the multi-modality clinical model for sbrt/sabr...

12/12/2016

1

Stereotactic Body Radiation Therapy (SBRT)

for Pancreatic Cancer

December 9, 2016

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The Multi-Modality Clinical Model for

SBRT/SABR

(Pancreatic Cancer)

Pancreatic Cancer: Stereotactic Body Radiation

Therapy (SBRT) & Translational Paradigms

Joseph Herman, MD, MSc

Professor

Director, Clinical Research

Department of Radiation Oncology

MD Anderson Cancer Center

12/12/2016

2

Disclosure

Relevant Financial Relationship(s)

AbbVie, Oncosil, and BTG: Consulting

Viragh Family Foundation: Funding for trial

Gonzalez and McKnight Family Foundations:

Translational Studies

Off Label Usage

Aduro: GVAX

Merck: Pembro

Overview

• In 2015, approximately 48,960 people

were diagnosed with PCA

• Nearly 40% of PCA patients present

with non-metastatic “localized” disease

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What stage am I?

• Resectable

• Borderline Resectable

• Unresectable or Locally Advanced

• Metastatic (tumor spread beyond the

pancreas and to another location)

Pancreatic MDC: Case Review

Review Images

CT/PET/MRI/

EUS

Discuss Case

and reach

consensus

Review

Pathology

See patients and

discuss options

Present Cases

using outline

Enroll in trials/studies

Dictate note and cc toreferring physician

Nutrition, Pain, Enzymes

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• Where is my pancreas?

• Where is my tumor?

Resectability: Contact with Veins

Less than 180º More than 180º Deformity

Slide(s) courtesy of Dr.

Mahmoud Al-Hawary ** Veins can be reconstructed

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Resectability: Contact with Arteries

Less than 180º More than 180º Deformity

Assessment based on:

• Degree of tumor contact with the vessel circumference

• Whether vessel caliber narrowing or contour deformity is present

Slide(s) courtesy of Dr. Mahmoud Al-Hawary

Difficult to resect arteries

Prospective Identification of Anatomically

Resectable Pancreatic Cancer by CT Scan

1. Absence of disease

outside of the pancreas

2. Tissue plane between

tumor and SMA/CA

3. Open SMV-PV confluence

2

3

1

Use of these criteria yield high rates of microscopically complete (R0) resection

T

VA

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Borderline Resectable and Locally

Advanced Pancreatic Cancer

Borderline Resectable Locally Advanced (Unresectable)

• Tumor abuts a major blood vessel(s)

• Deemed resectable

• Neoadjuvant therapy recommended

• Tumor encases a major blood vessel(s)

• Deemed unresectable or LAPC

• New role for “definitive therapy”

Patient Selection?

SMA

SMA

Resection Determined by Vessel

Involvement

AHPBA/SSO/SSAT/NCCN

Resectable BorderlineLocally

Advanced

SMV/PV No contactAbut, encase or

occlude

Not

reconstructable

SMA No contact Abut Encased

CHA No contactAbut or short-

segment encase

Long-segment

encase

Celiac Trunk No contact <180 >180

Borderline

Locally

advancedResectable

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We need better “systemic

therapy” AND radiation

therapy!

Medical

Oncology

Radiation

Oncology

Locally Advanced and

Borderline Resectable PCA

• Treatment focus is on performance status

rather than stage:

– ECOG 0-1, young FFX

– ECOG >1 or elderly GEM or GEM/NAB-P

• Maximize chemotherapy 4-6 months then re-

evaluate for local therapy (radiation +/-

surgery)

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Chemotherapy: “Systemic”

Therapy

• Gemcitabine

• Gemcitabine + X

• Gemcitabine + Abraxane

• FOLFIRINOX (5-FU, Irinotecan,

Oxaliplatin)

• Immunotherapy

• Targeted therapy

NCCN Guidelines

Rationale for More Intense Local

Treatment in LAPC

– 30% Local only disease JHU Autopsy Series

– 60% Local progression - MDACC phase II trial

– Patients die of biliary, gastric, SMV/portal

obstruction

Iacobuzio-Donahue et al, JCO, 2009Crane et al, JCO, 2011

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Potential Effects of Radiation

Tumor

Positive

Surgical

Margin

Slide courtesy of Chris Crane, MD

SMA

SMV

SBRT

CRT

Well-vascularized

rim, hypoxic coreOutline of Tumor Mass on CT

Stereotactic RT: Modern Treatment

Devices

CYBER-KNIFE

TR

ILO

GY

SY

NE

RG

Y

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Goldfinger (1964)

007: Stereotactic Body Radiation Therapy (SBRT)?

