Metastase Cerebrale 2

Review Article on the Modern Approaches to the Management of Brain Metastases
Page 1 of 19
Management of complications from brain metastasis treatment: a

narrative review
Kevin Diao1, Alan J. Sosa1, Gabriel Zada2, Seema Nagpal3, Eric L. Chang1,4
1
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Neurological
Surgery, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; 3Department of Neurology, Stanford University,
Stanford, CA, USA; 4Department of Radiation Oncology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
Contributions: (I) Conception and design: All authors; (II) Administrative support: EL Chang; (III) Provision of study materials or patients: K Diao,
EL Chang; (IV) Collection and assembly of data: K Diao, AJ Sosa; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All
authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Kevin Diao, MD. FCT6.5075, T. Boone Pickens Academic Tower, 1400 Pressler St., Houston, TX 77030, USA.
Email: [email protected].
Objective: To describe the range of potential side effects associated with modern brain metastasis treatment
and provide evidenced-based guidance on the effective management of these side effects.
Background: Brain metastases are the most commonly diagnosed malignant intracranial tumor and have
historically been associated with very poor prognosis. The standard treatment for brain metastases until
the 1990s was whole-brain radiation therapy (WBRT) alone. Since then, however, numerous advances have
established the role of neurosurgical resection, stereotactic radiosurgery (SRS), targeted systemic therapy,
and immunotherapy in the multidisciplinary management of brain metastases and led to improvements in
intracranial control, survival, and neurocognitive preservation among patients with brain metastases. As a
result, however, brain metastasis treatment is associated with a wider range of potential side effects than
ever before, and clinicians are tasked with the challenge of effectively managing these side effects without
compromising cancer outcomes.
Methods: We performed a narrative review of peer-reviewed articles related to the management of side
effects from multidisciplinary brain metastasis treatment and synthesized the data in the context of our
clinical experience and practice.
Conclusions: In this review, we summarize the major complications from intracranial radiotherapy,
neurosurgical resection, and brain metastasis directed systemic therapy with corresponding evidenced-based,
modern management principles to guide the practicing oncologist.
Keywords: Brain metastasis; treatment; complication; toxicity; management
Submitted Aug 09, 2021. Accepted for publication Sep 27, 2021.
doi: 10.21037/cco-21-90
View this article at: https://dx.doi.org/10.21037/cco-21-90
Introduction therapies which have led to longer periods of time during

which brain metastases may develop (3,4). In addition,
Brain metastases represent the most commonly diagnosed
malignant intracranial tumor (1), occurring in up to half improved systemic therapies used in the metastatic setting
of all patients with cancer (2). The incidence of brain may not achieve the same effects in the central nervous
metastases is increasing because of improved imaging system (CNS) due to the blood-brain barrier (5).
modalities allowing for more accurate detection of brain Historically, brain metastases were near-uniformly
metastases, better awareness among oncologists leading to associated with poor outcomes. The standard treatment for
more frequent surveillance imaging, and improved cancer brain metastases until the 1990s was whole-brain radiation
© Chinese Clinical Oncology. All rights reserved. Chin Clin Oncol 2022;11(2):11 | https://dx.doi.org/10.21037/cco-21-90
Page 2 of 19 Diao et al. Management of complications from brain metastasis treatment
therapy (WBRT) alone, which was associated with a median within 90 days of radiation treatment and late CNS toxicities
survival of 3–6 months (6). Since then, however, a plethora as those occurring after 90 days of treatment (21). From a
of research and treatment advances has fundamentally radiobiological standpoint, distinct histopathological types
transformed the landscape of brain metastasis management. of injury have been described in the acute, early-delayed, and
Level I data showed the addition of surgical resection to late timepoints. Acute injury has been described as occurring
WBRT for patients with a single brain metastasis improved within either 30 days after treatment, early-delayed injury
overall survival (OS), and the addition of WBRT to surgical as occurring 30 days to 6 months after treatment, and late
resection improved local and distant brain control and injury as occurring greater than 6 months after treatment
neurologic death, establishing the role of selective surgical (22,23). For the purposes of this practical review, we will
resection in patients with brain metastases (6,7). Multiple follow the RTOG definition of acute and late CNS toxicity.
trials compared stereotactic radiosurgery (SRS) versus
SRS + WBRT for patients with limited brain metastases and
Acute complications
found similar OS but better neurocognitive preservation
and health-related quality-of-life (QOL) with SRS alone Fatigue
(8-11). Two trials examined the role of post-operative SRS
which found improved local control (LC) compared to Fatigue is common during and after cranial radiotherapy
observation (12) and better QOL compared to WBRT (13). (Table 1). In patients receiving WBRT, up to 95% of all
M o r e r e c e n t l y, t a r g e t e d s y s t e m i c a g e n t s a n d patients experience excess fatigue and prospective studies
immunotherapy have demonstrated clinically meaningful have identified deterioration in validated fatigue scores
intracranial activity in patients with certain cancer from baseline to 1 month after WBRT (24,25). However,
histologies (2,14-17). In some carefully selected patients fatigue is common with brain metastases in general and may
with brain metastases, systemic agents can be used as a be difficult to separate from treatment-related fatigue, as
frontline treatment option. Certain novel immunotherapy demonstrated in the QUARTZ trial, where 40% of patients
agents are postulated to have a synergistic effect with who received WBRT vs. 44% of patients who received
radiotherapy and may offer an intracranial control and OS supportive care only reported tiredness (26). On the other
benefit when combined with SRS (18,19). hand, fatigue may be less common following SRS, reported
As patients survive longer following brain metastasis by only 28% of patients compared to 95% of patients who
treatment, however, late neurologic complications from underwent WBRT in one series (24).
brain metastasis directed therapy are also becoming more The primary management of acute fatigue in patients
likely. Furthermore, due to the number of treatment undergoing brain radiotherapy is supportive care, including
options now available, clinicians are faced with a wide range appropriate steroid taper, advising patients to take steroids
of potential treatment-related complications in patients earlier in the day (second dose no later than mid-afternoon)
with brain metastases from radiotherapy, surgical resection, to avoid sleep disturbance, and other good sleep hygiene
and systemic therapy and managing these complications measures. Numerous studies demonstrate that aerobic and
appropriately is increasingly complex. In this review, we resistance exercise can mitigate cancer-related fatigue to
aim to describe the major potential complications from an extent, and despite lack of data specifically in patients
brain metastasis treatment with an emphasis on modern, undergoing brain radiotherapy, we agree with the American
evidenced-based clinical management. We present the Society of Clinical Oncology (ASCO) recommendations for
following article in accordance with the Narrative Review 150 minutes of moderate aerobic exercise (including fast
reporting checklist (available at https://cco.amegroups.com/ walking, cycling, or swimming) per week with an additional
article/view/10.21037/cco-21-90/rc). 2–3 sessions of resistance exercise (such as weightlifting),
unless contraindicated for medical reasons (27-31).
Psychostimulants are not indicated for acute fatigue.
Complications after intracranial radiotherapy
The definition of CNS toxicity is variably categorized into

