adjuvant treatment of pancreatic ac
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Adjuvant Treatment of Pancreatic Carcinoma
2013Ahmed Zeeneldin, MD
Associate Prof of Medical OncologyENCI, CU
Agenda
• Overview of TX and stages• Why we need adjuvant Tx• Indications for Adjuvant Tx• Overview of the adjuvant strategies
– CRT– CT– RT
• summary
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
Staging of Pancreatic CAT1 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
SurgeryLocalized and
ResectableBordeline resectable Irresectable
M M0 M0 M1
N Within resection field Within resection field Beyond resection field
T T1, T2 T3 T4
SMV &PV No abutment, distortion, tumor
thrombus, or encasement
Abutment, encasement, or
occlusion with safe resection and reconstruction
Ubreconstructableocclusion
hepatic A Clear fat planes around
short segment abutment or encasement
Long segment encasement
SMA Clear fat planes around
Abutment <180 degrees
Abutment >180 degrees
celiac axis Clear fat planes around
No extension, encasement or
abutment
extension, encasement or abutment
Surgery
Facts– Only curative measure – Only 15-20% of patients are
potentially resectable– 5-y OS rates of R0 resection:
• R0N0: 30% • R0N1: 10%
Impacts
Surgery
Facts• Only curative measure
• Only 15-20% of patients are potentially resectable
• 5-y OS rates of R0 resection: – R0N0: 30% – R0N1: 10%
Impliactions
• Do your best to have surgery
• Measures to increase resctability i.e. neoadjuvant Tx
• Meaures to improve outcome i.e. adjuvant Tx
Treatment of pancreatic carcinomaStage Surgery CRT
5FU based
RT CT Targeted therapy
T1T2
Resectable Pancreatectomy No No ADJ No
T3 Bordelineresectable
Pancreatectomy Yes Yes NADJ No
T4 irresectable No Yes Yes Yes May
N1 Pancreatectomyif N1 in resection field
M1 No No May Palliative May
Adjuvant therapy
• Indications:– Resected: T1-T3, N0-N1– Non-metastatic
• Modalities:– Chemoradiotherapy: controversial – Chemotherapy: confirmed– Radiotherapy:
• Few data• IORT
Adjuvant chemo-radiotherapy
Adj 5FU-based CRT vs. observationGITSG study
Surgery
R0N0-N1 (30% N1)T1-T3PS 0-2 (45% PS2)
5FU based CRT5FU: 500 mg/m2 IV bolus
first 3 days of each RT courseRT: two split courses each 20
Gy(2 wks apart)
Observation
Arch Surg. 1985;120(8):899-903.
Maint Chemo5FU 500 mg/m D1-3 q month x 2 y
Adj 5FU-based CRT vs. observationGITSG 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.
Adj 5FU-based CRT vs. observationextension study
Obs 5FU-basedCRT
5FU-basedCRT*Extension
N 22 21 30
Median OS 11m 20m 18 mOS 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
Adj 5FU-based CRT vs. observationEORTC study
Surgery
R0N0-N1 (40% N1)T1-T2PANCREAS 114 ptsPeriamp 104 pts
5FU based CRT5FU: 25mg/kg/24h CI
first 3 days of each RT courseRT: two split courses each 20 Gy
(2 wks apart)
Observation
Ann Surg. 1999 Dec;230(6):776-82
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
Adj 5FU-based CRT vs. observationEORTC study
Obs 5FU-based CRT P
N 108 11021 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
Adj 5FU-based CRT vs. observationEORTC study
ESPAC-1 Trialtwo reports
Fear of poor accrual led the investigators to permit physicians to choose from 3 randomization schemes
ESPAC-1 Pooled analysis, 2001
CRT No CRT p
All 175 178
Median OS 15.5 m 16.1 m 0.24
2x2 design 145 144
Median OS 15.8 m 17.8 m 0.09
CT No CT p
All 238 235
Median OS 19.7 m 14 m 0.005
2x2 design 147 142
