisplatin 60 mg/m60 mg/m22 d1 d1
5-FU5-FU 200 mg/m200 mg/m22
d1-21d1-21
5-FU5-FU 200 mg/m200 mg/m22
d1-21d1-21
EpirubicinEpirubicin 40 mg/m40 mg/m22 d1 d1
CisplatinCisplatin 50 mg/m50 mg/m22 d1 d1
5-FU5-FU 200 mg/m200 mg/m22
d1-21d1-21
Randomized Trial of Adjuvant Chemoradiation After Resection of Gastric Adenocarcinoma
RR
AA
NN
DD
OO
MM
II
ZZ
EE
5-FU5-FU 5-FU IVCI5-FU IVCI 5-FU 5-FU
LeucovorinLeucovorin RTRT Leucovorin Leucovorin
X2X2
ECFECF 5-FU IVCI5-FU IVCI ECF ECF
RTRT X2 X2
540 eligible patients required to detect a 25% 540 eligible patients required to detect a 25%
improvement in overall survival improvement in overall survival
(alpha (alpha 0.05) 0.05)
CALGB 80101: Worst Grade Toxicity by Treatment Arm – Updated N =387
ToxicityToxicity
Arm AArm A
Mayo FU/LVMayo FU/LV
Arm BArm B
ECFECF
Grade 3 diarrheaGrade 3 diarrhea 16%16% 6%6%
Grade 3 nauseaGrade 3 nausea 17%17% 15%15%
Grade 3 emesisGrade 3 emesis 10%10% 11%11%
Grade 4 neutropeniaGrade 4 neutropenia 33%33% 17%17%
Any grade 4-5 eventAny grade 4-5 event 45%45% 23%23%
Magic Study: Perioperative ECFCunningham et al NEJM 2006
RRAANNDDOOMMIIZZEE
ECF X3ECF X3N = 250N = 250
N = 253N = 253
Resectable distal esophageal and gastric adenocarcinomaResectable distal esophageal and gastric adenocarcinoma
ECF X3ECF X3SurgerySurgery
SurgerySurgery
Recruitment: July 1994-April 2002Recruitment: July 1994-April 2002
MAGIC: Does Pre-op ECF Improve Resectability?
70% (166/70% (166/240240))
166166
240240
14 days14 days
Surgery aloneSurgery aloneN = 253N = 253
0.030.03
PP
66%
166/253
0.6468%R0 rate - intent to treat
169/250R0 resection - intent to treat
79% (169/79% (169/219219))R0 resection rateR0 resection rate
169169R0 resectionR0 resection
219219Proceeded to surgeryProceeded to surgery
99 days99 daysMedian time to surgeryMedian time to surgery
Pre-op ECFPre-op ECFN = 250N = 250
MAGIC: Progression-free survival*
Logrank p-value = 0.0001Hazard Ratio = 0.66 (95% CI 0.53 - 0.81)
Patients at risk
CSCS
250 159 99 68 46 32 23253 124 57 42 28 15 8
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from randomisation0 12 24 36 48 60 72
163 250
190 253
Events Total
CSC
S
Pro
gre
ssio
n-f
ree
Su
rviv
al r
ate
*Included relapse, PD and death from any cause.
MAGIC: Overall survival
Patients at risk
Logrank p-value = 0.009Hazard Ratio = 0.75 (95% CI 0.60 - 0.93)
CSCS
250 168 111 79 52 38 27253 155 80 50 31 18 9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from randomisation0 12 24 36 48 60 72
149 250
170 253
Events Total
CSC
S
Su
rviv
al r
ate
In operable gastric and lower oesophageal In operable gastric and lower oesophageal cancer, perioperative chemotherapy:cancer, perioperative chemotherapy:
• significantly improves progression-free significantly improves progression-free
survivalsurvival• significantly improves overall survivalsignificantly improves overall survival
MAGIC: Conclusions
Cunningham ASCO 2005
Randomized Trial of Adjuvant Chemoradiation After Resection of Gastric Adenocarcinoma
RR
AA
NN
DD
OO
MM
II
ZZ
EE
5-FU5-FU 5-FU IVCI5-FU IVCI 5-FU 5-FU
LeucovorinLeucovorin RTRT Leucovorin Leucovorin
X2X2
ECFECF 5-FU IVCI5-FU IVCI ECF ECF
RTRT X2 X2
540 eligible patients required to detect a 25% 540 eligible patients required to detect a 25%
improvement in overall survival improvement in overall survival
(alpha (alpha 0.05) 0.05)
Is Pre-op Therapy better than Post-op?
