Upper GI Cancers: Risk Stratification and Treatment Selection

David H. Ilson, MD, PhDGastrointestinal Oncology ServiceMemorial Sloan-Kettering Cancer Center

Disclosure

Research Funding

– Roche-Genentech

– Bayer

– sanofi-aventis

– BMS-Imclone

UGI Cancers, Risk Stratification and Therapy

Staging of Gastric and Esophageal Cancer for treatment selection

Benefits of adjuvant chemotherapy and radiation therapy

Appropriate selection of chemotherapy for Stage IV disease

Pancreatic Cancer adjuvant and advanced disease therapy

Esophageal and Gastric CarcinomaUS Incidence in 2011

38,500 new cases

Decline in Gastric Cancer Incidence

Increase in Esophageal , GE JX, cardia adeno

OS improvement, 1975-77, 1984-86, 1999-2006

– Gastric: 16% 18% 27%

– Esophageal: 5% 10% 19%

Highly virulent diseases with poor outcome

Jemal et al, CA 61: 212-236; 2011

New AJCC Staging: Survival in over 13,000 pts with gastric cancer, SEER database

McGhan J Gastro Surg 16: 53; 2012

Gastric Cancer Preop therapy:T3 or N+T1A: EMRT1B, T2: Primary resection

New AJCC Staging: Survival in over 4600 pts with esophageal and GEJ cancer

Rice Cancer 2010

Esophagus, GEJ Preop therapy:T2-3 or N+T1A: EMRT1B: Primary resection

PET SCAN:Staging (15% occult mets), and Determine Response to

Preop Chemo

SUV = 10.6 SUV = 2.2

Laparoscopy in Gastric Cancer

CT and PET scan may miss small volume liver or peritoneal disease

For gastric cancer, laparoscopy detects peritoneal or liver disease in 20-30% of patients

– Not mandated for GEJ cancers: < 5% positive lap findings

A positive cytology = Stage IV disease

– Patients do not benefit from immediate gastrectomy

– They should be treated with palliative chemotherapy

– ? Reassess response and consider selective surgery

No long term survivors with + cytology

Adjuvant Therapy in Gastric Cancer Improves OS Pre and post op chemo (U.K.)

– ECF, MAGIC:

13% 5 yr OS, HR 0.75

Post op chemo (Asia): 2 trials, 2000 pts, D2 resection

– S-1, ACTS-GC:

13% 5 yr OS, HR 0.67 (2011 update)

– Post op Cape-Oxali , CLASSIC Trial:

14% 3 yr DFS, HR 0.56

Post op RT + chemo (U.S.), less than a D1-2 resection

– 5FU-LV + RT, INT 116:

10% 5 yr OS, HR 0.65

Cunningham NEJM 355: 11; 2006 Sasako JCO 29: 4387; 2011 Bang LBA 4002, Proc ASCO 2011 Macdonald NEJM 345:725; 2001

Optimal Surgery for Gastric Cancer? D2 resection is the standard of care in Asia

Increasingly in the West D2 resection is considered the standard

Update of Dutch D1 vs D2 resection at 15 years supports D2:

Songun I et al Lancet Oncol 11: 439; 2010

Optimal Adjuvant Chemotherapy? Support of 5-FU monotherapy

– ACTS-GC: S-1

– CALGB 80101:

ECF no better than 5-FU/LV, when given post op with FU + RT

Support for 5-FU + platinum agent

– CLASSIC: Capecitabine-Oxaliplatin

– FNCLCC-FFCD and MAGIC: CF and ECF

Fuchs Abs 4003, Proc ASCO 2011 Bang LBA 4002, Proc ASCO 2011 Ychou J Clin Oncol 29: 1715; 2011

Surgically (D2) resected Stage II, IIIA, or IIIB GC, 6 weeks prior to randomization

