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Q & A
Personalisedmedicine in neuro-oncology: current status
In the neuro-oncology space, success in finding individualised targetable mutations has been limited, but with the emer-
gence of the utilisation of immune checkpoint inhibitors, this is about to change, says Dr Minesh Mehta in an interview
with Dr Farzanna Haffizulla.
Dr Haffizulla:
Let’s talk about preci-
sion medicine and personalised
advances, targeted treatment based
on the individual rather than having
a blanket standard of care treatment.
What are your thoughts, and what
are some of the advances to come?
Dr Mehta:
Well, obviously, finding
specific targets in each individual
patient’s tumour has become the
Holy Grail of oncology, and this has
been very successful, in, for exam-
ple, non-small cell lung cancer. Un-
fortunately, in the neuro-oncology
space, our successes have not been
that great in finding individualised
targetable mutations, for which spe-
cific drugs can be utilised.
This search continues, but there is
another direction in which this per-
sonalisation of therapy is beginning
to emerge, and that’s the utilisation
of immune checkpoint inhibitors.
Immune checkpoint inhibitors
have become the darling child in
the oncology world in the last 2 to
3 years, especially with all the dra-
matic advances in melanoma, and
they’re beginning to find application
in neuro-oncology in new clinical tri-
als and new concepts.
Dr Haffizulla:
Matrix metalloprotein-
ase, you mentioned melanoma – I
think about that – and isocitrate
dehydrogenase (IDH), co-deletions,
1p/19q, et cetera. Can you tell me
what else is on the horizon?
DrMehta:
All of the molecular markers
that you mentioned have now been
shown to have significant prognostic
implications in many brain tumours,
and in some situations they’re even
predictive of therapeutic benefit.
It’s quite likely that these molecular
markers will become incorporated in
the future classifications of brain tu-
mours, moving from histology-based
to molecular marker-based classifi-
cation, and some of them like IDH
might even provide us therapeutic
avenues using IDH inhibitors in
future practice.
Dr Haffizulla:
Fantastic. I know the
World Health Organisation classifi-
cation scheme that you mentioned
is based on the histology, and bring-
ing in the molecular signature of
the tumour itself, and using that
to further classify these particular
tumours, will help, as you said, gear
treatment in the correct direction.
What are your thoughts on when
this is coming out?
Dr Mehta:
In particular, for the lower-
grade gliomas, the grade II and the
grade III gliomas, there is such a
confluence in terms of the clinical
outcomes for patients with similar
molecular patterns that it’s very
likely that the molecular pattern,
rather than the grade, might become
the future driver of the newer clas-
sification. And such a classification
is being worked on as we speak.
Dr Haffizulla:
So, collaboration is
important. Making sure the different
specialties, not just in neuro-oncology,
oncology, radiation oncology, et cetera
– imaging – all come together to really
have that personalised approach.
Are there any other study designs
that are being thought up now that
might come to fruition a little bit
later down the road? Maybe not
just using a retrospective review of
the clinical trial data that we have
now, but taking a new lens, a new
approach, to how we’ve approached
some of the clinical trials for brain
tumour research.
Dr Mehta:
Well, let me give you two
examples that I think are about to
take off somewhat rapidly in the
neuro-oncology space.
The first is really the example of
combining immune checkpoint
inhibitors with radiation. It turns
out that radiation, especially high-
dose radiation, can be quite im-
munogenic by causing tumour cell
death, and combining that with an
immune checkpoint inhibitor that
allows a sustained anti-tumour re-
sponse to be maintained, might be
an innovative therapeutic avenue.
Clinical trials based on this concept
of combining radiation and immune
checkpoint inhibitors are about to be
launched, and these might be very
intriguing to study.
Dr Haffizulla:
I know it’s always sig-
nificantly challenging sometimes
to recruit the right number of pa-
tients, especially with this disease
type. How has it been to collaborate
among different groups? With the
different clinical trials and the de-
signs that we have today, we need
to have some good statistical power.
Dr Mehta:
In neuro-oncology where
we deal with tumours that are rela-
tively uncommon, compared with
many of the other tumours that we
see in the oncology space, collabora-
tion is crucial; so, we have mounted
transatlantic collaborations among
cooperative groups in the US, as well
as in Europe, and we’re even looking
at collaborations across the world to
complete some of these trials.
