1.
Brain metastasis
Topic: Is WBRT obsolete in multiple brain mets?
Moderator: Dr. Subhash Gupta
Addl. Professor
Dept. of Radiation oncology
AIIMS – New Delhi.

2.
WHOLE BRAIN RADIOTHERAPY
CAN NEVER BE OBSOLETE AS LONG AS
CANCER EXISTS!!!!

3.
Nature Reviews Clinical Oncology volume 17, pages 279–299 (2020)

4.
• MAJOR PROBLEM IMPORTANT DISCUSSION

5.
THIS IS WHAT WE KNOW!!!!
Median Survival Time:
Untreated 1 month
Dexamethasone alone 1-2 months
WBRT - Mostly 3-6 months.
► Short Overall Treatment Time

6.
• Larger lesions
(>4 cm)
• Rapid relief of
Mass effect
and edema
• WBRT remains standard of care
in multiple brain mets.
• Overall response rate 40-60%
• Good intracranial control-75%.
• Neurologic improvement is 25-
40%.
• HA-WBRT shown to minimise
Cognitive side effects.
TREATMENT OPTIONS
SURGERY WBRT SRS/SRT
• Treatment of small, deep
lesions or eloquent areas.
• Favourable toxic profile.
• Doesn’t eliminate all brain
mets.

7.
WBRT role in Brain metastasis
• Headache 40-70%
• Discontinuation of Corticosteroids 51%
• Improvement of Performance Status 57%
• Cerebral Dysfunction 40-50%
• Improvement in Paresis 30-40%
1. Wong J, et al., Int J Radiat Oncol Biol Phys. 2009 Nov 15;75(4):1125-31. (N=129)
2. Komosinska K, et al., Acta Oncol. 2010 Apr;49(3):382-8. (N=91; KPS <70)
3. Van Oorschot B, et al., Breast Care (Basel). 2011;6(1):14-19. (Review)

8.
SO WHY THE CONFUSION?????

9.
WBRT might still have a role for patients with the best prognoses according to GPA
score >2.5

10.
• 88% patients-UPFRONT BRAIN METS-already worse group!!!!
• Nearly 70% of patients had a KPS <70%.
• The duration between diagnosis and randomization could be ≤8 weeks, an excessively
long period.
• The median survival was 2 months, lower than that in most studies and less than the
poorest graded prognostic assessment class!!! How was QOL assessed??
• study design-SELECTION BIAS!!!!
“clinicians were encouraged to approach potential participants about the trial if
there was uncertainty in the clinicians’ or patients’ minds about the potential benefit of
WBRT”.
• Sub analysis has shown that the benefit in >5mets rather than 1-4 mets
Is This a Flawed One-Size-Fits-All Approach?

11.
• The clinical decision to treat brain mets with SRS or WBRT, or both depends
on multiple factors.
- Performance status
- Control of systemic disese
- Primary cancer type
- Disease burden within brain and
- Interval to progression.
PATIENT GROUPS ARE HETEROGENEOUS !!

12.
STUDY RESULT NOTES
RTOG 9508
(WBRT vs WBRT+SRS)
n=333
• SRS addition improved LC
• WBRT+SRS improved OS in single brain
metastasis, RPA-1, Size >2 cms.
• Early and late toxicities did not differ
greatly between treatment groups.(RTOG)
• No advantage in Survival, local failures,
neurological deaths with SRS in 2-3 mets.
-NEGATIVE TRAIL for multiple mets.
JROSG 99-1
Aoyama et al.
(SRS vs SRS+WBRT)
n=58
• At 12 months, adjuvant WBRT
resulted in an increased Local
control (p<0.05)
• Decreased risk for new brain
metastases (p<0.05).
• No OS difference
• SRS had 27.5% Local recurrence
• SRS had 64% distant recurrence
• SRS had 12months intracranial recurrence
of 74.6%.
• ?? Improved Neurocognition assessment. (
MMSE)
Chang et al.(MD Anderson)
(SRS vs SRS+WBRT)
• SRS alone had higher neurocognition intact
at 4 months.
• SRS alone had higher OS
• SRS had 87% retreatments.
• WBRT group had more systemic deaths
possible cause for lower OS
EORTC 22952-26001
Kocher et al.
(SRS/Sx Vs SRS/Sx+WBRT)
• No differences in functional independence
or OS between the study arms.
• Adjuvant WBRT reduced the 2-year relapse
rate at initial sites and new sites.
• They did not evaluate cognitive function
Brown et al.(N0574)
(N=213)
• Lesser cognitve deterioration by 28%
• Greater QoL with SRS alone
• No significant difference in functional
independence.
• Lesser intracranial failure with WBRT
addition by 18.4%
• Retreatments more in SRS alone 32%

13.
• Intracranial recurrence and need for salvage treatment greater when
WBRT was omitted.
STUDY INTRACRANIAL
RECURRENCE
RETREATMENT after SRS
Brown PD et al. 24.7% 32%
Chang et al 73% 87%
Aoyama H et al 74.6% 22%
Kocher M et al 48% 31%

14.
WBRT has doubled the OS.
Survival gain by 10months. In
NSCLC subgroup
WBRT +SRS
SRS
RTOG 9508 Secondary Analysis JROSG 99-1 Secondary Analysis
WBRT has doubled the OS.
Survival gain by 6.1 months in
NSCLC subgroup
Pirzkall et al.
WBRT addition resulted in
superior OS benefit by 7.1
months.

