Lung Cancer; Causes, Symptoms, Diagnosis, Treatment

Lung cancer

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Lung cancer is among the most deadly cancers for both men and women (). Its death rate exceeds that of the three most common cancers (colon, breast, and pancreatic) combined (). Over half of patients diagnosed with lung cancer die within one year of diagnosis and the 5-year survival is around 17.8% (). There are two main subtypes of lung cancer, small-cell lung carcinoma and non-small-cell lung carcinoma (NSCLC), accounting for 15% and 85% of all lung cancer, respectively (). NSCLC is further classified into three types: squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma.

Squamous-cell carcinoma comprises 25–30% of all lung cancer cases. It arises from early versions of squamous cells in the airway epithelial cells in the bronchial tubes in the center of the lungs. This subtype of NSCLC is strongly correlated with cigarette smoking ().

Cellular Classification of NSCLC

Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). There are three main subtypes of non-small cell lung cancer (NSCLC), including the following:

  • Squamous cell carcinoma (25% of lung cancers).
  • Adenocarcinoma (40% of lung cancers).
  • Large cell carcinoma (10% of lung cancers).

There are numerous additional subtypes of decreasing frequency.[]

WHO/IASLC Histologic Classification of NSCLC

Squamous cell carcinoma.

  • Papillary.
  • Clear cell.
  • Small cell.
  • Basaloid.

Adenocarcinoma.

  • Acinar.
  • Papillary.

Bronchioloalveolar carcinoma.

  • Nonmucinous.
  • Mucinous.
Mixed mucinous and nonmucinous or indeterminate cell type.
  • Solid adenocarcinoma with mucin.
  • Adenocarcinoma with mixed subtypes.

Variants.

  • Well-differentiated fetal adenocarcinoma.
  • Mucinous (colloid) adenocarcinoma.
  • Mucinous cystadenocarcinoma.
  • Signet ring adenocarcinoma.
  • Clear cell adenocarcinoma.

Large cell carcinoma, Variants.

  • Large cell neuroendocrine carcinoma (LCNEC).
  • Combined LCNEC.
  • Basaloid carcinoma.
  • Lymphoepithelioma-like carcinoma.
  • Clear cell carcinoma.
  • Large cell carcinoma with rhabdoid phenotype.

Adenosquamous carcinoma

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.

  • Carcinomas with spindle and/or giant cells.
  • Spindle cell carcinoma.
  • Giant cell carcinoma.
  • Carcinosarcoma.
  • Pulmonary blastoma.

Carcinoid tumor

  • Typical carcinoid.
  • Atypical carcinoid.

Carcinomas of salivary gland type.

  • Mucoepidermoid carcinoma.
  • Adenoid cystic carcinoma.
  • Others.
Unclassified carcinoma.

Squamous cell carcinoma

  • Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.

Adenocarcinoma

  • Adenocarcinoma is now the most common histologic subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.
  • Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.

Stage of Lung Cancer

Early disease stage I-IIIA

Stage IA

  • Once the histopathological diagnosis is made, if the patients generally consider fit for radical treatment these will undergo surgical intervention. Usually, lobectomy or greater resection is recommended rather than sublobar resections (wedge or segmentation).
  • In patients with stage I NSCLC who may tolerate operative intervention but not a lobar or greater lung resection because of comorbid disease or decreases in pulmonary functions segmentectomy/anatomical resection is recommended over non-surgical interventions.
  • Further management will base on the initial extent of the disease, postoperative information and on patient preference and decision. The use of pre-operative or post-operative chemotherapy or radiation therapy in stage I NSCLC is not recommended by small randomized studies.

Stage IB

  • The meta-analysis over review gave non-clear evidence-based for adjuvant or induction treatment in stage IB patients after radical tumor resection. Only selective patients and patients that are participating in protocols are candidates for further treatment.

Stage II

  • Patients with stage II are usually considered for multidisciplinary treatment strategies. The administration of postoperative radiation therapy for the improvement of survival is not recommended in patients who undergo radical resection of stage II tumor with N1 lymph node metastasis [stage II (N1) NSCLC].
  • In patients who undergo radical resection of stage II tumor and are in a good physical condition, adjuvant platinum-based chemotherapy should be offered between 4th and 8th week following the thoracotomy (adequate wood healing, non-residual inflammatory or infectious complications). Patients in stage II, who are not candidates for surgical approaches due to comorbidities (e.g., pulmonary risk factors), could be considered for chemo-radiotherapy strategies.

Locally advanced IIIA and selected IIIB

  • Patients in stage IIIA1-IIIA2 () are usually operated with mediastinal lymphadenectomy followed by platinum-based of adjuvant chemotherapy. Postoperative radiation therapy alone can reduce the relapse locally without increasing survival.
  • Multidisciplinary management of IIIA3 and IIIA4 patients becomes crucial. Patients with proven N2involvement (IIIA3 and IIIA4) could be treated by induction chemotherapy followed by surgery followed by platinum-based chemoradiotherapy.
  • Stage IIIB is typically considered for concurrent chemoradiotherapy approaches. In selected cases, surgery will be incorporated within clinical trials.

Causes of Lung Cancer

Cigarette Smoking

  • The emergence of the lung cancer epidemic in the 20th century has no doubt been caused by cigarette smoking. The effect of pipe and cigar use on the risk of lung cancer is similar to that of light cigarette smoking., In the United States and the United Kingdom, the decline in lung cancer rates is projected to level off in 2 decades because of the slow progress in smoking cessation at present. Lung cancer will remain among the top killers for decades unless radical reductions in smoking prevalence are achieved.

Second Hand or Passive Smoking

  • The causal association that has been established between secondhand tobacco smoking and lung cancer can explain 1.6% of lung cancers. Results from a meta-analysis and a comprehensive review showed a relative risk between 1.14 to 5.20 in people who had never smoked but who lived with a smoker. A more recent study reported that passive smoking during childhood increased lung cancer risk in adulthood by 3.6 fold.

Diet and Food Supplements

  • Fruits and vegetables that are a rich source of antioxidant vitamins and other micronutrients, particularly carotenoids, are thought to benefit health by decreasing the risk of lung and other cancers. Although some studies indicate carotenoids decrease lung cancer risk, results have been ambiguous, and some have even indicated that high-dose supplements can be harmful.
  • Lutein, zeaxanthin, lycopene, and α-carotene displayed a certain protective trend, yet β-cryptoxanthin showed a more consistent protective effect. There is some evidence of a protective role for vitamins C and E, but not vitamin A; no associations were observed between intakes of total or specific types of fat and lung cancer risk regardless of smoking status. In contrast, cured meat (eg, sausage, pressed duck, and cured pork), deep-fried cooking, and chili have been associated with an increased lung cancer risk.

Alcohol

  • From a pooled analysis of 7 prospective studies with 399,767 participants and 3137 lung cancer cases, a slightly greater risk of lung cancer was indicated among people who consumed at least 30 g/d of alcohol than among those who abstained from alcohol.

Exercise and Physical Activity

  • Available data suggest that physically active individuals have a lower risk of lung cancer: moderate to high levels of leisure-time physical activity were associated with a 13% to 30% reduction in lung cancer risk. Overall, physical activity could help to reduce lung cancer risk and mortality among heavy smokers.

Air Pollution

  • Lung cancer could be one of the long-term adverse effects of cumulated exposure to ambient air pollution, such as emissions rich in various polycyclic aromatic hydrocarbon compounds, likely through oxidative stress, inflammation, induction of a procoagulatory state, and dysfunction of the autonomic nervous system., The proportion of lung cancers attributable to urban air pollution in Europe is estimated to be 11%.

Occupational Exposure

  • Many work settings could have exposed workers to carcinogens, leading to an increased risk of lung and other cancers. Crystalline silica and chrysotile asbestos are well-known human carcinogens; as expected, workers exposed to silica dust and asbestos fiber are at a higher risk of developing lung cancer. Uranium miners and nuclear plant workers are also known to have an increased cancer risk because of exposure to radioactive particulate mass.

