Radiosurgery
for Brain
Metastases

Radiosurgery for a Single Brain Metastasis from Lung Cancer
MRI single met Computer Target MRI normal 3 months
after radiosurgery

Brain Metastases
Robert Miller MD
www.aboutcancer.com
Brain metastases: cancer that started elsewhere in the body (e.g. lung, breast,
melanoma) and then spread to the brain
Brain primary tumor: a normal brain cell (glial cell) becomes malignant and is called a
glioma or the most serious a glioblastoma multiforme (GBM)
Highly targeted radiation (i.e. radiosurgery) is most appropriate for a brain metastases
rather than a primary brain tumor. Brain mets are 10X more common than primary brain
tumors and 20-40% of all stage IV cancers will get brain mets
See video on brain metastases at goo.gl/vqt5mH

Normal tight blood brain barriers
(capillary endothelial cells, pericytes and
astrocytes) may prevent chemotherapy
drugs from reaching the brain (perhaps
not newer TKI drugs)
Sometimes tumor cells will
disrupt the barrier and
allow chemo to reach parts
of the cancer

Untreated, the median survival of patients with symptomatic brain metastases from
solid tumors is approximately one to two months.
In randomized trials composed primarily of patients with non-small cell lung
cancer (NSCLC) and breast cancer, the median survival in patients treated with
whole brain radiation therapy (WBRT) ranges from four to six months.
More prolonged survival is seen in selected patients and in certain subgroups, such
as patients with human epidermal growth factor receptor 2 (HER2)-positive breast
cancer and certain genotypes of NSCLC
Brain Metastases

A primary brain tumor spreads diffusely through the brain and makes a poor
target for radiation. A brain metastases is more well defined, pushes the normal
brain away and makes a much better target for radiosurgery
Glioblastoma Single Brain Metastases

Brain Met is easier to target with radiation.

VitalBeam Linac
Cyberknife
Gamma Knife Tomotherapy
Machines used to focus
highly targeted radiation or
radiosurgery (SRS or
stereotactic radiosurgery)

What is Radiosurgery?
• The concept of stereotactic radiosurgery (SRS) described by Lars Leksell
in 1951
• The first Gamma Knife using 60-cobalt was completed in 1968
• In 1983 a modified linear accelerator was developed in Buenos Aires
• The CyberKnife was invented at Stanford Health Care and first debuted
in 1994.
• Definition: image guided ionizing radiation in one to 5 sessions (the
focused convergence of multiple beams on a target)

Issues concerning
radiosurgery for brain mets
1. Patient selection: who is an appropriate candidate
2. How does this approach compare to other
treatments like surgery (craniotomy) , whole brain radiation,
or even chemotherapy?
3. Results
4. Side effects

Characteristics of Brain Metastases
That Make them Ideal Targets for
Radiosurgery
• Well defined on CT or MRI
• Spherical shape
• Most are < 4cm in max diameter
• Generally noninfiltrative
• Located at gray-white junction

Targeting a Brain Met

Targeting a Brain Met

Targeting a Brain Met
GTV PTV
Computer (or Lisa) will expand the target to radiate

Advantages of Stereotactic
Radiosurgery
• Treatment of small, deep lesions or
eloquent areas
• Minimally invasive
• General anesthesia not required
• Outpatient procedure
• Treatment of multiple lesions at same
setting
• Short recovery (<1 week)
• Potential avoidance of whole brain XRT
• Rapid initiation of chemoRx
Advantages of Surgery
• Treatment for larger lesions (>4cm)
• Rapid resolution of mass effect and
edema
• Removal of cancer
• Histologic confirmation
• Rapid tapering of steroids
• Less intensive follow up
• Lower risk of radiation necrosis

Cancers That Spread to the Brain
Primary Tumor
Type
Percentage of
Brain Mets
Index of
Radiosensitivity
Lung (NSCL) 24% Moderate
Lung (SCL) 15% High
Breast 17% Moderate
Melanoma 11% Low
Colorectal 6% Moderate
Renal 6% Low
Occult Primary 5% Moderate

Limited number (1 – 3) and stable systemic disease then surgery or
radiosurgery or whole brain (with RS favored over whole brain)
Multiple (>3) then whole brain or radiosurgery (consider RS if good
performance and low overall tumor burden)

Surgery +/- XRT better then Whole
Brain Radiation

A randomized trial of surgery in the treatment of single metastases to the
brain.
Patchell NEJM 1990:322:494
Outcome Surgery + XRT XRT alone
local recurrence 20% 52%
median survival 40 w 15 w
Functional 38 w 8 w

A randomized trial of surgery in the treatment of single metastases to the
brain.
Patchell NEJM 1990:322:494
100
90
80
70
60
50
40
30
20
10
0
Duration of Functional Independence (KS 70)
Surgery
No
Surgery
Weeks

