CLINICAL STUDY

Radionecrosis induced by stereotactic radiosurgery of brainmetastases: results of surgery and outcome of disease

Stefano Telera • Alessandra Fabi • Andrea Pace • Antonello Vidiri •

Vincenzo Anelli • Carmine Maria Carapella • Laura Marucci •

Francesco Crispo • Isabella Sperduti • Alfredo Pompili

Received: 21 August 2012 / Accepted: 16 March 2013

� Springer Science+Business Media New York 2013

Abstract Sterotactic radiosurgery (SRS) is an effective and

commonly employed therapy for metastatic brain tumors.

Among complication of this treatment, symptomatic focal

cerebral radionecrosis (RN) occurs in 2–10 % of cases. The

large diffusion of combined therapies as SRS followed by

WBRT and/or CHT, has significantly amplified the number of

patients who potentially might be affected by this pathology

and neurosurgeons are increasingly called to treat suspected

area of RN. Results of surgery of RN in patients with brain

metastases are rarely reported in literature, a standardization

of diagnostic work-up to correctly identify RN is still lacking

and the timing and indications in favour of surgical therapy

over medical treatments are not clear as well. In this

retrospective study, we review current concept related to RN

and analyze the outcome of surgical treatment in a series of 15

patients previously submitted to SRS for brain metastases and

affected by suspected radionecrotic lesions. After surgery, all

patients except one neurologically improved. No intra-

operative complications occurred. Brain edema improved in

all patients allowing a reduction or even suspension of corti-

costeroid therapy. Pure RN was histologically determined in 7

cases; RN and tumor recurrence in the other 8. Overall median

survival was 19 months. An aggressive surgical attitude may

be advisable in symptomatic patients with suspected cerebral

RN, to have histologic confirmation of the lesion, to obtain a

long-lasting relief from the mass effect and brain edema and to

improve the overall quality of life, sparing a prolonged cor-

ticosteroid therapy.

Keywords Brain metastases � Radionecrosis � Surgery �Radiosurgery

Introduction

Brain metastases (BM) are diagnosed in more than

20–40 % of patients with cancer and in 35–50 % of cases

these lesions are solitary. Surgery, whole brain radiation

therapy (WBRT), stereotactic radiosurgery (SRS) and

chemotherapy (CHT) variably combined, represent the

current treatment modalities of this pathology [1–7]. Such

integrated therapies allows for prolonged survival but may

expose the patient to several complications.

Stereotactic radiosurgery is an effective and increasingly

employed therapy for metastatic brain tumors, which pre-

cisely delivers a single finely focused high dose of radia-

tion to defined small intracranial targets. It has become a

primary treating tool followed or not by WBRT, for single

S. Telera (&) � C. M. Carapella � F. Crispo � A. Pompili

Division of Neurosurgery, Istituto Nazionale Tumori Regina

Elena, via Elio Chianesi 53, 00144 Rome, Italy

e-mail: telerasm@libero.it; telera@ifo.it

A. Fabi

Division of Medical Oncology A, Istituto Nazionale Tumori

Regina Elena, Rome, Italy

A. Pace

Department of Neurooncology, Istituto Nazionale Tumori

Regina Elena, Rome, Italy

A. Vidiri � V. Anelli

Department of Diagnostic Imaging, Istituto Nazionale Tumori

Regina Elena, Rome, Italy

L. Marucci

Division of Radiotherapy, Istituto Nazionale Tumori Regina

Elena, Rome, Italy

I. Sperduti

Biostatistics Unit, Istituto Nazionale Tumori Regina Elena,

Rome, Italy

123

J Neurooncol

DOI 10.1007/s11060-013-1120-8

and multiple BM with size not exceeding 3 cm and/or

positioned at inoperable sites.

High tumor control rates (C80 %), low serious com-

plications incidence (2–14 %) and a median overall sur-

vival of *8–14 months have been reported with SRS, by

randomized trials and multi-istitutional studies [7–15].