Dr Minesh Mehta is
professor of radiation
oncology; associate
director of clinical
research, radiation
oncology, University
of Maryland School
of Medicine; medical
director, Maryland Proton Treatment
Center, Baltimore, Maryland.
Dr Farzanna
Haffizulla is
national president
of the American
Medical Women’s
Association
(AMWA) 2014–
2015; private practice, Internal
Medicine, Davie, Florida.
JOURNAL SCAN
Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma
The New England Journal of Medicine
Take-home message
•
This was a multicentre, randomised phase III trial including 251 patients with
newly diagnosed low-grade gliomas designed to compare postoperative
radiation therapy (RT) alone vs radiation therapy followed by combination
chemotherapy with procarbazine, lomustine, and vincristine (RT+PCV).
•
At a median follow-up of 11.9 years, the median overall survival was sub-
stantially longer in the RT+PCV group compared with those who received
only radiation (OS, 13.3 vs 7.8 years). Grade 3 or 4 haematologic adverse
events occurred in nearly 50% of patients treated with RT+PCV.
Dr Jeremy Jones
BACKGROUND
Grade 2 gliomas occur
most commonly in young adults and
cause progressive neurologic dete-
rioration and premature death. Early
results of this trial showed that treat-
ment with procarbazine, lomustine
(also called CCNU), and vincristine after
radiation therapy at the time of initial di-
agnosis resulted in longer progression-
free survival, but not overall survival,
than radiation therapy alone. We now
report the long-term results.
METHODS
We included patients with
grade 2 astrocytoma, oligoastrocy-
toma, or oligodendroglioma who were
younger than 40 years of age and had
undergone subtotal resection or biopsy
or who were 40 years of age or older
and had undergone biopsy or resec-
tion of any of the tumour. Patients were
stratified according to age, histologic
findings, Karnofsky performance-status
score, and presence or absence of
contrast enhancement on preopera-
tive images. Patients were randomly
assigned to radiation therapy alone
or to radiation therapy followed by six
cycles of combination chemotherapy.
RESULTS
A total of 251 eligible patients
were enrolled from 1998 through 2002.
The median follow-up was 11.9 years;
55% of the patients died. Patients who
received radiation therapy plus chemo-
therapy had longer median overall
survival than did those who received
radiation therapy alone (13.3 vs 7.8 years;
hazard ratio for death, 0.59; P=0.003).
The rate of progression-free survival
at 10 years was 51% in the group that
received radiation therapy plus chemo-
therapy versus 21% in the group that
received radiation therapy alone; the
corresponding rates of overall survival
at 10 years were 60% and 40%. A Cox
model identified receipt of radiation
therapy plus chemotherapy and histo-
logic findings of oligodendroglioma as
favourable prognostic variables for both
progression-free and overall survival.
CONCLUSIONS
In a cohort of patients with
grade 2 glioma who were younger than
40 years of age and had undergone
subtotal tumour resection or who were
40 years of age or older, progression-
free survival and overall survival were
longer among those who received
combination chemotherapy in addition
to radiation therapy than among those
who received radiation therapy alone.
Radiation Plus Procarbazine, CCNU,
and Vincristine in Low-Grade
Glioma
N Engl J Med
2016 Apr
07;374(14)1344–1355, JC Buckner,
EG Shaw, SL Pugh, et al.
Future directions for targeted therapies in
neuro-oncology
INTERVIEW WITH DR PATRICK Y. WEN
What is the future of neuro-
oncology?
Dr Wen, director of
the Center for Neuro-Oncology
at Dana-Farber Cancer Institute
and professor
of neurology at
Harvard Medical
School shares his
perspective.
Generalised inflammation and brain
tumours: is the brain an
‘immunosanctuary’?
INTERVIEW WITH DR JEFFREY J RAIZER
Could a drug such as bevaci-
zumab be used in conjunction
with immunotherapy to decrease
oedema rather than using steroids?
Dr Jeffrey Raizer,
Director of Medical
Neuro-Oncology
at Northwestern
University, Chi-
cago, explains.
So, collaboration is
important. Making sure the
different specialties, not
just in neuro-oncology,
oncology, radiation
oncology, et cetera –
imaging – all come
together to really have that
personalised approach
BRAIN CANCER
PRACTICEUPDATE NEUROLOGY
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