A Review of Lung Cancer Research in Malaysia

Kan Chan Siang, MD1, Chan Kok Meng John, FRCS CTh1,2

1
Department of Cardiothoracic Surgery, Sarawak Heart Centre, 94300 Kota Samarahan, Kuching, Sarawak, Malaysia, 2National
Heart and Lung Institute, Imperial College London, U.K.

ABSTRACT
Lung cancer is a major cause of mortality and morbidity in
cancer death, while in females, it accounted for 13% of all

Malaysia and worldwide. This paper reviews all research and

cancer deaths, the second most common cancer death after

publications on lung cancer in Malaysia published between

breast cancer. 4,403 lung cancers were diagnosed in the

2000-2015. 89 papers were identified, of which 64 papers

country in 2014, 3,240 in males (the most common cancer

were selected and reviewed on the basis of their relevance

diagnosed), and 1,163 in females (the fourth most common

to the review. The epidemiology, risk factors, cell types,

cancer diagnosed).

clinical presentation, diagnosis, treatment, outcomes,

prevention, and the social impact of lung cancer in the
Information on the epidemiology of lung cancer was also

country are reviewed and summarized. The clinical

obtained from the National Cancer Registry (NCR). From its

relevance of the studies done in the country are discussed

last published report in 2007, lung cancer was the third most

along with recommendations for future research.

common cancer in the country, the second most common
cancer in males and the 4th most common in females.4

KEY WORDS: Age

Lung cancer; lung carcinoma; lung neoplasm The mean age at which lung cancer is diagnosed in Malaysia
is about 60 years with a peak age of diagnosis in the 7th

INTRODUCTION
decade. The incidence of diagnosed lung cancer in Malaysian
patients aged less than 40 years is relatively low at
Lung cancer is the leading cause of cancer related deaths approximately 6.2%.5 Younger patients were more likely
worldwide with 30-40% occurring in developing countries.1 In than older patients to have adenocarcinoma with poorer
2012, there were more than 1.8 million lung cancer World Health Organization (WHO) performance status.6 Late
diagnoses worldwide causing 1.6 million deaths. The stage presentation and therefore inoperability is very
incidence of lung cancer and consequent death from this common in the younger age groups as they usually remain
disease is anticipated to increase over the next decade due to asymptomatic or ignore symptoms longer. In one study, all
the high rates of smoking.2 patients less than 40 years old with non small cell lung
cancer (NSCLC) presented with either stage IIIb or metastatic
This review covers all studies on lung cancer done in disease, compared to 77% of older patients (p<0.001).6
Malaysia. A review of research done in the country on lung
cancer is important as results reported worldwide, Ethnicity
particularly in Western developed countries, may not There was an over representation of Chinese among patients
necessarily be the same in a developing Asian country. A with lung cancer. The ethnic distribution was similar for the
literature search of articles as detailed in the paper younger and older groups of lung cancer patients. (Chinese
“Bibliography of clinical research in Malaysia: methods and brief 71%, Malay 19%, Indian 9%, others 1%, p<0.001).5,6 The age-
results” covering the years 2000-2015 was undertaken. The standardized incidence of lung cancer amongst the Chinese is
PubMed search involved the medical subject heading (MeSH) two-fold that of non-Chinese. The precise reason for this
“lung neoplasm”. 89 papers were identified of which 64 were observation is uncertain but smoking volume and a genetic
selected for their relevance.3 predisposition to cancer may be partly responsible.7

SECTION 1: REVIEW OF THE LITERATURE

Primary lung cancer

EPIDEMIOLOGY
Historically, squamous cell carcinoma was the commonest
lung cancer cell type. However, over the years,
Incidence and prevalence adenocarcinoma has now replaced squamous cell carcinoma
According to the 2014 World Health Organization report, as the commonest lung cancer cell type (Table I). The reason
lung cancer accounted for 19.1 deaths per 100,000 for this shift of cell type is unknown. Possible reasons include
population in Malaysia or 4,088 deaths per year (3.22% of all diagnostic advances, switch of smoking from high-tar to low-
deaths), the second most common cause of death due to tar filtered cigarettes and changes in smoking patterns.5
cancer in the country after breast cancer, and the eighth most
common cause of death from all causes. In 2014, cancer of An eight-year retrospective study done at University of
the trachea, bronchus and lung accounted for 24.6% of all Malaya Medical Center revealed adenocarcinoma subtype as
cancer mortality in males in the country, the most common the most common cell type in all age groups with a
Corresponding Author: [email protected]

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 A Review of Lung Cancer Research in Malaysia

Table I: Histological Subtypes of lung cancer in different institution in Malaysia

