NCCN Guidelines for Patients

(1)

NCCN Guidelines for Patients

^®

Version 5.2020 , 04/15/21 © 2021 National Comprehensive Cancer Network^® (NCCN^®), All rights reserved. NCCN Guidelines^® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Central Nervous System Cancers

Version 5.2020 — April 15, 2021

Continue

(2)

*Louis Burt Nabors, MD/Chair Y

O'Neal Comprehensive Cancer Center at UAB

*Jana Portnow, MD/Vice-Chair † Y City of Hope National Medical Center Manmeet Ahluwalia, MD ‡ † Y Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute Joachim Baehring, MD Y

Yale Cancer Center/Smilow Cancer Hospital Steven Brem, MD ¶

Abramson Cancer Center at the University of Pennsylvania Nicholas Butowski, MD ^Y† UCSF Helen Diller Family Comprehensive Cancer Center Jian L. Campian, MD, PhD Y † Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine Stephen W. Clark, MD, PhD Y Vanderbilt-Ingram Cancer Center Andrew J. Fabiano, MD ¶

Roswell Park Comprehensive Cancer Center Peter Forsyth, MD Y

Moffitt Cancer Center Pierre Gigilio, MD Y

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Jona Hattangadi-Gluth, MD § UC San Diego Moores Cancer Center

*Matthias Holdhoff, MD, PhD † The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

*Craig Horbinski, MD, PhD ≠

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Larry Junck, MD Y

University of Michigan Rogel Cancer Center

*Thomas Kaley, MD Y

Memorial Sloan Kettering Cancer Center

*Priya Kumthekar, MD Y

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Jay S. Loeffler, MD § Y

Massachusetts General Hospital Cancer Center

*Maciej M. Mrugala, MD, PhD, MPH ^Y† Mayo Clinic Cancer Center

*Seema Nagpal, MD † Y Stanford Cancer Institute Ian Parney, MD, PhD Y ¶ Mayo Clinic Cancer Center Katherine Peters, MD, PhD Y Duke Cancer Institute

*Vinay K. Puduvalli, MD Y The University of Texas MD Anderson Cancer Center Ian Robins, MD, PhD † University of Wisconsin Carbone Cancer Center

Jason Rockhill, MD, PhD §

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

*Chad Rusthoven, MD §

University of Colorado Cancer Center Nicole Shonka, MD † Y

Fred and Pamela Buffet Cancer Center Dennis C. Shrieve, MD, PhD § Huntsman Cancer Institute at the University of Utah

*Lode J. Swinnen, MB, ChB ‡ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Alva Weir, MD †

St. Jude Children's Research Hospital/

The University of Tennessee Health Science Center

Stephanie Weiss, MD § Fox Chase Cancer Center

*Patrick Yung Wen, MD Y Dana-Farber Cancer Institute Nicole E. Willmarth, PhD ¥ American Brain Tumor Association NCCNSusan Darlow, PhD

Mary Anne Bergman

Continue

NCCN Guidelines Panel Disclosures

‡ Hematology/Hematology oncology

Þ Internal medicine/Primary

† Medical oncologycare

Y Neurology/Neuro-oncology

≠ Pathology

¥ Patient advocacy

§ Radiotherapy/Radiation oncology

¶ Surgery/Surgical oncology

* Discussion Section Writing Committee

Central Nervous System Cancers

(3)

NCCN Central Nervous System Cancers Panel Members Summary of the Guidelines Updates

Adult Low-Grade (WHO Grade I or II) Glioma/Pilocytic and Infiltrative Supratentorial Astrocytoma/Oligodendroglioma (ASTR-1)

Anaplastic Gliomas/Glioblastoma (GLIO-1)

Adult Intracranial and Spinal Ependymoma (Excluding Subependymoma) (EPEN-1) Adult Medulloblastoma (AMED-1)

Primary CNS Lymphoma (PCNS-1) Primary Spinal Cord Tumors (PSCT-1) Meningiomas (MENI-1)

Limited Brain Metastases (LTD-1) Extensive Brain Metastases (MU-1) Leptomeningeal Metastases (LEPT-1) Metastatic Spine Tumors (SPINE-1) Principles of:

• Brain and Spine Tumor Imaging (BRAIN-A)

• Brain Tumor Surgery (BRAIN-B)

• Radiation Therapy for Brain and Spinal Cord (BRAIN-C)

• Brain and Spinal Cord Tumor Systemic Therapy (BRAIN-D)

• Brain and Spine Tumor Management (BRAIN-E)

• Brain Tumor Pathology (BRAIN-F)

Clinical Trials: NCCN believes that the best management for any patient with cancer is in a clinical trial.

Participation in clinical trials is especially encouraged.

To find clinical trials online at NCCN Member Institutions, click here:

nccn.org/clinical_trials/member_

institutions.aspx.

NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.

See NCCN Categories of Evidence and Consensus.

NCCN Categories of Preference:

All recommendations are considered appropriate.

See NCCN Categories of Preference.

The NCCN Guidelines^® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network^® (NCCN^®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network^®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2021.

Central Nervous System Cancers

(4)

UPDATES Continued Updates in Version 2.2020 of the NCCN Guidelines for Central Nervous System Cancers from Version 1.2020 include:

BRAIN-D (8 of 15)

• Tucatinib + trastuzumab + capecitabine was added as a category 2A recommendation for HER2-positive breast cancer patients previously treated with 1 or more anti-HER2-based regimens.

