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Neuro-Oncology Practice 201
9(3), 201–207, 2022 | https://doi.org/10.1093/nop/npac004 | Advance Access date 14 January 2022
Short-term outcomes associated with temozolomide or
PCV chemotherapy for 1p/19q-codeleted WHO grade 3
oligodendrogliomas: A national evaluation
Nayan Lamba, Malia McAvoy, Vasileios K. Kavouridis, Timothy R. Smith, Mehdi Touat,
David A. Reardon, and J. Bryan Iorgulescu
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Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, Massachusetts, USA (N.L.); Harvard
Medical School, Boston, Massachusetts, USA (N.L., T.R.S., D.A.R., J.B.I.); Department of Neurological Surgery,
University of Washington Medical Center, Seattle, Washington, USA (M.M.); Department of Neurosurgery,
Computational Neuroscience Outcomes Center, Brigham and Women’s Hospital, Boston, Massachusetts, USA
(V.K.K., T.R.S., J.B.I.); Department of Neurosurgery, St. Olavs Hospital, Trondheim, Norway (V.K.K.); Service de
Neurologie 2-Mazarin, Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau, ICM, AP-HP, Hôpitaux
Universitaires La Pitié Salpêtrière-Charles Foix, Paris, France (M.T.); Sorbonne Université, INSERM, Unité Mixte
de Recherche Scientifique 938 and Site de Recherche Intégrée sur le Cancer (SIRIC) Cancer United Research
Associating Medicine, University & Society (CURAMUS), Centre de Recherche Saint-Antoine, Equipe Instabilité des
Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France (M.T.); Department
of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts, USA (M.T.); Department of Medical Oncology,
Center for Neuro-Oncology, Dana-Farber Cancer Center, Boston, Massachusetts, USA (D.A.R.); Department of
Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA (J.B.I.)
Corresponding Author: J. Bryan Iorgulescu, MD, FCAP, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St.,
Boston, MA 02115, USA (jiorgulescu@bwh.harvard.edu).
Abstract
Background. The optimal chemotherapy regimen between temozolomide and procarbazine, lomustine, and vin-
cristine (PCV) remains uncertain for WHO grade 3 oligodendroglioma (Olig3) patients. We therefore investigated
this question using national data.
Methods. Patients diagnosed with radiotherapy-treated 1p/19q-codeleted Olig3 between 2010 and 2018 were identi-
fied from the National Cancer Database.The overall survival (OS) associated with first-line single-agent temozolomide
vs multi-agent PCV was estimated by Kaplan-Meier techniques and evaluated by multivariable Cox regression.
Results. One thousand five hundred ninety-six radiotherapy-treated 1p/19q-codeleted Olig3 patients were iden-
tified: 88.6% (n = 1414) treated with temozolomide and 11.4% (n = 182) with PCV (from 5.4% in 2010 to 12.0% in
2018) in the first-line setting. The median follow-up was 35.5 months (interquartile range [IQR] 20.7-60.6 months)
with 63.3% of patients alive at the time of analysis. There was a significant difference in unadjusted OS between
temozolomide (5-year OS 58.9%, 95%CI: 55.6-62.0) and PCV (5-year OS 65.1%, 95%CI: 54.8-73.5; P = .04). However,
a significant OS difference between temozolomide and PCV was not observed in the Cox regression analysis ad-
justed by age and extent of resection (PCV vs temozolomide HR 0.81, 95%CI: 0.59-1.11, P = .18). PCV was more fre-
quently used for younger Olig3s but otherwise was not associated with patient’s insurance status or care setting.
Conclusions. In a national analysis of Olig3s, first-line PCV chemotherapy was associated with a slightly improved
unadjusted short-term OS compared to temozolomide; but not following adjustment by patient age and extent of
resection. There has been an increase in PCV utilization since 2010. These findings provide preliminary data while
we await the definitive results from the CODEL trial.