Author Institutions Sample Adenocarcinoma Squamous Large Poor or no Small Other
(ref) Size (n) (%) Cell (%) Cell (%) Differentiation Cell (%)
(%) (%)
C-K Liam et al UMMC 580 252 (43.4) 165 (28.4) 19 (3.3) 70 (12.1) 69 (11.9) 5 (0.9)
(1991-1999)
S.H How et al UMMC 503 206 (40.9) 153 (30.4) 14 (2.8) 65 (12.9) 65 (12.9) -
(Sept 1994 – Aug 2002)
A R M Fauzi Hospital Sultanah Aminah 236 66 (28.0) 73 (30.9) 19 (8.1) 28 (11.9) 45 (19.0) 5 (2.1)
et al (Jan 1997 – Dec 1999)
Catherine UMMC 50 19 (38.0) 17 (34.0) - - 5 (10.0) 7 (14.0)
MM et al (Mac 1998 – Oct 1999)
L-C Koh et all Seremban Hospital & 119 35 (29.4) 55 (46.2) 8 (6.7) - - 21 (17.6)
Nilai Cancer Institute
(Jan 1996 – Apr 2004)
S.H How et al UMMC 24 15 (62.5) 4 (16.7) 3 (12.5) 2 (8.3) -
(May 2001 – Jan 2002)
T.H. Ng et al HTAA§ 95 88 (92.6) 4 (4.2) 3 (3.2)
(Nov 2007 – Nov 2009)
S H How et al HTAA 149 78 (52.3) 28 (18.8) 1 (0.7) 21 (14.1) 6 (4.0) 6 (4.0)
(Aug 2007 – Aug 2010)
C-K Liam et al UMMC & HTAA 151 131 (86.8) 11 (7.3) 1 (0.7) - - 1 (0.7)
(Aug 2010 – Dec 2011)
N.S.Y Tiffany Sime Darby Medical 484 467 (96.5) 12 (2.5) 3 (0.6) - - 2 (0.4)
et al Center
(Jan 2011 – Apr 2012)
§ Hospital TengkuAmpuanAfzan, Kuantan, Pahang

Table II: Stage at presentation of lung cancer in different institutions in Malaysia

Author Institutions Sample Stage Ia Stage Ib Stage IIa Stage IIb Stage IIIa Stage IIIb Stage IV
(ref) Size (n) (%) (%) (%) (%) (%) (%) (%)
C-K Liam et al UMMC 510 16 (31.3) 35 (68.6) 2 (0.4) 15 (2.9) 41 (8.0) 186 (36.5) 215 (42.2)
(1991-1999)
L.N Hooi et al Penang GH 67 35 (52.2) 16 (23.9) 16 (23.9) -
(1995 – 2001)
L-C Koh et al Seremban Hospital & 119 8 (6.7) 111 (93.3) -
Nilai Cancer Institute
(Jan 1996 – Apr 2004)
Bassam Abd Penang General Hospital 118 11 (6.9) 25 (21.2) 47 (39.8) 29 (24.6)
Rasool Hassan (2003 – 2009)
et al
T.H. Ng et al HTAA 95 - - - - 3 (3.2) 50 (51.6) 43 (45.2)
(Nov 2007 – Nov 2009)
S H How et al HTAA 149 - - - - 5 (3.4) 76 (51%) 68 (45.6)
(Aug 2007 – Aug 2010)
C-K Liam et al UMMC & HTAA 151 4 (2.6) 4 (2.6) 2 (1.3) 2 (1.3) 7 (4.6) 9 (6.0) 123 (81.5)
(Aug 2010 – Dec 2011)

comparatively higher incidence in the younger patient less Several rare lung tumours were reported in Malaysia. Clear
than 40 years old 24/36 (77.7%) vs 228/544 (41.9%); p<0.001; cell tumours of the lung are rare type of primary lung
younger patients were less likely to develop squamous cell neoplasm. Shiran and colleague reported a case of clear cell
carcinoma (p = 0.047).6 Another study done by the same “sugar” tumour of the lung. Although the majority of clear
group revealed that the percentage of patients diagnosed cell tumours follow a benign course, there are reported cases
with adenocarcinoma increased from 25% during the period of malignant features such as lymphovascular invasion,
1967–1976 to 43% during the period 1991–1999 with a necrosis and pleomorphism.8 Primitive Neuroectodermal
corresponding drop in the incidence of large cell carcinoma Tumours (PNETs), a type of aggressive tumour arising from
from 12% to 3%. There was no significant shift in the mutation of the pluripotent neural crest cells, typically occur
incidence of squamous cell carcinoma.5 Small cell lung in the bone and soft tissues and rarely present as an organ-
cancer (SCLC) accounted for about 12% of all lung cancer based neoplasm. Primary lung PNETs may rarely occur but
cases. In recent years, the incidence of SCLC seems to be on involvement of the heart as the site of metastasis is even
the decline. Two-thirds of cases of SCLC are diagnosed with rarer. Harris, et al reported a rare case of pulmonary PNETs
advanced stage disease.5 with pericardial involvement.9