Is MAGIC better
than
INT-0116?
MAGIC v. 0116: Patient Characteristics
27%*27%* 43%43%≥ ≥ 4 pos. nodes4 pos. nodes
72%*72%* 85%85%Node positiveNode positive
28%*28%* 15%15%Node negativeNode negative
64%*64%* 68%68%T3/T4T3/T4
503503 554554No. of Pts.No. of Pts.
MAGICMAGIC INT 0116INT 0116
*Surgery alone arm*Surgery alone arm
Baseline pathologic characteristics:Baseline pathologic characteristics:
MAGIC v. 0116: Two-Year Survival
Surgery Surgery AloneAlone
ChemoradsChemorads
Or ChemoOr Chemo
MAGICMAGIC 40%40% 48%48%
01160116 52%52% 58%58%
Absolutely not:Absolutely not:
Due to differences in patient selection and study Due to differences in patient selection and study design:design:
Any cross-trial comparison is Any cross-trial comparison is flawedflawed and and essentially essentially uninterpretableuninterpretable
MAGICMAGICPatients with presumedPatients with presumed
resectable cancerresectable cancer
INT 0116INT 0116Patients with Patients with
R0-resected cancerR0-resected cancer
CALGB 80101: Adjuvant Chemoradiation After Resection of Gastric or Gastroesophageal
Adenocarcinoma
RR
AA
NN
DD
OO
MM
II
ZZ
EE
5-FU5-FU 5-FU IVCI5-FU IVCI 5-FU 5-FU
LeucovorinLeucovorin RTRT Leucovorin Leucovorin
X2X2
ECFECF 5-FU IVCI5-FU IVCI ECF ECF
RTRT X2 X2
540 eligible patients required to detect a 30% 540 eligible patients required to detect a 30%
improvement in overall survival improvement in overall survival
(alpha (alpha 0.05) 0.05)
MAGIC-B
RRAANNDDOOMMIIZZAATTIIOONN
Operable Operable gastricgastricororGEJXNGEJXNAdenocarcinomaAdenocarcinoma
ECX ECX X 3X 3
ECXECXbevacizumab bevacizumab X 3X 3
ECX ECX X 3X 3
ECX-BECX-BX 3X 3
SurgerySurgery
SurgerySurgery
Accrual: 1,100 patientsAccrual: 1,100 patients
CRITICS STUDY
RRAANNDDOOMMIIZZAATTIIOONN
788 patients788 patientswithwithoperable operable gastricgastriccancercancer
ECX ECX X 3X 3
ECX ECX X 3X 3
ECX ECX X 3X 3
RTRT45Gy/25 fx45Gy/25 fxCapecitabineCapecitabineCisplatinCisplatin
SurgerySurgery
SurgerySurgery
ONGOING AND FUTURE QUESTIONS
Does ECF improve the efficacy of post-op chemorads?Does ECF improve the efficacy of post-op chemorads?
What is the role of radiotherapy?What is the role of radiotherapy?
Neoadjuvant vs. post-operative therapy?Neoadjuvant vs. post-operative therapy?
Is ECF the optimal chemotherapy regimen?Is ECF the optimal chemotherapy regimen?
Role of biologics in adjuvant therapy?Role of biologics in adjuvant therapy?
Can we improve accrual to our trials?Can we improve accrual to our trials?
Failed Pre- and Postoperative Trials in Gastroesophageal Cancer
No. of pts. No. of pts. accruedaccrued
No. of pts. No. of pts. expectedexpectedTrialTrial
5454620620INTINT 9%9%
5959450450Dutch NeoadjuvantDutch Neoadjuvant 13%13%
278278400400FFCD 8801FFCD 8801 70%70%
206206760760EORTCEORTC 27%27%
191191480480ICCGICCG 40%40%
Percent Percent enrolledenrolled
7882,710Total 29%