Treatment of single brain metastasis: radiotherapy alone or combined
with neurosurgery?
Vecht Ann Neurol 1993;33:583
Outcome Surg + XRT XRT alone
Survival
stable extracranial 12 mos 7 mos
functional 9 mos 4 mos
progressive extracranial
5 mos 5 mos
functional 2.5 mos 2.5 mos

Benefits of Surgery over Radiation by Risk Group
Noordnik IJROBP 1994;29:711
Survival with Stable Extracranial
Disease
Survival with Progressive Disease

A randomized trial to assess the efficacy of surgery in addition to
radiotherapy in patients with a single cerebral metastasis.
Mintz. Cancer 1996;78:1470
Outcome Surgery +XRT XRT Alone
median survival 5.6 mos 6.3 mos
survival/1y 12% 30%

Surgery + PostOp Brain Radiation
? of whole brain XRT
After a resection there is 50 – 60% risk of local relapse by 6 - 12 months.
PostOp whole brain cuts this in half but with no impact on survival and
possible memory problems.

Postoperative radiotherapy in the treatment of single metastases to the brain:
a randomized trial.
Patchell. JAMA 1998;280:1485
Outcome Surgery Surgery + Postop
Whole Brain XRT
recurrence in brain 70% 18%
recur original site 46% 10%
other brain sites 37% 14%
neurologic death 44% 14%
Median survival 43 weeks 48 weeks

Surgery + PostOp Brain Radiation
should be SRS
Local Control Rates: 67 – 92%
Median survival: 1 0 – 15 months
Survival: 52-69%/1y and 32 – 34%/2y

Postoperative stereotactic radiosurgery compared with whole brain
radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a
multicentre, randomised, controlled, phase 3 trial.
one resected brain metastasis and a resection cavity less than 5·0 cm in
maximal extent were randomly assigned (1:1) to either postoperative SRS
(12-20 Gy single fraction with dose determined by surgical cavity volume)
or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5
Gy
Results SRS WB
cognitive impairment at 6 months 52% 85%
median survival 12. months 11.6 months
Brown Lancet Oncol. 2017;18(8):1049.

N107C/CEC.3: A Phase III Trial of Post-Operative Stereotactic Radiosurgery
(SRS) Compared with Whole Brain Radiotherapy (WBRT) for Resected
Metastatic Brain Disease
one to four brain metastases were randomized to either SRS or WBRT after
resection of one lesion.
Intracranial tumor control
WB SRS
90%/6 mos 74%
78.6%/12 mos 54.7%
Brown IJROBP 2016;96:937

Post-operative stereotactic radiosurgery versus observation for completely
resected brain metastases: a single-centre, randomised, controlled, phase 3
trial.
In this randomised, controlled, phase 3 trial, had a complete resection of one
to three brain metastases (with a maximum diameter of the resection
cavity≤4 cm).
12-month freedom from local recurrence was 43% in the observation group
and 72% in the SRS group). There were no adverse events or treatment-
related deaths in either group.
Mahajan Lancet Oncol. 2017;18(8):1040

Hypofractionated Stereotactic Radiation Therapy to the Surgical Bed for
Patients With Brain Metastases Provides Effective Local Control for Bed ≥ 48
Kumar IJROBP 2017;99:E85
40 surgical beds analyzed, 9 were treated with 3 fractions with median dose
24Gy and 31 were treated with 5 fractions with median dose 27.5Gy using an
every other day fractionation. 10 (33%) surgical beds developed local failure
with a median time to failure of 148 days.
30 Gy/5 fx the best local control (93%) A lower total dose in 5 fractions (ie 27.5
Gy or 25 Gy) had a local control rate of 70%. For 3 fraction SBRT, local control
was 100% using a dose of 27 Gy in 3 fractions and 70% if 24 Gy in 3 fractions
was used.
improved local control with BED>=48 (30Gy/5fx and 27Gy/3fx).

Do We Need to Dose-Escalate Fractionated Stereotactic Radiation Therapy for
Resected Brain Metastases?
Francis IJROBP 2017; 99:E519 U Wisconsin
Planning target volume was defined as gross lesion or resection cavity
plus 2-3 mm. FSRT schedules consisted of 25 Gy in 5-fractions (BED10 =
37.5 Gy, EQD2 = 31.25 Gy) and 30 Gy in 5-fractions (BED10= 48 Gy, EQD2 =
40 Gy)
There was a trend towards inferior LC with cavities treated with 25 Gy
compared to 30 Gy (59% vs 100%, p=0.06). No other clinical or dosimetric
parameters including histology or PTV size predicted for local failure.

