Introduction to Spine SBRT and Current TopicsSingapore IAEA IGRT Course 2012

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

Spinal metastasis

•Bone metastasis the most common reason for palliative XRT

•30-58% of patients with bone metastasis will experience spinal column metastasis

•20,000 cases of cord/cauda equina compression annually in the US

•Breast, lung, prostate cancers account for 50% of cord compression

•85% of lesions are located anterior to the spinal cord

Conventional XRT: Who Benefits?

• Patchell

• High grade epidural cord compressions do not do well with XRT alone

• Radioresistant disease does not respond well to conventional radiation

• XRT will not palliate mechanical instability

• Multilevel spine disease

• KPS/Systemic Disease/Survival

Dose and Fractionation

•High dose per fraction greater likelihood of lethal cell damage (same for tumor and normal tissue)

•Increasing the dose per fraction has an exponential biologic effect

•Increasing the number of fractions has a more linear biologic effect

•Smaller dose per fraction means less injury to normal tissue (and also tumor)

•Greater volume of irradiated tissue means a greater risk of serious radiation injury

Radiation Sensitivity for Spinal Metastases

Prostate Breast Lung Others Totals

CR0 analgesia score<2 pain score

90% 65% 42% 50% 62%

CR + PR1-2 analgesia score3-4 pain score

100% 87% 42% 60% 79%

G Arcageli et al. Int J Rad Onc Biol Phys 42(5): 1119-1126

Conventional RT Conformal RT

Dose per fraction Lower Higher

Treatment Volume Bigger Smaller

Normal Tissue More Less

Hypofractionation: A Short History• 1896--First single fraction treatment to depigment a

nevis=necrosis

• Further attempts at single fraction radiation: (1916 Friedrich, 1918 Seitz)

• Coutard: Fractionated radiation could cure deep seated tumors of the head and neck. Coutard H. Roentgen therapy of epitheliomas of the tonsillar region, hypopraynx and larynx from 1920-1926. Am J Roentgenol 1932; 28: 313-331.

• “...The greatest cellucidal effect is obtained by single -dose fractionation; however, as a rule, the concomitant damage to normal tissues...is not well tolerated...and we are forced to fractionate.” Marciel V. Time-dose fractionation relationships in radiation therapy. Natl Cancer Inst Monogr 1967; 24: 187-203

Hypo-fractionation’s effect on the Therapeutic Ratio

Dose

Conventional Fractionation

Hypo fractionation / Single-fraction

Problem with hypo-fractionation: •late responding tissues (normal tissues) have lower α/β than the tumor, thus are more responsive to higher dose per fraction.

•This pushes the curves closer together

NTC

P

TCP

NTC

P

TCP

Dose

)/

1(

dndBED

Effect of PTV Margin Size

• For 5 cm diameter CTV, the corresponding volumes:

CTV Diameter Normal Tissue Volume

0.3 271.0 1141.5 203

Margins and Normal Tissue Exposure

CTV diameter (cm)

CTV volume (cm3)

Margin (CTV-PTV) mm

1mm 2mm 3mm 4mm 5mm

1 0.5 0.4 0.9 1.6 2.5 3.4

2 4.2 1.4 3.1 5.0 7.3 10.0

3 14.1 3.0 6.4 10.3 14.6 19.4

4 33.5 5.3 11.1 17.5 24.4 31.9

5 65.4 8.2 17.0 26.5 37.7 47.7

Geometry

Dose

May allow significant dose escalation

leading to improved outcome

Hypo fractionation / Single-fraction Solution is often simply one of

geometry:• Improve the accuracy with which

the target is positioned with respect to the radiation beams

• Reduce the size of the PTV margins• Reduce the volume of normal

tissue in the high dose regionN

TCP

TCP

Dose

NTC

P

TCP

Hypo fractionation / Single-fraction with small margins, dose escalation

Image Guided Radiotherapy

•Near real time 3D imaging for position verification

•Positional corrections in X, Y,Z planes

•Accuracy within +/- 1mm

Spine RT: Systematic Literature ReviewGerzsten et al. Spine 2009

• Conventional (standard fractionation, 1-2 fields)