No prior chemotherapy or

radiotherapy

n=1035

Capecitabine: 1,000mg/m2 bid, d1–14, q3wOxaliplatin: 130mg/m2, d1, q3w

RANDO MIZATION

1:1†

n=520

n=515

• Primary endpoint: 3-year DFS‡

• Secondary endpoints: overall survival and safety profile

†Stratified by stage and country with age, sex, and nodal status as covariates‡GASTRIC project: 3-year DFS and 5-year overall survival are strongly associated, Burzykowski et al. ASCO 2009

CLASSIC study design

8 cycles of XELOX (6 months)

Observation: No adjuvant therapy

Primary endpoint (3-year DFS) met at interim analysis

ITT population; DFS = disease-free survivalMedian follow-up 34.4 months (range 16–51)

1.0

0.0

0.2

0.4

0.6

0.8

3-year DFS

74%

60%

HR=0.56 (95% CI 0.44–0.72)P<0.0001

Time (months)

Observation, n=515

XELOX, n=520

520 410 333 246 166 74 30 10443515 352 286 209 147 58 22 6414

XELOXObservation

No. left

0 6 12 18 24 30 36 42 48

Regional Therapies as Adjuvant?

Role of post op RT

– U.S. INT 116: < D1-2 resection, RT reduced local recurrence

– ARTIST (Korea, JCO in press), D2 resection

Cape-Cis vs Cape-Cis + RT

DFS benefit in node + patients for adding RT

5% improvement in 3 year DFS, HR 0.69

Ongoing Trials

– CRITICS:

Preop ECX, post op ECX + / - RT

– TOPGEAR:

Preop ECX + / - RT

Esophageal Adenocarcinoma: Adjuvant Therapy Improves OS

T2-3 or N1: Something more than surgery alone should be done

Preoperative chemotherapy ECF, CF improves overall survival in some but not all trials

– MAGIC (ECF): 13% ↑ OS at 5 yr (75% gastric, 25% esophageal)

– FFCD / FNLC (CF): 14% ↑ OS at 5 yr (gastric and esophageal cancer) same as MAGIC, no epirubicin

– MRC 0E0-2 (CF): Esophageal

5 year update: 6%, no impact on distant recurrence

– U.S. INT 113 (CF): no impact on OS

– EORTC 40954 (CF): no impact on OSMRC Lancet 359: 1727; 2002 Cunningham NEJM 355: 11; 2006 Schumacher JCO 28: 5210; 2010

Meta Analysis of Preop Chemo: Overall Survival (Thirion, ASCO 2007)

Patients at risk

Control 1054 321 144 74 38 20Chemo pre-op 1047 361 153 90 52 31

Su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

Time (years)

0 2 4 6 8 10

Absolute benefit at 5 years:4.3 %

Patients at risk

Control 1054 321 144 74 38 20Chemo pre-op 1047 361 153 90 52 31

Su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

Time (years)

0 2 4 6 8 10

Absolute benefit at 5 years:4.3 %

Squamous: 4% Adeno: 7%

CROSS Active Treatment Arm

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)

Major eligibility: Adeno- or squamous histology; N1 or >T2, PS < 2

Primary objective: Median overall survival 22 months (versus 16)

2020

CROSS: Major Results• EUS staged patients

• T3N0-1 75%, median age 60

• 74% Adenocarcinoma

• 93% received all courses chemotherapy

– 23% had > = grade 3 toxicity from pre-op therapy

• Post-operative morbidity and mortality almost identical (mortality 3.7-3.8%)

• Path CR rate of nearly 30% with chemo RT

Resection rate and resection margins

Resection rate of all randomised patients

Surgery alone CRT + surgery

162/188 (86%) 157/175 (90%)

Resection margins

Surgery alone CRT + surgery

R0 110 (67%) 145 (92.3%) p<0.002

R1 52 (33%) 12 (7.6%)

R0 = no tumor within 1 mm of the resection margins

CROSS study21

HR 0.67 95% CI (.49 - .91) P=0.012

CROSS: Overall Survival

HR 0.67 95% CI (0.49 - 0.91)

CRTx

Surgery

Adapted van der Gaast

•1-year survival 82 versus 70%

•2-year survival 67 versus 52%

•3-year survival 59 versus 48%

•Median survival 49 versus 26 months, HR 0.67, p = 0.011)

