Current concepts in management of metastatic brain tumour

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  • 10% to 15% of patients with a clinical diagnosis of brain metastasis and a known systemic primary tumor are instead found to have a nonmetastatic lesion, such as a primary tumor or a brain abscess complete resection of a metastasis immediately eliminates the source of mass effect, brain irritation, and vasogenic cerebral edema Procurement of tissue for pathologic diagnosis in cases in which a systemic primary cancer is unknown. Fifteen percent of patients with cancer present with neurologic symptoms before their systemic disease is diagnosed Significant mass effect opportunity to achieve local cure by means of complete tumor resection To improve symptoms To reverse or to retard progress of neurological deficits To prolong meaningful survival To improve QUALITY of LIFE Histological confirmation
  • EFNS guidelines -European Federation of Neurological Societies Surgical resection should be considered in patients with single brain metastasis in an accessible location, especially when the size is large, the mass effect is considerable and an obstructive hydrocephalus is present When the combined resection of a solitary brain metastasis and a non-small cell lung carcinoma (stage I and II) is feasible, surgery for the brain lesion should come first, with a maximum delay between the two surgeries not exceeding 3 weeks Patients with disseminated but controllable systemic disease (i.e. bone metastases from breast cancer) or with a radioresistant primary tumor (melanoma, renal cell carcinoma, and colon cancer) may benefit from surgery
  • patients who are expected to survive for more than 3 to 4 months are usually candidates for surgical resection
  • Improved surgical techniques, new surgical approaches, micro-instruments, endoscope, ultrasonic aspirator Imaging techniques include MRI, DTI, IGS, USG, microscope Pre and post-op care include pre-anaest review, neuro-anaest, general anesthesia, ICU facilities
  • Functional mapping of motor and sensory cortices can be performed by using somatosensory evoked potentials and recording the phase reversal between grid electrodes placed on the cortical surface DBS can be used to identify the motor cortex, it can further subdivide functional and nonfunctional areas.
  • Need to be individualised. No standard therapy. Assess prognostic factors Estimated duration of survival and QoL Response to previous therapies For patients with good response to previous treatment, retreatment should be considered. Different modality for patients with initial poor response. Generally dismal outcome because of systemic disease. 40% of patients had recurrence –local or distant 48 pts re-operated, 75% improved neurologically, median survival 11.5 months, 26% survived 2 years, 17% for 5 years – Bindal, J Neurosurgery 1995 In selected pts, re-operation can improve quality of life and increase survival
  • Need to be individualised. No standard therapy. Assess prognostic factors Estimated duration of survival and QoL Response to previous therapies For patients with good response to previous treatment, retreatment should be considered. Different modality for patients with initial poor response. Generally dismal outcome because of systemic disease. 40% of patients had recurrence –local or distant 48 pts re-operated, 75% improved neurologically, median survival 11.5 months, 26% survived 2 years, 17% for 5 years – Bindal, J Neurosurgery 1995 In selected pts, re-operation can improve quality of life and increase survival
  • {Vogelbaum, 2006 #27}
  • {Vogelbaum, 2006 #27}
  • Recurrence in the brain, as measured overall, at the original site or at distant brain sites, were all significantly lower in the group that received adjuvant post-operative WBRT than the group undergoing surgical resection alone The recommendation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma) delayed radiotherapy Class I: well-designed randomized controlled clinical trials. • Class II: well-designed nonrandomized controlled studies such as casecontrol retrospective analyses or cohort studies. • Class III: expert opinion, nonrandomized historical controls or case series and case reports
  • Level 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases
  • Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions ([3 cm) or for those causing significant mass effect ([1 cm midline shift).