Med J Malaysia Vol 71 Supplement 1 June 2016 71

Multiple primary malignancies involving the lung are proportion of people who develop lung cancer in Malaysia
extremely rare. Iqbal, et al published a case report describing are life-long non-smokers.48 The percentage of male patients
a patient with three simultaneous primary cancers: in the with lung cancer who were smokers increased significantly
larynx (well differentiated squamous cell carcinoma), lung from 86% in 1967–1976 to 92% in 1991-1999.5 The
(non-small cell carcinoma) and thyroid (sclerosing papillary percentage of people with lung cancer who had never
carcinoma).10 smoked was higher among the younger patients (58% vs
19%, p<0.001).6 This is in contrary to the Western
Secondary lung cancer populations, in which younger lung cancer patients are more
The common primary sites of metastasis to the lung are from likely to have been smokers. However, data regarding the
the colon, breast and bone. In one study, the median survival intensity of smoking was not available in 17% of the patients
for patients with lung metastasis from primary breast cancer studied.6 Another single institution prospective study done by
was found to be 24 months.11 A retrospective review of Catherine et al, support the fact that smoking was more
medical records in 31 patients diagnosed with giant cell common in older patients (60 years and above) (p=0.002)
tumour of the bone in University Malaya reported that 4 and there were significantly more smokers in the older
patients developed pulmonary metastasis.12 A similar study patients who had carcinoma. The subanalysis of the same
conducted by Faisham, et al revealed that 6 out of 24 patients study also revealed that the older age group smokers
with giant cell tumour of the bone had pulmonary averaged 67.7 (range 20–120) pack-years, while the younger
metastasis. 2 patients with resectable disease were treated smokers averaged 29.3 (range 10–92) pack-years.15
with surgical resection, 2 were treated with chemotherapy Adenocarcinoma and squamous cell carcinoma were both
and the disease remained non progressive, while the significantly less strongly associated with cigarette smoking
remaining 2 patients refused chemotherapy (in which one of in the younger than in the older patients. (p<0.001 and
them succumbed to the disease due to massive hemoptysis). p=0.027 respectively). A high percentage of non-smoking
The study concluded that aggressive treatment of pulmonary female patients with adenocarcinoma and a younger age of
metastases in patients with aggressive giant cell tumour of diagnosis of adenocarcinoma suggest that risk factors other
the bone is mandatory for overall prognosis.13 than active smoking may be involved in carcinogenesis in
these patients.49
Tumour size reflects tumour burden and/or the extent of

CLINICAL PRESENTATION
disease. A retrospective data review conducted at Universiti
Sains Malaysia studied the association between tumour
volume and the occurrence of lung metastasis in patients Clinical symptoms suggestive of lung cancer include cough,
with osteosarcoma. 47% of the 70 patients with osteosarcoma hemoptysis, weight loss and chest pain. A cohort study of 160
studied had evidence of lung metastasis. Tumour volume was patients done at a University Hospital showed that the main
directly associated with occurrence of lung metastasis cause of haemoptysis in older patients (60 years old and
(p=0.048). The proportion having lung metastasis when the above) was bronchogenic carcinoma (49%).15 The majority of
primary tumour volume exceeded 371 cm2 was 69% bronchogenic carcinoma in this study was located in the
compared to 34% in smaller tumours. An increase in tumour proximal airways.15
volume represented an increase in the probability of lung
metastasis with a positive predictive value of 69%.14 Pleural effusions were found to be a common sign of lung
cancer. In a retrospective study of 189 patients with mean

PUBLIC KNOWLEDGE AND AWARENESS

age 51.2 years, malignancy ranked as the second most
common cause of exudative pleural effusions (30%) after
A cross-sectional study on lung cancer awareness was tuberculosis. 95% of malignant pleural effusions were due to
conducted by Al-Naggar, et al in 2012, involving 150 primary lung cancer.16 Another prospective study done in the
secondary school teachers randomly chosen from three same institution 3 years later by How, et al, revealed that
different secondary schools in the Kudat district, Sabah. The neoplastic pleural effusions was more common than that due
overall knowledge on lung cancer was found to be low.51 More to tuberculosis (34% versus 23%).17 The histological diagnosis
than half the secondary school male teachers (57%) thought of malignant pleural effusion was made by bronchoscopic
that only males are affected by lung cancer, and 71% biopsy in 66% of cases, by pleural fluid cytology in 59%, and
thought that lung cancer can be transmitted from person to by pleural biopsy in 50%. The combination of these three
person.51 Knowledge on the risk factor for lung cancer was procedures significantly increased the diagnostic yield to
better with 91% of participants aware that cigarette smoking 96%.17 Malignant effusions were found to be more frequent
is the main risk factors for lung cancer.51 Similar results were among patients older than 50 years (75%) and were likely to
observed in another similar study involving 213 university be large at presentation.16
students, which revealed that 100% of the participants were
aware that smoking is the main risk factor for lung cancer, Clinical symptoms and signs due to Cushing’s disease may be
and 90% were aware of passive smoking as a risk factor.52 associated with pulmonary carcinoid tumour with ectopic
ACTH production and its precursors. Wong, et al reported a

PREVENTION
rare case of ectopic ACTH-producing atypical carcinoid
associated with a non-functioning pituitary macroadenoma,
According to the National Health and Morbidity Survey (III) which is strongly associated with multiple endocrine
conducted in 2006, the prevalence of smokers in Malaysia neoplasia (MEN) type 1.18 In a rare condition known as
was 27%. However, it is noteworthy that a significant Masquerade Syndrome, there is a presence of an ocular

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 A Review of Lung Cancer Research in Malaysia

involvement of lung cancer. Pathology involves exudative cytology specimens to endobronchial biopsy produced only a
type retinal detachment which is manifested as sudden and small insignificant increase in the positive result for cancer
progressive loss of visual field and reduction in visual acuity. and was not cost effective.22 The authors concluded that
Kalthum, et al reported a rare case of Masquerade Syndrome routine cytological specimen collection by BB and BW in
secondary to poorly differentiated adenocarcinoma of the cases of visible endobronchial lesions during bronchoscopy
lung in a 37 year-old gentleman.19 had low additional value and should be discouraged.

