Minesh Mehta, Northwestern University Chicago, IL * Radiation for Prevention and Treatment of Brain Metastases in Lung Cancer
Feb 24, 2016
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