Keywords
chemotherapy | grade 3 | oligodendroglioma | PCV | temozolomide
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European
Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.202 Lamba et al. TMZ vs PCV survival for 1p/19q-codel gr3 oligodendrogliomas
WHO grade 3 oligodendrogliomas (Olig3s; traditionally 71.0-71.9).18 Cases were defined using the primary brain-
referred to as “grade III anaplastic”) are a rare subset of specific variables for WHO grade 3 and for loss of hetero-
infiltrative gliomas—comprising about 6% of all gliomas— zygosity/deletion of both chromosome arms 1p and 19q.19
defined by the presence of both an IDH mutation and A subset of cases with 1p/19q codeletion were encoded in
1p/19q chromosomal arms codeletion.1–3 The 1p/19q the NCDB as WHO grade 4—likely reflecting the outmoded
codeletion is a strong prognostic marker associated with “glioblastoma with oligodendroglial features”—and
increased responsiveness to chemotherapy and superior herein were reclassified as WHO Olig3s in accordance with
outcomes in patients with diffuse gliomas.4,5 However, the 2016 and 2021 WHO classifications.2,3 Patients were
despite recent advances in understanding its distinct mo- excluded if they wereLamba et al. TMZ vs PCV survival for 1p/19q-codel gr3 oligodendrogliomas 203
Practice
Neuro-Oncology
doses (IQR 30-33) for multi-agent PCV patients. Single-
agent temozolomide chemotherapy often began on the
Results same day as radiotherapy (median difference 0 days after
One thousand five hundred ninety-six patients with start of radiotherapy, IQR: 0-0; likely representing concur-
radiotherapy-treated 1p/19q-codeleted WHO Olig3s met rent temozolomide followed by adjuvant temozolomide),
inclusion and exclusion criteria; of whom 88.6% (n = 1414) whereas multi-agent PCV chemotherapy often began fol-
received single-agent chemotherapy (from 94.6% in 2010 lowing radiotherapy (median difference 70 days after start
to 86.2% in 2013 and 88.0% in 2018) and 11.4% (n = 182) of radiotherapy, IQR: 0-84). Olig3s treated with multi-agent
received multi-agent chemotherapy (from 5.4% in 2010 to PCV were younger (median 48 years, IQR 36-59) as com-
13.8% in 2013 to 12.0% in 2018). The cohort represented pa- pared to temozolomide-treated Olig3s (median 52 years,
tients treated at 445 centers. IQR 40-62, P = .008). There was no difference in PCV vs
From 3 NCDB-reporting institutions, n = 73 1p/19q- temozolomide utilization by MGMT promoter methylation
codeleted Olig3s treated with chemotherapy between status (P = .17; only available for n = 692). The median KPS
2000 and 2017 were abstracted and submitted to regis- for temozolomide- and PCV-treated patients was 90 (IQR
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tries. Of these, 84.9% (n = 62) and 15.1% (n = 11) were 80-90; only available for n = 243). Furthermore, there were
encoded as first-line single-agent and multi-agent che- no differences in PCV vs temozolomide utilization by pa-
motherapy and were validated by medical chart review tients’ insurance status (P = .24) or managing cancer pro-
to represent temozolomide and PCV, respectively, in gram type (P = .74).
all cases. Although these institutional data may not be The median follow-up from the time of diagnosis was
wholly representative of chemotherapy coding prac- 35.5 months (IQR 20.7-60.6 months). At the time of anal-
tices nationwide, they provide some reassurance for the ysis, 63.3% of Olig3 patients in the national dataset were
validity of the assumptions made in the design of the alive, with 36.7% of patients reaching the endpoint of
methodology. mortality. Overall, the unadjusted OS difference between
In the national data, Olig3 patients presented at a me- single-agent temozolomide (5-year OS 58.9%, 95%CI:
dian of 51 years of age (interquartile range [IQR] 40-61). 55.6-62.0) and multi-agent PCV chemotherapy (5-year OS
By EOR, 18.0% of patients had biopsy-only, 35.7% STR, 65.1%, 95%CI: 54.8-73.5) reached significance (log-rank
and 46.4% GTR. Radiotherapy began a median of 37 days P = .04; Figure 1). In multivariable Cox regression analysis
(IQR 29-48) after definitive resection, with a median of 59.4 adjusted for age and EOR—factors were previously shown
Gy (IQR 59.4-60.0) in 30 fractions (IQR 30-33), including a to have crucial prognostic value in Olig3s—a significant
median of 59.5 Gy (IQR 59.4-60.0) in a median of 30 frac- difference in OS between first-line PCV (adjusted HR 0.81,
tions (IQR 30-33) for single-agent temozolomide patients, 95%CI: 0.59-1.11, P = .18) and temozolomide chemotherapy
and a median of 59.4 Gy (IQR 59.4-60.0) in a median of 33 was no longer detected (Table 1).
