Saint Agnes Medical Center
Oncology Symposium
October 15, 2011
Neoadjuvant, Adjuvant
and Palliative Management
Marshall Flam, MD
Hematology, Oncology Medical Group
00
01 yea
r
-0
4 s
y
05 e a
-0 rs
9
y
10 e a
-1 rs
4
1 5 ye a
-1 rs
9
y
20 e a
-2 rs
4
2 5 ye a
-2 rs
9
3 0 ye a
-3 rs
4
y
35 e a
-3 rs
9
4 0 ye a
-4 rs
4
4 5 ye a
-4 rs
9
y
50 e a
-5 rs
4
5 5 ye a
-5 rs
9
6 0 ye a
-6 rs
4
y
65 e a
-6 rs
9
7 0 ye a
-7 rs
4
y
75 e a
-7 rs
9
8 0 ye a
-8 rs
4
ye
85 ars
+
ye
ar
s
Age Specific Incidence Rates of Pancreas Cancer,
in California, by Race, 1988-2008
140
120
100
80
Rate/100,000
60
NH White rate
40
Black rate
20
0
Age at DX
Courtesy of Paul Mills, PhD, MPH
Stage at Diagnoses of PAC
Stage at DX
% of Patients
5 Yr. Survival
Distant Metastases
50
2%
Locally Advanced
Un-resectable
30
7%
Curative Resection of Operated
50 (10)
20%
Metastases Found at Surgery
Un-resectable
50 (10)

SINGLE AGENT CHEMOTHERAPY
Overall Survival: Gemcitabine vs 5-FU
Fixed Dose Rate vs. Standard Rate
Toxicity Summary
Grade 3 and 4 Toxicities
(% of Patients)
Toxicity per Patient
FDR
Standard
Anemia
23.3
20.9
37.2
18.4
14.3
10.2
48.8
39.5
7.3
4.7
26.5
22.5
2.2
8.2
Nausea/vomiting
Thrombocytopenia
Neutropenia
Leukopenia
ALT
Diarrhea
Abbreviation: FDR, fixed dose rate.
Assessment of Clinical Benefit
Analgesic
Consumption
Pain
Intensity
Performance
Status
PAIN
Responder
Improvement in both
Parameters. Stable in one
parameter, Improvement in
The other parameter
STABLE
In both Parameters
Non-responder
Worsening in either
Parameter
WEIGHT
Responder
Responder
> 7% Increase in body weight
Stable or decreased weight

COMBINATION CHEMOTHERAPY
Phase III Trials of Chemotherapy
in Advanced Pancreatic Cancer
Regimen
OS (mos)
5FU OS (mos)
P Value
RR (%)
5FU RR %
Gemcitabine + 5FU
6.7
5.4
0.09
9.9
5.6
Gemcitabine + Irinotecan
6.3
6.6
0.789
16.1
4.4
Gemcitabine + Cisplatin
7.5
6
0.15
10.2
8.2
Gemcitabine + Oxaliplatin
9.0
7.1
0.13
26.8
17.3
Gemcitabine + Premetrexed
6.2
6.3
0.848
14.8
7.1
Capecitabine + Gemcitabine
7.4
6
0.026
14.0
7.0
EGOC Trail: Survival –
Gemcitabine vs GEMOX
French Trial:
Survival Gemcitabine vs GEMOX
Objective Responses in the
Intention-to-Treat Population
Progression-free Survival
Overall Survival

TARGETED THERAPIES
Summary of the CAN-NCIC PA.3 Phase III Trial
Gemcitabine +Erlotinib vs Gemcitabine Alone
in Advanced Pancreatic Cancer
Gemcitabine
+
Erlotinib
No. of Patients
Response Rate
Median Survival
1 Yr. Survival
Rate
Progression-Free
Survival
285
8.6%
6.24 mos
23%
Gemcitabine
Alone
Hazard
Ratio
P Value
284
----- ------8.0%
----- ------5.91 mos 0.82 .038
17%
----- -------
3.75 mos 3.55 mos 0.77 .004
Data from Moore et al.23,24
Phase III Trial of Bevacizumba + Gemcitabine in Patients with
Advanced Pancreatic Cancer:
Median Overall and Progression-Free Survival
Gemcitabine +
Bevacizumab
Median Overall
Survival
(95% CI)
Progression-Free
Survival
(95% CI)
Gemcitabine
+ Placebo
5.7 mos
6.0 mos
(4.9, 6.5)
(5.0, 6.9)
4.8 mos
4.3 mos
(4.3, 5.7)
(3.8, 5.6)
P Value
0.40
----0.99
-----
Hazard
Ratio
1.09
------1.0
-------
Data from Kindler et al.11

