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Lung cancer
Lung cancer is a disease of uncontrolled cell growth in tissues of the lung. This growth
may lead to metastasis, invasion of adjacent tissue and infiltration beyond the lungs. The
vast majority of primary lung cancers are carcinomas of the lung, derived from
epithelial cells. Lung cancer, the most common cause of cancer-related death in men and
the second most common in women,[1][2] is responsible for 1.3 million deaths worldwide
annually.[3] The most common symptoms are shortness of breath, coughing (including
coughing up blood), and weight loss.[4]The most common cause of lung cancer is long
term exposure to tobacco smoke.[6] The occurrence of lung cancer in non-smokers, who
account for fewer than 10% of cases, appears to be due to a combination of genetic
factors,[7][8] radon gas,[9] asbestos,[10] and air pollution,[11][12][13] including second-hand
smoke.[14][15]
History
Lung cancer was extremely rare before the advent of cigarette smoking. Lung cancer was
first recognized as a distinct disease in 1761.[107] Different aspects of lung cancer were
described further in 1810.[108] Malignant lung tumors made up only 1% of all cancers seen
at autopsy in 1878, but had risen to 10–15% by the early 1900s.[109] Case reports in the
medical literature numbered only 374 worldwide in 1912.[110] A review of autopsies
showed that the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in
1952.[111] In Germany, in 1929 physician Fritz Lickint recognized the link between
smoking and lung cancer.[109] This led to an aggressive anti-smoking campaign.[112] The
British Doctors Study, published in the 1950s, was the first solid epidemiological
evidence of the link between lung cancer and smoking.[113] As a result, in 1964 the
Surgeon General of the United States recommended that smokers should stop
smoking.[114]
The connection with radon gas was first recognized among miners in the Ore Mountains
near Schneeberg, Saxony. Silver has been mined there since 1470. However these mines
are rich in uranium, with accompanying radium and radon gas. Miners developed a
disproportionate amount of lung disease, eventually recognized as lung cancer in the
1870s. An estimated 75% of former miners died from lung cancer. Despite this discovery,
mining continued into the 1950s due to the USSR's demand for uranium.[115]
The first successful pneumonectomy for lung cancer was carried out in 1933.[116] Initially,
pneumonectomy was the surgical treatment of choice.[117] However with improvements in
cancer staging and surgical techniques, lobectomy with lymph node dissection has now
become the treatment of choice.[118][119]
Palliative radiotherapy has been used since the 1940s.[117] Radical radiotherapy, initially
used in the 1950s, was an attempt to use larger radiation doses in patients with relatively
early stage lung cancer, but who were otherwise unfit for surgery.[120] In 1997, continuous
hyperfractionated accelerated radiotherapy (CHART) was seen as an improvement over
conventional radical radiotherapy.[78]
With small cell lung carcinoma, initial attempts in the 1960s at surgical resection [121] and
radical radiotherapy[122] were unsuccessful. In the 1970s, successful chemotherapy
regimens were developed.[123]
Epidemiology
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Worldwide, lung cancer is the most common cancer in terms of both incidence and
mortality with 1.35 million new cases per year and 1.18 million deaths, with the highest
rates in Europe and North America.[101] The population segment most likely to develop
lung cancer is over-fifties who 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. 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 have higher agestandardized lung cancer death rates than women.
Not all cases of lung cancer are due to smoking, but the role of passive smoking is
increasingly being recognized as a risk factor for lung cancer, leading to policy
interventions to decrease undesired exposure of non-smokers to others' tobacco smoke.
Emissions from automobiles, factories and power plants also pose potential risks.[11][13][102]
Eastern Europe has the highest lung cancer mortality among men, while northern Europe
and the U.S. have the highest mortality among women. Lung cancer incidence is
currently less common in developing countries.[103] With increased smoking in developing
countries, the incidence is expected to increase in the next few years, notably in China [104]
and India.[105]
Lung cancer incidence (by country) has an inverse correlation with sunlight and UVB
exposure. One possible explanation is a preventative effect of vitamin D (which is
produced in the skin on exposure to sunlight).[106]
Causes
The main causes of lung cancer (and cancer in general) include carcinogens (such as
those in tobacco smoke), ionizing radiation, and viral infection. This exposure causes
cumulative changes to the DNA in the tissue lining the bronchi of the lungs (the bronchial
epithelium).As more tissue becomes damaged, eventually a cancer develops.[5]
Smoking
The incidence of lung cancer is highly correlated with smoking. Source: NIH. Lung
cancer most commonly begins in the cells that line our lungs. Smoking causes the
majority of lung cancers — both in smokers and in people exposed to secondhand smoke.
Doctors believe smoking causes lung cancer by damaging the cells that line the lungs.
When we inhale cigarette smoke, which is full of cancer-causing substances
(carcinogens), changes in the lung tissue begin almost immediately. At first our body may
be able to repair this damage. But with each repeated exposure, normal cells that line our
lungs are increasingly damaged. Over time, the damage causes cells to act abnormally
and eventually cancer may develop. Our lungs are full of blood vessels and lymph
vessels, giving lung cancer cells easy access to travel to other parts of our body. For this
reason, lung cancer may spread to other parts of your body before we experience any
signs or symptoms. In many cases, lung cancer may spread before it can even be detected
in the lungs. Smoking, particularly of cigarettes, is by far the main contributor to lung
cancer. In the United States, smoking is estimated to account for 87% of lung cancer
cases (90% in men and 85% in women).[32] Among male smokers, the lifetime risk of
developing lung cancer is 17.2%. Among female smokers, the risk is 11.6%. This risk is
significantly lower in non-smokers: 1.3% in men and 1.4% in women.[33] Cigarette smoke
contains over 60 known carcinogens[34] including radioisotopes from the radon decay
sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the
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immune response to malignant growths in exposed tissue. The length of time a person
smokes as well as the amount smoked increases the person's chance of developing lung
cancer. If a person stops smoking, this chance steadily decreases as damage to the lungs is
repaired and contaminant particles are gradually removed.[35] Across the developed world,
almost 90% of lung cancer deaths are caused by smoking.[36] In addition, there is evidence
that lung cancer in never-smokers has a better prognosis than in smokers,[37] and that
patients who smoke at the time of diagnosis have shorter survival than those who have
quit.[38] Passive smoking—the inhalation of smoke from another's smoking—is a cause of
lung cancer in non-smokers. Studies from the U.S.,[39] Europe,[40] the UK,[41] and
Australia[42] have consistently shown a significant increase in relative risk among those
exposed to passive smoke. Recent investigation of sidestream smoke suggests it is more
dangerous than direct smoke inhalation.[43]
Radon gas
Radon is a colorless and odorless gas generated by the breakdown of radioactive radium,
which in turn is the decay product of uranium, found in the earth's crust. The radiation
decay products ionize genetic material, causing mutations that sometimes turn cancerous.