• Radiosurgery (hypofractionation, 1-5 fractions, conformal techniques)

• Pubmed/Embase/Cochrane Reviews

• 479 relevant articles

• 62 for in depth review

• 49 included

• 9 prospective papers

• 3 RCT

Conventional XRT: Pain

• 2 RCT reported improvement in pain

• 46-57% with 4-5 month median survival

• 3 prospective non-randomized results

• 73-82% improved pain (6 months median follow up)

• Retrospective data

• 70% report improvement in pain

Conventional Spine XRT: Local Control

• Local control = lack of cord compression/return of symptoms

• 885 patients in 7 retrospective studies

• 61-89% (mean 77%) local control

• Histology a significant predictor of outcome

• “Radioresistant” vs “radiosensitive”

IntroductionBasic principles of “conventionally” fractionated radiotherapy for metastases

Complete depletion of tumor stem cells is required for cure

The main mechanism is clonogenic/reproductive stem cell death

Cells/tumors exhibit a heterogenous response to radiation

Response may depend upon a number of factors:• Dose and fraction size (limited by spinal cord/irradiated

volume) impact upon tumor control probabilitiesThe 4 R’s

Radiation response broadly categorized by tumor phenotype (ie. histology)

Linear Quadratic formalism-α/β ratio

Histologic Classification•Radiosensitive:

•Prostate, H & N (SCC), Ovarian, Endometrial, Cervical, Breast

•Radioresistant:•GI, NSCLC, RCC, Melanoma, Sarcoma, NSGCT, Hurthle Cell,

Thyroid, Adnoid Cystic, Unknown PrimaryLymphomaSeminomaMyeloma

Breast Prostate Sarcoma Melanoma GI NSCLC Renal

Gilbert F F U U U U U U

Maranzano F F F U U U U U

Rades F I I I U I U I

Rades F F F U U U U U

Katagiri F F F U U U U U

Maranzano F F F U U U U U

Rades F I I I U I U I

Ambulatory Status After Conventional XRTN Breast Prostate NSCLC GI Renal Sarcoma

Maranzano 35 60%Rades 81 14%Rades 87 29%Smith 35 66%Rades 281 33%Rades 335 31%Bach 59 22%Rades 252 14%Merminsky 19 27%Rades 142 33%

133 40%52 29%

Maranzano 44 46%TOTALS 512 34%

493 36%363 17%81 14%87 29%19 27%

Histologic ClassificationRadiosensitivity to cEBRT (30 Gy in 10)

LymphomaSeminomaMyeloma

Breast Prostate Sarcoma Melanoma GI NSCLC Renal

Gilbert F F U U U U U UMaranzano F F F U U U U URades F I I I U I U IRades F F F U U U U UKatagiri F F F U U U U UMaranzano F F F U U U U URades F I I I U I U I

Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery for metastatic spine disease: What are the options, indications, and

outcomes. Spine 34(22S):S78-92, 2009

Responses: F-Favorable, I-Intermediate, U-Unfavorable

80% response

@ 16 months

Histologic ClassificationRadiosensitivity to cEBRT (30 Gy in 10)

LymphomaSeminomaMyeloma

Breast Prostate Sarcoma Melanoma GI NSCLC Renal

Gilbert F F U U U U U UMaranzano F F F U U U U URades F I I I U I U IRades F F F U U U U UKatagiri F F F U U U U UMaranzano F F F U U U U URades F I I I U I U I

Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery for metastatic spine disease: What are the options, indications, and

outcomes. Spine 34(22S):S78-92, 2009

Responses: F-Favorable, I-Intermediate, U-Unfavorable

20% response@ 3 months

Common Observations of Bone Metastases Palliation: Low Dose Single Fraction vs Multi Fraction

