1
The Essential Role of Radiotherapy in Pancreatic Cancer
Pretesh Patel, MDAssistant ProfessorRadiation OncologyWinship Cancer Institute, Emory University
2Winship Cancer Institute | Emory University
Agenda
Resectable Borderline Advanced
3Winship Cancer Institute | Emory University
Theory – Multi-modality Therapy
Efficacy of SYSTEMIC therapy
5FU
Gem
Gem/Abraxane
FOLFIRINOX
Impo
rtan
ceof
LOCA
L th
erap
y
4Winship Cancer Institute | Emory University
Agenda
Resectable Borderline Advanced
5Winship Cancer Institute | Emory University
Loco-regional Failure after Surgery
50%(13/26)
MGH ExperienceTepper et al. Cancer 1976
75%(18/24)
JapanHishinuma et al. J of Gastrointest Surg2006
72%(56/78)
ItalySperti et al.World J Surg 1997
6Winship Cancer Institute | Emory University
GITSG 9173 – Resected PCa
RANDOMIZE
N=42• R0 Resection• Excluded ampullary• No peritoneal disease
Observation
5FU+radiation -> 5FU- 40 Gy / 20 fx split
Kalser MH, et al. Arch Surg. 1985;120(8):899-903.
7Winship Cancer Institute | Emory University
GITSG 9173 – Resected PCa
Kalser MH, et al. Arch Surg. 1985;120(8):899-903.
8Winship Cancer Institute | Emory University
EORTC 40891 – Resected PCa
RANDOMIZE
N=218• T1-2N0-1 pancreas• T1-3N0-1 periampullary
Observation
5FU+radiation40 Gy / 20 fx split
Klinkenbijl JH, et al. Ann Surg. 1999;230(6):776-782.
9Winship Cancer Institute | Emory University
EORTC 40891 – Resected PCa Subset
Garofalo MC, et al. Ann Surg. 2006;244(2):332-333.
10Winship Cancer Institute | Emory University
Resected Pca – Randomized TrialsTrial N Treatment Arms R1-2 DFS/PFS
(mo)Median
Survival (mo)OS
GITSG(74-82)
43 ObsCRT then 5fu
NA 911
1120
15%42%
EORTC(87-95)
218 Obs5FU CRT
22% 14.418
19.224.5
22%25%
ESPAC-1(94-00)
289 No CT vs. CTNo CRT vs. CRT
18% 9.4 vs 15.315.2 vs 10.7
15.5 v. 20.117.9 v.15.9
8 vs 21%20 vs 10%
RTOG 9704(98-02)
451 5FU, CRT, 5FUGem, CRT, Gem
34% No diff 17.120.5
18%22%
CapR1(04-07)
132 5FU5FU/Cis+RT
39% 1115
2628
11Winship Cancer Institute | Emory University
Resected Pca – Randomized TrialsTrial N Treatment Arms R1-2 DFS/PFS
(mo)Median
Survival (mo)OS
CONKO(98-04)
368 ObsGem
17% 6.713.4
20.222.8
10%21%
ESPAC-2(87-95)
218 Obs5FU CRT
22% 14.418
19.221.6
22%25%
ESPAC-3(00-07)
1088 Gem5FU
35% 1414
2323
49% (2y)48% (2y)
ESPAC-4(08-14)
730 GemGem+5FU
60% 1314
2628
52% (2y)54% (2y)
12Winship Cancer Institute | Emory University
Resected Pca - Hopkins/Mayo Experience
• N=1092
• More adverse features in CRT group
• Grade 3-4: 58% vs. 51%• R1-2: 35% vs. 31%
• MS 21 vs. 15 months
Hsu CC, et al. Ann Surg Oncol. 2010;17(4):981-990.
13Winship Cancer Institute | Emory University
Resectable Pca - Neoadjuvant CRT Trial N Chemo
RegimenRT
DoseResection rate (%)
R1-2(%)
Median OS (mo)
Varadhacharay(JCO 2008)
79 Gem+Cis -> Gem
30 Gy 66 4 31* vs. 10
Evans et al. (JCO 2008)
86 Gem 30 Gy 74 11 34* vs. 7
Turrini et al. (Eur J Surg Onc 2010)
34 Doc 45 Gy 50 0 32*
Hong et al. (IJROBP 2014)
50 5FU 25 GyE(short course)
77 16 27*
14Winship Cancer Institute | Emory University
Agenda
Resectable Borderline Advanced
15Winship Cancer Institute | Emory UniversityRyan DP, et al. N Engl J Med. 2014;371(22):2140-2141.
16Winship Cancer Institute | Emory University
ALLIANCE A021101 – Borderline PCa
N=26• SMV/PV ≥180°• Any CHA involvement if reconstructable• SMA < 180°
mFOLFIRINOXCRT
50.4 Gy + 5FU
Surgery
[+Gem x2]
Katz MH, et al. JAMA Surg. 2016;151(8):e161137.
17Winship Cancer Institute | Emory University
ALLIANCE A021101 – Borderline PCa
• Median survival 21.7 mo
• Radiologic response 26%
• 15/22 patients resected (68%)
• 14/15 R0 resection (93%)
• 5/15 had < 5% viable cells
Katz MH, et al. JAMA Surg. 2016;151(8):e161137.