Radon exposure is the second major cause of lung cancer after smoking. [9] 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. The United States Environmental Protection Agency (EPA) estimates that
one in 15 homes in the U.S. has radon levels above the recommended guideline of 4
picocuries per liter (pCi/L) (148 Bq/m³).[44] Iowa has the highest average radon
concentration in the United States; studies performed there have demonstrated a 50%
increased lung cancer risk with prolonged radon exposure above the EPA's action level of
4 pCi/L.[45][46]
Asbestos
Asbestos can cause a variety of lung diseases, including lung cancer. There is a
synergistic effect between tobacco smoking and asbestos in the formation of lung
cancer.[10] In the UK, asbestos accounts for 2–3% of male lung cancer deaths.[47] Asbestos
can also cause cancer of the pleura, called mesothelioma (which is different from lung
cancer).
Viruses
Viruses are known to cause lung cancer in animals[48][49] and recent evidence suggests
similar potential in humans. Implicated viruses include human papillomavirus,[50] JC
virus,[51] simian virus 40 (SV40), BK virus and cytomegalovirus.[52] These viruses may
affect the cell cycle and inhibit apoptosis, allowing uncontrolled cell division.
Pathophysiology
Similar to many other cancers, lung cancer is initiated by activation of oncogenes or
inactivation of tumor suppressor genes.[53] Oncogenes are genes that are believed to make
people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes
when exposed to particular carcinogens.[54] Mutations in the K-ras proto-oncogene are
responsible for 20–30% of non-small cell lung cancers.[55] Chromosomal damage can lead
to loss of heterozygosity. This can cause inactivation of tumor suppressor genes. Damage
to chromosomes 3p, 5q, 13q and 17p are particularly common in small cell lung
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carcinoma. The TP53 tumor suppressor gene, located on chromosome 17p, is often
affected.[56]
Several genetic polymorphisms are associated with lung cancer. These include
polymorphisms in genes coding for interleukin-1,[57] cytochrome P450,[58] apoptosis
promoters such as caspase-8,[59] and DNA repair molecules such as XRCC1.[60] People
with these polymorphisms are more likely to develop lung cancer after exposure to
carcinogens.
Risk factors
A number of factors may increase our risk of lung cancer. Some risk factors can be
controlled, for instance, by quitting smoking. And other factors can't be controlled, such
as our sex. Risk factors for lung cancer include:
Smoking. Smoking remains the greatest risk factor for lung cancer. Our risk of lung
cancer increases with the number of cigarettes we smoke each day and the number of
years we have smoked. Quitting at any age can significantly lower your risk of
developing lung cancer.
Your sex. Current or former women smokers have a greater risk of lung cancer than do
men who have smoked an equal amount. Though it isn't known why, some experts
speculate that women have a greater susceptibility to the cancer-causing substances found
in tobacco. Others believe that estrogen may play a role. Women also are known to inhale
more than men do, and they are less likely to quit.
Exposure to secondhand smoke. Even if we don't smoke, our risk of lung cancer
increases if we're exposed to secondhand smoke.
Exposure to radon gas. Radon is produced by the natural breakdown of uranium in soil,
rock and water that eventually becomes part of the air you breathe. Although unsafe
levels of radon can accumulate in any building, the greatest exposure risk most people
face is at home. Radon testing can determine whether levels are safe.
Exposure to asbestos and other chemicals. Workplace exposure to asbestos and other
substances known to cause cancer — such as arsenic, chromium, nickel and tar soot —
also can increase our risk of developing lung cancer, especially if we're a smoker.
Family history of lung cancer. People with a parent, sibling or other first-degree relative
with lung cancer have an increased risk of the disease.
Excessive alcohol use. Drinking more than a moderate amount of alcohol — no more
than one drink a day for women or two drinks a day for men — may increase our risk of
lung cancer.
Prevention
Prevention is the most cost-effective means of fighting lung cancer. 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
prevention of lung cancer, and smoking cessation is an important preventative tool in this
process.[61]
Policy interventions to decrease passive smoking in public areas such as restaurants and
workplaces have become more common in many Western countries, with California
taking a lead in banning smoking in public establishments in 1998. Ireland played a
similar role in Europe in 2004, followed by Italy and Norway in 2005, Scotland as well as
several others in 2006, England in 2007, and France in 2008. New Zealand has banned
smoking in public places as of 2004.
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The state of Bhutan has had a complete smoking ban since 2005.[62] In many countries,
pressure groups are campaigning for similar bans. Arguments cited against such bans are
criminalisation of smoking, increased risk of smuggling and the risk that such a ban
cannot be enforced.[63]
Signs and symptoms
Lung cancer typically doesn't cause signs and symptoms in its earliest stages. Signs and
symptoms of lung cancer typically occur only when the disease is advanced.
Symptoms that suggest lung cancer include:[29]
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)
dysphagia (difficulty swallowing).
If the cancer grows in the airway, it may obstruct airflow, 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.[30] In lung cancer, these
phenomena may include Lambert-Eaton myasthenic syndrome (muscle weakness due to
auto-antibodies), hypercalcemia or syndrome of inappropriate antidiuretic hormone
(SIADH). Tumors in the top (apex) of the lung, known as Pancoast tumors,[31] 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.
Non-Small Cell Lung Carcinoma (NSCLC) manifests with symptoms produced by the
primary tumor, locoregional spread, metastatic disease, or ectopic hormone production.
Approximately 7-10% of patients with lung cancer are asymptomatic and their cancers
are diagnosed incidentally after a chest radiograph (CXR) performed for other reasons.
The symptoms produced by the primary tumor depend on its location (ie, central,
peripheral).
Symptoms due to primary tumor
Central tumors are generally squamous cell carcinomas and produce symptoms
of
cough, dyspnea, atelectasis, postobstructive pneumonia, wheezing, and hemoptysis.
Most peripheral tumors are adenocarcinomas or large cell carcinomas and, in
addition to causing cough and dyspnea, can cause symptoms due to pleural effusion
and severe pain as a result of infiltration of parietal pleura and the chest wall.
Symptoms due to locoregional spread
These symptoms can include superior vena cava obstruction, paralysis of the
recurrent laryngeal nerve, and phrenic nerve palsy, causing hoarseness and
paralysis of the diaphragm; pressure on the sympathetic plexus, causing Horner
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syndrome; dysphagia resulting from esophageal compression; and pericardial
effusion (ie, Pancoast tumor).
Superior sulcus tumors can cause compression of the brachial plexus roots as they
exit the neural foramina, resulting in intense, radiating neuropathic pain in the
ipsilateral upper extremity.
Paraneoplastic syndromes
Most paraneoplastic syndromes are caused by small cell lung cancer. Squamous
cell carcinomas are more likely to be associated with hypercalcemia due to
parathyroidlike hormone production.
