Lung cancer, the most common cancer in the world for several decades, which

was rare before 20th century, had become epidemic by the mid-twentieth century. 1.8
million new cases occurred in 2012 (12.9% of the total) and out of that 58% had
occurred in the less developed regions. In India, the number of new cases in 2012
were 70,275(6.9% of the total).1 The disease still remained as the most common
cancer in men worldwide (1.2 million, 16.7% of the total). In women, the incidence
rates are generally lower than men, mainly due to different historical exposure to
tobacco smoking.
Lung cancer, being the most common cancer, is also the most common cause
of death from cancer worldwide, estimated to be responsible for nearly one in five
deaths (1.59 million deaths, 19.4% of the total)1.
Lung cancer accounts for 7.5% of all cancers seen in Department of
Radiotherapy, Pt. B. D. Sharma Post Graduate Institute of Medical Sciences, Rohtak. 2
The commonest major histological type of tumour observed was non-small-cell
carcinoma in 70.8% of patients. Small cell lung carcinomas were reported in 15.2% of
patients. Around 14% of patients did not have histopathological subtyping. Male to
female ratio observed in these patients was 3:1.
The primary risk factor for lung cancer is smoking tobacco, which accounts
for most lung cancer-related deaths. The International Agency for Research on Cancer
lists several agents known to cause lung cancer, including arsenic, chromium,
asbestos, nickel, cadmium, beryllium, silica, and diesel fumes. In addition, other
possible risk factors include recurring lung inflammation, lung scarring secondary to
tuberculosis,

family

history,

and

exposure

to

other

carcinogens

(i.e.,

bis(chloromethyl)ether, polycyclic aromatic hydrocarbons etc. Cigarette smoke

contains many carcinogenic chemicals (e.g. nitrosamines, benzo(a)pyrene diol
epoxide).3 The risk for lung cancer increases with the number of packs of cigarettes
smoked per day and with the number of years spent smoking (i.e. pack-years of
smoking history). Exposed non-smokers also have an increased relative risk
(RR=1.24) of developing lung cancer from second-hand smoke. Radon gas, a
radioactive gas that is produced by the decay of Radium 226, also causes lung cancer.
The U.S. Environmental Protection Agency estimates that radon is the main cause of
lung cancer in non-smokers; however, second-hand smoke may also be a factor.

Asbestos, a mineral compound that breaks into small airborne shards, is a well known
carcinogen that increases the risk for lung cancer in people exposed to airborne fibers,
especially in individuals who smoke. It is estimated that about 3% to 4% of lung
cancers are caused by asbestos exposure. Asbestos also causes malignant pleural
effusion.
Lung cancers are generally divided into 2 main categories: Small Cell Lung
Carcinoma and Non-Small Cell Lung Carcinoma. Non-Small Cell Lung Carcinoma
accounts for approximately 85% of all lung cancers. Non-Small Cell Lung Carcinoma
is divided further into adenocarcinoma, squamous cell carcinoma, and large cell
carcinoma. All share similar treatment approaches and prognosis but have distinct
histologic and clinical characteristics.
Adenocarcinoma
Adenocarcinoma, arising from the bronchial mucosal glands, is the most
common Non-Small Cell Lung Carcinoma cancer in the United States, representing
35-40% of all lung cancers. India also shows the similar trend. It is the subtype
observed most commonly in persons who do not smoke. It usually occurs in a
peripheral location within the lung, in some cases at the site of pre-existing scars,
wounds, or inflammation (i.e., a scar carcinoma).
Bronchoalveolar carcinoma is a distinct subtype of adenocarcinoma with a
classic manifestation as an interstitial lung disease on chest radiograph.
Bronchoalveolar carcinoma arises from type II pneumocytes and grows along alveolar
septa. This subtype may manifest as a solitary peripheral nodule, multifocal disease,
or a rapidly progressing pneumonic form. A characteristic finding in persons with
advanced disease is voluminous watery sputum.
Squamous cell carcinoma
Squamous Cell Carcinoma accounts for 25-30% of all lung cancers. Whereas
adenocarcinoma tumors are peripheral in origin, squamous cell carcinoma is found in
the central parts of the lung. The classic manifestation is a cavitary lesion in a
proximal bronchus. This type is characterized histologically by the presence of keratin