18Winship Cancer Institute | Emory University
Borderline Pancreatic CaTrial N Regimen Resected R0 Survival
Katz, 2016 22 FOLFIRINOX -> CRT 68% 93% 21.7 mo
Takahashi, 2013 80 Gem-RT 54% 98% 34% 5y
Dholakia 2013 50 Gem/FOLFIRINOX ->CRT 58% 93% 17.2mo
Stokes, 2011 40 Cape-RT 40% 75% NR
Kim E, 2013 39 GEMOX-RT 62% NR 18.4 mo
Chun, 2010 109 Gem-RT or Cape-RTSurgery alone
100%100%
59%11%
23 mo15 mo
Katz, 2012 115 GemCis -> CRT 84% 95% 33 mo
Kharofa J, 2012 12 FOLFIRINOX -> CRT 58% 100% MS not reached
19Winship Cancer Institute | Emory University
SBRTSBRT
20Winship Cancer Institute | Emory University
Modern RT Delivery Systems
Target Definition
Patient Immobilization
Image guidance
Motion management
Inverse planning IMRT
SBRT
21Winship Cancer Institute | Emory University
SBRT Workflow
Fiducials
Image Guidance
Immobilization
Motion Management
Inverse Planning
22Winship Cancer Institute | Emory University
Comparison
3D IMRT SBRT
Biologic Dose ++ ++ / +++ ++++
Treatment Time 5-6 weeks 3-6 weeks 1 week
Irradiation volume Largest Varies Small
Elective Nodal Irradiation
Yes Yes/No No
Acute toxicity ++++ ++ +
Late toxicity +++ ++ ?
23Winship Cancer Institute | Emory University
Emory SBRT Study – Borderline PCa
Schema
Radiation Dose Escalation
Shaib WL, et al. Int J Radiat Oncol Biol Phys. 2016;96(2):296-303.
24Winship Cancer Institute | Emory University
36 Gy
45 Gy
25Winship Cancer Institute | Emory University
Emory SBRT Study – Borderline PCa
• DLT not reached • 8/13 (61%) resected• 100% R0 resection• Median FU 18 mo• 3/13 patients disease free
Shaib WL, et al. Int J Radiat Oncol Biol Phys. 2016;96(2):296-303.
26Winship Cancer Institute | Emory University
Agenda
Resectable Borderline Advanced
27Winship Cancer Institute | Emory University
Locally Advanced Pancreatic CancerTrial Treatment Arms N LF OS
GITSG (1988) 5FU-RT (54 Gy) -> SMFSMF
2221
45%48%
9.7mo7.4moP<0.02
ECOG (1985) 5FU-RT (40 Gy) -> 5FU5FU
4744
32%32%
8.3 mo8.2 mo
FFCD (2008)
5FU-CDDP-RT (60 Gy)Gem
5960
NRNR
8.6 mo13 moP=0.03
ECOG (2011) Gem-RT (50.4 Gy) -> GemGem
3437
12%30%
11 mo9.2 moP=0.017
Scallop (2013) Gem-Cape -> Gem-RTGem-Cape -> 5FU-RT
3836
NRNR
13.4 mo15.2 mo
28Winship Cancer Institute | Emory University
LAP07 Study Schema
29Winship Cancer Institute | Emory University
LAP07 - Results
Hammel P, et al. JAMA. 2016;315(17):1844-1853.
30Winship Cancer Institute | Emory University
LAP07 – Comments
• Single agent Gemcitabine now considered substandard
• Only 32% radiotherapy delivered per protocol
• Results confirm ACTIVITY of Chemoradiation• Progression-free survival borderline – 9.9 vs. 8.4 months (p=0.06)• Locoregional progression improved – 32% vs. 46% (p=0.04)
• Longer chemotherapy-free interval following chemoradiation• 6.1 vs. 3.7 months (p=0.02)
31Winship Cancer Institute | Emory University
NCDB Analysis - LAPC
Chemoradiation
Chemotherapy
Zhong, P Patel et al. Unpublished data.
32Winship Cancer Institute | Emory University
Phase II: Multi-Institutional SBRT Trial for LAPC
Gem x1 SBRT (6.6 Gy x 5) Gem
• Johns Hopkins, MSKCC, Stanford• N=49• Median OS 13.9 mo• Freedom from local progression: 1yr 78%• Late grade 2+ toxicity: 11% (1’ endpoint)
Herman JM, et al. Cancer. 2015;121(7):1128-1137.
33Winship Cancer Institute | Emory University
Phase II: Multi-Institutional SBRT Trial for LAPC
• PET-avid tumor worse survival on MVA (13.6 vs 18.8 mo, SS)• QOL scores unchanged pre- and post-SBRT
Herman JM, et al. Cancer. 2015;121(7):1128-1137.
34Winship Cancer Institute | Emory University
LAPC – Ablative IMRT
• Retrospective series MDACC• N=200
• Induction chemotherapy • 21% FOLFIRINOX
• Chemoradiation (Xeloda)• RT dose based on distance to
luminal GI structure
Krishnan S, et al. Int J Radiat Oncol Biol Phys. 2016;94(4):755-765.
35Winship Cancer Institute | Emory University
LAP07 v. IMRT v. SBRT
LAP07Gem
LAP075FU+RT
5FU+ Ablative IMRT
Gem+SBRT
Median PFS 8.4 mo 9.9 mo 8.6 mo 7.6 mo
FFLP NR NR 2yr: 50% 1yr: 78%
Median OS 16.5 mo 15.2 mo 17.8 mo 13.9 mo
2yr OS ~22% ~23% 36% 18%
G3/4 Fatigue NR NR 0% 0%
G3/4 GI 1% 13.7% 2% 8%
36Winship Cancer Institute | Emory University
Theory – Multi-modality Therapy
Efficacy of SYSTEMIC therapy
5FU
Gem
Gem/Abraxane
FOLFIRINOX
Impo
rtan
ceof
LOCA
L th
erap
y
37Winship Cancer Institute | Emory University
Resectable Borderline Advanced
• Adjuvant CT -> CRT• Neoadjuvant CRT
• CT -> CRT• CT -> SBRT
• CT -> CRT• CT -> SBRT
38Winship Cancer Institute | Emory University
Thank you!