Central Nervous System Cancers

Transcription

1 Clinical in Oncology Central Nervous System Cancers V Continue

2 * Steven S. Brem, MD/Chair H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida Panel Members Mark R. Gilbert, MD The University of Texas M. D. Anderson Cancer Center Alessandro Olivi, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Philip J. Bierman, MD UNMC Eppley Cancer Center at The Nebraska Medical Center Peter Black, MD, PhD Dana-Farber/Partners CancerCare Deborah T. Blumenthal, MD Huntsman Cancer Institute at the University of Utah * Henry Brem, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Marc C. Chamberlain, MD H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida Ennio A. Chiocca, MD, PhD Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University * Lisa M. DeAngelis, MD Memorial Sloan-Kettering Cancer Center Robert A. Fenstermaker, MD Roswell Park Cancer Institute Howard A. Fine, MD Consultant Allan Friedman, MD Duke Comprehensive Cancer Center Jon Glass, MD Fox Chase Cancer Center Stuart A. Grossman, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Amy B. Heimberger, MD The University of Texas M. D. Anderson Cancer Center * Larry Junck, MD University of Michigan Comprehensive Cancer Center * Jay J. Loeffler, MD Dana-Farber/Partners CancerCare * Moshe H. Maor, MD The University of Texas M. D. Anderson Cancer Center Burt Nabors, MD University of Alabama at Birmingham Comprehensive Cancer Center Ashwatha Narayana, MD Memorial Sloan-Kettering Cancer Center Herbert B. Newton, MD Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University Continue * Jana Portnow, MD City of Hope Cancer Center Michael Prados, MD UCSF Comprehensive Cancer Center Jeffrey J. Raizer, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University Dennis C. Shrieve, MD, PhD Huntsman Cancer Institute at the University of Utah Allen K. Sills, Jr., MD St. Jude Children s Research Hospital/University of Tennessee Cancer Institute Alexander M. Spence, MD Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance * Frank D. Vrionis, MD, MPH, PhD H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida Medical oncology Hematology/Hematology oncology Radiotherapy/Radiation oncology Neurology/neuro-oncology Surgery/Surgical oncology * Writing committee member Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of.

3 Table of Contents Panel Members Adult Low-Grade Infiltrative Supratentorial Astrocytoma/ Oligodendroglioma (excluding pilocytic astrocytoma) (ASTR-1) Adult Intracranial Ependymoma (EPEN-1) Anaplastic Astrocytoma/Anaplastic Oligodendroglioma/ Glioblastoma Multiforme (GLIO-1) Limited (1-3) Metastatic Lesions (LTD-1) Multiple (>3) Metastatic Lesions (MU-1) Carcinomatous/Lymphomatous Meningitis (CLMEN-1) Nonimmunosuppressed Primary CNS Lymphoma (PCNS-1) Metastatic Spine Tumors (SPINE-1) Principles of Brain Tumor Therapy: Surgical Issues (BRAIN-1) Radiation Therapy Guidelines (BRAIN-2) Print the Guideline For help using these documents, please click here Manuscript References Clinical Trials: The believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at member institutions, click here: nccn.org/clinical_trials/physician.html Categories of Consensus: All recommendations are Category 2A unless otherwise specified. See Categories of Consensus Summary of Guidelines Updates These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these 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 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. These guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any form without the express written permission of Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of.

4 RADIOLOGIC PRESENTATION CLINICAL IMPRESSION Adult Low-Grade Infiltrative Supratentorial Astrocytoma/Oligodendroglioma (Excluding Pilocytic Astrocytoma) SURGERY c ADJUVANT TREATMENT FOLLOW-UP Maximal safe resection feasible Maximal excision MRI d Age>45y Age 45 y Observe or RT e,f Observe f MRI compatible with primary brain tumor a Maximal safe resection not feasible Stereotactic or open biopsy Uncontrolled or progressive symptoms Stable/controlled symptoms RTe or Chemotherapy (category 2B) RTe or Observef or Chemotherapy (category 2B) MRI every 3-6 mo for 5 y then less frequently See Recurrence (ASTR-2) Observation b abiopsy first if MRI compatible with CNS lymphoma. bsurgery is generally recommended, but serial observations are appropriate for selected patients. csee Surgical Issues (BRAIN-1). dpost-op MRI should be done within 72 hours after surgery. esee Radiation Therapy Guidelines (BRAIN-2). fregular follow-up is essential for patients receiving observation alone after resection. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. ASTR-1