•Squamous HR 0.24, Adeno HR 0.82

Preop Chemo vs ChemoRT

Preop Chemo vs Chemo RT: Stahl

Arm Pts R0 pCR N0 Median Survival

3 yr OS Local Control

Chemo 59 70% 2% 37% 21 mos 28% 59%

Chemo RT

60 72% 16% 64% 33 mos 47%P = 0.07

77%P = 0.06

Stahl J Clin Oncol: 27: 836; 2009

•EUS, laparoscopy staged pts•Siewert I-III, T3-4 adenocarcinoma

MUNICON-1 trial: PET scan response during Induction Chemo

AEGtype I-II

AEGtype I-II

CTx

ResectionResection

ResectionResection

Non-Responder

Responder

CTx: 3 monthsCTx: 3 monthsPET d0PET d0

PET d14PET d14

Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35% Weber et al. J Clin Oncol 2001;19:3058-65 Ott et al. J Clin Oncol 2006;24:4692-8

Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35% Weber et al. J Clin Oncol 2001;19:3058-65 Ott et al. J Clin Oncol 2006;24:4692-8

Comparison with historic cohort

Ott et al. J Clin Oncol 2006;24:4692-8CTx for 12 weeks in all patients

Survival (median)Responders: not reachedNon-Responders: 18 months

MUNICON-1 study; 2007 CTx stopped after 2wks in Non-Responders

Survival (median)Responders: not reachedNon-Responders: 26 months

PET-Responder

PET-Non-Responder

Su

rviv

al

Survival time [months]

PET Scan Directed Therapy Trial Design: CALGB / RTOG 80803

T3/4 or N1 Esophageal

Adenoca

PET/CT: Induction Chemo: modified FOLFOX6 days

1,15, 22 or Carbo/Taxol days

1,8,22,29

PET-responders: ≥ 35% SUV decrease: continue

same chemo + concurrent RT (5040cGy in 180cGy fx)

PET Scan day 29-35

Surgical resection 6 weeks post-RT

PET- nonresponders: < 35% SUV decrease:

Cross over to alternate chemo + RT (5040cGy in

180cGy fx)

Hypothesis: changing chemo in PET non responding patients will improve pCR

during chemo + RT

Best Supportive Care vs Chemotherapy

Wagner J Clin Oncol 24: 2903; 2006

Advanced Gastric Cancer Chemotherapy: What regimen to use?

Oxali:

EOX or EOF

Cape:

ECX or EOX

XP FLO FUFIRI S-1 Cis

DCF ECF

Pts 489 513 160 109 170 305 221 126

%RR 44% 45% 41% 34% 32% 54% 36% 45%

TTP, mos 6.7 6.5 5.6 5.5 5.0 6.0 5.6 7.4

OS, mos 10.9 10.4 10.5 -- 9.0 13.0 9.2 8.9

Patient Selection for Chemotherapy

Assess age, functional status, comorbidites

Combination chemotherapy preferred over single agents

– Monotherapy with 5-FU, capecitabine, taxanes in elderly, poor PS patients

3 drug regimens (DCF, mDCF)

– High functional status, younger patients without comorbidities

– Willingness to tolerate side effects

– Access to frequent follow up and toxicity assessment

CALGB 80403 / ECOG E1206: Comparison of ECF, FOLFOX, Irino/Cis

Stratification:ECOG 0-1 vs 2ADC vs. SCC

ARM A: (ECF + cetuximab); 1 cycle = 21 days

Cetuximab 400 250mg/m2 IV, weeklyEpirubicin 50 mg/m2 IV, day 1Cisplatin 60mg/m2 IV, day 1Fluorouracil 200mg/m2/day, days 1-21

ARM B: (IC + cetuximab); 1 cycle = 21 days

Cetuximab 400 250mg/m2 IV, weeklyCisplatin 30 mg/m2 IV, days 1 and 8Irinotecan 65 mg/m2 IV, days 1 and 8

ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days

Cetuximab 400 250mg/m2 IV, weeklyOxaliplatin 85 mg/m2 IV, day 1Leucovorin 400 mg/m2, day 1Fluorouracil 400 mg/m2 IV bolus, day 1Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

