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Running head: LUNG CANCER SCREENING
Lung Cancer Screening
Integrative Literature Review
Sarah Thomas
State University of New York Institute of Technology
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LUNG CANCER
Lung Cancer Screening
Integrative Literature Review
Lung cancer is one of the most common malignancies diagnosed in the United States and
is the leading cause of cancer death among both men and women with the average age at
diagnoses being 70 years (American Cancer Society, 2013). It is estimated that new lung cancer
cases for 2014 total 224,210, resulting in 159,260 deaths (Kazandijian, Blumenthal, Yu CHen,
Kun He, Patel, Justice…Pazdur, 2014). Lung cancer is divided into 2 broad categories which
include non-small cell lung cancer (NSCLC) and small-cell cancer (SCLC).
NSCLC accounts for 85% of new lung cancer cases, with a 5-year survival rate of 1%–
16%, compared to 90% for breast, colon and prostate (American Cancer Society, 2013). Lung
cancer has a poor prognosis, with nearly 90% of persons diagnosed with lung cancer dying of the
disease (US Preventive Services Task Force, 2013). Unfortunately, more than 70% of NSCLC
cases are diagnosed at an advanced stage (Rossi et al., 2014). This is in large part due to a lack of
current standardized screening guidelines that would help detect NSCLC at an earlier stage
(American Lung Association, 2013)
Purpose Statement
The purpose of this review is to perform an integrative analysis of the most current
literature. The literature review is aimed at finding the current state of science and best practice
guidelines for the treatment of NSCLC. The goal is to provide scientific evidence that will
improve quality of care for patients with NSCLC by providing direction and insight for health
care providers and institutions.
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Methodology
Relevant articles for the purpose of this literature review were obtained using the State
University of New York Institute of Technology, Cayan Library electronic database.
MedlinePlus, CINAHL Plus with Full Text and PubMed were the primary databases utilized.
Google Scholar, Centers for Disease Control, American Cancer Society, American Lung
Association and the American Cancer Institute were also utilized for additional searches.
The key terms used to execute this literature review were lung cancer, lung cancer
screening, lung carcinoma, low- dose CT screening, lung cancer guidelines, non-small cell lung
cancer, non-small cell lung cancer treatment, non-small cell lung resection, non-small cell lung
cancer radiation therapy, non-small cell lung cancer chemotherapy. The literature search was
restricted to peer-review articles printed in the English language. The search was also restricted
to articles published between the years 2009 and 2014. Literature dated before 2009 was also
reviewed for comparison and analysis. Initially, a selection of over 25 articles was made. The
articles were reviewed for relevance, sorted by subject, and summarized for the purpose of this
literature review. 12 articles that focused on the management and treatment of non-small cell
lung cancer were finally chosen and an analysis of these articles was completed (see Appendix
A).
Literature Review
The number of new cases of lung cancer diagnosed annually worldwide is about 1.5
million (Rossi et al., 2014). About 85% to 90% of lung cancers are NSCLC (American Cancer
Society, 2014). The subtypes of NSCLC include squamous cell carcinoma, adenocarcinoma, and
large cell carcinoma. Although the cells in these subtypes differ in size, shape, and chemical
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make-up, they are grouped together because they have similar prognoses and approaches to
treatment (American Cancer Society, 2014).
Treatment
Patients with resectable tumors may be potentially cured by surgery or surgery followed
by chemotherapy if discovered at an early stage (Lin, Hu, Zhong & Zhao, 2013). Local control
can be achieved at advance stages with radiation therapy in a large number of patients with
unresectable disease, but cure is typically seen only in a small number of patients (Lin et al.,
2013). Chemotherapy is beneficial for patients with metastatic disease although NSCLC is
relatively insensitive to the treatment as compared with SCLC, and the administration of
concurrent chemotherapy and radiation is indicated for patients with stage III or IV NSCLC
(American Cancer Society; 2014, Molina et al., 2008) With the introduction of targeted
therapies, angiogenesis, epidermal growth factor receptor (EGFR) inhibitors, and other new
anticancer agents, there is a more positive outlook for the future treatment of NSCLC (Molina et
al., 2008).