  • Current concepts in management of metastatic brain tumour

    1. 1. Current Concepts in Management of Metastatic Brain Tumour Dr. Liew Boon Seng M.D., M.S. (Neurosurgery) USM Department of Neurosurgery Hospital Kuala Lumpur
    2. 2. Incidence• 25% of patients with cancer develop brain metastases during the course of their illness*• 2/3 to 3/4 of brain metastases are diagnosed among live patients with cancer*• In Malaysia, the annual crude rate for all cancers for males was 100.2 per 100,000 population and 132.1 per 100,000 for females***American Cancer Society, 2001**National Cancer Registry, Malaysia, 2003 - 2005
    3. 3. Incidence
    4. 4. Incidence• A total of 67,792 new cancers cases were diagnosed among Malaysians in Peninsular Malaysia in the years 2003 - 2005, comprising 29,596 males (43.7%) and 38,196 females (56.3%)*.• Percentage of metastatic tumour of brain and other nervous system in 2003-2005 is 1.5% of total 753 cases (12 cases)*• 850 patients with brain metastases per year in Japan***National Cancer Registry, Malaysia, 2003 – 2005** Japan Brain Tumour Registry
    5. 5. Primary Tumour Type in Patients with Brain MetastasesNussbaum et al., Brain Metastases: Histology, Multiplicity, Surgery, and Survival,CANCER October 15, 1996 / Volume 78 / Number 8
    6. 6. Presenting Signs or Symptoms in Patients with Brain MetastasesNussbaum et al., Brain Metastases: Histology, Multiplicity, Surgery, and Survival, CANCEROctober 15, 1996 / Volume 78 / Number 8
    7. 7. Principles of therapy• Patients with brain metastases now have many aggressive treatment options available to them, resulting in a longer life expectancy, better quality of life and better local tumour control• Treatment decisions must be individualized based on a complex array of both patient- specific and tumour specific characteristics• Treatment of metastatic disease is palliative, not curative.
    8. 8. Aims of Therapy• Improve survival• Improve QOL• Improve Functionally independent survival (FIS)• Reduce neurological death
    9. 9. Treatment Modalities• Surgery• Conventional Radiotherapy / WBRT• Radiosurgery / Stereotactic Radiotherapy• Chemotherapy• Medication / Supportive Care
    10. 10. Treatment goals:Advantages of surgical resection
    11. 11. Surgical Options• Surgical Resection• Biopsy• Others e.g. shunt or ETV for hydrocephalus
    12. 12. Indications for surgery• Survival or functional benefit• Single brain metastasis that is too large to treat safely with radiosurgery• Diagnosis remains elusive
    13. 13. Selection Criteria for Surgery• Patient’s Status• Status of the tumour• Surgeon’s Status• Availability of other treatment modalities
    14. 14. Patient’s Status: RPA classification duration of survival medical risk factors for surgeryGaspar L, Scott C, Rotman M et al. Recursive partitioning analysis (RPA) of prognosticfactors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. In JRadiat Oncol Biol Phys 1997; 37:745–751
    15. 15. Patient’s Status: RPA classificationKaal, E.C., C.G. Niel, and C.J. Vecht, Therapeutic management of brain metastasis.Lancet Neurol, 2005. 4(5): p.289-98
    16. 16. Karnofsky Performance Scale
    17. 17. Patient’s Status: Other Clinical Status • Systemic Disease Status – activity & extent of primary tumour & non-cerebral metastasis • Extent of Neurological Deficit – response to preoperative corticosteroid • Medical co-morbidities • Latent Interval - time from first diagnosis of cancer to the diagnosis of brain metastasis* Brain metastases were diagnosed Group A: within 12 months Group B: exceeded 1 year P <0.04 of diagnosis of the primary Tumour*Joseph H. Galicich, Narayan S, et al, Surgical Treatment of Single BrainMetastasis: Factors Associated with Survival, Cancer 45:381-386, 1980
    18. 18. Status of the tumour• Number• Size• Location• Histology Types• Recurrence
    19. 19. Number(s) of tumour • Surgical resection should be considered in patients with single brain metastasis – Level A • In patients with up to three brain metastases, surgical resection is an option when the lesions are in an accessible location – Level C Soffietti R, Cornu P, Delattre JY, et al, EFNS guidelines on diagnosis and treatment ofbrain metastases: report of an EFNS Task Force , Eur J Neurol 2006 Jul;13(7):674-81
    20. 20. The role of surgical resection for multiple brain metastases (< 4 lesions)• Retrospective review of 56 patients who underwent resection for multiple brain metastases 1. Group A (N = 30) had one or more lesions left unresected 2. Group B (N = 26) had undergone resection of all lesions 3. Group C -These patients were compared with a group of matched controls who had single brain metastases that were surgically resected Conclusion: The removal of multiple metastatic brain lesions is AS EFFECTIVE as resection of single metastases, as long as all lesions are removed Bindal RK, Sawaya R, Leavens ME, et al.: Surgical treatment of multiple brain metastases. J Neurosurg 1993; 79: 210–216
    21. 21. Resectability: Lesion size
    22. 22. Resectability: Location• With modern microneurosurgical techniques, there is no location within the brain that is not accessible to the neurosurgeon• Patients with metastases to the brainstem, thalamus, and basal ganglia are generally not considered surgical candidates• No good study demonstrating that there is more morbidity from surgery than from radiosurgery when the lesion is located in eloquent brain