The following reference was included: Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609.

Updates in Version 4.2020 of the NCCN Guidelines for Central Nervous System Cancers from Version 3.2020 include:

BRAIN-D (8 of 15)

• Lorlatinib added as a category 2A recommendation for brain metastases from ALK rearrangement positive non-small cell lung cancer.

The following reference was included: Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med 2020;383:2018-2029.

MS-1• The Discussion section was updated to reflect the changes in the algorithm.

BRAIN-D (2 of 15)

• Footnote "k" was added: An FDA-approved biosimilar is an appropriate substitute for bevacizumab. (Also for BRAIN-D,3 of 15, BRAIN-D,4 of 15 and BRAIN-D,7 of 15).

BRAIN-D (5 of 15)

• Footnote "p" was added: An FDA-approved biosimilar is an appropriate substitute for rituximab. (Also for BRAIN-D, 9 of 15).

BRAIN-D (9 of 15)

• Footnote "v" was added: An FDA-approved biosimilar is an appropriate substitute for trastuzumab.

MS-40

• The Discussion section was updated with the inclusion of lorlatinib.

Central Nervous System Cancers

(5)

UPDATES Updates in Version 1.2020 of the NCCN Guidelines for Central Nervous System Cancers from Version 3.2019 include:

Continued ASTR-1

Adjuvant Treatment

• Consider BRAF and MEK inhibitors if BRAF V600E activating mutation, is new to the page for pilocytic astrocytoma, PXA, ganglioglioma.

Follow-Up

• Modified, Brain MRI every 3–6 mo for 3–5 y then at least annually every 6-12 mo or as clinically indicated.

Footnotes

• "c": Modified to include, and BRAF V600E mutation.

ASTR-2

• Algorithm has been streamlined.

RT + adjuvant temozolomide for patients with high-risk disease is now a category 2A option.

ASTR-3 Treatment

Modified for prior fractionated EBRT, Consider reirradiation with highly focused RT...especially if progression-free survival is greater than 2 y after prior RT or GLIO-1

Footnotes

• "e": Biopsy first prior to administration of steroids if MRI compatible with CNS lymphoma.

GLIO-2

• Fractionated external beam RT replaced with Standard RT throughout the page. (Also for EPEN-2, EPEN-3, EPEN-4)

Follow-Up

• Brain MRI 2–8 wks (6 weeks). (Also for GLIO-3 and GLIO-4)

• corresponding to Standard brain RT + concurrent and adjuvant lomustine and temozoliomide (category 2B)

GLIO-3

• Standard brain RT + concurrent and adjuvant lomustine and temozoliomide (category 2B) for patients with good performance status and methylated tumors is new to the page.

Footnotes

• "r": Combination of agents modalities may lead to increased toxicity or radiographic changes. (Also for GLIO-4).

• "t":Moderate to significant myelosuppression was observed, but the toxicity profile for this regimen is not yet fully defined, is new to the page corresponding to Standard brain RT + concurrent and adjuvant lomustine and temozoliomide (category 2B)

GLIO-4 Footnotes

• "w":See NCCN Guidelines for Older Adult Oncology, corresponding to Age

>70 y Glioblastoma.

EPEN-2 Pathology

Ependymoma (Grades 1 and II). (Also for EPEN-3).

Footnotes

• "h":Lumbar puncture is indicated when there is clinical concern for meningeal dissemination. Lumbar puncture should be done after MRI of spine is performed to avoid a false-positive imaging result. Lumbar puncture for CSF should be delayed at least 2 weeks after surgery to avoid possible false-positive cytology. Lumbar puncture may be contraindicated (eg, posterior fossa mass). (Also for EPEN-3, EPEN-4).

• "k":Consider proton therapy if available to reduce toxicity, is a new to the page and corresponds to Craniospinal RT. (Also for EPEN-3, EPEN-4, AMED-2)

EPEN-3

Postoperative Staging

• Grade I, top pathway: Gross total En bloc resection EPEN-4

• Resectable, evidence of metastasis, Gross total or removed AMED-3

Follow-Up

Brain MRI: every 3 mo for 2 y; then every 6–12 mo for 5–10 y;

then every 1–2 y or as clinically indicated. For patients with previous spine disease, concurrent spine imaging as clinically indicated

PCNS-1 Footnotes

"f": Modified: Brain biopsy is recommended as the primary procedure to obtain diagnosis. CSF analysis should include flow cytometry, CSF cytology, cell count, and possibly gene rearrangements.

PCNS-2 Evaluation

• Lactate dehydrogenase (LDH) test, is new to the page.

Induction Therapy

• Modified: High-dose methotrexate-based regimen or other systemic therapy regimen if patient is unsuitable for or intolerant to high-dose methotrexate Changed vitreous to vitreoretinal for eye exam.

PCNS-2A Footnotes

• "m": Dose adjusted for GFR if dosing at 8 g/m². PSCT-4

Treatment for Recurrence

• Chemotherapy relative to cell type if further surgery or RT not possible

Central Nervous System Cancers

(6)

UPDATES Continued MENI-1

Footnotes

• "f" deleted: RT can be either external beam or SRS LTD-2

Treatment

• SRS in select patients for disseminated disease with poor systemic treatment options is new to the page

Footnotes

• "g": modified 2nd sentence to include: Consultation with a radiation oncologist and close MRI surveillance is strongly recommended.

