Brain Metastasis

1. BRAIN METASTASIS IN
SOLID TUMOURS
Dr. Chinmayee Agrawal
Moderator: Dr. Vinayak V Maka
Dr. Ram Alva
16.04.2021
References Used:
1. DeVita, Hellman, and Rosenbergs Cancer Principles
and Practice of Oncology – 11th Edition
2. Perez & Brady's Principles and Practice of Radiation
Oncology, 6th Edition
3. Ther Adv Med Oncol 2017, Vol9(12) 781-796

2. PATHOGENESIS
Formation of metastatic tumour lines
Metastatic tumour cells detach from primary site
Penetrate adjacent parenchyma to reach blood vessels
Cells invade and enter blood circulation
Disseminate within vascular system
Cells adhere to secondary sites; colonize and proliferate

4. COLONIZATION OF TUMOUR CELLS IN BRAIN
Overexpression of adhesion molecules
Tumour cells adhere to endothelial lining of
parenchyma
Endothelial adhesive interactions enhance the
possibility of brain metastasis

6.  Direct neurotropic interactions with brain homing
mechanism result in brain metastasis
 Vascular co-option  Ability of metastatic cells to
grow along pre-existing vessels
 Adherence to Vascular basement membrane
Extravasation of tumour cells into parenchyma

7. EPIDEMIOLOGY
 Incidence: 30%
 Site specific Distribution:
 Lung- 50%
 Breast-15-20%
 Other known Primary- 10-15%
 Unknown Primary- 10-15%
 Melanoma- 10%
 Colon- 5%

8.  Median Survival : <1year
 Mean age : 60years
 Autopsy incidence: 10-30%
 Clinical Incidence: 15-30%
 Metastatic/Primary ratio: 10:1

9. CLINICAL PRESENTATION
 Headache
 Motor weakness
 Sensory disturbances
 Nausea/Vomiting
 Cranial nerve abnormalities
 Change in mental status
 Seizures
 Ataxia
 Speech difficulties
 Coordination abnormalities

10. IMAGING AND DIAGNOSIS
 Investigation of choice: MRI
 Typical characteristics:
Solid or ring enhancing
Pseudospherical
Multiple in number
Grey-white junction
 Most common Location
Cerebral hemisphere(80%) > Cerebellum(15%) >
Brain stem(<5%)

11. NEWER IMAGING TECHNIQUES
 DW-MRI
 Ring enhancing cerebral lesions
 Diffusion is restricted in abscess as compared to brain
metastasis
 Perfusion MRI
 Brain metastasis vs Glioblastoma
 Lower cerebral blood volumes in Brain metastasis
 MR-Spectroscopy
 Lower choline to creatinine ratio: Favours Brain
Metastasis

12. IS THERE A ROLE OF PET-SCAN ?

13.  FDG-PET scan: No role
 Radiolabelled Amino acids
 Particular interest
 Increased uptake in neoplastic tissue
 Examples:
 Methionine
 Phenylalanine
 Tyrosine
 Ga68 Labelled PET scan
 Meningiomas and NET
 Owing to overexpression of somatostatin receptor

14. ROLE OF BIOPSY
 Histopathological analysis : Gold standard
 Indications:
 Accessible lesion with unknown primary
 Initial remote diagnosis of cancer
 Presumptive metastasis
 Active or recently diagnosed primary cancer

15. ROLE OF IHC
Cerebral adenocarcinoma of unknown primary
 TTF Positivity: NSCLC or Thyroid cancer
 CK7 Negative CK20 Positive: CRC
 Chromogranin, Synaptophysin: Neuroendocrine
differentiation
 Vimentin, Desmin, S100 : Mesenchymal tumor

16.  Serum and CSF Sampling
Not Much Role
 Liquid Biopsy

17. PROGNOSTIC SCORING
 RPA Score
 Age
 KPS
 Absence or presence of extracranial metastasis
 Primary tumour status
 GPA
 Age
 KPS
 Presence of extra-cranial metastasis
 Number of brain metastasis
 DS- GPA

18. MANAGEMENT OF BRAIN METASTASIS
Symptomatic Tumour Targeting
Therapies

19. CORTICOSTEROIDS
 Dexamethasone:
 Dose: 16mg/day (Max Dose)
 Common side effects: Insomnia, Increased
appetite, gastritis, fluid retention, mood swings,
acne, elevation of blood sugars
 Long term side effects: weight gain, facial plethora,
pedal edema, immunosuppression, proximal
muscle myopathy, cataract formation, aseptic
necrosis of femoral head and osteoporosis