Surgical resection. Radical surgery offers the greatest chance for curative treatment in
early stage NSCLC, and remains the preferred initial treatment for stage I and II NSCLC (Ilonen,
Rasaven, Knuuttila, Salo & Sihvo, 2011; Lee et al., 2013) According to Lin et al. (2014),
pulmonary lobectomy combined with systematic lymphadenectomy is the accepted current
standard treatment for early stage NSCLC. Pulmonary lobectomy is the total removal of one of
the five lobes of the lungs.
Samuels et al. (2013) discuss however that with the average age of diagnoses being 70
years, many elderly patients diagnosed with stage I and II NSCLC may be medically inoperable
due to coexisting morbidities. It is also discussed that many patients in then elderly population
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express a strong preference to avoid surgery.
Ilonen et al. (2011) and Sandhu et al. (2009) agree that NSCLC patients undergoing
surgery are often elderly with many co-morbid conditions and decreased performance status. It is
discussed that the morbidity of lung resection via thoracotomy may be unacceptable for many of
these patients. This is why video-assisted thoracoscopic surgery (VATS) as opposed to open
thoracotomy has gained more use and acceptance in the treatment of the elderly (Ilonen, et al.,
2011) The results for patients with clinical stage-I NSCLC, who undergo VATS lobectomy and
segmentectomy are similar to those of open surgery, and are also associated with fewer
complications and a shorter hospital stay post-operatively (Ilonen, et al., 2011)
Similarly, Lin et al. (2014) found that VATS wedge resections performed on elderly
high-risk patients with stage IA NSCLC could achieve overall survival rates and disease free
status similar to lobectomies and with lower risks. As opposed to a total lobectomy, wedge
resection is the removal of the tumor and a rim of healthy lung tissue around the tumor (Lin et
al., 2014).
Radiation therapy. According to Lee et al. (2013), rates of loco-regional recurrence
(LRR) after surgical resection range from 3% to 38%, depending on pathologic tumor stage.
Although a second resection is the preferred option for these patients, only a small percentage are
eligible for resection and may be alternatively treated with radiation therapy (RT) (Lee et al.,
2013). Studies show that patients with recurrent NSCLC after surgery who were treated with RT
had a promising prognosis (Lee et al., 2013).
Samuels et al. (2013) state that for inoperable patients, conventional RT provides poor
results. For inoperable patients, studies show that stereotactic body radiotherapy (SBRT) has
marked improvement over conventional RT with a progression-fee survival rate of 50% at 3
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years in patients over 75 years of age (Samuels et al., 2013). It can be argued from this study that
SBRT for early stage NSCLC should be considered viable treatment in elderly patients who are
inoperable, refuse surgery or are at greater risk for morbidity from surgery (Samuels et al.,
2013).
Conversely, Sandhu et al. (2009) argue that conventional RT at higher radiation doses is
also an effective method in improving local control rates of early stage NSCLC. The study
showed that for stage I patients, conventional RT is an effective and safe alternative to surgery
and that a large majority of patients remained free of local recurrence with minimal toxicity
(Sandhu et al., 2009). This study did however discuss that the results were favorable for those
under 70 years of age (Sandhu et al., 2009).
Chemotherapy. Receiving chemotherapy before radiation or surgery may help to shrink
the tumor and make it easier to resect, increasing the effectiveness of radiation and destroying
hidden cancer cells at the earliest possible time (American Cancer Society, 2014). For patients
with tumors that can be surgically removed, evidence suggests that chemotherapy after surgery,
or adjuvant therapy, may prevent relapse, which is particularly true for patients with stage II and
IIIA NSCLC (American Cancer Institute, 2014).
