Neuro-Oncology
Tracy Batchelor, M.D. Brigham and Women’s Hospital Dana-Farber/Harvard Cancer Center Harvard Medical School Primary CNS Tumors
All other, 13.9% Glioblastoma, 20.3% Lymphoma, 3.1%
Nerve sheath, 8.0%
Craniopharyngioma, Astrocytomas, 9.8% 0.7%
Pituitary, 6.3% Ependymomas, 2.3%
Oligodendrogliomas, 3.7%
Embryonal, including Meningioma medulloblastoma, 1.7% 2018 Estimates 30.1% 85,440 primary CNS Tumors 25,800 malignant 59,640 non-malignant
Neuro-Oncology 2018; 20(S4), 1-86 Gliomas Glioblastoma
• Most common glioma subtype, ~15,000 cases per year in the US • Young adult males (20-39) – 1st or 2nd leading cause of cancer death from 1998-2002 (malignant PBT) • Median Age = 64 • Median Survival < 12 months • 5-year Survival – All subjects = 3.3% – 65 and older = 0.4-0.5%
WHO 2016 Revision
• Anaplastic Oligoastrocytoma Discontinued – 1p-19q co-deletion = Anaplastic Oligodendroglioma – 1p-19q non-co-deletion = Anaplastic Astrocytoma • AA, IDH1 mutation • AA, IDH1 wild type Glioblastoma Imaging • Contrast-enhanced, multi-planar MRI optimal study • Infiltrative borders • 98.8% enhance • 88.4% single lesion Glioblastoma Prognostic Factors • Age – < 55-60 = better prognosis • Performance Status • MGMT status – Methylated MGMT = better prognosis (~35%) • IDH1 mutational status – IDH1 mutation = better prognosis (10%) Glioblastoma- Newly Diagnosed Treatment • Surgery – Biopsy versus Resection (5-ALA) • Radiation – Fractionated, external beam, focal – Novocure/TTF • Medical – Temozolomide – Lomustine – Bevacizumab Surgery Surgery
Rationale for Extensive Resection
• Provides adequate tissue for pathological diagnosis and molecular profiling • Palliates mass effect – Improvement in neurological symptoms and signs – Reduction of corticosteroids – Better tolerance of radiation • Survival?
NCCN. Practice Guidelines in Oncology: Central Nervous System Cancers. Volume 1. National Comprehensive Cancer Network, Fort Washington, PA; 2007. Surgery
Aminolevulinic Acid (ALA) Guided Resection • ALA = non-fluorescent pro-drug that is taken up by glioma cells and converted to fluorescent porphyrin • Randomized, multicenter, phase III study of newly diagnosed malignant glioma patients who are resection candidates • 243 GBM patients (out of 270 malignant gliomas enrolled) – GTR (N = 122) 16.7 mos OS vs STR (N = 121) 11.8 mos OS, p < 0.0001
FDA approved 5-ALA as adjunct to glioma surgery in 2017
Stummer W, et al. Lancet Oncol 2006 Stummer W, et al. Neurosurg 2008 Radiation Radiotherapy: Randomized Trials
Author N Schema Results Andersen 108 RT vs best supportive care Post-op RT significantly improves Acta Radiol survival compared to best supportive Oncol Radiat care Phys 1978
Walker 303 BCNU vs RT vs BCNU Patients receiving RT had significantly J Neurosurg +RT, vs best supportive longer MS than patients receiving BCNU 1978 care or best supportive care
Walker 467 Semustine vs RT vs Patients receiving RT had significantly N Engl J Med semustine + RT vs BCNU longer survival than patients receiving 1980 +RT semustine alone
Kristiansen 118 RT vs RT + bleomycin vs MS with RT alone 10.2 months Cancer 1981 supportive care compared to 5.2 months with supportive care
Keime-Guibert, 81 RT versus supportive care Hazard ratio of death for RT group = 0.47 et al in patients > 70 (p = 0.002) N Engl J Med 2007 NovoTTF (Optune®)
From Dr Stupp NovoTTF (Optune®) in GBM