MANAGEMENT
Transbronchial needle aspiration (TNBA) is another valuable
tool to diagnose lesions in the mediastinum and lung without
Diagnosis subjecting the patient to surgical biopsy.21 This technique is
In Malaysia, most lung cancer cases are diagnosed late with used to sample either suspected lesions or enlarged
either locally advanced disease or distant metastasis (Table paratracheal and subcarinal lymph nodes identified by CT
II). 75-88% of lung cancer cases are diagnosed in stage III or scanning. A retrospective review of patients undergoing
IV; these patients can only be offered palliative therapy.5 TNBA at Hospital Tengku Ampuan Afzan reported a success
Only about 12% of cases present early enough to be offered rate of 60% in yielding histological diagnosis.23 TBNA is
curative surgical resection.4 particularly useful in establishing histological diagnosis in
patients with peripheral lung lesions, mediastinal
Loh, et al, studied the time to diagnosis of lung cancer from lymphadenopathy (for staging or diagnosis), and drainage of
clinical presentation. Significant delay is present in the mediastinal cyst or abscess.23 However, the technique is
diagnosis of lung cancer with the median patient-delay being operator-dependent, and also dependent on other factors to
60 days (range 30–150 days) and the median doctor-delay achieve high yield, including type of needle used, technique,
being 33 days (range 18–72 days).20 Reasons for the delay in CT evaluation, tissue preparation and interpretation, as well
diagnosis of lung cancer include the failure to recognize as nodal site and size.23 Conventional TNBA is gradually
symptoms and patient beliefs in traditional complementary being superseded by endobrochial or endoscopic ultrasound
medicine.20 guided TNBA, which was reported to give a diagnostic yield
as high as 90%, and has been shown to reduce the need for
Following an abnormal CXR, bronchoscopy was diagnostic of surgical staging.24
lung cancer in 54% of older patients versus 33% in younger
patients (p=0.005). Bronchoscopy alone or combined with CT A case study done by Gita, et al, reported a successful
of the thorax achieved the highest yield of diagnosis diagnosis of a colloid carcinoma or mucinous carcinoma of
regardless of the age group and was significantly more the lung (a subtype of peripheral lung adenocarcinoma) with
diagnostic in older patients (60 years and above).15 Liam, et al CT-guided transthoracic-FNA. Cytological diagnosis of colloid
carried out a retrospective analysis on 503 patients with carcinoma is extremely difficult owing to the paucity of
confirmed lung cancer to determine if the diagnostic yield of tumour cells relative to the amount of mucin present.25
flexible bronchoscopy was dependent on tumour location.
Bronchoscopy sampling procedures involved several Sanchithanandan, et al reported a rare case of two
techniques including bronchial washing (BW), bronchial synchronous primary non-small cell lung cancers (NSCLC)
brushing (BB), broncho-alveolar lavage (BAL), diagnosed post-operatively following pathological
transbronchial biopsy (TBB) and endobronchial biopsy (EBB). examination of the resected lobe using
BW followed by EBB and then BB were performed immunohistochemistry markers (IHC); TTF-1 and the
sequentially for patients with bronchoscopically visible epithelial marker CK-7 are highly sensitive and specific for a
tumours. For patients with tumours which were not visible by primary NSCLC and non-reactive for metastatic lung
bronchoscopy, BAL was performed first, then BB, followed by adenocarcinomas.26
TBB. EBB was reported to be less likely to be diagnostic in
patients with tumours in the middle or lingular lobe bronchi. Biomarkers
The diagnostic yield of all the other sampling techniques Epidermal growth factor receptor (EGFR) is a transmembrane
were not influenced by the location of the tumours or tumour glycoprotein encoded by a gene located at the short arm of
visibility by bronchoscopy.21 Overall, the diagnostic yield of chromosome 7; it functions to stimulate a wide range of
bronchoscopy sampling in this study was 71%.21 Lung cancer cellular functions such as cell proliferation, differentiation,
lesions were most frequently located in the upper lobe migration and survival. Specific mutations in the tyrosine
(47.5%). Lesions in the upper lobes are often technically kinase (TK) domain of the epidermal growth factor receptor
difficult to access because of the acute angulation of the (EGFR) are associated with improved responses in NSCLC
bronchoscope needed to reach them. Squamous cell patients receiving EGFR-targeting tyrosine kinase inhibitors
carcinoma and small cell lung carcinoma were more (TKIs).
commonly associated with bronchoscopically visible tumours
compared to the other cell types.21 In another retrospective In Malaysian patients with NSCLC, the EGFR mutation rate
study of all bronchoscopy records for investigation of lung was found to be similar to that in other Asian populations
cancer at Hospital Sultanah Aminah, Johor Bahru, the but higher compared to Western populations.27 In a study
addition of cytological specimens from BB and BW to EBB conducted by Tiffany, et al, all of the EGFR mutations were
significantly increased the diagnostic yield by 17% (22/59 to found in adenocarcinoma tumours except one that was in
32/59) when no mass lesion was visible bronchoscopically. squamous cell carcinoma. The mutation rate was 46%
When endobrochial lesions were visible, the addition of (221/484) and was more frequent in women (61%, p<0.001).28