Alopecia and dermatitis
acute versus late or acute, early-delayed, and late by different
sources (20). The Radiation Therapy Oncology Group Complete alopecia is common following WBRT and may be
(RTOG) defines acute CNS toxicities as those occurring acute or chronic, typically beginning during WBRT or up to
Chinese Clinical Oncology, Vol 11, No 2 April 2022 Page 3 of 19
Table 1 Radiotherapy complications of brain metastasis treatment and management options

Complication Management options
Acute toxicity
Fatigue  Appropriate steroid taper and administration instructions (second dose no later than
mid-afternoon)
 Sleep hygiene counseling
 Moderate aerobic/resistance exercise
Dermatitis  Grade 1–2 without moist desquamation

 Gentle hydrophilic moisturizer
 Grade 2–3 with moist desquamation
 Topical silver sulfadiazine ± foam absorbent dressings
Alopecia  Scalp-sparing radiation techniques

 Topical minoxidil 5% BID
 Referral for hair prosthesis
Headaches  Mild
 OTC analgesics (i.e., acetaminophen) PRN
 Moderate
 Systemic corticosteroids (dexamethasone 2–4 mg PO BID)
 Severe
 Emergency evaluation
 Systemic corticosteroids (dexamethasone 10 mg IV followed by 4 mg q6 hours)
Nausea/vomiting  Without other signs/symptoms of elevated ICP

 Ondansetron 8 mg q8 hours PRN
 With other signs/symptoms of elevated ICP
 Systemic corticosteroids with dosing based on severity of presentation
 Routine nausea/vomiting prophylaxis during RT should be avoided, but if nausea
develops immediately after RT treatment, ondansetron can be given prophylactically 1–2
hours prior to subsequent treatments
Late toxicity
Chronic fatigue  Psychostimulants (including methylphenidate 10 mg BID, modafinil 200 mg QD) can be
considered for chronic cancer-related fatigue
Pseudoprogression/radiation necrosis  Clinically directed supportive care and symptom management