• EF14 trial • Pts with newly diagnosed GBM • Novo-TTF prolonged PFS and OS in patients with newly diagnosed GBM. • NovoTTF/TMZ is feasible, overall well tolerated and without substantial added toxicity other than skin reactions – 24% G1/2 vs 15%, no grade 3 or higher
FDA approved in 2015
Stupp R, et al JAMA 2015; 314: 2535-2543 Chemotherapy Temozolomide
• EORTC/NCIC trial1 – RT alone vs. RT plus TMZ • N = 573 patients EORTC/NCIC Trial – Primary endpoint: overall 5-Year Follow-up2 survival • RT = 12.1 mos Survival RT RT + TMZ • RT + TMZ = 14.6 mos Median 12.1 mo 14.6 mo • P < 0.0001 2-year 10.9% 27.2% – Secondary endpoints: progression-free survival, 3-year 4.4% 16.0% quality of life (QOL), safety 4-year 3.0% 12.1% – No negative impact on QOL 5-year 1.9% 9.8%
1. Stupp R, et al. N Engl J Med. 2005. 2. Mirimanoff R-O, et al. Lancet Oncol 2009. Glioblastoma - Methylated Treatment • CeTeG/NOA-4 Trial – Newly diagnosed, methylated, glioblastoma, ages 18-70 – N = 141 • Arm 1: Lomustine + Temozolomide during and after radiation • Arm 2: Temozolomide during and after radiation (Standard) – mITT analysis, 37.9 mos (arm 1) versus 31.4 mos (arm 2) • HR 0.90, 95% CI, 0.58 – 1.41 – Adjusted mITT analysis, HR 0.74 (CI 0.47 – 1.17) – Matched analysis, 48.1 mos (arm 1) vs 31.4 mos (arm 2) • HR 0.60, 95% CI, 0.35 – 1.03 – Toxicity • Grade 3 or 4 hematologic toxicity, 36% (arm 1) vs 29% (arm 2) • Nausea, 30% (arm 1) vs 19% (arm 2) • Rate of completion, 39% (arm 1) vs 60% (arm 2)
Herrlinger, et al Lancet 2019; 393: 678 Glioblastoma- Recurrent Treatment • Surgery – Repeat Resection; BCNU Polymer • Radiation – Re-irradiation • Chemotherapy – Conventional agents largely ineffective • Bevacizumab monotherapy • Lomustine 20-25% APF6 – Clinical Trials • Phase II Study in Recurrent GBM – N = 35 recurrent GBM patients • Outcomes in 35 GBM patients – PFS6 = 46% (95% CI: 32%, 66%) – 20/35 (57%) radiographic responses BRAIN – Recurrent glioblastoma
R a Bevacizumab + CPT-11 n d o m i z e Bevacizumab
• Randomized, non-comparative, phase 2 study • Centralized review of MRI scans • Primary endpoint: PFS6 • 167 subjects randomized
Friedman, HS, et al. J Clin Oncol 2009; 27: 4733-4740 Bevacizumab Bev + CPT-11 (N = 85) (N = 82)
ORR 28.2% 37.8%
PFS6 42.6% 50.3%
OS 9.2 mos 8.7 mos
Duration 5.6 mos 4.3 mos of ORR
FDA grant full approval for bevacizumab as monotherapy for recurrent glioblastoma on December 5, 2017
Friedman, HS, et al. J Clin Oncol 2009; 27: 4733-4740 Anaplastic Gliomas Anaplastic Oligodendroglioma
• Most AO contrast enhance, 1p-19q co-deleted tumors may occur more commonly in frontal/parietal/occipital lobes • Testing for 1p and 19q chromosome status now routine (FISH, LOH) • Variable clinical outcomes are observed in patients with oligodendroglial tumors
Jenkinson MD, et al. Acta Neurochirg 2010; 152: 1815-1825 Anaplastic Oligodendroglioma EORTC 26951 and RTOG 9402: RT vs RT + PCV • Background – Radiation = standard of care for newly diagnosed AO – 38-83% of newly diagnosed AO respond (PR, CR) to PCV – 1p deletion predicts chemosensitivity (100% to PCV, 90% to TMZ) – Will adjuvant PCV improve survival? • Study Designs – EORTC 26951: Randomized to RT (59.4 Gy) alone versus RT (59.4 Gy) followed by PCV (6 cycles) • Improved PFS, No difference OS – RTOG 9402: Randomized to RT (59.4 Gy) alone versus iPCV (up to 4 cycles) followed by RT (59.4) • Improved PFS, No difference OS Cairncross JG, et al. J Clin Oncol 2006; 24: 2707-2714, van den Bent MJ, et al. J Clin Oncol 2006; 24: 2715-2722 [TITLE]
