Use of molecular GPA for deciding management of brain metastasis from lung cancer. approach to asymptomatic and symptomatic patients. criteria to help personalisation of treatment

1. CARCIONMA LUNG WITH BRAIN
METASTASIS – TREATMENT
DECISIONS
DR. UPASNA SAXENA
SENIOR CONSULTANT
RADIATION ONCOLOGY
HCG, MUMBAI

2. INCIDENCE
• 20% lung cancers present with brain metastasis at diagnosis and 40-50%
develop up later
• Highest in small cell lung cancer
• About 5% in squamous and 10-16% in adenocarcinoma
• Of adenocarcinoma, 23-30% have EGFR mutation and 3-5% have ALK
mutation
• Of all the EGFR positive, about 23-32% have brain metastasis and of all
ALK positive about 24-42% (increasing to 58% at 3 years)
• Most common symptoms (depending on number and location of
metastasis are) – headache, altered mental status, seiaures, ataxia, focal
motor or sensory deficits etc
• With better systemic therapy  longer survival median survival has
improved to 12-15 months, esp for adenocarcinoma)  rising incidence of
brain metastasis
• Highest GPA score could entail a survival of upto 4 years

3. TREATMENT -ONE LINER ANSWER
• Extensive metastasis in body and brain – whole brain radiation with
or without boost to gross metastasis- 30Gy/10#, 20Gy/5#
• Few sites of deposit in brain and extracranial (oligometastatic) –
address all lesions with SRS/FSRS
• Brain Limited disease
– Multiple lesions – whole brain with boost to gross disease+/- hippocampal
avoidance
– Few lesions (evolving definition) – surgery or FSRS/FSRS or both

4. READING IN BETWEEN LINES
• Expected survival
• Importance of QOL and neurocognition
• Histopathology
• Response to therapy
• Available options of systemic therapy
• Possibility of FSRS + immunotherapy
Paradigm shift in
decision making for
brain metastasis
selection of
modality is essential

5. CRITERIA FOR TREATMENT CUSTOMISATION

6. RECURSIVE PARTITION ANALYSIS

7. DS-GPA
• Disease specific – graded prognostic assessment
• Purose is to
– Estimate survival
– Take clinical decisions about treatment
– To use as stratification in future trials

8. GPA- GRADED PROGNOSTIC
ASSESSMENT
• Age, PS, number of intracranial
lesions, extent of extracranial
disease
• Site of primary (lung, breast,
melanoma, renal cell carcinoma,
colorectal cancers)

9. SURVIVAL WITH BRAIN
METASTASIS
• Around 3-7 months
• Assess RPA and GPA score
– Gaspar et al – RPA II average survival 4.2 months and RPA III 2.3
months
– Sperduto et al – average survival for GPA 1.5-2.5 was 5.5 months
and GPA 0-1 was 3 months
– Indian data for the same in JP Agarwal et al 2020
• Median survival for RPA II and III 5.2mo and 2.6 mo respectively
• Median survival GPA 1.5-2.5 is 4 mo and 0-1 is 2.4 mo

10. Lung-molGPA
JAMA 2017
• In the various classes, survival
ranges from 3-46.8 months
• A molecular GPA score of 3.5-4
entailed a median survival of 4
years
• This makes mol GPA scoring
essential to decide the type of
brain radiation bearing in mind
neurocognitive decline, survival,
need for re RT

11. The DS-GPA (diagnosis specific graded prognostic assesment) has shown nuances
not seen previously
• EGFR/ ALK mutations shows superior survival and higher risk of
leptomeningeal disease
• Number of brain metastasis and extracranial metastasis is an important factor
affecting survival
• For score > 3, addition of WBRT to SRS gives survival benefit contrary to
practice to avoid WBRT- IJROBP 2014, Sperduto et al and JAMA 2015, Aoyama et al
• Accurate survival is crucial to take informed decision of treatment choice and
for prognostication
JAMA 2017

12. UPDATED Lung-molGPA- 2022

15. TREATMENT DECISION MAKING

16. EVOLVING GUIDELINES
Moravan et al

17. EVOLVING GUIDELINES
 Cost and Accesibility to
third generation TKI
 Regular MRI cost and
accessibility
 Education and awareness
to understand the same
 Risk of precipitating
symptoms in larger
metastasis
Moravan et al