5 Adult Low-Grade Infiltrative Supratentorial Astrocytoma/Oligodendroglioma (Excluding Pilocytic Astrocytoma) RECURRENCE Prior RT Resectable Unresectable Surgery c Chemotherapy Chemotherapy Progression Progression Reirradiation, especially if progression free survival is greater than 2 y after prior RT or if new lesion outside target of prior RT or the recurrence is small and geometrically favorable Recurrent progressive, low-grade disease g Resectable Surgery c No prior RT RT e ± chemotherapy Unresectable csee Surgical Issues (BRAIN-1). esee Radiation Therapy Guidelines (BRAIN-2). g Oligodendrogliomas, particularly those that have chromosomal loss of 1p or combined 1p19q loss, have been reported to be sensitive to alkylator chemotherapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. ASTR-2

6 Adult Intracranial Ependymoma RADIOLOGIC PRESENTATION CLINICAL IMPRESSION SURGERY b PATHOLOGY Maximal resection feasible Maximal excision Ependymoma or Anaplastic ependymoma Contrast enhanced MRI/CT compatible with primary brain tumor a See Adjuvant Treatment (EPEN-2) Maximal resection not feasible Stereotactic or open biopsy Ependymoma or Anaplastic ependymoma abiopsy first if MRI compatible with CNS lymphoma. bsee Surgical Issues (BRAIN-1). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. EPEN-1

7 Adult Intracranial Ependymoma PATHOLOGY POSTOPERATIVE STAGING ADJUVANT TREATMENT e Ependymoma, status post maximal resection Contrast enhanced brainc and spine MRI; d Consider CSF analysis Total resection, MRI ± CSF spine negative Subtotal resection, MRI ± CSF spine negative Total or subtotal resection, MRI ± CSF spine positive Limited-field RTe or Observe (category 2B for observation) Limited-field RT e Craniospinal RT e Anaplastic ependymoma, status post maximal resection Contrast enhanced brainc and spine MRI; d Consider CSF analysis Total or subtotal resection, MRI ± CSF spine negative Total or subtotal resection, MRI ± CSF spine positive Limited-field RT e Craniospinal RT e See Follow-up and Recurrence (EPEN-3) Ependymoma or anaplastic ependymoma status post stereotactic or open biospy Contrast enhanced brainc and spine MRI; d Consider CSF analysis MRI ± CSF spine negative MRI ± CSF spine positive Limited-field RT e Craniospinal RT e c Within hours. ddelayed by 2-3 weeks post surgery. esee Radiation Therapy Guidelines (BRAIN-2). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. EPEN-2

8 Adult Intracranial Ependymoma FOLLOW-UP RECURRENCE Brain and spine MRI (if initially positive) every 3 4 mo for 1 y, then every 4-6 mo for year 2, then every 6-12 mo Spine or brain recurrence Resectable Unresectable Resection with RT, if no prior RT e RT, f if no prior RTe Consider chemotherapy or Consider RT or Best supportive care Consider chemotherapy or Best supportive care e See Radiation Therapy Guidelines (BRAIN-2). f Consider SRS if geometrically favorable. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. EPEN-3

9 Anaplastic Astrocytoma/Anaplastic Oligodendroglioma/Glioblastoma Multiforme RADIOLOGIC PRESENTATION CLINICAL IMPRESSION SURGERY b PATHOLOGY MRI suggestive of high-grade glioma a Multidisciplinary input for treatment planning if feasible Maximal resection feasible Maximal resection not feasible Maximal excision ± BCNU waferc (category 2B) Stereotactic or open biopsy MRI d Anaplastic astrocytoma (AA) Anaplastic oligodendroglioma (AO) Glioblastoma multiforme (GBM) See Adjuvant Treatment (GLIO-2) abiopsy first if MRI compatible with CNS lymphoma. bsee Surgical Issues (BRAIN-1). cif frozen section diagnosis supports high-grade glioma. dpost-op MRI should be done within 72 hours after surgery. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. GLIO-1

10 Anaplastic Astrocytoma/Anaplastic Oligodendroglioma/Glioblastoma Multiforme PATHOLOGY ADJUVANT TREATMENT FOLLOW-UP Anaplastic astrocytoma (AA) Anaplastic oligodendroglioma (AO) Treated with BCNU wafer No BCNU wafer RT e ± chemotherapy Observe or Post RT chemotherapy Age<70y Good performance status AO > AA MRI 2-6 wk after RT, then every 2-3 mo for 2-3 y See Recurrence (GLIO-3) Treated with BCNU wafer RT e ± chemotherapy Glioblastoma multiforme (GBM) No BCNU wafer RT e ± concurrent and adjuvant temozolomide (category 1) f Age<70y Good performance status MRI 2-6 wk after RT, then every 2-3 mo for 2-3 y See Recurrence (GLIO-3) e See Radiation Therapy Guidelines (BRAIN-2). f Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352: Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. GLIO-2

