Upper Gastrointestinal Overview 2007-2008: Practical Implications of the Newest Data

Esophageal and Gastric Cancers

Johanna Bendell, MDSarah Cannon Research Institute

Conflict of Interest Disclosure• Consultant or Advisory Role

– Amgen – Array Pharmaceuticals – Genentech – Roche

• Honoraria– Amgen– Roche– Genentech– Array Pharmaceuticals

• Research Funding– Bristol-Myers Squibb – Genentech – Roche – Sanofi-Aventis– Novartis

Esophageal Cancer• 16,470 new cases estimated for 2008

– 14,280 estimated deaths

• Adenocarcinoma incidence rate increasing by 20% per year in U.S– EtOH, tobacco, obesity, genetics, diet– Barrett’s esophagus– Older trials have more patients with SCC– Adenocarcinomas predominate most trials now– Is there a difference?

• GE junctional cancers– Increase in distal esophageal and proximal gastric

cancers– Is there a difference?

Localized disease

• Controversy– Surgery alone– Preoperative chemotherapy– Preoperative chemoradiation therapy– Chemoradiation therapy alone

Preoperative chemotherapyStudy #

Patients

Pathology Chemotherapy Tumor Location

5-year survival

MRC OEO-2, 2002

Chemo: 400

Surgery: 402

SCC, Adeno

Cisplatin/5-FU Stomach10%Distal eso65%

Chemo: 23% Surgery: 17%P = 0.03

Cunningham et al, 2006

Chemo: 250

Surgery: 253

Adeno ECF Stomach 74%

GE jn12%Distal eso14%

Chemo: 36.3% Surgery:

23.0% P = 0.001

Kelsen et al, 2007

Chemo: 233

Surgery: 234

SCC, Adeno Cisplatin/5-FU Esophagus Chemo: 26% Surgery: 23%3 yearP = 0.53

FP FP (*)(*) x 2/3 every 28 days x 2/3 every 28 days

ResectionResection

Within 4 weeksWithin 4 weeks4 - 6 weeks4 - 6 weeks

ResectionResection

4 – 6 weeks4 – 6 weeks

FP x 3/4 or no treatmentFP x 3/4 or no treatmentFollow-upFollow-up

RandomizatioRandomizationn

CT + CT + SS

SS

ACCORD 07-FFCD 9703

(*) FP = 5FU: 800 mg/m² CI x 5 days - CDDP: 100 mg/m² at d1 or d2, 1-hr infusion Boige, ASCO 2007

CT + SCT + SN = 113N = 113

Preop CT (2-3 Preop CT (2-3 cycles)cycles)

N = 98 N = 98 (89%)(89%)

SurgerySurgeryN = 109 N = 109 (96%)(96%)

Postop CT (1-4 Postop CT (1-4 cycles)cycles)

N = 54 N = 54 (51%)(51%)

SSN = 111N = 111

SurgerySurgeryN = 110 N = 110 (99%)(99%)

Trial profile

Boige, ASCO 2007

Disease-free survival

5-year DFS: 21% (14-30%) vs 34% (26-44%)

Disease-free survivalusing landmark methods

681113141921242829354257111

14161717253134384448536277113

0.00

0.20

0.40

0.60

0.80

1.00

0 12 24 36 48 60 72Months

Surgery

Chemotherapy + Surgery

At risk

logrank : p = 0.0033

0-0.5 1 2 3 4 5 6 7

111 57 35 28 21 14 11 6 113 77 53 44 34 25 17 14

yearsyears

At riskAt risk

___ S___ CT + S

Logrank p value = 0.0033Logrank p value = 0.0033Hazard Ratio = 0.65 Hazard Ratio = 0.65 (95% CI 0.48-0.89)(95% CI 0.48-0.89)

Boige, ASCO 2007

713162738537911114172741536593113

0,00

0,20

0,40

0,60

0,80

1,00

0 1 2 3 4 5 6 7

A risque

logrank : p = 0,021

___ S___ CT + S

yearsyears

Overall survival

At riskAt risk

5-year OS: 24% (16-33%) vs 38% (28-47%)

Logrank p value = 0.021Hazard Ratio = 0.69 (95% CI 0.50-0.95)

Boige, ASCO 2007

ACCORD07-FFCD 9703

• Preoperative chemotherapy• 14% improvement in 5 year OS

– Similar to MAGIC (13%)– MRC Preop ECF vs. CF

• Decrease in systemic recurrence– Local recurrence 26% (S) vs. 24% (CT+S)– Systemic recurrence 56% (S) vs. 42%

(CT+S)

Preoperative ChemoradiationStudy # Patients Patholo

gyChemotherapy Radiatio

n (Gy)3-yearsurvival

Walsh et al, 1996

Trimodality: 58

Surgery: 55

Adeno Cisplatin/5-FU 40 Tri: 32% Surgery: 6%P = 0.01

Bosset et al (EORTC),

1997

Trimodality: 143

Surgery: 139

SCC Cisplatin 37 Tri: 37% Surgery:

