Skip to main content
. 2024 Mar 8;16(6):1093. doi: 10.3390/cancers16061093

Table 1.

Selected ongoing clinical trials assessing radiotherapy (SRS, SRT, and WBRT/HA-WBRT ± SIB) in patients with multiple brain metastases.

References Setting
Patients (n)
 BM (n) Main Inclusion/Exclusion Criteria CITV RT timing/
Systemic Agents Allowed		 RT Scheme Corticotherapy Primary Endpoint Statistical Endpoint Completion Date
HipSter

(NCT04277403) *

AUSTRIA
[33]		 SRS

vs.

HA-WBRT + SIB

N = 150


Phase III
 4–15 KPS ≥ 70; PS ≤ 2


Exclusion:

SCLC
Brainstem metastasis
Life expectancy < 3 months
Any prior brain radiotherapy		 25 cc SRS:
80% isodose

  • 18–22 Gy;


SRT:
80% isodose

  • 30 Gy-5 #


HA-WBRT
30 Gy-12 #
SIB
51 Gy-12 #		 Intracranial PFS up to 18 months February 2023
CAR-Study B

(NCT02953717)

Netherlands
[34]		 SRS

vs.

WBRT

N = 81		 11–20 KPS ≥ 70
Life expectancy > 3 months


BM diagnosed on a triple dose gadolinium-enhanced MRI

Exclusion:

SCLC
Lesion ≤ 3 mm from the optic apparatus


Prior brain radiation

Prior surgical BM resection		 ≤30 cc Chemotherapy at the discretion of the physician SRS:

  • 18–25 Gy;





HA-WBRT

20 Gy-5 #
30 Gy-10 #		 Monitored and registered Neurocognitive Performance:

HVLT-R		 HVLT-R:

5-point decrease from baseline based on 3 months		 August 2023
MDACC (NCT01592968) *

USA
[35]		 SRS

vs.

WBRT

N = 88


Phase III

Monocentric		 4–≤15

or up to 20 at the time of treatment (once the head frame is in place)





 Maximum diameter of largest lesion < 3.5 cm.

Exclusion:

Prior BM surgery

Previous SRS (n = 1–3) delivered within 6 weeks

SCLC
Melanoma		 Concurrent allowed at the discretion of the oncologist

Local control at 4 months

Neurocognitive performance at 4 months:

  • HVLT-R

 HVLT-R

5-point decrease from baseline based on 4 months		 September 2023
Sunnybrook

(NCT03775330) *

CANADA
[36]		 SRS
vs.

SRS + (±HA-) WBRT


N = 126



Parallel Prospective Observational
Monocentric		 5–30
 KPS ≥ 70

HVLT-R ≥ 6

Exclusion:

SCLC

Previous SRS (n ≥ 5) delivered within 6 months		 No concomitance allowed.

Immunotherapy 1 week before/after

Targeted therapies 1 day before/after

Chemotherapy 1 week before/after		 SRS:

  • 15–20 Gy



SRT:

  • 24–27 Gy-3 #

  • 25–32.5 Gy-5 #



(±HA-) WBRT:
30 Gy-10 #
20 Gy-5 #

+/−20% SRS reduction dose if SRS+ WBRT group		 Neurocognitive performance:

  • HVLT-R

 December 2023
CCTG CE.7

(NCT03550391) *

CANADA
[37]		 SRS

vs.

HA-WBRT, Memantine


Phase III

Multicentric		 5–15 PS ≤ 2

Lesion <2.5 cm

Exclusion:

SCLC

Prior BM surgical resection

Any prior brain radiotherapy

BM located ≤ 5 mm optic chiasm/nerve.

Use of NMDA agonists		 SRS:

  • 18–20 Gy

  • 22 Gy



(HA-) WBRT:
30 Gy-10 # +
Memantine 20 mg		 Overall Survival


Neurocognitive progression-free survival

 June 2024
Dana-Farber

(NCT 03075072)

USA
[38]		 SRS

vs.

(HA-) WBRT

N = 196		 5–20 KPS ≥ 70

Exclusion:

SCLC

Lesion > 5 cm
Age > 80 yo

Any prior brain radiotherapy		 SRS-SRT:

  • 1–5 #


WBRT:
30 Gy-10 #

HA when possible		 Quality of Life Survey at 6 months:
MDASI-BT		 July 2024
ENCEPHALON-Trial

(NCT03297788)

GERMANY
[39]		 SRS

vs.

WBRT,

N = 56

Phase II
Monocentric		 1–10 ED SCLC

Exclusion:

KPS < 60


Any prior brain radiotherapy 		Concurrent allowed,
Last administration of Immunotherapy/targeted therapy/chemotherapy ≥ 1 week		 SRS:
70% isodose

  • 20 Gy; < 2 cm

  • 18 Gy; 2–3 cm


SRT:
70% isodose

  • 30 Gy-6 #; <3 cm


WBRT:

  • 30 Gy-10 #

 Neurocognitive Performance:
HVLT-R		 HVLT-R
5-point decrease from baseline based on 3 months		 October 2024


CYBERChallenge

(NCT05378633) *

GERMANY [40]
 SRS

vs.