11 Anaplastic Astrocytoma/Anaplastic Oligodendroglioma/Glioblastoma Multiforme RECURRENCE SALVAGE Diffuse or multiple Best supportive care if poor performance status or Systemic chemotherapyg,h or Surgery for symptomatic, large lesion Recurrent disease Resection + BCNU polymer Consider highly conformal RTe (category 2B) Best supportive care Resectable Local Resection without BCNU polymer Systemic chemotherapyg,h or Reirradiation Unresectable Highly conformal RTe or Systemic chemotherapyg,h Chemotherapy using temozolomide or nitrosourea- e See Radiation Therapy Guidelines (BRAIN-2). ganaplastic oligodendrogliomas have been reported to be especially sensitive to chemotherapy. based regimens may be appropriate. ha response after two consecutive failures is unlikely. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. GLIO-3

12 Limited ( 1-3) Metastatic Lesions CLINICAL PRESENTATION WORKUP If concern exists regarding diagnosis of CNS lesions Stereotactic or open biopsy/resection 1-3 metastatic lesions on MRI Known history of cancer See Clinical Presentation and Primary Treatment (LTD-2) No known history of cancer Chest x-ray/ct Abdominal/ pelvic CT Other tests as indicated No other readily accessible tumor for biopsy Stereotactic or open biopsy/resection Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. LTD-1

13 Limited (1-3) Metastatic Lesions CLINICAL PRESENTATION PRIMARY TREATMENT c,d Small cell lung cancer or Disseminated systemic disease with poor systemic treatment options a Limited systemic disease or Reasonable systemic treatment options Resectable b Surgical resection, consider WBRT or Stereotactic radiosurgery (SRS), consider WBRT Brain MRI Whole-brain RT Observe or Whole-brain RT (WBRT) d See Follow-up and Recurrence (LTD-3) Unresectable Whole-brain RTd and/or radiosurgery a Consider surgery to relieve mass effect. b Choice of therapy depends in part on size of lesion, eg, small (< 2cm), deep, non-symptomatic lesions may consider treatment with SRS versus larger, symptomatic lesions that may be more appropriate for surgery. Decisions also depend on institutional practice. csee Surgical Issues (BRAIN-1). dsee Radiation Therapy Guidelines (BRAIN-2). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. LTD-2

14 Limited (1-3) Metastatic Lesions FOLLOW-UP RECURRENCE TREATMENT MRI every 3mofor 1 y then as clinically indicated Recurrent disease; local site Recurrent disease; distant brain Previous surgery or WBRT Prior stereotactic radiosurgery ± WBRT 1-3 lesions Surgery or Stereotactic radiosurgery Surgery Surgery or Stereotactic radiosurgery or WBRT If patient relapses, See LTD-4 > 3 lesions WBRT; Consider chemotherapy Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. LTD-3

15 Limited (1-3) Metastatic Lesions RECURRENCE TREATMENT d No prior RT Whole-brain RT Systemic disease progression, with limited systemic treatment options a Prior RT Best supportive care or Chemotherapye or Reirradiation, if prior positive response to RT or Highly conformal RT a Consider surgery to relieve mass effect. dsee Radiation Therapy Guidelines (BRAIN-2). echemotherapy selection consistent with sensitivity of primary site. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. LTD-4

16 Multiple ( >3) Metastatic Lesions CLINICAL PRESENTATION WORKUP PRIMARY TREATMENT b If concern exists regarding diagnosis of CNS lesions Stereotactic or open biopsy/resection a Multiple (> 3) metastatic lesions on CT or MRI Known history of cancer No known history of cancer CBC Chest x-ray/ct Abdominal/ pelvic CT Other tests as indicated No other readily accessible tumor for biopsy Stereotactic or open biopsy/resection a Whole-brain irradiation ± stereotactic radiosurgery c See Follow-up and Recurrence (MU-2) aconsider surgery to relieve mass effect. bsee Radiation Therapy Guidelines (BRAIN-2). c SRS should only be considered in selected cases (eg, limited number of lesions). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. MU-1

17 Multiple ( >3) Metastatic Lesions FOLLOW-UP RECURRENCE TREATMENT Systemic disease progression, with limited systemic treatment options a Best supportive care or Chemotherapy or Reirradiation if prior positive response to RT MRI every 3mofor1y Recurrent disease Stable systemic disease or reasonable systemic treatment options Surgery or Highly conformal RT or Reirradiation if prior positive response to RT or Chemotherapy or Stereotactic radiosurgery a Consider surgery to relieve mass effect. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. MU-2