 Advanced imaging techniques (perfusion MRI, diffusion-weighted MRI, MRI
spectroscopy, PET) if concern for tumor recurrence
 Close observation with follow up imaging
 If symptomatic, systemic corticosteroids with dose based on severity of symptoms and
consideration of PPI and infectious prophylaxis as indicated with gradual steroid taper over
>4 weeks
 If progressive symptoms after corticosteroids or inability to tolerate steroid taper and no
medical contraindications, consider IV bevacizumab (either 7.5 mg/kg q3 weeks or 5 mg/kg
q2 weeks for up to 4 cycles)
 Consider surgical resection for medically refractory or significant diagnostic uncertainty
 Insufficient evidence to recommend LITT, HBOT, therapeutic anticoagulation, and/or
antioxidant therapy
Neurocognitive preservation  Memantine during and for 6 months after WBRT (maintenance dose of 10 mg PO BID)
 SRS with omission of WBRT
 HA-IMRT techniques
Table 1 (continued)
Table 1 (continued)
Neurocognitive decline  Psychostimulants (including methylphenidate 10 mg BID, modafinil 200 mg QD) for
chronic cancer-related fatigue
 Donepezil ≥6 months after cranial irradiation for memory, motor speed, dexterity
(maintenance dose of 10 mg QD)
Optic neuropathy  In absence of other effective treatment options, consider HBOT ideally initiated within
72 hours of symptom onset or IV bevacizumab ± dexamethasone (dosing varies)
 Insufficient evidence to recommend corticosteroids, therapeutic anticoagulation, or ACE
inhibitor therapy
 Close clinical and imaging follow up of contralateral optic apparatus
Neuroendocrine dysfunction  Screening for hormone deficiencies triggered by symptoms or beginning 1 year after
WBRT
BID, twice daily; OTC, over-the-counter; PRN, as needed; IV, intravenous; ICP, intracranial pressure; RT, radiotherapy; QD, once daily;
MRI, magnetic resonance imaging; PET, positron emission tomography; PPI, proton pump inhibitor; LITT, laser interstitial thermal
therapy; HBOT, hyperbaric oxygen therapy; WBRT, whole brain radiation therapy; SRS, stereotactic radiosurgery; HA-IMRT, Hippocampal
avoidance intensity-modulated radiation therapy; ACE, angiotensin converting enzyme.
1–2 weeks afterwards. Risk factors for alopecia include older of radiation doses typically used for WBRT (20–37.5 Gy),
age, radiation dose, volume, and receipt of chemotherapy. moist desquamation is unlikely to occur (38). The
In most patients, hair regrowth occurs within 2–4 months management of radiation dermatitis of the scalp following
after completion of radiation (32). However, in others, cranial radiation is similar to other areas of the body.
chronic alopecia (incomplete hair regrowth >6 months after Patients should be counseled to use sunscreen, avoid sun
treatment) may occur. Only patients who experience acute exposure, and keep the area clean and dry. We typically use
alopecia can develop chronic radiation-induced alopecia (33). a gentle hydrophilic moisturizer (i.e., Aquaphor, Beiersdorf
In our experience, alopecia is uncommon following SRS, Inc., Wilton, CT, USA; Lubriderm, Johnson & Johnson,
although patchy alopecia is possible with higher doses New Brunswick, NJ, USA) for grade 1 dermatitis and topical
targeted to peripheral lesions (34). silver sulfadiazine with or without foam absorbent dressings
In patients experiencing chronic radiation alopecia, one (i.e., Mepilex, Mölnlycke, Gothenburg, Sweden) for grade 2
study found that topical minoxidil 5% BID improved hair dermatitis with moist desquamation. Topical corticosteroids,
regrowth in 82% of patients and given its favorable safety such as hydrocortisone 1% applied once to twice daily, can
profile, is a reasonable option for interested patients (35). be used to reduce irritation and itching.
Patients with significant chronic alopecia can also be
referred for hair prosthesis. Scalp-sparing radiation delivery
Headaches, vasogenic edema and nausea
techniques utilizing intensity-modulated radiation therapy
(IMRT) have been developed which appear to both reduce Headaches are a common complaint during and after
the severity of acute alopecia and significantly reduce the intracranial radiation therapy, including both WBRT and
likelihood of chronic alopecia (33,36,37). It should be noted SRS. The pathogenesis is thought to be due to transiently
that despite a reduction in scalp radiation dose with IMRT, increased vasogenic edema from an inflammatory response
most patients will still experience acute alopecia with >50% to tumor. In general, if headaches are mild, transient, and
hair loss and this technique should therefore be reserved not associated with any new or progressive neurologic
for patients with an expected survival of >4–6 months deficits, they can be managed conservatively with over-the-
or for those receiving IMRT for other indications (i.e., counter (OTC) analgesics such as acetaminophen.
hippocampal avoidance). On the other hand, more severe, persistent headaches
Radiation dermatitis is highly associated with total and those associated with nausea, vomiting, and new or
radiation dose to the skin. Therefore, while erythema and progressive neurologic deficits should prompt concern for
dry desquamation of the scalp are possible with the range vasogenic edema. Edema leading to increased intracranial
pressure (ICP) can be a medical emergency and all entities despite sometimes being used interchangeably in
patients should be evaluated for signs of elevated ICP and medical literature (48). Pseudoprogression is a radiation
impending herniation, including but not limited to lethargy, dose-dependent phenomenon, common following SRS
nausea/vomiting, severe headache, focal neurologic but rare with WBRT alone, and owing to heterogeneous
deficits, cranial nerve palsies, papilledema, and respiratory cohorts and definitions, has a reported incidence ranging
depression. In the outpatient setting, the mainstay of from 9–31% (49). Typically, pseudoprogression occurs
treatment for vasogenic edema are systemic corticosteroids within 3 months of radiation treatment whereas radiation
such as dexamethasone. necrosis can occur months to years afterwards. Numerous
The optimal starting dose of dexamethasone depends on studies have found MRI perfusion imaging to be helpful in
the severity of symptoms and underlying vasogenic edema differentiating pseudoprogression from tumor recurrence
(39,40). In the emergency setting, a loading dose of 10 mg (50-52). By definition, most cases of pseudoprogression
IV followed by 4 mg every 6 hours is commonly used. resolve spontaneously over 2–3 months and if suspected, can
However, in the outpatient setting, a reasonable starting be closely monitored with short interval follow-up MRI.
dose of dexamethasone is 2 to 4 mg PO BID. Clinical Symptoms from increased vasogenic edema can be managed
improvement typically occurs within 1–3 days, although with steroid therapy as previously described. Progression
improvement in vasogenic edema on imaging may lag by of imaging changes on subsequent imaging should prompt
1–2 weeks (41-43). The optimal timing for steroid taper evaluation for radiation necrosis and/or tumor recurrence.
is variable and depends on the status of the underlying
condition but should be considered after 7 days of therapy
and performed slowly over the course of several weeks. For Late complications
patients undergoing radiotherapy, we typically continue Radiation necrosis
steroids at least until the end of treatment. Reductions in
dose of 50% should occur no more frequently than every Radiation necrosis refers to necrosis of normal brain
3–4 days (40). Patients should be instructed to return to tissue secondary to radiation treatment. About 80% of
their previous dose if they experience rebound symptoms cases occur within 3 years after radiation treatment but in
such as worsening headache or recurrent neurologic deficits. rare cases have been reported up to a decade afterwards