Clubbing and hypertrophic pulmonary osteoarthropathy and the Trousseau
syndrome of hypercoagulability are caused more frequently by adenocarcinomas.
Summary of clinical characteristics by histologic subtype
Adenocarcinoma is the most frequent NSCLC in the United States, representing
35-40% of all lung cancers, usually occurring in a peripheral location within the
lung and arising from bronchial mucosal glands. Adenocarcinoma is the most
common histologic subtype, manifesting as a scar carcinoma. This is the subtype
observed most commonly in persons who do not smoke. This type may manifest as
multifocal tumors in a bronchoalveolar form.
Bronchoalveolar carcinoma is a distinct subtype of adenocarcinoma with the
classic manifestation as an interstitial lung disease on a CXR. 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 accounts for 25-30% of all lung cancers. 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 based on results
from cytologic studies because it has a tendency to exfoliate. It is the type most
often associated with hypercalcemia.
Large cell carcinoma accounts for 10-15% of lung cancers, typically manifesting as
a large peripheral mass on a CXR. Histologically, this type has sheets of highly
atypical cells with focal necrosis, with no evidence of keratinization (typical of
squamous cell carcinoma) or gland formation (typical of adenocarcinomas).
Patients with large cell carcinoma are more likely to develop gynecomastia and
galactorrhea.
In approximately two thirds to three fourths of patients, the cancer is diagnosed at an
advanced stage; patients may have lost weight and may have obvious respiratory distress.
Head and neck:Commonly, no signs are found upon examination of the head and neck
regions, but when the cancer has spread to the supraclavicular lymph nodes, careful
examination may reveal enlargement of involved nodes, which helps in the clinical
staging process.
Superior sulcus tumors, because of their presence at the apex of the lung, can
compress the cervical sympathetic plexus, causing classic Horner syndrome.
Findings include ipsilateral ptosis, miosis, and anhidrosis (ie, lack of sweating).
Superior vena cava syndrome is commonly caused by small cell carcinomas, but
any centrally located tumor or mediastinal spread can give rise to superior vena
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cava syndrome. This results from obstruction of blood flow to the heart from the
head and neck regions and upper extremities due to tumor compression of the
superior vena cava. Patients have facial edema, dusky skin coloration, and,
possibly, conjunctival edema. Edema of the upper extremities and prominent veins
on the upper thoracic wall with retrograde flow may be present.
Respiratory system: Findings are variable and depend on location and spread.
Centrally located obstructing tumors can cause collapse of the entire lung with an
absence of breath sounds on the side of the lesion.
Peripheral lesions can cause individual segments or lobes to collapse, leading to
findings of dullness to percussion and/or decreased breath sounds.
Pleural effusions give rise to characteristic findings of dullness and decreased
breath sounds, depending on the size.
Cardiovascular system: Cardiac findings are usually noted when the tumor causes an
effusion. Findings can range from simple effusion to tamponade.
Gastrointestinal system: The most common site of metastatic spread is the liver, which
may manifest as tender hepatomegaly.
Musculoskeletal system: Bone is another common site of spread for lung carcinomas.
Patients may report bone pain, and tender spots may be found during the examination.
The examination should include fist percussion of the spine to look for tender
spots, which may suggest vertebral column metastases.
Central nervous system: A neurologic examination should be performed to look for
focal neurological deficits caused by brain metastases and/or signs of spinal cord
compression.
For patients with Small Cell Lung Carcinoma (SCLC) to present without any
symptoms is very unusual. Less than 5% of patients have a small, asymptomatic primary
tumor at presentation. SCLC typically presents with a relatively short duration of
symptoms. The onset of symptoms usually is within 8-12 weeks prior to presentation. The
symptoms can result from local tumor growth, intrathoracic spread, distant spread, and/or
paraneoplastic syndromes. Symptoms include the following:
Constitutional symptoms
Fatigue
Anorexia
Weight loss
Symptoms due to primary tumor
Cough
Dyspnea
Hemoptysis
Symptoms due to intrathoracic spread
Superior vena cava obstruction
Hoarseness (ie, palsy of the recurrent laryngeal nerve)
Phrenic nerve palsy
Dysphagia (ie, compression of esophagus)
Stridor (ie, compression of the trachea)
Symptoms due to distant spread
Neurological dysfunction (ie, brain metastasis, spinal cord compression)
Bone pain (bone metastasis)
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Abdominal/right upper quadrant pain (ie, liver metastasis)
Local tumor growth: Small cell carcinomas usually are centrally located and may
cause irritation and/or obstruction of the major airway. Common symptoms resulting
from local tumor growth include cough, dyspnea, and hemoptysis. Patients give a short
history of symptoms of recent onset, with rapid worsening. Rapid tumor growth may
lead to obstruction of major airways, with distal collapse and consequent
postobstructive pneumonitis. Fever may result from infections distal to obstruction or
from the tumor itself.
Intrathoracic spread: Small cell carcinomas grow in size rapidly and metastasize to the
mediastinal lymph nodes relatively early in the course of the disease. At presentation,
patients may have a very large intrathoracic tumor, and distinguishing primary tumor
from lymph node metastasis may be impossible. Pressure on mediastinal structures can
cause a variety of symptoms.
Superior vena cava obstruction: Malignancy is the most common cause of superior
vena cava (SVC) obstruction, and lung cancer accounts for the overwhelming
majority of cases (60-90%). SCLC causes SVC obstruction more often than
NSCLC does. Patients present with swelling of the face and upper extremities.
Headache, dizziness, and other neurological symptoms are late occurrences.
Paralysis of the recurrent laryngeal nerve: The recurrent laryngeal nerve may be
compressed by a mediastinal mass (ie, primary tumor or lymph node metastasis) as
it traverses up on the left to supply the vocal cords. Patients complain of hoarseness
of recent onset.
Phrenic nerve palsy: Compression of the phrenic nerve causes paralysis of the
ipsilateral hemidiaphragm, contributing to respiratory symptoms.
Esophageal compression: Compression of the esophagus can lead to dysphagia and
odynophagia.
Tracheal compression: Compression of the mainstem bronchi and trachea can
cause severe shortness of breath and stridor.
Symptoms from distant spread: These symptoms depend upon the site of spread.
Common sites of spread include brain, bones, liver, adrenals, and bone marrow.
Table 1. Paraneoplastic Syndromes*
Organ
Syndrome
Mechanism
System
Frequency
Endocrine
SIADH
Antidiuretic hormone
5-10%
Ectopic secretion of
drenocorticotropic
5%
ACTH
hormone
Atrial natriuretic factor
Eaton-Lambert reverse
Neurological
5-6%
myasthenic syndrome
Subacute
cerebellar
degeneration
Subacute
sensory
neuropathy
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Anti-Hu,
Anti-Yo
antibodies
Physical findings in SCLC depend upon the extent of local and distant spread and the
organ system involved.