19. BRAIN METASTASIS FROM SMALL
CELL LUNG CANCER
• Prophylactic cranial irradiation for limited and extensive stage (with
good response to chemotherapy) small cell lung cancer is the norm
– No survival benefit
– reduces brain metastasis by half but at the cost of QOL and
neurocognitive decline
– based on NRC-CC001 trial, memantine or hippocampal sparing can be
used
– With improved survival using immunotherapy, neurocognitive decline
is a concern
• SWOG S1827 is evaluating the role of MRI surveillance both with and without
PCI
• Multiple studies have shown similar outocmes of SRS versus WBRT (similar OS)
for SCLC brain metastasis
• ENCHEPHALON , German study is evaluating WBRT versus SRS for 1-20
metastasis from SCLC.
• Intracranial penetration is seen with etoposide, irinotecan, topotecan,
temozolamide. Also with atezoleumab and durvalumab

20. ASCO-SNO-
ASTRO 2021
recommend
s WBRT not
SRS

21. Brain metastasis from NSCLC

22. SELCTION OF TREATMENT
MODALITY

23. • ASCO-SNO-ASTRO –
Dec 2021

26. SINGLE METASTASIS IN BRAIN
• Best outcome for Large/symptomatic – prefer surgery  SRS or
FSRS
– surgery  SRS or FSRS
– Also gives histopathology
• Cochrane review 2018 – OS and LC superior for surgery +SRS vs SRS
alone
• Surgery alone inferior to SRS alone EORTC 22952-26001
• If unfit for surgery – due to comorbs or eloquent areas
– SRS or FSRS is the choice

27. UPFRONT FOCAL RT
• Initial RTOG 9005 compared
– WBRT vs WBRT+SRS
– LC 71% vs 81% at 1 year, no survival advantage
• Subsequent trials advocated – JAMA 2006, Lancet 2009, JCO 2011, JAMA
2016
– SRS/FSRS for 1-4 lesions
– Omission of WBRT
• Larger lesions SRS vs FSRS – Vellayappan et al , Frontal Oncol 2018
– 1 year LC 79.2% vs 92.9%
– RN 7.5% vs 6.3%

28. ROLE OF SURGERY
• Indications – mass effect with good PS and prognosis OR diagnostic uncertainty, solitary
brain metastasis with no extracranial disease
• Superior outcome for surgery + SRS versus WBRT.
• Rades et al showed median OS of 6 months with WBRT alone and 11.5 months with
surgery +WBRT. IJROBP 2008
• Single versus multiple
– Surgery advisable for single metastasis (Vetch CJ et al, ANN Neurol 1993)
– Multiple are difficult to access, hence surgery not preferred
– Can be opted for multiple if – all accessible through single craniotomy, to release mass effect
at one of the sites
• Recurrent setting – surgery is preferred for
– <40 years, time to recurrence > 4 months, KPS>70, non breast/non melanoma histology
Kalkanis et al, J Neuronc 2010

29. POST OP RADIOTHERAPY
• Post op radiotherapy resulted in a 3 year OS of 17.5% - J Thorac Onco
2012
• Patchell et al – LC 18% vs 80%. Neurological death 44% vs 14%.
• Trials POST OP OBSERVATION VS SRS
– Observation – 60% LR in 1 year
– Both arms - 60% rate of new BM
– 12 month LC 72% for SRS and 43% for observation
• Trial WBRT vs SRS – NCCTG-N107C/CEC.3
– Freedom from cognitive decline – 3 versus 3.7 months
– Cognintive decline at 6 months – 85% vs 52%
– WBRT vs SRS – LC at surgical bed 80% vs 60% (less dose for larger cavities) –
can be managed with hypofractionated FSRS in 3-5 sessions
– Time to progression 27.5 mo vs 6.4 mo
– Similar OS 11.6 mo vs 12.2 mo
• ESTRON German trial has similar results
• Alliance trial evaluating SF-SRS verus F-SRS (3-5 #) – local control and
patterns of spread
• Another trial evaluating – rates of leptomeningeal spread, local control,
distant BM and OS in preop versus postop SRS
• Currently focal radiation is preferred
Cancer April 2020

30. NEOADJUVANT SRS
• Post op SRS might cause higher incidence of leptomeningeal disease as
compared to WBRT
• Newer forte
– Evaluated in PROPS-BS trial
– 16Gy/1# given few days (1-3) prior to surgery
– 1 yr LC 85%, median survival > 16 mo, LMD 7.9%, RN 7%.
• Better target definition, less risk of leptomeningeal disease (16.6% vs
3.2%)
• Under evaluation in trials – MD Anderson, Mayo and Alberta
• Promising approach for single lesions

32. WBRT
• Reduces growth temporaraily, reduces mass effect and
consequently neurologic symptoms
• Increases Neurocognitive decline and QOL
• Reduced risk of distant brain recurrence
• No benefit in OS by adding WBRT to surgery or SRS
• Preferably used sequentially with systemic agents
• ?? Role with immunotherapy