• 2 Meta Analysis of 12 (Sze et al) and 6 (Wu et al) RCT (N=3508 and 3260) of single fraction vs multifraction regimens for palliation of bone pain:

• 800cGyx1 - 4000cGy/20

• No difference in initial palliation (60%)

• No difference in complete response (30%)

• Short fractionation schedules results in a greater need for retreatment (7% vs 20%)

Conventional RT: Durability of Response

•UK/NZ Bone Mets RCT Trial

•N=761

•800cGyx1 vs 2000cGy/5 or 3000cGy/10

•30% available for FU at 12 months

•Nearly 50% increase in relapse at 12 months vs 3 months8 Gy single fraction radiotherapy for the treatment of metastatic

skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Bone Pain Trial Working Party.“ Radiother Oncol. 1999 Aug;52(2):111-21.)

Conventional Spine XRT: Local ControlGerszten et al. Spine 2009

• 1-2 beams, 800cGy-4000cGy/1-20 fractions

• Local control = lack of cord compression/return of symptoms

• 885 patients in 7 retrospective studies

• 61-89% (mean 77%) local control

• Histology a significant predictor of outcome

• “Radioresistant” vs “radiosensitive”

Local Control of Oligometastatic Tumors by Histology The MSKCC Series of SD-IGRT: Greco & Zelefsky, 2009 Unpublished

0 12 24 36 48

20

40

60

80

100

Prostate (n=42; 83%)

Colorectal (n=10; 50%)

Other (n=32; 62%)

Renal cell (n=37; 60%)

p=0.16

Time (months)

Loca

l Rel

apse

-free

Sur

viva

l

Loca

l Rel

apse

-free

Sur

viva

l

Time (months)

Prostate (n=19; 86%)

Renal cell (n=24; 81%)

Other (n=16; 83%)

0 10 20 30 40

20

40

60

80

100

18-24 Gy 24 Gy only

Tumors appear to respond with similar sensitivities to single-dose radiotherapy regardless of tumor type, stage or other

phenotypic features

Local control is dose-dependent within a narrow dose range (15-25 Gy)

Local cures of ~90% appear achievable within the range of 24 Gy

The uniformity of tumor response to single dose radiotherapy regardless of tumor type support a mechanism of response

different from that regulating fractionated radiotherapy

Spine IGRT: Radiobiologic Observations Unique to High Dose Single Fraction Radiation

High Dose/IGRT HypothesisHigh dose/single fraction radiation provides excellent tumor control

• Intracranial stereotactic radiosurgery experience

High dose radiation can be given safely if normal tissue dose and volume can be minimized

Sophisticated image guided technologies are able to provide high precision radiation

Image guidance + IMRT is able to deliver tumorcidal radiation safely near critical structures such as the spinal cord and esophagus.

Local control is an important and meaningful clinical goal

MSKCC Update: Where We Are Now• 413 lesions in 372 consecutive patients were treated with

SRS 2003-2010 at MSKCC.

• 1800-2400cGy in a single fraction with LINAC based IGRT

• Dose escalation 2003-2005 (1800-2400cGy)

• Extensive disease (ie circumferential) received reduced doses <2400cGy

• All patients followed with serial imaging until death

• Local failure = radiographic progression

Competing Risks Analysis N = 413

Local Control By Histology

Histology3 Yr Local Control

Breast 98%GI 98%H&N 93%Lung 98%Melanoma 90%Unknown 91%Prostate 98%Renal 89%Sarcoma 96%Thyroid 92%

Summary• In contrast to conventionally fractionated radiotherapy,

traditional phenotypical factors such as histology and volume are not significant prognostic factors with high dose single fraction therapy

• The dose of radiation is the only predictive factor for durable treatment success when utilizing high dose single fraction therapy

• Local tumor “cures” can be achieved at 2400cGy x 1

• Radioresistant histologies in particular should be considered for high dose single fraction therapy