Across the literature, studies show that platinum-based doublet therapy is the standard
first-line treatment option for patients with advanced NSCLC, with or without a molecular
targeted agent. (Aoki, Ebihara, Yogo, Suemasu & Sakamaki, 2013; Bennouna et al. 2014;
Gridelli, et al. 2014; Rossi et al. 2014). The doublet combinations that are the cornerstone of
current therapy of consist of carboplatin or cisplatin (platinums) with docetaxel or paclitaxel
(taxanes), gemcitabine or vinorelbine (Rossi, et al., 2014).
Although Bennouna et al. (2014) and Blais and Kassouf (2014) both recognize platinum-
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based chemotherapy as a standard first-line treatment; they both agree that the optimal duration
of chemotherapy for patients with advanced stage NSCLC has yet to be established. Bennouna et
al. (2014) determined that six cycles of first-line platinum-based chemotherapy did not improve
overall survival of advanced stage NSCLC, and that three or four courses was sufficient
treatment option. Similarly, a recent study deducted that four cycles of platinum-based
chemotherapy is an accepted standard of treatment and that treatment beyond four cycles had
limited benefit and resulted in cumulative toxicities and decreased quality of life (Blais &
Kassouf, 2014). It was also found that the maximum benefit reached after first line therapy can
be limited due to the toxicity of platinum drugs and many patients end up needing more than one
line of treatment (maintenance therapy). Permetrexed and erlotinib are two approved agents for
maintenance therapy in patients who have received up to four cycles of platinum-based
chemotherapy (Blais & Kassouf, 2014).
Additionally, Bordonaro et al. (2014) state that for elderly patients with advanced
NSCLC, current guidelines do not recommend a specific first-line chemotherapy with platinum
doublets due to the increased cytotoxic effects in the elderly as compared with younger patients.
Single-agent chemotherapy is usually preferred for the elderly population such as vinorelbine,
taxanes or gemcitabine, and has been found to an effective treatment option for elderly patients,
especially those with comorbidities that could increase toxicity risk (Bordonaro et al., 2014). In
this study, oral vinorelbine was specifically researched and was proven to represent an effective
first-line therapeutic option in patients 70 years and older with an improvement in quality of life
as well (Bordonaro et al., 2014).
Targeted therapy. As research continues, molecular targets such as epithermal growth
factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are being identified. This means
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that the standard treatment in patients with NSCLC containing specific genetic alterations is
evolving toward highly specific, more effective and less toxic therapies (Kazandijan, et al, 2014).
EGFR is a member of the receptor tyrosine kinase (TK) family. The EGFR pathway is
one of the most important pathways being researched in regards to NSCLC. This pathway affects
several vital processes in tumor development and growth including cell production, apoptosis
regulation, angiogenesis, and metastatic invasion (Nurwidya, Murakami, Takahashi & Kazuhisa,
2012). EGFR overexpression is seen in approximately 62% of NSCLC cases, and has historically
been associated with a less than favorable prognosis. The Food and Drug Administration has
recently however approved gefitinib and erlotinib (TK inhibitors) for the treatment of NSCLC
patients who are EGFR positive (Nurwidya et al., 2012).
According to Kazandijan et al. (2011), 5% of NSCLC cases involve Anaplastic
Lymphona Kinase (ALK) rearrangements. In 2011, crizotinib received approval by the FDA for
the treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive by
inhibiting the activity of the ALK fusion proteins (Kazandijan, et al., 2014). In this study, it was
found that crizotinib treatment of ALK positive patients resulted in a threefold increase in overall
response rate (ORR) compared with standard chemotherapy (Kazandijan, et al., 2014).
Similarities and differences. A trend that was apparent in much of the literature
involved exploring valid treatment options for the elderly population. Bennouna et al. (2014),
Ilonen et al. (2011), Rossi et al. (2014) and Sandhu et al. (2009) included research findings with
a median age range of approximately 60 years and included comparable findings for younger
patients vs elderly patients. Bordonaro et al. (2014), Lin et al. (2014) and Samuels et al. (2013)
specifically targeted patients 70 years and older in their research whether it was surgical or
medical intervention being explored.
