Advancements in Neuro- Oncology

Transcription

1 Advancements in Neuro- Oncology Ricky Chen, MD Director, Neuro-Oncology Providence St Vincent Medical Center November 30 th, 2018

2 No disclosures

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4 Recognizing a brain tumor New and *Persistent Headaches* New seizure Neurological deficits Lethargy, vomiting Multiple office or ED visits

5 Progressive neurologic deficit Frontal lobe Personality changes Parietal lobe weakness or loss of sensation Temporal lobe language problem (Aphasia) Occipital lobe visual field deficit(homonymous) Sella other visual field and endocrine abnormalities Brainstem Cranial nerve deficits Spinal cord back pain, weakness, numbness, bowel and bladder difficulties

6 Components of Diagnosis Threshold of suspicion IMAGING Histology Molecular markers

7 Classifying brain tumors by histology Oligodendroglioma Astrocytoma Ependymoma Meningioma

8 World Health Organization Grading of brain tumors

9 Brain tumor types & treatment Gliomas, a family of diseases and the intricacies of treatment Intro to radiation in brain tumors The role of chemotherapy in malignant tumors Meningioma Ependymoma Primary lymphomas of the CNS

10 Gliomas Tumors derived from supportive cells (Glial cells: Astrocytes, oligodendrocytes) Diffuse (infiltrative) vs Discrete gliomas

11 Discrete gliomas Pilocytic astrocytoma Pleomorphic Xanthoastrocytoma Subependymal giant cell astrocytoma Ganglioglioma Less common than diffuse gliomas and more often in children Surgery is primary treatment with radiation as adjunct Much better prognosis with some exceptions BRAF mutation offers possibility of targeted treatments.

12 Diffuse Gliomas Low grade gliomas Oligodendroglioma Astrocytoma (WHO II) High grade gliomas Anaplastic Oligo. or Anaplastic Astro. (WHO III) Glioblastoma (GBM) (WHO IV) Diffuse Midline Glioma (WHO IV)

13 Case Presentation: 56 year old executive presents with intermittent confusion over the last 3 months. He also noticed new headaches of moderate severity. Finally, one day at work, he has a convulsive seizure and coworkers called EMS. Imaging reveals a right frontal enhancing mass.

14 Glioblastoma (GBM) Most common malignant primary brain tumor: 45.2% of all malignant CNS tumors and 80% of all primary malignant CNS tumors Incidence of 3.19 cases per 100,000 person years Mean age at diagnosis is x more common in men than women 2x more common in whites than blacks Median overall survival is months. Without treatment, it is 6 months or less.

15 Initial Management - GBM Steroids for cerebral edema may relieve symptoms Dexamethasone 4mg q6h EXCEPT if primary CNS lymphoma or infection is in the differential diagnosis. Seizure control Keppra 1000mg BID Neurosurgery consultation Maximal safe resection extends survival Grabowski, J Neurosurg, 2014

16 Radiation Therapy Fractionated external beam Linear accelerator creates high energy electrons or photons that damage DNA 42 divided doses over 6 weeks Side effects: Short term memory and cognitive processing Fatigue Skin toxicity, alopecia Radiation necrosis

17 Chemotherapy Oral administration Daily treatment concurrent with RT Adjuvant treatment 4 weeks after RT for 6-12 cycles Side effects: Fatigue Confusion Constipation Bone marrow suppression: Thrombocytopenia more likely than neutropenia For recurrence: Temozolomide CCNU Irinotecan & Avastin Carboplatin

18 Recurrent tumors Next line chemotherapy Consider reoperation in select cases Clinical Trial options Tailoring individual treatment by tumor board review and consensus.

19 New Tumor Treating Field Therapy Optune Device from Novocure generates alternating electric fields via arrays of transducing electrodes (0.7V/cm, frequency 200 khz) Adhesive Arrays need to be replaced every 3-4 days and scalp reshaved. minimum of 18 hours to 24 hours a day of continuous use. Brief pauses for personal hygiene Main side effect is mild skin hypersensitivity

20 DA approved for use after RT Stupp R, et al. 2017, JAMA. 2017;318(23): doi: /jama

21 Potential for long-term survival benefit Ram, Z. Kim CY, GA Nicholas, S Toms Compliance and treatment duration predict survival in a phase 3 EF-14 trial of Tumor Treating Fields with Temozolomide in patients with newly diagnosed glioblastoma. Abstract presentation, Soc of Neuro-Oncology, Nov, 2017.

22 Design of a Phase 1 Trial Examining the Safety and Tolerability of Tumor Treating Fields Combined with Chemoradiation in Newly Diagnosed Glioblastoma Ricky Chen, MD 1 ; Nicholas Butowski, MD 2 ; Steve Braunstein, MD, PhD 2 ; Angelica Perez-Andujar, PhD 2 ; Eric Hansen, MD 1 1 Providence Brain and Spine Institute, Portland, OR; 2 University of California, San Francisco, San Francisco, CA Trial Design Abbreviations: Tumor Treating Field (TTF), radiation therapy (RT), temozolomide (TMZ), dose limiting toxicity (DLT), Response Assessment in Neuro-Oncology (RANO) Design abstract poster presented at ACRO, 2018

23 Low Grade Glioma Diffuse Astrocytoma, IDH mutant Presents similarly to Oligo s, 3 rd & 4 th decade of life Median OS ~10y Treatment based on risk: Surveillance, chemo alone, or combined chemoradiation upfront. Transforms to grade III and then grade IV Astrocytoma (Secondary GBM). Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rid: 9014