18 Carcinomatous/Lymphomatous Meningitis WORKUP DIAGNOSIS RISK STATUS Signs and symptoms suggestive of leptomeningeal disease Physical exam with careful neurologic evaluation Consider brain and spine MRI if patient is a candidate for treatment CSF exam (if safe) Positive CSF cytology or Positive radiologic findings with supportive clinical or CSF findings in a patient known to have a malignancy or Signs and symptoms with supportive CSF in a patient known to have a malignancy Poor risk a: Low KPS Multiple, serious, major neurologic deficits Extensive systemic disease with few treatment options Bulky CNS disease Encephalopathy Good risk: High KPS No major neurologic deficits Minimal systemic disease Reasonable systemic treatment options, if needed See Treatment (CLMEN-2) See Treatment (CLMEN-2) a Patients with exceptionally chemosensitive tumors, eg, SCLC, lymphoma; may be treated. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. CLMEN-1

19 Carcinomatous/Lymphomatous Meningitis RISK STATUS TREATMENT Poor risk a: Low KPS Multiple, serious, major neurologic deficits Extensive systemic disease with few treatment options Bulky CNS disease Encephalopathy Consider RT to symptomatic sites and Supportive care Good risk: High KPS No major neurologic deficits Minimal systemic disease Reasonable systemic treatment options, if needed Initial intrathecal or intraventricular chemotherapy b + RT to bulky disease, symptomatic sites and Consider systemic chemotherapy Strongly consider CSF flow scan via subcutaneous reservoir with ventricular catheter See CSF flow scan results (CLMEN-3) a b Patients with exceptionally chemosensitive tumors, eg, SCLC, lymphoma; may be treated. Initiation of chemotherapy should not be delayed for flow study. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. CLMEN-2

20 Carcinomatous/Lymphomatous Meningitis PRIMARY TREATMENT Normal flow Induction intrathecal chemotherapy for 4-6 wk, if otherwise stable disease Reassess CSF from site where CSF cytology was originally positive; if CSF cytology was originally negative reassess from lumbar region See CSF cytology negative (CLMEN-4) See CSF cytology positive (CLMEN-4) CSF flow scan Flow abnormalities RT to sites of obstruction ± intrathecal chemotherapy Repeat CSF flow scan Normal flow Flow abnormalities See pathway for normal flow, above See Treatment for poor risk (CLMEN-2) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. CLMEN-3

21 Carcinomatous/Lymphomatous Meningitis POSTINDUCTION THERAPY CSF cytology negative Continue induction intrathecal chemotherapy for1mo Maintenance intrathecal chemotherapy and Monitor CSF cytology every month CSF cytology positive Patient clinically stable or improving and there is no evidence of clinical or radiologic progression of leptomeningeal disease Continue induction intrathecal chemotherapy for 4 wk or Consider switching intrathecal drugs for 4 wk Negative cytology Cytology continually positive and/or evidence of clinical or radiologic progression of leptomeningeal disease Evidence of clinical or radiologic progression of leptomeningeal disease Supportive care, which may include RT to symptom sites or Chemotherapy Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. CLMEN-4

22 Nonimmunosuppressed Primary CNS Lymphoma DIAGNOSIS BY TISSUE EVALUATION Positive diagnosis of primary CNS lymphoma See Primary Treatment (PCNS-2) CT/MRI suggestive of lymphoma Hold steroids, if possible CSF sample or Eye exam with biopsy for tissue or Brain biopsy with hematopathology review of all slides Biopsy not diagnostic of primary CNS lymphoma See Primary Treatment (PCNS-2) Other CNS tumor See CNS guidelines Table of Contents Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. PCNS-1

23 Nonimmunosuppressed Primary CNS Lymphoma STAGING EVALUATION/WORK-UP PRIMARY TREATMENT Positive diagnosis of primary CNS lymphoma Slit lamp eye exam Lumbar puncture, (LP) if safe MRI HIV Chest x-ray CBC, platelets, liver function tests KPS 40a,b and creatinine clearance 50 KPS<40 a,b or creatinine clearance < 50 High-dose ( 3g/m 2) methotrexatebased regimen c ± RTe,f If LP positive or spinal MRI positive, consider intrathecal chemotherapy Whole-brain RT (45 Gy) If eye exam positive, RT to orbits If LP positive or spinal MRI positive, consider intrathecal chemotherapy + focal spinal RT or Chemotherapy d Biopsy not diagnostic of primary CNS lymphoma Prior steroids No prior steroids Discontinue steroids and rebiopsy when disease progresses Work-up for other CNS diagnosis or rebiopsy akps may improve dramatically with steroids. bage and performance status guidelines have not been firmly established and consultation between physician and patient regarding risks and benefits of aggressive therapy is mandatory. cparticipation in clinical trials is highly recommended. dconsider alternate chemotherapy regimens for patients who cannot tolerate methotrexate. eavoid RT in patients over 60 years of age when possible. f If eye exam positive, monitor carefully for response to treatment. Consider RT to orbits or intraorbital chemotherapy. See Progressive Disease (PCNS-3) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. PCNS-2

