Lungs' cancer

Lung cancer is a malignant lung tumor, usually classified as small cell or non-small cell cancer. Smoking cigarettes is a major risk factor for most tumor variants. Symptoms include coughing, chest discomfort and, less often, hemoptysis, but many patients are asymptomatic, and some develop metastatic lesions. Diagnosis is suspected in chest x-rays or computed tomography and is confirmed by biopsy. Treatment is carried out using surgical, chemotherapeutic and radiotherapy methods. Despite the successes in therapy, the prognosis is unsatisfactory, and attention should be focused on early detection and prevention of the disease.

[1], [2], [3],

Epidemiology

In the United States, approximately 171,900 new cases of malignant neoplasms of the respiratory organs are diagnosed each year and 157,200 deaths are recorded. The incidence increases in women and is likely to stabilize in men. Black men are in a particularly high risk group.

[4], [5], [6], [7], [8]

Causes of the lung cancer

Smoking cigarettes, including passive smoking, is the most important cause of lung cancer. The risk depends on the age and intensity of smoking, as well as on its duration; The risk is reduced after quitting, but probably never returns to the original. For non-smokers, the most important environmental risk factor is exposure to radon, a product of the destruction of natural radium and uranium. Professional hazards associated with exposure to radon (from miners of uranium mines); asbestos (for builders and workers, destroying buildings, plumbers, plumbers, shipbuilders and auto mechanics); quartz (miners and sandblasters); arsenic (for workers associated with the melting of copper, the production of pesticides and plant protection products); chromium derivatives (at stainless steel plants and pigment manufacturing plants); nickel (in factories, producing batteries and factories for the production of stainless steel); chloromethyl ethers; beryllium and emissions of coke ovens (for workers in the steel industry), lead to the development of a small number of cases annually. The risk of malignant neoplasms of the respiratory organs is higher when two factors are combined - occupational hazards and smoking of cigarettes, than in the presence of only one of them. COPD and pulmonary fibrosis may increase the risk of developing the disease; preparations containing beta-carotene may increase the risk of developing the disease in smokers. Contaminated air and cigar smoke contain carcinogenic substances, but their role in the development of lung cancer has not been proven.

[9], [10]

Symptoms of the lung cancer

Approximately 25% of all cases of disease occur asymptomatically and are found by chance in the study of the chest. Symptoms of lung cancer are made up of local manifestations of the tumor, regional spread and metastases. Paraneoplastic syndromes and common manifestations can occur at any stage.

Local symptoms include cough and, more rarely, shortness of breath due to airway obstruction, postobture atelectasis and lymphogenous spread. Fever can occur with the development of postobture pneumonia. Up to half of patients complain of vague or limited chest pain. Hemoptysis is less common, the loss of blood is minimal, except in rare cases when the neoplasm destroys a large artery, causing massive bleeding and death due to asphyxia.

Regional spread can cause pleural pain or dyspnea due to pleural effusion, dysphonia due to tumor germination into the recurrent laryngeal nerve, dyspnoea and hypoxia due to diaphragm paralysis with involvement of the diaphragmatic nerve.

Compression or invasion of the upper vena cava (upper vena cava syndrome) can lead to headache or a feeling of overflow in the head, swelling of the face or upper limbs, dyspnea and redness (plethora) in the back position. Manifestations of the syndrome of the superior vena cava - edema of the face and upper limbs, swelling of the cervical and subcutaneous veins of the face and upper half of the trunk and hyperemia of the face and trunk. Syndrome of the inferior vena cava is more common in patients with a small-celled species.

Apical neoplasms, usually non-small-celled, can sprout into the brachial plexus, pleura, or ribs, causing pain in the shoulder and upper limb and weakness or atrophy of one arm (Pancoast tumor). Horner's syndrome (ptosis, miosis, anophthalmus and anhidrosis) develops when a paravertebral sympathetic chain or cervical stellate ganglion is involved in the process. Spreading the neoplasm onto the pericardium can be asymptomatic or lead to constrictive pericarditis or cardiac tamponade. Rarely compression of the esophagus leads to dysphagia.

