Advances in the management of Vertebral Mets in the Era of Spine SRSIAEA Singapore SBRT SymposiumSingapore National Cancer Institute

Yoshiya (Josh) Yamada MD FRCPCDepartment of Radiation OncologyMemorial Sloan Kettering Cancer CenterNY NY USA

Disclosures

The Institute for Medical Education, Speakers Bureau

Varian Medical Systems, Consultant

Natural RadioactivityUranium ore Pitchblen

dUranium, Polonium

,&

Radium1896

“Radioactivity”

1898Isolated Radium

Marie Curie

Henri BecquerelApril 1896

Radium Therapy 1910-1920’s: Pitchblende and Carnotite

MalignancySubacute and Charcot Joint

Muscular ConditionsHigh Blood pressure

NephritisSimple and Pernicious Anemias

Radium Beer

Household Products

Early x-ray facilities

Early Radiation Technology: Fluoroscopy

Radiotherapy as an Emerging Technology• 1895 - Rontgen discovers x-rays. • 1896 - Becquerel discovers radioactivity.

• Victor Despeignes reports treating stomach cancer with X rays • 1901 - Rontgen receives the Nobel Prize in Physics for the discovery of x-rays. • 1905 - The first English book on Chest Radiography is published.

• Niels Finsen reports 50% success rate treating lupus with x rays• 1913 -Coolidge introduces the hot cathode tube. • 1914 - Von Laue receives the Nobel Prize in Physics for x-ray diffraction from

crystals. • 1915 - Bragg and Bragg receive the Nobel Prize in Physics for crystal structure

derived from x-ray diffraction. • 1917 - Barkla receives the Nobel Prize in Physics for characteristic radiation of

elements. • 1918 - Eastman introduces radiographic film. • 1920 - The Society of Radiographers is formed. • 1923 – Coutard reports 23% cure rate for head and neck cancers with

fractionated RT• 1924 - Siegbahn receives the Nobel Prize in Physics for x-ray spectroscopy. • 1951 – Co60 Teletherapy• 1953 – Linear accelerator

Emerging Technologies

•0.1 – 1.0 Gy per minute

•Used 1920-1950’s

•Over 10,000 in use in the early 1950’s

Scientific Shoe Fitting

IGRT as an Emerging Technology: Do We Have All the Facts?• Hypofractionation and high dose single fraction radiation

appear to have different responses compared to conventional fractionation

• Radiosensitivity is not histology dependent

• High dose hypofractionation/single fraction RT appears to be ablative “SABR”

• What are the mechanisms of response?

Deficiencies of the LQ Model for SBRTResponseKirkpatrick et al. Sem Radiat Oncol 18, 2008

• Brain metastases are well controlled with 15-20Gy (25-35Gy calculated)

• Cancer stem cells may require a higher threshold dose of radiation to overcome inherent radioresistance (>13 Gy for intestinal stem cells)

• LQ model doesn’t model threshold effects

• Classical radiobiology based upon in vitro rather than in vivo data

• LQ model can’t account for other in vivo mechanisms of response at high doses

Endothelial Apoptosis: Fuks/Kolesnick Model of an In Vivo Effect for High Dose Radiosurgery

14.5Gy (n=6) 14.5Gy + G6-31 (n=5)

0

250

500

750

1000

Tum

or v

olum

e(m

m3)

0 20 30 40 50 60 70 80 90Days after tumor implantation

0

250

500

750

1000

0 20 30 40 50 60 70 80 90Days after tumor implantation

Anti-VEGF G6-31 Sensitizes MCA/129 Fibrosarcoma to singly dose radiotherapy

when given immediately prior to radiation Anti-VEGF G6-31 Sensitizes MCA/129 Fibrosarcoma

Truman et al. PLoS One 2010

Modulating Response: VEGF and Endothelial Apoptosis

Uptake curves of representative voxels from DCE-MRI of B16 melanoma irradiated in wild-

type and asmase-/- mice

Time after GD-DTPA injection [seconds]

Fold

-cha

nge

in S

/S0 [

rel.u

.] Before 20Gy

After 20Gy

asmase-/-

20 Gy

asmase+/+

Before 20Gy

After 20Gy

Fold

-cha

nge

in S

/S0 [

rel.u

.] Before 20Gy

After 20Gy

20 Gy

Slide courtesy of Z Fuks MD

High Dose IGRT and Vascular Response•Vascular collapse an important aspect of high dose RT

response

•Significant endothelial apoptosis (ceramide repressed by VEGF inhibition) –within minutes of RT!

•Radioresistant phenotypes become radiosensitive with VEGF suppression—ceramide activiation

•Dose de-escalation for IGRT+ VEGF inhibitors?

•DCE MRI changes: Evidence for the vascular effect?

DCE Parameters

Two-compartment tracer pharmacokinetic model, in which Vp = intravascular volume, Ve = interstitial volume, Ktrans = rate constant of Gd leakage from the intravascular to

interstitial space, and Kep = elimination rate constant.

