Systemic%20Therapy%20for%20Gastric%20Cancer

1
Systemic Therapy for Gastric Cancer

• Charles S. Fuchs, MD
• Dana-Farber Cancer Institute
• Harvard Medical School
• Boston, MA

2
GASTRIC CANCER 2009
New Cases (rank) Deaths (rank)
United States (2008) 21,500 (14) 10,800 (13)
Worldwide (2002) 934,000 (4) 700,000 (2)
Jemal, et. al. CA Cancer J Clin 20085871 Jemal, et. al. CA Cancer J Clin 20085871 Jemal, et. al. CA Cancer J Clin 20085871
Parkin, et. al. CA Cancer J Clin 20055575 Parkin, et. al. CA Cancer J Clin 20055575 Parkin, et. al. CA Cancer J Clin 20055575
3
Gastric Cancer MortalityRegional Differences
China
Chile
Columbia
Japan
Hungary
Poland
Venezuela
Germany
United States
France
Jemal et al. CA Cancer J Clin. 2006. 56106.
4
(No Transcript)
5
(No Transcript)
6
Gastric Cancer Pathology
1. Adenocarcinomas (90), lymphoma,
leiomyosarcoma 2. Adenocarcinoma can be
subdivided

• Intestinal type
• Cohesive cells
• Forms discrete mass
• Distal stomach
• Endemic
• Better prognosis

• Diffuse type
• Lack cell cohesion
• Infiltrates without discrete mass
• Proximal stomach
• Not endemic
• Worse prognosis

7
Gastric Cancer Survival by Stage
National Cancer Data Base 1985-1996
IA
IB
II
IIIA
IIIB
IV
8
CASEA 62 yo man presents with new metastatic
gastric adenocarcinoma (liver mets). PS 0 to 1.
Your choice of front-line therapy

1. Docetaxel, cisplatin, 5-FU (DCF)
2. Irinotecan, cisplatin or FOLFIRI
3. Epirubicin, cisplatin (oxaliplatin), 5-FU
   (capecitabine)
4. Capecitabine/cisplatin (5-FU/cisplatin)
5. 5-FU, leucovorin, oxaliplatin (FOLFOX)
6. Single agent therapy
7. Other

9
Gastric Cancer Single Agent Chemotherapy
Response Rate
Drug
21
5-Fluorouracil
11
Methotrexate
30
Mitomycin C
17
Doxorubicin
19
Cisplatin
5-21
Paclitaxel
17-24
Docetaxel
18-31
Irinotecan
10
5-FU and Cisplatin in Advanced Gastroesophageal
Adenocarcinoma Trials Ohtsu et al. J
Gastro 2007
Japan Europe US/Europe
N 105 134 112
RR 34 20 23
Median PFS 3.9 mos. 4.1 mos. 3.7 mos.
Median OS 7.3 mos. 7.2 mos. 8.5 mos.
11
FAMtx vs. ELF vs. 5FU/CDDP in Advanced Gastric
Cancer
Response Median Rate
Survival FAMtx 12 9 mos ELF 9 7
mos 5-FUCDDP 20 9 mos
399 patients with advanced disease
12
Gastric Cancer Chemotherapy Versus Supportive
Care
13
5-FU/CDDP vs. Capecitabine/CDDP in Advanced
Gastric Cancer Kang et al. ASCO 2006
N RR Median TTP, mos Median OS, mos
5-FU/CDDP 137 29 5.0 9.3
Capecitabine/CDDP 139 41 5.6 10.5
P N.S.
14
S-1

• Oral fluoropyrimidine tegafur, CDHP, OXO
• Tegafur converted to 5-FU
• CDHP inhibits DPD in gut (prevents degradation)
• OXO inhibits phosphorylation of 5-FU in gut
  (reduces diarrhea)
• Asian and Caucasian population have different
  rates of activation of tegafur to 5-FU
• CYP2A6
• Different polymorphisms for Asians vs. Caucasians

