Lung cancer is one of the most common tumors in the world. The incidence of lung cancer is constantly increasing, and this malignancy is the leading cause of cancer-related death in both men and women. Based on historical data, an estimated 228,820 people were diagnosed with lung cancer in the United States in 2020, resulting in approximately 135,720 deaths. According to the National Cancer Registry, approximately 2,500 new cases of lung cancer are diagnosed in Israel each year
The Oncology department at Tel Aviv Medical Clinic provides comprehensive treatment for cancer diseases from the initial diagnosis stage, through imaging tests and to personalized treatment. The institute treats breast cancer, genitourinary system cancer, GI cancer, sarcoma, lung cancer, intestinal and liver cancer.
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Tel Aviv Medical Clinic is the best oncology clinic in Israel for private cancer treatment and a world leader in cancer prevention, treatment and research. The department provides a comprehensive response to oncology patients, including advanced and targeted treatments, innovative research and international collaborations.
The center employs the best leading Israeli oncologists who work in full cooperation with each other and treatment decisions are made in multidisciplinary team meetings.
Risk Factors in Lung Cancer
- Smoking: The main risk factor, depending on the number of years of smoking and the number of cigarettes smoked per day. Smoking is responsible for the development of approximately 85 percent of all lung cancer cases. Passive smoking also increases the risk of developing lung cancer.
- Chronic obstructive pulmonary disease (COPD) due to smoking is also considered a risk factor for developing lung cancer. We are witnessing an increase in the rate of lung cancer cases among non-smokers.
- Air pollution
- Occupational exposure [such as asbestos, silica, diesel fuel, radon gas]
- Exposure to ionizing radiation (such as therapeutic radiation for Hodgkin’s disease or in work accidents)
- Family history of lung cancer
Clinical features in Lung Cancer
Common symptoms of lung cancer include cough, shortness of breath, bloody sputum, chest pain, recurrent lung infections, loss of appetite, weight loss, and general weakness. In patients with symptoms, the disease is usually diagnosed at an advanced stage. However, early diagnosis—before the onset of symptoms—is both possible and highly recommended. Thus, early diagnosis (screening) of lung cancer based on computed tomography (CT) of the chest in people at risk for developing lung cancer (such as heavy smokers with a smoking history of 30 years/pack years or more) increases the rate of cases detected in the early stages and, as a result, causes a 20 percent decrease in the mortality rate from lung cancer.
The diagnosis of lung cancer is usually made by taking a biopsy using bronchoscopy or computed tomography-guided lung biopsy, which can also determine the histological type of the tumor. Imaging tests such as FDG-PET scan (Fluorodeoxyglucose-Positron Emission Tomography) and Magnetic Resonance Imaging (MRI) are used to determine the stage of the disease and the extent of tumor spread.
Classification of tumors in Lung Cancer
According to the 2015 World Health Organization (WHO) recommendation, lung tumors are generally divided into two main types: Non-Small Cell Lung Carcinoma (NSCLC), which accounts for approximately 80 percent of lung cancer cases, and neuroendocrine tumors, the predominant type of which is Small Cell Lung Carcinoma (SCLC).
Non-Small Cell Lung Carcinoma (NSCLC)
Comprises several histological subtypes
Adenocarcinoma (glandular lung cancer)
Adenocarcinoma is the most common subtype of NSCLC, and its incidence is steadily increasing. The origin of the tumor here is in the small airways, and therefore these tumors are usually located in the periphery of the lung. In terms of pathological characteristics and immunohistochemical staining (used to determine the different types of lung tumors), adenocarcinoma cells stain positive for TTF-1, Napsin A and negative for p40, p63
Squamous-cell carcinoma – squamous-type lung cancer
Squamous-cell carcinoma – its relative incidence is decreasing, and it accounts for about 20–30 percent of all NSCLC lung cancers.
Other types
Large cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, and salivary gland carcinoma – these types are rare.
The neuroendocrine tumors of the lung
which account for approximately 20 percent of lung cancers – include.
- Small-cell lung carcinoma – SCLC
The predominant subtype in this group, usually develops in heavy smokers, is characterized by an aggressive course and the development of distant spread in two-thirds of cases at the time of initial diagnosis. The tumor is usually located in the center of the chest, originating in the large bronchi. Histologically, this tumor is composed of small, round or oval cells, with neuroendocrine morphology, a high mitotic rate, and a low degree of differentiation. It stains positive for Synaptophysin, Chromogranin A, NSE, and CD56, which are typical of neuroendocrine tumors.
- Large-cell neuroendocrine carcinoma of lung
A rarer subtype, closely resembles to small-cell lung cancer, but morphologically different in terms of cell size as mentioned above
- Carcinoid
Here, a distinction must be made between the typical and atypical subtypes (the more aggressive of the two). Tumors whose development is not related to smoking are characterized by slow growth and a more benign course of the disease. Morphologically, they have neuroendocrine morphology, a low mitotic rate, and a high degree of differentiation.