Recommendations for CTV contouring for postoperative
completely resected cavity SRS (Soliman IJROBP 2018;100:436)
• CTV should include the entire contrast-enhancing surgical cavity using the
T1-weighted gadolinium-enhanced axial MRI scan, excluding edema
determined by MRI
• CTV should include entire surgical tract seen on postoperative CT or MRI
• If the tumor was in contact with the dura preoperatively, CTV should
include a 5- to 10-mm margin along the bone flap beyond the initial region
of preoperative tumor contact
• If the tumor was not in contact with the dura, CTV should include a
margin of 1 to 5 mm along the bone flap
• If the tumor was in contact with a venous sinus preoperatively, CTV
should include a margin of 1 to 5 mm along the sinus

Radiosurgery better than Whole
Brain Radiation

With Multiple Brain Mets Whole Brain Radiation is Often the Only Option

There hasn’t been much progress in
whole brain radiation with
survival in the trials at 3 to 6
months.
There has been efforts to reduce the
neuro toxicity with hippocampal
sparing (RTOG 0933) or Memantine
(RTOG 0614)

Preservation of Memory With Conformal Avoidance of the Hippocampal
Neural Stem-Cell Compartment During Whole-Brain Radiotherapy for Brain
Metastases (RTOG 0933): A Phase II Multi-Institutional Trial
Gondi JCO 2014;57:2909
The decline in memory
function using hippocampal
sparing was lower than
historical comparisons (e.g
13% compared to 31%)

RTOG 0614: Randomized Trial of Memantine for Prevention of Cognitive
Dysfunction in Whole Brain Radiation
WBRT (37.5Gy in 15 fx) +/- Memantine (20mg daily)
Results: 17% lower relative risk of cognitive decline at 24 weeks

Obviously with
multiple mets
(esp if large)
whole brain
radiation may be
the only option

May be Benefit of Repeating Whole Brain Radiation a second Time
response rates 27 to 80% and survival 2 to 5 months
Ozgen Radiat Oncol. 2013; 8: 186.

Whole brain radiation therapy with or without stereotactic radiosurgery
boost for patients with one to three brain metastases: phase III results of
the RTOG 9508 randomised trial.
Andrews Lancet 2004;363:1665
Outcome SRS + WB WB alone
Survival (1 lesion) 6.5 mos 4.9 mos
SRS = stereotactic radiosurgery
WB = whole brain radiation

Stereotactic radiosurgery plus whole brain radiotherapy versus
radiotherapy alone for patients with multiple brain metastases.
Kondziolka IJROBP 1999;45:427
Patients with two to four brain metastases (all < or =25 mm diameter and known primary tumor
type) were randomized to initial brain tumor management with WBRT alone (30 Gy in 12
fractions) or WBRT plus radiosurgery
Outcome SRS + WB WB alone
local failure 8% 100%
Time to local failure 36 mos 6 mos
median survival 11 mos 7.5 mos
SRS = stereotactic radiosurgery
WB = whole brain radiation

Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery
for the treatment of brain metastases.
Patil Cochrane Dat Syst Rvw 2012:Sept 12
• A meta-analysis of two trials with a total of 358 participants, found
no statistically significant difference in overall survival (OS)
between WBRT plus SRS and WBRT alone groups
• one brain metastasis median survival was significantly longer in
WBRT plus SRS group (6.5 months) versus WBRT group (4.9
months
• WBRT plus SRS group had decreased local failure compared to
patients who received WBRT alone (HR 0.27)
• Unchanged or improved Karnofsky Performance Scale (KPS) at 6
months was seen in 43% of patients in the combined therapy group
versus only 28% in WBRT group

Radiosurgery alone versus SRS +
Whole Brain XRT
A 2014 meta-analysis that included five randomized trials (663 patients) found
that the addition of WBRT to SRS or surgery decreased the relative risk of
intracranial disease progression at one year by 53 percent but did not improve
overall survival

The controversy about using whole brain radiation (whether the
benefits outweigh the toxicity on brain function)

Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic
radiosurgery alone for treatment of brain metastases: a randomized
controlled trial.
Aoyama JAMA 2006:295:2483
Outcome SRS SRS + WB
median survival 8 mos 7.5 mos
brain recurrence/12 mos 76% 47%
CNS mortality 19% 23%
Preliminary report of Japanese study, adding WB did nothing
SRS = stereotactic radiosurgery
WB = whole brain radiation

Stereotactic Radiosurgery With or Without Whole-Brain Radiotherapy for Brain
Metastases: Secondary Analysis of the JROSG 99-1 Randomized Clinical Trial.
Aoyama JAMA Onc 2015;457
The WBRT schedule was 30 Gy in 10 fractions over 2 to 2.5 weeks. The
mean SRS dose was 21.9 Gy in SRS alone and 16.6 Gy in WBRT + SRS.
prognoses determined by the diagnosis-specific Graded Prognostic
Assessment (DS-GPA).
SRS + WB SRS
DS-GPA 2.5-4 16.7 mos 10.6 OS
low performance no diff
Overall survival was much better with combination in the high
performance group

