Minesh Mehta, Northwestern UniversityChicago, IL

*Radiation for Prevention and Treatment of Brain Metastases in Lung Cancer

In partnership with

*COI Disclosure (2010-11)

• Consultant: Adnexus, Bayer, Merck, Tomotherapy• Stock Options: Colby, Pharmacyclics, Procertus, Stemina,

Tomotherapy• Board of Directors: Pharmacyclics• Data Safety Monitoring Boards: Apogenix• Medical Advisory Boards: Colby, Stemina, Procertus• Speaker: Merck• IP/Patents: Procertus

*Objectives

*Discuss the role of whole brain radiotherapy in preventing the development of brain metastases in small-cell and non-small cell lung cancer*Discuss the role of radiosurgery in

managing brain metastases from NSCLC*Discuss the role of WBRT in conjunction

with surgery or SRS

*PCI in SCLC

*Although SCLC responds dramatically to chemotherapy, it does not readily penetrate the BBB, resulting in a microscopic sanctuary site.*Intracranial failure rates therefore remain very high*Because of the innate sensitivity of SCLC to XRT, low

dose cranial treatment should reduce the likelihood of developing brain mets*Several clinical trials have validated this and a large

1999 meta-analysis showed that PCI reduces the 3-year rate of brain mets by 25% and improves survival by 5%

First-Line Chemo-RX:Response of Asymptomatic Brain Metastases From Small-Cell Lung Cancer to Systemic First-Line Chemotherapy*

Tatjana et al., J. Clin Oncol vol 24, pp2079-2083, 2006

Systemic Response Rate : 73%CNS Response Rate: 27%

*Cyt, Adria, & VP16

Meta-Analysis of Prophylactic Cranial Irradiation

Auperin et al, NEJM, 1999

7 randomized trials, 987 pts with CR; almost all had LS Dz

5% increase in survival at 3 yrs

Higher dose improved local recurrence but no effect on survival

Death Brain Mets

54% risk16% risk

PCI in ES-SCLC - Study DesignSlotman B et al NEJM: 2007

Chemotherapy (4-6 cycles)

No PCI

PCI20-30 Gy in

5-12 fractionsR

No response

Any response

< 5 weeks

4-6 weeks

Stratification: - Institute - Performance score

Primary endpoint – reduction in risk of symptomatic brain mets (HR=0.44)

Symptomatic brain metastases

Months from moment of randomization

Months from moment of randomization

Global Health Status

Hair Loss

Fatigue Role Functioning

Cognitive Functioning Emotional Functioning

Slotman JCO, 2009

Summary: PCI in ES-SCLC

PCI significantly reduces the risk of symptomatic brain metastases (p<0.001; HR=0.27; 14.6 vs. 40.4% at 1 yr) No difference in time to extra-cranial progression PCI significantly prolongs failure-free survival and overall survival (Overall survival: p=0.003; HR=0.68; 27.1 vs. 13.3% at 1 yr) PCI is well tolerated and does not substantially influence global QoL/health status/cognitive function

* A Phase III Comparison of Prophylactic Cranial Irradiation (PCI) versus Observation in Patients

with Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC):

QOL and Neurocognitive Analysis

RTOG 0214

*RTOG 0214: Schema

No progressio

n after curative

therapy for Stage IIIA/B

NSCLC*

STRATIFY

RANDOMIZE OBSERVATION

PCI30Gy at 2Gy/Fx

Stage1. IIIA2. IIIB

Histology3. SCCa4. Non-SCCa

Treatment5. Surgery6. No Surgery

*No CNS metastases by brain MRI or CT

*RTOG 0214

Accrual: Sept. 19, 2001 – Aug 30, 2007

Early closure due to slow accrualTargeted Accrual 1058

Actual 356

Ineligible 9

Withdrew Consent 7

Evaluable 340

All patients potentially followed a minimum of 12 months

Ove

rall

Surv

ival

(%)

