Transcript Challenging Cases in Gastric and Pancreatic Cancer

Challenging Cases in Cancer:
Integration of Findings from ASCO 2007
Gastric Cancers
David H. Ilson, MD, PhD
Associate Attending Physician
GI Oncology Service
Memorial Sloan-Kettering Cancer Center
New York, NY
Upper GI Cancer:
US Incidence in 2007
• 93,150 new cases gastric, esophageal, pancreatic,
hepatobiliary cancer
– 8% of new cancers
– 81% fatality rate
– 15% of American cancer deaths
• Decline in gastric cancer incidence
• Increase in esophageal , GE JX, cardia adeno
• Increase in hepatocellular Ca
Jemal et al, CA Cancer J Clin 57: 43-66; 2007
Gastric Cancer:
Current Therapy
• Adjuvant
– Post op 5-FU/LV + RT: increases 5-yr OS by 10% (U.S.
Standard, INT 116)
– Pre and Post op ECF: increases 5-yr OS by 13% (U.K.
Standard, MAGIC trial)
Case 1: GE Junction Adenocarcinoma
• A 79-year-old male presents with increasing
dysphagia, 15 pound weight loss, odynophagia
• Past history: NIDDM, BPH, hypercholesterolemia
• EUS: T3N1 adenocarcinoma, 50% circumferential
• CT scan: distal esophageal mass
• PET scan: uptake in the primary, SUV
• The patient is admitted from clinic for complete
dysphagia, and has endoscopy and Polyflex stent
placement
Case 1: GE Junction Adenocarcinoma
PET scan
CT scan
Case 1: GE Junction Adenocarcinoma
Which treatment option would you recommend?
 Esophagectomy
 Preop chemotherapy with ECF followed by
esophagectomy and post op ECF
 Preop combined chemoradiotherapy followed by
surgery
 Primary combined chemoradiotherapy without
surgery
Case 1: GE Junction Adenocarcinoma
• The patient received induction chemo
with weekly carboplatin and paclitaxel for
3 treatments.
• Dysphagia improved post stent and with
chemotherapy
• PET scan: response to induction chemo
(SUV 9.7  5.3), EGD: response, stent
was removed
• Combined chemotherapy with weekly
carbo/paclitaxel and RT 5040 cGy was
administered
• EGD post therapy x 2 (4 and 8 weeks
after RT): treatment related stricture
dilated, biopsy negative
• Repeat PET scan 2 months post RT:
SUV further reduced, 3.1
• Surgery deferred
PET 1
PET 3
PET 2
Case 1: GE Junction Adenocarcinoma
GE Junction and Esophageal Cancer:
Adjuvant Therapy
• Survival with surgery alone: 20-40%
• Adjuvant trials in esophageal cancer have evaluated
preop therapy
– Preop Chemotherapy
– Preop Chemo + radiotherapy
» Most common U.S. practice
Esophageal Cancer:
Preop Chemotherapy
• Negative Trials
• U.S. INT 113
– 3 pre, 3 post op cycles of
5-FU + Cisplatin
– 440 pts
– Adeno 54%, Squamous
46%
– No improvement in R0
resection rate, disease
free or overall survival
– Path CR 2.5%
100
80
60
40
20
0
0.5
1
1.5
2
2.5
3
3.5
4
Kelsen et al, NEJM 339: 1979; 1998
4.5
5
Esophageal Cancer:
Preop Chemotherapy
• Positive trials
• U.K. MRC OEO-2
– 2 preop cycles of 5-FU + Cisplatin
– 802 pts
– Adeno 66%, Squamous 31%
– 6% increase in R0 resection rate,
9% increase in 2-year OS
– Path CR 4%
• U.K. MAGIC: pre and post op ECF in
gastric cancer
– 25% of 500 pts had GE junction
or distal esophageal adeno
– No improvement in R0 resection
rate, 13% increase in 5-year OS
– No Path CRs
MRC Lancet 359: 1727; 2002, Cunningham NEJM 355: 11; 2006
Esophageal Cancer:
Consensus on Adjuvant Therapy
• Something more than surgery alone should be done
• Adenocarcinoma
– Preoperative chemotherapy improves overall survival
» MAGIC: 13% improvement at 5 yr
» MRC 0E0-2: 9% improvement at 2 yr
– No clear impact on rate of R0 resection
• Addition of RT to chemotherapy
