Impact Of Concomitant

Systemic Treatments
On Toxicity And Intracerebral Response
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After Stereotactic Radiotherapy
For Brain Metastases
May 24, 2021
Section Of Neurology
Cara Camille Matute, MD
Among patients with brain metastasis,
how effective is stereotactic radiotherapy
combined with systemic therapies to
control brain metastasis than stereotactic
radiotherapy alone?
CLINICAL
QUESTION
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STUDY OBJECTIVE

The aim of this study was to determine

the safety and efficacy of fractionated
stereotactic radiotherapy (SRT) in
combination with systemic therapies
(ST) for brain metastases (BM)

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 METHODS
Population
Treatment Planning
Evaluation of tumor response and toxicity

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METHODS:
POPULATION

 Patients treated with SRT for BM between 12/2014 and 06/2018 at University
Hospital Morvan, France
– All primary tumors histologies were considered
Diagnosis of brain metastasis: MRI FLAIR and T1 weighted sequences
 Extracranial disease status: thoraco-abdomino-pelvic CT with contrast or 18F-
fluorodeoxyglucose (FDG) PET/CT
 Treatment groups
– GROUP 1: SRT + systemic treatment (CONCURRENT)
(timing between the drug administration and SRT did not exceed 1 month)
– GROUP 2: SRT alone (or not concurrent)

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METHODS:
POPULATION

 All systemic treatments allowed: chemotherapy, immunotherapy, targeted therapy

and hormonotherapy
 Systemic treatments and SRT were suggested at multidisciplinary team meetings
 Treatment selection criteria for patients offered SRT:
1. Number of BM ≤ 6
2. Larger diameter <40 mm according to MRI
3. Life expectancy >3 months according to Diagnosis-Specific Graded
Prognostic Assessment (DSGPA)
4. Non-critical anatomic position

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METHODS: TREATMENT PLANNING FOR
STEREOTACTIC RADIOSURGERY

 Total dose prescribed at planning target volume (PTV) periphery: 21 to 23.1 Gy

in 3 fractions
 Patients treated until 06/2017: prescribed dose of 3 × 7.7Gy in the periphery of
the PTV
 In the subsequent patients, dose gradient was created inside the PTV: dose 3 ×
11 Gy at the isocenter with the 70% isodose line covering 99% of the PTV

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METHODS: TUMOR RESPONSE
ASSESSMENT AND TOXICITY

 Brain MRI and neurological examination 6 weeks after SRT completion and every
3 months thereafter
 Radiological response on MRI according to Response Assessment for BM (RANO-
BM) criteria
– Local control (LC) : absence of new enhancing abnormality in the irradiated
areas
– Distant brain metastasis (DBM): presence of new BM or leptomeningeal
enhancement outside the treated region
– Radionecrosis: central hypo-intensity and peripheral enhancement on T1

 Systemic disease: contrast enhanced total body CT scan, and/or 18-FDG CT-PET
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METHODS: OUTCOMES

 Local control (LC)

 Distant brain metastasis (DBM)
 Toxicity (Radionecrosis)
 Overall survival

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 DIRECTNESS
How well the PEO in the study (the research
question),
corresponds with our own PEO (the clinical question)

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 POPULATION (P)
RESEARCH Patients with brain metastasis

QUESTION EXPOSURE (E)

POPULATION (P) Stereotactic radiotherapy
Patients with brain metastasis +systemic treatment

EXPOSURE (E) OUTCOME (O)

Stereotactic radiotherapy
+ systemic treatment Local control of brain metastasis
or SRT alone
CLINICAL
OUTCOME (O)
Toxicity and intracerebral response QUESTION

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 VALIDITY
Depends on how fair the comparisons between
patients in the treatment and control groups

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 QUESTIONS ON VALIDITY

Question 1: Were patients randomly assigned to treatment groups?

Question #2: Was allocation concealed?
Question #3: Were baseline characteristics similar at the start of the trial?
Question #4: Were patients blinded to treatment assignment?
Question #5: Were caregivers blinded to treatment assignment?
Question #6: Were outcome assessors blinded to treatment assignment?
Question #7: Were all patients analysed in the groups to which they were originally
randomized?
Question #8: Was follow-up rate adequate?

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QUESTION 1: WERE PATIENTS RANDOMLY
ASSIGNED TO TREATMENT GROUPS?
No, patients were not randomized.

Page 2, column 1
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QUESTION #2: WAS ALLOCATION CONCEALED?

No, there was no mention of concealment of allocation.