0

25

50

75

100

Months since Randomization0 3 6 9 12

Ove

rall

Surv

ival

(%)

0

25

50

75

100

Months since Randomization0 3 6 9 12

Patients at RiskPCIControl

163177

157169

149160

136144

115129

Dead90100

Total163177

p= 0.86HR= 1.03 (0.77, 1.36)

PCIControl

/ / / /

/////

/ / //

/ / / /

*Overall Survival

PCI Observation1 yr OS 75.6% 76.9% p=0.86MS (mos) 25.8 24.8

Dis

ease

-Fre

e Su

rviv

al (%

)

0

25

50

75

100

Months since Randomization0 3 6 9 12

Dis

ease

-Fre

e Su

rviv

al (%

)

0

25

50

75

100

Months since Randomization0 3 6 9 12

Patients at RiskPCIControl

163177

147158

119121

101103

8686

Fail108132

Total163177

p= 0.11HR= 1.23 (0.95, 1.59)

PCIControl

/

/

/

////

/ //

/ / /

*Disease Free Survival

PCI Observation1 yr DFS 56.4% 51.2% p=0.11

CNS

Met

s Fa

ilure

(%)

0

25

50

75

100

Months since Randomization0 3 6 9 12

Patients at RiskPCIControl

163177

156165

145144

128129

109113

Fail1536

Total163177

p= 0.004HR= 2.35 (1.29, 4.30)

PCIControl

*Brain Metastases

PCI ControlCNS Mets 7.7% 18.0% p=0.004

*MMSE: No differences

Baseline Month 3 Month 6 Month 12-505

1015202530

PCI Raw Score

Time Point

MM

SE S

core

* HVLT-R: Early Decline Followed by Some Recovery

StudyCNS Failures

N No PCI PCI p value

VALG, JAMA 1981 281 13% 6% 0.04MDACC, J Neuro-Onc 1984 97 27% 4% 0.002RTOG 8403, IJROBP 1991 187 19% 9% 0.1Pottgen et.al, JCO 2007 112 24% 9% 0.02Movsas et.al, ASTRO 2009 340 18% 8% 0.004Cumulative Experience 1017 13-27% 4-9%

All PCI NSCLC Trials Show Benefit

Prospective Randomized Trials of PCI in NSCLC

*Where is the Balance?

*NCF deterioration occurs early and often.*We have analyzed the time course of NCF decline

employing 8 prospectively measured domains in 208 brain metastases patients treated with 30 Gy WBRT and have found that:*Median time to NCF deterioration was longer in good

than in poor responders.*Memory was most susceptible to early decline, even

in patients with non-progressing brain metastases: the role of the hippocampus

*Other Strategies

*Limit PCI to very high risk populations only*Non-squamous NSCLC patients have 27% risk

*Neuroprotectors*RTOG 0614, Memantine

*Use BBB-penetrating chemotherapy, e.g. TMZ*SP PO5416, randomized phase II trial

*Hippocampal avoidance*To protect the radiosensitive neuro-progenitor stem cell compartment (not anatomic protection)

* Definitive WBRT Alone

*WBRT: Survival vs. Class

152.3 monthsClass III – KPS <70

654.2 monthsClass II – all others

207.1 monthsClass I <65 (age) KPS >70 Controlled primary No extracranial mets

% in ClassMedian Survival

All brain metastases are not equal.

Gaspar L, et al. Int J Radiat Oncol Biol Phys. 2000;47:1001-1006.Gaspar L, et al. Int J Radiat Oncol Biol Phys. 1997;37:745-751.