24 Nonimmunosuppressed Primary CNS Lymphoma PROGRESSIVE DISEASE TREATMENT Prior wholebrain RT Consider chemotherapy ± intrathecal chemotherapy ± spinal RT Progressive disease Prior high-dose methotrexatebased regimen without prior RT Previous response with long duration No response or short duration Re-treat with high-dose methotrexate-based regimen Consider WBRT or involved field RT± chemotherapy Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. PCNS-3

25 Metastatic Spine Tumors PRESENTATION WORKUP TREATMENT Incidental finding (asymptomatic) Possible biopsy Treatment (surgery or focal RT or chemotherapy) or Close observation (MRI follow-up in 2-3 months) No tumor Patient diagnosed with cancer Severe, rapidly increasing back pain Neurologic symptoms Neurologic exam No spinal radiculopathy/ myelopathy Abnormal Spinal MRI a (Urgent) Spinal MRIa Steroidsb See Pain Guidelines Spinal cord compression Metastases to spine; no compression See SPINE-2 aif the patient is unable to have an MRI, then a CT myelogram is recommended. bthe recommended minimum dose of steroids is 4 mg of dexamethasone every 6 hours, although dose of steroids may vary ( mg). Methylprednisolone can be used instead of dexamethasone. For rapid neurologic deterioration or significant myelopathy, a stat MRI is recommended. A randomized trial supported the use of high-dose steroids (Sorensen PS, Helweg-Larsen S, Mouridsen H, Hansen HH. Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: A randomized trial. Eur J Cancer 1994;30A:22-27). Steroid use should be tapered within 3 days. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. SPINE-1

26 Metastatic Spine Tumors PRESENTATION TREATMENT No tumor Evaluate for other causes of pain and/or neurologic symptoms Pain management ( See Pain GL) Consider physical therapy Spinal cord Compression Strongly consider surgeryc,d if: Spinal instabilitye Radioresistantf Rapid neurologic deterioration Unknown primary Previous RT RT g All others RTg Consider chemotherapy if chemosensitive tumor (eg, lymphoma, breast) Consider surgery if: Intractable painh Radiographic and/or clinical progression Metastases to spine; no compression Spinal instability No spinal instability Surgery or vertebroplasty Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. RT g Surgery if: Deterioration during RT Intractable painh Tumor progression csurgery could involve tumor resection with or without spinal stabilization. Spinal instrumentation is recommended if there is preoperative spinal instability or if instability is expected to occur after tumor resection. dcategory 1 evidence supports the role of surgery (Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366(9486): ) in patients willing to undergo surgery. espinal instability is grossly defined as the presence of significant kyphosis or subluxation (deformity), or of retropulsed bone fragment. f Radioresistant tumors include renal carcinoma, melanoma or sarcoma. gshort RT regimens given over 2 weeks or less. hintractable pain can be treated by implantation of a subarachnoid pump, tumor resection/stabilization, or vertebroplasty/kyphoplasty depending on stability, extent of disease, and location in the spinal column. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. SPINE-2

27 Principles of Brain Tumor Therapy SURGICAL ISSUES GUIDING PRINCIPLES Maximal tumor removal Minimal surgical morbidity Accurate diagnosis FACTORS Age PS Feasibility of decreasing the mass effect with surgery Resectability, including number of lesions, location of lesions, time since last surgery (recurrent patients) New versus recurrent tumor OPTIONS Gross total resection where feasible Stereotactic biopsy Open biopsy/debulking) TISSUE Maximum to pathologist Review by experienced neuropathologist Postoperative MRI should be performed within hours to determine the extent of resection Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BRAIN-1

28 Principles of Brain Tumor Therapy RADIATION THERAPY GUIDELINES RADIATION THERAPY (fractionated external beam) Field to include tumor volume and margins Dose to brain tumor: Gy/day to a total dose of Gy Hypofractionation in patients with poor performance status Prophylactic dose to spine (if indicated): Gy Dose for metastases: Gy HIGHLY CONFORMAL RADIATION THERAPY Brachytherapy Stereotactic fractionated radiotherapy Stereotactic radiosurgery IMRT Protons Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. BRAIN-2

