CONTINUING PROFESSIONAL DEVELOPMENT

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1 23/09/15 POSTGRADUATE SCHOOL OF MEDICINE BRAIN METASTASES Prof M Brada and Dr John Green MDSC156/199: Acute Clinical Oncology A MEMBER OF THE RUSSELL GROUP CONTINUING PROFESSIONAL DEVELOPMENT Brain Metastases 2 Brain Metastases Common 20% - 50% of pajents may develop brain metastases The incidence of brain metastases is rising; which may be due in part to more sensijve diagnosjc procedures and increasing effecjveness for the treatment of cancer Brain metastases may be located in all areas of the brain and may be either single or mul1ple Brain Metastases 3 Brain Metastases Some types of cancer are more likely to spread to the brain Lung Breast Skin (malignant melanoma) Bowel Kidney (renal) Among pajents with lung cancer, the esjmate is as high as 50% of pajents will develop brain metastases Adenocarcinomas metastasise to the brain more frequently than squamous cell carcinomas 1

2 Pathogenesis of 4 Metastasis is a muljstage process in which malignant cells spread from the tumour of origin to colonize distant organs, following a sequence of steps which includes: local invasion, intravasajon, survival in circulajon, extravasajon and Jssue colonizajon) The mechanisms that allow tumour cells to colonize the brain are sjll not fully understood Several molecular mechanisms contribujng to brain metastasis have been proposed PresentaJon - Symptoms Not all brain tumours are symptomajc 5 Commonest presentajons are seizures and headaches Other symptoms may include: VerJgo Paraesthesias Headaches Visual changes CogniJve, personality and behavioural changes Bells palsy Nausea and vomijng Seizures Memory loss Confusion Lethargy Ataxia Diagnosis Diagnosis is made using imaging, including: CT with and without iodinated contrast agent MRI 6 Standard MRI includes T1WI (T1- weighted imaging) with and without contrast agent, T2WI (T2- weighted imaging) Brain positron emission tomography (PET) using 18 F- fluorodeoxyglucose (18 F- FDG) or amino acid tracers can occasionally be useful to differenjate hypometabolic postradiajon focal necrosis from hypermetabolic malignant lesion DiagnosJc biopsy can also be necessary dependent upon the locajon of the tumour 2

3 Imaging Diagnosis 7 Number of lesions (primary tumours are likely to be solitary) Brain metastases maybe single/muljple Establish whether brain metastases vs other SOL solitary multiple Need for histological confirmajon 8 Algorithm - need for histological confirmajon single or multiple brain lesions recognised malignancy yes no metastatic disease yes no clinical judgment:? likelihood of CNS dissemination, consider: initial primary tumour & stage disease free interval no biopsy no biopsy biopsy biopsy Treatment opjons 9 Factors influencing treatment opjons include: The size, loca1on and type of tumour The pa1ent's general health The extent, control and pathology of the primary tumour Prior an1cancer treatments 3

4 Brain metastases Oncological management options 10 Surgery Supportive care Radiosurgery Radiotherapy Chemotherapy Targeted therapy Combined Therapies 11 Combining therapies are possible to provide opjmal outcome. This is determined by a number of factors, notably: PaJent age FuncJonal status Primary tumour type Extent of extracranial disease Prior therapies Number of intracranial lesions Combined Therapies 12 Combined therapies omen includes chemotherapy with radiotherapy, i.e. whole brain therapy + chemotherapy stereotacjc radiosurgery + chemotherapy The decision to combine therapies must be considered fully as there are numerous disadvantages including increased toxicity, which can have the adverse effect on pa1ent outcome and prognosis. 4

5 Treatment of brain metastases 13 Decision making process Is treatment appropriate? survival quality of life multiple Prognosis 14 Prognosis is omen poor and pajents/families need to be counselled appropriately There are 4 defined prognosjc factors for the survival of pajents with brain metastases: 1. Age 2. Extent of and type of systemic disease 3. Number of brain metastases 4. Performance status Brain metastases and prognosis Graded prognosjc assessment (GPA) 15 score performance status (KPS) < age (years) > <50 no. brain mets > metastajc disease present - - absent GPA prognostic prognostic groups 0-1, , 3.0, Sperduto et al

6 Brain metastases and prognosis Graded prognosjc assessment (months) performance status age no. brain metastases metastajc disease GPA scores Sperduto et al 2007 IniJal management 17 If having seizures use anjconvulsants Consider use of steroids 8mg daily Chemotherapy - Brain metastases 18 Appropriate first line treatment in chemosensijve disease Germ cell tumours Sclc Lymphoma Breast cancer Inappropriate therapy in chemoresistant disease Recurrent non- chemoresponsive 6

7 Brain metastases 19 Primary targeted therapy - GefiJnib in NSCLC n ObjecJve response rates in the brain of 10-60% n Only class III evidence Lee et al 2008 MulJple brain metastases Role of radiosurgery Radiosurgery for muljple brain metastases Survival all pajents 100 p= Survival (%) WBRT alone WBRT + SRS Time (months) RTOG 9508 Andrews et al

8 StereotacJc irradiajon MulJple fixed field stereotacjc radiosurgery 22 Role of whole brain RT Survival solitary brain metastasis 23 EORTC Kocher et al 2011 CogniJve funcjon and whole brain radiotherapy Decline in cognijve funcjon (verbal memory) probability of decline in cogni1ve func1on (%) ψ* test + whole brain RT - whole brain RT total recall 57% (7/11) 24% (4/20) delayed recall 22% 6% delayed recognijon 11% 0% 24 *ψ test - Hopkins verbal learning test - decline defined as change in >5 points on verbal memory test at 4 months 31/58 pajents with 1-3 brain metastases tested MD Anderson CC , Chang et al 2009, 8

9 Mechanism of cognijve dysfuncjon of RT Target cells of radiajon damage Oligodendrocytes - demyelinajon Blood vessels - ischaemia Neural stem cells neuromal deplejon 25 References 26 Harouaka et al (2013) CirculaJng tumor cell enrichment based on physical properjes, J. Lab. Autom., 18 (6) Dawe et al (2014) in Non Small- Cell Lung Cancer, Clin. Lung Canc., 15, Lombardi et al (2014) Systemic treatments for brain metastases from breast cancer, non- small cell lung cancer, melanoma and renal cell carcinoma: An overview of the literature, htp://dx.doi.org/ /j.ctrv Seoane and Matos- Arruda (2014) Brain metastasis: New opportunijes to tackle therapeujc resistance, htp://dx.doi.org/ /j.molonc Perz- Larrya, Hildebrand (2014) Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III, Berghoff A.S, Preusser M., (2015) The future of targeted therapies for brain metastases, Future Onc., 11 (16), Fidler I.J, (2015) The Biology of Brain Metastasis: Challenges for Therapy, Cancer J., 21 (4), Gemici C, Yaprak G, (2015) Whole- brain radiajon therapy for brain metastases: detrimental or beneficial?, Radiat. Oncol., 10:153 FACULTY OF HEALTH & LIFE SCIENCES CPD InsJtute for Learning & Teaching Faculty of Health & Life Sciences Room 2.16A, 4th Floor Thompson Yates Building Brownlow Hill Liverpool L69 3GB and- teaching/cpd A MEMBER OF THE RUSSELL GROUP 9