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

Thank You

Ahmed Zeeneldinazeeneldin@gmail.com