Neurocognition in patients with brain metastases treated with radiosurgery
or radiosurgery plus whole-brain irradiation: a randomised controlled trial.
Chang Lancet Oncol 2009:1037.
Outcome SRS SRS + WB
memory decline/4mos 24% 52%
death/4 mos 13% 29%
CNS relapse/1y 73% 27%
SRS = stereotactic radiosurgery
WB = whole brain radiation

Adjuvant whole-brain radiotherapy versus observation after radiosurgery or
surgical resection of one to three cerebral metastases: results of the EORTC
22952-26001 study.
Kocher JCO 2011;29:134
Outcome S or SRS alone S or SRS + WB
Decline PS 10 mos 9.5 mos
median survival 10.7 mos 10.9 mos
local relapse/2y 59% (S) 27% (S)
31% (SRS) 19% (SRS)
other CNS 42% (S) 23% (S)
48% (SRS) 33% (SRS)
SRS = stereotactic radiosurgery / S = surgery
WB = whole brain radiation

Adjuvant whole-brain radiotherapy versus observation after radiosurgery or
surgical resection of one to three cerebral metastases: results of the EORTC
22952-26001 study. Kocher JCO 2011;29:134
Survival

NCCTG N0574 (Alliance): A phase III randomized trial of whole brain
radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1
to 3 brain metastases.
Brown.
randomized to SRS alone or SRS + WBRT and underwent cognitive testing before
and after treatment.
Conclusions: Decline in cognitive function, specifically immediate recall,
memory and verbal fluency, was more frequent with the addition of WBRT to
SRS. Adjuvant WBRT did not improve OS despite better brain control.
Initial treatment with SRS and close monitoring is recommended to better
preserve cognitive function in patients with newly diagnosed brain metastases
that are amenable to SRS.

A European Organisation for Research and Treatment of Cancer Phase III Trial
of Adjuvant Whole-Brain Radiotherapy Versus Observation in Patients With
One to Three Brain Metastases From Solid Tumors After Surgical Resection or
Radiosurgery: Quality-of-Life Results
Sofifietto JCO 2011;31:65
Health-related quality-of-life (HRQOL) results.
Patients in the observation only arm reported better HRQOL scores than did
patients who received WBRT. The differences were statistically significant and
clinically relevant mostly during the early follow-up period:
for global health status at 9 months,
physical functioning at 8 weeks,
cognitive functioning at 12 months
fatigue at 8 weeks).

Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for
Limited Brain Metastases: A Secondary Analysis of the North Central Cancer
Treatment Group N0574 (Alliance) Randomized Controlled Trial.
Churilla IJROBP 2017;99:1173
Group WB + SRS SRS Alone
DS-GPA 2+ 11.3 months 17.9 months
DS-GPA < 2 3.7 mos 6.6 mos
SRS alone better than combo in high performance patients
Median Survival Better Without Whole Brain

SRS Alone
SRS Alone
SRS +WB
SRS +WB
DS-GPA < 2 DS-GPA 2+
Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for
Limited Brain Metastases: A Secondary Analysis of the North Central Cancer
Treatment Group N0574 (Alliance) Randomized Controlled Trial.
Churilla IJROBP 2017;99:1173
Median Survival Better Without Whole Brain

Surgery versus Radiosurgery
SRS is a reasonable alternative to surgery for small tumors that are not surgically
accessible. Neurotoxicity and local failure after SRS increase with increasing
lesion size, and thus consideration of SRS rather than surgery should generally
be limited to lesions with a diameter of 3 cm or less. No randomized trials have
been conducted comparing SRS alone with surgery plus postoperative
radiation.

A multiinstitutional outcome and prognostic factor analysis of radiosurgery for
resectable single brain metastasis.
Auchter Int J Radiat Oncol Biol Phys. 1996;35(1):27.
following criteria: single-brain metastasis, surgically resectable lesion;
Karnofsky Performance Status (KPS)>or = 70 at time of RS; nonradiosensitive
histology. One hundred twenty-two patients were identified who met these
criteria
The overall local control rate (defined as lack of progression in the RS volume)
was 86%. Intracranial recurrence outside of the RS volume was seen in 27
patients (22%). The actuarial median survival from date of RS is 56 weeks, and
the 1-year and 2-year actuarial survival rates are 53% and 30%. The median
duration of functional independence (sustained KPS>or = 70) is 44 weeks.
Nineteen of 77 deaths were attributed to CNS progression (25% of all deaths)