Clinical deterioration long after brain radiotherapy (RT),

may be due to progression of the neoplasm, to radiation

induced cerebral necrosis (RN), or more frequently, to a

combination of these two conditions.

RN is a late and severe complication after RT for pri-

mary and metastatic brain tumors. Focal brain necrosis can

also be provoked by specific forms of RT, including SRS.

It generally appears months to years after irradiation, with

a peak onset around 12–15 months and it is considered a

chronic inflammatory process leading ultimately to brain

parenchymal necrosis [16–20]. The incidence of RN after

conventional WBRT ranges from 5 to 24 % while symp-

tomatic focal brain necrosis occurs in 2–10 % of patients

treated with SRS for BM [6, 7, 12, 15, 16, 20–24].

The clinical presentation of focal RN is that of a space-

occupying lesion, which it is difficult to distinguish from

tumor recurrence or progression on standard and even

functional neuroradiologic studies [8].

Definitive diagnosis of RN requires pathologic confir-

mation, however the frequent intermingling of areas of

tumoral cells with necrosis increases the possibility of

sampling error from a simple stereotactic biopsy. A dif-

ferential diagnosis is very important to dictate the appro-

priate therapies: recurrent tumor might be treated with

surgery, WBRT, or CHT; RN may benefit of corticoste-

roids, other medical therapies or surgery [15, 24].

Results of surgical treatment of RN in patients with BM

are rarely reported in literature.

Yet, the large diffusion of combined therapies has dra-

matically amplified the number of patients who potentially

might be affected by this complication and neurosurgeons

are increasingly called to treat suspected areas of RN.

We review current concept related to RN and analyzed

the diagnostic strategy, the results of surgery and the

prognosis in a consecutive series of 15 patients deemed

preoperatively to be affected by this complication.

Materials and methods

Between January 2005 and January 2011, 154 patients

affected by BM have been operated at Regina Elena Institute.

Among them, 15 cases (9.7 %) of cerebral suspected RN after

a full course of SRS ± WBRT, were observed.

Data were retrieved by reviewing patient’s hospital and

outpatients clinic records, imaging studies, radiotherapy

planning records, and slides of histopathological specimens.

Characteristic of patients are reported in Table 1: Ten

females and five men; mean age was 58 yrs (range

35–72 yrs); primitive tumors included eight non small cell

lung carcinomas (NSCLC); five breast and two renal car-

cinomas. Twelve patients underwent SRS alone, three SRS

plus WBRT. Three patients had been previously operated

for removal of a single BM. The mean dose of SRS was

20.3 ± 3.2 Gy administered via either a Gamma-knife or a

LINAC accelerator. WBRT consisted of a mean doses of

30 Gy delivered with a six. MV linear accelerator in ten

daily fractions.

One patient has been submitted to a second operation

after an interval of 5 months, due to the development of

RN in another different area of the brain. Twelve patients

presented with a single metastases, three patients with

multiple metastases one of which did not respond to SRS

and enlarges requiring surgical therapy.

Sites of the lesions were as follows: 5 occipital; 4 fron-

tal; 3 cerebellar; 2 parieto-occipital and 2 temporal. The

patients were divided according to the RPA classification:

8 belonged to Class I; 4 to Class II and 4 to Class III (one

patient was operated twice). Two patients had an uncon-

trolled primary disease at the time of our surgical

treatment.

RN was suspected considering (i) the adequate temporal

delay between SRS and appearance of the lesions and/or

(ii) functional neuroimaging: perfusional CT scan (PCT),

PET scan, MR spectroscopy, SPECT. Twelve patients

presented an iatrogenic Cushing syndrome. Mean dimen-

sions of the lesions were 3 cm (range 1.5–4.5 cm).

Pre-operative median KPS score was 80 (range 40–90),

making our population relatively healthy.

