Current Concepts in Management

of Metastatic Brain Tumour

Dr. Liew Boon SengM.D., M.S. (Neurosurgery) USM

Department of NeurosurgeryHospital Kuala Lumpur

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

Incidence

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

Primary Tumour Type in Patients with Brain

Metastases

Nussbaum et al., Brain Metastases: Histology, Multiplicity, Surgery, and Survival, CANCER October 15, 1996 / Volume 78 / Number 8

Presenting Signs or Symptoms in Patients with Brain Metastases

Nussbaum et al., Brain Metastases: Histology, Multiplicity, Surgery, and Survival, CANCER October 15, 1996 / Volume 78 / Number 8

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.

Aims of Therapy

• Improve survival• Improve QOL• Improve Functionally independent

survival (FIS)• Reduce neurological death

Treatment Modalities

• Surgery• Conventional Radiotherapy / WBRT• Radiosurgery / Stereotactic

Radiotherapy• Chemotherapy• Medication / Supportive Care

Treatment goals: Advantages of

surgical resection

Surgical Options

• Surgical Resection• Biopsy• Others e.g. shunt or ETV for

hydrocephalus

Indications for surgery

• Survival or functional benefit• Single brain metastasis that is too

large to treat safely with radiosurgery

• Diagnosis remains elusive

Selection Criteria for Surgery

• Patient’s Status• Status of the tumour• Surgeon’s Status• Availability of other treatment

modalities

Patient’s Status: RPA classification

Gaspar L, Scott C, Rotman M et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. In J Radiat Oncol Biol Phys 1997; 37:745–751

duration of survival

medical risk factors for surgery

Patient’s Status: RPA classification

Kaal, E.C., C.G. Niel, and C.J. Vecht, Therapeutic management of brain metastasis. Lancet Neurol, 2005. 4(5): p.289-98

Karnofsky PerformanceScale

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*

*Joseph H. Galicich, Narayan S, et al, Surgical Treatment of Single Brain Metastasis: Factors Associated with Survival, Cancer 45:381-386, 1980

Brain metastases were diagnosedGroup A: within 12 months Group B: exceeded 1 yearof diagnosis of the primary Tumour

P <0.04

Status of the tumour

• Number• Size• Location• Histology Types• Recurrence

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 of brain metastases: report of an EFNS Task Force , Eur J Neurol 2006 Jul;13(7):674-81

The role of surgical resection for multiple

brainmetastases (< 4 lesions)

Bindal RK, Sawaya R, Leavens ME, et al.: Surgical treatment of multiple brain metastases.J Neurosurg 1993; 79: 210–216

• 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 ASASEFFECTIVEEFFECTIVE as resection of single metastases, as long as all lesions are removed

Resectability: Lesion size

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

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

Surgeon’s Status

• Surgical Experience• Microsurgical Techniques• Intraoperative Guided Surgery

(IGS)• Brain Mapping / Functional MRI

Surgical Approaches

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

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

Surgery: Mortality

*Cushing H: Notes upon a series of two thousand verified cases with surgical-mortality percentages 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 of surgery. J. Neurooncol, 2009. 92(3): p.275-82

1930s

1990s

2000s

Cushing

modern techniques

38%*

3%**

2%***

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 metastases to 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.

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 3

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 3

Other Treatment Modalities

• Conventional Radiotherapy WBRT• Stereotactic Radiotherapy• Radiosurgery – Gamma Knife (Cobalt) – X Knife (Linac based) – Cyberknife (Robotic

Linac)• Chemotherapy

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 and treatment of brain metastases: report of an EFNS Task Force , Eur J Neurol 2006 Jul;13(7):674-81

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

Surgery Vs SRS

Vogelbaum, M.A. and J.H Suh, eds. Resectable brain metastasis. J Clin Oncol. Vol. 24. 2006. 1289-94

Surgery Vs SRS

Al-Shamy, G. and R Sawaya, Management of brain metastases: the indispensible role of surgery. J. Neurooncol, 2009. 92(3): p.275-82

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 and treatment of brain metastases: report of an EFNS Task Force , Eur J Neurol 2006 Jul;13(7):674-81

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 and treatment of brain metastases: report of an EFNS Task Force , Eur J Neurol 2006 Jul;13(7):674-81

Combined Therapies

• Surgical resection + WBRT vs Surgical resection alone

• Surgical resection + WBRT vs WBRT alone

• Surgical resection + WBRT vs SRS +/- WBRT

Adults with a newly diagnosed single brain metastasis amenable to surgical resection

Patchell 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 randomized trial. JAMA 280(17):1485–1489 - RCT

Gaspar LE, Mehta MP, Patchell RA, Burri SH, Robinson PD, Morris RE et al (2009) The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: Asystematic review and evidence-based clinical practice guideline. J Neurooncol. doi:10.1007/s11060-009-0060-9

Adults with a newly diagnosed single brain metastasis amenable to surgical resection

Muacevic A, Wowra B, Siefert A, Tonn JC, Steiger HJ, Kreth FW (2008) Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial. J Neurooncol 87(3):299–307Garell PC, Hitchon PW, Wen BC, Mellenberg DE, Torner J (1999) Stereotactic radiosurgery versus microsurgical resection for the initial treatment of metastatic cancer to the brain. J Radiosurg 2(1):1–5

Adults with a newly diagnosed single brain metastasis amenable to surgical resection

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 therapy

Timothy C. Ryken • Michael McDermott • Paula D. Robinson et al, The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline, J Neurooncol (2010) 96:103–114 –Level 3

Long-term sequelae of corticosteroid therapy

Hempen et al, Support Care, Cancer 2002 10:322-328

The role of chemotherapy

1. 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

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 prophylactic anticonvulsants in the managementof brain metastases: a systematic review and evidence-basedclinical practice guideline, J Neurooncol (2010) 96:97–102

Kaal, E.C., C.G. Niel, and C.J. Vecht, Therapeutic management of brain metastasis. Lancet Neurol, 2005. 4(5): p.289-98

Therapeutic strategy in brain metastases

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.

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.

Case 1

• 28 Years old MaleDiagnosed left testicular tumour with lungs metastasis 1 year ago.Underwent left orchidectomy and HPE diagnosis of Yolk sac TumourHe had completed radiotherapy and chemotherapyPresented with 1/12 history of progressive left sided body weakness and numbnessAssociated with worsening headacheAdmitted with 1 episode of generalised tonic clonic seizure

Case 1• GCS full

Higher mental function intactNo cranial nerves deficit notedLeft 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

Case 1

He underwent right parietal craniotomy and excision of tumour. The tumour was just below a thin grey matter of post central gyrus (detected using intra-operative ultrasound). Post-central gyrus transcortical approach.

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.

Case 2

• 53 Years old GentlemanChronic 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 notedLeft hemiparesis 4/5 with no sensory impairmentNo cerebellar sign

• Other examinations - Normal

Case 2

• MRI showed homogenous enhancing lesion at right motor cortex, left insular and left cerebellum

Case 2

• Tumour markers done – within normal value

• CXR - NAD• CT thorax and abdomen - NAD

Case 2

Right parietal craniotomy and excision of tumour done under IGS transsulcus approach

Unknown Primary

Case 2

Case 2

Case 2

Case 2

Case 2

Frozen 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

Conclusion

1. 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.

Conclusion

7. 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.

Thank You

Department of NeurosurgeryHospital Kuala Lumpur