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
ESPAC-1 Pooled analysis
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
ESPAC-1Pooled analysis, 2001
Lancet• 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
2nd report, 2004NEJM
• Corrections:– Only 2x2 trial
– ITT analysis
– Same
– same
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%
Local Rec 84% 74%
RFS 10.7 m 15.2 m
CT No CT p
N 147 142
Median OS 20.1 m 15.5 m 0.009
2y OS 40% 30%
5-y OS 21% 8%• After CRT, CT vs. no CT had no benefit• CT delay may explain the inferior results • Results are inferior than other reports of
CRT• Toxicity may be the reason for poor
outcome n engl j med 350;12 18, 2004
CT is beneficial whether CRT is given or not
ESPAC-1 2nd report, 2004
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
5FU vs gem CT before and after FU-based CRT following resection of pancreatic adenocarcinoma
RTOG
Surgery5 FU* FU CRT* 5 FU
Gem* FU CRT Gem
JAMA, 2008—Vol 299, No. 9
5FU: 250 mg/m2 CI q d x 3 w then FUCRT then same pre CRT dose for 12 wGem: 1000 mg/m2 IV q w x 3 w then FUCRT then same pre CRT dose for 12 wFU CRT: 5FU: 250 mg/m2 CI q d with RT
SM+ 33%N1 65%T3/4 in 70%
5FU vs gem CT before and after FU-based CRTRTOG
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 0.09Adjusted 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%
5FU vs gem CT before and after FU-based CRTRTOG
Adjuvant chemotherapy
ESPAC-1 trialAdj 5FU x 6 months
Pooled analysis
CT No CT p
N 238 235
Median OS 19.7 m 14 m 0.005
2x2 design
THE LANCET • Vol 358 • November 10, 2001
CT No CT p
N 147 142
Median OS 20.1 m 15.5 m 0.009
2y OS 40% 30%
5-y OS 21% 8%
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 ofrecurrence in the first 2 years following radical surgerybut increased cure rate was not observed
Eur J Cancer. 1993;29A(5):698-703.
Adj Gem vs. observationCONKO trial
J Clin Oncol 28:4450-4456. 2010
SurgeryGem
1000 mg/m2 W1-3 IV Q4 w x 6 cycles
Observation Gross resectionR0-R1 (R1in 19%)N0-N1 (N1 in 70%)T1-4 (T3 in 82%)
Adj Gem vs ObservationGem 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
Adj Gem vs. FU/LVESPAC-3 trial
JAMA. 2010 ;304(10):1073-81.
Surgery
Gem 1000 mg/m2 W1-3 IV Q4 w x 6 cycles
5FU/LVLV: 20mg/m2 IV d1-5
5FU:425mg/m2 IV d1-5 q 4 w x 6 cyclesGross resectionR0-R1 (R1in 19%)N0-N1 (N1 in 70%)T1-4 (T3 in 82%)
Adj Gem vs FUGem FU/LVz P
Median OS 23.6 m 23 m NS
G4 stomatitis 0 10%
Median DFS 14.3 m 14.1 m NS
Adj Gem vs. S1JASPAC-01 study
J Clin Oncol 30: 2012 (suppl 34; abstr 145)
SurgeryGem
1000 mg/m2 W1-3 IV Q4 w x 6 cycles
S140-60 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%
Adj Gem vs. Adj Gem-based CRTGERCOR Phase II trial
8 weeks post Surgery
R0T1-T4 (mostly T3)N0-N1 (2/3 N1)
Gem x 2CCRT
Weekly Gem 300 mg/m2RT: 50.4 Gy in 5-6 Wks
Gem x 4
J Clin Oncol 28:4450-4456. 2010
Adj Gem vs. Adj Gem-based CRTGERCOR Phase II trial
Gem x 4 Gem x 2 àGem-CCRT
P
Total n (Treated n) 45 (42) 45 (gem 42gemCRT 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%
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)
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
Treatment of pancreatic carcinomaStage Surgery CRT
5FU based
RT CT Targeted therapy
T1T2
Resectable Pancreatectomy No No ADJ No
T3 Bordelineresectable
Pancreatectomy Yes Yes NADJ No
T4 Irresectable No Yes Yes Yes May
N1 Pancreatectomyif N1 in resection field
M1 No No May Palliative May
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