Respiratory system: Patients usually complain of shortness of breath, and examination
may reveal use of accessory muscles of respiration (scalene muscles, intercostal muscles,
flaring of alae of nose). In addition, by virtue of central tumor location, patients may
develop distal atelectasis and postobstructive pneumonia. With pleural effusion,
examination reveals dullness to percussion and decreased or absent breath sounds on the
side of the effusion.
Cardiovascular system: SCLC may cause pericardial effusion and is the malignancy most
often causing obstruction of the SVC.
Pericardial effusion: Pericardial effusions may be asymptomatic when small or
may result in tamponade if they are large or accumulate over a short period.
Patients usually are short of breath. Heart sounds may be distant on auscultation.
Jugular venous pulsation is elevated; paradoxically, it rises with inspiration.
Pulsus paradoxus is a classic sign of pericardial tamponade. The diagnosis is
established with cardiac catheterization, which reveals equalization of pressures in
cardiac chambers. Tamponade is an emergency and requires immediate
decompression of the pericardium. Definitive management may include
chemotherapy and/or surgical creation of a pleuropericardial window.
Central nervous system: Patients with SCLC may have asymptomatic brain metastasis in
5-10% of cases, which may be picked up on staging workup.
Brain metastasis: Patients with symptomatic brain metastases may have raised
intracranial pressure secondary to mass lesions, as well as surrounding brain
edema, and may complain of headache (usually worse early in the morning),
blurring of vision, photophobia, nausea, vomiting, and various localizing
symptoms, eg, weakness of an extremity. The physical findings again are
dependent upon site of the brain lesions.
The examination should include funduscopy to look for signs of raised
intracranial pressure and a detailed neurologic examination, including
evaluation of cerebellar function, coordination, and gait.
The diagnosis is established with a CT scan of the brain with contrast (if
renal function is adequate). In difficult cases, a magnetic resonance scan of
the brain may be appropriate. Since MRI is more sensitive than CT with
contrast for detection of brain metastasis, it is used as the first-line imaging
study in many institutions.
Management includes high doses of corticosteroids (eg, dexamethasone 10
mg IV initially, followed by 4-6 mg IV/PO every 6 hours) and immediate
radiation therapy.
Vertebral and paraspinal metastases: The importance of early recognition of these
metastases is due to their close proximity to the spinal cord, potentially leading to
permanent loss of neurological function if diagnosis is delayed. The initial symptom
usually is back pain, with or without neurological dysfunction.
Limbic encephalopathy
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The main objective is to establish diagnosis early, before neurological
dysfunction is established. Once present, neurological dysfunction can
progress very rapidly (ie, within hours) to cause quadriplegia or paraplegia,
depending upon the location. This condition is an oncologic emergency.
Even though a CT myelogram can establish the diagnosis, MRI is
noninvasive and very sensitive in establishing the diagnosis.
Patients in whom spinal cord compression is suspected should receive a
dose of intravenous corticosteroids even before being sent to the MRI suite.
The typical dose is 10 mg of dexamethasone IV, followed by 4-6 mg
IV/PO every 6 hours. The authors prefer the intravenous route because of
the reliability of drug delivery.
If the etiological cause is known (ie, a prior histologic diagnosis of SCLC),
definitive management is radiation therapy, which should be started
without any delay. Otherwise, if the patient presents with spinal cord
compression and no prior diagnosis of cancer, surgical resection, if
technically feasible, provides both immediate decompression and tissue
diagnosis of the cancer.
Gastrointestinal system: The liver is the common site of spread, and physical examination
may reveal icterus (secondary to widespread liver metastasis or obstruction of biliary
outflow) or hepatomegaly. However, most patients do not have any specific finding
related to the GI tract on examination.
Lymphatic system: Lymph node examination should be carried out carefully. Currently,
enlarged ipsilateral supraclavicular lymph nodes are included in limited stage, but
enlarged axillary lymph nodes upstage the diagnosis to extensive-stage disease.
Extremities: Examination of the extremities may reveal clubbing, cyanosis, or edema. In
the presence of SVC obstruction, the right upper extremity usually is edematous.
Many of the symptoms of lung cancer (bone pain, fever, weight loss) are nonspecific; in
the elderly, these may be attributed to comorbid illness.[5] 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. About 10% of
people with lung cancer do not have symptoms at diagnosis; these cancers are
incidentally found on routine chest x-rays.[4]
Complications
Lung cancer can cause complications, such as:
Fluid in the chest (pleural effusion). Lung cancer can cause fluid to accumulate in the
space that surrounds the lungs in the chest cavity (pleural space). Pleural effusion can
result from cancer spreading outside the lungs or in reaction to lung cancer inside the
lungs. Fluid accumulating in the chest can cause shortness of breath. Treatments are
available to drain the fluid from the chest and reduce the risk that pleural effusion will
occur again. Cancer that spreads to the pleura is considered inoperable, so surgery isn't an
option for treatment.
Cancer that spreads to other parts of the body (metastasis). Lung cancer often spreads
(metastasizes) to other parts of the body — most commonly the opposite lung, brain,
bones, liver and adrenal glands. Cancer that spreads can cause signs and symptoms,
including pain, nausea, headaches or others based on what organ is affected. In some
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cases, treatments are available for isolated metastasis, but in most cases, the goal of
treatment for metastasis is only to relieve signs and symptoms.
Death. Unfortunately, survival rates haven't improved for people diagnosed with lung
cancer. In most cases, the disease is fatal. Almost 60 percent, or three out of every five
people, diagnosed with lung cancer die within a year. Keep in mind, however, that this
number includes people diagnosed with all types of lung cancer at all stages of the
disease. People diagnosed at the earliest stages have the greatest chances for a cure.
Classification
Frequency of histological types of
lung cancer[16]
Frequency
Histological type
(%)
Non-small cell lung
80.4
carcinoma
Small cell lung
16.8
carcinoma
Carcinoid[17]
0.8
Sarcoma[18]
0.1
Unspecified
lung
1.9
cancer
The vast majority of lung cancers are carcinomas—malignancies that arise from epithelial
cells. There are two main types of lung carcinoma, categorized by the size and
appearance of the malignant cells seen by a histopathologist under a microscope: nonsmall cell (80.4%) and small-cell (16.8%) lung carcinoma.[16] This classification, based on
histological criteria, has important implications for clinical management and prognosis of
the disease.
Non-small cell lung carcinoma (NSCLC)
The non-small cell lung carcinomas are grouped together because their prognosis and
management are similar. There are three main sub-types: squamous cell lung carcinoma,
adenocarcinoma and large cell lung carcinoma.
