Central Nervous System Cancers, Version 1.2015

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.

Abstract

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.

NCCN: Continuing Education

Accreditation Statement

This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-15-012-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/74932; and 4) view/print certificate.

Release date: October 22, 2015; Expiration date: October 22, 2016.

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Central Nervous System Cancers

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Central Nervous System Cancers

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NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2015

Version 1.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 10; 10.6004/jnccn.2015.0148

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

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

Overview

In 2015, an estimated 22,850 people in the United States will be diagnosed with primary malignant brain or other central nervous system (CNS) neoplasms, and these tumors will be responsible for approximately 15,320 deaths.1 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CNS Cancers focus on management of adult CNS cancers: anaplastic gliomas and glioblastoma, low-grade infiltrative astrocytomas, oligodendrogliomas, ependymomas, brain metastases, leptomeningeal metastases, non–AIDS-related primary CNS lymphomas (PCNSLs), metastatic spinal tumors, meningiomas, primary spinal cord tumors, and primitive neuroectodermal tumors. These NCCN Guidelines Insights focus on changes to the recommendations for treatment of gliomas based on new data, including changes to the chemotherapy, radiation therapy (RT), and chemoradiation regimens recommended for postoperative adjuvant treatment

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NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2015

Version 1.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 10; 10.6004/jnccn.2015.0148

of newly diagnosed high-risk low-grade gliomas (see ASTR-1, page 1193) and glioblastomas (see GLIO-3, this page). This article also summarizes the panel's assessment and discussion of the clinical data on alternating electric field therapy for newly diagnosed and recurrent glioblastoma.

New Adjuvant Treatment Options for High-Risk Low-Grade Gliomas

Whereas noninfiltrative astrocytomas, usually pilocytic astrocytomas (WHO grade I), are typically noninvasive and curable by surgery alone, diffuse astrocytomas are poorly circumscribed and invasive, and most gradually evolve into high-grade astrocytomas.2,3 Diffusely infiltrative low-grade gliomas include astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas; they are a diverse group classified as grade II under the WHO grading system4 that make up approximately 10% of newly diagnosed primary brain tumors.5 The aggressiveness of these tumors varies by subtype, and patients with grade II oligodendrogliomas have a much better 5-year survival rate (70%) than those with mixed gliomas (56%) and astrocytomas (37%).5 Other factors prognostic for progression-free survival (PFS) or overall survival (OS) in patients with grade II gliomas include age, tumor diameter, tumor crossing midline, neurologic or performance status prior to surgery, and the presence of certain molecular markers, such as a 1p19q codeletion in oligodendrogliomas and the presence of an isocitrate dehydrogenase (IDH) 1 or 2 mutation in grade II astrocytomas.615

For supratentorial WHO grade II gliomas, the NCCN Guidelines recommend that primary treatment aim to achieve as complete an excision as possible (based on postsurgical MRI verification) without compromising function. Multivariate analysis from a number of studies in patients with primary low-grade gliomas show that extent of resection is a significant

F3

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2015

Version 1.2015 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 10; 10.6004/jnccn.2015.0148

prognostic factor for PFS and/or OS.813,1620 Patients who undergo a subtotal resection, open biopsy, or stereotactic biopsy are therefore considered to be at higher risk for progression (see ASTR-1, page 1193).

Adjuvant RT after resection is supported by data from several retrospective studies comparing outcomes in patients with newly diagnosed low-grade gliomas who after surgery received no adjuvant treatment versus RT.17,21,22 The recommended dosing for postoperative RT is based on results from 2 phase III randomized trials showing that higher dose RT had no significant effect on OS or time to progression,8,10 and several retrospective analyses showing similar results.9,11,21 Because higher doses offer no clear advantages, the NCCN CNS Cancers Panel recommends low-dose RT (45–54 Gy) for treatment of low-grade gliomas (grades I/II), including high-risk cases (see ASTR-1, page 1193). The timing of postoperative RT was tested in a phase III multicenter study (EORTC 22845) that showed improved PFS and greater reduction in seizure frequency in patients who received RT soon after surgery versus at time of disease progression.23 Early versus late postoperative RT did not significantly affect OS, however, suggesting that observation is a reasonable option for some patients with newly diagnosed gliomas.23 Results of EORTC 22845 were corroborated by several other analyses. The positive effect of RT on seizure control was confirmed in a retrospective study in patients with low-grade gliomas and medically intractable epilepsy.24 A large meta-analysis, including data from 4 phase III trials (EORTC 22844 and 22845,8,23 RTOG 9802,25 and NCCTG 86-72-5110), confirmed that surgery followed by RT significantly improves PFS but not OS.26 A retrospective study (N=95) showed that administering RT within 3 months of surgery versus delaying RT until progression improved PFS but not OS.27 Although no consensus exists on the optimal timing of postoperative RT for low-grade gliomas in young healthy patients, the panel recommends immediate postoperative RT in patients who are older, symptomatic, or have less-than-total resection (see ASTR-1, page 1193).

