This is an overview of the adjuvant Tx of pancreatic CA. A Lecture that was given in the annual conference of NCI Egypt: 45 years against cancer in Egypt. Cairo, April, 2013

1. Adjuvant Treatment of Pancreatic
Carcinoma
2013
Ahmed Zeeneldin, MD
Associate Prof of Medical Oncology
ENCI, CU

2. Agenda
• Overview of TX and stages
• Why we need adjuvant Tx
• Indications for Adjuvant Tx
• Overview of the adjuvant strategies
– CRT
– CT
– RT
• summary

3. Treatment modalities
• Surgery:
• Radiotherapy
• Systemic therapy
– Chemotherapy:
• mono or poly
• Adjuvant, neoadjuvant, palliative
– Targeted therapy: erlotinib
• Supportive and palliative
– Jaundice
– Pain
– Gastric outlet obstruction
– Depression and malnutrition
– Pancreatic insufficiency
– Thromb-embolic disease

4. Staging of Pancreatic CA
T1 Inside pancreas < = 2 cm
T2 Inside pancreas > 2 cm
T3 Beyond pancreas Not Celiac axis NOT SMA
T4 Beyond pancreas in Celiac axis or SMA
(unresectable)
N1 Regional LNs
M1 Distant Metastases
T1 T2 T3 T4 M1
No IA IB IIA III IV
N1 IIB IIB IIB III IV

5. Surgery
Localized and Bordeline resectable Irresectable
Resectable
M M0 M0 M1
N Within resection field Within resection field Beyond resection field
T T1, T2 T3 T4
SMV &PV No abutment, Abutment, Ubreconstructable
distortion, tumor encasement, or occlusion
thrombus, or occlusion with safe
encasement resection and
reconstruction
hepatic A Clear fat planes short segment Long segment
around abutment or encasement
encasement
SMA Clear fat planes Abutment <180 Abutment >180 degrees
around degrees
celiac axis Clear fat planes No extension, extension, encasement or
around encasement or abutment
abutment

6. Surgery
Facts Impacts
– Only curative measure
– Only 15-20% of patients are
potentially resectable
– 5-y OS rates of R0 resection:
• R0N0: 30%
• R0N1: 10%

7. Surgery
Facts Impliactions
• Only curative measure • Do your best to have
surgery
• Only 15-20% of patients • Measures to increase
are potentially resctability i.e.
resectable neoadjuvant Tx
• 5-y OS rates of R0 • Meaures to improve
resection:
– R0N0: 30%
outcome i.e. adjuvant
– R0N1: 10% Tx

8. Treatment of pancreatic carcinoma
Stage Surgery CRT RT CT Targeted
5FU therapy
based
T1 Resectable Pancreatectomy No No ADJ No
T2
T3 Bordeline Pancreatectomy Yes Yes NADJ No
resectable
T4 irresectable No Yes Yes Yes May
N1 Pancreatectomy
if N1 in
resection field
M1 No No May Palliative May

9. Adjuvant therapy
• Indications:
– Resected: T1-T3, N0-N1
– Non-metastatic
• Modalities:
– Chemoradiotherapy: controversial
– Chemotherapy: confirmed
– Radiotherapy:
• Few data
• IORT

10. Adjuvant chemo-radiotherapy

11. Adj 5FU-based CRT vs. observation
GITSG study
Surgery 5FU based CRT
5FU: 500 mg/m2 IV bolus Maint Chemo
R0 first 3 days of each RT course 5FU 500 mg/m D1-
N0-N1 (30% N1)
RT: two split courses each 20 3 q month x 2 y
Gy
T1-T3 (2 wks apart)
PS 0-2 (45% PS2)
Observation
Arch Surg. 1985;120(8):899-903.

12. Adj 5FU-based CRT vs. observation
GITSG study
Observation 5FU-based CRT P
N 22 21
Median OS
11m 20m S
The study was terminated prematurely due to:
1. an unacceptably low rate of accrual
2. the observation of increasingly large survival
differences between the study arms.

13. Adj 5FU-based CRT vs. observation
extension study
Obs 5FU-based 5FU-based
CRT CRT*
Extension
N 22 21 30
Median OS 11m 20m 18 m
OS rate @
1-year 50% 67% 77%
2-years 18% 43% 46%
DFS rate @
1-year 41% 53% 71%
2-years 14% 48% 32%
Local recur 33% 47% 55%
Liver met 52% 40% 45%
* Better PS (0-1) Cancer 59:2006-2010, 1987