20. ANTICONVULSANTS
 Incidence: 25%
 Prophylactic use of anticonvulsants not
recommended
 Preferable: Levetiracetam
 Phenytoin can affect clearance of chemotherapy
 Precipitation of Stevens Johnson syndrome with RT

21. VENOUS THROMBOEMBOLISM
 Brain tumours and thromboembolism: Higher risk of
intracranial haemorrhage
 Prophylaxis: LMWH

22. WBRT
 Gold standard
 Standard protocols: 30Gy/10#
20Gy/5#
 Newer techniques: Hippocampal sparing
 Use of Memantine with WBRT
 NMDA receptor antagonist
 Neuroprotective properties
 Longer time to cognitive decline

23. TECHNIQUE
 Supine position with head rest
 Immobilisation: Custom skull cast
 2 Lateral opposing fields are used
 Conventional planning: German helmet technique
 Shielding maybe used for lens or extra-cranial contents
 6MV Linac

25. REPEAT WBRT
 Strong consideration
 Dose: 20Gy in 1.8/2Gy fraction
 Neurological improvement: 70%
 Median survival time: 5.2 months
 With stable extra-cranial disease: 19.8 months vs
2.5 months

26. ROLE OF SURGERY
 Immediate relief of tumour mass effect
 Indication:
 Single Brain metastasis
 Concept of Single Lesion vs Solitary Lesion
 3 Phase III trials :
Life threating complications
Good performance status

27. STEREOTACTIC RADIOSURGERY
 Dose: 15 to 24Gy
 Local control rates: 70 to 95%
 Effective in radioresistant histologies
 Melanoma
 Renal Cell Carcinoma
 Gamma Knife vs Cyber Knife

28. ADVANTAGES OF SRS
 Treatment of deep lesions or eloquent areas
 Minimally invasive
 No general anaesthesia use
 Outpatient procedure
 Treatment of multiple lesions at same session
 Short recovery time

29.  Potentially avoid whole brain radiation therapy
 Rapid initiation of systemic therapies
 Fewer immediate complications

30. RADIOSURGERY BOOST TRIALS
 SRS plus WBRT vs WBRT alone
 Survival rates similar
 Superior Local control
 Fewer Brain metastasis

31. POST OP OR POST SRS WBRT
 No improvement in duration of functional
independence
 No improvement in overall survival
 Decreased 2 year Local and distant brain relapse
rate
Conclusion:
 Meaningful benefit
 Prevention of neurological deaths and brain failure
 Adjuvant WBRT as a standard of care

32. PROPHYLACTIC CRANIAL IRRADIATION
 Small cell lung cancer have high propensity to
develop brain metastasis
 PCI: Prevent dissemination to brain
 Recommendation: Complete response to Induction
therapy
 Standard Dose: 25Gy/10#
 Increased OS at 1 year from 13.3% to 27.1%

33. SITE SPECIFIC SYSTEMIC
THERAPY

34. LUNG CANCER
 13-44% of patients develop brain metastasis
 MC- Small cell ca > Non small cell ca
 Median OS with WBRT is 4-5 months
 Chemotherapy: Temozolamide
 Several TKIs have been studied for Brain
metastasis

35.  2 Published phase II trials
 1st Generation TKIs as first line therapy
 Gefitinib or Erlotinib
 PFS – 14.5 months and 7.1 months
 OS – 21.9 months and 18.8 months

36.  2nd Generation TKI- Afatinib
 Time to tumour progression- 3.6 months
 Cerebral response rates- 35%
 Stable CNS disease- 39%

37. ALK REARRANGED NSCLC
 3-7% have oncogenic fusion of ALK and EML4
gene
 Relatively higher CNS metastasis 25% vs 16-20%
 PROFILE 1007 study
 Crizotinib vs Chemotherapy
 PFS and Response rates were significantly higher

38.  2nd Generation ALK inhibitors
 Ceritinib and Alectinib
 Better CNS penetration
 ASCEND 1 trial
 Ceretinib therapy
 ALK inhibitor naïve vs ALK inhibitor pretreated
 Intracranial response rates 79% vs 65%