35%P = NS

Urba et al, 2001

Trimodality: 50

Surgery: 50

SCC,Adeno

Cisplatin/5-FU/vinblastine

45 Tri: 30% Surgery:

16%P = 0.15

Burmeister et al, 2005

Trimodality: 128

Surgery: 128

SCC, Adeno

Cisplatin/5-FU 35 Tri: 33% Surgery:

30%P = 0.57

Tepper et al (CALGB), 2006

Trimodality: 30

Surgery: 26

SCC,Adeno

Cisplatin/5-FU 50.4 Tri: 39%Surgery:

16%5 yearP < 0.008

POET TrialArm 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. Leucovorin/5-FU 500mg/m2 2h / 2g/m2 24h, d 1,8,15,22,29,36PE: 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, ASCO 2007

Overall Survival

Logrank Logrank p = 0.07p = 0.07HR Arm B vs. AHR Arm B vs. A0.67 (0.41-1.07)0.67 (0.41-1.07)

Arm B

Arm A

Follow-up 45.6 mo

47.4%

27.7%

Stahl, ASCO 2007

Freedom from Local Tumor Progression

Logrank Logrank p = 0.06p = 0.06HR Arm B vs. AHR Arm B vs. A0.45 (0.19 -1.05)0.45 (0.19 -1.05)

76.5%

59.0%

Arm B

Arm A

Stahl, ASCO 2007

Neoadjuvant vs. adjuvant approach• Roth, et al. World GI 2007• Randomized 70 patients with locally

advanced gastric cancer to 4 cycles of preoperative or adjuvant DCF

• Original plan to randomize 252 patients– Closed early due to poor accrual

TCF => STCF => SN = 34N = 34

Preop CT (4 Preop CT (4 cycles)cycles)

Started N=33 Started N=33 (97%)(97%)

Completed N= Completed N= 25 (74%)25 (74%)SurgerySurgery

N = 32 (94%)N = 32 (94%)Postop CT (4 Postop CT (4

cycles)cycles)Started N = 23 Started N = 23

(66%)(66%)Completed N = Completed N =

12 (34%)12 (34%)

S =>TCF S =>TCF N = 35N = 35

SurgerySurgeryN = 35 (100%)N = 35 (100%)

SAKK Neoadjuvant vs. Adjuvant Trial

pCR in 4 patients (12.9%)pCR in 4 patients (12.9%)

Roth, World GI 2007

What do we see in local treatment of esophageal cancer?• Many of these trials are mixed populations

– Adeno, SCC– Esophageal, GE junction, gastric cancers –

accrual issues• Surgery alone is not enough• Preoperative chemotherapy improves survival for

patients (now 3/4 trials, 1 meta-analysis)• Preoperative chemoradiation therapy likely better

than surgery alone, and maybe better than chemotherapy alone– Chemoradiation more toxic– True for squamous and adenos– Subgroup of patients who do not need surgery?

What do we do now?• CRITICS Trial

– Preoperative ECX, rand postop chemoradation or chemo alone

• Korean Trial– Preoperative cisplatin/capecitabine, then randomization to

chemoradiation or chemo alone• CALGB 80101

– Postoperative chemoradiation with 5-FU or ECF• MRC OEO5

– Preoperative ECF vs. CF• MAGIC 2

– Preoperative ECX with or without bevacizumab• RTOG 0436

– Preoperative chemoradiation with or without cetuximab• CALGB 80302

– PET as prognostic indicator

Metastatic Gastric Cancer

• Gastric cancer– 21,500 new cases expected in the U.S. in

2008, 10, 880 deaths

• Unclear as to what is best metastatic regimen– ECF, DCF, IC, EOX?– Role of oral fluoropyrimidines

• Is combination therapy better than sequential?

S-1• Oral fluoropyrimidine consisting of tegafur,

CDHP, and OXO in a 1:0.4:1 molar ratio– tegafur is converted to 5-FU– CDHP (chloro-2.4-dihydroxypyridine) inhibits

DPD, preventing 5-FU degradation– OXO (potassium oxonate) protects against drug

induced diarrhea caused by phosphorylation of 5-FU by inhibiting the responsible enzyme – OPRT (oronate phosphoribosyl transferase)

S-1 40 mg/m2, po, bid, days 1-28q 6 weeks

5-FU CI

CPT-11 + CDDP

S-1

Randomization

800 mg/m2/day, ci, days 1-5q 4 weeks

CPT-11 70 mg/m2, div, days 1&15CDDP 80 mg/m2, div, day 1q 4 weeks

Phase III Study (JCOG9912)Phase III Study (JCOG9912)

Continued until disease progression, unacceptable toxicities, patient’s refusal

BSA < 1.25 80 mg/body/day 1.25 < BSA < 1.5 100

mg/body/day 1.5 < BSA 120

mg/body/day

Boku, ASCO 2007

Progression-free Survival and Response rateProgression-free Survival and Response rate

Response rate

- in pts with target lesion -

5-FU CI

CPT-11

+CDDP S-1

CR+PR 15 68 49

n 175 181 175

RR 9% 38% 28%

CR and PR were confirmedby central review

0.0010.62-0.900.754.2M234

<0.001

-

0.57-0.83

-

95%C.I.