Sub-types of non-small cell lung cancer[16]
Frequency
of all lung
Histological sub-type
cancers
(%)
Squamous cell lung carcinoma
31.1
Adenocarcinoma
Adenocarcinoma
(not
otherwise 23.2
specified)
Bronchioloalveolar
3.0
carcinoma
Adenosquamous
1.2
carcinoma
12
Papillary
0.7
adenocarcinoma
Mucoepidermoid
0.1
carcinoma[19]
Adenoid
cystic
0.04
[20]
carcinoma
Other
specified
1.1
adenocarcinoma
Large cell carcinoma
10.7
Giant cell and spindle cell carcinoma
0.4
Other/unspecified non-small cell lung
8.9
carcinoma
Accounting for 31.1% of lung cancers,[16] squamous cell lung carcinoma usually starts
near a central bronchus. Cavitation and necrosis within the center of the cancer is a
common finding. Well-differentiated squamous cell lung cancers often grow more slowly
than other cancer types.[5]
Adenocarcinoma accounts for 29.4% of lung cancers.[16] It usually originates in peripheral
lung tissue. Most cases of adenocarcinoma are associated with smoking. However, among
people who have never smoked ("never-smokers"), adenocarcinoma is the most common
form of lung cancer.[21] A subtype of adenocarcinoma, the bronchioloalveolar carcinoma,
is more common in female never-smokers, and may have different responses to
treatment.[22]
Accounting for 10.7% of lung cancers,[16] large cell lung carcinoma is a fast-growing
form that develops near the surface of the lung.[23] It is often poorly differentiated and
tends to metastasize early.[5]
Histologic Findings: The World Health Organization classification of lung cancer is
widely accepted. NSCLC includes squamous cell carcinoma, adenocarcinoma, and large
cell carcinoma. Sometimes, lung cancers can exhibit 2 or more histologic patterns.
Adenocarcinoma appears to be increasing in incidence, especially in women, compared
with squamous cell carcinoma, which was previously the most common type of NSCLC.
Squamous cell carcinoma has a distinct dose-response relationship to tobacco smoking
and usually develops in proximal airways, progressing through stages of squamous
metaplasia to carcinoma in situ. Well-differentiated squamous cell carcinomas contain
keratin pearls, while poorly differentiated squamous cell carcinomas may stain positive
for keratin. Microscopic examination reveals cells with large, irregular nuclei and coarse
nuclear chromatin with large nucleoli. Cells are arranged in sheets, and the presence of
intercellular bridging is diagnostic.
Adenocarcinoma is the most common type of NSCLC. Histologically, adenocarcinomas
form glands and produce mucin. Mucin production can be identified with mucicarmine or
periodic acid-Schiff staining. The World Health Organization classification of lung
cancer divides adenocarcinomas into (1) acinar, (2) papillary, (3) bronchoalveolar, and
(4) mucus-secreting. Bronchoalveolar carcinoma is a distinct clinicopathologic entity that
appears to arise from type II pneumocytes and may manifest as a solitary peripheral
nodule, multifocal disease, or a pneumonic form, which can spread rapidly from one lobe
13
to another. Stage for stage, adenocarcinomas are associated with worse prognoses than
squamous cell carcinomas, with the exception of T1 N0 M0 tumors.
Large cell carcinoma is the least common of all NSCLCs. It is composed of large cells
with prominent nucleoli, and no mucin production or intercellular bridging is identified.
Many tumors previously diagnosed as large cell carcinomas are identified as poorly
differentiated adenocarcinomas or squamous cell carcinomas after advanced
immunohistochemical staining, electron microscopy, and monoclonal antibody studies. A
variant of large cell carcinoma has been identified; it contains neuroendocrine features
and is called large cell neuroendocrine carcinoma. Large cell neuroendocrine carcinomas
are associated with a worse prognosis than large cell carcinomas.
Small cell lung carcinoma (SCLC)
Small cell lung carcinoma (SCLC, also called "oat cell carcinoma") is less common. It
tends to arise in the larger airways (primary and secondary bronchi) and grows rapidly,
becoming quite large.[24] The "oat" cell contains dense neurosecretory granules (vesicles
containing neuroendocrine hormones) which give this an endocrine/paraneoplastic
syndrome association.[25] Small cell carcinomas arise in peribronchial locations and
infiltrate the bronchial submucosa. Widespread metastases occur early in the course of the
disease, with common spread to mediastinal lymph nodes, liver, bones, adrenal glands,
and brain. In addition, production of a variety of peptide hormones leads to a wide range
of paraneoplastic syndromes. The most common paraneoplastic syndromes are the
syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and the syndrome
of ectopic adrenocorticotropic hormone (ACTH) production. In addition, autoimmune
phenomena may lead to various neurological syndromes. While initially more sensitive to
chemotherapy, it ultimately carries a worse prognosis and is often metastatic at
presentation. Small cell lung cancers are divided into Limited stage and Extensive stage
disease. This type of lung cancer is strongly associated with smoking.[26]
Histologic Findings: SCLC typically are centrally located, arising in peribronchial
locations. They are thought to arise from Kulchitsky cells.
The tumor is composed of sheets of small, round cells with dark nuclei, scant cytoplasm,
fine granular nuclear chromatin, and indistinct nucleoli.
Crush artifact leading to nuclear molding is a common finding, but it is not considered
diagnostic.
Very high rates of cell division are observed, and necrosis, sometimes extensive, may be
seen. Because of the central location, the cells exfoliate in sputum and bronchial
washings.
Neurosecretory granules can be identified on electron microscopy, and the
neuroendocrine nature of the neoplasm is suggested by its frequent association with
paraneoplastic syndromes caused by peptide hormones.
Immunohistochemical stains for chromogranin, neuron-specific enolase, and
synaptophysin usually are positive.
Approximately 5% of SCLCs exhibit features of mixed small cell and large cell
components and, less frequently, may exhibit mixed small cell and squamous cell
components.
The WHO classified SCLCs into 3 subcategories: oat cell carcinoma, intermediate cell
type, and combined oat cell carcinoma. This subclassification has been difficult to
reproduce, however, even by expert lung cancer pathologists, and in 1988, the
14
International Association for the Study of Lung Cancer recommended dropping the
intermediate cell type from the classification and adding the category of mixed small and
large cell carcinoma.
Metastatic cancers
The lung is a common place for metastasis from tumors in other parts of the body. These
cancers are identified by the site of origin, thus a breast cancer metastasis to the lung is
still known as breast cancer. They often have a characteristic round appearance on chest
x-ray.[27] Primary lung cancers themselves most commonly metastasize to the adrenal
glands, liver, brain, and bone.[5]
Screening
Screening refers to the use of medical tests to detect disease in asymptomatic people.