*Does Histology Matter?Database Analysis for GPA

Sperduto, et al, ASTRO 2010

Tumor N (%) Age ≥60 KPS ≥70 Mets >3 EC MetsNSCLC 1888 (44) 57 % 85 % 24 % 33 %Breast 642 (15) 29 % 89 % 36 % 48 %

Melanoma 483 (11) 40 % 92 % 30 % 67 %Total 4259 (100) 50 % 85 % 27 % 41 %

*Does Histology Matter?Database Analysis for GPA

Tumor MS GPA 0-1

GPA 1.5-2.5

GPA 3 GPA 3.5-4

p

NSCLC 7 3 6.5 11.3 14.8 <.0001Breast 12 6 9.4 16.9 18.7 <.0001

Melanoma 6.7 3.4 4.7 8.8 13.2 <.0001

Sperduto, et al, ASTRO 2010

* Regression of brain mets after WBRT correlates with survival and improved neurocognitive function

Median tumor volume reduction at 2 mo: 45%

Good responders

Poor responders

135 pts at 2 mo

Volume reduction > 45%

Volume reduction < 45%

WBRT + MGd Response Analysis

Response MS Good 300+26 d Poor 240+19 dP-value 0.03

Tumor Shrinkage Prolonged Survival

* Tumor Shrinkage Better Neurocognitive Function

PEGND Test

*Who Benefits From Radiosurgery?

*Survival of Pts with 1 Brain Met

RT + RS (MS=6.5 mos)RT alone (MS=4.9 mos)

P=0.0470

100

80

60

40

20

00 6 12 18 24

Months

% A

live

Andrews DW, et al. Lancet 2004;363:1665-1672.

*Local Control with SRS Boost

Study WBRT + SRS P value When

RTOG 71% 82% .01 1yr

Tufts 87% 91% NS ?

Pittsburgh 8% 100% .0005 1 yr

*Radiosurgery for Multiple Mets*Bhatnagar et al., IJROBP, 2006. *Retrospective study:*205 patients with various malignancies*Radiosurgery for 4 or more metastases.*Median marginal dose of 16 Gy.*Median overall survival was 8 months.*RPA classes I, II, and III: 18, 9, and 3 months

*Tumor volume was the most significant predictor of survival and the only significant predictor of local control; number of lesions was not a significant prognostic factor.

* What is the Impact of WBRT after Local Therapy ?

*Very High Brain Relapse After Surgery if WBRT is Omitted

Complete resection without WBRT leads to 70% actuarial relapse

This is a relative risk of 3

Patchell, JAMA.1998:280:1485

*Failure with SRS/S Alone    No

WBRTNoWBRT

NoWBRT

WBRT WBRT WBRT

Author,Year

Localtherapy

Anybrainfailure

Localbrainfailure

Distantbrainfailure

Anybrainfailure

Localbrainfailure

Distantbrainfailure

Patchell,1998

S 70% 68% 50% 24% 21% 18%

Aoyama,2006

SRS 76% 27% 64% 47% 11% 42%

Chang,2010

SRS 73% 33% 55% 27% 0% 27%

Kocher,2010

S   59% 42%   27% 23%

Kocher,2010

SRS or S 78%     42%    

Range   70-78% 27-69% 42-64% 24-47% 0-27% 18-42%

*Impact of WBRT on MMSE

• 82 pts on JROSG 99-1 had MMSE 27

• Median time to 3 point drop:• 16.5 vs. 7.6 months, in favor of WBRT+SRS (p = .05)

• 12 and 24 month freedom from 3 point drop:• 76 and 69% for WBRT+SRS vs. 59 and 52% for SRS alone

• Progressive disease is worse than WBRT

Aoyama, Int J Radiat Oncol Biol Phys, 68:1388-395, 2007

MeanProbability of NCF Decline

SRS 23%

SRS+WBRT 49%

MDACCC Trial: Neurocognitive Decline by HVLT

*Conclusions•Roles of WBRT for NSCLC Brain Mets

• Preventative• SCLC• NSCLC

• Therapeutic• Multiple Brain Mets

• Adjunctive• To reduce local failure after SRS/S• To reduce regional failure after SRS/S

• Toxicities• MMSE changes are minor to none and might even improve• Finer tools pick up some decline, mostly early, with some late recovery