Metastases always, in the final analysis, cause manifestations associated with their localization. Metastases in the liver cause gastrointestinal symptoms and, ultimately, hepatic insufficiency. Metastases in the brain lead to behavioral disorders, amnesia, aphasia, convulsions, paresis or paralysis, nausea and vomiting, and, ultimately, coma and death. Bony metastases cause intense pain and pathological fractures. Malignant neoplasms of the respiratory organs often metastasizes to the adrenal glands, but rarely leads to adrenal insufficiency.

Paraneoplastic syndromes are not caused by cancer directly. Frequent paraneoplastic syndromes in patients are hypercalcaemia (caused by the production of a tumor of the protein associated with the parathyroid hormone), the syndrome of inadequate secretion of antidiuretic hormone (SIADH), thickening of the terminal phalanges of fingers with hypertrophic osteoarthropathy or without, hypercoagulation with migrating surface thrombophlebitis (Tissot syndrome), myasthenia gravis (Eaton-Lambert syndrome) and a variety of neurological syndromes, including neuropathies, encephalopathies, encephalitis, myelopathies, and cerebellar lesions . The mechanism of development of neuromuscular syndromes involves the expression of a tumor of autoantigens with the formation of autoantibodies, but the cause of most others is unknown.

Common symptoms usually include weight loss, malaise, and sometimes are the first manifestations of a malignant neoplasm.

Stages

Primary tumor
Tis	Carcinoma in situ
T1	A tumor <3 cm without infestation, is located proximal to the lobar bronchus (that is, not in the main bronchus)
T2	A tumor with any of the following features:> 3cm involves the main bronchus at> 2 cm distal to the carina Sprouts into the visceral pleura of Athelectasis or post-obstructive pneumonia that extends to the root, but does not involve all lung
TK	Tumor of any size with any of the following features: Sprouts into the chest wall (including lesions of the superior groove), diaphragm, pleura of the mediastinum or parietal pericardium. The main bronchus is <2 cm distal from the carina, but without involvement of the carne Atelektas or postobture pneumonia of the entire lung
T4	Tumor of any size with any of the following features: Sprouts into the mediastinum, heart, large vessels, trachea, esophagus, vertebral body, carina Malignant pleural or pericardial effusion Satellite nodules of the neoplasm within the same lobe as the primary tumor
Regional lymph nodes (N)
N0	There are no metastases in the regional lymph nodes
N1	Unilateral metastases to the peribronchial lymph nodes and / or lymph nodes of the lung root and intrapulmonary lymph nodes in the path of direct spread of the primary neoplasm
N2	One-sided metastases to the lymph nodes of the mediastinum and / or subcarynal lymph nodes
N3	Metastases in the contralateral nodes of the mediastinum, contralateral nodes of the root, in the staircase of the corresponding side or the contralateral or supraclavicular lymph nodes
Remote metastases (M)
M0	No distant metastases
M1	Remote metastases are present (including metastatic nodes in shares of the relevant side, but different from the primary tumor)

Stage 0 Tis IA T1 N0 M0 IB T2 N0 M0 IIA T1 N1 M0

Stage IIB T2N1 M0 or T3 N0 M0 IIIA T3 N1 M0 or TI-3 N2 M0 IIIB Any T N M0 or T4 of any N M0 IV of any T of any N M1

[11], [12], [13]

Forms

Malignant

• Carcinoma
  • Small cell
  • Ovsyannokletochnaya
  • Transitional cell
  • Mixed
  • Non-small cell
• Adenocarcinoma
  • Acinar
  • Bronchioloalveolar
  • Papillary
  • Solid
  • Adenovascular
  • Large cell
  • Clear cell
  • Giant cell
  • Squamous cell
  • Spindle-bearing
• Carcinoma of the bronchial glands
  • Adenoid cystic
  • Mucoepidermoid
• Carcinoid
• Lymphoma
  • Primary pulmonary Hodgkin's
  • Primary pulmonary non-Hodgkin's disease

Benign

• Laringotraheobronchial
  • Adenoma
  • Hamartoma
  • Myoblastoma
  • Papilloma
• Parenchymal
  • Fibroma
  • Hamartoma
  • Leiomyoma
  • Lipoma
  • Neurofibroma / Schwannoma
  • Sclerosing hemangioma

For malignant transformation of respiratory epithelial cells, prolonged contact with carcinogenic substances and the accumulation of multiple genetic mutations are necessary. Mutations of genes that stimulate cell growth (K-RAS, ICC), encode growth factor receptors (EGFR, HER2 / neu) and inhibit apoptosis (BCL-2), contribute to the proliferation of pathological cells. The same effect has mutations that inhibit tumor suppressor genes (p53, APC). When there is a sufficient accumulation of these mutations, malignant neoplasm of respiratory organs develops.