Possible screening tests for lung cancer include chest x-ray or computed tomography
(CT) of the chest. . Some studies show that these tests can find cancer earlier, when it
may be treated more successfully. But other studies find that these tests often reveal more
benign conditions that require invasive testing and expose people to unnecessary risks.
Screening for lung cancer is controversial among doctors. So far, screening programs for
lung cancer have not demonstrated any clear benefit. Randomized controlled trials are
underway in this area to see if decreased long-term mortality can be directly observed
from CT screening.[64]
Diagnosis
If there's reason to think that the patient may have lung cancer, the doctor can order a
number of tests to look for cancerous cells and to rule out other conditions. In order to
diagnose lung cancer, the doctor may recommend:
Imaging tests. An X-ray image of the lungs may reveal an abnormal mass or nodule. A
CT scan can reveal small lesions in the lungs.
Sputum cytology. If the patient has a cough and is producing sputum, looking at the
sputum under the microscope can sometimes reveal the presence of lung cancer cells.
Before the test, thepatient may be asked to breathe a mildly irritating mist to help him
produce more sputum.
Tissue samples (biopsy). A sample of abnormal cells may be removed in a procedure
called a biopsy in order to diagnose lung cancer. The doctor can perform a biopsy in a
number of ways, including bronchoscopy, in which the doctor examines abnormal areas
of the lungs using a lighted tube that is passed down the throat and into the lungs;
mediastinoscopy, in which an incision is made at the base of the neck and surgical tools
are inserted behind the breastbone to take tissue samples; and needle biopsy, in which the
doctor uses X-ray or CT images to guide a needle through the chest and into a suspicious
lump or nodule to collect cells. A biopsy sample may also be taken from lymph nodes or
other areas where cancer has spread, such as the liver.
15
Chest x-ray showing a cancerous tumor in the left lung
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 (pneumonia), or pleural effusion. If there are no x-ray findings but the
suspicion is high (such as a heavy smoker with blood-stained sputum), bronchoscopy
and/or a CT scan may provide the necessary information. Bronchoscopy or CT-guided
biopsy is often used to identify the tumor type.[4]
CT scan showing a cancerous tumor in the left lung
The differential diagnosis for patients who present with abnormalities on chest x-ray
includes lung cancer, as well as nonmalignant diseases. These include infectious causes
such as tuberculosis or pneumonia, or inflammatory conditions such as sarcoidosis. These
diseases can result in mediastinal lymphadenopathy or lung nodules, and sometimes
mimic lung cancers.[5]
Lab Studies:
Diagnostic strategy: Apart from a handful of asymptomatic patients, in whom lung cancer
is diagnosed incidentally, virtually all patients with lung cancer are symptomatic at
presentation. In the presence of a long history of smoking or other risk factors for lung
cancer, the presence of persistent respiratory symptoms should prompt a CXR. Because
benign conditions and metastatic malignancies can mimic lung cancer on radiographs,
histologic confirmation is necessary. This can be achieved by sputum cytologic studies,
bronchoscopy, or CT-guided transthoracic needle biopsy of the mass, depending on the
location of the tumor.
Sputum cytologic studies
Centrally located endobronchial tumors exfoliate malignant cells into sputum.
(This location and tendency to exfoliate are most common in squamous cell
carcinomas.) Therefore, sputum cytology can be a quick and inexpensive
diagnostic test, if results are positive.
The false-positive rate for sputum cytology is 1%, but the false-negative rate is as
high as 40%.
A positive finding for malignancy from a cytologic specimen is accurate in as
many as 90% of cases, but any distinction between different histologic subtypes is
not accurate. Discordant results are often observed between cytologic and
histologic findings of specimens obtained from bronchoscopy or transthoracic
biopsy.
Complete blood cell count: This should be obtained in every patient, especially before
instituting chemotherapy.
16
Electrolytes and renal function studies: Because of the propensity of lung cancers to cause
paraneoplastic syndromes, serum electrolyte levels are evaluated.
Staging workup for lung cancer(LC)
Because of the importance of stage on the therapeutic decision-making process, all
patients with LC must be staged adequately.
In the United States, the standard staging workup for LC includes at least the
following:
Complete history and physical examination
CT scan of the chest and upper abdomen (including liver and adrenals)
Complete blood cell counts
Liver and kidney functions tests
Serum electrolytes
Information obtained from these tests can then be used to guide further testing (eg,
imaging studies).
Invasive staging procedures such as mediastinoscopy and mediastinotomy may be
required to assess mediastinal lymph nodes in patients who are candidates for
potentially curative surgical resection.
Imaging Studies:
A complete staging workup for LC should evaluate the extent of disease.
CXR: A chest radiograph is usually the first test ordered in patients in whom a lung
malignancy is suggested.
If the tumor is clearly visible and measurable, a CXR can sometimes be used to
monitor response to therapy.
Popcorn calcification is usually a radiologic characteristic of benign lesions.
CT scan
Because common sites of spread of a LC include the liver and adrenals, a CT scan
of the chest and upper abdomen, to include the liver and adrenals, is the minimum
standard for a staging workup for a person newly diagnosed with LC.
A CT scan or MRI of the brain may be required if neurological symptoms or signs
are present. Most thoracic surgeons perform imaging of the brain before attempting
definitive resection of a lung malignancy.
Bone scintigraphy: The skeletal system is another common site of metastases for lung
cancers. If patients report bone pain or if their serum calcium and/or alkaline phosphatase
levels are elevated, a bone scan should be obtained to search for bone metastases.
Positron emission tomography
Positron emission tomography (PET) scanning is approved by the US Food and
Drug Administration (FDA) for the workup of solitary lung nodules.
Recent studies suggest that PET scanning is useful for searching for systemic
spread if other diagnostic modalities cannot clarify an abnormality that may change
the treatment of the patient's condition. However, false-positive and false-negative
results can occur.
Recently, additional data have emerged that underscore the importance of PET
scanning in patients with LC. PET scans appear to be more sensitive, specific, and
accurate than CT scans for staging mediastinal disease. While radiographs and CT
scans show images of structures, PET scans reveal the nature of the area under
study. PET scans often detect abnormalities not demonstrated on CT scans.
17
Published reports suggest that staging of LC may be influenced by PET scan
results in up to 60% of the cases and as many as 25% may be up-staged after PET
scanning.
Caution is required when interpreting the results of PET scans in patients who may
be denied potentially curative surgical resection based on PET results.
MRI: MRI is most useful when evaluating a patient in whom spinal cord compression is
suggested. In addition, brain MRI has a greater sensitivity than CT scan for detection of
central nervous system metastasis.
Procedures:
Bronchoscopy
When a lung cancer is suggested, especially if centrally located, bronchoscopy
provides a means for direct visualization of the tumor, allows determination of the
extent of airway obstruction, and allows collection of pathologic material under
direct visualization.
