Radiation Therapy for Brain

Metastases:
An ASTRO Clinical Practice Guideline

Developed in collaboration with the American Association

of Neurological Surgeons/Congress of Neurological
Surgeons, American Society for Clinical Oncology, and
Society for Neuro-Oncology

Endorsed by the American Society for Clinical Oncology, Society for Neuro-
Oncology, Canadian Association of Radiation Oncology, European Society for
Radiotherapy and Oncology, and Royal Australian and New Zealand College of
Radiologists
 Citation
This slide set is adapted from the Radiation Therapy for
Brain Metastases Guideline to be published in the
July/August 2022 issue of
Practical Radiation Oncology (PRO)
Web posted link:
https://www.practicalradonc.org/

The full-text guideline is also available on the ASTRO Web site:

www.astro.org
 Guideline Task Force
Chairs
– Paul Brown, MD
– Vinai Gondi, MD

Members
– Glenn Bauman, MD – Lianne Kraemer
– Lisa Bradfield – Jing Li, MD, PhD
– Stuart Burri, MD – Seema Nagpal, MD
– Alvin Cabrera, MD – Chad Rusthoven, MD
– Danielle Cunningham, MD – John Suh, MD
– Bree Eaton, MD – Wolfgang Tomé, PhD
– Jona Hattangadi‐Gluth, MD – Tony Wang, MD
– Michelle M. Kim, MD – Alexandra Zimmer, MD
– Rupesh Kotecha, MD – Mateo Ziu, MD
 Task Force Composition
• Radiation oncologist
– Drawn from academic, private, and community practices
– Includes a RO resident and a member of the Guidelines
Subcommittee
• Related specialties*
– Medical oncologist
– Neurosurgical oncologist
– Medical physicist
• Patient representative

*Representatives nominated by specialty societies.

 Introduction to Guideline
• Brain mets develop in 20%-40% of cancer patients
– Significant impact on cognitive function, neurologic
symptoms, and survival
• Evolving treatment approach
– Stereotactic radiosurgery (SRS)
– Hippocampal avoidance whole brain radiation therapy
(HA-WBRT)
– Utilization systemic therapies
– Selective use of WBRT
 Guideline Scope
To provide recommendations on the radiotherapeutic
management of intact (i.e., unresected) and resected brain
metastases from non-hematologic solid tumors.

Guidance is provided on the reasonable use of modern RT

strategies, including single-fraction and fractionated (i.e.,
hypofractionated SRS) SRS and HA-WBRT, and discusses clinical
considerations in selecting the optimal RT strategy or in deferring
RT in favor of best supportive care or close neuro-oncologic
surveillance
 AHRQ Systematic Review
• Guideline based on Agency for Healthcare Research and Quality (AHRQ)
systematic review, commissioned and funded by the Patient-Centered
Outcomes Research Institute (PCORI), included studies from 1990 through July
2020. See the published manuscript for details:
https://www.practicalradonc.org/article/S1879-8500(21)00109-0/fulltext
• Population: Adults with brain metastases
• Intervention: WBRT and SRS alone or in combination, as initial or postoperative
treatment, with or without systemic therapy
• Comparator: Studies comparing eligible interventions (SRS, WBRT, HA-WBRT)
• Outcomes: Intracranial control, PFS, OS, neurocognitive function and patient-
reported outcomes
• 9265 citations screened  1520 full-text articles assessed  97 studies included
(reported in 190 publications)
• In addition, the Task force evaluated study outcomes (eg, neurocognitive
function, QoL) that were part of the systematic review but were excluded by
AHRQ’s methodology.
 Rating Strength of Recommendation
ASTRO’s recommendations are based on evaluation of multiple factors including the quality of evidence (QoE)
and panel consensus, which among other considerations inform the strength of recommendation. QoE is based
on the body of evidence available for a particular key question and includes consideration of number of studies,
study design, adequacy of sample sizes, consistency of findings across studies, and generalizability of samples,
settings, and treatments.

Strength of Definition Overall QoE Recommendation

Recommendation Grade Wording
 Benefits clearly outweigh risks and burden, or Any
risks and burden clearly outweigh benefits. (usually high, “Recommend/
Strong  All or almost all informed people would make moderate, or expert Should”
the recommended choice. opinion)
 Benefits are finely balanced with risks and
burden or appreciable uncertainty exists
about the magnitude of benefits and risks.
 Most informed people would choose the
Any
recommended course of action, but a
(usually moderate, “Conditionally
Conditional substantial number would not.
low, or expert Recommend”
 A shared decision-making approach regarding
opinion)
patient values and preferences is particularly
important.
 Rating Quality of Evidence
Overall QoE
Type/Quality of Study Evidence Interpretation
Grade
• 2 or more well-conducted and highly-generalizable RCTs The true effect is very likely to lie close to the
High or meta-analyses of such trials. estimate of the effect based on the body of
evidence.
• 1 well-conducted and highly-generalizable RCT or a meta-
analysis of such trials OR
The true effect is likely to be close to the
• 2 or more RCTs with some weaknesses of procedure or estimate of the effect based on the body of
Moderate generalizability OR
evidence, but it is possible that it is
• 2 or more strong observational studies with consistent substantially different.
findings.