In patients presenting with nausea temporally related (53,54). The clinical presentation of radiation necrosis is
to radiation therapy without other signs or symptoms, variable and depends on the anatomic location affected.
treatment with a 5-HT3 antagonist such as ondansetron, In general, radiation necrosis can be asymptomatic, cause
prescribed 8 mg every 8 hours as needed is reasonable. global symptoms such as headache, nausea, or vomiting
Cranial radiation is categorized as “low risk” for from increased ICP, seizures or focal neurologic deficits
radiotherapy-induced nausea and vomiting and routine that localize to the region of radiation necrosis (54). In
anti-emetic prophylaxis should be avoided (44-46). If most cases, tissue is not obtained and therefore imaging
other signs or symptoms are present that may be explained and clinical correlates are used to inform diagnosis. The
by underlying vasogenic edema, corticosteroids with or incidence of symptomatic radiation necrosis following SRS
without a 5-HT3 antagonist should be used as a first-line ranges from 4–20% and is commonly estimated at 10%
option. overall (55-58). Conversely, the risk of radiation necrosis is
minimal (<1%) following WBRT alone and standard dosing
regimens.
Pseudoprogression
The imaging diagnosis of radiation necrosis is
Pseudoprogression describes an imaging finding on challenging, and biopsy or resection is required for
magnetic resonance imaging (MRI) which cannot reliably be definitive diagnosis. Some authors advocate for the use of
differentiated from tumor progression on conventional MRI, terms such as adverse radiation effect (ARE) and treatment-
typically characterized by increasing size, T1-weighted related imaging changes (TRIC) as broader terms to capture
contrast enhancement, and peritumoral vasogenic both reversible and irreversible radiation changes (19,57).
edema of a treated tumor (47). There may be overlap Advanced imaging techniques, including perfusion MRI,
between pseudoprogression and radiation necrosis, diffusion-weighted MRI, MRI spectroscopy, and positron
which is a pathologic diagnosis, but the two are distinct emission tomography (PET) can be useful as diagnostic
adjuncts (59-65). The objectives in the management of perforation, or poorly controlled hypertension.
radiation necrosis are to palliate symptoms and prevent Surgical resection may be necessary for cases of
progressive neurologic deficits. In asymptomatic patients refractory radiation necrosis with significant symptoms,
after initial diagnosis of radiation necrosis, close observation contraindication to medical therapy, or uncertainty as to
with a repeat MRI in 6–8 weeks followed by spacing to whether a lesion represents radiation necrosis or tumor
every 2–3 months after lesion stability or regression is recurrence. Surgery can offer rapid decompression leading
reasonable as there is no evidence that treatment at this to reduced steroid requirement but is also associated with
stage will alter disease course. In many patients, the imaging significant morbidity as represented by one contemporary
changes will stabilize and improve over the course of weeks series where overall morbidity from surgery was 54% (68).
to months. The authors advocated for the use of surgery for radiation
In patients with symptomatic radiation necrosis, systemic necrosis only in cases where all medical therapy had failed.
corticosteroids such as dexamethasone are the first-line In recent years, laser interstitial thermal therapy (LITT) has
treatment. For patients with mild to moderate symptoms, also been used successfully to manage refractory radiation
a starting dose of 2 to 4 mg dexamethasone PO BID is necrosis, and offers a minimally invasive alternative guided
reasonable (39,40). Patients with severe symptoms should by MRI. Retrospective data suggests local outcomes
be considered for emergent evaluation and potential comparable to craniotomy albeit with inferior symptom
inpatient management. Symptom improvement occurs relief (69).
rapidly after initiation of steroids but imaging changes, such Hyperbaric oxygen therapy (HBOT) has only been
as improvement in perilesional vasogenic edema, can lag studied in small, retrospective series (70-72). In one cohort
for several weeks. As such, we typically wait at least 4 weeks of 10 patients who underwent HBOT, all either had
prior to obtaining repeat imaging. Steroid dose should stabilization of improvement of symptoms and/or imaging
be maintained for at least 1–2 weeks, and then gradually findings without severe toxicities (70). Patients were
tapered afterwards over the course of several weeks. Most treated at 2.0–2.4 atmospheres for 20–30 sessions lasting
patients will not require any additional therapy, but for 90–120 minutes each. HBOT should not be used in patients
those with either progressive symptoms or inability to with pneumothorax or at high risk for pneumothorax (i.e.,
tolerate a steroid taper, more aggressive treatments may be chronic obstructive pulmonary disease, lung blebs/bullae,
considered. recent thoracic surgery). Its adoption has been limited
Bevacizumab is a monoclonal antibody that inhibits due to the need for expensive, specialized equipment and
vascular endothelial growth factor (VEGF). It has the significant time commitment. Anticoagulants such
been studied for treatment of radiation necrosis in two as warfarin and heparin have also been studied in small
randomized controlled trials (66,67). In both trials, high retrospective series (73,74). The larger included 8 patients
rates of radiographic response (100% and 66%) and with radiation necrosis, of whom 5 symptomatically
neurologic symptom improvement (100% and 62%) improved after anticoagulation for a total of 3–6 months (73).
were observed, which were significantly better than with One small, retrospective study of 8 patients with radiation
corticosteroid therapy alone. A dose of either 7.5 mg/kg necrosis found improvement in edema volume after
every 3 weeks or 5 mg/kg every 2 weeks for up to 4 cycles, treatment with vitamin E and pentoxifylline (75). Overall,
lower than those typically used in anti-cancer regimens, the evidence to support HBOT, anticoagulation, and
can be used. Imaging response can be detected on MRI antioxidant therapy for radiation necrosis is weak and these
as early as after 2 cycles. Follow-up MRI can be obtained therapies cannot be recommended for routine use.
8–12 weeks after initiation of therapy and steroid taper
can begin around 72 hours after cycle #1. Retreatment
Neurocognitive decline
with bevacizumab is feasible and appears efficacious but
is not well-studied. Rates of serious adverse events with Neurocognitive decline is common in patients with brain
bevacizumab were low but included pulmonary embolism, metastases, both due to tumor progression as well as from
sagittal sinus thrombus, and ischemic stroke. The studies brain metastasis therapy. As many as 90% of patients
excluded patients with active or high risk of bleeding, with brain metastases will have one or more impaired
recent intracranial hemorrhage or major surgery/trauma, neurocognitive functions at baseline (76). The management
significant cardiovascular disease, abdominal fistula or of neurocognitive decline has primarily been directed at
prevention rather than treatment. The use of fraction receiving radiotherapy (85,86). Psychostimulants such as
sizes >3 Gy with WBRT appeared to lead to higher risk methylphenidate and modafinil have been successfully used
for developing severe dementia (77). Two randomized for cancer-related fatigue (87-91). A small, randomized
controlled trials have found better neurocognitive study of methylphenidate (immediate release, 10 mg
preservation with SRS alone compared to SRS with BID) and modafinil (200 mg qAM) given for 4 weeks in
WBRT with similar OS in patients with limited (1-3) brain patients with primary brain tumors found improvements in