39.  Role of Osimertinib:
 FLAURA Trial
 Untreated EGFR mutated Advanced NSCLC
 Known or suspected CNS metastasis were eligible
 Median OS was 38.6months vs 31.8 months

40. BREAST CANCER
 10-20% develop brain metastasis
 25-30% have Her2neu overexpression
 Her2Neu enriched – 2 to 4 times more CNS spread
 30-50% of Her2Neu enriched : Brain metastasis
 Limited role of chemotherapy

41. LAPATINIB
 TKI
 Interferes with Her2 and EGFR signalling
 Cross the BBB
 Open Label, Multicentric Phase II trial
 BM with Her2 positive
 Treated with Trastuzumab plus WBRT/SRS/Both
 Treated with Lapatinib

42.  Partial CNS Response : 6%
 Stable disease: 37%
 Progressive disease: 46%
 OS: 6.4 months
 PFS: 2.4 months
EXTENTION PHASE:
 Treated with Capecitabine + Lapatinib
 Partial CNS response: 20%
 Median PFS 3.7 months

43.  LANDSCAPE TRAIL
 Lapatinib + Capecitabine
 RT naïve
 Partial CNS response rate: 66%
 Median OS : 17 months
 OS at 6 months : 90.9%
 Median time to disease and CNS progression: 5.5
months
 WBRT was deferred for median of 8.3 months

44. TDM1
 Antibody drug conjugate of trastuzumab and the
cytotoxic microtubule inhibitor
 EMILIA TRIAL
 TDM1 vs Lapatinib + Capecitabine
 PFS 9.6 months vs 6.4 months
 Median OS 30.9 months vs 25.1 months
 Objective response rates: 43.6% vs 30.8%
 CNS metastasis at enrolment
 OS 26.8 months vs 12.9 months
 PFS similar

45. RECENT ADVANCEMENTS
 Tucatinib + Trastuzumab + Capecitabine
 PFS at 1 year: 24.9% vs 0%
 Median PFS 7.6 months vs 5.4 months

46. MELANOMA
 50% patients with advanced malignant melanoma
develop BM
 Multiple Brain metastasis:
Poor prognosis
Survival 6 months
 SRS preferred treatment of choice over WBRT

47.  BRAF mutant melanoma: Higher CNS involvement
(24% vs 12%)
 Current recommendations:
 Vemurafenib
 Dabrafenib
 Longer OS and PFS

48.  Vemurafenib In Brain Metastasis
 Intracranial response rates: 50%
 OS at 12 months: 30-59%
 Median PFS: 4.1 months

49. RENAL CELL CARCINOMA
 Brain metastasis : 2-10%
 Usually found within 1st year of primary tumour
diagnosis
 Median survival <1 year

50.  Sunitinib
 Significantly prolong OS and PFS
 Stable CNS disease: 31%
 Median time to progression: 2.3 months
 Median Overall survival : 6.3 months

51. RECENT ADVANCES
 TKI + PD1/PDLI
 Pembrolizumab plus Axitinib vs Sunitinib
 Median PFS: 15.1 months vs 11.1 months
 Objective Response rates: 59.3% vs 35.7%

52. IMMUNOTHERAPY
 Ipilimumab
 Nivolumab
 Pembrolizumab
 Phase II study
 Efficacy of Ipilimumab in Melanoma with brain
metastasis
 Phase II study
 Pembrolizumab
 Lung carcinoma with brain metastasis : RR 33%
 Melanoma with Brain Metastasis : RR 22%

53.  Ipilimumab + Nivolumab
 Activity in Asymptomatic brain metastasis in Melanoma

54. LEPTOMENINGEAL CARCINOMATOSIS
 Poor Prognosis
 Lung cancer (22-36%)
 Breast carcinoma (27-50%)
 Symptoms:
 Spinal symptoms
 Cerebral symptoms
 Cranial nerve symptoms

55.  Investigation of choice: MRI
 Management:
 WBRT
 Focal Spinal Irradiation
 IT chemotherapy

56. TAKE HOME MESSAGE
 Gold Standard Investigation: MRI
 WBRT: Standard of care
 Single lesion: Surgery preferred
 Radioresistant tumours: SRS preferred
 No role of Higher doses of steroids
 No role of Prophylactic anti-convulsants
 Targeted therapies: Promising results
 Leptomeningeal carcinomatosis: Poor Prognosis