Lung cancer is usually subdivided into small cell (MCL) and non-small cell (NSCLC). Small cell is a very aggressive neoplasm, almost always found in smokers and causes widespread metastasis in 60% of patients at the time of diagnosis. Symptoms of non-small cell type are more variable and depend on the histological type.

[14], [15], [16]

Complications and consequences

For the treatment of malignant pleural effusion, first the pleurocentesis is performed. Asymptomatic effusions do not require therapy; symptomatic effusions, which recur despite multiple thoracocentes, are drained through the pleural drainage tube. The introduction of talc (or sometimes, tetracycline or bleomycin) into the pleural cavity (a procedure called pleurodesis) leads to sclerotherapy of the pleura, removes the pleural cavity and is effective in more than 90% of cases.

Therapy of the syndrome of the superior vena cava is similar to the treatment of lung cancer: chemotherapy, radiation therapy, or both. Glucocorticoids are commonly used, but their effectiveness is not proven. Apical tumors are treated with surgical methods with preoperative radiotherapy or without or radiotherapy with adjuvant chemotherapy or without. Therapy of paraneoplastic syndromes depends on the specific situation.

[17], [18], [19], [20]

Diagnostics of the lung cancer

The first study is chest x-ray. It allows to clearly identify certain pathological formations, for example, single or multiple infiltrates or an isolated node in the lung, or more subtle changes, for example a thickened interlobar pleura, dilatation of the mediastinum, tracheobronchial constriction, atelectasis, intractable parenchymal infiltrate, cavitary lesions or unexplained pleural overlap or effusion. These findings are suspicious but not diagnostic for lung cancer and require additional examination using high resolution CT (CT) and cytologic confirmation.

When performing CT, you can identify many characteristic structures and changes that allow you to confirm the diagnosis. Under CT control, a puncture biopsy of the available lesions can also be performed, and it also has a role in determining the stage.

The methods of cellular or tissue diagnostics depend on the availability of tissue and the location of lesions. Sputum or pleural fluid analysis is the least invasive method. In patients with productive cough, sputum samples obtained after awakening can contain high concentrations of malignant cells, but the effectiveness of this method does not exceed 50%. Pleural fluid is another convenient source of cells, but effusions do not occur in more than a third of all cases of the disease; However, the presence of malignant effusion indicates the presence of neoplasm, at least at stage IIIB and is a poor prognostic sign. In general, false negative results of cytological studies can be minimized by obtaining the largest possible amount of sputum or liquid at the beginning of the day and by immediately transporting samples in the laboratory in order to reduce the delay in processing the material that leads to cell disintegration. Percutaneous biopsy is the next of less invasive procedures. It is more important in the diagnosis of metastatic sites (supraclavicular or other peripheral lymph nodes, pleura, liver and adrenal glands) than for lung lesions due to a 20-25% risk of developing pneumothorax and the risk of false negative results that probably will not change the accepted tactics treatment.

Bronchoscopy is the procedure most commonly used for diagnosis. Theoretically, the method of choice for obtaining tissue is one that is least invasive. In practice, bronchoscopy is often performed in addition or in place of less invasive procedures, since diagnostic capabilities are higher and because bronchoscopy is important for determining the stage. The combination of the study of washing water, brush biopsy and fine needle biopsy of visible endobronchial lesions and paratracheal, subcarynal, mediastinal and lymph nodes of the lung root allows the diagnosis to be established in 90-100% of cases.

Mediastinoscopy is a procedure of higher risk, usually used before surgery to confirm or exclude the presence of a tumor in enlarged mediastinal lymph nodes of an indeterminate species.

An open lung biopsy performed with open thoracotomy or video endoscopy is prescribed when less invasive methods do not allow diagnosis in patients whose clinical characteristics and radiographic data strongly suggest the presence of an operable neoplasm.