Stage of the disease at diagnosis in Lung Cancer
The stage of the disease has prognostic significance, and the therapeutic approach is determined accordingly. The stage of the disease is defined according to the TNM classification and is based on the size of the primary tumor, invasion of adjacent organs, involvement of lymph nodes in the hilus, isthmus and supraclavicular region, as well as distant secondary spread.
To determine treatment strategy, the TNM classification system assesses the following three factors:
- T characteristic – size and degree of invasion of the primary tumor
- N characteristic – determined according to the degree of involvement and location of regional lymph nodes
- M characteristic – describes the presence of distant metastases in various organs (such as lung, bones, liver, adrenal glands and brain)
The eighth version of the classification is in use. At the same time, a two-stage classification is used in SCLC lung cancer, where the limited stage corresponds to the definition of disease contained in one radiation field, while in the extensive stage there is distant spread or alternatively such disease Large enough that a single radiation field cannot encompass the entire tumor.
Approximately 57 percent of new patients are diagnosed in the metastatic stage (stage 4), which explains the relatively low 5-year survival rate from the date of diagnosis of the disease – which stands at 19 percent. However, 5-year survival rates in early stages of the disease (stages 1, 2) are much higher and range from 55 to 90 percent. Prognosis in stage 3 of the disease is determined by the degree of involvement of the regional nodes, with 5-year survival rates here ranging from 15 to 40 percent.
Treatment is determined by the stage of the disease and includes surgery, radiation, chemotherapy, immunotherapy, targeted biological therapy, and palliative care as needed. In most cases (except in the early stages of the disease, where the main treatment is surgery or radiation alone), lung cancer treatment combines different treatment methods (multi-modality treatment).
Innovations in advanced-stage treatment in Lung cancer in Israel
Over 50% of lung cancer patients are diagnosed after the disease has metastasized to distant organs, including the bones, liver, adrenal glands, and brain. Until the first decade of the 21st century, the therapeutic approach at this stage was based on chemotherapy. A revolutionary change that occurred in the second decade of the 21st century led to a significant improvement in the prognosis of all treatment methods in two main directions:
- Targeted biological therapies – the method here is based on the identification of the molecular mechanism responsible for the development of cancer (Driver mutation) and the use of targeted biological therapy against the activating mechanism
- Immune checkpoint inhibitors – the method that reduces the effect of the inhibitory factors of the body’s immune system and thereby allows it to attack the cancerous tumor
Targeted biological therapies in Lung Cancer
This is a personalized biological therapy, made possible by the identification of activating mutations in tumor cells (such as mutations in the genes EGFR, ROS-1, ALK (Anaplastic Lymphoma Kinase), NTRK (Neurotrophin Tyrosine Kinases), BRAF, c-MET, RET (REarranged during Transfection) and HER-2 (Human Epidermal Growth factor Receptor 2) and the development of drugs that act against these mutations. Thus, approximately 30–40 percent of metastatic lung tumors of the Adenocarcinoma type may be tumors carrying an activating mutation, against which there are targeted therapies administered orally. Over the years, new generations of biological agents have been developed for these mutations, including agents that are able to deal with acquired resistance mechanisms (resistance that cancer cells develop during treatment) and allow the administration of several Biological therapies in sequence one after another. For example, several generations of EGFR inhibitors (such as Gefitinib, Erlotinib, Afatinib, Osimertinib), ALK inhibitors (Crizotinib, Alectinib, Ceritinib, Brigatinib, Lorlatinib), ROS-1 inhibitors (Crizotinib, Entrectinib, Repotrectinib, Lorlatinib) and c-MET inhibitors (Crizotinib, Capmatinib, Tepotinib, Savolitinib) have already been developed. These treatments have positively changed the course of the disease in patients whose tumors carry an activating mutation, allowing some patients to survive for 5 years or more, and have also significantly improved their quality of life.
Patient Selection
Selecting patients who are suitable for targeted therapies is critical, and to find the activating mutation in a particular tumor, it is recommended to perform an in-depth molecular diagnosis with a preference for methods based on genomic sequencing of the new generation – Next Generation Sequencing (NGS). These tests, known as comprehensive genomic tests, diagnose the molecular profile of the tumor, and by sequencing hundreds of genes simultaneously, they more accurately match targeted treatment options aimed at the activating mutations.
Immunotherapy
One of the characteristics of many types of cancer is that cancer cells find a way to evade the immune system’s response.
Modern immunotherapy “takes the brakes” off the immune system and thus increases the immune system’s ability to fight cancer. Immunotherapy has been a significant breakthrough in the treatment of advanced lung cancer. For example, in advanced NSCLC, many studies have shown that immunotherapy compared to chemotherapy results in longer survival, less toxicity, and a better quality of life. The notable advantage of immunotherapy is that patients who respond to treatment may survive for many years. For example, 14-25 percent, depending on the level of PD-L1 (Programmed Death Ligand-1) expression in tumor cells, of patients with advanced NSCLC may survive 4 years or more from the time of initiation of immunotherapy.
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