Brain Metastases

Ashraf Hamed Hassouna

Professor of Radiation Oncology

NCI, Cairo University

10 times more common than primary brain tumors.

Increasing (improvement in systemic therapy and

greater use of MRI).

10% of adults with cancer will develop symptomatic

brain metastases.

Autopsy: 10-30% of cancer patients have brain mets

(Lung cancer 34%, breast cancer 30%, melanoma 72%).

Incidence

Single metastasis = only one lesion in the brain, regardless of

extracranial status.

Solitary metastasis = CNS metastasis as the only site of

disease.

The distribution of brain metastases generally parallels blood

flow, with 80% occurring in the cerebral hemispheres, 15% in

the cerebellum, and 5% in the brainstem.

In the era of MRI, the majority of patients have multiple brain

metastases at diagnosis.

Solitary or multiple brain masses (40% of all intracranial

tumors are metastatic).

Multiple intracranial lesions without history of cancer (in older

patients, metastases should be considered).

Single supratentorial lesion and a history of systemic cancer

(nearly 90% of such patients are diagnosed with brain metastasis).

Single brain lesion and no history of cancer (15% of such

patients receive a histologic diagnosis of brain metastasis).

Common clinical features: headache, nausea,

vomiting, neurological deficit, and seizures.

Cognitive impairment occurs in 65% of patients.

Neurologic deficits may be a result of destruction or

displacement of brain tissue by tumor, peritumoral

edema, increased ICP, and/or vascular compromise.

Clinical Picture

Work Up

Differential Diagnosis

Solitary lesion:

• Primary neoplasm

• Inflammatory

• Cerebrovascular

• Degenerative

Multiple lesions:

• Multifocal abscesses

• Toxoplasmosis

• Multiple enhancing

infarcts

• Brain vasculitis

• Lymphoma

• Multicentric glioma

• Performance status

• Age

• Number of brain metastases

• Primary tumor type

• Systemic tumor activity

• Time from primary tumor diagnosis to development

of brain metastases

Prognostic factors

RTOG proposed a system based on recursive partitioning

analysis (RPA) of RTOG studies (1979-1993).

Prognosis

Management

The mainstay of treatment for brain metastases over the

past five decades has been corticosteroids and WBRT.

Non-randomized studies suggest that WBRT increases

the median survival by 3-4 months (over approximately 1

month without treatment and 2 months with corticosteroids alone).

Median Survival

Best supportive care 1-2 months

Corticosteroids 3 months

WBRT 4-6 months

WBRT + (SRS or surgery) 9 months

The initial treatment of choice.

Should be used:

at onset for all symptomatic patients.

at least 48 hours before WBRT.

Dexamethasone is the drug of choice: No

mineralocorticoid effect, No cognitive effects, lower

risk of infection.

Steroids

Reduce peritumoral edema and local brain

compression within hours.

The mechanism of action is not fully understood:

Down regulate VEGF

Upregulate angiopoeitin-1

Facilitating the transport of fluid into the ventricles

Repairing the leaky capillary permeability

Dose: 10-24 mg iv bolus (usually 16 mg) followed by

4 mg QID or 8 mg BID.

Two dosing schedules:

Start 8 mg bid x 4 D, then 4 mg bid x 4 D, then 2 mg bid

until treatment completed.

Start 8 mg bid, begin taper during Week 2 of RT by 2-4 mg

every 5th day.

If symptoms relapse (tumor or steroid withdrawal), go back

up a level for 4-8 days, then restart taper. If symptoms relapse

after steroids discontinued, restart full regimen.

In severe cases, use mannitol or hyperventilation.

The effects of both are transient.

These should be reserved for critical cases.

Hyperventilation

The most rapid method to decrease ICP.

Intubate and ventilate the patient decrease in pCO2

(25-30 mmHg) vasoconstriction decreasing

cerebral blood volume decreasing ICP.

The effect will only last a few hours before the kidney’s

compensation brings the body back to equilibrium.

Mannitol

It is a hyperosmotic used to lower the ICP.

It works by creating an osmotic gradient between the

blood and brain causing water from the brain to follow

the gradient into the blood.

The effect is seen within minutes and lasts for hours.

