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

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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

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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

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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

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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%