– Improves rates of curative resection in some trials
– Achieves pathologic complete responses in 10-30%
– Phase III trials: only 2 of 5 recent trials showed a survival
benefit for preop chemo + RT
MRC Lancet 359: 1727; 2002, Cunningham NEJM 355: 11; 2006
Preop Chemo in Esophageal and Gastric Cancer:
FFCD / FNLCC
CT + S
(N = 113)
S
(N = 111)
Preop CT (2-3 cycles)
(N = 98) 89%
Surgery
(N = 109) 96%
Postop CT
(N = 145)
Surgery
(N = 110) 99%
CT = 5-FU + Cisplatin
Boige, et al. ASCO 2007. Abstract 4510
Surgical and Pathological Results
S
N = 110
CT = S
N = 109
No. pts (%)
Extent of resection
10 (9)
7 (6)
R0
81 (74)
95 (87)
R1
6 (5)
4 (4)
R2
12 (11)
2 (2)
RX
1 (1)
1 (1)
No. resection
P = 0.04
Boige, et al. ASCO 2007. Abstract 4510
Overall Survival
5-year DFS: 24% (16 - 33%) vs. 38% (28 - 47%)
Boige, et al. ASCO 2007. Abstract 4510
Disease-free Survival
5-year DFS: 21% (14 - 30%) vs. 34% (26 - 44%)
Boige, et al. ASCO 2007. Abstract 4510
Preop Chemotherapy in Esophageal
Adenocarcinoma
• Survival benefit for preop chemotherapy with CF
(cisplatin and 5-FU)
• 14% improvement in 5-yr OS, HR 0.69
– Similar to survival for gastric cancer in MAGIC trial
• 13% rate of improvement in R0 resection rate
• Impact on tumor downstaging: not statistically
significant
Boige, et al. ASCO 2007. Abstract 4510
Preop Chemotherapy in Esophageal
Adenocarcinoma
• Major impact was reduction in systemic recurrence
– Systemic: 56% for surgery  42% for chemo + surgery
– Local: 26% for surgery = 24% for chemo + surgery
• Similar results for CF compared to ECF-MAGIC
– Epirubicin may not be needed
• Role of epirubicin?
– OEO-05 (U.K. MRC)
– Preop ECF vs. CF in esophageal cancer
Boige, et al. ASCO 2007. Abstract 4510
Preop Chemotherapy in Esophageal
Adenocarcinoma
• Preop Chemo in esophageal and GE JX adeno
improves survival
• Relative small sample 224 pts, differences of 10-15%
come down to outcomes in only 10-15 patients
• Preoperative staging
– EUS not performed
– Accuracy of pre-therapy stage ?
– No stratification for stage
Boige, et al. ASCO 2007. Abstract 4510
Individual Patient Data-based Meta-analysis Assessing
Pre-operative Chemotherapy in Resectable
Oesophageal Carcinoma
• Individual patient data from preop chemo trials (esophageal
squamous and adenocarcinoma)
• 9 trials OS (2102 pts)
• 7 trials DFS (1849 pts)
• 2 dominant trials:
– U.S. INT 113 (467 pts)
– U.K. MRC OEO-2 (802 pts)
• Slightly more than 50% of patients had squamous ca
• Preop Chemo: Overall survival improvement with a HR of 0.87
(P = 0.0033)
– Translates into 4.3% improvement in OS at 5-yrs
Thirion P, et al. ASCO 2007. Abstract 4512
Primary End-point: Overall Survival
1.0
Survival
0.8
Absolute benefit
at 5 years:
4.3 %
0.6
0.4
0.2
0.0
0
2
1054
1047
321
361
4
6
Time (years)
8
10
Patients at risk
Control
Chemo pre-op
144
153
74
90
38
52
20
31
Thirion P, et al. ASCO 2007. Abstract 4512
Secondary End-point: DFS
Disease free survival
1.0
0.8
Absolute benefit
at 5 years:
4.1 %
0.6
0.4
0.2
0.0
Patients at risk
Control
Chemo pre-op
0
2
927
922
178
236
4
6
Time (years)
87
111
43
61
8
10
22
38
10
20
Thirion P, et al. ASCO 2007. Abstract 4512
Individual Patient Data-based Meta-analysis Assessing
Pre-operative Chemotherapy in Resectable
Oesophageal Carcinoma
• Although overall survival benefit independent of
histology
– Adeno:
– Squamous:
20%  27%
16%  20%
• Other endpoints:
– R0 resection rate improved by 5%
– Post Operative Mortality: not increased with preop chemo
• Conclusions: Preop chemotherapy
– Modest improvement in 5-yr OS (4.3%)
