- A 58-year-old female nurse presented with headache, nausea, and mental status changes. Imaging showed 3 brain metastases with no known primary site. - She had a KPS of 90, age <60, controlled primary (pending further workup), and no extracranial mets, placing her in RPA class I and GPA group with a predicted median survival of 7.1-11.3 months. - Treatment options included WBRT alone or WBRT with boost to reduce risk of neurocognitive toxicity based on the RTOG 0933 trial, which showed reduced memory decline with hippocampal avoidance. Patient selection focused on tumor types likely to benefit and survival duration to gain

1. Radiation Oncology
Case Rounds
21ST MAY 2015

2. • Physicist and chemist
• Winnipeg, Manitoba, Canada
• 2nd person to die of criticality
accident (Manhattan Project)
• Proposed dollar unit of reactivity
• Louis Slotin
May 21st 1946

3. IN THE MEDIA

4. TICKLING THE DRAGON’S TAIL

6. IN THE MEDIA

7. BACK TO BUSINESS

8. HA-WBRT (Hippocampal
Avoidance WBRT)
Judy Morrow

10. “Everything I do is slow. I walk, talk, and think slowly… I still
have no short-term memory…
Much of the time I can't even remember the names of relatives
and close friends… I am always confused…
Because I look normal and often sound normal, people
assume I am normal. But I'm not…
I get depressed a lot knowing that I will never have my
competence back.”
-Sontag Foundation Distinguished Scientists Awards ceremony speech
at the Society for Neuro-Oncology Meeting, Toronto, Canada, November
20, 2004
- Susan Sontag (full time homemaker and mother / Cancer & brain radiation survivor )

11. • Whole-brain radiotherapy (WBRT) is the most widely
used treatment option for patients with multiple brain
metastases
• Benefits
• rapid palliation of neurologic symptoms
• improved local control as an adjuvant to resection or
radiosurgery.
• prolongs time to neurocognitive function (NCF)
decline.( deterioration in NCF preceded self-reported quality of
life decline by up to 153 days)
WBRT

12. • Before 1970, the human brain was thought
to be radioresistant;
• the acute central nervous system (CNS)
syndrome occurs after single doses of ≥30
Gy, and white matter necrosis can occur at
fractionated doses of ≥60 Gy
CNS Toxicity

13. • Radiation necrosis of the brain typically
occurs 3 months to several years after
radiotherapy (median 1–2 years)
• Emami et al
• 5% risk of radionecrosis at 5 years with
a dose of 60 Gy to one-third of the brain
with standard fractionation
• Quantec : For standard fractionation, the
incidence of radionecrosis appears to be
• <3% for a dose of <60 Gy.
• 5% with a dose of 72 Gy
• 10% with a dose of 90 Gy. However
But that’s not what we are talking
about!!

14. • Early neurocognitive decline, within the
first 1-4 months, which primarily reflects
memory.
• Long-term serious and permanent adverse
effects, including cognitive deterioration in
other domains and cerebellar dysfunction
• As many as11% of long-term brain
metastases survivors (>12 months) treated
with WBRT develop severe dementia,
especially with the use of larger dose-per-
fraction schedules
Neuro-cognitive toxicity in
WBRT

15. • According to the principle of double effect,
• “sometimes it is permissible to cause a harm as a
side effect (or “double effect”) of bringing about a
good result even though it would not be permissible
to cause such a harm as a means to bringing about
the same good end.”
Doctrine of Double Effect
St. Thomas Aquinas;
Summa Theologica (II-II, Qu. 64, Art.7)

16. • radiation-induced injury to proliferating
neuronal progenitor cells in the
subgranular zone of the hippocampi
PATHOGENESIS

17. • Approximately 100 000 patients per year
in the United States with primary and
metastatic brain tumor survive long
enough (>6 months) to develop
radiation-induced brain injury
Is this a big deal in these stage IV
patients?

19. • At 4 months
• HA-WBRT versus WBRT
• 7% vs 30% memory score decline
• measured by the Hopkins Verbal
Learning Test (HVLT).
• By 6 months post-treatment, decline was 2
percent, on average
RTOG 0933
American Society for Radiation Oncology
(ASTRO) 55th Annual Meeting; 2013