A multiinstitutional outcome and prognostic factor analysis of radiosurgery for
resectable single brain metastasis.
Comparison of Current Study with Randomized Trials
Treatment Survival Functional CNS Deaths
SRS + WB 56 weeks 44 weeks 25%
S + WB 40 – 43 w 33 – 38 w 20%
WB 15 – 26 w 8 – 15 w 52%
Auchter Int J Radiat Oncol Biol Phys. 1996;35(1):27.
SRS = stereotactic radiosurgery / S = surgery
WB = whole brain radiation

A comparison of surgical resection and stereotactic radiosurgery in the
treatment of solitary brain metastases.
O’Neill IJROBP 2003;55:1169
To determine whether neurosurgery (NS) or stereotactic radiosurgery (RS)
provided better local tumor control and enhanced patient survival. review
of all solitary brain metastases (SBM) patients newly diagnosed at Mayo
Clinic Rochester between 1991 and 1999.
Outcome Surgery Radiosurgery
Survival/1y 62% 56%
local recurrence 58% 0%

Whole brain radiotherapy plus stereotactic radiosurgery (WBRT+SRS)
versus surgery plus whole brain radiotherapy (OP+WBRT) for 1-3 brain
metastases: results of a matched pair analysis.
Rades Eur J Cancer 2009;45:400
Outcome Surg + WB SRS + WB
Survival/1y 47% 56%
CNS control 50% 66%
local control 66% 82%
SRS = stereotactic radiosurgery / S = surgery
WB = whole brain radiation

Management of Brain Metastases in Tyrosine Kinase Inhibitor–Naïve
Epidermal Growth Factor Receptor–Mutant Non–Small-Cell Lung Cancer: A
Retrospective Multi-Institutional Analysis
Magnuson JCO 2017;35:1070
351 patients from six institutions with EGFR-mutant NSCLC developed
brain metastases treated with SRS followed by EGFR-TKI, WBRT followed
by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial
progression.
The median OS for the
SRS (n = 100), WBRT (n =
120), and EGFR-TKI (n =
131) cohorts was 46, 30,
and 25 months,
respectively

Results with Radiosurgery
• In controlled studies in patients with tumors up to 3 cm in diameter, SRS
produces local control rates of approximately 70 percent at one year
following treatment . This rate improves to up to 90 percent when
adjunctive WBRT is provided
• Prospective nonrandomized data in patients with newly diagnosed
brain metastases suggest that up to 10 tumors with a total cumulative
volume ≤15 mL may be treated in a single session with similar efficacy
and no increase in toxicity
• When patients are treated with SRS alone, new or recurrent brain
metastases develop in approximately 25 to 50 percent of patients within
the first 6 to 12 months

The tumors start shrinking with about a week of treatment and continue to
regress for months

Typical Radiosurgery Case with Cyberknife

Typical Radiosurgery Case with Gamma Knife

NSCL Lung Cancer. Radiosurgery may permanently
eliminate the cancer

Large left inferior
frontal metastases
Lesion virtually
gone at 20 months

Radiosurgery for Melanoma Brain Metastasis
Left frontal met Radiosurgery 18Gy MRI at 11 months

Jan 2011 - Radiosurgery
Aug 2012 – Treated tumor is virtually gone, but there
is a new tumor on the opposite side of the brain
For a single lesion, radiosurgery alone may be used, but there is a higher
risk of a new lesion showing up in the brain

Treatment for Patients
with Multiple Brain
Metastases

Stereotactic radiosurgery for patients with multiple brain metastases
(JLGK0901): a multi-institutional prospective observational study.
Yamamoto Lancet Oncol 2014:15:387
Tumor volumes smaller than 4 mL were irradiated with 22 Gy at the lesion
periphery and those that were 4-10 mL with 20 Gy.
1194 eligible patients between March 1, 2009, and Feb 15, 2012. largest
tumour <10 mL in volume and <3 cm in longest diameter; total cumulative
volume ≤15 mL
Median overall survival after stereotactic radiosurgery:
13·9 months in the 455 patients with one tumor,
10·8 months in the 531 patients with two to four tumors
10·8 months in the 208 patients with five to ten tumors.

A Multi-institutional Prospective Observational Study of Stereotactic
Radiosurgery for Patients With Multiple Brain Metastases (JLGK0901 Study
Update): Irradiation-related Complications and Long-term Maintenance of Mini-
Mental State Examination Scores.
Yamamoto IJROBP 2017;99:31
1194 eligible patients were categorized into the following groups: group A, 1
tumor (n=455); group B, 2 to 4 tumors (n=531); and group C, 5 to 10 tumors
(n=208).
Cumulative complication incidences by competing risk analysis for groups A, B,
and C were 7%, 8%, and 6%, respectively, at the 12th month after SRS; 10%, 11%,
and 11%, respectively, at the 24th month; 11%, 11%, and 12%, respectively, at the
36th month; and 12%, 12%, and 13%, respectively, at the 48th month