– Greater effect for adenocarcinoma then squamous cell
carcinoma of the esophagus
Thirion P, et al. ASCO 2007. Abstract 4512
Abstract 4511
Preoperative Chemotherapy (CTX) Versus
Preoperative Chemoradiotherapy (CRTX) In Locally
Advanced Esophagogastric Adenocarcinomas: First
Results of A Randomized Phase III Trial
M. Stahl, M. K. Walz, M. Stuschke, N. Lehmann, M. H.
Seegenschmiedt, J. Riera Knorrenschild, P. Langer, M.
Bieker, A. Königsrainer, W. Budach, H. Wilke
Trial Design
Arm A
(N = 60)
Cisplatin 50 mg/m2
Folinic Acid 500 mg/m2
5-FU 2 g/m2
for 2.5 courses
Patients with locally
advanced esophagogastric
adenocarcinoma
Arm B
(N = 60)
Cisplatin 50 mg/m2
Folinic Acid 500 mg/m2
5-FU 2 g/m2
for 2 courses
Cisplatin 50 mg/m2
Etoposide 80 mg/m2
Radiation 30 Gy
for 3 wks
Stahl M, et al. ASCO 2007. Abstract 4511
Results at Surgery
CTX
(N = 59)
CRTX
(N = 60)
Patients with S
88.1 %
81.7 %
R0-resection
69.5 %
71.7 %
R1/R2
13.6 %
3.3 %
3
4
Exploration (N)
Peritoneal mets. 2 Peritoneal mets. 3
Unresected 1
Hepatic mets. 1
Stahl M, et al. ASCO 2007. Abstract 4511
Pathohistologic Results
CTX
(N = 49)
CRTX
(N = 45)
P
T0N0M0
2.0 %
15.6 %
0.03
T1-4N0M0
34.7 %
48.9 %
T0-4N0M0
36.7 %
64.4 %
T0-4N+M0
55.1 %
31.1 %
T0-4N+M1
8.2 %
4.4 %
0.01
Stahl M, et al. ASCO 2007. Abstract 4511
Mortality After Surgery
CTX
(N = 52)
CRTX
(N = 49)
2 (3.8 %)
5 (10.2 %)
Pneumonia
1
2
Anastom. leakage
1
2
Cardiac shock
0
1
Hospital mortality
Fisher’s exact P = 0.26
Stahl M, et al. ASCO 2007. Abstract 4511
Overall Survival
Survival Distribution Function
1.00
0.75
CRTX
47.4%
0.50
Log rank
P = .07
HR arm B vs. A: 0.67 (0.41-1.07)
0.25
Follow-up: 45.6 mos
CTX
27.7%
0
0
1
2
3
4
5
6
Years
Stahl M, et al. ASCO 2007. Abstract 4511
Freedom from Local Tumor Progression
Survival Distribution Function
1.00
CRTX
76.5%
0.75
0.50
CTX
0.25
59.0%
Log rank
P = 0.06
HR arm B vs. A: 0.45 (0.19 1.05)
0
0
1
2
3
Years
4
5
6
Stahl M, et al. ASCO 2007. Abstract 4511
Preop Chemo vs. Preop Chemo RT
•
•
•
•
Preop Chemo and Preop Chemo RT are feasible
No difference in rate of R0 resection, + RT
Higher post op mortality, + RT in multi institution trial
Strong trend favoring improved OS, + RT
– 20% at 3 years (P = 0.07)
• Strong trend favoring improved local PFS, + RT
– 18% at 3 years (P = 0.06)
Stahl M, et al. ASCO 2007. Abstract 4511
Preop Chemo vs. Preop Chemo RT
• Cannot conclude that the addition of RT improves
outcome
– Trial underpowered for primary endpoint
• Further trials of pre and post op chemo ± RT are
warranted
• Netherlands: CRITICS Trial
– Preop ECX  Surgery 
– Post op chemo ± RT
• Korea:
– Preop Capecitabine + Cisplatin  Surgery 
– Cape/Cis ± RT
Stahl M, et al. ASCO 2007. Abstract 4511
Gastric/Esophageal Cancer:
Current Therapy
• Gastric Cancer:
– Metastatic: 5-FU + cisplatin, RR of 20%, Med S 8-9 mos
» Epirubicin (ECF), docetaxel + CF (DCF):
• 35-40% RR, med survival 9 mos
» Capecitabine, oxaliplatin = CIV 5-FU, cisplatin
Gastric Cancer Chemotherapy:
What Regimen to Use?
