This document discusses 5 common misconceptions that clinicians have regarding treatment of patients with brain metastases. It summarizes a presentation given by Dr. Tossif Ghodiwala aimed at reevaluating the management of these patients. The 5 misconceptions are: 1) all tumor histologies are the same, 2) number of lesions matters most rather than total tumor volume, 3) micrometastases are always present, 4) whole brain radiation is always harmful, and 5) most metastases cause obvious symptoms. For each misconception, the document provides the current evidence and perspective that these views are outdated and that a more personalized approach is needed.

1. Douglas Kondziolka, MD, MSc,FRCSC
Steven N. Kalkanis, MD
Minesh P. Mehta, MD
Manmeet Ahluwalia, MD
Jay S. Loeffler, MD
It Is Time to Reevaluate the Management
of Patients With Brain Metastases
Presented by Dr Tossif Ghodiwala. MD
MOSCOW 2015

2.  There are many elements to the science that
drives the clinical care of patients with brain
metastases. Although part of an
understanding that continues to evolve, a
number of key historical misconceptions
remain that commonly drive physicians’ and
researchers’ attitudes and approaches.

3.  By understanding how these relate to current
practice, we can better comprehend our
available science to provide both better
research and care.

4. "We are in an era of personalized medicine,"
Dr. Kondziolka said in press statement, "and we
need to begin thinking that way
[with brain metastases]."

5. So the team took the initiative to dust off and
clear out 5 "key" misconceptions that linger
and "commonly drive" clinicians' approaches
to treatment.
 Douglas Kondziolka, MD, MSc,FRCSC
 Steven N. Kalkanis, MD
 Minesh P. Mehta, MD
 Manmeet Ahluwalia, MD
 Jay S. Loeffler, MD

6. Review
"The authors did a great job looking at the current
issues with respect to the evidence and highlight
5 areas of controversy,“ But the truth is, the list
could be longer. There are "many" areas of
treatment and management that are based on
misconceptions and are in need of clinical trials
and evidence.
Arjun Sahgal, MD,
(Associate professor of radiation oncology
at the Sunnybrook
Odette Cancer Centre in Toronto.)

7. For now, the authors submit the
following 5 misconceptions.
1. Misconception: All histologies are created equal.
2. Misconception : Actual numbers of lessions matter
most.
3. Misconception: When a metastatic brain tumor is
present, micrometastases are also always present
and in need of management.
4. Misconception: WBRT is always harmful —
eventually
5. Misconception: Most brain metastases cause very
obvious symptoms, making regular screening
unnecessary.

8. MISCONCEPTION 1: ALL HISTOLOGIES ARE
CREATED EQUAL
 The first misconception is assuming that "all
histologies are created equal" - that the type of
cancer doesn't matter once it has spread to the
brain.
WHAT DO YOU THINK?

9. All tumor cell types act the same way once they
spread to the brain?
 This oversimplification means that doctors
assume that histologically diverse cancers
respond the same way to chemotherapy and are
equally sensitive (or insensitive) to radiation. It
also means that patients are all assumed to be at
the same risk of subsequent brain cancer
relapses, and development of additional
metastatic lesions; and that survival rates are
similar as well.
This is "one size fits all" approach
WHAT IS YOUR POINT OF VIEW?

10.  The authors point out that this type of thinking
overlooks important biological differences in brain
metastases resulting from different types of
cancer, such as those originating in the lung,
breast or skin.
AUTHORS POINT OF VIEW

11. Correction:
Clinicians should recognize that brain
metastases are not all the same and will have
biologic differences resulting from different types
of the original extracranial cancer, such as those
from the lung, breast, or skin.
Thus "one size fits all" approach is incorrect

12. MISCONCEPTION 2: ACTUAL NUMBERS OF
LESIONS MATTER MOST
 Many brain metastasis randomized trials included
the number of brain metastases identified using
whatever imaging was available at that time as
either a stratification or a prognostic variable.
 Common thresholding patterns included single
lesions (often further subclassified as single or
solitary), 2 to 4 tumors, fewer than 5, more than
5, or more than 10 tumors (with 1 or more of
these categories being recognized as multiple
lesions).
This simple numerical approach arose from 4
biases.

13. 4 biases
First, surgical resection was almost exclusively used in
patients with 1 known tumor, although some small
series in the literature reported resection of 2 to 3
lesions.
Second, single-tumor patients (and. more importantly,
those with solitary tumors) were believed to live
longer and perhaps deserved greater attention in
terms of the aggressiveness of achieving intracranial
control.
Third, the number of tumors was thought to be a
reasonable estimate of tumor burden as well as tumor
biology, leading to the concept of oligometastatic vs
miliary spread of intracranial disease.
Fourth, it was easy to count tumors for stratification and
response analysis.