Evolution of Radiation Therapy

3-D CRT IMRT Plan

SBRT Plan

IMRT

ABC IGRT

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What Are Fiducials?

Placed via endoscopic ultrasound (similar to biopsy)

Civco Knurled Gold Fiducials

Civco Coupled Markers

Core Oncology

Visicoil

Gold Anchor

Plan Quality AssuranceRespiratory Control

SBRT Planning & Delivery (videos)

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GI Atlas

Intensity Modulated RT Planning & Delivery

Treatment Plan (1.75 Gy x 30

fractions)

IMRT Dose Volume Histogram

PTV

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MDACC Dose Escalation - LAPC

IMRT 63-70 Gy/Image guided + breath hold

N=49

63Gy-70Gy / 28 fx

ms-22.6 mo

N=177

50.4Gy / 28fx

ms- 17.9mo

2006-2014

Krishnan and Crane IJROBP 2016

Treatment Plan (5-6.6 Gy x 5

fractions)SBRT Dose Volume Histogram

Stereotactic Body Radiation Therapy (SBRT)

Planning & Delivery (fiducials and breath hold)

Tumor

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JHU SBRT: Overall Survival

Median OS from diagnosis

= 20.1 mos (95% CI: 15.6 – 23.5)

• Data with standard chemoradiation for

pancreas cancer

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Patient with

BLR PDAC

(Intergroup

Definition)

P

R

E-

R

E

GI

S

T

E

R

E

N

R

O

L

L

m

FOLFIRINOX

2 months

R

E

S

T

A

G

E

R

E

S

T

A

G

E

SURGERY

R

E

S

T

A

G

E

50.4g

EBRT

+ CAPE

F

O

L

L

O

W

GEM

2

months

• Centralized radiographic review of pretreatment and restaging studies

• Prospective QC of all modalities

• Protocol-mandated operative indications and procedures

• Analysis and reporting of survival rates and objective response metrics

What did we learn from A021101?

• FOLFIRINOX and Radiation is Acceptable in Borderline (non-metastatic disease)

• R0 operations possible in 64% patients…but vascular resection 80%

• 33% resections <5% viable cells, 13% pCR (no tumor)

• 1/3 resected patients did not start postop chemo, emphasizing need for more preoperative Rx

• Median OS of all enrolled patients: 22 months

Katz, JAMA Surg 2016

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Role of Radiation Therapy in Locally

Advanced Disease (LAPC)?

UnresectablePCA

Gemcitabine x 4 months

Gemcitabine x 2 months

None

RT (5400 cGy) + capecitabine

None

Gemcitabine plus erlotinib x 4

months

Gemcitabine plus erlotinib x 2

monthsErlotinib

RT (5400 cGy) + capecitabine

Erlotinib

1st

Hummel et al, JAMA 2016

GERCOR LAP-07 Trial

2nd

Role of Radiation Therapy in Locally

Advanced Disease (LAPC)?

• No survival benefit

with RT

• Only 60% included in

2nd randomization

• Local control benefit

with RT

With better

chemotherapy,

perhaps RT would

have a larger impact

Hummel et al, JAMA 2016

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What Is The Role of “Neoadjuvant

Therapy” in LAPC? - LAP 07 Study

• 449 patients (4%) underwent a curative-intent

resection

• Eleven patients (2.5%) had an R0 resection

• Median OS was 30.9 months

• Can we increase the proportion of

patients getting surgery with improved

“systemic therapy” and IMRT or SBRT?Hammel et al 2016, JAMA

Benefits of SBRT vs. Standard

Chemoradiation

• Shorter duration of radiation (3-5 days vs. 30 days)

– Improved quality of life

– Limit delay of chemotherapy and time to surgery

– Easily combined with other modalities

– Higher resection rates??