20–25% solution of mannitol is given at a dose of 0.5–2.0

g/kg IV over 20–30 minutes. Can be repeated.

No prophylaxis against seizures is

recommended.

A Meta-Analaysis showed lack of efficacy for

seizure prophylaxis.

(Mayo Clin Proc. 2004;79(12):1489-94)

Seizures

Valproic acid was the preferred

anticonvulsant in patient with seizures

and brain tumors because of its efficacy

and relatively good tolerability.

Among brain tumor patients in the US today, levetiracetam

may be the most commonly prescribed AED. An increasing

number of physicians who treat brain tumors recommend it as

the 1st line.

Advantages: no drug-drug interaction - excellent tolerability -

affordable (recently acquired generic drug status) - rapid onset

of action - does not require blood level monitoring - effective

in treating both focal and generalized seizures - available in

SR oral and dose equivalent IV formulation - has antiemetic

properties - inhibit MGMT and potentially increase survival.

The duration of AED use remains controversial.

In practice, particularly for patients who are tolerating AED

therapy well, many physicians continue AEDs indefinitely.

Very limited published data concerning predictors of seizure

recurrence upon AED withdrawal.

Physicians should rely on established principles from the

general epilepsy population to make individualized

determinations about AED withdrawal.

In the general epilepsy, one study enrolled patients

who were seizure free for a minimum of 2 years on

AEDs.

Risk of seizure relapse in patients who tapered off of

AEDs was 15% vs 7% for those remaining on AEDs.

However, there was an improvement of

neurocognitive function from 11% to 28% with

cessation of seizure medication.

Treatment

Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

Treatment decisions must take into account:

• Performance status

• Age

• Number of intracranial lesions

• Extent of extracranial disease

• Primary tumor type

• Prior therapy

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

WBI

Meta-analyses suggest that differences in dose,

timing, and fractionation did not significantly

affect the median survival.

The standard schedule: 30Gy/10f.

With expected longer survival (>6 months),

neurocognitive sequelae can be severe with ≥ 3

Gy/f.

Whole Brain Irradiation

(WBI)

WBRT late effects

Patients with a favorable prognosis may suffer

debilitating late complications of WBRT that include

leukoencephalopathy and cerebral atrophy (resulting in

neurocognitive deterioration), cerebrovascular disease,

and neuroendocrine dysfunction such as

hypothyroidism.

Concerns were initially raised by a small randomized trial by

the MD Anderson Cancer Center. 58 patients were randomly

assigned to SRS±WBRT. The primary endpoint was

neurocognitive function, objectively measured as a significant

deterioration in Hopkins Verbal Learning Test-Revised

(HVLT-R) total recall at 4 months.

Trial was stopped early because the evidence was

overwhelming that adding WBRT significantly increased the

likelihood of a decline in learning and memory function (52 vs

24% at 4 months).

These results were subsequently corroborated by a larger

randomized trial conducted by the North Central Cancer

Treatment Group. In this multi-center trial, 213 patients with

1-3 brain metastases were randomly assigned to SRS±WBRT.

The primary end point was cognitive deterioration, defined as

a decline of more than 1 standard deviation from baseline on

any of six cognitive tests at 3 months in participants who

completed the baseline and 3-month assessments.

Less cognitive deterioration in SRS group compared with the

combined SRS + WBRT group (64 versus 92%, p < 0.001).

Single randomized trial of memantine, an oral N-

methyl-d-aspartate (NMDA) receptor antagonist,

suggest that it may delay time to cognitive decline.

In this study, 508 patients with brain metastases were

randomized to receive WBRT concurrently with

memantine or placebo. The drug was initiated within

3 days of starting WBRT and continued for 6 months.

The authors found that there was less decline in the primary

endpoint of delayed recall at 6 months but this did not reach

statistical significance possibly due to patient attrition.

Patients treated with memantine had better cognitive function over

time; the probability of cognitive function failure at 6 months was

53.8% in the memantine arm and 64.9% in the placebo arm.

Memantine reduced the rate of decline in memory, executive

function, and processing speed in patients receiving WBRT.

Superior results were seen in the memantine arm for executive

function at 8 (p = 0.008) and 16 weeks (p = 0.004) and for

processing speed (p = 0.014) and delayed recognition (p = 0.015) at

24 weeks.

