november, 2019 | The Health
Breathing Easy
C37 M0 Y12 K0
/ R161 G255 B224
C100 M50 Y0 K67 / R0 G42 B84
C10 M100 Y50 K0 / R230 G0 B128
C5 M50 Y25 K0
23
/ R242 G128 B191
C0 M0 Y0 K80 / R51 G51 B51
A female patient
presenting with over
50 brain metastases
and raised intra-
cranial pressure.
She was dysphasic,
drowsy and had
impaired mobility
and confined to
a wheelchair. The
patient received
radiotherapy and
an oral EGFR TKI
and improved
dramatically. Her
neurological function
returned to normal
within 3 months
and MRI Brain
showed marked
improvement.
FIGHTING CANCER
Hitting
the bull’s-eye
managed to receive a sustained benefit for
a year.
Her MRI brain showed near complete
resolution of the disease. Brain metastases
which occurs in about 30 to 40 per cent
NSCLC patients is the most debilitating site
of metastases and is the most difficult to
manage. TKI have afforded us an effective
treatment for this condition.
Targeted therapy proves to be the better bet against the big C
L
ung cancer is generally divided into
non-small cell lung cancer (NSCLC)
comprising 85 per cent of cases
and neuroendocrine lung cancer
including small cell which comprises
approximately 10 to 15 per cent of
cases. The prognosis for advanced stage
NSCLC has historically been very poor with
hardly any survivors at five years.
The traditional way of treating such
patients was with chemotherapy, which can
produce significant side effects and impacts
unfavourably upon quality of life. Further-
more, the benefit of chemotherapy tends
to be short-lived with these cancers usually
progressing after six months.
All this changed about a decade ago when
it was discovered that a subset of lung cancer
patients, more typically females who have
never smoked responded very well to oral
tyrosine kinase inhibitors (TKI) targeting the
epidermal growth factor receptor (EGFR).
Not only did their progression free sur-
vival double compared to chemotherapy,
they experienced less side effects as a result
of treatment. This led to a whole new field of
using targeted therapy in lung cancer.
Current trend in lung cancer
Fast forward to today, we now know that
just over 40 per cent of lung cancer suffers in
Malaysia harbour a mutation in EGFR gene,
usually an exon 19 deletion mutation or an
L858R substitution mutation, which renders
these tumours therapeutically amenable to
oral EGFR TKIs.
A mutated EGFR gene produces an over-
active oncogenic cell receptor protein that
signals cell growth and multiplication. Using
an oral TKI, the drug binds to the intracel-
lular kinase domain which inactivates the
receptor.
Better outcome with osimertinib
Presently, there are three generations
of EGFR TKI available in Malaysia; First
generation (gefitinib, erlotinib), second
generation (afatinib) and third generation
(osimertinib).Each has been compared to
chemotherapy in randomized controlled
trials and have proven superior.
The third generation TKI has been com-
pared to the first generation in a randomised
control trial (FLAURA study) and the results
show third generation TKI to be superior
in terms of progression free and overall
survival.
Side effects of treatment
Common side effects vary from drug to
drug, but in general, it may cause a skin
rash ranging from mild dermatitis to an
acneiform rash. Patients are advised to stay
out of direct sunlight and use emollients,
hydrating skin lotions and in more severe
cases anti-histamines and antibiotics.
These medications can also cause pimple
like changes in the nails termed paronychia
which can be painful. Rarely they may affect
liver function or result in lung inflammation
and low platelets counts.
TKI over chemotherapy
Even in patients with a heavy disease burden
which may even impair organ function,
treatment with TKI is preferred over chemo-
therapy as it has a higher response rate (60 to
80 per cent) compared to chemotherapy (40
per cent) and has a quicker onset of action
(within 2-3 weeks).
This phenomenon has been sometimes
termed the “Lazarus” effect, whereby
patients with severe life-threatening
disease in ICU manage to recover back to
normality.
Enhanced effectiveness
As recent as two decades ago such patients
would not have any effective therapies
available. Chemotherapy has very poor
blood brain barrier penetration and we
would be concerned about subjecting some-
one in such poor general health to cytotoxic
treatment.
Whole brain radiotherapy alone has also
been proven to be no better than best sup-
portive care in a phase three randomised
trial. However, with a combination of
radiotherapy and oral TKI treatment, this
patient made a full neurological recover and
By Dr Tho Lye Mun
&
Prof
Pathmanathan
Rajadurai
Revolutionary treatment
In addition to EGFR mutation, other
genomic aberrations are now recognised
within NSCLC for which there are effective
TKI treatments.
The College of Pathologists, Academy of
Medicine Malaysia, the Malaysian Thoracic
Society, and the Malaysian Oncological
Society have recently published a consensus
statement recommending that mutations in
EGFR, ALK (anaplastic lymphoma kinase)
and ROS-1 genes be routinely tested for in
advanced NSCLC to enable consideration of
TKI therapy.
These therapies include for ALK -
crizotinib, ceritinib, alectinib, lorlatinib,
brigatinib and for ROS-1 - crizotinib, ceri-
tinib, lorlatinib. Provision of such testing
is however, not universal in Malaysia and is
limited to certain laboratories with advanced
technologies.
Patient samples will then need to be
transported to these laboratories in a timely
fashion to enable testing.
What the future holds
Looking to the future, many more genetic
mutations are being recognised in NSCLC
for which drugs are being or have been devel-
oped. Among these are RET, MET, NTRK,
BRAF, HER2, KRAS.
Therefore, the field will have to move
away from sequential single gene testing to
a concurrent multi-gene testing platform.
Fortunately in Malaysia, such efforts are
already underway and will be available soon.
We will need to work closely with our
respiratory and interventional radiology col-
leagues to ensure adequate tissue is taken at
the time of biopsy to ensure sufficient DNA
is available for testing.
To this extent the Lung Cancer Network
of Malaysia (LCNM) will be working in a
multi-disciplinary fashion to encourage
closer working relationships between differ-
ent specialties for the benefit of lung cancer
sufferers nationwide. — The Health
Dr Tho Lye Mun is the Vice President of the Lung
Cancer Network of Malaysia (LCNM) and a
senior consultant clinical oncologist
Prof Pathmanathan Rajadurai is a senior
consultant pathologist and a member of LCNM