24 Low Grade Glioma Oligodendroglioma, IDH mutant WHO grade II Defining chromosomal deletions in 1p and 19q 2/3 presents with seizure Nonenhancing mass with mild edema, CT often has calcifications. Peak incidence age Median OS ~15+ years Eventually transform to Anaplastic Oligo (grade III) Treatment stratified by risk: Complete removal, age <40, neuro intact: observe and treat upon recurrence Others may receive chemo alone vs chemoradiation upfront

25 Molecular Aids in Diagnosis and Treatment Decision Making June 10, 2015 DOI: /NEJMoa

26 Molecular subtypes better predicts survival and led to revised diagnostic criteria TCGA, NEJM 2015

27 IDH mutation & 1p19q codeletion form distinct molecular pathways Mostly Oligo Mostly Astro TCGA, NEJM 2015

28 Therapy and Prognostic Implications Even grade III tumors with 1p19q codeletion can have survival > 15 years MGMT methylation codeletion more sensitive to TMZ chemotherapy and radiation 2 Investigational treatments against molecular targets: IDH inhibitors for low grade gliomas EGFR, PARP, MTOR, MEK and other pathways being explored. 2 Chen, Ravindra, et al. Neurosurg Focus, 2015

29 H mutation leads to 2HG oncometabolite Produces 2- hydroxyglutarate >100x normal Alters cellular regulation and epigenetic programs for proliferation. TCGA, NEJM 2015 Highly sensitive and specific for IDH mutant gliomas.

30 Highly sensitive and specific for IDH-mutant gliomas. Promising new approach to assess treatment response and progression Chen, Ravindra, et al. Neurosurgical Focus 2015

31 Treatment response initial treatment Treatment after progression Predicts recurrence Journal of Clinical Oncology 34, no. 33 (November 2016)

32 Meningioma Derived from arachnoid cells Most common (36%) of all brain tumors, female bias Dural based enhancing mass ~75% are grade I ~20% grade II ~1 6% grade III Benign Surgery is the primary treatment and cures 80% of tumors Up to 20% may recur within 20 years Radiation can be adjunct if inaccessible to surgery or for recurrence. Case images courtesy of P Canoll, SNO review 2016

33 Ependymoma Derived from fluid-lining (ependymal) cells, pseudorosettes on histology Spinal ependymoma, grade I More common in adults, frequent NF2 mutation, better prognosis (over 98% survival in 5y) Extramedullary and intradural, most common in the conus/filum Treatment: Surgery, radiation as adjunct In children, ependymomas more often arise in supratentorial brain or posterior fossa and are more aggressive (grade I-III)

34 Primary CNS lymphoma Diffuse large B cell lymphoma ~3% of all brain tumors, peak incidence 5th to 7 th decade of life. Can occur anywhere in CNS, as well as ocular involvement Increased risk with immunodeficiency/aids Imaging Avidly and homogeneously enhancing tumor with diffusion restriction. Favors deep structures & periventricular areas Histology: Large B lymphocytes, stains CD 20+

35 Primary CNS lymphoma Diagnosis CSF cytology/flow cytometry Biopsy Rule out extracranial disease: PET scan, CT, testicular ultrasound AVOID STEROIDS delays diagnosis, sometimes months Treatment No role for surgery beyond biopsy Whole brain radiation is toxic and OS 11.6mo Chemotherapy is first line Best induction therapy regimens are given in combination with methotrexate: eg, high dose methotrexate (IV), rituxumab, and temozolomide (PO). followed by consolidation tx: etoposide & cytarabine Estimated 4yr OS 65%, mos not yet reached (2013) *Rubenstein, JCO. 2013;31(25):3061-8

36 Case presentation A 26 year old woman G1PO (16 weeks pregnant) noticed that she is more fatigued and sometimes more clumsy, bumping into things (especially on the right side). She has almost no headaches. When asked, she has also had difficulty driving, feeling her vision seems dimmer on the right. She was seen by PCP, reassured with return precautions. 2 months later, she feels like her balance gradually worsened and ultimately presents with an hour long episode of drooling and facial droop, and imaging reveals an enhancing mass in the occipital lobe. She has a body CT and PET scan which are both negative (except for brain mass). She undergoes surgery and is later treated with radiation to the resection cavity.

37 Brain Metastases Prognoses vary based on primary histology, commonly Breast or Lung Could also be melanoma, lymphoma, GI and others Management: Steroids for edema Surgery if solitary or dominant/symptomatic met Radiation is mainstay of treatment Traditional chemo agents are shielded by blood brain barrier.

38 Gamma Knife Stereotactic Radiosurgery For lesions less than 2cm Effective for brain metastases, meningioma, other small tumors Now standard for treating up to 5 lesions, often with very good local control and well tolerated. Whole brain radiation has significant risk of cognitive deficits, and should be reserved for large number of mets.

39 Studied molecular targets in Brain Metastases Some examples NSCLC: ALK, EGFR, BRAF Breast: HER 2 Melanoma: BRAF Newer agents cross the BBB and have shown efficacy in the CNS as well as systemically *Also a current study of Tumor Treating Fields in NSCLC Brain Mets before SRS

40 Leveraging the Immune system to fight cancer Nature 562, (2018)

41 Nivolumab + Ipilimumab for metastatic melanoma N Engl J Med Oct 5; 377(14):

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43 Immunotherapies under investigation for brain tumors Checkpoint inhibition Viruses and Vectors Vaccines Car T cells N Engl J Med 2016;375:2561-9

44 Neuro-oncology goals for 2019 Listen to my patients and colleagues. Let there be hope along with realistic expectations. Support the goal to improve treatments and outcomes by improving access to promising therapies. "Nothing in life is more liberating than to fight for a cause larger than yourself, something that encompasses you, but is not defined by your existence alone."