Quick “washout” if Kep is highNecrosis: slow Kep

High “leakage” if Ktrans is high

Modified From Figure Provided by A Holodny MD

Tumor lower Vp than Normal Tissue

Materials and Methods

5 male patients with spine metastasis

• 4 metastatic prostate: T5, T10, L2, L3

• 1 metastatic thyroid: L4

• T1 weighted DCE MRI performed on a 1.5 Tesla magnet utilizing dynamic imaging processing software (NordicICE) prior to and within one hour after undergoing single fraction HD-IGRT

• All metastasis were treated to 24Gy in a single fraction

• Patients were given steroids before treatment.

- MRI studies were acquired with a 1.5T GE scanner using an 8 channel cervical-thoracic-

lumbar (CTL) surface spinal coil.

- T1 weighted DCE MR images were obtained with 3D fast SPGR sequence with following

MR parameters:

- NordicNeuroLab T1DCE perfusion software

TR= 3.6secTE= 1.1secnumber of phases = 80 slice thickness = 10 mm

flip angle =30°

FOV=34 cmmatrix size 256 × 256

Materials and Methods

• Vp and Ktrans of the metastasis were normalized as a ratio to adjacent nonirradiated marrow and compared pre and 1 hour post RT

T1 Ktran Vp

Courtesy Eric Lis MD

Materials and Methods• Ratios of Vp and Ktrans to adjacent marrow were plotted

on a graph. Percent change Pre and one hour Post RT also computed.

9/27/2009 10/8/2009 (tx) 11/27/20090

5

10

15

20

25

30

Vp

K12

L2 % change from baseline

Vp -60%Ktrans -29%

L2 metastatic prostate

Results Patient 1

10/20/2009 11/10/2009 1/4/20100

0.5

1

1.5

2

2.5

3

3.5

4

4.5

T5 metastatic prostate

VpK12

tx

Local control at 26 month follow up.

Courtesy Eric Lis MD

Results•On average Vp decreased by 64% after 1 hour•On average Ktrans decreased by 34% after 1 hour•Average follow up of 23 months- No local progression

L4 % change from baseline

Vp -63%Ktrans -16%

L3 % change from baseline

Vp -84%Ktrans -60%

L2 % change from baseline

Vp -60%Ktrans -29%

T10 % change from baseline

Vp -31%Ktrans -52%

T5 % change from baseline

Vp -81%Ktrans -15%

DCE: A Window into the TumorL4

L4

L4 L

4

L4

2400cGyx1

Prior to RT Day 10 Day 50

L4

Case 1• 57 yo F w/ oligometastatic breast cancer • HPI:

• Dx w/ T2N1 triple neg IDC of left breast on 9/1/10• Neoadjuvant ddAC-T, L WLE/ALND w/ re-excision, adjuvant

RT (completed 1/4/11)• Staging CT CAP (5/2012)

MR sacrum (6/15/12): right sacral metastasis

•Palliative RT to Sacrum:•2400cGy in 1 fx

(7/9/12)• Presents for follow-up on 9/13/12

Imaging: MRI of Sacrum (S1)

Pre-RT (6/15/12) Post-RT (9/6/12)

Case 1- Perfusion Images

Change in Vp = -70.6%

Pre-RT (6/15/12

)

Post-RT (9/6/12)

Vp = 13.73 Vp = 4.04

Plasma Volume and Recurrence

Results

p>0.0001

∆ Vp Range

Local Control -66% -21% -

99%

Local Failure +176% +145%,

+208%

-150

-100

-50

0

50

100

150

200

250

300

% c

hang

e in

par

amet

er v

alue

(pre

to p

ost t

reat

men

t)

Vp Ktrans AUC Peak

Local Recurrence

Vp Ktrans AUC Peak

Recurrence 1: Patient #40

5/2/11 7/20/11 9/11/11 10/13/11 3/17/12 4/28/12 7/25/120

1

2

3

4

5

6

7

8

9

10

11

T12-L1 RCC

KtransVp

Rela

tive

SI T

umor

/BM

Perfusion parameters increased at least 4

mos before recurrence!

Fractions: 1Tx date: 5/18/11Recurrence date: 11/10/11Time to recurrence: 6 mosSurgery date: 7/30/12Time to last FU: 14 mos

Date Mos Since Tx K12 Lesion/BM Change in K12 % Change Vp Lesion/BM Change in Vp % Change5/2/11 4.5881     5.6513    ---Tx---7/20/11 2 4.1424 0.9029 -10 6.4740 1.1456 +159/11/11 4 1.8315 0.3992 -60 5.6282 0.9959 0

10/13/11 5 1.5963 0.3479 -65 4.5717 0.8090 -193/17/12 10 2.2898 0.4991 -50 6.1176 1.0825 +84/28/12 11 1.1392 0.2483 -75 4.6275 0.8188 -187/25/12 14 5.1269 1.1174 +12 10.2377 1.8116 +81

Recurrence 6: Patient #78

Perfusion parameters may have increased 18 mos before recurrence!