14. Adj 5FU-based CRT vs. observation
EORTC study
Surgery 5FU based CRT
5FU: 25mg/kg/24h CI
R0 first 3 days of each RT course
N0-N1 (40% N1) RT: two split courses each 20 Gy
(2 wks apart)
T1-T2
PANCREAS 114 pts
Periamp 104 pts Observation
EORTC trial Vs. GITSG trial:
• No maintenance 5-FU for two years
• 5-FU given in a different dose and by CI
• Second course 5-FU may be adjusted
• Inclusion of pancreatic CA and periampullary CA
Ann Surg. 1999 Dec;230(6):776-82

15. Adj 5FU-based CRT vs. observation
EORTC study
Obs 5FU-based CRT P
N 108 110
21 pts had no Tx
Toxicity Minor
Median OS: all 19 m 24.5 m 0.21
Median OS: Panc 12.6m 17.1m 0.09
2-years OS: all 41% 51% NS
2-years OS: Panc 23% 37% NS
Median PFS 16 m 17.4 m NS
2-y DFS 38% 37% NS
Site of 1st progression
Local recur 15 15
Liver met 29 32

16. Adj 5FU-based CRT vs. observation
EORTC study

17. ESPAC-1 Trial
two reports
Fear of poor accrual led the investigators to permit physicians to choose from
3 randomization schemes

18. ESPAC-1 Pooled analysis, 2001
CRT No CRT p CT No CT p
All 175 178 All 238 235
Median OS 15.5 m 16.1 m 0.24 Median OS 19.7 m 14 m 0.005
2x2 design 145 144 2x2 design 147 142
Median OS 15.8 m 17.8 m 0.09 Median OS 17.4 m 15.9 m 0.19
Positive resection margins and LN involvement were poor prognostic factors
THE LANCET • Vol 358 • November 10, 2001

19. ESPAC-1 Pooled analysis

20. ESPAC-1 pooled analysis, 2001
• Criticism:
– Bias: trial and CT or CRT choice
– Per protocol analysis and not intent to treat
analysis
– Split RT course and variable dose (40-60 Gy)
– No CT maintenance

21. ESPAC-1
Pooled analysis, 2001 2nd report, 2004
Lancet NEJM
• Criticism: • Corrections:
– Bias: trial and CT or CRT – Only 2x2 trial
choice
– Per protocol analysis and not – ITT analysis
intent to treat analysis
– Split RT course and variable – Same
dose (40-60 Gy)
– No CT maintenance
– same

22. ESPAC-1 2nd report
CRT No CRT p
n 145 144
Median OS 15.9 m 17.9 m 0.05
2y OS 29% 41%
5-y OS 10% 20%
CT No CT p
Local Rec 84% 74%
N 147 142
RFS 10.7 m 15.2 m
Median OS 20.1 m 15.5 m 0.009
2y OS 40% 30%
• After CRT, CT vs. no CT had no benefit
• CT delay may explain the inferior results 5-y OS 21% 8%
• Results are inferior than other reports of
CRT CT is beneficial whether CRT is given or not
• Toxicity may be the reason for poor
outcome n engl j med 350;12 18, 2004

23. ESPAC-1 2nd report, 2004

24. ESPAC-1 2nd report
Observation CRT CT Combination
n 69 73 72 72
Median OS 16.9 m 13.9 m 21.6 m 19.9 m
5-y OS 11% 7% 29% 13%
Not powered to compare 4 groups
n engl j med 350;12 18, 2004

25. 5FU vs gem CT before and after FU-based CRT
following resection of pancreatic adenocarcinoma
RTOG
5 FU* FU CRT* 5 FU
Surgery
SM+ 33%
Gem* FU CRT Gem
N1 65%
T3/4 in 70%
5FU: 250 mg/m2 CI q d x 3 w then FUCRT then same pre CRT dose for 12 w
Gem: 1000 mg/m2 IV q w x 3 w then FUCRT then same pre CRT dose for 12 w
FU CRT: 5FU: 250 mg/m2 CI q d with RT
JAMA, 2008—Vol 299, No. 9

26. 5FU vs gem CT before and after FU-based CRT
RTOG
FUàFUCRT àFU Gem à FUCRT àGem P
Total n 230
Head (n = 388)
G4 Toxicity Less (1%) More (14%) <0.001
Median OS 16.9 m 20.5 m 0.09
Adjusted 0.05
Median OS, update 17.1 m 20.5 m
3 y OS rate 22% 31%
5 y OS rate 8% 22%
1st progression site
Local recurrence 28% 23%
Distant 70% 70%

27. 5FU vs gem CT before and after FU-based CRT
RTOG

28. Adjuvant chemotherapy

29. ESPAC-1 trial
Adj 5FU x 6 months
Pooled analysis 2x2 design
CT No CT p CT No CT p
N 238 235 N 147 142
Median OS 19.7 m 14 m 0.005 Median OS 20.1 m 15.5 m 0.009
2y OS 40% 30%
5-y OS 21% 8%
THE LANCET • Vol 358 • November 10, 2001

30. Adjuvant combination chemotherapy (FAM x 6) following
resection of carcinoma of the pancreas and papilla of Vater
FAM CT No CT p
N 238 235
Median OS 23 m 11m 0.02
1-y OS rate 70% 45% S
2-y OS rate 43% 32% S
3-y OS rate 27% 30% NS
5-y OS rate 4% 8%
Adjuvant chemotherapy does postpone the incidence of
recurrence in the first 2 years following radical surgery
but increased cure rate was not observed
Eur J Cancer. 1993;29A(5):698-703.

