Brain mets Flashcards
Common primary sites associated with brain mets
Lung
Melanoma
Breast
Renal cell carcinoma
Colorectal cancer (and other GI tract adenocarcinoma)
These 5 account for 80% of brain mets
Pathophysiology of brain mets
Metastatic cancer passes through the bloodstream and enters the central nervous system through a breakdown of the blood-brain barrier. Clonal cells then proliferate, causing local invasion, displacement, inflammation, and edema. Distribution throughout the central nervous system is more common in areas of high blood flow
Pathophysiology of leptomeningeal disease
Metastatic malignant cells may invade the meninges by:
(1) direct invasion via surrounding structures, such as the dura mater, bone, or nerves;
(2) hematogenous spread often by way of venous vasculature;
(3) entry of the fenestrated pores of the choroid plexus typically permitting solute transport
What are the management options of intact brain metastases?
Surgery
SRS
WBRT
HA-WBRT
Targeted systemic therapy or immunotherapy if relevant tumour type
Best supportive care
In what situations may supportive care alone be the most appropriate for a patient with brain mets?
The QUARTZ trial showed that omitting WBRT in poor prognosis patients did not significantly affect quality of life or overall survival when these patients also had access to supportive care.
The Quality of Life after Treatment for Brain Metastases (QUARTZ) noninferiority trial studied patients with poor prognosis and NSCLC with brain metastases not suitable for resection or SRS. Patients were randomized to WBRT with supportive care versus supportive care alone (oral dexamethasone).
There was no evidence of a difference in overall survival, QoL, or dexamethasone usage between the 2 groups.
What are strategies to reduce RT related toxicity in brain mets?
HA-WBRT
Memantine
SRS over WBRT
Where do brain mets most commonly occur?
grey-white matter junction in cerebral hemispheres due to decrease in diameter of blood vessels, or in arterial watershed areas
What % of brain mets are found in different locations in the brain?
80% supratentorial
15% cerebellum
5% brainstem
Which types of histologies are most assoc with haemorrhagic brain mets?
Melanoma
Choriocarcinoma
Testicular
Thyroid
Renal cell carcinoma
CT appearances of brain mets
Variable
On pre-contrast imaging:
isodense, hypodense or hyperdense (classically melanoma) compared to normal brain parenchyma with variable amounts of surrounding vasogenic oedema.
Post contrast: enhancement is also variable and can be intense, punctate, nodular or ring-enhancing
Brain met appearance on T1 MRI
typically iso- to hypointense
Brain met appearance on T2 MRI
typically hyperintense
Brain met appearance on MRI T1 + contrast
enhancement pattern can be uniform, punctate, or ring-enhancing, but it is usually intense
delayed sequences may show additional lesions, therefore contrast-enhanced MR is the current standard for small metastases detection
Brain met appearance on MRI FLAIR
typically hyperintense
hyperintense peri-tumoural oedema of variable amounts
What prognostic systems exist for brain mets? Why are they useful?
Original Graded prognostic assessment (GPA)
Diagnosis specific GPA
RTOG RPA classes
Useful because they allow estimation of Median survival which can help inform which treatment is most appropriate
What features are part of the original GPA
CNS metastases
Age
KPS
Extracranial mets
What are the 3 RPA classes?
Class I: KPS>70
Age <65
primary controlled and no extra cranial mets
Class II:
KPS >70
Either age >65 or primary uncontrolled
Class III:
KPS <70
What features make up the diagnosis specific GPA?
For each histological type: NSCLC, Breast, renal, Melanoma, GI
Domains for Age, KPS, number of brain mets, extra cranial mets plus specific feature for diff types
Lung- EGFR or ALK
Breast- subtype
Renal- Hb
Melanoma- BRAF
What is the ASTRO recommendation for ECOG 0-2 and up to 4 intact brain mets
SRS
What is the ASTRO recommendation for ECOG 0-2 and 5-10 intact brain mets?