Fiberoptic bronchoscopy has the advantage of providing direct visualization of the
bronchial tree. Diagnostic material can be obtained with direct biopsy of the
visualized tumor, bronchial brushings and washing, and transbronchial biopsies.
Mediastinoscopy: This is usually performed to evaluate the status of enlarged mediastinal
lymph nodes (seen on CT scan) before attempting definitive surgical resection of lung
cancer.
Thoracoscopy: This is usually reserved for tumors that remain undiagnosed after
bronchoscopy or CT-guided biopsy. Thoracoscopy is also an important tool in the
management of malignant pleural effusions.
CT-guided biopsy with transthoracic percutaneous fine-needle aspiration: This
procedure is preferred for tumors located in the periphery of the lungs because peripheral
tumors may not be accessible through a bronchoscope.
Biopsy of other sites: Diagnostic material can also be obtained from other abnormal sites
(eg, enlarged palpable lymph nodes, liver, pleural and pericardial effusions).
Staging
Once the lung cancer has been diagnosed, the doctor will work to determine the extent, or
stage, of this cancer. The cancer's stage helps the doctor decide what treatment is most
appropriate. Staging tests may include imaging procedures, that allow the doctor to look
for signs that cancer has spread beyond the lungs, such as magnetic resonance imaging
(MRI), positron emission testing (PET) and bone scans. Lung cancer staging is an
assessment of the degree of spread of the cancer from its original source. It is an
important factor affecting the prognosis and potential treatment of lung cancer.
The current TNM staging system came into effect in 1997 after revisions for stage
groupings for stages I, II, and III. The most important prognostic indicator in lung cancer
is the extent of disease. The American Joint Committee for Cancer Staging and End
Results Reporting has developed the TNM staging system, which takes into account the
degree of spread of primary tumor, the extent of regional lymph node involvement, and
the presence or absence of distant metastases. The TNM system is used for all lung
carcinomas except small cell lung carcinomas. For TNM staging, lung cancer is divided
into 4 stages, with further subdivision of stages I-III into A and B subtypes.
Tumor (T)
TX - Positive malignant cytology results, no lesion seen
18
T1 - Diameter smaller than or equal to 3 cm
T2 - Diameter larger than 3 cm
T3 - Extension to pleura, chest wall, diaphragm, pericardium, within 2 cm of
carina, or total atelectasis
T4 - Invasion of mediastinal organs (eg, esophagus, trachea, great vessels, heart),
malignant pleural effusion, or satellite nodules within the primary lobe
Regional lymph node involvement (N)
N0 - No lymph nodes involved
N1 - Ipsilateral bronchopulmonary or hilar nodes involved
N2 - Ipsilateral mediastinal or subcarinal nodes
N3 - Contralateral mediastinal, hilar, any supraclavicular nodes involved
Metastatic involvement (M)
M0 - No metastases
M1 - Metastases present
Stage groupings
IA - T1 N0 M0
IB - T2 N0 M0
IIA - T1 N1 M0
IIB - T2 N1 M0 or T3 N0 M0
IIIA - T1-3 N2 M0 or T3 N1 M0
IIIB - Any T4 or any N3 M0
IV - Any M1
Non-small cell lung carcinoma is staged from IA ("one A", best prognosis) to IV ("four",
worst prognosis).[28] Small cell lung carcinoma is classified as limited stage if it is
confined to one half of the chest and within the scope of a single radiotherapy field.
Otherwise it is extensive stage.[24]
Stages of non-small cell lung cancer
Stage I. Cancer at this stage has invaded the underlying lung tissue but hasn't spread to
the lymph nodes.
Stage II. This stage cancer has spread to neighboring lymph nodes or invaded the chest
wall.
Stage IIIA. At this stage, cancer has spread from the lung to lymph nodes in the center of
the chest.
Stage IIIB. The cancer has spread locally to areas such as the heart, blood vessels,
trachea and esophagus — all within the chest — or to lymph nodes in the area of the
collarbone or to the tissue that surrounds the lungs within the rib cage (pleura).
Stage IV. The cancer has spread to other parts of the body, such as the liver, bones or
brain.
Stages of small cell lung cancer
Limited. Cancer is confined to one lung and to its neighboring lymph nodes.
Extensive. Cancer has spread beyond one lung and nearby lymph nodes, and may have
invaded both lungs, more remote lymph nodes or other organs.
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,
19
chemotherapy, and radiation therapy.[4] The main types of lung cancer are small cell lung
carcinoma and non-small cell lung carcinoma. This distinction is important because the
treatment varies; non-small cell lung carcinoma (NSCLC) is sometimes treated with
surgery, while small cell lung carcinoma (SCLC) usually responds better to
chemotherapy and radiation.[5]
Treatment options for non-small cell lung cancers
Stage
Common options
I
Surgery
II
Surgery, chemotherapy, radiation
IIIA
Combined chemotherapy and radiation, sometimes surgery based on results
of treatment
IIIB
Chemotherapy, sometimes radiation
IV
Chemotherapy, targeted drug therapy, clinical trials, supportive care
Treatment options for small cell lung cancers
Stage
Common options
Limited
Combined chemotherapy and radiation, sometimes surgery
Extensive
Chemotherapy, clinical trials, supportive care
Lung cancer surgery
If investigations confirm lung cancer, CT scan 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 where it cannot be cured surgically.
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 poor respiratory reserve
(often due to chronic obstructive pulmonary disease), surgery may be contraindicated.
Surgery itself has an operative death rate of about 4.4%, depending on the patient's lung
function and other risk factors.[65] Surgery is usually only an option in non-small cell lung
carcinoma limited to one lung, up to stage IIIA. This is assessed with medical imaging
(computed tomography, positron emission tomography). A sufficient pre-operative
respiratory reserve must be present to allow adequate lung function after the tissue is
removed.
Lung cancer surgery involves the surgical excision of cancer tissue from the lung and is
used mainly in non-small cell lung cancer with the intention of curing the patient.
