Brain mets Flashcards

Question

Above which size is SRS discouraged

Answer 1

Surgery is preferred option If surgery cannot be performed then multifraction SRS

Answer 2

Must be able to offer them MRI follow up regular as there is an increased risk of local recurrence for SRS than with WBRT

Answer 3

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.

Answer 4

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.

Answer 5

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.

Answer 6

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).

Answer 7

For tumours exerting mass effect and/or are >4 cm in size, multidisciplinary discussion with neurosurgery to consider surgical resection is suggested.

Answer 8

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.

Answer 9

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.

Answer 10

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

Answer 11

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.

Answer 12

- 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).

Answer 13

Yes - SRS or WBRT Because modern prospective series report local reccurence in the resection cavity with surgery alone of at least 50%

Answer 14

multiple RCTs demonstrated a reduction in risk of local failure, distant intracranial failure, and neurologic death compared with surgery alone.

Answer 15

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.

Answer 16

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.

Answer 17

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.

Answer 18

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.

Answer 19

Patients with ineligible for surgery or SRS with favourable prognosis

Answer 20

30GY/10# Based on a Cochrane analysis and analysis of NCCTG N107C

Answer 21

No- increased toxicity without conferred benefit

Answer 22

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)

Answer 23

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.

Answer 24

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.

Answer 25

RTOG-0933 NRG-CC001

Answer 26

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.

Answer 27

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.

Answer 28

Simultaneous integrated boost or sequential SRS of metastases combined with WBRT with hippocampal avoidance for patient populations with better prognosis

Answer 29

- 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

Answer 30

N/S + post op SRS If not surgical candidate consider multi fraction SRS or HA-WBRT + memantine

Answer 31

SRS <2cm Single fraction 20-24Gy/1# >= 2cm - multi fraction SRS 27Gy/3#

Answer 32

If NS candidate --> resection and consider adjuvant RT If not NS candidate --> WBRT (consider 20GY/5# or multiFx SRS)

Answer 33

Brain met symptoms controlled on steroids --> best supportive care Not controlled with steroids --> WBRT ( consider 20GY/5#)

Answer 34

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). 1. 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. 2. 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.

Answer 35

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

Answer 36

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

Answer 37

grade 1, imaging only; grade 2, symptomatic; grade 3, disabling; grade 4, life- threatening; grade 5, death.

Answer 38

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

Answer 39

- 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

Answer 40

- 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

Answer 41

(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

Answer 42

- 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 -