Non surgical tx for spinal metsTumor Neurologic Pain Function

Breast 93% 87% 93%

Prostate 91% 64% 82%

Myeloma 90% 100% 90%

SCLC 86% 86% 86%

Ovarian 100% 100% 100%

RESPONSIVE 87% 83% 85%

NSCLC 47% 65% 53%

Hepatocellular 33% 44% 33%

Gastric 50% 50% 25%

Colon 50% 50% 75%

Cholangio 50% 0 50%

Renal 67% 67% 67%

Sarcoma 50% 100% 50%

Thyroid 0 0 0

RESISTANT 49% 55% 47%

Total 67% 67% 64%

Hypofractionated Salvage Spine IGRT: 400cGyx5 vs 600cGyx5 Local ControlDamast et al. IJROBP 2010

p=0.04

23%

40%

• N = 97

• Median FU= 14.7 months

• 38 LF

• Overall LF = 30%

Tumor Control Outcomes after hypo-fractionated and single – dose stereotactic image-guided intensity modulated RT for extra-cranial metastases from renal cell carcinoma

Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma. Zelefsky MJ, Greco C, Motzer R, Magsanoc JM, Pei X, Lovelock M, Mechalakos J, Zatcky J, Fuks Z, Yamada Y. Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):1744-8.

Actuarial local control (Kaplan-Meir method) as a function of prescription regimen for renal cell cancer (p = 0.001). Y axis represents local relapse-free survival (%). PFS = progression-free survival.

Importance of dose

Dose /fractionation

N patients

PFS*

High dose 1 frac 24 Gy

45 88%

Low dose1 frac <24 Gy

14 21%

Hypo fraction3 frac, 20-30 Gy

46 17%

Spine Radiosurgery: Proof of Principle of the IGRT Hypothesis

•Hypothesis: IGRT will improve outcomes by:•↓ Toxicity•↑ Tumor control

•Spine Radiosurgery a test of the IGRT paradigm•Proximity of spinal cord:

•Demands high precision•Rapid dose fall off to limit dose to spinal cord

•Many spine tumors are “resistant” to conventional fractionation• Significant experience with high dose single

fraction radiation for intracranial brain metastases of radioresistant histologies

}↓Uncertainties and Systematic Errors

Tumors appear to respond with similar sensitivities to single-dose radiotherapy regardless of tumor type, stage or other phenotypic features

Local control is dose-dependent within a narrow dose range (15-25 Gy)

Local cures of ~90% appear achievable within the range of 24 Gy

The uniformity of tumor response to single dose radiotherapy regardless of tumor type support a mechanism of response different from that regulating fractionated radiotherapy

Spine IGRT: Radiobiologic Observations Unique to High Dose Single Fraction Radiation

IGRT Hypothesis: Improving Tumor Control to Improve the Therapeutic Ratio

• Higher tumor control particularly with lower α/β “radioresistant” tumors

-Dose remains the only predictive factor for tumor control

• Not at the expense of toxicity

-Limiting normal tissue volume and dose Dose

Summary: Hypofractionation ParadigmDose is an important predictor of tumor controlHypofractionation appears to be superior to conventional fractionation• Dose is an important predictor of local control• Histology is an important factor in tumor controlSingle fraction appears to be superior to conventional fractionation• Single fraction local control is dose dependent but independent of

histology• Single fraction radiation is superior to all other dose fractionation

schedules for radioresistant disease• Redefining traditional radiobiologic constructs of radiosensitivity

•IGRT is changing the management of metastatic lesions at MSKCC

Spine:• Careful patient immobilization• Image guidance

Lymph nodes• Careful patient immobilization• Soft tissue imaging

Liver, Pancreas, Adrenal• Motion management• Image guidance• Implanted fiducial markers

Lung• Cone beam soft tissue imaging

Prostate• Daily setup on implanted markers• Radio frequency tracking beacons real time

prostate position readout

Improvements in outcome largely come down to geometry• Each site has its own, sometimes unique challenges• Many opportunities for therapy physicists to work with physicians to

develop new protocols, treatment procedures