15
S-1/CDDP in First-Line Advanced Gastric Cancer
(FLAGS)
1,000 patients worldwide
S-1 Cisplatin
R A N D O M I Z E
5-FU Cisplatin
16
FLAGS Results
Ajani et. al. GI ASCO 2009 Ajani et. al. GI ASCO 2009 Ajani et. al. GI ASCO 2009 Ajani et. al. GI ASCO 2009 Ajani et. al. GI ASCO 2009 Ajani et. al. GI ASCO 2009
Outcome Outcome Outcome Outcome
pts response rate median PFS median OS
S-1 Cisplatin 521 29.1 4.8 mos 8.6 mos
p0.40 p0.92 p0.20
5-FU Cisplatin 508 31.9 5.5 mos 7.9 mos
17
ECF Versus FAMtx in Advanced Esophagogastric
Cancer
J Clin Oncol 1997 Br J Cancer 1999
18
REAL-2 Trial Design for Advanced and Metastatic
Gastro-Esophageal Cancer
1,000 patients randomized to
N Eng J Med 2008
ECF
EEF
E Eloxatin 130 mg/m2every 3 weeks
EEX
ECX
X Xeloda 1250 mg/m2daily
2x2 multifactorial design
19
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)
N Eng J Med 2008
HR for ITT population 0.88 (0.77 1.00) p
0.058
20
Overall Survival (Per-protocol) Platinum
comparison
N Median 1 year 95 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 for ITT population 0.91 (0.79-1.04) p0.159
N Eng J Med 2008
21
Survival by Regimen ECF vs EOX (ITT)
Arm OS (m) 1 year survival (95 CI) p-value HR (95 CI)
ECF EOX 9.9 11.2 37.7 (31.8-43.6) 46.8 (40.4-52.9) 0.020 1 0.80 (0.66-0.97)
22
Phase II Studies of 5-FU/Oxaliplatin in Advanced
Gastroesophageal Adenocarcinoma
Study Regimen N ORR() TTP(months) TTP(months) Median OS(months)
Louvet et al1 FOLFOX-6 41 45 6.2 8.6 8.6
Al-Batran et al2 FOLFOX-6 41 43 5.6 9.6 9.6
Chao et al3 FLOX 55 56 5.2 10.0 10.0
DeVita et al4 FOLFOX-4 61 38 7.1 11.2 11.2
Lordick et al5 FUFOX 48 54 6.5 11.4 11.4
Cavanna et al7 FOLFOX-4 56 43 6.0 10.0 10.0
NCCTG North Central Cancer Treatment Group
1. Louvet et al. J Clin Oncol. 2002. 204543. 2.
Al-Batran et al. J Clin Oncol. 2004. 22658.3.
Chao et al. Br J Cancer. 2004. 91453. 4. De Vita
et al. Br J Cancer. 2005. 921644.5. Lordick et
al. Br J Cancer. 2005. 93190. 6. Jatoi et al.
ASCO, 2005. Abstract 4059.7. Cavanna et al. Am J
Clin Oncol. 2006. 29371.
23
5-FU, LV, Oxaliplatin vs. 5-FU, LV, Cisplatin in
Advanced Gastroesophageal Adenocardinoma Al-
Batran et al, J Clin Oncol 2008
220 patients with advanced gastric cancer
R A N D O M I Z E
5-FU 2,600mg/m2/24hr Leucovorin
200mg/m2 Oxaliplatin 85mg/m2
Q 2 weeks
5-FU 2,000mg/m2/24hr Leucovorin
200mg/m2 Cisplatin 50mg/m2
Q 2 weeks
24
FLO vs FLP in Advanced Gastroesophageal
Cancer Al-Batran et al.
RR Median PFS Median OS
FLO 35 5.8 mos 10.7 mos
FLP 25 3.9 mos 8.8 mos
P-value 0.077 NS
25
FLO vs FLP in Advanced Gastroesophageal
Cancer Al-Batran et al.
Grade ?3 Toxicity Grade ?3 Toxicity
FLO N112 FLP N102 P-value
Nausea () 4.5 8.8 0.003
Vomiting () 2.7 5.9 0.002
Fatigue () 3.6 6.9 0.03
Neurosensory () 14.3 2.0 lt0.001
Any grade renal () 10.7 34.3 0.03
26
FLO vs FLP Patients gt65 years (N94) Al-Bat
ran et al.
RR Median PFS Median OS
FLO 41 6.0 mos 13.9 mos
FLP 17 3.1 mos 7.2 mos
P-value 0.012 0.029 0.083
27
Irinotecan, 5-FU, LV vs. Cisplatin, 5-FU, LV in
Advanced Gastroesophageal Adenocarcinoma Dan
k et al. Ann Oncol 2008
N RR Median TTP Median OS
FU/LV/IRI 170 32 5.0 mos 9.0 mos
FU/LV/CDDP 163 26 4.2 mos 8.7 mos
P-value 0.23 0.088 0.53
28
CPT-11 and Cisplatin in Advanced Gastric Cancer
Author

No. of Pts

RR

G3-4 Diarrhea

G4 Neutropenia

Boku

44

48

20

57

Takincki

19

38

--

--

Ajani

36

58

22

15

Median survival 9 mos.