Hippocampal-avoidance

(HA) WBRT

Recent studies suggest that RT-induced damage to the

hippocampus plays a considerable role in the neurocognitive

decline of patients after cranial irradiation.

In particular, deficits in learning, memory, and spatial

processing observed in patients who have received WBRT are

thought to be related to hippocampal injury.

Moreover, hippocampus RT has been associated with

pronounced cognitive impairment in the learning and memory

domain in patients receiving RT for nasopharyngeal, maxillary,

pituitary, and skull base tumors.

Preliminary results from a recent MD Anderson study of low-

grade or anaplastic brain tumors treated with RT have

observed a dose-response phenomenon, wherein the maximum

dose to the left hippocampus was correlated with subsequent

decline in learning and delayed recall (p = 0.01).

Similarly, Jalali et al. prospectively observed a significant

correlation between IQ decline and dose to the left temporal

lobe in patients with benign and low-grade brain tumors .

‘‘stem-cell compartmental” hypothesis

Memory function is associated with the pyramidal and

granule cells located in the dentate gyrus of the

hippocampus.

New granule cells are generated from mitotically active

neural stem cells (NSCs) located in the subgranular zone of

the dentate gyrus and migrate into the granular cell layer.

The pathogenesis of RT-induced neurocognitive deficit may

involve RT-induced injury to this NSC compartment.

The hippocampus (orange) is contoured by focusing on the dentate

gyrus and cornus ammonus, rather than the entire limbic circuit,

using T1-weighted MRI.

The hippocampal avoidance region (green) is 5 mm around the

hippocampus to account for setup error.

Isodose distribution at the level of the hippocampi for hippocampal-

avoidance during WBI (30Gy/10f) using helical tomotherapy.

Orange contour represents the hippocampal avoidance region.

Green isodose represents 12 Gy; light blue, 27 Gy; pink, 29 Gy;

yellow, 30 Gy; red, 38 Gy.

Feasibility of avoiding the hippocampus

For a WBI dose of 30 Gy/10f we are able to reduce:

The mean dose/fraction to the hippocampus (normalized to 2Gy/f)

by 87% to 0.49 Gy2 using helical tomotherapy and by 81% to 0.73

Gy2 using LINAC-based IMRT

The maximum dose to the hippocampus to 12.8 Gy using helical

tomotherapy and 15.3 Gy using LINAC based IMRT.

Sparing of the hippocampus with IMRT is accomplished with

acceptable target coverage and homogeneity.

These IMRT techniques allow the optimal

balance between:

Intra-cranial disease control (achieved with

WBRT and simultaneous boost)

Preservation of neurocognition (theoretically

achieved with hippocampal avoidance)

Using this approach to targeted hippocampal contouring,

multi-institutional study reviewed 371 patients who

presented with 1133 metastases:

Metastasis within the hippocampal avoidance region in 8.6%.

No metastasis within the hippocampus proper.

These data corroborate the results of an earlier, single-

institution study (100 patients with brain metastases were

reviewed and observed 8% of patients to have a

perihippocampal metastasis at presentation).

In summary, preclinical and clinical evidence suggest

that RT dose received by the neural stem cells of the

subgranular zone in the hippocampus may play a role

in RT-induced neurocognitive decline.

Given the experimental nature of this hypothesis, at

this point, hippocampal sparing should not be used

outside of clinical trials.

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

Surgery

Since the 1980s, resection of single brain metastases has

become a standard treatment in patients with good PS

and controlled or indolent extracranial disease.

Benefits: provision of a definitive diagnosis, rapid relief

of neurological symptoms caused by mass effect, and

establishment of local control.

Although many retrospective case series in the 1980s

suggested a survival benefit from resection of single

brain metastases, concern for selection bias remained

until three randomized trials in the 1990s were

published (WBRT ± surgery in patients with a single

operable brain metastasis).

Patchell et al: WBRT + surgery had a longer MST (9.2

vs 3.4 months; p=0.01), higher LC (80% vs 48%;

p=0.02), longer duration of functional independence.

In patients with multiple metastases, surgery is usually limited

to patients with a dominant, symptomatic, or life threatening

lesion and/or those who require a tissue diagnosis.