100
90
80
70
Survival (%)
60
50
40
95% CI
30
TMZ
20
10 PCV
0
0 12 24 36 48 60
Overall survivial (mos)
Number at risk
TMZ 1164 1006 786 573 426 306
PCV 148 142 118 78 47 29
Figure 1. Unadjusted overall survival (OS) associated with first-line single-agent temozolomide vs multi-agent PCV for radiotherapy-treated
WHO grade 3 oligodendroglioma patients. Kaplan-Meier OS estimates for radiotherapy-treated Olig3 patients who received either single-agent
TMZ (solid line) or multi-agent PCV (dashed line) treatment. Log-rank test P = .04. OS is measured from the date of surgical diagnosis. Patients
with204 Lamba et al. TMZ vs PCV survival for 1p/19q-codel gr3 oligodendrogliomas
Table 1. Multivariable Cox Regression Analysis of Overall Survival in Olig3s
OS Measured From Pathological Diagnosis
HR 95% CI P value
Chemotherapy
Temozolomide Referent
PCV 0.81 (0.59-1.11) .18
Age at diagnosis 1.06/yr (1.05-1.07)
Extent of resection
Biopsy-only Referent
Subtotal resection 0.83 (0.65-1.05)
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Gross total resection 0.82 (0.65-1.04)
Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival; PCV, procarbazine, lomustine, and vincristine.
Complete multivariable data were available for n = 1299 radiotherapy-treated Olig3s. Patients withLamba et al. TMZ vs PCV survival for 1p/19q-codel gr3 oligodendrogliomas 205
Practice
Neuro-Oncology
by chemotherapy agent, PCV-alone demonstrated im- PCV in the first line was not associated with patients’ insur-
proved time-to-progression (median 7.6 months com- ance status or their treating hospital’s type (ie, community
pared to 3.3 months in temozolomide-alone, P = .02), but vs academic/NCI-comprehensive care center).This increase
no difference in OS (P = .16).28 In the Olig3s that also re- in multi-agent PCV utilization may reflect the timely pub-
ceived radiotherapy, there was no difference in either lication of results from the RTOG 9402 and EORTC 26951
time-to-progression or OS for PCV vs temozolomide.28 randomized controlled trials, which firmly established the
In the Neuro-Oncology Working Group (NOA) phase III survival benefit of adding PCV to radiotherapy for 1p/19q-
trial NOA-04, in which patients with anaplastic gliomas codeleted gliomas. In line with the aforementioned clinical
(only 69 with 1p/19q codeletion) were randomized to up- trials’ survival findings, we found no difference in short-
front radiotherapy or upfront chemotherapy (either PCV term OS between radiotherapy-treated Olig3s treated with
or temozolomide), researchers ultimately found that che- first-line PCV vs temozolomide following adjustment for
motherapy alone was not superior to radiotherapy.29 In age and EOR. However, in unadjusted analyses, PCV was
the subset (n = 33) of CpG island hypermethylated (CIMP) associated with slightly improved short-term OS. Although
1p/19q-codeleted cases, PCV-alone demonstrated im- only results from a randomized trial comparing PCV and
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proved PFS, but not OS, compared to temozolomide-alone. temozolomide will be able to ultimately answer the ques-
Notably, although NOA-04 demonstrated better tumor con- tion of differences in long-term outcomes, our findings
trol with PCV, it also demonstrated worse toxicity with PCV. suggest that either PCV or temozolomide may offer com-
Among the anaplastic glioma patients treated with upfront parable early OS outcomes in conjunction with radio-
chemotherapy, treatment was discontinued in 33% of pa- therapy in the first-line management of newly diagnosed
tients treated with PCV (n = 54), all due to toxicity, while Olig3s when taking into account patients’ age and EOR—
none of the temozolomide-treated patients (n = 53) re- which supports tailoring the temozolomide vs PCV selec-
quired temozolomide discontinuation due to toxicity.30 tion to each patient’s unique circumstances.