SRS conditionally recommended
ASTRO recommends which dose for intact brain mets <2cm in diameter
Single fraction SRS using 20-24Gy
Multifraction 27GY/3# or 30Gy/5#
What should the estimated life expectancy be for patients undergoing SRS
Atleast 6mo
Dose for brain mets 2-3cm diameter (ASTRO)
Single fraction 18Gy
Multifraction 27GY/3# or 30Gy/5#
Dose for brain mets 3-4cm in size (ASTRO)
Multifraction 27GY/3# or 30GY/5#
If single fraction choses, 15Gy/1#
Above which size is SRS discouraged
> 6cm
Management of brain met >4cm (ASTRO)
Surgery is preferred option
If surgery cannot be performed then multifraction SRS
What is a requirement (logistical) of offering a patient SRS rather than WBRT
Must be able to offer them MRI follow up regular as there is an increased risk of local recurrence for SRS than with WBRT
What is the evidence for adding WBRT to SRS or surgery for brain mets?
Three RCTs compared SRS alone to SRS plus WBRT, (Brown, 2016. Chang, 2009. Aoyama, 2006) and 2 RCTs compared local therapy alone (SRS or surgery) to local therapy plus WBRT (Kocher, 2011. Hong, 2019.)
1 to 3 brain metastases (1 trial allowed up to 4) and a performance status of either Karnofsky performance status ≥70 or Eastern Cooperative Oncology Group 0 to 2.
Outcome:
WBRT to SRS or surgery improves intracranial control, neither improved survival. Two RCTs found worse performance on the recall portion of the Hopkins verbal learning test revised at 4 months in their respective WBRT arms, and N0574, the study with the most robust assessment of neurocognition and QoL, found worse neurocognitive deterioration and QoL after SRS plus WBRT compared with SRS alone.
Why is SRS recommended over WBRT for patients with 1-4 Brain mets and good PFS?
WBRT offers no survival benefit over SRS and worse neurocognitive outcomes, so SRS for patients with up to 4 intact brain metastases and reasonable performance status is recommended.
What factors need to be taken into account when considering SRS for patients for brain mets?
(ie. other than the number of brain mets)
Tumour related:
- tumour size/volume
- location of tumour
- brain metastasis velocity (number of distant brain relapses divided by the years or fraction of a year)
- Histology
- Molecular profile
Patient related:
- Age
- PFS
- Baseline neurocognitive function
Treatment related:
- access to MRI surveillance post treatment and further SRS if needed
- systemic treatment options
- access high-resolution imaging for planning, appropriate immobilization, accurate dosimetry, precise image guidance and localization, and robust quality assurance.
What are the follow up requirements after SRS (ASTRO)
Given the higher risk of intracranial relapse because of the emergence of distant brain metastases, for SRS to be used in the absence of WBRT requires close radiographic surveillance (eg, brain MRI every 2-3 months for 1-2 years, then every 4-6 months indefinitely).
When is neurosurgery for brain mets recommended
For tumours exerting mass effect and/or are >4 cm in size, multidisciplinary discussion with neurosurgery to consider surgical resection is suggested.
What evidence supports the use of SRS in 5-10 brain mets?
Optimal treatment for patients with 5 or more metastases remains controversial because of the lack of published prospectively randomized data in this patient population.
A prospective observational study in patients with 1 to 10 brain metastases and cumulative brain metastasis volume of ≤15 cm3 treated with SRS (JLGK0901) demonstrated noninferiority in the post-SRS survival time in patients with 5 to 10 brain metastases compared with those with 2 to 4 metastases. (Yamamoto, 2014)
There was no difference in the incidence of neurologic death, deterioration of neurologic function, local recurrence, new lesion appearance, salvage treatment (repeat SRS or WBRT), mini-mental state examination scores, or adverse events observed between these 2 cohorts.
Based on this prospective comparative registry trial, the task force conditionally recommends SRS to patients with 5 to 10 intact brain metastases who have a performance status of Eastern Cooperative Oncology Group 2 or better. (Hughs 2019)
Additional evidence to support this recommendation came from a large retrospective study analyzing over 2000 patients from 8 institutions that demonstrated similar overall survival in patients with 2 to 4 versus 5 to 15 brain metastases.