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Another similarity across the literature was gender. In the majority of the articles, males
outnumbered females significantly. Bennouna et al. (2014), Lin et al. (2014), Ilonen et al. (2011
and Rossi et al. (2014) had samples where the men outnumbered the women by almost double,
while Aoki et al. (2013) and Sandhu et al. (2009) had samples where the number of men was
approximately three times that of the number of women (see Appendix A). Adversely,
Kazandijan et al. (2014) was the only article that had 257 female subjects vs 90 male. The
studies did not specify the reason for differences in gender numbers. It is known however that
there is a higher incidence of males diagnosed with NSCLC than females, which could account
for the higher number of NSCLC positive patients in the current trials (Alberg et al., 2013).
Conclusion
With elderly patients representing a rapidly growing portion of the early lung cancer
population, studies on lung cancer treatment are starting to focus on the differences in treatment
and the effects that treatment can have on this population. Although many of these patients may
not have a good prognosis due to age and co-morbidities, it is still essential and an ethical
obligation to offer valid treatment options for this population that can prolong survival time
(even if just minimally), and improve overall quality of life. It is essential for health care
providers to work as an integrative team to monitor and control the co-morbidities of elderly
patients with NSCLC, especially if they are undergoing treatment.
New and upcoming treatment of NSCLC looks to be heading towards targeted therapy as
opposed to chemotherapy. These therapies are highly specific, typically more effective and have
less severe side effects than the standard chemotherapy regimens. Targeted therapy is typically
seen in advanced stages of NSCLC or when chemotherapy drugs have failed. According to the
reviewed literature, EGFR and ALK are the two main targeted mutations that are being treated
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with good results, but there is much more to know about these mutations and why certain people
are resistant to therapy. The logical direction for treatment research at this time would be towards
trying to identify and target multiple other types of gene mutations and histological markers in
patients with NSCLC and to try and identify these markers at earlier stages in the disease
process. These advances in treatment and targeted therapies will hopefully increase the number
of NSCLC survivors and bring greater quality of life to those diagnosed with the disease.
Another conclusion that can be made from the literature analysis is that a growing
number of patients are seeking out alternative therapies to medications. Whether it is due to
adverse medication affects, financial burden or not being properly controlled on medications,
CAM therapy is becoming a part of many treatment regimens. Patients are going to ask questions
about these treatment modalities and want the opinions of medical professionals. In order to
provide patients with Clinicians should become more aware of the alternative therapies that are
available and those that have been shown to be effective in managing hypertension.
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Appendix A
Literature Review Table
Studies
Aoki et al. (2014)
Focus
Continuous
chemotherapy
after platinum
based doublet
therapy
Vinorelbine plus
cisplatin for first
line chemo in
nonsquamous
NSCLC
Maintenance
therapy for
NSCLC
Subjects
N=21
17 males
4 females
Population
Inoperable stage IIIB and
IV NSCLC without prior
chemo
Age
46-77,
median
65
Method
Statistical analysis
Kaplan Meier method
Findings
Effective and safe if continuous multiple-cycle
first-line treatment with CBDCA and docetaxel in
advanced NSCLC patients, could go beyond 4,
even 6 cycles
N=153
95M
58F
NS NSCLC patients stage
IIIB/IV or relapsing after
treatment and life
expectancy longer than
12 weeks
Studies on maintenance
therapy
18-75
years
Randomized control
clinical trial, ITT
analysis, quantitative
Q 3 weeks for 4 cyles, ,male and female,
leukopenia and neutropenia. The doublet oral
vinorelbine and cisplatin were effective as
pemetrexid and cisplatin. Disease control rates
averaged 75%
n/a
Literature review
Maintenancetherapy, whether in switch
Or continuation approach, has proved to
Be beneficial in patients with advanced
NSCLC who have received up to 4 cycles
of platinum based chemo
Bordonaro et al.