Cairncross G, et al J Clin Oncol 2013; van den Bent M, et al J Clin Oncol 2013 Anaplastic Glioma 1p-19q Non-Codeleted (CATNON, EORTC 26053- 22054)
ASCO 2019: Concurrent TMZ did not Improve OS in all patients
ASCO 2019: in IDH1 mt AG aTMZ improved OS, Van den Bent M, etl al ASCO 2019 cTMZ showed trend to improved OS van den Bent M, et al Lancet 2017 Low-Grade Gliomas RTOG 9802 – Low Grade Glioma
Buckner JC, et al N Engl J Med 2016; 374: 1344-1355 Primary CNS Lymphoma PCNSL Rare, extranodal NHL, confined to CNS ~1,300 new cases/year in US Median age at diagnosis = 65 90% = DLBCL > 90% = ABC
CALGB 50202 Treatment Induction MTX-based chemo Consolidation WBRT = neurotoxic Other chemo (EA) HDT/ASCT
66% CR to MTR; PFS2 = 57% HDT/ASCT Conditioning thiotepa, carmustine -Median PFS = 85 mos; Median OS = 121 mos (N = 105, retrospective, Illerhaus) -One-Year and Two-Year OS = 92%, 87% (N = 79, prospective, Illerhaus, ASH 2012) -Ten HDT/ASCT trials for newly diagnosed PCNSL published (2003-present)
ANOCEF-GOELAMS PRECIS Study • Randomized, intergroup, phase 2 trial – Newly diagnosed primary CNS DLBCL – 140 patients randomized • WBRT versus HDT/ASCT (TBC) consolidation – Induction • 2 cycles of R-MBVP (rituximab, methotrexate, BCNU, VP16) • 2 cycles of R-Ara-C • Primary Endpoint – 2-Year Progression Free Survival • 63% for WBRT and 87% for HDT/ASCT (pre-defined thresholds reached for each arm) • Secondary Endpoints – Cognitive • Cognitive impairments noted after WBRT, Cognitive preservation or improvement after HDT/ASCT
Houillier C, et al J Clin Oncol 2019 Ibrutinib – Bruton’s Tyrosine Kinase (BTK) Inhibitor
Ibrutinib + DA-TEDDI-R – N = 18 PCNSL patients – 94% tumor reduction with ibrutinib alone – CARD11 and CD79b mutations associated with resistance
Ibrutinib Monotherapy – N = 13 heavily pretreated relapsed or refractory PCNSL or SCNSL patients – 10/13 (77%) responses • 5 complete responses Grommes C, et al Cancer Discovery 2017 – 1 resistant case harbored CARD11 Lionakis MS, et al Cancer Cell 2017 mutation Chamoun K, et al Neurology 2017 Phase 1b trial of ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma
• Regimen – Ibrutinib (560 mg, 840 mg) – Methotrexate (3.5 g/m2 Q2 weeks, 8 doses, 4 cycles) – Rituximab (500 mg/m2) • Primary Objective – MTD of ibrutinib in combination with MTX and rituximab • Results – 15 patients with r/r CNS lymphoma • 9 PCNSL, 6 SCNSL – No dose limiting toxicity – Responses • 12/15 completed induction and 11/15 entered maintenance ibrutinib • 12/15 had responses (8 CR, 4 PR) = 80% response rate • 1/15 had SD, 2/15 had PD – Recommended phase 2 dose of ibrutinib in combination with MTX and rituximab is 840 mg
Grommes, et al Blood 2019; 133: 436-445 PCNSL Summary – Uncommon subtype of NHL (90% DLBCL, 95% ABC) – No role for surgical resection – WBRT alone is palliative and associated with clinical neurotoxicity – MTX-based chemotherapy is standard induction (MTR, MATRix, R-MPV, MBVP) • Role of rituximab unclear, randomized P3 trial = no OS benefit – Optimal consolidation therapy after CR not clearly defined (HDT/ASCT, WBRT, Chemotherapy) • Two randomized trials demonstrate efficacy of HST/ASCT comparable to WBRT and with less neurotoxicity – Adapted regimens under development for elderly PCNSL patients – Novel therapeutics under study • Ibrutinib, lenalidomide, ICIs, CAR T Brain Metastases