[21], [22], [23], [24], [25], [26]

Determination of staging

Small cell lung cancer is classified as a limited or common stage of the disease. A limited stage is a tumor bounded by one half of the chest (including unilateral involvement of the lymph nodes), which can be covered by one valid site of radiotherapy, excluding the presence of pleural effusion or effusion in the pericardial cavity. The started stage of the disease is a tumor in both halves of the chest and the presence of malignant pleural or pericardial effusion. About a third of patients with small cell lung cancer have a limited lesion; the rest often have extensive distant metastases.
 
The definition of the stage of non-small cell lung cancer involves determining the size, location of the neoplasm and lymph nodes and the presence or absence of distant metastases.

CT scan of thin sections from the neck to the upper abdominal cavity (for the detection of cervical, supraclavicular, hepatic and adrenal metastases) is a study of the first step for both small cell and non-small cell lung cancer. However, CT often can not distinguish between post-inflammatory and malignant intrathoracic enlarged lymph node, or benign and malignant lesions of the liver or adrenal glands (differences that determine the phase of the disease). Thus, other studies are usually performed if CT results reveal changes in these areas.

Positron Emission Tomography (PET) is an accurate, atraumatic method used to identify malignant lymph nodes in the mediastinum and other distant metastases (metabolic definition). Integrated PET-CT, in which PET and CT are combined into a single image by combined scanners, is more accurate for determining the non-small-cell disease phase than CT or PET or the visual correlation of the two studies. The use of PET and CT-PET is limited by cost and availability. When PET is not available, bronchoscopy and, more rarely, mediastinoscopy or videotoracoscopy can be used to perform a biopsy of dubious mediastinal lymph nodes. Without performing PET, suspicious lesions in the liver or adrenal glands should be evaluated by puncture biopsy.

MRI of the chest is a little more accurate than high-resolution CT scan when examining the upper chest in the diagnosis of apical tumors or neoplasms located close to the diaphragm.

Patients with headache or neurological disorders should undergo CT or NMR of the head and diagnose the syndrome of the superior vena cava. Patients with bone pain or increased serum calcium or alkaline phosphatase should undergo radioisotope scanning of the bones. These studies are not shown in the absence of suspicious symptoms, signs or violations of laboratory tests. Other blood tests, such as a clinical blood test, serum albumin, creatinine, do not play a role in determining the phase, but provide important predictive information about the patient's ability to undergo treatment.

[27], [28], [29]

Treatment of the lung cancer

Treatment of lung cancer usually involves assessing the appropriateness of performing a surgical procedure followed by surgery, chemotherapy and / or radiation therapy, depending on the type of tumor and phase. Many unrelated factors can affect the possibility of surgical treatment. Weak cardiopulmonary reserve; exhaustion; weakened physical condition; Concomitant pathology, including cytopenia, as well as mental or cognitive disorders, can lead to the selection of palliative rather than intensive treatment strategies, or the abandonment of treatment in general, even if the cure could be technically possible.

Surgical intervention is performed only in those cases when the patient has sufficient pulmonary reserve after resection of the lobe or whole lung. Patients who before the operation have a forced expiratory volume in 1 second (FEV1) of more than 2 liters, usually suffer a pulmonectomy. Patients with a FEV1 of less than 2 liters should be quantified radionuclide perfusion scintigraphy to determine the amount of loss of function that a patient can expect as a result of resection. Postoperative FEV1 can be predicted by multiplying the percentage of perfusion of unresected lung with preoperative FEV. The predicted FEV1> 800 ml or> 40% of normal FEV1 suggests adequate postoperative lung function, although studies of surgical lung volume reduction in COPD patients suggest that patients with FEV1 <800 ml can resect if the neoplasm is located in poorly functioning bullous (more often apical ) areas of the lung. Patients who undergo resection in hospitals where they operate more often have fewer complications and are more likely to survive, compared to patients operated in hospitals with little experience of operations.

Numerous regimens of chemotherapy have been developed for therapy ; no regime has proved its advantages. Therefore, the choice of treatment often depends on local experience, contraindications and toxicity of drugs. The choice of the drug for relapse after treatment is dependent on localization and includes repeated chemotherapy of local relapse, radiotherapy of metastases and brachytherapy with an endobronchial form of the disease, when additional external irradiation is impossible.

