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lung
cancer
Lung cancer is the malignant transformation and
expansion of lung tissue, and is the most lethal of all cancers
worldwide, responsible for up to 3 million deaths annually. Although
lung cancer was previously an illness that predominantly affected
males, the incidence in women has been increasing in the last few
decades, which has been attributed to the rising ratio of female to
male smokers. Currently, lung cancer is the leading cause of cancer
death in women, overshadowing breast cancer, ovarian cancer and
uterine cancers combined.[1] However, it is of note that there are
certain types of lung cancers that appear in otherwise healthy
patients who have never smoked.
Current research indicates that the factor with the greatest impact on
risk of lung cancer is long-term exposure to inhaled carcinogens. The
most common means of such exposure is tobacco smoke.
Treatment and prognosis depend upon the histological type of cancer,
the stage (degree of spread), and the patient's performance status.
Treatments include surgery, chemotherapy, and radiotherapy.
Signs and symptoms
Symptoms that suggest lung cancer include:
dyspnea (shortness of breath)
hemoptysis (coughing up blood)
chronic coughing or change in regular coughing pattern
wheezing
chest pain or pain in the abdomen
cachexia (weight loss), fatigue and loss of appetite
dysphonia (hoarse voice)
clubbing of the fingernails (uncommon)
difficulty swallowing
If the cancer grows into the lumen it may obstruct the airway, causing
breathing difficulties. This can lead to accumulation of secretions
behind the blockage, predisposing the patient to pneumonia.
Many lung cancers have a rich blood supply. The surface of the cancer
may be fragile, leading to bleeding from the cancer into the airway.
This blood may subsequently be coughed up.
Depending on the type of tumor, so-called paraneoplastic phenomena may
initially attract attention to the disease. In lung cancer, this may
be Lambert-Eaton myasthenic syndrome (muscle weakness due to
auto-antibodies), hypercalcemia and SIADH. Tumors in the top (apex) of
the lung, known as Pancoast tumors, may invade the local part of the
sympathetic nervous system, leading to changed sweating patterns and
eye muscle problems (a combination known as Horner's syndrome), as
well as muscle weakness in the hands due to invasion of the brachial
plexus.
In many patients, the cancer has already spread beyond the original
site by the time they have symptoms and seek medical attention. Common
sites of metastasis include the bone, such as the spine (causing back
pain and occasionally spinal cord compression), the liver and the
brain.
Diagnosis
Performing a chest X-ray is the first step if a patient
reports symptoms that may be suggestive of lung cancer. This may
reveal an obvious mass, widening of the mediastinum (suggestive of
spread to lymph nodes there), atelectasis (collapse), consolidation
(infection) and pleural effusion. If there are no X-ray findings but
the suspicion is high (e.g. a heavy smoker with blood-stained sputum),
bronchoscopy and/or a CT scan may provide the necessary information.
In any case, bronchoscopy or CT-guided biopsy is often necessary to
identify the tumor type.
If investigations have confirmed lung cancer, scan results and often
positron emission tomography (PET) are used to determine whether the
disease is localised and amenable to surgery or whether it has spread
to the point it cannot be cured surgically. PET is not useful as
screening, as not all malignancies are positive on PET scan (such as
bronchoalveolar carcinoma), and lung infections may be positive on PET
Scan.
Blood tests and spirometry (lung function testing) are also necessary
to assess whether the patient is well enough to be operated on. If
spirometry reveals a very poor respiratory reserve, as may occur in
chronic smokers, surgery may be contraindicated.
Types
There are two main types of lung cancer categorized by the
size and appearance of the malignant cells seen by a histopathologist
under a microscope: non-small cell (80%) and small-cell (roughly 20%)
lung cancer. This classification although based on simple
pathomorphological criteria has very important implications for
clinical management and prognosis of the disease.
Non-small cell lung cancer
The non-small cell lung cancers (NSCLC) are grouped
together because their prognosis and management is roughly identical.
When it cannot be subtyped, it is frequently coded to 8046/3. The
subtypes are:
(M8070/3) Squamous cell carcinoma, accounting for 20% to 25% of NSCLC,
also starts in the larger breathing tubes but grows slower meaning
that the size of these tumours varies on diagnosis.
(M8140/3) Adenocarcinoma is the most common subtype of NSCLC,
accounting for 50% to 60% of NSCLC. It is a form which starts near the
gas-exchanging surface of the lung. Most cases of the adenocarcinoma
are associated with smoking. However, among non-smokers and in
particular female non-smokers, adenocarcinoma is the most common form
of lung cancer. A subtype of adenocarcinoma, the bronchioalveolar
carcinoma, is more common in female non-smokers and may have different
responses to treatment.
