Upper GI Cancers: Risk Stratification and Treatment Selection

David H. Ilson, MD, PhD Gastrointestinal Oncology Service Memorial 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 Carcinoma US 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: EMR T1B, 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: EMR T1B: 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

CLASSIC study design

Surgically (D2) resected Stage II, IIIA, or IIIB GC, 6 weeks prior to randomization No prior chemotherapy or radiotherapy n=1035 R A N D O M I Z A T I O N 1:1 † n=520 8 cycles of XELOX (6 months) Capecitabine: 1,000mg/m 2 bid, d1 –14, q3w Oxaliplatin: 130mg/m 2 , d1, q3w Observation: No adjuvant therapy 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

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

3-year DFS 1.0

74% 0.8

0.6

60% XELOX, n=520 Observation, n=515 0.4

0.2

HR=0.56 (95% CI 0.44

–0.72) P<0.0001

0.0

0 No. left XELOX Observation 520 515 6 443 414 12 410 352 18 333 286 ITT population; DFS = disease-free survival Median follow-up 34.4 months (range 16 –51) 24 30 Time (months) 246 209 166 147 36 74 58 42 30 22 48 10 6

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 OS MRC Lancet 359: 1727; 2002 Cunningham NEJM 355: 11; 2006 Schumacher JCO 28: 5210; 2010

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

Squamous: 4% Adeno: 7%

CROSS Active Treatment Arm

 Paclitaxel 50mg/m 2 + 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)

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 R0 110 (67%) R1 52 (33%) CRT + surgery 145 (92.3%) p<0.002

12 (7.6%) R0 = no tumor within 1 mm of the resection margins 21

CROSS study

CROSS: Overall Survival

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

•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

Adapted van der Gaast

Preop Chemo vs ChemoRT

Preop Chemo vs Chemo RT: Stahl

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

Arm Pts

Chemo 59

R0

70%

pCR

2%

N0 Median Survival 3 yr OS Local Control

37% 21 mos 28% 59% Chemo RT 60 72% 16% 64% 33 mos 47% P = 0.07

Stahl J Clin Oncol: 27: 836; 2009 77% P = 0.06

MUNICON-1 trial: PET scan response during Induction Chemo Non-Responder Resection AEG type I-II PET d0 CTx PET d14 Responder CTx: 3 months Resection Response definition: Decrease of the SUV mean PET d14 / PET baseline > 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;24:4692-8 CTx for 12 weeks in all patients

PET-Responder

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

PET-Non-Responder Survival time [months]

Survival (median) Responders: not reached Non-Responders: 18 months Survival (median) Responders: not reached Non-Responders: 26 months

PET Scan Directed Therapy Trial Design: CALGB / RTOG 80803

PET-responders: ≥ 35% SUV decrease: continue same chemo + concurrent RT (5040cGy in 180cGy fx) 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 Scan day 29-35 Surgical resection 6 weeks post-RT

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

PET nonresponders: 35% SUV decrease: < Cross over to alternate chemo + RT (5040cGy in 180cGy fx)

Best Supportive Care vs Chemotherapy

Wagner J Clin Oncol 24: 2903; 2006

Pts

Advanced Gastric Cancer Chemotherapy: What regimen to use?

Oxali: EOX or EOF Cape: ECX or EOX XP FLO FUFIRI S-1 Cis DCF ECF 489 513 160 109 170 305 221 126 %RR 44% 45% 41% 34% 32% 54% 36% 45% TTP, mos 6.7

OS, mos 10.9 6.5

10.4

5.6

10.5

5.5

- 5.0

9.0

6.0

5.6

7.4

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

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 Stratification:

ECOG 0-1 vs 2 ADC vs. SCC

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)

CALGB 80403/ECOG 1206: Response

Response CR PR SD PD 0 37 15 4 ECF-C N=64 (58%) (23%) ( 6%) Not eval / unknown 5 / 3 (8% /5%) Objective Response Rate* (CR+PR)/total (90% C.I.) 46.8 57.8 68.3 p vs. H 0 <0.25 Response duration (mos) <.0001 median range 6.1 0.5 - 22.7 IC-C N=68 FOLFOX-C N=69 1 30 23 10 ( 1%) (44%) (34%) (15%) 2 / 2 (3% /3%) 2 35 19 8 ( 3%) (51%) (28%) (12%) 3 / 2 (4% /3%) 35.2 45.6 56.3 <.0001 5.3 0.5 - 20.1 43.1 53.6 64.0 <.0001 5.7 2.4 - 18.2 *RECIST - confirmed; restaging every 6 weeks