Although the Lassman et al’s study and NOA-04 had
moderate follow-up durations of approximately 10 years,
it is likely that their data had not yet reached maturity and Limitations
were underpowered with respect to the question of OS for
PCV vs temozolomide for Olig3s. Similar to these studies, Although our analysis encompassed a national dataset,
our data only capture the short-term outcomes of PCV vs the NCDB’s limited encoding of 1p/19q codeletion status
temozolomide for Olig3s, and it is possible that with much (starting in 2010) constrained the cohort’s follow-up to a
longer follow-up, one regimen may prove superior at later median of 36 months (IQR 21-61 months). As a result, our
landmarks. To rigorously answer this question, the phase III findings only apply to the short-term outcomes of 1p/19q-
CODEL trial (NCT00887146) was redesigned as a random- codeleted Olig3 patients and do not capture any delayed
ized noninferiority comparison of radiotherapy either fol- differences between PCV and temozolomide. For example,
lowed by adjuvant PCV or with concomitant temozolomide in RTOG 9402 and EORTC 26951, the survival benefits
followed by adjuvant temozolomide for grade 2 and 3 from chemotherapy were observed after approximately
newly diagnosed 1p/19q-codeleted oligodendrogliomas, 6 years—suggesting that Olig3 patients that experienced
powered for PFS, and secondarily assessing OS, tox- an early death did not benefit from the addition of PCV.
icity, and quality of life outcomes. Herein, the majority of Although both trials indeed confirmed that long-term anal-
first-line temozolomide was started concurrently with ra- ysis is key in this population, it remained unclear whether
diotherapy, whereas the majority of first-line PCV was temozolomide might outperform PCV in the short term.
administered following radiotherapy. The appropriate For instance, the lack of short-term benefit with PCV could
scheduling of chemotherapy with radiotherapy remains correspond to an increased rate of toxicity-related death
a key question. Additional important therapeutic con- with this regimen. Our findings add to the previous liter-
siderations are under investigation, including the role of ature and will be helpful in decision making—especially
deferring radiotherapy in reducing late toxicity (POLCA for elderly Olig3 patients with shorter life expectancy. The
trial, NCT02444000). relatively short follow-up and a comparably small number
Because the final results of CODEL are likely years away, of PCV patients also restricted the effect size that we were
we evaluated the short-term OS outcomes associated with able to measure. Based on a 2-tailed log-rank power
PCV or temozolomide as first-line treatment in a contem- analysis using the Schoenfeld method and the 62.4% of
porary national cohort of patients with 1p/19q-codeleted temozolomide-treated patients that were censored in this
Olig3s. Based on the recent trial results demonstrating im- cohort, this analysis had 80% power to detect a change
proved efficacy associated with radiotherapy (compared to in the 5-year OS from 58.9% (as seen for temozolomide-
chemotherapy monotherapy), we restricted our analysis to treated patients) to 71.2%; which was modestly larger than
those Olig3 patients who received radiotherapy. Although the change that we detected.
single-agent temozolomide was the most common reg- Furthermore, first-line chemotherapy was encoded as
imen, utilization of PCV increased between 2010 and 2018— single-agent and multi-agent, without details about agents,
despite a concerning increase in the cost of lomustine doses, early and late toxicities, or duration of treatment;
of approximately 1500% from 2013 to 2018 in the United therefore, it is possible that some patients received multi-
States.31 The NCDB does not report details about which agent chemotherapy that included temozolomide and
chemotherapeutic agents are administered, so regimens other investigational agents. To help address this limitation,
incorporating Carmustine (BCNU) instead of lomustine registry-submitted data for Olig3s from 3 Commission on
would be grouped together with PCV. Notably, in our ana- Cancer-accredited institutions were evaluated, in which we
lyses, choice of single-agent temozolomide vs multi-agent noted that all single-agent cases were temozolomide and206 Lamba et al. TMZ vs PCV survival for 1p/19q-codel gr3 oligodendrogliomas
all multi-agent cases were PCV. Although these institutions
may not be wholly representative of all institution types na- Conflict of interest statement. M.T. reports consulting or advi-
tionally, NCDB coding standards are standardized across all sory role from Agios Pharmaceuticals, Integragen, and Taiho
Commission on Cancer-accredited institutions nationwide. Oncology, outside the submitted work; research funding from
However, there remains the possibility that some multi-agent Sanofi, outside the submitted work. The other authors report no
chemotherapy represented less common regimens such relevant conflicts of interest.
as CCNU and procarbazine (without vincristine), whereas
some single-agent chemotherapy may have represented
CCNU monotherapy. The second or subsequent courses
of therapy were not reported by the NCDB, so it could not
be determined whether patients that received concurrent Authorship statement. Conception and study design: J.B.I. Data
temozolomide with radiotherapy additionally received adju- collection: N.L., M.M., and V.K.K. Data analysis: J.B.I. Data inter-
vant temozolomide or not. IDH mutational status is not sep- pretation and manuscript writing: all authors. Critical review and
arately encoded in registry data, so all oligodendrogliomas revisions: all authors.