-2.9M234

0.694.8M236

HRMedian n P-value† 　

12 24 (months)

0

50

(%)100

†: one-sided log-rank test (superiority)

S-1

5-FU CI

CPT-11+CDDP

PFS

Boku, ASCO 2007

12 24 36 (months)0

50

(%)100

Overall SurvivalOverall Survival

P-value 　

0.034†

0.055†

-

0.68-1.01

0.70-1.04

-

95%C.I.

-44.0%10.8M2345-FU CI

0.8347.9%11.4M234S-1

0.8552.5%12.3M236CPT-11+CDDP

HR1-yrMSTn

†: one-sided log-rank test (superiority)non-inferiority <0.001

‡: multiplicity adjusted by Holm’s method

Significancelevel‡

0.05

0.0250.025

Boku,ASCO2007

JCOG 9912

• S-1 is non-inferior to CI 5-FU• Cisplatin/irinotecan better than CI 5-

FU• Cisplatin/irinotecan (this regimen)

more toxic• S-1 results approximate combination

therapy

SPIRITS TrialSPIRITS Trial

AGCAGC

No priorNo priorChemo.Chemo.

RR

S-1 aloneS-1 aloneS-1: 40-60 mg BID for 28 days q6wksS-1: 40-60 mg BID for 28 days q6wks

S-1 + CDDPS-1 + CDDPS-1: 40-60 mg BID for 21 days q5wksS-1: 40-60 mg BID for 21 days q5wks

CDDP: 60 mg/mCDDP: 60 mg/m22 iv on day 8 iv on day 8

Central RandomizationCentral Randomization (dynamic balancing)(dynamic balancing)Adjustment Factors:Adjustment Factors: InstituteInstitute PSPS Unresectable vs RecurrentUnresectable vs Recurrent

Narahara, ASCO 2007

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54

MonthsMonths

Esti

mate

d p

rob

ab

ilit

y

Esti

mate

d p

rob

ab

ilit

y

(%)

(%)

11.011.0 13.013.0

Overall SurvivalOverall Survival

S-1S-

1+CDDP

No. of pts 150 148MST 11.0 13.0

1 yr survival46.7

%54.1 %

2 yr survival15.3

%23.6 %

Log-rank p-value:Log-rank p-value: 0.0366 0.0366HR: HR: 0.774 0.774 [ 95% CI: 0.608 – 0.985][ 95% CI: 0.608 – 0.985]Median follow-up time (M): Median follow-up time (M): 34.634.6

Narahara, ASCO 2007

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54

Progression-Free SurvivalProgression-Free Survival

Log-rank p-value: Log-rank p-value: <0.0001<0.0001HR:HR: 0.5670.567 [ 95% CI: 0.437 – 0.734] [ 95% CI: 0.437 – 0.734]

Esti

mate

d p

rob

ab

ilit

y

Esti

mate

d p

rob

ab

ilit

y

(%)

(%)

MonthsMonths

6.06.04.04.0

S-1 S-1+CDDP

No. of pts 150 148PFS 4.0 6.0

Narahara, ASCO 2007

Overall ResponseOverall Response

No. Response

Overall RR CR PR SD PD NE

S-1 106 1 32 34 34 5 31 %S-1+CDDP

87 1 46 13 24 3 54 %

Criteria : RECIST (Extramural Review)Criteria : RECIST (Extramural Review)

Fisher’s Exact Test p-value: Fisher’s Exact Test p-value: 0.00180.0018

Narahara, ASCO 2007

IRIS GC0301/TOP-002

• Randomized phase III study• 326 patients randomized• S-1 alone vs. S-1 plus irinotecan• Response rate

– 26.9% vs. 41.5%

• 1-year survival– 44.9% vs. 52.0%, NS

• 22% of patients were censored

Imamura, GI ASCO 2008

Metastatic Gastric Cancer• We still don’t know the optimal regimen for

patients with metastatic disease– Combination vs. sequential therapy– Role of oral fluoropyrimidines, newer platinum agents,

taxanes

• More S-1 studies are forthcoming– FLAGS - 1053 pts, accrual completed 3/07– 5-FU/cis vs. S-1/cis

• Trials of biologics are underway– AVAGAST – capecitabine/cisplatin with or without

bevacizumab– CALGB 80403 – FOLFOX-cetuximab, cisplatin/irinotecan-

cetuximab, ECF-cetuximab– ToGA – capecitabine/cisplatin with or without

trastuzumab