pearls and can be detected with cytologic studies because it has a tendency to
exfoliate. It is the type most often associated with hypercalcemia.
Large-cell carcinoma
Large-cell carcinoma accounts for 10-15% of lung cancers, typically
manifesting as a large peripheral mass on chest radiograph. Histologically, this type
has sheets of highly atypical cells with focal necrosis, with no evidence of
keratinization (as is typical of squamous cell carcinoma) or gland formation (as is
typical of adenocarcinomas).
Through the 1960s the predominant type of non-small cell carcinoma was
squamous cell type. Although overall incidence of lung cancer increased over 30
years, the incidence of squamous cell carcinoma decreased and adenocarcinoma
became the more dominant type- due to changes in tobacco blend and use of filters in
cigarettes.4
The spread pattern of lung cancer may be divided into three pathways: local
(intrathoracic), regional (lymphatic) and distant (hematogenous). In most cases,
lymph node metastases seem to occur earlier than distant hematogenous spread. For
right lung tumors, the most commonly involved mediastinal areas are the lower
paratracheal nodes, followed by the subcarinal nodes. For left upper lobe lesions, the
subaortic nodes are most commonly involved. For lingular and left lower lobe lesions,
the most frequently involved nodes are subcarinal. Skip metastases are frequent and
occur more commonly in adenocarcinoma than in squamous cell carcinoma. By direct
extension, the primary tumour can invade contiguous structures, such as the
mediastinal pleura, great vessels, heart, oesophagus, diaphragm, or chest wall. Bone,
liver, adrenals, and brain are the most frequent sites of distant disease.
The signs and symptoms manifested by patients suffering from lung cancer
depend on the histology of the tumour and the extent of loco regional invasion, as
well as the location, size, and number of distant metastases. Symptoms secondary to
central or endobronchial growth of the primary tumour are cough, hemoptysis,
wheeze, and stridor. Symptoms secondary to peripheral growth of the primary tumour
include pain due to pleura and chest wall involvement, cough and dyspnea. Symptoms
due to loco regional spread and distant metastasis includes tracheal obstruction,

hoarseness, dyspnea due to phrenic nerve palsy, superior vena cava syndrome due to
vascular involvement, Horner syndrome and pancoast syndrome. Lung cancer
accounts for 65% to 90% of all cases of SVC syndrome, and in approximately 85% of
these cases the primary lung tumour is on the right, primarily in the right upper lobe
or right main stem bronchus.
Diagnostic evaluation includes a detailed history and physical examination,
smoking history, occupational/environmental exposures, and family history. Physical
examination should determine the presence of supraclavicular or cervical
lymphadenopathy, signs of airway obstruction or pleural effusion, as well as
organomegaly or pain referable to visceral or skeletal metastatic lesion. Extremity
examination to rule out paraneoplastic syndrome and neurologic examination to rule
out cognitive as well as focal motor deficits attributable to metastatic disease.
Radiological investigations include posterioanterior and lateral chest x-rays, CT scan
of chest preferably HRCT, PET scan, PET CT. FDG-PET scans are extremely useful
for the detection of mediastinal lymph node as well as visceral and bony metastases.
FDG-PET scans are considerably superior to CT scans for the detection of N1 disease
(42% vs. 13%) with a positive predictive value 60%, the negative predictive value of
90%. Tissue diagnosis is established by sputum cytology, percutaneous FNAC,
bronchoscopy, mediastinoscopy, endoscopic USG, thoracocentesis, thoracoscopy and
in rare cases thoracotomy. The American Joint Committee on Cancer (AJCC) 2010
staging is used for carcinomas of lung.
In patients with NSCLC, the most important prognostic factor is tumour stage.
This factor largely determines treatment. Surgery is the standard mode of treatment of
patients with stage I and II tumors and for selective patients with stage III tumors.
Only about 20% of all patients presenting with lung cancer are suitable candidates for
curative surgery.
In general, the nonsurgical treatment of NSCLC can be divided into broad
categories:
1. Radiation therapy alone: this is used primarily for early-stage (stage I and II)
patients. For patients with locally advanced disease (stage IIIA and IIIB) it is
used for the rare patients who cannot tolerate any chemotherapy due to
comorbid conditions or poor performance status.