29
Taxanes in Advanced Gastric Cancer
30
V325 Phase III Study of DCF
J Clin Oncol 2006
Docetaxel 75 mg/m2 Cisplatin 75 mg/m2 5-FU
750 mg/m2/d CI days 1-5 every 3 weeks
R A N D O M I Z A T I O N
n221
Cisplatin 100 mg/m2 5-FU 1000 mg/m2/d CI days
1-5 every 4 weeks
n224
31
V325 DCF in Gastric Cancer
J Clin Oncol 2006
DCF N221 CF N224 P-value
Response Rate 37 25 0.01
Median TTP (months) 5.6 3.7 0.001
Median OS (months) 9.2 8.6 0.02
32
V325 DCF in Gastric Cancer
J Clin Oncol 2006
CF
DCF
57
82
Grade 3/4 Neutropenia
12
29
Febrile Neutropenia
21
24
Discontinuation due to adverse event
12
22
Withdrawal of Consent
33
46
Early treatment discontinuation
33
Phase II Study of Taxotere, Cisplatin, CPT-11
(TPC) in Metastatic Esophagogastric Adenocarcinoma
Enzinger et al. Ann Oncol. 2009

• Taxotere 30 mg/m2
• Cisplatin 25 mg/m2
• CPT-11 50 mg/m2
• weekly x 2 then one week rest
• 56 patients
• Response rate 54
• Median progression-free survival 7.1 months
• Median overall survival 12 months
• Grade 3/4 neutropenia 21

34
Do you use any of the following biologic
therapies in advanced gastric cancer study?

1. Bevacizumab
2. Cetuximab
3. Panitumumab
4. Erlotinib
5. Sunitinib
6. Sorafenib
7. None

35
Phase II Study of Irinotecan, Cisplatin,
Bevacizumab in Metastatic Gastroesophageal
Adenocarcinoma Shah et al. J Clin Oncol.
2006

• Irinotecan 65mg/m2 d1,8
• Cisplatin 30mg/m2 d1,8
• Bevacizumab 15mg/kg d1
• 47 patients
• RR 65
• Median TTP 8.3 mos
• Median OS 12.3 mos
• Grade 3/4 HTN 28
• Two patients had gastric perforation
• One patient had significant UGI bleed

Q 21 days
36
Phase II Study of mDCF and Bevacizumab in
Metastatic Gastroesophageal Adenocarcinoma Jh
awer et al. GI ASCO 2009

• Docetaxel 40 mg/m2 d1
• 5-FU 400 mg/m2
• 5-FU 1000 mg/m2/d d 1,2
• Bevacizumab 15mg/kg d1
• Cisplatin 40 mg/m2 d3
• 44 patients
• RR 67
• Median TTP 12 mos
• Median OS 16 mos
• grade 3/4 neutropenia 51 vs. 82

Q 14 days
37
Taxotere, Cisplatin, CPT-11, Bevacizumab (TPCA)
in Metastatic Esophagogastric Adenocarcinoma
Enzinger et al. GI ASCO 2008

• Taxotere 30 mg/m2 d1, 8
• Cisplatin 25 mg/m2 d1, 8
• CPT-11 50 mg/m2 d1, 8
• Bevacizumab 10 mg/kg d1
• q 3 weeks
• 33 patients
• Response rate 63

38
Weekly Docetaxel and Bevacizumab (AvaTax) in
Previously Treated Metastatic Esophagogastric
Cancer Enzinger et al.

• Docetaxel 35mg/m2 d1, 8, 15
• Bevacizumab 5mg/kg d1, 15
• 40 pts previously treated
• RR 20
• Median PFS 3.5 mos.
• Median OS 9.3 mos.
• Grade 3/4 bleeding 18
• One patient (2.5) had gastric perforation

Q 28 days
39
Bezacizumab in First-Line Advanced Gastric Cancer
(AVAGAST)
760 patients with previously untreated disease
R A N D O M I Z E
Capecitabine Cisplatin Placebo
Primary Endpoint Overall Survival
Capecitabine Cisplatin Bevacizumab
40
Phase III Study of IMC-1121B in Second-Line
Gastric Cancer
615 patients who failed FU or CDDP-based therapy
R A N D O M I Z E
IMC-1121B
Primary Endpoint Overall Survival
Placebo
41
Phase II Study of Erlotinib in Gastroesophageal
Adenocarcinoma SWOG 0127 Dragovich et al. J
Clin Oncol. 2006
68 pts with previously untreated disease
GE jxn (N43) Gastric (N25)
Response Rate 9 0
Median TTF 2 mos. 1.6 mos.
Median OS 6.7 mos. 3.5 mos.
42
Phase II Study of FOLFIRI-Cetuximab in Advanced
Gastroesophageal Adenocarcinoma Pinto et
al. Ann Onc 2007