metastases (8,9). Later reports have validated the use of SRS processing speed, executive function, and patient-reported
alone in patients with up to 15 brain metastases (78,79). fatigue, mood, and QOL (92). The acetylcholinesterase
Hippocampal avoidance IMRT (HA-IMRT) has inhibitor donepezil was studied in a phase III randomized
also been demonstrated to have better neurocognitive trial among patients ≥6 months after partial or whole brain
preservation in a randomized phase III trial, although radiation, which failed to find a difference in its primary
patients with leptomeningeal disease or metastases within composite endpoint, but did result in improved memory,
5 mm of either hippocampus were excluded (80). Due to motor speed, and dexterity (93). The dose of donepezil
the time and resource-intensive nature of the treatments, was 5 mg daily for 6 weeks followed by 10 mg daily for
both SRS and HA-IMRT are best suited for patients 18 weeks. The benefit of drugs such as methylphenidate,
who are either asymptomatic or only mildly symptomatic modafinil, and donepezil appear to be greatest in patients
from brain metastases and with good performance status. with worse baseline functioning. These medications can
Another scenario where HA-IMRT may be ideal is for be considered in patients with significant neurocognitive
prophylactic cranial irradiation (PCI) in small cell lung decline following radiation for brain metastases. The choice
cancer (SCLC). Two recent randomized trials of HA-IMRT of a specific agent should be dependent on the side effect
for PCI in SCLC with a dose of 25 Gy in 10 fractions found profile and tolerability.
divergent results with one study finding improved cognitive
preservation based on delayed free recall (81), and the other
Optic neuropathy
finding no improvement in cognitive preservation based
on verbal learning compared to standard WBRT (82). As Radiation-induced optic neuropathy (RION) is one of the
there was no difference in brain failure, HA-IMRT should most feared complications of intracranial radiation due to
be considered for this group of favorable patients without its devastating consequences. RION is characterized by
clinically apparent brain metastases. progressive partial to complete monocular or binocular
The use of the N-methyl-D-aspartate (NMDA) receptor vision loss with corresponding contrast enhancement
antagonist memantine during and for 6 months after WBRT and thickening of the affected anterior visual pathway on
improved preservation of cognitive function, executive MRI with a history of radiation exposure to that anatomic
function, processing speed, and delayed recognition distribution (94,95). RION is rare below conventionally
although its primary endpoint of delayed recall did not reach fractionated radiation doses of 50 Gy or less. The risk of
statistical significance (83). Memantine was started at 5 mg RION is greater when SRS is used to treat brain metastases
AM for week 1, 5 mg BID for week 2, 10 mg AM and 5 mg in close proximity to the optic nerves with an estimated risk
PM for week 3, and 10 mg BID for week 4 and maintenance. of 1% for single fraction SRS doses of >8 Gy and 10% for
Due to its favorable side effect profile, memantine should be >12 Gy (96).
initiated in most patients receiving WBRT. A randomized Proven treatment options for RION are limited.
trial failed to show benefit of prophylactic methylphenidate Corticosteroids and therapeutic anticoagulation have been
on fatigue scores in patients undergoing radiotherapy for studied but do not appear to be effective when given alone
primary or metastatic brain cancers and methylphenidate (97-100). HBOT is controversial for this indication, as
should not be administered prophylactically for this some studies have reported improvement in vision with
indication (84). HBOT (101-103), whereas others have found no benefit
Data regarding treatments for patients who have already (100,104,105). When given, treatment should ideally be
developed significant neurocognitive deficits are scarce. A initiated within 72 hours of symptom onset (102). HBOT
randomized trial comparing a structured multidisciplinary delivery regimens are variable but range from 14–30
intervention to standard care improved overall patient daily sessions lasting 90–120 minutes each at 2.4–2.8
QOL but failed to show improvement in fatigue in patients atmospheres. There are case reports of bevacizumab
improving RION in conjunction with or following a favored, and care should be delivered by a team comprised
failed trial of corticosteroids (106-108). Farooq et al. of a neurosurgeon, neuro-intensivists, anesthesiologists,
gave bevacizumab at 7.5 mg/kg q3 weeks for 3 doses and specialized nursing staff (121). Timely detection of
with dexamethasone and pentoxifylline while Dutta et al. neurologic changes is crucial for early diagnosis and quick
gave bevacizumab 5 mg/kg alone initially followed by intervention of any post-surgical complications (Table 2).
10 mg/kg q2 weeks for up to 6 doses. Animal models
have demonstrated efficacy of the ACE inhibitor ramipril
Neurologic deficit
in mitigating RION after SRS, but this therapy remains
experimental in humans (109,110). As many as 20–40% of patients with metastatic brain
When monocular RION occurs, the contralateral eye tumors will present with focal neurologic deficits (122).
should be carefully observed with serial clinical exams Surgery aims to remove the tumor and reverse or improve
and imaging as patients are at higher risk of developing neurologic symptoms, but injury to normal brain structures
subsequent contralateral RION. Unfortunately, there is is possible, which may result in permanent neurologic
no evidence that prophylactic treatment is effective in deficits. Numerous modalities are used to preserve
preventing RION, but early HBOT can be considered if neurological function when possible, including advanced
imaging changes develop, even in the absence of clinical neuro-imaging with diffusion tractography imaging,
symptoms (103). minimally invasive approaches, awake craniotomy for
speech monitoring, and use of cortical and subcortical
motor mapping during tumor resection. The overall
Neuroendocrine dysfunction
neurologic morbidity is estimated to be 3.9–6% (120).
Historically, patients with brain metastases rarely survived Patients with new neurologic deficits after surgery should
long enough to develop clinically significant hypothalamic- be rapidly assessed to identify potentially reversible causes,
pituitary (HP) axis dysfunction following treatment of brain including ICH, hematoma, cerebral edema, and seizures. In
metastases with radiotherapy and HP dysfunction in this many cases, however, the probable cause is not discovered,
population is therefore not well-described in literature. HP though most deficits improve over time (123). In one
dysfunction is related to dose to the pituitary gland and is study of neurologic deficits after surgery for primary brain
rare with doses of <20 Gy but occurs frequently with doses tumors, two-thirds of patients were able to make a complete
of >50 Gy (111). Reported latency times range widely from recovery, and another ~15% had a near-complete recovery
1–26 years after radiation treatment, but most cases are with no impairment of function (124). Neurological and/
thought to occur between 1–5 years after radiation (112). or neurocognitive rehabilitation have been associated with
Extrapolating from data in patients with primary brain improved motor and cognitive function and QOL and
tumors, it would be reasonable to screen patients with should be tailored to each patient’s specific impairments and
brain metastases surviving longer than 1 year after goals (125).
WBRT annually for endocrine deficiencies with hormone
replacement as clinically indicated (113-115).
Intracranial hemorrhage
Hypertension and coagulopathy are the main predisposing