Radiation therapy has the risk of developing radiation pneumonitis, when large areas of the lung are exposed to large doses of radiation for a long time. Radiation pneumonitis can occur within 3 months after a complex of therapeutic measures. Cough, shortness of breath, low temperature or pleural pain can signal the development of this condition, like wheezing or pleural friction noise. The results of chest X-ray may be uncertain; A CT can show an indefinite infiltration without a discrete mass. The diagnosis is often established by the method of elimination. Radiation pneumonitis is treated with prednisolone 60 mg for 2-4 weeks, followed by a gradual decrease in dose.

Since many patients die, care must be taken in a pre-state. Symptoms of dyspnea, pain, anxiety, nausea and anorexia are most common and can be treated parenterally with morphine; oral, transdermal or parenteral opioids and antiemetics.

Treatment of small cell lung cancer

Small cell lung cancer of any stage is usually initially sensitive to therapy, but this persists for a short time. Surgery usually plays no role in the treatment of small cell type, although it can be a therapy method in rare patients who have a small central tumor without spreading (such as an isolated single nodule in the lung).

In the phase of a limited disease, four courses of combined therapy with etoposide and platinum (cisplatin or carboplatin) are probably the most effective scheme, although combinations with other drugs, including vinca alkaloids (vinblastine, vincristine, vinorelbine), alkylating drugs (cyclophosphamide, isophosphamide), doxorubicin , taxanes (docetaxel, paclitaxel) and gemcitabine are also used frequently. Radiation therapy further improves the response; the very definition of a limited disease as a process confined to half of the chest is based on a significant increase in survival observed with the use of radiation therapy. Some experts offer skull irradiation to prevent metastases in the brain; micrometastases are often found in small cell lung cancer, and chemotherapeutic drugs do not pass through the blood-brain barrier.

With a common disease, the treatment is the same as at a limited stage, but without parallel radiation therapy. Replacement of etoposide with topoisomerase inhibitors (irinotecan or topotecan) can improve survival. These drugs in monotherapy or in combination with other drugs are also commonly used in a resistant disease and malignant neoplasms of respiratory organs of any phase in the event of a relapse. Irradiation is often used as a palliative method for the therapy of metastases in the bone or brain.

In general, small cell lung cancer suggests a poor prognosis, although patients who have good functional status should be invited to participate in a clinical study.

Treatment of non-small cell lung cancer

Treatment of non-small cell lung cancer depends on the stage. For stage I and II, the standard is surgical resection with lobectomy or pulmonectomy, in combination with a selective or total removal of mediastinal lymph nodes. Resection of a smaller volume, including segmentectomy and wedge resection, is considered for patients with a weak pulmonary reserve. The surgical method allows to cure approximately 55-75% of patients with stage I and 35-55% of patients with stage II. Adjuvant chemotherapy is probably effective in the early phases of the disease (Ib and II). An increase in the overall five-year survival (69% versus 54%) and progression-free survival (61% compared to 49%) is observed with cisplatin plus vinorelbine. Because the improvement is small, the decision to conduct adjuvant chemotherapy should be made on an individual basis. The role of neoadjuvant chemotherapy in the early stages is in the phase of the study.

Stage III of the disease is one or more locally advanced tumors involving regional lymph nodes, but without distant metastases. In the IIIA tumor stage with latent metastases to the mediastinal lymph nodes that are found during surgery, resection provides a five-year survival of 20-25%. Radiotherapy with or without chemotherapy is considered the standard for an inoperable disease in stage IIIA, but survival is low (median survival 10-14 months). Recent studies have shown somewhat better results with preoperative chemotherapy plus radiotherapy and chemotherapy after surgery. This remains the area of further research.

Stages IIIB with contralateral involvement of mediastinal lymph nodes, lymph nodes of the supraclavicular area or malignant pleural effusion require the use of radiotherapy, or chemotherapy, or both methods. The addition of radiosensitizing chemotherapeutic drugs such as cisplatin, paclitaxel, vincristine and cyclophosphamide somewhat improves survival. Patients with locally advanced tumors that grow in the heart, large vessels, mediastinum, or vertebral column usually receive radiation therapy. In rare cases (T4N0M0), surgical resection with neoadjuvant or adjuvant chemoradiotherapy may be performed. The 5-year survival rate for patients receiving treatment in stage IIIB is 5%.