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herein were defined by their 1p/19q codeletion and thus
were also likely IDH-mutant.18 Nor did the NCDB report data
regarding patients’ seizure status, symptomatology, de-
velopment of pseudo-progression, or radiotherapy effects.
Data availability statement. Data are available by application to
Additionally, only OS was encoded for outcomes, precluding
the NCDB.
the evaluation of PFS for PCV vs temozolomide in Olig3s.
Conclusions
References
In this real-world study of patients with newly diagnosed
1p/19q-codeleted Olig3 who received post-surgical radio-
therapy—63% of whom were still alive at the time of anal- 1. Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS.
ysis—we found a significant improvement in short-term CBTRUS statistical report: primary brain and other central nervous
unadjusted OS associated with first-line multi-agent PCV com- system tumors diagnosed in the United States in 2013-2017. Neuro
pared to single-agent temozolomide chemotherapy, which did Oncol. 2020;22(12 Suppl 2):iv1–iv96.
not persist following adjustment for the key prognostic factors 2. Louis DN, Ohgaki H, Cavenee WK. World Health Organization
of age and EOR. While results from the CODEL trial will ulti- Histological Classification of Tumours of the Central Nervous System.
mately offer guidance with respect to optimal management for Vol. 1, revised 4th ed. Lyons: International Agency for Research on
patients with newly diagnosed Olig3, our results offer prelimi- Cancer; 2016.
nary evidence that both PCV and temozolomide chemotherapy 3. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO classification
regimens when combined with radiotherapy may be viable of tumors of the central nervous system: a summary. Neuro Oncol.
options in the first-line setting with respect to short-term OS 2021;23(8):1231–1251.
outcomes after taking into account patients’ age and EOR. 4. Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors
of chemotherapeutic response and survival in patients with anaplastic
oligodendrogliomas. J Natl Cancer Inst. 1998;90(19):1473–1479.
5. Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a
clinical review. JAMA. 2013;310(17):1842–1850.
Funding 6. Ruff MW, Buckner JC, Johnson DR, Van Den Bent MJ, Geurts M. Neuro-
No funding supported this work. Oncology Clinical Debate: PCV or temozolomide in combination with ra-
diation for newly diagnosed high-grade oligodendroglioma. Neurooncol
Pract. 2019;6(1):17–21.
7. Rudà R, Touat M, Soffietti R. Is chemotherapy alone an option as ini-
tial treatment for low-grade oligodendrogliomas? Curr Opin Neurol.
Acknowledgments 2020;33(6):707–715.
8. National Comprehensive Care Network (NCCN). NCCN Clinical Practice
The authors are grateful to the cancer registrars at BWH, DFCI, Guidelines in Oncology: CNS Tumors. Version 2. 2021. https://www.
and MGH for their assistance in data acquisition. J.B.I. grate- nccn.org/professionals/physician_gls/pdf/cns_blocks.pdf
fully acknowledges support from the National Cancer Institute 9. Van Den Bent MJ, Brandes AA, Taphoorn MJB, et al. Adjuvant
(K12CA090354) and Conquer Cancer Foundation/Sontag procarbazine, lomustine, and vincristine chemotherapy in newly diag-
Foundation. The National Cancer Data Base (NCDB) is a joint nosed anaplastic oligodendroglioma: long-term follow-up of EORTC
project of the Commission on Cancer (CoC) of the American brain tumor group study 26951. J Clin Oncol. 2013;31(3):344–350.
College of Surgeons and the American Cancer Society. The 10. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy
CoC’s NCDB and the hospitals participating in the CoC NCDB are for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin
the source of the de-identified data used herein; they have not Oncol. 2013;31(3):337–343.
verified and are not responsible for the statistical validity of the 11. Panageas KS, Iwamoto FM, Cloughesy TF, et al. Initial treatment pat-
data analysis or the conclusions derived by the authors. terns over time for anaplastic oligodendroglial tumors. Neuro Oncol.