29 Summary of the Guidelines updates Highlights of major changes in the version of the guidelines from the version include: Radiation Therapy: Dose for metastases changed from Gy to Gy (BRAIN-2). Highlights of major changes in the 2006 version of the guidelines from the version include: It was noted that brain MRI should be done within hours and spine MRI should be delayed 2-3 weeks postsurgery (EPEN-2). Consideration of RT was added as an option for resectable recurrence of adult intracranial ependymoma (EPEN-3). A footnote was added to clarify the use of BCNU wafer if frozen section supports the diagnosis of high-grade glioma (GLIO-1). Footnote g regarding chemotherapy with anaplastic oligodendrogliomas was clarified (GLIO-3). Brain and spine MRI are a consideration if the patient is a candidate for treatment (CLMEN-1). Consideration of RT to symptomatic sites was added as a treatment option for poor risk patients (CLMEN-2). A reference was added to footnote b (SPINE-1). Footnote f was changed to define RT as short regimens given over 2 weeks or less (SPINE-2). Gross total resection where feasible replaced major tumor removal (BRAIN-1). Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. UPDATES

30 Manuscript Categories of Consensus Category 1: There is uniform consensus, based on high-level evidence, that the recommendation is appropriate. Category 2A: There is uniform consensus, based on lowerlevel evidence including clinical experience, that the recommendation is appropriate. Category 2B: There is nonuniform consensus (but no major disagreement), based on lower-level evidence including clinical experience, that the recommendation is appropriate. Category 3: There is major disagreement that the recommendation is appropriate. All recommendations are category 2A unless otherwise noted. Overview In the year 2006, an estimated 18,820 new cases of primary brain and other nervous system neoplasms will be diagnosed in the United States. These tumors will be responsible for approximately 12,820 deaths. 1 The incidence of primary malignant brain tumors has been increasing over the last 25 years, especially in elderly persons (rates are increasing at about 1.2% each year). 2 Metastatic disease to the central nervous system (CNS) occurs much more frequently, with an incidence about 10 times that of primary brain tumors. It is estimated between 20% and 40% of patients with systemic cancer will develop brain metastases. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. Primary brain tumors range from the very uncommon, noninvasive, surgically curable, pilocytic astrocytomas to glioblastoma multiforme, the most common intraparenchymal brain tumor in adults, which is highly invasive and virtually incurable. Likewise, patients with metastatic brain disease may have rapidly progressive systemic disease or no systemic cancer at all. These patients may have one or dozens of brain metastases, and they may have a malignancy that is highly responsive or, alternatively, highly resistant to radiation or chemotherapy. Because of this marked heterogeneity, the prognostic features and treatment options for brain tumors must be carefully reviewed for each patient. The involvement of an interdisciplinary team (including neurosurgeons, radiation therapists, oncologists, neurologists, or neuroradiologists) is a key factor in the appropriate management of these patients. These CNS Cancers guidelines focus on management of adults with CNS cancers. Treatment Principles Several important principles guide surgical and radiation therapy (RT) for adults with primary brain tumors. Regardless of tumor histology, neurosurgeons generally provide the best outcome for their patients if they remove as much tumor as possible, keep surgical morbidity to a minimum, and ensure an accurate diagnosis (see BRAIN-1). Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. MS-1

31 Decisions regarding aggressiveness of surgery for a primary brain tumor are complex and depend on the (1) age and performance status (PS) of the patient; (2) proximity to eloquent areas of the brain; (3) feasibility of decreasing the mass effect with aggressive surgery; (4) resectability of the tumor (including the number and location of lesions); and (5) in patients with recurrent disease, the time since the last surgery. 3 The surgical options include stereotactic biopsy, open biopsy or debulking procedure, or gross total tumor resection where feasible, which is usually characterized as removal of more than 90% of a tumor. The pathologic diagnosis is critical and often difficult to determine accurately; therefore, as much tissue as possible should be delivered to the pathologist. Review by an experienced neuropathologist is highly recommended. In addition, a postoperative magnetic resonance imaging (MRI) scan, with and without contrast, should be obtained 24 to 72 hours after surgery to document the extent of disease after surgical intervention. Radiation therapists use several different treatment approaches in patients with primary brain tumors, including brachytherapy, stereotactic fractionated RT, and stereotactic radiosurgery. Threedimensional conformal external-beam radiation is the most common approach, but intensity-modulated radiation therapy (IMRT) may also be administered to selected patients. RT for patients with primary brain tumors usually involves only the tumor volume and margins (see BRAIN-2). Tumor volume is commonly defined as the region showing T2-weighted abnormalities on an MRI scan plus a 1- to 2-cm margin. Although the dose of radiation administered can vary, the total dose prescribed to most primary brain tumors is 45 to 60 Gy using 1.8 to 2.0 Gy/day. If the spine is also treated, it should receive a prophylactic dose of 24 to 36 Gy. The dose for metastases is 30 to 40 Gy. Hypofractionation can be administered to patients with poor PS to accelerate completion of therapy and to minimize the number of hospital visits. Tumor Types The CNS Cancer Guidelines focus on high-grade invasive astrocytomas, low-grade invasive astrocytomas, oligodendrogliomas, ependymomas, brain metastases, carcinomatous/lymphomatous meningitis, primary CNS lymphoma (non-aids), and metastatic spinal tumors. These guidelines are updated annually to include new information or treatment philosophies as they become available. However, because this field changes continually, practitioners should use all of the available information to determine the best clinical options for their patients with primary or metastatic brain tumors. High-Grade Invasive Astrocytomas Grade III (anaplastic astrocytoma) and grade IV (glioblastoma multiforme) astrocytomas are the most common primary brain tumors in adults and account for 2.3% of all cancer-related deaths. Glioblastoma multiforme tumors account for more than 50% of all gliomas, and 8000 to 10,000 new cases are diagnosed per year in North America; peak incidence occurs from ages 45 to 55 years. The Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. MS-2