Surgery was performed with standard microsurgical tech-

nique and tools. Neuronavigation and intraoperative ecogra-

phy were routinely used in supratentorial tumors. Due to the

accurate localization of the lesion assured by neuronavigation,

a linear incision was preferred over U-shaped flap as it heals

better and help to avoid subcutaneous blood and/or CSF col-

lections. Removal of pathological tissue was performed with

ultrasonic aspirator and bipolar cautery. When necessary, the

dura was repaired with additional patches taken from viable

pericranial flap, avoiding whenever possible, exogenous

material. These issues may be of paramount importance for

prompt healing in irradiated patients.

As follow-up, data were reported to November 2011 and

at this time six patients were still alive.

The median duration of follow-up was 14 months (range

6–38 months).

Association between variables were analysed by the

Fisher’s exact test. Comparisons between groups were

carried out for different variables using t Student unpaired

test. Wilcoxon paired test was employed to evaluate pre-

and post-operative differences.

J Neurooncol

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rig

ht

fro

nto

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al

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12

mo

nth

s

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tal

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al/

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r

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s/

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emic

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ease

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rs/

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ast

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tal

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mo

nth

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rs/

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ng

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tal

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sis/

12

mo

nth

s:C

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esis

/SR

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pse

of

dis

ease

J Neurooncol

123

Survival was calculated by the Kaplan–Meier product

limit method; the log-rank and Tarone-Ware tests were

used to assess differences between subgroups. The SPSS�

(20.0) statistical program was used for all analyses.

Results

To relieve cerebral mass effect, a complete exeresis of the

lesions was obtained in all patients, except in two cases

with posterior cranial fossa involvements, where tiny

pathological components adherent to the lower cranial

nerves were left untouched.

No intra-operative complications occurred and the

mean stay at the hospital was 9 days (range 4–30). After

surgery all patients except one (which presented a severe

deficit to the right arm), remained neurologically stable or

improved. One patient was affected by a post-operative

seizure and one had a CSF fistula at the surgical wound

which healed with a lumbar drain (Figs. 1, 2). Two

patients presented a transient dysphasia and one a tran-

sient cerebellar ataxia.

Median KPS score at discharge from hospital was 80

(range 60–90) with no significant difference between pre-

and post-operative status (p = 0.12).

Post-operatively, brain edema progressively resolved in

all cases within 4 weeks, allowing a substantial reduction

or suspension of corticosteroid therapy by that time.

Pure RN was histologically confirmed in seven patients

(two different radionecrotic lesions appeared in the same

patient); RN and tumor recurrence in the other eight.

We further analyzed the following factors that in liter-

ature have been cited to be predictive of RN, to verify how

they were distributed in our series and if they could be

preferentially associated to the subgroup of pure RN

compared to the subgroup of RN and tumor recurrence:

(i) tumor location; (ii) diameter of the lesion; (iii) previous

irradiation; (iv) male sex; (v) systemic conditions like

hypertension and diabetic vascular diseases; (vi) total SRS

delivered dose; (vii) concomitant use of CHT; (viii) depth

from the cortical brain surface of the SRS target [5 mm

(Location Grade); (ix) time interval between SRS and

recurrent lesion.

None of them could be positively associated to one

subgroup compared to the other: p C 0.3 for all considered

factors (data not showed). Location Grade [5 mm, could

have been possibly significant in the group with pure RN, if

the number of patients had been higher.

In nine circumstances pre-operative neuro-radiological

functional studies (sometimes more studies were available

for a single patient) proved to be right (6 with perfusional

CT scan, 2 with SPECT and 1 with PET) and in six they

failed to correctly define the lesion (2 with PET, false

negatives; 2 with SPECT, false negatives; one with per-

fusional CT, false negative; one with MRI spectroscopy,

false negative). In two cases the PCT yielded inconclusive

results.