Large cell carcinoma is a fast-growing form that grows near the
surface of the lung. It is primarily a diagnosis of exclusion, and
when more investigation is done, it is usually reclassified to
squamous cell carcinoma or adenocarcinoma.
Small cell lung cancer
Lung small cell carcinoma (microscopic view from a core needle
biopsy)(M8041/3) Small cell carcinoma (SCLC, also called "oat cell
carcinoma") is the less common form of lung cancer. It tends to start
in the larger breathing tubes and grows rapidly becoming quite large.
The oncogene most commonly involved is L-myc. The "oat" cell contains
dense neurosecretory granules which give this an endocrine/paraneoplastic
syndrome association. It is initially more sensitive to chemotherapy,
but ultimately carries a worse prognosis and is often metastatic at
presentation. This type of lung cancer is strongly associated with
smoking.
Other types
Carcinoid
Adenoid cystic carcinoma
Cylindroma
Mucoepidermoid carcinoma
Metastatic
The lung is a common place for metastasis from tumors in
other parts of the body. These cancers, however, are identified by the
site of origin, i.e., a breast cancer metastasis to the lung is still
known as breast cancer. The adrenal glands, liver, brain, and bone are
the most common sites of metastasis from primary lung cancer itself.
Causes
Exposure to carcinogens, such as those present in tobacco
smoke, immediately causes cumulative changes to the tissue lining the
bronchi of the lungs (the bronchial mucous membrane) and more tissue
gets damaged until a tumour develops.
There are four major causes of lung cancer (and cancer in general):
Carcinogens such as those in cigarette smoke
Radiation exposure
Genetic susceptibility
Viral infection
The role of smoking
The incidence of lung cancer is highly correlated with smoking.
Source:NIH.Smoking, particularly of cigarettes, is by far the main
contributor to lung cancer, which at least in theory makes it one of
the easiest diseases to prevent. In the United States, smoking is
estimated to account for 87% of lung cancer cases (90% in men and 79%
in women), and in the UK for 90%. Cigarette smoke contains 19 known
carcinogens[2] including radioisotopes from the radon decay sequence,
nitrosamine, and benzopyrene. Additionally, nicotine appears to
depress the immune response to malignant growths in exposed tissue.
The length of time a person continues to smoke as well as the amount
smoked increases the person's chances of contracting lung cancer. If a
person stops smoking, these chances steadily decrease as damage to the
lungs is repaired and contaminant particles are gradually vacated.
More recent work has shown that, across the developed world, almost
90% of lung cancer deaths are caused by smoking.[3]
Passive smoking—the inhalation of smoke from another's smoking— is
claimed to be a cause of lung cancer in non-smokers. Studies from the
USA (1986,[4][5] 1992,[6] 1997,[7] 2001,[8] 2003[9]), Europe
(1998[10]), the UK (1998,[11][12]), and Australia (1997[13]) have
consistently shown a significant increase in relative risk among those
exposed to passive smoke.
The EPA in 1993 claimed that about 3,000 lung cancer-related deaths a
year were caused by passive smoking. However, since this report was
based on a study that was alleged to be heavily biased and was ruled
by a federal judge to be "unscientific", the EPA report was declared
null and void by a federal judge in 1998(,[14][15]).
Percentage of lung cancer deaths attributable to smoking in the
developed world 35-69 years 70 years+ All ages
Men 93.9 90.3 92.5
Women 68.8 68.9 68.8
Both 88.7 84.3 86.6
The extensive attempts made by Philip Morris to delay the release of
the 1997 IARC study, to affect the wording of its conclusions, to
neutralise its negative results for their business, and to counteract
its impact on public and policymakers' opinion have been documented by
Ong & Glantz in The Lancet journal.[16] Their work was based on 32
million pages of documents made public as part of the settlement of
the 1998 legal case of State of Minnesota and Blue Cross/Blue Shield
of Minnesota vs Philip Morris Inc, et al. and available at Philip
Morris' own website.[17]
Recent investigation of sidestream smoke suggests it is more dangerous
than direct smoke inhalation.[18]
Asbestos
Asbestos can cause a variety of lung diseases. It increases
the risk of developing lung cancer. There is a synergistic effect
between tobacco smoking and asbestos in the formation of lung cancer.