Med J Malaysia Vol 71 Supplement 1 June 2016 73

Similar results were observed in a retrospective study done on was observed after the 3rd cycle of treatment with
patients from 44 private and public hospitals between 2009 gemcitabine plus cisplatin, and the 4th or 5th cycle for
and 2011 where 40% of tumours from 812 patients with etoposide plus cisplatin. Reduction in number of metastasis
advanced adenocarcinoma were EGFR mutation positive.29 In and/or disappearance of cancer invasion was noticeable after
a study by Liam, et al, EGFR mutations were significantly the 5th cycle of treatment with gemcitabine plus cisplatin
more frequent among females (53% vs 28%, p<0.001) and in and the 6th cycle of treatment with etoposide plus cisplatin.32
non-smokers (55% vs 21%, p<0.001). Non-smoking status In another study on 33 patients done by Leow, et al, at the
was the only independent predictor of EGFR mutation same institution, patients who received gemcitabine-
positivity (OR: 3.82, p=0.002). These observations may carboplatin combination chemotherapy over a 2.5 years
suggest some association with preferential occurrence of period had a 27% overall response rate. The median survival
EGFR mutations in non-smoking women.29 Most EFGR rate among patients with an Eastern Cooperative Oncology
mutations involved deletions in exon 19 and 21 (24% and Group (ECOG) performance status of 1 was 11 months, as
19% respectively) and were significantly more common in compared to 4 months in patients with ECOG performance
females (p<0.001). Exon 19 deletions in tumours tended to status of 2, with the difference being statistically significant.33
occur in younger patients (mean age 57.4 years) compared to The results of this study also suggests that three cycles of
exon 21 deletions (mean age 65.1 years), a mean difference cytotoxic chemotherapy may suffice as only 14% of all
of 7.8 years.27 Complex mutations were also observed, where patients (2/14) undergoing the full course of six cycles
8 tumours carried 2 mutations and 1 tumour carried 3 showed further tumour regression. However, the number of
mutations. patients in this study was very small and may not represent
the actual response rate. Future studies involving larger
Direct sequencing is considered the “gold standard” in numbers of patients should compare the efficacy of three-
nucleic acids studies, but its use was limited due to low cycle and six-cycle regimens of carboplatin-gemtacibine
sensitivity, high cost and long turnaround time. High combination chemotherapy.33
resolution melting (HRM) and Scorpion amplification
refractory mutation system (ARMS) are emerging techniques In another study, data from two local institutions, Seremban
for rapid detection of DNA sequence variation. Both methods General Hospital and Nilai Cancer Institute, were collected.
were found to be useful for detection of EGFR mutations; all The median survival of NSCLC patients who accepted cancer-
mutations identified by ARMS in one study were correctly specific therapy i.e. surgery, chemotherapy or radiotherapy,
matched in HRM analysis.28 The detection of EGFR mutation- was significantly longer compared to those who opted out of
positive tumours by Scorpion ARMS was comparable to that cancer-specific treatment (8.6 months versus 2.2 months,
by direct sequencing in one study (170 of 396 tumours or p<0.001). However, despite the small significant survival
42.9% compared to 151 of 416 tumours or 36.3%).29 benefit in accepting cancer-specific treatment, the overall
prognosis for patients with NSCLC remains poor.34 How, et al