However, 2 retrospective studies suggest that patients with

good prognostic features and 2-3 metastases may gain similar

benefit from surgery when the dominant lesion is resected.

Bindal et al reported similar results for patients with multiple

metastases undergoing resection of all lesions, whose MST

was 14 months, again suggesting that a highly selected patients

with a limited number of metastases may benefit from

aggressive surgical management.

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

ChemotherapyChemotherapy

CT played a limited role and was reserved for patients

who have failed other treatment modalities or for

chemo-sensitive tumors (lymphoma, SCLC, germ-cell tumors).

Skepticism regarding the usefulness of CT stems

primarily from concerns that most agents are either too

large or hydrophilic to cross the BBB.

The degree to which a given agent is believed to

penetrate the BBB is usually based on pharmacokinetic

animal and/or human studies comparing plasma with

CSF drug concentration after IV or oral administration.

This method may underestimate the concentration of

drug delivered to the tumor, because brain metastases

are known to have local BBB breakdown (demonstrated

by contrast enhancement and peritumoral edema).

Studies shows equivalent intracranial and extracranial response

rates to CT agents assumed to have little BBB penetration.

The success of an agent depends on its inherent activity against

the systemic tumor than its ability to cross BBB.

Clinical data are limited to small phase II studies, often in

heavily pretreated patient populations.

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

Surgery ± WBI

Randomized trial, 95 patients, complete resection of solitary

brain metastasis (verified by MRI) ± WBRT (50.4 Gy/5.5w).

RT was associated with less recurrence anywhere in the brain

(18% vs 70%), at resection site (10% vs 46%), and other brain

areas (14% vs 37%). Decreased neurologic death (14 vs 44%).

No difference in OAS or length of time patient remained

independent.

Criticism: non-standard whole brain RT dose.

(Patchell RA. JAMA. 1998;280(17):1485-9)

PORT in single brain metastasis

The routine use of postoperative WBRT is becoming outdated.

Recent phase III trial of post-operative SRS vs WBRT for

resected brain metastasis suggest that SRS to the surgical cavity

is a viable treatment option to improve LC with less impact on

cognitive function and QoL compared to WBRT.

The results of this trial are practice-defining and indicate that

SRS to the postoperative surgical cavity should be considered

the new standard of care.

Brown PD, et al. N107C/CEC.3: a phase III trial of post-operative stereotactic radiosurgery (SRS) compared with whole brain

radiotherapy (WBRT) for resected metastatic brain disease. Int J Radiat Oncol Biol Phys 2016:96:937.

With a median FU 15.6 months, no statistically significant difference in OAS

between the treatment groups. While WBRT has higher overall intracranial tumor

control (90 and 78.6% with WBRT vs 74 and 54.7% with SRS at 6 and 12 months

respectively, p < 0.0001), there was no difference in median surgical bed relapse

free survival (7.7 vs.7.5 months, p = 0.04).

SRS patients experienced significantly longer survival without cognitive decline,

with a median cognitive deterioration free survival of 3.2 months for SRS and 2.8

months for WBRT (p < 0.0001).

Lower proportion of SRS patients experienced cognitive decline at 6 months

(53.8% with SRS vs 85.7% with WBRT, p = 0.0006), with superior rates of

immediate recall, memory and attention compared to those treated with WBRT.

Patients treated with SRS also experienced better QoL than those who received

WBRT. At 3 months following treatment, declines in QoL and physical wellbeing

were significantly smaller after SRS than WBRT and at 6 months, physical

wellbeing remained significantly better for SRS patients.

This approach is further supported by preliminary

results of a randomized trial comparing postoperative

SRS with observation in 131 patients with resected

brain metastases.

Although the median survival was similar in both

groups (17 months), SRS significantly improved LC

at 12 months (72% vs 45%).

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

WBI ± Surgery

Three randomized trials were performed; 2 showed

benefit, while 1 showed no difference.

Patchell et al found that patients in the surgery + WBRT

arm had a longer MS (9.2 vs 3.4 months; p=0.01),

higher LC (80 vs 48%; p=0.02), longer duration of

functional independence.

Overall, surgery + WBRT offers better local

control, decreased recurrence, and probably

improved survival over WBRT alone.

