with adjuvant chemotherapy in anaplastic astrocytoma.
2017 Aug 8. pii: S0140-6736(17)31477-0. doi:
10.1016/S0140-6736(17)31477-0. [Epub ahead of print]
on: van den Bent MJ et al, Interim results from the CATNON trial
(EORTC study 26053-22054) of treatment with concurrent and
adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma:
a phase 3, randomised, open-label intergroup study.
of chemotherapy for newly diagnosed anaplastic gliomas,
particularly when combined with radiotherapy, has long been
the past few decades, despite no conclusive data, study findings
have suggested that the addition of nitrosourea-based chemotherapy
to radiotherapy could be beneficial.
NOA-04 trial revealed that initial treatment with chemotherapy
(either temozolomide or procarbazine, lomustine, and vincristine
[PCV]) or radiotherapy alone yielded similar results.
of patients with anaplastic glioma has been recognised as being
strongly dependent on the presence or absence of the favourable
discovery resulted in secondary analyses of US and European
trials, revealing improved survival in patients with co-deleted
tumours who received combined radiation and PCV chemotherapy.[2,3]
clear benefits were found with adding temozolomide to radiotherapy
to treat newly diagnosed glioblastoma, which led to
investigations of whether radiation plus temozolomide would
benefit patients with non-co-deleted anaplastic gliomas (ie,
Martin van den Bent and colleagues report interim
findings from the CATNON trial, an ambitious international
collaboration launched in 2005 and the first glioma study to base
eligibility on a molecular marker.
trial was designed to assess the effects of temozolomide
concurrent with, and adjuvant to, radiotherapy in patients with
1p/19q non-co-deleted anaplastic gliomas.
A 2 ×
2 factorial design, creating four treatment groups (radiotherapy
alone or with 12 cycles of adjuvant temozolomide or radiotherapy
with concurrent temozolomide, with or without adjuvant
temozolomide) was selected to answer two questions: whether use of
concurrent temozolomide improves overall survival irrespective of
treatment with adjuvant temozolomide, and whether administration
of adjuvant temozolomide improves overall survival irrespective of
concurrent treatment with temozolomide.
interim analysis presented addresses the second question in 745
significant overall survival benefit was seen with adjuvant
temozolomide (5-year overall survival 55,9%, 95% CI 47,2–63,8
vs 44,1%, 36,3–51,6
without adjuvant temozolomide; hazard ratio for survival 0,65,
99,145% CI 0,45–0,93).
median progression-free survival increased from 19 to 43 months.
overall survival curves diverged throughout the reported follow-up
and, therefore, the benefit might increase with additional
we will need to wait several years for the first question to be
answered, these interim findings suggest a
new standard of care for patients with
non-co-deleted anaplastic gliomas that no longer involves
receiving monotherapy with radiation or chemotherapy as initial
many positive studies, CATNON raises new questions, and the issues
it set out to address have evolved substantially during patient
accrual and data maturation.
discovery of IDH1 or IDH2 mutations in roughly 80%
of grade II and III diffuse gliomas in 2009 substantiated their
importance as pathogenic features.
than 90% of glioblastomas do not have these mutations, and
lower-grade gliomas with wildtype IDH typically have a
clinical course much closer to that of glioblastoma than
grade-matched gliomas with mutant IDH.
in 2016 to the WHO brain tumour classification created a category
of anaplastic astrocytoma, IDH-mutated.
classification notes that anaplastic astrocytomas have the highest
incidence of wild-type IDH among grade II and III diffuse
gliomas, and most of these share molecular features with wild-type
some of the patients enrolled in CATNON had tumours that
biologically were fundamentally different from what would now be
viewed as appropriate for this study population (ie, IDH-mutated
van den Bent and colleagues are analysing the benefits of adjuvant
temozolomide separately in participants with IDH-mutated
and wild-type IDH tumours, although, unfortunately, no data
are yet available.
this point, a post-hoc analysis of the RTOG 9402 study suggested a
benefit in overall survival with radiotherapy and adjuvant PCV
chemotherapy in patients who had nonco-deleted, IDH-mutated
questions remain on the timing and duration of treatment with
CATNON data do not yet elucidate the role of concurrent
temozolomide in anaplastic glioma, and clinicians will have to
decide whether to give this drug during radiotherapy, as is done
in the treatment of glioblastoma.
chose to administer adjuvant temozolomide for 12 cycles partly
because, unlike in glioblastoma, not all patients received the
drug concurrently with radiotherapy.
studies of glioblastoma, however, have suggested that there is no
benefit beyond six cycles after radiotherapy.[9,10]
suggestion by van den Bent and colleagues that the similarities
between low-grade and anaplastic gliomas warrant consideration of
adjuvant temozolomide in the former, based on the CATNON results,
might be a stretch.
low-grade and anaplastic glioma tumours form a biological
continuum, but the CATNON data stratified by IDH status
have not yet been analysed.
in low-grade gliomas, data from a phase 3 study support use of PCV
chemotherapy after radiotherapy, with particular benefit being
seen in IDH-mutated tumours.
relative activity of temozolomide versus PCV in all low-grade
gliomas remains unclear, although given the challenges of
comparative trials, the favourable side-effect profile of
temozolomide might make it more popular until more effective
agents are developed.