14. In this way
an 8-mm diameter frontal lobe melanoma metastasis was
given the same “weight” as a 2-cm diameter thalamic tumor
from non-small cell lung cancer.
Given the fact that patients with these differing lesions
might present with vastly different symptomatic
presentations with different degrees of brain edema,
potentially different radiation responses, and different
forms of extracranial disease therapy, it is not surprising
that clinical series containing such information could
provide results that were often disparate.
Even though higher quality studies attempted to match clinical
criteria according to age, sex, number of patients with lung
cancer, and Karnofsky Performance Scale score, they still
failed to account for tumor biology andtumor volume.

15. Correction:
 Total tumor volume might be more predictive of survival, local
control, and distant brain failure than the number of tumors.
YES "One cannot dismiss tumor number as being unimportant, but
real tumor burden should be our new focus,".
They cite a number of contemporary studies to back up this point.
 For example, in a study of 251 patients with brain metastases
who underwent radiosurgery, the number of brain metastases (1
to 9) was not predictive of survival, local control, or distant brain
failure. Instead, total tumor volume greater than 2 mL was
predictive of survival and local control, which was 94% at 1 year
(Int J Radiat Oncol Biol Phys. 2013;85:656-661).
 Dr. Kondziolka told Medscape Medical News that the myth about
tumor number even influences insurance payments. "Payers
often approve treatment of the brain depending on the number of
tumors present, which may have little to do with outcome," he
emphasized.

16. MISCONCEPTION 3: THERE IS NO SUCH
THING
AS A SINGLE BRAIN METASTASIS
When a metastatic brain tumor is present,
micrometastases are also always present and
in need of management.
"It is still held that micrometastases...create a
diffuse problem no matter how many [bigger]
tumors might be visible on an imaging study,"

17. Lets think !!!
 If this thinking was accurate, then whole-brain
radiation therapy (WBRT) should improve survival
when it is added to a focal therapy, such as
stereotactic radiosurgery (SRS),
BUT
 That is not what happens. "In no large study does
the addition of WBRT to SRS improve survival,".

18. Correction:
"Blindly managing assumed metastases is no longer best
practice when such tumors can be defined with serial
images," the authors assert.
 Micromets will surface if they are significant. "If
micrometastases are present and not treated, they should
become apparent on later imaging."
 WBRT is not needed for every patient.
 Indeed, "strong evidence" indicates that focal therapies for
isolated metastatic lesions improve survival, compared
with the more diffuse WBRT.
Citing 2010 guidelines, the authors explain that both
single-dose SRS and WBRT are effective for treating
patients with brain metastases, but single-dose SRS alone
provides a survival advantage over WBRT alone for
patients with as many as 3 metastases.

19. MISCONCEPTION 4: WBRT IS ALWAYS
HARMFUL EVENTUALLY
The idea behind this myth is that WBRT is
generally unjustified because it will cause
cognitive dysfunction if a patient survives long
enough.
Whole-brain radiation therapy invariably causes
disabling cognitive dysfunction if a patient lives
long enough.

20. Correction:
 Ultimately, a "balanced approach that allows for
individualization" of treatment.
 Cognitive deficits occur as a result of WBRT, but
also occur in the absence of WBRT — because of
tumor progression. Such progression can be
slowed by WBRT, so "an appropriate balance"
needs to be sought.
 Examples of patients who should avoid WBRT
are someone who is "high-functioning" and
concerned about cognitive decline or those in
whom extended survivals are expected.

21. MISCONCEPTION 5: MOST BRAIN
METASTASES
ARE SYMPTOMATIC AND SCREENING DOES
NOT HAVE A MAJOR IMPACT
Most brain metastases cause very obvious
symptoms, making regular screening
unnecessary.
 This misconception did not apply until recently
and still is not a full-blown myth. In past years,
imaging for neurologic screening was rare, and it
is still not commonplace, the authors
acknowledge. As a result, the majority of brain
metastases have been found because of
symptoms — headaches, seizures, or neurologic
deficits.

22. Correction:
 The tumor was most commonly found on a
screening scan and caused no or minimal
symptoms. Thus, the goal of modern brain
metastasis treatment is not usually to improve
overall prognosis or function, but rather to prevent
neurological deterioration while care for the
extracranial cancer continues uninterrupted.
 With increased use of MRI, metastases are now
being detected before they cause any symptoms.

23. Thus, it is time for fresh thinking
and new critical analyses.

24. CME QUESTIONS:
1. An asymptomatic patient with known melanoma
is found to have a new isolated 1 cm intracranial
metastatic tumor. What is the most significant
factor in determining the prognosis for this
patient?
A. Age
B. Gender
C. Tumor size
D. Single brain metastasis
E. Extracranial melanoma

25. 2. What factor is most predictive of response to
radiotherapy for patients with brain metastases?
A. Total tumor volume
B. Tumor number
C. Tumor volume and number
D. Anatomical location

26. 3. Single dose radiosurgery has a survival
advantage over WBRT alone for patients with
what number of brain metastases?
A. 1-3
B. 3-5
C. 5-7
D. 7-9

27. REFERENCES:
 Neurosurgery 75:1–9, 2014 DOI:
10.1227/NEU.0000000000000354
www.neurosurgery-online.com