Adjuvant treatment of pancreatic AC
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Adjuvant treatment of pancreatic AC

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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

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

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Adjuvant treatment of pancreatic AC Adjuvant treatment of pancreatic AC Presentation Transcript

  • Adjuvant Treatment of Pancreatic Carcinoma 2013 Ahmed Zeeneldin, MD Associate Prof of Medical Oncology ENCI, 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 cmT2 Inside pancreas > 2 cmT3 Beyond pancreas Not Celiac axis NOT SMAT4 Beyond pancreas in Celiac axis or SMA (unresectable)N1 Regional LNsM1 Distant Metastases T1 T2 T3 T4 M1 No IA IB IIA III IV N1 IIB IIB IIB III IV
  • Surgery Localized and Bordeline resectable Irresectable ResectableM M0 M0 M1N Within resection field Within resection field Beyond resection fieldT T1, T2 T3 T4SMV &PV No abutment, Abutment, Ubreconstructable distortion, tumor encasement, or occlusion thrombus, or occlusion with safe encasement resection and reconstructionhepatic A Clear fat planes short segment Long segment around abutment or encasement encasementSMA Clear fat planes Abutment <180 Abutment >180 degrees around degreesceliac axis Clear fat planes No extension, extension, encasement or around encasement or abutment abutment
  • SurgeryFacts Impacts – Only curative measure – Only 15-20% of patients are potentially resectable – 5-y OS rates of R0 resection: • R0N0: 30% • R0N1: 10%
  • SurgeryFacts 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
  • Treatment of pancreatic carcinomaStage Surgery CRT RT CT Targeted 5FU therapy basedT1 Resectable Pancreatectomy No No ADJ NoT2T3 Bordeline Pancreatectomy Yes Yes NADJ No resectableT4 irresectable No Yes Yes Yes MayN1 Pancreatectomy if N1 in resection fieldM1 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. observation GITSG study Surgery 5FU based CRT 5FU: 500 mg/m2 IV bolus Maint ChemoR0 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 GyT1-T3 (2 wks apart)PS 0-2 (45% PS2) Observation Arch Surg. 1985;120(8):899-903.
  • Adj 5FU-based CRT vs. observation GITSG study Observation 5FU-based CRT P N 22 21 Median OS 11m 20m SThe study was terminated prematurely due to:1. an unacceptably low rate of accrual2. the observation of increasingly large survival differences between the study arms.
  • 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
  • Adj 5FU-based CRT vs. observation EORTC study Surgery 5FU based CRT 5FU: 25mg/kg/24h CIR0 first 3 days of each RT courseN0-N1 (40% N1) RT: two split courses each 20 Gy (2 wks apart)T1-T2PANCREAS 114 ptsPeriamp 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
  • 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
  • Adj 5FU-based CRT vs. observation EORTC study
  • ESPAC-1 Trial two reportsFear of poor accrual led the investigators to permit physicians to choose from 3 randomization schemes
  • ESPAC-1 Pooled analysis, 2001 CRT No CRT p CT No CT pAll 175 178 All 238 235Median OS 15.5 m 16.1 m 0.24 Median OS 19.7 m 14 m 0.0052x2 design 145 144 2x2 design 147 142Median 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
  • 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-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
  • 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
  • ESPAC-1 2nd report, 2004
  • ESPAC-1 2nd report Observation CRT CT Combinationn 69 73 72 72Median OS 16.9 m 13.9 m 21.6 m 19.9 m5-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 5 FU* FU CRT* 5 FUSurgerySM+ 33% Gem* FU CRT GemN1 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
  • 5FU vs gem CT before and after FU-based CRT RTOG FUàFUCRT àFU Gem à FUCRT àGem PTotal n 230Head (n = 388)G4 Toxicity Less (1%) More (14%) <0.001Median OS 16.9 m 20.5 m 0.09 Adjusted 0.05Median OS, update 17.1 m 20.5 m3 y OS rate 22% 31%5 y OS rate 8% 22%1st progression siteLocal recurrence 28% 23%Distant 70% 70%
  • 5FU vs gem CT before and after FU-based CRT RTOG
  • Adjuvant chemotherapy
  • ESPAC-1 trial Adj 5FU x 6 monthsPooled analysis 2x2 design CT No CT p CT No CT pN 238 235 N 147 142Median 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
  • Adjuvant combination chemotherapy (FAM x 6) followingresection 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.
  • Adj Gem vs. observation CONKO trial Gem 1000 mg/m2 W1-3 IV Q4 w x 6 cyclesSurgeryGross resection ObservationR0-R1 (R1in 19%)N0-N1 (N1 in 70%)T1-4 (T3 in 82%) J Clin Oncol 28:4450-4456. 2010
  • Adj Gem vs Observation Gem Observation PMedian 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/LV ESPAC-3 trial Gem 1000 mg/m2 W1-3 IV Q4 w x 6 cycles Surgery 5FU/LV LV: 20mg/m2 IV d1-5Gross resection 5FU:425mg/m2 IV d1-5 q 4 w x 6 cyclesR0-R1 (R1in 19%)N0-N1 (N1 in 70%)T1-4 (T3 in 82%) JAMA. 2010 ;304(10):1073-81.
  • Adj Gem vs FU Gem FU/LVz PMedian OS 23.6 m 23 m NSG4 stomatitis 0 10%Median DFS 14.3 m 14.1 m NS
  • Adj Gem vs. S1 JASPAC-01 study Gem 1000 mg/m2 W1-3 IV Q4 w x 6 cyclesSurgery 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)
  • Adj Gem vs. Adj Gem-based CRT GERCOR Phase II trial 8 weeks post CCRT Surgery Gem x 2 Weekly Gem 300 mg/m2R0 RT: 50.4 Gy in 5-6 WksT1-T4 (mostly T3)N0-N1 (2/3 N1) Gem x 4 J Clin Oncol 28:4450-4456. 2010
  • Adj Gem vs. Adj Gem-based CRT GERCOR Phase II trial Gem x 4 Gem x 2 à P Gem-CCRTTotal n (Treated n) 45 (42) 45 (gem 42 gemCRT 36)Tx completion 87% 73%G4 toxicity 0% 5%Median OS 24 m 24 m NSMedian DFS 11 m 12 m NS1st progression siteLocal 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 RT CT Targeted 5FU therapy basedT1 Resectable Pancreatectomy No No ADJ NoT2T3 Bordeline Pancreatectomy Yes Yes NADJ No resectableT4 Irresectable No Yes Yes Yes MayN1 Pancreatectomy if N1 in resection fieldM1 No No May Palliative May
  • Thank You Ahmed Zeeneldinazeeneldin@gmail.com