The Essential Role of Radiotherapy in Pancreatic Cancer · 1 The Essential Role of Radiotherapy in...

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


Theory – Multi-modality Therapy

Efficacy of SYSTEMIC therapy

5FU

Gem

Gem/Abraxane

FOLFIRINOX

Impo

rtan

ceof

LOCA

L th

erap

y


Agenda



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


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.


GITSG 9173 – Resected PCa

Kalser MH, et al. Arch Surg. 1985;120(8):899-903.


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.


EORTC 40891 – Resected PCa Subset

Garofalo MC, et al. Ann Surg. 2006;244(2):332-333.


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


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)


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.


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*


Agenda


15Winship Cancer Institute | Emory UniversityRyan DP, et al. N Engl J Med. 2014;371(22):2140-2141.


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.


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.


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


SBRTSBRT


Modern RT Delivery Systems

Target Definition

Patient Immobilization

Image guidance

Motion management

Inverse planning IMRT

SBRT


SBRT Workflow

Fiducials

Image Guidance

Immobilization

Motion Management

Inverse Planning


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 +++ ++ ?


Emory SBRT Study – Borderline PCa

Schema

Radiation Dose Escalation

Shaib WL, et al. Int J Radiat Oncol Biol Phys. 2016;96(2):296-303.


36 Gy

45 Gy


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.


Agenda



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


LAP07 Study Schema


LAP07 - Results

Hammel P, et al. JAMA. 2016;315(17):1844-1853.


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)


NCDB Analysis - LAPC

Chemoradiation

Chemotherapy

Zhong, P Patel et al. Unpublished data.


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.


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.


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.


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%


Theory – Multi-modality Therapy

Efficacy of SYSTEMIC therapy

5FU

Gem

Gem/Abraxane

FOLFIRINOX

Impo

rtan

ceof

LOCA

L th

erap

y



• Adjuvant CT -> CRT• Neoadjuvant CRT

• CT -> CRT• CT -> SBRT

• CT -> CRT• CT -> SBRT


Thank you!

The Essential Role of Radiotherapy in Pancreatic Cancer · 1 The Essential Role of Radiotherapy in...

Documents

Transcript of The Essential Role of Radiotherapy in Pancreatic Cancer · 1 The Essential Role of Radiotherapy in...