Combination chemotherapy with procarbazine, lomustine, and vincristine (PCV) has been used in the adjuvant setting for patients with newly diagnosed low-grade gliomas based on small retrospective and phase II studies showing positive outcomes in patients who had partial resection or biopsy.2830 These data showing clinical activity of PCV as adjuvant therapy for newly diagnosed low-grade gliomas prompted a multicenter phase III randomized clinical trial, RTOG 9802, which assessed the efficacy of adjuvant RT versus RT followed by 6 cycles of PCV in patients with newly diagnosed supratentorial WHO grade II gliomas and at least 1 of 2 risk factors for disease progression: subtotal resection or age of 40 years or older.25 For randomization, patients were stratified by age, tumor histologic subtype, Karnofsky performance status (KPS), and presence of enhancement on preoperative MRI. Although the interim analysis (median follow-up, 5.9 years) showed that addition of PCV significantly improved PFS but not OS,25 results from long-term follow-up (median, 11.9 years) showed significant improvements in both PFS and OS.31,32 With the addition of PCV, median survival time increased from 7.8 to 13.3 years (P=.02), and the 10-year survival rate increased from 41% to 62%. Based on these results, the NCCN CNS Cancers Panel voted to include RT plus adjuvant PCV chemotherapy as a category 1 recommendation for adjuvant treatment of patients with newly diagnosed low-grade gliomas at high risk for recurrence as per the trial criteria: patients older than 40 years or of any age with residual disease after surgery (subtotal resection, open biopsy, stereotactic (see ASTR-1, page 1193). It is important to note, however, that roughly three-quarters of the study patients had a KPS of 90 to 100, and the median age was approximately 40 years.25 Given that the addition of PCV to adjuvant RT significantly increased the percent of patients who experienced grade 3 or 4 adverse events,25 the risk versus benefit of adjuvant PCV has yet to be determined for patients who are elderly or infirm. Furthermore, whether PCV is appropriate for all patients with high-risk low-grade glioma is not yet clear. For example, for patients with astrocytoma, the benefit provided by PCV (vs observation) was diminished relative to those with other tumor subtypes, such as oligodendroglioma or oligoastrocytoma. Significant improvement was observed for PFS but not OS in the patients with astrocytoma.32

Use of temozolomide as adjuvant monotherapy for newly diagnosed low-grade gliomas after surgery is supported by results from noncomparative studies showing objective responses and reduced seizure frequency.3337 One retrospective comparative study showed that for patients with low-grade gliomas and new-onset seizures at presentation, adjuvant temozolomide monotherapy provided significant reduction in seizure frequency in significantly more patients compared with observation after surgery or biopsy.38 Preliminary results from a large multicenter phase III randomized trial (EORTC 22033-26033, N=477) show that PFS is not significantly different for adjuvant RT versus dose-dense temozolomide in patients with resected or biopsied supratentorial grade II glioma and more than 1 risk factor: age of 40 years or older; progressive, new, or worsening neurologic symptoms; and intractable seizures.39 Combined treatment with RT plus temozolomide is supported by a phase II multicenter trial (RTOG 0424) in patients with supratentorial WHO grade II tumors and at least 3 risk factors (age ≥40 years, astrocytoma, bihemispheric, tumor diameter 6 cm, neurologic function status >1).40 Patients treated with concurrent and adjuvant temozolomide had OS rates ≥ at 3 and 5 years of 73.1% and 57.1%, respectively, which are positive results when compared with survival estimates for patients with similar risk factors treated with postoperative RT alone in previous trials (EORTC trials 22844 and 22845, and North American Intergroup trial 86-72-51).6,7,26 However, because the historical controls included patients treated in an earlier period using different RT protocols, prospective controlled trials are needed to confirm the positive effect of adding temozolomide to adjuvant RT for the treatment of low-grade gliomas. Because panel consensus was nonuniform regarding the inclusion of RT with adjuvant temozolomide and RT with concurrent and adjuvant temozolomide, these options were included as category 2B recommendations for adjuvant treatment of patients with high-risk newly diagnosed low-grade gliomas (see ASTR-1, page 1193).