Median time between diagnosis of the primary tumor

and SRS was 24 months (range 1–156) while median time

interval between SRS and appearance of suspected RN was

15 months (range 6–36): it was 16.5 months (range 1–84)

for patients with tumor and RN while it was 36 (12–156)

for patients with pure RN (p = 0.19).

Overall median survival after surgical treatment was

19 months (CI 95 % 7–49); mean survival was 22 months

(CI 16–29).

Not surprisingly, patients affected by pure RN displayed

a tendency toward longer survival than patients with tumor

and necrosis: 1 and 2 yr overall survival was respectively

85.7 and 68.6 % in the first group, comparing to 50 and

33.3 % in the second group (p = 0.11 log rank test); mean

survival was 28 months (CI 20–37) for patients with RN

and 17 months for patients with RN and tumor (CI 8–26;

p = 0.11; Test Tarone-Ware 0.089) (Fig. 3).

Discussion

SRS is an effective therapy followed or not by WBRT, for

BM, allowing local tumor control, palliation of neurolog-

ical symptoms and decreased likelihood of death from

neurological causes [25]. Through the release of multiple

radiation beams focused to a specific target, it delivers a

much higher radiation dose to the lesion than other RT

techniques, minimizing the damage to brain tissues. Due to

its limited invasiveness, rapid delivery modalities and low

costs, SRS indications have progressively expanded for

treatment of multiple or single brain metastases, with a

diameter not exceeding 3 cm, positioned at inoperable sites

and not causing a midline shift greater than 1 cm [3]. When

surgery is not feasible, even tumors of larger volumes

could display favorable clinical and imaging responses,

after upfront SRS [13].

Limited data exist in the literature on the most advan-

tageous SRS doses for BM: a dose–response relationship

for local tumor control and a dose-dependent increase of

side effects have been firstly recognized on the basis of the

incidence of cerebral RN [26, 27]. To obtain an optimal

balance between the treatment efficacy and the risk of

complications, a median dose of 20 Gy in a single fraction

has been advocated in most of the recent series for brain

metastases B2 cm. SRS doses [20 Gy resulted in

improved local control, but at the expense of higher level

of complications [11, 28]. Adding WBRT after SRS is also

controversial, since even if it does not seem to affect

J Neurooncol

123

overall survival, it clearly reduces brain recurrence rate

[2, 28–31].

While radiation injury after WBRT typically involves large

areas of the brain and may not be amenable to surgical therapy,

radiation injury after SRS tends to be restricted to the site of

radiosurgical treatment and may respond well to surgical

resection [15, 32]. Symptomatic focal brain necrosis occurs in

2–10 % of patients treated with SRS for BM, despite precise

target localization and rapid dose fall-off, while neuroradio-

logic changes may be apparent in up to 46 % of patients

manifesting as a progressive contrast enhancement lesions on

follow-up serial MR imaging with the highest incidence after

11–15 months [7, 9–11, 15, 20, 22, 30, 33–35].

The most common histologies in radionecrotic lesions

are BM from breast and lung cancer; the frontal and pari-

etal lobes are most commonly affected and the mean pre-

scribed dose is 18 Gy (range 12–22 Gy) [28, 29]. Clinical

manifestations of localized RN are not specific and depend

mainly on location of the lesions, resulting in focal neu-

rological deficits or more generalized signs and symptoms

of increased intracranial pressure [9, 19, 23].

RN should be suspected in any patient who deteriorates

neurologically within an appropriate interval after brain

irradiation. In many patients, the collateral effects of a

prolonged use of corticosteroid therapy to control symp-

toms, may also significantly decrease their quality of life.

Vecil reported some degree of steroid dependency in up to

40 % of patients submitted to surgery after failed SRS

[11, 25, 36].