Lung Cancer Susceptibility Genes

  • Familial clustering or aggregation of lung cancer has been reported repeatedly in the past 60 years, suggesting a hereditary base to disease development. An increased risk of lung cancer was found in the carriers of TP53 (for expansion of gene symbols, use the search tool at www.genenames.org) germline sequence variations, and carriers who smoked cigarettes are more than 3 times more likely to develop lung cancer than carriers who did not smoke.
  • The germline epidermal growth factor receptor (EGFR) T790M sequence variation was reported in a family with multiple cases of NSCLC. Finally, a genome-wide linkage study of 52 extended families identified a new major susceptibility locus influencing lung cancer risk at 6q23–25p. Laryngeal and throat cancers were also included in this study. Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include the following:
  • History of or current tobacco use: cigarettes, pipes, and cigars.[]
  • Exposure to cancer-causing substances in secondhand smoke.[,]
  • Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.[]
  • Radiation exposure from any of the following:
  • Radiation therapy to the breast or chest.[]
  • Radon exposure in the home or workplace.[]
  • Medical imaging tests, such as computed tomography (CT) scans.[]
  • Atomic bomb radiation.[]
  • Living in an area with air pollution.[]
  • The family history of lung cancer.[]
  • Human immunodeficiency virus infection.[]
  • Beta carotene supplements in heavy smokers.[,]
  • Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk of lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk.[]

Other Causes of Lung Cancer

Numerous other substances, occupations, and environmental exposures have been linked to lung cancer. The International Agency for Research on Cancer (IARC) states that there is some “sufficient evidence” to show that the following are carcinogenic in the lungs:[rx]

  • Some metals aluminumm production, cadmium and cadmium compounds, chromium(VI) compounds, beryllium and beryllium compounds, iron and steel founding, nickel compounds, arsenic and inorganic arsenic compounds, and underground hematite mining)
  • Some products of combustion (incomplete combustion, coal (indoor emissions from household coal burning), coal gasification, coal-tar pitch, coke production, soot, and diesel engine exhaust)
  • Ionizing radiation (X-radiation, gamma radiation, and plutonium)
  • Some toxic gases (methyl ether (technical grade), and bis-(chloromethyl) ether, sulfur mustard, MOPP (vincristine-prednisone-nitrogen mustard-procarbazine mixture) and fumes from painting)
  • Rubber production and crystalline silica dust
  • There is a small increase in the risk of lung cancer in people affected by systemic sclerosis.

Types of Lung Cancer

Types of Lung Cancer.

Lung Cancer Type % of All Lung
Cancer
Anatomic Location
Squamous cell lung cancers (SQCLC) 25–30% Arise in main bronchi and advance to the carina
Adenocarcinomas (AdenoCA) 40% Arise in peripheral bronchi
Large cell anaplastic carcinomas (LCAC) 10% Tumors lack the classic glandular or squamous morphology
Small cell lung cancers (SCLC) 10–15% Derive from the hormonal Cells Disseminate into submucosal lymphatic vessels and regional lymph nodes almost without a bronchial invasion

TNM classification of lung cancer in the 6th edition () and proposal for the 7th edition ()

6th edition Proposal for the 7th edition
T TX Primary tumor cannot be assessed, or evidence of malignant cells in sputum or bronchial lavage fluid but no visualization of tumor on imaging or bronchoscopy TX Primary tumor cannot be assessed, or evidence of malignant cells in sputum or bronchial lavage fluid but no visualization of tumor on imaging or bronchoscopy
T0 No evidence of primary tumor T0 No evidence of primary tumor
Tis Carcinoma in situ Tis Carcinoma in situ
T1 Tumor ≤ 3 cm greatest diameter, surrounded by lung tissue or visceral pleura, no bronchoscopic evidence of invasion proximal to the lobar bronchus (i.e., main bronchi are free)*1 T1 Tumor ≤ 3 cm greatest diameter, surrounded by lung tissue or visceral pleura, no bronchoscopic evidence of infiltration proximal to the lobar bronchus (i.e., main bronchi are free)*1
T1a Tumor ≤ 2 cm greatest diameter
T1b Tumor > 2 but ≤ 3 cm greatest diameter
T2 Tumor > 3 cm or tumor with one of the following features: T2 Tumor > 3 but ≤ 7 cm with one of the following features:
  • invasion of the main bronchus, ≥ 2 cm dis tal to the carina
  • invasion of the visceral pleura
  • associated atelectasis or obstructive pneumonia extending as far as the hilus but not involving the whole lung
  • invasion of the main bronchus ≥ 2 cm distal to the carina
  • invasion of the visceral pleura
Associated atelectasis or obstructive pneumonia extending as far as the hilus but not involving the whole lung
T2a Tumor > 3 but ≤ 5 cm greatest diameter
T2b Tumor > 5 but ≤ 7 cm greatest diameter
T3 Tumor of any size with direct invasion of one of the following structures: T3 Tumor > 7 cm or any tumor with direct invasion of one of the following structures:
  • chest wall (including tumors of the superior sulcus)
  • diaphragm
  • phrenic nerve
  • mediastinal pleura
  • parietal pericardium
  • chest wall (including tumors of the superior sulcus)
  • diaphragm
  • phrenic nerve
  • mediastinal pleura
  • parietal pericardium
or tumor in the main bronchus < 2 cm distal to the carina, without the involvement of the carina and without associated atelectasis or obstructive pneumonia of the whole lung or tumor in the main bronchus < 2 cm distal to the carina, without the involvement of the carina and without associated atelectasis or obstructive pneumonia of the whole lung or satellite tumor nodule(s) in the same lobe
T4 Tumor of any size invading one of the following structures: T4 Tumor of any size invading one of the following structures:
  • mediastinum
  • heart
  • great vessels
  • trachea
  • recurrent laryngeal nerve
  • esophagus
  • vertebral body
  • carina
  • mediastinum
  • heart
  • great vessels
  • trachea
  • recurrent laryngeal nerve
  • esophagus
  • vertebral body
  • carina
  • or separate tumor nodule(s) in another ipsilateral lobe
or separate tumor nodule(s) in the same lobe or tumor with malignant pleural* 2 or pericardial effusion
N NX Regional lymph nodes could not be evaluated NX Regional lymph nodes could not be evaluated
N0 No regional lymph node metastases N0 No regional lymph node metastases
N1 Metastasis/metastases in the ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary lymph nodes, including involvement by direct extension of the primary tumor N1 Metastasis/metastases in the ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary lymph nodes, including involvement by direct extension of the primary tumor
N2 Metastasis/metastases in the ipsilateral mediastinal and/or subcarinal lymph nodes N2 Metastasis/metastases in the ipsilateral mediastinal and/or subcarinal lymph nodes
N3 Metastasis/metastases in the contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes N3 Metastasis/metastases in the contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes
M MX Distant metastases could not be evaluated MX Distant metastases could not be evaluated
M0 No distant metastases M0 No distant metastases
M1 Distant metastases, including separate tumor nodules in another pulmonary lobe M1 Distant metastases
M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural*2 nodes or malignant pleural (or pericardial) effusion
M1b Distant metastases
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Symptoms and findings of lung cancer and frequency distribution of important symptoms

Symptoms and findings of endobronchial growth

  • Cough (8% to 75%), hemoptysis (6% to 35%), pain, wheezing (0% to 2%), poststenotic pneumonia, dyspnea (3% to 60%), stridor (0% to 2%)

Symptoms and findings of intrathoracic extension

  • Chest pain (20% to 49%), hoarseness, upper airway inflow obstruction, Horner’s triad, pleural effusion, pericardial effusion, dysphagia, raised diaphragm

Systemic signs of cancer

  • Weight loss (0% to 68%), night sweats, fatigue, fever (0% to 20%)

Symptoms and findings of distant metastases

  • Bone pain (6% to 25%), headache, neurological or psychiatric abnormalities, paraplegia, hepatomegaly, pathological fractures

Symptoms of paraneoplastic syndromes

  • Cushing syndrome, syndrome of inappropriate ADH secretion, Lambert-Eaton syndrome, Perre-Marie-Bamberger syndrome, etc.

