1. Management of CNS Oligometastases
Liam A. Mulroy
Radiation Oncology
October 2011
Department of
Radiation Oncology

2. Disclosures
No financial disclosures!
But...

3. 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

4. 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
Department of
Radiation Oncology

5. What is Oligometastatic Disease?
I’m not sure...
Oligo means “a few”
RTOG and EORTC 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

6. 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?

7. What is “Oligometastatic” Disease?

8. 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

9. RTOG RPA Classification Gaspar et al,IJROBP 1997 Vol. 37: 745-741

10. 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

11. Brain Mets DS GPA Sperduto 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

12. Brain Mets GPA Sperduto et al IJROBP Vol.77,No.3 pp.655-61,2010
Prognostic index based on 4,259 patients
Retrospective
S,SRS,WBRT
Disease specific

13. Brain Mets GPA Sperduto et al IJROBP Vol.77,No.3 pp.655-61,2010

14. Brain Mets GPA Sperduto et al IJROBP Vol.77,No.3 pp.655-61,2010

15. 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

16. 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

17. 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

18. 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?

19. Brain Metastases: Current Perspectives
Which are the most important endpoints when assessing whole brain radiation therapy?
Remember that the treatment intent is palliative ....

20. Early Season Overachievers

21. EORTC 22952-26001 Kocher 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

22. 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

23. CEREBELLAR MET Primary NSCLC

24. EORTC 22952-26001: SRS or S +/- WBRT

25. EORTC

26. EORTC

27. EORTC
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

28. EORTC
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?

29. Neurocognition and WBRT
Neurocognition in Patients Treated with SRS or SRS plus WBRT: A Randomized Controlled Trial
Chang et al Lancet Oncol :
58 patients randomized
Primary endpoint: HVLT-R at 4 months
WBRT 30 Gy/12 fractions

30. 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 :

31. Does WBRT Adversely Effect Overall Survival. Chang et al Lancet Oncol
Inferior survival in SRS+WBRT arm
Patients in SRS arm received more chemo and started earlier
Salvage surgery more common in SRS arm

32. Does WBRT Adversely Effect Overall Survival
Does WBRT Adversely Effect Overall Survival? Aoyama et al, JAMA 2006; 295:
No adverse effect in JROSG-99-1)
132 patients, accrual , 1-4 mets
median survival 7.5 months WBRT + SRS vs. 8.0 months SRS

33. Does WBRT Adversely Effect Overall Survival?
Negative effect in Chang trial not seen in JROSG-99-1, EORTC (reviewed earlier) and a surgical trial published by Patchell
No survival benefit as an “adjuvant” therapy

34. Hippocampal Avoidance Section
HIPPOCAMPUS
HIPPOPOTAMUS

35. 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

36. Hippocampal Avoidance

37. 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

38. 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

39. Hippocampal Avoidance Gondi et al, Radiother. Oncol
Hippocampal Avoidance Gondi et al, Radiother. Oncol. 95: % mets occur outside HAR

40. Hippocampal Avoidance HA-WBRT technique (Gondi et al)

41. Hippocampal Avoidance
Save the hippos!
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

42. 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

43. WBRT and SIB 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 months
Rodrigues et al, IJROBP Vol.80, No.4, pp , 2011

44. WBRT and SIB Rodrigues et al, IJROBP Vol.80, No.4, pp. 1128-1133, 2011

45. WBRT and SIB Rodrigues et al, IJROBP Vol.80, No.4, pp. 1128-1133, 2011

46. WBRT with SIB and HA It can be done if you let Fred do it!
Planning study at BCCA
10 patients,18 mets
SIB mets Gy
WBRT Gy/15 fr
Mean hippocampal dose 5.23 Gy-2
Hsu et al, IJROBP 2009

47. WBRT with SIB and HA Hsu et al, IJROBP 2009

48. WBRT with SIB and HA Hsu et al, IJROBP 2009

49. 63 y. o. woman. Originally diagnosed with breast cancer 7 years ago
63 y.o. woman. Originally diagnosed with breast cancer 7 years ago. Left mastectomy. In 2007 had right hip fracture – hip replacement and XRT (Dr. Rutledge). Recently feels “off balance”. Presents with left homonymous hemianopsia, headache and vomitting.

50. Example Case Various options...
63 year old female,metastatic breast cancer,excellent condition
RTOG RPA class 2
GPA 3 or 4, median survival months
6 mets, largest/symptomatic met excised

52. 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