Predictive factors associated with the development of

RN have been evaluated in several series from the litera-

ture. Patients related factors included: (1) tumor location;

(2) diameter of the lesion; (3) previous irradiation; (4) male

sex; (5) systemic conditions like hypertension, diabetic

Fig. 1 Patient No. 3. a T1 weighted MRI after gadolinium and b flair

MRI sequence showing a left occipital recurrent metastatic tumor

after SRS. Note the associated relevant cerebral edema. c A low

cerebral blood volume (CBV) at the site of the contrast enhanced

lesion was suggestive for radionecrosis. d, e Intraoperative view

during and the end of the operation. Radionecrosis was histologically

confirmed. f, g Post-operative CT scan with contrast showing total

removal of the lesion

J Neurooncol

123

vascular disease or individual sensitivity. Treatment related

factors included (1) total delivered dose; (2) fraction size;

(3) treatment duration; (4) target irradiated volume;

(5) number of treated isocenters and prescription isodose

volume; (6) concomitant use of CHT [16, 17, 20].

However, on the basis of the existing literature, (i) SRS

treated volume and (ii) Location Grade (LG), emerged on

multivariate analysis, as significant factors associated with

development of RN and neuroimaging changes, for BM.

Volume of brain irradiated to 12 Gy (V12) has been

identified as the most relevant dosimetric variable;

increased risk of RN being associated to irradiated volumes

larger than 8 cm3 (cut-off values between 8 and 10 cm3)

[9, 20, 37, 38].

Location Grade refers to the depth from brain surface of

each SRS target: grade 1 (superficial) encompasses lesions

B5 mm from the brain surface; grade 2 (deep), lesions

[5 mm from the brain surface; grade 3 (central), lesions

involving the brainstem, cerebellar peduncle, diencepha-

lon, or basal ganglion. The deeper the lesion, the higher the

risk of RN. A combined assessment of SRS treated vol-

umes and LG, has been recently suggested to predict more

accurately the possibility of RN after SRS [9, 20, 37, 38].

Due to the limited number of patients in our series, we

were not able to add any relevant data on this matter.

A thorough understanding of the pathophysiology of RN

is still lacking: endothelial cell loss due to abnormal

microvascular circulation, ‘‘nutritional’’ insufficiency,

demyelination and axonal swelling as well disruption of the

blood brain barrier promoted by the activated immuno-

logical system, are the most cited causal sequences of the

development of gliosis, vascular injury, and progressive

tissue necrosis of the surrounding brain parenchyma [10,

11, 16–19, 22, 23, 39, 40].

Fig. 2 Patient No. 10. a, b sagittal and axial T1 weighted MRI after

gadolinium showing a right parieto-occipital recurrent metastatic

tumor after SRS. c The lower CBV at the site of the contrast enhanced

lesion compared with the contralateral site was suggestive for

radionecrosis. d Intraoperative view after removal of lesion including

the infiltrated ependymal wall of the right lateral ventricle. e Histo-

logic examination confirming a radionecrotic lesion with white matter

demyelinization and fibrinoid necrosis of the vessel wall with luminal

narrowing; H&E 920. f Post-operative CT scan with contrast

showing total excision of the lesion

J Neurooncol

123

New or growing contrast enhancing lesions discovered

on follow-up brain imaging at the site of a previously SRS

treated BM could be a radiologic dilemma. Cerebral RN

temporally overlaps with appearance of tumor recurrence

and unfortunately these two conditions are often indistin-

guishable with standard CT or MRI scans since they

share (i) an origin at or close to the primitive tumor site

(ii) a patchy or ring contrast enhancement (iii) a sur-

rounding cerebral edema (iv) a mass effect and (v) a

growth over time [10, 41, 42].

Attempts to identify imaging features that could reliably

distinguish RN from tumor recurrence making use of

magnetic resonance (MR) spectroscopy, perfusion MR and

CT (PCT), positron emission tomography (PET) and single

photon emission tomography (SPECT), although effective,

have not been yet fully validated in larger studies and there

is no evidence that any of these investigations is clearly

superior to other modalities in terms of diagnostic sensi-

tivity or specificity while no standard options are available

[15, 19, 22, 41–43].