2012;14(6):761–767.Lamba et al. TMZ vs PCV survival for 1p/19q-codel gr3 oligodendrogliomas 207
Practice
Neuro-Oncology
12. Lassman AB, Cloughesy TF. Early results from the CODEL trial for 22. Taliansky-Aronov A, Bokstein F, Lavon I, Siegal T. Temozolomide treat-
anaplastic oligodendrogliomas: is temozolomide futile? Neuro Oncol. ment for newly diagnosed anaplastic oligodendrogliomas: a clinical effi-
2021;23(3):347–349. cacy trial. J Neurooncol. 2006;79(2):153–157.
13. Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and 23. Ahluwalia MS, Xie H, Dahiya S, et al. Efficacy and patient-reported
temozolomide for newly diagnosed glioblastoma: recursive partitioning outcomes with dose-intense temozolomide in patients with newly
analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. diagnosed pure and mixed anaplastic oligodendroglioma: a phase II
J Clin Oncol. 2006;24(16):2563–2569. multicenter study. J Neurooncol. 2015;122(1):111–119.
14. Jaeckle KA, Ballman KV, van den Bent M, et al. CODEL: phase III study 24. Mikkelsen T, Doyle T, Anderson J, et al. Temozolomide single-agent
of RT, RT + TMZ, or TMZ for newly diagnosed 1p/19q codeleted oligo- chemotherapy for newly diagnosed anaplastic oligodendroglioma. J
dendroglioma. Analysis from the initial study design. Neuro Oncol. Neurooncol. 2009;92(1):57–63.
2021;23(3):457–467. 25. Ducray F, Sierra Del RM, Carpentier C, et al. Up-front temozolomide in eld-
15. Weller M, van den Bent M, Tonn JC, et al. European Association erly patients with anaplastic oligodendroglioma and oligoastrocytoma. J
for Neuro-Oncology (EANO) guideline on the diagnosis and treat- Neurooncol. 2011;101(3):457–462.
ment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 26. Touat M, Li YY, Boynton AN, et al. Mechanisms and ther-
Downloaded from https://academic.oup.com/nop/article/9/3/201/6507353 by guest on 29 June 2022
2017;18(6):e315–e329. apeutic implications of hypermutation in gliomas. Nature.
16. Boffa DJ, Rosen JE, Mallin K, et al. Using the national cancer database 2020;580(7804):517–523.
for outcomes research: a review. JAMA Oncol. 2017;3(12):1722–1728. 27. Barthel FP, Johnson KC, Varn FS, et al. Longitudinal molecular trajec-
17. Mallin K, Browner A, Palis B, et al. Incident cases captured in the national tories of diffuse glioma in adults. Nature. 2019;576(7785):112–120.
cancer database compared with those in U.S. population based central 28. Lassman AB, Iwamoto FM, Cloughesy TF, et al. International retrospec-
cancer registries in 2012–2014. Ann Surg Oncol. 2019;26(6):1604–1612. tive study of over 1000 adults with anaplastic oligodendroglial tumors.
18. Iorgulescu JB, Torre M, Harary M, et al. The misclassification of diffuse Neuro Oncol. 2011;13(6):649–659.
gliomas: rates and outcomes. Clin Cancer Res. 2019;25(8):2656–2663. 29. Wick W, Roth P, Hartmann C, et al.; Neurooncology Working Group
19. Harary M, Kavouridis VK, Torre M, et al. Predictors and early survival (NOA) of the German Cancer Society. Long-term analysis of the
outcomes of maximal resection in WHO grade II 1p/19q-codeleted NOA-04 randomized phase III trial of sequential radiochemotherapy
oligodendrogliomas. Neuro Oncol. 2019;22(3):369–380. of anaplastic glioma with PCV or temozolomide. Neuro Oncol.
20. Iorgulescu JB, Harary M, Zogg CK, et al. Improved risk-adjusted sur- 2016;18(11):1529–1537.
vival for melanoma brain metastases in the era of checkpoint blockade 30. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III
immunotherapies: results from a national cohort. Cancer Immunol Res. trial of sequential radiochemotherapy of anaplastic glioma with
2018;6(9):1039–1045. procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol.
21. Boyle FM, Eller SL, Grossman SA. Penetration of intra-arterially ad- 2009;27(35):5874–5880.
ministered vincristine in experimental brain tumor. Neuro Oncol. 31. Taylor JW, Armstrong T, Kim AH, et al. The lomustine crisis: awareness
2004;6(4):300–305. and impact of the 1500% price hike. Neuro Oncol. 2019;21(1):1–3.You can also read
