Download Treatment of non-small cell lung carcinoma with gefitinib: a case report

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Treatment of non-small cell lung
carcinoma with gefitinib:
a case report
A. Lefebure, P. Germonprè
Targeted therapy for non-small cell lung carcinoma (NSCLC) is a possible treatment option
for patients with tumours expressing an activating mutation of the epidermal growth factor
receptor (EGFR). Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase
inhibitor (TKI) that was approved for treatment of EGFR mutation-positive NSCLC in
Europe in 2009. In Belgium, gefitinib was only approved as a monotherapy for EGFR mutation-positive NSCLC stage IIIB-IV, whatever the line of treatment. When treatment was
initiated, limited data were available relating to the use of TKIs for treating Caucasian
patients with EGFR mutation-positive NSCLC. Thus, information on EGFR TKI use, in the
real-life clinical setting and particularly in Caucasian patients and patients with brain
metastases is still needed. Here, we report the case of a patient with NSCLC and brain
metastases being treated with gefitinib.
After twelve months of treatment, the chest and brain scans still showed improvement with
lung function normalising and the patient reporting a good quality of life. As this patient
was not previously treated with chemotherapy, there is still an opportunity of treating
her later, when the tumour becomes resistant to gefinitib, with cisplatinum-pemetrexed.
This is still possible because she remains chemotherapy-naive, which is required to request
reimbursement in Belgium of that type of chemotherapy.
(Belg J Med Oncol 2012;6:169-175)
Introduction
The treatment of non-small cell lung cancer (NSCLC)
has progressed significantly in the last fifteen years.1
The discovery that a proportion of patients with
NSCLC have activating mutations of the epidermal
growth factor receptor (EGFR) has allowed the
development of targeted therapies for NSCLC.2-4
These therapies act as inhibitors of the tyrosine
kinase domain of the EGFR (EGFR-TKI). There are
different EGFR-TKIs available with gefitinib (IressaTM,
AstraZeneca) and erlotinib (TarcevaTM, N.V. Roche
S.A.) the first to be approved for clinical use.3
This patient case aims to describe the diagnosis and
treatment with gefitinib of a patient with advanced
lung cancer. At the time that this patient was treated,
gefitinib was the only EGFR-TKI that was reimbursed in Belgium as first-line treatment for NSCLC
patients with activating mutations of the EGFR tyrosine kinase domain. Gefitinib is a selective small
molecule inhibitor of the EGFR tyrosine kinase,
Authors: Ms. A. Lefebure PhD, Department of Respiratory Medicine, Saint Erasmus Hospital, Antwerp Hospital Network, Antwerp,
Belgium; P. Germonprè, Department of Respiratory Medicine, Antwerp University Hospital, Antwerp, Belgium.
Please send all correspondence to: Ms. A. Lefebure PhD, Saint Erasmus Hospital (ZNA Sint-Erasmus), Department of Respiratory Medicine,
Luit. Lippenslaan 55, B-2140 Borgerhout, Belgium tel: +32 (0)3 270 80 24, E-mail: [email protected].
Conflict of interest: A. Lefebure and P Germonprè have both received unrestricted research grants from AstraZeneca for participation
in clinical trials.
Keywords: EGFR-TKI, non-small cell lung carcinoma, brain metastasis, therapeutic options.
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Figure 1. Response of metastases throughout treatment. A: Chest CT prior to treatment; B: Brain CT prior to treatment;
Abbreviation: CT – computerised tomography scan
which has been demonstrated to be an effective
treatment for patients with tumours containing activating mutations of the EGFR-TKI.5,6 No clinically
relevant activity has been shown in patients with
known EGFR mutation-negative tumours.
Patient history
A 60-year-old female never smoking patient presented with a protracted cough associated with a mild
shortness of breath despite the use of antibiotics.