Is SRS recommended for patients with 10-15 brain mets ? (ASTRO)
No
A large retrospective study analyzing over 2000 patients from 8 institutions that demonstrated similar overall survival in patients with 2 to 4 versus 5 to 15 brain metastases. (Hughs, 2019)
Of note, despite the inclusion of patients with 11 to 15 brain metastases in this retrospective study, the task force did not extend the conditional recommendation of SRS to patients with 11 to 15 brain metastases because only 10 patients in this study had 11 to 15 brain metastases (vs 190 patients with 5-10 brain metastases and 882 patients with 2-4).
Furthermore, another large Japanese retrospective study comparing patients with 5 to 15 versus 2 to 4 brain metastases showed a shorter post-SRS survival time in the subgroup with 5 to 15 brain metastases with increased need for salvage WBRT, raising the possibility that the worse survival in these patients could be driven by the subgroup of patients with 11 to 15 brain metastases.
What study established single fraction doses for SRS?
RTOG 90-05
maximum tolerated dose found to be:
24Gy for ≤2 ,
18Gy for 2.1 to 3 cm,
15 Gy for 3.1 to 4 cm maximum diameter
What is the evidence for treating metastasis ≥2 cm with multi fraction SRS?
Metastases ≥2 cm treated with single-fraction SRS doses of 15 to 18 Gy have been associated with poor local control.
For metastases of this size, one study compared 15 to 18 Gy single-fraction SRS (median size 8.8 cm3) with 27 Gy in 3 fractions SRS (median size 12.5 cm3) and demonstrated that multifraction SRS was associated with significantly higher local tumor control and lower rates of radionecrosis.
(Minniti, 2016)
The benefit of multifraction SRS was most pronounced for tumor sizes >3 cm, which demonstrated the highest rates of local failure and radionecrosis when treated with single-fraction SRS.
What features should be considered when selecting asymptomatic patients for primary immunotherapy or CNS-active targeted therapy and delay of local therapy?
- brain metastasis size, location, and number;
- Whether brain mets are in or close to eloquent areas which will cause morbidity if they progress
- expected response rates and durability with systemic therapy;
- access to close neuro-oncologic surveillance;
- relative pace and burden of extracranial systemic disease;
- facilities capable of delivering appropriate local salvage therapies (RT and/or surgery).
Is radiotherapy recommended after resection of brain mets?
Yes - SRS or WBRT
Because modern prospective series report local reccurence in the resection cavity with surgery alone of at least 50%
What is the rationale for WBRT after surgery?
multiple RCTs demonstrated a reduction in risk of local failure, distant intracranial failure, and neurologic death compared with surgery alone.
Why has SRS supplanted WBRT as the preferred modality after resection of brain mets?
Desire to to reduce the risk of neurocognitive toxicities associated with WBRT.
Compared with WBRT, focal therapies (such as postoperative SRS or salvage SRS for recurrences in the surgical bed) have been associated with longer neurocognitive deterioration-free survival and lower overall risk of neurocognitive dysfunction.
What evidence supports the use of post op SRS
Two prospective trials evaluated the role of single-fraction postoperative SRS to the surgical cavity in patients with limited metastatic disease in the brain.
Mahajan et al, Lancet Oncol. 2017.
Postop SRS (within 30 days of surgery) versus observation showed a significant improvement in surgical bed control in the SRS group (72% vs 43% at 12 months).
Brown, NCCTG N107C/CEC.3, Lancet Oncol 2017
- randomized patients with resected brain metastases to postoperative SRS versus WBRT.
- inferior surgical bed control for SRS versus WBRT, - - - similar overall survival and significantly less neurocognitive decline with SRS.
Thus, with equivalent survival and reduced neurocognitive toxicity, postoperative SRS has become the preferred treatment modality for appropriately selected patients with surgically resected brain metastases and limited metastatic disease in the brain.
What is a unique type of local recurrence which has been seen with the swap to SRS from WBRT for post op treatment of brain mets?
Nodular meningeal disease
Thought to be due to surgical perturbation of the tumour can lead to the risk of tumour spillage via the cerebrospinal fluid and the development of nodular tumour recurrence outside the resection cavity.
What evidence is there for pre-operative SRS?