• Less acute GI toxicity

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A B C

D E F

Treatment Volumes and Dosimetry: SBRT vs. IMRT

Study N DoseLocal Control

at 1 YearOS (mos) Toxicity

Schellenberg (2008) 16 25Gy x1 100% 11.4 47% G2-4

Didolkar (2010) 85 5-10Gy x3 92% 18.6 22.3% G3+

Mahadevan (2010) 36 8-12Gy x3 78% 14.3 33% G1-2, 8% G3

Polistina (2010) 23 10Gy x3 50% 10.6 20% G1

Mahadevan (2011) 39 8-12Gy x3 85% 20 41% G1-2, 9% G3

Rwigema (2011) 71 24Gy x1* 49% 10.3 39.5% G1-2, 4.2% G3

Schellenberg (2011) 20 25Gy x1 94% 11.8 15% G1-2, 5% G3

Goyal (2012) 19 20-25Gy x1* 81% 14.4 11% G1-2, 16% G3

Lominska (2012) 28 4-8Gy x3-5 86% 5.9 7% G3

Gurka (2013) 10 5Gy x5 40% 12.2 0%

Chuong (2013) 73 5-10Gy x5 81% 15-16 5% G3

Pancreas SBRT Studies

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Johns Hopkins, Stanford, Memorial Sloan Kettering

• Primary endpoint: Late GI Toxicity > 4 months (40% to 20%)

• Secondary endpoints: Tumor Progression Free Survival, pre-tx

biopsy, PET/CT, QOL, biomarkers

• Key features: Central review, dose constraints, RT quality

assurance

(Gem, up to 1

Cycle allowed)1 week

break

F-SBRT

6.6 Gy x 5

Mon-Fri

Gem (3 wks on, 1 wk

off) until toxicity or

progression1 week

break

Phase II Multi-institutional Trial:

Gemcitabine + SBRT (n=49)

Herman JM et al. Cancer 2015

Median OS:

13.9 mosMedian PFS:

7.9 mos


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Phase II Multi-institutional Trial: SBRT

Toxicity and QOL

• Toxicity

– Acute GI

• Grade 2: 0%

• Grade ≥3: 12.2%

– Late GI

• Grade 2: 2.1%

– Enteritis

• Grade ≥3: 8.5%

– Fistula (1)

– Ulcer (3)

• Quality of Life (EORTC)

– Mean global QOL:

• Scores unchanged pre/post SBRT

• Surgery– 5 (10%) were deemed resectable

after therapy

• 1 (2%) denied surgery

• The remaining 4 (8%) patients

underwent margin- and node-negative

resection


LAPC patients may

successfully be resected?!

Simultaneous Integrated Boost (SIB)-

Based SBRT Dose Escalation

Tuli et al. Rad Res. 2014

• SIB delivers high doses to the tumor/

vessel interface

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Current

Approach

Appropriate

Staging

Maximize

chemo (4-6

months)

Maximize

chemo (≥6

months)

Radiation

therapy

Radiation

therapy

Maintenance

chemotherapy ??

ULTIMATE GOAL

Surgery +/- IRE

LAPC: Neoadjuvant Multi-agent

Chemotherapy +/- Radiation Therapy

Study Surgery

N

Neodjuvant

Chemo

Radiation

Type

R0

Resection

Med OS or

Path

Reponse

Moffitt

N=159

BR: 51

LAPC: 5

GTX 81% BR

FFX 43% LA

SBRT: All

30-50 Gy/5 Fx

BR: 96%

LAPC: 100%34.2 mos

Hopkins

N=88

BR: 4

LAPC: 15Mixed

SBRT: All

33 Gy/5 Fx84% 22 mos

MSKCC

N=101LAPC: 31

FFX

6 mosCRT: 50%*

Chemo: 79%

**CRT: 33%

PR: >50%

(75 vs. 22)#

MGH

N=188

BR: 14

LAPC: 26FFX

CRT: 14

CRT/IORT: 10

Proton: 6

92% ~32 mos

*75% Gem based, **Vasc resection rate 47 vs. 7,

# favor of CRT Mellon; Moningi; Sadot; Ferrone et al.

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Which Patients Should Be Taken to

Surgery Following Neoadjuvant Therapy?