She reported symptoms of mild lethargy, tickling
cough and headache lasting a couple of days. The
clinical examination revealed that she was in good
overall condition: PS=1 and normal heart, ear, nose
and throat function. The lung examination revealed
a normal vesicular respiratory sound but the lung
function was restrictive with the Forced Expired
Volume (FEV) in 1 second being 65% and Total Lung
Capacity was 71%. A mass on the upper left lobe
was detected after chest X-ray, which was confirmed
by chest computerised tomography (CT) (Figure 1A)
and positron emission tomography-CT (PET-CT)
scans. Furthermore, a brain CT scan revealed the
presence of several metastases with oedema (Figure
1B). Bronchoscopy with biopsies showed a stenosis
of the left upper lobe, which proved on anatomopathological examination to be an adenocarcinoma
of the lung that was poorly differentiated to undifferentiated, TTF1 positive and CK7 immunohistochemistry were positive. Carcinoembryonic antigen
(CEA) level was 45 ng/mL.
Three therapeutic options were proposed to the
patient: upfront whole brain radiotherapy due to
the size of the laesions and the neurological symptoms followed by first-line systemic treatment with
cisplatinum-pemetrexed chemotherapy (the first
choice for treating a metastatic adenocarcinoma of
the lung), or treatment with gefitinib (at that moment,
only used in Belgium as part of a compassionate use
protocol but not yet reimbursed) in case of an EGFR
mutation-positive tumour, or the option to take
neither therapy. As the patient preferred the second
option, if possible, a second bronchoscopy was
performed to obtain new tumour samples, since not
enough material was remaining from the first set of
biopsies to test for the EGFR mutation status. At the
start of the first compassionate use protocol in
2001, EGFR mutation testing was not common
practice and initially gefinitib was available as part
of the protocol without patient selection being
based on EGFR mutation status. However, in the
months before reimbursement in Belgium (FebruaryJune 2010), the mutation analysis became a necessary
requirement for gefitinib treatment. Genetic testing
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Figure 1. C: Chest CT after two months gefitinib treatment; D: Brain CT after two weeks of gefitinib treatment;
Abbreviation: CT – computerised tomography scan
of the tumour-DNA revealed an EGFR mutation
(deletion in exon 19). The patient first received 30 Gy
of cerebral radiation therapy in twelve sessions as
the initial treatment to reduce the size of the laesions.
The radiotherapy was well tolerated but methylprednisolone (MedrolTM, Pfizer) was administered to
protect against headaches. Following confirmation
of EGFR mutation status, the patient received firstline treatment with 250 mg/day gefitinib (IressaTM,
AstraZeneca), at that moment approved in Belgium
for that indication, which was also well tolerated.
Over the course of the treatment, the chest CT
scans showed improvement (Figure 1C) and the brain
CT scans demonstrated a near-total disappearance
Figure 1. E: Reduction of CEA levels throughout therapy; F: Brain CT after four months of gefitinib treatment
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Figure 2. Response of metastases at the end of treatment. A: Brain CT after fifteen months of treatment; B: Chest CT after
eighteen months of treatment.
of the oedema, more pronounced than would be expected from radiotherapy alone (Figures 1D and 1F).
Serum CEA levels decreased to 15 ng/mL one
month after the start of the therapy and decreased
further to 4 ng/mL after two months (Figure 1E).
After four months, the brain CT showed further
improvement, CEA was 1 ng/mL and lung function
had normalised. Although the patient continued
to lose weight, she described herself as being full of
energy and able to perform normal daily activities.
The treatment planned for this patient was a chest
CT every other second month until progression and
a follow-up of the CEA results. The chest and brain
CT scans remained stable during treatment with
gefinitib until approximately fourteen months after
starting gefinitib. The cerebral metastasis became
discretely more prominent (Figure 2A), but as the patient did not have any complaints, gefitinib treatment
was continued. By the next consultation, the patient
has started to cough a little and, on the chest CT
scan, the tumour remained the same. However, there
were signs of inflammation of the lymph vessels
(lymphangitis carcinomatosa) on the left side. At this
time, CEA had risen to 8 ng/mL, and by the following
month to 16 ng/mL (Figure 2C). We are presently
discussing how to proceed with the treatment and
will begin cisplatinum-pemetrexed treatment soon.