Analysis of radiosurgical results in patients with brain metastases
according to the number of brain lesions: is stereotactic radiosurgery
effective for multiple brain metastases?
Chang J NeuroSurg 2010;113:73
323 patients (Korea) who underwent SRS between October 2005 and October
2008 for the treatment of metastatic brain lesions.
Survival
Group 1, 1–5 lesions 10 months
Group 2, 6–10 lesions 10 months
Group 3, 11–15 lesions 13 months
Group 4, > 15 lesions 8 months

Clinical Outcomes of Upfront Stereotactic Radiosurgery Alone for Patients With
Greater Than 4 Brain Metastases
Hughes. IJROBP 2017;99:E80
767 patients, Wake Forest / 375 with 1 treated metastasis, 302 with 2-4
metastases, and 90 patients with 5-15 metastases. Median marginal dose
was 19 Gy (IQR 17-21).
Outcome 1 2 – 4 5 – 15
survival 9.8 mos 7.6 mos 4.7 mos
CNS death 30% 37% 48%
Rates of local control and toxicity were similar in all groups

Survival and Prognosis for People with Brain
Metastases
1.Do best if the cancer is confined to the brain only
2.Do better if they are young (< 65y)
3.Do better if they have a good performance score (i.e. a high
Karnofsky score of 70 or better)
Karnofsky Score (KPS) 70 = Cares for self; unable to carry on normal activity or
do active work
KPS 60 = Requires occasional assistance, but is able to care for most personal
needs

Median Survival Based on RTOG Class for People with Brain Metastases
I (KPS =70, age < 65y, mets to brain only) =
7.1 to 10.5 months
II KPS = 70 = 3.5 to 4.2 months
III KPS < 70 = 2.0 to 2.3 months

JCO October 20, 2015 vol. 33no. 30 3475-3484

Survival by Treatment (WB whole brain, S surgery, SRS radiosurgery)
and Performance Score (RTOG)
RTOG Whole
brain
Surgery SRS
I 7.1 mos 14.8 mos 16.1 mos
II 4.2 mos 9.9 mos 10.3 mos
III 2.3 mos 6.0 mos 8.9 mos

JCO October 20, 2015 vol. 33no. 30 3475-3484

Median Survival in Best Performance Group (DS-GPA 3.5 – 4)by Cancer Type
0 5 10 15 20 25 30
NSCL
SCL
Melanoma
Breast
Renal
GI
Months

Survival Curves Using Grade Prognostic Assessment (GPA)
Journal of Clinical Oncology 30, no. 4 (February 2012) 419-425.
Breast Cancer NSCL Lung Cancer

Typical Radiation Doses based on maximum diameter
RTOG 90-05 / 95-08 / 0320 (combined with WB):
2cm = 24 Gy
2.1 – 3cm = 18Gy
3.1 - 4cm = 15Gy
ACOSOG Z0300
WB No WB
< 2cm = 22Gy 24Gy
2.9cm = 18Gy 20Gy
New studies base the dose on volume
rather than diameter
NCCN SRS: max marginal dose from 15 – 24Gy based on tumor
volume / SRS favored over WB for 1-3 lesions all under 3 cm unless poor
performance score or uncontrolled systemic disease

Common Radiation Dose Schemes
Volume Dose
1-4cc 24Gy
4 – 10 cc 20 – 22Gy
10 cc 18Gy
Large areas consider 8-10Gy X 3 or 6Gy X 5

Diameter Radius Volume
0.25 0.125 0.01
0.5 0.25 0.07
0.75 0.375 0.22
1 0.5 0.52
1.25 0.625 1.02
1.5 0.75 1.77
1.75 0.875 2.81
2 1 4.19
2.25 1.125 5.96
2.5 1.25 8.18
2.75 1.375 10.89
3 1.5 14.14
3.25 1.625 17.97
3.5 1.75 22.45
3.75 1.875 27.61
4 2 33.51
4.25 2.125 40.19
4.5 2.25 47.71
4.75 2.375 56.12
5 2.5 65.45
5.25 2.625 75.77
Formula for the
volume of a
sphere
New studies base the dose on volume
rather than diameter

What dose for small lesions if multiple?
Impact of SRS (stereotactic radiosurgery) dose on survival among 98 patients
with 1–3 brain metastases ≤2 cm
Shehata IJROBP 2004;60:S411
Outcome Dose < 20Gy Dose 20Gy or +
Median survival if
confined to primary/brain 4.5 months 12 months
15%/18 mos 35%/18 mos

