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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

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radiation for prevention and treatment of brain metastases in lung cancer

Radiation for Prevention and Treatment of Brain Metastases in Lung Cancer

Minesh Mehta, Northwestern University

Chicago, IL

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
COI Disclosure (2010-11)
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
Objectives
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%
PCI in SCLC
slide6

First-Line Chemo-RX:

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

CNS Response Rate: 27%

Systemic Response Rate : 73%

*Cyt, Adria, & VP16

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

slide7

Meta-Analysis of Prophylactic

Cranial Irradiation

Auperin et al, NEJM, 1999

Death

Brain Mets

  • 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

16%  risk

54% risk

slide8

PCI in ES-SCLC - Study Design

Slotman B et al NEJM: 2007

PCI

20-30 Gy in

5-12 fractions

Chemotherapy

(4-6 cycles)

No response

R

Any response

No PCI

< 5 weeks

4-6 weeks

Stratification: - Institute

- Performance score

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

slide9

Symptomatic brain metastases

Months from moment of randomization

slide10

Slotman JCO, 2009

Hair Loss

Global Health Status

Role Functioning

Fatigue

Emotional Functioning

Cognitive Functioning

Months from moment of randomization

slide11

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
slide12

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
RTOG 0214: Schema

RANDOMIZE

STRATIFY

PCI

30Gy at 2Gy/Fx

No progression after curative therapy for Stage IIIA/B NSCLC*

  • Stage
    • IIIA
    • IIIB
  • Histology
    • SCCa
    • Non-SCCa
  • Treatment
    • Surgery
    • No Surgery

OBSERVATION

*No CNS metastases by

brain MRI or CT

slide20

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

Where is the Balance?
other strategies
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)
wbrt survival vs class

Median Survival

% in Class

Class I

<65 (age) KPS >70

Controlled primary

No extracranial mets

7.1 months

20

Class II – all others

4.2 months

65

Class III – KPS <70

2.3 months

15

WBRT: Survival vs. Class

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.

median tumor volume reduction at 2 mo 45

WBRT + MGd Response Analysis

Volume reduction > 45%

Good responders

135 pts at 2 mo

Poor responders

Median tumor volume reduction at 2 mo: 45%

Volume reduction < 45%

slide29

Tumor Shrinkage  Prolonged Survival

Response MS

Good 300+26 d

Poor 240+19 d

P-value 0.03

survival of pts with 1 brain met

100

RT + RS (MS=6.5 mos)

RT alone (MS=4.9 mos)

80

P=0.0470

60

% Alive

40

Survival of Pts with 1 Brain Met

20

0

0

6

12

18

24

Months

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

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.

Radiosurgery for Multiple Mets
very high brain relapse after surgery if wbrt is omitted
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

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

Impact of WBRT on MMSE

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

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

Conclusions
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