• 1 RCT with some weaknesses of procedure or

generalizability OR
• 1 or more RCTs with serious deficiencies of procedure or The true effect may be substantially different
generalizability or extremely small sample sizes OR from the estimate of the effect. There is a risk
Low • 2 or more observational studies with inconsistent that future research may significantly alter the
findings, small sample sizes, or other problems that estimate of the effect size or the
potentially confound interpretation of data. interpretation of the results.

• Consensus of the panel based on clinical judgement and

experience, due to absence of evidence or limitations in Strong consensus (≥90%) of the panel guides
the recommendation despite insufficient
Expert evidence.
evidence to discern the true magnitude and
Opinion† direction of the net effect. Further research
may better inform the topic.
 Consensus Methodology
• Modified Delphi approach
• Task force members rated their level of agreement for
each recommendation via consensus survey
- 5-point Likert scale from “strongly disagree” to
“strongly agree”
- Consensus defined using pre-specified threshold of
≥75% (≥90% for expert opinion recommendations)
agreement
• Recommendations for which consensus is not achieved
are removed or are revised and then re-surveyed.
• Recommendations achieving consensus edited with
substantive changes after the first round are also re-
surveyed.
KQ 1: What are the indications for SRS alone for patients with
intact brain metastases?
 KQ 1: What are the indications for SRS alone for patients with intact brain metastases?

Strength of Quality of
KQ1 Recommendations
Recommendation Evidence
1. For patients with an ECOG performance status of 0
to 2 and up to 4 intact brain metastases, SRS is Strong High
recommended.
2. For patients with an ECOG performance status of 0
to 2 and 5 to 10 intact brain metastases, SRS is Conditional Low
conditionally recommended.
3. For patients with intact brain metastases measuring
<2 cm in diameter, single-fraction SRS with a dose of
2000 to 2400 cGy is recommended.
Implementation remark: If multifraction SRS were Strong Moderate
chosen (eg, V12Gy >10 cm3 [see KQ4]), options
include 2700 cGy in 3 fractions or 3000 cGy in 5
fractions.
 KQ 1: What are the indications for SRS alone for patients with intact brain metastases? (con’t)

Strength of Quality of
KQ1 Recommendations
Recommendation Evidence
4. For patients with intact brain metastases measuring ≥2
cm to <3 cm in diameter, single-fraction SRS using 1800
cGy or multifraction SRS (eg, 2700 cGy in 3 fractions or Conditional Low
3000 cGy in 5 fractions) is conditionally recommended.
(see KQ4)
5. For patients with intact brain metastases measuring ≥3
cm to 4 cm in diameter, multifraction SRS (eg, 2700 cGy in
3 fractions or 3000 cGy in 5 fractions) is conditionally
recommended.
Implementation remarks: Conditional Low
 If single-fraction SRS were chosen, doses up to 1500
cGy may be used. (see KQ4)
 Multidisciplinary discussion with neurosurgery to
consider surgical resection is suggested for all tumors
causing mass effect, irrespective of tumor size.
 KQ 1: What are the indications for SRS alone for patients with intact brain metastases? (con’t)

Strength of Quality of
KQ1 Recommendations
Recommendation Evidence
6. For patients with intact brain metastases
measuring >4 cm in diameter, surgery is
conditionally recommended, and if not feasible,
multifraction SRS is preferred over single-fraction Conditional Low
SRS.
Implementation remark: Given limited evidence,
SRS for tumor size >6 cm is discouraged.
7. For patients with symptomatic brain metastases
who are candidates for local therapy and CNS-
Strong Low
active systemic therapy, upfront local therapy is
recommended.
 KQ 1: What are the indications for SRS alone for patients with intact brain metastases? (con’t)

Strength of Quality of
KQ1 Recommendations
Recommendation Evidence
8. For patients with asymptomatic brain metastases
eligible for CNS-active systemic therapy,
multidisciplinary and patient-centered decision making
is conditionally recommended to determine whether
local therapy may be safely deferred.
Implementation remark: The decision to defer local
therapy should consider factors such as brain Expert
Conditional
metastasis size, parenchymal brain location, number Opinion
of metastases, likelihood of response to specific
systemic therapy, access to close neuro-oncologic
surveillance, and availability of salvage therapies.
KQ 2: What are the indications for
observation, preoperative SRS, or
postoperative SRS or WBRT in
patients with resected brain
metastases?
 KQ 2: What are the indications for observation, preoperative
SRS, or postoperative SRS or WBRT in patients with resected
brain metastases?
Strength of Quality of
KQ2 Recommendations Recommendation Evidence
1. For patients with resected brain metastases,
radiation therapy (SRS or WBRT) is recommended Strong High
to improve intracranial disease control.
2. For patients with resected brain metastases and
limited additional brain metastases, SRS is
recommended over WBRT to preserve Strong Moderate
neurocognitive function and patient-reported
QoL.
3. For patients whose brain metastasis is planned
for resection, preoperative SRS is conditionally
Conditional Low
recommended as a potential alternative to
postoperative SRS.
KQ 3: What are the indications for
WBRT in patients with intact brain
metastases?
KQ 3: What are the indications for WBRT in patients with intact
brain metastases?
Strength of Quality of
KQ3 Recommendations Recommendation Evidence
1. For patients with favorable prognosis (estimated using a
validated brain metastases prognostic index) and brain
metastases ineligible for surgery and/or SRS, WBRT (eg,
3000 cGy in 10 fractions) is recommended as primary Strong High
treatment. (See KQ1, recommendations 7 and 8 for
consideration of systemic therapy)