• "l": Hippocampal avoidance preferred, See BRAIN-C, corresponding to WBRT, (Also for LTD-3).

LTD-3 Follow-Up

• Brain MRI modified: every 2–3 mo for 1–2 y then every 4–6 mo indefinitely (Also for MU-2)

Treatment

• Surgery, modified: followed by SRS or RT to the surgical bed

• Chemotherapy was changed to Systemic therapy for all pathways on the page (Also for MU-2)

Follow-Up

• "n": modified: After SRS, recurrence on MRI radiograph can be...

(Also for MU-2) LTD-4

• The following treatment options were added for patients with stable systemic disease or reasonable systemic treatment options:

Surgery

SRS

WBRT if no prior WBRT

Systemic therapy

• SRS in select patients was added as a treatment option for patients with systemic disease progression.

MU-1Primary Treatment

• WBRT, or SRS or Systemic therapy, with the following corresponding footnotes:

"g": If an active agent exists (eg, cytotoxic, targeted, or immune

modulating), trial of systemic therapy with good CNS penetration may be considered in select patients (eg, for patients with small asymptomatic brain metastases from melanoma or ALK rearrangement-positive NSCLC or EGFR-mutated NSCLC); it is reasonable to hold on treating with radiation to see if systemic therapy can control the brain metastases.

Consultation with a radiation oncologist and close MRI surveillance is strongly recommended. There are no data from prospective clinical trials comparing the two strategies to assess what the impact of delayed radiation would be in terms of survival or in delay of neurologic deficit development.

"h": See Principles of Brain and Spinal Cord Tumor Systemic Therapy (BRAIN-D)

LEPT-2 Treatment

• For Good Risk Status: SRS or RT (involved-field and/or whole brain) to bulky disease and neurologically symptomatic (such as cranial

neuropathies) or painful sites. This replaced "WBRT and/or involved-field RT"

BRAIN-A

• 1st bullet, 4th sub-bullet, Limitations modified: patients with implantable devices are unsafe for cannot have an MRI...or renal insufficiency may occur

BRAIN-C 1 of 8

Adult Low-Grade (WHO Grade I or II) Glioma/Pilocytic and Infiltrative Supratentorial Astrocytoma/Oligodendroglioma

• Tumor volumes are best defined using pre- and postoperative MRI

imaging, usually T2 fluid-attenuated inversion recovery (FLAIR)/T2 and T1, occasionally, enhanced T1post-contrast sequences,...

• New MRI for radiation treatment planning is recommended as there can be changes in mass effect and cytotoxic edema. Distinguishing non- enhancing tumor from vasogenic edema can be challenging and may warrant consultation with a neuroradiologist to inform treatment planning.

Central Nervous System Cancers

(7)

UPDATES Continued BRAIN-C 1 of 8 (continued)

Anaplastic Gliomas/Glioblastoma High-Grade (Grades III/IV)

• Tumor volumes are best defined using pre- and postoperative MRI imaging using enhanced post-contrast T1 with/without and FLAIR/T2 sequences to define GTV. To account for sub-diagnostic tumor infiltration, the GTV is expanded 1–2 cm (CTV) for grade III up to 2-2.5 cm (CTV) for grade...

• Consider proton therapy for patients with good long-term prognosis (grade III IDH-mutant tumors [Buckner 2016] and grade III 1p19q co- deleted tumors [Shih 2015]) to better spare un-involved brain and preserve cognitive function, is new to the page.

RT Dosing Information

• 4th bullet, second sentence modified: Typical fractionation schedules are 34 Gy/10 fx, 40.05 Gy/15 fx, or 50 Gy/20 fx.

BRAIN-C 4 of 8

• WHO Grade 1 Meningiomas

2nd, sub,sub-bullet modifed (25–30 Gy in 5 fractions) BRAIN-C 6 of 8

• 1st sub-bullet under RT dosing modified: ..spinal cord and/or nerve root

• 4th sub-bullet modified: When lower BED regimens are utilized upfront (ie, BED ≤60 Gy², which includes up to 20 Gy in 5 fractions but does not include 30 Gy in 10 fractions), retreatment with similar BED regimens, such as 20 Gy in 5 fractions or 8 Gy in 1 fraction, can safely be considered as early as 4 weeks to 6 weeks from initial treatment for pain relief.

• 5th sub-bullet modified: In other cases of retreatment, doses ranging from 15 Gy in 1 fraction with SBRT to 40 Gy in 20 fractions with a conformal approach have been utilized for tumor control, with careful consideration of tolerance of the spinal cord and/or nerve roots. In these instances, it is generally recommended that 6 months or more of time between treatments is required.

BRAIN-D (1 of 15) Adjuvant Treatment

Useful in Certain Circumstances; modified as follows:

• Pilocytic astrocytoma, PXA, ganglioglioma if BRAF V600E activiting mutation

BRAF/MEK inhibitors:

◊dabrafenib/trametinib

◊vemurafenib/cobimetinib

BRAIN-D (2 of 15) Anaplastic Gliomas

• Carboplatin category 2B removed under Other Recommended Regimens for Recurrence Therapy (Also for BRAIN-D 3 of 15)

Footnotes

"j": modified: Bevacizumab + chemotherapy can be considered if

bevacizumab monotherapy fails and it is desirable to continue the steroid sparing effects of bevacizumab (Also for BRAIN-D 3 of 15).