Complications after neurosurgical resection
risk factors for ICH after neurosurgical resection,
The morbidity and mortality of neurosurgical interventions and efforts should be focused on prevention and early
for brain metastases have improved considerably in the last correction to reduce this risk. Hypertension can be
few decades (116,117). An analysis of over 13,500 admissions precipitated by pain or may be part of the Cushing
for metastatic brain tumor resections across the US reflex. Strict blood pressure control is encouraged during
demonstrated that the mortality rate had decreased by surgery and postoperatively. A retrospective study of over
49% from 1988 to 2000 (118). The mortality risk is now 11,000 patients undergoing craniotomy found that patients
estimated to be approximately 0.7–1.9% based on modern who experienced hypertension of ≥160/90 during surgery or
series (119,120). Nevertheless, caring for the neurosurgical in the early postoperative period were more likely to have
patient requires close observation in the immediate an ICH event (126).
postoperative period. A multidisciplinary approach is Patients with ICH should be managed in an intensive
Table 2 Neurosurgical complications of brain metastasis treatment and management options

Neurologic deficit  Identify and treat potential reversible causes (i.e., intracranial hemorrhage, hematoma, cerebral
edema, seizure)
 Neurologic and/or neurocognitive rehabilitation program
Intracranial hemorrhage  Strict blood pressure control with goal <140 mmHg systolic blood pressure
 ICP lowering measures including elevation of the head of bed to 30 degrees, optimizing pain control,
and mild sedation for comfort
 For refractory or severe cases, consider invasive ICP monitoring, osmotic therapy, hyperventilation,
complete sedation, ventricular drainage, and surgical evacuation
Cerebral edema  Perioperative parenteral corticosteroids followed by oral taper