2. Sequential chemotherapy followed by radiation therapy: this approach is

reserved for patients with locally advanced disease who are unable to tolerate
concurrent chemotherapy and radiation therapy.
3. Concurrent chemotherapy and radiation therapy: this is the standard of care for
fit patients with locally advanced disease.
4. Endobronchial brachytherapy for patients with obstructing endobronchial
lesions.
5. Palliative radiation therapy for patients with metastatic disease.
Radiotherapy
Sir Wilhelm Conrad Roentgen discovered the X-rays on Friday 8th November,
1895. Madam Curie discovered radium in 1898 and almost immediately the biologic
effects of ionizing radiations were recognized. Conventional fractionated radiotherapy
(60 to 66 Gy in 1.8- or 2-Gy fractions) was used, with reported 5-year local control
and overall survival rates ranging from 30% to 50% and 10% to 30% respectively in
stage I/II Non-Small Cell Lung Carcinoma. For the locally advanced carcinomas (T3
and T4 tumours) the local and regional control rate is extremely poor with three-year
disease free survival of about 10 - 22%.5 Several strategies including physical
modifiers, radio-protectors, hyperthermia and cytotoxic agents/chemotherapy have
been advocated to improve the effect of radiation.
Various altered fractionation schemes used to increase the local control rate in
lung cancers are Hyperfractionation, Accelerated Hyperfractionation, Continuous
Hyperfractionated

Accelerated

Radiotherapy

(CHART),

Concomitant

Boost

Accelerated Fractionation schedules and Hypofractionation.

A. HYPERFRACTIONATION
The basic rationale of hyperfractionation is that the use of small dose fractions
allows higher total doses to be administered within the tolerance of late-responding
normal tissues, and this translates into a higher biologically effective dose to the
tumor. Other rationales for hyperfractionation are radiosensitization through
redistribution and lesser dependence on oxygen effect.
B. ACCELERATED HYPERFRACTIONATION
The potential benefits of both hyperfractionation and accelerated treatment can
be achieved by delivering smaller than standard dose fractions in a shorter than

standard overall treatment duration. The limitation of accelerated hyperfractionation is

acute toxicity because both strategies independently increase acute reactions. The late
effects should be the same or less than acute toxicity.
C.CONTINUOUS

HYPERFRACTIONATED

ACCELERATED

RADIOTHERAPY (CHART)
In this type of altered fractionation technique
total dose is decreased, number of fractions is increased, total treatment days
decreased with increased local control and early reactions. Late reactions are
decreased except for myelopathy.
D.CONCOMITANT

BOOST

ACCELERATED

FRACTIONATION

TECHNIQUE
This is another variant of accelerated radiotherapy in which the second daily
fraction dose (boost) is delivered by a reduced field to the primary site or primary site
along with massive local extension site only which requires higher dose for a given
radiation effect.
E. HYPOFRACTIONATION
In hypofractionation, the total dose of radiation is divided into multiple doses
of high dose per fraction, the size of dose per fraction is significantly increased,
decreasing the no. of fractions and total time.
Brock et al reviewed the published clinical data on non-small cell lung cancer
treated with radical radiotherapy to confirm a dose response relationship as a basis for
further dose escalation trials. Twenty four published clinical trials were identified,
sixteen of which with different standard, hyper and hypofractionated schedules
analysed for disease free survival data after converting prescription doses to
biologically equivalent dose. Results shows hypofractionated schedules with
treatment time of six weeks or less are predicted to be more beneficial than short
hyperfractionated schedules or prolonged conventionally fractionated treatments.6
Chemotherapy
Over the past decades, the treatment in oncology has advanced promisingly.
The patients can be treated by surgery, chemotherapy, radiotherapy (RT) or