•
•
•
•
Docetaxel + CF > CF: toxicity
Irinotecan + CIV 5-FU = CF: less toxicity
Oxaliplatin + Capecitabine: non inferior
Doublets:
Platin: + Irinotecan or Taxane or Fluor
Flour: + Irinotecan or Taxane or Platin
Oxaliplatin
EOX or EOF
Cape ECX
or EOX
XP
FLO FUFIRI DCF ECF
Pts
489
513
160
109
170
221
%,RR
44%
45%
41% 34%
32%
36% 45%
TTP, mos
--
--
5.6
5.5
5.0
5.6
NS
OS, mos
10.9
10.4
10.5
--
9.0
9.2
8.9
126
Case 2: GE Junction Adenocarcinoma
• A 50-year-old man presents with
increasing solid food dysphagia
and a 20 pound weight loss.
• EGD reveals a GE junction mass
with a biopsy revealing
adenocarcinoma.
• A CT scan reveals multiple
hepatic mets, lung and adrenal
mets.
• Past history is only noted for
asthma.
• PS 0.
CT Scan
PET
Scan
Case 2: GE Junction Adenocarcinoma
Which treatment option would you recommend?
 Single agent 5-FU or capecitabine
 5-FU/Cisplatin or FOLFOX
 ECF, ECX, or EOX
 DCF: Docetaxel, 5-FU, Cisplatin
 FOLFIRI
 Irinotecan + Cisplatin
Case 2: GE Junction Adenocarcinoma
• Phase III trials indicate that ECF is superior to FAMTX, and that
DCF is superior to CF
• The patient was treated on a phase II trial of modified DCF
– Docetaxel 40 mg/m2 day 1
– Bolus 5-FU 400 mg/m2, Leucovorin 400 mg/m2 day 1, followed by
5-FU 1000 mg/m2/day x 2 days
– Cisplatin 40 mg/m2 day 3
– Cycled every 2 weeks
– + Bevacizumab 10 mg/kg day 1
• Scans every 6 weeks showed progressive response, dysphagia
resolved, PET scan normalized in the liver
• Dose reductions of 5-FU and docetaxel for mucositis
• No significant neutropenia or diarrhea
• Patient continues on therapy at 6 months
Case 2: GE Junction Adenocarcinoma
CT Scan 1
PET Scan 1
CT Scan 2
PET Scan 2
Gastric / Esophageal Cancer Abstracts:
ASCO 2007
• Metastatic disease: gastric cancer
–
–
–
–
S-1 vs. S-1 + Irinotecan
S-1 vs. 5-FU vs. 5-FU/Cisplatin
S-1 vs. S-1/Cisplatin
DCF vs. Docetaxel + Capecitabine
S-1
• S-1: novel oral fluorouracil formulation
•
•
•
•
FT: Tegafur, 5-FU prodrug +
CDHP: DPD inhibitor +
Oxo: bowel protectant
Molar ratio of 1.0: 0.4: 1.0
• Developed as orally absorbed 5-FU preparation with
potentially less bowel toxicity
S-1
• CDHP: inhibits DPD, which degrades 5-FU
– 180-fold higher DPD inhibitory activity than Uracil
• A high blood level of 5-FU retained when CDHP is
combined with FT
• CDHP enhances oral FT uptake by blocking
degradation by DPD in the bowel
S-1
• Oxo: orotate phosphoribosyltransferase inhibitor
• Oxo: inhibits conversion of FT to FU in the bowel
• Reducing GI toxicity
S-1: Mechanism of Action
Irinotecan Plus S-1 (IRIS) Versus S-1 Alone as First-line
Treatment for Advanced Gastric Cancer: Preliminary
Results of a Randomized Phase III Study
• S-1 vs. S-1 + Irinotecan
–
–
–
–
–
326 pts
RR 27% vs. 42% (P = 0.035)
Grade 3/4 neutropenia: 9% vs. 27%