 Close monitoring and management of postoperative blood glucose with goal <180 mg/dL
Post-operative seizure  Identify and treat potential reversible causes (i.e., hypoglycemia, electrolyte disturbances, hypoxemia,
hypercarbia, cerebral edema, intracranial hemorrhage, hematoma)
 Intravenous benzodiazepines if seizure does not spontaneously resolve within 2–5 minutes
 Maintenance anti-epileptic drugs with individualized duration of treatment
Meningitis  Intraoperative antibiotic prophylaxis with cefazolin

 CSF gram stain, cell counts, and culture for diagnosis with adjuncts such as cell index, CSF lactate,
and procalcitonin
 Empiric parenteral antibiotics with vancomycin + anti-pseudomonal cephalosporin or carbapenem
ICP, intracranial pressure; CSF, cerebrospinal fluid.
care unit with close management of blood pressure with a Post-operative seizure
goal of <140 mmHg systolic and ICP lowering measures
The incidence of postoperative seizure following
including elevation of the head of bed to 30 degrees,
craniotomy is approximately 5–15% (130). Precipitating
optimizing pain control, and mild sedation for comfort.
medical factors may include hypoglycemia, electrolyte
More aggressive measures such as invasive ICP monitoring,
disturbances, hypoxemia, and/or hypercarbia. Prophylactic
osmotic therapy, hyperventilation, complete sedation,
antiepileptic drugs (AEDs) are not indicated for patients
ventricular drainage, and surgical evacuation are options for
with brain metastases as they have not shown a benefit
refractory patients or severe cases (127). in seizure reduction, even in the peri-operative setting
(130,131). Most acute seizures spontaneously resolve
Cerebral edema within two minutes, but more protracted seizures may
require infusion of intravenous benzodiazepines. An urgent
Cerebral edema is commonly seen after craniotomy and CT scan is recommended if a reversible surgical cause is
may be exacerbated by prolonged brain retraction and suspected such as cerebral edema, hemorrhage, hematoma,
hypertension. The symptoms are generally insidious and/or elevated ICP. In addition to treating the underlying
and non-specific (nausea, diffuse headache). Severe cases condition, AEDs such as levetiracetam or phenytoin
may be associated with neurologic deficits depending on should be added for maintenance in the recovery period.
the location of the edema. Corticosteroids are usually Postoperative seizures have a low risk of progression to
administered at the time of surgery and then transitioned epilepsy overall but decisions on length of time to continue
to a short oral taper to reduce the risk of cerebral edema. AEDs should be individualized.
Typical dosing is 10 mg IV dexamethasone followed
by 4 mg every 6 hours, but the dosing is individualized
Meningitis
based on the patient’s symptoms before and after surgery.
Hyperglycemia is a common side-effect of corticosteroids Infections following a craniotomy can include surgical site
and blood glucose is closely monitored and corrected infections and, rarely, meningitis. Postoperative meningitis
postoperatively when levels are >180 mg/dL (128,129). is a severe disease with high morbidity and mortality rates,
making early diagnosis and treatment crucial. The use of Organ-specific practice guidelines exist for management of
indwelling catheters or other CSF draining devices can irAEs (138-140). Most grade ≥2 toxicities should be discussed
increase the risk for meningitis. Antibiotic prophylaxis can and managed carefully with appropriate organ specialists.
be used intraoperatively and most guidelines recommend Potential options for irAEs include continued treatment
cefazolin as the antibiotic of choice for prophylaxis with observation, symptom management, temporary or
in craniotomies, but there is no evidence to support permanent suspension of immunotherapy, topical or systemic
continuation after surgery (132). corticosteroids, disease-modifying antirheumatic drugs, and
Symptoms of postoperative meningitis compared to other organ-specific interventions (140).
community-acquired meningitis are non-specific and Immunotherapy can rarely be associated with an
should be suspected with fever and/or an altered level autoimmune meningoencephalitis typically occurring between
of consciousness (133). The diagnosis is made primarily 1–7 weeks following initiation of immunotherapy (141).
through CSF gram stain, cell counts, and culture. A positive Meningeal enhancement can be seen on MRI and this
gram stain should prompt empiric treatment but with a must be differentiated from leptomeningeal disease or
negative gram stain, classic CSF findings of leukocytosis infectious etiologies with CSF analysis. Autoimmune
and neutrophilia have low specificity in the postoperative meningoencephalitis responds to high-dose corticosteroids.
setting. As a result, other lab values may be used to guide Pseudoprogression of brain metastases after treatment
clinical decision making. An elevated cell index of ≥5 (a ratio with immunotherapy has also been reported (142). If
of white blood cells to erythrocytes), high CSF lactate suspected, the evaluation of pseudoprogression in patients
(>4 mmol/L), and elevated procalcitonin have all been receiving immunotherapy is similar to that of other patients
associated with bacterial meningitis (133). The treatment is (See above “Pseudoprogression” section). Corticosteroids
empiric parenteral antibiotics with vancomycin plus either should be administered when clinically indicated for
an anti-pseudomonal cephalosporin or carbapenem per neurologic symptoms with a slow taper over at least
the 2017 Infectious Diseases Society of America (IDSA) 4–6 weeks, as in other irAEs. A starting dose of either
guidelines (134). prednisone at 1 mg/kg or dexamethasone equivalent are
acceptable options.
There is no consensus on the optimal timing of
Complications after brain metastasis directed immunotherapy with radiotherapy. Overall, the toxicity
systemic therapy profile of combination therapy is not significantly worse
Checkpoint inhibitor immunotherapy than with immunotherapy alone (143), although some have
reported higher rates of radiation necrosis (144). However,
Checkpoint inhibitors include antibodies against cytotoxic as there is no evidence that withholding immunotherapy
T lymphocyte-associated antigen 4 (CTLA-4) such as during radiotherapy reduces side effects, we do not advocate
ipilimumab, programmed cell death receptor 1 (PD-1) for this approach.
such as nivolumab, and programmed cell death ligand 1 In general, for mild, grade 1 irAEs, immunotherapy can
(PD-L1) such as atezolizumab. Combination ipilimumab continue with close clinical supervision, and corticosteroids
and nivolumab were studied for upfront treatment of are not necessary. Grade ≥2 events require temporary
melanoma brain metastases (14). Checkpoint inhibitors suspension of immunotherapy with optional administration
are associated with a wide range of potential side effects, of low-dose corticosteroids if the irAEs do not promptly
referred to as immune-related adverse events (irAEs), improve with discontinuation of immunotherapy.
caused by enhancement of the immune system and the Immunotherapy may be resumed after improvement of
ubiquitous presence of immune cells throughout the body the irAE to grade 0–1 and tapering of corticosteroids to a
(Table 3). Well-documented irAEs include pruritic skin prednisone equivalent of <10 mg/day (139). Grade ≥3 events
rash, arthralgias/myalgias, colitis, pneumonitis, hepatitis, should be managed with high-dose systemic corticosteroids,
and endocrinopathies, although many other potential irAEs possibly as an inpatient, and resumption of immunotherapy
exist. The incidence of any irAE is as high as 90% while should be considered on a case-by-case basis depending on
the incidence of severe grade ≥3 irAE ranges from 10–43% the perceived risk/benefit ratio. Immunotherapy should be
depending on the agent, population, and study (135-137). permanently discontinued following a grade 4 event.
The treatment-related death rate is as high as 2% (138). When initiated, low-dose prednisone is dosed at
Table 3 Systemic therapy complications of brain metastasis treatment and management options
Immunotherapy
irAE  Grade 1
 Symptom management
 Continue with immunotherapy treatment with close clinical supervision
 Grade 2
 Consider consultation with organ-specific specialist
 Temporary suspension of immunotherapy until improvement to grade 0–1 toxicity and tapering
of corticosteroid therapy to prednisone equivalent <10 mg/day
 Low-dose corticosteroids (0.5–1 mg/kg/day prednisone equivalent) if symptoms do not promptly
improve with cessation of immunotherapy with gradual taper over at least 4–6 weeks
 Grade 3
 Consider inpatient management
 Suspension of immunotherapy with resumption on a case-by-case basis depending on risk/
benefit ratio after improvement to grade 0–1 toxicity and tapering of corticosteroid therapy to
prednisone equivalent <10 mg/day
 High-dose corticosteroids (1–2 mg/kg/day prednisone equivalent) with gradual taper over at
least 4–6 weeks
 Grade 4
 Inpatient management; permanent cessation of immunotherapy
Small molecule TKIs
HFSR  Grade 1
 Topical moisturizers and topical urea (20–40%)
 Soft gloves and/or socks
 Grade 2
 Dose reduction in TKI by 50% until improvement to grade 0–1 toxicity
 High-potency topical corticosteroids (i.e., clobetasol 0.05%) and topical 2% lidocaine
 Grade 3
 Supportive care as above for grades 1–2
 Hold TKI for at least 7 days and resume at lower dose after improvement to grade 0–1 toxicity;
if no recurrent symptoms after 4 weeks, can increase dose
Acneiform rash/folliculitis  Grade 1