BRAIN-D (3 of 15)

Adjuvant Treatment for Glioblastoma Preferred Regimens; modified as follows:

• RT with concurrent and adjuvant TMZ ± TTF

Useful in Certain Circumstances; the following is new to the page:

• RT with concurrent and adjuvant lomustine and TMZ (for patients with MGMT promoter methylated tumors, KPS ≥60, and age ≤70 years) (category 2B), with the following corresponding footnote: Moderate to significant myelosuppression was observed, but the toxicity profile for this regimen is not yet fully defined.

Recurrence Therapy for Glioblastoma Preferred Regimens:

Regorafenib is new to the page BRAIN-D (5 of 15)

Induction Therapy for Primary CNS Lymphoma Useful in Certain Circumstances

• Patient is unsuitable for or intolerant to high-dose methotrexate

See "Other Recommended Regimens" for Relapsed or Refractory Disease

Relapsed or Refractory Disease

Other Recommended Regimens; modified as follows:

• Retreat with high-dose methotrexate

with or without rituximab and ibrutinib

• Topotecan

• Dexamethasone, high-dose cytarabine, cisplatin BRAIN-D (7 of 15)

Other Recommended Regimens for Meningioma; modified as follows:

• Interferon alfa (category 2B)

• Somatostatin analogue, if octreotide scan positive Useful in Certain Circumstances;modified as follows:

• Somatostatin analogue (category 2B) if octreotide scan positive Updates in Version 1.2020 of the NCCN Guidelines for Central Nervous System Cancers from Version 3.2019 include:

Central Nervous System Cancers

(8)

BRAIN-D (8 of 15)

This page has been significantly revised. Newly diagnosed and recurrent disease have been combined.

Brain Metastases

• Breast Cancer/HER2 positive

Capecitabine + neratinib (category 2B)

Capecitabine (category 2B)

• Breast Cancer/HER2 non-specific

Cisplatin (category 2B)

Etoposide (category 2B)

High-dose methotrexate (category 2B)

• Melanoma, BRAF non-specific

lpilimumab + nivolumab (preferred)

• Non-Small Cell Lung Cancer

EGFR-sensitizing mutation positive

◊Afatinib (category 2B)

◊Gefitinib (category 2B)

◊Pulsatile erlotinib

ALK rearrangement positive

◊Ceritinib (category 2B)

ALK rearrangement positive or ROS1 positive

◊Crizotinib (category 2B)

PD-L1 positive

◊Nivolumab (category 2B)

• Small Cell Lung Cancer

◊Topotecan (category 2B) Footnotes

• "n": Consider glucarpidase (carboxypeptidase G2) for prolonged methotrexate clearance due to methotrexate-induced renal toxicity.

• "r": For patients with asymptomatic brain metastases, it is reasonable to treat with these systemic therapies in lieu of upfront WBRT and SRS.

BRAIN-D (9 of 15)

Leptomeningeal and Spine Metastases

• Treatment

Intra-CSF chemotherapy

◊Interferon alfa (category 2B)

Lymphoma-leukemias

◊Intra-CSF chemotherapy

– Cytarabine (moved to the Treatment section for all leptomeningeal metastases)

– Methotrexate (moved to the Treatment section for all leptomeningeal metastases)

– Rituximab (lymphoma only)

◊High-dose methotrexate (lymphoma only)

BRAIN-D (9 of 15) (continued)

Breast Cancers

◊Intra-CSF chemotherapy – Trastuzumab (HER2 positive)

• The references have been updated for this section BRAIN-F 6 of 8

Principles of Brain Tumor Pathology Molecular Markers

• Medulloblastoma Molecular Subtyping

3rd bullet, 2nd sentence modified: Unlike in children, 50% of adult medulloblastomas with loss of 6q and positive nuclear catenin had no CTNNB1 mutations, pointing towards the possibility of alternative mechanisms of WNT pathway activation in adult medulloblastoma. Adult and pediatric medulloblastomas are genetically distinct and require different algorithms for molecular risk stratification. WNT-driven tumors will also usually contain monosomy 6. 6q loss is not confined to WNT in adults; it is also described in SHH and Group 4. Monosomy 6 is a specific marker for pediatric WNT, but not for adult WNT.

5th bullet, 2nd and 4th sentences modified: behavior, whereas often in the setting of germline TP53 mutations, wildtype SHH-activated medulloblastomas have a variable course, and are uncommon in adults.

Non-WNT/non-SHH medulloblastomas also show a variable course. WNT tumors and Group 4 tumors have worse prognosis in adults compared to children based on retrospective data. 6q loss and positive nuclear catenin have no clear prognostic role in adult medulloblastoma.

References:

• The following references are new to this section:

Korshunov A, Remke M, Werft W, et al. Adult and pediatric medulloblastomas are genetically distinct and require different algorithms for molecular risk stratification. J Clin Oncol 2010;28:

3054-3060.

Remke M, Hielscher T, Northcott PA, et al. Adult medulloblastoma comprises three major molecular variants. J Clin Oncol

2011;29(19):2717-2723.