Frequency data from []; ADH, antidiuretic hormone

  • Respiratory symptoms – coughing, coughing up blood, wheezing, or shortness of breath
  • Systemic symptoms – weight loss, weakness, fever, or clubbing of the fingernails
  • Symptoms due to the cancer mass pressing on adjacent structures – chest pain, bone pain, superior vena cava obstruction, or difficulty swallowing
  • If cancer grows in the airways, it may obstruct airflow – causing breathing difficulties. The obstruction can lead to accumulation of secretions behind the blockage, and predispose to pneumonia.[rx]
  • Depending on the type of tumor, paraneoplastic phenomena—symptoms not due to the local presence of cancer—may initially attract attention to the disease.[rx] In lung cancer, these phenomena may include hypercalcemia, syndrome of inappropriate antidiuretic hormone (SIADH, abnormally concentrated urine and diluted blood), ectopic ACTH production, or Lambert–Eaton myasthenic syndrome (muscle weakness due to auto-antibodies).
  • Tumors in the top of the lung, known as Pancoast tumors, may invade the local part of the sympathetic nervous system, leading to Horner’s syndrome (dropping of the eyelid and a small pupil on that side), as well as damage to the brachial plexus.[rx]
  • Coughing, especially if it persists or becomes intense
  • Pain in the chest, shoulder, or back unrelated to pain from coughing
  • A change in color or volume of sputum
  • Shortness of breath
  • Changes in the voice or being hoarse
  • Harsh sounds with each breath (stridor)
  • Recurrent lung problems, such as bronchitis or pneumonia
  • Coughing up phlegm or mucus, especially if it is tinged with blood
  • Coughing up blood

If the original lung cancer has spread, a person may feel symptoms in other places in the body. Common places for lung cancer to spread include other parts of the lungs, lymph nodes, bones, brain, liver, and adrenal glands.

Symptoms of lung cancer that may occur elsewhere in the body

  • Loss of appetite or unexplained weight loss
  • Muscle wasting (also known as cachexia)
  • Fatigue
  • Headaches, bone or joint pain
  • Bone fractures not related to accidental injury
  • Neurological symptoms, such as unsteady gait or memory loss
  • Neck or facial swelling
  • General weakness
  • Bleeding
  • Blood clots
  • appetite loss
  • changes to a person’s voice, such as hoarseness
  • frequent chest infections, such as bronchitis or pneumonia
  • a lingering cough that may start to get worse
  • shortness of breath
  • unexplained headaches
  • weight loss
  • wheezing

Diagnosis of Lung Cancer

Chest X-ray

  • A chest X-ray is usually the first test used to diagnose lung cancer. Most lung tumors show up on X-rays as a white-grey mass.
  • However, chest X-rays can’t give a definitive diagnosis because they often can’t distinguish between cancer and other conditions, such as a lung abscess (a collection of pus that forms in the lungs).
  • If your chest X-ray suggests you may have lung cancer, you should be referred to a specialist (if you haven’t already) in chest conditions such as lung cancer.
  • A specialist can carry out more tests to investigate whether you have lung cancer and, if you do, what type it is and how much it’s spread.

CT scan

  • A computerized tomography (CT) scan is usually carried out after a chest X-ray. A CT scan uses X-rays and a computer to create detailed images of the inside of your body. Before having a CT scan, you’ll be given an injection of a contrast medium. This is a liquid containing a dye that makes the lungs show up more clearly on the scan. The scan is painless and takes 10-30 minutes to complete.

PET-CT scan

  • A PET-CT scan (which stands for positron emission tomography-computerized tomography) may be carried out if the results of the CT scan show you have cancer at an early stage.
  • The PET-CT scan can show where there are active cancer cells. This can help with diagnosis and treatment.
  • Before having a PET-CT scan, you’ll be injected with slightly radioactive material. You’ll be asked to lie down on a table, which slides into the PET scanner. The scan is painless and takes around 30-60 minutes.

Bronchoscopy and Biopsy

  • If the CT scan shows there might be cancer in the central part of your chest, you’ll have a bronchoscopy. A bronchoscopy is a procedure that allows a doctor or nurse to remove a small sample of cells from inside your lungs. During a bronchoscopy, a thin tube called a bronchoscope is used to examine your lungs and take a sample of cells (biopsy). The bronchoscope is passed through your mouth or nose, down your throat and into the airways of your lungs.
  • The procedure may be uncomfortable, but you’ll be given a mild sedative beforehand to help you relax and a local anesthetic to make your throat numb. The procedure is very quick and only takes a few minutes.

Other Types of Biopsy

  • You may be offered a different type of biopsy. This may be a type of surgical biopsies such as thoracoscopy or a mediastinoscopy, or a biopsy carried out using a needle inserted through your skin.

Percutaneous needle biopsy

  • A percutaneous needle biopsy involves removing a sample from a suspected tumor to test it at a laboratory for cancerous cells.
  • The doctor carrying out the biopsy will use a CT scanner to guide a needle to the site of a suspected tumor through the skin.
  • A local anesthetic is used to numb the surrounding skin, and the needle is passed through your skin and into your lungs. The needle will then be used to remove a sample of tissue for testing.

Thoracoscopy

  • A thoracoscopy is a procedure that allows the doctor to examine a particular area of your chest and take tissue and fluid samples. You’re likely to need a general anesthetic before having a thoracoscopy. Two or three small cuts will be made in your chest to pass a tube (similar to a bronchoscope) into your chest. The doctor will use the tube to look inside your chest and take samples. The samples will then be sent away for tests. After a thoracoscopy, you may need to stay in the hospital overnight while any further fluid in your lungs is drained out.

Mediastinoscopy

  • A mediastinoscopy allows the doctor to examine the area between your lungs at the center of your chest (mediastinum). For this test, you’ll need to have a general anesthetic and stay in the hospital for a couple of days. The doctor will make a small cut at the bottom of your neck so they can pass a thin tube into your chest. The tube has a camera at the end, which enables the doctor to see inside your chest. They’ll also be able to take samples of your cells and lymph nodes at the same time. The lymph nodes are tested because they’re usually the first place that lung cancer spreads to.

Staging

  • Once these tests have been completed, it should be possible to work out what stage your cancer is, what this means for your treatment and whether it’s possible to completely cure cancer.

Non-small-cell lung cancer

  • Non-small-cell lung cancer (the most common type) usually spreads more slowly than small-cell lung cancer and responds differently to treatment. The stages of non-small-cell lung cancer are:

Stage 1

The cancer is contained within the lung and hasn’t spread to nearby lymph nodes. Stage 1 can also be divided into two sub-stages:

  • stage 1A – the tumor is less than 3cm in size (1.2 inches)
  • stage 1B – the tumor is 3-5cm (1.2-2 inches)

Stage 2

Stage 2 is divided into two sub-stages: 2A and 2B.

In stage 2A lung cancer, either

  • the tumor is 5-7cm
  • the tumor is less than 5cm and cancerous cells have spread to nearby lymph nodes

In stage 2B lung cancer, either

  • the tumor is larger than 7cm
  • the tumor is 5-7cm and cancerous cells have spread to nearby lymph nodes
  • cancer hasn’t spread to lymph nodes but has spread to surrounding muscles or tissue
  • cancer has spread to one of the main airways (bronchus)
  • cancer has caused the lung to collapse
  • there are multiple small tumors in the lung

Stage 3

Stage 3 is divided into two sub-stages: 3A and 3B.

In stage 3A lung cancer, cancer has either spread to the lymph nodes in the middle of the chest or into the surrounding tissue. This can be:

  • the covering of the lung (the pleura)
  • the chest wall
  • the middle of the chest
  • other lymph nodes near the affected lung

In stage 3B lung cancer, cancer has spread to either of the following:

  • lymph nodes on either side of the chest, above the collarbones
  • another important part of the body, such as the gullet (esophagus), windpipe (trachea), heart or into the main blood vessel

Stage 4

In stage 4 lung cancer, cancer has either spread to both lungs or to another part of the body (such as the bones, liver or brain), or cancer has caused fluid-containing cancer cells to build up around your heart or lungs.

Small-cell lung cancer

Small-cell lung cancer is less common than non-small-cell lung cancer.