• Most tumors do not “shrink” after neoadjuvant therapy

• There is a “treatment effect”

Chemo SBRT Surgery

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Hopkins: Neoadjuvant Chemo

vs. Chemo + SBRT (N=177)

• 2008 – 2016: Median Follow-up 17.0 mos

Characteristic Chemo group, n

(%)

Chemo/SBRT group,

n (%)

No. patients 67 110

Age ≥65 29 (43%) 45 (41%)

Male gender 39 (58%) 56 (51%)

Caucasian race 60 (90%) 98 (89%)

Head of pancreas lesion 50 (75%) 77 (70%)

Locally advanced disease 16 (24%) 56 (51%)

FOLFIRINOX-based

chemotherapy

34 (51%) 79 (72%)

Chemotherapy duration ≥4

months

20 (30%) 63 (57%)



0

10

20

30

40

50

60

70

80

90

100

Chemo SBRT

% Margin Negativity

0

10

20

30

40

50

60

70

80

90

100

Chemo SBRT

% Node Negativity

57%

83%

40%

60%

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Pathologic Complete Response or

Near Pathologic Complete Response

• Pathologic complete response (pCR)

– No residual tumor can be identified or measured

• Near pCR

– Scattered microscopic foci of single cells or

groups of single cells

– Typically within a dense area of fibrosis

– Demonstrating marked treatment effect

0

5

10

15

20

25

30

Chemo SBRT

% pCR

0

5

10

15

20

25

30

35

40

Chemo SBRT

% Near pCR



30%

8%

18%

0%

SBRT does improve pathologic response but higher doses

are needed for ablation

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• Central review of baseline imaging

• Central review of radiation QI

• Central review of preoperative imaging

• Central review of pathology

• Know Your Tumor “KYT” at enrollment

P

R

E

-

R

E

G

I

S

T

R

A

T

I

O

N

E

N

R

O

L

L

mFFX x 4

cyclesSurgery

F

O

L

L

O

W

R

A

N

D

O

MI

Z

E

FOLFOX x

4 cyclesmFFX x 4

cycles

Proposed Alliance A021501: Preoperative

Extended Chemotherapy Vs. Chemotherapy Plus

Hypofractionated Radiation Therapy for BRPC of

the Head of The Pancreas

mFFX x 4

cyclesSurgery

F

O

L

L

O

W

FOLFOX x

4 cyclesmFFX x

3 cyclesSBRT

= Re-staging

Arm A

Arm B

Surgical Exploration in LAPC

• Under multidisciplinary review, consider the

following:

1. ≥4 months of chemotherapy and no distant metastases

2. Good performance status/no limiting comorbidities

3. Stable or improved CA 19-9, “technically resectable”

4. Ideally, <12 weeks after SBRT

Katz MH, et al. Cancer. 2012;118(23):5749-5756

Dholakia AS, et al.. J Radiat Oncol. 2013 Dec;2(4):413-25

Radiographic evidence of tumor downstaging is

not required for surgical evaluation

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Does multi-agent chemotherapy

combined with SBRT lead to

improved survival and improve the

likelihood that patients with LAPC

undergo surgery?

Results: Patient & Tumor

Characteristics

• July 2010 to April 2015, 117 patients with

LAPC received definitive Chemo + SBRT

Patient or tumor characteristic N=117

Median age at diagnosis, years (range) 65 (36-88)

Caucasian race 84%

Male gender 52%

Median baseline KPS (range) 90 (80-100)

Head of pancreas tumor 58%

Rosati and Herman et al.