Preoperative SRS is under investigation as a potential strategy to mitigate the risk of surgical perturbation failure and resultant nodular meningeal disease.
A retrospective comparative analysis of preoperative versus postoperative SRS reported a reduction in nodular meningeal disease from 16.6% (postoperative) to 3.2% (preoperative), in addition to lower rates of radionecrosis.
Who is recommended for WBRT?
Patients with ineligible for surgery or SRS with favourable prognosis
What dose is recommended for WBRT?
30GY/10#
Based on a Cochrane analysis and analysis of NCCTG N107C
Was there benefit to dose escalation to 37.5Gy/15# for WBRT?
No- increased toxicity without conferred benefit
What evidence is there for Donepezil for neuroprotection in WBRT?
Donepezil administered daily for >6 months after partial or whole brain irradiation demonstrated improved recognition memory, motor speed, and dexterity, but did not improve the study’s overall composite score, and results were not reported separated by primary versus metastatic tumors. (Rapp et al, J Clin Oncol. 2015)
What were the results of the RTOG 0614 study?
Memantine improved neurocognitive outcomes in patients having WBRT
RTOG 0614 randomized patients with brain metastases to receive placebo or memantine (starting with WBRT 5-mg morning dose week 1, 5 mg twice a day week 2, morning dose 10 mg, and evening dose 5 mg week 3, and 10 mg twice a day weeks 4-24).
Among memantine-treated patients there was a nonsignificant trend toward less decline in delayed recall (the primary endpoint) and significantly longer time to neurocognitive decline as well as superior executive functioning, processing speed, and delayed recall.
What is the ASTRO recommendation regarding memantine?
Memantine is very well tolerated and appears to delay neurocognitive decline in specific domains, so use of memantine for patients with favourable prognosis receiving WBRT or HA-WBRT is recommended, but with a “low” level of evidence given the primary endpoint was not met.
Which studies investigated HA-WBRT?
(just names of studies, not details)
RTOG-0933
NRG-CC001
Describe the evidence for HA-WBRT
RTOG-0933- Phase II study
- reduction in radiation dose to Hippocampus used
- This study demonstrated a reduction in the mean relative decline in performance on the Hopkins verbal learning test revised delayed recall test of 7% at 4 months with HA-WBRT compared with the historical control of 30% with standard WBRT.
NRG-CC001- Phase III Study
- compared the efficacy and safety of standard WBRT with that of HA-WBRT, with both arms receiving memantine.
- The group receiving HA-WBRT had significantly lower neurocognitive failure (26% relative risk reduction) compared with standard WBRT.
Who is HA-WBRT not appropriate for?
For patients with brain metastases in close proximity to the hippocampi or with leptomeningeal disease, hippocampal avoidance may not be appropriate, as these were exclusion criteria for RTOG 0933 and NRG-CC001.
What are emerging strategies for neuroprotection of patients with brain mets
Simultaneous integrated boost or sequential SRS of metastases combined with WBRT with hippocampal avoidance for patient populations with better prognosis
What are situations where WBRT may be better than SRS?
- Tumour >4- 6cm
- When intracranial control is preferred over neurocognitive outcome
e.g multiple recurrent brain metastases and/or high brain metastasis velocity. - When there is not access to MRI surveillance, SRS or Neurosurgery for salvage
What treatment is recommended for ECOG 0-2 and limited brain mets, largest brain met >4cm or mass effect
(Astro decision tree)
N/S + post op SRS
If not surgical candidate consider multi fraction SRS or HA-WBRT + memantine
Treatment for:
ECOG 0-2
Limited brain mets
Brain met<4cm and no mass effect
SRS
<2cm Single fraction 20-24Gy/1#
> = 2cm - multi fraction SRS 27Gy/3#
Treatment for:
ECOG 3-4
Stable systemic disease
Largest brain met >4cm or mass effect
If NS candidate –> resection and consider adjuvant RT
If not NS candidate –> WBRT (consider 20GY/5# or multiFx SRS)
Treatment for:
Limited brain mets
ECOG 3-4
Progressing systemic disease or poor systemic options
Brain met symptoms controlled on steroids –> best supportive care
Not controlled with steroids –> WBRT ( consider 20GY/5#)
What is the evidence supporting the use of 20GY/5# vs 30Gy/10# for WBRT?