TREATMENT AND OUTCOMES

reported an overall median survival of 18 weeks in 149
patients with histologically confirmed lung cancer in their
Surgical resection study. This study was conducted in a single referral hospital
The most effective option for treatment of lung cancer is of the state of Pahang from 2007 to 2010. They also revealed
surgical resection, when feasible. However, most patients that among NSCLC patients on treatment, 1- and 2-year
with lung cancer do not undergo surgical resection; in a survival rates were only 27% and 15% respectively. The
single institution study, only 8% of patients with NSCLC median survival of patients who received treatment was 35
underwent surgical resection. The main reason for the low weeks as compared to 16 weeks for those who did not
operative rate was the high proportion of patients who (p<0.001).35
presented with advanced inoperable disease.31 Following
surgical resection, the 5-year survival was 29% and the Hypercalcemia can occur in cancer patients with and without
median survival was 27 months (Table III).31 Completeness of bone metastasis. Chemotherapy lowered serum calcium
resection was the main determinant of survival outcomes. levels significantly in lung cancer patients who were initially
Complete resection had significantly better median survival hypercalcemic at diagnosis, in particular with chemotherapy
than those in whom the tumour could not be totally removed regimen: Gemcitabine + Cisplatin (after the 3rd cycle of
(31 months vs 10 months). The overall five-year survival rate treatment) in lung cancer, probably by reducing parathyroid
was 34% in the group with complete resection, whereas there hormone-related protein (p=0.003). 32
was no patient with incomplete resection who survived to 5
years in this study.31 Biologically Targeted Therapy
Recently, oncogenic driver mutations have been detected in
Chemotherapy and Radiotherapy NSCLC and tumours with mutations in oncogenes such as
The majority of patients are diagnosed at an advanced or epidermal growth factor receptor (EGFR), ALK, ROS1 and
metastatic stage of disease in which case chemotherapy others can be treated with appropriate oncogene-driven
and/or concurrent administration of chemotherapy and targeted therapy with improved outcomes. Tumours with
radiation is the most beneficial form of treatment. Current EGFR deletions in exons 19 and 21 have improved response
chemotherapeutic drugs kill cancer cells mainly by inducing to treatment with EGFR-targeted tyrosine kinase inhibitors
apoptosis. In a retrospective observational study on 814 cases (TKIs) such as gefitinib and erlotinib.
of lung cancer between 2003 and 2009, treatment response
(reduction in the size of the primary lesion) to chemotherapy

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 A Review of Lung Cancer Research in Malaysia

EFGR-TKIs have been approved as monotherapy for the Lung carcinoma in pregnancy is rare especially in never
treatment of patients with locally advanced or metastatic smokers. Treatment of advanced lung cancer in pregnancy is
non-small cell lung cancer (NSCLC) after failure of at least challenging because one has to weigh the benefits and risks
one prior chemotherapy regimen. Studies have shown that of treatment, both to the mother and the fetus. Compared to
when given alone, oral gefitinib showed significant durable cytotoxic chemotherapy, EFGR tyrosine kinase inhibitors
anti-tumour activity in a significant proportion of Malaysian treatment is more effective, targeted and associated with
patients with locally advanced and metastatic primary fewer side effects. Lee, et al, reported a successful pregnancy
adenocarcinoma of the lung.36 The relatively high prevalence in a patient diagnosed with stage IV lung adenocarcinoma
of epidermal growth factor receptor (EGFR) mutations with multiple lung secondaries and lymphangitis
predicting altered biology and more favourable response to carcinomatosis, who showed both clinical and radiological
EGFR tyrosine kinase inhibitors may explain the better responses to oral EGFR-tyrosine kinase inhibitor (Erlotinib
survival rate of lung cancer patients in Asians compared to and Gefitinib).40
Caucasians.29
Traditional & Complementary Medicine
A retrospective study done by the Liam and colleagues A study conducted by Lee, et al, showed the cytotoxic
involving a total of 23 patients receiving gefitinib potential of the Phyllanthus plant in inhibiting A549 (lung
monotherapy reported disease control in 14 patients (61%); carcinoma) and MCF-7 (breast carcinoma) cell growth by
of these, 11 patients (48%) showed at least 30% reduction in effectively reducing invasion, migration, and adhesion of the
tumour size of the primary and/or metastatic tumours cells in a time- and dose-dependent manner (p<0.05). The
(partial response), while 3 patients (13%) had stable disease extract of this plant had lower toxicity in normal cells with
(absence of either response or progressive disease for a the cell viability percentage remaining above 50%. The
minimum of 8 weeks). The response rate was significantly authors concluded that the extract of various species of
higher in those who had never smoked (10 of 15 or 67%) Phyllanthus was shown to be capable of inducing apoptosis in
compared with that of smokers (1 of 8 or 13%) (p=0.027). The conjunction with its anti-metastatic action due to the
median time to symptom improvement was 1.5 weeks (range presence of polyphenol compounds in the plant. However,
0.5–6). 37 Adverse effects associated with gefitinib treatment the exact bioactive compounds in Phyllanthus exerting the
were generally mild and consisted of grade 1 or 2 skin anti-metastasis have not yet been identified.41
toxicity, which included dry skin, acne, pruritic rash, loss of
finger nails and toe nails.36 Another study done by the same Distant metastases
authors several years later on advanced lung The skeletal system is the most commonly affected organ in
adenocarcinoma patients with unknown EGFR mutation lung metastasis. A study done at University Malaya showed
status also similarly reported that the response rate to that 21% of primary lung cancer result in bone metastasis
gefitinib was higher in women and never-smokers compared with male predominance observed (n=21, 65.6%). The
to men and ever-smokers.37 They also reported that patients survival of patients with metastatic disease is generally
with good WHO performance status 1 or 2 had a response dependent on the type of primary tumour. Patients with
rate of 61%, whereas none of the patients with WHO primary lung cancer with bone metastases had the shortest
performance status 3 or 4 responded to treatment given.30 mean survival time (16.0 ±1.7 months) as compared to other
primary cancer. This study also showed a marginally higher
The phase III, randomized, open-label ENSURE study incidence of long bone metastasis than axial skeleton
evaluated first-line erlotinib versus gemcitabine/cisplatin in metastasis.42 The treatment of bone metastasis is usually
patients from China, Malaysia and the Philippines with palliative and aims to adequately control pain, and to
epidermal growth factor receptor (EGFR) mutation-positive anticipate or stabilize pathological fracture.43
non-small cell lung cancer (NSCLC). In this study, it was
reported that the median progression-free survival was 11 It is sometimes challenging to distinguish spinal tuberculosis
months in the erlotinib group versus 5.5 months in the from metastatic lung adenocarcinoma. Zamzuri, et al
gemcitabine/cisplatin group, regardless of EGFR tumour reported a rare case of metastatic adenocarcinoma of the
mutation type (HR 0.34, 95% CI 0.22-0.51, p<0.0001), and lung to the spine with T7 vertebra body collapse which was
objective response rate was 62.7% for erlotinib and 33.6% for thought to be spinal tuberculosis due to a positive Mantoux
gemcitabine/cisplatin.39 Treatment-related serious adverse test and elevated erythrocyte sedimentation rate (ESR).
events occurred in 2.7% patients receiving first-line erlotinib However, the patient did not respond to anti-tuberculosis
compared to 10.6% of patients with cytotoxic chemotherapy drugs. CT thorax subsequently revealed a peripherally
(gemcitabine/cisplatin).38 located right lower lobe lesion which was an
adenocarcinoma in histopathological examination.44
The use of EGFR-TKIs is associated with unique dermatologic
side effects. Ong, et al, reported two cases of NSCLC Primary lung cancers also have tendencies to metastasize to
developing atypical (papulo-pustular) eruptions shortly after the brain with an estimated incidence of around 20–40%.
initiation of EGFR-TKIs. Both patients received oral erlotinib Patients with brain metastases from an underlying lung
and gefitinib following radiotherapy/chemotherapy. They primary seem to fare less well in terms of overall survival
developed acneiform over the face and upper trunk (after 10 compared with other primary tumour sites such as breast or
days and 2 weeks commencement of erlotinib and gefitinib colorectal cancer. A retrospective study by Tang, et al on 125
respectively). The cutaneous side effects of both patients patients with confirmed non-small cell lung carcinoma and
resolved with oral doxycycline and topical benzoyl brain metastases reported the overall median survival of 3.4
peroxide.39 months (95% CI: 1.7–5.1).45 Median survival of patients with