• 38 patients
• OR 44
• Median TTP 8 mos.
• Median expected OS 16 mos.
• Grade 3/4 neutropenia 42
• Grade 3/4 diarrhea 8

43
Cetuximab in Advanced Gastroesophageal
Adenocarcinoma EXPAND Trial
870 patients with previously untreated disease
Capecitabine Cisplatin
R A N D O M I Z E
Primary Endpoint Progression-Free
Survival
Capecitabine Cisplatin Cetuximab
44
Trastuzumab in Gastric Cancer
584 patients with HER-2 positive, previously
untreated advanced gastric cancer
R A N D O M I Z E
Capecitabine Cisplatin
Primary endpoint Overall Survival
Capecitabine Cisplatin Trastuzumab
45
Paclitaxel vs. Placlitaxel/Lapatinib in
Second-line ErbB2 Amplified Gastric Cancer
314 patients following first-line therapy
R A N D O M I Z E
Weekly Paclitaxel
Primary endpoint Overall Survival
Weekly Paclitaxel Lapatinib
46
c-Met Pathway in Human Cancer
47
MET Amplification as a Predictor of Drug
Sensitivity in Gastric and Esophageal
Adenocarcinoma
Smollen et al PNAS, 2006
48
CASE56 yo man presents with new resectable
distal gastric adenocarcinoma. CT scan
demonstrates gastric wall thickening without
metastatic disease.You recommend

1. Surgery alone
2. Pre-operative ECF (ECX, EOX)
3. Pre-operative 5-FU/CDDP
4. Surgery followed chemotherapy
5. Surgery followed by 5-FU-based chemotherapy plus
   external beam radiotherapy

49
Adjuvant Therapy for Gastric Cancer
Meta-analysis
Earle, 1999
50
Adjuvant S-1 in Stage II/III Gastric
Cancer Sakuvamoto et al, NEJM 2007
1,059 patients following resection of stage
II/III gastric cancer
R A N D O M I Z E
S-1 80 mg/m2 qd x 4 weeks followed by 2 week rest
x 1 year
observation
51
Adjuvant S-1 in Gastric Cancer Sakuvamoto
et al.
3-year Relapse-free Survival 3-year Overall Survival
S-1 72 80
Observation 60 70
P-value lt0.001 0.003
Hazard Ratio (95 CI) 0.62 (0.50-0.77) 0.68 (0.52-0.87)
52
Adjuvant Radiotherapy in Resectable Gastric
Cancer Hallissey et al, 1994
436 patients following gastrectomy randomized to
Locoregional
5-Year
Relapse ()
Survival
Observation
57
20
Radiation (45
Gy)
34
12
FAM chemotherapy
41
19
53
Intergroup 0116
OBSERVATION 5-FU/LV 5-FU/LV 5-FU/LV
RADIATION 5-FU/LV x2 4,500 cGy
R A N D O M
RESECTED STAGE IB-IV (MO) GASTRIC ADENOCARCINOMA
54

• 54 improvement in relapse-free survival

55
32 improvement in overall survival
56
Intergroup 0116
Sites of Recurrence
57
Conclusions from Intergroup 0116

• Post-op. chemo-RT is a potential standard in
  therapy of resectable gastric cancer.
• Toxicity of post-op. chemo-RT is acceptable.
• Post-op. chemo-RT improved locoregional
  recurrence gt distant recurrence.

58
A Pilot Study of Adjuvant Chemoradiation After
Resection of Gastric or Gastroesophageal
Adenocarcinoma

Post
-
Pre

-
RT Chemo

Chemo with RT
RT Chemo

(1 cycle)

(45 Gy)
(2 cycles)








Epirubicin 50 mg/m2 d1


Epirubicin 40 mg/m2 d1





Cisplatin 60 mg/m2 d1
Cisplatin 50 mg/m2 d1




5-FU 200 mg/m2 d1-21
5-FU 200 mg/m2 d1-21
5-FU 200 mg/m2 d1-21
59
Randomized Trial of Adjuvant Chemoradiation After
Resection of Gastric Adenocarcinoma
R A N D O M I Z E
5-FU 5-FU IVCI 5-FU Leucovorin RT
Leucovorin X2 ECF 5-FU IVCI
ECF RT X2 540 eligible
patients required to detect a 25 improvement in
overall survival (alpha ? 0.05)
60
CALGB 80101 Worst Grade Toxicity by Treatment
Arm Updated N 387
Toxicity Arm A Mayo FU/LV Arm B ECF
? Grade 3 diarrhea 16 6
? Grade 3 nausea 17 15
? Grade 3 emesis 10 11
? Grade 4 neutropenia 33 17
Any grade 4-5 event 45 23