31. Adj Gem vs. observation
CONKO trial
Gem
1000 mg/m2 W1-3 IV Q4 w x 6 cycles
Surgery
Gross resection
Observation
R0-R1 (R1in 19%)
N0-N1 (N1 in 70%)
T1-4 (T3 in 82%)
J Clin Oncol 28:4450-4456. 2010

32. Adj Gem vs Observation
Gem Observation P
Median OS 22.1 m 20.2 m 0.06 Update: 22.8 vs 20.2 m (0.005)
Median DFS 13.4 m 6.9 m <0.001 Both N0 & N1 and SM- & SM+
3 y DFS 23.5% 7.5%
5 y DFS 16.5% 5.5%
Local Rec 34% 41% Gem delay rather than prevent

33. Adj Gem vs. FU/LV
ESPAC-3 trial
Gem
1000 mg/m2 W1-3 IV Q4 w x 6 cycles
Surgery 5FU/LV
LV: 20mg/m2 IV d1-5
Gross resection 5FU:425mg/m2 IV d1-5 q 4 w x 6 cycles
R0-R1 (R1in 19%)
N0-N1 (N1 in 70%)
T1-4 (T3 in 82%)
JAMA. 2010 ;304(10):1073-81.

34. Adj Gem vs FU
Gem FU/LVz P
Median OS 23.6 m 23 m NS
G4 stomatitis 0 10%
Median DFS 14.3 m 14.1 m NS

35. Adj Gem vs. S1
JASPAC-01 study
Gem
1000 mg/m2 W1-3 IV Q4 w x 6 cycles
Surgery S1
40-60 mg PO qd d1-28 q 6 w x 4
Gem S1 P
2-y OS rate 53% 70% S
Leukopenia 39% 9%
Transaminitis 5% 1%
J Clin Oncol 30: 2012 (suppl 34; abstr 145)

36. Adj Gem vs. Adj Gem-based CRT
GERCOR Phase II trial
8 weeks post CCRT
Surgery Gem x 2 Weekly Gem 300 mg/m2
R0 RT: 50.4 Gy in 5-6 Wks
T1-T4 (mostly T3)
N0-N1 (2/3 N1)
Gem x 4
J Clin Oncol 28:4450-4456. 2010

37. Adj Gem vs. Adj Gem-based CRT
GERCOR Phase II trial
Gem x 4 Gem x 2 à P
Gem-CCRT
Total n (Treated n) 45 (42) 45 (gem 42
gemCRT 36)
Tx completion 87% 73%
G4 toxicity 0% 5%
Median OS 24 m 24 m NS
Median DFS 11 m 12 m NS
1st progression site
Local recurrence 24% 11%
Local & distant 13% 20%
Distant 42% 40%

38. Summary
• GITSG trial showed that 5FU-CRT à 2 y 5FU is
better than observation
– Median OS 20 m vs 11 m (P<0.05)
• EORTC trial (5FU-CRT) failed to confirm such
finding
– Median OS 17 m vs 13 m (p = 0.09)
• ESPAC-1 trial (5FU-CRT) showed a deleterious
CRT effect compared to no CRT
– Median OS 16 m vs 18m (p = 0.05)

39. Summary
• ESPAC-1 trial showed a survival benefit of Adj CT (
5FU x 6) vs no CT
– Median OS : 20 m vs 15 m (p <0.001)
• Updated CONKO trial showed a survival benefit of
Adj CT ( Gem x 6) vs observation
– Median OS: 23 m vs 20 m ( p 0.005)
• ESPAC-3 trial showed that Adj Gem is similar to
5FU/LV but with lower toxicities
• GERCOR trial showed that adj Gem is not inferior
to Gemx2 àGem-CRT
– Median OS: 24 m for both

40. Treatment of pancreatic carcinoma
Stage Surgery CRT RT CT Targeted
5FU therapy
based
T1 Resectable Pancreatectomy No No ADJ No
T2
T3 Bordeline Pancreatectomy Yes Yes NADJ No
resectable
T4 Irresectable No Yes Yes Yes May
N1 Pancreatectomy
if N1 in
resection field
M1 No No May Palliative May

41. Thank You
Ahmed Zeeneldin
azeeneldin@gmail.com