WBRT

N = 190

Phase II		 4–15
NSCL

Exclusion:

SCLC

>15 BM

Any prior brain radiotherapy		 SRS



WBRT 		Overall Survival

Quality of life:

EORTC QLQ-C15-PAL

EORTC QLQ-BN-20		 February 2025
National Cancer Center

(NCT04452084)

SINGAPORE
[41]		 HA-WBRT

vs.

HA-WBRT + SIB

N = 100		 4–25



Phase II
Monocentric		 PS ≤ 2
Life expectancy > 6 months

All histology

Lesion or cavity < 5 cm


Exclusion:

Age > 80

Prior WBRT (prior SRS allowed)

Concomitant systemic treatment		 Total PTV < 60 cc No concomitance allowed.

Immunotherapy or Chemotherapy 7 days before/after

Targeted therapies 3 days before/after		 HA-WBRT

30 Gy-10 #

SIB
40 Gy-10 # (surgical cavity)
45 Gy-10 #		 Not mandatory but recommended if
symptoms, edema, large target posterior fossa



Memantine recommended.		 Target lesion control:

RANO-Criteria

RECIST 1.1-Criteria		 Target lesion control at 6 months June 2025
Dana-Farber

(NCT 03391362)

USA
[42]		 SRS

Single
Arm

N = 100

Phase II		 1–10 SCLC
Exclusion:


Lesion > 5 cm if not resected.


Any prior brain radiotherapy		 SRS:

  • 20-1 #


<2 cm

  • 18-1 #


2–3 cm

SRT:

  • 30-5 #


>3 cm


 Death due to progressive neurologic disease June 2025
WHOBI-STER

(NCT04891471)

ITALY
[43]		 SRS

vs.
WBRT

N = 100




Multicentric		 ≥5-unlimited 1
 KPS ≥ 70

Life expectancy > 3 months


Appropriate extracranial disease staging

Controlled/ controllable extracranial disease.

Exclusion:

BM <5 mm from Hippocamp		 Not including a maximum of BM, unless


V12 Gy (1:10)

V14 Gy (1:7)		 Induction/Concomitant
PD1-, PDL1-, CTL4-, BRAF-
MEK-inhibitors		 SRS:

  • 15–24 Gy


SRT:

  • 27 Gy-3 #


WBRT:

  • 30 Gy-10 #
Dexamethasone 4 mg b.i.d 2 weeks		 Neurocognitive performance,

  • Moca Score

  • HVLT-R


Quality of life

  • EORTC QLQ-C15-PAL

  • BN-20


Autonomy in daily-life activities

  • Barthel Index

 30% between subjects of the two arms starting 6 months
September 2025
NRG Oncology

(NCT04804644) *

USA
[44]		 SRS
vs.
HA-WBRT, memantine

N = 200

Phase III

Multicentric		 ≤10
KPS ≥70

De novo or recurrent
SCLC

Lesion
≤3 cm
>5 mm from
Hippocampi

Exclusion:

Any prior brain radiotherapy 		30 cc Initiation before RT allowed if symptomatic.

Concurrent immunotherapy allowed.


Concurrent chemotherapy not allowed.


 Neurocognitive Performance:

HVLT-R
COWA
TMT		 Time to Neurocognitive Failure on at least on tests at 1 year

HVLT-R
COWA
TMT		 July 2030
HIPPORAD

(DRKS00004598)

GERMANY
[45]		 HA-WBRT + SIB

vs.

WBRT + SIB

N = 132
 4–≤10


Phase II

Multicenter
Double blinded


Exclusion:

SCLC

Age > 80 yo
BM < 7 mm from Hippocampi

previous SRS-SRT (n > 1, >3 cm or n > 3, >1 cm) delivered within 3 months

Previous Surgical resection within 4 weeks

Brainstem metastases:

N > 1, ≥5 mm,
>2 cm		 Administration of chemotherapy/immunotherapy/targeted therapy > 1 week before randomization
HA-WBRT

30 Gy-12 #

SIB
42 Gy-12 # (surgical cavity)
51 Gy-12 #		 Allowed
Neurocognitive Performance:

VLMT
VLMT
difference
(word count, 0–75 words)
at 3 months after radiation therapy and at
baseline.

SRS: stereotactic radiosurgery; SRT: stereotactic radiation therapy; WBRT: whole-brain radiation therapy; Gy: Gray; HA-WBRT: hippocampus-avoidance whole-brain radiation therapy, SIB: simultaneous integrated boost; NSCL: non-small cell lung cancer treatment; SCLC: small cell lung cancer; #: fractions; CITV: cumulative intracranial tumor volume; HVLT-R: Hopkins Verbal Learning Test – Revised; EORTC QLQ-C15-PAL: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care; EORTC QLQ-BN-20: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 20 Brain neoplasm; MRI: magnetic resonance imaging; yo: years-old; VLMT: Verbaler Lern- und Merkfähigkeitst est (German version of the Auditory Verbal Learning Test); PTV: Planning Target Volume; COWA: Controlled Oral Word Association; TMT: Trail Making Test (TMT) Parts A and B, ED: extensive disease; MDASI-BT/ MD Anderson Symptom Inventory-Brain Tumor; PFS: Progression Free Survival. 1: The WHOBI-STER study does not include a maximum number of brain metastases; V12 (1:10): the needed requirement is that the V12 of brain less PTVs should not exceed 10 times the number of metastases (1:10); V14 (1:7). *: protocol not published.