Debnarayan Dutta, MDSr Consultant, Dept of Radiation Oncology & RadiosurgeryApollo Speciality Cancer Hospital, Chennai

WBRT for brain metastases - the end of an era?

Solitary brain metastasis Multiple brain metastasisLimited brain metastasis

- 42 Yr Female- K/C/O Early Ca Breast diagnosed 1 yr back

- BCS + adequate CT + RT done- On HT

- ER/PR +Ve ; Her2neu –ve

- C/o Headache 1 month back

- MRI Showing 3 lesions in brain - Deep seated lesions

- PET scan – No disease in any other region

- Good GC- Neurological status- normal

Usual treatment: Biopsy for the parietal lesion in brainWBRT – 30Gy/10# + Systemic therapy

Expected survival approx. 6 monthsQOL / Cognitive function preservation – not considered

Case scenario # 1

Brain metastasis: Conventional Treatment • WBRT (30Gy/10#) IS STANDARD OF CARE

• Outcome of treatment: Survival 6-12 months

• German helmet Field • 30Gy/10# = 40Gy/16# = 20Gy/5#

• Prognosis based on RPA (Gasper 1997)• RPA is based on KPS, age, Extra-cranial site

disease, Controlled primary

RPA Class

Age (Yr)

KPS Systemic disease Survival(Mo)

I <65 >70 Controlled primaryNo other disease 7.1

II NS >70 NS 4.2

III NS <70 NS 2.3

Gasper et al, IJROBP 1997

WBRT fractionation schedule: NO difference in outcome

Overall Survival: 30Gy/10# = 40Gy/15# = 20Gy/5#

Sperduto 2008

Brain metastasis: Graded prognostic Score

• Favorable group of patient median survival is 12 months• >25% pt live >2 yrs

- GDA Scoring 3.5- Median Survival 11 months- Survival probability >2 yr 25%

- NEED to consider QOL & IQ

- Newer Systemic therapies have increased hope for longer extra-cranial disease control & survival

Case Scenario #1

Brain metastasis: Solitary mets: WBRT+SRS/Surgery

- Single brain metastasis: WBRT + SRS/Sur boost have 2 months survival benefit

Brain metastasis: Solitary mets: WBRT+SRS/Surgery

- Single brain metastasis: WBRT + SRS/Sur boost have 2 months survival benefit

Tallet et al, Radiat Oncol 2012

Issues with WBRT: Cognitive function impairment

Decline in domain scores after WBRT

Brain metastasis: WBRT Issues

• WBRT (30Gy/10#) WAS STANDARD OF CARE TILL 1990s• Outcome of treatment: Survival 6-12 months

• In 1990s, Patchel et al & RTOG study in solitary/ oligo brain mets showed survival advantage of SRS/Surgery + WBRT vs WBRT alone

• Last 2 decades, in limited brain mets std of care is Surgery/SRS + WBRT• Multiple mets WBRT alone

• WBRT have issues with cognitive function• With better systemic therapy & improved survival, cognitive function is an important issue

• After ONLY surgery, if no RT then high local recurrence (74% vs 25%) (Benedett et al)• Adj RT even after surgery is a must

• Role of WBRT is argued vis a vis SRS/ Surgery

Hall et al, JNS, 2014

Brain metastasis Ph II: Survival function (n=294)

Chang E et al, Lancet 2009

Randomized studies 1-3 brain metastasis: SRS Vs SRS+WBRT

Age<50, ECOG 0, Controlled primary: SRS= SRS+WBRT

Tsao et al, Cancer 2012SRS/Surgery: Then WBRT or Observation

Meta-analysis of Randomized trials: WBRT Vs SRSOverall Survival

p-value=0.88

p-value=0.003

Meta-analysis of Randomized trials: WBRT Vs SRSLocal Control

Higher local failures with Surgery/ SRS alone

Soon et al, Cochrene metaanalysis, 2014

Brain metastasis: Cochrane meta-analysis 2014Surgery/SRS+ WBRT Vs SRS/Surgery alone: Over all Survival

No difference in over all survival

p-value=0.47

Soon et al, Cochrene metaanalysis, 2014

Brain metastasis: Cochrane meta-analysis 2014Surgery/SRS+ WBRT Vs SRS/Surgery alone: Progression free Survival

WBRT: Definite reduction in local failure

p-value=0..14

New brain lesion free survival (%)

Group Score 6 mo 12 mo P-value

Gr I 16-17 36 27<0.001Gr II 18-20 65 44

Gr III 21-22 80 71

Prognostication“New brain lesion free survival” after SRS only (n= 214)