Zhukova N, Ramaswamy V, Remke M, et al. Subgroup-specific prognostic implication of TP53 mutation in medulloblastoma. J Clin Oncol. 2013;31(23):2927-2935.

Kool M, Jones DT, Jager N, et al. Genome sequencing of SHH

medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25(3):393-405.

Waszak SM, Northcott PA, Buchhalter I, et al. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol.

2018;19(6):785-798.

UPDATES

Central Nervous System Cancers

(9)

RADIOLOGIC

PRESENTATION^a CLINICAL

IMPRESSION SURGERY^a,b,c,d

MRI

compatible with a low-grade glioma^e,f

Maximal safe resection feasible

Maximal safe resection not feasible

Attempted gross total resection

Subtotal resection or open biopsy orstereotactic biopsy

ADJUVANT TREATMENT FOLLOW-UP^a PATHOLOGY

• Pilocytic astrocytoma

• Pleomorphic

xanthoastrocytoma (PXA)

• Subependymal giant cell astrocytoma (SEGA)^g

• Ganglioglioma

• Pilocytic astrocytoma, PXA, ganglioglioma

If complete resection, no further treatment indicated

If incomplete resection, biopsy, or surgically inaccessible location:

◊Observation

◊Consider radiation therapy only if

significant growth or neurologic symptom development

◊Consider BRAF and MEK inhibitors if BRAF V600E-activating mutation^h

• SEGA^g

Consider testing for tuberous sclerosis with referral for genetic counseling

Consider treatment with an mTOR inhibitor (eg, everolimus)^h

If Grade II infiltrative

supratentorial/astrocytoma/

oligodendroglioma (See ASTR-2)

aSee Principles of Brain and Spine Tumor Imaging (BRAIN-A).

bSee Principles of Brain Tumor Surgery (BRAIN-B).

cRecommended molecular diagnostics include 1p19q chromosomal status, IDH1/2 mutation status, and BRAF V600E mutation. See Principles of Brain Tumor Pathology (BRAIN-F).

dPostoperative brain MRI within 48 hours after surgery.

eConsider a multidisciplinary review in treatment planning, especially once pathology is available. See Principles of Brain and Spine Tumor Management (BRAIN-E).

fIf radiographically the tumor appears to be a high-grade glioma, see GLIO-1.

gThe need to treat SEGAs or other findings in the appropriate tuberous sclerosis patient population should be determined by the patient's symptoms and/or change on serial radiologic studies. Referral to a neurofibromatosis or specialty center is recommended.

hSee Principles of Brain and Spinal Cord Tumor Systemic Therapy (BRAIN-D).

See Recurrence (ASTR-3) Brain

MRI every 3–6 mo for 3–5 y then at least annually as clinically indicated If anaplastic (WHO III)

(See GLIO-2 Anaplastic astrocytoma)

ASTR-1

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Infiltrative Supratentorial Astrocytoma/Oligodendroglioma

(10)

ASTR-2

PRESENTATION^c,e,f ADJUVANT TREATMENT FOLLOW-UP

Grade II infiltrative supratentorial astrocytoma/

oligodendroglioma

Consider clinical trial (preferred for eligible patients)

or Observe^k,l Low riskⁱ

High risk^j

Brain MRI every 3–6 mo for 5 y then at least every 6–12 mo or as clinically indicated

See Recurrence (ASTR-3) Consider clinical trial (preferred for eligible

patients)

or RT^m + adjuvant PCV chemotherapyⁿ(category 1) orRT^m + adjuvant temozolomideⁿ

orRT^m + concurrent and adjuvant temozolomideⁿ orObserve^oin highly select patients

cRecommended molecular diagnostics include 1p19q chromosomal status, IDH1/2 mutation status, and BRAF V600E mutation. See Principles of Brain Tumor Pathology (BRAIN-F).

iLow-risk features: ≤40 y and gross total resection (GTR).

jHigh-risk features: >40 y or subtotal resection (STR) or open or stereotactic biopsy.

Other high-risk factors that are sometimes taken into consideration are tumor size, neurologic deficits, and presence of sequencing verified IDH wild type.

kRegular follow-up is essential for patients receiving observation alone after resection.

lIn the event that other risk factors are considered and treatment is warranted, treat as high risk. There may also be rare circumstances in which treating a patient with fractionated external beam RT alone (category 2B) or chemotherapy alone

(category 2B) may be considered. See Principles of Brain and Spinal Cord Tumor Radiation (BRAIN-C) or Principles of Brain and Spinal Cord Tumor Systemic Therapy (BRAIN-D).

mFor low-grade gliomas, See Principles of Brain and Spinal Cord Tumor Radiation Therapy (BRAIN-C).

nSee Principles of Brain and Spinal Cord Tumor Systemic Therapy (BRAIN-D).

oThe results of RTOG 9802 showed that there was a significant improvement in median overall survival in high-risk low-grade glioma patients treated with RT followed by PCV x 6 cycles compared with RT alone after a tissue diagnosis was made. However, this important study did not address whether all of these patients should be treated right away. Observation after diagnosis may be a reasonable option for a high-risk low-grade glioma patient who is neurologically asymptomatic or stable. Close monitoring with brain MRIs is important.