Personalized Radiosurgery for Brain Metastasis: Moving beyond Tumor Size in the
Modern Stereotactic Radiosurgery Era
Kotecha IJROBP 2017;99:E85
Cleveland Clinic / 1997-2015 were reviewed / 1,475 patients with 5,711 intracranial
metastases were included; 4,233 lesions were treated according to RTOG
prescription dosing and 1,478 lesions were treated to reduced prescription doses
12 Month Local Failure Rate by Size and Dose
2cm 8.7% (24Gy) 11.8% (12-23Gy)
2-3 cm 22.1% (18Gy) 25.9% (12-17Gy)
>3cm 22.9% (15Gy) 25.9% (10-14Gy)
For 5mm lesions local failure was 3.9% vs 4.4%

Secondary Analysis of RTOG 9508, a Phase 3 Randomized Trial of Whole-Brain
Radiation Therapy Versus WBRT Plus Stereotactic Radiosurgery in Patients
With 1-3 Brain Metastases; Poststratified by the Graded Prognostic Assessment
(GPA)
Sperduto IRROBP 2014:90:526
An improved prognostic index, the graded prognostic assessment (GPA) has
been developed.
there was no survival benefit overall for patients with 1 to 3 metastases;
however, there was a benefit for the subset of patients with GPA 3.5 to 4.0
(median survival time WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months
regardless of the number of metastases.
Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for
patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively.

Radiation Therapy Oncology Group (RTOG) Protocol 0320

A phase 3 trial of whole brain radiation therapy and stereotactic
radiosurgery alone versus WBRT and SRS with temozolomide or
erlotinib for non-small cell lung cancer and 1 to 3 brain metastases:
Radiation Therapy Oncology Group 0320.
After 126 patients were enrolled, the study
closed because of accrual limitations. The
median survival times (MST) for WBRT +
SRS, WBRT + SRS + TMZ, and WBRT + SRS
+ ETN were qualitatively different (13.4,
6.3, and 6.1 months, respectively)
Overall Survival
Months
Worse with Tarceva
or Temodar

Is it possible to cure patients with brain metastases?
Long-Term Survival in Patients With Synchronous, Solitary Brain Metastasis From Non–Small-Cell
Lung Cancer Treated With Radiosurgery
Flannery. IJROBP 2008;72:19
42 patients presented with a single brain met at the time of diagnosis for
lung cancer and the brain lesion treated with radiosurgery.
Survival: 71%/1y, 34%/ 2y and 21% lived 5 years
Among those who had definitive treatment to the lung (surgery or
chemoradiation) the cure rate was much better:
Survival Lung Rx No Lung Rx
median 26 months 13 months
5 year 35% 0%

Side Effects and
Toxicity

Radiosurgery for Brain Metastasis
Local control Rates of 73 to 94%
Risk of radiation necrosis of 5 to 10%
The most common delayed complication of SRS for treatment of brain
metastases is radiation necrosis, which occurs in approximately 10 percent of
treated tumors anywhere from six months to several years after treatment.
Reported rates of radiation necrosis after postoperative SRS range from 4 to 18
percent.
For tumors treated with prior SRS, the risk of symptomatic adverse radiation
effects may be as high as 20 percent within 12 months of retreatment

Complications of Radiosurgery
• Short term side effects are uncommon (2%) with worsening symptoms or
new seizures
• About one third mild swelling (headaches, nausea)
• Radionecrosis in 5% to 10%
Patients with radiation necrosis may be asymptomatic (approximately 50
percent) or present with focal neurologic signs and symptoms related to
cerebral edema. Imaging typically shows increased enhancement at the site
of prior SRS accompanied by surrounding edema. Treatment is largely
symptomatic with corticosteroids. Resection may be required
or bevacizumab may be useful in severe cases.

Radionecrosis
Sometimes the MRI will look worse after
radiosurgery due to radionecrosis of the cancer
but with time this should fade away

A 60-year-old man underwent surgical
resection followed by stereotactic radiosurgery
for an isolated left frontal metastasis secondary
to lung adenocarcinoma. A year later, he
developed an asymptomatic new contrast-
enhancing lesion. (A) T1 postcontrast magnetic
resonance imaging (MRI) demonstrating a
heterogeneously contrast-enhancing left
periventricular mass. (B) Dynamic contrast-
enhanced perfusion MRI demonstrating lack of
increased plasma volume in the contrast-
enhancing left periventricular mass, strongly
suggesting this is radiation necrosis. The
patient was monitored with serial imaging with
no significant growth of mass or new metastatic
lesions.
Radionecrosis from Radiosurgery

Long Term Toxicity
Most of the concern is about the harm from whole brain radiation
with the development of leukoencephalopathy or memory
(cognitive) problems

Magnetic resonance images showing grade
of leukoen-cephalopathy using the grading
system

By 3 years most people have some white matter changes after
whole brain radiation
IJROBP Volume 93, Issue 4, Pages 870–878