33. WBRT
• Reduces distant BM rates 50% and improves LC 25-30%
• Some studies report a better OS with use of WBRT than with SRS for good
PS patients- RTOG 9508
• HA-IMRT and memantine (Bowler et al) helps reduce neurocognitive
decline
• HA-IMRT- more costly, not for metastasis near hippocampus, risk of
recurrence in hippocampal area
• Going out of favour due to better survival with newer systemic, similar OS
+less neurocognitive decline with SRS

34. SRS Vs WBRT+SRS
• Adding WBRT – lower LR, same OS, more neurotoxicity at 3-12 months – Alliance and EORTC trials
• JROSG – DS-GPA 2.5-4 – OS 10.6 mo VS 16.7 mo. Benefit not seen for unfavourable DS-GPA
• SRS+WBRT has similar outcomes as surgery for 1-3 metastasis –Rades et al Eur J Cancer 2009, Schlogg et al
Acta Neurachir 2000
• A better alternative is WBRT with SIB to gross disease with HA – if patient is a candidate for HA
• JCOG0506 – For upfront WBRT vs salvage SRS – OS was 15.6 mo for both. PFS was 10.4 mo versus 4 mo, NC
decline 16.4% vs 7.7%
• As of now SRS is preferred over WBRT
• With improving prognosis and systemic therapy options, could conclude
to use WBRT+SRS +HA for molGPA 4 – NRG BN009

36. Polymetastatic
• Yamomoto et al and Nichol et al, Dutch et al, showed that SRS to five or
more lesions was non inferior to when used for 2-3 lesions. Lancet, 2014
• Trial [JLGK0901]evaluating SRS in 1-10 BM – reported similar OS with no
increase in toxicity. Didn’t evaluate OS. Only 17% had more than 5 mets
• Another ongoing trial [NCT03550391] – evaluating SRS versus WBRT in 5-
15 metastasis. Outcomes are OS and neurotoxicity PFS.

38. Polymetastatic
• MDACC

39. NEUROPROTECTORS
• RTOG 0614
– Uses memantine for 24 weeks during and after radiation
– Improves all components of neurocognitive decline - short term
memory issues, executive function, attention and concentration,
severe dementia and learning difficulties
• Under evaluation – none shown beneficial yet
– Donepezil use has shown some but not significant improvement
– Motexafin Gadolinium
– BMX-001

40. HIPPOCAMPAL AVOIDANCE
• For 30Gy/10#
• Hippocampal max 15.3Gy and mean 7.8Gy on linac
and 12.8Gy, 5.5Gy on tomotherapy respectively
• First Genda et al, then RTOG 0933 evaluated for
the same – Hopkin’s verbal learning test at 4
months 7% vs 30%
• NRG-CC001 showed decreased neurocognitive
decline with WBRT+HA+memantine versus
WBRT+HA (58.5% vs 68.2%)
• Hippocampus is 2% of brain volume and risk of
recurrence in those areas is less than 10%
• Trials evaluating the sub areas of hippocampus, eg
cornu ammonis, are underway

41. WBRT+SIB+HA
• Improves LC while preserving
from neurocognitive decline
• SIB improves PFS 9.1 mo vs
5.9 mo and medican OS 14
mo bs 11 mo

42. Combined brain radiation and systemic
therapy
• Most systemic therapy have no brain penetration
• Erlotinib and Gefitinb has penetration due to tumour induced disruption
of BBB. Lou U et al, Oncotarget 2015
• Welsch et al (JCO2013), Erlotinib +WBRT for brain metastasis showed 86%
control with no increase in neurotoxicity
• Nagwa et al, Nat rev cancer 2018 – using immunotherapy to enhance the
abscopal effect
• Improved ORR, OS, PFS = WBRT+TKI
• No increased toxicity with ICI, slight increase in RN

44. POOR PEFROMANCE STATUS OR
PROGNOSIS
• Do not opt for surgery or SRS
• WBRT is preferred
• Assess individually the number, location of the metastasis to decide benefit
from WBRT
• If PS is too poor, keep option of BSC
• QUARTZ Trial show no benefit of OS of use of WBRT, just of quality of life
adjusted years- median survival 2 months (9.2 weeks vs 8.5 weeks )
• Tibdewal et al reported 25% patients succumbed within 30 days of diagnosis
of brain metastasis – 16% were RPA I-II and 36% were GPA > 2.5
• ASCO-SNO-ASTRO 2021 – omit WBRT for KPS<=50 and <70 with no systemic
options

45. THANKYOU