Asbestos can also cause cancer of the pleura, called mesothelioma
(which is distinct from lung cancer).
Radon gas
Radon is a colorless and odourless gas generated by the
breakdown of radioactive radium, which in turn is the decay product of
uranium, found in the earth's crust. Radon exposure is the second
major cause of lung cancer after smoking. The radiation decay products
ionize genetic material, causing mutations that sometimes turn
cancerous. Radon gas levels vary by locality and the composition of
the underlying soil and rocks. For example, in areas such as Cornwall
in the UK (which has granite as substrata), radon gas is a major
problem, and buildings have to be force-ventilated with fans to lower
radon gas concentrations. In the US, the EPA estimates that one in 15
homes has radon levels above the recommended guideline of 4 pCi/L (150
Bq/m3). Iowa has the highest average radon concentrations in the
United States. Studies performed by R. William Field, Daniel J. Steck,
Charles F. Lynch, Brian J. Smith and colleagues at the University of
Iowa have demonstrated a 50% increased lung cancer risk with prolonged
radon exposure at the EPA's action level of 4 pCi/L ([3]) . Recent
pooled epidemiologic radon studies by Dan Krewski et al. (2005; 2006)
and Sarah Darby et al. (2005) have also shown an increased lung cancer
risk from radon below the U.S. EPA's action level of 4 pCi/L.
Radon causes lung cancer because it causes arbitrary damage to the
chromosomes and DNA molecules contained in the nucleus of the cell.
Genetics and viruses
Oncogenes are genes that are believed make people more
susceptible to cancer. Proto-oncogenes are believed to turn into
oncogenes when exposed to particular carcinogens. Viruses are also
suspected of causing cancer in humans, as this link has already been
proven in animals. Genetic susceptibility and viral infection are not
of major importance in lung cancer, but they may influence
pathogenesis.
Lung cancer staging
Lung cancer staging is an important part of the assessment
of prognosis and potential treatment for lung cancer.
See non-small cell lung cancer staging.
Treatment
Treatment for lung cancer depends on the cancer's specific
cell type, how far it has spread, and the patient's performance
status. Common treatments include surgery, chemotherapy, and radiation
therapy.
See also Manchester score.
Surgery
Surgery is usually only an option in non-small cell lung
cancer (NSCLC) and if the disease is limited to one lung and has not
spread beyond its confines. This is assessed with medical imaging
(computed tomography, positron emission tomography). Furthermore, as
stated, a sufficient respiratory reserve needs to be present to allow
for the removal of lung tissue. Procedures performed include lobectomy
(removal of one lobe), bilobectomy (two lobes) or pneumonectomy
(removal of a whole lung). Smaller resections include wedge excision
or segmentectomy (part of a lobe).
The role of sub lobar resection (extended wedge resection) continues
to be debated for the primary management of NSCLC. Although overall
survival appears to be equivalent to that of lobectomy resection, the
local recurrence rate has been documented to be over three times more
common (19% compared to 5%). Accordingly, sub lobar resection has
historically been used as a "compromise resection" approach for the
management of small (less than 3 centimeters diameter) stage I
peripheral NSCLC identified in patients with impaired cardiopulmonary
reserve. Recent reports of the use of intraoperative radioactive
iodine brachytherapy implants at the margins of sublobar resection
suggest that local recurrence can be reduced to that of lobectomy when
this is used as a surgical adjunct to sublobar resection.
The role of anatomic segmentectomy (a larger sublobar resection) with
complete lymph node staging has also been found to have potential
survival benefits similar to lobectomy. Such resections should be
limited to peripheral small (less than 2 cm diameter) stage I NSCLC
where a margin of resection equivalent to the diameter of the tumor
can be achieved.
Five-year prognosis is often as good as 70% following complete
resection of limited (lesions limited to the lung tissue without lymph
node spread - stage I) disease.
After surgery, adjuvant chemotherapy may be recommended if lymph nodes
within the lung tissues resected (stage II) or the mediastinum (lymph
nodes in the peri-tracheal region, stage III) are found to be positive
for cancer spread. Survival may be improved by up to 15% above
patients receiving only surgical resection in these circumstances. The
role of adjuvant chemotherapy for patients with large stage I NSCLC
(tumor diameter greater than 3 cm without lymph node involvement,
stage IB) remains controversial.