The cancerous cells responsible for the condition are smaller in size when examined under a microscope than the cells that cause non-small-cell lung cancer.

Small-cell lung cancer only has two possible stages:

  • limited disease – cancer has not spread beyond the lung
  • extensive disease – cancer has spread beyond the lung

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Treatment of Lung Cancer

Standard Treatment Options for NSCLC

Stage (TNM Staging Criteria) Standard Treatment Options
Occult NSCLC Surgery
Stage 0 NSCLC Surgery
Endobronchial therapies
Stages IA and IB NSCLC Surgery
Radiation therapy
Stages IIA and IIB NSCLC Surgery
Adjuvant chemotherapy
Neoadjuvant chemotherapy
Radiation therapy
Stage IIIA NSCLC Resected or resectable disease Surgery
Neoadjuvant therapy
Adjuvant therapy
Unresectable disease Radiation therapy
Chemoradiation therapy
Superior sulcus tumors Radiation therapy alone
Surgery
Chemoradiation therapy followed by surgery
Tumors that invade the chest wall Surgery
Surgery and radiation therapy
Radiation therapy alone
Chemotherapy combined with radiation therapy and/or surgery
Stages IIIB and IIIC NSCLC Sequential or concurrent chemotherapy and radiation therapy
Radiation therapy dose escalation for concurrent chemoradiation
Additional systemic therapy before or after concurrent chemotherapy and radiation therapy
Radiation therapy alone
Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC Cytotoxic combination chemotherapy
Combination chemotherapy with monoclonal antibodies
Maintenance therapy following first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
EGFR tyrosine kinase inhibitors (for patients with EGFR mutations)
ALK inhibitors (for patients with ALK translocations)
ROS1 inhibitors (for patients with ROS1 rearrangements)
BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations
Immune checkpoint inhibitor for PD-L1 expressing NSCLC.
Local therapies and special considerations
Progressive Stage IV, Relapsed, and Recurrent NSCLC Chemotherapy
EGFR-directed therapy
ALK-directed TKI
ROS1-directed therapy
BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations)
Immunotherapy

ALK = anaplastic lymphoma kinase; BRAF = V-raf murine sarcoma viral oncogene homolog B1; EGFR = epidermal growth factor receptor; MEK = MAPK kinase 1; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; TKI = tyrosine kinase inhibitors; TNM = T, size of tumor and any spread of cancer into nearby tissue; N, spread of cancer to nearby lymph nodes; M, metastasis or spread of cancer to other parts of body.

Drugs and corresponding targets.

Drug Target Type
Aflibercept (AVE0005) VEGF Humanize VEGFR-trap
AMG 655/Conatumumab TRAIL-R2 Monoclonal antibody
Apomab DR5/TRAIL-R2/TNFRSF10B Monoclonal antibody
Axitinib PDGFR Tyrosine kinase inhibitor
Bendamustine DNA (SSB and DSB) Alkylating agent
Bevacizumab VEGF Monoclonal antibody
Carboplatin DNA Small molecule inhibitor
Cediranib PDGFR Tyrosine kinase inhibitor
Cediranib VEGF Small molecule inhibitor
CI-994 Histone deactylases (HDACs) Small molecule inhibitor
Cisplatin DNA Small molecule inhibitor
Cixutumumab IGF-IR Monoclonal antibody
Dalotuzumab IGF-IR Monoclonal antibody
Docetaxel Tubulin Small molecule inhibitor
Entinostat Histone deactylases (HDACs) Small molecule inhibitor
Erlotinib EGFR Tyrosine kinase inhibitor
Etoposide Topoisomerase II Small molecule inhibitor
Figitumumab IGF-IR Monoclonal antibody
Gefitinib EGFR Tyrosine kinase inhibitor
Ifosfamide DNA Alkylating agent
Iniparib PARP-1 Small molecule inhibitor
Ipilimumab CTLA-4 Monoclonal antibody
Irinotecan Topoisomerase I Small molecule inhibitor
Linifinib PDGFR Tyrosine kinase inhibitor
Mapatumumab DR4/TRAIL-R1 Monoclonal antibody
Medl-4736 PD-L1 Monoclonal antibody
Motesanib PDGFR Tyrosine kinase inhibitor
MPDL-3280A PD-L1 Monoclonal antibody
Nintedanib VEGFR-1/2/3, PDGFR-α/β, FGFR-1/2/3, Flt-3, Src family Multiple target Tyrosine kinase inhibitor
nivolumab PD-1 Monoclonal antibody
Olaparib PARP-1 Small molecule inhibitor
Paclitaxel Tubulin Small molecule inhibitor
Panobinostat Histone deactylases (HDACs) Small molecule inhibitor
Pazopanib VEGFR-1/2/3, PDGFR-α/β, and FGFR-1 and 3 Multiple target Tyrosine kinase inhibitor
Pemetrexed Thymidylate Synthase Small molecule inhibitor
Pembrolizumab/MK-3475 PD-1 Monoclonal antibody
Pivanex Histone deactylases (HDACs) Small molecule inhibitor
Romidepsin (Depsipeptide, FK228) Histone deactylases (HDACs) Small molecule inhibitor
Sorafenib VEGFR-2/3, PDGFR-β, c-Kit, Raf, and Flt-3 Multiple target Tyrosine kinase inhibitor
Sunitinib VEGFR-1/2/3, PDGFR-α/β, c-Kit, Flt-3, and RET Multiple target Tyrosine kinase inhibitor
Talactoferrin Immune-modulatory function Glycoprotein, recombinant
Topotecan Topoisomerase I Small molecule inhibitor
Tremelimumab CTLA-4 Monoclonal antibody
Veliparib PARP-1 Small molecule inhibitor
Vinblastine Tubulin Small molecule inhibitor
Vinorelbine Tubulin Small molecule inhibitor
Vorinostat Histone deactylases (HDACs) Small molecule inhibitor
YM155/Sepantronium bromide Survivin Small molecule inhibitor

Treatment of Early Stage (stage I and Stage II) Non- Small-Cell Lung Cancer

  • The primary treatment for resectable and operable early stage disease (Stage I and II) is surgery [] which provides the best option for long-term survival []. Five-year survival rates after surgical resection are 60%–80% for stage I NSCLC and 30%–50% for stage II NSCLC patients []. For patients refusing surgical resection or with unresectable tumors, primary radiotherapy can be used such as stereotactic body radiotherapy (SBRT) for high-risk patients or unresectable tumors [].
  • However, post-surgery radiotherapy is not recommended for stage I and II patients []. To date, adjuvant platinum-based chemotherapy was shown to be beneficial for stage II NSCLC patients [] and is the recommended treatment strategy for completely resected patients []. Conversely, a clear benefit has so far not been proven for adjuvant chemotherapy in stage I NSCLC patients [].

Treatment of stage III Non- Small-Cell Lung Cancer

  • More than 70 % of NSCLC patients are diagnosed in advanced stages or metastatic disease [] (stages III and IV). Stage III NSCLC is a heterogeneous disease and varies from resectable tumors with microscopic metastases to lymph nodes to an unresectable, bulky disease involving multiple nodal locations. The 5-year OS rate varies between 10% to 15% for stage IIIA-N2 disease and 2% to 5% for stage IIIA bulky disease with mediastinal involvement. In this heterogeneous population of stage III NSCLC patients, the treatment strategies, including radiotherapy, chemotherapy, and surgical resection are determined by the tumor location and whether it is resectable.
  • The standard treatment consists of surgery followed by chemotherapy for patients with resectable stage IIIA NSCLC. It has been shown that the adjuvant chemotherapy significantly prolonged OS rate in clinical studies [] and that adjuvant radiation therapy can improve control of resected stage IIIA-N2 disease []. Meta-analyses of numerous clinical studies showed that neoadjuvant chemotherapy provides a modest 5% to 6% improvement in survival at five years [].
  • For unresectable stage IIIA patients – standard treatment may include either a sequential or concurrent combination of chemotherapy and radiation therapy (chemoradiation), and external radiation therapy for patients who cannot be treated with combined therapy. Meta-analyses of multiple randomized clinical studies showed that platinum-based chemoradiation therapy provides a significant 10% reduction in the risk of death when compared with radiation therapy alone []. Several clinical investigations showed that the radical surgery in Stage IIIA patients with bulky primary tumors may provide up to 50% increase in the 5-year survival rate as compared to patients with incomplete resection [].
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Eastern Cooperative Oncology Group (ECOG) Performance Status. The ECOG scale and criteria are used to assess how a patient’s disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis.