    23. 23. Histologic Types• Radiosensitivity & Chemosensitivity• SCLC, Lymphoma, Germ Cell Tumour – radiosensitive & chemosensitive• NSCLC, Breast Ca – Intermediate• Melanoma, Renal Cell Ca, Sarcoma -Resistant• Indicator of Survival – poor for melanoma but relatively good for Renal Cell Ca after surgery
    24. 24. Surgeon’s Status• Surgical Experience• Microsurgical Techniques• Intraoperative Guided Surgery (IGS)• Brain Mapping / Functional MRI
    25. 25. Surgical Approaches
    26. 26. Technological adjuncts to surgery • Most metastatic lesions are echogenic • Portray an image of the tumor and operating field in “real time,” allowing visual tracking of changes in the tumor and shifts • 3-D reconstructions of the operative region generated from preoperative imaging studies • Allows the path to deep lesions to be predetermined
    27. 27. Technological adjuncts to surgery • For identification of the position of sensorimotor cortex through SSEPs • Proximity of the lesion to the functionally identified motor gyrus can then be determined. • To guide the placement of the cortical incision required for removal of a tumor located directly within the precentral gyrus • Language mapping can be done in awake craniotomy
    28. 28. Surgery: Mortality 1930s Cushing 38%* 1990s 3%** modern techniques 2000s 2%****Cushing H: Notes upon a series of two thousand verified cases with surgical-mortalitypercentages pertaining thereto. Springfield, IL, Charles C Thomas, 1932, 105pp.**Bindal AK, Bindal RK, Hess KR, et al.: Surgery versus radiosurgery in the treatment ofbrain metastasis. J Neurosurg 1996; 84: 748–754***Al-Shamy, G. and R Sawaya, Management of brain metastases: the indispensible role ofsurgery. J. Neurooncol, 2009. 92(3): p.275-82
    29. 29. Surgery: Morbidity• The risk of hemorrhage or neurologic deterioration associated with surgery is less than 5%*• Meningitis or intracranial abscess less than 1%*• Superficial wound infection, deep vein thrombosis, pulmonary embolism, or pneumonia, occur in 8% to 10%****Patchell RA et al. A randomized trial of surgery in the treatment of single brain metastasesto the brain: A randomized trial. N Eng J Med 1990; 322:494–500.**Bindal RK et al. Surgical treatment of multiple brain metastases. J Neurosurg 1993;79:210–216.
    30. 30. The role of retreatment in recurrent / progressive brain metastases• Treatment should be individualized based on – patient’s functional status, – extent of disease, – volume/number of metastases, – recurrence or progression at original versus non-original site, – previous treatment – type of primary cancer Mario Ammirati, Charles S. Cobbs, Mark E. Linskey, et al, The role of retreatment in the management of recurrent/ progressive brain metastases: a systematic review and evidence-based clinical practice guideline, J Neurooncol (2010) 96:85–96 –Level
    31. 31. The role of retreatment in recurrent / progressive brain metastases• The following can be recommended depending on a patient’s specific condition: – no further treatment (supportive care), – reirradiation (either WBRT and/or SRS), – surgical excision or, – chemotherapy. Mario Ammirati, Charles S. Cobbs, Mark E. Linskey, et al, The role of retreatment in the management of recurrent/ progressive brain metastases: a systematic review and evidence-based clinical practice guideline, J Neurooncol (2010) 96:85–96 –Level
    32. 32. Other Treatment Modalities• Conventional Radiotherapy WBRT• Stereotactic Radiotherapy• Radiosurgery – Gamma Knife (Cobalt) – X Knife (Linac based) – Cyberknife (Robotic Linac)• Chemotherapy
    33. 33. Radiosurgery • Radiosurgery uses precisely targeted radiation to destroy lesions anywhere in the body in 1-5 fractions/stages • SRS is considered in patients with metastases of a diameter of <3–3.5 cm and/or located in eloquent cortical areas, basal ganglia, brain stem or with comorbidities precluding surgery (level B). • Gamma-knife or linear accelerator (Linac) are equally effective (level B). • SRS may be effective at recurrence after prior radiation treatment (level B).Soffietti R, Cornu P, Delattre JY, et al, EFNS guidelines on diagnosis andtreatment of brain metastases: report of an EFNS Task Force , Eur J Neurol2006 Jul;13(7):674-81
    34. 34. Radiosurgery• In patients with up to three brain metastases, good performance status (KPS of 70 or more) and controlled systemic disease, SRS is an alternative to WBRT (level B),• Advantages – Non-invasive, no surgical incision, no surgical risk, shorter hospital stay, small deep seated lesion• Disadvantages – Not suitable for lesions > 3cm, worsening peritumoural oedema, radionecrosis
    35. 35. Surgery Vs SRSVogelbaum, M.A. and J.H Suh, eds. Resectable brain metastasis. J Clin Oncol. Vol. 24.2006. 1289-94
    36. 36. Surgery Vs SRSAl-Shamy, G. and R Sawaya, Management of brain metastases: the indispensible role ofsurgery. J. Neurooncol, 2009. 92(3): p.275-82