CALGB 80403/ECOG 1206: Response

ECF-C N=64

IC-C N=68

FOLFOX-C N=69

Response CR 0 1 ( 1%) 2 ( 3%)

PR 37 (58%) 30 (44%) 35 (51%)

SD 15 (23%) 23 (34%) 19 (28%)

PD 4 ( 6%) 10 (15%) 8 (12%)

Not eval / unknown 5 / 3 (8% /5%) 2 / 2 (3% /3%) 3 / 2 (4% /3%) Objective Response Rate*

(CR+PR)/total 57.8 45.6 53.6

(90% C.I.) 46.8 68.3 35.2 56.3 43.1 64.0

p vs. H0<0.25 <.0001 <.0001 <.0001 Response duration (mos) median 6.1 5.3 5.7

range 0.5 - 22.7 0.5 - 20.1 2.4 - 18.2

*RECIST - confirmed; restaging every 6 weeks

ECF-C IC-C FOLFOX-C Total N=67 N=71 N=72 N=210

Mos 95% c.i. Mos 95% c.i. Mos 95% c.i. Mos 95% c.i. OS median 11.5 (8.1,12.5) 8.9 (6.2,13.1) 12.4 (8.8,13.9) 11.0 (8.8,12.3) # dead 51 52 51 154 PFS median 5.9 (4.5,8.3) 5.0 (3.9,6.0) 6.7 (5.5,7.4) 5.8 (5.1,6.8) # dead/pd 57 64 63 184 TTF median 5.5 (3.9,7.2) 4.5 (3.6,5.6) 6.7 (4.8,7.2) 5.5 (4.5,5.9)

#dead/pd/ off forAE 58 66 64 188

CALGB 80403/ECOG 1206: Survival

CALGB 80403: Esophageal, GE Junction Cancers

Phase II trial of Chemo + Cetuximab

FOLFOX behaved as well as ECF with less toxicity

– Irinotecan and cisplatin had lowest efficacy and highest toxicity

Optimal irinotecan combination?

– Irinotecan + cisplatin; significant second line activity

– First Line: Irinotecan + infusional 5-FU preferred

Colorectal Style Chemotherapy and Gastric Cancer

Both FOLFOX and FOLFIRI like regimens have acceptable activity in gastric cancer

– Can be considered first line therapy

Toxicity profiles favor these regimens over conventional high dose cisplatin + 5 day infusion 5-FU

Molecular Targets: Gastric Cancer

KRAS mutation: < 5-10%

BRAF mutation: < 5%

EGFr IHC over expression: 50-80%

– EGFr mutation: < 5%

CMET amplification: < 10%

– IHC over expression 40%

HER2 over expression: 10-25%

– Trastuzumab + chemo improves OS in HER2+ disease

Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006 Gold GI CA

Symp 2008 Abs 96

Targeted Agents Phase III: Met Disease

REAL 3: ECX + / - Panitumumab (U.K.)

EXPAND: Cape-Cis + / Cetuximab

LOGIC: Cape-Ox + / - Lapatinib (HER2+)

TYTAN: second line, paclitaxel + / - Lapatinib (HER2+)

Paclitaxel + / - Everolimus– GRANITE: Single agent Everolimus inactive, no

improvement in OS, 656 patients

Resected Pancreatic Cancer OS (MSK)1983- 2001, N= 618

• 5- year OS N= 75, 12%

• 10-year OS N= 18, 5%

• Predictors of SurvivalNegative marginsAJCC stage

Ferrone, et al. J Gast Surg, 2008

Adjuvant Chemoradiation TrialsRandomized Phase III

Trial Therapy N Med Surv2-Yr Surv

5-Yr Surv

GITSG 1985 FU+RT+FU 21 20 mths 43% 19%

Observation 22 11 mths 18% 5%

EORTC 1999 FU + RT 60 17.1 mths 37% 20%

Observation 54 12.6 mths 26% 10%

Kalser. GITSG. Arch Surg, 1985. Klikenbilj. EORTC. Ann Surg, 1999.