32 high-grade astrocytomas diffusely infiltrate surrounding tissues and frequently cross the midline to involve the contralateral brain. Patients with these neoplasms often present with symptoms of increased intracranial pressure, seizures, or focal neurologic findings related to the size and location of the tumor and to associated peritumoral edema. These tumors usually do not have associated hemorrhage or calcification but produce considerable edema and mass effect in image study as well as enhance after the administration of intravenous contrast. Tumor cells have been found in the peritumoral edema, which corresponds to the T2-weighted MRI abnormalities. As a result, this volume is frequently used to define radiation treatment portals. It is difficult to assess the results of therapy using computerized tomographic (CT) scans or MRI scans, because the extent and distribution of contrast enhancement, edema, and mass effect are more a function of blood-brain barrier integrity than of changes in the size of the tumor. Thus, other factors that exacerbate blood-brain barrier dysfunction (such as surgery, radiation, and tapering of corticosteroids) can mimic tumor progression by increasing contrast enhancement, T2-weighted abnormalities, and mass effect. The most important prognostic factors in patients with high-grade astrocytomas are histologic diagnosis, age, PS, type and duration of symptoms, and extent of surgical resection. 4 Treatment Overview The goals of surgery are to obtain a diagnosis, alleviate symptoms related to increased intracranial pressure or compression, increase survival, and decrease the need for corticosteroids. The median survival with surgery alone is approximately 4 months. A prospective study in patients with malignant glioma showed that extensive surgery was valuable when compared with biopsy alone as a strong prognostic factor. 5 Most studies suggest that the extent of resection lengthens survival and is especially effective in patients older than 50 years with glioblastoma multiforme and a Karnofsky performance score (KPS) more than 70. Using current microneurosurgical techniques, it is possible to resect malignant gliomas in gross total fashion. An aggressive approach in which 98% or more of the tumor mass is resected results in a statistically significant survival advantage. 6 Surgery also improves the outcome for patients with recurrent high-grade astrocytomas. 7 Radiation is standard therapy for patients with high-grade astrocytomas after either maximal excision or biopsy, based on a randomized trial conducted in the 1970s comparing postoperative supportive care, carmustine (BCNU), radiation, and radiation plus BCNU. 8 Survival at 1 year was 3% with surgery alone, 12% with postoperative BCNU, and 24% with postoperative radiation. Currently, Gy (divided into 30 to 33 fractions) is administered to the involved field. A shorter course of radiation, such as 40 Gy in 15 fractions over 3 weeks, can be used in elderly patients with equivalent results. 9 Alternative doses, fractions, and schedules have been Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. MS-3