    37. 37. WBRT • The role of adjuvant whole-brain radiotherapy (WBRT) after surgery or radiosurgery remains to be clarified. • In case of absent/controlled systemic disease and Karnofsky Performance score of 70 or more, one can either withhold initial WBRT if close follow-up with MRI (every 3 to 4 months) is performed or deliver early WBRT with fractions of 1.8–2 Gy to a total dose of 40–55 Gy to avoid late neurotoxicity. • In patients with more than three brain metastases WBRT with hypofractionated regimens is the treatment of choice (level B)Soffietti R, Cornu P, Delattre JY, et al, EFNS guidelines on diagnosis andtreatment of brain metastases: report of an EFNS Task Force , Eur J Neurol2006 Jul;13(7):674-81
    38. 38. WBRT • For patients with active systemic disease and/or poor performance status, WBRT alone is the therapy of choice and should employ hypofractionated regimens such as 30 Gy in 10 fractions or 20 Gy in five fractions (level B). • For elderly patients with poor performance status and bedridden patients, it should be considered to withhold active radiation treatment and restrict therapy to supportive care.Soffietti R, Cornu P, Delattre JY, et al, EFNS guidelines on diagnosis andtreatment of brain metastases: report of an EFNS Task Force , Eur J Neurol2006 Jul;13(7):674-81
    39. 39. Combined Therapies• Surgical resection + WBRT vs Surgical resection alone• Surgical resection + WBRT vs WBRT alone• Surgical resection + WBRT vs SRS +/- WBRT
    40. 40. Adults with a newly diagnosed single brain metastasis amenable to surgical resectionPatchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ et al (1998)Postoperative radiotherapy in the treatment of single metastases to the brain: a randomizedtrial. JAMA 280(17):1485–1489 - RCT
    41. 41. Adults with a newly diagnosed single brain metastasis amenable to surgical resectionGaspar LE, Mehta MP, Patchell RA, Burri SH, Robinson PD, Morris RE et al (2009) Therole of whole brain radiation therapy in the management of newly diagnosed brainmetastases: Asystematic review and evidence-based clinical practice guideline. J Neurooncol.
    42. 42. Adults with a newly diagnosed single brain metastasis amenable to surgical resectionMuacevic A, Wowra B, Siefert A, Tonn JC, Steiger HJ, Kreth FW (2008) Microsurgery pluswhole brain irradiation versus Gamma Knife surgery alone for treatment of singlemetastases to the brain: a randomized controlled multicentre phase III trial. J Neurooncol87(3):299–307Garell PC, Hitchon PW, Wen BC, Mellenberg DE, Torner J (1999) Stereotactic radiosurgeryversus microsurgical resection for the initial treatment of metastatic cancer to the brain. JRadiosurg 2(1):1–5
    43. 43. The role of steroids• Mild symptoms related to mass effect – Recommended – 4–8 mg/day of dexamethasone• Moderate to severe symptoms related to mass effect – Recommended – 16 mg/day or more of dexamethasone• Tapered slowly over a 2 week time period, or longer in symptomatic patients, based upon – an individualized treatment regimen – a full understanding of the long-term sequelae of corticosteroid therapyTimothy C. Ryken • Michael McDermott • Paula D. Robinson et al, The role of steroids inthe management of brain metastases: a systematic review and evidence-based clinicalpractice guideline, J Neurooncol (2010) 96:103–114 –Level 3
    44. 44. Long-term sequelae of corticosteroid therapyHempen et al, Support Care, Cancer 2002 10:322-328
    45. 45. The role of chemotherapy1. The lack of clear survival benefit with the addition of chemotherapy to WBRT*.2. Enhanced response rates, specifically in NSCLC with the addition of chemotherapy to WBRT*.3. Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumors, like small cell lung cancers, lymphomas, germ cell tumors and breast cancers, or if an effective chemotherapy schedule for the primary is still available ** *Minesh P. Mehta, Nina A. Paleologos, Tom Mikkelsen, et al, The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline, J Neurooncol (2010) 96:71–83 ** Soffietti R, Cornu P, Delattre JY, et al, EFNS guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force , Eur J Neurol 2006 Jul;13(7):674-81
    46. 46. The role of prophylactic anticonvulsants • For adults with brain metastases who have not experienced a seizure due to their metastatic brain disease, routine prophylactic use of anticonvulsants is not recommended.Tom Mikkelsen, Nina A. Paleologos, Paula D. Robinson, et al, The role of prophylacticanticonvulsants in the managementof brain metastases: a systematic review and evidence-basedclinical practice guideline, J Neurooncol (2010) 96:97–102
    47. 47. Therapeutic strategy in brain metastasesKaal, E.C., C.G. Niel, and C.J. Vecht, Therapeutic management of brain metastasis.Lancet Neurol, 2005. 4(5): p.289-98
    48. 48. Decision-making: Tumour Board• Treatment of patients with brain metastases is a multidisciplinary process, including neurosurgery, neurology, radiation oncology, and medical oncology.• A clinician’s focus will vary based on differing clinical perspectives and patient factors such as the functional status, systemic extent of cancer, and preference.• Decision-making is complicated further by the fact that several treatment modalities are available to treat metastatic brain tumors including various forms and combinations of surgery, radiation, and chemotherapy.