(2014)
Oral chemo for
elderly with
advanced NSCLC
Age 70 and older with
advanced NSCLC
candidates for 1st line
treatment chemo
70 and
above
mean
77.1
Statistical analysis
Shapiro-Wilk test
Quality of life
questionnaire
Single-agent chemo is a valuable option,
especially in elderlys. Oral vinorelbine may
provide an advantage in terms of patient
preferenceas as regards the control of
symptoms, with an efficacy comparable to IV.
chemo and with an acceptable toxicity profile.
Kazandjian D.K et
al. (2014)
Treatment of
NSCLC with
Crizotinib
N=128
52 oral
vinorelbine
54 IV
gemcitabin
e
N=347
90M
257F
Patients with ALKpositive advanced
NSCLC., White, Asian and
Black
International multicenter randomized trial
The FDA granted regular approval to
crizotinib based on a favorable benefitrisk assessment for treatment of NSCLC
whose tumors are ALK positive
Lee, et al. (2013)
Definitive
radiation therapy
with recurrent
NSCLC after
surgical resection
Thoracoscopic
wedge resection
for elderly highrisk patients
VATS vs. open
thoracotomy for
N = 38
N = 35 men
N=3
women
Locoregional recurrent
NSCLC after surgical
resection
Crizotini
b = 2281
Chemo =
24-85
44-75
years,
median
64
Quantitative
long-term survival is possible and an
aggressive treatment approach is warranted
N=47
29 M
18 F
Elderly patients with
stage I NSCLC
>70
years
Statistical analysis, T
test. Kaplan-Meier
method.
It is safe, minimally invasive to perform VATS
wedge resection on the elderly high-risk patients
with stage I NSCLC
N= 116
VATS
Stage I NSCLC patients
undergoing surgery
37-83
years
Statistical Analysis
Comparisons made by
P < .050.outcomes of VATS lobectomy and
Bennouna et al.
(2014)
Blais & Kassouf,
2014
Lin et al. (2014)
Ilonen, I. et al.
(2011)
N=16
segmentectomy are similar to those of open
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Nurwidya, et al.
(2012)
Rossi, A et al.
(2014)
Samuels, et al.
(2013)
Sandhu, A. et al
(2009)
stage I surgical
intervention
N = 212
Open
thoracotom
y
164 M vs 144 W
Resistance to TK
targeted therapy
for EGFR
Platinum-based
chemotherapy –
6 cycles vs less
cycles
N=148
NSCLC patients with
EGFR mutations
N=1139
N= 568 6
cycles
N= 571 3
cycles
N=46
N=102
17 F
85 M
Stereotactic
body
radiotherapy for
stage I
inoperable
patients (elderly)
Conventional
radiation therapy
for stage I NSCLC
log rank test
surgery. The minimally invasive approach
was, however, associated with fewer
complications and a shorter postoperative
hospital stay
Not
reported
Statistical analysis,
quantitative
There should be more advances on EGFR
genotyping for lung adenocarcinoma
Patients who received
cisplatin and carboplatin
752 M vs 369 F
Median
years
55-69
Randomized control
trial, meta analysis,
quantitative
6 cycles of first-line platinum-based
chemotherapy did not improve overall survival in
patients with advanced NSCLC
Inoperable stage I NSCLC
patients with comorbidities
(median
82,
range
75-92
Quantitative
crizotinib is FDA approved received for
the treatment of patients with locally
advanced or metastatic (NSCLC) that is
ALK-positive as
Inopreable stage T1/T2
N0 NSCLC
Median
73
(37-86)
years
Statistical analysis
Gray’s tests
Kaplan-Meier curves
Quantitative
Conventional radiation therapy is effective and
safe alternative for surgery for selected patients
and a large majority remained free of local
occurrence without significant toxicity
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