Procedures include wedge resection (removal of part of a lobe), segmentectomy (removal
of an anatomic division of a particular lobe of the lung), lobectomy (one lobe),
bilobectomy (two lobes) or pneumonectomy (whole lung). In patients with adequate
respiratory reserve, lobectomy is the preferred option, as this minimizes the chance of
local recurrence. If the patient does not have enough functional lung for this, wedge
resection may be performed.[66] Radioactive iodine brachytherapy at the margins of
wedge excision may reduce recurrence to that of lobectomy.[67]
Patient selection
20
Not all patients are suitable for operation. The stage, location and cell type are important
limiting factors. In non-small cell lung cancer, stages IA, IB, IIA, and IIB are suitable for
surgical resection.[2] In addition, patients who are very ill with a poor performance status
or who have inadequate pulmonary reserve would be unlikely to survive. Even with
careful selection, the overall operative death rate is about 4.4%.[1]Pulmonary reserve is
measured by spirometry. The minimum forced vital capacity (FVC) for pneumonectomy
in men is 2 liters. The minimum for lobectomy is 1.5 liters. In women, the minimum FVC
values for pneumonectomy and lobectomy are 1.75 liters and 1.25 liters respectively. [3]
Types of surgery
Lobectomy (removal of a lobe of the lung)
Segmentectomy (removal of an anatomic division of a particular lobe of the lung)
Pneumonectomy (removal of an entire lung)
Wedge resection
Sleeve/bronchoplastic resection (removal of an associated tubular section of the
associated main bronchial passage during lobectomy with subsequent reconstruction of
the bronchial passage)
Chemotherapy
Small cell lung carcinoma is treated primarily with chemotherapy and radiation, as
surgery has no demonstrable influence on survival. Primary chemotherapy is also given in
metastatic non-small cell lung carcinoma.
The combination regimen depends on the tumor type. Non-small cell lung carcinoma is
often treated with cisplatin or carboplatin, in combination with gemcitabine, paclitaxel,
docetaxel, etoposide or vinorelbine.[68] In small cell lung carcinoma, cisplatin and
etoposide are most commonly used.[69] Combinations with carboplatin, gemcitabine,
paclitaxel, vinorelbine, topotecan and irinotecan are also used.[70][71]
Adjuvant chemotherapy for non-small cell lung carcinoma
Adjuvant chemotherapy refers to the use of chemotherapy after surgery to improve the
outcome. During surgery, samples are taken from the lymph nodes. If these samples
contain cancer, then the patient has stage II or III disease. In this situation, adjuvant
chemotherapy may improve survival by up to 15%.[72][73] Standard practice is to offer
platinum-based chemotherapy (including either cisplatin or carboplatin).[74]
Adjuvant chemotherapy for patients with stage IB cancer is controversial as clinical trials
have not clearly demonstrated a survival benefit.[75][76] Trials of preoperative
chemotherapy (neoadjuvant chemotherapy) in resectable non-small cell lung carcinoma
have been inconclusive.[77]
Radiotherapy
Radiotherapy is often given together with chemotherapy, and may be used with curative
intent in patients with non-small cell lung carcinoma who are not eligible for surgery.
This form of high intensity radiotherapy is called radical radiotherapy. A refinement of
this technique is continuous hyperfractionated accelerated radiotherapy (CHART), where
a high dose of radiotherapy is given in a short time period.[78] For small cell lung
carcinoma cases that are potentially curable, in addition to chemotherapy, chest radiation
is often recommended.[79] The use of adjuvant thoracic radiotherapy following curative
intent surgery for non-small cell lung carcinoma is not well established and controversial.
Benefits, if any, may only be limited to those in whom the tumor has spread to the
mediastinal lymph nodes.[80][81]
21
For both non-small cell lung carcinoma and small cell lung carcinoma patients, smaller
doses of radiation to the chest may be used for symptom control (palliative radiotherapy).
Unlike other treatments, it is possible to deliver palliative radiotherapy without
confirming the histological diagnosis of lung cancer.
Patients with limited stage small cell lung carcinoma are usually given prophylactic
cranial irradiation (PCI). This is a type of radiotherapy to the brain, used to reduce the
risk of metastasis.[82] More recently, PCI has also been shown to be beneficial in those
with extensive small cell lung cancer. In patients whose cancer has improved following a
course of chemotherapy, PCI has been shown to reduce the cumulative risk of brain
metastases within one year from 40.4% to 14.6%.[83]
Recent improvements in targeting and imaging have led to the development of
extracranial stereotactic radiation in the treatment of early-stage lung cancer. In this form
of radiation therapy, very high doses are delivered in a small number of sessions using
stereotactic targeting techniques. Its use is primarily in patients who are not surgical
candidates due to medical comorbidities, though a current RTOG protocol is investigating
its use in early-stage patients who would be surgical candidates.
Interventional radiology
Radiofrequency ablation should currently be considered an investigational technique in
the treatment of bronchogenic carcinoma. It is done by inserting a small heat probe into
the tumor to kill the tumor cells.[84]
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
tyrosine kinase domain of the epidermal growth factor receptor (EGF-R) which is
expressed in many cases of non-small cell lung carcinoma. It was not shown to increase
survival, although females, Asians, non-smokers and those with bronchioloalveolar
carcinoma appear to derive the most benefit from gefitinib.[22]
Erlotinib (Tarceva), another tyrosine kinase inhibitor, has been shown to increase survival
in lung cancer patients[85] and has recently been approved by the FDA for second-line
treatment of advanced non-small cell lung carcinoma. Similar to gefitinib, it appeared to
work best in females, Asians, non-smokers and those with bronchioloalveolar
carcinoma.[86]
The angiogenesis inhibitor bevacizumab (in combination with paclitaxel and carboplatin)
improves the survival of patients with advanced non-small cell lung carcinoma.[87]
However this increases the risk of lung bleeding, particularly in patients with squamous
cell carcinoma.
Advances in cytotoxic drugs,[88] pharmacogenetics[89] and targeted drug design[90] show
promise. A number of targeted agents are at the early stages of clinical research, such as
cyclo-oxygenase-2 inhibitors,[91] the apoptosis promoter exisulind,[92] proteasome
inhibitors,[93] bexarotene[94] and vaccines.[95] Future areas of research include ras protooncogene inhibition, phosphoinositide 3-kinase inhibition, histone deacetylase inhibition,
and tumor suppressor gene replacement.[96]
Prognosis
Prognostic factors in non- small-cell lung cancer include presence or absence of
pulmonary symptoms, tumor size, cell type (histology), degree of spread (stage) and
metastases to multiple lymph nodes, and vascular invasion. For patients with inoperable
22
disease, prognosis is adversely affected by poor performance status and weight loss of
more than 10%. [97] Prognostic factors in small-cell lung cancer include performance
status, gender, stage of disease, and involvement of the central nervous system or liver at
the time of diagnosis. [98]
For non-small cell lung carcinoma, prognosis is generally poor. Following complete
surgical resection of stage IA disease, five-year survival is 67%. With stage IB disease,
five-year survival is 57%.[99] The 5-year survival rate of patients with stage IV NSCLC is
about 1%.[6]
For small cell lung carcinoma, prognosis is also generally poor. The overall five-year
survival for patients with SCLC is about 5%.[4] Patients with extensive-stage SCLC have
an average five-year survival rate of less than 1%. The median survival time for limitedstage disease is 20 months, with a five-year survival rate of 20%.[6]
According to data provided by the National Cancer Institute, the median age of incidence
of lung cancer is 70 years, and the median age of death by lung cancer 71 years.[100]
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32