Survival outcomes are not improved with

surgery for patients with active extra-cranial

disease, or poor performance status.

Surgery in patients with multiple brain

metastases:

Dominant symptomatic lesion

Life threatening lesion

Tissue diagnosis

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

WBI ± Radiosensetizer

The following radiosensitizers have been studied in randomized

controlled trials, all failing to show benefit in either LC or OAS:

• Lonidamine

• Metronidazole

• Misonidazole

• Motexafin gadolinium

• Bromodeoxyuridine

• Efiproxiral

All trials reported serious adverse effects with radiosensitizers

Based on a subgroup analysis:

Patients with lung cancer showing a longer median time to

neurological progression (5.5 months for WBRT + Motexafin vs 3.7

months for WBRT alone) and improved neurologic function.

Similarly, the small subset of 42 breast cancer patients in the

Efiproxiral study showed a doubling of MST with the addition of

Efiproxiral (HR=0.51; p=0.003).

Randomized trials for these subgroups has been launched.

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

WBI ± Chemotherapy

Several agents have been studied in combination with

WBRT, including Chloroethylnitrosoureas, Tegafur,

Fotemustine, and Teniposide.

Although most have shown higher RR in the experimental

arm, all have been at the expense of greater toxicity with no

benefit in OAS.

More recently, WBRT + Temozolomide (TMZ, daily low-

dose 75 mg/m2) has shown promising RR with acceptable

toxicity in newly diagnosed brain metastases from a variety

of solid tumors.

Antonadou et al: 96% RR (38% CR, 58% PR) in 24

patients randomized to TMZ plus WBRT, versus 66% (33%

CR, 33% PR) in 21 patients treated with WBRT alone,

although the MST did not differ (8.6 vs 7 months; p=0.45).

A more recent study by Verger et al enrolling 82 patients with the

same study design, failed to replicate the high RR found by the

previous authors, although the authors found a significantly

higher neurological PFS in the TMZ arm (72% vs 54%; p=0.03).

A randomized phase III trial (134 patients) was completed by

Antonadou et al with similar results to their first, but final results

have not yet been published.

In summary, although several studies have shown promising

tolerability and response rates for concurrent TMZ and WBRT,

particularly for NSCLC and melanoma, current data do not yet

support the widespread use of this combination.

A future treatment strategy may be to assess tumor methylation

status as a way of preselecting a group of patients with a greater

likelihood of responding to TMZ.

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

SRS

Most brain metastases have distinct radiographic and

pathologic margins, making them attractive targets for SRS.

SRS has emerged as a common treatment modality for:

Newly diagnosed patients ± WBRT

Salvage therapy for progressive disease after WBRT.

Dose (established by RTOG 90-05 protocol):

24 Gy for tumors 2 cm

18 Gy for tumors 2-3 cm

15 Gy for tumors 3-4 cm

One-year LC of 71%–79% was reported with the use of SRS

alone for single and multiple brain metastases. RR are mixed for

tumors that have traditionally been considered radioresistant (e.g.

renal cell carcinoma, melanoma, and sarcoma)

Importantly, SRS does not address distant failure in the brain.

SRS Complications:

Edema: 4%–6% of patients within 1–2 weeks of treatment.

Seizures: 2%–6% of patients within the first 1-2 days.

Radiation necrosis: 2%-17% (risk increase with larger tumor

volume, higher RT dose, and prior RT).

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

WBI ± SRS

Three randomized and two retrospective studies have directly

examined whether the addition of SRS to WBRT provides

therapeutic benefit over WBRT alone.

In the RTOG 95-08 trial, 333 RPA class 1 and 2 patients with

1-3 brain metastases ≤ 4 cm in largest diameter were

randomized to WBRT (37.5 Gy/15F) ± SRS. Patients were

stratified by number of mets and extracranial disease status.

No significant difference was seen in MST (5.7 months for

WBRT+SRS vs 6.5 months for WBRT alone, p=0.14).

However, in subset of patients with single lesions, the MST

was longer in the WBRT+SRS group (6.9 vs 4.9 months;

p=0.04).

These results are analogous (though not directly

comparable) to the surgical randomized trials, which have

shown survival benefit in select patients with single lesions

treated with WBRT + resection vs WBRT alone.