combination of these. Neoadjuvant or adjuvant therapy is recommended for many

patients with stage II and III disease. The use of combined-modality therapy including
radiation and chemotherapy is recommended for locally advanced stage III disease. A
phase III randomized trial reported that an albumin-bound paclitaxel/carboplatin
regimen is associated with less neurotoxicity and improved response rate, when
compared with standard paclitaxel/carboplatin, in patients with advanced NSCLC. 7
The FDA has approved albumin-bound paclitaxel/carboplatin for patients with locally
advanced or metastatic NSCLC who are not candidates for curative surgery or RT.
Epithelial Growth Factor Receptor (EGFR) Mutations & Tyrosine Kinase
Inhibitor (TKIs) therapy
EGFR is normally found on the surface of epithelial cells & is often
overexpressed in a variety of human malignancies. Presence of EGFR activating
mutations represents a critical biological determinant for proper therapy selection in
patients with lung cancer. There is significant association between EGFR mutationsespecially exon 19 deletion, exon 21, exon 18 and exon 20 mutations and sensitivity
to TKIs therapy. The exon 20 insertion mutation may predict resistance to clinically
achievable levels of TKIs.
The prevalence of EFGR mutations in adenocarcinoma is 10% of Western and
50% of Asian patients, with higher EGFR mutation frequency in non-smokers,
women and non-mucinous cancers.8 Mutations are more common in non-mucinous
lung adenocarcinoma with lepidic pattern and in lung adenocarcinoma with papillary
pattern.
Increased EGFR expression has been observed in many experimental cancer
cell lines and human tumors, including NSCLC, and it has been associated with
advanced tumor stage, metastasis, and poor prognosis. Previous studies have
suggested that high expression of EGFR is associated with resistance to cancer
therapy, including radiation therapy. Conversely, EGFR inhibitors have been shown to
enhance the effects of ionizing radiation (IR), although the effective subset of tumors
for radiosensitization by these agents has not yet been defined.9
Patients with EGFR mutations have significantly better response to gefitinib.
Gefitinib, at the cellular level, radiosensitizes EGFR with NSCLC H358 by blocking

EGFR nuclear translocation as one of its mechanisms. Pharmacokinetic studies have

shown that oral bioavailability of gefitinib 250 mg reaches at peak plasma
concentration within 3 hrs.10 Retrospective studies have shown an objective response
rate of approximately 80% with a median progression free survival of 13 months to
single agent in patient with adenocarcinoma lung with EGFR mutation. A prospective
study has shown that the objective response rate in North American patients with nonsquamous NSCLC and EGFR mutations (53% Exon19del [LREA deletion], 26%
L858R, 21% other mutations) is 55% with a median PFS of 9.2 months. EGFR
mutation testing is not usually recommended in patients with pure squamous cell
carcinoma, unless they are never smokers, if only a small biopsy specimen (i.e., not a
surgical resection) was used to assess histology, or if the histology is mixed. 11 Data
suggest that EGFR mutations can occur in patients with adenosquamous carcinoma,
which is harder to discriminate from squamous cell carcinoma in small specimens. 11
Moreover recent data also suggest that erlotinib (or gefitinib) or afatinib (instead of
standard first-line chemotherapy) should be used as first-line systemic therapy in
patients with EGFR mutations documented before first-line therapy. Data show that
progression-free survival (PFS) is improved with use of EGFR TKI in patients with
EGFR mutations when compared with standard chemotherapy, although overall
survival is not statistically different.12
Gefitinib
Gefitinib is the first selective inhibitor of epidermal growth factor receptor's
(EGFR) tyrosine kinase domain. Thus gefitinib is an EGFR inhibitor. The target
protein (EGFR) is a family of receptors which includes Her1(erb-B1), Her2(erb-B2),
and Her 3(erb-B3). Structurally it is N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3morpholin-4-ylpropoxy)quinazolin-4-amine. US-FDA approved in May 2003
for NSCLC, Gefitinib is currently marketed in over 64 countries. In June 2005 the
FDA withdrew approval for use in new patients due to lack of evidence that it
extended life. In Europe gefitinib is indicated since 2009 in advanced NSCLC in all
lines of treatment for patients harbouring EGFR mutations. This label was granted
after gefitinib demonstrated as a first line treatment to significantly improve
progression-free survival vs. a platinum doublet regime in patients harbouring such
mutations. IRESSA Pan-Asia Study (IPASS) has been the first of four phase III trials
to have confirmed gefitinib superiority in this patient population.

