YEAR IN REVIEW

NEURO-ONCOLOGY IN 2016 Another international trial led by the

European Organisation of Research and

Advances in brain tumour Treatment of Cancer (EORTC) registered

707 patients with histologically proven WHO
grade II gliomas, and explored the efficacy of

classification and therapy radiotherapy (50.4 Gy, 1.8 Gy per fraction)

compared with dose-dense temozolomide
chemotherapy (75 mg/m2 daily for 21 days,
Matthias Preusser and Christine Marosi in up to 12 cycles of 28 days)4. Patients were
stratified according to age, WHO perfor-
Brain tumours encompass a heterogeneous collection of neoplasms, mance status, presence or absence of contrast
traditionally classified by histopathological criteria. In 2016, the WHO enhancement in MRI, 1p deletion status,
published an updated classification that, for the first time, defines brain and recruitment site. Patients underwent
tumour types according to integrated histological and molecular randomization when active treatment was
parameters. Furthermore, clinical trial results were reported that inform required, and they had to fulfil at least one of
the following criteria: age >40 years, new or
therapeutic decision-making in diffuse gliomas.
worsening neurological symptoms, refractory
seizures, and radiological tumour progression.
May 2016 saw the publication of CNS4+, an grade III), and in glioblastomas (WHO grade The trial included 477 patients, who were
update to the WHO classification of tumours IV) affecting elderly patients (aged ≥65 years). followed up for a median of 48 months. Tissue
of the CNS1. For the first time, this new clas- LGGs account for ~15% of all gliomas, mainly for molecular characterization was available
sification integrates histomorphological and affect people in the third and fourth decade from 318 patients.
molecular parameters for the diagnosis of of life, are associated with tumour-related
primary brain tumours. It builds on recent epilepsy, have a distinct tendency to recur and
advances, such as the demonstration that progress into malignant gliomas, and limit life 2016 brought some
different genetic subtypes of morphologi- expectancy. Treatment strategies for LGGs important clinical trial results
cally identical tumours have different natural include neurosurgical resection (which is often in low-grade gliomas … and
histories, and may differ significantly in their not possible due to tumour extent or location),
response to treatment. watchful waiting, radiotherapy, and alkylating anaplastic gliomas
The new WHO classification is certainly a chemotherapy with procarbazine, vincristine
milestone in the evolution of neuro-­oncology, and lomustine (PCV) or temozolomide2. The This trial confirmed that patients with
and will change the landscape of brain tumour question of which LGG treatment strategy IDH1 mutation and 1p/19q codeletion had
research by providing a novel reference system to use in which patient, and how to combine the longest periods of progression-free sur-
for the diagnostic work‑up in the clini­cal set- or sequence these treatments, has long been vival (62 months, 95% CI 41 to not reached),
ting, as well as for basic and clinical research. unresolved. Important trial results shedding followed by the patients showing IDH muta-
It will also introduce new challenges, however. light on this issue were presented in 2016. tions only (48 months, 95% 41–55 months).
The sophisticated molecular evaluation that Between 1998 and 2002, Buckner et al. Patients with wild-type  IDH1 had the
is required for a fully integrated diagnosis via recruited 251 patients with LGG who had shortest period of progression-free survival
the CNS4+ classification is not readily avail- undergone biopsy or at least partial resection (20  months, 95%  CI 12–26  months). Of
able in every diagnostic laboratory, thereby of their tumour3. Patients were randomly note, IDH-mutated, non-codeletion patients
creating a need to upgrade services or to cen- assigned in a 1:1 ratio to treatment either had a longer period of progression-free sur-
tralize neuropathology services at national with fractionated radiotherapy up to 54 Gy vival with radiotherapy than with chemo­
and international levels. Furthermore, clinical with 1.8 Gy per fraction, or to radio­therapy therapy (55.4 versus 36.0 months, P = 0.013).
trials will need to base patient selection on the followed by six adjuvant cycles of PCV Importantly, temozolomide chemotherapy
new tumour classification, which has poten- chemotherapy. After a median follow‑up of and radiotherapy did not differ with regard to
tial implications for trial logistics and patient 11.2 years, it became clear that patients treated their adverse effects on health-related quality
accrual if molecularly defined patient subsets with radiation alone had significantly shorter of life or global cognitive functioning5.
are to be targeted. Hopefully, these efforts survival than those who subsequently received For patients with newly diagnosed ana­
will lead to better treatments for well-defined chemotherapy (7.8  years and 13.3  years, plastic gliomas, van den Bent et al. presen­
adult and paediatric patient populations. respectively; HR 0.59, P < 0.003). Molecular ted the first interim results of the EORTC
With regard to the treatment of brain characterization, which was available for CATNON trial 26053, which used a 2:2
tumours, 2016 brought some important clini­ 45% of the tumours, indicated greater benefits factorial design to explore the added value
cal trial results in low-grade gliomas (LGGs, for patients with 1p/19q codeletions and of temozolomide as concomitant or adjuvant
WHO grade II) and anaplastic gliomas (WHO isocitrate dehydrogenase (IDH) mutations. therapy to radiation (59.4 Gy in 33 fractions)6.