Med J Malaysia Vol 71 Supplement 1 June 2016 75

multiple metastases receiving whole brain radiotherapy SOCIAL IMPACT
(WBRT) was 1.5 months, 1-3 metastases receiving WBRT was Debilitating impact and traumatic effect of the diagnosis of
3.6 months and 1-3 metastases receiving surgery or cancer on the quality of life (QOL) of the afflicted individuals,
stereostatic radiosurgery/stereostatic radiotherapy was their spouses and their families is inevitable. A cross-sectional
prolonged to 8.9 months (2.5 fold increase for those received study was performed recruiting 95 adolescent children from
on WBRT).45 ECOG score, presence of seizure, treatment 50 families aged 13–18 years to parents who were suffering
modalities (receiving either SRS/SRT±WBRT or WBRT alone) from colorectal, breast or lung cancer (the three most
as well as receiving post-therapy systemic treatment were common cancers in Malaysia). Adolescents with parental
significant factors affecting prognosis on both univariate and cancer had significantly lower scores in emotional
multivariate analysis.45 functioning (p<0.05). Male adolescents had significantly
higher quality of life overall and in physical functioning
A case report revealed a rare complication of metastatic lung compared to female adolescents. Furthermore, monthly
cancer leading to intussusception of the bowel. The patient household incomes (household incomes of less vs more than
presented with upper gastrointestinal bleeding suggestive of RM 5,000) had significant differences in emotional QOL and
duodenal ulcer; subsequent CT thorax/abdomen showed a school QOL.54
mass at the head of pancreas and lesion at the left lung. The

SECTION 2: RELEVANCE OF FINDINGS FOR CLINICAL

histopathological examination of both lesions showed

PRACTICE
similar histology, findings were suggestive of small cell
carcinoma of the lung with metastasis to the small bowel and
pancreas, with an incidental finding of intussusception at the This review of the research studies done in Malaysia
jejunum intra-operatively.46 contributes towards our overall knowledge, understanding
and management of patients with lung cancer in the
Catherine, et al published a case report describing two country. Lung cancer has been identified as an important
patients with metastatic lung cancer diagnosed during cause of mortality and morbidity in the country;3,7 adequate
pregnancy. Both ladies were diagnosed to have lung resources must be allocated towards better primary
carcinoma (squamous cell carcinoma and adenocarcinoma) prevention, earlier and more effective diagnosis, better
at 31 and 35 weeks respectively. They managed to deliver treatment and palliation, and better support for patients and
healthy babies with adequate birth weight prematurely. their families.
However, due to the advanced stage of the disease, both of
them did not survive. In both cases, palliative chemotherapy Smoking has been shown to be the main risk factor for lung
was declined because of the mothers’ concern for their fetus. cancer.5,6,48 Knowledge of this amongst the general public is
There is no published data on optimal chemotherapy and good but there are still significant numbers of smokers in the
radiotherapy strategies for lung cancer patients who are country. Efforts are needed to discourage smoking amongst
pregnant.47 the population through both financial disincentives and
restrictions on smoking in public places. Greater efforts must