Each of these techniques, although fairly reliable in

cases of ‘‘pure’’ RT necrosis or ‘‘pure’’ recurrent tumor,

may yields false positives and false negatives results in

particular when a mixture of tumor proliferation and

necrosis is observed due to limited spatial resolution, par-

tial volume effect, and/or the frequent intermingling of

tumor cells and radiation induced changes. Unfortunately

this appear very often the case in our and other studies,

where histologic analysis of enhancing tissues removed at

surgery, resulted in more than 50 % of cases, necrosis and

tumor [15, 20, 22, 44, 45]. As far as our small series is

concerned, in which however the diagnosis was

histologically confirmed in all patients and not inferred by

indirect means, we observed better predictive results with

perfusional studies than with other techniques. The use of

more than one imaging modality may possibly improve the

overall diagnostic capability.

There is no a standard therapy for RN. High doses of

corticosteroid have been employed as medical treatment

and usually produce clinical and radiographic improvement

in patients with focal RN. In many, but not all the cases,

this response is temporary, leading to steroid-dependency

with associated severe systemic complications [9, 11, 16,

36].

Other treatments such as hyperbaric oxygen and Bev-

acizumab, a monoclonal antibody against VEGF, which

acts to decrease vascular permeability and normalize blood

brain barrier, are promising and could have future devel-

opments [23, 35, 46].

Surgery is usually indicated for focal necrotic lesions in

viable areas of the brain, which (i) exert a mass effect,

(ii) are associated with significant cerebral edema respon-

sible of elevated intracranial pressure, neurological signs or

intractable seizures and/or (iii) display a volumetric pro-

gression after conservative management [6, 16–18].

The necrotic tissue that gives rise to contrast-enhance-

ment, is the major culprit of brain edema. Macroscopically

it is much firmer and well demarcated than the surrounding

cerebral parenchyma, and it is easily identifiable under the

operating microscope. Surgical removal of this necrotic

brain tissue seems to be the most effective treatment to

obtain a reliable histological diagnosis and to achieve a

rapid control of cerebral hypertension. Usually brain edema

resolves promptly after surgery (within 2–4 weeks) and the

recurrence rate is low [7, 18, 36]. Overall a clinical and/or

radiological improvement has been observed in up to 83 %

of operated patients [7, 24].

Prognostic data regarding patients surgically treated for

recurrent or radionecrotic cerebral lesions after SRS are

scarce in literature [3, 47]. In selected patients, mean sur-

vival time after surgery are comprised between 7.7 and

22 months.

Kano et al. [6] reported that following surgery for SRS

failure, patient’s survival was 62 and 43 % at 12 and

24 months, respectively. One month after surgery median

KPS score improved from 80 to 90.

Patient’s RPA classification (11.1 months median sur-

vival for RPA II vs 2.4 months for RPA III), controlled

primary disease and delayed local progression (more than

3 months) appeared to be the most important factors to

predict better prognosis [6, 36, 48].

It has been suggested that patients who undergo surgery

after SRS, have a better prognosis than patients not oper-

ated, but this may be due to the usually restricted criteria

that have been used to identify patients who may benefit

Fig. 3 Kaplan–Meyer estimate of overall survival (OS) for the 15

patients in the study after being subgrouped according to histology.