Short answer: For the endpoint of overall survival, randomised studies have shown that 20 Gy in 5 fractions is neither inferior or superior to higher prescription doses.
Long answer:
RCR guidelines: Only one small study of 70 patients has compared the 6-month survival rate after 30 Gy in 10 fractions with that after 20 Gy in 5 fractions, and this found no significant difference. (Tsao MN et al)
A Radiation Therapy Oncology Group (RTOG) study reported in 1980 compared three regimens: 40 Gy in 15 fractions, 30 Gy in 10 fractions and 20 Gy in 5 fractions. The MS in all three groups was between 3.2 months and 3.5 months (p>0.05). There is, therefore, no clear evidence that 20 Gy in 5 fractions is inferior to, or better than, 30 Gy in 10 fractions (Level 1b). No improvement in survival has been shown when dose is increased beyond 30 Gy in 10 fractions (Level 1b).
- Tsao MN, Rades D, Wirth A et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 2012 Jul; 2(3): 210–25.
- Borgelt B, Gelber R, Kramer S et al. The palliation of brain metastases: final results of the first two studies by the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 1980 Jan; 6(1): 1–9.
EviQ recommends 20GY/5# based on ^
The majority of the published studies have used 30 Gy in 10 fractions in their control arms.
Treatment for:
Extensive brain mets
ECOG 0-2
Largest brain met >4cm or mass effect
If NS candidate –> resection then post op SRS if can target that many lesions or HA-WBRT +memantine
If not NS candidate –> multi Fx SRS if centre can treat that many or HA-WBRT + memantine
Treatment for:
Extensive brain mets
ECOG 0-2
Largest brain met <4cm and no mass effect
5-10 brain mets
- SRS if centre can deliver (based on size, if <2cm single fx SRS, >2cm multi fx SRS)
- if not HA-WBRT + memantine
> 11 brain mets:
- HA WBRT + memantine
Rate of radionecrosis with WBRT
0-1.6%
Describe grades of cerebral radio necrosis
grade 1, imaging only;
grade 2, symptomatic;
grade 3, disabling;
grade 4, life- threatening;
grade 5, death.
Which systemic agents may be assoc with higher rates of Radionecrosis after SRS?
TKI
T-DM1
What is the QUANTEC recommendation on dose constraints for single fraction SRS?
V12Gy to 5 -10 cm3
Support by HyTEC report on brain metastases treated with SRS:
for single-fraction SRS for brain metastases, total irradiated volumes (normal brain plus target volumes) of 5 cm3, 10 cm3, or >15 cm3 receiving 12Gy (V12Gy) were associated with risks of symptomatic radionecrosis (gr2) of approximately 10%, 15%, and 20%, respectively
In which cases of lung cancer does ASCO guidelines recommend deferral of local treatment for asymptomatic brain mets?
- In NSCLC with EGFR mutant caner, Osimertinib can be offered and local therapy can be delayed until there is evidence of progression
- In NSCLC with ALK rearrangement, Alectinib, brigatinib can be offered and local therapy can be delayed until there is evidence of progression
In which cases of melanoma does ASCO recommend deferral of local treatment of asymptomatic brain mets?
- in Melanoma: Ipilimumab plus nivolumab (for all patients regardless of BRAF status) or dabrafenib plus trametinib (for patients with BRAF-V600E mutation) may be offered to patients with asymptomatic brain metastases from melanoma. If these agents are used, local therapy may be delayed until there is evidence of intracranial progression
In which cases of breast cancer does ASCO recommend deferral of local treatment of asymptomatic brain mets?
(HER2)–positive metastatic breast cancer who have asymptomatic brain metastases and are on combination of tucatinib, trastuzumab, and capecitabine.
Local therapy may be deferred until intracranial progression
What factors need to be taken into account when considering deferring local treatment for CNS-active therapies for asymptomatic brain mets?
- close monitoring for progression is crucial to ensure that local therapy can be offered when it will be most valuable.
- ## eloquent vs non eloquent location must be considered