15.
JAMA Oncol. 2015;1(4):457-464. doi:10.1001/jamaoncol.2015.1145
• Superior median OS with DS-GPA 2.5-4.0 group in
WBRT+SRS vs SRS is 16.7 vs 10.6 months.(p=0.04)
• Increased 1-year rate of distant brain relapse (HR
8.31; p=0.04),
• Increased 1-year local tumor failure (P = .002).
• This resulted in more frequent use of salvage
therapy (P <.001) in the SRS-alone arm.
• Improved OS was attributed to fewer brain
recurrences after WBRT.
• MMSE deterioration was significantly longer for the
WBRT plus SRS arm (16.5 months vs. 7.6 months; P
= .05)
Phase III trial of 1-4 lesions, NSCLC subgroup. SRS vs SRS+WBRT.

16.
Sx+WBRT
Sx+WBRT
Sx
Sx
Sx+WBRT
Sx
-WBRT has decreased
intracranial recurrence by 52%.
-Improved Local control by
36%.(p<0.01)
-Decreased neurological
death.(p=0.03)
Postoperative radiotherapy in the treatment of brain metastasis
Patchell RA, JAMA. 1998
• leptomeningeal disease
adjacent to the surgical
cavity after
radiosurgical treatment
was reported to be as
high as 16·9%
Sx vs Sx+WBRT
Sx vs Sx+SRS

17.
-Those with >1 brain metastases also had a significantly greater risk of
distant brain failure with a HR of 1.59 (95% CI 1.14-2.2)
-SRS alone had 21% local failures & 47% distant failures.
-Neurocognitive outcomes better with selected population .
Data for QoL, functional status, cognitive effects were insufficient to
determine effects of WBRT.
-SRS only treatment approach results in significantly high incidence of
local and distant failure.
-No difference was observed for adverse effects and neurologic death
between the treatments.
-SRS only results in better QOL in short term
Whole brain radiotherapy for the treatment of
newly diagnosed multiple brain metastases:
meta-analysis
-The addition of WBRT to radiosurgery improved local and distant brain
control.
-No differences in OS.
-Many of these trials lacked quality of life outcomes, neurocognitive outcome.
-Trials are needed to evaluate the use of neurocognitive protective agents and
hippocampal sparing with WBRT.

18.
Did the Brain RECURRENCES impact Neurocognition?
• MMSE were worse in patients with uncontrolled tumours than in
patients with controlled tumor.
-Regine et al (2 studies)
-Taylor et al..
The side effects of recurrent tumours are worse than the side effects
of Preventive tumors.
Regine WF et al,IJROBP 2002; 52

19.
The value of 4-month neurocognitive function as an endpoint
in brain metastases trials
• NC primary deterioration – 4ms
• Recovery - 8ms
• Secondary deterioration – 12ms
(Upto Baseline ONLY!!!)
• MMSE is not a standard cognitive
battery.
• Sec.deterioration relating to ?NSC.
Shunsuke O et al, J Neurooncol (2014)
So, LONG FOLLOW-UP DATA IS NECESSARY TO DRAW CONCLUSION

20.
Flaws in assessing cognition
• Most studies use a time-to-event analysis instead of reporting cognitive function
serially over time.
• There is no prefect cognitive test. (Janelsins MC, Int Rev Psychiatry. 2014)
• Most studies with median survival upto 4 to 6 months.
• Short follow up data, most Cognitive functions recover later.(Armstrong et al,
Shunsuke O et al,)
• Validity of cognitive batteries used across studies- INCONSISTENT (Susan GR
McDuff et al.)
• The effects of chemo-brain on these analyses should be considered.
• Impact of Local failures & distant failures on QoL not well reported.
• Discordance between objective cognitive test results and subjective complaints is
frequently observed in many neurologic populations.

21.
RTOG 0614
Memantine during WBRT considered standard of care
Brown et al. Neuro-Oncol 2013

22.
Primary end point : the Hopkins Verbal Learning Test–Revised
Delayed Recall (HVLT-R DR) at 4 months
HA-WBRT is a technique that involves conformal avoidance of sub-
granular zones of the hippocampi.
• HVLT delayed recall of 7% compared to 30% in WBRT.
(P=0.0003).
• Comparable to that observed with SRS alone at a similar
point in time in the prospective Chang et al.
• Quality of life, assessment showed improvement in emotional
well-being over the course of 6 months.
• D100% of the hippocampus, predicted for greater decline in HVLT-
DR.
Journal of Clinical Oncology 32, no. 34 (December 01, 2014) 3810-3816.