38 Brain Metastases Case Definition • Brain Metastases – Metastatic deposit in brain parenchyma – Solitary: 1 brain lesion without evidence of systemic disease – Single: 1 brain lesion with systemic disease present • Brain and Leptomeningeal Metastases are diagnosed concurrently in 33-75% patients
39 Brain Metastases Diagnosis- Imaging
40 Post-Contrast Axial Cranial MRI Images 80% of Patients Have > 1 Brain Metastasis
# of Lesions N %
1 65 19.3 2 54 16.1 3 45 13.4
<3 164 50.0
4 35 10.4 ≥5 133 39.6 N=336 41 Mehta, ASCO 2001. Brain Metastases Diagnosis
• In patient without history of cancer biopsy or resection necessary • In patient with history of cancer and a single lesion biopsy or resection recommended – 11% of lesions in one study were non- cancerous* • In patient with history of cancer and multiple lesions with appearance typical of metastases biopsy usually not necessary
*Patchell42 RA, et al. N Engl J Med. 1990;322:494-500 Brain Metastases Supportive Care • Corticosteroids – Treatment of vasogenic brain edema and increased intracranial pressure – Dexamethasone most commonly used • Anticonvulsants – Not recommended for prophylaxis* – Recommended for patients with history of seizures • Levetiracetam most common • Enzyme (CYP450)-inducing anticonvulsants may alter pharmacokinetics of many other drugs, including chemotherapy – Phenytoin, carbamazepine, phenobarbital
Glantz MJ, et al. Practice Parameter: Anticonvulsant prophylaxis in patients with newly diagnosed43 brain tumors. Neurology 2000; 54: 1886-1893 Brain Metastases Treatment
• Surgery • Radiation – Whole brain radiation therapy (WBRT) – Radiosurgery • Medical Therapy – Immunotherapy – Targeted therapies
44 Brain Metastases Surgery
• 2 out of 3 randomized controlled trials support resection of single metastasis • Retrospective data suggests benefit for removal of 2 - 4 lesions • Other Indications – To establish a tissue diagnosis – To relieve mass effect • Re-resection maybe used in selected cases
45 Brain Metastases Radiation • Whole Brain Radiation Therapy – Treatment of whole brain necessary for visible and microscopic disease – WBRT alone indicated for multiple metastases – Does not treat CSF axis – Response rates: 40 - 60% depending on tumor type – Median survival: 15-21 weeks – Risk of neurotoxicity
46 Brain Metastases Radiosurgery- Rationale • Less invasive, outpatient procedure • Spherical/pseudospherical lesions • Usually < 4 cm in size • Generally noninfiltrative/discrete • Typically near cortical surfaces
If surgery works, so should radiosurgery
47 Brain Metastases Radiosurgery for 1-3 brain metastases
• ~50% of patients have 1-3 metastases • Radiosurgery- RTOG 9508 (RCT) – Randomized Clinical Trial- WBRT + SRS versus WBRT alone for patients with 1-3 brain metastases (RTOG 9508) • N = 333 • Stratified by # of brain metastases (1 versus 2-3) and extent of extracranial disease (none versus present) • No overall survival advantage for radiosurgery over WBRT alone for patients with 1-3 brain metastases
48Andrews DW, et al. Lancet 2004;363:1665-1672 RTOG-9508 Single Brain Metastasis
100 RT + SRS (MS=6.5 mos) 80 RT alone (MS=4.9 mos) P=0.0470 60 40 20 % Alive % 0 0 6 12 18 24 Months 49 Andrews DW, et al. Lancet 2004;363:1665-1672 Is WBRT beneficial or detrimental after SRS?