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Results: Treatment

Characteristics

*31% of patients received gemcitabine alone on a clinical trial or due to poor performance status

N=117

Induction chemotherapy agent(s)

None

Gemcitabine-based (alone*, gem+nab-P, GTX, gem/cis)

FOLFIRINOX-based

Combination of both

8%

49%

33%

10%

Induction chemotherapy duration (months)

Median (range)

≥4 months

2.8 (0-22.3)

38%

SBRT dose (Gy)

Median (range)

33 Gy

33.0 (25.0-33.0)

73%

Time in months, median (range)

From diagnosis to SBRT

From SBRT to the end of follow-up

From diagnosis to the end of follow-up

4.0 (0.4-25.8)

13.6 (1.1-62.4)

19.4 (4.0-68.5)

Results: Overall Survival

• Median OS from SBRT = 14.5 mos (95% CI: 12.2 – 18.6)

Median OS from diagnosis

= 20.1 mos (95% CI: 15.6 – 23.5)

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Overall Survival By Induction

Chemotherapy Type / Duration

No chemo

Single-agent GEM

Multi-agent chemo

<4 months chemo

≥4 months chemo

Gem-based chemo

FFX-based chemo

Results: Surgical Implications

LAPC (n=117)

Surgery (n=42)

Successful resection*

(n=33)

R0 Resection (91%)

N0 Resection (82%)

Path CR (15%)

Aborted (n=3) IRE (n=6)

No Surgery (n=75)

Distant Mets (n=46)

Vessel Involvement

(n=17)

Performance Status (n=10)

Other (n=2)

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LAPC (n=117)

Surgery (n=42)


(n=33)

R0 Resection (91%)

N0 Resection (82%)

Path CR (15%)


No Surgery (n=75)

Distant Mets (n=46)

Vessel Involvement

(n=17)


Other (n=2)

*Three patients went to surgery + IRE


LAPC (n=117)

Surgery (n=42)


(n=33)

R0 Resection (91%)

N0 Resection (82%)


No Surgery (n=75)

Distant Mets (n=46)

Vessel Involvement

(n=17)


Other (n=2)


39%

15%

9%

2%

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LAPC (n=117)

Surgery (n=42)


(n=33)

R0 Resection (91%)

N0 Resection (82%)


No Surgery (n=75)

Distant Mets (n=46)

Vessel Involvement

(n=17)


Other (n=2)


39%

15%

9%

2%

Results: Surgical Resection

and Overall Survival

Median OS (mos) P-value

Surgery vs. no surgery 29.7 vs. 17.0 0.0001

R0 resection vs. R1/R2 resection 34.7 vs. 23.1 0.170

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Induction Chemotherapy:

mFOLFIRINOX x 4 cycles Restage

Progression Off Study

Stable or Better

Disease

mFOLFIRINOX

SBRT+mFOLFIRINOX

Randomize

Arm 1

Arm 2

Current Study: Pancreatic Cancer

Research Study (PanCRS)

Participating Institutions:

Stanford, UCSF, UCLA, Loyola, BC Cancer Agency, Duke, UTSW

8 Gy x 5

Pancreas SBRT:

Patient selection for surgery

• Clinical stage is determined by imaging

• Can biomarkers determine a “local” vs. “systemic” profile at diagnosis and guide management

– Imaging (PET, CT)

– Tumor Sequencing

– Immunohistochemistry (core/cell block)

– ctDNA (tumor/plasma)

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Association of stroma and delta measurement

(A) (B)

(C)

• High delta tumors have lower stroma content.

Test set (12 cases)

Validation set (37 cases)

Courtesy of Eugene Koay

Patient cohort: 101 patients who underwent upfront surgery for resectable PDAC

Clinical associations for low and high delta tumors

Patients with high delta tumor showed poor prognosis (early distant metastasis, shorter overall survival ).

The “delta” classification is an independent predictor of distant metastasis-free survival and overall survival.