In patients with multiple metastases, the addition of SRS did not

improve survival or LC in the RTOG 95-08 trial, contrary to results of a

previous small randomized study and a large retrospective series by

Sanghavi et al comparing survival in 500 patients from 10 institutions

who had received WBRT + SRS to all lesions against the historical

RTOG RPA cohort (treated with WBRT alone).

A cautionary note is that the Sanghavi et al cohort, by being eligible

and selected for SRS after WBRT, may have an inherently better

prognosis than the patients in the historical WBRT cohort, above and

beyond what can be adjusted for by RPA class.

In summary: firm data indicate that SRS boost after WBRT

improves survival in selected patients with single brain

metastases.

Although the addition of SRS to WBRT improves local control in

patients with ≤ 4 metastases, it does not affect OAS in patients

with multiple metastases, and it remains speculative whether

select patients with multiple metastases and indolent extracranial

disease may benefit from SRS boost.

WBI ± Boost (In summary)

Surgical excision or SRS boost after WBRT

improves survival in selected patients with single

brain metastases.

The addition of SRS to WBRT improves LC in

patients with ≤ 4 metastases, it does not affect

OAS in patients with multiple metastases.

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

SRS ± WBI

Significant controversy exists over whether a

subset of patients, particularly those with a

limited number of brain metastases can be

treated effectively with SRS alone.

To date, one randomized trial, six retrospective

comparative studies has been published

examining this question.

Aoyama et al reported results of 132 patients, 1-4 brain

metastases, each 3 cm, randomized to SRS ± WBRT.

No significant difference in the median OS (7.5 months for

WBRT + SRS vs 8.0 for SRS alone; p=0.42).

Superior combined local and distant intracranial control

rates with the addition of WBRT (1-yr actuarial overall

control rate, 53.2% vs 23.6%; p=0.001).

Salvage for CNS progression was required significantly

more often in the SRS group (43% vs 15%; p=0.001).

No significant difference in neurological outcome.

The impact of WBRT on neurocognitive function has

not been well studied.

The most frequently cited article detailing the

detrimental effects of WBRT is a case series published

15 yrs ago in patients who received higher RT fractions

(3–6 Gy) than are used today.

The only randomized data available for SRS ± WBRT in

patients with brain metastases is from the recent Aoyama et al

trial, which failed to show worse neurological outcomes in the

WBRT arm.

In addition, two randomized trials in SCLC patients receiving

PCI have shown no difference in neurocognitive outcome up

to 2 years after WBRT.

Many have argued that with-holding WBRT actually worsens

neurologic outcomes because of higher rates of symptomatic

intracranial relapse.

In summary

There are randomized controlled data from both surgical

and SRS trials that the omission of WBRT results in

significantly worse LC and distant intracranial disease

control, though it does not affect OAS.

No studies to date have adequately addressed whether the

negative impact of poorer intracranial disease control on

QoL is higher than the risk for delayed neurotoxicity in

long-term survivors.

SRS for Recurrence

The use of SRS for recurrent brain metastases after WBRT

appears to be an effective treatment in patients with good PS

and controlled or indolent extracranial disease.

Local control rates: 57% - 100%.

Overall brain control rates: 65% - 78%.

Acute (seizure, nausea/vomiting, alopecia, headache) and

subacute (edema, radionecrosis, hemorrhage) complications are

reported in 7%–33%, with large tumor diameter or volume

being the most important risk factor for necrosis.

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

Chemotherapy

Surgery

SRS

No randomized study has directly compared the two modalities. Several

retrospective comparisons have reported longer survival times after surgical

resection; however, most have found essentially no difference.

The choice must therefore be made on a case-by-case basis, with consideration

given to the following factors:

Large tumors with extensive edema and mass effect, surgery is probably

superior to SRS for quick and reliable relief of symptoms, provided the lesion

can be safely resected.

Surgery is often recommended for cerebellar metastases because even minor

swelling in the posterior fossa can cause hydrocephalus.

SRS has the advantage of being noninvasive and can be used to treat surgically

inaccessible lesions in the brain stem, basal ganglia, and eloquent cortex.