33 explored without significant improvements in adult patients with malignant gliomas. The role of focal radiation techniques in this diffusely infiltrative disease remains undefined. The Radiation Therapy Oncology Group (RTOG) conducted a randomized trial of conventional radiotherapy to 60 Gy and BCNU alone or preceded by a radiosurgery boost (to Gy) in patients with glioblastoma multiforme of 4 cm or less. 10 However, the results were disappointing with no improvement in local control or survival with stereotactic radiosurgery boost. Similarly, a trial done at Princess Margaret Hospital randomly assigned patients to 50 Gy external-beam radiation with or without temporary I-125 seed implant to 60 Gy; however, this trial did not show any survival benefit. 11 The Gliasite balloon has been approved by the FDA as a novel device to provide local postoperative irradiation to high-grade gliomas, but no efficacy trials have been conducted to date. 12 Traditionally, chemotherapy was felt to be of marginal value in the treatment of newly diagnosed patients with high-grade gliomas. Walker and colleagues did a randomized study of (1) a nitrosourea alone, versus (2) radiation alone, versus (3) radiation plus a nitrosourea. 13 Although a slight improvement in survival was noted at 18 months in the group of patients who were treated with radiation plus BCNU compared with those who had received radiation alone, the difference in survival curves between the two groups was not statistically significant. More than 20 years later (2001), the Medical Research Council reported results from the largest randomized trial of adjuvant chemotherapy in high-grade gliomas. 14 In this study, 674 patients were randomly assigned to either radiation alone or radiation plus PCV (procarbazine, lomustine [CCNU], and vincristine). No survival benefit was seen with the addition of PCV, even in patients with anaplastic astrocytomas. In contrast, two meta-analyses reviewed data from randomized trials of high-grade glioma patients, and both found a modest survival 15, 16 benefit when chemotherapy was added to postoperative radiation. Specifically, in the most recently published meta-analysis (GMT Group, 2002) of 12 studies involving approximately 3000 patients with high-grade gliomas who were treated either with postoperative radiation alone or with radiation plus chemotherapy, there was an absolute increase in 1-year survival from 40% to 46% and a 2-month increase in median survival when chemotherapy was added to postoperative radiation. 16 Most of these trials studied nitrosourea-based chemotherapy regimens. Temozolomide, a newer drug that is classified as an atypical alkylating agent, received U.S. Food and Drug Administration (FDA) approval for the treatment of patients newly diagnosed with glioblastoma multiforme in March Temozolomide received accelerated FDA approval for recurrent anaplastic astrocytomas in 1999; however, the accelerated approval requirements no longer apply. In Europe, temozolomide s approved indication is for the treatment of both recurrent anaplastic astrocytoma and recurrent glioblastoma multiforme. A recent phase III, randomized study assessed temozolomide in 573 patients with glioblastoma multiforme Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. MS-4

34 who received either (1) daily temozolomide (75 mg/m 2 ) administered with postoperative RT followed by 6 cycles of adjuvant temozolomide ( mg/m 2 /day given 5 days during each 28-day cycle); or (2) radiotherapy alone. 17 Temozolomide resulted in a statistically better median survival (14.6 versus 12.1 months) and 2-year survival (26.5% versus 10.4%) when compared with RT. 17 However, the design of this study does not shed light on what is responsible for the improvements in survival: the temozolomide administered with radiation, following radiation, or both. Subsequent analyses suggest that MGMT (O-6- methylguanine-dna methyltransferase) status may determine which patients obtain benefit from adjuvant temozolomide therapy. 18 MGMT (a DNA repair enzyme) may cause resistance to DNA-alkylating drugs commonly used in the treatment of anaplastic oligodendrogliomas and other malignant gliomas. 19 Note that side effects for temozolomide include nausea, vomiting, headaches, fatigue, and anorexia. Preventive treatment for Pneumocystis carinii pneumonia (PCP) is required when temozolomide is administered with radiotherapy (FDA Talk Paper, March 16, 2005). In elderly patients with glioblastoma multiforme, temozolomide alone may be useful to avoid side effects with RT (eg, excessive fatigue and frequent worsening of neurologic deficits). 20 However, in elderly patients with good performance status, adjuvant chemotherapy and RT may be useful. 21 In terms of adjuvant treatment for anaplastic astrocytomas, the PCV regimen has commonly been used, in large part, based on the results of a phase III trial that compared BCNU to PCV following RT in patients with high-grade gliomas. 22 This study found a survival benefit for patients with anaplastic astrocytomas who received PCV. However, a subsequent retrospective analysis determined that there is little difference between PCV and BCNU. 23 Additionally, the Medical Research Council study (2001) previously discussed found no improvement in survival when patients with anaplastic astrocytomas were treated with PCV. 14 There are no published data directly comparing the benefit of postoperative chemotherapy with temozolomide to a nitrosourea in patients with newly diagnosed anaplastic astrocytomas. This study is currently underway through the RTOG; however, no results have been reported yet. Given the better side-effect profile of temozolomide and the recent positive results of the phase III trial reported by Stupp and colleagues, temozolomide is recommended (category 1) for postoperative chemotherapy in patients with glioblastoma multiforme. 17 Unfortunately, currently available chemotherapy does not provide cures in any of these patients. In addition to temozolomide and the nitrosoureas, agents that also have some activity against gliomas and are commonly used as second-line chemotherapy include procarbazine, irinotecan, cisplatin, and carboplatin. 24, 25 Many other agents are currently being studied. For chemotherapy-naïve patients with glioblastoma multiforme who experience recurrence or progression, temozolomide and cisplatin may be useful. 26 Other routes of drug delivery have been evaluated. Local administration of BCNU using a biodegradable polymer (Gliadel wafer) placed intraoperatively in the surgical cavity has demonstrated a statistically significant, improvement in survival for patients with recurrent highgrade gliomas. 27 As a result, the FDA approved the Gliadel wafer for Version , 10/16/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. MS-5