CALGB 80403/ECOG 1206: Survival

OS PFS TTF ECF-C IC-C FOLFOX-C Total median # dead median Mos 11.5 51 5.9 # dead/pd 57 median #dead/pd/ 5.5 off forAE 58 N=67 95% c.i. (3.9,7.2) N=71 Mos 95% c.i. (8.1,12.5) 8.9 52 (4.5,8.3) 5.0 64 4.5 66 (6.2,13.1) 12.4 (8.8,13.9) 11.0 (8.8,12.3) 51 154 (3.9,6.0) 6.7 (5.5,7.4) 5.8 (5.1,6.8) (3.6,5.6) Mos 95% c.i. 63 6.7 64 N=72 (4.8,7.2) 184 5.5 188 N=210 Mos 95% c.i. (4.5,5.9)

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 Survival Negative margins AJCC stage Ferrone, et al. J Gast Surg, 2008

Adjuvant Chemoradiation Trials Randomized Phase III

Trial

GITSG 1985

Therapy

FU+RT+FU Observation

N

21 22

Med Surv

20 mths 11 mths

2-Yr Surv

43% 18%

5-Yr Surv

19% 5% EORTC 1999 FU + RT Observation 60 54 17.1 mths 12.6 mths 37% 26% 20% 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 Chemo No chemo

Med Surv

20.1 mths 15.5 mths

5-Yr Surv

21% 8%

P-Value

0.09

HR 0.71

ChemoRT No chemoRT 15.9 mths 17.9 mths 10% 20% 0.05

HR 1.28

CONKO-001 Randomized Phase III

Resected Pancreatic Cancer N= 368

R A N D O M I Z E

Gemcitabine D 1, 8, 15 q 28 x 6 cycles Observation D1 q 4 weeks ₋ ₋ Stratification R0 vs R1 resection; T stage; N(+) vs N(-) Ca 19-9 < 2.5x ULN (eligibility) Primary Endpoint: Disease-Free Survival Secondary Endpoints: Overall Survival, Toxicity

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

CONKO-001: Efficacy Results

Median DFS Median OS 1-Year OS 3-year OS 5-Year OS

Gemcitabine (N= 179)

13.4 mths 22.8 mths 72%

Observation (N= 175)

6.9 mths 20.2 mths

P-value

< 0.001

0.005

72.5% 36.5% 19.5% 21% 9% Neuhaus, et al. ASCO, 2008 (LBA #4504)

ESPAC-3 (v2)

Resected PC R0/R1 N= 1,030

R A N D O M I Z E

Observation 5-FU + LV Gemcitabine Primary Endpoint: 10% improvement in 2-year OS Neoptolemos, et al. JAMA, 2010

ESPAC-3 Overall Survival

Median OS= 23 months Median OS= 23.6 months

c

2 LR =0.74, p=0.39, HR GEM VS 5FU/FA =0.94 (95%CI: 0.81, 1.08) LCTU Liverpool Cancer Trials Unit

ESPAC-4: Phase III

(recruiting) Resected PC N= 1,080

R A N D O M I Z E

Gemcitabine Gemcitabine + Capecitabine Primary Endpoint: Overall Survival

Neoptolemos, J (PI)

US Intergroup RTOG 97-04

Resected PC N= 518 R0/R1

R A N D O M I Z E Gemcitabine ↓ 5-FU + RT ↓ Gemcitabine 5-FU infusion ↓ 5-FU + RT ↓ 5-FU infusion

Regine, et al. JAMA, 2008

Pancreatic Head Tumors (N= 388)

Gemcitabine Arm 5-FU Arm

Median OS 20.5 mths 3-Year Survival 31% HR 0.82 (CI 0.65- 1.03), p= 0.09

16.9 mths 21% Survival trend for gemcitabine, but not significant Body/tail tumors included (N= 451, p= 0.013) Regine, et al. JAMA, 2008

