radiation for prevention and treatment of brain metastases in lung cancer
DESCRIPTION
Radiation for Prevention and Treatment of Brain Metastases in Lung Cancer. Minesh Mehta, Northwestern University Chicago, IL. In partnership with . Consultant: Adnexus , Bayer, Merck, Tomotherapy Stock Options: Colby, Pharmacyclics , Procertus , Stemina , Tomotherapy - PowerPoint PPT PresentationTRANSCRIPT
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