Grade ECOG
Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 Dead

Treatment of Stage IV Non-Small Cell Lung Cancer

  • Stage IV NSCLC accounts for 40% of the newly diagnosed NSCLC patients. The choice of treatment for stage IV NSCLC patients depends on many factors including, comorbidity, PS, histology, and molecular genetic features of cancer [].
  • Standard treatment options for stage IV NSCLC disease may include palliative external radiation therapy, combination chemotherapy, combination chemotherapy and targeted therapy, and any Laser therapy or internal endoscopic radiation therapy as needed. Similar to radiation therapy, surgery could also be used in some cases to alleviate disease-related symptoms.

Chemotherapy

  • For NSCLC, Chemotherapy is usually well tolerated by patients with PS 0 and 1 but rarely effective in patients with a PS 3 and 4 where palliative care is preferred.
  • Use of chemotherapy is controversial in PS 2 NSCLC patients, which represent nearly 40% of advanced stage NSCLC patients. Chemotherapy is recommended only for PS 2 patients who are reasonably fit, and awake for more than 50 % of the day.

i. First-line Chemotherapy

  • The median OS is 4.5 months when no chemotherapy is given to advanced metastatic NSCLC or after failure of all treatments. Use of chemotherapy improves the 1-year OS rate from 10%–20% up to 30%–50% []. A combination of two cytotoxic drugs is the recommended first-line therapy for Stage IV NSCLC patients with a PS of 0 or 1.
  • Platinum (Cisplatin or carboplatin)-based combination therapies yield better response and OS rates than the non-platinum combination therapies. First line platinum-based chemotherapeutics may include doublets of cisplatin or carboplatin given in combination with taxanes (paclitaxel, docetaxel, or vinorelbine), antimetabolites (gemcitabine or pemetrexed), or vinca alkaloids (vinblastine) with comparable activity []. Use of single cytotoxic chemotherapy is preferred in stage IV patients with a PS of 2 due to their greater risk of toxicity and drug intolerance, comparing to patients with a PS of 0 to 1.

ii. First-line combination chemotherapy with targeted therapy

  • Currently, the addition of bevacizumab, an antibody targeting VEGF, to first-line doublet combination chemotherapy, is supported for the treatment of stage IV NSCLC patients with the exception (squamous carcinoma histology, brain metastasis, significant cardiovascular disease or a PS greater than 1) due to fatal bleeding concerns. The combination of bevacizumab with carboplatin and paclitaxel doublet appeared to be superior to the combination with cisplatin and gemcitabine.

EGFR Tyrosine Kinase Inhibitors (first line)

  • The first of the approved targeted drugs for NSCLC patients are agents that specifically block the EGFR) such as tyrosine kinase inhibitor (TKI) Erlotinib (Tarceva) and gefitinib (Iressa). Mutations of EGFRs can lead to abnormal activation of this receptor triggering uncontrolled cell growth, which may account for several subsets of cancers including NSCLC.
  • Evidence from several randomized clinical trials demonstrated that use of single-agent gefitinib as a first-line therapy might be recommended for patients with activating EGFR mutations, particularly for patients who have contraindications to platinum therapy. Conversely, cytotoxic chemotherapy is preferred if EGFR mutation status is negative or unknown.
  • Three large controlled and randomized trials showed that gefitinib or erlotinib are better than platinum combination chemotherapy as first-line treatment for stage IIIB or IV lung adenocarcinomas in nonsmokers or former light smokers in East Asia [,,,].

Maintenance Therapy Following First-Line Chemotherapy

  • Maintenance therapy is the treatment continuation until disease progression of cancer that has not advanced following the first-line therapy. The primary goal is to improve cancer-related symptoms, and, hopefully, improve survival time beyond that provided by the first-line therapy.
  • It has lately gained great interest in the treatment of advanced NSCLC (stage IIIB and stage IV) []. Evidence from two randomized controlled clinical trials showed a statistically significant improvement of PFS, with the addition of pemetrexed as maintenance therapy following standard first-line platinum-based combination chemotherapy [].
  • Remarkably, pemetrexed maintenance therapy appears to be effective only in patients with adenocarcinoma and large cell carcinoma as well as in patients with EGFR mutations in their tumors, but not in patients with squamous cell lung carcinoma.

Second- and Third-Line Therapies in the Treatment of Advanced NSCLC

  • Docetaxel (Taxotere), pemetrexed, erlotinib, and gefitinib, are currently approved as second-line therapy for patients with advanced NSCLC who have failed first-line platinum-based therapy and have an acceptable PS.
  • Evidence from several randomized clinical trials and meta-analyses [] showed that docetaxel in the second-line setting leads to better survival and quality of life (QoL) when compared to best supportive care [] or to single-agent ifosfamide or vinorelbine [].
  • Pemetrexed yielded similar clinical response comparing to docetaxel (a median survival of about 8 months, one-year survival of 30%, and a response rate of 10%) [] with better toxicity profile that may benefit older patients with a PS of 3 [].
  • Pemetrexed also provided better outcome in lung adenocarcinoma patients, whereas docetaxel treatment was more effective in lung squamous cell carcinoma patients []. Erlotinib related response was more common in women with adenocarcinoma, never-smokers, or east-Asians, which is correlated with more frequent EGFR activating mutations [].

Standard Treatment Options for Recurrent NSCLC

  • Recurrent or relapsed NSCLC is a cancer that has progressed or returned following an initial treatment with surgery, radiation therapy, and/or chemotherapy. Cancer may return in the lung, brain, or other parts of the body. For NSCLC patients who have never been treated with chemotherapy, the treatment plan is similar to that of Stage IV NSCLC. For those patients who have already been treated with chemotherapy, standard treatment options may include
  • External palliative radiation therapy, which achieves palliation of symptoms from a localized tumor mass [], to relieve pain and other symptoms and improve the quality of life;
  • Cytotoxic chemotherapy [,,];
  • EGFR inhibitors (TKIs) in patients with or without EGFR mutations.;
  • EML4-ALK inhibitor (Crizotinib) in patients with EML-ALK translocations.[,];
  • Surgical resection of isolated cerebral metastases (for selected patients who have a very small amount of cancer that has spread to the brain) [];
  • Laser therapy or interstitial radiation therapy using an endoscope (for endobronchial lesions) [].
  • Stereotactic radiation surgery (for selected patients who cannot have surgery) [,].

Cytotoxic Chemotherapy for Recurrent NSCLC

  • Evidence from clinical studies showed that use of cytotoxic chemotherapy and targeted therapy may achieve objective responses, albeit with a small improvement in survival for patients with recurrent NSCLC []. In some trials, platinum based chemotherapy has also been shown to achieve palliation of symptoms, which occurred more often than the objective response in patients with good PS [,].
  • Treatment options for NSCLC patients whose cancer has recurred after platinum-based chemotherapy may include either new cytotoxic chemotherapy such as docetaxel [,] and pemetrexed [], or a targeted therapy such as erlotinib [], gefitinib [], and crizotinib for cancers with EML4-ALK translocations [,]. Patients with squamous lung carcinomas benefit more from docetaxel, whereas those with non-squamous NSCLC appeared to benefit more from pemetrexed [].

EGFR Inhibitors for Recurrent NSCLC

  • A large randomized phase III trial comparing gefitinib to placebo in recurrent NSCLC patients suggested that gefitinib might be a valid treatment for recurrent NSCLC patients with improved survival compared to placebo in never-smokers[], In two large randomized, placebo-controlled trials, erlotinib has also been shown to improve survival and quality of life in patients with recurrent NSCLC after first-line or second-line chemotherapy compared to placebo [,].
  • Moreover, erlotinib treatment also induced a greater improvement in patients’ symptoms, such as a cough, pain, and difficulty in breathing, compared to placebo []. Conversely, erlotinib did not improve survival when compared to standard second-line chemotherapy with docetaxel or pemetrexed [], in recurrent NSCLC patients after a first-line platinum combination therapy.