The goal of therapy in stage IV is to reduce the symptoms of lung cancer. Chemotherapy and radiotherapy can be used to reduce neoplasm, treat symptoms and improve quality of life. However, the median survival rate does not exceed 9 months; less than 25% of patients live 1 year. Surgical palliative procedures include pleurocentesis and pleurodesis with repeated effusions, placement of drainage pleural catheters, bronchoscopic destruction of the tumor tissue affecting the trachea and major bronchi, placement of stents to prevent occlusion of the airways and, in some cases, spinal stabilization with threatening compression of the spinal cord.

Some new biological drugs have a targeted effect on the tumor. In patients who did not respond to therapy with platinum and docetaxel, gefitinib, an inhibitory tyrosine kinase receptor of epidermal growth factor (EGFR), can be used. Other biological preparations on the study phase include other EGFR inhibitors, antisense oligonucleotides to EGFR mRNA (RNA mediators), and farnesyltransferase inhibitors.

It is important to distinguish between non-small cell relapse, an independent second primary tumor, locally recurring non-small cell lung cancer, and distant metastases. Treatment of an independent second primary tumor and recurrence of non-small cell disease is performed in accordance with the same principles that apply to primary neoplasms in stages I-III. If surgery was originally used, the main method is radiation therapy. If relapse manifests as distant metastases, patients are treated as in stage IV with an emphasis on palliative procedures.

In a complex of medical measures, it is very important to follow a diet for lung cancer.

Prevention

Prevent lung cancer only if smoking is stopped. The effectiveness of any of the active interventions is not proven. Reducing high levels of radon in residential areas removes radiation that causes cancer, but the decline in lung cancer incidence is not proven. Increasing the consumption of fruits and vegetables with high retinoids and beta-carotene content probably has no effect on the occurrence of lung cancer. Supplemental use of vitamins in smokers or has no proven effectiveness (vitamin E), or harmful (beta-carotene). Preliminary data indicating that NSAIDs and supplemental vitamin E supplementation can protect earlier lung cancer patients require confirmation. New molecular approaches aimed at cellular signaling pathways and regulation of the cell cycle, as well as tumor-associated antigens, are being studied.

[30], [31], [32], [33], [34], [35], [36],

Forecast

Lung cancer has an unfavorable prognosis, even with new therapies. On average, without treatment, patients with early non-small cell type live for about 6 months, whereas a five-year survival rate for the treated patients is approximately 9 months. Patients with a common small cell type of neoplasm have a particularly poor prognosis, a five-year survival rate of less than 1%. The average life expectancy for a limited disease is 20 months, the five-year survival rate is 20%. In many patients with small cell lung cancer, chemotherapy prolongs life and improves its quality to a sufficient degree, which justifies its use. The five-year survival rate of patients with non-small cell lung cancer depends on the phase, ranging from 60% to 70% for patients in the first stage to virtually 0% for Stage IV; The available data suggest better survival of patients in the early stages of the disease in chemotherapy regimens using platinum-based drugs. Given the disappointing results of treatment of the disease at a later stage, efforts to reduce lethality are increasingly focusing on early detection and proactive prevention measures.

Screening chest radiography in patients at risk can detect lung cancer in the early stages, but does not reduce mortality. Screening CT is more sensitive in detection of neoplasm, but a large number of false positive results increases the number of unnecessary invasive diagnostic procedures used to confirm CT results. Such procedures are costly and have the risk of complications. The strategy of an annual CT scan of smokers with subsequent implementation of PET or high-resolution CT to evaluate uncertain changes is being studied. While this strategy, apparently, does not allow to reduce lethality and can not be recommended for wide practice. Future studies may involve a combination of molecular analysis of marker genes (eg, K-RAS, p53, EGFR), sputum cytometry and the detection of cancer-related organic compounds (eg, alkane, benzene) in exhaled air.

[37], [38], [39], [40]