SECOND LINE THERAPIES
Clinical Trials Investigating second-line combination chemotherapy in gemcitabinepretreated patients with advanced pancreatic cancer
Treatment Regimen
No. of
patients
Metastatic
Disease (%)
RR
(%)a
DCR
(%)a
PFS/TTP
(months)
OS
(months)
Oxa/5-FU CI/LV vs. BSC14
46
NA
NA
NA
OFF: 5.25
BSC: 2.5
OFF: 10
BSC: 8.5
Oxa/5-FU CI/LV vs. 5-FU CI/LV36, 27
168
OFF: 85.5
FF: 89.2
NA
NA
OFF: 3.25
FF: 2.25
OFF: 6.5
FF: 3.25
Oxa/5-FU CI/LV28
30
97
23
53
5.1
5.8
FOLFOX-429
42
83
14
52
4
6.7
Modified FOLFOX(a) vs. modified
FOLFIRI.3(b)30
(a) 30
(b) 30
NA
NA
(a) 20
(b) 28
(a) 1.4
(b) 1.9
(a) 4
(b) 4
Oxa/5-FU CI31
18
94.5
0
17
0.9
1.3
Oxa + Gem33
33
64
21
58
4.2
6.0
Oxa + Cap34
39
NA
3
23
NA
5.8
Oxa + Cap36
15
100
7
40
4.1
10
Oxa + irinotecan37
30
100
10
33
4.1
5.9
Oxa + pemetrexed38
16
NA
20
60
3.3
NA
Oxa + ralitrexed39
41
100
24
51
1.8
5.2
L-Cisplatin
24
79
8
67
NA
4.0
Cisplatin + irinotecan + Gem + 5-FU
+ LV41
34
100
34
55
3.9
10.3
Cisplatin + S-142
17
53
29
NA
NA
9.0
Cap + Gem + docetaxel43
35
100
29
60
NA
11.2
Mitomycin + docetaxel + Irinotecan44
15
100
0
20
1.7
6.1
Irinotecan + ralitrexed18
19
100
16
47
4.0
6.5
+ Gem40
a Intention-to-treat analysis.
b KPS 80-100%
(OFF:77;
FF91)
CONKO 003
Phase II trial of capecitabine + erlotinib in
gemcitabine-refractory advanced pancreatic cancer
ADJUVANT THERAPY
FOLLOWING RESECTION OF PAC

Key Trials of Adjuvant Therapy in
Resectable Pancreatic Cancer
Trial
GITSG (1985)
Regimen
5FU + 40GY XRT
Surgery Only
GITSG (1987)
EORTC (1999)
5FU + 40GY XRT
5FU + 40GY XRT
Surgery Only
# of Patients
Median Survival
(mos)
21
20
22
11
30
18
110
17.1
108
12.6
ESGCP (2004)
Chemoradiotherapy
145
15.9
ESGCP (2004)
No Chemoradiotherapy
144
17.9
Maintenance Chemotherapy
142
20.1
No Maintenance Chemotherapy
147
15.5
5FU + 50.4Gy
270
16.7
Gemcitabine + 5FU + 50.4Gy
268
18.8*
Gemcitabine
179
22.1
177
20.2
RTOG (2006)
CONKO-001 (2007)
Surgery Only
* Statistically Significant
NEO-ADJUVANT
(PRE-OPERATIVE) THERAPY
Advantages Pre-operative Chemo radiation
over Post-operative Chemo radiation








More effective chemotherapy delivery with an intact blood supply
Avoidance of hypoxia related chemo radiation resistance
Avoidance of late radiation toxicity by surgical removal of irradiated duodenum and use
of unirradiated jejunum use in reconstruction
Immediate use of systemic therapy for a disease that is systemic at diagnosis in
the majority of patients
Improved patient selection for pancreatic surgery
Pancreatic surgery is safer following chemo radiation due to reduced risk of
pancreatic anastomotic leak due to pancreatic fibrosis
Timely access to therapy. No delays due to post-operative recovery complications
Increases R0 (complete) resection rates in patients with borderline resectable
tumors
Operability Classification of Localized PAC based on
high-quality cross-sectional imaging

Resectable

Borderline Resectable

Locally Advanced

Metastatic
Selected Trials of Neoadjuvant Chemoradiation for
Patients with Potentially Resectable Pancreatic Cancer
Author
Evaluable
Patients
EBRT
Dose (Gy)
Resected
Chemotherapy
Regimen
Median Survival
All Patients (Mo)
Median Survival
Resected Patients (Mo)
Evans et al. (119)
28
17 (61%)
50.4 + IORT
CI 5-FU
NA
18
Hoffman et al. (121)
53
24 (45%)
50.4
Bolus 5-FU
9.7
15.7
Pisters et al. (120
35
20 (57%)
30 + IORT
PVI 5-FU
7
25
White et al.
53 resectable
28 (53%)
45
PVI 5-FU
NR
NR
Moutardier et al (261)
19
15 (79%)
30 or 45
Bolus 5-FU +
CDDP
20
30
Arnoletti et al (262)
26
14 (54%)
59.4
5-FU and/or MMC or
NA
34
Gem
Pisters et al. (123)
35
20 (57%)
30 and 10 IORT
Paclitaxel
12
19
Wolff et al. (125)
86
64 (75%)
30
Gem
22
36
Magnin et al. (263)
32
19 (59)%
30 or 45
PVI 5-FU + CDDP
16
30
Talamonti et al. (126)
20
17 (85%)
36 Gy
Gem
NA
NA
Kaplan-Meier curves compare overall survival in patients
according to timing of systemic therapy.
MS indicate medial survival.
Kaplan Meier curves compare overall survival in patients with extra
pancreatic disease (ie, T3 or T4 Disease) according to timing of
sytematic therapy. MS indicates median survival.
Add Title
Need Title
Survival adjusted for age, sex, and comorbidity for patients receiving
treatment versus untreated patients.
Need Title
Kaplan-Meier overall survival curves in patients with good Karnofsky performance
score (90 to 100). Gem, gemcitabine; GemCap, Gemcitabine plus capecitabine.