ALK/MET Inhibitors for Recurrent NSCLC

  • Crizotinib therapy has shown improvement in survival of patients with advanced, ALK-positive NSCLC compared to standard therapies for advanced NSCLC [] []. Similar to the kinase inhibitors already used in the clinic, such as imatinib and EGFR inhibitors, resistance to crizotinib frequently develops in patients’ tumors [].
  • These tumors might either acquire additional ALK kinase domain mutations (i.e., L1196M, C1156Y mutations) that alter drug sensitivity [], or other ALK alterations, including amplification, gain in copy number, and loss of ALK genomic rearrangement [].
  • Furthermore, signaling through other kinases, such as EGFR, might compensate for ALK inhibition, thereby mediating resistance to ALK inhibitors []. Mutation in the KRAS gene was also shown to play a role in resistance to crizotinib and around 8 % of ALK-positive NSCLC patients were shown to harbor either a KRAS or EGFR mutation in addition [].

Treatment of Metastatic Lung Cancer

  • Many phases 3 studies have shown the superiority of systemic chemotherapy over best supportive care in patients with locally advanced and metastatic lung cancer. Platinum-based chemotherapy has been widely accepted as the standard of care.
  • Several randomized clinical trials, as well as meta-analyses, have suggested the superiority of platinum-based over non–platinum-based therapy., Agents such as PTX, docetaxel, gemcitabine, and vinorelbine have been incorporated into platinum-based therapy doublets and have proven to be equally effective.

Chemotherapeutic Regimens

  • Because of the toxicities associated with platinum-based chemotherapy, non–platinum-based regimens, in particular, taxane-based regimens, have been the focus of intense research. A recent meta-analysis compared platinum-based with non–platinum-based chemotherapy in patients with advanced NSCLC.

Epidermal Growth Factor Receptor Inhibitors

  • In 40% to 80% of patients with NSCLC, EGFR is overexpressed, and its overexpression is associated with a poor prognosis. During the past few years, several EGFR inhibitors have been developed that are in either the receptor TK domain or are monoclonal antibodies.
  • Gefitinib is the first targeted therapy to be registered and later approved by the Food and Drug Administration (FDA) for use in lung cancer.Unfortunately, the results from two phase 3 randomized trials of gefitinib failed to show a survival benefit for gefitinib vs placebo. The Iressa Survival Evaluation in Lung Cancer trial was a randomized phase 3 study comparing daily therapy with 250 mg of gefitinib vs placebo.

Sequence Variations in EGFR and Response to EGFR-TK Inhibitors

  • The observation that certain subgroups of patients, particularly female patients, those who have never smoked, those who have adenocarcinoma histology, and those who are of Asian descent, have a higher response rate and clinical benefit with gefitinib and erlotinib therapy prompted research to elucidate the molecular mechanism responsible for this increased response. Three research groups have presented studies showing a positive relationship between the presence of activating mutations in the EGFR TK domain and clinical response to gefitinib.

Vascular Endothelial Growth Factor Inhibitors

  • Vascular endothelial growth factor (VEGF) binds to the VEGF receptors (VEGFRs) VEGFR1 (FLT1) and VEGFR2 (kinase insert domain-containing receptor) on vascular endothelial cells. Activation of VEGFR2 alone is necessary and sufficient to affect the VEGF-induced processes of mitogenesis, angiogenesis, and vascular permeability.
  • Previous attempts to combine chemotherapy and targeted therapy in lung cancer have been unsuccessful. In fact, several negative studies have compared standard chemotherapy doublet and targeted therapy (including agents such as EGFR inhibitors, antisense molecules, and immune modulators) to first-line regimens. Eastern Cooperative Oncology Group trial E4599

Stereotactic RT

  • Stereotactic RT techniques include fixation, ultraprecise treatment planning, RT directed to gross disease alone, and high doses per fraction. They are used to treat small lung tumors (T1-2, N0, M0). In a study of 257 patients, the local control rate was 92% and the 5-year survival rate was 81% for a biologically effective dose of 100 Gy or more. Pulmonary complications (grade, >2) occurred in 5.4% of patients.

Hadron Therapy

  • hadron is a subatomic particle (proton, neutron, or heavy ion) composed of quarks that are influenced by a strong nuclear force. Potential advantages of hadron RT compared with conventional RT (x-rays and electrons) include higher relative biologic effectiveness, higher linear energy transfer, lower oxygen-enhancement ratio, and excellent dose distribution. The major disadvantages of hadron therapy are its complexity and extremely high cost.

Treatment of Second Primary Tumor

  • A second primary cancer is a separate cancer arising in a patient who had another cancer in the past. Second or higher order primary tumors account for about 6 to 10% of all cancer diagnoses, and are the fifth most commonly diagnosed cancer in Western countries. The risk of developing a second primary cancer may increase with the use of cancer therapies, such as chemotherapy and radiation therapy.
  • However, it is crucially important to remember that this cancer therapy-related risk is minimal when compared to the benefits of treating the original primary cancer. Patients with lung cancer are at high risk of developing second primary lung cancers. However, it may be difficult to accurately determine whether the new tumor is a second primary cancer or metastasis from original cancer.
  • Studies have shown that in the majority of lung cancer patients the new lesion is a second primary tumor. When the original primary tumor has been surgically removed, surgical resection of second primary tumors may achieve a 5-year survival rate of 60%, with a comparable expected operative morbidity and mortality to the primary surgery. Tumors 2 cm or smaller are associated with significant positive long-term prognostic factors for survival and freedom from recurrence following resection of the second primary cancer []

Treatment of Brain Metastases

  • Brain metastases are a common problem in lung cancer patients and a significant cause of morbidity and mortality. Brain metastases are found in about 80% of SCLC and 30% NSCLC at two years from diagnosis [,]. Among the various histologies of NSCLC, the incidence of brain metastases in patients with adenocarcinoma and large cell carcinoma is greater than in patients with squamous cell carcinoma [,].
  • The median survival for untreated lung cancer patients with brain metastases is 4 to 7 weeks []. The treatment may be for the relief of symptoms or therapeutic strategies. Treatment options for lung cancer patients with brain metastases may include Whole Brain Radiotherapy (WBRT), surgical resection, Stereotactic Radiosurgery (SRS), Systemic therapy and Radiosensitization, or a combination of these various treatment modalities.

Whole Brain Radiotherapy (WBRT)

  • WBRT is the standard of care for cerebral metastasis in lung cancer patients. Several randomized trials have assessed numerous WBRT dose and fractionation schedules but showed no significant difference in either survival times, or symptomatic response rates and duration.
  • Nevertheless, the results of these trials have suggested better palliative effects from the more prolonged schedules and the choice of dose fractionation schedule should be based on patients’ prognosis [].
  • Additionally, a systematic imaging study of dose-response based on tumor size and histology, following WBRT (30 Gy in 10 fractions) [], showed an improved response rate for smaller tumors without necrosis. The complete response rate was 37% for SCLC, 25% for squamous cell carcinoma, and 14% for non-breast adenocarcinoma.

Surgery

  • In patients with multiple brain metastases, surgery is typically limited to the resection of the dominant, symptomatic lesion. Various studies have shown that surgery combined with adjuvant WBRT or stereotactic radiosurgery (SRS) has similar survival outcome in patients with multiple lesions compared with patients with single brain metastasis or a single lesion [].
  • About 50% of patients treated with resection and postoperative radiation therapy develop recurrence in the brain []. Few patients with recurrent brain metastasis and good PS, but without progressive metastases outside of the brain, may be treated with surgery or stereotactic radiation surgery [,]. However, most patients with recurrent brain metastasis may be treated with additional radiation therapy, albeit with a limited palliative benefit [].