23.
• Phase 3 trial, non-blinded, Study time:2015-
18, n=518, Med follow-up:7.9 mos.
• No increase in hippocampal relapses.
• Significant reduction in cognitive failure risk
was noted (HR, 0.76; P = 0.03).
• Less fatigue (P = .04), less difficulty with
remembering things (P = .01), and less
difficulty with speaking.
February,2020. DOI https://doi. org/10.1200/JCO.19. 02767

24.
HR= 0.74
RTOG 0614 NRG CC001
HR= 0.78
Contributes to debate over SRS vs. WBRT for brain metastases
RTOG 0614: HR=0.78 with addition of memantine to WBRT
NRG CC001: HR=0.74 with addition of HA to WBRT+memantine
Combined HR with memantine+HA = 0.78 x 0.74 = 0.58
Comparable to phase III trials favoring SRS in lieu of WBRT
The incidence of
cognitive
deterioration with
SRS alone at 12
months = 60%
Paul D. Brown et al., JAMA 2016

25.
Studies undergoing recruitment
• Several trials are underway comparing the use of HA-WBRT against
SRS
• NCT03550391,
• NCT03075072,
• NCT04277403(HA-WBRT vs SRS in Patients With Multiple Brain Metastases
HipSter),
• NCT01592968,
• ENCEPHALON trial.
• AIIMS-IRCH-Dr Subhash Gupta/ Dr Sai Kumar

26.
Will this model work out in INDIA?
• Indian GDP per capita in India is expected to
reach 1,45,679 Rs. (2020-21).
• Cancer with a monthly expenditure of ₹ 5,121
tops the list.
• Govt contribution in a person’s health
expenditure is 20% only.
• Did the QALY gained with SRS alone weighs
considering retreatment costs ?

27.
Is WBRT an
evolution or
revolution?

28.
What about patients?
• Recurrences in clinical practice can be devastating both physiologically
and Psychologically to patients.
• High recurrence rates makes close surveillance with imaging
-COSTING TO PATIENT BOTH IN COMPLIANCE AND FINANCIALLY.
• Always kept in mind about ‘Shared decision making’.
• SOMETIMES PATIENTS MAY NOT GET WHAT DOCTOR IS
CONVEYING.
• IN METASTATIC SETTING, PATIENTS ACCEPT SOME RISK OF
TOXICITY IN AN EFFORT TO IMPROVE THE HEALTH.
• No difference in functional independence with addition of WBRT.
• An OS benefit seen in patients with NSCLC who have favourable
prognosis with addiction of WBRT to SRS.

29.
WHOLE BRAIN RT IS HERE TO
STAY!!!!

30.
REBUTTAL

31.
Are Reports of Whole Brain
Radiation Therapy's Demise
Exaggerated?

32.
• JLGK0901 SRS for multiple brain mets
- Non randomised study
- The investigators included multiple pathologies, multiple RPA
classes, other prognostic indicators – CONFOUND RESULT,
DIFFICULT CONCLUSION.
- No of lesions not necessarily decide OS.
- Treating multiple lesions – greater integral doses to Brain
- equals to single fraction WBRT doses to Brain – isn’t it a
contraindication??

33.
• Chang et al: Found greater neurocognitive failure at 4months with
WBRT+SRS vs SRS alone.
Limitations:
-Trend toward worse baseline cognition on TMT-Part A in the
WBRT+SRS group
-The lack of follow-up beyond 4 months.
- Large volume disease in WBRT group
-Significant difference in survival time between the
treatment groups –?Selection bias.
- WBRT group had more systemic deaths possible cause for
lower OS.

34.
Sometimes guidelines are confusing??
SRS = Cost + follow-up Imaging cost + Hospital visits + Psychological stress+ Retreatment costs+
Fear of recurrence

35.
• Global HRQoL worsened more after the second disease progression.
• The most affected scale scores- Loss of appetite, physical functioning,
• Patients who experienced shorter survival – Severely deteriorated QoL.
• Patient’s preference weighing tumor control vs treatment-related toxic
effects remains a highly individual decision.
No improved QoL

36.
• HA-WBRT may be cost-effective for controlling brain
metastases compared with other treatments.
• Survive a median of 3 months - HA-WBRT is cost-effective
• At 6 months, radiosurgery with whole-brain radiotherapy
salvage was cost-effective,.
• At 12 months, HA-WBRT is cost-effective
• At 24 months, HA-WBRT is much more cost-effective
• The highest value treatment in patients with notably
prolonged survival was SRS plus HA-WBRT.
• Radiosurgery was cost-effective in patients with short (3-6
months) prognosis, whereas HA-WBRT and SRS were
both cost-effective in patients with longer (12-24
months) prognosis.

37.
WHOLE BRAIN RT IS HERE TO STAY!!!!
“ARE THE RESULTS OF SRS IN MULTIPLE BRAIN METS,
OVEREMPHASISED??”

38.
Is the Case Closed in Favour of WBRT for Brain
Metastasis?
• I believe the answer is YES.
• The issue is neither closed nor simple.
• Each patient should receive appropriate unbiased information of the
pros and cons of each approach.

39.
“No protocol fits every patient and
no protocol perfectly fits any patient.”
-James Brent
Thank You
(Bohmer et al. 2002)