Grade 3/4 diarrhea: 6% vs. 16%
OS pending (powered to detect 3.5 mos inc OS)
Chin K, et al. ASCO 2007. Abstract 4525
Randomized Phase III Study of 5-fluorouracil (5-FU) Alone Versus
Combination of Irinotecan and Cisplatin (CP) Versus S-1 Alone In
Advanced Gastric Cancer (JCOG9912)
• S-1 vs. CIV 5-FU vs. irinotecan/cisplatin 704 pts, primary
endpoint irinotecan arm: increase 1-yr OS by 10%
– Grade 3/4 neutropenia, nausea, diarrhea
» 65% for IC vs. 1-5% for S-1 or 5-FU
» 21% for IC vs. 0-1% for S-1 or 5-FU
» 9% for IC vs. 1-8% for S-1 or 5-FU
– RR:
– PFS:
– OS
IC: 38%
4.8 mos
12.3 mos
5-FU: 9%
2.9 mos
10.8 mos
S-1: 28%
4.2 mos
11.4 mos
• Irinotecan/cisplatin and S-1 are superior to 5-FU, S-1 single agent
approaches combination therapy activity
Boku, et al. ASCO 2007. Abstract LBA4513
Randomized Phase III Study of S-1 Alone Versus S-1 + Cisplatin
In the Treatment for Advanced Gastric Cancer (The SPIRITS trial)
SPIRITS
S-1
S-1 +
Cisplatin
Number
150
148
RR
31%
54%
0.0018
OS
11
mos
13 mos
0.0366
1-year
47%
54%
2-year
15%
24%
PFS
4 mos
6 mos
Grade 3/4
Neut
11%
40%
Grae 3/4
Diarrhea
3%
3%
Grade 3/4
Nausea
1%
12%
• S-1 vs. S-1 + Cisplatin
• S-1 40-60 mg BID x 3 weeks
alone, vs. S-1 + Cisplatin 60
mg/m2 day 8, 2 weeks rest
• Primary endpoint OS: 8 mos 
12 mos, 284 pts
• S-1: Active single agent,
superior to CIV 5-FU alone
• Combination + cisplatin superior
• S-1 + Cisplatin a new standard in
Japan
• FLAGS: Western trial of 5-FU vs.
S-1 + Cisplatin
Narahara et al. ASCO 2007. Abstract 4514
P
0.0089
Weekly Docetaxel-based Chemotherapy Combinations
in Advanced Esophago-gastric Cancer
• DCF in gastric cancer: 35% RR,
TTP 5.6 mos, OS 9.2 mos
– 82% grade 3/4 neut., 30%
neut. fever, 20% diarr and
stomatitis
• Phase II:
– DCF: Doc 30 mg/m2 day 1
and 8, 5-FU 200 mg/m2/day
x 21 days, Cisplatin 60
mg/m2 day 1 vs.
– DX: Doc 30 mg/m2 day 1
and 8, Cape 1200
mg/m2/day x 14 days
DCF
DX
50
56
RR
49%
26%
Febrile
Neutro
4%
2%
Gr 3/4
Diar
10%
7%
Gr 3/4
Stomat
22%
2%
PFS
5.9 mos
4.2 mos
OS
12.8 mos
10.1 mos
Tebbutt et al. ASCO 2007. Abstract 4528
Challenging Cases in Cancer:
Integration of Findings from ASCO 2007
Pancreatic Cancer
Pancreatic Cancer: Current Therapy
• Primary Disease: Surgical Resection:
–
Only curative option
» <20-30% operable
» 5 yr survival 0-20%
–
Adjuvant:
» Chemo + RT: post op 5-FU/XRT (U.S)
» Chemo Alone: 5-FU + leucovorin (Europe, ESPAC trial), or Gemcitabine
alone (Europe, CONKO trial)
• Metastatic Disease:
–
Gemcitabine 1000 mg/m2/wk, 30 minute infusion
» RR 6%, median survival 5.6 mos, 1-yr survival 18%
–
Gem + second drug: negative phase III trials for 5-FU, cisplatin, irinotecan,
oxaliplatin, capecitabine
–
Gem + Erlotinib increases 1-year survival
–
ECOG: Gemcitabine FDR = Gemcitabine FDR + Oxaliplatin (10% RR, med.