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 QUESTION #3: WERE BASELINE
CHARACTERISTICS SIMILAR AT THE START OF
THE TRIAL?
 Similar in terms of SRT
parameters, however with
differences on:
Primary tumor, RPA class,
presence of extracerebral
metastases, systemic therapy
subtype

Page 3, column 2
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QUESTION #4: WERE PATIENTS BLINDED TO
TREATMENT ASSIGNMENT?
No, there was no mention of blinding to treatment.

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QUESTION #5: WERE CAREGIVERS BLINDED
TO TREATMENT ASSIGNMENT?
No, there was no mention of caregivers being blinded to treatment
assignment.

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QUESTION #6: WERE OUTCOME ASSESSORS
BLINDED TO TREATMENT ASSIGNMENT?
No, there was no mention of outcome assessors being blinded to
treatment assignment.

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QUESTION #7: WERE ALL PATIENTS ANALYZED
IN THE GROUPS
TO WHICH THEY WERE ORIGINALLY
RANDOMIZED?
Yes, the number of patients in each groups is equal to the number of
patients analyzed at the end of the study. This may suggest that
patients were not excluded from the analysis.

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QUESTION #8: WAS FOLLOW-UP RATE
ADEQUATE?
Yes, follow-up rate was adequate. Some of the patients had bad
outcomes (i.e. death), but none of the study participants left the study
due to adverse events or dissatisfaction.

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APPRAISING RESULTS

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RESULTS
 Total 194 patients treated with SRT for 302 BM
 Group 1 (SRT+ concurrent systemic treatments): 99 patients with total 171 BM
 Group 2 (SRT alone, without concurrent treatment): 95 patients with total of
131 BM
 Median age was 60 years
 Majority were:
─ Male (56%)
─ RPA class II (64%)
─ KPS of 90–100% (70%)
─ DS-GPA score of 2.5–3 (53%)
─ primary lung cancer (71.1%)
─ Whole brain RT had been performed prior to SRT (25%) 26
RESULTS- LOCAL CONTROL

 Local control at 6-months: 93% (IC95% [91– 96])

 Local control at 1 year: 87% (IC95% [83–91])
 Local failure in 17% (52/302) of irradiated metastases (p = 0.3)
─15.7% not controlled in Group 1 (27/171)
─19.1% not locally controlled in group 2 (25/131)

 Estimated 1-year LC rates were 96% if with concomitant IT

vs 78% in BM without concomitant IT (p = 0.02)

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RESULTS- LOCAL CONTROL

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RESULTS- DISTANT BRAIN FREE METASTASES
SURVIVAL
 Brain distance failures occurred 27.3% in group 1 vs 34.7% in group 2
(p = 0.3)
 1-year freedom for distant brain metastases (FFDBM) rate was 58% (IC95%
[53.8–60.6])

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RESULTS- DISTANT BRAIN FREE METASTASES
SURVIVAL

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RESULTS- OVERALL SURVIVAL

 Overall 1-year survival rate was 80% (IC95% [77.6–82.9])

 Estimated 1-year OS rate was 89% in Group 1
vs 77% in Group 2 (p = 0.02)

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RESULTS- OVERALL SURVIVAL

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RESULTS- TOXICITY (RADIONECROSIS)

 No significant difference between the 2 groups on RT-related

adverse events (nausea, headache)
 RN was suspected in 19 patients (10%) (p = 0.9). Histological
confirmation was obtained in 11/19 patients (58%)
 1-year freedom from RN was 80% in patients having received
concurrent IT versus 90% in patients who did not (p = 0.03)

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ASSESSING APPLICABILITY
Can the results can be applied to our own patients?

- Biologic issues: Sex, Co-morbidities, Race, Age,

Pathology
- Socioeconomic issues

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 LIMITATION
 Inclusion and exclusion criteria were not elaborated
 Co-morbidities were not considered
 No randomization, concealment and blinding*
 At baseline, there were more patients treated with immunotherapy in the Group
1 than Group 2
 Group 2 (labeled as SRT alone) but consist of SRT plus systemic treatment also
 Time period to consider as concurrent was 1 month is controversial

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CONCLUSION OF THE STUDY

SRT delivered concurrently with IT seems to be

associated with improved local control, freedom for
distant brain metastases and overall survival as well as
with a higher rate of radionecrosis.

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Click icon to add picture THANK
YOU !
 RECOMMENDATION

• Methods: Study design retrospective study

• Clear delineation of the groups in focus

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