Upper GI Cancers: Risk Stratification and Treatment Selection

1
Upper GI Cancers Risk Stratification and
Treatment Selection

• David H. Ilson, MD, PhD

Gastrointestinal Oncology Service Memorial
Sloan-Kettering Cancer Center
2
Disclosure

• Research Funding
• Roche-Genentech
• Bayer
• sanofi-aventis
• BMS-Imclone

3
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

4
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
5
New AJCC Staging Survival in over 13,000 pts
with gastric cancer, SEER database
McGhan J Gastro Surg 16 53 2012
6
Gastric Cancer Preop therapy T3 or N T1A
EMR T1B, T2 Primary resection
7
New AJCC Staging Survival in over 4600 pts with
esophageal and GEJ cancer
Rice Cancer 2010
8
Esophagus, GEJ Preop therapy T2-3 or N T1A
EMR T1B Primary resection
9
PET SCANStaging (15 occult mets), and
Determine Response to Preop Chemo
SUV 10.6
SUV 2.2
10
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 lt 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

11
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 345725 2001
12
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
13
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
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CLASSIC study design
RANDO MIZ ATION
Surgically (D2) resected Stage II, IIIA, or IIIB
GC, 6 weeks prior to randomization No prior
chemotherapy or radiotherapy n1035
n520
8 cycles of XELOX (6 months)
Capecitabine 1,000mg/m2 bid, d114,
q3w Oxaliplatin 130mg/m2, d1, q3w
11
Observation No adjuvant therapy
n515

• 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
15
Primary endpoint (3-year DFS) met at interim
analysis
3-year DFS
1.0
74
0.8
XELOX, n520
0.6
60
Observation, n515
0.4
0.2
HR0.56 (95 CI 0.440.72) Plt0.0001
0.0
0
6
12
18
24
30
36
42
48
Time (months)
No. left
520
410
333
246
166
74
30
10
XELOX
443
515
352
286
209
147
58
22
6
414
Observation
ITT population DFS disease-free
survival Median follow-up 34.4 months (range
1651)
16
Regional Therapies as Adjuvant?

• Role of post op RT
• U.S. INT 116 lt 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

17
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
18
Meta Analysis of Preop Chemo Overall Survival
(Thirion, ASCO 2007)
Squamous 4 Adeno 7
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CROSS Active Treatment Arm

• Paclitaxel 50mg/m2 Carboplatin AUC2 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 gtT2, PS lt 2
• Primary objective Median overall survival 22
  months (versus 16)

20
CROSS Major Results

• EUS staged patients
• T3N0-1 75, median age 60
• 74 Adenocarcinoma
• 93 received all courses chemotherapy
• 23 had gt 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

21
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)
  plt0.002
• R1 52 (33) 12 (7.6)
• R0 no tumor within 1 mm of the resection
  margins

CROSS study
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CROSS Overall
Survival
CRTx
Surgery
HR 0.67 95 CI (.49 - .91) P0.012
HR 0.67 95 CI (0.49 - 0.91)

• 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

Adapted van der Gaast
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Preop Chemo vs ChemoRT
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Preop Chemo vs Chemo RT Stahl

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

Stahl J Clin Oncol 27 836 2009
25
MUNICON-1 trial PET scan response during
Induction Chemo
Non-Responder
Resection
CTx
AEGtype I-II
PET d14
CTx 3 months
PET d0
Responder
Resection
Response definition Decrease of the SUVmean
PETd14 / PETbaseline gt 35 Weber et al. J
Clin Oncol 2001193058-65 Ott et al. J Clin
Oncol 2006244692-8
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Comparison with historic cohort
Ott et al. J Clin Oncol 2006244692-8 CTx for 12
weeks in all patients
MUNICON-1 study 2007 CTx stopped after 2wks in
Non-Responders
PET-Responder
Survival
PET-Non-Responder
Survival time months
Survival (median) Responders not
reached Non-Responders 18 months
Survival (median) Responders not
reached Non-Responders 26 months
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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
Surgical resection 6 weeks post-RT
PET Scan day 29-35
PET- nonresponders lt 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
28
Best Supportive Care vs Chemotherapy
Wagner J Clin Oncol 24 2903 2006
29
Advanced Gastric Cancer Chemotherapy What
regimen to use?
30
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

31
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
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
Stratification ECOG 0-1 vs 2 ADC vs. SCC
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)
32
CALGB 80403/ECOG 1206 Response
RECIST - confirmed restaging every 6 weeks
33
 
CALGB 80403/ECOG 1206 Survival
34
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

35
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

36
Molecular Targets Gastric Cancer

• KRAS mutation lt 5-10
• BRAF mutation lt 5
• EGFr IHC over expression 50-80
• EGFr mutation lt 5
• CMET amplification lt 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
37
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

38
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

39
Adjuvant Chemoradiation TrialsRandomized Phase
III
40
ESPAC-1 Update (NEJM, 2004)

• 289 pts (53 of all enrollees)
• 237 deaths (82) median follow-up 47 mths

41
CONKO-001 Randomized Phase III
R A N D O M I Z E
Gemcitabine D 1, 8, 15 q 28 x 6 cycles
Resected Pancreatic Cancer N 368
Observation D1 q 4 weeks

• Stratification
• R0 vs R1 resection T stage N() vs N(-)
• Ca 19-9 lt 2.5x ULN (eligibility)
• Primary Endpoint Disease-Free Survival
• Secondary Endpoints Overall Survival, Toxicity

42
CONKO-001 Efficacy Results
43
ESPAC-3 (v2)
Primary Endpoint 10 improvement in 2-year OS
44
ESPAC-3 Overall Survival
Median OS 23 months Median OS 23.6 months
c2LR0.74, p0.39, HRGEM VS 5FU/FA0.94 (95CI
0.81, 1.08)
45
ESPAC-4 Phase III (recruiting)
Primary Endpoint Overall Survival
46
US Intergroup RTOG 97-04
Gemcitabine ? 5-FU RT ? Gemcitabine
R A N D O M I Z E
Resected PC N 518 R0/R1
5-FU infusion ? 5-FU RT ? 5-FU infusion
47
Pancreatic Head Tumors (N 388)
Survival trend for gemcitabine, but not
significant Body/tail tumors included (N 451, p
0.013)
48
US Intergroup/RTOG 0848
R A N D O M I Z E
Gemcitabine x 4 cycles
Resected Pancreas Cancer N 952
2nd Randomization /- ChemoRT
Gemcitabine Erlotinib x 4

• 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

49
Gemcitabine vs 5-FU, Advanced pancreatic cancer
Median Survival Gemcitabine 5.6 months 5-FU 4.3
months
50
Randomized Phase III Trials Gemcitabine
51
Gemcitabine vs Gemcitabine Another
Drug?Heinemann, BMC Cancer 8822008 Meta
Analysis
Gemcitabine combination therapy 10-15 OS
improvement
52
Prodige 4 - ACCORD 11 trial design
R A N D O M I Z E
Folfirinox
Metastatic pancreatic cancer
Gemcitabine

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

53
Objective Response Rate
54
Progression-Free Survival
Median PFS Folfirinox 6.4 mo. Median PFS
Gemcitabine 3.3 mo
55
Overall Survival
Median follow up 26.6 months 95 CI 20.5
44.9
56
Overall Survival
57
Time to definitive QoL degradation
58
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

59
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