Surv. 6 months)
Case 3: Pancreatic Adenocarcinoma
• A 56 year old man with worsening diabetic control
presents with abdominal pain and a 20 pound weight
loss
• A CT scan reveals a pancreatic mass and
innumerable hepatic metastases,
• Liver biopsy reveals pancreatic adenocarcinoma
• Past history is notable for now insulin dependent
diabetes, hypertension, peptic ulcer disease and
hypercholesterolemia.
• PS is 0
Case 3: Pancreatic Adenocarcinoma
Which treatment option would you recommend?
 Gemcitabine
 Gemcitabine by fixed dose rate infusion
 Gemcitabine + erlotinib
 Gemcitabine + capecitabine
 Gemcitabine + cisplatin/oxaliplatin
Case 3: Pancreatic Adenocarcinoma
• The patient was treated with
gemcitabine (FDR) and oxaliplatin
every 2 weeks.
• His CT scans showed substantial
response and he gained weight.
• After 4 months doses were reduced
due to thrombocytopenia.
• Erlotinib was added at 6 months
• Oxaliplatin was reduced to every
3rd cycle at 8 months, although
neuropathy remains grade 1.
• The patient continues on therapy at
22 months.
Case 3: Pancreatic Adenocarcinoma
CT Baseline
CT 3 months
CT 22 months
Pancreatic Cancer Abstracts: ASCO 2007
• Metastatic Disease, Phase III
–
–
–
–
Meta Analysis: gemcitabine vs. gem combination chemo
Second Line: 5-FU vs. 5-FU/oxaliplatin
SWOG S0205: gemcitabine ± cetuximab
CALGB 80303: gemcitabine ± bevacizumab
Gemcitabine vs. Gemcitabine + Another Drug?
HR
Survival
P-Value
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
0.04
N
1,108, 5 trials
574
Patients with good performance status benefit from Gemcitabine
combination chemotherapy: Gem + 5-FU/Cape, or Gem + platinum
agent. For poor PS, single agent Gem ± erlotinib
Heinemann , et al. ASCO 2007. Abstract 4515
CONKO-003
Phase III 5-FU+FA+Ox vs. 5-FU+FA, Second-line
• Primary endpoint: 2 month improvement in OS
– Patients with POD on Gemcitabine
• Secondary: TTP, RR, toxicity
N
5-FU+FA+Ox
76
5-FU+FA
89
TTP
OS
(N = 145)
(N = 130)
12.3 weeks
45 weeks
(10.9 – 123.7)
(40.5 – 49.5)
8 weeks
35.6 weeks
(6.4- 9.5)
(29.6 – 41.5)
P > 0.05
Riess , et al. ASCO 2007. Abstract 4517
SWOG S0205:
Study Schema
Stratify
Locally advanced vs.