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YEAR IN REVIEW

Correspondence to C.M.
Key advances christine.marosi@meduniwien.ac.at
• CNS4+, the updated WHO classification of nervous system tumours, integrates doi:10.1038/nrneurol.2017.3
histomorphological and molecular genetic parameters for the diagnosis of primary brain tumours1 Published online 20 Jan 2017
• Adjuvant chemotherapy with procarbazine, vincristine and lomustine following radiotherapy led
1. Louis, D. N. et al. The 2016 World Health
to a survival gain in high-risk patients with diffuse gliomas3 Organization Classification of Tumors of the Central
• The results of the EORTC trial 22033 confirm the predictive value of molecular genetic Nervous System: a summary. Acta Neuropathol. 131,
803–820 (2016).
subgroups in low-grade glioma4 2. van den Bent, M. J. Chemotherapy for low-grade
• Adjuvant chemotherapy with temozolomide prolongs survival in patients with anaplastic glioma: when, for whom, which regimen? Curr. Opin.
Neurol. 28, 633–938 (2015).
gliomas without 1p/19q codeletion6 3. Buckner, J. C. et al. Radiation plus procarbazine,
• Chemoradiation with temozolomide is beneficial for otherwise fit elderly patients with newly CCNU, and vincristine in low-grade glioma. N. Engl.
J. Med. 374, 1344–1355 (2016).
diagnosed glioblastoma8 4. Baumert, B. G. et al. Temozolomide chemotherapy
versus radiotherapy in high-risk low-grade glioma
(EORTC 22033–26033): a randomised, open-label,
After a median follow‑up of 27  months, considered as a feasible treatment option in fit phase 3 intergroup study. Lancet Oncol. 17,
the interim analysis showed a hazard ratio elderly patients with glioblastoma. 1521–1532 (2016).
5. Reijneveld, J. C. et al. Health-related quality of life in
reduction of 0.645 (95%  CI 0.450–0.926, In the field of neuro-oncology, the main patients with high-risk low-grade glioma (EORTC
P = 0.0014) for overall survival when adjuvant advances over the past year lie in a refined 22033–26033): a randomised, open-label, phase 3
intergroup study. Lancet Oncol. 17, 1533–1542
temozolomide was used. Whether concomi- classification of primary brain tumours using (2016).
tant chemotherapy is also beneficial in these increasingly sophisticated techniques, and in 6. van den Bent, M. J. et al. Results of the interim
analysis of the EORTC randomized phase III CATNON
patients will be known in 2021. the extension of our knowledge on indica- trial on concurrent and adjuvant temozolomide in
For elderly patients with glioblastoma, tions for and sequencing of classic radiation anaplastic glioma without 1p/19q co‑deletion: an
intergroup trial [abstract]. J. Clin. Oncol. 34 (Suppl.),
therapeutic concepts have evolved consid- and alkylating chemotherapy approaches. LBA2000 (2016).
erably in recent years, and radiotherapy Unfortunately, like previous years, 2016 7. Wirsching, H. G., Happold, C., Roth, P. & Weller, M.
Management of diffusely infiltrating glioma
and chemotherapy monotherapy regimens failed to deliver positive trial results for bio- in the elderly. Curr. Opin. Oncol. 27, 502–509
adapted to patient age and O6-methylguanine- logical agents in gliomas. The ACT‑IV trial (2015).
8. Perry, J. R. et al. A phase III randomized controlled
DNA-methyltransferase (MGMT) promoter evaluating rindopepimut, a vaccine target- trial of short-course radiotherapy with or without
methylation status have been defined7. In ing epidermal growth factor receptor var- concomitant and adjuvant temozolomide in elderly
patients with glioblastoma (CCTG CE.6, EORTC
2016, Perry et al. reported the results of a iant III (EGFRvIII), was stopped early for 26062–22061, TROG 08.02, NCT00482677)
Canadian-led phase III trial, in which short- futility, thereby dashing the hopes raised [abstract]. J. Clin. Oncol. 34 (Suppl.), LBA2 (2016).
9. Phillips, A. C. et al. ABT‑414, an antibody-drug
course radiation therapy (40 Gy in 15 frac- by earlier smaller trials. Hopefully, ongoing conjugate targeting a tumor-selective EGFR epitope.
tions over 3 weeks) combined with concurrent trials with other novel agents, such as immune Mol. Cancer Ther. 15, 661–669 (2016).
10. Preusser, M., Lim, M., Hafler, D. A., Reardon, D. A.
and adjuvant temozolomide was compared checkpoint inhibitors targeting programmed & Sampson, J. H. Prospects of immune checkpoint
with radiotherapy alone in fit newly diag- death 1 (PD‑1), or the drug–antibody conju- modulators in the treatment of glioblastoma. Nat.
Rev. Neurol. 11, 504–514 (2015).
nosed glioblastoma patients aged ≥65 years8. gate ABT‑414, which targets amplified EGFR,
The addition of temozolomide to radiother- will produce more-encouraging results in Competing interests statement
apy extended the median overall survival 2017 and beyond9,10. M.P. has received research support from Boehringer
Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme and
from 7.6 months to 9.3 months, and quality Roche, and honoraria for lectures, consultation or advisory
Matthias Preusser and Christine Marosi are at the
of life was not diminished with the com- Department of Medicine I, Clinical Division of Oncology,
board participation from Bristol-Myers Squibb, Novartis,
Gerson Lehrman Group, CMC Contrast, GlaxoSmithKline,
bined therapy. These findings indicate that Comprehensive Cancer Center CNS Unit (CCC-CNS), Mundipharma, Roche and Astra Zeneca. C.M. declares no
multimodal therapy is beneficial and can be Waehringer Guertel 18–20, 1090 Vienna, Austria. competing interests.

NATURE REVIEWS | NEUROLOGY www.nature.com/nrneurol

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