Brown PD, et al JAMA 2016; 316: 401-409 Cognitive progression and QOL decline more common after WBRT
For patients with brain metastases amenable to SRS, authors advise SRS alone and close monitoring to preserve cognitive function and QOL. Osimertinib for Brain Metastases from EGFRm NSCLC
Osimertinib has superior CNS penetration vs 1st generation of EGFR TKI
CNS activity demonstrated in prior phase II studies
Pre-planned, exploratory analysis on 128 patients enrolled in FLAURA with brain metastases
Blinded central neuroradiology review
Primary endpoint = CNS PFS
Reungwetwattana T, et al J Clin Oncol 2018 Osimertinib for Brain Metastases from EGFRm NSCLC CNS Progression-Free Survival
Reungwetwattana T, et al J Clin Oncol 2018 Osimertinib for Brain Metastases from EGFRm NSCLC Radiographic responses for measurable disease
Reungwetwattana T, et al J Clin Oncol 2018 Nivolumab + Ipilimumab for Melanoma Metastatic to Brain
• Phase 2, multicenter, single arm trial • Mets up to 3 cm, no neurological symptoms • 26% CR, 30% PR • Median time to response: 2.3 mos • Median duration of response: NR • Concordant with extracranial responses • 90% still responding at time of analysis • Grade III/IV Neuro AE in 7%
Tawbi HA,et al N Engl J Med 2018; 379: 722-730 Brain Metastases Conclusions • Biopsy (or resection) is recommended for diagnosis and treatment of single or solitary lesion – 11% of lesions not tumors in Patchell study • Biopsy usually not necessary when there are multiple lesions in a patient with metastatic carcinoma • Resection + WBRT improves survival compared to WBRT alone in patients with a single brain metastasis • SRS + WBRT improves survival compared to WBRT alone in patients with a single brain metastasis • WBRT after SRS improves local/brain control but does not improve survival and leads to earlier decline in cognitive function and QOL
56• Immunotherapy and targeted therapy are emerging in cancer subtypes Leptomeningeal Metastases
57 Leptomeningeal Metastases Background
• Incidence: ~8% of all cancer patients at autopsy • ~7,000 – 110,000 cases diagnosed each year in U.S. • >60-80% of patients have progressive, refractory systemic disease at time of diagnosis • Median survival without treatment is 4-6 weeks; with treatment, median survival is 12-16 weeks • Patients with breast cancer and hematological malignancies have a better prognosis • Patients with disseminated primary brain tumors, melanoma and lung cancer have a worse prognosis
1. Patchell RA, et al. Neurol Clin. 1985;3:729-750. 2. CNS Drugs. 1998;10:25-41. 3. Wasserstrom WR, et al. Cancer. 1982;49:759-772. 58
Leptomeningeal Metastases Pathophysiology • LM cause symptoms/signs by one of several mechanisms . Obstruction of CSF flow and communicating hydrocephalus . Compression of adjacent neural structures (brain parenchyma, cranial nerves, spinal nerve roots) . Reduced blood supply to brain (ischemia) due to tumor infiltration of the Virchow-Robin spaces
60 Leptomeningeal Metastases Clinical Characteristics • Signs and symptoms are related to damage to the brain, cranial nerves, spinal cord, and spinal nerve roots • Clinical hallmark is multifocal neurological symptoms and signs • Neurologic progression is particularly devastating and includes the loss of:
Vision
Hearing
Motor function Balance 61
Bladder and bowel control Leptomeningeal Metastases CSF Results • OP increased in ~ 50% • Pleocytosis (usually lymphocyte predominance) in ~ 50% • Protein typically increased due to disruption of the blood brain barrier • Glucose < 40 mg/dl in 25-30% • CSF cytology is gold standard
62 CSF Cytology
First LP 55%
Second LP 80%
Each subsequent LP (3-7) 2%
Persistently negative ~20% . Autopsy Proven
Ventricular or Cisternal Only 5%
63 Leptomeningeal Metastases