metastatic
Prior pancreatectomy
Yes vs. No
Performance status
0/1 vs. 2
R
A
N
D
O
M
I
Z
E
Gemcitabine
+
Cetuximab
Gemcitabine
Philip et al. ASCO 2007. Abstract LBA4509
S0205:
Study Objectives
• Primary
– Overall survival
• Secondary
–
–
–
–
–
Time to treatment failure
Objective response
Pain and quality of life (QoL)
Toxicity
EGFR expression and its correlation with outcome
Philip et al. ASCO 2007. Abstract LBA4509
S0205:
Patient Characteristics
Gem + Cetux
(N = 366)
Gem
(N = 369)
Median Age (years)
63.7
64.3
Female
49%
46%
Performance Status 0/1
87%
87%
Locally Advanced
21%
22%
Measurable Disease
86.3%
88.3%
Prior Pancreatectomy
10%
11%
Philip et al. ASCO 2007. Abstract LBA4509
S0205 Primary Endpoint:
Survival of all Patients
Overall Survival by Treatment Arm
100%
Gemcitabine
Gemcitabine and Cetuximab
80%
N
369
366
Events
338
331
Median
in Months
5.9
6.4
P = 0.14
60%
HR = 1.09 (95% CI: 0.93, 1.27)
40%
20%
0%
0
12
24
Months After Registration
36
Philip et al. ASCO 2007. Abstract LBA4509
S0205:
Progression-free Survival
Progression-free Survival by Treatment Arm
100%
80%
Gemcitabine
N
369
Gemcitabine and Cetuximab
366
Events
360
Median
in Months
3.0
3.5
351
P = 0.058
60%
HR = 1.13 (95% CI: 0.97, 1.31)
40%
20%
0%
0
6
12
18
Months After Registration
24
30
Philip et al. ASCO 2007. Abstract LBA4509
S0205:
Objective Tumor Response
Gem + Cetux (%)
(N = 316)
Gem (%)
(N = 326)
CR
0
1
PR
12
13
SD
38
30
CR + PR + SD
50
44
PD
40
47
Response
Philip et al. ASCO 2007. Abstract LBA4509
CALGB 80303:
Trial Design
Advanced
Pancreatic
Cancer
N = 590
R
A
N
D
O
M
I
Z
E
Gemcitabine
Bevacizumab
Gemcitabine
Placebo
Stratification:
• Performance status: 0/1 vs. 2
• Extent of disease: metastatic vs. locally advanced
• Prior radiation: yes/no
Kindler et al. ASCO 2007. Abstract 4508
CALGB 80303: Endpoints
Primary Endpoint:
• Overall survival
Secondary Endpoints:
• Objective response rate
• Duration of response
• Progression-free survival
• Toxicity
Kindler et al. ASCO 2007. Abstract 4508
Patient Characteristics
Characteristic
Median age (years)
Male
Female
Performance status
0
1
2
Locally advanced
Metastatic
Prior radiation
Gemcitabine
Bevacizumab
(N = 302)
63.8
58%
42%
Gemcitabine
Placebo
(N = 300)
65.0
51%
49%
36%
53%
11%
15%
85%
11%
39%
52%
9%
16%
84%
11%
Kindler et al. ASCO 2007. Abstract 4508
CALGB 80303: Objective Response
Gemcitabine
Bevacizumab
Gemcitabine
Placebo
Complete
Response
1%
2%
Partial
Response
10%
8%
Stable
Disease
36%
31%
Disease Control:
CR + PR + SD
47%
40%
Kindler et al. ASCO 2007. Abstract 4508
0.6
0.8
Bevacizumab 4.9 mos
Placebo Bevacizumab
4.7 mos
Placebo
HR = 1.00
P = 0.99 HR=1.00
0.2
0.4
p=0.99
0.0
Proportion Surviving
1.0
CALGB 80303: Progression-free Survival by
Treatment Arm
0
5
10
15
20
25
Months from Study Entry
Kindler et al. ASCO 2007. Abstract 4508
0.8
Bevacizumab 5.8 mos
Placebo Bevacizumab
6.1 mos
Placebo
0.2
0.4
0.6
HR = 1.03
P = 0.78
0.0
Proportion Surviving
1.0
CALGB 80303:
Overall Survival by Treatment Arm
0
5
10
15
20
25
Months from Study Entry
Kindler et al. ASCO 2007. Abstract 4508
Conclusions
• Preoperative chemotherapy and preoperative chemoradiotherapy
for adjuvant treatment of GE junction adenocarcinoma
• Potential benefit with the addition of radiation to preoperative
chemotherapy with improvements in overall survival and local
disease control
• Advanced metastatic gastric cancer – new oral drug S1 has
promising activity as a single agent and significant activity in
combination with either irinotecan or cisplatin
• Modified DCF regimen has improved toxicity profile in the
treatment of advanced metastatic gastric cancer
• Important meta-analysis indicates gemcitabine combination
therapy with either a 5-FU or a platinum agent maybe used in
pancreatic cancer patients with good performance status