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

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.

By understanding how these relate to current

practice, we can better comprehend our

available science to provide both better

research and care.

"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]."

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

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.)

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.

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?

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?

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

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

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.

4 biasesFirst, 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 tumorbiology, leading to the concept of oligometastatic vsmiliary spread of intracranial disease.

Fourth, it was easy to count tumors for stratification and response analysis.

In this wayan 8-mm diameter frontal lobe melanoma metastasis was

given the same “weight” as a 2-cm diameter thalamic tumorfrom 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.

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.

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,"

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,".

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.

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.

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.

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.

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.

Thus, it is time for fresh thinking

and new critical analyses.

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

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

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

REFERENCES:

Neurosurgery 75:1–9, 2014 DOI:

10.1227/NEU.0000000000000354

www.neurosurgery-online.com