Stereotactic Radiosurgery (SRS) with and without WBRT

  • Stereotactic radiosurgery (SRS) is a form of non-invasive radiation therapy that focuses on high-power energy on a precisely defined small target (e.g. the center of the tumor). The suggested mechanisms of SRS-induced tumor killing are radiation-induced DNA damage, endothelial cell apoptosis, microvascular dysfunction, and induction of T-cell response against the tumor [].
  • Because of the generally small size and well-defined margin of brain metastases at presentation [,], SRS may be an effective alternative to surgery for up to four small brain metastases (up to 4 cm in size) [].
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Systemic Therapy and Radiosensitization

  • In 30–70% of patients with single brain metastasis, lung cancer is the primary disease []. Generally, most chemotherapeutic agents are unable to cross the blood-brain barrier reach the CNS. However, the endothelium leakiness of the tumor vessels, which may disrupt the blood-brain barrier, is well documented in human cancer, particularly in case of macroscopic metastases or relapsed disease.
  • In keeping, several small phase II studies demonstrated that chemotherapy alone yields response rates of brain metastases of 43%–100% and 0%–38% for metastases from SCLC and NSCLC, respectively []. However, combining chemotherapies (thalidomide, teniposide, topotecan, paclitaxel, and cisplatin) to WBRT did not demonstrate survival benefit although some showed enhanced response rates [].
  • Radiosensitizing agents, such as motexafin gadolinium (Xcytrin) and efaproxyn (efaproxiral or RSR-13), may increase oxygen levels in the tumor and therefore enhance its sensitivity to radiation therapy.

Role of Angiogenesis Inhibitors in NSCLC

  • Angiogenic pathways provide an important target in NSCLC treatment since they foster tumor growth through the development of new blood vessels. The complex process of angiogenesis is regulated by pro-angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), as well as angiopoietins [].
  • Currently, only the monoclonal antibody bevacizumab, targeting circulating VEGF, is approved for first-line treatment of advanced NSCLC in combination with platinum-based chemotherapy []. Several anti-angiogenic agents are under clinical investigation, including sorafenib and sunitinib.

Other Molecular Targeted Agents, under Clinical Evaluation for NSCLC Treatment

Talactoferrin

  • The glycoprotein lactoferrin was first described as an iron-binding protein in breast milk and shows immune-modulatory functions [,]. The human recombinant lactoferrin, talactoferrin, is given orally, and is able to recruit immature dendritic cells (DC) into the gut-associated lymphoid tissue, where cross-presentation of tumor antigens and subsequent DC maturation can occur [].
  • Preclinical data also showed an increase in splenic NK cell activity and inhibition of NSCLC tumor growth with lactoferrin []. A double-blind, placebo-controlled phase II study using lactoferrin as monotherapy showed improved OS (median 6.1 vs, 3.7 months after a follow-up of 15.2 months).
  • When combining with chemotherapy (carboplatin and paclitaxel) in treating advanced stage IIIB/IV NSCLC patients, lactoferrin also showed a promising trend for disease-control rates in the intention-to-treat and evaluable population [].

Insulin-like Growth Factor Inhibitors

  • The insulin-like growth factor system (IGF system) comprises two receptors: Insulin-like growth factor 1 receptor (IGF-IR) and IGF-IIR with their respective ligands: Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) and six high-affinity IGF binding proteins (IGFBP) that function as carrier proteins for these ligands. IGF 1 and 2 are involved in the regulation of the development and growth of somatic tissues, as well as carbohydrate metabolism [,].
  • The IGF signaling pathway promotes cell growth by stimulating cell proliferation and differentiation. Additionally, IGF-IR, but not IGF-IIR, signaling inhibits apoptosis []. These ligands bind to the extracellular domain of the IGF receptor 1 (IGF-1R), which is expressed on many normal human cells [,], and overexpressed in many cancers, including lung cancer. Furthermore, increased IGF-1 levels, and decreased IGFBP-3/4 level correlate with a higher risk of lung cancer [,].

Histone Deacetylase Inhibitors

  • Histones are nuclear structural enzymes and, as part of the chromatin, are involved in nucleosomal DNA organization and gene regulation. Conformational changes in DNA structure are regulated by histone acetylation and deacetylation, a mechanism that is often affected in tumor cells [].
  • Histone deacetylases (HDACs) are involved in chromatin condensation and repression of gene expression and are frequently overexpressed in many cancers []. Contrary to genetic mutations, the epigenetic modifications induced by HDACs are reversible, and therefore, HDACs are an attractive target for cancer therapy [].
  • Various HDAC inhibitors have been developed and shown to modulate the acetylation status of several important cellular proteins involved in tumor cell growth and proliferation, including p53, HSP90, STAT3, subunits of NFκ-B and α-tubulin [,,].

Pro-Apoptotic Agents

  • Apoptosis has long been known as a hallmark of cancer, and cancer cells exploit both upregulations of antiapoptotic as well as downregulation of pro-apoptotic mechanisms [,]. Novel pro-apoptotic drugs are currently being investigated for the treatment of NSCLC. To date, both Mapatumumab, a high-affinity monoclonal antibody against the death receptor DR4/TRAIL-R1, and a pro-apoptotic agent apomab did not show clinical benefit as monotherapy or in combining with chemotherapies (carboplatin and paclitaxel) in clinical trials [,] [] [,].
  • A number of other new pro-apoptotic agents, such as Conatumumab (targeting DR1) and YM155 (targeting survivin), are currently under clinical investigation for the treatment of NSCLC and have shown synergistic effects in combination with chemotherapy [,,].

Immunotherapy

Immune Checkpoint Inhibitors

CTLA4

  • Tumors ascribe certain immune-checkpoint pathways as a chief mechanism of immune resistance, particularly against T cells that are specific for tumor antigens. Several of these immune checkpoints are initiated by ligand-receptor interactions, and thus are amenable to inhibition by antibodies or modulated by recombinant forms of ligands or receptors []. Two monoclonal antibodies, ipilimumab and tremelimumab, have been used successfully in NSCLC against the cytotoxic T-lymphocyte-associated antigen (CTLA-4), an inhibitory T-cell co-receptor found on activated T-cells and regulatory T-cell subsets [,].
  • A multicenter double-blind phase II trial showed that the combination of ipilimumab and chemotherapy (carboplatin or paclitaxel) significantly improved the immune-related PFS in advanced stage IIB/IV NSCLC patients with squamous cell carcinoma (without prior chemotherapy) [,]. Tremelimumab has also been tested in a randomized, phase II trial as maintenance after first-line chemotherapy, compared to best supportive care. However, the results of this trial showed no improvement in PFS [].

PD-1 and PD-L1

  • The immune-checkpoint receptor, programmed death-1 (PD-1), is a promising target, for stimulation of antitumor immune responses by the patient’s own immune system. Unlike CTLA4, the main role of PD-1 is to control the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity []. This translates into a major immune resistance mechanism within the tumor microenvironment [].
  • Another interesting immunotherapeutic option is the direct targeting of PD-1 ligands (PD-L1), B7-H1/PD-L1 and B7-DC/PD-L2. It has been shown that B7-H1/PD-L1 is selectively upregulated in many human cancers including lung cancer [,]. An encouraging phase I study showed the clinical activity of PD-L1 blocking agents in NSCLC [,].
  • A dose-escalation study testing a monoclonal antibody against PD-1 (MDX-1106) in the treatment of refractory metastatic solid tumors (melanoma, renal cell cancer, colon cancer, NSCLC), showed objective responses in five of 49 NSCLC patients [].

 Vaccine Therapy for NSCLC

  • Vaccination against pathogens is one of the most important developments in modern medicine and saves millions of lives each year. For advanced NSCLC patients, median OS is about one year, and only 3.5 % survive five years after diagnosis, despite the addition of new therapies to standard chemotherapy [].
  • Therefore, vaccinations for solid tumors, either preventive (for tumors related to infections such as human papillomavirus-associated cervical cancer []) or therapeutic (breaking tolerance and achieving llong-lastingresponse in tumors such as ipilimumab (anti-CTLA-4) in advanced melanomas [,]), have long been seen as the ultimate treatment option for cancer patients.

Types of vaccine Therapy for NSCLC.