Huttenlocher S et al Radiat Oncol 2015

Chang E et al, Lancet 2009

- No difference in OS- Impaired recall with WBRT- No difference in cumulative distant

brain recurrence

Soffietti R et al, JCO 2013

Cognitive function: Randomized study Post Surgery/SRS WBRT Vs Observation

Soffietti R et al, JCO 2013

Cognitive function: Randomized study Post Surgery/SRS WBRT Vs Observation

Global Score Physical functioning

Cognitive functioning

FatigueRole functioning

Emotional functioning

Soffietti R et al, JCO 2013

Cognitive function: Randomized study Post Surgery/SRS WBRT Vs Observation

EORTC domain scores reduce with WBRT at 6 & 12 mo FU

JROG 99-01RTOG 95-08MDACC

Limited Brain metastasis: Concerned over cognitive function

1-3 brain metsControlled primary diseaseBreast/Lung CaECOG 0Age<65

Post surgery limited field RTHippocampal sparing RT

Mehta M et alGondi V et al

Randomized studyMeta-analysis

Cognitive function benefit

Ph-II StudySmall numberOngoing Ph III study

ONLY SRS

Ph II studies

Hippocampal sparing preserves congitive function domains

Hopkins verbal learning scale

Single lesion: Post surgery SRS in resection bed

Salvage WBRT only in 30-40% patient78% LC at 12 monthsMedian survival: 12-15 months

Vogel et al. Radiat Oncol (2015) 10:221

Median survival 12-15 monthsRequirement of salvage WBRT only in 25-30%

Post surgery & SRS: Requirement of salvage WBRT

Single lesion: Post surgery SRS in resection bed

Sneed et al, Neurosurg 2015

SRS in brain mets - Issues

- Radionecrosis- 5-17%

- Steroid dependence- few

- MRI changes/ persistent oedema

- Leptomengial spread- Not consistent

- Issues with larger cavity

- Appropriate planning/ contouring

- Expertize

Cost Effectiveness of treatment

Kemmel TK et al, World Neurosurg. (2015) 84, 5:1316-32.

Efficacy of treatment of Brain metastasis

Brain metastasis: RPA according to primary sites

Brain metastasis: RPA according to primary sites

Brain metastasis: RPA according to IHC status

Brain metastasis: May NOT consider RT in specific group

Brain metastasis: Molecules targeted at primary sites

Brain metastasis: Immunotherapy adding to SRS

Evolving standard of care in brain metastasis

Till 1990s: • Whole brain RT is standard of care• Studies were focused on dosage schedule• 30Gy/10# equivalent to 40Gy/16#• Median survival 6-12 months

Since 1990s:

• Limited brain mets- WBRT+ SRS is standard of care (Level 1 evidence, Rec A)• Randomized studies showed 2 mo survival benefit on addition of SRS• 30Gy/10# + 12 Gy Boost• Median survival 2 months benefit

Evolving standard of care in brain metastasis

• Gondi et al Hippocampal sparing RT randomized study is onging• Ph III study (N107c study): Sur +WBRT Vs Sur+ SRS boost

Since 2012: • Limited brain metastasis- SRS alone (Level 1A evidence, Rec A)• Randomized studies showed no OS benefit with WBRT• Meta-analysis confirmed: No OS benefit with WBRT, only LC benefit• Randomized studies confirmed Cognitive function decline with WBRT• WBRT only on recurrence / leptomeningial disease• SRS boost after surgery: reduce local recurrence (Level II, Rec B)• Preservation of cognitive function• Hippocampal sparing RT is new & exciting (Level II, Rec B)• Need randomized study for confirmation of it’s effectiveness

Future:

Conclusions: Role of WBRT

- Limited brain metastasis: SRS alone is the standard of care (Level 1A evidence, Rec A)- Multiple brain mets with poor prognosis: WBRT is standard of care

- In limited metastasis, role of WBRT arguable- There is no overall survival benefit with addition of WBRT vis a vis SRS ONLY- Declines in cognitive function & QOL

- Hippocampal sparing RT in limited brain disease is new & exciting (Level II, Rec B)- Need randomized evidence with adequate end-point for confirmation of it’s effectiveness

- SRS boost after surgery: reduce local recurrence (Level II, Rec B)- Preservation of cognitive function

WBRT may be history soon

- 42 Yr Female- K/C/O Early Ca Breast diagnosed 1 yr back

- BCS + adequate CT + RT done- On HT

- ER/PR +Ve ; Her2neu –ve

- C/o Headache 1 month back

- MRI Showing 3 lesions in brain - Deep seated lesions

- PET scan – No disease in any other region

- Good GC- Neurological status- normal

Standard of care in 2016?

QOL & Cognitive function issuesOverall Survival issuesBetter systemic therapy improves extra-cranial disease control

Case scenario # 1

Acknowledgements

Prof Rakesh JalaliDr Tejpal GuptaBrain Tumour Foundation

Dr Litan Naha BiswasDr Kalyan Bhattacharya

Prof Alexender MuacevicProf Bernard WowraProf John AdlerProf Riccardo SoffiattiDr Rudo