Based on the strength of the RTOG 9802 results, the panel agreed with adding RT with chemotherapy as a treatment option for patients with recurrent or progressive low-grade gliomas who have not had prior RT (see ASTR-2, available online, in these guidelines, at NCCN.org). Although patients with recurrent or progressive low-grade gliomas were not included in RTOG 9802, there are very few data to inform treatment of these patients, because most of the studies in recurrent or progressive low-grade gliomas include patients who have had prior RT. There are a few small noncomparative studies in patients with no prior RT showing that temozolomide or PCV provide clinical responses (radiologic) and reduction in seizures or other neurologic symptoms.4144 In addition, as mentioned earlier, the EORTC 22033-26033 phase III trial included patients with progressive low-grade gliomas, and initial results suggest similar PFS for adjuvant temozolomide (monotherapy) versus RT.39 Results from this and other randomized trials are needed to better inform treatment of recurrent/progressive low-grade gliomas.

Adjuvant Therapy for Glioblastomas

Glioblastomas (grade IV astrocytomas) are the most common primary malignant brain tumors in adults, accounting for 54.7% of all gliomas.45 Glioblastomas are the most aggressive brain tumor, with fewer than 50% of patients surviving for 1 year, and only 5% living beyond 5 years.4547 For first-line treatment of glioblastomas, the NCCN Guidelines recommend maximal safe resection with or without placement of a carmustine (BCNU) wafer. If gross total resection is not feasible, then subtotal resection or stereotactic/open biopsy are options. After surgical intervention, the choice of adjuvant therapy for glioblastoma depends on a patient's age and performance status.4851 To improve readability, the panel reorganized the algorithm, providing recommendations for adjuvant treatment of newly diagnosed glioblastomas (see GLIO-3, page 1194). Table 1 shows the recommended adjuvant treatment options from the 2014 and 2015 NCCN Guidelines for specific subgroups of patients based on age and performance score. These recommendations are primarily based on results from large randomized trials (Table 2). The notable changes include (1) removing standard RT as a treatment option for elderly patients (age >70 years) with poor performance status (KPS <60), and (2) adding hypofractionated RT with concurrent and adjuvant temozolomide for elderly patients who have a good performance status.

Hypofractionated Radiation Therapy for Elderly Patients With a Poor Performance Status

Fractionated RT as adjuvant therapy for high-grade gliomas is based on several randomized trials showing improved survival compared with supportive care or BCNU alone.5255 Two randomized trials and a large retrospective analysis have shown that, in elderly patients (age >60 years), adjuvant therapy with hypofractionated RT (34-40 Gy in 10–15 fractions over 2–3 weeks) has similar or better efficacy compared with standard RT (60 Gy in 30–33 fractions over 6–7 weeks; Table 2).48,50,56 The Nordic Clinical Brain Tumor S udy Group (NCBTSG) phase III multicenter randomized trial also showed that, for patients aged 60 to 70 years, there was no significant difference in survival between standard versus hypofractionated RT, but patients older than 70 years had better median survival with hypofractionated versus standard RT (Table 2).48 In the NCBTSG trial, hypofractionated RT was better tolerated than standard RT, and more patients were able to complete their full RT course. For elderly patients (age >70 years) with glioblastoma who opt for adjuvant treatment with RT alone, these findings support the recommendation to use hypofractionated RT rather than standard RT.