Infiltrative Supratentorial Astrocytoma/Oligodendroglioma

(11)

ASTR-3

dPostoperative brain MRI within 48 hours after surgery.

mFor low-grade gliomas, See Principles of Brain and Spinal Cord Tumor Radiation Therapy (BRAIN-C).

pIf GTR is achieved in a patient with low-risk disease, consider further observation.

qRecurrence on neuroimaging can be confounded by treatment effects. To confirm

tumor recurrence and assess for possible transformation of tumor to higher grade, strongly consider tumor tissue sampling (biopsy at minimum) if there is a high index of suspicion of recurrence. Sixty percent or more of astrocytomas and 40%–50% of oligodendrogliomas will eventually undergo transformation to a higher grade. For treatment of patients with transformation to high-grade disease, see GLIO-1.

rBrain MRI every 2–3 months while on treatment, then every 6 months indefinitely, to assess disease recurrence/progression during treatment with chemotherapy.

(See BRAIN-A).

sRT alone is not encouraged, but may be appropriate for select cases (eg, poor performance status).

RECURRENCE^p

Recurrent orprogressive, low-grade disease^p

Prior

fractionated external beam RT^m

No prior fractionated external beam RT^m

Resectable

Unresectable

Resectable

Unresectable

Surgery^e,f,p

Consider clinical trial (preferred for eligible patients) Change chemotherapy regimen^n,r

orChemotherapy^n,r

or Consider reirradiation with highly focused RT^m± chemotherapy^n,rin select cases, if new lesion outside target of prior RT or the recurrence is small and geometrically favorable

or Consider observation for patients with low-risk disease orPalliative/best supportive care

Consider clinical trial (preferred for eligible patients) or RT^m+ adjuvant PCV^r

RT^m+ adjuvant TMZ^r

RT^m+ concurrent and adjuvant TMZ^r orFractionated external beam RT^m,s orChemotherapy^n,r(category 2B) Brain MRI^a,d

Brain MRI^a,d Consider

biopsy^f,q

Consider biopsy^f,q

Surgery^e,f,p

TREATMENT

Infiltrative Supratentorial Astrocytoma/Oligodendroglioma

(12)

GLIO-1 RADIOLOGIC

PRESENTATION^b CLINICAL

IMPRESSION SURGERY^c PATHOLOGY^d

MRI suggestive of high-grade glioma^e,f

Multidisciplinary input for

treatment planning if feasible

Maximal safe resection feasible with goal for image-verified complete resection

Maximal safe

resection not feasible

Stereotactic biopsy or Open biopsy

orSubtotal resection (MRI after resection)ⁱ

Brain MRI^b^,ⁱ • Anaplastic

• Anaplastic

oligoastrocytoma^j

• Anaplastic astrocytoma

• Anaplastic gliomas

Glioblastoma^k

See Adjuvant Treatment (GLIO-2)

See Adjuvant Treatment (GLIO-3) Maximal safe

resection^g,h

aThis pathway includes the classification of mixed anaplastic oligoastrocytoma (AOA), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and other rare anaplastic gliomas.

bSee Principles of Brain and Spine Tumor Imaging (BRAIN-A).

cSee Principles of Brain Tumor Surgery (BRAIN-B).

dSee Principles of Brain Tumor Pathology (BRAIN-F).

eBiopsy prior to administration of steroids if MRI compatible with CNS lymphoma.

fConsider a multidisciplinary review in treatment planning, especially once pathology is available. See Principles of Brain and Spine Tumor Management (BRAIN-E).

gIf frozen section diagnosis supports high-grade glioma.

hConsider carmustine (BCNU) wafer implant during maximal safe resection (category 2B). Treatment with carmustine wafer may impact enrollment in adjuvant clinical trials.

iPostoperative brain MRI within 48 hours after surgery.

jThe 2016 WHO Classification of Tumors of the CNS has deleted

oligoastrocytoma as a category, although “anaplastic oligoastrocytoma, NOS”

may continue to be used for 1) patients with mixed histology and no available molecular data (ie, no tissue available for analysis) for determining whether to classify as oligodendroglioma versus astrocytoma; or 2) rare instances in which the tumor has regions with histologic features of oligoastrocytoma with 1p19q-codeletion, and distinct regions with histologic features of astrocytoma without 1p19q-codeletion.

kThis pathway also includes gliosarcoma.

Anaplastic Gliomas /Glioblastoma

(13)

GLIO-2

PATHOLOGY^d ADJUVANT TREATMENT FOLLOW-UP^b

See Recurrence (GLIO-5) Anaplastic

oligodendroglioma (1p19q codeleted)

Consider clinical trial (preferred for eligible patients)

or Standard RT^l and neoadjuvant or adjuvant^m PCV (category 1)ⁿ orStandard RT^l with concurrent and adjuvant temozolomideⁿ orStandard RT^l and adjuvant temozolomideⁿ

Brain MRI 2–8 wks after RT,^p then every 2–4 mo for 3 y, then every 3–6 months indefinitely

Anaplastic astrocytoma, Anaplastic

oligoastrocytoma, NOS^j

Consider clinical trial (preferred for eligible patients) or Standard RT followed by adjuvant temozolomideⁿ

orStandard RT^l with concurrent and adjuvant temozolomideⁿ or Standard RT^l + neoadjuvant or adjuvant^m PCV

Anaplastic gliomas^a Poor performance status (KPS <60)

