management of cns oligometastases liam a. mulroy radiation oncology october 2011
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Management of CNS Oligometastases
Liam A. MulroyRadiation OncologyOctober 2011
LAM 2011
Disclosures
No financial disclosures! But...
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Disclosures
I have given an awful lot of whole brain radiation therapy in my career
I am bald (Rogaine did not help)
I am a Toronto Maple Leafs fan
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Presentation Outline I
What is Oligometastatic Disease? Prognostic Factors: From RPA to GPA WBRT and SRS: Current Perspectives Neurocognitive Impairment from RT Hippocampal Avoidance(HA) IMRT for WBRT and SIB of Metastases Example Case Conclusions
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What is Oligometastatic Disease?
I’m not sure... Oligo means “a few” RTOG 95-08 and EORTC 22952-
26001 enrolled patients with 1-3 mets
JROSG-99-1 enrolled 1-4 mets PMH “oligo brain mets clinic”
accepts patients with up to 6 mets
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What is Oligometastatic Disease?
Should we think about total volume of intracranial mets as well as the # of mets?
SRS alone for “oligomets” and delay WBRT?
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What is “Oligometastatic” Disease?
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What is Oligometastatic Disease?
Should we think about the total volume of intracranial metastases?
M.Follwell/PMH presentation at CARO 2011: Baseline Cumulative Volume >6.0 cc predictive for decreased O.S.
I am still confused about “oligometastatic” disease….
RCT have included 1-4 mets
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RTOG RPA Classification Gaspar et al,IJROBP 1997 Vol. 37: 745-741
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RTOG RPA Survival Gaspar et al, IJROBP 1997 Vol. 37: 745-741
RPA CLASS MEDIAN SURVIVAL (months)
I 7.1
II 4.2
III 2.3
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Brain Mets DS GPASperduto et al IJROBP Vol.77,No.3 pp.655-61,2010
Disease specific and includes patients treated with S, SRS and WBRT
Far more complicated than traditional RTOG RPA
GPA score out of 4 makes sense in USA
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Brain Mets GPASperduto et al IJROBP Vol.77,No.3 pp.655-61,2010
Prognostic index based on 4,259 patients
Retrospective S,SRS,WBRT 1985-2007 Disease specific
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Brain Mets GPASperduto et al IJROBP Vol.77,No.3 pp.655-61,2010
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Brain Mets GPASperduto et al IJROBP Vol.77,No.3 pp.655-61,2010
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Brain Metastases:Current Perspectives
WBRT improves CNS disease control i.e. micrometastases in the rest of the brain
WBRT results in significant neurocognitive impairment
WBRT does not improve overall survival
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Brain Metastases:Current Perspectives
What are some of the endpoints to be considered when assessing RT (WBRT or SRS) for brain metastases?
Local Control of existing mets
CNS Control (mets and “micro-mets”)
Overall Survival
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Brain Metastases:Current Perspectives
What are some of the endpoints to be considered when assessing RT (WBRT or SRS) for brain metastases?
Quality of Life Functional
Independence Neurocognitive
Function Steroid
Requirements
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Brain Metastases:Current Perspectives
What other aspects should be considered when assessing RT (WBRT or SRS) for brain metastases?
$$$$ Availability and
timely access to RT
How much RT, how often to deliver RT in patients with limited life expectancy?
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Brain Metastases:Current Perspectives
Which are the most important endpoints when assessing whole brain radiation therapy?
Remember that the treatment intent is palliative ....
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Early Season Overachievers
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EORTC 22952-26001Kocher et al, JCO 29:134-141, 2011
Adjuvant WBRT vs. Observation after SRS or S in Patients with 1-3 Cerebral Metastases
359 patients accrued 1996-2007
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EORTC 22952-26001
SRS in 199, S in 160
53% NSCLC S arm: 95% had
single mets; larger lesions vs. SRS and more often in post. fossa
WBRT 30 Gy/10 fr.
SRS 20 Gy peripheral dose, maximum lesion diameter 35 mm
Patient groups well balanced
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CEREBELLAR METPrimary NSCLC
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EORTC 22952-26001:SRS or S +/- WBRT
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EORTC 22952-26001
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EORTC 22952-26001
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EORTC 22952-26001
WBRT in patients with 1-3 mets does not prolong overall survival or survival with functional independence after S or SRS
WBRT reduces local progression, intracranial progression and improves PFS
After S alone local progression rate is 59% at 2 years
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EORTC 22952-26001
Greater incidence of serious adverse events in WBRT arm(13 vs. 3 SAE)
Results very similar to Patchell (S) and JROSG-99-1 (SRS) trials
Reasonable to delay WBRT in patients with limited # mets
Local therapy (e.g SRS) to surgical bed after resection?