61
Magic Study Perioperative ECF Cunningham
et al NEJM 2006
Resectable distal esophageal and gastric
adenocarcinoma
R A N D O M I Z E
ECF X3
Surgery
ECF X3
N 250
N 253
Surgery
Recruitment July 1994-April 2002
62
MAGIC Does Pre-op ECF Improve Resectability?
Surgery alone N 253
P
Pre-op ECF N 250
14 days
99 days
Median time to surgery
240
219
Proceeded to surgery
166
169
R0 resection
70 (166/240)
0.03
79 (169/219)
R0 resection rate
63
MAGIC Progression-free survival
1.0
0.9
Logrank p-value 0.0001 Hazard Ratio 0.66
(95 CI 0.53 - 0.81)
0.8
0.7
0.6
Progression-free Survival rate
0.5
0.4
0.3
Events
Total
0.2
Included relapse, PD and death from any cause.
CSC
163
250
0.1
S
190
253
0.0
0
12
24
36
48
60
72
Months from randomisation
Patients at risk
159
CSC
250
99
68
46
32
23
S
253
124
57
42
28
15
8
64
MAGIC Overall survival
1.0
Logrank p-value 0.009 Hazard Ratio 0.75 (95
CI 0.60 - 0.93)
0.9
0.8
0.7
0.6
Survival rate
0.5
0.4
0.3
Events
Total
149
250
CSC
0.2
S
170
253
0.1
0.0
0
12
24
36
48
60
72
Months from randomisation
Patients at risk
CSC
250
168
111
79
52
38
27
S
253
155
80
50
31
18
9
65
MAGIC Conclusions

• In operable gastric and lower oesophageal cancer,
  perioperative chemotherapy
• significantly improves progression-free survival
• significantly improves overall survival

Cunningham ASCO 2005
66
Randomized Trial of Adjuvant Chemoradiation After
Resection of Gastric Adenocarcinoma
R A N D O M I Z E
5-FU 5-FU IVCI 5-FU Leucovorin RT
Leucovorin X2 ECF 5-FU IVCI
ECF RT X2 540 eligible
patients required to detect a 25 improvement in
overall survival (alpha ? 0.05)
67
Is Pre-op Therapy better than Post-op?
Is MAGIC better than INT-0116?
68
MAGIC v. 0116 Patient Characteristics
MAGIC
INT 0116
503
554
No. of Pts.
Baseline pathologic characteristics
64
68
T3/T4
28
15
Node negative
72
85
Node positive
27
43
4 pos. nodes
Surgery alone arm
69
MAGIC v. 0116 Two-Year Survival
Surgery Alone Chemorads Or Chemo
MAGIC 40 48
0116 52 58
70

• Absolutely not

MAGIC Patients with presumed resectable cancer
INT 0116 Patients with R0-resected cancer
Due to differences in patient selection and study
design Any cross-trial comparison is flawed and
essentially uninterpretable
71
CALGB 80101 Adjuvant Chemoradiation After
Resection of Gastric or Gastroesophageal
Adenocarcinoma
R A N D O M I Z E
5-FU 5-FU IVCI 5-FU Leucovorin RT
Leucovorin X2 ECF 5-FU IVCI
ECF RT X2 540 eligible
patients required to detect a 30 improvement in
overall survival (alpha ? 0.05)
72
MAGIC-B
R A N D O M I Z A T I O N
ECX X 3
ECX X 3
Surgery
Operable gastric or GEJXN Adenocarcinoma
ECX-B X 3
ECX bevacizumab X 3
Surgery
Accrual 1,100 patients
73
CRITICS STUDY
R A N D O M I Z A T I O N
ECX X 3
ECX X 3
Surgery
788 patients with operable gastric cancer
RT 45Gy/25 fx Capecitabine Cisplatin
ECX X 3
Surgery
74
ONGOING AND FUTURE QUESTIONS

• Does ECF improve the efficacy of post-op
  chemorads?

• What is the role of radiotherapy?

• Neoadjuvant vs. post-operative therapy?

• Is ECF the optimal chemotherapy regimen?

• Role of biologics in adjuvant therapy?

• Can we improve accrual to our trials?

75
Failed Pre- and Postoperative Trials in
Gastroesophageal Cancer
No. of pts. accrued
No. of pts. expected
Percent enrolled
Trial
76
(No Transcript)