Hypofractionated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Elderly Patients With a Good Performance Status

Standard RT with concurrent and adjuvant temozolomide is the standard of care for adjuvant treatment of newly diagnosed glioblastoma in patients who are younger and have a good performance status, based on the EORTC 26981-22981/NCIC CE3 multicenter international phase III randomized controlled trial showing significantly improved PFS and OS compared with RT alone (Table 2).51 The use of this regimen in patients who are elderly or frail has been debated because this landmark clinical trial did not include patients older than 70 years and was not adequately powered to assess treatment effects in the subset of patients aged 60 to 70 years. For patients older than 70 years but with good performance, some evidence from small single-center studies suggests the usefulness of temozolomide in addition to adjuvant RT.57,58

Building on the findings that hypofractionated RT (monotherapy) has similar or better efficacy and safety compared with standard RT (monotherapy) for adjuvant treatment of glioblastoma in the elderly, a number of noncomparative studies have reported

Table 1

Recommendations for Adjuvant Treatment of Glioblastomaa

Table 1
positive results from patients treated with hypofractionated RT plus concurrent and adjuvant temozolomide. These studies have shown median OS ranging from 15 to 20 months for adult populations with good performance status and broad age range,5966 and median OS of 12.4 to 14.4 months for studies in patients who were elderly or had other risk factors.6769 A large retrospective analysis of elderly patients treated with RT plus concurrent and adjuvant temozolomide found no significant differences in OS and PFS with standard versus hypofractionated RT (Table 2).50 This finding was confirmed by analysis of 90 propensity-score matched pairs and by stratified analyses of prognostic factors. However, standard RT therapy was associated with increased rates of failure to complete the course of RT, grade 2/3 neurologic toxicities, decline in KPS scores during treatment, and corticosteroid dose increase during or soon after their RT course (Table 2). Patients included in this retrospective analysis had a KPS of 60 or greater, so these findings support the use of hypofractionated RT with concurrent and adjuvant temozolomide as a reasonable adjuvant treatment option for elderly patients with a good performance status.

Alternating Electric Field Therapy

Alternating electric field therapy for treatment of high-grade gliomas is a topic of ongoing debate as evidence continues to emerge. In 2011, the FDA approved a portable medical device that generates low-intensity alternating electric fields, termed tumor treating fields (TTF), for the treatment of recurrent glioblastoma. Approval was based on the results of a clinical trial (EF-11) that randomized 237 patients with recurrent glioblastoma to either TTF or the treating oncologist's choice of chemotherapy.70 Although similar survival was observed in the 2 arms, TTF therapy was associated with lower toxicity and improved quality of life. This study was not blinded, however, and therefore quality-of-life assessments may have been compromised. A recent development in this area includes the publication of an analysis of the Patient Registry Dataset (PRiDe) reporting real-world outcomes for 457 patients who received TTF for recurrent glioblastoma.71 Although OS with TTF was significantly higher in the PRiDE data set analysis than in the EF-11 phase III trial,71 patients in the former may have received concomitant therapy that could account for the improvement in survival. Other recent developments that were discussed among the panel members were abstract presentations of EF-14,72,73 a phase III trial in patients with newly diagnosed glioblastoma (n=700) that showed an improvement in median PFS and OS in patients treated after radiation and concurrent temozolomide with temozolomide plus TTF versus adjuvant temozolomide monotherapy (PFS, 7.1 vs 4.2 months; P=.0010; OS, 19.4 vs 16.6 months; P=.0222).73

Table 2

Key Trials in Adjuvant Care for Newly Diagnosed Glioblastomaa

Table 2
Some panelists expressed the opinion that the results from EF-14 and PRiDE provide additional evidence of clinical activity and thus give further support for TTF treatment in patients with recurrent glioblastoma. Others argued that data from the prospective, randomized EF-11 study provided a more accurate measure of the true efficacy in recurrent disease than the PRiDE data. Based on the 2015 panel vote, the inclusion of “Consider alternating electric field therapy for glioblastoma” changed from a category 3 to a category 2B recommendation (see GLIO-4, page 1195). The panel awaits peer-reviewed publication of results from the EF-14 trial before deciding whether to add TTF as a treatment option for newly diagnosed glioblastoma.

Conclusions

The NCCN Guidelines for CNS Cancers are updated annually to include new information or treatment philosophies as they become available. The NCCN Guidelines are sometimes updated more often if new high-quality clinical data become available. Because this field evolves continually, practitioners should use all of the available information to determine the best clinical options for their patients. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient for providing optimal care. The physician and the patient have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. When possible, consistent with NCCN philosophy, the NCCN CNS Cancers Panel strongly encourages participation in prospective clinical trials.

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