2. For patients with favorable prognosis and brain

metastases receiving WBRT, hippocampal avoidance is
recommended.
Strong High
Implementation remark: Hippocampal avoidance is not
appropriate in cases of brain metastases in close proximity
to the hippocampi or in cases of leptomeningeal disease.
3. For patients with favorable prognosis and brain metastases
receiving WBRT or hippocampal avoidance WBRT, addition Strong Low
of memantine is recommended.
KQ 3: What are the indications for WBRT in patients with intact
brain metastases? (con’t)
Strength of Quality of
KQ3 Recommendations Recommendation Evidence
4. For patients with favorable prognosis and limited brain
metastases, routine adjuvant WBRT added to SRS is not
recommended.
Implementation remark: To maximize intra-cranial control Strong High
and/or when close imaging surveillance with additional
salvage therapy is not feasible, adjuvant WBRT may be
offered in addition to SRS.
5. For patients with poor prognosis and brain metastases ,
early introduction of palliative care for symptom
management and caregiver support are recommended.
Implementation remarks: Strong Moderate
 Supportive care only (with omission of WBRT) should
be considered.
 If WBRT is utilized, brief schedules (eg, 5 fractions) are
preferred.
 KQ 4: What are the risks of
symptomatic radionecrosis with
WBRT and/or SRS for patients
with brain metastases?
 KQ 4: What are the risks of symptomatic radionecrosis with
WBRT and/or SRS for patients with brain metastases?

Strength of Quality of
KQ4 Recommendation Recommendation Evidence
1. For patients with brain metastases, limiting
the single-fraction V12Gy to brain tissue
(normal brain plus target volumes) to ≤10 cm3
is conditionally recommended.
Conditional Low
Implementation remark: Any brain metastasis
with an associated tissue V12Gy >10 cm3 may be
considered for fractionated SRS to reduce risk
of radionecrosis (see KQ1).
Figure 1:
Limited Brain
Metastases
*For patients with asymptomatic
brain metastases eligible for CNS-
active systemic therapy,
multidisciplinary and patient-
centered decision making is
conditionally recommended to
determine whether local therapy
may be safely deferred.

†Hippocampal avoidance is not

recommended if brain metastases
are in close proximity to
hippocampi or if LMD. In certain
situations, SIB or sequential SRS
combined with HA-WBRT plus
memantine may be considered.

‡Preoperative SRS is conditionally

recommended as an alternative to
postoperative SRS.

§While outside the scope of the

guideline's evidence review, SRS is a
reasonable option based on the
expert opinion of the task force.
Figure 2:
Extensive
Brain
Metastases
*For patients with
asymptomatic brain
metastases eligible for CNS-
active systemic therapy,
multidisciplinary and patient-
centered decision making is
conditionally recommended
to determine whether local
therapy may be safely
deferred.

†Hippocampal avoidance is
not recommended if brain
metastases are in close
proximity to hippocampi or if
LMD. In certain situations, SIB
or sequential SRS combined
with HA-WBRT plus
memantine may be
considered.

‡For single-fraction brain plus

target V12Gy >10 cm3,
multifraction SRS is
conditionally recommended.

§Preoperative SRS is
conditionally recommended
as an alternative to
postoperative SRS.
 Key Take Away Messages
• Patient-centered multidisciplinary evaluation and discussion
prior to initiation of treatment are essential for optimal
management
• SRS for patients with limited brain mets and ECOG PS 0-2
• Multidisciplinary discussion with neurosurgery to consider
surgical resection for all tumors causing mass effect and
tumors greater than 4 cm
• For patients with symptomatic brain metastases upfront local
therapy is recommended
• For patients with asymptomatic brain metastases eligible for
CNS-active systemic therapy, multidisciplinary and patient-
centered decision-making to determine whether local therapy
may be safely deferred
 Key Take Away Messages
• For patients with resected brain metastases, SRS is
recommended to improve local control
• For patients with favorable prognosis and brain metastases
receiving WBRT, hippocampal avoidance and memantine is
recommended
• For patients with poor prognosis, early introduction of
palliative care for symptom management and caregiver
support are recommended
– If brain metastases are asymptomatic or symptoms controlled with
steroids, omission of WBRT should be considered