Ornstein D. L., Frederickson K. Images in Clinical Medicine: Meningeal Carcinomatosis in Breast Cancer N Engl J Med 2000; 342:1093, Apr 13, 2000 Leptomeningeal Metastases Diagnosis - Brain MRI
65 Stratification for Treatment (NCCN)
Poor Risk Group Good Risk Group • Low KPS • High KPS • Multiple, serious, or major • No major neurological deficits neurological deficits • Minimal systemic disease • Extensive systemic disease with few treatment options • Reasonable systemic • Bulky CNS disease treatment options • NM-related encephalopathy • No CSF block • CSF block
KPS = Karnofsky Performance Status. NCCN Guidelines. V.2.2006. Accessed February 5, 2007. Standard Therapy
Radiation . Focal to sites of visible/bulky disease and to sites of CSF obstruction . Craniospinal
Intrathecal chemotherapy . MTX (12 mg 2/week) . Ara-C (25-100 mg 2-3/week) . Liposomal Ara-C (50 mg 2/month)* . Thiotepa (10 mg 2-3/week)
Systemic therapy . MTX, Ara-C, capecitabine, temozolomide, bevacizumab
*Discontinued 2017 67 Experimental Therapy
Intrathecal . Topotecan . Pemetrexed . Rituximab (CD20+ lymphomas) . Trastuzumab (HER2+ breast cancer) . IL-2 (melanoma) . CAR T cells
Systemic therapy . Tyrosine Kinase Inhibitors . EGFR mutant NSCLC . Gefitinib, afatinib, osimertinib . ALK mutant NSCLC . Ceritinib, alectinib . Immunotherapy . Checkpoint inhibitors for melanoma
68 Intralumbar versus Intraventricular Chemotherapy
Advantages Disadvantages
No requirement for surgery Pain and inconvenience associated Lumbar with multiple lumbar punctures
Minimal risk of iatrogenic infection or meningitis 10% drug administered by intralumbar route is delivered into subdural or epidural space
Limited and variable distribution of drugs into ventricular CSF
Ommaya Ease of use Surgical procedure
Improved drug distribution Potential for bacterial meningitis
69
Why does treatment fail?
• Treatment-resistant histologies • Progression of systemic disease • Poor functional status at time of diagnosis • Marginally effective drugs • Pharmacologic barriers
71 ASCO 2018 Phase II trial of pembrolizumab in leptomeningeal carcinomatosis
• Baseline brain MRI and systemic • CSF q3wks staging • Brain MRI and systemic staging q6wks • Pre-treatment CSF
• Neoplastic meningitis Clinical • Histologically confirmed Pembrolizumab q3 wks neurologic solid malignancy deterioration • Positive cytology
Primary endpoint Secondary endpoints Exploratory endpoints 3-month OS CNS PFS Duration of response Systemic PFS (RECIST and irRC) First site of progression CNS ORR Patient reported outcomes ORR (RECIST and irRC) Whole exome sequencing of Safety tumor, CSF cfDNA Single cell sequencing
Courtesy of Priscilla Brastianos, M.D., ASCO 2018, Abstract #2007 73 Outcomes • 18 patients received at least 1 dose of pembrolizumab – 2 patients still on treatment (As of April 2018, 1 patient received 12 cycles, 1 patient received 9 cycles) • 12 patients stopped due to disease progression, 3 due to withdrawal consent, 2 due to death, 1 due to grade 3 liver toxicity • 11 patients were alive at three months after enrollment (OS3) at Interim analysis (Exceeded goal of 6) • OS3 for patients who received one dose of protocol treatment (n=18): 0.61 (90% CI: 0.24 to 0.66). • Study achieved primary endpoint
Courtesy of Priscilla Brastianos, M.D., ASCO 2018, Abstract #2007 Leptomeningeal Metastases Conclusions • Leptomeningeal metastasis is under diagnosed • Incidence may be increasing for certain cancers (breast, melanoma) • CSF cytology remains gold standard for diagnosis although imaging is critical • Prognosis is poor although subsets (breast cancer, lymphoma, leukemia) in which patients may fare better exist • Effective palliation can be achieved for most patients • Radiation and intrathecal chemotherapy remain standard therapy . Bulky disease requires radiation • Better treatments are needed
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