ESPAC-1 Update (NEJM, 2004)

• 289 pts (53% of all enrollee’s)• 237 deaths (82%); median follow-up 47 mths

Med Surv 5-Yr Surv P-Value

Chemo 20.1 mths 21% 0.09

No chemo 15.5 mths 8% HR 0.71

ChemoRT 15.9 mths 10% 0.05

No chemoRT 17.9 mths 20% HR 1.28

Neuhaus, et al. ASCO, 2008 (Abst #4504)

Resected Pancreatic

CancerN= 368

ObservationD1 q 4 weeks

CONKO-001 Randomized Phase III

GemcitabineD 1, 8, 15 q 28 x 6 cycles

Stratification₋ R0 vs R1 resection; T stage; N(+) vs N(-)₋ Ca 19-9 < 2.5x ULN (eligibility)

Primary Endpoint: Disease-Free SurvivalSecondary Endpoints: Overall Survival, Toxicity

RANDOMIZE

Neuhaus, et al. ASCO, 2008 (LBA #4504)

CONKO-001: Efficacy Results

Gemcitabine

(N= 179)

Observation

(N= 175)P-value

Median DFS 13.4 mths 6.9 mths < 0.001

Median OS 22.8 mths 20.2 mths 0.005

1-Year OS 72% 72.5% -

3-year OS 36.5% 19.5% -

5-Year OS 21% 9% -

ESPAC-3 (v2)

Neoptolemos, et al. JAMA, 2010

Resected PCR0/R1

N= 1,0305-FU + LV

ObservationRANDOMIZE

Gemcitabine

Primary Endpoint: 10% improvement in 2-year OS

LCTU

Liverpool Cancer Trials Unit

ESPAC-3 Overall Survival

Median OS= 23 monthsMedian OS= 23.6 months

2LR=0.74, p=0.39, HRGEM VS 5FU/FA=0.94 (95%CI: 0.81, 1.08)

ESPAC-4: Phase III(recruiting)

Primary Endpoint: Overall Survival

Resected PCN= 1,080

Gemcitabine + Capecitabine

GemcitabineRANDOMIZE

Neoptolemos, J (PI)

Resected PCN= 518R0/R1 5-FU infusion

↓5-FU + RT

↓5-FU infusion

US Intergroup RTOG 97-04

Gemcitabine↓

5-FU + RT↓

Gemcitabine

RANDOMIZE

Regine, et al. JAMA, 2008

Regine, et al. JAMA, 2008

Pancreatic Head Tumors (N= 388)

Gemcitabine Arm 5-FU Arm

Median OS 20.5 mths 16.9 mths

3-Year Survival 31% 21%

HR 0.82 (CI 0.65- 1.03), p= 0.09

Survival trend for gemcitabine, but not significant

Body/tail tumors included (N= 451, p= 0.013)

Resected Pancreas CancerN= 952 Gemcitabine

+ Erlotinib x 4

US Intergroup/RTOG 0848

Gemcitabine x 4 cycles

Stratification₋ R0 vs R1 resection; T stage; N(+) vs N(-)

Primary Endpoint: Overall Survival +/- Erlotinib, +/- RTSecondary Endpoints: DFS +/- Erlotinib, +/- RT, toxicityTissue acquistion/ correlative science

RANDOMIZE

2nd Randomization

+/-ChemoRT

Burris, et al. J Clin Oncol, 1997

Gemcitabine vs 5-FU, Advanced pancreatic cancer

Log-Rank Testp = 0.0009

Median Survival

Gemcitabine 5.6 months

5-FU 4.3 months

Randomized Phase III Trials: Gemcitabine

Drug N RR Med Surv (mths)

1-Yr Surv (% )