Statistical significance was not reached. RN radionecrosis, NE not

evaluable

J Neurooncol

123

Ta

ble

2R

esu

lts

of

surg

ical

rese

ctio

no

fb

rain

met

asta

ses

afte

rS

RS

Au

tho

rsN

o.

of

pat

ien

ts/

mea

nag

e

Mea

nS

RS

do

ses/

tem

po

ral

del

ayfr

om

SR

S/m

edia

np

re-o

pK

PS

/

Hy

sto

log

ic

dia

gn

osi

s

Sig

nifi

can

tp

rog

no

stic

fact

ors

fav

ora

bly

affe

ctin

gsu

rviv

al

Mo

rtal

ity

/ov

eral

l

maj

or

mo

rbid

ity

/

Mea

np

ost

-op

KP

S

Mea

nF

Um

on

ths/

med

ian

surv

ival

mo

nth

s/C

ause

of

dea

th

Vec

il

[36]a

61

pz/

55

yrs

(30

–8

3)

No

tre

po

rted

/5.2

mo

nth

s

(0.3

–3

4.4

)/K

PS

80

/

Tu

mo

r4

3%

;

tum

or

?R

N

49

%;

RN

8%

Lo

wer

RP

Acl

assi

fica

tio

n�

3%

/12

%/K

PS

80

19

.1m

on

ths

(5.5

–4

6.8

)/1

1.1

mo

nth

s/

Neu

rolo

gic

al1

5%

;n

euro

log

ical

and

syst

emic

34

%sy

stem

ic4

3%

un

det

erm

ined

8%

Tru

on

g

[24]

32

pz/

53

yrs

(38

–8

4)

16

.5G

y(1

4–

20

)/K

PS

90

Tu

mo

r?

RN

87

.5%

;R

n

12

.5%

Ag

e\

66

yrs

seco

nd

rese

ctio

n(o

n

un

ivar

iate

anal

ysi

s)

�3

%/1

9%

/N

R/8

.9m

on

ths/

neu

rolo

gic

al4

8%

Sw

inso

n

[30]

56

pz/

17

.5G

yT

um

or

61

%

tum

or

?R

N

18

%R

N

21

%

NR

Wil

liam

s

[25]

45

pz

18

Gy

Tu

mo

r7

1%

tum

or

?R

N

29

%

NR

Kan

o[6

]5

8p

z/5

4y

rs

(24

–8

0)

12

–2

0G

y/7

.2m

on

ths

(0.3

–2

7.7

)/K

PS

80

/

Tu

mo

r5

5%

tum

or

?R

N

45

%

Inte

rval

bet

wee

nS

RS

and

rese

ctio

n

\3

mo

nth

s;lo

wer

RP

Acl

assi

fica

tio

n;

con

tro

lled

syst

emic

dis

ease

�1

.7%

/6.9

%/K

PS

90

7.6

mo

nth

s(0

.03

–1

05

)/7

.7m

on

ths/

neu

rolo

gic

al3

8%

Mo

leen

ar

[34]

5p

zR

N1

00

%N

R/1

4.8

mo

nth

s

Fri

so[1

0]

4p

z/4

8y

rs

(36

–6

8)

19

.5G

yT

um

or

?R

N

75

%;

RN

25

%

NR

/22

.5m

on

ths

Min

nit

i

[9]b

12

pz

15

–2

0G

y/1

1m

on

ths

(2–

32

mo

nth

s)

Vo

lum

ere

ceiv

ing

10

Gy

(V1

0)

and

12

Gy

(V1

2)

NR

Tel

era

20

13

15

pz/

58

yrs

(35

–7

2)

20

Gy

/15

(6–

36

mo

nth

s)/K

PS

80

Tu

mo

r?

RN

53

%;

RN

47

%

�0

%/6

.7%

/KP

S

80

14

mo

nth

s(6

–3

8m

on

ths)

/19

mo

nth

s/sy

stem

ic

47

%n

euro

log

ical

6.7

%o

ther

cau

ses

6.7

%

pat

ien

tsal

ive

40

%

NR

no

tre

po

rted

an

op

rev

iou

sW

BR

Tb

no

pre

vio

us

surg

ery

�p

eri-

op

erat

ive

mo

rtal

ity

J Neurooncol

123

from surgery, including a KPS at least C60 and a con-

comitant stable disease. In our series the median pre-

operative KPS was 80, most of the patients had a controlled

disease and a long temporal delay between cancer diag-

nosis and appearance of BM. These relevant selection bias

may explain the prolonged overall survival that we also

observed.