IPASS was a randomized, large-scale, double-blinded study which compared

Gefitinib vs. carboplatin/ paclitaxel as a first line treatment in advanced
NSCLC. IPASS studied 1,217 patients with confirmed adenocarcinoma histology who
were former or never smokers. A pre-planned sub-group analyses showed that PFS
was

significantly

longer

for

Gefitinib

than

chemotherapy

in

patients

with EGFR mutation positive tumours (HR 0.48, 95 per cent CI 0.36 to 0.64, p value
less than 0.0001), and significantly longer for chemotherapy than Gefitinib in patients
with EGFR mutation negative tumours (HR 2.85, 95 per cent CI 2.05 to 3.98, p less
than 0.0001). This, in 2009, was the first time a targeted monotherapy has
demonstrated significantly longer PFS than doublet chemotherapy.13
Wang et al has done prospective study on epidermal growth factor receptor
tyrosine kinase inhibitors concurrent with individualized radiotherapy for patients
with locally advanced or metastatic non-small-cell lung cancer. Between June 2007
and January 2010, 26 patients with Stage III/IV NSCLC were enrolled in this
prospective study. These patients were treated with EGFR-TKIs (gefitinib 250 mg or
erlotinib 150 mg, oral daily) concurrent with individualized RT with curative intent.
The thoracic RT plans were individually designed on the basis of tumor size and
normal tissue volume constraints. All patients were assessed for toxicity, and 25
patients were available for efficacy. The primary endpoints were acute toxicity,
overall survival, and median survival time. The secondary endpoints included local
control rate, time to tumor progression, and progression-free survival (PFS). With a
median follow-up of 10.2 months, a local control rate of 96% was achieved for
thoracic tumor. Median time to progression, median PFS, and median survival time
were 6.3, 10.2, and 21.8 months, respectively. The 1- and 2-year PFS rates were both
42%, and 1-, 2-, and 3-year overall survival rates were 57%, 45%, and 30%,
respectively. Concurrent EGFR-TKIs with individualized RT shows a favorable safety
profile and promising outcome, therefore serving as a therapeutic option for patients
with locally advanced or metastatic NSCLC.14
Chang et al has done a study in 25 patients with stage IIIb or IV nonsquamous cell, non-small cell lung cancer (NSCLC) who responded to upfront TKI
treatment. Multi-target radiotherapy was administered during the TKI treatment
course. Tomotherapy comprising a hypofractionated schedule with a dose of 40-50 Gy
in 16-20 fractions was used for individual metastatic lesions. The overall response