Reference

Gem + Cisplatin 201 13% 7.2 mos 31% - Colucci 2010 Gemcitabine 199 10% 8.3 mos 34% - Gem + Cisplatin 98 10% 7.5 mos 30% Heinemann 2006 Gemcitabine 97 8% 6.0 mos 30% Gem + Irinotecan 173 16% 6.3 mos 20% Rocha Lima 2004 Gemcitabine 169 4% 6.6 mos 20% Gem + DX-8951f 175 7% 6.7 mos 23% Abou-Alfa 2006 Gemcitabine 174 5% 6.2 mos 21% Gem + Pemetrexed 273 15% 6.2 mos 21% Richards 2006 Gemcitabine 273 7% 6.3 mos 20% Gem + Oxaliplatin 157 27% 9.0 mos 35% Louvet 2005 Gemcitabine 156 17% 7.1 mos 28% p= 0.13 Gem + Xeloda 267 19% 7.1 mos 24% Cunningh. 2009 Gemcitabine 266 12% 6.2 mos 22% p= 0.08

Gemcitabine vs Gemcitabine + Another Drug?

Heinemann, BMC Cancer 8:82;2008: Meta Analysis

HR

Survival

P-Value N

Gem + platinum 0.85 0.01 623, 5 trials

Gem + 5-FU 0.90 0.03 901, 6 trials

Good PS 90%+

Poor PS 60- 80%

0.76

1.08

<0.0001

0.40

1,108, 5 trials

574

Gemcitabine combination therapy: 10-15% OS improvement

Prodige 4 - ACCORD 11 trial design

Stratification :

center performance status: 0 versus 1 location of the tumor: head versus other location of the primary

Metastaticpancreaticcancer

RANDOMIZE

Folfirinox

Gemcitabine

6 months of chemotherapy recommended

CT scans: obtained

every 2 months

for both arms:

Objective Response Rate

FolfirinoxN=171

GemcitabineN=171

p

Complete response 0.6% 0%

Partial response 31% 9.4% 0.0001

CR/PR 95% CI [24.7-39.1] [5.9-15.4]

Stable disease 38.6% 41.5%

Disease control

CR+PR+SD70.2% 50.9% 0.0003

Progression 15.2% 34.5%

Not assessed 14.6% 14.6%

Median durationof response

5.9 mo. 4 mo. ns

Progression-Free Survival

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

171 121 85 42 17 7 4 1 1 0 0 0 0Folfirinox171 88 26 8 5 2 0 0 0 0 0 0 0Gemcitabine

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33 36Months

Gemcitabine Folfirinox

p<0.0001

HR=0.47 : 95%CI [0.37-0.59]

Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo

Overall Survival

Folfirinox

N=171

Gemcitabine

N=171 p HR

Median survival[CI 95%]

11.1 mo.[ 9 - 13.1]

6.8 mo.[ 5.5 - 7.6]

<0.0001 0.57

1-yr. survival 48.4% 20.6%

18-mo. survival 18.6% 6%

Median follow up: 26.6 months [95% CI: 20.5 – 44.9]

Overall Survival

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

171146116 81 62 34 20 13 9 5 3 2 2Folfirinox171134 89 48 28 14 7 6 3 3 2 2 2Gemcitabine

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33 36Months

Gemcitabine Folfirinox

Stratified Log-rank test, p<0.0001

HR=0.57 : 95%CI [0.45-0.73]

Time to definitive QoL degradation

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

163 89 35 13 4 1 1Folfirinox157 53 9 1 0 0 0Gemcitabine

Number at risk

0 3 6 9 12 15 18Months

Gemcitabine Folfirinox

p=.001

Kaplan-Meier estimation for TUDD ofGlobal health status/QoL (MCID 10 points)

Pancreatic Cancer

• Chemotherapy with Gemcitabine has modest improvement in OS and QOL

• Good PS patients may benefit for Gem + platin or Gem + 5-FU

• FOLFIRINOX is the new standard for good PS patients

• Targeted Agents– Marginal benefit for Erlotinib– Negative results for Bevacizumab and Cetuximab

Pancreatic Cancer

• Adjuvant chemotherapy with 5-FU or Gemcitabine improves OS– Role of RT unclear– Current RTOG trial delivers RT at the end

of chemo to select patients to best benefit– Locally unresectable disease

• Similar approach of chemo first, selective use of RT if no POD