BEC2/BCG glycosphingolipid GD3
vaccine
Combines a monoclonal antibody
that mimics the glycosphingolipid
GD3 with the adjuvant bacillus
Calmette-Guerin
Belagenpumatucel-L Allogeneic vaccine Four irradiated lung cancer cell lines and an antisense plasmid against TGF-beta
CimaVax EGF EGF vaccine Cyclophosphamide and EGF
CRS-207 Mesothelin vaccine Genetically-engineered Listeria monocytogenes
INGN-225 p53 vaccine Produced from patients’ autologous peripheral blood mononuclear cells (PBMCs)
L-BLP25/emepepimut-S MUC-1 vaccine Synthetic peptide derived from the mucin 1
MAGE-A3 Melanoma-associated antigen A3 vaccine Tumor-specific antigen Mage-A3
PRAME PRAME vaccine Recombinant PRAME protein combined with the AS15 Adjuvant System
TG4010 MVA-MUC1-IL2 vaccine Modified vaccinia Ankara encoding human MUC-1 antigen and interleukin-2

A. MUC1

  • Mucin-1 (MUC1) is a glycoprotein present on normal epithelial tissue and in various cancers, including NSCLC [,]. A mutated MUC1protein overexpressed in cancer cells shows aberrant glycosylation pattern that is antigenically different from wild-type protein expressed on normal epithelial cells []. L-BLP25 is a synthetic vaccine against the core peptide of MUC1 combining the peptide with cyclophosphamide as an adjuvant [,]. Recently updated data from a phase IIB randomized study treating stage IIIB/IV NSCLC patients with L-BLP25 showed significant improvement in the vaccine group comparing to the supportive group (3-year survival rates: 31 vs. 17 % [])

B. EGF

  • CimaVax EGF is a new vaccine that is being developed for NSCLC treatment. This vaccine is made up of low dose cyclophosphamide and EGF. It works as an immunoadjuvant to reduce the inhibition of T-suppressor cells and to stimulate the production of anti-EGF antibodies that may inhibit EGF binding EGFR on cancer cells, and consequently decrease cancer cells growth [,,,].
  • A phase I study showed that the production of anti-EGF antibodies and serum EGF levels after use of the EGF-based vaccine, correlate with increased survival rates in NSCLC patients [].

C. Melanoma-associated antigen (MAGE)

  • Melanoma-associated antigen A3 vaccine (MAGE-A3) uses a tumor-specific antigen, which is expressed in 35 % of NSCLC, most frequently in squamous cell carcinomas []. It ranges from 16 % in stage IA to 48 % in stage IIIB and may be associated with poor prognosis [,,]. The MAGE-A3 vaccine, initially developed for metastatic melanoma patients, showed a positive sign of activity after 28 months in a phase II adjuvant therapy study in early-stage NSCLC []. Prior to treatment, the NSCLC tumors were analyzed by gene expression profiling to identify a gene signature that correlates with the clinical activity of the vaccine [].D. TGF beta

E. PRAME

  • Another important tumor antigen for vaccine therapy is PRAME (preferentially expressed antigen of melanoma), which has recently been shown to contribute to carcinogenesis in NSCLC []. As the name suggests, it was first detected in a melanoma patient [], and is expressed in a variety of tumors [].
  • PRAME seems to function via the suppression of the retinoic acid receptor (RAR), a signaling pathway which regulates cell death and cell cycle [,].
  • Overexpression of PRAME might be used by tumor cells to escape suppressive RAR signaling, thereby fostering tumor-progression []. Clinical data suggests that poor clinical outcome of some patient subpopulations correlates with PRAME expression in neuroblastoma [] and breast cancer [].

Targeted Therapies in SCLC

VEGF inhibitors

  • Inhibition of circulating VEGF with bevacizumab has been studied in ES-SCLC. Chemotherapy naïve patients treated with cisplatin, irinotecan, and bevacizumab, showed an ORR of 75 %, a median OS of 11.6 months, and a median PFS of 7.0 months []. A study investigating cisplatin, etoposide, and bevacizumab in previously untreated ES-SCLC patients showed that a higher baseline level of vascular cell adhesion molecule (VCAM) was associated with a higher risk of progression or death, compared to lower levels of VCAM, but no other biomarkers could be correlated with treatment outcome [].

EGFR inhibitors

  • Mutation of the EGFR is less frequent in SCLC compared to NSCLC, and only around 4% of patients were shown to harbor the mutation []. In a phase II study, patients were stratified according to chemosensitive or chemo-refractory relapsed SCLC and treated with gefitinib. However, the abovementioned study could not demonstrate a gefitinib benefit for SCLC patients [].

Bendamustine

  • This cytotoxic agent causes DNA breaks through its alkylating activity. Compared with other alkylating agents, bendamustine causes more extensive and durable DNA single- and double-strand breaks []. Combining bendamustine with carboplatin in treating ES-SCLC [], the ORR was 72.7 %, with a median TTP of 5.2 months and median survival time of 8.3 months. As a single agent in second- and third-line setting in patients with relapsed/refractory SCLC, Bendamustine is well tolerated and effective agent [].

Immunotherapy

  • To date, only a few studies have evaluated immunotherapy in the treatment of SCLC []. The BEC2/BCG vaccine combines a monoclonal antibody that mimics the glycosphingolipid GD3, which is selectively expressed in SCLC, with the adjuvant bacillus Calmette-Guerin [].
  • The BEC2/BCG vaccine has been demonstrated to develop antibodies against GD3 in Melanoma patients. In an early clinical study, although only 30% of the SCLC patients (5/15, ES/LS-SCLC=8/7) developed measurable anti-GD3 antibodies, the median OS was 20.5 months (relapse-free survival was longer in patients who developed measurable anti-GD3 antibodies) ,,].

Palliative Care for Patients with Lung Cancer

  • A high percentage of lung cancer patients suffers from substantial symptom burden, including fatigue, loss of appetite and weight loss, as well as dyspnea, hemoptysis, and chest pain []. Better quality of life, lower depressive symptoms, higher median survival and fewer needs on aggressive end-of-life care were observed in patients receiving early palliative care combined with standard oncologic care compared to standard oncologic alone for metastatic NSCLC.[]. Megestrol acetate (MA), an appetite stimulant, is one of the supporting treatments that have shown success in treating cancer-related anorexia (CRA) and improve quality of life.

Mesothelin

  • Mesothelin is an immunogenic glycoprotein specifically overexpressed in malignant mesothelioma, NSCLC, ovarian, and pancreatic cancers []. CRS-207 is a genetically-engineered, double-deleted bacteria Listeria monocytogenes strain expressing the human mesothelin []. Phagocytic cells, such as macrophages and dendritic cells, take up CRS-207, and mesothelin is subsequently expressed and processed through the MHC I presentation pathway.
  • This process is predicted to activate T cells in order to attack mesothelin-positive mesothelioma cells. In preclinical studies, CRS-207 was shown to elicit anti-mesothelin cell-mediated immunity []. In a phase I dose-escalation study treating patients with advanced mesothelin expression and treatment-refractory cancers, with CRS-207, mesothelin-specific T-cell responses were in one of five patients with mesothelioma, with 15 months or more survival after the first dose []. Patients who received sequential CRS-207 treatment with prior immunotherapy or subsequent local radiation therapy benefited the most. CRS-207 is currently investigated in combination with first-line chemotherapy in mesothelioma patients.

WT1 analog peptide vaccine

  • The transcription factor Wilms’ tumor suppressor gene 1 (WT1) is frequently overexpressed in mesothelioma and other solid and hematopoietic tumors []. Recently, a multivalent WT1 peptide analog vaccine was developed []. A CD-4+ T-cell proliferation to WT1-specific peptides was seen in six of nine patients, and a CD8+ T-cell response was detected in six of six HLA-A0201 patients in an early study investigating the WT1 peptide analog vaccine in MM and NSCLC patients. Stimulated T-cells also showed cytotoxicity against WT1 positive cells []. A subsequent randomized phase II study is currently investigating the adjuvant WT1 analog peptide vaccine in MM patients who have completed combined modality therapy [].

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6 thoughts on “Lung Cancer; Causes, Symptoms, Diagnosis, Treatment”

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