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Neurocognition and WBRT
Neurocognition in Patients Treated with SRS or SRS plus WBRT: A Randomized Controlled Trial
Chang et al Lancet Oncol. 2009 10: 1037-1044
58 patients randomized 2001-2007
Primary endpoint: HVLT-R at 4 months
WBRT 30 Gy/12 fractions
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Neurocognition and WBRT
Trial closed early (58 patients)
Significant difference in total recall at 4 months, SRS and WBRT inferior to SRS
Chang et al Lancet Oncol. 2009 10: 1037-1044
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Inferior survival in SRS+WBRT arm
Patients in SRS arm received more chemo and started earlier
Salvage surgery more common in SRS arm
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Does WBRT Adversely Effect Overall Survival?Chang et al Lancet Oncol. 2009 10: 1037-1044
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No adverse effect in JROSG-99-1)
132 patients, accrual 1999-2003, 1-4 mets
median survival 7.5 months WBRT + SRS vs. 8.0 months SRS
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Does WBRT Adversely Effect Overall Survival?Aoyama et al, JAMA 2006; 295: 2483-2491
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Does WBRT Adversely Effect Overall Survival?
Negative effect in Chang trial not seen in JROSG-99-1, EORTC 22952-26001(reviewed earlier) and a surgical trial published by Patchell
No survival benefit as an “adjuvant” therapy
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Hippocampal Avoidance Section
HIPPOCAMPUS HIPPOPOTAMUS
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Hippocampal Avoidance
Emerging evidence suggests that a neural stem cell compartment in the hippocampus is key to the pathogenesis of neurocognitive deficits observed after cranial RT
Neural progenitor cells are anatomically clustered within the dentate gyrus of the hippocampus
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Hippocampal Avoidance
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Hippocampal Avoidance
Following RT neural progenitor cells become less proliferative, more apoptotic, more likely to adopt a gliogenic fate
Inflammation in the area surrounding the neural stem cells is a major contributing factor to RT effect
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Hippocampal Avoidance
Hippocampus + 5 mm= Hippocampal Avoidance Region
Planning study by Gondi et al (5 patients) showed mean HAR of 3.3 cubic cm
HAR represents approx. 2% of whole brain volume
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Hippocampal Avoidance Gondi et al, Radiother. Oncol. 95: 327-321 91% mets occur outside HAR
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Hippocampal AvoidanceHA-WBRT technique (Gondi et al)
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Hippocampal Avoidance
HA-WBRT may prevent/reduce neurocognitive impairment
RTOG 0933 is evaluating HA-WBRT and NCF
HA-WBRT should only be done within clinical trials at this time
Save the hippos!
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WBRT and SIB
SIB=simultaneous integrated boost of metastases
Tomotherapy or VMAT are efficient ways of delivering SIB with WBRT
UWO (Rodrigues et al) performed an elegant Phase I clinical to assess safety of this approach using helical tomotherapy
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WBRT and SIB
Rodrigues et al, IJROBP Vol.80, No.4, pp. 1128-1133, 2011
Phase I Trial 48 patients, 70 mets WBRT 30 Gy/10 fr.
with SIB 5-30 Gy in 5 Gy increments
Well tolerated, no dose limiting toxicities even at 60 Gy/10 fr.
Median O.S. 5.29 months
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WBRT and SIBRodrigues et al, IJROBP Vol.80, No.4, pp. 1128-1133, 2011
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WBRT and SIBRodrigues et al, IJROBP Vol.80, No.4, pp. 1128-1133, 2011
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WBRT with SIB and HA
Hsu et al, IJROBP 2009
It can be done if you let Fred do it! Planning study at
BCCA 10 patients,18 mets SIB mets 63-70.8 Gy WBRT 32.25 Gy/15 fr Mean hippocampal
dose 5.23 Gy-2
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WBRT with SIB and HA Hsu et al, IJROBP 2009
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WBRT with SIB and HA Hsu et al, IJROBP 2009
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Example Case
Various options... 63 year old female,metastatic
breast cancer,excellent condition RTOG RPA class 2 GPA 3 or 4, median survival 16-18
months 6 mets, largest/symptomatic met
excised
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Conclusions
Various management options should be considered and treatment should be individualized
WBRT should not be abandoned but must evolve/improve
HA-WBRT and SIB should be studied- in clinical trials that Atlantic Canadians can participate in
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