20. HIPPOCAMPAL CONTOURING

21. HIPPOCAMPAL CONTOURING

22. My interest

23. • MRI:
• 3D-SPGR axial MRI scan of the head with standard axial and coronal
FLAIR, axial T2-weighted and gadolinium contrast-enhanced T1-
weighted sequence acquisitions .
• 1.25mm slice thickness is preferred to contour the hippocampus
accurately. Slice thickness of 1.5mm or less is permitted.
• Obtain in supine position; immobilization devices used for CT simulation
and daily radiation treatments not necessary.
• CT Simulation:
• Non-contrast treatment-planning CT scan of the entire head region.
• 1.25-1.5mm slice thickness is preferred for accurate hippocampal
sparing planning. Slice thickness of 2.5mm or less is permitted.
• Immobilize patient in supine position using an immobilization device such
as an Aquaplast mask over the head. Treat patients in the
immobilization device.
• MRI-CT Fusion:
• Fuse the 3D-SPGR MRI and the treatment-planning CT.
SIM INFO (0933)

25. HA-WBRT IMRT
Planning
PTV D2% ≤ 37.5 Gy
D98% ≥ 25 Gy
Hippocampus D100% ≤ 9 Gy
Maximum dose ≤ 16 Gy
Optic Nerves
and Chiasm
Maximum dose ≤ 37.5 Gy
0933 dose constraints

26. IS THS FOR ALL BRAIN METS
PATIENTS??
HOW DO WE SELECT THE PATIENTS
FOR SUCH APPROACH??

27. Recursive Partitioning Analysis
(RPA)
RPA Stages For Brain Metastases
Stage Characteristics Median Survival (mo)
I
KPS >=70, age <65, primary
controlled, no other extracranial
mets
7.1
II all others 4.2
III KPS <70 2.3

28. GPA Criteria For Brain
Metastases
Variable 0 Points
0.5
Points
1 Point 2 Points 3 Points 4 Points
NSCLC/SCLC
Age >60 50-59 <50 - - -
KPS <70 70-80 90-100 - - -
No.
Cranial
Mets
>3 2-3 1 - - -
Extra-
cranial
Mets
Present - Absent - - -
Renal/Melanoma
KPS <70 - 70-80 90-100 - -
No.
Cranial
Mets
>3 - 2-3 1 - -
Breast/GI
KPS <70 - 70 80 90 100
Median OS Survival (months)
GPA
Score
NSCL
C
SCLC
Melano
ma
Renal
cell
Breast GI
0-1 3.0 2.8 3.4 3.3 6.1 3.1
1.5-2.5 6.5 5.3 4.7 7.3 9.4 4.4
3.0 11.3 9.6 8.8 11.3 16.9 6.9
3.5-4.0 14.8 17.0 13.2 14.8 18.7 13.5
Overall 7.0 4.9 6.7 9.6 11.9 5.4

29. Which tumor types??
• RTOG 0933
• other than small cell lung cancer and
germ cell malignancy

30. • 58 y/o nurse & smoker
• c/o headache, nausea, mental status
changes
• CT showed 3 metastasis : radiologic
diagnosis
• No other site of primary on CT T/A/P
• no other etiology suspected
CASE SUMMARY

31. CECT

32. MRI BRAIN

33. • No other site of primary detected on
staging CT scan. No pathology!
• Awaiting PET CT for staging

34. 1. WBRT (of course!)
2. WBRT + VMAT Boost
?? Double effect / risk of toxicity
OPTIONS

35. RPA Stages For Brain Metastases
Stage Characteristics Median Survival (mo)
I
KPS >=70, age <65, primary
controlled, no other extracranial
mets
7.1
II all others 4.2
III KPS <70 2.3

36. GPA Criteria For Brain
Metastases
Variable 0 Points
0.5
Points
1 Point 2 Points 3 Points 4 Points
NSCLC/SCLC
Age >60 50-59 <50 - - -
KPS <70 70-80 90-100 - - -
No.
Cranial
Mets
>3 2-3 1 - - -
Extra-
cranial
Mets
Present - Absent - - -
Renal/Melanoma
KPS <70 - 70-80 90-100 - -
No.
Cranial
Mets
>3 - 2-3 1 - -
Breast/GI
KPS <70 - 70 80 90 100
Median OS Survival (months)
GPA
Score
NSCL
C
SCLC
Melano
ma
Renal
cell
Breast GI
0-1 3.0 2.8 3.4 3.3 6.1 3.1
1.5-2.5 6.5 5.3 4.7 7.3 9.4 4.4
3.0 11.3 9.6 8.8 11.3 16.9 6.9
3.5-4.0 14.8 17.0 13.2 14.8 18.7 13.5
Overall 7.0 4.9 6.7 9.6 11.9 5.4

39. • Patients ≤50 years old
• SRS alone
• median survival of 13.6 months
• SRS plus WBRT
• 8.2 months for patients ≤50 who
were treated.
• Patients >50 years old had a median
survival of 10.1 months when treated with
SRS alone, and 8.6 months for those who
received SRS plus WBRT.

41. THANK YOU FOR YOUR PATIENCE!