    49. 49. Decision-making: Tumour Board• A collective decision from all the members of the tumour board (neurosurgeon, neurologist, radiologist, radiation oncologist, and medical oncologist) will ensure a comprehensive and effective treatment plan for the patient.
    50. 50. Case 1• 28 Years old Male Diagnosed left testicular tumour with lungs metastasis 1 year ago. Underwent left orchidectomy and HPE diagnosis of Yolk sac Tumour He had completed radiotherapy and chemotherapy Presented with 1/12 history of progressive left sided body weakness and numbness Associated with worsening headache Admitted with 1 episode of generalised tonic clonic seizure
    51. 51. Case 1• GCS full Higher mental function intact No cranial nerves deficit noted Left hemiparesis 3/5 with sensory impairment MRI showed a solitary tumour just below cortex of right precentral and post-central gyri, 3cm in it’s greatest diameter
    52. 52. Case 1He underwent right parietal craniotomy andexcision of tumour. The tumour was just below athin grey matter of post central gyrus (detectedusing intra-operative ultrasound). Post-centralgyrus transcortical approach.
    53. 53. Case 1• Post-operatively he was extubated and maintained on dexamethasone. Clinically he still having left hemiparesis power of 3/5 but improved headache• CT scan (plain) post-operative day 1 showing pneumocranium with edema, no post- operative bleeding.
    54. 54. Case 2• 53 Years old Gentleman Chronic smoker with underlying COAD• Developed progressive left sided limbs weakness for 2 months, associated with headache.• No other symptoms on systemic review• GCS full, PEARL• Higher mental function intact No cranial nerves deficit noted Left hemiparesis 4/5 with no sensory impairment No cerebellar sign• Other examinations - Normal
    55. 55. Case 2• MRI showed homogenous enhancing lesion at right motor cortex, left insular and left cerebellum
    56. 56. Case 2• Tumour markers done – within normal value• CXR - NAD• CT thorax and abdomen - NAD
    57. 57. Case 2 Unknown PrimaryRight parietal craniotomy and excision of tumourdone under IGS transsulcus approach
    58. 58. Case 2
    59. 59. Case 2
    60. 60. Case 2
    61. 61. Case 2
    62. 62. Case 2Frozen section sent- Metastatic tumour• Post-operatively, his weakness remain same.• On follow-up 2 weeks after surgery his weakness improved to 5/5• HPE = Metastatic squamous cell carcinoma
    63. 63. Conclusion1. A tissue diagnosis is necessary when the primary tumor is unknown.2. Surgery should be considered in patients with up to three brain metastases, being effective in prolonging survival when the systemic disease is absent/controlled and the performance status is high.3. Stereotactic radiosurgery should be considered in patients with metastases of 3- 3.5 cm of maximum diameter.4. Dexamethasone is the corticosteroid of choice for cerebral edema.5. Anticonvulsants should not be prescribed prophylactically.
    64. 64. Conclusion7. WBRT alone is the treatment of choice for patients with single or multiple brain metastases not amenable to surgery or radiosurgery.8. Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumours.9. A collective decision by the members of the tumour board on the treatment modalities offered to a patient with metastatic brain tumour should be practiced in all centers.
    65. 65. Thank YouDepartment of Neurosurgery Hospital Kuala Lumpur

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