 Medium (face) or high (body) potency topical corticosteroids alone
 Grade 2
 Add oral minocycline 50 mg BID
 Grade 3
 Add prednisone 10 mg QD ×7 days
 Hold TKI for at least 7 days and resume at lower dose after improvement to grade 0–1 toxicity;
if no recurrent symptoms after 4 weeks, can increase dose
Diarrhea  Loperamide initial 4 mg followed by 2 mg every 2–4 hours after each loose stool, maximum
16 mg/day
 Regular clinical fluid status and laboratory monitoring with intravenous fluid and electrolyte
repletion as indicated
 Hold TKI for persistent (>14 days) or severe diarrhea with resumption at a lower dose after
improvement to grade 0–1 toxicity
irAE, immune-related adverse event; TKI, tyrosine kinase inhibitor; HFSR, hand-foot skin reaction; BID, twice daily; QD, once daily.
0.5 to 1 mg/kg/day and high-dose prednisone at 1 to with worse dermatologic toxicity (154), numerous studies
2 mg/kg/day (139). Corticosteroids should be tapered slowly have not found TKIs to be associated with worse neurologic
over at least 4–6 weeks. Although data is still evolving, toxicity with WBRT or SRS (155). A study in non-
there does not appear to be a significant negative impact on small cell lung cancer patients with ≥2 brain metastases
immunotherapy overall response rate if corticosteroids are randomly assigned patients to either WBRT or WBRT
initiated after the appearance of irAEs (145). with erlotinib. There was no difference in intracranial PFS
or cognitive function with concurrent erlotinib compared
to WBRT alone suggesting safety but no justification for
Small molecule tyrosine kinase inhibitors (TKIs)
adding concurrent EGFR-TKI with WBRT (156). Thus,
Small molecule TKIs are orally bioavailable targeted for treatment-naïve patients with brain metastases, we
therapy agents, a number of which have been studied prefer upfront radiotherapy followed by TKI, but for those
for brain metastasis treatment in recent years including patients already receiving TKI administration at the time
erlotinib, gefitinib, neratinib, and tucatinib (2,15-17). TKIs of radiotherapy evaluation, interruption of TKI therapy
are associated with a unique dermatologic side effect profile. may not be necessary. If TKI interruption is preferred,
Multi-targeted TKIs (i.e., sorafenib, sunitinib) cause a a one-week period before and after radiotherapy is
characteristic hand-foot skin reaction (HFSR) in up to 60% sufficient.
of treated patients (146-149). HFSR is characterized by Diarrhea should be managed with supportive care.
hyperkeratotic, calloused lesions on the palms and soles with Loperamide can be used with an initial dose of 4 mg
surrounding erythema within the first 2–4 weeks of TKI followed by 2 mg every 2–4 hours after each loose
initiation. For grade 1 HFSR, TKI dose can be maintained stool, titrating to 1–2 bowel movements a day with a
with supportive care including topical moisturizers, topical maximum daily dose of 16 mg (157-159). In the setting
urea (20–40%), and soft gloves or socks (148,150). For of diarrhea, clinical fluid status assessment should be
grade 2 HFSR, TKI dose should be reduced by 50% performed regularly with a low threshold for intravenous
until improvement to grade 0–1 and high-potency topical fluid administration. Electrolytes should be monitored
corticosteroids (i.e., clobetasol 0.05%) with topical 2% and repleted as needed, and patients who are acutely ill
lidocaine given. For grade 3 HFSR, treatment should be should be managed as an inpatient. TKI therapy should
interrupted for at least 7 days and supportive treatment as be withheld for severe or persistent (>14 days) diarrhea
in grades 1–2 HFSR given. After improvement to grade 0–1, with consideration of resumption at a reduced dose after
the TKI may be resumed at a lower dose and after at least improvement to grade 0–1.
4 weeks without recurrence or worsening of HFSR, the
dose may be increased.
Conclusions
The most common side effects caused by EGFR
selective TKIs (i.e., erlotinib, gefitinib) include a dose- The incidence of brain metastases is increasing due to more
dependent acneiform rash/folliculitis and diarrhea (151,152). advanced imaging modalities, more frequent brain imaging,
Acneiform rash is managed according to severity and for and improved cancer treatments for metastatic disease.
grade 1 can be treated with medium-high potency topical Furthermore, numerous new and effective multimodality
steroids alone. Oral minocycline 50 mg BID should brain metastasis therapies have been developed over recent
be added for grade 2 toxicity and a short course of oral years that have led to both improved survival in patients with
prednisone 10 mg daily × 7 days should be added for grade brain metastases and better preservation of neurocognitive
3 toxicity (151). Co-management with dermatology should function. As a result, however, brain metastasis therapies are
be considered for grade 2–3 rash. Severe rash unresponsive associated with a greater range of potential side effects than
to medical treatment should prompt interruption of TKI ever before, and clinicians are tasked with the challenge of
therapy with consideration of resumption at a reduced dose effectively managing these side effects without compromising
after improvement to grade 0–1 toxicity. Severe cutaneous cancer outcomes. In this review, we have summarized
reactions should alert providers to the possibility of Stevens- the major complications from intracranial radiotherapy,
Johnsons syndrome (SJS)/toxic epidermal necrolysis (TEN) neurosurgical resection, and brain metastasis directed
as rare cases have been reported with TKIs (153). systemic therapy and corresponding evidenced-based, modern
While TKIs concurrent with WBRT may be associated management principles to guide the practicing oncologist.
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Attribution-NonCommercial-NoDerivs 4.0 International 2011;29:134-41.
License (CC BY-NC-ND 4.0), which permits the non- 12. Mahajan A, Ahmed S, McAleer MF, et al. Post-operative
commercial replication and distribution of the article with stereotactic radiosurgery versus observation for completely
the strict proviso that no changes or edits are made and the resected brain metastases: a single-centre, randomised,
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formal publication through the relevant DOI and the license). 13. Brown PD, Ballman KV, Cerhan JH, et al. Postoperative
See: https://creativecommons.org/licenses/by-nc-nd/4.0/. stereotactic radiosurgery compared with whole brain
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Cite this article as: Diao K, Sosa AJ, Zada G, Nagpal S,

Chang EL. Management of complications from brain metastasis
treatment: a narrative review. Chin Clin Oncol 2022;11(2):11.
doi: 10.21037/cco-21-90

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Review Article on the Modern Approaches to the Management of Brain Metastases

Management of complications from brain metastasis treatment: a

Keywords: Brain metastasis; treatment; complication; toxicity; management

Introduction therapies which have led to longer periods of time during

The definition of CNS toxicity is variably categorized into

Table 1 Radiotherapy complications of brain metastasis treatment and management options

Dermatitis  Grade 1–2 without moist desquamation

Alopecia  Scalp-sparing radiation techniques

Nausea/vomiting  Without other signs/symptoms of elevated ICP

Pseudoprogression/radiation necrosis  Clinically directed supportive care and symptom management

Complication Management options

Hypertension and coagulopathy are the main predisposing

Table 2 Neurosurgical complications of brain metastasis treatment and management options

Cerebral edema  Perioperative parenteral corticosteroids followed by oral taper

Meningitis  Intraoperative antibiotic prophylaxis with cefazolin

Small molecule TKIs

Acneiform rash/folliculitis  Grade 1

Acknowledgments 2. Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab,

distinction between radiation necrosis and recurrence of metastases. Neurosurgery 1989;24:798-805.

therapy: A systematic review and meta-analysis. Radiother 2013;69:463-72.

Cite this article as: Diao K, Sosa AJ, Zada G, Nagpal S,

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