The NCI Canada study JBR.10 treated patients with stage IB to IIB
NSCLC with vinorelbine and cisplatin chemotherapy and showed a
significant survival benefit of 15% over 5 years. However subgroup
analysis of patients in stage IB showed that chemotherapy did not
result in any survival gain in them. Similarly, while the Italian
ANITA study showed a survival benefit of 8% over 5 years with
vinorelbine and cisplatin chemotherapy in stages 1B to 3A patients,
subgroup analysis also showed no benefit in the IB stage.
The Cancer and Leukemia Group B (CALGB) study was a randomized study
which examined the use of carboplatin and paclitaxel chemotherapy in
patients with stage 1B disease. Unfortunately, although initial
results in 2004 were encouraging, an update at the recent American
Society of Clinical Oncology meeting (June 2006) reported that the
findings are now negative with no survival advantage with the use of
adjuvant chemotherapy in patients with this stage of disease. However,
exploratory analysis of patients in the CALGB study suggested that
perhaps those with tumors equal or greater than 4 cm in size may still
benefit.
At present, it is standard practice to offer patients with resected
stage II-IIIA NSCLC adjuvant third generation platinum-based
chemotherapy (e.g. cisplatin and vinorelbine). Adjuvant chemotherapy
for patients with stage 1B remains controversial as clinical trials
have not clearly demonstrated a survival benefit.
Chemotherapy
Small-cell lung cancer is treated primarily with
chemotherapy, as surgery has no demonstrable influence on survival.
Primary chemotherapy is also given in metastatic NSCLC.
The combination regimen depends on the tumour type:
NSCLC: cisplatin or carboplatin, in combination with gemcitabine,
paclitaxel, docetaxel, etoposide or vinorelbine. In metastatic lung
cancer, the addition of bevacizumab when added to carboplatin and
paclitaxel was found to improve survival (though in this study,
patients with squamous cell lung cancer were excluded because of
problems with pulmonary hemorrhage in this group in the past).
SCLC: cisplatin or carboplatin, in combination etoposide or ifosfamide;
combinations with gemcitabine, paclitaxel, vinorelbine, topotecan and
irinotecan are being studied.
Targeted therapy
In recent years, various molecular targeted therapies have
been developed for the treatment of advanced lung cancer. Gefitinib (Iressa)
is one such drug, which targets the epidermal growth factor receptor (EGF-R)
which is expressed in many cases of NSCLC. However despite an exciting
start it was not shown to increase survival, although females, Asians,
non-smokers and those with the adenocarcinoma cell type appear to be
deriving most benefit from gefitinib.
A newer drug called erlotinib (Tarceva), another EGF-R inhibitor, has
been shown to increase survival in lung cancer patients and has
recently been approved by the FDA for second-line treatment of
advanced non-small cell lung cancer.[Similar to gefitinib, it appeared
to work best in females, Asians, non-smokers and those with the
adenocarcinoma cell type.
A number of targeted agents are at the early stages of clinical
research, such as cyclo-oxygenase-2 (COX-2) inhibitors, the pre-apoptic
inhibitor exisulind, proteasome inhibitors, bexarotene (Targretin) and
vaccines[19]
Treatment of non-small cell lung cancer is evolving.
Radiotherapy
Radiotherapy is often given together with chemotherapy, and
may be used with curative intent in patients who are not eligible for
surgery. A radiation dose of 40 or more Gy in many fractions is
commonly used with curative intent in non-small cell lung cancer;
typically in North America, the dose prescribed is 60 or 66 Gy in 30
to 33 fractions given once daily, 5 days a week, for 6 to 6˝ weeks.
For small cell lung cancer cases that are potentially curable, in
addition to chemotherapy, chest radiation is often recommended. For
these small cell lung cancer cases, chest radiation doses of 40 Gy or
more in many fractions are commonly given; typically in North America,
the dose prescribed is 45 to 50 Gy and can be given in either once
daily treatments for 5 weeks or twice daily treatments for 3 weeks.
For both non-small cell lung cancer and small cell lung cancer
patients, radiation of disease in the chest to smaller doses
(typically 20 Gy in 5 fractions) may be used for symptom control.
Interventional radiology
Radiofrequency ablation is increasing in popularity for
this condition as it is nontoxic and causes very little pain. It seems
especially effective when combined with chemotherapy as it catches the
cells inside a tumor—the ones difficult to get with chemotherapy due
to reduced blood supply to the inside of the tumor. It is done by
inserting a small heat probe into the tumor to cook the tumor cells.
The body then disposes of the cooked cells through its normal
eliminative processes.