Histologic examination of resected lesions indicate in

different series a clear tumoral recurrence in 43–90 % of

cases, mixed tumors in 45–49 %, while pure necrosis was

observed in 0–47 % [5, 6, 24, 25, 36]. In our series 53 % of

the patients presented a tumor recurrence mixed with RN.

The median KPS score did not differ significantly before

and after the operation, the mean hospital stay was limited

and the serious complication rate very low, indicating that

surgery in these patients is a safe option. Similar obser-

vations have also been reported by Vecil in 61 patients,

submitted to surgery after failed SRS [36].

Table 3 Algorithm of treatment for patients with suspected radionecrotic lesions, currently employed at our Institution

J Neurooncol

123

Two year actuarial survival rate in the presented series

was 50.8 % which can be favorably compared with the

47 % reported by Truong in 32 patients re-operated due to

local recurrence after SRS [24] (Fig. 3).

Our patients found to be affected by pure RN at histo-

logic examination, survived more than patients affected by

RN and tumor: this difference had only a trend toward

significance (p = 0.11), possibly due to the small number

of the sample. In Friso’s series of 31 patients, the mean

survival was longer for the patients having RN

(13.4 ± 8.6 months) than for patients having a tumor

recurrence (8.4 ± 7.1 months), however statistical signifi-

cance was not reached and most of the lesions were not

histologically confirmed [10]. Overall survival was not

affected by histology in Vecil’s series while conflicting

results were observed by other authors [34, 36] (Table 2).

Although no definitive conclusion can presently be

drawn, based on our experience and the data from the lit-

erature, we believe that cases of recurrent lesion after SRS

treatments for brain metastases should be promptly

addressed. Diagnostic work-up should include different

neuroimaging studied to improve the diagnostic accuracy

[43, 49]. If the lesion presents a small size, without sig-

nificant edema, asymptomatic or incidentally discovered,

and the functional studies are negative for tumor recur-

rence, conservative management could be initially war-

ranted. On the contrary, we advocate early neurosurgical

intervention if symptomatic mass develops or if it is not

resolving following a short-term steroid therapy and other

non-operative management [24, 39].

On the basis of this preliminary experience, we have

devised a flow-chart, which is currently employed in our

center, to evaluate suspected case of RN lesions (Table 3).

Differently from what reported by McPherson, in our

series surgical operation appeared to be safe and successful

in rapidly improve the clinical conditions and overall sur-

vival of patients affected by pure RN. A prompt and

uncomplicated surgery may be well tolerated by the

patients, it may confirm diagnosis and spare a protracted

corticosteroid therapy which significantly affects quality of

life and increase systemic complications. Even in the more

frequent cases of recurrent tumors associated to RN,

reoperation with gross total resection, could afford some

benefits in terms of prolonged survival and improvement of

disabilities, particularly if patients are young, in good

functional status (RPA class I-II) and with a long interval

after initial SRS [5–7, 24, 36, 50]. Due to the larger employ

of SRS, it is conceivable that the number of RN to be

treated are going to increase in the following years. We

think that oncologist should be aware and more alert about

this complication, not delaying the neurosurgical evalua-

tion. These and other analyses may be useful to formulate

more complete diagnostic and treatment guidelines for

such challenging recurrent cerebral lesions and to identify

issues to be addressed by future tailored and possibly,

prospective randomized, multi-istitutional studies.

Acknowledgments The authors thank Mrs. Mariantonia Carosi MD

(Department of Pathology, Istituto Nazionale Tumori ‘‘Regina Ele-

na’’) for her review of the histologic material, Mrs. Marzia Piccoli and

Mrs. Maria Di Santo for the editorial and archives assistance.

Conflict of interest The authors declare that they have no conflict

of interest.

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