Risk of white matter changes (leukoencephalopathy) 1 year after
whole brain radiation for brain mets
U Pitt Study E Monaco (AANS 2012, Medscape Med News 2012-05-01)
WB+SRS SRS
1 year 97.3% 3.2%
So by one year 97% has some changes and by 2 years 70%
had grade 3 changes on the MRI (but no symptoms)

Prophylactic cranial irradiation for patients with small-cell lung cancer in
complete remission.
Arriagada J Natl Cancer Inst. 1995;87(3):183.
300 patients who had small-cell lung cancer that was in complete remission.
The patients were randomly assigned to receive either prophylactic cranial
irradiation delivering 24 Gy in eight fractions during 12 days (treatment
group) or no prophylactic cranial irradiation
Outcome Control WB XRT
Brain mets/2y 67% 40%
Survival/2y 21.5% 29%
Neurocognitive Testing no difference
CT appearance no difference
Older Trials using CT scans noted no problems

Primary Analysis of a Phase II Randomized Trial Radiation Therapy Oncology Group
(RTOG) 0212: Impact of Different Total Doses and Schedules of Prophylactic Cranial
Irradiation on Chronic Neurotoxicity and Quality of Life for Patients With Limited-
Disease Small-Cell Lung Cancer
Comparing 25Gy versus 36Gy
Measureable Neurotoxicity at 12 months
Low dose (62%) High dose (85-89%)
Age 60y (56%) Age > 60y (83%)
Wolfson IJROBP 2011;81:77
series have clearly demonstrated that many patients with SCLC
have demonstrable neurologic and cognitive impairments before
the onset of PCI

Neurocognition in patients with brain metastases treated with radiosurgery
or radiosurgery plus whole-brain irradiation: a randomised controlled trial.
Chang Lancet Oncol 2009:1037.
Outcome SRS SRS + WB
memory decline/4mos 24% 52%
death/4 mos 13% 29%
CNS relapse/1y 73% 27%
SRS = stereotactic radiosurgery
WB = whole brain radiation

Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation
Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A
Randomized Clinical Trial. (NCCTG N0574)
At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive
SRS or SRS plus WBRT between February 2002 and December 2013. The WBRT dose schedule was 30 Gy
in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone.
Outcome SRS + WB SRS
cognitive deterioration/3mos 91.7% 63.5%
cognitive deterioration/12 mos 94.4% 60%
survival 7.4 mos 10.4 mos
Brown JAMA. 2016 Jul;316(4):401-9.
SRS = stereotactic radiosurgery
WB = whole brain radiation

Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy
on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized
Clinical Trial.
Intracranial Progression Overall Survival
Brown JAMA. 2016 Jul;316(4):401-9.

Percent of patients who
experienced cognitive
deterioration by 3 months
by treatment groups ,
everything worse in the
whole brain group

Neurocognitive functioning and health-related quality of life in patients treated
with stereotactic radiotherapy for brain metastases: a prospective study
Habets Neuro Oncol 2016;18:435
Stereotactic radiotherapy (SRT) is expected to have a less detrimental effect
on neurocognitive functioning and health-related quality of life (HRQoL)
than whole-brain radiotherapy. Neurocognitive functioning and HRQoL of
97 patients with brain metastases were measured before SRT and 1, 3, and 6
months after SRT
Median overall survival of patients was 7.7 months.
Prior to SRT, neurocognitive functioning and HRQoL are moderately
impaired in patients with brain metastases, Over time, SRT does not have
an additional detrimental effect on neurocognitive functioning

Attention Executive Functioning
Working Memory Information Processing Speed
Neurocognitive functioning and health-related quality of life in patients treated
with stereotactic radiotherapy for brain metastases: a prospective study
Habets Neuro Oncol 2016;18:435

Future Questions for Brain Radiosurgery
1. Combining SRS with new drugs (e.g. TKI) that better pass
through the blood brain barrier
2. Combining SRS with immunotherapy ( abscopal effect
synergize with immunotherapy agents)

Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy.
Grimaldi Oncoimmuno 2014;14:3
An abscopal effect was noted in 52% (11 or 21 patients). In those who
had a local response to radiation (62%) of those 85% had an abscopal
effect (these patients lived much longer (22.4 mos vs 8.3 mos)
Survival
abscopal
response
No
abscopal

Use of Concurrent TKIs With SRS is Associated With an Increased Rate of
Radiation Necrosis Among Patients With Renal Cell Carcinoma Brain Metastasis
Juloori. IJROBP 2017;99:S159
Outcome TKI No TKI
Survival 16.8 months 7.3 months
Radionecrosis 10.9% 6.4%
Use of targeted therapies in patients with RCC BM treated with
intracranial SRS improves OS. However, the use of TKIs within 30
days of SRS significantly increases the rate of radiation necrosis
without improving LC or DIC

youtube.com/user/robertmillermd AboutCancer.com