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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 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

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