Treatment Options

WBI

WBI ± Surgery

WBI ± SRS

WBI ± Radiosensetizer

WBI ± Chemotherapy

Surgery

Surgery ± WBISRS

SRS ± WBI

Brachytherapy

ChemotherapyBrachytherapy

GliaSite RT system for the treatment of newly diagnosed,

resected single brain metastasis

• Phase II - Single met only - 62 patients implanted GliaSite - 60 Gy

prescribed at 1 cm - No WBRT - 43% had extracranial mets.

• Outcome: MRI-based LR 82-87%; median OS 10 months; cause of death

neurological in 11%.

• Reoperation in 13/62 patients: 9 RT necrosis, 2 tumor recurrence, 2 mixed.

• Predictors of survival: extracranial mets, tumor size, radionecrosis.

• Conclusion: GliaSite has similar outcome (LR, OS, functional

independence) as WBRT.

(Rogers LR, J Neurosurg. 2006;105(3):375-84)

Prophylactic Cranial Irradiation

Definition: Administering WBRT to cancer patients at high

risk for brain relapse but without overt brain metastases at

diagnosis.

In patients with SCLC, who have a 50% estimated 2-year

risk for CNS relapse, PCI reduces the risk for brain

metastases by 50% and increases OAS by 16%-18% in

patients with a CR to chemotherapy based on a metaanalysis

of 12 randomized trials.

The risk for late cognitive decline in SCLC patients after PCI has been addressed in six

prospective studies, including two randomized trials.

Arriagada et al studied 300 patients with SCLC in CR who were randomized to PCI or

observation and found no significant difference in the 2-year incidence of

neuropsychological changes.

Similarly, Gregor et al carried out detailed psychometric and QoL testing on 136 patients

enrolled in a multicenter randomized trial of PCI vs observation and found no difference

in neurocognitive function at 12 months.

Based on available data, it is probable that PCI delivered either as 20Gy/10f or 30Gy/10f

causes little significant toxicity up to 2 years after PCI, but longer FU are needed to fully

assess late toxicity.

Ongoing trials

NRGCC003 (conducted by NSABP, RTOG, and GOG):

randomized trial of PCI comparing WBRT with hippocampal-

avoidance (HA) WBRT in patients with SCLC (both limited

and extensive stage) who achieve at least a PR to CT.

NRGCC001: randomized phase III trial of HA-WBRT plus

memantine versus standard WBRT plus memantine.

Management of Recurrence

Re-irradiation

Re-RT techniques

WBRT

SRS

FSRT

Brachytherapy

Whole brain re-RT

Salvage WBRT after previous SRS is a common treatment

option with survival results indistinguishable from those of

first-line WBRT (i.e., median survival 3–6 months).

A repeat course of WBRT is not commonly employed due

to concerns about lack of efficacy and the potential for

neurocognitive deficits.

• Reirradiation after PCI:

Analysis of 505 in two randomized trials (+/- PCI)

Overall 5-yr rates of brain metastases were 59% (PCI-)

and 43% (PCI+). PCI dose was 24-30 Gy (with 3Gy/f);

commonly 24 Gy (3Gy x 8f) was used.

Per protocol, patients developing brain metastases were

treated with 50Gy/28f if no prior PCI or 39Gy/22f (1.77

Gy/f) if prior PCI.

(Arriagada R, Ann Oncol. 2002 May;13(5):748-54.)

FUTURE DIRECTIONS

In the next years, the results of several ongoing multicenter

randomized trials will become available to further define the role

of various radiosensitizers and CT in combination with SRS,

WBRT, or both.

Phase II trials is being initiated to examine the utility of targeted

agents in specific disease groups. The safety and efficacy of

angiogenesis inhibitors in the treatment of stable and active brain

metastases. (this point understudied because of concerns regarding

intracranial hemorrhage. There is a growing evidence in GBM patients

suggests that these agents are relatively safe and carry a low risk for bleeding).

An additional benefit of angiogenesis agents may be their ability

to control peritumoral edema and reduce steroid dependence

(factors contribute greatly to morbidity and mortality in brain metastases patients).

As suggested in GBM patients treated with concurrent TMZ and

RT, the combination of traditional cytotoxic agents or targeted

molecular drugs with RT may hold promise for improving upon

control rates of WBRT alone.

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