rate after radiotherapy was 84.0%, and the median PFS was 16 months. The 3-year
overall survival rate was 62.5% (95% confidence interval [CI], 39.1-85.8%).
Toxicities were generally tolerated but it was necessary to prevent radiation-induced
pneumonitis. It showed that combined first-line TKI therapy and early multi-target
radiotherapy are very effective in selected patients that respond to TKI, when the
status of mutations in the epidermal growth factor receptor (EGFR) are not known
before the treatment.15
Radiation therapy remains an important part of the treatment regimen for
NSCLC, especially for patients with unresectable tumors. The concurrent
administration of radiation therapy and chemotherapy is the first-choice treatment
option for stage III unresectable NSCLC which makes up over 30% of total NSCLC
patients. However, concurrent chemo-radiation therapy is frequently toxic and a
significant number of patients suffer from complications such as radiation esophagitis
and radiation pneumonitis during or after this treatment. Therefore, it may be
beneficial in terms of reducing toxicity and enhancing the effect of radiation therapy if
we can administer radiation therapy and EGFR inhibitors concurrently to EGFRinhibitor-responsive patients instead of administering concurrent chemotherapy.
Palliative Intent Therapy
If there are pressing symptomatic need for palliation such as significant
obstruction of a major airway, severe hemoptysis, Superior Vena Cava obstruction, the
initial treatment is palliative radiotherapy. So palliative radiotherapy is treatment of
choice in symptomatically advanced cancers which present mostly in inoperable stage
III and stage IV patients.
EBRT has played a major role in the palliative therapy of NSCLC. The
primary

symptoms

evaluated

have

included

dyspnea,

cough,

hemoptysis,

postobstructive pneumonia, collapse or atelectasis, and pain. In a series by the

Medical Research Council (MRC), Macbeth et al randomized 509 patients and
compared outcomes of 17 Gy in 2 fractions versus 39 Gy in 13 fractions for palliative
treatment. Results showed that 17 Gy in 2 fractions provided a more rapid palliation
of symptoms, but the 39 Gy in 13 fractions yielded a longer Mean Survival Time (9
months vs 7 months).16

The Medical Research Council reported on a randomized trial comparing 17

Gy in 8.5 Gy fractions in one fraction per week versus 30 Gy in 10 fractions over 2
weeks. There was no difference in survival or palliation of symptoms. In general,
hemoptysis was palliated the best, with 81%-86% having relief of this symptom.
Cough was relieved in 56%-65%, and chest pain was relieved in over half of the
patients.17
A systematic review of 13 randomized controlled trials involving 3,473
patients compared lower-dose and higher dose radiation therapy. Higher-dose
radiation did not improve specific symptoms (hemoptysis, cough, or chest pain), but
there was a significant improvement in overall symptoms. There was also a significant
improvement in OS at 1 year with higher-dose radiation. Higher-dose radiation was
defined as a biologic equivalent dose of 35 Gy in 10 fractions which is approximately
30 Gy in 10 fractions.18
According to 2015 National Cancer Comprehensive Network guidelines, for
palliation of thoracic symptoms, higher dose/longer-course thoracic RT (e.g., 30 Gy
in 10 fractions) is associated with modestly improved survival and symptoms,
particularly in patients with good performance status.19
Chemotherapy has been compared to best supportive care (BSC) in many
meta-analyses. These metaanalyses have favored chemotherapy for palliation, and
some have shown that it increases median survival time. 20 Targeted agents such as
erlotinib, gefitinib, and bevacizumab have been implemented in patients with
advanced NSCLC21-23. Erlotinib demonstrated a survival benefit compared to placebo
controls in the second- and third-line setting in unselected patients with advanced
NSCLC, many of whom were PS 2 or 3; it also yielded a delay in symptomatic
deterioration.

RELEVANCE OF THE PRESENT STUDY

Lung cancer patients account for 7.5% of all cancer patients seen in
Department of Radiotherapy, Pt. B. D. Sharma PGIMS, Rohtak. Palliative
radiotherapy is an established treatment modality in such patients. Gefitinib has
radiosensitizing effect in EGFR positive lung adenocarcinoma. The prevalence of
EFGR mutations in adenocarcinoma is 10% of Western and 50% of Asian patients.

No earlier study was done at our institute which has shown the role of palliative
radiotherapy concomitant with gefitinib. The present study has been designed to
evaluate symptomatic relief, local control, quality of life and progression-free survival
in patients with locally advanced adenocarcinoma lung.