Epidemiology
Lung cancer distribution in the United States.The population segment
most likely to develop lung cancer is the over-fifties who also have a
history of smoking. Lung cancer is the second most commonly occurring
form of cancer in most western countries, and it is the leading
cancer-related cause of death for men and women. In the US, 175,000
new cases are expected in 2006:[20] 90,700 in men and 80,000 in women.
Although the rate of men dying from lung cancer is declining in
western countries, it is actually increasing for women due to the
increased takeup of smoking by this group. Among lifetime non-smokers,
men who have never smoked have higher age-standardized lung cancer
death rates than women. Of the 80,000 women who are diagnosed with
lung cancer in 2006, approximately 70,000 are expected to die from
it.[21]
Lung cancer was extremely rare prior to the advent of cigarette
smoking. In 1878, malignant lung tumors made up only 1% of all cancers
seen at autopsy; this had risen to 10-15% by the early 1900s[22]. Case
reports in the medical literature numbered only 374 worldwide in
1912[23]. The British Doctors Study, published in the 1950s, first
offered solid epidemiological evidence on the link between lung cancer
and smoking.
Not all cases of lung cancer are due to smoking, but the role of
passive smoking is increasingly being recognised as a risk factor for
lung cancer, leading to policy interventions to decrease undesired
exposure of non-smokers to others' tobacco smoke.
In the Second World and Third World, smoking-related lung cancer is
rising rapidly in incidence. Countries such as China are expected to
see a marked increase in lung cancer cases as smoking is exceedingly
common and other causes of death (such as infections) are becoming
less common, revealing an "iceberg" of pulmonary neoplasms. Cheap
tobacco products and heavy advertising are seen by health campaigners
as a major problem in these countries.
Prevention
Primary prevention
Prevention is the most cost-effective means of fighting
lung cancer on the national and global scales. While in most countries
industrial and domestic carcinogens have been identified and banned,
tobacco smoking is still widespread. Eliminating tobacco smoking is a
primary goal in the fight to prevent lung cancer, and smoking
cessation is the most important preventative tool in this process.
Policy interventions to decrease passive smoking (e.g. in restaurants
and workplaces) have become more common in various Western countries,
with California taking a lead in banning smoking in public
establishments in 1998, Ireland playing a similar role in Europe in
2004, followed by Italy and Norway in 2005 and Scotland as well as
several others in 2006. New Zealand has also recently banned smoking
in public places. (See Smoking ban).
Only the Asian state of Bhutan has a complete smoking ban (since
2005). In many countries pressure groups are campaigning for similar
bans. Arguments cited against such bans is criminalisation of smoking,
increased risk of smuggling and the risk that such a ban cannot be
enforced.
Screening and secondary prevention
Regular chest radiography and sputum examination programs
were not effective in reducing mortality from lung cancer.[24] Earlier
studies (Mayo Lung Project and Czechoslovakia lung cancer screening
study, combining over 17,000 smokers) showed earlier detection of lung
cancer was possible but mortality was not improved. Simply detecting a
tumor at an earlier stage may not necessarily yield improved
mortality. For example, plain radiography resulted in increased time
from diagnosis of cancer until death and those cancers being detected
by screening tended to be earlier stages. However, these patients
continued to die at the same rate as those who are not screened. At
present, no professional or specialty organization advocates screening
for lung cancer outside of clinical trials.
A computed tomography (CT) scan can uncover tumors not yet visible on
an X-ray. CT scanning is now being actively evaluated as a screening
tool for lung cancer in high risk patients, and it is showing
promising results. The USA-based National Cancer Institute is
currently completing a randomized trial comparing CT scans with chest
radiographs. Several single-institution trials are ongoing around the
world. The International Early Lung Cancer Action Project published
the results of CT screening on over 31,000 high-risk patients in late
2006 in the New England Journal of Medicine.[25] In this study 85% of
the 484 detected lung cancers were stage I and thus highly treatable.
Mathematically these stage I patients would have an expected 10-year
survival of 88%. However, there was no randomization of patients (all
received CT scans and there was no comparison group receiving only
x-rays) and the patients were not actually followed out to 10 years
post detection (the median followup was 40 months). Other studies are
underway in this area to see if decreased long-term mortality can be
directly observed from CT screening.
It should be noted that screening studies have only been done in high
risk populations, such as smokers and workers with occupational
exposure to certain substances. This is important when one considers
that repeated radiation exposure from screening could actually induce
carcinogenesis in a small percentage of screened subjects, so this
risk should be mitigated by a (relatively) high prevalence of lung
cancer in the population being screened.
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