US Intergroup/RTOG 0848

Resected Pancreas Cancer N= 952 R A N D O M I Z E Gemcitabine x 4 cycles Gemcitabine + Erlotinib x 4 2 nd Randomization +/ ChemoRT ₋ Stratification R0 vs R1 resection; T stage; N(+) vs N(-) Primary Endpoint: Overall Survival +/- Erlotinib, +/- RT Secondary Endpoints: DFS +/- Erlotinib, +/- RT, toxicity Tissue acquistion/ correlative science

Gemcitabine vs 5-FU, Advanced pancreatic cancer Median Survival Gemcitabine 5.6 months 5-FU 4.3 months Log-Rank Test p = 0.0009

Burris, et al. J Clin Oncol, 1997

Drug Randomized Phase III Trials: Gem + Cisplatin Gemcitabine Gem + Cisplatin Gemcitabine Gem + Irinotecan Gemcitabine Gem + DX-8951f Gemcitabine Gem + Pemetrexed Gemcitabine Gem + Oxaliplatin Gemcitabine Gem + Xeloda Gemcitabine N Gemcitabine RR 201 13% 199 10% 98 97 10% 8% 173 169 175 174 273 273 157 156 267 266 16% 4% 7% 5% 15% 7% 27% 17% 19% 12% Med Surv (mths) 7.2 mos 8.3 mos 7.5 mos 6.0 mos 6.3 mos 6.6 mos 6.7 mos 6.2 mos 6.2 mos 6.3 mos 9.0 mos 7.1 mos 7.1 mos 6.2 mos 1-Yr Surv (%) 31%- 34%- 30% 30% 20% 20% 23% 21% 21% 20% 35% 28% 24% 22% Reference Colucci 2010 Heinemann 2006 Rocha Lima 2004 Abou-Alfa 2006 Richards 2006 Louvet 2005 p= 0.13 Cunningh. 2009 p= 0.08

Gemcitabine vs Gemcitabine + Another Drug?

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

Gem + platinum HR Survival 0.85

P-Value 0.01

N 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

Metastatic pancreatic cancer R A N D O M I Z E Folfirinox Gemcitabine for both arms: CT scans: obtained every 2 months 6 months of chemotherapy recommended Stratification :

  

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

Objective Response Rate

Complete response Partial response CR/PR 95% CI Stable disease Disease control CR+PR+SD Progression Not assessed Median duration of response Folfirinox N=171 0.6% 31% [24.7-39.1] 38.6% Gemcitabine N=171 0% 9.4% [5.9-15.4] 41.5% p 0.0001

0.0003

70.2% 15.2% 14.6% 5.9 mo.

50.9% 34.5% 14.6% 4 mo.

ns

Progression-Free Survival

Median PFS Folfirinox: 6.4 mo.

1.00

Median PFS Gemcitabine: 3.3 mo

HR=0.47 : 95%CI [0.37-0.59] 0.75

0.50

0.25

p<0.0001

0.00

0 3 6 9 12 15 18 Months 21 Number at risk Gemcitabine Folfirinox 171 88 171 121 26 85 8 42 5 17 2 7 Gemcitabine 0 4 0 1 24 27 30 33 36 0 1 0 0 0 0 Folfirinox 0 0 0 0

Overall Survival

Median follow up: 26.6 months [95% CI: 20.5 – 44.9] Median survival [CI 95%] 1-yr. survival 18-mo. survival Folfirinox N=171 Gemcitabine N=171 11.1 mo.

[ 9 - 13.1] 48.4% 18.6% p HR 6.8 mo.

[ 5.5 - 7.6] 20.6% 6% <0.0001

0.57

Overall Survival

1.00

0.75

0.50

0.25

HR=0.57 : 95%CI [0.45-0.73] Stratified Log-rank test, p<0.0001

0.00

0 3 6 9 12 15 18 21 24 27 30 33 36 Months Number at risk Gemcitabine Folfirinox 171 134 89 48 28 14 7 6 3 171 146 116 81 62 34 20 13 9 3 5 2 3 2 2 2 2 Gemcitabine Folfirinox

Time to definitive QoL degradation

Kaplan-Meier estimation for TUDD of Global health status/QoL (MCID 10 points) 1.00

0.75

0.50

0.25

0.00

p=.001

0 Number at risk Gemcitabine Folfirinox 157 163 3 53 89 6 9 35 9 Months 12 1 13 Gemcitabine 0 4 15 0 1 Folfirinox 18 0 1

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