Discussion
Our patient reported a very good quality of life
while being treated with an EGFR-TKI and her
symptoms were under control for more than fourteen months. After twelve months of treatment, her
CEA had remained at 1 ng/mL; after which it started
to rise slowly again. Although this patient initially
was still suffering from weight loss while in remission,
this had stabilised after a few months.
The only problem before being able to choose treatment with gefitinib was that it required a new biopsy,
as there was not enough tissue remaining from the
first biopsy to accurately determine the EGFR mutation status of the patient.
Testing for mutations of the EGFR is very important
in determining the correct treatment strategy for
NSCLC. Lung biopsies are not always easy to do
and with new techniques like endoscopic ultrasound (EUS) and endobronchial ultrasound (EBUS)
obtaining adequate tissue amounts to perform immunohistochemistry and mutation-analyses becomes even more difficult. A subset of patients with
NSCLC, approximately 5-20% of patients depending
on the population being studied, have activating
mutations of the tyrosine kinase domain of the
EGFR (in Europe, mostly exon 19 deletion or L858R
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Figure 2.C: Evolution of CEA levels throughout therapy; Abbreviation: CEA – carcinoembryonic antigen;
point mutation in exon 21) which may be targeted
by TKIs such as gefitinib or erlotinib.3,4 Along with
having an adenocarcinoma, our patient was a woman
who had never smoked; these three factors (adenocarcinoma, female, non-smoker) are known to be
associated with a higher frequency of EGFR mutations
in the tumour. The presence of an EGFR mutation
increases the likelihood of a clinical response to
EGFR-TKI.7 Routine screening for some mutations,
including MET gene overexpression and the T790M
mutation of the EGFR (which renders the tumour
resistant to TKIs), is becoming more widespread.8
Most patients will have some sort of mutation. Some
of them are already known, such as the activating
BRAF and K-Ras mutations, PIK3CA, HER2, AKT1,
and mutations of the EML4-ALK fusion gene; however,
some are niche mutations, which have no specific
treatments currently available.8,9 For others, therapy
is or will become available, e.g. crizonitib for treating NSCLC associated with an ALK fusion gene.10
Brain metastases develop in approximately 25% of
patients with lung cancer and 60% of all brain
metastases may be attributable to lung cancer.11 In
comparison to NSCLC, determining the treatment
for brain metastases is more straightforward. For
patients with symptomatic metastases, steroids in
conjunction with radiation therapy are the standard
approach until the metastases are under control
and there is an improvement in symptoms. If the
brain metastases are asymptomatic, there are usually
three treatment options: systemic chemotherapy,
surgery or radiotherapy.11 The main issue is, which
treatments to use after radiation therapy. Different
trials have used different first-line treatments. Interestingly, the brain metastases of our patient continued
to decrease in size throughout gefitinib treatment
(Figure 1F versus 1D), raising the question about the
efficacy of EGFR-TKIs on brain metastases. Previous
studies have also suggested an effect of gefitinib on
brain metastases, but the question remains whether
previous radiotherapy is needed to render the blood
brain barrier more accessible to these drugs.12,13
Although it should be noted that normally the CT
scans of the brain are not monitored as frequently
as occurred in this case.
This patient case provides a real-life case in a Caucasian woman that confirms many of the trial
results.14-17 Furthermore, this patient has been stable
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Key Messages for clinical practice
1.
Typical fast and prolonged response of EGFR-TKI in EGFR mutant lung cancer.
2.
Good symptom control.
3.
Well-tolerated and linked with an improved quality of life.
with up to twelve months of gefitinib treatment,
which is close to the median progression-free survival (PFS) seen in most phase III trials.17-19 There
are still good treatment options available if there is
disease progression due to the patient becoming
resistant to EGFR-TKI treatment. Cisplatinumpemetrexed treatment could be the preferential firstline chemotherapy given the adenomatous histology
of the tumour, and this patient is still chemo-naive,
a requirement in Belgium to give this therapy.20-22
Furthermore, it is known that tumours with an
EGFR mutation are more sensitive to chemotherapy
than wild-type tumours.23
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