Fractions: 1Tx date: 12/3/09Recurrence date: 8/4/11Time to recurrence: 21 mosSurgery date: 8/5/11Time to last FU: 21 mos

Date Mos Since Tx K12 Lesion/BM Change in K12 % Change Vp Lesion/BM Change in Vp % Change10/30/09   3.4575     2.5544    

--Tx 12/3/09-- 1/28/10  2 1.9965 0.5774 -42 2.7426 1.0737 +711/1/10  11 2.1580 0.6242 -38 2.1763 0.8520 -157/3/11  19 2.2439 0.6490 -35 1.9203 0.7518 -258/4/11  20 1.7721 0.5126 -49 4.3357 1.6974 +70

10/30/09 1/28/10 11/1/10 7/3/11 8/4/110

1

2

3

4

5

L2 Breast

KtransVp

Rela

tive

SI T

umor

/BM

10/30/09 1/28/10 8/4/110

1

2

3

4

5L2 Breast (edited)

KtransVp

Rela

tive

SI T

umor

/BM

Prelim Results

• Local control (n=36)

• Average Vp decreased 70%

• Average Ktrans decreased 60%

• Local recurrence (n=6)

• Average Vp increased 34%

• Average Ktrans decreased 15%

•Vp: p=0.0007

Discussion• DCE MRI is feasible in spine metastases

• Plasma volume was the only factor that was associated with tumor response

• Decreases in Vp likely represent reduced tumor vascularity and hence treatment response

• mean reduction of 66% for locally controlled leisons

• Increases in Vp represent increased tumor vasculature and hence tumor growth

Conclusion• Vascular changes may be important in the response of

tumors to high dose RT

• Supports endothelial apoptosis

• MRI DCE may be predictive of tumor response to high dose per fraction RT

• MRI DCE may provide a “window” into the tumor even when standard MRI only demonstrates “stable” findings within the marrow

• Continued work is ongoing to confirm these findings in a larger dataset

Future Directions

•Diagnostic tool: sensitivity and specificity

•Threshold values for control and failure

•Predictive tool

•Preliminary results suggest that DCE findings can predict for tumor recurrence before standard MRI findings

•Other body sites?

•Assess response to other types of therapy?

High Dose Radiotherapy: Multi Compartment Targets

High Dose RT and Immunologic Response with Ipilimumab

Abscopal effect of CTLA 4 (T cell) stabilizer

Phenomenon noted with Hypofractionation

Increased immunogenicity with high dose RT

RT Dec 2010

Mucosal Melanoma• 65 yo M with mucosal melanoma of the right maxilla.

• Maxillectomy, orbital extent /  flap reconstruction

• Multiorgan metastases

• Chemo (cis/decarbazine/vinblastine, 6/2011)

• Post op bed: Hypofractionated radiation (9/2011, 36Gy/3 fractions)  with Ipilimumab

9/23/2011

3/29/2012

Abscopal Effect • Systemic response on PET imaging

• Near complete resolution of all multiple peritoneal, hepatic, splenic, osseus, LN lesions

• No evidence of maxillary recurrence

9/23/2011

3/29/2012

Multiple Osseus and Visceral Metastases

Near Complete Systemic Response

IL 2 and Melanoma and RCC + SBRTS Seung, BD Curti, et al. Science Translational Medicine 2012

• IL 2 CR + PR = 6% and 10% for melanoma

• IL 2 CR + PR = 8% and 7% for RCC

• Median time of response 40 months and 54 months

• 70% of melanoma CR are without recurrence at 15 years

• 70% of RCC CR are disease free at 10 years

• SBRT: 20Gy x 1-3

• IL 2 (600,000 IU/kg every 8 hours x 14 doses) start Monday after RT, repeated 16 days later

• 100% CR of irradiated lesions

IL 2 and High Dose SBRT: Abscopal EffectsS Seung, BD Curti, et al. Science Translational Medicine 2012

IL 2 and High Dose SBRT: T Cell EffectsS Seung, BD Curti, et al. Science Translational Medicine 2012

T cell deficient (nude mice) significantly less

response to 25Gyx1 compared to the wild type

Reduced response to 20Gyx1 if the wild

type CD8+ T cells are depleted

Lee et al. Blood 2009 114(3): 589-595.

SBRT/SABR and Tumor Immunology

From: Finkelstein SE, Timmeramn R, et al. The Confluence of Stereotatic Ablative Radiotherapy and Tumor Immunology. Clinical and Developmental

Immunology 2011

Threshold Effect for High Dose Radiosurgery

Immune Respons

e

High Dose Radiotherapy: Multi Compartment Targets

Increased Immune Response ?

Summary

•SBRT/high dose radiation is an evolving paradigm with excellent tumor control (better than expected)•The dose of radiation delivered is important to maximize the therapeutic ratio

•New biology: Beyond traditional radiobiology•Endothelial/vascular effects•Immune response•Others???