RT^l(hypofractionated [preferred] or standard) or Temozolomide (category 2B)^n,o

or Palliative/best supportive care

ANAPLASTIC GLIOMAS (SEE GLIO-3/GLIO-4 FOR GLIOBLASTOMA)

aThis pathway includes the classification of mixed AOA, AA, AO, and other rare anaplastic gliomas.

jThe 2016 WHO Classification of Tumors of the CNS has deleted oligoastrocytoma as a category, although “anaplastic oligoastrocytoma, NOS” may continue to be used for 1) patients with mixed histology and no available molecular data (ie, no tissue available for analysis) for determining whether to classify as oligodendroglioma versus astrocytoma; or 2) rare instances in which the tumor has regions with histologic features of oligoastrocytoma with 1p19q-codeletion, and distinct regions with

histologic features of astrocytoma without 1p19q-codeletion.

lSee Principles of Brain and Spinal Cord Tumor Radiation Therapy (BRAIN-C).

mThe panel recommends that PCV be administered after RT (as per EORTC 26951) since the intensive PCV regimen given prior to RT (RTOG 9402) was not tolerated as well.

oConsider temozolomide if tumor is MGMT promoter methylated.

pWithin the first 3 months after completion of RT and concomitant temozolomide, diagnosis of recurrence can be indistinguishable from pseudoprogression on neuroimaging.

Anaplastic Gliomas /Glioblastoma

(14)

GLIO-3

ADJUVANT TREATMENT FOLLOW-UP^b

Glioblastoma^k

Good

performance status (KPS ≥60)

Poor

performance status (KPS <60)

Consider clinical trial (preferred for eligible patients) or Standard brain RT^l+ concurrent temozolomide and adjuvant temozolomide + alternating electric field therapy (category 1)^n,r,s,v

orStandard brain RT^l+ concurrent temozolomide and adjuvant temozolomide (category 1)^n,r,s

orStandard brain RT^l+ concurrent and adjuvant lomustine and temozolomide (category 2B)^n,r,s,t

Brain MRI 2–8 wks after RT,^p then every 2–4 mo for 3 y, then every 3–6 mo indefinitely

See Recurrence (GLIO-5) GLIOBLASTOMA

PATHOLOGY^d

Age ≤70 y

Age >70 y

Hypofractionated brain RT^l(preferred) ± concurrent or adjuvant temozolomideⁿ

orTemozolomide^n,o

orPalliative/best supportive care

qMGMT= O6-methylguanine-DNA methyltransferase.

rCombination of modalities may lead to increased toxicity or radiographic changes.

sBenefit of treatment with temozolomide for glioblastomas beyond 6 months is unknown.

tModerate to significant myelosuppression was observed, but the toxicity profile for this regimen is not yet fully defined.

uClinical benefit from temozolomide is likely to be lower in patients whose tumors lack MGMT promoter methylation.

vAlternating electric field therapy is only an option for patients with supratentorial disease.

Methylated

Unmethylated or indeterminate

Consider clinical trial (preferred for eligible patients) or Standard brain RT^l+ concurrent temozolomide^uand adjuvant temozolomide^u+ alternating electric field therapy (category 1)^n,r,s,v

orStandard brain RT^l+ concurrent temozolomide^uand adjuvant temozolomide (category 1)^n,r,s,u

or Standard brain RT alone^l

See GLIO-4

MGMT^q PROMOTER STATUS

Anaplastic Gliomas /Glioblastoma

(15)

GLIO-4

ADJUVANT TREATMENT FOLLOW-UP^b

Brain MRI 2–8 wks after RT,^p then every 2–4 mo for 3 y, then every 3–6 mo indefinitely

See Recurrence (GLIO-5) GLIOBLASTOMA

PATHOLOGY^d

Age >70 y Glioblastoma^k,w

Hypofractionated brain RT alone^l orTemozolomide^n,o

orPalliative/best supportive care Good

performance status (KPS ≥60)

Poor performance status (KPS <60)

Methylated

Unmethylated or indeterminate

Consider clinical trial (preferred for eligible patients) or Hypofractionated brain RT^l

+ concurrent and adjuvant temozolomide (category 1)^n,r,s

orStandard RT^l+ concurrent temozolomide and adjuvant temozolomide + alternating electric field therapy (category 1)^n,r,s,v

orStandard RT^l+ concurrent temozolomide and adjuvant temozolomide^n,r,s or Temozolomideⁿ

orHypofractionated brain RT alone^l

Consider clinical trial (preferred for eligible patients)

or Standard RT^l+ concurrent temozolomide^uand adjuvant temozolomide^u + alternating electric field therapy (category 1)^n,r,s,v

or Standard RT^l+ concurrent temozolomide^uand adjuvant temozolomide^n,r,s,u orHypofractionated brain RT^l

+ concurrent and adjuvant temozolomide^n,r,s or Hypofractionated brain RT alone^l

MGMT^q PROMOTER STATUS

qMGMT= O6-methylguanine-DNA methyltransferase.

rCombination of modalities may lead to increased toxicity or radiographic changes.

sBenefit of treatment with temozolomide for glioblastomas beyond 6 months is unknown.

uClinical benefit from temozolomide is likely to be lower in patients whose tumors lack MGMT promoter methylation.

vAlternating electric field therapy is only an option for patients with supratentorial disease.

wSee NCCN Guidelines for Older Adult Oncology.