PATIENT COMPLIANCE
be made to increase the numbers and availability of smoking
cessation clinics in the country, and every encouragement
Patients who fail to attend follow-up may after initial and incentive must be given to smokers to attend these
investigations result in delays in the appropriate treatment clinics.
which affect outcomes. A prospective study was done by Ng,
et al involving 95 patients aimed at determining the Public awareness of the symptoms, signs and nature of lung
prevalence, patient characteristics and reasons for defaulting cancer was found to be poor.52,53 This has been identified as a
follow-up and treatment among patients with lung cancer. cause of late presentation of the disease at an inoperable
The prevalence of patients defaulting treatment and follow- stage in many patients, and also a delay in diagnosis.6
up was 21% (20/95), two thirds of them were persistent Greater efforts must be made towards educating the public on
defaulters (defined as defaulting two consecutive the symptoms and signs of lung cancer and the need to seek
appointments), while the other one third were intermittent early medical attention at a stage when the disease is still
defaulters (defined as defaulting at least one follow-up or curable. In addition, protocols must be in place for general
planned treatment at a given appointment date).53 Most of practitioners and physicians for early referral for imaging
the defaulters gave the reason of being “too ill” to come and other diagnostic procedures in patients with symptoms
(39%) and logistic difficulties. There was no correlation and signs suggestive of lung cancer.
between patient education, income, Eastern Cooperation
Oncology Group (ECOG) performance status, stage of the Studies using bronchoscopy to obtain tissue diagnosis
disease, race or gender. However, education level of their reported good diagnostic yields using bronchial washing
children was found to be significantly associated with (BW), bronchial brushing (BB), broncho-alveolar lavage
defaulter rate.53 In another study, Hooi, et al, reported 16% of (BAL), transbronchial biopsy (TBB) and endobronchial
patients were lost to follow-up even with concerted efforts to biopsy (EBB).21,22 Chest physicians must become familiar with
locate them. Patients commonly requested for discharge from these techniques with or without endobronchial ultrasound
hospital once they are terminally ill and did not return for (EBUS) guidance and make this the standard of care.
follow-up.31
Adenocarcinoma has been identified as the most common
subtype of lung cancer in Malaysia (Table I).5,6 Studies have

76 Med J Malaysia Vol 71 Supplement 1 June 2016

 A Review of Lung Cancer Research in Malaysia

identified a large proportion of adenocarcinoma patients in condition, and the long term outcomes. To this end, the
Malaysia with mutations in the epidermal growth factor recent launch of the National Thoracic and Cardiovascular
receptors (EGFR), similar to other Asian countries but much Surgical Database (NCTSD) Registry is timely.
higher rates compared to Western countries.28,29 These
patients demonstrate increased responsiveness to treatment The high prevalence of exon 19 and 21 EGFR mutations in
with EGFR-targeted tyrosine kinase inhibitors, with improved lung adenocarcinoma tumours amongst Malaysian patients
survival being reported.36,38 Testing for EGFR mutations in is promising due to its improved responsiveness to EGFR
lung adenocarcinoma patients is therefore mandatory and inhibitors. However, acquired resistance to EGFR inhibitors
all histopathology laboratories in the country receiving lung develops after a period of treatment and research is needed to
tumour biopsies and specimens must make this their routine better understand and overcome this.
practice and be adequately trained and equipped for this. In
addition, EGFR-targeted tyrosine kinase inhibitor therapy More recent developments in lung cancer therapy include the
must be readily available to chest physicians and oncologists. use of immunotherapy in advanced disease with the
potential for improved survival. Genomic profiling and
Several small studies using chemo and radiotherapy in biomarker analysis is likely to identify tumours which would
advanced lung cancer were reported.32,33 Insights were offered respond to immunotherapy. Studies on this are needed in the
into the optimal choice, regime and duration of country as our population may differ from that in western
chemotherapy agents. However, these observations need to countries where most of these research is currently being
be confirmed in larger studies. done.

ACKNOWLEDGEMENT
A study on the social impact of lung cancer on the patient’s
family and carers reminds us that support for the patient and
family is needed beyond the medical treatment given.54 This We would like to thank the Director General of Health for his
is too often forgotten and adequate training and provision of permission to publish the paper, Prof Teng Cheong Leng of
these services are needed in the country. International Medical University for making the literature
search, Dr Goh Pik Pin and Dr. Kirubashni Mohan of Clinical

SECTION 3: FUTURE RESEARCH DIRECTION

Research Centre for their valuable contribution and
assistance in editing and formatting the review articles.
An important observation of this review is that survival rates

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