• Overall survival • Proportions of patients having

metastasis within 6 months

Courtesy of Eugene Koay

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SBRT Tumor Response by PET

• Mean SUVmax

– 5.14 3.13

(p<0.001)

• Mean SUVpeak

– 4.01 2.40

(p<0.001)B

efo

reA

fter

On MVA, PET avidity at baseline predicted for poor survival

Herman et al. Cancer 2015

Total Lesion Glycolysis Predicts

Path Response to Neoadj Therapy

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Patient Selection

Dpc4/Smad4 Wild-Type

(Local)

Dpc4/Smad4 Mutant

(Systemic)

Gross tumor pathology comparison. A) Pancreas specimen from

pt with locally advanced disease. B) Liver specimen from pt with

extensive metastatic disease.

Iacobuzio-Donahue et al, JCO, 2009

Smad4 (Dpc4) Status

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How can we enhance the

effects of RT or use RT to

enhance immunotherapy?

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Small Animal Radiation Research Platform: Bioluminescent

Imaging (BLI) and Targeted Radiation in Small Animals

SARRP Research Platform.

http://www.xstrahl.com/sarrp.htm.

Mouse SBRT

C

PARP Inh – In Vivo

Tuli et al, Trans Onc 2015

Tuli, et al, Rad Res 2013

Tuli, et al, Trans Onc 2012

http://www.xstrahl.com/sarrp.htm

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73

Phase I study: ABT-888 in combination with

gemcitabine and IMRT for LAPC (VelGemRad)

• Gemcitabine: IV infusion of 1000 mg/m2 on days 1, 8, 15 of the cycle

• IMRT: 36 Gy in 15 fractions (2.4 Gy/day, M-F)

• Veliparib: administered per dose escalation schema, 60 mg BID

• 1° Objective: to determine the MTD, safety and toxicity profile

• 2° Objectives:

Measure the clinical activity of the treatment (RECIST 1.1)

Evaluate tumor/blood pre/during/post treatment for DNA damage/repair proteins

Assess pre-tx germline/somatic/epigenetic mutations in BRCA1/2, PALB2, PTEN

Tuli et al, in preparation

SBRT: Immune Modulation

Kamrava M., Hodge JW., et al. Mol. BioSyst., 2009 - Adapted with Permission (Andrew Sharabi)

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Gross: 3.8 cm (Extensive Treatment Effects)

SBRT Treatment Response

GVAXGM-CSF

Dendritic Cell

Antigen uptake &

Activation

T CellT Cell Activation & Proliferation

Tumor Cell

Destruction

• May Inhibit recurrence

• Limited toxicity

• Combined with other

therapies

Mesothelin

Tumor antigen

Future Directions: Pancreas VaccineGVAX: GM-CSF Secreting, Allogeneic, Whole Tumor Cell

Vaccine

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T cellTumor cell

MHCTCR

PD-L1PD-1

- - -T cell

Dendritic

cell

MHCTCR

CD28

B7 CTLA-4- - -

Activation

(cytokines, lysis, proliferation,

migration to tumor)

B7+++

+++

CTLA-4 Blockade PD-1 Blockade

anti-CTLA-4anti-PD-1

Tumor Microenvironment

+++

PD-L2PD-1

anti-PD-1

- - -

Blocking CTLA-4 and PD-1

FFX +SBRT + GVAX + Anti-PD-1 in

Patients with LAPC

Anti-PD-1

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Proton Beam Therapy

Ling TC et al. Transl Cancer Res 2012;1(3):150-158

Conclusions:

• Multi-agent chemotherapy improves survival (>4

months)

• FFX > Gem/Abx

• SBRT improves R0 resections and path

response with limited toxicity or delay

• Select LAPC patients can have surgery with

favorable OS

• Local and distant progression still common

• Need better maintenance therapies

• Support clinical trials

• P’s: Pain, Panc Enzymes, PANCAN, PMDC

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Johns Hopkins

MD Anderson

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42

May the force be with you and

Happy Holidays!

Thank you for your participation.

If you have questions, please contact Patient Central at

877-2-PANCAN or e-mail [email protected].

www.pancan.org

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