Anaplastic Gliomas /Glioblastoma

(16)

GLIO-5

RECURRENCE TREATMENT^y

Recurrent disease^p,zfor:

• Anaplastic

oligoastrocytoma, NOS^j

• Anaplastic astrocytoma

• Anaplastic gliomas

• Glioblastoma

Diffuse ormultiple

Local

Resectable

Unresectable or resection not recommended/

elected

Consider clinical trials (preferred for eligible patients)

orSystemic chemotherapy^n,aa

or Surgery for symptomatic, large lesion or Consider alternating electric field therapy for glioblastoma (category 2B)

orPalliative/best supportive care if poor performance status

Consider clinical trials (preferred for eligible patients)

orSystemic chemotherapy^n,aa

orConsider reirradiation (category 2B)^l,bb or Consider alternating electric field therapy for glioblastoma (category 2B)

orPalliative/best supportive care if poor performance status

Palliative/best supportive care See NCCN Guidelines For Palliative Care Brain MRI^b,i

Consider clinical trial orResection^x

iPostoperative brain MRI within 48 hours after surgery.

jThe 2016 WHO Classification of Tumors of the CNS has deleted oligoastrocytoma as a category, although “anaplastic oligoastrocytoma, NOS” may continue to be used for 1) patients with mixed histology and no available molecular data (ie, no tissue available for analysis) for determining whether to classify as oligodendroglioma versus astrocytoma; or 2) rare instances in which the tumor has regions with histologic features of oligoastrocytoma with 1p19q-codeletion, and distinct regions with histologic features of astrocytoma without 1p19q-codeletion.

xConsider carmustine (BCNU) wafer implant during resection. Treatment with carmustine wafer may impact enrollment in clinical trials.

yThe efficacy of standard-of-care treatment for recurrent glioblastoma is suboptimal, so for eligible patients consideration of clinical trials is highly encouraged. Prior treatment may impact enrollment in clinical trials.

zConsider biopsy, MR spectroscopy, MR perfusion, brain PET/CT, or brain PET/MRI, or re- image to follow changes that may be due to progression versus radionecrosis.

aaAnaplastic oligodendrogliomas have been reported to be especially sensitive to

chemotherapy. Chemotherapy using temozolomide or nitrosourea-based regimens may be appropriate.

bbEspecially if long interval since prior RT and/or if there was a good response to prior RT.

Anaplastic Gliomas /Glioblastoma

(17)

EPEN-1

bConsider a multidisciplinary review in treatment planning, especially once pathology is available. See Principles of Brain and Spine Tumor Management (BRAIN-E).

cIf image-confirmed GTR not achieved, consider multidisciplinary review and reresection.

dSee Principles of Brain Tumor Surgery (BRAIN-B).

eTesting for RELA fusion may be recommended for ependymomas. See Principles of Brain Tumor Pathology (BRAIN-F).

RADIOLOGIC

PRESENTATION^a CLINICAL

IMPRESSION SURGERY^d PATHOLOGY^e

Contrast-enhanced MRI/CT compatible with primary brain tumor or spinal cord tumor^b

Gross total resection feasible^c

Gross total resection not feasible

Gross total resection

Stereotactic biopsy or Open biopsy

or Subtotal resection

Intracranial ependymoma

(supratentorial, posterior fossa)

Spinal ependymoma

See Adjuvant Treatment (EPEN-2)

See Adjuvant Treatment (EPEN-3)

(Excluding Subependymoma)

(18)

EPEN-2 INTRACRANIAL EPENDYMOMA

POSTOPERATIVE STAGING

PATHOLOGY ADJUVANT TREATMENTⁱ

Ependymoma (GradeII)

Anaplastic ependymoma (Grade III)

Brain and spine MRI;^a,f,g CSF analysis^h

SeeFollow-up andRecurrence (EPEN-4)

MRI spine negative, CSF negative

Evidence of metastasis (brain, spine, or CSF)

Standard RTⁱ

Craniospinal RTⁱ^,^k Brain and

spine MRI;^a,f,g Cerebrospinal fluid (CSF) analysis^h Consider

re-operation to complete resection

MRI spine negative, CSF negative

Evidence of metastasis (brain, spine, or CSF)

Standard RTⁱ or Observe^j

Standard RTⁱ

Craniospinal RTⁱ^,^k Post gross

total resection

Post stereotactic or open biopsy or Subtotal resection

Post gross total resection

Post biopsy or subtotal resection

Post gross total resection

Post stereotactic or open biopsy or Subtotal resection

fPostoperative brain MRI within 48 hours after surgery.

gIf not done preoperatively, spine MRI should be delayed by at least 2–3 weeks post surgery to avoid post-surgical artifacts.

hLumbar puncture is indicated when there is clinical concern for meningeal dissemination. Lumbar puncture should be done after MRI of spine is performed to avoid a false-positive imaging result. Lumbar puncture for CSF should be

delayed at least 2 weeks after surgery to avoid possible false-positive cytology.

Lumbar puncture may be contraindicated (eg, posterior fossa mass).

iSee Principles of Brain and Spinal Cord Tumor Radiation Therapy (BRAIN-C).

jData supporting observation alone are based on retrospective studies.

kConsider proton therapy if available to reduce toxicity.

Consider re-operation to complete resection